Abstract and case study poster sessions will be conducted during the 2015 College of American Pathologists Annual Meeting, which is scheduled for October 4 to 7, 2015. The meeting will take place at the Gaylord Opryland Resort and Convention Center, Nashville, Tennessee. The poster sessions will occur in the CAP '15 Exhibit Hall. Specific dates and times for each poster session are listed below; “poster focus” times are dedicated poster-viewing periods. Also shown before each poster session are the subject areas that will be presented during each session.
Endocrine Pathology; Gastrointestinal and Liver Pathology; Hematopathology; Transfusion Medicine and Coagulation Sudden Death in Inuit Child Possibly Due to CPT1A: Challenges in Interpretation of Biochemical Results: (Poster No. 1)
Carnitine palmitoyltransferase 1A (CPT1A) deficiency is an autosomal recessive disorder of fat metabolism, more prevalent in the Inuit populations. Screening is paramount as CPT1A deficiency can lead to very rapid onset of hypoglycemic seizures, coma, and sudden death during times of illness or fasting, even in heterozygotes. We present the case of a previously healthy 2-year-old Alaskan boy, who had a normal newborn screen result at days 1 and 15, who became acutely ill with influenza A, had a seizure (notably similar to a prior hypoglycemic seizure following a diarrheal illness), and died. His heritage, constellation of symptoms, along with autopsy findings of hepatomegaly, microvesicular steatosis, and vitreous glucose concentration of 35 mg/ dL, raised the suspicion for CPT1A. Retrospective analysis of newborn blood spots, although inconclusive, showed higher C0/(C16 + C18) ratio than 99% of infants in United States and Canada, indicating a possible CPT1A deficiency (Figure 1). As sudden unexpected death in infancy rates are up to 7 times national average in predominantly Inuit-inhabited areas, correlation of high infant death rate and CPT1A mutation is currently under study. Despite the expanded newborn screening in Alaska to include screening for CPT1 (classic type), there are increasing reports of false-negative newborn screenings for CPT1A (arctic subtype). This may be due to current cutoff values for long-chain fatty acids, where differences in CPT1A enzyme metabolic profile are not separately accounted for. This case highlights the challenges in interpretation of inconclusive biochemical results in autopsy.
Steroid Receptor Coactivator-1: A Marker for Adrenal Cortical Carcinoma?: (Poster No. 2)
Context: Adrenal cortical carcinomas are difficult to differentiate from other adrenal neoplasms owing to similar clinical presentations, histologic appearance, and immunophenotypic features. Several studies to find a specific immunohistochemical stain for adrenal cortical carcinomas have met with little success. Recent studies suggest that steroid receptor coactivator-1 (SRC-1) is a promising specific stain for adrenal cortical carcinomas. We aimed to assess sensitivity and specificity of SRC-1 expression in primary adrenal neoplasms.
Design: We evaluated SRC-1 expression (SRC-1 monoclonal antibody 1.28E +0.9, Cell Signaling, Beverly, Massachusetts) in adrenal cortical carcinomas, adrenal cortical adenomas, metastatic clear cell renal cell carcinomas, and pheochromocytomas. The stain was evaluated and scored by grading the intensity of staining and percentage of positive neoplastic cells. Statistical analysis was done by using analysis of variance.
Results: See the Table. There is no significant difference between the intensity of SRC-1 (P =.60), the number of neoplastic cell nuclei staining for SRC-1 (P =.05), and the score (P =.28) for the 4 tumor types.
Conclusions: While adrenal cortical carcinomas do express SRC-1, cortical adenomas, metastatic clear cell renal cell carcinomas, and pheochromocytomas also stain for SRC-1. SRC-1, although sensitive, is not specific for adrenal cortical carcinoma and should not be used to differentiate adrenal cortical carcinoma from other adrenal neoplasms.
An Unusual Case of Diffuse Amyloid Deposition in an Atypical Parathyroid Adenoma: (Poster No. 3)
Amyloid deposition in parathyroid adenomas is rare and a relatively uncharacterized finding. We report a case of a 46-year-old woman with an atypical parathyroid adenoma showing extensive amyloid deposition. She presented with primary hyperparathyroidism and was found to have a left extrathyroidal mass with punctate internal calcifications, measuring 0.9 cm in greatest dimension on ultrasonography. Histologic examination showed a lesion with a thickened and a concerning irregular capsule, which was not diagnostic for capsular invasion. The hypercellular parathyroid proliferation had multiple dense eosinophilic, interfollicular concentric amyloid deposits, which were confirmed with Congo red staining. A negative calcitonin stain excluded medullary thyroid carcinoma. The tumor was positive for a Galectin-3 immuno-histochemical stain; however, the mitotic index rate (Ki-67) was low. There are few reports of parathyroid amyloid deposition. The largest study, from 1970, reviewed 88 cases of primary hyperparathyroidism and found only 9 cases with intrafollicular amyloid deposits. Reports of endocrine involvement with systemic amyloidosis are rare, and parathyroid involvement is even less well characterized in the literature. This patient did not have any clinical findings suggestive of systemic amyloidosis. These findings favored an atypical adenoma rather than a carcinoma. This case highlights the rare presentation of amyloid deposition in an atypical parathyroid adenoma (Figure 2).
Coexistence of Adrenocortical Adenoma and Pheochromocytoma in the Same Adrenal Gland: A Rare Case Report: (Poster No. 5)
The adrenal gland is composed of 2 embryologically and functionally different parts, the cortex and the medulla. Pheochromocytoma is a rare catecholamine-secreting tumor derived from the chromaffin cells in the adrenal medulla, whereas adrenocortical adenoma is a benign epithelial tumor derived from adrenal cortical cells. We report an extremely rare case of a 64-year-old white woman with a pheochromocytoma and an adrenocortical adenoma in the same adrenal gland. She was found to have an adrenal mass on a computed tomography scan taken for abdominal pain. She had mild elevation of 24-hour urine metanephrine and normetanephrine. She also had hypertension, headache, fatigue, back pain, and frequent urination. Her random serum cortisol was normal with a mildly reduced potassium level. Her blood pressure was under control with medication. She was initially followed up but a decision was made to operate 4 years later, because of the increase in size and appearance of another nodule in the same adrenal gland. During surgery, she became acutely hypertensive upon manipulation of the adrenal gland. After resection of the mass, the patient became hypotensive. Histologic examination revealed the presence of an adrenocortical adenoma (Figure 3, a) and a pheochromocytoma (Figure 3, b) in the same gland. Although rare, the present case is noteworthy in highlighting the possibility of these 2 tumors being present simultaneously, especially that even minimally functional pheochromocytomas can be difficult to deal with during surgery.
Poorly Differentiated Thyroid Carcinoma in a Pediatric Patient: A Rare Diagnosis: (Poster No. 6)
Poorly differentiated thyroid carcinoma (PDTC) is a rare thyroid malignancy, first described as a diagnostic entity in 2004. Its reported incidence varies from <1% of thyroid cancers in Japan, 2% to 3% in North America, to 15% in Northern Italy. PDTC is defined by the World Health Organization as a follicular neoplasm that shows limited evidence of follicular cell differentiation and occupies both morphologically and behaviorally an intermediate position between differentiated and undifferentiated carcinoma. A consensus conference held in Turin in 2006 proposed an algorithmic approach for diagnosis of PDTC that includes presence of solid/trabecular/insular growth pattern, absence of conventional nuclear features of papillary carcinoma, and presence of at least one of the following: convoluted nuclei, mitotic activity ≥ 3/10 high-power fields, or tumor necrosis. PDTC occurs primarily in older patients (>45 years) with a reported mean age of 60.6 years and is a challenging diagnosis for surgeons, endocrinologists, and pathologists. We present a rare case of PDTC in a 17-year-old otherwise healthy adolescent girl with no prior history of radiation, who presented with a 7 × 4.8 × 3-cm pale tan, lobulated mass occupying >90% of her right thyroid lobe. Histology showed a solid tumor with focal trabecular growth pattern and residual areas suggestive of follicular differentiation (Figure 4, A). Abundant mitotic figures, focal tumor necrosis (Figure 4, A and B), and vascular invasion were identified. Immunohistochemical results revealed strong positive TTF-1, focal weak positive thyroglobulin (Figure 4, C and D), and negative synaptophysin and chromogranin. Molecular analysis revealed slightly reduced PTEN expression. A diagnosis of PDTC was rendered.
Giant Epithelial Splenic Cyst: A Rare Cause for Operative Intervention: (Poster No. 9)
True splenic cysts (also referred to as epithelial or epidermoid cysts) are rare, with an incidence of 0.07%. Differentiating “true” from “false” splenic cysts may be difficult radiologically; therefore, gross and histologic examination is required for definitive diagnosis. Surgical treatment has become progressively nonoperative for these benign lesions. This has resulted in fewer pathologists laying eyes on this unusual entity. The current recommendation is that splenic cysts >4 to 5 cm should be considered for resection. We present a case of one of the largest true splenic cysts reported in the literature. A splenic cystic lesion was found incidentally on computed tomography in a 23-year-old man after a motor vehicle collision. The patient was referred by his primary care physician to the surgical oncology clinic nearly 5 years later for increasing left upper and lower quadrant discomfort, asymmetric abdominal distension, and worsening subdiaphragmatic pain (Figure 5, A). Owing to the size (>25 cm) and symptomatic nature, an open splenectomy was performed (Figure 5, B). The cyst was decompressed intraoperatively, yielding 3 L of fluid. The specimen weighed 866 g (post fixation) and consisted of an enlarged spleen with a multiloculated, previously decompressed cystic component filled with serosanguineous fluid varying from clear/yellow to red/brown. The cyst wall varied in thickness from 2 to 10 mm. Microscopic examination revealed a cyst lined by stratified squamous epithelium consistent with an epidermoid cyst. The patient was discharged on postoperative day 2 without complications. Although rare in incidence, giant splenic cysts may occasionally warrant resection for symptomatic relief.
Distinction Between Telangiectatic/Inflammatory Adenoma and Mass Effect on Liver Sampling: (Poster No. 10)
Context: Telangiectatic/inflammatory hepatocellular adenoma (TIA) is characterized by sinusoidal dilation, inflammation, and occasionally a bile ductular reaction. However, these changes can also be seen in nonneoplastic liver tissue adjacent to a mass lesion. This differential may arise in biopsy tissue when attempting to sample a liver mass, and the distinction is crucial in situations such as distinguishing adenoma from unsampled metastatic disease, both of which may present as multiple liver lesions. Serum amyloid A (SAA) immunostaining is useful for the diagnosis of TIA but is not entirely specific. Additionally, the histologic pattern of mass effect (ME) has received little formal scrutiny, and SAA has not been evaluated in this context. To help resolve this differential, this study compares the morphologic and immunohistochemical findings in TIA and ME.
Design: Forty-eight cases were retrieved from our departmental archives, including 36 examples of ME and 12 TIAs. Several histologic findings were evaluated in all cases. SAA staining was performed in cases with available blocks and was scored by using previously published criteria.
Results: Strong SAA immunostaining was observed in 100% of TIAs and 58% of ME cases (P = .02). Histopathologic findings that significantly differed between TIA and ME included ductular reaction (P =.02), cholestasis (P =.04), and unpaired arteries (P < .001) (Table).
Conclusions: Unpaired arteries and strong SAA staining best distinguish TIA from ME. However, the former may be absent owing to sampling, and the latter is not available in all laboratories. Cholestasis may also help suggest the diagnosis of TIA, while ductular reaction may suggest ME.
Rare MAI and CMV Double Infection in the Gut of an Immunocompromised Adult: (Poster No. 12)
Opportunistic gastrointestinal (GI) infections are common among immunocompromised patients. We report an unusual case of mixed infection of the gastrointestinal tract with Mycobacterium avium intra-cellulare (MAI) and cytomegalovirus (CMV) organisms in a chronic lymphocytic leukemia patient. Our patient, a 71-year-old man with a 10-year history of chronic lymphocytic leukemia on regular chemotherapy, reported to his oncologist with a recent history of heartburn, nausea, recent change in bowel habits, and weight loss. Gastrointestinal endoscopy and colonoscopy showed white plaquelike lesions in the proximal duodenum, mucosal erythema in the distal ileum, and a small 3-mm “polyp” in the transverse colon along with unremarkable gastric mucosa. Representative biopsies from these lesions (including that from the polyp) showed a similar histologic picture consisting of a prominent expansion of the lamina propria by a sheet of histiocytic proliferation along with interspersed stromal cells showing intranuclear inclusions (characteristic of a viral cytopathic effect). Special stains revealed the histiocytes to be filled with acid-fast bacilli consistent with M avium intracellulare organisms, while the stromal cells showed CMV positivity by immunostaining. Although it is not unusual for immunocompromised patients to have either MAI or CMV infection in the gut, such a combined/double infection is extremely rare and has not been described in literature. Our case shows that finding one causative agent of opportunistic infection does not rule out the other despite minimal endoscopic findings, something that should be kept in mind while performing a workup for suspicious GI biopsies of immunocompromised patients (Figure 6).
A Giant Primary Clear Cell Hepatocellular Carcinoma in a Young Woman Without Cirrhosis: (Poster No. 15)
Primary clear cell carcinoma of the liver (PCCCL) is an uncommon variant of hepatocellular carcinoma, usually occurring in older patients with longstanding cirrhosis. We report a case of a giant PCCCL rupturing in a young woman without cirrhosis. A 29-year-old woman, who presented with a 3-month history of abdominal pain, nausea, vomiting, food intolerance, and unintentional weight loss, was found to have gastric varices and a large liver mass measuring 22.8 cm × 17.8 cm × 13.8 cm. Magnetic resonance imaging showed the liver mass involving the left lobe and most of the right lobe (Figure 7, A). Microscopic examination revealed the tumor was composed of sheets of clear cells with delicate vesicular architecture and brisk mitotic figures (Figure 7, B, arrows). The tumor cells were positive for hepar 1 (Figure 7, C), glypican 3, CD34 in a diffuse staining pattern, and CD10 in a canalicular staining pattern (Figure 7, D) by immunohistochemistry. A diagnosis of PCCCL was established. Minute fragments of nonneoplastic hepatic parenchyma showed mass effect and no significant steatosis or fibrosis. The patient died of hemorrhagic shock secondary to tumor rupture within 2 weeks of diagnosis. Although PCCCL most often occurs in older patients with cirrhosis, this uncommon variant of HCC can arise in younger patients without a history of liver disease. It is important to diagnose PCCCL early owing to the favorable prognosis of this specific cancer and in order to prevent catastrophic complications.
Spectral Imaging Distinction of Hepatocellular Carcinoma From Dysplastic, Nondysplastic, and Normal Hepatocytes Using Nuclear Cytoplasmic Ratio and Level of FOXM1 Immunoexpression: (Poster No. 16)
Context: Hepatocellular carcinoma (HCC), the most common primary type of liver cancer, usually arises as a complication of longstanding cirrhosis. Typically, the progression to HCC begins with cirrhosis, to large cell dysplasia, then small cell dysplasia, and finally HCC. Our aim is to determine whether we can use cellular morphologic characteristics and staining features of FOXM1, a known tumor marker for HCC and other cancers, to distinguish normal, dysplastic, and malignant hepatocytes, using Vectra Automated Quantitative Pathology Imaging System (PerkinElmer, Waltham, Massachusetts).
Design: FOXM1 immunohistochemistry was performed on a liver tumor progression tissue array consisting of 82 HCC, 107 dysplastic, 57 cirrhotic, and 6 normal cores. The nuclear to cytoplasmic ratio (NCR) and FOXM1 staining were obtained by using the Vectra multispectral imaging system. The Vectra data were used to compute the average median and range of NCR and FOXM1 staining for each tissue type.
Results: The median and range values were computed for NCR and FOXM1 staining (Table). HCC cores were compared to normal, cirrhotic, and dysplastic cores with pairwise 1-tailed t tests. P values for each comparison are in parentheses.
Conclusions: Using data from Vectra we found that as liver disease progress from cirrhosis to dysplasia to HCC, the median and range for NCR and FOXM1 staining increased and values for HCC were significantly different from other tissue types. This suggests that hepatocyte NCR and FOXM1 immunostaining as computed by Vectra can be used to distinguish HCC from other lesions.
Sclerotic “Plywood” Fibroma of the Rectum: A Hitherto Undescribed Mesenchymal Polyp in a Patient With Cowden Syndrome: (Poster No. 18)
A 37-year-old woman with a 10-year history of rectal “prolapse polyps” was found to have numerous diminutive gastric and duodenal polyps upon esophagogastroduodenoscopy. Given the histologic appearance and the patient's young age, these new gastric polyps were suspected to represent hamartomatous polyps. The pathology reports and slides from the prior “prolapse” polyps were subsequently reviewed, and additional desmin staining revealed no smooth muscle encroachment into the lamina propria, indicating that the original rectal polyps were likely also hamartomatous. Also reviewed was a rectal mesenchymal polyp that had lacked a definitive pathologic diagnosis at the time of biopsy. This submucosal-based polyp consisted of a hypocellular proliferation of bland, fusiform, spindle cells embedded within a densely collagenous stroma with prominent clefting (Figure 8, A). Immunohistochemical staining showed strong CD34 positivity of this spindle cell proliferation but negative staining for S100, CD117, STAT-6, SMA, EMA, and GLUT-1, excluding common gastrointestinal mesenchymal polyps (eg, mucosal neuroma/ganglioneuroma, solitary fibrous tumor, leiomyoma, and perineurioma). The histology and staining profile of this rectal polyp are remarkably similar to those of the sclerotic “plywood” fibroma, a dermal lesion known to occur in Cowden syndrome (Figure 8, B). The patient received molecular genetic analysis, which identified a germline PTEN mutation and confirmed a diagnosis of Cowden syndrome. To our knowledge, this is the first case of a sclerotic “plywood” fibroma identified as a rectal polyp in a patient with Cowden syndrome and expands the class of mesenchymal polyps that should trigger consideration of this rare hamartomatous polyposis syndrome.
Adenocarcinoma, an Incidental Finding in Meckel Diverticulitis in a 7-Year-Old Boy: (Poster No. 20)
Meckel diverticulum (MD) is the most common congenital defect of the gastrointestinal tract. It is a part of the vitelline duct, which connects the growing fetus with the yolk sac. When the vitelline duct is not fully absorbed, an MD develops in the lower part of the small intestine. Histologically, it is a true diverticulum, containing all tunicae of gastrointestinal tract and may or may not contain ectopic gastric or pancreatic epithelium. Meckel diverticula can mimic appendicitis clinically or be asymptomatic, and it may be complicated by bleeding, diverticulitis, obstruction, and rarely, neoplasia. We report an adenocarcinoma as an incidental finding in an MD. A 7-year-old boy presented to the emergency department for evaluation of acute abdominal pain and tenderness. Radiography showed enteric obstruction, prompting diagnostic laparoscopy. Above the level of mid-ileum an intact MD was identified. Macroscopy showed a prominent, inflamed, and indurated MD. Microscopy showed acute suppurative diverticulitis with ectopic pancreatic and gastric tissue. Moreover, foci of infiltrative small atypical glands with desmoplastic reaction suggestive of invasive adenocarcinoma were identified (Figure 9). However, the surgical margin was clear. We report this case to emphasize that neoplastic processes such as adenocarcinoma can happen in MD, even in the pediatric group. Apparently, making the accurate diagnosis in such cases requires more careful histopathologic examination of the surgical cases. In such a case, the patient required more evaluation and closer follow-up.
Adenomyomatous Pancreas Heterotopia of the Ileum: A Case Report and Review of the Literature: (Poster No. 22)
Pancreatic heterotopia is a rare developmental anomaly defined as the existence of ectopic pancreatic tissue without any continuity to the main pancreas. It is usually an incidental finding, though it may cause inflammation, pain, bleeding, and obstruction. Ectopic pancreas occurs most often in the stomach, duodenum, and jejunum, and very rarely, in the ileum. Here we report a case of a 59-year-old woman who presented with intestinal obstruction due to adhesions from previous laparotomy for ovarian cystadenocarcinoma. Unexpectedly, a polypoid mass lesion was found in the terminal ileum where obstruction occurred. Grossly, the lesion was covered by normal-appearing ileal mucosa, measuring 2.5 × 0.7 × 0.6 cm (Figure 10, A). The cut sections showed a tan white, soft, and solid surface. Microscopically, the lesion occupied submucosa and muscularis propria, and consisted of ductal structures of variable sizes surrounded by interlacing smooth muscle bundles (Figure 10, B). No cytologic atypia was seen. Small foci of pancreatic acini were also identified (Figure 10, C). Immunohistochemically, the ductal structures were positive for CK7 (Figure 10, D) and CA19-9, and negative for CK20. A diagnosis of adenomyomatous pancreatic heterotopia was made. On the basis of Heinrich classification, our case can be classified as class III pancreatic heterotopia, which almost always presents as an adenomatous lesion in the gastrointestinal tract. The differential diagnosis includes enteritis cystica profunda, metastatic adenocarcinoma, pneumatosis cystoides intestinalis, and hamartomatous polyp in Peutz-Jeghers syndrome. In summary, this case study shows that although rare, heterotopic pancreas should be included as a differential diagnosis of a mass lesion in the ileum.
Expression of ALOX15 in Adult Patients With Eosinophilic Inflammation of the Esophagus: (Poster No. 23)
Context: We have previously shown that immunohistochemistry (IHC) for ALOX15 correlates with eosinophilic inflammation of the esophagus and is positive in 95% of pediatric patients with eosinophilic esophagitis (EoE) and in a proportion of patients with >15 eosinophils/ high-power field (HPF) who respond to proton pump inhibitor (PPI) therapy. We now aim to study the expression of ALOX15 in adults with eosinophilic inflammation of the esophagus.
Design: Consecutive biopsies from adult patients with at least 1 esophageal biopsy with >15 eosinophils/HPF were retrieved from our surgical pathology files from 2010–2014. Results of IHC were correlated with the clinical presentation, history of atopy, and endoscopic findings. We included 10 cases with <15 eosinophils/HPF (average, 5.6 eosinophils/HPF) as controls. Five patients who responded favorably to PPI with remission of symptoms were classified as having reflux.
Results: Moderate cytoplasmic staining in 10% or more of squamous cells was considered positive. The average number of eosinophils/HPF was 46 in ALOX15+ versus 23 in ALOX15– cases (P =.004). All control cases were negative. The IHC results and the clinical findings are summarized in the Table.
Conclusions: Positive immunostaining correlated with higher number of eosinophils/HPF and with involvement of both proximal and distal esophagus. ALOX15+ patients present more frequently with features characteristic of EoE, including food impaction or history of allergy. While not entirely sensitive or specific, immunostaining for ALOX15 in patients with eosinophilic inflammation of the esophagus correlates with more severe disease and features that are more characteristic of EoE than reflux.
Skull Base Metastasis With Involvement of Multiple Cranial Nerves as the First Manifestation of Hepatocellular Carcinoma: (Poster No. 24)
Hepatocellular carcinoma (HCC) frequently spreads via hematogenous and lymphatic routes, most commonly to the lung and regional lymph nodes. However, skull base metastasis as the initial manifestation of HCC without clinical evidence of primary tumor in the liver is extremely uncommon. Here we describe a case of skull base lesion with multiple cranial nerve palsies that subsequently was confirmed to be metastatic HCC. A 62-year-old African American man presented to our hospital with diplopia, left ptosis, and retrobulbar pain. Neurologic examination showed left third, fourth, and partial sixth cranial nerve palsies. Magnetic resonance imaging of brain demonstrated a lobulated soft tissue mass with relatively homogenous intensity in left cavernous sinus, extending into the sphenoid sinus and pituitary gland (Figure 11, A). Laboratory evaluation revealed moderate elevation of liver enzymes and hepatitis C seropositivity. Serum α-fetoprotein levels were normal. Transnasal biopsy of skull base lesion was performed and histopathologic examination revealed moderately differentiated HCC (Figure 11, B and C). Immunohistochemical studies revealed tumor cells were positive for Hep Par 1, arginase, CD10, and polyclonal CEA in a canalicular pattern and negative for GFAP, neurofilament, and Neu-N (Figure 11, D). A computed tomography scan of the abdomen demonstrated a large enhancing mass in the right lobe of the liver. The final diagnosis of primary HCC with skull base metastasis was established. Very few cases of metastatic HCC to the skull base have been described thus far. Our case and review of literature emphasize the need to include metastatic HCC in the differential diagnosis of skull base lesions.
Evaluation of Expression of Human Epidermal Growth Factor Receptor 2 in Gastric and Gastroesophageal Junction Adenocarcinoma Using Immunohistochemisty and Dual In Situ Hybridization: (Poster No. 25)
Context: In 2010, trastuzumab was approved for the treatment of patients with human epidermal growth factor receptor 2 (HER2/neu)–overexpressing metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma. The current study compares HER2/neu expression in early-stage versus late-stage tumors and investigates if dual in situ hybridization (ISH) can be used as an alternative to fluorescence in situ hybridization for testing HER2/neu in gastric/GEJ adenocarcinomas.
Design: Two-hundred adenocarcinomas, including 50 early-stage gastric, 50 late-stage gastric, 50 early-stage GEJ, and 50 late-stage GEJ tumors, were included. Tissue microarray was built and HER2/neu was analyzed by immunohistochemistry (IHC; anti-HER2/neu [4B5] rabbit monoclonal antibody, Ventana) and dual ISH (Ventana INFORM HER2 Dual ISH DNA Probe Cocktail assay).
Results: One hundred sixty-eight of 200 cases (84%) had satisfactory results with at least 1 testing methodology. There were 32 undetermined/insufficient cases by IHC and 90 by dual ISH. When enough tissue was present for both tests, discrepancy in the results was found in 5 cases (2.5%) (Table). All discrepancies consisted of negative IHC (0) with amplified dual ISH. Seven equivocal (2+) cases were amplified by dual ISH. Dual ISH identified 12 additional HER2/neu-positive cases. Overexpression/amplification was observed in 10% of gastric/GEJ tumors.
Conclusions: Our result of 10% overall overexpression/amplification in gastric/GEJ adenocarcinomas is in concordance with previous reports. No difference in HER2/neu expression was found between early- and late-stage tumors. From these results, we suggest that all gastric/GEJ adenocarcinomas should be tested, including early-stage tumors, since these patients may benefit from anti-HER2/neu therapy. Determination of HER2/neu using IHC alone in biopsy samples may cause a significant false-negative/equivocal/or insufficient rate. Combination of IHC and ISH is recommended.
Inflammatory Bowel Disease–like Gastrointestinal Manifestations in a Patient With Common Variable Immunodeficiency: (Poster No. 27)
Common variable immunodeficiency (CVID) is a primary antibody deficiency characterized by recurrent bacterial infections and frequent occurrence of autoimmune and neoplastic diseases. Gastrointestinal CVID displays a wide spectrum of histologic patterns that can mimic lymphocytic colitis, collagenous enterocolitis, celiac disease, lymphocytic gastritis, granulomatous disease, acute graft-versus-host disease, and inflammatory bowel disease (IBD). We present a case of gastrointestinal tract CVID displaying microscopic features mimicking IBD. A 20-year-old man was seen in consultation for chronic diarrhea and weight loss. The patient had a history of agammaglobulinemia and was receiving replacement therapy. Upper and lower gastrointestinal (GI) endoscopy revealed unremarkable esophagus, stomach, duodenum, and small intestine. The entire colon showed friability with contact bleeding. Multiple biopsies were taken from the entire GI tract. Duodenal biopsy revealed paucity of plasma cells (Figure 12, A and B). Stomach and terminal ileum biopsies did not show any significant histologic changes. Right colon, left colon, and rectum biopsies showed colonic mucosa with patchy active colitis and mild distortion of crypt architecture simulating IBD, particularly Crohn disease (Figure 12, C and D). The morphologic features in colon and duodenal biopsies are thought to be representing gastrointestinal manifestations of CVID. Pathologists should be aware of various GI tract histologic presentations of CVID to prevent misdiagnosis of this entity, which can be easily confused with other conditions with entirely different management.
Loss of ATRX or DAXX in Pancreatic Neuroendocrine Tumors Is Associated With Distant Metastases and Poor Survival: (Poster No. 29)
Context: Sporadic, well-differentiated pancreatic neuroendocrine tumors (PanNETs) comprise a heterogeneous group of neoplasms with variable clinical behavior. Several prognostic markers and classification systems exist, but they do not consider the underlying biology of PanNETs. Recently, whole exome studies have identified recurrent mutations in the α-thalassemia/mental retardation syndrome X-linked (ATRX) and death domain–associated protein (DAXX) genes. Further, mutations in these genes result in loss of expression of their respective proteins. To assess the prognostic significance of ATRX and DAXX loss in PanNETs, immunolabeling was performed on a large cohort and correlated with various clinicopathologic features.
Design: Immunolabeling for ATRX and DAXX was performed on 303 surgically resected PanNETs. Loss of expression was defined as the absence of nuclear staining within neoplastic cells. Results were correlated with patient demographics, pathologic features, disease-free survival, and disease-specific survival. The follow-up period ranged from 1.6 to 18.8 years.
Results: ATRX and/or DAXX loss was identified in 69 of 303 PanNETs (23%). ATRX/DAXX-negative PanNETs correlated with increased mean tumor size (5.0 versus 2.4 cm), higher histologic grade, lymphovascular and perineural invasion, advanced T stage, lymph node involvement, synchronous metastases, and disease recurrence (all P < .01). ATRX/DAXX loss correlated with shorter disease-free (mean, 5.6 versus 17.2 years, P < .01) and disease-specific survival (mean, 12.5 versus 17.7 years, P = .01) (Figure 13, A and B, respectively). By multivariate analysis, ATRX/DAXX loss was an independent predictor of shorter disease-free survival (P < .01).
Conclusions: Loss of ATRX/DAXX is a poor prognostic factor associated with disease recurrence and decreased survival in patients with surgically resected PanNETs.
Benign Florid Vascular Proliferation Mimicking Vascular Neoplasm: Two Case Reports and Review of the Literature: (Poster No. 30)
Florid vascular proliferation is a rare lesion of the gastrointestinal tract and presents as an exuberant, lobular proliferation of small vessels that extends from the submucosa to the subserosal connective tissue, often creating a raised submucosal “mass.” Clinically and microscopically, it can mimic a neoplasm, especially a vascular neoplasm. It is hypothesized that repeated mechanical forces caused by intussusception may cause these reactive changes within the bowel wall. Here, we report 2 cases of benign florid vascular proliferation. Both patients are women, ages 47 and 71 years, and presented with intussusception clinically and were found to have a bowel “mass.” Both patients were treated with surgical resection and no complications were noted postoperatively. Grossly, one lesion presented as a “raised brown-tan necrotic mass” with adjacent wall invasion and thickening and the other as a “raised nodule.” Histologic sections revealed florid proliferation of small vessels extending into the subserosa. On low-power magnification, the vascular lesion maintained a distinct lobular architecture, which was highlighted by immunohistochemical stain CD31. The endothelial cells lining the vessels were plump with only mild reactive nuclear atypia. No significant hyperchromasia, nuclear pleomorphism, or mitoses were identified. The adjacent mucosa showed prolapsed-type changes as well as ischemia and focal frank necrotic debris. A diagnosis of florid vascular proliferation was rendered. There were a total of 2 published articles on florid vascular proliferation. It is important to recognize this entity and differentiate it from other gastrointestinal or vascular neoplasms (Figure 14).
Kayexalate-Associated Colitis: A Rare Cause of Colon Ulcer: (Poster No. 33)
Kayexalate or sodium polystyrene sulfonate (Sanofi-Aventis LLC, New Jersey), a cation exchange resin usually used in combination with sorbitol, is commonly used to treat hyperkalemia and usually given orally. However, this treatment rarely causes ulceration, stenosis, and even perforation in renal failure and posttransplant patients. A 62-year-old woman with a history of recent hospital admission due to hyperkalemia and acute renal failure returned to her primary physician with complaints of abdominal pain, vomiting, and diarrhea. Colonoscopy (Figure 15, A) revealed multiple discontinuous ulcers between sigmoid colon and hepatic flexure along with a benign-appearing stenosis in the sigmoid colon. Biopsies taken from these sites revealed an ischemic pattern of colonic mucosal injury with basophilic crystals having a fish-scale appearance in the submucosa (Figure 15, B), consistent with kayexalate-sorbitol injury. Studies have shown that sorbitol rather than kayexalate is actually responsible for the colonic ulceration/necrosis, while the stenosis is more often due to local tissue reaction from the kayexalate crystals. Pseudomembranous colitis, Crohn colitis, and infectious colitis are the main differential diagnoses. Sevelamer, a phosphate-binding drug and cholestyramine crystals, have also been implicated in causing similar histopathologic changes on ingestion. While both sevelamer and kayexalate show fish-scale appearance on histology, they can usually be reliably distinguished on hematoxylineosin and periodic acid–Schiff stains. Cholestyramine crystals lack fish-scale appearance altogether. Pathologists and clinicians need to be aware of such crystal-causing enteropathies in the workup of a renal failure patient with abdominal complaints.
Massive Gastrointestinal Bleeding in Metachromatic Leukodystrophy Patient Predicates Presence of Gallbladder Polyp: (Poster No. 36)
A 4-year-old girl with a history of metachromatic leukodystrophy and developmental delay presented to the hospital with gastrointestinal (GI) bleeding of unknown source. The hematochezia was initially worked up by colonoscopy but no positive findings resulted. An upper GI workup revealed hemobilia. She continued to have ongoing bleeding, manifesting both hematemesis and melena, and received a large amount of blood transfusion. A computed tomography scan revealed active extravasation coming from the cystic duct, and a right upper quadrant mass in the gallbladder mass. Urgent exploratory laparotomy and cholecystectomy followed and showed a sessile polypoid mass at the fundus, measuring 2.5 cm in greatest dimension. Histology examination revealed an inflamed gallbladder without lithiasis. This polypoid mass was a villous papilloma or florid papillary fronds hyperplasia, with some minimal degree of dysplasia. Frank hemorrhage was observed dissecting the polypoid mass and gallbladder wall, explaining the massive hemobilia clinically. Literature search pointed to exceptionally strong association between one type of very rare gallbladder polyp and massive hemobilia and acalculous cholecystitis in the background of metachromatic leukodystrophy, a rare inborn metabolic disorder with primary clinical features of neuropsychiatric symptoms and cognitive disturbances; the mechanism of this repeatedly observed association is speculated owing to the toxic biliary secretion of metabolics (cerebroside sulfide) injuring the biliary epithelium. The recognition of this association pattern of gallbladder polyp in the setting of metachromatic leukodystrophy is well worthwhile bringing to the attention of clinicians, radiologists, and pathologists alike (Figure 16).
A 2-Case Series Describing Clinicopathologic Features of Lymphoepithelioma-like Hepatocellular Carcinoma and Lymphoepithelioma-like Cholangiocarcinoma: (Poster No. 39)
Lymphoepithelioma-like hepatocellular carcinoma (LEL-HCC) and lymphoepithelioma-like cholangiocarcinoma (LELC) are extremely rare entities with relatively favorable prognoses. Few cases are currently reported, making clinicopathologic correlation of identified cases important. Both types feature abundant lymphocytic infiltrates. Both can be Epstein-Barr virus positive or negative. We report a 2-case series: (1) LEL-HCC, the largest reported, in a 35-year-old woman; and (2) LELC in a 69-year-old woman with synchronous gastric adenocarcinoma. In the first case, a 29.2-cm liver mass was identified during cesarian delivery. Histologic examination showed pleomorphic malignant cells positive for hepatocyte-specific antigen, glypican-3, and AFP, consistent with hepatocellular carcinoma (Figure 17, A). The tumor was infiltrated predominantly by T cells (mixed CD4+ CD8+), yielding a diagnosis of LEL-HCC. EBER-1 was negative, and the patient's serology was negative for hepatitis B and C. The second patient was diagnosed with gastric adenocarcinoma “metastatic to the liver” 2 years prior. The liver lesion responded to systemic therapy, so gastrectomy with partial hepatectomy was performed. Instead of metastatic gastric adenocarcinoma, the liver lesion displayed infiltrating glandular structures strongly positive for CK7, and negative for HepPar1, glypican-3, CK20, and CDX2, consistent with cholangiocarcinoma (Figure 17, B). Abundant mixed CD3+ T-cell (predominant) and CD20+ B-cell infiltrate led to a diagnosis of LELC. EBER-1 in situ hybridization was positive. The synchronous gastric adenocarcinoma showed different morphology and was EBER-1 negative. Histopathologic findings of our cases are consistent with those reported to date in the literature. Reporting features of these rare, more favorable entities will help distinguish them from hepatocellular carcinoma and cholagiocarcinoma.
Enhancement of Helicobacter pylori Immunostain by Use of Romanowski-Based Counterstain: (Poster No. 40)
Context: Helicobacter pylori infection remains a significant source of global morbidity. While adjunct stains as an enhancement technique have been used extensively in hematology, their use as an aid in immunohistochemistry (IHC) is less studied. We propose a protocol for the use of a Romanowski-based counterstain to augment the identification of H pylori by IHC in endoscopic biopsies. The most practical applications were explored, including cases with abundant, mixed bacterial species from oropharyngeal introduction confounding interpretation, as well as cases with only a few organisms present. The addition of the counterstain, which enhances the DAB, can additionally highlight the morphology of the organisms in a background of nonspecific material sometimes seen with IHC staining.
Design: Slides were prepared by using the laboratory protocol for IHC with an additional level prepared on the same slide if possible. Before the coverslip step, 1 level was additionally stained with Diff-Quik (Siemens B4132-1A). The strengths of our protocol lie in that it is inexpensive, readily available, and already used in most anatomic pathology laboratories.
Results: In cases exhibiting positive staining for the H pylori IHC antibody, a Romanowski-based counterstain enhances the visibility of the organisms, staining them black. Other, nonspecific bacteria not taking up the IHC antibody will be additionally stained by the counterstain (Figure 18).
Conclusions: In cases in which H pylori is to be studied by IHC, the addition of a Romanowski-based counterstain can provide an inexpensive and efficient adjunct to identify the organisms, particularly in certain situations.
A Case of Brown Bowel Syndrome (Ceroidosis, Intestinal Lipofuscinosis): A Rare Cause of Megacolon: (Poster No. 42)
First described in 1861, brown bowel syndrome is a rare entity with only 27 other scientific reports in the literature. We report a case of a 57-year-old woman who was found unresponsive with extreme hypoglycemia and hypotension, requiring intubation. Past history included malnutrition, diabetes mellitus, chronic obstructive pulmonary disease, alcoholic cirrhosis, multiple vascular stents, and remote right colectomy. During hospitalization, the abdomen became greatly distended with abdominal imaging concerning for diffuse colitis involving all of her remaining colon down to the rectosigmoid junction, or mesenteric ischemia. She underwent completion colectomy. Grossly, the colon was boggy and edematous throughout with megacolon distally. Transverse sections showed a thinned, discolored, muddy orange-brown muscular coat (Figure 19, A). Microscopically, granular brown pigment occupied the cytoplasm of the smooth muscle cells of both the outer and inner muscular coats of the small and large bowel (Figure 19, B). Ultrastructurally, smooth muscle cells had atrophy, loss of myofilaments, and dense bodies with abundant secondary lysosomal inclusion in the cytoplasm (Figure 19, C). Brown bowel syndrome is associated with chronic primary malabsorption and also chronic liver disease. Accumulation of lipofuscin pigment in affected cells is postulated to be due to vitamin E deficiency. Vitamin E, an antioxidant, protects against oxidation of the mitochondrial membrane by free radicals. Lipofuscin is a degradation product of degenerating mitochondria. Thus, chronic malabsorption of lipid soluble vitamins (vitamins A, D, E, and K) may lead to brown bowel syndrome.
Histopathologic Features of Late Gastrointestinal Graft-Versus-Host Disease in Patients Taking Mycophenolate Mofetil: A 5-Year Retrospective Study: (Poster No. 43)
Context: Gastrointestinal (GI) graft-versus-host disease (GVHD) is a common complication of hematopoietic stem cell transplant (HSCT) that typically occurs within a few months of HSCT but can present later. Mycophenolate mofetil (MMF), a commonly used immunosuppressant, can mimic GI GVHD clinically and histologically. There are no specific histologic features for late GVHD or MMF toxicity.
Design: All GI biopsies from adult patients who received an allogeneic HSCT between January 1, 2005, and December 31, 2010, and underwent endoscopy >100 days post HSCT, were jointly reviewed by 2 pathologists who were blinded to the clinical findings. A chart review was performed. The clinical diagnosis was used to determine GVHD status.
Results: A total of 397 patients underwent allogeneic HSCT, of which 176 had an endoscopy. Seventy-nine of those were performed after day 100 (8 were for nonsymptomatic reasons and excluded), leaving 71 patients with endoscopies for late GI symptoms. Of these, 34 were taking MMF, of which 23 had a clinical diagnosis of GI GVHD (Table). Thirty-seven patients were not taking MMF, of which 22 had a clinical diagnosis of GI GHVD. One patient was clinically diagnosed with MMF toxicity.
Conclusions: Clinical GI GVHD >100 days from HSCT was associated with moderate/severe apoptosis, moderate/severe crypt destruction, and gland/crypt dropout or atrophy. These features may be helpful when evaluating for GI GVHD in the setting of MMF. In contrast to recent studies, having >15 lamina propria eosinophils per high-power field did not correlate with MMF administration and was also seen in patients with a clinical diagnosis of GI GVHD.
Aberrant Expression of c-Met and Correlation With Hep Par1 in Hepatocellular Carcinoma: (Poster No. 44)
Context: c-Met receptor tyrosine kinase pathway plays a key role in carcinogenesis of multiple human malignancies, including hepatocellular carcinoma (HCC). We studied c-Met expression and clinicopathologic associations in HCC.
Design: Fifty-six patients with primary HCC were included. c-Met expression was evaluated by using immunohistochemistry on formalin-fixed, paraffin-embedded tumor resections. Stain intensity was scored on a scale of 0 (absent) to 3 (strongest). HCC with 2 to 3+ staining intensity in ≥30% tumor cells was considered c-Met positive. c-Met status was correlated with Hep Par1 expression and clinicopathologic variables.
Results: Thirty cases (53.5%) showed absent c-Met, 16 cases (28.6%) showed weak expression, and 10 cases (17.9%) were c-Met positive, while background liver showed absence of c-Met expression. No correlation was found between c-Met expression and etiology of underlying liver disease; patient age; sex; presence or absence of cirrhosis; and tumor size, grade, or stage. However, a significant inverse relationship (P < .01) was found between c-Met and Hep Par1 expression (Figure 20). Further imaging studies confirmed that tumor cells with increased c-Met expression had reduced Hep Par1 expression.
Conclusions: We report increased c-Met expression in HCC compared to background nontumor liver. There was a significant correlation between increased c-Met expression and reduced Hep Par1 expression. Decline in c-Met expression and gain in carbamoylphosphate synthetase, the known antigen for Hep Par1, heralds the onset of hepatocyte maturation in embryonic liver development. Increased c-Met expression and reduced Hep Par1 expression may indicate poor hepatocyte differentiation and serve as worse prognostic indicators in HCC.
Massive Extramedullary Hematopoiesis Leading to Graft Dysfunction in a Liver Transplant Patient With Myelodysplastic Syndrome: (Poster No. 45)
A 59-year-old man underwent a liver transplant (LT) for end-stage liver disease in 2008. The explanted liver showed cirrhosis due to sclerosing cholangitis with increased IgG4 plasma cells, consistent with IgG4 autoimmune sclerosing cholangitis. In 2011, the patient developed anemia and pancytopenia. A bone marrow biopsy performed early in 2012 showed mild hypercellularity with dysplastic changes in the myeloid series and megakaryocytes, consistent with myelodysplastic syndrome (MDS). The bone marrow contained 1% to 3% blasts. However, fluorescence in situ hybridization studies for the MDS panel were negative. The patient also had generalized lymphadenopathy. A cervical lymph node excision in 2014 showed an extramedullary myeloid proliferation. In 2015, while being evaluated for chronic diarrhea, he was found to have abnormal liver function test results. A liver biopsy showed diffuse infiltration of the sinusoids by erythroid precursors and myeloid cells in different stages of maturation, confirmed by immunohistochemistry. There were very few CD34+ blasts present but many cells expressed the immature myeloid antigen CD117. These features, in the absence of tumoral masses, were most consistent with massive extramedullary hematopoiesis within the liver. A subsequent bone marrow biopsy revealed features of MDS and myeloproliferation with marked monocytosis, indicating advancement of his MDS and characterization as chronic myelomonocytic leukemia. MDS subsequent to LT, as compared to other solid organ transplants, is rare, and only a few cases have been reported in the literature. Furthermore, our case highlights an important rare cause of liver allograft dysfunction (massive extramedullary hematopoiesis), which should be suspected in any post-LT patient with an underlying hematologic disorder (Figure 21).
Gastric Polyps With an Unusual Serrated Morphology in a Case of Attenuated Familial Adenomatous Polyposis: (Poster No. 47)
Serrated polyps of the stomach are a rare entity. Most of the reported cases have been sporadic with only 1 patient with Lynch syndrome. Gastric serrated polyps have been associated with increased risk of invasive carcinoma. This case represents an example of a gastric polyp with serrated/papillary morphology in a patient with attenuated familial adenomatous polyposis (FAP). The patient is a 49-year-old woman who was diagnosed with FAP, attenuated type, 32 years ago. She had first presented at the age of 17 years with multiple pilomatricomas. Given her positive family history, she was tested and found positive for APC gene mutation. She had undergone a prophylactic total colectomy at that time and presented recently with multiple polyps in the stomach. On microscopy, in addition to multiple fundic gland polyps, there were polyps with a hyperplastic papillary configuration. These glands were lined by hyperplastic foveolar epithelium (supported by positive MUC5AC immunohistochemical stain) with a serrated morphology or “star-shaped” lumina (Figure 22, A through C). These polyps also had occasional foci of mucin depletion, low-grade dysplasia, and glands exhibiting abnormal nuclear localization of β-catenin (Figure 22, D). This case represents the first example of gastric polyps with serrated/ papillary morphology in FAP. Though the clinical significance of this histologic finding is not known, given the increased risk of invasive carcinoma with gastric serrated polyps, these patients may have a higher risk of malignancy than patients with fundic gland polyps alone.
Exploring the Prognostic Values of the Nuclear Protein COUP-TFII in Pancreatic Ductal Adenocarcinoma: (Poster No. 48)
Context: Chicken ovalbumin upstream promoter–transcription factor II (COUP-TFII), also known as NR2F2, is a member of the nuclear receptor superfamily. Loss of COUP-TFII expression is seen in pancreatic ductal adenocarcinoma (PDAC). Here we explore the prognostic values of this protein by investigating its expression and correlating it with the clinicopathologic features of PDACs.
Design: One hundred thirty-five consecutive cases of primary PDAC with available clinical data were selected for study (mean age, 68 years; male to female ratio, 62:73). Immunohistochemical study was performed by using monoclonal antibody anti-NR2F2 (AbCam, Cambridge, Massachusetts). The immunostains were interpreted as negative (–) when >80% of tumor cells showed no expression of protein. The results were analyzed by statistical methods with the clinical and histopathologic features of this cancer population.
Results: Loss of COUP-TFII expression was seen in most PDACs (91 of 135, 67%) (Table). Compared to the COUP-TFII+ group, the COUP-TFII– group showed higher possibilities in association with high-grade PDAC, nodal metastasis, lymphovascular invasion, and perineural invasion, and possessed a shorter median survival time. Among these, the increased likelihood of nodal metastasis was statistically significant (P = .03).
Conclusions: Loss of COUP-TFII in PDAC carries an increased possibility of nodal metastasis, with a tendency to develop high-grade PDAC, lymphovascular invasion, perineural invasion, and a worse clinical outcome.
Synchronous Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma: A Study of 4 Unusual Cases: (Poster No. 49)
Context: While risk factors for hepatocellular carcinoma (HCC) and extrahepatic cholagiocarcinoma are well understood (chronic hepato-cellular disease versus biliary disease), those for intrahepatic cholangiocarcinoma (ICC) are less well known. We report 4 cases of synchronous HCC/ICC and comment on their relationship.
Design: Four cases of synchronous HCC/ICC were identified among 279 hepatectomies (1.4%) identified from 2005–2015. The clinical history, gross descriptions, photographs, and H&E slides (Figure 23, A and C) were reviewed, along with immunohistochemistry for cytokeratin (Figure 23, B) and Hepar-1 (Figure 23, D).
Results: Age ranged from 54 to 63 years for the 2 male and 2 female patients; 3 of 4 were Hispanic. All cases developed in a background of cirrhosis due to hepatitis C (2 cases) or steatohepatitis (1 alcoholic and 1 nonalcoholic). There was no evidence of biliary disease. HCC size ranged from 2.2 to 14 cm. All ICCs were mass forming, measured 1.2 to 4 cm, and included 2 small duct and 2 ductular types. All tumors displayed characteristic immunohistochemistry for either Hepar-1 (HCC) or cytokeratin (ICC).
Conclusions: All patients had previous chronic hepatocellular disease, but no biliary disease. The findings are consistent with the hypothesis that both HCC and ICC arise from a common stem cell, and they are also consistent with recently published data suggesting that hepatitis C infection, steatohepatitis, and Hispanic race may be associated with both ICC and HCC, but not with extrahepatic cholangiocarcinoma. In keeping with the recent observation that ICC is on the rise in developed countries, we found almost twice as many ICCs (38) as HCCs (20) among 58 cases of all cholangiocarcinomas.
Collagenous Sprue in a 12-Year-Old Boy: (Poster No. 54)
Collagenous sprue (CS) is a rare intestinal malabsorptive disorder characterized by villous blunting, increased intraepithelial lymphocytes, and thickened subepithelial collagen bands. There is a female predominance and most cases involve adults. Only 4 pediatric patients have been reported so far with no gastric involvement. We report a case of collagenous sprue in a 12-year-old boy with marked gastric involvement. The patient presented with prolonged encopresis and elevated anti–tissue transglutaminase IgA titer (approximately 30 units). Upper endoscopy revealed nodularity only in the antrum. Microscopically, patchy thickened subepithelial collagen bands and markedly increased intraepithelial CD8+ lymphocytes were present in duodenal and antral mucosa. Villous atrophy and focal foveolar metaplasia were seen in the duodenal bulb with no evidence of Helicobacter infection. The exact etiology of CS is unknown and multifactorial. To date, CS is found to be related with gluten sensitivity, autoimmune diseases and immunodeficiencies, medications, and other conditions or agents causing chronic mucosal injury. In addition, CS is frequently refractory to strict gluten-free diets and patients often require steroids and total parenteral nutrition. In a subset of adult cases, a subepithelial collagen band is also present in colon and stomach. To our knowledge, this is the first reported pediatric case of CS with gastric involvement. The endoscopic nodularity and collagen band are located in the antrum in contrast to collagenous gastritis secondary to chronic gastritis where corpus is typically involved. In conclusion, CS can involve both duodenal and antral mucosa in pediatric patients (Figure 24).
Primary Malignant Solitary Fibrous Tumor of the Liver: (Poster No. 55)
Solitary fibrous tumor is a rare soft tissue neoplasm of mesenchymal origin that predominantly arises in the pleura, meninges, orbit, upper respiratory tract, thyroid, and peritoneum. Even more uncommonly reported tumors are those arising in the liver. Solitary fibrous tumors are classified as benign versus malignant on the basis of cellularity, cytologic atypia, mitotic activity (cutoff value is 4/10 high-power fields), and presence of necrosis. We report a case of an 83-year-old woman with the incidental finding of a 17.5 × 16.1 × 11.4-cm heterogeneous mass in the right hepatic lobe detected by computed tomography scan during a cardiac workup for dyspnea. An ultrasound-guided biopsy was performed and demonstrated a spindle cell neoplasm arranged in a fascicular pattern with mild cytologic atypia, alternating hypocellular and hypercellular areas, and prominent staghorn vessels. The tumor exhibited areas of necrosis, increased mitotic activity (up to 5/10 high-power fields), and high proliferation index (Ki-67, 10%). The neoplastic cells were immunoreactive to CD34, vimentin, and Bcl-2 and negative for desmin, S100, CD117 (c-kit), and AE1/AE3. Further workup did not find any other extrahepatic neoplastic process. The clinical finding, in conjunction with the histology and immunophenotypic features of the tumor, supports the diagnosis of a primary malignant solitary fibrous tumor of the liver (Figure 25).
Diffuse Gastric Ganglioneuromatosis: (Poster No. 58)
Gastrointestinal ganglioneuromatous proliferations, usually found in the left colon, are of 3 types: polypoid ganglioneuromas, ganglioneuromatous polyposis, and diffuse ganglioneuromatosis. We report the first case of gastric diffuse ganglioneuromatosis located in the posterior gastric wall of a 9-year-old girl. A 3-cm polypoid mass with endoscopic features of juvenile polyposis was found on upper endoscopy. On histologic examination, a nodular and diffuse transmural spindled cell proliferation, positive for S100 and Sox10, with intermixed ganglion cells involving the superficial mucosa, submucosal and myenteric plexuses, and the muscularis propria was found (Figure 26). No features suggestive of paraganglioma were noted, and the presence of ganglion cells excluded schwannoma. The transmural involvement of the gastric wall confirms the diagnosis of diffuse ganglioneuromatosis over polypoid ganglioneuroma. Only 3 cases of gastric ganglioneuromatous proliferations have been previously reported and none are diffuse ganglioneuromatosis. A diagnosis of diffuse ganglioneuromatosis is significant because most cases are syndromic, associated with neurofibromatosis type 1, multiple endocrine neoplasia type 2b, or Cowden syndrome, also know as PTEN multiple hamartoma syndrome. The patient's father has Cowden syndrome and our patient has the noted gastrointestinal hamartoma with a history of learning disability and esophageal glycogenic acanthosis, fulfilling 1 major criterion and 2 minor criteria for Cowden syndrome, respectively. This syndrome, associated with the PTEN gene mutation on chromosome 10q23, manifests with hamartomas in all 3 germ cell layers, as well as an increased risk of breast, thyroid, and endometrial cancers. Early diagnosis enables early screening for associated malignancies.
Hepatic Adenoma in a Male Patient: β-Catenin–Mutated Subtype: (Poster No. 59)
We present a case of a 28-year-old black man with thrombotic thrombocytopenic purpura who developed a hepatocellular adenoma. In December 2013, abdominal imaging detected 2 liver masses, the largest measuring 11.0 × 8.7 cm, whereas the previous ultrasound scan in 2011 was clear. In February 2014, fine-needle aspiration of the largest mass showed atypical monotonous sheet of cells with pseudoinclusions. The differential diagnosis included hepatic adenoma and a well-differentiated hepatocellular carcinoma. A right lobe resection was performed on May 14, 2014. On postoperative day 4, the patient died from internal hemorrhage thought to be secondary to the underlying thrombotic thrombocytopenic purpura. The final histology revealed hepatic adenoma. Upon review, the patient was taking 40 mg of prednisone daily. Gross examination showed a right liver (1263.1 g) with a cut surface revealing multiple masses. The largest mass was solid, well-circumscribed, and tan-yellow. Microscopic examination of each mass showed mature vacuolated hepatocytes with absent portal and biliary structures. Areas within the adenoma showed architectural atypia with varying degrees of small cell dysplasia. Stains performed included β-catenin, which showed positive nuclear and cytoplasmic staining in the adenoma. There was negative staining for glypican-3, focal loss of reticulin fibers with the reticulin stain, and Masson trichrome stain showed mild periportal fibrosis. Hepatocellular adenomas are rare, benign hepatic neoplasm with a female predilection and are linked to steroid use. They are profiled into 4 phenotypic subtypes. Based on our immunoprofile, this case is an example of a β-catenin–mutated subtype. This subtype is significant owing to a greater risk of malignant transformation (Figure 27).
Congenital Mesothelial Cyst of Hepatic Origin: A Very Rare and Unusual Presentation in a Newborn: (Poster No. 60)
Congenital mesothelial cysts of hepatic origin are very rare congenital lesions that are derived from coelomic remnants. We report the case of a 2-day-old girl with history of mother's pregnancy significant for polyhydramnios and concern for fetal bowel obstruction with perforation and ascites. On ultrasound study, an intra-abdominal mass was seen. The imaging shows multiple finely septated cystic structures located throughout the abdomen and pelvis. During the surgical procedure, the 13.5-cm cyst turned out to be a large, complex multiloculated cyst coming off the anterior edge of the liver, anterior to the gallbladder. The remainder of the abdominal cavity appeared normal. Preoperative diagnostic imaging studies, including computed tomography and magnetic resonance imaging, did not identify the etiology, but the cyst appeared to be of hepatic origin. Sections from the liver showed a cystic lesion lined by cuboidal and plump cells with adjacent compressed liver parenchyma showing portal acute and chronic inflammation and prominent extramedullar hematopoiesis. The cystic lining cells were positive for WT-1, keratin 5/6, calretinin, keratin OSCAR, and D2-40 but negative for CD34, ERG, and MOC31. This immunohistochemical staining pattern supports a mesothelial origin for this cyst and is most consistent with a mesothelial cyst. Here we present a rare case of mesothelial cyst of the liver, which was difficult to diagnose definitively before surgery, and immunohistologic staining of the cyst was useful for determining the origin of the cyst (Figure 28).
Calculous Cholecystitis With Diffuse Mural Fibrosis and Elevated IgG4 Plasma Cells: A Diagnostic Challenge: (Poster No. 62)
IgG4-related cholecystitis is a recently recognized entity characterized by the presence of 2 of the following criteria: dense lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis. The threshold for considering an IgG4-related disease process is currently contentious with proposed IgG4+/IgG+ ratio of more than 40% and greater than 50 IgG4+ plasma cells per high-power field. We present a case of a 64-year-old man who underwent cholecystectomy owing to severe right upper quadrant abdominal pain. The resected gallbladder contained numerous choleliths measuring up to 2.7 cm, causing pitting of the mucosa with prominent mural thickening up to 0.9 cm (Figure 29, A). Histologic examination revealed diffuse mural fibrosis and prominent lymphoplasmacytic infiltrate. Classic storiform pattern of fibrosis and obliterative phlebitis was absent. However, immunohistochemistry demonstrated significantly elevated IgG4+plasma cells up to 75 per high-power field with an IgG4+/IgG+ratio of 47%, meeting the criteria for IgG4-related disease (Figure 29, B). Though these values raised the possibility of IgG4-related disease, there were no other histologic features characteristic of IgG4-related cholecystitis, and further clinical workup did not reveal systemic manifestations of IgG4-related disease. Therefore, we hypothesized that the increase in IgG4+plasma cells in this case represented a nonspecific inflammatory response. Detection of increased IgG4+ plasma cells should raise clinical suspicion for localized or systemic IgG4-related disease. However, clinicopathologic correlation is required to differentiate IgG4-related cholecystitis from a nonspecific inflammatory reaction. This case contributes to growing evidence for increased IgG4+ plasma cells in conditions unassociated with classic IgG4-related disease.
Inflammatory Myofibroblastic Tumor of the Liver After Hematopoietic Stem Cell Transplantation: (Poster No. 63)
Inflammatory myofibroblastic tumor (IMT) is a neoplasm of myofibroblasts most commonly seen in the retroperitoneum and mesentery of children and young adults. IMTs are rare in post hematopoietic stem cell transplant (HSCT) patients with only 6 cases reported in the literature, of which only 1 patient had hepatic disease. Herein we report a case of hepatic IMT that developed after allogeneic HSCT in a 20-year-old man. The patient was diagnosed with osteosarcoma of right distal femur at age 17 years and underwent chemotherapy and limb-sparing resection. Two years after chemotherapy he developed secondary acute myeloid leukemia with monosomy 7 and was treated with chemotherapy and umbilical cord HSCT. Thirteen months after HSCT the patient presented with clinical features of graft-versus-host disease (GVHD). Magnetic resonance imaging revealed a
3.0-cm lesion within the left hepatic lobe concerning for metastatic osteosarcoma. A needle biopsy of the lesion demonstrated a well-circumscribed tumor composed of bland spindled myofibroblastic cells admixed with an inflammatory infiltrate of lymphocytes and plasma cells. The spindle cells were positive for caldesmon and smooth muscle actin by immunohistochemistry and showed cytoplasmic immunore-activity with anaplastic lymphoma kinase 1 (ALK-1, Figure 30), supporting the diagnosis of IMT. In situ hybridization for EBV was negative. Although a rare entity, IMT should be considered in the differential diagnosis of patients with prior history of HSCT with unexplainable symptoms of systemic inflammation and a mass lesion. Identifying this entity is important as the management is excision, after which symptoms are reported to resolve.
Mixed Adenoneuroendocrine Carcinoma Arising in Inflammatory Bowel Disease–Associated Dysplasia: (Poster No. 64)
Inflammatory bowel disease may be complicated by dysplasia-associated lesions or masses that pose a high risk of adenocarcinoma. There are only rare reports of neuroendocrine neoplasms arising in mucosa involved by inflammatory bowel disease. As some of these inflammatory bowel disease–associated neuroendocrine neoplasms are adjacent to glandular dysplasia, it has been proposed that neuroendocrine differentiation may arise from multipotential cells in dysplastic epithelium. We report a mixed adenoneuroendocrine carcinoma arising in polypoid ulcerative colitis–associated dysplasia. A 64-year-old man with a 45-year history of ulcerative colitis underwent surveillance colonoscopy with biopsies showing high-grade dysplasia. The subsequent proctocolectomy showed gross features consistent with pancolonic ulcerative colitis, as well as multiple plaquelike lesions throughout the colon and a 2-cm sessile cecal lesion. Sections revealed pancolonic chronic active colitis with multifocal flat low-grade dysplasia. The superficial portion of the sessile cecal lesion exhibited high-grade dysplasia and submucosally, invasive adenocarcinoma. In the deep portion of the lesion, the neoplastic crypt bases merged into a grade 2 neuroendocrine tumor (7 mitoses per high-power field, Ki-67 index approximately 5%) measuring 0.9 cm. The neuroendocrine component was reactive for chromogranin and synaptophysin, and these stains also showed increased neuroendocrine cells in the adjoining dysplasia and adenocarcinoma. The adjacent nonneoplastic mucosa showed architectural features of chronic colitis including crypt distortion and pseudopyloric metaplasia. In this case, the direct association of the neuroendocrine neoplasm with neoplastic crypts further suggests that neuroendocrine differentiation arises from multipotential cells in inflammatory bowel disease–associated dysplastic epithelium (Figure 31).
Extramedullary Hematopoiesis Presenting as Gastric Nodules: (Poster No. 66)
Extramedullary hematopoiesis (EMH) is known to occur during failed bone marrow production. The liver, spleen, kidney, lymph nodes, and posterior mediastinum are common sites for alternative hematopoiesis. It is extremely rare for EMH to occur in the gastric mucosa. A 76-year-old woman with a history of gastroesophageal reflux disease presented with lethargy and weakness. She was found to have splenomegaly, profound anemia, thrombocytopenia, and blasts in the peripheral blood. A bone marrow biopsy revealed extensive fibrosis, megakaryocytic hyperplasia with atypia, left-shifted granulocytic hyperplasia, erythroid hypoplasia, and increased blasts (5%–10%). Molecular testing was positive for a JAK2 mutation. These findings were consistent with primary myelofibrosis. Esophagogastroduodenoscopy showed multiple small gastric mucosal nodules. Histologic examination revealed numerous cells within the lamina propria with enlarged, pleomorphic nuclei and occasional multinucleated forms (Figure 32). The cells showed positivity for CD61 (Figure 32), identifying these cells as megakaryocytes and confirming EMH. The disease process of primary myelofibrosis displaces and mobilizes stem and progenitor cells from the bone marrow, which changes the site of hematopoiesis to the spleen and liver. The JAK2 mutation, increased inflammatory cytokines, and angiogenesis-promoting factors also play a role in EMH. This case highlights the importance of considering EMH in the differential diagnosis of gastric polyps, especially in the context of diseases resulting in failed bone marrow hematopoiesis. Detection of EMH without a diagnosis of bone marrow failure warrants additional hematologic evaluation. To our knowledge, there are only 2 reported cases of gastric polyps with EMH and 4 reported cases in total with gastric EMH.
Coexistence of Appendiceal Neuroendocrine Tumor (Typical Carcinoid) and Low-Grade Mucinous Neoplasm: Unusual Presentation: (Poster No. 68)
Appendiceal neoplasms are rare, and almost all are found incidentally. The most common neoplasm is the well-differentiated neuroendocrine tumor (typical carcinoid [TC]), which is derived from enterochromaffin cells. The low-grade appendiceal mucinous neoplasms (LAMNs) are glandular epithelial tumors that arise in association with dysplastic mucinous epithelium. We report a rare co-occurrence of LAMN and TC in the appendix, with an unusual presentation. A 38-year-old woman presented with dysmenorrhea and a vague discomfort in the pelvic area during each period. She was diagnosed with stage IV endometriosis and polycystic ovarian syndrome 4 years ago and had several laparotomies. During her last exploratory laparotomy, she was found to have a dilated appendix with nodular areas, concerning for endometrial implants. Grossly, the appendix was slightly enlarged with multiple red-pink stippling. It was filled with thick mucinous material. Histologically, the appendiceal lumen was lined by mucin containing pseudostratified columnar epithelium that lacked significant cytologic atypia. The tumor showed pools of extracellular mucin associated with fibrosis and scant strips of simple mucinous epithelium (Figure 33, A). A small focus (6 mm) of TC with nested growth pattern was also seen. It was composed of uniformly small and round nuclei with finely stippled chromatin, and abundant eosinophilic cytoplasm (Figure 33, B). Despite having different pathways, the coexistence of TC and LAMN has been reported in very rare cases. The possibility of common mutation has been considered. In our patient, however, the unusual presentation and the association with endometriosis and ovarian lesions warrant further investigation.
Gastrointestinal Stromal Tumors: Characteristics of Cases Diagnosed in 205 Patients at Scott & White Hospital From 1990 to 2014: (Poster No. 72)
Context: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal (GI) tract; most were classified as smooth muscle tumors before the late 1980s. GISTs account for 94% of gastric tumors previously classified as smooth muscle tumors, and now account for 2.2% of all primary GI malignancies. We describe our institution's experience with this entity.
Design: We searched our pathology database for all diagnoses of “gastrointestinal stromal tumor.”
Results: From 1990–2014, the diagnosis of GIST was made in 242 specimens procured from 198 patients, including 2 autopsies, 206 surgical specimens, and 34 fine-needle aspirations (FNAs). Forty-four patients had multiple specimens. Twenty-seven GISTs were incidental. Forty-eight percent were from men and 52% were from women; age range was 24 to 97 years, with an average age of 67 years. The locations were stomach or perigastric soft tissue (61%), small bowel (17%), colorectal (3.5%), esophagus (1.2%), and abdominal/pelvis/retroperitoneal soft tissue (10.5%). There were 13 metastases: 11 to the liver and 2 to soft tissue of an extremity. FNA was performed on 47 occasions. In 34 FNA cases (72%), GIST was diagnosed, including as the first-time diagnoses in 16 patients, the sole diagnosis in 15 patients, and 3 metastatic GISTs. See Table for immunohistochemistry results.
Conclusions: Our experience is somewhat similar to published characteristics of GIST with respect to sex, age, and location, with some variation in published immunohistochemistry results. Notably, FNA plays a significant role in the diagnosis of GISTs at our institution.
Intrabiliary Hepatic Metastasis of Colorectal Carcinoma Mimicking Primary Cholangiocarcinoma: (Poster No. 73)
Intrabiliary metastasis from colorectal carcinoma (CRC) growing within or invading bile ducts is not a very common pattern. Accurate diagnosis of metastatic lesions is very important for selection of adjuvant therapy and prognosis. We report a case of a 71-year-old man who developed painless jaundice due to hepatobiliary obstruction. Magnetic resonance imaging demonstrated a 1.4-cm intraductal mass at the hepatic hilum with severe intrahepatic ductal dilation consistent with cholangiocarcinoma. Endoscopic retrograde cholangiopancreatography showed intraductal segmental biliary stricture. Biopsy from the lesion showed adenocarcinoma with favoring primary cholangiocarcinoma owing to the papillary morphology and location of the mass. His past history was significant for rectosigmoid carcinoma (pT1N0) 10 years ago and liver resection for metastatic CRC 4 years ago. He subsequently underwent central hepatectomy with resection of common bile duct. Grossly, there was a 1.2-cm intraductal mass at the bifurcation of bile ducts with multiple nodules in liver parenchyma. Microscopic examination revealed intraductal carcinoma with papillary architecture colonizing bile duct epithelium (Figure 34) with resultant dilation and tortuosity of ducts. Occasional liver parenchymal nodules showed classical metastatic pattern resembling CRC. Because of 2 distinct morphologic patterns and our patient's past history, immunostains were performed. CK7 stained uninvolved bile duct epithelium with no staining in intrabiliary metastatic growth. CK20 and CDX2 were positive, thus confirming intrabiliary growth as metastatic growth from CRC. In summary, findings from our case indicate that intrabiliary growth of metastatic CRC can easily be overlooked with major duct involvement. Pathologic evaluation with use of immunhistochemical stains is very important to achieve the correct diagnosis.
Extensive Benign Signet Ring Cell Changes in Gastric Mucosa: (Poster No. 74)
Signet ring cells in stomach generally connote adenocarcinoma with a poor prognosis. Signet ring cell change may also be noted in various benign conditions of the stomach, typically gastritis, but such a change is usually isolated/focal and involves rare cells. We report a gastricnodule biopsy with reactive gastropathy and extensive signet ring cell change in various biopsy parts, as illustrated in the figure (Figure 35). At H&E staining, the signet ring cells were well clustered and confined within the glandular basement membrane, without cellular atypia, nuclear hyperchromasia, prominent nucleoli, mitotic activity, or overall dysplasia typically identified with malignancy. Lamina propria was completely devoid of signet ring cells. At reticulin staining, the basement membrane surrounding foveolae and glands was well demarcated and appeared undisturbed. The signet ring cells were not immunoreactive with anti-p53 antibody, and anti–E-cadherin nicely delineated the cell membranes of all the benign epithelial cells, including signet ring type cells, also confirming the absence of any signet ring cells in the lamina propria. This case will add to the very rare reports of extensive benign signet ring cell change in gastric glandular epithelium. Simple stains such as reticulin, anti-p53, and anti–E-cadherin can affirm the benign nature of this otherwise alarming cytomorphology.
Fibrosing Cholestatic Hepatitis Due to Reactivation of Hepatitis B Following Treatment With Rituximab for Marginal Zone B-Cell Lymphoma: (Poster No. 75)
Fibrosing cholestatic hepatitis is a rapidly progressive, sometimes fatal form of hepatitis, originally described in hepatitis B virus– or hepatitis C virus–infected recipients after liver transplant. We present a case of a 65-year-old man with chronic hepatitis B diagnosed in May 2013 with normal liver function. In May 2013, the patient was diagnosed with marginal zone B-cell lymphoma and treated with rituximab chemotherapy. The patient had normal liver function test results before, during, and immediately after finishing chemotherapy. In mid November 2014 he was hospitalized with acute liver failure. His liver function tests showed ALT 1138 UI/mL and AST 831 UI/mL. Serum HBV DNA level was 400 000 UI/mL, for which lamivudine was switched to entecavir. For worsening liver function, a transjugular liver biopsy was performed. Histology showed diffuse hepatocyte injury with hepatocyte ballooning/swelling, degenerative changes, frequent apoptosis, bridging necrosis, and marked hepatocanalicular cholestasis with only mild lobular and portal inflammatory infiltrates. Trichrome stain showed extensive pericellular fibrosis, particularly in the periportal area. Immunohistochemical stains showed diffuse cytoplasmic stain for HBsAg (>90% cells) and diffuse nuclear positivity for HBcAg (>90% cells). The findings were consistent with fibrosing cholestatic hepatitis secondary to hepatitis B reactivation. Owing to worsening liver function, the patient received a liver transplant. This case illustrates that fibrosing cholestatic hepatitis can occur after immunosuppressive therapy in patients with hepatitis B. Frequent viral analysis might be indicated in patients with low-grade B-cell lymphoma after rituximab treatment (Figure 36).
A Distinct Pattern of Beclin-1 Staining Helps Distinguish Sessile Serrated Adenomas: (Poster No. 76)
Context: Diagnostic criteria of serrated polyps (SPs) are frequently difficult to apply and revisited owing to the clinical implications of polyp subtype related to malignant potential and pathophysiology. Autophagy has cell survival and death-promoting capabilities; its specific role in SPs is not fully described. We used Beclin-1 protein, a general autophagy marker, to examine autophagy expression in SPs.
Design: Immunohistochemistry was performed on 58 paraffin-embedded SPs (9 hyperplastic polyps, 38 sessile serrated adenomas [SSAs], 4 SSAs with dysplasia, 4 traditional serrated adenomas +/– dysplasia) and normal colon from the patients with SPs by using anti–Beclin-1 antibody (Abcam, Cambridge, Massachusetts). Staining was graded by proportion of cells (0, no staining; 1, 2, 3 diffuse [>50%]) and intensity (0, negative; 1, 2, 3, strong). Surface staining score (proportion × intensity) was calculated. Two-sample independent t test assessed the difference between the SSA group mean score versus the other samples. The Thomas Jefferson Internal Review Board approved this study.
Results: Eighty-two percent of SSAs demonstrated a diffuse, strong staining of the crypt with weaker surface staining, compared to predominantly diffuse, strong staining throughout the crypt and surface in the other samples (Figure 37). The difference between the mean surface staining scores of SSA group versus other samples was statistically significant (P < .001).
Conclusions: Autophagy is significant in SPs with probable divergent functions throughout the pathway. Additionally, Beclin-1 staining pattern suggests a potentially useful tool to distinguish SSAs in diagnostic challenges. Hyperplastic polyps with SSA-type staining pattern may represent intermediate SPs. Patients with SPs may have higher baseline autophagy activity in normal colonic mucosa.
Primary Adenosquamous Carcinoma of the Colon in a Patient With Lynch Syndrome: A New Histologic Subtype Associated With Microsatellite Instability?: (Poster No. 80)
Microsatellite instability (MSI), caused by loss-of-function defects in DNA mismatch repair genes, can lead to increased susceptibility to a variety of neoplasms. Pathologic features associated with MSI-high colorectal carcinomas (CRCs) are right-sided location, mucinous/signet ring or medullary histology, and tumor-infiltrating lymphocytes. Adenosquamous carcinoma of the colon is a rare histologic subtype composed of malignant squamous and glandular elements, with a worse prognosis than conventional CRC. The role of MSI in the pathogenesis of colorectal adenosquamous carcinoma is unknown. We report a case of a 53-year-old woman with a primary adenosquamous carcinoma of the right colon. The patient had a strong family history of CRC; her mother and maternal uncle died of CRC at age 35 and 55 years, respectively, and a first cousin has Lynch syndrome. The patient presented with rectal bleeding due to a 9.5-cm hemicircumferential ascending colon mass. A chest/abdomen/pelvis computed tomography scan was otherwise negative. A right hemicolectomy specimen revealed a pT3N0 adenosquamous carcinoma (Figure 38, a, and b). Immunohistochemistry revealed loss of MLH1 and PMS2 expression (Figure 38, c and d, respectively) and retention of MSH2 and MSH6 expression in both squamous and glandular components. Tumor was negative for MLH1 gene promoter hypermethylation, suggestive of germ line mutation; a diagnosis of Lynch syndrome was made. To our knowledge this is the first reported case of an MSI-high CRC showing adenosquamous histology. Further evaluation of MSI status in colorectal adenosquamous carcinomas may be warranted as this may be yet another histologic type of CRC associated with MSI.
Rare Collision of Pancreatic Invasive Intraductal Papillary Mucinous Carcinoma and Endocrine Neoplasm: Case Report With Brief Literature Review and Implication on Patient Follow-up: (Poster No. 83)
Pancreatic endocrine neoplasm (PEN) and intraductal papillary neoplasm (IPMN) are relatively rare. Even rarer are cases of concomitant IPMN and PEN (C-IPMN/PEN). The 2 components in C-IPMN/PEN can be intermingled or separate (collision). PubMed search revealed 20 cases of C-IPMN/PEN. In only 4 of these cases, IPNM was associated with invasive carcinoma and a low-grade PEN. A 77-year-old man presented with nausea and vomiting. Computed tomography scan revealed a pancreatic head multiseptated mass (3.4 × 2.9 cm). Grossly, the duodenopancreatectomy specimen revealed a multiloculated cystic mucinous mass in the head of pancreas (5.5 × 3.5 × 3.5 cm). Histologically, the tumor was a collision tumor formed of invasive intraductal papillary mucinous carcinoma and intermediate-grade PEN. The prevalence rates of C-IPMN/PEN (2.8% to 4.6%) in large series studies indicate that the frequency is higher than thought in the past because small PENs may escape diagnosis. C-IPMN/PENs are thought to arise from a different cell origin (neuroendocrine cell and ductal cells). A common neoplastic progenitor cell origin is currently suggested or transdifferentiation of some tumor cell of origin into another cell type. Whether the postoperative course and management of C-IPMN/PEN differ from those of PEN or IPMN only is unknown; no definitive guidelines have been established owing to the small number of reported cases. It seems logical that the management should be optimized to the more aggressive component. Both tumors tend to be multifocal with significant risk of recurrence in the remaining pancreatic tissue. This risk is increased in C-IPMN/ PEN, mandating close patient follow-up after surgical treatment (Figure 39).
TGR5 Expression in Benign, Preneoplastic, and Neoplastic Lesions of Barrett Esophagus: Case Series and Findings: (Poster No. 84)
Context: Bile acids may play an important role in the progression from Barrett esophagus (BE) to esophageal adenocarcinoma (EA). Here we examined the expression of the bile acid receptor TGR5 in normal squamous mucosa, Barrett mucosa, dysplasia, and EA.
Design: Slides were stained with TGR5 antibody (1:1000, Sigma). The staining intensity was scored as 1+, 2+, and 3+. The extent of staining (percentage of cells staining) was scored as follows: 1+, 1% to 10%; 2+, 11% to 50%; and 3+, 51% to 100%. A combined score of intensity and extent was calculated and categorized as negative (0), weak staining (1), moderate staining (2–3), or strong staining (4–6).
Results: A total of 56 cases were used, including 18 cases with normal squamous mucosa, 15 cases with BE, 8 cases with low-grade dysplasia, 3 cases with high-grade dysplasia, and 13 cases with adenocarcinoma (Table). A total of 93.3% of Barrett mucosa cases showed weak to moderate TGR5 staining, which was significantly higher than that of squamous mucosa (27.8%). Moderate to strong TGR5 staining was significantly higher in EA cases (92.3%) than in BE (13.3%, P < .001) or in low-grade dysplasia (37.5%, P < .05). Two of 3 high-grade dysplasia cases showed moderate to strong staining. Moderate to strong staining was slightly higher in low-grade dysplasia (37.5%) than in BE mucosa (13.3%), but there was no statistical significance. All (100%) stage III and IV cases showed moderate to strong staining, which was not significantly different from that of stage I and II cases (75%).
Conclusions: TGR5 immunostaining was much stronger in EA than in BE mucosa or low-grade dysplasia.
A Case of Adult Annular Pancreas With Pancreatic Duct Atresia and Subsequent Chronic Pancreatitis: (Poster No. 90)
Annular pancreas (AP) is a rare congenital abnormality characterized by a ring of pancreatic tissue surrounding the descending duodenum and originates from incomplete rotation of the pancreatic ventral bud. Symptoms from AP can occur at any age, although it is estimated that almost two-thirds of the patients remain asymptomatic for life. We report the case of a female adult with AP who was diagnosed at age 21 years. The patient presented with 6 months of abdominal pain, nausea, and vomiting. Laboratory tests showed significantly increased amylase (338 U/L) and lipase (239 U/L). A computed tomography scan suggested inflamed accessory pancreatic tissue with duct obstruction. She was treated with pancreaticoduodenectomy. Gross examination showed an AP located superiorly to the head and uncinate pancreas (Figure 40, A), measuring 5.7 × 4.3 × 3.3 cm. A dilated central duct (Figure 40, B, arrows) was noted measuring 0.5 cm in diameter and filled with tan, grumous material. The duct coursed toward a blind pouch at duodenal bulb but was not patent. This accessory pancreas was covered with a thin layer of adipose tissue containing numerous lymph nodes. The parenchyma of accessory pancreas appeared pale tan to yellow with a glistening lobulated cut surface. The duodenum was not constricted. Microscopic examination demonstrated dilated pancreatic ducts and diffuse chronic pancreatitis only in the accessory pancreas. The patient reported occasional pain, nausea, and vomiting for 3 weeks at post operation follow-up and was treated with medication. This case is valuable in guiding clinical diagnosis and management of young patients with chronic pancreatitis.
A Rare Cause of Gastrointestinal Bleeding—Blue Rubber Bleb Nevus Syndrome: (Poster No. 91)
Blue rubber bleb nevus syndrome (BRBNS) is a rare congenital disorder typically presenting with multifocal venous malformations usually involving the skin and gastrointestinal tract. We report the oldest case of BRBNS diagnosed in a man at 97 years of age. Before admission, the patient reported up to 2 melenic stools per day, requiring multiple transfusions with packed red blood cells. Outside video capsule endoscopy was reviewed. An anterograde double-balloon enteroscopy was performed followed by repeated video capsule endoscopy, which revealed dark blue to purple mucosal bowel protuberances in the jejunum, some with active bleeding (Figure 41, A). A small-bowel surgical resection was performed with approximately 90 cm of jejunum removed. Pathologic examination revealed multiple blue-purple submucosal lesions up to 2.5 cm, as well as white-yellow submucosal nodules up to 0.6 cm (Figure 41, B). Histologically, these constituted submucosal and transmural hemorrhage associated with abnormal blood vessels as well as lymphatics (Figure 41, C and D). The main differential diagnosis for multifocal vascular malformation includes congenital diseases with vascular malformations such as BRBNS, hereditary hemorrhagic telangiectasia, and Klippel-Trenaunay syndrome. A diagnosis of BRBNS was made from the endoscopic and pathologic findings and lack of skin lesions for other entities. The prognosis for BRBNS is generally favorable. While most reported cases are sporadic, an autosomal dominant inheritance pattern has been identified on chromosome 9p, which encodes tyrosine kinase TIE-2. This entity represents an uncommon cause of gastrointestinal bleeding, which pathologists should consider when presented with multifocal vascular malformations.
Extra-appendiceal Presentation of Adenocarcinoma Ex–Goblet Cell Carcinoid Co-occurring in a Patient With Neurofibromatosis Type 1: A Case Report and Review of the Literature: (Poster No. 92)
We report a rare case of an extra-appendiceal adenocarcinoma ex–goblet cell carcinoid occurring in a 62-year-old woman with clinical history of type 1 neurofibromatosis. The patient presented with rectal bleeding and abdominal pain. A computed tomography scan demonstrated rectal thickening and perirectal lymphadenopathy. Two rectal biopsies were obtained, one demonstrating goblet cell carcinoid (Figure 42, A) and the other showing adenocarcinoma ex–goblet cell carcinoid, signet ring cell type. The background lamina propria showed nodular spindle cell proliferation positive for S100 (Figure 42, B), consistent with mucosal neurofibroma. The positive stains for synaptophysin (Figure 42, C) and chromogranin (Figure 42, D) supported the histologic impression of goblet cell carcinoid. The Ki-67 immunostain demonstrated a mitotic index of 18% to 20%. Goblet cell carcinoids are known to arise exclusively in the appendix, whereas adenocarcinoma ex–goblet cell carcinoids have been very rarely reported at nonappendiceal primary sites. Both entities frequently demonstrate lymphatic spread and metastases, raising the possibility of undetected appendiceal primary. However, our patient had an appendectomy 40 years prior and abdominal computed tomography scan did not demonstrate any extrarectal lesions. To our knowledge, there is only 1 previously reported such case of concurrent neurofibromatosis type 1 and goblet cell carcinoid occurring in the appendix. Our case represents a rare incidence of an extra-appendiceal adenocarcinoma ex–goblet cell carcinoid and coexisting neurofibromatosis type 1, both occurring in the rectum.
Primary Undifferentiated Embryonal Sarcoma of the Liver in a 73-Year-Old Woman: The Oldest Reported Patient: (Poster No. 93)
Primary undifferentiated embryonal sarcoma of the liver (UESL) is a rare malignant neoplasm of unknown pathogenesis. UESL is usually encountered in children and young adults and extremely rarely in older age. We report the case of a 73-year-old woman who presented with abdominal discomfort. Computed tomography (CT) of the abdomen showed a multilobulated 10-cm solid mass in the left lobe of the liver. All laboratory findings other than mildly elevated alkaline phosphatase were normal. She had no underlying liver disease (negative viral and autoimmune serology) and no other abdominal, pelvic, or thoracic mass on CT. Based upon dynamic imaging, a presumptive diagnosis of hepatocellular carcinoma was made, and given the surgical resectability (left lobe), a left lateral segmentectomy was performed. Grossly, the tumor was a well-circumscribed, solid gray-tan variegated mass (Figure 43, A). Microscopically, the tumor consisted of sheets of polymorphous cells including polygonal, oval, stellate, multinucleated giant cells (Figure 43, B), and spindled cells (Figure 43, C). Immunophenotypically, however, these varied cells were uniformly positive for vimentin, CD68, and smooth muscle actin and negative for cytokeratins (8/18, 7, 19, 20), CEA-p, HepPar1, synaptophysin, chromogranin, glypican 3, AFP, CDX-2, TTF-1, CD31, CD34, S100, desmin, myogenin, AAT, and DOG-1. Many tumor cells showed characteristic PAS-D–positive cytoplasmic hyaline globules (Figure 43, D). The microscopic and immunophenotypic features were consistent with UESL despite the advanced age of the patient. We believe that this is the oldest reported patient with the diagnosis of UESL. As such, UESL should be included in the differential diagnosis of all primary liver tumors regardless of patient age.
p16 Used in the Diagnosis of Anal Squamous Intraepithelial Lesions: New Guideline Application and Interobserver Agreement Results: (Poster No. 97)
Context: A 2-tiered terminology sponsored by the College of American Pathologists and American Society for Colposcopy and Cervical Pathology (LAST project) addressed p16 immunostain with very specific criteria for its use. The indiscriminatory use of p16 was not recommended. In clinical practice, it is well known to pathologists that the interpretation of diffuse block versus patchy staining can sometimes be challenging. We analyzed the appropriate use of p16 and interpretation of results among pathologists.
Design: Database search for anal lesions at an academic center (AC) and 2 community hospitals (CHs) was conducted (September 2013–April 2014). The cases were blindly and independently reviewed by 4 pathologists with different areas of expertise (1 gynecological, 3 gastrointestinal). p16 stain (clone E6H4, predilute, Ventana) was interpreted as negative, patchy, or diffuse block staining. A consensus p16 interpretation was also obtained (3–4 of 4 results in agreement required).
Results: p16 was originally ordered in 14 of 132 cases (13 of 56 AC, 1 of 76 CH). Based on hematoxylin-eosin interpretation, reviewers additionally ordered p16 in 10 to 41 cases (1 pathologist), 17 cases (2 pathologists), 27 cases (3 pathologists), and 4 cases (4 pathologists). All pathologists reviewed p16 in 18 cases (Table). In 7 of 18 cases (38.9%), all reviewers agreed that p16 was needed and was appropriately ordered. Discrepancy in p16 interpretation was noted in 4 of 18 cases (22%). The overall interobserver agreement among all reviewers was excellent (κ = 0.83).
Conclusions: p16 was more frequently used in AC, but varied greatly. Discrepancy rate between the original diagnosis with p16 interpretation and the reviewers' interpretation was 22%; however, the overall interobserver agreement among reviewers was excellent.
Rectal Prolapse Due to Schistosomiasis: (Poster No. 100)
A 57-year-old Filipino woman presented with rectal prolapse progressing during the past several months with bowel movements. Her symptoms were initially thought to be due to hemorrhoids. On physical examination, a 2-cm full-thickness rectal prolapse was noted when the patient was asked to bear down. A colonoscopy identified 3 benign polyps and no other significant lesions. The patient underwent partial sigmoid colectomy and rectopexy to correct the prolapse. Pathologic examination revealed numerous submucosal and intramuscular Schistosoma eggs averaging less than 100 μm and inconspicuous lateral spines. One egg out of several hundred did demonstrate a clear, small lateral spine. No inflammation was present. The size and clinical presentation was most consistent with Schistosoma japonicum. Schistosomiasis is an uncommon cause of rectal prolapse, most likely due to extensive infiltration of the muscularis propria (Figure 44).
New Proposed Terminology for Anal Squamous Lesions: Its Application and Interobserver Agreement Among Pathologists in Academic and Community Hospitals: (Poster No. 101)
Context: Recently, a 2-tiered terminology sponsored by the College of American Pathologists and American Society for Colposcopy and Cervical Pathology was conceived for HPV-associated squamous lesions throughout the lower anogenital tract: low-grade squamous intraepithelial lesions/LSIL (condyloma and mild dysplasia) and high-grade squamous intraepithelial lesions/HSIL (moderate to severe dysplasia and carcinoma in situ). We analyzed the use of this nomenclature and examined the interobserver agreement among pathologists.
Design: Following database search for anal lesions at an academic center (AC) and community hospitals (CHs) (September 2013–April 2014), cases were independently reviewed by 4 pathologists (1 gynecologic, 3 gastrointestinal) and reclassified by using new terminology. p16 stain (clone E6H4, predilute, Ventana) was only ordered by the reviewers if needed. A consensus diagnosis (3–4 of 4 pathologists' agreement required) was then rendered.
Results: A total of 132 biopsies (AC, 56; CHs, 76) from 104 patients (71 male; mean age, 49 years [range, 19–82 years]) were originally diagnosed as reactive/negative (37), LSIL (59), HSIL (29), and invasive squamous cell carcinoma (SCC) (7). New terminology was appropriately used in 47 of 95 cases (49%; AC, 32; CHs, 15). Consensus diagnoses were benign/reactive (38), LSIL (54), HSIL (33), and invasive SCC (7). Discrepancy between original and consensus diagnosis was found in 23 of 132 cases (17%; AC, 8 cases; CHs, 15 cases) (Table). p16 stain was requested more frequently in AC (14 of 56) than CH (1 of 76). The overall interobserver agreement was substantial (κ = 0.63) and improved with the selective use of p16 stain (κ = 0.71; P < .001).
Conclusions: New terminology was used in 49% of original diagnoses, mainly in the AC, as well as the use of p16. Interobserver agreement among reviewers was substantial. p16 stain in challenging cases had a significant impact in the final diagnosis.
Mucinous Adenocarcinoma Arising From Perianal Fistulae in Crohn Disease: A Rare Case Report and Review of the Literature: (Poster No. 102)
Perianal fistula is a common manifestation of Crohn disease. Adenocarcinoma arising from perianal fistulae in patients with Crohn disease is rare. There were only 65 cases with anorectal adenocarcinoma arising from a perianal fistula in patients with Crohn disease reported from January 1946 until September 2009. We present a case of a 44-year-old man diagnosed with Crohn disease in 2012. The patient presented with worsening perirectal fistulas and posterior anal mass in 2014. Biopsy of posterior anal mass and right lateral anal margin revealed mucinous adenocarcinoma. Given the findings of a perianal adenocarcinoma and extensive perianal Crohn disease, the patient underwent neoadjuvant treatment followed by abdominoperineal resection. Tumor size was an estimated 4.0 cm, as a discrete mass was not seen. This moderately differentiated adenocarcinoma was arising from the lining of the perianal fistula tracts. The malignant cells and mucinous pools were diffusely involving the anal canal and part of the perianal fibroadipose tissue. The tumor demonstrated irregularly shaped tubules lined by cells with basally located, uniform, and hyperchromatic nuclei with abundant mucinous cytoplasm. The positive stainings with CK20 and CDX2 in the tumor cells by immunochemistry suggest that tumor originated from colonic epithelial lining the fistula tracts. This case is unusual because of the very short duration between the initial diagnosis of Crohn disease and development of adenocarcinoma in the perianal fistula tracts (Figure 45).
An Unusual Case of Starvation-Induced Liver Injury Secondary to Anorexia Nervosa: (Poster No. 105)
Patients with anorexia nervosa (AN) often have elevated transaminases, the severity of which inversely correlates with body mass index (BMI). Herein, we present a case of AN with massively increased aminotransferases and unusual ultrastructural findings. A 17-year-old adolescent girl presented with hypothermia, nausea, and fatigue. Her BMI was 10.5. Electrocardiogram revealed sinus bradycardia and a septal infarct. Aminotransferases were markedly elevated: aspartate aminotransferase 4671 U/L and alanine aminotransferase 6030 U/L. Her international normalized ratio was 1.5, and alkaline phosphatase was 471 U/L. Her medical history was notable for extensive rheumatologic workup secondary to elevated anti-histone antibodies (all other autoimmune markers negative). In addition to starvation-induced liver injury, the clinical differential included autoimmune hepatitis, drug-induced liver injury, or ischemic injury secondary to bradycardia. A liver biopsy was performed on the fourth day of hospitalization. Biopsy showed zone 3 hepatocellular atrophy with minimal early necrosis, a finding compatible with previous reports of starvation/anorexia-induced liver injury. Electron microscopy (EM) from reprocessed formalin-fixed, paraffin-embedded tissue showed mitochondrial para-crystalline inclusions and microvesicular steatosis. No autophagosomes were identified. Liver biopsies in AN characteristically show subtle histologic findings (glycogen loss, cellular swelling, and clarification) and evidence of autophagic cell death by EM. Microvesicular steatosis is uncommonly seen but is thought to represent protein malnutrition. To our knowledge, this case represents the first report of mitochondrial paracrystalline inclusions with microvesicular steatosis in a patient with AN and acute liver injury. These findings may suggest an etiology other than autophagy in some cases of AN (Figure 46).
An Unusual Case of Noninvasive Adenocarcinoma Arising in a Localized Adenomyoma of the Gallbladder: (Poster No. 108)
Adenomyoma or adenomyomatosis of the gallbladder generally carries little or no risk of malignant transformation. Rare cases of such malignant transformation are described in the literature only in segmental type of adenomyomatosis and not in a localized adenomyoma. We report the case of a 58-year-old asymptomatic woman found to have an incidental 3.2 × 3 × 2.8-cm well-circumscribed exophytic mass on surveillance ultrasonography, originating from the fundus of the gallbladder and abutting the liver capsule. The patient underwent open cholecystectomy with resection of the mass and underlying segment of the liver. The mass was discrete and well circumscribed with a peripheral pseudocapsule (Figure 47, A) and had histologic features typical of a benign adenomyoma with variably sized distended microcysts within fibromuscular stroma (Figure 47, B). Within the lesion however, multiple small foci amounting to approximately 5% showed high-grade dysplasia or adenocarcinoma in situ (Figure 47, C). Apart from cytologic distinctiveness, these foci were also selectively highlighted by positive immunostaining for p53 (Figure 47, D). Away from this lesion, the gallbladder showed cholelithiasis, mild cholecystitis, and no additional adenomyoma. There was no invasion into the gallbladder mucosa or adjacent liver. This case is highly unusual, since transformation to carcinoma is not previously described in a localized or discrete adenomyoma. In the short available follow-up period (2 months so far), there is no evidence of recurrence or metastasis. The long-term prognosis is expected to be favorable owing to lack of invasion and complete excision, even if there is no documented literature on its course.
Reporting the Presence or Absence of Steatosis Within Hepatocellular Carcinoma and Nontumoral Tissue: (Poster No. 109)
In hepatocellular carcinoma (HCC) cancer protocol reporting, steatosis is listed as an additional finding that may be clinically important but not yet validated or regularly used in patient management. Hence, this finding is often omitted in reports. However, magnetic resonance imaging (MRI) detection of intratumoral fat/ steatosis as a biomarker for a more favorable prognosis has been investigated. Non–fat-containing HCC had significant tumor progression and distant metastasis versus fat-containing HCC. We present a case of HCC in a 57-year-old woman with a history of hepatitis C and invasive ductal carcinoma of the right breast. She presented with right upper quadrant abdominal pain and a mass increasing in size in a noncirrhotic liver, revealed by noncontrast computed tomography and MRI. The mass was initially thought to be metastatic breast cancer. Liver biopsy revealed a localized primary, well-differentiated HCC with steatosis and extensive Mallory hyaline present within the tumor (Figure 48, A through C). However, surrounding nonneoplastic liver was free from steatosis and Mallory hyaline (Figure 48, D). Trichrome staining showed no evidence of cirrhosis. The incidence of steatosis in HCC has been reported as 19.5%. There are no data on the incidence of steatosis exclusively in the tumor and its absence outside the tumor. Steatosis in tumor has been associated with a well-differentiated HCC. A localized resection may be therapeutic in these cases. Pathologists should mandatorily and routinely incorporate the reporting of steatosis in the tumor and the nontumor tissue. This would facilitate future studies of the therapeutic and prognostic significance of steatosis in these tumors.
Intravascular Diffuse Large B-Cell Lymphoma Presenting as Abnormal Uterine Bleeding: (Poster No. 111)
Intravascular diffuse large B-cell lymphoma (IVLBCL) is a rare subtype of extranodal diffuse large B-cell lymphoma. As of 2015, only 6 cases of uterine IVLBCL have been reported. We report a case of this highly malignant lymphoma presenting with abnormal uterine bleeding. A 55-year-old woman with a history of hypertension and diabetes mellitus presented to the emergency department with acute altered mental status and weight loss. Computed tomography of the head showed no acute intracranial abnormality and only mild chronic microvascular ischemia and atherosclerotic disease. A complete blood count showed pancytopenia which, along with weight loss, led to a differential diagnosis of myelodysplastic syndrome, acute leukemia, and other neoplasms. A bone marrow biopsy was unsuccessful at obtaining tissue owing to the patient's body habitus. A sternal marrow aspirate analysis including flow cytometry and cytogenetic testing failed to yield definitive findings, but myelodysplastic syndrome could not be excluded. The patient had abnormal uterine bleeding and an endometrial biopsy was obtained. The hematoxylineosin sections showed aggregates of large atypical lymphoid cells within the lumen of capillaries and small vessels and rare individual cells within the stroma. Immunohistochemical staining of the specimen demonstrated that the atypical lymphoid cells expressed CD5, CD20, and CD79a and were negative for CD3, CD10, CD117, myeloperoxidase, and TdT. Clinical signs and symptoms of IVLBCL are highly variable and most often related to the anatomic sites of involvement. This case shows that abnormal uterine bleeding may represent a presenting concern for this rare and aggressive disease (Figure 49).
Drug-Induced Hypersensitivity Syndrome: A Clinical and Histologic Mimic of Lymphoma: (Poster No. 112)
An 18-year-old woman presented with cervical lymphadenopathy, fevers, and a macular rash. She was found to have renal failure and elevated liver enzymes. Abdominal ultrasonography showed splenomegaly and enlarged porta hepatis lymph nodes. A positron emission tomography scan revealed diffuse hypermetabolic lymphadenopathy involving cervical, supraclavicular, axillary, pelvic, and inguinal nodes, and findings consistent with malignant infiltration of the bilateral kidneys and spleen (Figure 50, A). Lymph node biopsy showed partial effacement of the nodal architecture by a mixed infiltrate of small lymphocytes, eosinophils, histiocytes, and plasma cells, and scattered, large, CD30+ Reed-Sternberg–like cells (Figure 50, B through D). The imaging and biopsy findings initially raised concern for a malignant process, with a differential diagnosis that included classical Hodgkin lymphoma and T-cell lymphoma. However, the morphologic and immunophenotypic features were not entirely typical for those diagnoses. Molecular studies showed no evidence of clonal B- or T-cell gene rearrangements. On further review of the clinical history, the patient was found to have been recently exposed to minocycline. The overall findings supported a diagnosis of drug-induced hypersensitivity syndrome (DIHS; also known as drug reaction with eosinophilia and systemic symptoms, or DRESS). DIHS/DRESS typically presents with fever, rash, organ dysfunction, and lymphadenopathy 2 to 8 weeks after drug exposure. A number of medications have been implicated, including minocycline. Affected lymph nodes show marked paracortical expansion, increased eosinophils, and a variable immunoblastic proliferation; these findings may mimic classical Hodgkin or angioimmunoblastic T-cell lymphoma. Recognition of this syndrome and careful investigation of clinical history can help prevent misdiagnosis of malignancy.
A Rare Case of Epstein-Barr Virus–Negative Inflammatory Pseudotumor-like Follicular Dendritic Cell Sarcoma Presenting as a Solitary Colonic Mass in a 53-Year-Old Woman: Case Report and Review of the Literature: (Poster No. 120)
Follicular dendritic cell (FDC) sarcoma is a rare neoplasm occurring predominantly in lymph nodes. One-third of FDC sarcomas occur in extranodal sites. There are 2 morphologic variants of this tumor: conventional and inflammatory pseudotumor–like (IPT-like). IPT-like FDC sarcomas are reported mostly in females, usually involve the spleen and liver, and have a strong Epstein-Barr virus (EBV) association. However, conventional FDC of the gastrointestinal tract is not strongly associated with EBV and the association of EBV with IPT-like FDC sarcoma occurring within the gastrointestinal tract is unknown. This is a case of a 53-year-old woman who presented with abdominal discomfort. A colonoscopic examination revealed a right colon mass. The patient underwent a right hemicolectomy, in which a sessile, polypoid, well-circumscribed, brown-purple 3-cm mass confined to the mucosa and submucosa was identified. Microscopically, there was prominent lymphoplasmacytic infiltration with interspersed large pleomorphic stromal cells, some with spindle cell morphology and dendritic processes and others with marked atypia, multilobation, multinucleation, eosinophilic nucleoli, and hyperchromatic smudged chromatin. Immunohistochemical studies showed that atypical stromal cells were strongly positive for CD10, vimentin, and D2-40, but negative for CD21, CD23, clusterin, and EGFR. EBV-encoded mRNA was negative. A diagnosis of IPT-like FDC sarcoma was made. FDC sarcoma is difficult to diagnose, because it can be similar to IPT-like conditions and because of the rarity of neoplastic follicular dendritic cells in the tumor itself. To our knowledge, this is the second reported case of EBV-negative IPT-like FDC sarcoma of the gastrointestinal tract (Figure 51).
Hemophagocytic Lymphohistiocytosis as a Harbinger of Undetected NK/T-Cell Neoplasms: (Poster No. 124)
Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disease often with hemophagocytic histiocytes (HHs). Most adult cases develop secondary to viral infections or lymphoma. We describe 2 cases involving 2 men for whom HLH was the presenting sign of a previously undiagnosed lymphoproliferative disorder. Case 1 involves a 35-year-old man with fevers, splenomegaly, hemoglobin 10.7 g/dL, platelets 40 × 109/L, hypertriglyceridemia (307 mg/dL), and hyperferritinemia (5977.0 ng/mL). Bone marrow (BM) showed HHs (Figure 52, A). He was given dexamethasone and etoposide for HLH. He presented a week later with febrile neutropenia and Epstein-Barr virus > 5 million/mL. Repeated BM showed rare HHs, and also large atypical lymphocytes with abundant cytoplasm, azurophilic granules, irregular nuclei, open chromatin, and conspicuous nucleoli (Figure 52, B). Flow cytometry showed 10% NK cells expressing CD2, CD16, CD56, CD45, and HLA-DR. CD3 (cytoplasmic), granzyme B, perforin, TIA-1, and EBER were positive by tissue stains, consistent with aggressive NK-cell leukemia. He died 1 day later. Review of previous BM showed no NK-leukemia. Case 2 involves a 63-year-old man with lymphadenopathy and fever. Lymph nodes showed nonnecrotizing granulomas; sarcoidosis was diagnosed. A month later he represented with splenomegaly, hemoglobin 7.2 g/dL, platelets 77 × 109/L, triglyceride 763 mg/dL, and ferritin 6872.0. BM showed rare HHs. He died 3 days later. On autopsy lymph nodes showed granulomas and rare large lymphocytes positive for CD3 and TIA1, and negative for CD5, CD7, CD8, and CD30. Peripheral T-cell lymphoma was diagnosed postmortem. HHs in BM may precede overt lymphoma. In HLH patients, rebiopsy may be necessary to detect an underlying neoplasm.
Red Blood Cell Profile in Chronic Kidney Disease: (Poster No. 128)
Context: Chronic kidney disease (CKD) is a major public health problem worldwide. Renal diseases are associated with a variety of hematologic changes. Anemia parallels the degree of renal impairment. This study aims to analyze changes in various red blood cell (RBC) parameters in patients with CKD.
Design: This is a retrospective study conducted for a period of 2½ years. A total of 300 cases of CKD were evaluated and their RBC parameters, including red cell count, Hb, PCV, MCV, MVCH, and MCHC, were studied.
Results: The Table shows the various RBC parameters in CKD patients. The major hematologic abnormality in CKD patients was anemia with 67% of cases having a Hb value below 10 gm/dL and the degree of anemia worsening with the stage of the disease. Deviation in Hb levels is directly proportional to RBC count and hematocrit. But there was no significant change in MCV, MCH, and MCHC values indicating normocytic normochromic type of anemia. Only 3.4% of cases had microcytic hypochromic anemia and 2.6% cases had macrocytic anemia. Features of hemolysis were seen in 21% cases.
Conclusions: Chronic kidney disease is often complicated by anemia, and the major causes of anemia are failure of renal erythropoietin secretion and anemia of chronic disease. Other causes include chronic blood loss hemolysis, bone marrow suppression, inflammatory factors, and vitamin deficiency.
Plasmablastic Lymphoma of Hindgut in HIV-Positive Patient: (Poster No. 132)
Plasmablastic lymphoma (PBL) is a rare lymphoma associated with immunosuppression. It represents 2.6% of all HIV-related lymphomas with the oral cavity being the most common site. MYC rearrangements, usually t(8;14), have recently been described to be a finding in approximately half of PBL cases. This is a case of a 36-year-old HIV-positive man who presented with rectal pain and bleeding. A 6×5×2-cm anal mass was identified. There were no B symptoms, prior history of malignancy, prior highly active antiretroviral therapy, and no available CD4 counts. Imaging showed irregularity of the rectoanal region. A biopsy of the anal mass was performed then the patient was lost to follow-up. The biopsy showed sheets of intermediate-sized to large monotonous cells with immunoblastic features including vesicular chromatin, prominent nucleoli, and scant to moderate amounts of amphophilic cytoplasm. Mitoses were frequent with areas of necrosis (Figure 53, A). Immunohistochemistry showed the tumor cells to be positive for CD45RA (subset, weak), CD79a, CD138, CD10, MUM-1(Figure 53, C), and Epstein-Barr virus–encoding RNA (EBER) by in situ hybridization (Figure 53, B) and negative for CD3, CD20, CD5, ALK-1, CD30, BCL-6, BCL-2, PAX-5, CD56, CD68, synaptophysin, chromogranin, p63, AE1/3, CK5/6, and CAM 5.2. Ki-67 proliferation index was more than 90%. Fluorescence in situ hybridization was positive for c-MYC rearrangement (Figure 53, D) and negative for BCL-2 and BCL-6 aberrations. This case demonstrates an unusual hindgut presentation of PBL. Per our literature review, this is only the second reported case of MYC-positive rectal PBL.
Triple-Hit Diffuse Large B-Cell Lymphoma in Leukemic Phase With Leukocytosis Greater Than 1 Million: (Poster No. 133)
Triple-hit diffuse large B-cell lymphomas are aggressive lymphomas either categorized as diffuse large B-cell lymphoma, not otherwise specified, or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma. We report a rare case presenting in leukemic phase with an initial leukocyte count of more than 1 million. A 55-year-old white man presented with mild chest pain, breathlessness, and a 2-week history of progressive fatigue, headache, and visual disturbance. Physical examination showed cervical lymphadenopathy. Initial laboratory studies showed WBC count of 1.1 million, hemoglobin 8.3 g/dL, hematocrit 21%, platelets 12 000, and LDH 1841 IU/L. Peripheral blood revealed mostly mature small to medium-sized lymphocytes with clefted nuclei and few larger immature-appearing cells with fine chromatin and prominent nucleoli (Figure 54, A). Differential diagnoses included either a chronic lymphoproliferative disorder or acute leukemia. Flow cytometric analysis of peripheral blood showed a monoclonal B-cell population with coexpression of CD10 and CD20 (negative for CD5, CD34, MPO, and TdT). Bone marrow biopsy (Figure 54, B through D) revealed diffuse infiltrate of large B cells positive for CD10 and negative for cyclin D1. Cytogenetic studies showed t(14,18)(q32;q21) rearrangement and fluorescence in situ hybridization studies were positive for break-apart pattern of MYC and BCL6 genes. A final diagnosis of triple-hit diffuse large B-cell lymphoma was rendered. Leukocytosis was reduced significantly with plasmapheresis, and tissue biopsy was not performed at diagnosis. Despite aggressive chemotherapy, the patient soon developed central nervous system metastasis. Although leukemic phase can be seen in DLBCL, this case presentation is unusual given the magnitude of leukocytosis at presentation.
Complete Remission of Escherichia coli–Negative Primary Urinary Bladder Marginal Zone Lymphoma Post Ciprofloxacin Therapy: (Poster No. 134)
Primary marginal zone lymphoma (MZL) of the urinary bladder is extremely rare, comprising less than 0.2% of all non-Hodgkin lymphomas. While the association with bacterial infections is often reported in MZLs in other locations, we found a single case report of a primary urinary bladder MZL, with urine cultures positive for Escherichia coli, treated with ciprofloxacin for 6 weeks that achieved complete remission (Lucioni et al, 2013). Our patient is a 71-year-old woman presenting with pressure in the lower abdomen and incomplete voiding due to a 1.6-cm pediculated mass at the bladder neck. She underwent transurethral resection of her bladder tumor and on morphologic examination, a prominent vaguely nodular infiltrate of predominately small to medium-sized lymphoid cells with round to irregular nuclei was noted to expand the lamina propria (Figure 55, A). Rare ill-demarcated germinal centers were also seen. By immunohistochemistry, there was a large B-lymphoid population coexpressing CD20 (Figure 55, B), bcl-2, in a subset being also weakly CD43+ and negative for bcl6, cyclin D1, CD10, and CD5. The proliferation rate was rather low (range, 5%–15%). Polymerase chain reaction analysis did not detect bacterial DNA with 16S rDNA primer set. The patient underwent therapy with ciprofloxacin for 6 weeks with complete remission of her lymphoma on follow-up cystoscopy with biopsy, and is currently in remission 2 years post therapy. The rarity of this lymphoma and the remission after antibiotic therapy despite a demonstrable bacterial infection are noticeable in our case and suggest a more conservative therapeutic approach for these patients.
Novel Case of B-Cell Acute Lymphoblastic Leukemia With RUNX1 Amplification in Pregnancy: (Poster No. 139)
Acute leukemia in pregnancy occurs in only 1 of 75 000 pregnancies, with acute lymphoblastic leukemia accounting for 28% of cases. Amplification of RUNX1 (defined as ≥4 copies on a single chromosome) is a rare and clinically more aggressive subtype of B-cell acute lymphoblastic leukemia occurring in only 2% of newly diagnosed leukemic cases. We report the first documented case of RUNX1 amplification–positive B-cell acute lymphoblastic leukemia in pregnancy. Our 22-year-old woman patient was diagnosed at 20 weeks' gestation with RUNX1 amplification (red) identified by metaphase and interphase fluorescence in situ hybridization (Figure 56, left and upper right, respectively). She chose to continue with her pregnancy and was given cytarabine, vincristine, daunorubicin, pegaspargase, and metho-trexate. Her course was complicated by pneumonia and, on induction day 12 (at 22 weeks' gestation), hemoptysis, which progressed to disseminated intravascular coagulation and her untimely death. On autopsy, there was a 60% reduction in bone marrow blast volume from time of diagnosis. Blasts were not present in the placenta, umbilical cord, or amniotic fluid. The fetus was intact with no leukemic engraftment or other significant gross or histopathologic abnormality. Patchy pulmonary hemorrhage was seen in the mother, and her cause of death was suggested as bone marrow failure with consequential coagulopathy caused by both leukemia and chemotherapy. Additional investigation is needed to examine if this subtype of B-cell acute lymphoblastic leukemia and pregnancy have a negative synergistic effect. This aggressive subtype may require a different management approach in pregnant patients.
CD23 Expression in Diffuse Large B-Cell Lymphoma, Not Otherwise Specified, May Indicate Favorable Outcome: (Poster No. 140)
Context: CD23, the FC fragment of the IgE receptor, is a surface marker present on follicular dendritic cells as well as an activation marker on B cells, promoting differentiation into plasma cells. It has been suggested by a prior study that CD23 positivity may confer a more favorable outcome in diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS). We compare CD23+ versus CD23− tumors for 1-year survival.
Design: A natural language search was performed for DLBCL, NOS diagnosed between January 2004 and January 2013. The cases were then divided into 2 groups: CD23+ (Figure 57) and CD23− tumors. Those for which CD23 testing was not performed were dropped from the study. The electronic medical records were reviewed by a researcher blinded to the CD23 expression results and compared for any significant difference of survival after 1 year of diagnosis and standard treatment.
Results: Eighty DLBCL, NOS cases had been tested for CD23 expression of which 19 (26%) tested positive. Those that were CD23− had approximately 75% survival rate after the first year, whereas for those that were CD23+, the 1-year survival was approximately 90%.
Conclusions: CD23 expression is a favorable prognostic indicator for short-term survival and/or treatment response to standard therapy.
Review of Test Utilization of Body Fluids by Flow Cytometry: (Poster No. 141)
Context: We reviewed the utilization of body fluid examination by flow cytometry, which includes cerebrospinal fluid (CSF), pleural fluids, pericardial fluids, and bronchioalveolar lavage fluid to determine if utilization of tests was appropriate.
Design: This is a retrospective study of data collected during a period of 1 year and was separated into categories by specimen type and by ordering service type, that is, hematology/oncology, neurology, medical ICU, and emergency department. Tests results were separated on the basis of whether a hematologic malignancy was detected.
Results: One of 59 bronchioalveolar lavage (BAL) specimens was positive and it was for a patient who was recently diagnosed with acute myelogenous leukemia (Table). Six of 34 pleural fluids were positive, all of which were from patients who were either previously diagnosed or were undergoing treatment for a hematologic malignancy. Six of 377 CSF specimens were positive for a hematologic malignancy and they were from patients who were previously diagnosed with a malignancy. Two of 35 pericardial fluids were positive for a malignancy.
Conclusions: Based on these data and other preliminary data for pericardial and peritoneal fluid specimens, it is suspected that the inclusion of flow cytometry in the basic order set is leading to overutilization of this test. If a hematologic malignancy is suspected in patients without a prior diagnosis, then a pretest evaluation before flow cytometry may be of value.
A Case of Synchronous Langerhans Cell Histiocytosis and Follicular Lymphoma: (Poster No. 142)
Transdifferentiation between mature B-cell lymphomas and Langerhans cell histiocytosis (LCH) is a rare phenomenon that has recently been studied. Rare cases of follicular lymphoma with coexisting LCH have been reported. This is a case of a 57-year-old woman who presented with diffuse lymphadenopathy. An excision of an enlarged submandibular lymph node showed atypical lymphoid infiltrate with a follicular pattern (Figure 58, A). The neoplastic cells were positive for CD10, BCL-2, CD19, and CD20. The findings were diagnostic of follicular lymphoma, grade 1. A bone marrow biopsy was negative for lymphoma involvement. She was diagnosed with stage III disease and achieved complete remission following chemotherapy. Seven years after therapy, she presented with vulvar lesions. The biopsy showed sheets of abnormal histiocytic cells with oval nuclei with grooves and finely dispersed chromatin and abundant pale eosinophilic cytoplasm in a background of lymphocytes and eosinophils. The atypical histiocytes were positive for S100 and CD1a by immunohistochemical staining, consistent with a diagnosis of LCH. Her condition progressed with multiorgan involvement by LCH, including cervical lymph nodes, gastrointestinal tract, and bones. All subsequent biopsies were negative for follicular lymphoma. A retrospective review of the submandibular lymph node revealed focal involvement by LCH (Figure 58, B). This is a rare case of synchronous follicular lymphoma and LCH. The biologic relationship between the 2 neoplasms is not clear. It is likely related to lineage plasticity of mature lymphoid cells.
Two Cases of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Associated With Peripheral Blood Eosinophilia at the Time of Variant Richter Transformation: (Poster No. 143)
Richter transformation (transformation to high-grade lymphoma) is estimated to occur in 10% to 15% of the chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL) cases and the “variant” transformation—transformation to classical Hodgkin lymphoma (CHL)—has an incidence of 0.5%. We present 2 cases involving 2 patients with CLL/SLL who developed sustained peripheral blood eosinophilia at the time of their transformation to CHL. The first is a 79-year-old woman with a clinical history of thymoma (58 years ago), invasive breast carcinoma (17 years ago), and more recently with a diagnosis of CLL/SLL with associated deletions of chromosome 13q and 17p (TP53). She underwent therapy with bendamustine and progressed to CHL 2 years after her CLL/SLL diagnosis (Figure 59, A and B). Two months before her CHL transformation her CBCs showed eosinophilia that disappeared after the ABVD therapy. The second patient is a 59-year-old man with a 6-year history of CLL/SLL with initially reported deletion of 13q and trisomy 12, who subsequently developed del TP53 and was given ibrutinib; he continued to show progression of his retroperitoneal lymphadenopathy and was diagnosed with progression to CHL on bone marrow and presacral biopsies. His complete blood cell count was also remarkable for lymphocytosis and eosinophilia at the time of Richter transformation; and furthermore in the first patient, the biopsy sections showed an increased population of eosinophils in the residual CLL/SLL areas (Figure 59, C). This unusual association has not been previously reported to our knowledge, and the patients' eosinophilia appears to be connected with the CHL transformation and not drug induced.
Monomorphic B-Cell Posttransplant Lymphoproliferative Disorder With Concurrent Plasmacytoma-like and Diffuse Large B-Cell Lymphoma: (Poster No. 144)
Posttransplant lymphoproliferative disorders (PTLDs) represent a heterogeneous group of diseases that occur in patients with a history of transplant and include a spectrum of disorders ranging from hyperplasia to high-grade lymphomas. Most cases are associated with Epstein-Barr virus (EBV), which drives tumor formation in B cells and is a consequence of the detrimental effect of immunosuppressive agents on the immune control of EBV. We present a rare case of a 62-year-old man with a history of IgA nephropathy status post kidney transplant 13 years prior and receiving maintenance triple therapy consisting of prednisone, azathioprine, and cyclosporin A. He presented with multiple subcutaneous nodular lesions (Figure 60, A). A punch biopsy of the forearm lesion showed a dense lymphoplasmacytic infiltrate within the deep dermis/subcutaneous fat and sparing the epidermis (Figure 60, B). The plasma cells (CD138+, CD19+, CD79a+, MUM-1+ with focal CD30+) had a high proliferation index (Ki-67 positive in 70% of cells) and were negative for PAX5, CD20, cyclin D1, and CD56 (Figure 60, C). Separate concurrent foci of large transformed B cells (CD20+, CD19+, CD79a+, PAX-5+, Bcl-2+, CD138−) with κ light-chain restriction were consistent with a diffuse large B-cell lymphoma (DLBCL) (Figure 60, D). EBER in situ hybridization and latent membrane protein-1 highlighted several of the cells. The differential diagnosis included DLBCL with exuberant plasmacytic differentiation (anaplastic plasmacytoma-like lesion), plasmablastic lymphoma with plasmacytic differentiation, and DLBCL arising in a background of a low-grade B-cell lymphoma. This rare case represents a variant of PTLD with features that are not commonly described in the literature.
Large Cell Transformation of a Classic Mantle Cell Lymphoma: A Rare Entity: (Poster No. 145)
Transformation to large cell morphology in mantle cell lymphoma (MCL) is extremely rare and here we present 2 such cases of transformation. A 51-year-old man presented with B symptoms and hepatosplenomegaly. Positron emission tomography–computed tomography (PET-CT) showed diffuse increase of metabolic activity in spleen and multiple lymph nodes. Bone marrow biopsy showed involvement by classic MCL (Figure 61, A). The neoplastic cells were positive for CD5, CD20, and BCL-1. FISH studies were positive for t (11;14) and deletion of TP53. He achieved complete remission following chemotherapy. A PET-CT 6 months later detected discrete areas of increased uptake in the spleen without any increased uptake elsewhere. A splenectomy was performed, which showed lesions with morphology of a large cell lymphoma (Figure 61, B). The phenotype and FISH findings were similar to previous diagnosis. Immunoglobulin heavy-chain gene rearrangement studies in the bone marrow and spleen showed identical clonal peaks affirming large cell transformation. The second case involves a 76-year-old man who presented with colonic polyps. The biopsies showed classic MCL morphology with small cleaved atypical lymphoid cells. The neoplastic cells were positive for CD5, CD20, and BCL-1. Thirteen years later, he presented with bilateral scalp masses. These lesions were composed of large cells with pleomorphic nuclei and increased mitoses. The morphology was significantly different from that of his prior biopsies. Immunophenotype was consistent with MCL. The findings were diagnosed as large cell transformation. Large cell transformation of MCL is rare and documentation of such cases can contribute to our understanding of disease evolution.
Epstein-Barr Virus–Associated Hemophagocytic Lymphohistiocytosis: A Report of 2 Cases and a Review of the Literature: (Poster No. 147)
Hemophagocytic lymphohistiocytosis (HLH) is found in many life-threatening conditions that feature ineffective immunity and an uncontrolled hyperinflammatory response. Hemophagocytosis is the engulfment of hematopoietic cells by activated macrophages acting outside of usual immune system regulations. Possible causes include certain autosomal recessive familial disorders or underlying pathologic triggers, often infections. Multiorgan failure secondary to widespread inflammation may result. Epstein-Barr virus–related hemophagocytic lymphohistiocytosis (EBV-HLH) is a form of acquired, infection-related HLH that typically starts with an acute EBV infection and has a high mortality rate. Here we present 2 cases of EBV-HLH. A 56-year-old EBV+ woman and a 29-year-old EBV+ man with no significant past medical history presented with altered mental status, acute renal failure, acute respiratory distress syndrome, elevated serum lactate dehydrogenase, and progressive pancytopenia. Serum studies revealed marked hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia, elevated soluble CD25, and very high EBV titers (>1 million). Bone marrow biopsies in both cases showed florid lymphohemophagocytosis (Figure 62, A) and a prominent interstitial histiocytic infiltrate (CD163+) (Figure 62, B and C). The acute onset and aggressive course of the disease proved fatal in both patients. While fulminant infectious mononucleosis may overlap with EBV-associated HLH, higher viral loads are seen in EBV-HLH (Figure 62, D). It appears that new infection as well as reactivation of latent EBV infection may predispose individuals to HLH. Quantitative determination of EBV genome copy numbers in peripheral blood may be useful in predicting prognosis and effectiveness of therapy.
Myeloid/Natural Killer Cell Precursor Leukemia With Cytoplasmic Granules: (Poster No. 148)
Myeloid/natural killer cell precursor leukemia (MNKL) is a rare aggressive neoplasm that presents with lymphadenopathy, hepatosplenomegaly, and bone marrow involvement. This immature NK-cell neoplasm, which is derived from thymic precursors that give rise to T cells and NK cells, has no definitive myeloid or lymphoid differentiation. MNKL lymphoblasts have agranular cytoplasm and fine chromatin. Immunophenotypically, MNKL may resemble acute myeloid leukemia (AML) with minimal differentiation due to the expression of CD11b, CD13, CD33, and CD34. This phenotype distinguishes MNKL from another immature NK-cell tumor, blastic plasmacytoid dendritic cell neoplasm. In addition, MNKL can be differentiated from T-lymphoblastic leukemia by the absence of T-cell receptor (TCR) gene rearrangements. We report a case of MNKL in a 21-year-old man who presented with lymphadenopathy followed by blood, marrow, and skin involvement. The leukemic blasts showed moderate pale basophilic cytoplasm with azurophilic granules (Figure 63) and expressed cCD3, CD11b, CD13, CD33, CD34, and variablemyeloperoxidase, as well as NK-cell markers CD7 and CD56. They were negative for CD4, CD8, CD16, and CD57. TCR gene rearrangement studies showed a germline configuration. AML-type induction chemotherapy yielded an initially favorable response, but the patient experienced multiple episodes of relapse starting 3 months after his initial presentation, finally dying 16 months after his diagnosis. MNKL is a rare aggressive malignancy that can mimic other acute leukemias and hematolymphoid neoplasms. This case showed unusual cytoplasmic azurophilic granularity without definitive immunophenotypic evidence of NK-cell differentiation, consistent with an immature NK-cell neoplasm.
Preleukemic Phase of Chronic Myelogenous Leukemia: Morphologic and Immunophenotypic Characterization of 5 Cases: (Poster No. 150)
Context: Chronic myelogenous leukemia (CML) presents with an elevated white blood cell count (WBC) ranging from 20 to 500 K/mm3 with evidence of the BCR-ABL1 fusion gene. We identified 5 BCR-ABL1–positive patients with a normal to mildly elevated WBC without clinical manifestations of CML. They were considered as preleukemic CML (pre-CML). This study characterizes the morphology and immunophenotypic features of pre-CML.
Design: The initial peripheral blood smears and bone marrow biopsies from pre-CML patients (n = 5) were reviewed. Cases of CML in chronic phase (CML-CP) (n = 5) at initial presentation and leukemoid reaction bone marrows (n = 5) served as controls. CD34 and CD61 immunostains were performed on all cases.
Results: Peripheral blood absolute basophilia (≥200/mm3) was noted in 4 of 5 cases of pre-CML. The mean ± SD of microvascular density (MVD) of pre-CML cases (10.9 ± 4.7 vessels/×200 field), highlighted by CD34 immunostains, was twice that of leukemoid reaction (5.0 ± 1.0) (P < .05; Student t test), but similar to that of CML-CP (12.5 ± 3.6). Microvessels in pre-CML were tortuous with abnormal branching; however, the proportion with vascular branching and tortuosity was less than that of CML-CP. Microvessels in leukemoid reaction were generally straight (Figure 64, A through C). The percentage of small, hypolobated megakaryocytes in pre-CML was 45%, 3 times that of leukemoid reaction cases (13%), but less than that of CML-CP (86%).
Conclusions: Pre-CML should be suspected in patients with a normal to mildly elevated WBC and peripheral blood absolute basophilia. Bone marrow biopsies of pre-CML can be distinguished from leukemoid reaction by MVD, morphology, and the percentage of small, hypolobated megakaryocytes.
Adult T-Cell Leukemia/Lymphoma Presenting as a Tracheal Mass: (Poster No. 151)
A 49-year-old man presented to the emergency department with concerns of persistent nonproductive cough for 3 days and subjective fevers. He had been diagnosed with adult T-cell leukemia/lymphoma (ATLL) 3 years prior and finished a course of rituximab, ifosfamide, carboplatin, and etoposide chemotherapy. On admission his leukocyte count was elevated to 21 000, his platelet count was markedly decreased to 22 000, and he was noted to be HTLV-1 positive. To assess for disease burden and in an effort to workup the patient's symptoms, a computed tomography scan of the chest was ordered, which displayed a filling defect in the posterior trachea (Figure 65). Bronchoscopic evaluation found an exophytic lesion in the posterior wall of the trachea in the immediate subglottic region, which was biopsied. Biopsy was consistent with adult T-cell leukemia/lymphoma, as it was found to have mitotically active irregular lymphoid cells positive for CD3, CD4, CD25, and CD30 and negative for FOX-P3, CD10, and ALK-1. Cryoablation was successfully performed on the lesion and palliative romidepsin was given. This is a rare example of endobronchial involvement of a highly aggressive malignant neoplasm that frequently involves the bones, skin, liver, and spleen. In a literature review there was 1 reported case out of Japan (a high prevalence area of ATLL), presenting as a circumferential tracheal narrowing but there are no previously reported cases in the United States.
CD5− Mantle Cell Lymphoma Within Extensive Sarcoid-like Granulomatous Inflammation: (Poster No. 152)
An otherwise healthy 52-year-old man presented with lymphadenopathy. An axillary lymph node biopsy demonstrated extensive sarcoidlike granulomata intermixed with small patches of lymphocytes (Figure 66, A). Flow cytometric analysis identified a monoclonal B-cell population, which was negative for both CD5 and CD10. Given the flow and routine histologic findings, a marginal zone lymphoma was initially favored. However, to rule out the small chance of mantle cell lymphoma, a cyclin D1 immunostain was also performed. Stains for acid-fast and fungal organisms were both negative. Cyclin D1 was positive (Figure 66, B), consistent with CD5− antle cell lymphoma, coexisting in a background of sarcoidlike granulomatous inflammation. This underscores the importance of having a low threshold for ordering cyclin D1 when evaluating small B-cell lymphomas, even when CD5 is negative. The patient subsequently underwent chemotherapy; follow-up radiologic scans demonstrated only mild improvement. The apparent poor response to therapy could potentially be explained by the sarcoidlike granulomas remaining post treatment, even if there was a good response in the lymphoma component (a posttreatment biopsy was not performed). Currently, the patient remains in remission. This rare case of CD5− mantle cell lymphoma, seen in association with extensive sarcoidlike granulomatous inflammation, highlights the importance of a thorough evaluation of all surgical specimens. The diagnosis might have stopped at “sarcoidlike granulomatous inflammation,” or “marginal zone lymphoma in a background of granulomatous inflammation” if additional studies had not been performed. The differences in management and prognosis between these 3 entities are substantial.
A Case of Crystal-Storing Histiocytosis in Waldenström Macroglobulinemia: (Poster No. 154)
Intracellular immunoglobulin crystal formation is an unusual finding in multiple myeloma and lymphoplasmacytic tumors. We present a case of an incidentally discovered Waldenström macroglobulinemia with crystal-storing histiocytosis in a 75-year-old man, with ischemic cardiomyopathy and class IV heart failure requiring a left ventricular assist device (Heart Mate II LVAD), who was discovered to have inguinal lymphadenopathy during placement of the LVAD. Histology of the lymph node showed lymphoplasmacytic lymphoma with sinus histiocytosis with intracellular globules and material expressing IgM κ. A possible mechanism of crystal formation may involve overproduction of κ light chains. Serum protein electrophoresis for this patient showed an IgM κ with free κ light chain and IgM levels of 3010 mg/dL. This case presents diagnostic difficulties, as areas may resemble a storage disorder or infection. The patient was not treated owing to his poor performance status (Figure 67).
Acute Promyelocytic Leukemia With Intermediate Relapse Risk Presenting With Central Nervous System Involvement at Relapse: A Report of 2 Unique Cases: (Poster No. 156)
Acute promyelocytic leukemia (APL) is characterized by t(15;17)(q22;q12), resulting in a PML-RARα fusion. Patients are clinically stratified into 3 relapse risk groups: low, intermediate, and high according to a combination of pretreatment white blood cell and platelet counts. Introduction of all-trans retinoic acid has significantly improved the disease-free survival rate. However, 3% to 12% of the patients, typically presenting with overt leukocytes > 10 000/μL, have an extramedullary relapse (EMR). The central nervous system (CNS) is one of the most common sites of EMR in addition to skin. Several efforts have been made to identify additional risk factors for predicting risk of EMR and CNS involvement. It has been proposed that treatment, including all-trans retinoic acid, may result in CNS relapse, possibly owing to an induction of adhesion molecule (eg, CD11c, CD13, and CD56) expression in APL cells. More risk factors continue to be under investigation and remain controversial. We report 2 unique cases of APL with CNS involvement at relapse in patients with platelet counts below 40 000/μL without leukocytosis (intermediate risk) at initial presentation. CNS involvement occurred regardless of their risk group, and no acquisition of additional adhesion markers was noted at the time of CNS involvement (Table). Additionally, we considered acquired or underlying genetic aberrations (eg, FLT3 mutation), which may increase risk of EMR. A large-scale genetic profile study is necessary to have a better understanding of the mechanism of APL with EMR and to help guide management.
Unusual Expression of CD56 in a Case of POEMS Syndrome With Triclonal Gammopathy: (Poster No. 157)
POEMS (polyneuropathy, organomegaly, endocrinopathy, edema, M-protein, and skin abnormalities) syndrome is a rare paraneoplastic syndrome secondary to a plasma cell dyscrasia. We present a case of a 78-year-old man who presented with edema, polyneuropathy, and a sacral lytic lesion. A serum immunofixation showed an IgG and IgA λ and κ triclonal gammopathy (Figure 68, A). The bone marrow biopsy was hypercellular (70%) and had a mildly increased number of polyclonal plasma cells, whereas a biopsy of a sacral lytic lesion showed involvement by a plasmacytoma. In the latter, the plasma cells showed an unusual morphology, with elongated and/or cleaved nuclei, and surrounding thin bands of fibrosis (Figure 68, B). By immunohistochemistry, the plasma cells were positive for CD138 and CD56 (Figure 68, C), and in situ hybridization demonstrated λ light-chain restriction (Figure 68, D). To our knowledge, the expression of CD56 and the production of a clonal κ light chain (in addition to clonal λ light chains) are an extremely rare association in POEMS syndrome. In addition, the unusual plasma cell morphology seen in this case has not been previously described in the literature. Our conclusion is that pathologists and clinicians should be aware of the spectrum of clinical and laboratory findings that can be associated with POEMS syndrome, some of which can be unusual as in our case.
Persistent Indolent Transcolonic Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue With Plasmacytic Differentiation: (Poster No. 158)
Marginal zone lymphoma of mucosa-associated lymphoid tissue often occurs in the setting of a chronic inflammatory disorder with accumulation of extranodal lymphoid tissue. We present the case of a 40-year-old woman with history of autoimmune hepatitis status post liver transplant in 1997 and ulcerative colitis diagnosed in 2004. Results of a recently performed surveillance colonoscopy were unremarkable. Random biopsies from the colon and rectum revealed a dense plasmacytic infiltrate with atypical morphology, causing expansion of lamina propria without significant glandular destruction (Figure 69, A and B). These cells showed λ restriction (Figure 69, C and D) and were positive for CD79a and CD138; CD20, CD43, CD56, HHV8, and EBER were negative. Prior colorectal biopsies were retrospectively reviewed. A similar transcolonic infiltrate was identified in all biopsies from 2010 and 2012. Subsequent computed tomography of the abdomen revealed no bowel wall thickening or enlarged lymph nodes. Involved biopsies were sent out for expert consultation; molecular studies demonstrated clonal immunoglobulin gene rearrangement within biopsies from 2010 and 2015. MYD88 mutation was not detected. The overall morphologic features, indolent clinical behavior, and absence of Epstein-Barr virus (EBV) were deemed indicative of marginal zone lymphoma of mucosa-associated lymphoid tissue. Although low-grade B-cell lymphomas are not considered part of the posttransplant lymphoproliferative disorder spectrum, given the history of liver transplant, an unusual manifestation of EBV-negative posttransplant lymphoproliferative disease could not be excluded. To our knowledge, this is the first reported case of transcolonic marginal zone lymphoma of mucosa-associated lymphoid tissue with plasmacytic differentiation presenting in an indolent, asymptomatic fashion with persistence for more than 5 years.
Megakaryocyte-like Giant Myeloma Cells: Unusual Presentation in Multiple Myeloma: (Poster No. 160)
Multiple myeloma is a cytologically heterogeneous clonal proliferation of plasma cells, with cells showing a variety of morphologic features including immunoblasts/plasmablasts, proplasmacytes, and mature plasma cells. Binucleated and multinucleated forms are common with immature nuclear characteristics. We had an interesting case where the plasma cells were atypical, larger, and morphologically resembled megakaryocytes. A 43-year-old African American woman with a history of hypertension and end-stage renal disease was diagnosed with multiple myeloma 3 months before the recent bone marrow evaluation. She had received high-dose cyclophosphamide therapy with partial response. Bone marrow biopsy was performed for follow-up. The bone marrow showed large cells resembling megakaryocytes with increased anisocytosis, nuclear to cytoplasmic ratio, and nucleus surface area (Figure 70, A and B). These cells were negative for CD61 (Figure 70, C), a megakaryocyte marker. They were positive for CD138 (Figure 70, D) and κ immunostain consistent with plasma cells and with coexpression of CD20. They comprised ~5% to 10% of overall cellularity but, owing to their large size, occupied 10% to 20% of overall marrow space. Flow cytometry did not show definitive monoclonal plasma cell population owing to loss of large atypical cells on flow processing. When compared to the previous biopsy, these plasma cells were much more bizarre. It is questionable whether this unusual morphology is from progression of disease or from chemotherapeutic effect. Studies suggest that plasma cells with irregular nuclei are known to be an unfavorable prognostic factor. As dysmegakaryopoiesis may be an associated feature in plasma cell myeloma, careful distinction between the two is important.
Adult T-Cell Leukemia/Lymphoma Presenting With Cardiac Involvement and Bilateral Hilar Lymphadenopathy Mimicking Sarcoidosis: (Poster No. 164)
While adult T-cell leukemia/lymphoma (ATLL) is uncommon in the United States, with an incidence of 0.04 per 100 000 person-years, cardiac involvement by ATLL is exceedingly rare. We describe a unique presentation of ATLL, in which the patient presented with symptoms of congestive heart failure exacerbation with subsequent imaging suggestive of sarcoidosis. The patient, a 51-year-old African American woman with a history of diabetes mellitus and congestive heart failure, presented with dyspnea and a nonproductive cough. A transthoracic echocardiogram revealed an inferolateral wall motion abnormality, and additional imaging studies revealed infiltrative disease of the ventricular myocardium as well as mediastinal lymphadenopathy, chiefly concerning for sarcoidosis. An endomyocardial biopsy was taken, which demonstrated a lymphocytic infiltrate extending into the myocardium, composed of intermediate-sized cells with pleomorphic nuclei, inconspicuous nucleoli, and relatively clear cytoplasm (Figure 71). By immunohistochemistry, the cells expressed CD3, CD4, CD5, as well as CD30 and were negative for CD20, CD7, and CD8. Serologic studies demonstrated human T-cell leukemia virus type I/II mixed infection, and the heart biopsy was given a diagnosis of ATLL. Upon diagnosis, the patient underwent bone marrow biopsy for staging. No abnormal T-cell population was identified on the peripheral smear associated with the biopsy. However, the bone marrow showed involvement by ATLL with flow cytometry on the aspirate, highlighting an abnormal T-cell population expressing CD2, CD3, CD4, CD5, and CD25. Given the original clinical and radiologic diagnosis, this case underscores the importance of histologic correlation in the context of a rare disease and unique presentation.
Spectrum of Hematopoietic Malignancies Presenting as an Extramedullary/Extranodal Mass in Pediatric Population: A Single Institute Experience: (Poster No. 165)
Context: Hematopoietic malignancies occasionally present as an extramedullary/extranodal mass in the pediatric population and need to be distinguished from other common solid malignancies (neuroblastoma, Wilms tumor, and glioma). However, there has not been a systematic study performed in this area. Only small numbers of bona fide examples exist in the literature. To characterize these tumors, we conducted a retrospective study analyzing pertinent clinicopathologic features of pediatric hematopoietic malignancies presenting as an extramedullary/extranodal mass at our institute.
Design: We retrieved lymphoma/leukemia cases in patients aged <20 years from July 2004–2014. The reports were reviewed and histopathologic data and molecular/cytogenetic studies were analyzed.
Results: We retrieved 20 000 cases of hematopoietic pediatric malignancies. Twenty-four cases presented as extramedullary/nodal mass; of these, 15 were males and 9 were females (age, 18 months–19 years). The histologic diagnosis was high-grade B-cell lymphoma, Burkitt lymphoma, acute lymphoblastic lymphoma, and myeloid sarcoma. Most cases were from the gastrointestinal tract (37.5%), mediastinum (29%), neck and brain (12.5% each), bilateral ovaries, and testis. Interestingly, 18 of 24 cases (75%) did not have any evidence of bone marrow, peripheral blood, or nodal involvement (Table).
Conclusions: Pediatric hematopoietic malignancies rarely present as an extramedullary/extranodal mass. The 2 most common entities are high-grade B-cell lymphoma and Burkitt lymphoma. Other common malignancies are myeloid sarcoma and acute lymphoblastic lymphoma. The most common location is gastrointestinal tract and mediastinum. The pathologic diagnosis is usually not problematic. However, some extremely rare case may present without marrow/nodal involvement. For such cases, thorough knowledge of their existence during intraoperative consultation, biopsy, or diagnostic excision is critical for patient management.
Relapsed T-Cell Lymphoblastic Lymphoma/Leukemia Presenting as Bilateral Intraocular/Intraretinal Masses: (Poster No. 168)
Orbital involvement of precursor T-cell or B-cell lymphoblastic leukemia has been reported in the literature, though rarely as bilateral intraocular/intraretinal masses. We present the case of an adult male patient with a history of precursor T-cell lymphoblastic leukemia in remission following hyper-CVAD chemotherapy. A recent bone marrow biopsy revealed no residual disease. He presented with the new onset of decreased vision in both eyes and pain and redness in the right eye of 2 weeks' duration. Fundoscopic examination revealed bilateral retinal detachment with diffuse retinal hemorrhages and retinal whitening. Brain magnetic resonance imaging revealed bilateral intraocular soft tissue masses involving the posterior poles of both globes. Left epiretinal and retinal biopsies showed a lymphoblastic infiltrate. The tumor cells were positive for CD3, CD79a, CD10, TdT (30%), and CD34 (rare); CD20 was negative. A Ki-67 antibody showed a mitotic index of 50%. Flow cytometric analysis of the left vitreous fluid revealed a clonal blastic cell population that expressed CD34, TdT, cCD3, CD7, CD10, CD38, cCD79a, CD43, and CD52. These findings were diagnostic of relapsed T-cell lymphoblastic lymphoma/leukemia as bilateral intraocular/intraretinal masses (Figure 72).
Primary Nodular Lymphocyte Predominant Hodgkin Lymphoma of the Small Bowel: (Poster No. 169)
A 65-year-old man with past history of hypertension and atrial fibrillation presented with lower abdominal pain and discomfort. Computed tomography scan of the abdomen showed a small-bowel mass that was surgically resected. Grossly, the resection specimen showed a segment of small bowel with a submucosal pink-tan, fleshy mass measuring 4.2 × 2.4 × 1.3 cm. Histologically, the lesion showed nodular growth pattern with scattered large atypical cells, embedded in a rich background of small lymphocytes and histiocytes (Figure 73, A). The large atypical cells had large monolobated or multilobated nuclei with basophilic nucleoli (Figure 73, B). No eosinophils or neutrophils were identified. Immunohistochemically, the large atypical cells were positive for CD20 (Figure 73, C), CD79a, PAX5, and CD45 and negative for CD30 (Figure 73, D) and CD15. These large cells were partially ringed by CD57+ T cells and resided in an expanded follicular dendritic meshwork, as demonstrated by CD21. The background lymphocytes in the nodules were positive for CD20 and CD79A. These findings were consistent with the diagnosis of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). NLPHL comprises 5% of Hodgkin lymphomas. The most common sites of involvement of NLPHL are the peripheral lymph nodes, including cervical, axillary, and inguinal. Primary extranodal NLPHL is rare, occurring in less than 15% of cases. The most frequently involved extranodal sites include spleen, liver, bone marrow, and lung. Small-bowel involvement is extremely rare. In summary, we report a rare case of NLPHL with primary involvement of the small bowel.
IGH-BCL2–Negative Low-Grade Follicular Lymphoma With Reed-Sternberg–like Cells: (Poster No. 172)
The small subset of t(14;18)-negative follicular lymphomas is less well understood and seems to have distinct molecular features (including BCL6 rearrangements and trisomy 3). We are presenting an unusual case of low-grade t(14;18)-negative follicular lymphoma with associated Reed-Sternberg–like cells. A 89-year-old woman patient had bilateral cervical lymphadenopathy and a 3×2.2×2-cm left forearm mass. The excised forearm mass was remarkable for a dense intradermal lymphoid population with a predominant diffuse pattern of infiltration in the upper dermis and a nodular/follicular pattern in the deeper regions sampled. Some lymphoid follicles had a monotonous appearance of their germinal centers with predominance of small centrocytes and very few centroblasts, and in the upper dermis, scattered transformed lymphoid cells with a Reed-Sternberg–like morphology were identified (Figure 74, A). By immunohistochemistry, the Reed-Sternberg–like cells were CD30+ (Figure 74, B), CD20+, CD79a+, PAX5+, bcl6+, MUM1+, and bcl2+ and negative for CD15, while the neoplastic lymphoid follicles were CD20+, CD10+, bcl2+ (Figure 74, C), CD10+, and BCL6+ (Figure 74, D) and had proliferation rates of approximately 20% to 30%. Molecular and fluorescence in situ hybridization studies were reported negative for IGH-BCL2 fusion. Bayer et al (2004) demonstrated that the Reed-Sternberg cells in follicular lymphoma are clonally related, which also appears true in the current case given the strong expression of B-cell markers by the Reed-Sternberg–like cells. Skin involvement by t(14;18)-negative low-grade follicular lymphoma with associated Reed-Sternberg cells has not been previously reported and may constitute a diagnostic challenge if a limited immunohistochemical analysis is performed.
Central Nervous System Involvement by Triple-Hit B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between DLBCL and Burkitt Lymphoma: (Poster No. 175)
Triple-hit lymphomas are rarely occurring hematolymphoid neoplasms and have a growing diagnostic and research interest. As defined, these lymphomas harbor 3 translocations involving BCL2, BCL6, and MYC. Approximately 50 cases are reported, with most triple-hit lymphomas confined to lymph nodes and bone marrow and classified as either diffuse large B-cell lymphoma (DLBCL) or B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma (BCLU). We report, to the best of our knowledge, the first case of triple-hit BCLU involving brain parenchyma. A 39-year-old man presented with altered mental status and impaired speech to the emergency department. Magnetic resonance imaging revealed a 6-cm lesion in the left frontal lobe with midline shift. Computed tomography showed lymphadenopathy and multiple lesions of the abdomen, pleura, and paraspinal soft tissue suggestive of lymphoma. Neurosurgery proceeded with emergent resection to relieve mass effect. Histologic sections of the frontal lobe mass revealed a diffuse infiltrate of medium-sized to large lymphocytes with scant cytoplasm and nuclear irregularities (Figure 75). Prominent mitoses and tingible body macrophages were noted. Immunohistochemistry revealed a CD20+ B-cell population with strong expression of BCL2 and negative CD43 and BCL6 expression. Ki-67 approached 100%. Concurrent flow cytometry demonstrated a λ-restricted CD10+ B-cell population. Fluorescence in situ hybridization was positive for t(14;18) (IGH-BCL2), as well as translocations of 3q27 (BCL6) and 8q24 (MYC). Despite the Burkitt-like morphology of the lymphocytic infiltrate, the immunophenotypic findings and genetic features supported the diagnosis of BCLU. In summary, this case report documents a rare triple-hit lymphoma involving the brain and adds valuable information for future studies.
Primary Uterine Corpus and Cervical Lymphoma: An Incidental Finding in Hysterectomy Due to Uterine Prolapse: (Poster No. 177)
Uterine corpus primary lymphoma is a rare entity. The clinical presentation is variable but mainly presents as abnormal vaginal bleeding in middle to older age women. The most common type is diffuse large B-cell lymphoma. We report 2 cases of uterine corpus primary lymphoma. Case 1 involves a 64-year-old woman who presented to clinic with signs and symptoms of uterine prolapse. Hysterectomy and bilateral salpingooophorectomy was performed. Microscopic examination of the uterus showed normal-appearing endometrium with variably sized, poorly formed lymphoid follicles. Germinal centers demonstrated loss of polarity and were composed predominantly of centrocytes with few centroblasts. Immunohistochemical stains showed that the follicles and germinal centers were positive for CD20, CD23, CD10, and BCL2 with low Ki-67, consistent with follicular lymphoma grade 1 (Figure 76, A through D). The ovaries, fallopian tubes, and cervix did not show any histopathologic abnormality. Case 2 involves a 56-year-old woman who presented to clinic with AVB. Imaging showed a 3.0 × 2.5-cm cervical mass with no other masses or lymphadenopathy. Hysterectomy was performed and histologic examination showed a proliferation of large atypical lymphoid cells extensively involving both squamous and glandular epithelium. Immunohistochemical stains showed positivity for CD20, CD10, and BCL6 with Ki-67 of 70% to 80% in atypical lymphoid cells, consistent with diffuse large B-cell lymphoma. Neither patient received any further treatment. Follow-up of both patients did not show any evidence of disease after 1 year.
Type I Cryoglobulinemia in Chronic Lymphocytic Leukemia: A Rare Association: (Poster No. 181)
Most cases of type I cryoglobulinemia arise in the setting of Waldenström macroglobulinemia or multiple myeloma. We present a rare case of type I cryoglobulinemia in a patient with chronic lymphocytic leukemia (CLL). A 59-year-old woman presented with abdominal pain and bilateral, cutaneous, distal leg lesions. Computed tomography showed a retroperitoneal hematoma due to right gonadal artery rupture. Simultaneously, the patient was found to have renal insufficiency with proteinuria and a lymphocytosis of 45 000/μL. Flow cytometry showed an sIg κ-restricted B-cell population (54%) with a phenotype consistent with CLL: CD19+, CD20+, CD5+/−, CD10−, CD23+/−, FMC7+, CD38+, CD11c+/−, and HLA-DR+. Fluorescence in situ hybridization revealed deletions of ATM/11q and 13q, and trisomy 12. Renal biopsy was complicated by hemorrhage, resulting in nephrectomy. Microscopically, the kidney showed interstitial and perirenal lymphoid infiltrates consistent with CLL. Also seen was membrano-proliferative glomerulonephritis with extensive segmental luminal deposition of hyaline material suggestive of cryoglobulin. Immunofluorescence of the deposits was strongly positive for IgG and weak for IgM with κ more extensive than λ (Figure 77, A through D). Serum cryoglobulin testing revealed a cryocrit of 5% with IgG κ specificity by immunofixation. Cryoglobulin was visualized on peripheral blood smear and resulted in aberrant platelet counts by automated analysis. Tests for HIV, HTLV-1 and HTLV-2, hepatitis B, hepatitis C, cytomegalovirus, and ANA were negative, further supporting CLL as the sole cause of the cryoglobulinemia. We reiterate that CLL with type I cryoglobulinemia is a rarely reported association and should be suspected in cases of CLL with renal failure.
Two Cases of Postmortem Diagnosis of Intravascular Large B-Cell Lymphoma Presenting With Lactic Acidosis and Gastrointestinal Tract Symptoms: (Poster No. 182)
Intravascular large B-cell lymphoma is a rare type of extranodal large B-cell lymphoma, characterized by large lymphoid cells lodged inside capillaries and small blood vessels. We present 2 cases with unusual symptomatology and rapid course. The first patient was a 79-year-old woman who presented with 1-month history of epigastric and right upper quadrant pain, and on admission had lactic venous acidosis (10.4 MEQ/L), hypocalcemia, hypomagnesemia, leukocytosis (14.4 × 109/L), mild thrombocytopenia (139 × 109/L), and no abnormalities on an abdominal computed tomography (CT) and exploratory laparotomy. An intraoperative liver biopsy was performed. The patient died 6 days post admission. The second case involved an 85-year-old man with 3-week history of dysphagia and 3-day history of fever and coughing who had no abnormalities on an abdominal and brain CT. On admission he had lactic acidosis (6.6 MEQ/L), hyponatremia, hypocalcemia, anemia (12.7 g/dL), and mild thrombocytopenia (143 × 109/L), and he died after 8 days. In both cases, a diagnosis of intravascular large B-cell lymphoma with an activated immunophenotype (MUM1+) and high proliferation index was made postmortem. In case 1, the lymphoma involved the heart, lungs, liver, gastrointestinal tract, kidneys, para-aortic ganglia, pancreas, lymph nodes, and spleen. Case 2 was a chest-limited autopsy, and the lymphoma involved the esophagus, lungs, cardiac and epicardial tissue, and bone marrow. We want to draw attention to the unusual presentation of this rare type of large B-cell lymphoma especially when encountering rapid progression to lactic acidosis and gastrointestinal tract symptoms without imaging abnormalities (Figure 78).
Appendiceal Intravascular Lymphocytosis: A Rare Finding With Initial Misdiagnosis as Chronic Leukemia of Lymphoid Origin: (Poster No. 183)
The accumulation of lymphocytes within markedly dilated vessels in appendectomy specimens is an unusual phenomenon that may be mistaken for a hematolymphoid malignancy. Herein we describe the case of a 27-year-old man who presented with abdominal pain, fever, nausea, and findings on imaging studies compatible with acute appendicitis. The patient underwent an emergent laparoscopic appendectomy and although no evidence of acute appendicitis or periappendicitis was noted upon microscopic examination, focal mucosal erosion and several dilated mesoappendiceal vessels occluded by predominantly small mature lymphocytes and a few centroblastic-looking forms were observed. Therefore, concurrent involvement by a chronic leukemia of lymphoid origin was suspected. However, immunohistochemistry for CD3 and CD20 showed a mixture of T and B cells within the vessels, respectively, with predominance of the former. CD34 highlighted the endothelial cells and Ki-67 was positive in approximately 20% of the intravascular lymphocytes. No obvious coexpression of CD5, CD23, CD43, or cyclin D1 was noted on the B cells. Additional immunostains for BCL2 and BCL6 showed a preserved follicular immunoarchitecture. Importantly, a complete blood cell count showed no absolute lymphocytosis. The accumulation of monomorphic small lymphocytes in appendectomy specimens is an unusual finding that may be due to a robust immune response in young patients or manipulation of the appendix during surgery. To our knowledge, this finding has not been described in detail in any of the major pathology textbooks. We believe this can represent a challenge for inexperienced pathologists, who may recommend unnecessary additional testing or even issue an incorrect diagnosis (Figure 79).
Synchronous Presentation of Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia and Primary Amyloidosis in a Patient With Chronic Renal Insufficiency: (Poster No. 184)
Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia is an indolent low-grade B-cell lymphoma characterized by marrow infiltration of lymphoplasmacytic cells associated with a paraprotein usually of IgM type. Primary amyloidosis is a neoplasm in which clonal plasma cells produce amyloid, usually composed of λ Ig light chains that accumulate in tissues and result in end-organ damage. We describe the case of a patient with renal insufficiency who is found to have 2 distinct clonal lymphoid cell populations in bone marrow with amyloid deposition in marrow and kidney. A 70-year-old man presented with lower extremity edema. Serum protein electrophoresis with immunofixation demonstrated an IgM-κ M-component, elevated quantitative serum IgM, and depressed IgG and IgA levels. Serum-free κ and λ light chains were elevated, but with a normal ratio. Elevated urine total protein and low creatinine clearance was seen on 24-hour urine. A bone marrow examination with immunohistochemistry and flow cytometry identified 2 distinct lymphoid populations. A monoclonal κ small mature B-lymphocyte population characteristic of lymphoplasmacytic lymphoma was present (Figure 80, A [H&E] and B [κ]). Additionally, a second plasma cell population with λ light-chain restriction (Figure 80, C [CD138] and D [λ]) and vascular amyloid deposition, characteristic of primary amyloidosis, was seen. A subsequent renal biopsy confirmed AL-λ amyloid within blood vessels and glomeruli. Simultaneous presentation of primary amyloidosis and lymphoplasmacytic lymphoma/Waldenström macroglobulinemia is very unusual. We describe a patient with these 2 distinct synchronous clonal immunosecretory disorders. Establishing the diagnosis of each disorder and determining the contribution of each disorder to this patient's clinical disease is discussed.
Diagnostic Utility of Fluorescence In Situ Hybridization in T-Cell Blast Crisis of Chronic Myelogenous Leukemia: (Poster No. 185)
T-cell blast crisis of chronic myelogenous leukemia (CML) is a rare disorder, as most blast phase cases in CML have a myeloid blast (70%) and primitive B-lymphocyte phenotypes (20%–30%). We describe a case of a 42-year-old man, without a past medical history, who presented with general weakness, shortness of breath, and weight loss for several months. Peripheral smear revealed high white blood cell count (406 000/μL) with 50% blasts. Flow cytometry of the peripheral blood and immunohistochemistry on bone marrow confirmed the T-cell lymphoblast lineage. Moreover, BCR-ABL1 transcript was detected by using real-time reverse transcriptase polymerase chain reaction. The differential diagnoses at this point include de novo Philadelphia chromosome–positive acute lymphoblastic leukemia and T-cell blast crisis of CML. Fluorescence in situ hybridization (FISH) revealed that BCR/ABL1 fusion was seen in 97.6% of the cells (positive in lymphoblasts and neutrophils). This finding was supportive of the diagnosis of T-cell blast crisis of CML. The patient underwent 4 cycles of hyper-CVAD chemotherapy followed by allogeneic hematopoietic stem cell transplant. The patient developed graft-versus-host disease (skin and liver involvement) and relapse of T-cell lymphoblastic leukemia approximately 5 months after the transplant. He received tyrosine kinase inhibitor and immunosuppressant dose adjustment for his relapse. At the time of this writing, the patient is doing well without evidence of disease recurrence, and the engraftment assessment shows complete donor chimerism. We demonstrated the utility of FISH to distinguish T-cell blast crisis of CML from de novo Philadelphia chromosome–positive acute lymphoblastic leukemia (Figure 81).
De Novo Immunoblastic Follicular Lymphoma: Case Report of a Vanishing and Poorly Understood Entity: (Poster No. 186)
Chan et al initially reported a case of de novo immunoblastic follicular lymphoma (FL) in 1990, suggesting it represented a neoplastic overgrowth of intrafollicular immunoblasts. In the current World Health Organization lymphoma classification, it is characterized as FL 3B, albeit its clinical course is variable. Here, we characterize a similar lesion that has followed an indolent clinical course. A 40-year-old man presented with a persistent left cervical mass, with no fever or night sweats, attributed to a prior dental procedure. A biopsy yielded a 3.5-cm lymph node with areas reminiscent of progressively transformed germinal centers. Cytologically, atypical follicles comprised sheets of immunoblasts with occasional residual germinal centers. The patient has remained asymptomatic after excision with no further treatment. The immunoblasts were CD20+, CD79a+, CD3−, CD10−, BCL-2+, BCL-6 (weakly +), MUM1+, CD138−, ALK1−, CD30−, ISH κ−/λ+, with Ki-67 index of 10% to 20%. There was no IGH/BCL2 rearrangement and genomic sequencing identified a CD36 k36fs*41 mutation and was negative for IRF4 mutations. We present an example of a very rare entity referred to as immunoblastic FL 3B with an indolent clinical course. We postulate that the cell precursor represents a postfollicular BCL6+ MUM1+ B lymphocyte that has not yet transited to the marginal zone, hence the follicular growth pattern. While most of these precursors conceivably give rise to non–GC-type diffuse large B-cell lymphoma, it would appear that low-grade lesions might happen if the transforming event occurs at the intrafollicular stage (Figure 82).
Composite Lymphoma With Concurrence of Marginal Zone Lymphoma and Angioimmunoblastic T-Cell Lymphoma: (Poster No. 188)
Composite lymphoma is a rare entity that has been reported in recent literature. The accepted definition for composite lymphoma is the incidence of 2 or more distinct lymphomas in a single anatomic site. Unlike disease progression or transformation in lymphoma, composite lymphoma should include 2 distinct clones proven by morphologic and immunohistochemical staining or molecular studies. No single definite mechanism has been suggested and the etiology is variable, complex, and differs according to the types of involved lymphomas. We report the case of a 72-year-old woman who presented to clinic with a 3-month history of edema in the lower extremities and generalized lymphadenopathy. Computed tomography of the chest/abdomen/pelvis revealed extensive axillary, mediastinal, retroperitoneal, and pelvic lymphadenopathy. Axillary node excisional biopsy was performed. Microscopic sections revealed effacement of the nodal architecture by a diffuse low-grade process. Immunohistochemical staining showed 2 distinct lymphomas. One was positive for CD20 and CD5, consistent with B-cell lymphoma. Moreover, the cells were negative for cyclin D1, SOX11, and CD23, which suggested the possibility of marginal zone lymphoma. The other lymphoma showed predominant expression of CD4 with partial loss of CD3 and CD7. The scattered Epstein-Barr virus positivity and PD1 positivity suggested the possibility of a follicular T-cell origin for the lymphoma, such as angioimmunoblastic T-cell lymphoma (Figure 83). Flow cytometry concurred with the diagnosis. Finally, bone marrow biopsy did not show any involvement by lymphoma. We report another case of composite lymphoma with unusual histology pattern. Moreover, whole exon sequencing is pending for further subclassification and understanding of the tumor nature.
Composite Blastoid Mantle Cell Leukemia and Chronic Myelomonocytic Leukemia: (Poster No. 189)
Composite hematopoietic malignancy is a rare entity that has been reported in recent literature. The accepted definition for composite malignancy is the incidence of 2 or more distinct tumors in a single anatomic site. Unlike disease progression or transformation, it should include 2 distinct clones proven by morphologic and immunohistochemical analysis or molecular studies. An 83-year-old man presented to clinic with a 6-month history of abdominal discomfort and mild diarrhea. Complete blood cell count revealed mild anemia, monocytosis, and thrombocytopenia. Computed tomography revealed para-aortic and retroperitoneal lymphadenopathy. Bone marrow biopsy showed hypercellular marrow (40%–50% cellularity) with abnormal blastoid cells with large bilobed complex nuclei and variable amounts of cytoplasm (Figure 84, A). Immunohistochemical staining showed the abnormal cells were strongly positive for CD20, CD5, and cyclin D1, and negative for CD3, TdT, CD34, and myeloperoxidase. Flow cytometry supported the immunohistochemical findings. The diagnosis of blastoid mantle cell lymphoma was made. Further examination revealed increased numbers of monocytes with dysplastic small megakaryocytes (Figure 84, B) and erythroid precursors with mega-loblastoid chromatin (Figure 84, C). CD163 confirmed bone marrow monocytosis (Figure 84, D). In addition, cytogenetic analysis showed loss of chromosome Y and gain of 11q23 to be consistent with diagnosis of chronic myelomonocytic leukemia. Although the patient initially showed response to chemotherapy including rituximab, his condition quickly declined and he died 6 months after diagnosis.
CD3+ and CD4+ Plasma Cell Neoplasm With Immature Morphology Presenting as a Mandibular Lesion: A Diagnostic Pitfall: (Poster No. 193)
A plasma cell neoplasm with aberrant expression of T-cell antigen is exceedingly rare and when present mostly involves only 1 T-cell–related antigen. It is typically reported in plasmablastic lymphoma or plasmablastic myeloma. We report a case of nonplasmablastic plasma cell neoplasm with CD3 and CD4 dual expression. A 62-year-old man presented to an oral surgeon for a large radiolucent lesion of right posterior mandible. Tooth No. 31 was mobile and symptomatic. The man reported no significant medical history. An incisional biopsy was performed and tissue was submitted for microscopic examination to rule out a dentigerous cyst versus malignancy. The biopsy showed multiple fragments with sheets of neoplastic cells with immature morphology, moderately abundant cytoplasm, evenly dispersed fine chromatin, single to few nucleoli, and numerous mitotic figures. Morphologic differential diagnosis included a non-Hodgkin lymphoma. These cells were strongly positive for CD3 but negative for B-cell lineage–associated antigens in the initial immunohistochemical work-up. However, they also expressed cyclin D1, prompting further workup, which identified strong CD4 expression in addition to CD138, MUM1, and κ light chain (Figure 85). EBER-ISH was negative. Fluorescence in situ hybridization/molecular analysis confirmed a t(11;14) BCL1-IGH and B-cell IGH clonality. The final diagnosis was κ light-chain restricted plasma cell neoplasm aberrantly coexpressing CD3 and CD4. To our knowledge, dual expression of T-cell antigens in nonplasmablastic plasma cell neoplasm has not been previously reported. This case demonstrates the ability of neoplastic plasma cells to mimic non-Hodgkin lymphoma not only histomorphologically, but also immunophenotypically. Recognition of such lineage infidelity on immunophenotypic grounds is essential to avert misclassification.
Management of Concomitant Factor VII Deficiency and Factor V Leiden Mutation: (Poster No. 197)
Factor V leiden (FVL) mutation is the most common inheritable thrombophilia. Factor VII (FVII) deficiency is a rare bleeding disorder (1 in 500 000). We report a case of a 58-year-old man diagnosed with both of these entities with no previous medical history. The patient presented to our emergency department with persistent and increasing abdominal pain. Computed tomography scan revealed extensive occlusive thrombosis in the main, left, and right portal veins, splenic vein, superior mesenteric vein and its branches. Heparin drip was started (1750 U/h). Thrombolysis with tPA was initiated (12.5 mL/h/4 d) with concurrent SC heparin (5000 U/TID). Following successful thrombolysis, enoxaparin (100 mg SC) was started with bridge to warfarin (5 mg). However, on follow-up imaging rethrombosis was perceived 7 days after the initial presentation. Another cycle of heparin/tPA was started. INR at that point was found to be elevated (5.7). Hemoperitoneum was then detected and anticoagulation therapy was held. Further investigation revealed FVII level of 7% (normal: 66%–159%) with no inhibitor pattern. A dose of 2384 U (21.6 U/kg) of Kcentra was administered and an acceptable level of FVII was achieved and maintained over the next day. A series of small doses of NovoSeven (0.1–1 mg) was then started to maintain acceptable levels of FVII during 12 days (Figure 86). Further workup revealed FVL heterozygous mutation. The patient was discharged with enoxaparin without reoccurrence of bleeding or thrombosis. This case demonstrates the narrow therapeutic window in a patient with both hypercoagulable and hypocoagulable states and successful treatment of a life-threatening bleed, using both Kcentra and NovoSeven.
Protein C Test Utilization Practices: (Poster No. 200)
Context: Oral anticoagulation and acquired vitamin K deficiency reduce serum protein C (PC) levels, which may affect interpretation of results for assessing thrombophilia.
Design: The frequency of testing and effects on serum PC levels at various INR ranges among 102 Veteran Affairs facilities were evaluated. PC and INR results performed on the same day during 2000–2014 were analyzed. Chromogenic PC tests were excluded. A PC value ≤54% was considered low.
Results: A total of 18 743 functional and 6718 antigenic (PCag) PC with concomitant INR results were analyzed. At INRs of ≤1.0, we observed that 379 of 11 695 PC results (3.2%) were low. The proportion of low PC results rose with higher INRs: 275 of 4477 (6.1%) at 1.1; 282 of 2000 (14.1%) at 1.2; 249 of 1016 (24.5%) at 1.3; 225 of 627 (35.9%) at 1.4; and 216 of 499 (43.3%) at 1.5. PCag levels declined less than functional PC at INRs > 1.5 (Figure 87). PC was frequently tested when INR results were elevated; 17.2% and 10.9% of cases with INRs of ≥1.5 and ≥2.0, respectively.
Conclusions: PC was often measured when INRs were elevated, which might cause results to be misinterpreted. Furthermore, PCag, which is not indicated for initial assessment of PC deficiency, was commonly used. While this study is limited by lack of information about clinical indications for ordering PC, these results nevertheless suggest that PC utilization practices could be improved by using INR (≤1.1) as prerequisite for testing and by measuring functional PC for initial thrombophilia assessment.
Grading of Symptoms of Leukostasis: A Valuable Tool to Guide Management of Acute Myeloid Leukemia With Leukapheresis: (Poster No. 201)
Context: The aim of this study is to correlate the severity of leukostasis, by using a grading algorithm to early death in acute myeloid leukemia (AML).
Design: We retrospectively analyzed all AML patients who underwent leukapheresis between February 2004 and July 2013. A scale of 0 to 3 was used to score the severity of leukostasis according to symptoms (Table). Risk factors were compared against the “early death” group (survival ≤7 days) versus “survival” group (>7 days), with t test. All patients underwent leukapheresis with a Cobe Spectra system, software version 4.7, using the MNC procedure. Approximately 2 to 3 blood volumes were processed.
Results: Thirty-nine AML patients underwent leukapheresis. Early death occurred in 2 acute promyelocytic leukemia patients (APL) (100%). The mortality within 1 week, 2 weeks, and 1 month in the remaining AML patients was 35.1%, 37.8%, and 45.9%, respectively. Only severity of the grade of leukostasis was significantly associated with early death (survival ≤ 7 days). When patients presented with category 3 symptoms, there was early death in 100% of patients. Notably, age, white blood cell (WBC) count, number of procedure, decrease in WBC count with leukapheresis, blast percentage, total blast number, hemoglobin, creatinine, and lactate dehydrogenase were not predictive for early death.
Conclusions: Our results show that leukapheresis is not helpful for APL management. We further demonstrate that the clinical leukostasis grading scale is the only valuable tool to predict early death. When patients with AML presented with category 3 leukostasis, leukapheresis did not prevent early death and leukapheresis is therefore not recommended.
Elevated D-dimer Concentrations: Implications for Lupus Anticoagulant False Negatives: (Poster No. 203)
We report a case of a 65-year-old man with a recent abdominal aorta repair in which postoperative recovery was complicated by a pelvic hematoma. PTT was found to be prolonged at 56.6 seconds (normal: 25.3–37.4). Further workup revealed a negative lupus anticoagulant (LA). However, the PTT mixing study was consistent with a nonspecific anticoagulant inhibitor. Both factor VIII and IX activity were performed and showed decreased levels with indication of inhibitor interference. Additional testing showed a markedly elevated D-dimer concentration (28 mcg/mL; normal <0.5 mcg/mL). Reviewing the patient's medical records showed a prolonged PTT from 4 years earlier with no further workup. As it is extremely rare for a patient to have 2 specific factor inhibitors with no clinical findings, it was hypothesized that the LA result was falsely negative. At an outpatient follow-up visit 12 days later, the D-dimer was decreased to 6.32 mcg/mL and LA was found to be positive. Known causes of false-negative LA tests include warfarin, heparins, factor deficiencies, and thrombosis. We hypothesized that high D-dimer concentrations interfere with the LA assay. To test this, we mixed known LA-positive sera with sera known to have elevated D-dimer levels at a ratio of 1:1. Subsequent LA testing was negative in 75% of the cases (Table), suggesting that an elevated D-dimer level could lead to a false-negative LA. To our knowledge, this is the first report indicating that high D-dimer concentrations may play an integral role in the confounding of LA testing.
Intracranial Hemorrhage Due to a Rare Factor V Inhibitor With Lupus Anticoagulant-Like Properties: (Poster No. 205)
Factor V inhibitors are rare, and they can have varying presentations. We report a case of a 76-year-old woman with numerous drug allergies and red blood cell antibodies who presented with pneumonia. She was treated with ceftriaxone, azithromycin, and meropenem at another hospital. She was transferred to our hospital and upon arrival to our intensive care unit, she had a severe drug rash and unremarkable coagulation studies (PT 15.6 seconds; reference range 12.5–15.5 seconds) and a PTT of 35 seconds (reference range 25–35 seconds). Her antibiotic regimen was simplified to levofloxacin only, and her condition improved. On hospital day 10, she noted left upper extremity weakness, confusion, and a headache. A head computed tomography scan revealed a subdural hematoma, her PT had increased to 59.1 seconds, and the aPTT was unmeasurable. A thrombin time was normal, and a mixing study with normal plasma did not correct the clotting times. Furthermore, the plasma demonstrated the presence of a strong lupus anticoagulant with nonspecific inhibition of multiple coagulation factors (Table). Factor V remained inhibited with serial dilutions, and an inhibitor was identified with an activity of 70 BU. Despite administration of corticosteroids, platelet transfusions, and hemostatic agents, she succumbed to effects of the intracranial hemorrhage. Factor V inhibitors are unusual in that they can display lupus anticoagulant properties with bleeding, yet there are cases of factor V inhibitors associated with thrombosis. Our case illustrates that these inhibitors can develop quickly and that patients who are prone to developing antibodies may be at higher risk.
Frequency of Antibodies in Delayed Hemolytic and Delayed Serologic Transfusion Reactions: (Poster No. 206)
Context: Delayed transfusion reactions (DTRs) can be divided into delayed hemolytic and delayed serologic transfusion reactions. Among the blood group antigens, Rh antigens are the most immunogenic. Outside of the Rh group, antibodies to the Kidd blood group are the most frequent cause of DTR. Other clinically important red cell antibodies causing DTR are in Duffy, Kell, and MNS blood groups. We sought to determine the frequency of different antibodies causing DTR within our patient population.
Design: We conducted a retrospective review of all DTRs that occurred at our level 1 trauma center from January 2009 to November 2014. Newly identified antibodies that developed within 3 months of red blood cell transfusion along with patients' demographic information were collected and evaluated.
Results: The study pool consisted of 91 patients with 118 antibodies detected. The mean age was 56, ranging from 14 to 86. White and African American race were approximately equal, with a slight female predominance (1.4:1). The Rh antigen group was found to have the highest prevalence (53 of 91), with anti-E antibody being the most frequent (42 of 91; Table). Among the non-Rh groups, Jka antibodies were more prevalent (18 of 91), with the next highest being anti-K (12 of 91). In our patient population of DTRs, the E antibody developed at a higher rate than all the other antibodies (χ2 = 64.5932, P < .001).
Conclusions: The results from our retrospective review of DTRs shows that alloanti-E formation occurs in the majority of patients at our institution. Our results are in agreement with published data showing similar results.
Cardiovascular Pathology; Clinical Chemistry; Cytopathology; Dermatopathology; Head, Neck, and Oral Pathology; Informatics; Microbiology; Molecular Pathology; Neuropathology; Pathology Education; Practice Management; Pulmonary and Mediastinal Pathology; Quality Assurance Fatal Severe Left Main Coronary Artery Stenosis and Diffuse Arteriopathy in an Infant With Williams-Beuren Syndrome: (Poster No. 1)
Williams-Beuren syndrome (WBS) is a developmental disorder mainly of the connective tissue and the central nervous system. A common feature of WBS is supravalvular aortic stenosis, though aortic coarctation and coronary artery disease are rare occurrences. Patients with WBS show allelic loss of elastin (ELN), exhibiting a submicroscopic deletion at 7q11.23, detectable by fluorescence in situ hybridization (FISH). We present a case of a 3-month-old girl with WBS. The patient had unremarkable prenatal care. Hypertension diagnosed after full-term birth led to the diagnosis of coarctation of aorta, branch pulmonary artery stenosis, and WBS, confirmed by FISH. She underwent surgical repair for the aortic coarctation at 8 weeks, but had residual aortic coarctation on follow-up echocardiogram. During a balloon angioplasty, she developed coronary spasm and cardiac arrest. Patient had another cardiac arrest 1 day after and subsequently died after an attempt of resuscitation. On autopsy, gross sections of muscular and elastic arteries show diffuse arteriopathy, characterized by concentric and contiguous thickening of the arterial wall at the expense of the lumen, including slitlike orifice of the left coronary artery (Figure 88, A). Microscopically, these arteries had thickened and disorganized elastic fibers throughout. The elastic fibers appeared shortened and fractured (Figure 88, C and D). Trichrome stain showed the thickened vessel walls to be composed mostly of fibrous tissue with a markedly diminished amount of smooth muscle (Figure 88, B). This case report highlights the necessity of careful cardiology assessment, medical team awareness, and a detailed microscopy of rare features in patients with WBS.
Malignant Perivascular Epithelioid Cell Tumor: A Rare Pericardial Tumor: (Poster No. 2)
The prevalence of primary cardiac tumors is 0.001%–0.03% in autopsy series, 25% of which are malignant, mainly sarcoma. Primary pericardial sarcomas are exceedingly rare with a dismal prognosis. Perivascular epithelioid cell tumor (PEComa) is a very rare tumor with distinctive immunophenotype positive for smooth muscle and mela-nocytic markers. PEComas >8 cm and mitosis >1/50 high-power fields (HPF) are considered malignant. Only 3 cases are reported in myocardium/pericardium. We present a case of pericardial sarcomatous PEComa in a 64-year-old woman. The patient presented with progressive shortness of breath on exertion, bilateral lower extremity edema, and loss of 12 lb within the past 2 months. Computerized tomography scan of the chest, TTE, and cardiac magnetic resonance imaging revealed a cystic-solid, heterogeneous, pericardial mass (9.9 × 11.5 × 14.2 cm) compressing the anterior right ventricle. Computerized tomography core needle biopsy revealed a spindle and epithelioid sarcoma. The tumor involved the myocardium, making the sarcoma unresectable. The patient refused chemoradiotherapy and opted for home hospice care. The debulked tumor fragments (12.2 × 10.8 × 4.0 cm) consisted of high-grade spindle and epithelioid cell sarcoma with prominent perivascular tumor cell condensation (Figure 89, A and B), moderate nuclear pleomorphism, scattered multinucleated tumor giant cells, and brisk mitoses with abnormal figures (>30 mitoses/10 HPF). Immunostains were positive for desmin, SMA (Figure 89, C), HMB-45 (Figure 89, D), Melan-A, CD99 (membranous), and BCl-2, and negative for cytokeratins (CK-AE1/AE3 and CK5/6), TTF-1, mammaglobin, breast GCDFP-15, estrogen/progesterone receptors, and CD34, consistent with the diagnosis of PEComa. To our knowledge this is the fourth reported case of PEComa in the heart/pericardium with overt high-grade sarcomatous features.
Eosinophilic Myocarditis: A Case Report and Review of Literature: (Poster No. 4)
Eosinophilic myocarditis (EM) is rare, potentially fatal if left untreated, and pathologically characterized by myocardial inflammatory infiltration with eosinophils and focal myocyte necrosis. Etiology of EM is not clear but it can associate with eosinophilic syndromes or allergic reactions that result in left ventricular compromise. The spectrum of clinical presentation is variable. EM clinically can present as acute coronary artery syndrome/acute heart failure/cardiogenic shock, etc. We report an EM case presented with acute heart failure with left ventricle hypertrophy. A 64-year-old man presented with acute and progressive shortness of breath. An echocardiogram was highly suspicious for an infiltrative cardiomyopathy with severe concentric left ventricle hypertrophy. The laboratory evaluation was remarkable for high leukocyte count (21 900/cmm) with peripheral eosinophilia (about 2000/cmm) and high troponin (14.04 ng/mL). Promptly the patient was started on pulse steroid. Patient showed significant improvement following pulse steroid. An endomyocardial biopsy under fluoroscopy was performed. Histologic section showed diffuse inflammatory infiltrate with a large predominance of eosinophils, interstitial edema, and focal myocyte necrosis. EM is a rare form of myocarditis and often underdiagnosed in the acute setting. To our best knowledge, less than 40 EM cases have been reported in literature. We conclude that EM should be considered as differential diagnosis of acute cardiac conditions. If there is high clinical suspicion of EM, prompt pulse steroid therapy and an endomyocardial biopsy should be considered (Figure 90).
Acute Myocardial Infarction Secondary to Giant Lambl Excrescence of the Aortic Valve: (Poster No. 5)
Cardiac papillary fibroelastomas (CPFEs) are rare benign tumors of the endocardium and represent the most common primary valvular tumors of the heart. CPFE is sporadically reported with an incidence between 0.002% and 0.33% at autopsy. Although many papillary fibroelastomas do not cause symptoms, early diagnosis of CPFE is of prior importance to prevent patients from fatal complications. Nevertheless, this tumor can present with a variety of clinical manifestations, making diagnosis challenging. We report an unusual case of aortic valve papillary fibroelastoma, which was found on autopsy in a 64-year-old man patient with evidence of myocardial ischemic damage. Histopathologic examination of heart revealed a 1.5 × 1.0-cm, bulky, tan-white, nonencapsulated, rubbery lesion composed of multiple papillary fronds on the aortic valve. The tumor mass completely occluded the right coronary ostium. An acute inferior wall myocardial infarction was also present. Histology showed a benign papillary lesion composed of a single layer of endocardial cells overlying a thin layer of mucopolysaccharide matrix and underlying, almost acellular, avascular stroma composed predominantly of elastic fibers and a small amount of collagen. Transesophageal echocardiography is known to have high sensitivity to detect excrescences and should always be included in the diagnostic assessment. Asymptomatic patients who are found to have evidence of CPFE should be monitored closely. Here, we describe a rare case of acute myocardial infarction secondary to CPFEs of the aortic valve completely occluding the right coronary ostium leading to sudden cardiac death (Figure 91).
Cardiac Allograft Transmission of Toxoplasmosis: (Poster No. 8)
We present a case of a 60-year-old man with ischemic cardiomyopathy status posttransplant who developed cardiac toxoplasmosis. Two months posttransplant, he developed diarrhea, fatigue, and heart failure with concern for rejection, myocarditis, and infectious colitis. A week after admission, the patient had Toxoplasma gondii parasitemia detected by polymerase chain reaction (PCR); quantitative PCR testing for T gondii demonstrated 1 100 000 DNA copies/mL. The donor was a young man who grew up in Mexico and immigrated to North Carolina. After the recipient became ill, further testing was performed, and the donor T gondii IgG and IgM serologies were positive whereas the recipient serologies were negative pretransplant. The recipient had been off trimethoprim-sulfamethoxazole prophy-laxis for 1 month prior to his death. An endomyocardial biopsy performed days prior to the patient's death demonstrated cardiac toxoplasmosis with diffuse ongoing and healing myocyte necrosis and maturing fibrosis. His clinical course continued to worsen, and he died 2 weeks later. At autopsy, rare cysts containing bradyzoites were seen in myocytes, and there was extensive myocyte necrosis, consistent with partially treated cardiac toxoplasmosis. Cardiac toxoplasmosis is an uncommon, but highly morbid posttransplantation infection most commonly seen in cardiac transplantations. The presentation of posttransplantation cardiac toxoplasmosis can include myocarditis, cardiomyopathy, brain abscess, pneumonia, empyema, or disseminated infection. The highest risk of transmission is between a seropositive donor and a seronegative recipient (50%–75%). Thus, some institutions perform toxoplasmosis testing on the donor and recipient prior to transplantation to determine the need for prophylaxis in the posttransplant period (Figure 92).
Initial Assessment for Blood by Urinalysis Improves Test Utilization for Myoglobinuria: (Poster No. 12)
Context: Positive results for blood by dipstick urinalysis may indicate myoglobinuria in patients with suspected rhabdomyolysis, especially in the absence of urine red blood cells. The aim of this study was to evaluate the reliability of urine blood testing for initial assessment and processing of specimens submitted for urine myoglobin measurements.
Design: Results were obtained from urine dipstick blood and quantitative myoglobin tests performed on the same day among 81 Veteran Affairs health care facilities from 2000 to 2014. Trace blood by urinalysis was interpreted as negative whereas any other amount was considered positive.
Results: Among 7579 cases evaluated, quantitative urine myoglobin levels were >100 μg/L in 1244 (16.4%) and >1000 μg/L in 540 (7.1%). Sensitivity of positive urine blood results at myoglobin levels of >100 μg/L and >1000 μg/L was 90.8% and 96.9% whereas specificity was 60.0% and 55.4% respectively. The positive predictive values for urine myoglobin concentrations of >100 μg/L and >1000 μg/L were 30.8% and 14.3%, whereas negative predictive values were 97.1% and 99.6%, respectively. Of 540 specimens with myoglobin values >1000 μg/L, only 17 (3.1%) tested negative for urine blood (Table).
Conclusions: This retrospective study shows that dipstick urinalysis for blood can exclude the presence of elevated urine myoglobin with high probability and provides evidence-based support for prerequisite evaluation prior to testing. Limiting urine myoglobin measurements to only specimens having positive urine blood results could substantially reduce unnecessary urine myoglobin testing and provide rapid diagnostic information about the likelihood of clinically significant myoglobinuria.
Short-Term Individual Variation of Troponin I Using the Biosite Triage Point of Care Assay Version 2.0: (Poster No. 16)
Context: The Alere Triage Troponin I point-of-care assay version 2.0 was released in 2012 to enhance the sensitivity of detection of myocardial infarction. It has a claimed 99th-percentile cutoff of 20 ng/ L with a CV <20% at this cutoff. This assay was implemented as an upgrade from version 1.0 in the clinical laboratory at 40 rural hospitals in the province of Alberta. We have identified sporadic discordant results between Triage and the Abbott I-Stat used as a point-of-care device in the ED at the same facilities. As well, we have received complaints from cardiologists about patients erroneously referred to major hospitals in the city of Edmonton because of “falsely elevated troponin I” using Triage.
Design: We sought to assess the short-term individual variation of this assay, a combination of preanalytical and analytical variation by data mining 3 years of retrospective troponin I patient results. We examined differences in repeat measurements requested by clinicians within 2 hours (n = 329 patients). The data were censored to values <150 ng/L, at which level the repeats were all positive.
Results: See Table.
Conclusions: Based on the discordant results observed in some patients, repeat testing for borderline elevated troponin I at 4–6 hours is warranted to ascertain positive results. Testing of patients with discordant results with a different device may help resolve these discrepancies.
Brunner Gland Adenoma—A Cytologic Diagnostic Challenge: (Poster No. 17)
Brunner gland adenomas are rare, constituting about 10% of benign duodenal tumors. They are usually smaller than 4 cm and asymptomatic. We report a case of a 64-year-old woman who presented with a chief complaint of abdominal pain and occasional melena. Imaging studies demonstrated a right upper quadrant large heterogenous mass inseparable from the distal stomach and duodenum. The clinical-radiographic impression suggested a gastrointestinal stromal tumor (GIST). An FNA cytology sample of the lesion revealed spindled smooth muscle cells and fibroblasts, rounded clusters of epithelioid cells with eccentrically placed nuclei, and gastrointestinal mucosa. A c-KIT immunostain was positive in few spindle cells and a diagnosis of GIST was favored. The patient was treated with imatinib for 3 months; however, the mass did not significantly change. She underwent surgical resection. The pathology specimen revealed a 6-cm submucosal mass. The mass consisted of Brunner gland proliferation, with no atypia, dysplasia, or admixed adipose tissue, consistent with Brunner gland adenoma (Brunneroma). In retrospect, the rounded clusters of epithelioid cells were numerous, and this confirmed to be the cytologic correlate to the Brunneroma. Brunner gland adenoma constitutes a diagnostic challenge. Pathologists should be aware of this unusual diagnosis, especially in cytology specimens. The abundant presence of epithelioid cells in rounded clusters with eccentrically placed nuclei should raise the possibility of this differential diagnosis. The focal presence of c-KIT staining in the benign spindle cells of the duodenum can become a pitfall and lead to an erroneous diagnosis of GIST. The histopathologic study confirms the definitive diagnosis (Figure 93).
Cytologic Diagnostic Aspects of Different Echinococcal Structures in Various Cytologic Preparations of Hydatidosis: (Poster No. 19)
Hydatidosis is a slow-growing disease caused by Echinococcus species, most commonly affecting the liver and lung. In this study we focused on detailed morphologic features of Echinococcus in various cytology preparations acquired by fine-needle aspiration, namely Papanicolaou and Romanowski (Diff-Quik) staining on liquid-based (ThinPrep), conventional smear, and cytospin slides and H&E cell block sections (Figure 94, A through D, respectively). Two patients presented to our institution with significant peripheral blood eosinophilia up to 19% (2.76 K/mm3); imaging studies showed similar 9-cm cysts in the liver. Aspiration of the cysts demonstrated yellow cloudy fluid, termed hydatid sand. Cytologic studies showed numerous parasite structures, including protoscoleces (arrowhead, Figure 94, A through C) and scoleces (thick arrow, Figure 94, A); degenerating forms contained multiple calcareous corpuscles (thin arrow, Figure 94, A), a feature commonly seen in cestodes. Unstained refractile hooklets (Figure 94, A through D) with a sharp, curved distal end and 2 proximal blunt projections were also present throughout the specimens. Partial acellular laminated cyst wall was noted only on cell block (Figure 94, D). Liquid-based cytology (Figure 94, A) removed the dirty background of hydatid sand and demonstrated the best preservation of parasite structures. This allowed for easier identification compared with Romanowski stain, which still contained abundant background debris (Figure 94, B). Our recommendations are that liquid-based preparations offer the best visualization of parasite components, and that cell block is useful for demonstration of the cell wall, thereby giving a complete cytopathologic picture of echinococcal disease.
Prostate-Specific Membrane Antigen Is a Useful Marker in Detecting Metastatic Prostatic Adenocarcinoma in Cytology Specimens: A Report of 2 Cases: (Poster No. 20)
Here we report 2 cases of metastatic prostatic adenocarcinoma in fine-needle aspiration cytology specimens. On direct smear slides, cytomorphology in one case resembles small cell carcinoma, in another case resembles lymphoid tissue. Immunocytochemistry studies on cell block slides in both cases were negative for prostate-specific antigen (PSA) and prostatic acid phosphatase (PRAP). Both cases had some degree of neuroendocrine differentiation with positivity of some of the neuroendocrine markers (Table). However, prostate-specific membrane antigen (PSMA) immunostain was positive in both cases, which confirmed the nature of metastatic prostatic adenocarcinoma, and avoided misdiagnosis. Neuroendocrine differentiation in prostatic adenocarcinoma can happen following hormonal treatment. Poorly differentiated metastatic prostatic carcinoma frequently loses the expression of normal tissue-specific markers such as PSA and PRAP. All these make diagnosis of metastatic prostatic adenocarcinoma challenging. PSMA, a prostate-specific marker, is upregulated in malignancy and along disease progression. Here we showed that PSMA is a useful marker in diagnosing metastatic prostatic adenocarcinoma when morphology and other immunoprofile are equivocal.
Diagnosis of Angiosarcoma on Fine-Needle Aspirates: Report of 2 Cases: (Poster No. 21)
Angiosarcomas are rare and aggressive malignant tumors that can be associated with prior therapy for malignancy or sequelae of treatment such as lymphedema. There is currently limited literature describing the primary cytologic diagnosis of angiosarcoma. We present 2 cases of postcancer treatment angiosarcoma diagnosed on fine-needle aspirates. The first case is a 57-year-old woman with history of mastectomy and radiation for right breast cancer, followed by 7 years of chronic lymphedema, who presented with an enlarging, red skin lesion on her right arm. The second case is a 49-year-old man with history of Hodgkin lymphoma treated with radiation 15 years prior who presented with an enlarging subcarinal mass suspected to be a recurrence. Cytologic evaluation in both cases demonstrated highly cellular and mostly discohesive cells with epithelioid features (Figure 95, A) and spindle cell morphology (Figure 95, B). The cells showed pleomorphic vesicular nuclei and prominent nucleoli. Mitoses, necrosis, and intracytoplasmic lumens were also observed (Figure 95, C). Diagnosis was supported by cell block positive immunostaining for CD31 (Figure 95, D) and negative staining for cytokeratin, desmin, and S-100. These cases contribute to the limited literature describing the primary diagnosis of angiosarcoma on fine-needle aspirates. Although rare, angiosarcoma should be considered when evaluating cytologic specimens from patients with history of treated malignancies. Cell block immunostains are helpful in distinguishing angiosarcoma from a differential diagnosis that includes sarcomatoid carcinoma, melanoma, and other sarcomas.
Utility of IMP3 Immunocytochemical Stain in the Characterization of Atypical Glandular Cells in Liquid-Based Cervical Cytology: (Poster No. 22)
Context: Atypical glandular cells (AGC) interpretation in gynecologic cytopathology presents many diagnostic challenges. We sought to determine whether insulin-like growth factor II mRNA-binding protein 3 (IMP3) may be used in liquid-based cervical cytology to differentiate between benign reactive and malignant glandular cells.
Design: Thirty-eight cases of AGC with documented histologic follow-up were reviewed. Immunocytochemical stain for IMP3 (monoclonal anti-IMP3, clone 69.1; DAKO) was performed on liquid-based cytology, evaluated in a blinded fashion by 2 pathologists, and correlated with subsequent biopsy findings.
Results: Ten of 38 cases (26%) of AGC exhibited IMP3 expression. Of these, on histologic follow-up, 3 of 3 were endocervical carcinoma in situ, 6 of 10 adenocarcinomas (4 of 4 endocervical adenocarcinomas and 2 of 3 papillary serous carcinomas), and 1 of 1 melanoma. Instead, 28 of 38 cases (74%) of AGC were IMP3 negative and included 0 of 3 endometrial adenocarcinomas, 0 of 1 papillary serous carcinoma, 0 of 1 low-grade squamous intraepithelial lesion, 0 of 6 high-grade squamous intraepithelial lesions, and 0 of 17 benign lesions (Table). The sensitivity of IMP3 in the diagnosis of malignancy was 71.9%, specificity 100%, positive predictive value 100%, and negative predictive value 72.7% (P = .001) Instead, the sensitivity of IMP3 in the diagnosis of adenocarcinoma was 69.2%, specificity 96%, positive predictive value 90%, and negative predictive value 85.7% (P = .002).
Conclusions: IMP3, when used in liquid-based cervical cytology to further characterize AGC, predicts the presence of a significant glandular lesion on subsequent histology with a high specificity (96%) and a positive predictive value of approximately 90%, and can be used as an aid to differentiate between benign reactive and malignant glandular cells.
Clear Cell Chondrosarcoma—A Rare Tumor, Even Rarer on Cytology Preparations: Case Report and Review of the Literature: (Poster No. 23)
Clear cell chondrosarcoma (CCC) is a rare variant of chondrosarcoma comprising 2% of all chondrosarcomas. It is characterized in most instances by indolent behavior with long interval to disease progression. The age range is 25–50 years and there is a male predominance (male to female, 3:1). The proximal ends of the humerus and femur are the 2 most common sites of CCC. We report a case of a 59-year-old woman with a history of marginal zone lymphoma of the thyroid, who presented with right hip pain. Magnetic resonance imaging of the right hip showed an abnormal signal within the greater trochanter. The patient subsequently underwent a fine-needle aspiration and a core biopsy of the right femur. Cytology slides revealed numerous atypical chondroid cells with vacuolated cytoplasm, eccentric nuclei, and prominent nucleoli (Figure 96, A). The core biopsy showed numerous fragments of bone, along with numerous areas of chondroid cells with enlarged nuclei, and prominent nucleoli, in a background of giant cells (Figure 96, B through D). These findings were consistent with the diagnosis of malignant cartilaginous tumor with features of CCC. Subsequently, the patient underwent surgical resection of the lesion, revealing a 5.0 × 4.0-cm, white, fleshy mass involving the greater trochanter. Histologically, the lesion consisted of sheets of large epithelioid cells with abundant clear cytoplasm, large round nuclei, and prominent nucleoli, admixed with osteoclast-like giant cells. These findings confirmed the diagnosis of CCC made on cytology preoperatively. Our case report adds to the limited existing literature on cytologic diagnosis of CCC.
Fine-Needle Aspiration Findings in a Case of Chondroid Syringoma: (Poster No. 24)
A 67-year-old woman presented with a superficial, painless, firm 1.0-cm nodule in her right axilla, of 1 year duration, at the site of a remote lipoma excision. Fine-needle aspiration of the nodule yielded abundant thick material. Diff-Quik–stained smears showed clusters of monomorphic cells embedded in abundant magenta-colored myxoid material (Figure 97, A). Individual cells appeared epithelioid, with a moderate amount of cytoplasm, round to ovoid nuclei, and inconspicuous nucleoli (Figure 97, B). These features were reminiscent of pleomorphic adenoma, possibly representing chondroid syringoma (CS). Upon excision, CS was confirmed (Figure 97, C), and extensive chondroid and bone formation was present within the lesion (Figure 97, D). There is no recurrence after 7 months. CS is a rare benign biphasic skin adnexal tumor reported among <1% of skin tumors, and is composed of eccrine and apocrine epithelium in a chondromyxoid ground substance. It usually presents in middle-aged males as a painless, slow-growing tumor in the head and neck. It is also called “benign mixed tumor of the skin” because of its morphologic resemblance to pleomorphic adenoma of salivary glands. There are only a few cases of CS in the cytology literature, as it is rarely encountered in fine-needle aspiration. in addition, only 6 cases of extensive ossification in CS have been reported, all located in the head. This case study demonstrates the cytologic features of CS and reveals some unusual clinical and histologic features, enhancing pathologists' ability to recognize this tumor on fine-needle aspiration and biopsy.
Primary Salivary Gland Type Tumor of the Lung Initially Presenting As a Hamartoma: (Poster No. 25)
Primary salivary gland–type tumors (SGTTs) of the lung are rare neoplasms that originate from submucosal glands of the tracheobronchial tree. We report a case of an 82-year-old woman with an incidentally found peripheral coin lesion in the right upper lobe of the lung. Clinical suspicion was for a hamartoma; however, the lesion appeared to be enlarging radiologically. Aspiration cytology showed bland spindle and epithelioid cells embedded within metachromatic fibrillary matrix with frayed edges (Figure 98, A). The cells in fibromyxoid clusters were positive for S100 and vimentin with a lowKi-67 proliferation index. The differential diagnosis included a hamartoma, benign mesenchymal tumor, metastatic gastrointestinal tumor, and an SGTT. Histopathology of the core biopsy showed bilayered tubular structures containing eosinophilic material within their lumens (Figure 98, B). Peripheral spindle cells were S100 positive (Figure 98, C), p63 positive and CKIT negative, and the epithelioid cells within the tubular structures were cytokeratin positive (Figure 98, D). These findings were diagnostic of a SGTT in the lung with epithelial and myoepithelial cells, and favored an epithelial-myoepithelial carcinoma. A subsequent lobectomy revealed a well-circumscribed lesion with 2 distinct growth patterns, including an epithelial-myoepithelial carcinoma and pleomorphic adenoma with lymphovascular invasion indicating carcinoma arising from pleomorphic adenoma. This case study emphasizes the importance of recognizing the cytomorphology and diagnostic pitfalls of rare SGTTs of the lung, and the importance of looking for atypical features (high cellularity, bilayered glandular structures, and lesional growth) in a fibromyxoid lesion in the lung.
Fine-Needle Aspiration Biopsy of Prostate Synovial Sarcoma: A Case Report and Review of the Literature: (Poster No. 26)
Synovial sarcomas of the genitourinary tract are exceedingly rare, with only 7 reported cases arising from the prostate. We report another case diagnosed by fluorescent in situ hybridization on fine-needle aspiration material. A 38-year-old man presented with back and lower abdominal pain. Computed tomography showed a complex, hypodense mass involving prostate, seminal vesicles, and rectum with mild infiltration. The smears and cell block showed dispersed and aggregated monotonous cells with oval nuclei, fine chromatin, inconspicuous nucleoli, and scant cytoplasm (Figure 99, A and B), immunoreactive for AE1:3, CAM5.2, vimentin, BCL2 (Figure 99, C) and focal CK7. CD99 was noncontributory. All other immunostains were negative. Fluorescent in situ hybridization revealed rearrangement of SYT in 80% of cells (Figure 99, D). Histologic, immunohistochemical, and cytogenetic studies on the surgical specimen reconfirmed diagnosis of monophasic synovial sarcoma. A review of reported cases showed a mean age of 43 years. Most frequent complaints were lower urinary tract symptoms. Prostate-specific antigen levels were normal or slightly elevated. Tumor size varied from 5.5 to 14 cm. Six of 7 cases and our case were monophasic type, and all showed SYT-SSX fusion. Five patients including ours showed no recurrence or metastasis on follow-up. Three patients died from disease 3 to 32 months after diagnosis; they were slightly younger with larger masses. In conclusion, synovial sarcoma should be considered in the differential diagnosis of particularly deep-seated small round blue cell or spindle cell lesions, and even limited cytology material may allow detection of distinct immunohistochemical and cytogenetic characteristics.
Metastatic Anal Basaloid (Cloacogenic) Squamous Cell Carcinoma Mimicking Small Cell Carcinoma on Liver Fine-Needle Aspiration: (Poster No. 27)
Fine-needle aspiration (FNA) is an essential tool in the diagnosis of liver masses. Most liver malignancies diagnosed by fine-needle aspiration are metastases. Adenocarcinoma is the most common type of metastatic tumor, accounting for more than 90% of cases. Metastatic small cell/neuroendocrine carcinomas are rare and metastatic squamous cell carcinomas (SCC) are even rarer. Tumors combining small cell and squamous morphology are exceedingly unusual and not thought of initially. We report a case of a 67-year-old man with recently diagnosed anal carcinoma who presented with a liver mass concerning for metastasis. FNA was cellular and showed tight clusters of small to intermediate-size tumor cells with high nuclear to cytoplasmic ratios, scant cytoplasm, hyperchromatic stippled nuclei, and nuclear molding seen on Diff-Quik (Figure 100, A) and Papanicolaou stain (Figure 100, B). There was no overt squamous differentiation or necrosis. An adenoid cystic-type pattern with abundant basement membrane–like material was noted focally on Diff-Quik (Figure 100, C) and on cell block (Figure 100, D). These features were most concerning for small cell carcinoma or a basaloid upper aerodigestive/salivary gland tumor. Immunohistochemistry for CD56, chromogranin, and synaptophysin was negative, whereas p63 and p40 showed strong staining. Based on cytomorphologic and immunohistochemical features, a diagnosis of metastatic basaloid (cloacogenic) SCC was made. Additional history and review of outside slides confirmed the anal primary as basaloid SCC. This case highlights the differential diagnosis of small cell lesions on liver FNA. Our case shows that basaloid (cloacogenic) SCC, rarely seen on liver FNA, can closely mimic small cell carcinoma.
Cytologic Features of Basaloid Squamous Cell Carcinoma of Uterine Cervix on Liquid-Based Papanicolaou Smear: (Poster No. 30)
Basaloid squamous cell carcinoma (BSCC) is a rare aggressive variant of squamous cell carcinoma with basaloid features. It's most common in the head and neck and rarely involves uterine cervix. BSCC of the uterine cervix is an underrecognized entity. Differential diagnosis includes adenoid cystic carcinoma, neuroendocrine carcinoma, and low-grade adenoid basal carcinoma. To the best of our knowledge, there is no reported cytology case of BSCC on liquid-based cytology in the literature. Here, we describe a case of BSCC with emphasis on the cytology, histology, and immunohistochemistry. An 83-year-old woman presented with postmenopausal bleeding. ThinPrep was prepared and cell block was made with the leftover material after reviewing the cytology. Subsequent cervical and endometrial biopsies were received. ThinPrep showed small to large clusters of basaloid cells with scant cytoplasm, high N:C ratio, and hyperchromatic nuclei. No visible nucleoli or significant nuclear molding was observed. Scant tumor diathesis was present. Cell block showed a basaloid tumor with some peripheral nuclear palisading. Tumor cells were positive for p16 and CK5/6. The subsequent biopsy showed a basaloid carcinoma with significant nuclear palisading, cords, trabecular architecture, prominent myxoid stroma, and focal areas of keratinization. Tumor cells were diffuse positive for p40 and p16. BSCC is a rare disease in uterine cervix, and its cytology resembles HSIL; thus, cytology diagnosis of BSCC may be very difficult. BSCC should be differentiated from few other mimics, and cell block tissue biopsy with immunohistochemistry is often needed to render the diagnosis (Figure 101).
Diagnosis of Respiratory Papillomatosis in Cytology Preparations: Case Report and Brief Review of the Literature: (Poster No. 31)
Recurrent respiratory papillomatosis (RRP), a chronic upper respiratory condition characterized by diffuse multiple recurring papillomas, is thought to result from human papillomavirus (HPV). A 24-year-old man presented with a lung nodule, cystic bronchiectasis, and multiple laryngeal nodules. Fine-needle aspiration including cell block preparation of the lung nodule was performed, revealing scattered groups and sheets of mildly atypical squamous cells with focal papillary configuration, in a background of acute inflammatory changes (Figure 102, A through C). Immunohistochemical analysis revealed that the cells were positive for P16, P53, and HPV (16 of 18; Figure 102, D) leading to the diagnosis of respiratory papillomatosis in cytology preparation. Surgical biopsy of the laryngeal nodules confirmed the diagnosis of respiratory papillomatosis. The lung and laryngeal nodules were excised, but the patient suffered multiple episodes of recurrence. The last recurrence showed a possible transformation to squamous cell carcinoma. Although RRP is an intractable disease, its malignant transformation is rare. A previous report described the clinical course of a patient who underwent more than 130 operations for RRP associated with HPV infection and subsequently suffered spontaneous malignant transformation to squamous cell carcinoma. The underlying mechanism of the malignant transformation has not been completely elucidated. It might result from a genomic defect, such as p53 inactivation, leading to stimulation of uncontrolled cell proliferation by HPV for an extended period, but not directly because of HPV itself. Our case indicates that RRP can be diagnosed in cytologic specimens and should be included in the differential diagnosis of lung nodules.
A Rare Infectious Agent Identified in a Routine Liquid-Based Papanicolaou Test: (Poster No. 32)
Infectious agents, contaminants, and artifacts can be seen in Papanicolaou (Pap) tests. Rare infectious agents that cannot be confirmed by concurrent microbial cultures pose a diagnostic dilemma of infection versus contaminant. A 66-year-old woman with arthritis, osteopenia, hyperlipidemia, and remote right knee arthroplasty presented for a routine health maintenance visit, which included a routine liquid-based Pap test. Her physical examination was unremarkable. Evaluation of her Pap test was negative for intraepithelial lesions or malignancy. However, in the background, many globoid eosinophilic structures with multiple buddings were noted. To characterize the globoid structures Gomori methenamine silver, lactophenol cotton blue, and calcofluor white stains were performed. All stains highlighted the globoid structures, which have several thin-necked, round buds of varying sizes that protrude from a parent cell resembling the “mariner's wheel,” morphology consistent with Paracoccidioides brasiliensis (Figure 103). Paracoccidioides brasiliensis is endemic to South America and is a chronic progressive granulomatous disease that usually presents as a primary pulmonary infection that can spread to the oral, nasal, and gastrointestinal mucosa. As in other reported cases, our patient's organism cleared spontaneously, and she had no significant travel history, no evidence of systemic disease, no obvious source of infection, and no confirmation with microbial culture. Morphologic features that favor colonization are lack of marked inflammatory background and no rimming of the organism by neutrophils. Once identified on Pap test, immediate resampling for culture and if feasible microbial molecular studies are recommended to clarify the role of this organism in the lower genital tract.
Parathyroid Pitfall: Cytology of an Incidental Enlarged Parathyroid Gland Mimicking a Neuroendocrine Tumor: (Poster No. 35)
Cytologic diagnosis relies heavily upon the appreciation of cytomorphology and immunohistochemistry (IHC) with minimal architectural context. Misinterpretation can occur when morphologic and IHC features overlap between entities. This problem is illustrated by our case of a 58-year-old female smoker with a history of renal cell carcinoma and recurrent pneumonia. Workup for pneumonia revealed a solid 1.3-cm lung nodule, and a 1.9-cm right paratracheal mass suspicious for metastatic disease. Endobronchial ultrasound-guided fine-needle aspiration of the paratracheal mass, submitted as “[Level] R2 lymph node,” returned mostly blood and a few atypical cells on immediate assessment. Cell block revealed clustered cells with organoid architecture and finely dispersed chromatin (Figure 104, A) that stained positively for CKAE1/3 (Figure 104, B), focally positive for synaptophysin (Figure 104, C) and diffusely positively for chromogranin (Figure 104, D), engendering a diagnosis of neuroendocrine tumor, favor carcinoid. A biopsy of the lung mass confirmed primary lung adenocarcinoma. Following pulmonary lobectomy, the presumed carcinoid tumor was removed. Histology revealed an enlarged, hypercellular parathyroid gland. No clinical evidence of hyperparathyroidism was documented. This case illustrates the important consideration of parathyroid tissue in the differential diagnosis for neck lesions/ masses. Of note, focal to weak staining for synaptophysin (Figure 104, C) is a commonly encountered phenotype of parathyroid tissue, whereas the majority of well-differentiated neuroendocrine tumors display diffuse synaptophysin reactivity—a helpful clue. Parathyroid hormone IHC can confirm parathyroid tissue and potentially prevent unnecessary medical intervention or overstaging of a malignancy. It is imperative to recognize the possibility for misdiagnosis among these entities with similar cytologic characteristics.
Utility of IMP3 Immunocytochemical Stain in the Diagnosis and Subtyping of Adenocarcinoma in Liquid-Based Cervical Cytology: (Poster No. 36)
Context: Previous histologic studies have demonstrated that insulin-like growth factor II mRNA-binding protein 3 (IMP3), may be used as a tool in the differential diagnosis of adenocarcinoma of the female genital tract. The aim of our study was to determine whether IMP3 may be used as an ancillary tool in liquid-based cervical cytology to differentiate among the different types of adenocarcinomas.
Design: Thirty-one adenocarcinomas with documented histologic follow-up were reviewed. On liquid-based cervical cytology 18 cases were diagnosed as adenocarcinoma, and 13 were originally interpreted as atypical glandular cells and on histologic follow-up as adenocarcinoma. Immunocytochemical stain for IMP3 was performed on liquid-based cytology slides.
Results: Twenty-two of 31 adenocarcinomas (70.9%) were IMP3 positive, including 8 of 9 invasive and in situ endocervical adenocarcinomas (89%), 9 of 11 papillary serous carcinomas (82%), 3 of 3 clear cell carcinomas (100%), and only 2 of 6 endometrioid adenocarcino-mas (33%). Two metastatic carcinomas (1 colon and 1 Paget disease of vulva) were negative (Table). The sensitivity of IMP3 in the diagnosis of adenocarcinoma was 75.8%, specificity 100%, positive predictive value 100%, and negative predictive value 22.2% (P = .07). The difference in expression of IMP3 between endocervical (89%) and endometrioid adenocarcinoma (33%) was statistically significant (P = .05), as was the difference in expression of IMP3 between papillary serous carcinoma and clear cell carcinoma (86%) versus endometrioid (33%) (P = .04).
Conclusions: IMP3 may be used in liquid-based cervical cytology in differentiating endocervical (89%) from endometrioid adenocarcinoma (33%; P = .05) and uterine papillary serous carcinoma and clear cell carcinoma (86%) from endometrioid adenocarcinoma (33%; P = .04).
Cerebrospinal Fluid Cytology of Primary Leptomeningeal Oligodendrogliomatosis: (Poster No. 37)
Primary leptomeningeal gliomatosis, also known as leptomeningeal oligodendrogliomatosis, refers to a rare neoplastic proliferation of glial cells, often with vacuolated-like oligodendrogliomas, limited to the leptomeninges. These lesions are also known as leptomeningeal neurogliomatosis as neuronal markers have been demonstrated by immunohistochemistry in these lesions. However, no cytologic description of the CSF in these patients is known to us. We are reporting here a case with cerebrospinal fluid involvement. The patient was a 6-year-old girl who was diagnosed at outside institutes with primary diffuse low-grade leptomeningeal glioneuronal neoplasm (leptomeningeal neurogliomatosis) 2 years ago. The patient underwent chemotherapy and presented later with progressive disease leading to obstructive hydrocephalus requiring ventriculoperitoneal shunt. Magnetic resonance demonstrated numerous disseminated small and smooth enhancing nodules along the leptomeninges (Figure 105, A). Biopsy by then showed a thickened fibrotic dura infiltrated by monotonous neoplastic clear cells reminiscent of oligodendrocytes with synaptophysin demonstrated in these cells (Figure 105, B). Neurofilaments like cytoplasmic processes but not neurosecretory granules were also demonstrated by electron microscopy. Cytology of her cerebrospinal fluid showed clusters of moderately sized atypical cells with high nuclear to cytoplasm ratio, clumped chromatin, prominent nucleoli, and variation in nuclear size (Figure 105, C). These cells were positive for Olig2, S100, and CD56 (Figure 105, C) but negative for glial fibrillary acidic protein, HMB-45, cytokeratin, CD163, and CD45. These findings were interpreted as persistence/recurrence of primary diffuse leptomeningeal neurogliomatosis. Cytologic examination of the cerebrospinal fluid should be part of the diagnostic and/or follow-up procedure of these patients.
Diagnostic Utility of Whole Slide Imaging for Nongynecologic Cytopathology: (Poster No. 38)
Context: The feasibility of whole slide imaging (WSI) compared with traditional light microscopy for primary diagnosis in cytopathology is unknown. The goal of this study was to investigate the use of WSI for cytologic diagnosis on nongynecologic cytopathology (NGC) specimens.
Design: Twenty-two de-identified, previously diagnosed NGC cases were scanned using the Leica SCN400 digital slide scanner. Cases included smears from neoplastic and nonneoplastic fine-needle aspiration (FNA) specimens and liquid-based preparations (LBP) from exfoliative samples (×40). Ancillary slides (cell block [CB] and immunohistochemical [IHC] stains) were scanned if available (×20). Three cytopathologists were blinded to the diagnosis and were provided with the specimen source and relevant clinical information. Cytopathologists rendered an initial diagnosis (negative, atypical, suspicious, positive) upon review of the scanned smears and LBP, and a final diagnosis after reviewing scanned ancillary slides. Concordance was based on agreement with the glass slide diagnosis.
Results: Cases included FNA from lung, pancreas, lymph node and liver and exfoliative cytology from ureter/pelvic washings and pancreas. Results are shown in the Table. Initial smear/LBP-based diagnoses revealed a mean concordance of 79% with moderate agreement amongst cytopathologists. Cases with ancillary studies showed greater interobserver agreement however did not significantly increase diagnostic concordance. A total of 14/66 disagreements were recorded (79% occurred on LBP, P = .007). Diagnostic concordance and interobserver agreement was greatest amongst lesional cases, smears, and cases with ancillary studies, and was poor for initial diagnosis on LBP and negative cases.
Conclusions: WSI appears feasible for diagnosis of NGC smears and cases with ancillary studies. WSI of LBP showed low concordance rates and poor interobserver agreement.
Cytology-Histology Correlation: A Key Element in Cytologic Diagnosis of Metastatic Lesions: (Poster No. 39)
Cytologic features of solid papillary breast carcinoma (SPBC) are not well described because it is a rare entity with infrequent metastasis and generally favorable prognosis. However, half of cases are associated with invasive carcinoma and metastasis can occur without axillary lymph node involvement. Up to 65% of SPBCs express neuroendocrine markers. Increased use of aspiration biopsy for metastatic lesions requires cytologic-histologic correlation, which becomes challenging when patient samples cross multiple health care systems. We describe a cytologic case of high-grade metastatic papillary breast carcinoma with lung metastases in a 50-year-old woman with history of stage mpT2N0Mx low-grade invasive ductal carcinoma, diagnosed 8 years prior at an outside institute. She presented in our hospital with mediastinal masses and pulmonary nodules. Endobronchial ultrasound biopsy yielded a hypercellular specimen, predominantly single cells with pink granular cytoplasm and intermediate round nuclei with unusual prominent nucleoli (Figure 106, A). They were positive for synaptophysin, chromogranin, ER, E-cadherin, and keratin, but negative for TTF1, GCDFP, mammaglobin, and Her2, yielding diagnosis of metastatic neuroendocrine carcinoma. The patient's original outside case was reviewed showing grade 3 invasive carcinoma in large nests (Figure 106, B) with papillary architecture significantly different from the original grade 1 invasive ductal carcinoma diagnosis. Once the correct histologic diagnosis was established, her cytologic diagnosis was compatible with metastatic breast carcinoma. This case emphasizes 2 practice points: (1) cytologic-histologic correlation is imperative; (2) recognizing and reporting SPBC with neuroendocrine differentiation is important, and may aid identifying metastatic lesions when reviewing original material is not possible.
Metastatic Ductal Carcinoma of the Breast to the Thyroid Gland Diagnosed With Fine-Needle Aspiration: A Case Report With Emphasis on Morphologic and Immunophenotypic Features: (Poster No. 45)
Metastases to the thyroid gland (TG) are uncommon, accounting for 0.16% of thyroid fine-needle aspirations. Breast carcinoma accounts for approximately 14% of metastases to the TG. The diagnosis of metastasis to the TG has important therapeutic and prognostic implications. To our knowledge, a morphologic comparison of metastatic ductal carcinoma of the breast and primary thyroid carcinomas has not been reported. Here, we report the case of a 37-year-old woman with a history of metastatic ductal carcinoma of the breast (modified Bloom-Richardson grade 2; ER+, PR+, HER-2/neu+) diagnosed 6 years prior. She developed hoarseness, prompting a computed tomography scan. Multiple TG nodules were found, including a 1.5-cm hypoechoic, solid, irregularly shaped nodule. A fine-needle aspiration was performed. Cells were arranged singly and in crowded groups, varied in size and degree of pleomorphism, and exhibited rare nuclear grooves, inconspicuous nucleoli, and rare intracytoplasmic lumens with no nuclear pseudoinclusions or colloid (Figure 107, A). These findings raised the differential of papillary thyroid carcinoma (Figure 107, B), follicular carcinoma (Figure 107, C), medullary carcinoma (Figure 107, D), and metastatic breast carcinoma. Immunostaining of our case for GATA-3 (+), ER (+), PAX-8 (–), and TTF-1 (–) was consistent with metastatic breast carcinoma. We conclude that metastatic breast carcinoma to the TG may morphologically mimic primary thyroid carcinoma on fine-needle aspiration; a panel of immunomarkers, such as GATA-3, hormonal marker(s), PAX-8, and TTF-1, may be useful in some cases. GATA-3 immunostaining for metastatic breast carcinoma was helpful in our case and has not been previously reported in a thyroid metastasis.
Fine-Needle Aspiration of Microcystic/Reticular Schwannoma in the Submandibular Gland: An Unusual Variant of a Common Entity: (Poster No. 49)
Microcystic/reticular schwannoma is a newly described morphologic variant of schwannoma that predominately occurs in the gastrointestinal tract. Its presence in the head and neck region and cytologic features have rarely been described in the literature. It is an unusual differential diagnostic consideration in salivary gland lesions. We present a case of a microcystic/reticular schwannoma arising in the salivary gland, biopsied by fine-needle aspiration, and describe cytologic features. A 34-year-old man presented with a slow-growing 2-cm mass in the left submandibular gland. Fine-needle aspiration was performed. Differential and ultrafast Papanicolaou-stained air-dried smears showed a moderately cellular aspirate of bland-appearing spindle cells forming long cords and surrounding tight balls of dense matrix that stained purple on differential stain, suggestive of a myxoid consistency (Figure 108, A). This matrix stained light blue on ultrafast Papanicolaou stain and did not demonstrate pale pink staining characteristic of mucin (Figure 108, B, and C). The nuclei were bland, oval and elongated, with indistinct cytoplasm, surrounding the myxoid globules (Figure 108, D). No mucin vacuole or necrosis was identified. A diagnosis of spindle cell lesion with myxoid material present, favor benign salivary gland neoplasm was rendered. On surgical resection, the lesion showed a microcystic/reticular pattern and showed positive reactivity for S-100 and CD34. The diagnostic considerations included mucoepidermoid carcinoma, pleomorphic adenoma, myoepithelioma, and adenoid cystic carcinoma. Distinguishing this benign entity from more common salivary gland carcinomas is important for conservative surgical treatment.
Solitary Mastocytoma: A Case of Mistaken Identity: (Poster No. 51)
The World Health Organization classifies mastocytosis into the following: cutaneous mastocytosis, indolent systemic mastocytosis, systemic mastocytosis with associated clonal hematologic non–mast cell lineage disease, aggressive systemic mastocytosis, mast cell leukemia, mast cell sarcoma, extracutaneous mastocytoma. Cutaneous mastocytoma is further subclassified into urticarial pigmentosa, diffuse cutaneous mastocytosis, and solitary mastocytoma of skin. In childhood, mastocytosis is usually cutaneous with a benign course, and the systemic forms are uncommon. Systemic disease with involvement of the gastrointestinal tract and bone marrow is more commonly encountered in adults. However, often cutaneous lesions are the first sign of systemic disease. We present a case of solitary mastocytoma in a 10-month-old boy. He was being evaluated for surgery because of extralobar pulmonary sequestration when a brown papule was noted on his right chest, which had been present since birth. The lesion was thought to be an accessory nipple and was removed for cosmetic purposes. The specimen was sent to pathology where the gross examination showed a slightly raised tan-red lesion measuring 0.2 × 0.2 cm. Microscopic examination revealed a nest of cells in the papillary and reticular dermis that looked very similar to a nevus but without maturation. On high power, the cells had abundant eosinophilic cytoplasm with central nucleus and scattered eosinophils (Figure 109). Immunostain for CD117 confirmed mast cells. In the pediatric population, the solitary mastocytoma usually resolves as time passes. Excision is curable. However, it is good to keep it in the differential of skin lesions in children, because it can be mistaken for another entity.
Parameatal Cyst: A Rare Congenital Disease: (Poster No. 55)
Parameatal urethral cysts are rare benign lesions that have male predilection. Approximately 50 cases have been published in the literature. The pathogenesis of these cysts is not clear yet; however, there are beliefs that parameatal urethral cysts occurred in the process of delamination or separation of the foreskin from the glans penis. The cysts are usually congenital with small size of about 1 cm. They usually present with urinary flow obstruction symptoms such as urinary retention, painful micturition, or splashing of urine during urination, although in asymptomatic cases it is an incidental finding. When the cysts are traumatized they may bleed, rupture, or become infected. The treatment of choice for such cysts is complete excision; however, needle aspiration has also been reported but recurrences are common with this method. Histologic examinations have shown that these cysts may have different types of epithelium, such as squamous, columnar, and transitional, depending on the segmental origin of the urethra. We report a 5-year-old boy who presented to the clinic with swelling of glans penis and splashing of urine during urination. On physical examination a cystic translucent parameatal mass measuring 1.1 cm in greatest dimension was identified. Elective surgical resection was done. Histology sections showed benign cyst with transitional epithelium lining consistent with parameatal cyst (Figure 110). Follow-up examination did not show any evidence of recurrence after 1 year.
Combined Melanocytic Nevus, Superficial Congenital, and Deep Penetrating Types With Fibroepithelioma of Pinkus, Collision Tumor: (Poster No. 56)
We present a case of collision tumor composed of a combined melanocytic nevus with superficial congenital and deep penetrating components and a fibroepithelioma of Pinkus on the left lumbar back of a 21-year-old man. He presented to the dermatologist for evaluation of numerous moles, and the lesion in question was described as a brown variegated papule with slightly irregular shape and irregular borders. Microscopic examination showed a proliferation of melanocytes with 2 separate cellular components, and an epithelial proliferation. The central part of the lesion showed melanocytes with abundant, pale cytoplasm and moderately enlarged nuclei, arranged as small nests, with many interposed melanophages and fibrotic stroma. Around and beneath these nests were cords and strands of small oval to round melanocytes that matured with descent from the junction. Above the melanocytic proliferation, a proliferation of anastomosing epithelial strands in a lacelike pattern was observed. A MART-1 stain highlighted the melanocytic proliferation and no pagetoid pattern was seen. A human melanoma black 45 (HMB-45) stain showed focal staining at the superficial part of the melanocytic proliferation; however, the deeper part did not stain. This case is being reported as the combination of fibroepithelioma of Pinkus, and congenital and deep penetrating nevus is rare and unusual (Figure 111).
Impact of Tissue Decalcification on Immunohistochemical Detection of Melanoma Markers: (Poster No. 57)
Context: We investigated the impact of decalcification on the detection of commonly used melanoma markers using melanoma cell lines.
Design: Three melanoma cell lines were obtained from American Type Culture Collection. Cell blocks were constructed from each cell line. A set of immunohistochemical markers (Table) were tested on each cell line. The cell pellets containing a mixture of the 3 cell lines were first fixed in 10% formalin for 8 hours and then decalcified in Decalcifier B for the durations indicated in the Table. A tissue microarray block containing these cell line cores with the different decalcification times was constructed. The aforementioned immuno-histochemical markers were applied to the tissue microarray sections. The staining intensity and percentage was recorded.
Results: The results are summarized in the Table.
Conclusions: These data demonstrate that tissue decalcification has a significant negative impact on SOX 10 detection and on S100, S100A6, HMB45, Mart-1, and MiTF detection after 60 minutes and 3 hours of decalcification, respectively.
Aluminum Chloride Tattoo With Cells Positive for Melanocytic Markers: A Potential Pitfall in Re-Excision Biopsies: (Poster No. 59)
Context: Topical aluminum chloride is commonly used as a hemostatic agent after performing shave biopsies. It often causes distinct microscopic findings: histiocytes with abundant aluminum-containing basophilic granules surrounded by a florid inflammatory response, stromal changes of a developing scar, and occasionally nuclear enlargement and mitoses. Because many re-excision specimens are from melanocytic lesions, these findings could be concerning for melanoma, especially for general surgical pathologists unfamiliar with the entity.
Design: Eight re-excisional biopsies from basal cell carcinoma (n = 2), squamous cell carcinoma in situ (n =3), nevus (n =2) and tumor of follicular infundibulum (n = 1) from patients treated with aluminum chloride were stained with Melan-A, MiTF-1, S-100, SOX-10, AE1/AE3, and CD68.
Results: None of the patients had a history of melanoma. All cases demonstrated histiocytes laden with coarse basophilic granules. Florid inflammation was noted in 6 cases (75%) and mitoses were seen in 6 (75%). All cases showed cells with granular cytoplasmic staining for Melan-A, which was weaker than that of the overlying epidermal melanocytes (Figure 112). Six of 8 biopsies (75%) showed scattered S-100 positive cells within the area of scar/inflammation. One case was focally positive for MiTF-1. These cells were also diffusely positive for CD68 and negative for cytokeratin AE1/AE3.
Conclusions: The immunostaining of histiocytes with Melan-A, and less commonly S-100 and/or MiTF-1, within an aluminum chloride could be a diagnostic pitfall, especially in cases of re-excision of melanocytic lesions. The characteristic presence of coarse basophilic cytoplasmic granules and the diffuse positive staining for CD68 are the most helpful features to avoid a misdiagnosis.
Cutaneous Apocrine Adenocarcinoma Presenting as an Axillary Abscess: (Poster No. 62)
We report the case of a 61-year-old woman with a right axillary mass and puslike discharge, which did not resolve despite incision and drainage and antibiotic treatment. Physical examination revealed an ovoid subcutaneous mass (5.0 cm in greatest dimension) with minimal warmth. Examination of the breasts was unremarkable. The mass was excised and the specimen consisted of a 4.0 × 3.0 × 2.5-cm tan, firm, ill-defined subcutaneous mass. Microscopically, the mass was composed of infiltrating well-differentiated glands with comedo-type necrosis. The malignant glands consisted of low columnar cells with abundant eosinophilic cytoplasm and large round to oval nuclei with prominent nucleoli. Immunohistochemical staining showed tumor cells positive for CK7 and CK5/6 and negative for ER, PR, TTF-1, CDX2, p40, p63, and CK20. PAS-positive diastase-resistant material was focally identified in tumor cells. These findings were consistent with cutaneous apocrine adenocarcinoma. Cutaneous apocrine adenocarcinoma is a rare and slow-growing malignant tumor of sweat glands with an annual incidence of <1/100 000. Most tumors are solitary and arise in the axilla of middle-aged women. The overall mortality is low with frequent recurrences and metastases to lymph nodes. There is no clear consensus on the management of this tumor because of its rarity. Histologically, metastatic extramammary or breast carcinoma and apocrine carcinoma arising in ectopic breast tissue in the axilla may mimic cutaneous apocrine adenocarcinoma. Immunohistochemical and clinical workup to exclude metastasis from other primary sites are therefore crucial in arriving at the correct diagnosis (Figure 113).
Disseminated Cutaneous Curvularia Infection in an Immunocompromised Host: Diagnostic Challenges and Our Experience With Voriconazole: (Poster No. 66)
An increasing spectrum of opportunistic fungal pathogens have been reported to cause disease in immunocompromised individuals during the past decade. Disseminated phaeohyphomycosis caused by Curvularia, a saprophytic dematiaceous mold, has a high mortality rate, and because of the low number of cases reported in the literature there is no consensus on treatment and duration of therapy. We report a case of a patient with acute myelogenous leukemia on fluconazole prophylaxis that developed neutropenic fevers and several distant skin nodules approximately 1 week after completion of her first dose of consolidation chemotherapy. Punch biopsy of the largest lesion on the ankle showed central ulceration of the epidermis with associated superficial dermal abscess formation. Within the abscess were fungal hyphae that were variable in size and morphology as highlighted by hematoxylin and eosin stain and Fontana-Masson stains (Figure 114). The variability in the histologic appearance of the hyphae, likely because of fluconazole effect, and the lack of growth in culture precluded a diagnosis based on morphology alone. Definitive diagnosis was made by polymerase chain reaction amplification and sequencing of mold RNA extracted from paraffin-embedded tissue. The patient was treated with 2 doses of IV voriconazole 6 mg/kg q 12 hours for 1 day, followed by 4 mg/kg IV q 12 hours for 3 days. She was transitioned to oral voriconazole 200 mg twice a day and her skin nodules regressed within a few weeks. Because of recurrent neutropenic fevers, treatment was extended for 21 weeks and no further fungal nodules developed at 24-week follow-up.
Extraordinary Case of Apocrine Carcinoma in a Vulvar Mass: Case Study and Review of the Literature: (Poster No. 67)
A 60-year-old woman presented to the clinic complaining of vaginal bleeding. On inspection, a vulvar ulcerated mass was found. The mass measured 3 cm. The patient did not have a prior history of malignancy. The clinical differential diagnosis was squamous cell carcinoma versus melanoma. A biopsy was taken and the lesion showed an ill-defined dermal lesion composed of nests of large, polygonal cells with abundant eosinophilic cytoplasm. The nuclei showed moderate pleomorphism with prominent central nucleoli. Increased mitotic activity with scattered areas of necrosis was evident. Immunohistochemical studies were performed and all the tumor cells showed membranous expression of CK7 while negative for P63. Given the cytologic atypia and stain pattern it was difficult to arrive unequivocally to the diagnosis of apocrine carcinoma. Primary vulvar adenocarcinomas are rare and are classified into Bartholin gland carcinoma, extramammary Paget disease, sweat gland carcinomas (eccrine and apocrine), and a rare form of adenocarcinoma arising from mammary-like glands. Apocrine adenocarcinoma is rare and most documented cases have affected the axilla; however, occasionally the tumor may present at a variety of other sites including the scalp, eyelid, and anogenital region. Apocrine carcinoma is often characterized by a prolonged course and, although recurrences and nodal metastases are common (like our case), the overall mortality is low. The presence of widespread metastases is associated with poor prognosis. Apocrine carcinoma of the vulva can arise from the native apocrine sweat glands, in which case the tumor is composed of adenopapillary cords and tubules (Figure 115).
Laryngeal Tuberculosis: A Report of Late and Atypical Clinical Presentation: (Poster No. 72)
A 38-year-old man who was a shepherd presented with sudden hoarseness of voice while he was singing. After then hoarseness continued and dry cough appeared gradually. Previous medical history was unremarkable. He neither smoked nor drank alcohol. He received antibiotic and common treatments for laryngitis, to which he did not respond well. Physical examination revealed a thin, healthy man with normal head and neck and no adenopathies. Blood investigation results were normal and HIV was negative. Video laryngoscopy revealed severe asymmetric edema of bilateral vocal folds with limitation of vocal cord movement (Figure 116, A). Chest x-ray and computed tomography of the thorax showed bilateral apical located fibrosis suggestive of pulmonary tuberculosis (Figure 116, B and C). Sputum analysis showed presence of acid-fast bacillus that was confirmed with culture (Figure 116, D). Laryngeal biopsy was not taken because of apical pulmonary tuberculosis involvement and positive smear. Standard antituberculosis treatment according to the directly observed treatment strategy started. He showed relative relief from symptoms in 3 weeks and complete relief in about 2 months. Sputum cultures became negative after a 3-month follow-up. After the end of 6 months of therapy, chest x-ray showed clearance of active lung lesions, and video-laryngoscopic examination revealed complete withdrawal of the edema in the vocal cords. Pure laryngeal tuberculosis has become quite rare and occurs in less than 1% of tuberculosis cases. Vocal folds are the commonest site of involvement, and hoarseness is the commonest symptom. But asymptomatic pulmonary tuberculosis growing to laryngeal involvement is quite rare and amazing.
A Thyroglossal Duct Cyst of the Superior Mediastinum With Concurrent Ectopic Parathyroid: (Poster No. 73)
Thyroglossal duct cyst (TGDC) is the most clinically significant congenital anomaly of the thyroid. TGDC commonly occurs in the midline of the neck between the foramen cecum and the thyroid, and frequently presents in childhood as a midline neck mass rarely larger than 2 to 3 cm. We report a case of a 76-year-old woman with a 5.3-cm TGDC of the superior mediastinum. The patient had a 24-year known history of a superior mediastinal cyst and she underwent 2 percutaneous aspirations over the years. Computed tomography scan confirmed the presence of a 5.3-cm, sausage-shaped, hypoattenuating cystic structure within the superior mediastinum. Transcervical excision revealed a thin-walled cyst with a smooth inner surface and tan-brown viscous cyst contents. The histologic sections showed that the cyst wall was lined by nonkeratinizing squamous epithelium with thyroid follicles and lymphocytic infiltrates noted within the cyst wall (Figure 117, A). The thyroid origin of the epithelia was supported by the strong nuclear expression of TTF-1. It is interesting that hypercellular parathyroid tissue was incidentally identified in the attached soft tissue (Figure 117, B). There was no evidence of hypocalcemia during follow-up. To the best of our knowledge, this is the third report of TGDC in the mediastinum in the literature. This case is particularly unusual in that it concurs with ectopic parathyroid tissue, it increases the latest known age of presentation, and it is up to 5.3 cm in size. Although exceedingly rare, TGDC should be considered in the differential diagnosis of a mediastinal cystic mass.
Pediatric Intraoral Squamous Cell Carcinoma: (Poster No. 74)
In pediatric patients, squamous cell carcinoma is rare, constituting less than 4% of cases of all oral cancers, with sarcomas being far more common. Pediatric squamous cell carcinoma is etiologically distinct, aggressive, and associated with a poorer prognosis than in the adult population. We present 2 cases of primary mandibular squamous cell carcinoma. A 10-year-old boy presented with a 2-cm red sessile lesion of the left mandibular alveolus. The biopsy showed subepithelial islands of atypical keratinizing squamous epithelium with prominent keratin pearl formation (Figure 118, A). Intravascular invasion was readily identified (Figure 118, B). The second patient, a 7-year-old girl, presented with a 1-cm swelling of the right mandible. Histopathologically, the lesion showed an atypical squamous epithelial proliferation (Figure 118, C), individual cell keratinization (Figure 118, D) and abundant keratin debris, consistent with well-differentiated squamous cell carcinoma. Neither of our patients had a history of genetic syndromes or previous radiotherapy. In the pediatric population, the tongue and the maxillary gingiva are the most common sites of oral squamous cell carcinoma, whereas our cases involved the mandibular gingiva. Typical etiologic factors like tobacco smoking and alcohol abuse would rarely be seen in children. Delay in diagnosis because of lack of biopsy is cited as one factor for the poorer outcome. In conclusion, timely biopsy will help in early diagnosis and, although rarely, squamous cell carcinoma could be included in the differential diagnosis of some oral lesions in the pediatric population.
Melanotic Neuroectodermal Tumor of Infancy: A Case Report of a Rare Rapidly Growing Lesion: (Poster No. 75)
Melanotic neuroectodermal tumor of infancy is a rare fast-growing tumor of neural crest origin composed of primitive pigment-producing cells and is most commonly seen to arise from the head and neck region. Although it is a relatively benign tumor, it can recur, but rarely metastasizes. We report a case of a 3-month-old, full-term healthy male infant with right cheek and palate swelling. Magnetic resonance imaging demonstrated a 3.8-cm osteolytic enhancing mass involving the maxillary bone and sinus. Surgical excision of the mass was performed and microscopic examination revealed a biphasic population of epithelioid melanin-containing cells and small neuroblastic cells. The large epithelioid cells were positive for AE1/AE3, HMB-45, and CD99 and weak for CD56 immunostains. The smaller cells were positive for synaptophysin immunostain. Vimentin and CD56 positivity were present in both populations. Immunostains for chromogranin-A, S-100, myogenin, SOX-10, TTF-1, NF, and GFAP were negative excluding other differential diagnoses. Ki-67 staining was present in 10%–20% of tumor and stromal cells. Electron microscopy confirmed the presence of 2 different cell populations with the small neuroblastic cells with microtubules and neurosecretory granules and the large epithelioid cells containing numerous cytoplasmic melanosomes. The histologic features were consistent with malignant behavior; however after re-excision with negative margins, there has been no tumor recurrence. The infant subsequently had postoperative complications and is under surveillance for future relapse. The biological behavior of melanotic neuroectodermal tumor of infancy cannot be predicted by gross or histologic characteristics, thus early diagnosis and careful follow-up after the complete surgical excision are required (Figure 119).
Cryptococcal Laryngitis in an Immunocompetent Adult Patient Masquerading as Laryngeal Papillomatosis: (Poster No. 77)
Recurrent laryngeal papillomatosis is a rare condition mainly affecting the pediatric population and is usually associated with low-risk HPV subtypes 6/11. We report a case of a 44-year-old woman who presented to the otolaryngology clinic with hoarseness and dry cough of 2 years' duration. Her past medical history was significant for asthma controlled with inhaled fluticasone/salmeterol and oral montelukast sodium. Laryngoscopy revealed diffuse papillomatous growth involving all laryngeal regions and computed tomography scan showed diffuse thickening of laryngeal mucosa with no lung/mediastinal abnormalities. Subsequently, she underwent videostroboscopy showing multiple papillomatous lesions in the supraglottic, glottic, and infraglottic regions. Histologic examination of the resected lesions revealed ulcerated papillomatous squamous proliferation with focal dyskeratosis and underlying inflamed granulation tissue (Figure 120, A). Within the ulcer bed, rounded yeast forms surrounded by a thick halo were noted (Figure 120, B). GMS stain confirmed the presence of round budding yeasts, ranging in diameter from 4 to 12 μm (Figure 120, C) and a mucin stain highlighted the surrounding capsule (Figure 120, D). Overall, the findings were compatible with laryngeal infection by Cryptococcus neoformans and this was further confirmed by a positive sputum culture. Human papillomavirus in situ hybridization for both low- and high-risk subtypes was negative. The patient is currently under treatment with fluconazole, resulting in drastic symptomatic relief. The correct diagnosis of this rare condition is crucial for optimal outcome with conservative management without unnecessary surgical intervention.
IgG4-Associated Sialadenitis: (Poster No. 79)
IgG4-related disease (IgG4-RD) is a newly recognized multiorgan disorder characterized by tumorlike swelling of involved organs, lymphoplasmacytic infiltrate enriched in IgG4-positive plasma cells, “storiform” fibrosis, and elevated serum IgG4 in the majority of cases. Although salivary gland involvement is a common feature, the changes can be subtle compared with other organs. A significant percentage of cases involving salivary glands previously classified as Mikulicz disease and Küttner tumor are now considered to be a spectrum of IgG4-RD. A 49-year-old man with history of right submandibular gland excision that was consistent with chronic sclerosing sialadenitis presented with enlarging left submandibular gland, bilateral lacrimal glands and left retro-orbital mass. The excised submandibular gland (12 g, 4.0 × 3.5 × 1.5 cm) was enlarged with firm yellow-tan appearance and vague nodularity on the cut surface. The lobular architecture was preserved. There was moderate lymphoplasmacytic inflammation, follicular hyperplasia, and interlobular fibrosis (Figure 121, A). Multiple foci of obliterative phlebitis were noted and confirmed by elastic stain (Figure 121, B). There was a predominance of IgG4-positive plasma cells (>100/HPF) with an IgG4:IgG ratio of >0.5 (Figure 121, C and D). The clinical presentation and histomorphologic features were consistent with IgG4-associated chronic sialadenitis. Recognizing IgG4-RD is extremely important as it may affect several organs and cause significant dysfunction from uncontrolled and progressive inflammatory and fibrotic changes. In salivary gland the characteristic features of IgG4-RD like storiform fibrosis may not be seen. Careful evaluation of the subtle morphologic features should be performed in cases of chronic sialadenitis to exclude IgG4-RD.
Cardiac Metastasis From Squamous Cell Carcinoma of the Base of the Tongue Presenting With Chest Pain: (Poster No. 80)
The most common sites for squamous cell carcinoma of the base of the tongue to metastasize are lymph nodes followed by lung. Cardiac metastases are rare and more commonly associated with leukemia, lymphoma, melanoma, and lung and breast carcinomas. This is a case of a 49-year-old African American man with a history of squamous cell carcinoma of the base of the tongue diagnosed by needle biopsy of a right submandibular lymph node. Staging workup via whole-body positron emission tomography scan revealed extension into the right oropharyngeal wall and bilateral cervical lymph node involvement. He was classified as pT3N2cM0, stage IVA, and completed a definitive course of concurrent chemoradiation. A 3-month follow-up positron emission tomography scan showed significant reduction in tumor volume within the head and neck. Focal, nonspecific FDG activity was also seen in the right ventricle, which was reported with a radiologic differential: focal infarction, sarcoidosis, or other lesions could not be excluded. Approximately 3 months later, the patient presented to the emergency department complaining of shortness of breath and chest pain. Computed tomography of the chest showed a 7.2 × 3.8-cm heterogeneous mass extending from the right ventricle through the pericardium (Figure 122, A). A biopsy confirmed the mass to be strongly positive for CK5/6 and p63, consistent with poorly differentiated metastatic squamous cell carcinoma (Figure 122, B through D). This case illustrates a rare presentation of cardiac metastasis from squamous cell carcinoma of the base of the tongue and provides an impetus for discussing the clinical utility of radiologic surveillance.
High-Grade Basal Cell Adenocarcinoma of Salivary Gland—A Real Entity or a Solid Variant of Adenoid Cystic Carcinoma? A Case Report and Literature Review: (Poster No. 81)
Basal cell adenocarcinoma (BCAC) is a rare malignant tumor of the salivary gland that is a low-grade malignancy. High-grade BCAC has not been reported, or established as a clinical entity and should be distinguished from solid variant of adenoid cystic carcinoma. We present a case of maxillary tumor in a 56-year-old white man. Microscopically, the tumor demonstrates a predominantly solid growth pattern with jigsaw puzzle–like islands or lobular configuration, peripheral palisading, brisk mitosis, and no perineural invasion. Immunostains show that the tumor cells are strongly positive for CK5/6, c-kit, S-100, and β-catenin (cytoplasmic) with high Ki-67 index (>50%), and negative or peripherally variable for SMA, p63, and calponin. There are some overlapping features among adenoid cystic carcinoma, solid variant, and BCAC on morphology, immunohistochemistry, and even cytogenetics. Diagnosis is mainly based on morphology because immunohistochemistry has not established its definitive role. The distinct histologic features (jigsaw puzzle–like islands, lobular configuration, and peripheral palisading) of our case support BCAC, but the nuclear features and high mitoses highlight a high-grade tumor. The immunohistochemistry displays a mixed pattern with positive CK5/6 and largely negative SMA, p63, and calponin supporting BCAC, but positive c-Kit, S100, and nonnuclear β-catenin staining favoring adenoid cystic carcinoma. Although BCAC and solid variant of adenoid cystic carcinoma share morphologic and immunohistochemistry features, our case favors a high-grade BCAC. Hence, we recommend putting forth a new entity of high-grade BCAC, although more clinical evidence is required from a large cohort of case studies (Figure 123).
Microcystic/Reticular Schwannoma Arising in a Major Salivary Gland: A Potential Diagnostic Pitfall: (Poster No. 83)
Microcystic/reticular schwannoma is a recently described variant of schwannoma with a predilection for the gastrointestinal tract that rarely involves the head/neck region. We present a rare case in a 34-year-old man with a slow-growing 4.5-cm submandibular mass during a 6-month period. Fine-needle aspiration suggested a spindle cell lesion. Frozen section evaluation raised the possibility of mucoepidermoid carcinoma. Resection showed a well-circumscribed, unencapsulated mass with a mucoid and fleshy appearance. Histologic findings included a lobular architecture surrounded by fibrous septa with lymphoplasmacytic infiltrate and scattered lymphoid aggregates at the periphery (Figure 124, A). There were 2 distinct histologic patterns with solid areas of spindle cells (Figure 124, B) with focal nuclear palisading, and areas of spindle/ovoid cells with a microcystic pattern in a myxoid background (Figure 124, C). The tumor had a pushing border, with focal extension into adipose and adjacent parenchyma, without cytologic atypia or necrosis. Immunohistochemical stains to classify this as a salivary neoplasm showed positive staining for S-100 (Figure 124, D) and CD34 and negative reactivity for calponin, mammaglobin, ALK-1, p63, ER, GFAP, desmin, c-kit, and CK-7. Mucicarmine stain was negative. Based on the immunohistochemical stains, primary salivary gland neoplasms such as adenoid cystic carcinoma, myoepitheliomas, and mucoepidermoid carcinomas were excluded. Recognition of this unusual variant of schwannoma, which rarely occurs in a salivary gland, is paramount for appropriate conservative treatment because of the morphologic and immunohistochemical stain overlap with primary salivary gland neoplasms.
Large Infiltrating (Intramuscular) Angiolipoma Mimicking Thyroid Malignancy: Report of a Unique Case: (Poster No. 85)
Angiolipoma exists in 2 forms, circumscribed and diffuse. It is primarily the circumscribed form that is commonly seen in the trunk and the extremities. Infiltrating (intramuscular) angiolipoma (IAL) is a rare lesion characterized by a prominent vascular component infiltrating the surrounding structures, particularly skeletal muscle. IAL is very uncommon in the head and neck region. Hereby, we present an extremely rare case of IAL that was suspected to be a thyroid mass based on the physical and imaging findings. A 41-year-old man presented with increasing left neck swelling for 5–6 months. A nontender mass was palpated at the anterior left upper neck. Computer tomography demonstrated a mass overlying the left thyroid lobe and ultrasound localized the large heterogeneous nodule with vascularity within the thyroid. Repeated fine-needle aspirations to rule out a thyroid neoplasm were nondiagnostic. These findings led to a left hemithyroidectomy with excision of the mass. During surgery, the mass appeared anterior to and separate from the thyroid although it was connected to the thyroid and the surrounding musculature by significant scar tissue. Grossly, the mass showed tan-pink, solid, vaguely lobulated surfaces (Figure 125, A). Microscopically, mature lipocytes and proliferating numerous small blood vessels, some containing microthrombi, were seen infiltrating the skeletal muscle (Figure 125, B). Architectural complexity or cellular atypia was not present. No pathologic changes were identified within the separately submitted thyroid lobe. This case broadens the differential of anterior neck lesions by presenting an extremely rare case of IAL mimicking thyroid malignancy.
Intraoral Epithelioid Sarcoma–Like (Pseudomyogenic) Hemangioendothelioma: (Poster No. 86)
Epithelioid sarcoma–like (pseudomyogenic) hemangioendothelioma is a rare vascular tumor of the skin of distal extremities. Histopathologically, it is misdiagnosed as an epithelioid sarcoma. We document one such lesion in a 21-year-old woman who presented with a 2-year history of a slowly enlarging “red, puffy, spongy” growth of the gingiva. Clinically, the mass measuring 14 × 10 × 10 mm was diagnosed as a pyogenic granuloma. Histopathologic examination of the excised specimen revealed subepithelial sheets of short spindle to epithelioid cells arranged in irregular loosely cohesive fascicles. The slightly plump cells had an intensely eosinophilic cytoplasm but cytoplasmic boundaries were indistinct (Figure 126, A). Scattered rhabdomyoblast-like cells and a stromal neutrophilic infiltrate were also noted (Figure 126, B). The tumor expressed minimal cytologic atypia and mitotic activity. No vessel formation or intracytoplasmic vacuoles were seen. The tumor cells were positive for cytokeratins AE1 and AE3 (Figure 126, C). The cells expressed membranous CD31 reactivity (Figure 126, D) but were nonreactive to CD34 and desmin. Despite the tumor's indolent behavior, regional soft tissue invasion and multicentric disease is common over the skin. Aggressive initial surgical treatment and prolonged follow-up is recommended. This is the first report of an intraoral mucosal lesion.
Pleomorphic Rhabdomyosarcoma of the Neck: A Rare Initial Presentation of Lynch Syndrome in a 33-Year-Old Man: (Poster No. 87)
Lynch syndrome (LS) is a hereditary cancer predisposition syndrome caused by mutations in DNA mismatch repair proteins. Early identification is important for tailored screening for primary and synchronous tumors. Colorectal malignancies are common primary manifestations of LS with comparable or better outcome than sporadic colon cancers. We present a 33-year-old man with a family history of LS, MLH-1 gene c.1855delG mutation, and rapidly growing neck mass during a 4-month period. Magnetic resonance imaging demonstrated a 7-cm lesion at right sternocleidomastoid muscle. A core biopsy and subsequent resection showed pleomorphic rhabdomyosarcoma (Figure 127, A and B) and lymph node metastases. Preoperative evaluation identified multiple colonic masses. The resected colon showed 2 synchronous morphologically distinct colonic adenocarcinomas with medullary (Figure 127, C) and mucinous differentiation (Figure 127, D) in the right colon without lymph node involvement (pT2N0). Immunohistochemistry for mismatch repair proteins showed different expression pattern in the rhabdomyosarcoma and colon carcinomas. Loss of MSH6 in addition to MLH1 and PMS2 was seen in rhabdomyosarcoma. The patient was started on a pediatric protocol for adjuvant chemotherapy and radiation. Within the next year, he developed biopsy-confirmed metastases of rhabdomyosarcoma in the lung, brain, and duodenum. Imaging identified innumerable metastases in the liver, adrenal, and kidney. He ultimately succumbed to his illness within a year of initial diagnosis. Recognition of the association of infrequent LS-associated tumors should prompt screening for detection and treatment of synchronous tumors in LS patients. Special attention is imperative because these unusual tumors have the potential for a more aggressive clinical course.
Congenital Salivary Gland (Anlage) Tumor: Report of a Unique Tumor With Intracranial Extension and Review of the Literature: (Poster No. 90)
Congenital Salivary Gland (Anlage) Tumor (CSGT) is a rare cause of nasal airway obstruction in neonates. We encountered one case with cribriform plate erosion, intracranial extension, and meningitis as clinical presentation. Our case involves a 3-week-old female infant who presented with bacterial meningitis and nasal obstruction. Computed tomography and magnetic resonance imaging studies revealed a 3-cm intranasal mass extending into the left ethmoid sinus with septal deviation and extension through the cribriform plate into the intracranial cavity (Figure 128, A and B). The tumor was resected through a frontal craniotomy with nasal orbital osteotomy. Histologic examination revealed features of CSGT including solid and cystic cords and nests of benign squamous epithelium, irregular ductlike structures lined by benign columnar to cuboidal epithelium, and benign stromal nodules of densely packed spindle cells. There was mild cellular atypia, 1–2 mitoses/HPF, and no necrosis (Figure 128, C and D). Immunohistochemistry showed negative immunoreactivity for S100, desmin, myogenin, chromogranin, and synaptophysin. Literature review yielded 31 case reports of CSGT, and one previous case at our institution, in which presenting symptoms included respiratory distress in first days/ weeks of life. Tumors were attached to nasopharynx by thin fibrovascular pedicle. In all cases, microscopy revealed benign features similar to our case. To the best of our knowledge, this is the first reported case mimicking an aggressive neoplasm with erosion of cribriform plate, intracranial extension, and presentation as bacterial meningitis. CSGT is a rare benign condition that should be considered in the differential diagnosis of respiratory distress in neonates, and complete surgical excision is curative.
Aberrant Expression of CDX-2 and Thyroid Transcription Factor 1 in Undifferentiated Oropharyngeal Carcinoma: (Poster No. 91)
Context: Undifferentiated oropharyngeal carcinomas (UOPCs) are rare and most are human papillomavirus (HPV)–related. Morphologically, UOPCs overlap with undifferentiated carcinomas from other organ sites, including the nasopharynx, lung, and gastrointestinal tract. Most have lymph node metastases at presentation and, when initially encountered in a lymph node, immunostains may be performed to determine the most likely primary site. We recently reviewed a UOPC in consultation that strongly and diffusely expressed both thyroid transcription factor 1 (TTF-1) and CDX-2, 2 markers that are considered relatively lineage specific for lung/thyroid and intestinal differentiation, respectively. Unexpected expression of these markers could be misleading. However, they have not been previously assessed in UOPCs.
Design: Immunohistochemistry for CDX-2 and TTF-1 was performed on primary tumors and/or lymph node metastases from 11 patients with previously characterized UOPCs from 1992 to 2008.
Results: Most patients were men, with an average age of 57, and 5 (45.5%) initially presented with a neck mass. All were Epstein-Barr virus negative and 10 (90.9%) were p16 positive. Immunohistochemistry results are summarized in the Table. CDX-2 was positive in 6 of 11 cases (55%). However, staining was generally weak to moderate and/or nondiffuse. TTF-1 was negative in all cases. Staining was recorded by extent (in quartiles) and intensity (w =weak, m =moderate, s =strong).
Conclusions: CDX-2 immunoreactivity is common in UOPC, whereas TTF-1 expression is rare. An aberrant immunophenotype could cause diagnostic confusion, especially in a tumor presenting as an unknown primary in the neck. One should be cautious interpreting CDX-2 in undifferentiated carcinomas, particularly when staining is not strong and diffuse.
A Rare Case of Parathyroid Carcinoma: (Poster No. 94)
Parathyroid carcinoma is a rare neoplasm. The reported incidence is from 0.5% to 5% of primary hyperparathyroidism cases. It occurs in men and women in the third to fourth decade. Patients usually present with severe symptoms of hypercalcemia and mostly succumb to complications of relentless hypercalcemia rather than tumor invasion and spread. A rare case of parathyroid carcinoma is presented. A 36-year-old man presented with multiple lucent bone lesions, solid left neck mass, elevated calcium 17.3 mg/dL (normal 8.6–10.0 mg/dL), elevated parathyroid hormone (PTH) 2500 pg/mL (normal range 16–65 pg/mL) and elevated creatinine. Core needle biopsy of the rib lesion revealed osteoclast-like giant cells, fibroblastic stroma and hemosiderin deposition consistent with brown tumor (Figure 129, A). Resection of the neck mass revealed a well circumscribed tan/pink soft mass (4.5 × 4.5 × 3.5 cm) with hemorrhagic and cystic areas filled with necrotic debris (Figure 129, B). Histologically the tumor was composed of large bands of fibrosis, nests and trabeculae of cohesive cells with moderate nuclear pleomorphism and large nucleoli, foci of necrosis and prominent mitotic activity (Ki67 >20%) with atypical mitoses (Figure 129, C). The tumor invaded the capsule, but no definite vascular or perineural invasion was seen. The tumor was positive for CKAE1/3 and chromogranin. One out of 29 lymph nodes was positive for metastatic carcinoma (Figure 129, D). Overall morphologic features, tumor behavior, and clinical presentation were consistent with parathyroid carcinoma. Pathologic diagnosis of parathyroid carcinoma can be difficult as the microscopic appearance of parathyroid carcinoma can be similar to adenoma and high clinical suspicion is needed to diagnose these cases initially.
Keratocystic Odontogenic Tumor Transforms Into Orthokeratinized Odontogenic Cyst at Recurrence: (Poster No. 96)
The keratocystic odontogenic tumor (KCOT) is a benign but locally aggressive cystic neoplasm with a recurrence rate up to 40%. It may be associated with Gorlin syndrome. Aggressive management with a peripheral ostectomy or injection of intraluminal chemical cautery results in lesser recurrences. Unlike the KCOT, the orthokeratinized odontogenic cyst (OOC) is an uncommon lesion of the jaws. It is distinct from the KCOT with a low recurrence rate. It is managed by enucleation or curettage. We report an unusual case of KCOT that transformed into an OOC upon recurrence. A 61-year-old man presented with a cystic lesion of the mandible from tooth 31 to the sigmoid notch. Histopathologic examination revealed a typical KCOT with a uniform stratified squamous epithelium. The epithelial surface was parakeratinized and corrugated. The basal layer of tall columnar cells with a polarized nucleus showed a palisaded appearance. This histopathology was consistent with a KCOT. The cyst was managed by aggressive curettage. It recurred 3 years later. At this time, the phenotype was consistent with a diagnosis of an OOC. The lining epithelium was stratified squamous with a thick layer of orthokeratin and a prominent granular cell layer. There was no evidence of tall columnar basilar cells or nuclear palisading. Such a transformation of a KCOT to an OOC has not been previously recorded and it suggests a potential temporal relationship between KCOT and OOC. Future studies need to characterize these clinicopathologically distinct entities by immunohistochemistry and molecular analysis to demonstrate their relationship, if any (Figure 130).
Maxillary Antrolith: A Rare Sequela of Chronic Sinusitis: (Poster No. 98)
Developing out of a nidus within the maxillary antrum, these rare stones can be a diagnostic challenge. Herein we describe the case of a 71-year-old man with a history of frontal bone osteomyelitis (Potts Puffy tumor) who presented with alcohol intoxication and a purulent draining forehead lesion. Radiologic imaging demonstrated chronic maxillary sinusitis and a large, ill-defined, calcified mass within the left maxillary antrum. Endoscopic exploration discovered a stone measuring 2.0 × 2.0 × 1.8 cm and a large soft tissue mass later determined to be a benign nasal polyp on histologic examination. The patient was placed on broad-spectrum antibiotics and made a full recovery. Maxillary antroliths are diagnoses of exclusion with broad differentials including benign and malignant bony neoplasms, calcified fungal balls of Aspergillus fumigatus, supernumerary teeth, buccal exostosis, torus palatinus, and even foreign bodies. Most are clinically asymptomatic but some cause pain, epistaxis, malodorous drainage, or recurrent sinusitis. Typically, antroliths begin as foreign particles, and when combined with mucociliary dyskinesis can accumulate concentric layers of calcium-based salts leading to stone formation. Chronic sinusitis with maladaptive drainage may provide these stones the opportunity to reach substantial sizes and become clinically apparent. Despite its rarity, it is important to keep maxillary antroliths in the differential diagnosis for any radiopacity in the paranasal sinuses, as well as to exclude an underlying cause such as neoplasia or infection (Figure 131).
Utility of Open-Source Macro Software for Real-Time Prevention of Typographic Errors: (Poster No. 99)
Context: Typographical errors (TEs) in pathology reports, although easy to commit, may just as easily be missed upon proofreading. TEs in reports can be embarrassing and may imply a lack of professionalism to clinicians. Although some workflows integrate built-in proofreading tools (eg, dictation-based systems, spell-checkers in word processors, etc) to limit TEs, some information systems have no such built-in capability, leaving the pathologist to make manual corrections prior to sign-out.
Design: AutoHotKey (AHK; version 1.1.21.02, Chris Mallett, AHK Foundation, Charlestown, Indiana), a free open-source macro utility, was deployed to minimize TEs. Lists of common TEs were copied to an AHK script file. Instructions were created in the script file to automatically replace TEs with corrected words as users committed TEs. The numbers of TEs in accessioning, grossing, and final diagnosis entry before and after AHK implementation were recorded using simple keystroke-tracking software, created with Python (version 3.4.3, Python Software Foundation, Beaverton, Oregon).
Results: Results are summarized in the Table. During an 8-month testing period, TEs in accessioning and clinical history entry were reduced by 77.4%. TEs during grossing were reduced by 52.9%. Although TEs in final diagnosis lines were essentially nonexistent before AHK deployment, pathologists appreciated the real-time correction that AHK provided, which reduced the time needed to retroactively check for TEs before releasing pathology reports.
Conclusions: For laboratories running information systems without built-in dictation or spell-checking abilities, AHK provides a free, simple, and easily implemented method to reduce TEs in pathology reports.
Prevalence of Multiple Primary Cancers in Guernsey: A Pathologic Review: (Poster No. 101)
Context: Multiple primary cancers (MPCs) in patients who survive the first cancer are due to improved diagnosis and treatment, increased longevity, genetic predisposition, and different lifestyles.
Design: This was a pathologic review of the prevalence of MPCs during a period of 15 years at different anatomical sites, excluding skin cancers, in a small community.
Results: Fifty-four women and 58 men had MPCs, with a prevalence of 2.5% (Figure 132). Breast cancer (red) was the most common first (59%) and second (28%) PC in women followed by bowel cancer (blue; 24%) as a second PC. Urinary tract cancer (29%; yellow) was the most common first PC in men followed by prostate (21%; brown) and large bowel (19%). Bowel cancer was the most prevalent second PC in men (28%). Lung cancer (green) patients did not survive to develop second or third PCs. These patients tend to present with advanced disease. The Sankey diagrams illustrate the number of patients with primary cancer who develop second or third cancers. The arrows represent patients with first PCs at the site of origin and those who later developed a second PC at the site of the arrowhead. The thickness of the arrow represents the number of patients with a specific cancer. To the authors' knowledge this is the first time the Sankey diagrams, originally used in engineering are applied to clinical assessment.
Conclusions: This study highlighted a significant prevalence of MPCs in a small population, with the breast being the most common site for MPCs. Sankey diagrams are effective in assessing MPCs.
Quantifying Potential and Realized Pharmacy Cost Savings Associated With Testing for Heparin-Induced Thrombocytopenia: (Poster No. 103)
Context: Patients suspected of having heparin-induced thrombocytopenia (HIT) are treated with expensive anticoagulants such as Argatroban. Opportunities for reducing the use of Argatroban include reducing unnecessary workup for HIT, improving turnaround time, and facilitating the discontinuation of the drug when a negative test result is received
Design: We first quantified realized cost savings from avoiding unnecessary testing through use of the 4 Ts scoring system, a pretest probability test calculator for HIT, by collecting utilization figures for 2007–2011. We next joined laboratory, pharmacy, and financial data from another hospital system to evaluate potential Argatroban cost because of the long turnaround time for HIT testing, and failure to discontinue use of alternate anticoagulants after a negative HIT result.
Results: Use of the pretest probability calculator reduced annual HIT testing from 224 tests in 2007 to 67 tests in 2011, leading to an annual reduction in testing costs of $18 448 (Table). Of greater interest, the reduced testing also led to a decrease in use of Argatroban, with an average annual variable cost reduction of $220 055. Waiting for the result of negative HIT test results led to the administration of 946 extra units of Argatroban with an annual variable cost of $28 412. The annual variable cost associated with continuing Argatroban treatment after reporting a negative HIT test result was $95 752.
Conclusions: The impact of coagulation testing reaches far beyond just the test itself and projects to optimize the evaluation of suspected HIT would result in $362 667 in annual variable cost savings.
Disseminated Coccidioidomycosis as a Cause of Fetal Demise and Maternal Death: (Poster No. 108)
A 29-year-old woman at 23 weeks gestation presented with 2 months cough and 2-week history of worsening shortness of breath, fever, chills, fatigue, and anorexia. She lived in Arizona 3 years prior. The chest x-ray suggested interstitial lung disease. Complete blood count revealed normocytic anemia and leukocytosis with absolute eosinophilia (2.8 k/μL). She was treated with antibiotics and corticosteroids for eosinophilic pneumonia. Despite treatment, the patient became ventilator dependent and developed septic shock. A nonviable fetus was spontaneously delivered. Histology of the placenta showed coagulative necrosis, giant cells, neutrophils, lymphocytes, and plasma cells. Spherules filled with fungal endospores and occasional individual sporangiospores of Coccidioides were seen. The umbilical cord and fetal membranes were unremarkable. Coccidioides immitis/posadasii was isolated from a bronchoalveolar lavage; amphotericin B was initiated. The patient continued to deteriorate and died 10 days after the admission. Autopsies of the fetus and the patient were not performed. Risk of disseminated disease in infected pregnant women is 40 to 100 times that of the general population. It is presumed that congenital coccidioidomycosis does not occur. Current evidence indicates that neonatal infection is uncommon, most likely acquired during delivery. Transplacental passage is thought not to occur because of entrapment in inflammatory exudate and fibrin due to the large size of Coccidioides. A few case reports describe involvement of the placenta but not the fetus. We present a case of a pregnant woman infected with Coccidioides likely years ago and now presenting with disseminated coccidioidomycosis causing death and fetal demise (Figure 133).
Experience With Rapid Molecular Diagnosis of Mycobacterium tuberculosis Infection and Rifampicin Resistance in Indian Patients: (Poster No. 110)
Context: The annual incidence of pulmonary and extrapulmonary tuberculosis (PTB and EPTB) in India exceeds 1.98 million and represents a significant disease burden across the world. Traditional diagnostics methods (sputum smear and culture with Lowenstein-Jensen media) for detecting Mycobacterium tuberculosis (MTB) have low sensitivity and are time consuming. This delay precludes early diagnosis and initiation of therapy, both prerequisites to breaking the cycle of disease transmission. Because molecular methods are faster and more sensitive, we evaluated the feasibility and utility of a novel molecular method in our outpatient pathology practice and evaluated its performance across a spectrum of specimen types.
Design: During a 16-month period, specimens from consecutive patients with clinical suspicion of PTB and EPTB were analyzed through Xpert MTB/RIF on GeneXpert Dx (Cepheid, Sunnyvale, California), a nested real-time polymerase chain reaction and molecular beacon technology–based assay designed to detect the presence of MTB and determine rifampicin sensitivity. Parallel testing with traditional methods was also performed.
Results: Three hundred six specimens obtained from patients (9 months–94 years) were analyzed. All results from the molecular method were available within 3 hours from time of specimen collection. The number of cases found to be positive with molecular methods was higher compared with traditional methods (Table).
Conclusions: This assay has performed very well across the entire spectrum of PTB and EPTB cases and has provided expedient test results to our patients. We hope that other laboratories will also adopt molecular-based assays and improve patient care.
Significance of Catheter Tip Cultures in Bloodstream Infection: (Poster No. 111)
Context: We studied the microbiological analysis of venous catheter tips and their correlation with peripheral blood cultures in the diagnosis of catheter-related bloodstream infections (CRBSIs). We also aimed to determine the prevalence of catheter tip cultures in the setting of negative blood cultures.
Design: Retrospective analysis of catheter tips cultured by semi-quantitative sonication at UF Health Shands Hospital Clinical Microbiology Laboratory from July 2013 to June 2014 was performed.
Results: Of the 370 catheter tips cultured, 178 had microbial growth. Blood culture was not performed in 21 and they were excluded from the study. Of the remaining 157, 103 (66%) grew >1000 col/mL. Blood culture was positive in 53 of these cases (51%) as shown in Figure 134. Forty-one of these patients had concordant organisms grown from blood and the catheter tip whereas 12 grew different organisms. Additionally, 20 patients had catheter tips that grew >1000 col/mL with potential bloodstream pathogens (Staphylococcus aureus 2, Candida 4, Enterobacter 3, Enterococcus 3, Proteus 1, Acinetobacter 2, Achromobacter 1, Pseudomonas 2, and Klebsiella spp. 2) but negative blood cultures.
Conclusions: In summary, semiquantitative catheter tip cultures correlated well with blood cultures. Additionally, they may be useful in detecting infections when no pathogen is detected on blood culture. Further studies are needed to determine the clinical significance of this finding.
Nocardiosis of the Lung in Posttransplant Patient: A Case Report and Review of the Literature: (Poster No. 113)
Organ transplant recipients are increasingly recognized as a subgroup of immunocompromised patients, in whom Nocardia is an important pathogen. Nocardia infection has been reported in heart, kidney, and liver transplant recipients. We report a case of nocardiosis in a 65-year-old man after the kidney transplant. The patient is a 63-year-old man on steroid therapy after the renal transplantation in for end-stage renal disease. He presented with a solitary brain and multiple pulmonary lesions. The patient underwent a computed tomography–guided lung biopsy. Cytology slides and cell block slides showed scattered viable clusters of epithelioid histiocytes in a background of severe acute necrotizing inflammatory process (Figure 135, A). Branching filamentous organisms were noted in the Diff Quik–stained cytology slides (Figure 135, B) Special stains including GMS (Figure 135, C) and AFB showed branching filamentous bacteria, indicative of Nocardia. The diagnosis was compatible with a clinical history of immunocompromised patient. The frequency of Nocardia infection in kidney transplant patients varies, with lung being the most common site of primary infection and the period of greatest risk lying in the first 6 months after transplantation. Because dissemination to the brain is a lethal complication, patients merit surveillance, early recognition, and treatment.
Actinomycosis of the Cervical Vertebrae in a Pediatric Patient: (Poster No. 114)
Actinomyces species are often found in the normal flora of the oral cavity and vaginal tract and are occasionally responsible for indolent infections causing abscess formation and draining sinuses. Cervicofacial manifestations of actinomycosis involve the soft tissue of the head and neck with facial osteomyelitis; however, spread to the cervical spine is a rare condition. We report an immunocompetent 8-year-old boy who presented with neck pain for 1 month with an insidious onset and denying a recent history of trauma or dental procedures. Cervical computed tomography scan and magnetic resonance imagining revealed an ulceration of the posterior oropharyngeal mucosa with a soft tissue defect extending to and involving the C1-C2 vertebra. Destruction of the anterior arch and lateral masses were concerning for a pathologic fracture from a neoplastic process. The patient underwent laryngoscopy and subsequent biopsies of the ulcer and C1 showed severe acute osteomyelitis with osteonecrosis, remodeling, fragments of granulation tissue, and fibrosis. In addition to acute inflammation, intraosseous filamentous organisms, morphologically consistent with Actinomyces species, were identified and supported by Gomori methenamine silver stain (positive) and acid-fast bacilli stain (negative). Culture of the tissue was noncontributory and did not grow organisms. On follow-up, the boy responded to long-term antibiotic treatment. Actinomycosis has rarely been reported in the cervical vertebra of pediatric patients. Histologic evaluation is warranted because the radiology can mimic neoplasia, microbiology may be nondiagnostic, and prompt antibiotic treatment is lifesaving (Figure 136).
Analysis of KRAS/NRAS Mutations in the Phase 3 PRIME Study of Panitumumab +FOLFOX versus FOLFOX as First-Line Treatment for Metastatic Colorectal Cancer (mCRC): (Poster No. 116)
Context: Analysis of a phase 3 panitumumab +chemotherapy study indicated that KRAS and NRAS mutations beyond KRAS exon 2 are predictive of panitumumab resistance. Since the publication of the Peeters et al landmark study in 2013, further RAS testing examinations support the predictive value of extended RAS analysis among patients receiving anti-EGFR therapy for mCRC.
Design: The primary objective of the prospectively defined retrospective analysis of PRIME was to assess the effect of panitumumab + FOLFOX versus FOLFOX on overall survival (OS) in patients with mCRC according to RAS mutation status. Gold standard bidirectional Sanger sequencing was used to detect mutations in KRAS exon 3 and exon 4 and NRAS exon 2, exon 3, and exon 4.
Results: RAS ascertainment rate was 90%. A meaningful proportion of patients (17%) have activating RAS mutations outside KRAS exon 2. OS and PFS results in patients with wild-type (WT) RAS and mutant (MT) RAS are shown (Table). Evaluation of mutations in exons 2, 3, and 4 of KRAS/NRAS (extended RAS analysis) improves identification of patients unlikely to respond to treatment with panitumumab versus evaluation of KRAS exon 2 alone, improving clinical outcomes.
Conclusions: In PRIME, statistically significant OS and PFS benefits were observed in patients with WT RAS mCRC, and statistically significant OS and PFS detriments were observed in patients with MT RAS treated with panitumumab + FOLFOX versus FOLFOX. The less frequently observed RAS mutations outside of KRAS exon 2 appear to confer resistance to panitumumab + FOLFOX. Extended RAS analysis should therefore be performed at mCRC diagnosis to choose an optimal systemic treatment.
Drs Oliner, Hei, and Patterson are employees and shareholders of Amgen, Inc. Dr Douillard is a consultant to Amgen, Inc., and has received grant or research support from Amgen, Inc., as well as payment for lectures, including for service on the Amgen, Inc. speakers bureau. Dr Siena is a consultant to Amgen, Inc. and Amgen, Inc. has provided clinical trial research support to his institution. Dr Tabernero is a consultant to Amgen, Inc., has received grant or research support from Amgen, Inc., and has received payment for lectures including for service on the Amgen, Inc. speakers bureau. Dr Burkes has received payment for lectures including for service on the Amgen, Inc. speakers bureau. Dr Barugel has received payment for lectures, including service on speakers bureaus, as well as payments for participation in review activities from Amgen, Inc. Drs Humblet, Ruff, and Canon declare that their institutions have received payments for research support from Amgen, Inc. Dr Rivera is a consultant to Amgen, Inc., has received grant or research support from Amgen, Inc., and has received payment for travel to meetings for the study or other purposes from Amgen, Inc. Dr Rother is a consultant to Amgen, Inc., and has received payment for lectures, including for service on the Amgen, Inc. speakers bureau.
ALK and ROS1 Double-Hit Non–Small Cell Lung Carcinoma: Case Report and Literature Review: (Poster No. 117)
It has been well accepted that ALK and ROS1 gene rearrangements are both driver mutations and they are mutually exclusive in the tumor cells. ALK and ROS1 double-hit non–small cell lung carcinoma (NSCLC) is rare and has not been well documented. We describe a case of a 62-year-old woman with NSCLC who underwent surgical resection of the tumor. Clinical, pathologic, and molecular findings are presented. ALK FISH assay was FDA approved, but ROS1 FISH assay was laboratory developed. A 62-year-old white woman was found to have a right middle lobe lesion by PET scan. Video-assisted thoracoscopic surgery excision with lymph node dissection was performed. Grossly, the specimen was a right middle lobe wedge resection with a small nodule measuring 1.5 × 1 × 1 cm on histology; the mass was a poorly differentiated NSCLC with TTF1 positivity favoring adenocarcinoma (Figure 137, A and B). Lung biomarkers assay revealed double positivity for ALK and ROS1 rearrangement (Figure 137, C and D). The tumor tissue was reanalyzed by another CLIA-approved clinical laboratory that performs ROS1 FISH with its own LDT probes. The result was also positive for ROS1 gene rearrangement. In conclusion, ROS1 rearrangement is a relatively new discovery in NSCLC. Our case presents a unique picture of NSCLC in terms of clinical appearance and molecular pathology. The findings might signify a shift in the current literature with respect to defining and categorizing NSCLC and its prognosis and treatment.
A Novel NSD3-NUT Fusion in a Rare Nut Midline Carcinoma With Orbital Involvement: (Poster No. 121)
NUT midline carcinoma (NMC) is a poorly differentiated squamous cell carcinoma that is genetically defined by chromosomal rearrangements involving the nuclear protein of the testis (NUT, aka NUTM1) and clinically characterized by an aggressive course with no effective therapy. In the majority of cases, the partner gene fused to NUT is one of the bromo and extraterminal domain (BET) family of bromodomain-containing proteins, BRD4 or BRD3. The gene encoding the nuclear receptor binding SET domain protein 3 (NSD3, aka WHSC1L1) was recently identified as a novel partner. We report a NSD3-NUT NMC with an unusual clinical presentation. A 53-year-old man presented with left eyelid swelling, headache, and nausea. Initial imaging studies show a periorbital mass. An orbital biopsy revealed monomorphic, intermediate-sized cells with oval nuclei, nucleoli, and variable amounts of cytoplasm infiltrating soft tissue. Immunohistochemical stains demonstrated the epithelial nature of the neoplastic cells but were otherwise inconclusive. Later, a mediastinal and retroperitoneal involvement was detected. The tumor on subsequent mediastinal biopsy displayed similar undifferentiated morphology as well as focal squamous differentiation. The possibility of NMC was considered and confirmed at Brigham and Women's Hospital by immunohistochemical stain for NUT fusion protein. FISH studies identified the partner gene as NSD3 (Figure 138). The patient survived 7 months after initial diagnosis. Recognition and study of additional cases of this rare entity will aid understanding role of NUT fusion proteins in pathogenesis of NMC and advance development of therapeutic agents targeting epigenetic proteins such as the BET bromodomains.
A Novel, High-Sensitivity, Quantitative Hepatitis C Virus Assay: (Poster No. 123)
Context: More than 170 million individuals are chronically infected with hepatitis C virus (HCV), which is a major cause of liver-related mortality. Successful HCV treatment is defined as undetectable levels of HCV RNA in the blood 12 or more weeks after completing treatment; therefore, a sensitive method to quantify HCV RNA is paramount to the management of patients undergoing antiviral therapy. This study evaluated a novel technology's ability to meet the performance characteristics exhibited by currently FDA-approved products.
Design: The AmpiProbe HCV Assay Kit (Enzo Life Sciences, Farmingdale, New York) provides a real-time reverse transcription quantitative polymerase chain reaction assay that incorporates fluorescent reporter and quencher labelled primer pairs. The limit of detection of the assay for use with the QIAGEN QIAsymphony SP and Rotor-Gene Q systems was determined using spiked plasma and serum specimens with the AcroMetrix HCV-S panel (Life Technologies, Grand Island, New York).
Results: The limit of detection in plasma specimens was 7.91 IU/mL by a 95% probit analysis with a limit of quantitation of 10 IU/mL as per a 95% hit rate analysis (Table). The limit of detection and limit of quantitation in serum samples were found to be 5.46 IU/mL (via 95% probit) and 10 IU/mL (via 95% hit rate) respectively.
Conclusions: The AmpiProbe technology can provide an alternative method of HCV RNA viral load quantification given it has successfully shown the ability to yield statistically consistent results at and below the lowest limit of detection of 11 IU/mL provided by currently FDA-approved HCV diagnostics.
Mr Hauser and Dr Schapfel are employees and shareholders of Enzo Clinical Labs. Dr Wang is a consultant to Enzo Clinical Labs.
Prevalence and Surveillance in Endocervical Specimens of High-Risk Human Papilloma Virus Strains That Are Not Represented in Current Vaccine Formulations: (Poster No. 126)
Context: Human papilloma viruses (HPV) are the causal agent of cervical cancers. Twelve strains of HPV have been classified as carcinogenic to humans (Grade 1). The purpose of this study was to assess the prevalence of grade 1 HPV strains not represented in the current approved HPV vaccines and to identify if surveillance of these additional strains is warranted.
Design: We evaluated 454 deidentified patient endocervical samples for the presence or absence of HPV infection using the Autogenomics HPV genotyping assay, which detects 24 high-risk and 2 low-risk HPV strains. Rates of grade 1 HPV infections of individual strains as well as rates of coinfections were determined.
Results: Of the 454 samples evaluated, 43 (9.5%) were positive for grade 1 HPV (Table). Of the 43 positive specimens, 70% (30 of 43) contained HPV strains that are targets of the current quadrivalent and nonavalent vaccines. Additionally, 30% (13 of 43) were positive for at least one strain of grade 1 HPV that is not a current target of these vaccines. The presence of these less common strains was detected as coinfections with other grade 1 HPV strains in 9 of 43 positive specimens.
Conclusions: This study demonstrates the benefit of screening for both more and less common strains of high-risk HPV in cervical specimens and argues for continued surveillance of less common grade 1 HPV strains in concomitant HPV infections that may contribute to a higher incidence of cervical cancer.
Extended RAS Mutation Testing in Metastatic Colorectal Cancer: (Poster No. 127)
Context: Metastatic colorectal cancer (mCRC) patients lacking mutations in KRAS/NRAS (RAS) exons 2–4 have improved overall survival (OS) and/or progression-free survival (PFS) with panitumumab alone or in combination with other therapies (FOLFOX or FOLFIRI). RAS mutation prevalence is approximately 50% in mCRC; accurate determination of patient tumor RAS status is important for treatment decisions. Because multiple RAS alleles must be interrogated, sequencing is preferred. Detection can be affected by analytical methods and sample preparation.
Design: Bidirectional Sanger sequencing assays for KRAS exons 3–4 and NRAS exons 2–4 were validated for identification of variants in formalin-fixed, paraffin-embedded (FFPE) CRC tissue. Hematoxylin and eosin sections were assessed to determine total tissue area and percentage neoplastic content. The tumor region was marked to aid in enrichment to ≥50%. Controls were assessed to ensure sequencing run quality. Metastatic CRC samples from panitumumab clinical trials, including 2 phase 3 studies, were tested.
Results: Sanger sequencing assay variant detection range was 5%–100%. Limit of detection was amplicon dependent and between 5% and 10%. Diagnostic specificity was 100%. The most informative controls for sensitivity analysis closely mimicked FFPE CRC patient samples with mutation frequencies near the limit of detection. Sequencing of RAS genes in CRC samples from multiple trials including more than 2000 patients indicated that the frequency of targeted mutations was consistent (Table). RAS mutations are predictive of lack of response to panitumumab using this method (data to be presented).
Conclusions: The use of validated assays, relevant controls, and assay-specific tissue requirements results in highly reproducible Sanger sequencing data from FFPE clinical specimens.
Drs Lofton-Day, Patterson, and Oliner are all employees and shareholders of Amgen, Inc. Dr Legendre Jr is an employee and shareholder of Transgenomic, Inc.
The New 2013 ASCO/CAP HER2 Guideline Increased the Numbers of Breast Cancer Patients Eligible for HER2-Targeted Therapy by 26.6%: Preliminary Data of Our First 100 Cases: (Poster No. 133)
Context: The accurate identification of HER2 status in patients with breast cancer is of high interest, because HER2-targeted therapy can improve patients' survival. In 2013, the American Society of Clinical Oncology and College of American Pathologists (ASCO-CAP) released updated recommendations for HER2 testing in breast cancer. Here we report the HER2 status in the first 100 cases of breast cancer diagnosed in our institute by dual-color FISH implementing the 2013 ASCO-CAP HER2 testing guideline.
Design: The first 100 cases were all verified histologically. The HER2 status of these cases was tested by FISH using dual-color probe HER2 and CEP17 and HER2 amplification was decided according to the 2013 HER2 testing guideline. Concordance of HER2 amplified/positive status diagnosed by dual-probe FISH according to 2013 was compared with the 2007 guidelines.
Results: Of these 100 cases, 13 cases (12 patients) were diagnosed as HER2 amplified, 3 cases (2 patients) equivocal, 2 indeterminate, and 82 negative (not amplified). Two cases (from the same patient with different parts) that initially diagnosed equivocal were confirmed positive by reflex immunohistochemical testing; one case remains equivocal. In summary, 15% (15 cases) of the first 100 cases of breast cancer were diagnosed in our institute as HER2 positive adopting all the changes of the 2013 HER2 testing guideline (Table).
Conclusions: The 2013 guideline aims to enhance the identification of patients who could benefit from targeted therapy. Indeed, implementation of the 2013 guideline increased the identification of patients by 26.7% who could benefit from effective HER2-targeted therapies.
Intracranial Dura-Based Marginal Zone Lymphoma: (Poster No. 135)
Intracranial dura-based marginal zone lymphomas (MZLs) are rare low-grade B-cell neoplasms with less than 100 reported cases. We present the case of a 23-year-old woman who presented with signs and symptoms of intracranial pressure. Computed tomography showed a 5.4-cm lenticular mass along the left frontal convexity. The preoperative diagnosis was meningioma or epidural hematoma. Frozen section showed marked plasmacytoid cell proliferation. Final diagnosis was differed to permanent section. Resection specimen showed a tan-white, homogeneous, lenticular mass entirely encapsulated in dura. Microscopically, the tumor showed diffuse, vaguely nodular follicular lymphoid proliferation with plasmacytic differentiation, intercepted by fibrous bands. Lymphoid cells were medium sized with condensed chromatin and scant pale cytoplasm. CD20 stain highlighted lymphoid follicles with attenuated germinal center. Sheets of CD138+ plasmacytic cells were κ–light-chain restricted as demonstrated by IHC and ISH. The plasma cells were weakly positive for IgM. Ki-67 was positive 20%–30% of cells with scattered distribution. Studies for B-cell clonality by PCR were negative. The specimen was received in formalin; consequently, flow cytometry was not possible. These findings are consistent with a diagnosis of B-cell non-Hodgkin lymphoma with plasmacytoid differentiation, most consistent with MZL. Systemic disease with lymph node involvement was largely ruled out by clinical and imaging studies confirming a diagnosis of extranodal MZL. Although rare, extranodal MZL should be considered in patients who present with a dural-based mass (Figure 139).
Tubulin BII, Important Marker for Differentiating Oligodendroglioma From Astrocytoma: (Poster No. 136)
Context: Tubulin BII synthesis increases in regeneration and development of neurons. Its expression seems to increase during axonal outgrowth. Differentiating oligodendroglioma from astrocytoma is important for prognostic and therapeutic implications.
Design: We performed tubulin BII immunostaining on paraffin blocks on 9 cases of astrocytomas of various grades (3 glioblastomas, 3 anaplastic astrocytomas, and 3 low-grade fibrillary astrocytomas) and on 6 cases of oligodendroglioma.
Results: Tubulin BII immunostaining was seen in all astrocytic tumors. Strong staining was seen in glioblastoma and in anaplastic astrocytomas (Figure 140). Grade II fibrillary astrocytoma cases show moderate staining pattern. All oligodendroglioma cases show no staining.
Conclusions: Tubulin BII is an important immunohistochemical marker in differentiating astrocytoma from oligodendroglioma.
Colloid Cyst Lining Consists of 2 Distinct Epithelial Cell Layers: (Poster No. 137)
Context: Colloid cell lining is typically described as pseudostratified ciliated columnar epithelium. The literature does not emphasize its 2 distinct cell layers lining. We prove in this study that colloid cells have 2 distinct cell layers lining, the superficial and the basal, with different immunostaining patterns.
Design: We examined 9 colloid cells in our collection with age range 13–77 years (average 36 years). All of them were in the third ventricle. Immunostainings for high-molecular-weight cytokeratin (HMWC), low-molecular-weight cytokeratin (LMWC), epithelial membrane antigen (EMA), p63, cytokeratin 19, cytokeratin 7, cytokeratin 5/6, and cytokeratin 20 were performed in all cases.
Results: All colloid cells showed 2 distinct stainings of the cell layers: one superficial layer that was positive for EMA (luminal pattern) and the other basal cell layer that was positive for HMWC (Figure 141), p63, and cytokeratin 5/6. Both layers were positive for cytokeratin 19 and cytokeratin 7. Both layers were negative for cytokeratin 20.
Conclusions: The epithelial lining of the colloid cyst consists of 2 distinct cell layers, 1 superficial and 1 basal. The recognition of this pattern is important in differentiating it from other cysts in the central nervous system.
Squamous Cell Carcinoma Arising in Cervical Spina Bifida: (Poster No. 138)
A 29-year-old man with known history of cervical spina bifida presented with pain and drainage from the skin overlying a posterior cervical neck mass. Physical examination revealed a draining wound in the midline posterior cervical cutaneous surface at C4. Preoperative magnetic resonance imaging demonstrated spina bifida occulta at C3 and C4. In addition, a large dorsal overlying, signal abnormality with both solid and cystic areas was seen including a narrow stalk abutting the posterior aspect of the spinal canal with no definite communication. The bulbous lesion and surrounding skin and soft tissue were completely excised. The appearance of the specimen was concerning both presurgically and intraoperatively for a neoplastic process. The specimen consisted of a segment of skin with both a raised lesion containing a central defect and an underlying soft tissue mass. Histology showed a cutaneous surface with a centrally located sinus tract. Appearing to arise from the lining were underlying invasive squamous sheets. On higher power, these squamous cells showed moderate to focally severe cytologic atypia with brisk mitotic activity compatible with squamous cell carcinoma. Tissue adjacent to the sinus tract was characterized by dense fibrosis and chronic inflammation. Additional tissue types seen within the resection specimen included meningothelial and nervous tissue fragments. The meningothelial component was seen surrounding collagen bundles with numerous psammomatous calcifications. The nervous tissue consisted of neuropil, pigmented neurons, and cells reminiscent of the internal granular layer of the cerebellum. The lesion was excised with clear margins (Figure 142).
A Case of Idiopathic Hypertrophic Pachymeningitis With Brain Parenchyma Involvement: (Poster No. 139)
Idiopathic hypertrophic pachymeningitis (IHPM) is a chronic inflammatory and fibrosing condition involving the dura without identifiable etiology. We are reporting a case with rare parenchymal involvement. The patient was a 65-year-old white woman with a history of seizures and new-onset balancing issues, frequent falls, visual problems, and urinary incontinence. Electroencephalogram (EEG) suggested generalized nonspecific cortical dysfunction or encephalopathy. Magnetic resonance imaging (Figure 143, A) demonstrated extensive and multifocal enhancing dural thickening up to 4.8 cm in greatest dimension involving both the cranial and spinal dura with accompanying parenchymal edema in the cranial lesions. The right frontal lesion was excised and yielded an intensely fibrotic pial thickening with intense lymphocytic infiltration (Figure 143, B). The lesion followed the contour of the cortex and extended into the Virchow-Robin space with perivascular lymphocytic infiltrations and spilling into the surrounding brain parenchyma accompanied by gliosis (Figure 143, C). The lymphocytes were mostly CD4+T cells with a minor presence of CD8+ T cells, and no T-cell clonality was detected by molecular studies. No plasma cells were noted either by morphology or immunohistochemistry for CD138. A small number of B cells were demonstrated by immunohistochemistry for CD20 and no immunore-activity for IgG4 was demonstrated. There were neither histopathologic nor immunohistochemical evidence of meningothelial proliferation to suggest a lymphocyte-rich meningioma. IHPM is rare and differential diagnoses include lymphoproliferative disorders, lymphocyte-rich meningioma, and IgG4 diseases. Involvement of parenchyma leading to an encephalopathy-like EEG picture is uncommon and should be included in the differential diagnoses of seizure patients.
α -Thalassemia/Mental Retardation Syndrome X-Linked Gene Expression Profiles by Immunohistochemical Analysis in Different Subtypes of Brain Tumors: (Poster No. 141)
Context: Recent studies have demonstrated the utility of α-thalassemia/mental retardation syndrome X-linked (ATRX) to distinguish anaplastic astrocytomas from anaplastic oligodendrogliomas. Its use in other brain malignancies has not been widely explored. Herein we document our experience with ATRX immunoexpression in different central nervous system tumor types.
Design: A search in our institutional archival database for different brain tumors types was performed, from June 2008 to June 2013 including 5 tumors per central nervous system tumor category (Table). The cases were stained with anti-ATRX antibody (1:400; Rabbit Anti-ATRX Polyclonal Antibody, Sigma-Aldrich). Two pathologists established agreement regarding immunoexpression of ATRX, using the Allred scoring system.
Results: Most gliomas showed variable degree of immunoreactivity for ATRX, except for anaplastic and diffuse astrocytomas, being negative. Regardless of the tumor category, tumors positive for ATRX demonstrated focal areas of negativity. Atypical meningiomas showed marked immunoreactivity (score = 8) compared with grade I meningiomas (scores 6 or 7). Four of 5 metastatic tumors were ATRX immunoreactive (melanoma, ductal carcinoma of the breast, squamous cell carcinoma and neuroendocrine carcinoma of the lung), except a metastatic renal cell carcinoma. ATRX is also expressed in benign meningothelial cells.
Conclusions: We present a case series of ATRX immunoexpression in glial, nonglial, and metastatic tumors. We confirmed the utility of anti-ATRX to distinguish anaplastic and low-grade astrocytomas (ATRX loss) from anaplastic oligodendrogliomas (ATRX retention). However, interpretation should be performed with caution because of ATRX heterogeneous expression in different glial and nonglial tumors including metastases, especially in samples with scant tissue. Menin-gothelial cells can also serve as an internal control during the evaluation of this marker.
Genetics of Glioblastomas in Rare Anatomical Locations: Spinal Cord and Optic Nerve: (Poster No. 142)
Context: Diffuse astrocytomas of spinal cord are known not to harbor the same genetic features as supratentorial counterparts (IDH1 negative); it is unknown whether glioblastomas (GBMs) of spinal cord or optic nerve share the mutations common to supratentorial GBMs (epidermal growth factor receptor [EGFR] or loss of PTEN). Rarity of GBMs in either location (<1%–3% of all GBMs) limits study size.
Design: Case search of departmental databases, 2006–present.
Results: Biopsies from 6 spinal cord and 2 optic nerve GBMs were identified. Two of 6 cord cases occurred in pediatric patients, ages 8 and 17 years; the latter represented the only radiation-induced example. Only the 2 most recent (less than 3 months from diagnosis) patients survive. Cervicomedullary and upper cervical regions were affected in 3 patients, with C7-T1, T12-L2, and T8-T12 in the other 3. Two spinal cord GBMs manifested EGFR amplification, while 3 of 5 informative spinal cord cases were negative for both markers, without site correlation. Both optic chiasm tumors occurred in adult males and both had amplification of EGFR and loss of PTEN. One spinal cord GBM patient with survival more than 1 year developed anterograde, biopsy-proven spread to the cerebellum. One each of the optic chiasm and spinal cord GBM patients came to autopsy. Both died 48 hours postsurgery and no parenchymal or cerebrospinal fluid dissemination was identified (Figure 144).
Conclusions: GBMs from spinal cord and optic nerve are rare, usually arise de novo, affect children and adults, and share genetic features of supratentorial primary GBM counterparts (EGFR amplification, loss of PTEN).
Congenital Hypomyelinating Neuropathy: (Poster No. 145)
Congenital hypomyelinating neuropathy (CHN) is a rare, often fatal, infantile disorder with prenatal, neonatal, or early infantile onset of hypotonia, paresis, and areflexia. We report a case of CHN in a baby girl, born at 35 weeks gestation by emergency cesarean section for fetal distress. The mother was a 33-year-old white woman with gestational diabetes and polyhydramnios. The father had a history of systemic lupus erythematosus that started at age 13. The infant was born with severe hypotonia, including poor gag and suck, limited response to tactile stimulation, hypotonic facial features, and required intubation. No evidence of metabolic diseases, myotonic dystrophies, spinal muscular atrophy, or maternal myasthenia gravis was demonstrated. At 2 months of age, a sural nerve and muscle biopsy was performed. While no significant findings were found in the muscle biopsy, the sural nerve appeared hypercellular and contained small fibers and free of inflammatory cells. Immunohistochemistry for neurofilament demonstrated preservation of axons (Figure 145, A). On semithin sections, only scant myelinated fibers were noted (arrows in Figure 145, B) and most of the axons were shown to be nonmyelinated on electron microscopy (Figure 145, C). No evidence of axonal destruction or concentric proliferations of Schwann cells (onion bulbs) were noted. CHN is likely a shared manifestation of multiple genetic abnormalities including mutations of MPZ, EGR2, PMP22, and MTMR2, and likely within the Dejerine-Sottas syndrome. Demonstration of preserved axons with marked hypomyelination on special stain in an infant is a hint for this diagnosis.
Calcifying Biphasic Pineal Parenchymal Tumor With Pineoblastoma and Gangliocytoma Components: (Poster No. 148)
Pineal parenchymal tumors span a spectrum from the most differentiated to least differentiated: from pineocytoma to pineal parenchymal tumor of intermediate differentiation (PPTID) to pineoblastoma (World Health Organization [WHO] grades I to IV). These rare tumors constitute less than 1% of all intracranial tumors and less than one-third of all pineal tumors. PPTID, of WHO grade II to III, is of intermediate differentiation and focal maturation can occur. We are reporting an unusual case of a heavily calcified biphasic pineal parenchymal tumor composed of a pineoblastoma component and a mature gangliocytoma component. The patient was a 20-month-old girl with a 2-month history of headaches and progressive loss of milestones. Imaging studies demonstrated a heavily calcified, large (6.1 cm), enhancing pineal mass that extended into the third ventricle with downward displacement of the brainstem (Figure 146, A). Histologically, it contained well-circumscribed islands of mature neuropil harboring large ganglionic cells (Figure 146, B) that were positive for neurofilament and NeuN but negative for glial fibrillary acidic protein (GFAP). No classic pineocytomatous rosettes were noted. The neuropil islands were embedded in a background of a small blue cell neoplastic component (Figure 146, C) with a Ki-67 labeling index up to 50%, reminiscent of a pineoblastoma. Calcifications were found exclusively in the ganglionic-neuropil islands. In contrast to PPTID, this tumor contains the most mature and primitive components without many areas with intermediate differentiation. The prognosis is likely to be dictated by the pineoblastoma component. The ganglionic-neuropil component, however, can create a diagnostic challenge, particularly with small biopsies.
Granulomatous Balamuthia Amoebic Encephalitis in an Immunocompetent Man: (Poster No. 150)
Granulomatous amebic encephalitis (GAE) is a rare and fatal disease. We report a case of a 33-year-old white man with GAE due to Balamuthia mandrillaris. The patient was previously healthy with a past medical history significant only for a traumatic injury with 2 subdural hematomas sustained in a car versus train accident underwent drainage. He stabilized thereafter. Around 1 year later he presented with new seizure and magnetic resonance imaging of the brain demonstrated parietal ring-enhancing lesions suspicious for abscess versus tumor. The first brain biopsy missed the lesion and revealed “reactive gliosis.” The second brain biopsy demonstrated necrotizing meningoencephalitis containing organisms morphologically consistent with amoeba. The trophozoites were located at perivascular spaces, which measured ~25 μm in diameter with a large nucleus and a large, centrally located nucleolus. No cyst forms were observed. Granuloma formation, necrosis, and plasmacytic inflammation were also present (Figure 147). Because B mandrillaris and Acanthamoeba spp. cannot be differentiated merely by morphology. The brain tissue was sent to CDC for further testing. Immunofluorescence assay and multiplex real-time PCR both identified the organism as B mandrillaris. The patient was treated empirically with a multidrug regimen including miltefosine, the most promising investigational agent based on CDC recommendation. However, the repeat magnetic resonance imaging of the brain showed new lesions in the thalamus and cerebellum. He became more encephalopathic and developed respiratory failure. The patient's family elected to take the patient home with hospice care services. He eventually expired. This case illustrates the necessity of considering the diagnosis of GAE in immunocompetent patients.
Central Nervous System Masson Tumors: Frequent Association With Therapeutic Radiation: (Poster No. 151)
Context: Masson tumor (MT; intravascular papillary endothelial hyperplasia) is an exaggerated form of thrombus reorganization, rarely occurring in the central nervous system (CNS), where it presents as a mass or hemorrhage in parenchyma, meninges, or venous sinuses. MT is subclassified as type 1, arising from a histologically normal vessel (no underlying pathology), and type 2, associated with a ruptured vascular malformation. Only singular reports after external radiation/radiosurgery have emerged.
Design: Search of databases for cases, 2008–present.
Results: Nine cases (8 surgical and 1 autopsy) were identified, 6 of which were associated with receipt of radiation for a known lesion, with intervals of 1–25+ years to MT development (4 neoplasms = external beam; 1 neoplasm = external beam + radiosurgery, 1 arteriovenous malformation = radiosurgery). MTs were coassociated with radiation-induced vascular malformations (1 cavernoma-like, 1 massive) only in the 2 of the 6 with longest intervals, whereas the other 4 had MTs only. The 3 nonradiated were 2 type 1 MTs and 1 spontaneously developing in a hemangioblastoma. Eight of 9 MTs were parenchymal and 1 was subdural within the radiation portals. Papillary MT architecture was appreciated better by CD31 or CD34 than H&E, and ERG immunohistochemistry verified the nearly pure endothelial population, paralleling findings in 5 non-CNS examples.
Conclusions: The majority of CNS MTs at our institution have arisen in patients who have received therapeutic cranial radiation. Some could conceivably represent early, albeit severe, phases of radiation-induced cavernomas. This study extends our knowledge of types of CNS radiation-induced vascular abnormalities (Figure 148).
Cystic Meningioma, a Rare Variant, Mimicking an Arachnoid Cyst: (Poster No. 152)
Meningiomas account for approximately 15% of intracranial neoplasms, most of which can be readily assessed preoperatively. Cystic meningioma, a rare variant, can be difficult to assess and has been mistaken preoperatively for astroglioma, arachnoid cyst, intracranial abscess, hemangioblastoma, and in at least one case report a subdural hematoma. Most cystic meningiomas are composed of at least 2 cystic components with a solid component. The mechanism of cyst formation is poorly understood. In this case, a 64-year-old man presenting with left-sided headache, unsteady gait, and memory loss was preoperatively diagnosed with a large arachnoid cyst because of the solitary cystic nature of his lesion on radiology (Figure 149, A and B). Intraoperative treatment was tailored to such a diagnosis, which included drainage and fenestration of the cyst. Portions of the cyst wall were examined histologically, which revealed a significant layer of meningothelial cells without an epithelial lining consistent with a cystic meningioma (Figure 149, C). This case, although rare, demonstrates the importance of consideration of a cystic meningioma in the differential diagnosis of a cystic intracranial lesion.
Hypertrophic Hyalinizing Vasculopathy Presenting as a Cerebellar Mass: (Poster No. 156)
Vasculopathy involving the central nervous system often presents as a diffuse or multifocal process. We are reporting an unusual case of hypertrophic hyalinizing vasculopathy mimicking a space-occupying lesion in the cerebellum. The patient was a 56-year-old man with 1-week history of progressively worsening severe headache, emesis, balancing issues, and fatigue. He had hypertension but not diabetes, shortness of breath on walking, and intermittent swollen ankles. Imaging demonstrated an ill-defined lesion that was hyperintense on T2-weighted images (Figure 150, A) with negligible enhancement. The tumor diffusely enlarged the right cerebellar hemisphere with minimal midline shift and the radiographic impression was Lhermitte-Duclos disease. Surgical resection yielded portions of cerebellar folia with normal architecture. Neither inflammatory cells nor loss of myelin were demonstrated. There were diffuse, prominent hyalinized sclerotic changes of small blood vessels in the leptomeninges, cortex, and white matter (Figure 150, B, arrows) with complete obliteration in the smaller vessels (Figure 150, C). No abnormal depositions were demonstrated on PAS and Congo red stain. Marked muscular hypertrophy (“arterialization”) and sclerosis were noted in vessels that lacked elastic fibers and consistent with veins. Cerebellar parenchyma showed edema, variable loss of Purkinje cells and granule cells, Bergmann gliosis, neuroaxonal spheroids, and diffuse gliosis. These features reflect diffuse injury secondary to the vascular changes. The edema contributed to the space-occupying lesionlike appearance on imaging. No recurrence with similar features was found after 14 months follow-up. It is our understanding that this type of vasculopathy is not previously described.
Incorporation of Pathology-Driven Ancillary Testing Into Graduated Resident Responsibility: (Poster No. 157)
Context: Integration of cytogenetic and molecular testing is essential for efficient and accurate diagnosis of bone marrow (BM) specimens. These tests provide vital diagnostic and prognostic information, but their appropriate use and interpretation present challenges to pathology residents.
Design: At our institution, pathologists led the development of BM-testing algorithms to support a pathology-driven ancillary testing (PDAT) approach for ordering of ancillary studies. Results are integrated into a summary report when the BM workup is complete. We use this model for teaching residents and to provide graduated responsibility for residents rotating on the hematopathology service. To assess for educational benefit, residents have been given a knowledge-based test regarding test selection and biomarker interpretation prior to and (when applicable) after rotations since PDAT implementation.
Results: Residents actively participate in test selection for workup of BM specimens. Based on the resident's clinical and morphologic impression, he or she orders necessary cytogenetic and molecular tests for each BM specimen. After completion of testing, a senior resident generates a summary report that provides a final diagnosis along with an interpretive comment and biomarker results. Results of the knowledge-based test (Table) suggest that residents with limited but PDAT-enhanced experience (1) have higher mean scores than residents with the same amount of training but no exposure to PDAT and (2) score similarly to residents who have completed hematopathology training but with no exposure to PDAT.
Conclusions: Incorporating PDAT into residency training enables residents to actively learn about effective use and interpretation of biomarker studies during the evaluation of BM specimens.
Stepping Beyond the Paraffin Curtain: Attitudes and Experience on Error Disclosure Among Pathologists and Trainees: (Poster No. 158)
Context: Pathologists face unique disclosure challenges in conveying pathology errors to patients.
Design: An anonymous and voluntary self-administered multiple-choice survey using a 4-point Likert scale was prepared to assess pathologists' and pathology trainees' attitudes and experience in the disclosure of medical errors. After institutional review board approval we invited participants at a statewide annual conference, a nationwide conference of residents, and members of the Association of Pathology Chairs Program Directors Section (PRODS) listserve to participate.
Results: While 98% (90 of 92) of the participants had been involved in an error, only 39% (21 of 54) of practicing pathologists and 13% (5 of 38) of trainees had recently disclosed an error to a treating clinician and knew if it had been conveyed to the patient. A minority of practicing pathologists (13%) had disclosed an error directly to a patient. In addition, the majority of participants were unfamiliar with hospital and pathology department error disclosure policies (Table).
Conclusions: Pathologists in practice and pathology trainees receive limited feedback to assess how patients respond and understand pathology errors. Increased training and education during residency may encourage more robust participation among future pathologists in the error disclosure process.
A Differential Diagnosis Map for Breast Cancers: (Poster No. 162)
Context: Honing skills in diagnosis and development of a differential diagnosis requires recognition that many lesions exist in a continuum from benign to malignant, and often share their histologic appearance with other benign and malignant conditions. This is often difficult to convey in a textbook or other traditional teaching source.
Design: One such area of difficulty is in breast lesions. Using Microsoft Publisher, a 2-D differential diagnosis map was made of the major breast cancers as well as other histologically related benign and intermediate lesions, using images and links to describe similarity and text to elucidate the distinguishing features.
Results: More than 25 breast lesions are portrayed on the differential map (Figure 151). The graphic portrays both the progression of lesions from hyperplasia to cancer, as well as linking histologically similar lesions that should be included in a differential diagnosis (http://www.drdoubleb.com/BreastMap).
Conclusions: The differential map is a useful way to teach medical students and residents to formulate a differential diagnosis of breast lesions, and which entities could be considered given a certain histologic appearance.
A Minimum-Requirement Model to Start Up a Histology Laboratory in Developing Countries: (Poster No. 163)
Context: Despite the rapid advancement of technology used in pathology laboratories aimed to better screen for and diagnose the diseases in developed countries, a large subset of the world's population in underdeveloped countries (including Central and South America, Africa, and East Asia) still remains underserved. The limited access to basic diagnostic methodologies is largely due to the lack of existing histology laboratories equipped with a basic armamentarium of technical resources. The aim of this initiative is to offer a model of optimally equipped histology laboratory for developing countries at a minimal cost.
Design: The basic histology laboratory includes the following components: equipment, reagents, and supplies/consumables. As a result of searching for basic components and comparing their costs among different providers, we constructed a systematized list of resources needed to be used for a minimum-cost histology laboratory in underserved communities. We also believe and hope that the funding for such an undertaking can be possibly obtained through grants for developing countries supported by donors with a passion for pioneering medical initiatives.
Results: As a collaborative effort, we have constructed an itemized listing and estimated a minimum budget necessary to start up a basic cost-effective histology laboratory (Table).
Conclusions: The role of a basic histology laboratory is critical for timely diagnosis of the diseases and use of preventive health care. This minimum requirement model could guide the initial planning and budgeting to start up a histology laboratory in developing countries, hopefully by financial support through appropriate grants.
The Decline and Fall of Red Cell Folate: (Poster No. 164)
Context: Folate deficiency, while uncommon because of fortification of grains and cereals, is detected by measurement of serum folate (SF), red cell folate (RCF), or serum homocysteine. RCF is considered a more accurate indicator of tissue stores because levels do not change during the red cell's lifespan and are minimally affected by recent consumption. However, RCF measurement is complex, costly, and imprecise. Furthermore, RCF has proven to generally have no diagnostic advantage over SF.
Design: SF and RCF test volumes were collected from 125 Veterans Affairs health care facilities between 2000 and 2014.
Results: There were 7 752 294 SF and 661 020 RCF results reported. Annual RCF volume as percentage of all folate tests declined from 11.5% in 2000 to 3.2% in 2014 (Figure 152); the most rapid decline was observed from 2011 (8.2%) to 2013 (3.4%). Since 2010, the number of facilities with <5% RCF results increased from 73.6% to 85.6%. In 2014, 48 of 125 facilities (38.4%) reported no RCF results and 2 reported >97%. Annual RCF test volume exceeded 90% at one time in 16 facilities. Within this group, RCF testing declined to 0% in 10 (62.5%) within 2 years or less.
Conclusions: These results show that Veterans Affairs facilities have largely discontinued RCF testing in accordance with good test utilization practices and supportive clinical evidence that finds this test generally adds no diagnostic value when compared with SF. In facilities with high annual RCF testing rates, conversion to SF was generally rapid and sustained.
Cryoglobulinemia-Associated Alveolitis: (Poster No. 166)
Cryoglobulins are a complex of one or more different classes of immunoglobulins and complement components that precipitate at low temperatures. Cryoglobulins are associated with hematologic, autoimmune, and chronic infections such as hepatitis C. They may cause systemic vasculitides affecting small and medium-sized arteries and veins of the skin, kidneys, and peripheral nerves. Only a few cases of patients with hepatitis C virus infection and mixed cryoglobulinemia with interstitial lung fibrosis have been reported. Here we report a case of a 52-year-old man with history of hepatitis C viral infection and end-stage renal disease from cryoglobulinemia presenting to the emergency department for dyspnea, fever, and back pain for 2 days. He was admitted to the intensive care unit requiring noninvasive ventilator support and peritoneal dialysis. Peritoneal fluid, blood, and urine cultures were negative for acute infection. Chest computed tomography scan revealed bilateral patchy alveolar opacities suggestive of pulmonary edema or alveolar hemorrhage as well as mediastinal lymphadenopathy. Bronchoscopic transbronchial biopsy of the left upper lobe revealed organizing pneumonitis, interstitial fibroblastic foci, interstitial fibrosis, and diffuse lymphocytic alveolitis obliterating alveolar airspaces (Figure 153). The trichrome stain highlighted the presence of extensive interstitial fibrosis leading to a final diagnosis of nonspecific interstitial pneumonitis due to patient's mixed cryoglobulinemia. The patient's respiratory symptoms improved after supportive measures and he is currently being evaluated for a kidney transplant.
Frequency of EGFR Mutations in South Ohio/North Kentucky: A 4-Year Retrospective Study: (Poster No. 169)
Context: EGFR mutation testing is used to select lung adenocarcinoma patients for EGFR-targeted TKI therapy. The frequency of EGFR mutation varies dependent on demographic and clinical pathologic characteristics.
Design: A retrospective database search from September 2011 to August 2014 was conducted at University of Cincinnati to analyze EGFR testing results from cytology, biopsy, and resection of formalin-fixed, paraffin-embedded specimens. EGFR mutation testing was performed by an outside company. The overall and specimen-type–specific frequency, mutation types of INDEL, and point mutation variants of EGFR were analyzed.
Results: A total of 226 lung adenocarcinoma patients were tested in 4 years' duration. The overall EGFR mutation frequency is 7.8% (16 out of 226). The frequency of cytology cell blocks, biopsy and resection specimens is 7.9% (8 of 101), 8.5% (5 of 59), and 5% (3 of 66). Among cell blocks, the frequency of FNA is 7.2% (6 of 83) and effusion 11% (2 of 18). Among 16 EGFR mutation–positive cases, female to male ratio is 9:7 and the average age of women is 63.3 and men is 60.1 years. Among types of EGFR mutations, DEL, in, and point mutations are 62.5%, 6.25%, and 31%, respectively. Frequency of exons 18, 19, 20, and 21 is 0%, 62.5%, 6.25%, and 25%, respectively (Table).
Conclusions: EGFR mutation frequency in South Ohio/North Kentucky area is significantly lower than the national average. Biopsy has the highest EGFR mutation frequency and resection the lowest. Among EGFR mutations, DEL of exon 19 is the commonest and 18 the least common. Lower EGFR mutation frequency may be related to high prevalence of cigarette smoking.
Incidental Diagnosis of Primary Pleural Angiosarcoma in a Patient Presenting With Traumatic Hemothorax: (Poster No. 170)
Angiosarcoma is an uncommon malignant tumor accounting for 1% of all soft tissue malignancies. Primary pleural angiosarcoma is an even rarer tumor with an aggressive clinical course. Its etiopathogenesis is uncertain with occasional reported association with tuberculosis, asbestos exposure, and radiation. Pleural angiosarcomas are often epithelioid and can be misdiagnosed as mesothelioma or adenocarcinoma. We report a case of primary epithelioid angiosarcoma of right pleura incidentally diagnosed in a 63-year-old woman who initially presented with traumatic right sided hemopneumothorax and rib fractures. A computed tomography chest scan post–initial drainage of hemothorax showed a loculated pleural effusion and a focal anterior density that was interpreted as possible postsurgical hematoma. Frozen section diagnosis of pleural biopsies showed atypical epithelioid and spindle cells, interpreted as reactive versus neoplastic. Unfortunately, the patient died; an autopsy was performed that revealed multiple bilateral rib fractures and a large right hemothorax with clotted blood adherent to pleural surface. The right pleura was thickened (2 cm) and showed a shaggy, fleshy, and hemorrhagic appearance. Histology showed epithelioid tumor cells with moderate amount of eosinophilic to amphophilic cytoplasm infiltrating a collagenized stroma (Figure 154, A). Focally slitlike vascular channels lined by tumor cells were identified (Figure 154, B). Tumor cells were associated with necrosis, hemorrhage, and numerous mitotic figures. Immunohistochemically, tumor cells were strongly positive for CD31 (Figure 154, C), and vimentin. Tumor nuclei showed strong positive staining for FLI-1 (Figure 154, D) and ERG. There was no evidence of malignancy in other organs. A diagnosis of primary pleural epithelioid angiosarcoma was made.
Utility of Immunohistochemical Staining in Differentiating Radiation-Induced Atypia From Recurrent Squamous Cell Carcinoma: A Case Report and Literature Review: (Poster No. 172)
Radiation-induced atypia presents a diagnostic challenge in differentiation with squamous cell carcinomas of the upper aerodigestive tract and lung. It is important to understand the different features of radiation-induced atypia and differentiate it from squamous cell carcinoma. Immunohistochemical staining plays an extremely important role in present-day pathology practice. It is being used for diagnosis of primary and metastatic cancers, as a prognostic marker, targeted therapy, and identification of certain infectious agents. We report here a case of a 73-year-old man with past medical history including poorly differentiated squamous cell carcinoma of the tongue and larynx metastatic to esophagus and lungs and hepatocellular carcinoma treated with radiotherapy. Previously, fine-needle aspiration of a left lung nodule showed rare groups of highly atypical epithelial cells with high nuclear to cytoplasmic ratios, irregular nuclear membranes with uneven chromatin distribution, and moderate dense cytoplasm, and atypical cells were positive for p16 and p40. The patient now presented with a right upper lobe lung mass. Postradiotherapy histologic assessment of the lung mass with H&E stain shows features suggestive of squamous cell cancer including subpleural fibrosis, type II pneumocyte atypia, and metaplastic and vascular changes with organizing thrombus formation. Immunohistochemical stains for p16, p40, p53, cytokeratin cocktail, CK7, TTF1, Hepar, CD163 (Figure 155, D), and Ki67 (MIB1) performed on the specimen, however, supported the finding of radiation-induced type II pneumocyte atypia. This supports the use of immunohistochemistry in complicated cases that present a diagnostic challenge between recurrent cancer and radiation-induced changes.
Posterior Mediastinal Ganglioneuroblastoma in an Adult: A Rare Case Report and Literature Review: (Poster No. 173)
Ganglioneuroblastoma is a rare neuroblastic tumor of sympathetic nervous system with more than 90% of cases occurring in children (<5/ 1 000 000 per year). Based on International Neuroblastoma Pathology Committee, neuroblastic tumors are classified into ganglioneuroma (benign), ganglioneuroblastoma (intermediate malignant) and neuro-blastoma (malignant). Ganglioneuroblastoma is particularly rare in adults. Through PubMed literature search (2012–1964), only 47 cases have been reported in adults: 10 cases in adrenal gland; 7 cases in brain/skull base; 6 cases for each location in retroperitoneal, spinal cord/bone marrow, and mediastinum (superior or anterior); 4 cases in the lung; 3 cases in the kidney; 1 in nasal fossa; 1 in abdomen; and 1 disseminated. Here we present a ganglioneuroblastoma in posterior mediastinum in an adult as, to our knowledge, the first reported case. A 33-year-old man with a several-year history of chronic back pain was found to have an abnormal mediastinal contour and computed tomography and magnetic resonance imaging showed a large, homogeneous, intensely enhancing prevertebral mass from T4 to T9 level with small cystic/ necrotic areas and 2 tiny foci of calcification. Biopsy revealed the mass composed of mature gangliocyte and immature neuroblasts intermixed with stroma. The stroma shows both schwannian and neurofibrillary features. Immunohistochemical staining for neurofilament is positive in some of the cells and focally in the stroma (Figure 156). This first case report demonstrates that ganglioneuroblastoma should be considered in the differential diagnoses of a posterior mediastinal mass in an adult.
Well-Differentiated Lipoma-Like Liposarcoma Arising From a Pulmonary Hamartoma: An Uncommon Presentation of 2 Otherwise Typical Lesions: (Poster No. 177)
Pulmonary hamartomata are the most common benign tumors of the lung. They are commonly described as solitary, well-circumscribed nodules with characteristic “popcorn” pattern on imaging. Malignant transformation of hamartomata is possible but exceedingly rare. A 43-year-old woman presented with a 25-cm right chest mass, which was resected and diagnosed as a low-grade mixed lipoma-like and myxoid liposarcoma. She presented 3 years later for excision of recurrent disease, and recently presented with a 14-cm mediastinal mass with multiple smaller right pleural masses, which were all resected. Grossly, the specimen consisted of multiple pink-yellow soft tissue fragments with an embedded 2.5-cm papillomatous structure. Histologically, the lesion consisted of adipose tissue with variably sized adipocytes and atypical cells within interspersed sclerotic areas (Figure 157, a and b). A second component consisted of papillomatous areas with broad, frondlike architecture lined by flat epithelium. The stroma contained smooth muscle, adipose tissue, and disorganized hyaline cartilage without cytologic atypia (Figure 157, c and d). Immunohistochemistry revealed stromal positivity for SMA and desmin, and epithelial positivity for TTF-1 and AE1/3. The lesion was diagnosed as well-differentiated liposarcoma (WDLS) arising from a pulmonary hamartoma. Rare cases of carcinomata or sarcomata arising out of hamartomata have been described. Three previous cases documenting WDLS arising out of a pulmonary hamartoma have been reported. One study discovered similar genetic anomalies in both WLDS and hamartomatous components, offering evidence of the WDLS's origin within the hamartoma. Because of the extremely rare presentation of this tumor, the prognosis remains uncertain, necessitating close patient follow-up.
Pulmonary Cryptococcus Presenting as Inflammatory Myofibroblastic Tumor: (Poster No. 178)
Inflammatory myofibroblastic tumors (IMTs), also known as inflammatory pseudotumors, encompass a heterogeneous spectrum of reactive, infectious, and neoplastic entities that may occur at any site in the human body. They are characterized by a clinical mass composed of spindle myofibroblastic cells in a background of inflammatory cells and collagen fibers. IMTs are frequently located in the lung, and when of infectious etiology are most often due to mycobacteria. Cryptococcal IMTs have rarely been reported and primarily involve skin and soft tissue. We present a 60-year-old woman with a past medical history significant for smoking and chronic low back pain recently treated with steroids. She developed a productive cough with hemoptysis. There was no history of travel. Computed tomography scan of the chest revealed a 1.3-cm nodule in the left lower lobe. Core biopsy of the lesion revealed lung parenchyma with fibrosis and dense lymphoplasmacytic and granulomatous inflammation, consistent with IMT. Special stains revealed budding yeast forms, morphologically consistent with Cryptococcus (Figure 158). Culture of the lesional tissue grew Cryptococcus neoformans. Serum cryptococcal antigen was negative. Currently, the patient is well and opted to have her disease process monitored without antifungal therapy. IMTs caused by Cryptococcus are very rare and primarily associated with immunocompromised patients with cutaneous and soft tissue IMTs. We present a rare case in which the pulmonary IMT is the initial and only manifestation of Cryptococcus in an immunocompetent person. This case also illustrates the importance of ruling out infectious etiology in the setting of IMT.
Isolated Pulmonary Nodular Light Chain Deposition Disease Diagnosed by Core Needle Biopsy: (Poster No. 181)
Light chain deposition disease (LCDD) is an uncommon entity characterized by tissue deposition of nonamyloid κ light chains. Pulmonary involvement typically manifests as solitary or multiple spiculated nodules radiographically resembling lung cancer. Less frequently LCDD may present radiographically as cystic transformation of the lung. Histologically, LCDD may be mistaken for amyloidosis. We report a case of a 58-year-old woman who presented with dyspnea, fatigue, and multiple, bilateral pulmonary nodules on chest computed tomography scan. A transthoracic needle core biopsy of a nodule revealed amorphous, dense, eosinophilic deposits, suggestive of amyloid, in a background fibrous stroma associated with focal ossification, foreign body giant cells, and a moderate infiltrate of plasma cells showing κ–light-chain restriction by immunohistochemistry. The deposits stained strongly with PAS/diastase, and were negative for amyloid by Congo red and crystal violet stains. Electron microscopy showed electron-dense granular deposits in blood vessel walls and in the basement membrane of epithelial cells. Subsequent bone marrow biopsy was negative for plasma cell dyscrasia. Serum and urine electrophoresis were also negative for paraproteins and Bence-Jones protein, respectively. This case is interpreted as a rare presentation of isolated pulmonary nodular LCDD diagnosed by core needle biopsy. The diagnostic features of LCDD and its distinction from nodular amyloidosis are emphasized for the proper classification of deposition diseases of the lung (Figure 159).
Well to Moderately Differentiated Non–Small Cell Lung Carcinoma: To Stain or Not to Stain?: (Poster No. 182)
Context: Diagnosis of non–small cell lung carcinoma (NSCLC) with subclassification of adenocarcinoma (ADCA) and squamous cell carcinoma (SQCC) is important. Given the differences in chemotherapeutic options and associated fatal side effects, a trend of “pulmono-phobia” is growing among some physicians in relying on morphology-based diagnosis. The immunohistochemical-based diagnosis on small biopsies, if practiced in excess, conflicts with the molecular testing for EGFR and ALK.
Design: A cohort of 50 consecutive cases (26 ADCA, 19 SQCC, and 5 NSCLC, not otherwise specified) was reviewed. Diagnostic material consisted of cytology and/or biopsies. Three newly trained pathologists participated in the study. Two rounds of slide reviews were conducted, individually (prerating) and as a 90-minute group session (postrating). Interrater agreement was assessed using κ coefficients, calculated overall and for each diagnosis, along with 95% CI.
Results: Twenty-six of 50 cases (18 ADCAs and 8 SCCAs) or 52% of well to moderately differentiated NSCLCs were diagnosed on both attempts by all participants (Figure 160, A and B). The interobserver variation derives from the poorly differentiated NSCLCs (Figure 160, C and D) specifically; the overall prerating κ value is 0.573; values are 0.624 and 0.687 for ADCA and SQCC, respectively. In comparison, the overall postrating κ value is 0.523; 0.653 and 0.537 for ADCA and SCCA, respectively. There is no statistical difference between the 2 ratings (difference 0.050; 95% CI for difference, –0.104–0.226).
Conclusions: More than half of NSCLCs are well to moderately differentiated and are diagnosable morphologically. Such results add to the body of evidence supporting morphology-based diagnosis as the gold standard and could implicate in tissue conservation for EGFR and ALK testing.
Disseminated Ochroconis gallopava Infection in a Lung Transplant Patient: (Poster No. 183)
Ochroconis gallopava is an emerging cause of mycosis in solid organ transplant recipients. We report a case of disseminated O gallopava infection that involved lung, eye, and brain in a lung transplant recipient. A 65-year-old woman with a history of idiopathic pulmonary fibrosis and asthma status post single lung transplant is on chronic immunosuppression. Fifteen months posttransplant, she developed visual hallucination, confusion, and pleural effusion. She was admitted for respiratory failure and found to have disseminated O gallopava with empyema necessitans, pulmonary nodules, fungemia, and endophthalmitis. The histopathologic examination of the lung nodule showed extensive acute inflammatory infiltrate with necrotizing granulomatous inflammation and irregular branching septate hyphae. Respiratory cultures grew O gallopava. Colonies of O gallopava are characteristically flat, dry, and tobacco brown to brownish black in color. This principal pigment is melanin and it is distributed throughout the conidia and hyphae. The fungus also releases a dark brown soluble pigment into agar growth media. Infection owing to O gallopava occurs late after transplantation, suggesting that this is a community-acquired rather than a nosocomial or endogenously acquired infection. The most common presentation is pulmonary infection, although O gallopava is neurotropic. Occult central nervous system involvement may be present and should be suspected even in the absence of neurologic symptoms. O gallopava is a rare but important pathogen in immunosuppressed individuals and organ transplantation is the most common underlying condition. Pulmonary involvement is the most common manifestation among patients with organ transplant. Prognosis in organ transplant recipients is good if infection is diagnosed prior to dissemination (Figure 161).
Localized Giant Emphysematous Bullae With Placental Transmogrification in a 42-Year-Old Patient: (Poster No. 184)
Emphysematous lesions of the lung refer to a spectrum of diseases that are characterized by destruction of alveolar wall and permanent enlargement of the airspaces distal to the terminal bronchioles. Localized giant emphysematous bulla is an extremely rare form of emphysematous lesions of the lung. It is typically found in young to middle-aged adults and has a characteristic histologic pattern known as placental transmogrification (formation of placental villuslike structure in the lung). The pathophysiology of giant emphysematous bullae is not clear. Localized giant emphysematous bullae are often cured by surgical treatment. Here, we report a case of a 42-year-old man who presented with dyspnea. The patient is a nonsmoker and had no significant past medical history. Computed tomography showed markedly hyperinflated left upper lobe, which was replaced by thick- and thin-walled complex cysts causing mass effect with mediastinal shift (Figure 162, A). Radiologic findings were suspicious for a late onset of bronchopulmonary foregut malformation and surgical wedge resection of the left upper lobe was performed. Gross examination of the wedge resection specimen, which measured 21 cm in the greatest dimension, showed a complete replacement of lung parenchyma by multiple bullae. The largest bullae measured 7.5 cm. Microscopically, the cystic pulmonary lesion showed severe emphysematous changes. Within the cystic spaces, there are patchy areas with papillae lined by hyperplastic pneumocytes that resemble placental villi (placental transmogrification). Some of the cyst walls are fibrotic and contains adipose tissue (Figure 162, B through D). A diagnosis of localized giant emphysematous was made.
Pneumocytoma and Brenner Tumor in a Patient With Colonic Mucinous Adenocarcinoma: A Unique Case to Suggest a Novel Syndromic Relationship: (Poster No. 187)
We present the first case of a 69-year-old woman with a pneumocytoma, Brenner tumor, and colonic mucinous adenocarcinoma. All 3 cases of pneumocytoma associated with colonic adenocarcinomas reported in the literature are associated with syndromes; 1 in Lynch syndrome, 1 in Familial Adenomatous Polyposis (FAP) Syndrome, and 1 in Cowden syndrome. In the pneumocytoma in FAP, the pneumocytoma was found to have aberrant/nuclear expression of β-catenin. However, in the other 2 case reports, no specific abnormalities were identified (microsatellite instability or β-catenin expression. More recently, genetic analysis of pneumocytomas has shown loss of heterozygosity at 5q and 10q adjacent to the APC and PTEN tumor suppressor genes that are involved in FAP and Cowden syndromes. During metastatic workup for colonic mucinous adenocarcinoma of this 69-year-old woman, a suspected metastatic lung mass was identified as pneumocytoma. Later bilateral Brenner tumors were found. Interestingly, no aberrant expression of β-catenin or microsatellite instability was identified in the colon adenocarcinoma, Brenner tumor, or pneumocytoma. β-catenin exhibits membranous staining in all 3 tumors by immunohistochemistry. Nuclear staining of MSH2, MLH1, PMH2, and MSH6 is also preserved in all 3 tumors. No clinical presentations of Cowden syndrome are identified. This is the first case in which a colonic mucinous adenocarcinoma, a histologic type often seen in syndromic colon adenocarcinomas (particularly Lynch Syndrome), is associated with 2 other unusual tumors. The constellation of these 3 tumors suggests a novel syndromic relationship. Further molecular characterization of this case is warranted to reveal novel molecular pathways (Figure 163).
Primary Proximal-Type Epithelioid Sarcoma of the Lung: (Poster No. 188)
Epithelioid sarcoma is an uncommon sarcoma first described by Enzinger in 1970. A more aggressive, “proximal” subtype, mostly found in the perineal region of young to middle-aged adults, has been also recognized. We present the case of a 41-year-old HIV-positive man with a 2-month history of hemoptysis and weight loss. A computed tomography scan revealed a right lung mass. Endobronchial biopsies revealed an undifferentiated neoplasm. The pneumonectomy specimen showed a 5-cm hemorrhagic brown mass in the middle lobe, partially obstructing the main bronchus. Microscopically, it was composed of spindled to epithelioid cells with abundant eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli, arranged in solid sheets with a focal pseudovascular pattern and necrosis. Focal rhabdoid features were evident (Figure 164, A through C). Immunohistochemical stains were positive for EMA, CD34, and vimentin, while negative for cytokeratin AE1/AE2, CK5/6, CAM 5.2, CD31, HHV-8, S-100 protein, desmin, actin, myogenin, CD45, CD30, and CD99 with loss of nuclear INI-1 expression. A diagnosis of epithelioid sarcoma, proximal type, was established. Because there was no evidence of a primary tumor elsewhere, we considered it to be primary of the lung. To our knowledge, this is the first case report of primary lung parenchyma proximal-type epithelioid sarcoma. Only one case, localized to the pleura, has been previously reported. This entity should be considered in the differential diagnosis of an undifferentiated neoplasm of the lung. The use of an appropriate immunohistochemical panel and awareness of the molecular characteristics of this tumor will lead to a correct diagnosis and adequate therapy.
A Unique Case of a Composite Ganglioneuroma-Paraganglioma With Glandular Differentiation Arising in the Anterior Mediastinum: (Poster No. 190)
A 69-year old man presented with shortness of breath for 6 months. A chest computed tomography scan revealed a 3.6-cm mass located in the anterior mediastinum. Grossly, the lesion was well circumscribed with a homogenous, tan cut surface and surrounded by fat. Microscopic sections showed a well-defined lesion composed of 3 components. The most predominant component consisted of bland spindle cells with varying cellularity and interspersed foci of ganglion-like cells. A minor component consisted of nodules of round, epithelioid cells with eosinophilic and granular cytoplasm. Lastly, a small component consisted of rare microscopic foci of glandular structures lined by columnar, ciliated epithelium. The spindle cells were strongly positive for S100 and synaptophysin and focally positive for CKAE1/AE3. The ganglion-like cells were positive for synaptophysin, focally positive for CKAE1/AE3, and negative for S100. The epithelioid cells were positive for CD56, SOX10, NSE, synaptophysin, chromogranin, TTF-1, and calretinin and focally positive for CKAE1/AE3. All components were negative for CD34, EMA, glypican, myoD1, SMA, inhibin, Melan A, HBME1, CD5, CD30, PTH, and GFAP. Electron microscopy of the spindle cells showed features consistent with schwannian differentiation. The epithelioid cells contained mitochondria and lacked dense-core neurosecretory granules. Based on these findings, the closest entity to our lesion is a composite ganglioneuroma-paraganglioma. However, glandular differentiation has never been described in this entity, nor has it been reported in the mediastinum. Furthermore, neurogenic tumors arising in the anterior mediastinum are very rare. We presented here a unique case of a composite ganglioneuroma-paraganglioma with glandular differentiation arising in the anterior mediastinum (Figure 165).
Pulmonary Mucormycosis Presenting as a Lung Mass in Renal Transplant Patient: (Poster No. 191)
Mucormycosis is a highly invasive fungal infection caused by fungi in the proposed subphylum Mucoromycotina order Mucorales that commonly affects immunocompromised hosts, particularly those with hematologic malignancies and solid organ transplants. Patients present with several clinical forms, including rhinocerebral and pulmonary mucormycosis. We present a case of a 64-year-old man with medical history significant for coronary artery disease, diabetes mellitus with end-stage renal disease status post renal transplantation complicated by chronic rejection. He was admitted for treatment of his allograft rejection. Imaging studies revealed a new cavitary mass within the right upper lobe of the lung measuring 3.0 cm. The lesion was biopsied revealing broad, nonseptated, ribbonlike fungal elements and necrosis morphologically consistent with Mucorales species (Figure 166). The patient was started on amphotericin B and aggressive surgical resection was recommended. The patient then underwent right upper lobectomy, which showed necrotizing granulomatous inflammation and angioin-vasive mucormycosis. Postoperatively the patient deteriorated clinically and expired shortly thereafter. Invasive fungal infection following renal transplant occurs in 1%–2% of patients in developed countries. Tissue biopsy is the gold standard for diagnosis of pulmonary mucormycosis. Predisposing factors include uncontrolled diabetes mellitus, solid tumors, immunosuppressive therapy, and solid organ transplantation. A combination of surgical excision and antifungal therapy has been shown to be optimal treatment along with correction of the underlying condition. Our patient received optimum treatment, but ultimately expired. It is likely that his debilitated clinical state and comorbid factors contributed to his demise.
Idiopathic Pleuropulmonary Fibroelastosis—A Recently Defined Entity: (Poster No. 193)
Idiopathic pleuroparenchymal fibroelastosis is introduced as a distinct entity in the revised classification of idiopathic interstitial pneumonia in 2013. The etiology is unknown; however, associations with recurrent infections, chemotherapy, and other conditions have been described in literature. We present a case of this rare clinicopathologic syndrome that raises the possibility of a multifactorial etiopathogenesis. A 72-year-old woman with a past medical history significant for hypertension, gout, and hyperlipidemia, and taking multiple medications including amlodipine, allopurinol, sildenafil, and ergocalciferol, was admitted for presumed exacerbation of right heart failure. A right-heart catheterization revealed normal right-heart pressures. Subsequent pulmonary evaluation for worsening dyspnea led to a provisional diagnosis of interstitial pulmonary fibrosis. Computed tomography scan demonstrated right-side–predominant disease, with right–upper-lobe fibrosis, traction bronchiectasis, and ground glass opacities in all lobes; findings that are atypical for interstitial pulmonary fibrosis. The patient then underwent open lung biopsy for diagnosis. Histology showed upper lobe–predominant pulmonary fibrosis with pleural thickening and sub-pleural and septal fibroelastosis. An elastic stain (EVG) highlighted collections of elastic fibers; otherwise the lung showed preserved normal architecture. The lower lobe showed organizing aspiration pneumonia. The final diagnosis was pleuroparenchymal fibroelastosis. Although we do not know the exact reason for this pathologic change, potential explanations such as aspiration pneumonia or medications could possibly be the inciting event in this case. This mystery remains unsolved, as the term “idiopathic” suggests. The diagnosis of this disease is established on the basis of compatible radiologic and pathologic findings of typical subpleural fibroelastosis (Figure 167).
Piloting a Surgical Pathology Workflow Reprioritization: Increasing Resident Preview Time While Sustaining, If Not Improving, Turnaround Time: (Poster No. 195)
Context: The pressure to shorten large-specimen turnaround time (TAT) to expedite patient care can negatively impact residency education by diminishing the time allotted to residents for independent slide preview (resident preview time [RPT]). In our laboratory, large specimens received after 2 PM (day 0) are dissected the following day (day 1) and are processed that evening beginning at 8 PM on an 8-to 12-hour cycle. Small and rush biopsy prioritization by first-shift histotechnologists delays slide preparation for large specimens on day 2, resulting in either diminished RPT or increased TAT. To improve RPT on day 2 without negatively impacting TAT, an alternative workflow method was instituted.
Design: Large specimens were divided into 2 groups. Group A was dissected and processed according to usual protocol. Group B was grossed the evening of day 0 or early morning of day 1 and run on supplemental processor beginning 6 AM on day 1, with slides prepared by second-shift histotechnologists the evening of day 1 alongside small biopsies. This allowed RPT to begin early morning of day 2. For both groups, number of blocks submitted, time of slide readiness, and overall RPT (defined as hours prior to 3:30 PM) were recorded.
Results: The Table demonstrates the improved RPT and TAT.
Conclusions: A small change to standard workflow resulted in a dramatic increase in RPT for group B specimens, and did not negatively affect TAT. Easily done on a small scale, this pilot study promises to improve this essential component of residency training.
Clinical Experience Using Genetic Identity Testing in an Anatomic Pathology Laboratory: (Poster No. 198)
Context: Specimen misidentification or contamination can occur before the specimen arrives in the laboratory or at any point in the anatomic pathology workflow, and has major implications for patient safety. We describe our institution's experience with genetic identity testing to resolve such cases.
Design: Thirty-nine cases were identified at or referred to our facility between 2010 and 2015 for genetic identity testing because of suspicion for specimen misidentification or contamination. Testing was performed by multiplex polymerase chain reaction of 15 polymorphic microsatellite loci followed by capillary electrophoresis (AmpFlSTR Identifiler, Applied Biosystems, Foster City, California).
Results: Overall, 25 of 39 cases (64%) were confirmed to represent misidentification or contaminant (Table). Two (8%) of the cases of misidentification or contamination occurred prior to specimen arrival in the laboratory, 19 (76%) occurred in the laboratory, and in 4 cases (16%) it was unknown where the error occurred. Twenty cases were tested because of concern for a “floater” or carryover; 14 (70%) were confirmed to represent contaminant. Four cases were tested after diagnosis because of concerns raised by an apparent lack of clinicopathologic correlation; in each (100%), testing confirmed that no contamination or misidentification had occurred.
Conclusions: Specimen misidentification or contamination arises in a wide variety of scenarios, and pathologists are a key safeguard in such cases. Suspicions about possible specimen contamination or misidentification are frequently confirmed. Genetic identity testing is a highly effective tool for the anatomic pathologist in cases of suspected misidentification, and can prevent unnecessary repeat diagnostic testing, unwarranted therapeutic interventions, and delays in diagnosis.
Review of Cytology Cases With Improper Patient and/or Specimen Identification: (Poster No. 201)
Context: Proper patient identification and specimen labeling is required to protect patients from the adverse consequences of errors. The same patient-specific identifiers must be directly associated with the individual and with the specimen containers. The aim of this study was to review cytology cases with improper patient and/or specimen identification and to analyze the most common errors.
Design: This was a retrospective review of cytology cases with improper identification during a 2-year period (January 2012–December 2013) received in the Department of Pathology at University of Florida Health, Jacksonville.
Results: We reviewed 146 cytology cases with improper patient and/ or specimen identification. Registration error (RE), including improper patient registration like misspelled names, error in the date of birth or patient sex upon registration, or failure of timely registration was identified in 102 cases (70%) (Figure 168). Unlabeled specimen containers and mismatches in the name, sex, date of birth, or laterality on the container and requisition sheet was identified in 39 cases (27%) and attributed to a submitting error; 11 of these cases were rejected because of failure of an appropriate identification. Five cases (3%) were mislabeled by a cytotechnologist during the specimen processing and were designated as a processing error.
Conclusions: The analysis of all cases with improper patient and/or specimen identification during a 2-year period revealed the RE to be the most common error (70% of cases), whereas the submitting error was found to be the more significant because 11 of these cases were rejected. There was no impact on patient care in any of these cases.
Preanalytic Errors in the Clinical Laboratory: A 5-Year Follow-up: (Poster No. 203)
Context: Medical errors account for 98 000 deaths in US hospitals each year; the actual number is higher because hospitalized patients are a small percentage of the population. Reducing medical error is one of the main patient-safety goals in laboratories. Order entry accuracy is part of the quality management indicators to improve the performance and overall quality of the laboratory.
Design: Data were collected based on order-entry accuracy from 2010 to 2014. Errors were divided into 3 levels: level 1, failure to update information; level 2, failure to enter/add information; and level 3, entering wrong patient name, incorrect tests entered, or missing tests. Statistical analysis was done using Analyse-it.
Results: The percentage total error ranged from 4.3% in 2010 to 1.1% in 2014. Most errors were level 2; physician name discrepancy was the most common. New employees increased the error percentage until they received training. Increasing online ordering and implementing in-service sessions to educate staff about the common errors helped lower the error rate (Table).
Conclusions: We were able to decrease errors by encouraging clients to use online order entry and by increasing our ongoing monitoring of the accuracy of the order-entry error and then using the results as a quality indicator. In addition, having supervisors and employees involved in the error reduction by having regular meetings to discuss common mistakes and strategies to reduce them was one of the most successful tools to reduce errors.
Hematology Sample Rejection by Cause and Phlebotomist Type: A Single-Center Experience: (Poster No. 205)
Context: Specimen rejection may adversely affect patient care by delaying results and causing phlebotomy-associated anemia. It is important to monitor specimen rejections in relation to published benchmarks as part of the laboratory quality management program. Likewise, the reasons for sample rejection must also be monitored to promptly address caregiver in-service needs and to intervene appropriately.
Design: We reviewed the sample rejections in our hematology laboratory for 12 consecutive months from January to December 2014. We obtained the data via the laboratory information system and paper documentation. Our rejection rate was compared against the College of American Pathologists survey data published in July 2012. Specimen rejections were then categorized by rejection reason, phlebotomy-collection, unit-collection, and hospital unit.
Results: The mean specimen rejection rate in our hematology laboratory was 0.24%. Rejections were triggered by clotted samples (90%), specimen insufficiency (5%), and other reasons (5%) (Figure 169). We determined that 80% of specimen rejections were unit-collected specimens, and the units with highest volume of specimen rejections were then identified.
Conclusions: Our hematology specimen-rejection rate is well below published benchmarks, and 95% of rejections were due to improper phlebotomy technique; 80% of rejections were collected by nursing staff. Our data show that phlebotomy in-service should be directed to specific nursing units. Preanalytic errors, such as improper collection technique, are a major contributor to rejection, and an effective phlebotomist education and training program is essential to delivering high-quality patient care.
Bone Marrow Collection Technique to Accommodate Precollection Uncertainties: (Poster No. 209)
Context: Bone marrow (BM) samples must be suitable for morphologic exam, flow cytometry, cytogenetics, fluorescence in situ hybridization (FISH), and molecular tests. Often the required tests, and thus, the number and types of samples, cannot be anticipated at the time of collection. In addition, BMs without a tube for polymerase chain reaction (PCR) or FISH had been a recurring problem. We developed a BM collection protocol that ensures adequate numbers and types of specimen tubes are collected.
Design: We determined sample requirements for an uncomplicated exam and those requiring specialized FISH and/or PCR. When placing the order, the provider includes the clinical history and indicates whether the exam is for myeloma/monoclonal gammopathy of undetermined significance (MGUS), pancytopenia, or acute leukemia. These questions determine what samples are collected (Table). Six months of specimen-collection data were reviewed to determine how well the protocol was followed. An anonymous survey was administered to technologists to evaluate the protocol's impact on workflow.
Results: One hundred sixty-eight BM specimens were collected from adult patients. The protocol was followed in 156 (93%) cases. All specimens that were collected by the standardized protocol had adequate material for diagnostic and prognostic testing. Patient-related factors were a documented barrier among the nonconforming cases. Technologists indicated that the procedure was easier to follow, improved collection of the correct samples, and enhanced communication with clinicians.
Conclusions: Standardization of BM collection procedures ensured that adequate samples were procured, even when testing requirements were uncertain at the time of the procedure. Clinicians and technical staff successfully used the protocol implemented at our institution.
Autopsy and Forensic Pathology; Bone and Soft Tissue Pathology; Breast Pathology; Gynecologic and Placental Pathology; Kidney and Genitourinary Pathology; Ophthalmic Pathology The Important Role of Autopsy to Finalize the Cause of Death: (Poster No. 1)
Autopsy serves an important role in diagnosis and as a teaching tool for clinicians. The deceased was a 66-year-old man with a history of unknown fever for 6 months. He also had a history of weight loss and anorexia for that period. The biochemistry panel did not show any abnormalities except a high erythrocyte sedimentation rate. The panculture did not grow any microorganisms. Whole-body imaging, including brain magnetic resonance imaging and chest/abdominopelvic computed tomography scan, with and without contrast, did not show any abnormality. His condition deteriorated over time and ended with cardiopulmonary arrest. A complete autopsy was performed to show heavy lungs, with 100-cm3 serosanguinous pleural effusion on both sides. No other gross abnormality was identified. Microscopy sections of the lung showed diffuse, perivascular lymphocytic infiltration. Immunohistochemical stain was done to show positivity for CD20, CD10, and BCL6, with high Ki-67, to confirm the diagnosis of diffuse large B-cell lymphoma (Figure 170). This case exemplifies the important role of autopsy in diagnosis and clinician education, although, unfortunately, many people, including clinicians, pay less attention to its critical role.
Methicillin-Resistant Staphylococcus aureus Prostatic Abscess and Multiorgan Microabscesses: An Autopsy Case Report and Review of the Literature: (Poster No. 2)
Prostatic abscess is a rare medical condition that can occur in the setting of acute bacterial prostatitis, and it is primarily diagnosed in patients with preexisting comorbidities or immunocompromised states. It is largely caused by gram-negative organisms and seldom by Staphylococcus aureus. Community-acquired, methicillin-resistant Staphylococcus aureus (MRSA) causes a significant number of skin and soft tissue infections, but rarely causes infections of the genitourinary system. To our knowledge, there are currently 7 reported cases of prostatic abscess caused by MRSA. The patients in the reported cases were either diabetic, had a history of AIDS, or had a history of intravenous drug abuse with hepatitis C infection. Only one patient in the literature died from complications of prostatic abscess. We present the eighth case of prostatic abscess caused by MRSA, and the second case resulting in death from this rare condition. This case is unique because our patient did not have diabetes, AIDS, or any history of intravenous drug abuse. Additionally, the prostatic abscess was found at autopsy (Figure 171, A and B), and the urine culture results indicating the presence of MRSA were not available until after the patient's death. Other unique findings at autopsy included sepsis, evidenced by widespread microabscesses in the lungs (Figure 171, C), liver, heart, and kidney. Additionally, Roth spots were found in the right eye (Figure 171, D). This case adds important, new information about prostatic abscess caused by MRSA, including increased morbidity and the possibility of this unique infection in healthy, immunocompetent patients.
Autopsy Confirmed Signet-Ring Cell Adenocarcinoma of the Gallbladder With an Endometrial Polyp Metastasis: (Poster No. 7)
Gallbladder cancer accounts for 0.5% of gastrointestinal malignancies in the United States. Signet-ring cell adenocarcinoma is a rare variant, accounting for 3% of gallbladder neoplasms and is often missed radiographically. We present a 60-year-old woman with worsening bone pain who was diagnosed with metastatic signet-ring cell carcinoma with unknown primary by bone marrow biopsy. A primary neoplasm from the breast and colon was unlikely based on immunohistochemical staining. Computed tomography imaging showed stones in the gallbladder without an overt mass (Figure 172, A) and positron emission tomography demonstrated multiple metastases without an identifiable primary tumor. After her death, the family requested an autopsy to determine the primary cancer site. At autopsy, her gallbladder had a visible, tan-white fundal discoloration with wall thickening and 2 pigmented calculi (Figure 172, B). Porta hepatis lymph nodes and a right temporal bone lesion had a similar tan-white appearance on gross examination. No masses or wall thickening involved the stomach, intestines, or appendix. Histopathologic examination of the gallbladder showed cells with signet-ring cell appearance mixed with less than 50% poorly differentiated adenocarcinoma (Figure 172, C). Metastases, composed predominately of signet-ring cells, were in the ovaries, liver, temporal bone, lymph nodes, and a uterine polyp (Figure 172, D), with lymphatic invasion of the leptomeninges, choroid plexus, adrenal glands, lungs, epicardium, and pancreas. This case illustrates the utility of the autopsy in the setting of a rare, radiographically challenging neoplasm and documents an endometrial polyp metastasis, which has been previously reported in the literature only once to our knowledge.
Infective Endocarditis: An Advanced Undiagnosed Case and Its Autopsy Findings: (Poster No. 9)
A 44-year-old man who had been hospitalized for 6 days in Mexico with a working diagnosis of pneumonia was transported across the international border and admitted to University Medical Center in El Paso, Texas, with a chief complaint of acute, altered mental status. He had been experiencing intermittent low-grade fevers and malaise for approximately 1 month for which he had received several doses of intramuscular penicillin with no improvement. The patient had begun experiencing left-sided weakness, aphasia, and right gaze preference just before transport. Upon arrival, he presented with a septic-shocklike picture with fever, tachypnea, tachycardia, hypotension, and leukocytosis with left shift. Otherwise, his examination was consistent with right-sided stroke and possible low-pitched middiastolic murmur. Computed tomography showed multiple wedge-shaped hypodensities within the spleen, kidneys, and brain. Chest radiograph showed pulmonary edema consistent with poor cardiac contractility. Blood cultures grew gram-positive cocci in clusters presumed to be Staphylococcus aureus. Although he had no known risk factors, endocarditis with systemic septic emboli was the working diagnosis. Autopsy confirmed endocarditis with evidence of septic emboli. His aortic valve harbored an irregular, friable vegetation on the posterior cusp (Figure 173, A). Microscopically, the valve showed extensive neutrophilic inflammation extending to the myocardium with frequent bacteria (Figure 173, B). Sites of visceral infarction included the kidneys, spleen, liver, and the heart itself. (Figure 173, C1 through C4) This patient presented with diagnostic criteria for endocarditis. A higher degree of clinical suspicion could have prevented the delay in proper treatment.
Autopsy Findings in a Case of Disseminated Extranodal NK/T-Cell Lymphoma: (Poster No. 11)
We report the autopsy findings of a case of natural killer (NK)/T-cell lymphoma in a patient who presented with disseminated disease after being in remission for more than 4 years. A 34-year-old, Hispanic woman presented with abdominal pain. Her medical history included nasal cavity NK/T-cell lymphoma, diagnosed 4.5 years previously, after chemotherapy and radiation therapy. She had multiple hospitalizations during the prior 2 years, with pancytopenia. Bone marrow biopsy and cerebrospinal fluid and lymph node biopsies performed during these admissions were negative for lymphoma. During her current admission, laboratory results revealed severe pancytopenia and disseminated intravascular coagulation. Reverse-transcription polymerase chain reaction for Epstein-Barr virus DNA revealed very high copies. The patient was managed with multiple units of platelet transfusions and supportive therapy. However, she succumbed to her illness after 11 days. A complete autopsy was performed. The most significant finding was multiple organ involvement (mediastinal and hilar lymph nodes, liver, spleen, epicardium, pancreas, uterus, and bone marrow) by NK/T-cell lymphoma, nasal type. Sections from the lymph nodes showed diffuse effacement by medium- to large-sized, atypical lymphocytes associated with extensive areas of necrosis and prominent apoptosis. The neoplastic cells revealed strong expression of CD3 and CD56. In situ hybridization for Epstein-Barr virus-encoding region showed positive results (Figure 174). The extranodal sites revealed patchy nodular involvement by neoplastic lymphoid cells. We present this case to highlight the unpredictable and often relentless nature of this rare lymphoma.
Multiorgan Tissue Eosinophilia of a Preterm Infant: An Autopsy Case Report: (Poster No. 15)
Neonatal tissue eosinophilia involving multiple disparate organ systems is rarely encountered. We report a case of multiorgan tissue eosinophilia of uncertain etiology in a decedent, preterm neonate. An African-American male weighing 925 g was born at 26 weeks, 4 days gestation to a healthy 26-year-old woman via spontaneous vaginal delivery. On day 16 of life, sepsis was diagnosed, and antibiotics were started. After a period of worsening hypoxia, acidosis, and hypotension, the patient expired. A severe, necrotizing bronchopneumonia secondary to Escherichia coli and Pseudomonas aeruginosa infection was diagnosed at the postmortem examination. Incidentally, widespread tissue eosinophilia involving the pancreas, gallbladder, kidneys, adrenals, testes, thymus, and bone marrow was found. The infiltrates were most prominent in the pancreas (>100 eosinophils per ×400 high-power field) and gallbladder (>80 eosinophils per ×400 high-power field). In the pancreas, the eosinophils showed diffuse infiltration of the interlobular connective tissue septa with sparing of the acini and islets (Figure 175). In the gallbladder, the infiltrate primarily involved the smooth muscle layer. Interestingly, there was no tissue damage associated with the infiltrates, and only a mild peripheral blood eosinophilia was noted. The infiltrates were thought to be an abnormal immune response to the severe bronchopneumonia. A review of the literature failed to reveal any similar case reports. To our knowledge, this is the first case report to demonstrate widespread tissue eosinophilia of a preterm infant involving multiple, disparate organ systems in the absence of organ damage.
Anomalous Origin of Left and Right Coronary Arteries From a Single, Common Ostium in the Right Sinus of Valsalva: A Rare Autopsy Finding: (Poster No. 17)
A common left coronary artery (LCA) and right coronary artery (RCA) origin from a single right coronary sinus ostium (RCSO) is a very rare congenital anomaly associated with significant risk for myocardial ischemia/infarction, arrhythmias, and sudden death. We present a case of a 71-year-old woman with history of hypertension, diabetes, chronic heart failure, carotid endarterectomy, and bilateral inguinal grafts for peripheral and carotid artery stenosis. She presented with acute chest pain radiating to the back, elevated troponins, and electrocardiogram findings of posterior ventricular wall and septal infarction. Urgent catheterization revealed aberrant a LCA origin and critical RCA narrowing. She died from intractable ventricular fibrillation. The autopsy revealed a right-dominant coronary circulation with common LCA and RCA origin from a single RCSO (Figure 176, A and B). The anomalous LCA coursed behind the pulmonary artery before dividing into the left anterior descending and left circumflex arteries. Severe atherosclerosis (80% narrowing) was present in the single RCSO and proximal RCA segment. Acute myocardial infarction of 1–4 days was present in the left posterior ventricular wall and septum. Anomalous LCA origin from RCSO is described in 0.02% of autopsies. Most cases arise from a separate RCSO. In our case, LCA and RCA branched from single RCSO. Anomalous LCA may take 1 of 4 courses: posterior to aorta, anterior to pulmonary artery, interarterial (between aorta and pulmonary arteries), and septal course. The later 2 courses have a greater risk of myocardial ischemia/infarction. Surgical correction is generally recommended because of the high risk of myocardial infarction and sudden death.
Gestational Alloimmune Liver Disease and Neonatal Hemochromatosis: (Poster No. 19)
Neonatal hemochromatosis is a very rare disorder characterized clinically by early onset hepatic failure in neonates and elevated ferritin, α-fetoprotein, liver enzymes, and cortisol levels. The current hypothesis is an in utero, alloimmune disease caused by maternal antibodies against fetal hepatocytes, which leads to destruction of hepatocytes associated with hepatic and extrahepatic hemosiderin deposition. A term, 2900-g, male neonate presented with hepatorenal failure. Iron deposition was seen on a buccal mucosa biopsy (Figure 177, A). Multiple exchange transfusions and intravenous immuno-globulin were administered. Despite aggressive treatment, he developed multiorgan failure and died on day 17 of life. At autopsy, no hematopoiesis was noted in the liver. The lobular architecture of the liver and the limiting plate were poorly defined. Biliary cirrhosis with regenerative nodules, diffuse hepatocellular iron deposition, and giant cell transformation were seen (Figures 177, B and C). Hepatic cholestasis, cholemic nephrosis, renal medullary erythropoiesis, and dyserythropoiesis in the bone marrow were also seen. Precocious development of adult adrenal cortical gland, adenomatous hyperplasia of pancreatic islets, thymic dysplasia, diffuse lymphedema, and degeneration of anterior horn cells were additional findings. Sheets of nucleated red cells were present in the maternal lakes of the placenta, which support the alloimmune hypothesis of in utero sensitization (Figure 177, D); the pathogenesis of gestational, alloimmune liver disease with neonatal hemochromatosis appears to begin in the placenta as an immune attack on fetal vasculosyntitial membranes with a possible role for fetal hepcidin.
Intrauterine Fetal Demise From Fetal Thrombotic Vasculopathy: (Poster No. 21)
Fetal thrombotic vasculopathy is characterized by hypovascular and avascular villi and villous stromal-vascular karyorrhexis. These lesions are classified based on the extent of involvement of the placental parenchyma. Cases with 15 or more avascular villi per section are classified as extensive. Severe lesions can be associated with adverse pregnancy outcomes. We present a case of a 33-year-old woman (gravida 2, para 0010) with a medical history significant for morbid obesity (body mass index, 45). The prenatal history was significant for decreased fetal movement, which was monitored by weekly nonstress tests. She presented with intrauterine fetal demise at 34 6/7 weeks of pregnancy and delivered a stillborn fetus by cesarean section. The major findings at autopsy were in the placenta. Histologic evaluation of the placenta revealed areas of avascular villi, with 15 or more avascular villi per section, and villous stromal-vascular karyorrhexis. In addition, there were intimal fibrin cushions in the placental vessels with calcifications in the walls, causing narrowing of the vascular lumen, and intervillous thrombohematomas with necrosis of entrapped villi. Compromised umbilical cord flow with stasis is the risk factor for avascular villi, and severe lesions are associated with central nervous system damage in term pregnancies and adverse pregnancy outcomes. The cause of death in this case was intrauterine fetal demise from fetal hypoxia as a result of fetal thrombotic vasculopathy (Figure 178). Immunohistochemical staining with CD34 highlighted normovascular, hypovascular, and avascular chorionic villi.
Staphylococcus lugdunensis Infective Endocarditis Leading to Septic Shock With Severe Hypoglycemia and Multiple Emboli: An Autopsy Case Report: (Poster No. 22)
Staphylococcus lugdunensis (SL) is a relatively rare cause of infective endocarditis (IE), accounting for 1% of all cases of IE and 2% of cases involving nondrug abusers. Most reports of SL IE occur following surgical procedures or skin trauma/infection in the pelvic/perineal region. Although SL IE often involves the native aortic or mitral valves, less than 15% of cases involve both left-sided valves. Often, SL IE results in cardiac failure, abscess formation, and multiple septic emboli, and is fatal in 30%–50% of cases. We report a case of a 49-year-old man, nondrug user, with end-stage renal disease and no history of pelvic surgery/injury who presented with complaints of chronic cough, abdominal pain, and diarrhea with fever. During his hospital stay, SL bacteremia was discovered, and imaging revealed cardiomegaly and large aortic and mitral valve vegetations. He died 3 days postadmission from septic shock after exhibiting severe hypoglycemia (glucose <10) and a non–ST-elevation myocardial infarction. At autopsy, there were large, aortic and mitral valve vegetations with perforation of the right aortic valve leaflet (Figure 179, A); a large, right pulmonary artery bifurcation, nonseptic thromboembolus (Figure 179, B); and multifocal areas of full-thickness hemorrhagic necrosis of the large intestines, consistent with septic emboli (Figure 179, C). This case highlights an unusually low glucose level as an indicator of fatal septic shock and the contributory effects of nonseptic emboli as cause of death from SL IE.
Novel Autopsy Findings in a Case of Costello Syndrome: (Poster No. 24)
We report multisystem autopsy findings from a 7-year-old boy with genetically confirmed Costello syndrome (G12A mutation of the HRAS gene) who died suddenly. The patient displayed a complete phenotype of this rare syndrome (estimated to affect 300 individuals to date). His clinical course was typical, with normal weight and height at birth and thereafter, progressive growth retardation, delayed bone age, failure to thrive despite feeding gastrostomy, and central nervous system developmental delay. Infancy and childhood were complicated by seizure disorder, cardiac disease, and multisystem endocrinopathy. Increasingly recognized in Costello syndrome, our patient manifested a complex endocrinopathy involving pituitary, adrenal, thyroid, and pancreas. He remained unable to speak or stand, only slept for 2 to 3 hours at a time, and preterminally had advanced cardiac decompensation. Autopsy findings, apart from small organs for age, included cardiac disease comprising severe left ventricular hypertrophic cardiomyopathy (Figure 180, A) with myofiber disarray (Figure 180, C) and polyvalvular dysplasia. A newly described pulmonary arterial and venous structural musculoelastic dilation (Figure 180, D) was observed throughout sections of lung, representing the second report, to our knowledge, to date. Finally, the pancreas showed diffuse nesidioblastosis/pancreatic islet cell hyperplasia (Figure 180, B). Although recently, an insulin-producing islet cell tumor was reported in Costello syndrome, our endocrine pancreatic pathology represents the first morphologically confirmed association, to our knowledge, of nesidioblastosis with hypoglycemia in a patient with G12A mutation Costello syndrome.
Cirrhosis and Emphysematous Change in a 12 Month-Old Male Infant: (Poster No. 25)
A preterm, male infant, born at 24 and 5/7 weeks gestation, with history of necrotizing enterocolitis and respiratory distress syndrome, expired at 1 year old of acute bronchopneumonia. The patient required mechanical ventilation and total parenteral nutrition for most of his life. The patient also had a history of elevated alkaline phosphatase, hypertriglyceridemia, transaminitis, and hyperbilirubinemia. Autopsy was performed at the request of the parents. Gross findings included hepatomegaly and pulmonary congestion. Histologic examination revealed cirrhotic liver with prominent bile duct proliferation and plugging (Figure 181, A). Emphysematous change with hypertrophy of bronchiolar smooth muscle was identified in the lungs (Figure 181, C). Given the unusual hepatic and pulmonary findings in a 1 year old, the diagnosis of α1-antitrypsin (A1AT) deficiency was considered. Immunohistochemical stains for A1AT revealed extensive deposits of A1AT in the liver (Figure 181, B). Periodic acid–Schiff-diastase stain, however, revealed diastase-sensitive intrahepatic glycogen. The lungs displayed extensive A1AT staining (Figure 181, D). An A1AT deficiency presents with diastase-resistant intrahepatic glycogen deposits and markedly decreased A1AT staining in pulmonary sections. Given these findings, A1AT deficiency was ruled out. A search of the literature revealed that prolonged parenteral feeding may induce cirrhosis and hepatic/biliary derangements, including those seen in this patient. Prolonged ventilator dependence may also lead to emphysematous change and hypertrophy of bronchiolar smooth muscle. Thus, the unusual pulmonary and hepatic findings were consistent with prolonged parenteral feedings and mechanical ventilation. This case demonstrates A1AT deficiency may mimic the histologic changes seen in critically ill patients dependent on intravenous nutrition and mechanical ventilation.
Gas Gangrene of the Pancreas: (Poster No. 26)
Primary gas gangrene of the pancreas caused by Clostridium perfringens is a rare condition. The decedent was a 46-year-old man admitted to the emergency department for confusion and shortness of breath. He complained of nausea, vomiting, diarrhea, and abdominal pain for a day. He had no fever, chills, or recent hospital admissions. On admission, he had cardiac arrest and respiratory failure. Physical examination showed marked abdominal distension. Computed tomography scan of the abdomen showed gas in the portal venous system and free air in the peritoneum. Blood cultures were positive for Clostridium perfringens. His condition deteriorated, and he died. At autopsy, significant findings included massive fatty liver, multinodular goiter, and Hashimoto thyroiditis. There was no evidence of bowel perforation. On gross examination, the cut section of the pancreas was soft and hemorrhagic without the normal coarse and lobular appearance. On microscopic examination, the pancreas showed multiple empty spaces filled with clusters of gram-positive organisms (Figure 182) and extensive necrosis with no inflammatory response. The blood culture, histology, Gram stain, and clinical findings were consistent with gas gangrene from Clostridium perfringens. There was no evidence of Clostridium perfringens infection in other organs. Abdominal infections from Clostridium perfringens are rare and include necrotizing jejunitis, emphysematous cholecystitis, and gas gangrene of the pancreas. Among the 16 cases of gas gangrene of the pancreas previously reported, 5 cases were primary infections. Here, we report an additional case of this rare occurrence.
Full Urorectal Septum Malformation Sequence: (Poster No. 30)
Full urorectal septum malformation (URSM) sequence is characterized by the absence of perineal and anal openings in association with urogenital, colonic, and musculoskeletal anomalies and ambiguous genitalia. The incidence is 1 in 50 000–250 000 neonates. We report such a rare entity presenting like prune belly syndrome. A 2147-g preterm fetus was born at 32 weeks gestation, to a healthy 28-year-old African American woman (gravida 8, para 6), with multiple congenital malformations who survived for 2 hours. The placenta was large with a single umbilical artery, acute ascending infection, and mild villous edema. Autopsy demonstrated minor dysmorphism with a short-webbed neck, low-set ears, epicanthal folds, high palate arch, single palmar crease, and rocker-bottom feet. A volume of 390 mL of ascites was present (Figure 183, A). No perineal openings were present (Figure 183, C). Ambiguous external genitalia were present. A common cloacal sac with ovaries and fallopian tubes was present (Figure 183, B). Meconium was not present in the cloacal sac. The anorectum, urinary bladder, uterus, urethra, and vagina were not identified grossly. Bilateral pulmonary hypoplasia was present. The left kidney, ureter, and adrenal gland were absent. A short small bowel and blind-ended colon were present. Costovertebral segmentation anomalies, mild scoliosis, iliac bone hypoplasia, knee dislocation, and equinovarus feet were identified. Delayed brain development and agenesis of the corpus callosum were also present. Hypotheses of caudal mesodermal arrest, vascular steal, teratogens, and lateral compression of the caudal embryo have been suggested pathogenic mechanisms. Sonic hedgehog (SHH), HOX, PAX, and Ephrin-B2 genes have been reported related to this sequence.
Unexpected, Fatal, Massive Meningeal Cryptococcal Meningitis in a Patient With AIDS: Autopsy Case Report: (Poster No. 32)
Cryptococcus meningitis (CM) is a rare complication of immunocompromisation, affecting 1 in 200 000 people per year in the United States; however, CM is a major cause of morbidity and mortality in the immunocompromised. The rate of CM has been decreasing because of improved therapies and increased awareness. Studies have characterized a fluctuating epidemiology, which remains as an important threat in the United States. We report a case of cryptococcal meningitis in a 51-year-old man. The patient presented with headache followed by a syncopal episode, anorexia, and weight loss. The patient was noncompliant with highly active antiretroviral therapy, with a CD4 count of 64. The patient had a history of pulmonary cryptococcal pneumonia. During the course of admission, he deteriorated and expired. On autopsy, the lungs were congested, and 2 focal nodules were present in the left lower lobe (2 and 0.5 cm in diameter), with an enlarged mediastinal lymph node present. The brain had a mushy consistency, and the meninges had a slimy texture. Histologically, the meninges, lung nodules, and enlarged lymph node contained a large number of cryptococci, identified through special stains (Figure 184, A through D). Ultimately, the patient had died of cryptococcal meningitis, secondary to residual cryptococcal pneumonia AIDS. Cryptococcal meningitis is a rare phenomenon in the developed world thanks to advances in medical therapy and preventive strategies. However, an increasing burden of immunocompetent infections with a fluctuating epidemiology as well as severe complications makes cryptococcal meningitis an important public health focus.
Primary Rosai-Dorfman Disease of the Bone: (Poster No. 34)
Rosai-Dorfman disease, also known as sinus histiocytosis with massive lymphadenopathy, is an idiopathic histiocytosis of uncertain etiology. It usually presents with lymphadenopathy, fever, an elevated erythrocyte sedimentation rate, and leukocytosis. Up to 43% of patients exhibit concurrent extranodal disease, including bone involvement in 2%–10% cases. Primary Rosai-Dorfman disease of the bone, however, is extremely rare, with 47 cases reported in the literature. This entity almost invariably poses a diagnostic challenge on biopsy because of its rarity, lack of specific clinical and radiologic findings, and a histologic appearance mimicking osteomyelitis or granulomatous disease. Here, we describe our encounter with such a case with clinical, radiologic, and histologic findings and discuss the treatment and follow-up. Importantly, we also document features seen on fine-needle aspiration cytology and intraoperative frozen section examination. A 44-year-old, African-American woman presented with swelling and tenderness of her right distal thigh. No lymphadenopathy was noted. Imaging revealed a 1.0-cm intramedullary lucent lesion with a lamellated periosteal reaction in the distal femoral metadiaphysis. Biopsy showed mixed, chronic inflammatory cells, suggestive of chronic osteomyelitis. Flow cytometry and microbiologic culture results were negative. Concurrent fine-needle aspiration cytology, however, demonstrated atypical histiocytes with extensive emperipolesis. Subsequent intraoperative and permanent sections showed numerous foamy histiocytes with frequent emperipolesis infiltrating the bone marrow, admixed with scattered benign lymphocytic aggregates (Figure 185). These histiocytes were positive for S100 protein. The patient was treated with additional curettage and grafting for fracture at the site of her residual disease 1 year later but has been disease free for 4 years.
Evaluation of PRKCB Expression in Ewing Sarcoma: A Promising, Novel Immunohistochemical Diagnostic Marker: (Poster No. 38)
Context: Histologic diagnosis of Ewing sarcoma (ES) can be challenging because of overlapping features with various small, round cell sarcomas. CD99 and FLI1 antibodies are frequently used but lack robust sensitivity and specificity. Microarray gene-expression studies have demonstrated significant PRKCB overexpression in ES. PRCKB was shown to be directly regulated by the chimeric fusion oncogene EWSR1/FLI1. Is PRKCB immunostain (IHC) useful in ES diagnosis?
Design: With institutional review board approval, representative sections (4 μm) of formalin-fixed, paraffin-embedded tissue of 64 ESs and 35 non-ESs were subjected to PRKCB immunohistochemistry. An EWSR1 break-apart fluorescence in situ hybridization (FISH) probe was used to detect EWSR1 rearrangements. EWSR1/FLI1 fusion was detected by reverse transcription-polymerase chain reaction (RT-PCR). Three cases were analyzed by cytogenetics. Seven distinctive tumors did not require molecular testing.
Results: Two samples that were positive for a rearrangement of the EWSR1 locus by FISH but negative for PRKCB expression were desmoplastic small round-cell tumors (DSRCTs), for which EWSR1/WT1 fusion is the genetic hallmark. The RT-PCR confirmed the EWSR1/FLl1 status in 17 cases, which were directly correlated with PRKCB expression. Although the EWSR1 break-apart probe used in most of the cases does not identify its fusion partner, evidence from 17 cases with RT-PCR confirmed EWSR1/FLI1 fusion status combined with the absence of PRKCB expression in DSCRT, which strongly suggests that PRKCB expression is predictive for the EWSR1/FLI1 rearrangement (Table).
Conclusions: PRKCB expression is a valuable diagnostic marker in ES, with excellent sensitivity/specificity. Furthermore, PRKCB may serve as a potential therapeutic target in the treatment of ES by small-molecule inhibitors, such as enzastaurin.
Adult Sino-Orbital Rhabdomyosarcoma Mimicking a Neuroendocrine Tumor: (Poster No. 40)
Rhabdomyosarcoma is the most-common pediatric soft tissue sarcoma, but it is exceedingly rare in adults. Soft tissue sarcomas make up less than 1% of all adult malignancies, and rhabdomyosarcoma accounts for 3% of all soft tissue sarcomas. We present the case of a 48-year-old woman with a 2-month history of progressive, right-sided proptosis and diplopia. Computed tomographic imaging showed a right orbital mass extending into the sinonasal area with opacification of the right nasal cavity and right maxillary, sphenoid, and ethmoid sinuses (Figure 186, A). This was consistent with a neoplastic process suspicious for lymphoma. She underwent debulking surgery. Microscopic examination of the tissue showed a tumor composed of small, round blue cells with focal necrosis (Figure 186, B). The differential diagnosis of small, round blue cell tumors of the head and neck is broad and includes malignancies of epithelial, hematolymphoid, and mesenchymal origin as well as malignant melanoma. The extensive immunohistochemistry panel performed showed that the tumor cells were positive for MyoD1 (Figure 186, C) and desmin but also for neuroendocrine markers—synaptophysin (Figure 186, D), NeuN, and CD56. Multiple cytokeratins, lymphoid markers, S100, and EBER were negative. A diagnosis of alveolar rhabdomyosarcoma with aberrant expression of neuroendocrine markers was made. Fluorescence in situ hybridization testing showed deletion or monosomy of 13q in 16% of the nuclei. This case emphasizes the diagnostic challenges in small, blue cell tumors of the head and neck area in adults and the diagnostic pitfalls caused by aberrant expression of neuroendocrine markers.
Tibia Osteoma Presenting as a Radiopaque, Well-Circumscribed Medullary Cavity Lesion: (Poster No. 46)
Osteomas are commonly seen in the head and neck bones, may occur in the limbs, and do not require treatment unless they are large and symptomatic. We present the case of a medullary cavity tibial osteoma with a unique radiographic presentation. A 22-year-old woman presented with right proximal anterior leg pain, who, on x-ray, was found to have a well-circumscribed radiopaque, right proximal diaphysis lesion involving the medullary cavity that required operative management. Surgical excision was performed, and the specimen was submitted as an aggregate of bony fragments. Microscopically, the fragments showed thick, bony trabeculae with haversian canals and no osteoblastic activity. The differential diagnosis included osteoblastoma, fibrous dysplasia, osteofibrous dysplasia of Campanacci, localized Paget disease, and a heterogeneous group of rare congenital and metabolic diseases, such as Erdheim-Chester disease, Camurati-Engelmann disease, intramedullary sclerosing lesion, Van Buchem disease, and osteosclerotic lesions. Bone marrow osteoma was favored because of the thick trabeculae with Haversian canals. Haversian canals are commonly seen in the cortex of long bones but can be seen in parosteal osteomas and conventional osteomas of the head and neck. Previous reports of tibia bone marrow osteomas have described a radiopaque nidus in the bone with a radiographic blurred margin. However, the radiographic findings in our case showed a well-circumscribed lesion, which, to our knowledge, has never been described in tibia bone marrow osteomas. Awareness of this entity is essential to ensure accurate diagnosis (Figure 187).
Similarities in Morphology, Immunohistochemistry, and Cytogenetics of Solitary Fibrous Tumor and Giant Cell Angiofibroma in a Rare Site Presentation of Solitary Fibrous Tumor: (Poster No. 48)
A 49-year-old man presented with a 2.0-cm, raised, firm lesion on his left pinna. The lesion had been present for 30 years. The patient denied associated symptoms. Histology revealed a well-circumscribed, nonen-capsulated lesion with alternating areas of hypocellularity and hypercellularity. An abundance of bland, spindled fibroblasts were observed in a background of wiry, wavy collagen. Floretlike giant cells were identified with thick-walled, hyalinized vasculature (Figure 188, A). Immunohistochemical stains were ordered, which revealed CD34 (Figure 188, B) and Bcl2 (Figure 188, C) positivity. CD31, S100, and smooth muscle antigen were negative. This morphologic and immunohistochemical profile was consistent with solitary fibrous tumor and giant cell angiofibroma. Solitary fibrous tumor, however, typically presents in the pleura, abdomen, and retroperitoneum, whereas giant cell angiofibroma commonly presents in the periorbital region. A review of the literature suggested that, given the morphologic and immunohistochemical similarities between solitary fibrous tumor and giant cell angiofibroma, it is likely giant cell angiofibroma is a variant of solitary fibrous tumor and not a distinct entity. In addition, recent studies have found both solitary fibrous tumor and giant cell angiofibroma display NAB2-STAT6 gene fusion on chromosome band 12q13 in nearly 100% of cases. STAT6 immunohistochemical staining was used in this case and displayed strong nuclear staining in lesional cells (Figure 188, D). The lesion was thus classified as solitary fibrous tumor, giant cell angiofibroma variant. This case illustrates a rare site presentation of solitary fibrous tumor and highlights the morphologic, immunohistochemical, and cytogenetic continuum between solitary fibrous tumor and giant cell angiofibroma.
Deep, Mitotically Active Angiomatoid Fibrous Histiocytoma in a Child: (Poster No. 49)
Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue tumor comprising only 0.3% of all soft tissue tumors. It is typically a slowly growing, bland-appearing tumor arising in superficial hypodermis and subcutaneous tissues of children and young adults and can occasionally be confused with a lymph node. A 12-year-old girl presented with a 1-month history of a right thigh mass. Imaging studies revealed a 6.5 × 4.3-cm, well marginated, multicystic, peripheral enhancing mass, centered at the vastus intermedius muscle. Gross examination of the radical surgical-resection specimen showed an intramuscular, circumscribed, solid cystic mass with tan to dark-brown, friable, and hemorrhagic foci (Figure 189, A). Histopathologic exam revealed a multinodular growth pattern of uniform histiocyte-like cells with oval nuclei, fine chromatin, inconspicuous nucleoli, and moderate, pale eosinophilic cytoplasm, consistent with AFH. Blood-filled pseudovascular spaces and moderate lymphoplasmacytic infiltrates were also present. Mitotic activity ranged from 4 to 12 per 10 high-power fields (Figure 189, B). Tumor cells showed diffuse positivity for vimentin and minimal staining for EMA. Typically, AFH is a superficial lesion of the extremities with bland histopathology. In our case, because of its deep location and moderate mitotic rate, a diagnosis of adult-type sarcoma was initially entertained. However, significant mitotic activity and nuclear atypia have been noted in a subset of AFH and do not seem to correlate with more-aggressive behavior. Usually, AFH has an indolent clinical course with a low incidence of recurrence or metastasis. On follow-up, patient remains free of tumor at 8 months postsurgery.
Unusual Presentations of Alveolar Soft Part Sarcoma: (Poster No. 51)
Alveolar soft part sarcoma (ASPS) is a rare neoplasm, with a frequency estimated at 0.4% to 1.0% of all sarcomas. It is most often seen in individuals 15 to 35 years old. In adults, it is seen predominantly in the lower extremities. When the pediatric age group is affected, the head and neck region, typically the tongue and orbit, is most commonly involved. It has been reported to arise in unusual locations, including the female genital tract, breast, urinary bladder, and bone. Here, we present 2 cases of ASPS with unusual sites of involvement affecting patients of differing ages. Case 1 was a woman who originally presented at age 23 with a diagnosis of nasal glial heterotopia at the nasal root. Following resection, the diagnosis was revised favoring a smooth muscle neoplasm thought to be benign. Nine years later, at age 32, the patient presented with a recurring mass at the nasal root (Figure 190, A). Biopsy revealed characteristic features of ASPS, and TFE3 immunohistochemical reactivity was strong and diffuse. TFE3 immunohistochemical staining was performed on the original resection specimen from 9 years previous and demonstrated strong and diffuse reactivity. Case 2 was a 67-year-old woman with a 6.0 × 4.0 × 3.3-cm paraspinal mass extending from C6 to T2. En bloc resection was preformed (Figure 190, B). The histologic and immunohistochemical findings were consistent with ASPS (Figure 190, C). It is important for the pathologist to recognize that ASPS can arise in unusual locations and in diverse age groups.
Fibrosarcoma of the Foot Clinically Presenting as a Resilient Cellulitis: (Poster No. 52)
Adult fibrosarcoma (AF) accounts for less than 1% of all soft tissue tumors and is extremely rare in the foot. The tumor is considered a diagnosis of exclusion and has an overall mediocre prognosis, with high recurrence and metastatic potential. A case of moderate-grade AF of foot in a 62-year-old man is presented. Clinical and pathologic findings are presented, followed by a discussion on clinicopathologic correlation and implications for prognosis. A 62-year-old man presented with a nonhealing, superficial, right ankle wound for 2 years, which became worse in the previous 3 months. X-ray revealed a large (5 cm) soft tissue lesion involving the distal right leg (Figure 191, A). The lesion was diagnosed as cellulitis, and the wound was excised. The specimen (4.5 × 4.5 × 2.5 cm) was rubbery, tan-brown, with necrotic-appearing, friable surface exudate. Histologically, the mass was consistent with AF of moderate differentiation with surface ulceration and fibrinopurulent exudate (Figure 191, B). The tumor demonstrated the classic “herring-bone” pattern of hypercellular fascicles (Figure 191, C) with a mitotic rate greater than 20 per 10 high-power fields (Figure 191, D). Immunostains for CK AE1/3, BCL2, CD34, desmin, EMA, CK MAK-6, S100, and SMA were all negative. Usually, AF, a rare type of sarcoma, is seen in deep soft tissues. In our case, the tumor arose in subcutaneous tissue. Given the rarity of superficial AF, study of many cases can help determine the prognostic effect of its superficial location to optimize patient care and follow-up.
Liposclerosing Myxofibrous Tumor: A Case Report and Review of the Literature: (Poster No. 54)
We report a case of a 46-year-old man who presented with right hip pain of more than 20 years' duration, which had worsened in the 6 months prior. Computed tomography, magnetic resonance imaging, and routine imaging revealed a mixed lytic and sclerotic lesion in the intertrochanteric region of the proximal right femur. Close follow-up monitoring, with periodic steroid injections for pain relief, failed to control pain. Open biopsy with frozen section followed by curettage, grafting, and internal fixation of the right femur were performed. Histologic examination revealed areas of myxofibrous tissue with low cellularity, ischemic-pattern ossification, curvilinear trabeculae of woven bone (somewhat fibrous dysplasia like), woven bone with mosaic cement lines (pseudo-Paget bone), and focal lipomatous areas. The variable histologic patterns along with distinct radiographic findings supported a diagnosis of liposclerosing myxofibrous tumor of bone. Liposclerosing myxofibrous tumor is a benign, fibro-osseous lesion with characteristic clinical and radiographic features and variable histology. This tumor is a rare, not universally recognized, entity; however, a reported risk of malignant potential encourages further research into this lesion and potentially related entities. This lesion, typically presenting in the fourth decade of life, has a strong predilection for the proximal femur, and characteristic radiographic features. These features often provide an initial clue to this diagnosis. Several reports suggest a risk of malignant transformation and a potential overlap with fibrous dysplasia, encouraging clinicians and pathologists to consider this in differential diagnosis for benign fibro-osseous lesions (Figure 192). (To access virtual slides for our case, the following URL is available: http://moon.ouhsc.edu/kfung/PosterWSI/Deel-2015.mht.)
Chondromyxoid Fibroma of the Rib: (Poster No. 55)
We report a case of chondromyxoid fibroma (CMF) involving a rib. Only 9 other cases of costal CMF have been reported in literature since 1952. A 59-year-old woman presented with a complaint of vague neck and back pain that had lasted several years. An expansile radiolucent lytic lesion was discovered in the right posterior eighth rib by x-ray. A computed tomography–guided core biopsy was performed. Histologic examination showed bland spindle to stellate cells in abundant chondroid matrix arranged in lobules that were separated by fibrous septa. No mitoses were seen (Ki-67 immunostain, 0% positive). S100 protein immunostain was negative. Chondromyxoid fibroma is a rare skeletal neoplasm (1% of all bone tumors) that is benign but locally aggressive. Most-common location is the long bones, although cases involving scull, vertebrae, and small bones of hands and feet have been reported. Patients have wide age range, and a slight male predominance. Radiologically, it is a well-circumscribed solid or cystic mass (soft tissuelike density on computed tomography scans) with or without calcifications. Secondary aneurismal bone cyst formation has been reported. Histology is as described above. S100 is positive in 85% of cases. Mitotic activity is very low. Treatment of CMF is wide excision with negative margins. It has not been shown to metastasize, although local recurrence has been documented. Adequacy of excision is the main predictor of recurrence. Differentiating CMF from other skeletal neoplasms, especially well-differentiated chondrosarcoma, may be a challenge, especially in such an unusual location as rib (Figure 193).
Benign Notochordal Cell Tumor of Sacrum: (Poster No. 56)
Benign notochordal cell tumor is a lesion of notochord origin, which can be found incidentally during autopsy. Larger lesions may cause clinically significant low-back pain. Here, we report a case of a 48-year-old man, a warehouse worker, who, one day after lifting heavy boxes, presented with back pain and sciatica down the right leg. Magnetic resonance imaging demonstrated a fibrofatty placode at the distal aspect of the spinal canal adjacent to the sacrum, cystic dilation of the canal, and associated erosive changes of the first 2 coccygeal segments. It also revealed isointense signal on T1- and T2-weighted images. The patient underwent S2–S5 laminectomy. The pathology revealed sheets of large, polyhedral cells with abundant eosinophilic to large vacuolated cytoplasm and round to ovoid hyperchromatic nuclei, resembling adipose tissue. The cells had focal, mild to moderate nuclear atypia with mitotic figures in a myxoid matrix that were difficult to identify. The tumor cells did not infiltrate into the trabecular bone. Immunohistochemical stains showed tumor cells were positive for AE1/3, CAM 5.2, EMA, brachyury, and S100 (focal) and were negative for GFAP, synaptophysin, chromogranin, Melan-A, inhibin, and PAX8. Ki-67 labeled less than 1% of tumor cell nuclei. The combined findings support the diagnosis of benign notochordal cell tumor. In rare cases, this entity can be present in association with chordoma (Figure 194).
A Case of Adamantinoma Presenting in an Exceedingly Rare Location to Mimic a Small Blue Cell Tumor in a 17-Year-Old Adolescent Boy: (Poster No. 57)
Adamantinoma is a primary, low-grade, malignant bone tumor with incidence of 0.1%–0.5% of all primary bone tumors. The most-common location is the mid part of the tibia. The etiology of the tumor is still a matter of debate. However, based on immunohistochemical and electron microscopy data, it has an epithelial origin. The clinical symptoms depend on location and extent of the disease, and the radiology findings are not specific other than location. We are reporting on a 17-year-old adolescent boy, who presented with swelling and pain around his right elbow. On exam, he had a firm, solid mass on the posterior aspect of his forearm with mild elbow joint tenderness but no limitation of motion. Radiology showed a 5.4-cm, well-circumscribed osteolytic lesion involving the proximal part of ulna. Diagnostic excisional biopsy was performed to show highly cellular spindle cell proliferation with fibroblastic stroma (Figure 195). The tumor cells showed plump, uniform spindle cells with small amount of indistinct cytoplasm and oval hyperchromatic nuclei forming solid and compact sheets with basaloid appearance. Myxoid changes, hyalinized collagen, and focal calcification were also noted. Scattered mitotic activity was identified. By immunohistochemical staining, the neoplastic cells were positive for cytokeratin, EMA, and CD99 and negative for desmin, myogenin, smooth muscle actin, S100, FLI1, TLE1, and synaptophysin. The fluorescence in situ hybridization study for EWSR1 gene rearrangement was negative. The patient received chemotherapy and radiation with good tumor-burden response. The follow-up imaging did not show any evidence of recurrence or metastasis after 6 months from the initial diagnosis.
A Case of Intrapelvic Lipoblastoma Mimicking Myxoid Liposarcoma With Pleomorphic Adenoma Gene 1 Rearrangement Confirmed by Fluorescence In Situ Hybridization: (Poster No. 58)
Lipoblastoma is a rare, benign tumor of embryonal adipose tissue mainly arising from superficial subcutis of the extremities, with only one case reportedly originating in the pelvis, so far. Diagnosis of lip-oblastoma in an unusual location based only on morphology is challenging because of its overlapping histologic features with myxoid liposarcoma. Molecular studies identifying characteristic gene rearrangements are often essential in rendering a correct diagnosis. We report such a case in a 1-year-old girl who presented with a large, intrapelvic myxoid lipomatous tumor, which we eventually diagnosed as lipoblastoma by fluorescence in situ hybridization (FISH). The patient had a history of right buttock mass with a magnetic resonance imaging scan showing a large, predominantly T2, hyperintense mass in lower right pelvis. Excision of the mass revealed a large, well-circumscribed, partially lobulated fatty tumor with a thin, fibrous capsule. Histologically, the lesion was mainly composed of adipocytes, lipoblasts, and occasional atypical spindle cells with hyperchromatic nuclei and rare mitoses. A delicate plexiform vasculature with prominent myxoid background was apparent. Areas of immature lipoblasts were present at the periphery. The FISH studies confirmed the presence of a PLAG1 (pleomorphic adenoma gene 1) locus rearrangement and were negative for a rearrangement of the DDIT3 (DNA-damage-inducible transcript 3) gene locus. A final diagnosis of lipoblastoma was rendered. To our knowledge, this is the first case report of intrapelvic lipoblastoma diagnosed by FISH. Awareness of the close histologic resemblance between lipoblastoma and myxoid liposarcoma and the use of molecular cytogenetics for discrimination are critical to avoid misdiagnosis and overtreatment in pediatric patients (Figure 196).
Clinicopathologic Study of Myxofibrosarcoma: A Retrospective Overview of the University of Florida Cases: (Poster No. 60)
Context: Despite previous studies, there has been great variability in the diagnostic and grading criteria of myxofibrosarcoma. The aims of this study were to determine the validity of FNCLCC (Fédération Nationale des Centres de Lutte Contre le Cancer) grading system in a series of myxofibrosarcoma patients treated in our institution and to identify clinicopathologic predictors of clinical outcome.
Design: Our surgical pathology archives were searched for primary, nontreated cases of myxofibrosarcoma. Only cases with sufficient material to establish an accurate FNCLCC grade were evaluated.
Results: The Table summaries the histopathologic features of 32 cases. The tumors occurred in 16 women and 16 men, ranging from 18 to 87 years (mean, 62.3 years). Follow-up information was available for all patients (range, <1 month to 13.2 years; mean, 3.2 years). Two of 32 died of disease at 12 and 34 months. Recurrence developed in 4 patients (range, 5–103 months; mean, 33.2). Six patients developed metastasis to the lung (range, 5–103 months; mean, 27.3). By Cox regression model analysis, a significantly lower relapse/metastasis-free survival (R/MFS) was found in the tumors with decreased myxoid component (<5%), whereas other clinicopathologic parameters including FNCLCC grade showed no significant association with R/MFS. Although the tumor size was correlated with R/MFS, it was not statistically significant because of the small sample size.
Conclusions: Tumors with decreased myxoid component (<5%) predicted a significantly lower R/MFS. Our preliminary data also suggested that the current FNCLCC grading system may not be useful as prognostic indicator for this tumor type. Further larger, multiinstitutional studies are necessary to confirm our initial findings.
Intraosseous Leiomyosarcoma Arising in Bone Infarct: (Poster No. 63)
Bone infarct-associated sarcomas are rare and behave aggressively with poor prognosis. The most-common histologic type is undifferentiated pleomorphic sarcoma (formerly known as malignant fibrous histiocytoma), followed by osteosarcoma. To our knowledge, there is only one case of bone infarct–associated leiomyosarcoma in the current literature. Herein, we reviewed the clinicopathologic and radiographic features of 2 patients with intraosseous leiomyosarcoma in this unusual setting. Two cases of bone infarct-associated leiomyosarcoma were retrieved from our surgical pathology archives. To be included in this study, the tumor had to be intraosseous, with other primary sites of origin clinically excluded. Also, all lesions had to be of intramedullary location with associated bone infarct. Radiographically, both cases showed an aggressive, destructive intramedullary lesion with soft tissue extension and areas of prior bone infarct. Case 1 was that of a 55-year-old man with a 10-cm distal femur lesion. Despite chemotherapy and radiation therapy, the patient subsequently developed lung metastases and died 3 years later. Case 2 was that of a 68-year-old woman with a 7.5-cm tibial lesion. Six months after the diagnosis, multiple metastatic lesions were noted in the lung and spine. The patient opted for palliative care only and died 9 months later. The clinicopathologic and radiographic features of previously reported case and the 2 current cases are summarized in the Table. We present this study to raise awareness of the intraosseous leiomyosarcoma arising in bone infarct because early detection might be helpful in improving the otherwise poor prognosis of these patients.
Congenital Infantile Fibrosarcoma With Immunohistochemical Positivity for FLI1 and TLE1 Can Mimic Ewing Sarcoma and Synovial Sarcoma, Respectively: (Poster No. 64)
Pediatric small, blue cell tumors have a broad differential diagnosis, which requires a multidisciplinary approach to make the final diagnosis. The clinical history, radiology and histopathology features, immunophenotype, and molecular study are all needed for an accurate diagnosis. We report a 5-week-old boy who presented to the emergency department with a rapid-growing mass in his neck and mouth floor. Radiology showed a well-circumscribed mass displacing the trachea, with a cystic area suggestive of necrosis. The tumor's rapid growth forced the clinician to intubate the patient and do urgent diagnostic biopsy. Microscopy showed a small, spindly blue cell tumor with a large area of necrosis (Figure 197). A panel of immunohistochemical stain was used to show moderate to strong cytoplasmic CD99 and nuclear FLI1 and TLE1 positivity, highly suggestive of Ewing sarcoma versus synovial sarcoma. The tumor cells showed INI-1 nuclear expression with 70%–80% Ki-67. However, the tumor cells were mostly negative for other markers like MyoD1, desmin, synaptophysin, PGP 9.5, tyrosine hydroxylase, AE1/AE3, BCL2, CD34, CD79a, CD3, and Tdt. Fluorescence in situ hybridization (FISH) was negative for EWS gene rearrangement and t(X;18) to rule out both Ewing and synovial sarcomas. Interestingly, the FISH was positive for t(12;15)(p13;q21) to show ETV6 gene rearrangement characteristic of infantile fibrosarcoma. We want to report this case to emphasize the immunohistochemical stains, such as CD99, FLI1, and TLE1, are sensitive but not specific markers for definite diagnosis. It may be that a panel of FISH studies at the beginning would be more helpful for further classification of these tumors.
A Rare Case of Scapular Glomangioma: Case Report and Clinical Management: (Poster No. 66)
Glomus tumors/glomangiomas are benign neoplasms arising from modified smooth muscle cells of the glomus body, a specialized arteriovenous anastomosis involved in body temperature regulation. These tumors are most commonly seen in the subungual region of the hands, and less commonly within other areas of the body, such as the shoulder, where only 14 cases have been previously reported. In this case report, we discuss the management of a 49-year-old woman with a history of recurrent glomus tumor arising from the scapula. The patient's initial glomus tumor was resected 13 years before her current presentation. On this resection, histologic sections demonstrated a deep-seated intraosseous tumor (Figure 198, A) arranged in sheets and lobules (Figure 198, B) and separated by scattered, slitlike vessels (Figure 198, C). The cells were small and round, with centrally located nuclei, fine chromatin, well-defined cell borders, and abundant eosinophilic cytoplasm. Mitoses were rare at 0–1 per 50 high-power fields (Figure 198, D). Because of the deep-seated location larger than 2 cm, meeting one criterion for malignancy in glomus tumors, this case was classified as glomangioma of uncertain malignancy, and the patient was, therefore, managed with frequent surveillance. Clinical follow-up 1 year after resection was favorable, showing no recurrence of tumor. In addition to presenting a rare case of glomus tumor arising from the shoulder, this case highlights the challenges of managing patients for which clinical experience is limited. Because our understanding of the behavior of deep-seated glomus tumors larger than 2 cm is not well defined, we recommend frequent follow-up in these patients to ensure no recurrence.
Impact of Tissue Decalcification on Immunohistochemical Detection of Lymphoid Markers: (Poster No. 68)
Context: We investigated the effect of decalcification on the detection of commonly used lymphoid markers with lymphoma cell lines.
Design: Three lymphoma cell lines were obtained from American Type Culture Collection. Cell blocks were constructed from each cell line to test the markers listed in the Table. The cell pellets containing a mixture of the 3 cell lines were first fixed in 10% neutral-buffered formalin for 8 hours and then decalcified in Decalcifier B for the following durations listed in the Table. A tissue microarray (TMA) block containing these tissue/cell line cores with the different decalcification times was constructed. The aforementioned immunohistochemical markers were applied to the TMA sections. The staining intensity and percentage were recorded.
Results: The results are summarized in the Table.
Conclusions: Tissue decalcification has a significant negative impact on 79a, Tdt, and BCL2 detection; on CD2, CD5, BCL6, and EBV in situ hybridization detection; on CD3, CD10, and PAX5 detection; and on CD20 and LCA detection after 30 minutes, 60 minutes, 3 hours, and 6 hours of decalcification, respectively.
Primary Intraosseous Myoepithelial Carcinoma: Two Rare Cases, Including Immunohistochemical Profile With EWSR1 Rearrangement in One Case: (Poster No. 71)
Primary intraosseous myoepithelial carcinomas are rare tumors that mimic chondrosarcomas, osteosarcomas, adamantinomas, and meta-static carcinomas. We report 2 cases of this tumor. Case 1 was a 34-year-old man, who presented with pain in his left hip joint for 3 years with increasing intensity during previous 10 days. Clinically, his hip movements were restricted. Plain radiograph disclosed a lytic lesion with calcification in his proximal femur. Magnetic resonance imaging disclosed a 10-cm lesion with abnormal signal intensity involving proximal epimetadiaphysis of the left femur with a soft tissue component. Additionally, fluorine-18 fluorodeoxyglucose positron emission tomography/contrast-enhanced computed tomography scan revealed bilateral lung metastases. He underwent a biopsy and was scheduled for surgical resection. Case 2 was a 23-year-old man, who presented with swelling of his right lower leg for 16 months. Plain radiograph revealed an expansile, lytic lesion in the diaphysis of the lower one-fourth of the fibula. He underwent a biopsy, followed by wide resection. Histopathology in both cases revealed cellular tumors comprising mostly polygonal cells, exhibiting moderate nuclear atypia, arranged in cords, and diffusely in an osteochondromyxoid matrix. The second tumor, in addition, revealed squamous differentiation. On immunohistochemistry (IHC), both tumors were diffusely positive for epithelial membrane antigen, pancytokeratin, cytokeratin 5/6, and S100-P. The first tumor also expressed glial fibrillary acidic protein. Although the first tumor displayed Ki-67/MIB1 positivity in 15%–20% of tumor cells, the second tumor revealed 3–4 mitoses per 10 high-power fields. Furthermore, the first tumor exhibited EWSR1 rearrangement by fluorescence in situ hybridization technique (Figure 199, A through D). These rare cases of intraosseous myoepithelial carcinomas/malignant mixed epithelial tumors highlight the value of IHC in their recognition, especially differentiating them from their diagnostic mimics. Some of these tumors exhibit EWSR1 rearrangement.
A Case of Malignant Epithelioid Solitary Fibrous Tumor: Histologic, Immunohistochemical, and Cytogenetic Features: (Poster No. 74)
Solitary fibrous tumor (SFT) is a mesenchymal neoplasm composed of short, spindled cells in a “patternless pattern,” which rarely involves the extremities. Epithelioid SFT, composed of sheets of ovoid cells having pleomorphic vesicular nuclei with abundant cytoplasm and indistinct cytoplasmic borders, is a rare histologic variant. We report an unusual case of a 54-year-old man with a large left thigh mass, consistent radiographically, with a soft tissue sarcoma. Incisional biopsy showed an epithelioid mesenchymal neoplasm of uncertain malignant potential that was positive for CD34, CD99, β-catenin, and BCL2 (negative smooth muscle, epithelial, melanoma, and neuroendocrine markers). Subsequent resection of a 13.5 × 9.0 × 5.3-cm pink-gray mass showed similar epithelioid histology in addition to short, spindled cells in fascicles, hyalinized fibrosis, hemangiopericytoma-like vasculature, multifocal necrosis, and infiltrative margins. The nuclei exhibited pleomorphism and atypia, with 1–2 mitoses per 10 high-power fields and a Ki-67 index of 20%. Based on the gross, microscopic, and immunohistochemical features, a diagnosis of malignant epithelioid SFT was made. Chromosomal analysis showed a balanced translocation involving chromosomes X and 12 at 12q13, consistent with SFT. Soft tissue neoplasms represent a diagnostic challenge, especially in small biopsies with unusual morphology. Adequate tissue sampling, appropriate immunohistochemical markers, and molecular/cytogenetic analysis will enhance the diagnostic accuracy. The NAB2-STAT6 rearrangement within 12q13 (usually an inversion within 12q13) was recently identified as a consistent finding in SFT. The present case emphasizes the epithelioid pattern as an uncommon but important variant of SFT, which must be recognized and included in the differential diagnosis of soft tissue tumors (Figure 200).
Is DOG1 Immunoreactivity Still Specific to Gastrointestinal Stromal Tumor? A Literature Review and a Sarcoma Pathologist's Perspective: (Poster No. 75)
Context: DOG1 (discovered on gastrointestinal stromal tumors 1) is a novel gene on gastrointestinal stromal tumors (GISTS) that encodes the chloride channel protein anoctamin-1 (ano1). DOG1 has been shown to be sensitive and specific as antibodies against CD117+ and CD34+ GIST, as well as CD117− and CD34− GIST. DOG1 was shown to be independent of the KIT/PDGFRA mutation status and considered specific for GIST when it was first discovered in 2004. This study is to explore the immunoreactivity of DOG1 in non-GIST neoplasms to provide useful information for practicing pathologists.
Design: PubMed search of past 10 years yielded related articles. Critical review of 12 relevant studies show DOG1 tested positive in 250 cases out of 2360 tested non-GIST neoplasms (10.6%) at different anatomic sites using monoclonal (SP31, K9, DOG1.1), polyclonal, or nonspecified antibodies. Criteria for positivity varied among the studies.
Results: Monoclonal and polyclonal DOG1 antibodies were expressed in various non-GIST tumor types spanning 8 organ systems, in addition to normal salivary tissue and pancreatic tissue. The main tumors included renal oncocytoma (100%), renal cell carcinoma chromophobe type (86%), solid pseudopapillary neoplasm of pancreas (51%), salivary gland neoplasm (46.5%), synovial sarcoma (15%), leiomyoma (10%), pancreatic adenocarcinoma (7%), and leiomyosarcoma (4%) (Figure 201).
Conclusions: These studies revealed that in contrast to the original notion that DOG1 antibodies are specific to GIST neoplasms, there is emerging data showing DOG1 positivity in some non-GIST tumors. We hope to raise awareness not to use DOG1 alone for the diagnosis of GIST.
HER2 Testing and Breast Cancer Metastases to Bone: (Poster No. 77)
Context: Approximately 80% of patients who develop metastatic breast cancer will experience a skeletal metastasis. National guidelines recommend biopsy and repeat biomarker testing for metastatic breast cancers to guide further treatment. Human epidermal growth factor-receptor-2 (HER2) analysis in bone biopsies is challenging because of the detrimental impact of decalcification solutions on tissue.
Design: We routinely separate bone from blood clot for biopsies in suspected skeletal metastases to provide nondecalcified tissue for possible biomarker analysis. A review of bone biopsies from metastatic breast cancer was performed, and all cases found to be negative or equivocal by HER2 immunohistochemistry were reviewed. Testing for HER-2 used US Food and Drug Administration (FDA)–approved tests (HercepTest, DAKO). The FISH tests were also FDA approved (HER-2 IQFISH pharmDx, DAKO).
Results: Eight cases of metastatic breast cancer to the bone were negative or equivocal by HER2 immunohistochemistry. Subsequent FISH testing performed on nondecalcified blood clot with tumor revealed 2 of 8 patients as being HER2 amplified (25%). One of 8 cases was found to be inadequate for FISH testing (Table).
Conclusions: Biomarker testing in skeletal biopsies is challenging because of the detrimental effects of decalcification. Given the clinical importance of this testing in recurrent breast cancer, techniques that avoid decalcification are needed. Our data show that routinely separating blood clot from bone to avoid decalcification may yield tumor tissue for biomarker analysis to aid subsequent treatment planning.
A Note of Caution: Variable Cytokeratin Staining in Sentinel Node Metastases: (Poster No. 78)
Sentinel lymph node biopsy is the current standard procedure used to stage patients with breast cancer. The best histologic method in evaluating sentinel nodes is highly debated among institutions and is thus not standardized. The optimal histologic analysis is a balance between comprehensive evaluation of the sentinel nodes and cost effectiveness. One commonly used approach is serial sectioning and alternately staining with hematoxylin-eosin (H&E) and AE1/AE3 cytokeratin immunohistochemistry analysis. We report 2 cases of a macrometastasis and a micrometastasis demonstrating negative staining for AE1/AE3. The first case is a 54-year-old woman with invasive ductal carcinoma treated with needle-localized partial mastectomy and sentinel lymph node biopsy (SLNB) with sampling of adjacent nonsentinel nodes for cancer staging. The sentinel node showed macrometastasis in one node on H&E (Figure 202, A). The tumor cells were negative on our reflexively performed AE1/AE3 (Figure 202, B). Additional studies showed the metastatic carcinoma to be negative for subsequent cytokeratins, CK5/6 and 34βE12, and positive for CK7 (Figure 202, C). In the second case, a 59-year-old woman with invasive ductal carcinoma was treated with needle-localized lumpectomy and SLNB. The sentinel node showed micrometastatic carcinoma in 1 of 2 lymph nodes with H&E stain. The micrometastasis was negative for AE1/AE3. The tumor cells were positive for 34βE12 (diffusely) and CAM 5.2 (focally). These cases highlight a rare but potential pitfall to H&E and reflexive AE1/AE3 staining, a commonly used strategy in assessing sentinel lymph node biopsies in breast cancer.
Müllerian Inclusion Cysts in an Intramammary Lymph Node: Mimicking Breast Cancer: (Poster No. 81)
Benign inclusions occur in lymph nodes and are typically found incidentally. Müllerian inclusion cysts (MICs) are small glands lined by Müllerian-type epithelium found almost exclusively in the pelvic, paraaortic, and peritoneal lymph nodes of women. We report a case of MIC in an intramammary lymph node of a 53-year-old, nulliparous woman, who presented with a breast mass mimicking breast cancer. The patient's medical history was significant for stage III, grade I serous ovarian cancer at age 30. She underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy, debulking, and 6 courses of cisplatinum therapy. She had taken estrogen therapy for the previous 11 years. Breast examination was without palpable masses or axillary lymphadenopathy. Mammogram showed a 12-mm, circumscribed mass in the deep-central right breast that increased in size from prior studies. The patient underwent an ultrasound-guided needle biopsy. The biopsy showed a lymph node with reactive germinal centers and glandular structures lined by a monolayer of columnar, ciliated cells. The cells had uniform, round nuclei and resemble fallopian tube epithelium (Figure 203, A and B). Immunohistochemically, the lining epithelium was positive for WT1 (Figure 203, D) and PAX8 (Figure 203, C), consistent with Müllerian epithelium. The present case highlights a rare clinical and radiographic mimic of breast cancer. It most commonly arises as a possible metastasis in axillary lymph nodes. Our case highlights an occurrence in breast tissue, as well as the challenge of differentiating this benign inclusion from a metastatic ovarian carcinoma.
The Outcome of Diagnosing Atypical Lobular Lesions in Breast Core Biopsies That Underwent Subsequent Excisions: One Institution's Experience: (Poster No. 88)
Context: Atypical lobular lesion (ALL) defines a spectrum of changes ranging from atypical lobular hyperplasia (ALH) to lobular carcinoma in situ (LCIS), conferring an increased risk for subsequent invasive breast cancer on the ipsilateral breast at the same or different site and/or on the contralateral breast. Management varies from follow-up with imaging to excision. We evaluated the outcome of patients with ALL on breast core biopsies that underwent subsequent excisions.
Design: Retrospective study of 37 breast core biopsies with findings of ALH, LCIS, and a mixture of ALH and/or LCIS with papilloma that underwent excision during a 7-year period (2008–2015).
Results: Results were grouped as “Downgrade” (no atypia identified upon excision), “No change” (lobular and/or ductal atypia, ie, ALH, flat epithelial atypia [FEA], atypical ductal hyperplasia [ADH], and/or LCIS), “Upgrade” (invasive carcinoma and/or ductal carcinoma in situ), “Papillary neoplasm,” or “Other” (cancer at a different site on the ipsilateral breast or on the contralateral breast) in the Table. Initial biopsy was prompted by calcification (n =10), mass (n =8), nodule (n = 3), enhancing foci (n =2), distortion (n =1), mass and calcification (n = 1), ductogram (n = 1), and unknown (n = 11).
Conclusions: Most patients showed no change in diagnosis with similar upgrade and downgrade rate. However, downgrades were only seen in ALH patients with small cluster microcalcification. This limited data weakly justifies follow-up excision of patients with ALL on core biopsy and suggests that the biopsy indication might help stratify patients for management.
Validation of HER2/neu Gene Amplification Testing by Fluorescence In Situ Hybridization on Breast Cancer Specimens Decalcified by Immunocal: (Poster No. 91)
Context: The revised breast cancer HER2/neu testing guidelines include testing on metastatic sites. Bony metastases require decalcification before processing. Currently, no guidelines or consensus statements exist for testing decalcified specimens. Immunocal is a decalcification solution routinely used in processing bone marrow specimens with reliable downstream immunohistochemical and fluorescence in situ hybridization (FISH) results. We sought to validate HER2/neu FISH testing on specimens decalcified by Immunocal.
Design: In this prospective study, thus far, 19 leftover breast cancer specimens were collected. They were bisected; one-half was processed normally, and the other was subjected to at least 30 minutes of Immunocal. Hematoxylin and eosin-stained slides were marked for tumor and made into tissue arrays for FISH testing. All the samples were processed, scored, and interpreted as per revised guidelines. Benign trabecular femoral bones were used to ensure adequate decalcification.
Results: One case was discarded because of the absence of tumor cells. The results of the remaining 18 cases are summarized in the Table. One discordant case showed HER2/neu amplification in the control but not in the decalcified sample (HER2/neu ratios 2.2 and 1.8, respectively).
Conclusions: Hybridization was successful, with very high concordance (94%) between the decalcified and control specimens with minimal differences in average HER2/neu copy number and ratio. To optimize the hybridization and further minimize the differences in the decalcified and control group, the protocol was revised to ensure at least 3 hours of formalin fixation before decalcification. This study will benefit patients with breast cancer and bony metastases to accurately identify their HER2/neu status.
A Case of HER2-Amplified, Metastatic Mucinous Carcinoma With Pathologic Complete Response to Neoadjuvant Chemotherapy: (Poster No. 93)
Pure mucinous breast cancer is typically a localized, low-grade carcinoma that is ER+/PR+ and HER2 gene-amplification negative. It often has poor response to neoadjuvant chemotherapy. Herein, we present a case of pure mucinous breast carcinoma with HER2 gene amplification, positive axillary lymph node metastasis, and a pathologic complete response in a 47-year-old white woman. The patient, who had a maternal history of breast cancer and a personal history of Premarin (Pfizer, New York, New York) use, was referred for biopsy of an impalpable mass identified on mammogram. A core needle biopsy showed grade II, invasive, triple-positive mucinous carcinoma (Figure 204, A). Magnetic resonance imaging did not show evidence of lymph node metastasis. The tumor size was 1.9 cm on mammogram and clinically staged as T1cN0. The patient was placed on neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab for 6 cycles. Five months later, a lumpectomy with sentinel node biopsy was performed, which showed a residual mucocele-like lesion in the lumpectomy (Figure 204, B) and a similar mucocele-like lesion in 1 of the 4 sentinel nodes (Figure 204, C). The sentinel node was interpreted to be positive before the neoadjuvant chemotherapy. Therefore, this patient had a pathologic complete response in both the primary site and the node. Pathologic stage is ypT0N0. In addition, the patient completed postoperative radiation therapy (45 Gy with 16-Gy boost) and is currently on trastuzumab for 1 year. In summary, mucinous carcinoma with HER2 gene amplification and axillary lymph node metastasis is rare. Neoadjuvant chemotherapy may represent an effective strategy in managing such cases.
Incidental Papilloma—Triage for Surgery Based on Size and Excision on Core Biopsy?: (Poster No. 100)
Context: We hypothesized small papillomas without atypia appearing completely excised on core biopsy do not warrant excision.
Background: Standard management for intraductal papillomas diagnosed on core biopsy is excision based on association with high-risk lesions. Presence or absence of atypia in papilloma itself further complicates the picture. We focused on small lesions without atypia, further exploring the new concept suggesting papillomas of 2 mm or less (incidental papillomas) were likely to be completely excised in the core biopsy.
Design: We identified 163 biopsy-diagnosed intraductal papilloma cases with follow-up excision in the previous 5 years. We stratified cases by the presence or absence of atypia, comparing upgrade and downgrade rates in our practice to those reported. We analyzed cases where no papilloma was found in excision. Cases where papilloma was small but fragmented, precluding measurement, were excluded. Future studies will explore histologic features of small papillomas without atypia that either upgraded or persisted in excision.
Results: Of all the cases, 107 (65.6%) had the same diagnosis on biopsy and excision, 15 (9.2%) were downgraded, and 17 (10.4%) were upgraded (Figure 205). Significantly, 24 cases (14.7%) showed no evidence of papilloma in resection suggesting complete excision by biopsy. The measured mean papilloma size was 3.6 mm (SD, 1.85). The 84th percentile (1 SD above mean) was 5.5 mm. Most (92%) of the papillomas in this group appeared completely excised in 2 dimensions on biopsy.
Conclusions: Our data suggest resection can be avoided for papillomas without atypia measuring up to 5.5 mm when combined with 2-dimensional complete excision in biopsy.
Comparison of PHH3 and Ki-67 Proliferative Index Markers in Invasive Breast Carcinoma: (Poster No. 101)
Context: Proliferation has a significant role in predicting the behavior of invasive breast cancer. Ki-67 and mitotic count are universally used as proliferative markers. PHH3, a eukaryotic histone protein, has been used recently to measure proliferating malignant cells in malignancies, including breast cancer, meningioma, and sarcomas. PHH3 targets cells in the mitotic phase only; in contrast, Ki-67 targets all nuclei in cell cycle. There is scant literature on the utility of PHH3 in breast cancer. Our goal was to perform a comparison between Ki-67 and PHH3 on invasive breast carcinoma.
Design: A database search performed for core biopsies of invasive breast carcinoma. Grade 1 carcinomas were eliminated because of low proliferation with the PHH3 marker (<1%). Thirty-seven biopsies of grade 2 and 3 carcinomas were reviewed; 33 biopsies were adequate for PHH3 and Ki-67 immunostains. Proliferation was determined by visual estimation of positive staining malignant cells on 3 representative ×40 fields using 10 × 10 square-grid eyepiece graticule, and results were compared with Ki-67 on the same biopsies using standardized method.
Results: Twenty-three biopsies with grade 2, and 10 with grade 3, carcinomas were reviewed. The mean, SD, and P value of Ki-67 and PHH3 are summarized in the Table.
Conclusions: PHH3 labeled fewer cells than Ki-67 did. Of note, in grade 2 invasive carcinomas, the proliferation rates between the 2 markers were dramatically different (14% for Ki-67 versus just more than 1% for PHH3). We suggest, therefore, that PHH3 and Ki-67 are not interchangeable, and PHH3 should not be used as a surrogate marker of proliferation over Ki-67.
Rare Adenoid Cystic Carcinoma of the Breast Mimicking Infiltrating Syringomous Tumor of the Nipple and Low-Grade Adenosquamous Carcinoma: (Poster No. 105)
Adenoid cystic carcinoma of the breast is a rare type of invasive ductal carcinoma, which accounts for less than 1% of breast cancers. The tumor shows an invasive growth pattern with 2 cell populations of luminal (epithelial) and basal (myoepithelial) cells. In this report, we describe a unique adenoid cystic carcinoma of the breast mimicking a syringomatous tumor and adenosquamous carcinoma in a 71-year-old woman. Sonographically, the lesion appeared as a round, hypoechoic mass with irregular margins, suspicious for carcinoma. Ultrasound-guided needle biopsy rendered a diagnosis of atypical complex sclerosing lesion. Surgical excision revealed a 6-mm expansile nodule with an irregular, infiltrative edge. The tumor was composed of an admixture of well-formed glands and solid cords of cells, haphazardly arranged in a heavily collagenized stroma with multiple aggregates of lymphocytes in the periphery of the lesion. There was no mitosis, no apparent keratin pearl formation, no cribriforming architecture, or basement membrane material. The differential diagnosis included an adenoid cystic carcinoma, a low-grade adenosquamous carcinoma, or a syringomatous tumor. Immunohistochemically, the tumor cells were positive for keratin cocktail, CK7 (luminal), p63, and CK5/6 (basal myoepithelial cells). It was also triple negative with a proliferation index of 10%–20% by Ki-67 immunohistochemistry. Detailed radiologic correlation revealed the tumor was 2 cm from the nipple and 2 cm from the closest skin and did not appear to be associated with a major duct. In conclusion, the overall features were most consistent with an adenoid cystic carcinoma, and the patient was managed with surgery alone (Figure 206, A through D).
Primary Breast Lymphoma With Spindle Cell Morphology: (Poster No. 107)
Primary breast diffuse large B-cell lymphoma (DLBCL) accounts for only 2% of extranodal non-Hodgkin lymphoma and less than 1% of all breast malignancies. We present the case of a 29-year-old woman who presented with a palpable left breast mass (Figure 207, A). Ultrasound imaging revealed a 1.6-cm, lobulated, oval hypoechoic mass in the retroareolar region. A core biopsy showed a proliferation of atypical spindle cells infiltrating the breast parenchyma (Figure 207, B) and perivascular spaces that were devoid of red blood cells and were lined by attenuated cells (Figure 207, C). The lining cells were shown to be positive for CD34 and negative for CD31, factor VIII, and D2-40. The diagnosis of a DLBCL was entertained and confirmed by demonstrating positive immunoreactivity of the spindle cells for CD20 (Figure 207, D), CD45, and PAX5 and monoclonality by flow cytometry performed on the subsequent excisional specimen. This is a case of primary breast DLBCL with spindle cell morphology and infiltrating perivascular spaces analogous to the prelymphatic spaces described by Hartveit. Correct observation on the core biopsy is of paramount importance because knowledge of possible lymphoma, particularly DLBCL, primes the pathologist to procure fresh tissue for flow cytometry at the time of surgical excision and helps plan an appropriate management. We conclude that DLBCL should be included in the differential diagnosis of spindle cell lesions of the breast. The involvement of the perivascular spaces by the lymphoma underlines the significance of these spaces as potential conduits for systemic spread.
Abdominal Pregnancy: A Rare and Potentially Fatal Entity: (Poster No. 110)
Ectopic pregnancies occur when the fertilized egg implants in the fallopian tube, ovary, or abdomen. The incidence ranges from 6%–16% and seems to increase in the summer and winter. Abdominal pregnancies are rare entities with fewer than 200 reported worldwide in the past 70 years. They can be primary or secondary. They can cause significant maternal and fetal morbidity and mortality, although there have been several case reports of successfully delivered live births. We present a case of a 41-year-old woman with a remote history of myomectomy, who presented with pelvic pain. Her β-HCG was positive, and an ultrasound showed a 7-cm complex mass in the left adnexa extending to the midline with thick fluid and calcifications. The endometrium was thickened, but no evidence of intrauterine pregnancy was seen. At surgery, the cystic mass was removed from the cul-de-sac with debris and old blood. It was attached to the left tube, ovary, and large and small bowel. There were extensive adhesions to the appendix and some to the bladder. Gross examination revealed a mixture of placental tissue with umbilical cord and what appeared to be fetal bone (Figure 208). Abdominal pregnancy is rare, and early recognition and diagnosis is key to decreased mortality risk. The fetus in this case did not develop properly, but the presence of a placenta with cord and fetal bone show that there was a pregnancy implanted in the abdomen that, perhaps, because of its location, was not able to progress.
Molecular Markers in Uterine Papillary Serous Carcinoma: Correlation Between Endometrial Biopsy and Hysterectomy Specimens: (Poster No. 111)
Context: Uterine papillary serous carcinoma (UPSC) has a poor prognosis and a molecular profile characterized by alterations in p53, Her2/neu, and PIK3/AKT/mTOR. Neoadjuvant targeted therapy is a potential new treatment paradigm, but it is unclear whether there is a correlation between molecular alterations in the biopsy and final hysterectomy specimens; this would determine whether biopsy results could be used to guide neoadjuvant treatment. Our aim was to determine whether molecular markers in endometrial biopsy specimens showing diagnosis of UPSC are accurate predictors of final hysterectomy specimens.
Design: Patients with biopsy and hysterectomy specimens and pathologically proven UPSC were identified. Demographic, surgicopathologic, and survival data were obtained. Immunohistochemistry was used to measure the status of 7 biomarkers significant in endometrial cancer: p110, AKT, ER, PR, EGFR, Her2, and PTEN. Laboratory analysis was performed using formalin-fixed, paraffin-embedded tissue and standard, validated laboratory techniques. Staining was evaluated to calculate the correlation between hysterectomy and biopsy specimens.
Results: The most recent 28 patients who met criteria were identified. Average age was 72 years, and average body mass index was 29. Twenty-one patients were fully surgically staged. The distribution of disease was 61% stage I (n = 17), 14% stage II (n = 4), 22% stage III (n = 6), and 4% stage IV (n = 1) (Table).
Conclusions: The measurement of specific biomarkers correlated well between biopsy and hysterectomy specimens in women with UPSC as measured by pathologists using routine techniques. It appears that endometrial biopsy may be a useful tool for guiding neoadjuvant targeted therapy in UPSC.
Well-Differentiated Cerebellar Tissue Within a Mature Teratoma: A Case Report and Review of the Literature: (Poster No. 112)
Mature teratomas (MTs) are the most-common germ cell tumors of the ovary. The MTs originate from pathogenically activated oocytes. These oocytes can give rise to early embryonic structures that originate from the 3 germ layers: ectoderm, mesoderm, and endoderm. Ectoderm derivatives represent the most-abundant component. Organized neural tissue is a common finding. However, the presence of cerebellum within MTs is a peculiar finding and has seldom been discussed in the literature. In fact, as of 2014, only 14 cases have been reported. We report here a case of a 39-year-old woman who was found to have an 11 × 11-cm pelvic mass. Gross examination demonstrated a unilocular mass consisting of sebaceous material. Histologic examination revealed a mature teratoma with well-differentiated glial elements and a 0.5-cm focus of cerebellar tissue with distinct molecular, Purkinje, and internal granular cell layers. This case emphasizes the importance of recognizing this unusual finding in MTs and to distinguish it from its immature counterpart. The diagnosis of immaturity requires tissue with embryonic-appearing neuroepithelium. Our case highlights a unique finding in MTs and discusses the key diagnostic features to differentiate them from immature elements and malignant neuroectodermal tumors (Figure 209).
Chronic Histiocytic Intervillositis for the Nonplacental Pathologist: One Institution's Experience: (Poster No. 116)
Context: In 1987, Labarrere and Mullen first described chronic histiocytic intervillositis (CHI) in the Journal of Reproductive Immunology as “Fibrinoid and Trophoblastic Necrosis with Massive Chronic Intervillositis: An Extreme Variation of Villitis of Unknown Etiology.” Chronic histiocytic intervillositis is described as an idiopathic inflammatory condition with infiltration of the intervillous space by CD68+ mononuclear cells. The infiltration may be massive or multifocal. A specific etiology is unknown, but an immunologic cause has been suggested. The incidence is low, occurring in less than 1% of spontaneous abortions and second and third trimester placentas. However, it has been associated with intrauterine growth restriction and stillbirth with a high rate of recurrence. The literature suggests that often times the diagnosis is missed.
Design: The pathology database at Jackson Memorial Hospital/University of Miami was searched, and a total of 15 cases were found in the previous 5 years in a center where more than 2000 placentas are seen yearly. Maternal, fetal, and placental factors were reviewed.
Results: All women were multiparous, with 8 in their twenties. One case involved fetal demise, 2 with intrauterine growth restriction, and 1 with spontaneous abortion. The placenta associated with fetal demise also showed abundant fibrin and vasculopathy. Eleven women had comorbidities including hypertension, diabetes, and positive antinuclear antibody. Five placentas also showed concurrent villitis or chorioamnionitis (Figure 210).
Conclusions: It appears that CHI is more common in multiparous women with chronic disease. It is important for the general pathologist to be aware of CHI and to look for the placental changes, especially in this specific population.
Endometrioid Carcinoma With Choriocarcinomatous Differentiation: A Report of 2 Cases: (Poster No. 119)
We report on 2 cases of the rarely identified, choriocarcinomatous differentiation of high-grade endometrioid carcinoma (EMCA). The ages at diagnosis were 69 and 44 years, each demonstrating an elevated serum β-hCG at presentation. Our first patient was a 69-year-old woman who presented with postmenopausal bleeding and subsequently underwent a total hysterectomy. Histologically, the tumor displayed distinct transition from EMCA to the choriocarcinomatous component and demonstrated greater than 50% myometrial invasion with metastases to the left fallopian tube, left ovary, and left and right pelvic lymph nodes. An incidental steroid cell tumor measuring 1.0 cm was identified in the left ovary. A subsequent lung biopsy demonstrated metastatic EMCA with choriocarcinomatous differentiation. The second patient was 44 years old, who presented with elevated serum β-hCG level with suspected pregnancy. An endometrial curettage was performed and revealed a poorly differentiated endometrioid carcinoma with focal choriocarcinomatous differentiation, lacking transitional distinction. Each case demonstrated diffuse intense immunohistochemical staining for β-hCG (Figure 211) and CK7, whereas CK20, TTF1, WT1, p16, CEA, vimentin, ER, PR, and CK5/6 were negative. Previous reports have demonstrated weak to strong β-hCG immunohistochemical staining in the choriocarcinomatous component and absent staining in the endometrioid component. We report 2 cases demonstrating strong β-hCG immunohistochemical staining in both the endometrioid and choriocarcinomatous components, indicating a possible clonal evolution. Although the prognosis of metastatic choriocarcinoma is good, patients with EMCA with choriocarcinomatous differentiation have a drastically reduced prognosis. Future studies to confirm clonal evolution may provide insight for a subsequent therapeutic strategy.
Peritoneal Deciduoid Mesothelioma: An Unusual Presentation Complicating an Already Challenging Diagnosis: (Poster No. 121)
Deciduoid mesotheliomas are epithelioid mesotheliomas characterized by cytomorphologic features resembling decidua. Originally described as occurring solely in the peritoneum of younger women and portending a poor prognosis, the diagnosis has since been made in the pleura involving a broader patient population, with a less universally dismal prognosis. We present a case of diffuse deciduoid mesothelioma occurring in the peritoneum of a 25-year-old woman, 8 months postpartum at the time of diagnosis. Tumor specimens removed from the abdomen and pelvis all had consistent morphologic features comprising sheets of polygonal cells in solid, trabecular, and pseudopapillary arrangements. These cells exhibited vesicular nuclei with small nucleoli and occasional grooves. Immunohistochemical stains revealed diffuse positivity for WT1, mesothelin, and AE1/AE3; focal positivity for EMA, D2-40, MOC31, and inhibin; and negativity for a barrage of other markers, including calretinin. Electron microscopy demonstrated epithelioid cells with only scattered, thin, long, branching cellular projections. Cytogenetic testing revealed balanced translocations of 12p and 1q and 16p. Based on compiled ancillary studies, as well as consultations from experts at 2 outside facilities, a diagnosis of deciduoid mesothelioma was rendered. This unique case highlights the diagnostic challenge of a rare entity, which demonstrated negative immunohistochemical stain results, calretinin in particular, which had been previously reported as universally expressed, and only occasional microvilli by electron microscopy, which were expected to be a dominant feature. Additionally, previously unpublished cytogenetic aberrations were identified. At the time of presentation, the patient is alive and undergoing treatment with early progression of disease (Figure 212, A through D).
Fetal-Type Rhabdomyoma Arising From Ovarian Teratoma: A Novel Subtype of Monodermal Teratoma?: (Poster No. 123)
Rhabdomyosarcoma arising in germ cell tumors is a well-known occurrence in the testis and mediastinum but very rare in the ovary. To our knowledge, a well-differentiated rhabdomyomatous tumor (rhabdomyoma) arising in ovarian teratoma has not previously been described. A 67-year-old woman presented with abdominal pain. Computed tomography revealed a large left pelvic mass. Hysterectomy and bilateral salpingo-oophorectomy revealed a large, solid, left ovarian mass measuring 22 cm. The cut surface was yellow and fleshy, with rare cysts and no gross necrosis (Figure 213, A). Microscopically, almost the entire neoplasm was composed of tumor cells with prominent skeletal muscle differentiation, ranging from immature skeletal muscle cells to ganglion cell-like rhabdomyoblasts with prominent nucleoli, and numerous strap cells with abundant eosinophilic cytoplasm and prominent cross-striations, arranged in fascicles (Figure 213, B). Rare foci contained squamous-lined cysts with cutaneous adnexal structures (Figure 213, C) and gastrointestinal-type epithelium, supporting an origin from a teratoma. Nuclear pleomorphism, a primitive small cell component, and atypical mitotic figures were absent, although scattered mitotic figures were present. Immunohistochemically, the tumor cells labeled diffusely for desmin and in a patchy distribution for myogenin (Figure 213, D) and smooth muscle actin. No extraovarian disease was detected. Pure overgrowth of a well-differentiated rhabdomyomatous neoplasm in an ovarian teratoma is a novel finding, potentially analogous to other forms of monodermal ovarian teratoma. Absence of a primitive cellular component, widespread mature strap cell differentiation, and absent cytologic atypia argue for distinction from embryonal rhabdomyosarcoma.
Ovarian Fibrothecoma With Heavy Deposition of Hyaline Globules: (Poster No. 126)
Hyaline globules occur in various ovarian tumors. The best known is the occurrence of hyaline globules in yolk sac tumors. Other tumors like malignant mixed Müllerian tumors, surface epithelial tumors, and cellular fibromas have also been reported to show hyaline globules. The presence of these in benign tumors can imitate other tumors and lead to erroneous diagnosis in gynecologic pathology. We present a case of fibrothecoma of the ovary with heavy deposition of hyaline globules. A 34-year-old woman presented with abdominal pain and was found to have a left ovarian cyst. The resected specimen grossly was a cystic mass measuring 7.5 cm with hemorrhagic areas. Microscopy showed fibrothecoma composed of bundles of spindle cells intermixed with fascicles and sheets of plump ovoid cells and areas of cystic change, hemorrhage, and heavy deposition of hyaline globules. The histogenesis of these globules can differ; however, in many of these lesions, degeneration of red blood cells is implicated as the proper cause of the formation of these globules. Krukenberg tumor, metastasizing gastrointestinal stromal tumor, yolk sac tumor, and signet-ring stromal tumor are the main differential diagnoses to be considered. We could not retrieve any reports of fibrothecomas with similar findings, and to our knowledge, this is the first case to be reported in the literature. Ovarian fibromas with hyaline globules are shown to follow a benign course. Thus, it is important to distinguish these from other malignant tumors that more commonly show hyaline globules in their cells (Figure 214).
Synchronous Endometrial Endometrioid Adenocarcinoma and Uterine Leiomyosarcoma Occurring in a 67-Year-Old Woman: (Poster No. 128)
Uterine leiomyosarcoma is an uncommon entity with an incidence in the United States of 3–7 per 100 000 women. In contrast, endometrial carcinoma is the most-common invasive gynecologic malignancy with an incidence of 24.6 per 100 000 women. However, synchronous uterine leiomyosarcoma and endometrial carcinoma are extremely rare with only 2 cases previously reported. We report the case of a 67-year-old woman who presented with heavy vaginal bleeding requiring urgent uterine artery embolization. Subsequent workup demonstrated an enlarged uterus with a thickened endometrium. The patient underwent a radical hysterectomy with bilateral salpingo-oophorectomy and pelvic and aortic lymphadenectomy. The resection specimen consisted of a 23 × 23 × 12-cm uterus with diffuse myometrial involvement by a multinodular tan-white mass with widespread hemorrhage and necrosis. The endometrium, although distorted and flattened by the myometrial mass, was grossly unremarkable. Microscopic examination demonstrated 2 primary uterine malignancies: a large leiomyosarcoma, and a superficially invasive endometrioid adenocarcinoma. The leiomyosarcoma was characterized by marked nuclear pleomorphism, robust mitotic activity (up to 85 mitotic figures per 10 high-power fields), coagulative necrosis, extensive vascular invasion, and strong smooth muscle actin immunohistochemical staining (Figure 215, A and inset). The endometrial carcinoma was a well-differentiated FIGO grade 1 endometrioid adenocarcinoma with 5-mm of myometrial invasion (Figure 215, B). Although our differential diagnosis included carcinosarcoma, no admixture of carcinomatous and sarcomatous elements was present, and no heterologous elements were identified (Figure 215, C). Therefore, we interpret our case as a true occurrence of synchronous endometrial endometrioid adenocarcinoma and uterine leiomyosarcoma, which represents only the third described case to date.
Is Focal Cervical Intraepithelial Neoplasia 2 Clinically Relevant? A Study Stratified by Age With Follow-up: (Poster No. 135)
Context: Cervical intraepithelial neoplasia 2 (CIN2) is an ambiguous lesion that can be treated with conization or managed conservatively. A growing body of evidence shows CIN2 behaves as a low-grade lesion where conservative management is suitable. Focal CIN2 is a lesion where only a microscopic portion of the biopsy shows CIN2. This study investigated how frequently focal CIN2 is diagnosed, the follow-up, and the impact of age on clinical management.
Design: Cervical biopsies from 2007 were reviewed for CIN2. Cases with focal CIN2 were identified. Clinical management and outcome of focal CIN2 were evaluated, stratified by age into 2 groups, 25 years or younger, and older than 26 years.
Results: There were 1082 cervical biopsies from 2007, of which 228 were CIN2. The patients were followed for an average of 3.9 years with 14% of patients lost to follow-up. Focal CIN2 accounted for 88 cases (39%). Forty-nine patients (56%) with focal CIN2 were treated with conization, where 40 cases (82%) showed CIN2 or greater, and 9 cases showed CIN1 or less (18%). There were 39 patients (44%) with focal CIN2 managed conservatively. Patients 26 years or older were more likely to be treated with conization. For long-term follow-up of focal CIN2 after conization and conservative management refer to the Table.
Conclusions: Patients 25 years or younger with focal CIN2 who were managed conservatively did not have a higher incidence of CIN2 or greater then did patients treated with conization. A conservative approach in treating focal CIN2 is acceptable thus minimizing overtreatment in younger patients.
Utility of a Standardized Protocol for Submitting Clinically Suspected Endometrial Polyps: (Poster No. 136)
Context: Endometrial biopsy, curettage, and polypectomy are common specimens in surgical pathology practice. There is no standardized protocol for submitting these specimens to pathology. The purpose of this study was to assess whether a protocol for submitting specimens for clinically suspected polyps would improve the detection rate of polyps and evaluation of the background endometrium.
Design: A retrospective review of cases accessioned as “endometrial polyp” from September 2013 through March 2015 was performed. Cases were divided into 2 groups: polyps and curetting (1) placed in 2 separate containers (separate, n = 46), and (2) placed in the same container (combined, n = 52).
Results: Patient's age ranged from 24 to 80 years (average, 51 years) and 24–81 years (average, 49 years) in the separate and combined groups, respectively. The Table summarizes the frequency of endometrial polyp detection and evaluation of the background endometrium in each group. Endometrial polyps were identified in 46 of 46 (100%) of cases in the separate, compared with 48 of 52 cases (92%) in the combined group (P = .05). The 4 cases with no polyp in the combined group were diagnosed as proliferative, adenocarcinoma, complex atypical hyperplasia, and leiomyoma. The background endometrium was evaluable in 42 of 46 cases (91%) and 42 of 52 cases (81%) in the separate and combined groups, respectively (P = .14).
Conclusions: The enhanced rate of polyp detection and evaluation of the background endometrium in the separate group is minimal with no statistically significant difference. This supports the recommendation of a protocol for submitting endometrial polyps and curetting combined in one container. This protocol will decrease health care costs and the number of containers submitted without adversely affecting diagnosis.
Prostatic Tissue in Mature Cystic Teratoma of the Ovary: (Poster No. 138)
Mature ovarian cystic teratomas (OCT) are benign tumors characterized by the presence of a mixture of mature tissue types from one or more germ layers, resembling a variety of normal organs. The presence of prostatic-like tissue in OCT is a rare finding with poorly understood pathophysiology. We report the case of a 22-year-old woman with bilateral adnexal masses on abdominal ultrasound. Magnetic resonance imaging was suggestive of OCT. The patient underwent robotic-assisted, bilateral ovarian cystectomies for 5-cm and 6.5-cm unilocular cysts. The pathologic examination of the cysts demonstrated OCT with areas of prostatic-like tissue (Figure 216, A and B). Prostate-specific antigen (Figure 216, D) and prostatic acid phosphatase immunostains (Figure 216, C) were positive, supporting a prostatic immunophenotype. The absence of male genital tissue in most cases of OCT is likely related to the lack of a Y chromosome in these tumors. Prostatic-like tissue may be linked to Skene gland, the female prostate analogue. Previous case reports have also suggested embryonic remnants of the endodermal buds of the urogenital sinus as possible source of prostatic-like tissue in OCT. Other groups have recently reported the presence of very small, embryonic-like, pluripotent stem cells in various tissues, including the adult ovary. Very small, embryonic-like cells are diploid cells, 3.5 μm in diameter, and express markers of pluripotency. These have the ability to differentiate into almost any tissue type and might be a plausible reason for the presence of male tissue in a female organ.
Primary Peritoneal Squamous Cell Carcinoma Arising in Peritoneal Endometriotic Cyst: (Poster No. 139)
Squamous cell carcinoma (SCC) arising within ovarian endometriosis is a rarely reported condition. We report a case of a 55-year-old woman who presented with severe pelvic pain and was found to have SCC arising in a peritoneal endometrioma. A 55-year-old woman presented with severe pelvic pain and 30 lb weight loss. Computed tomography scan showed a 7-cm, hypodense, calcified lesion within the left adnexa. The patient underwent total hysterectomy with bilateral salpingo-oophorectomy. Intraoperative findings were a pelvic wall cyst, a presacral abscess, and a friable area in the rectum. Specimens were sent for frozen section which showed SCC in situ in the cyst wall and SCC in the rectal biopsy colonic mucosa. Gross examination of the uterus and bilateral ovaries and tubes was unremarkable. On histology, the cervix showed no dysplasia. The endomyometrium showed adenomyosis, inactive endometrium, and a small endometrial polyp. Permanent sections of the rectal biopsy showed microscopic foci of SCC in the lamina propria. The pelvic cyst wall showed extensive SCC in situ with focal invasion, and a hemorrhagic lining with foamy histiocytes and chronic inflammation consistent with an old endometrioma. The tumor cells were positive for p16, p63, CK5/6, and CK7 and negative for CK20, consistent with SCC arising in an endometriotic cyst. Malignant transformation has been reported in extragonadal endometriosis although all were adenocarcinoma. This patient had a rare malignant squamous transformation in an endometrioma of the rectovaginal septum. The tumor in the rectum probably represents a direct extension from this tumor (Figure 217).
Unlike Prostate, ERG Is Not Expressed in Endometrial Lesions: (Poster No. 142)
Context: Avian v-ets erythroblastosis virus E26 oncogene homolog (ERG) is highly sensitive and specific for endothelial neoplasms. Multiple studies have shown that ERG (21q.22.2) is an important protooncogene in various human malignancies, such as Ewing sarcoma and acute myeloid leukemia. It has a regulatory role in endothelial differentiation, angiogenesis, and vasculogenesis. ERG overexpression is considered a novel diagnostic marker for prostate carcinoma and has been found to be expressed in 40%–70% of them. However, little is known about the role of the TMPRSS2:ERG gene fusion in endometrial cancer. In the current study, we examined the potential of ERG transcription factor in endometrial tissues.
Design: Formalin-fixed, paraffin-embedded endometrial tissues obtained from 535 cases were used to construct an endometrial tissue microarray. Endometrial tissue samples were randomly collected from 207 patients by curettage, biopsy, or hysterectomy procedures dating from 1982 to 2002 (UCLA Medical Center). Antigen retrieval was performed in Tris/borate/EDTA buffer. Sections were then incubated with an anti-ERG mouse monoclonal antibody (Biocare Medical).
Results: None of the 535 cores, including benign endometrium, hyperplasia with or without atypia, and endometrial carcinoma, showed expression with ERG immunohistochemical stain. The spiral arteries and small vessels of the endometrium showed strong positive nuclear staining in these cases (Figure 218; A [hematoxylin-eosin]; immunohistochemistry [B]).
Conclusions: These results suggest that the oncogenic gene fusion TMPRSS2:ERG does not occur in endometrial cancer relative to prostate cancer. Therefore, development of ERG expression profile would not be a useful diagnostic or prognostic marker for screening patients with endometrial cancer.
c-Kit+ Uterine Myxoid Leiomyosarcoma in the Setting of a JAK3 Germline Mutation: (Poster No. 146)
Uterine myxoid leiomyosarcoma (UML) is a neoplasm arising from the smooth muscle cells of the myometrium. Although uterine leiomyomatas are common, the malignant counterpart is exceedingly rare (1.3% of uterine malignancies), and its atypical variants are quite unique. In this case, a 66-year-old, African American woman presented with irregular postmenopausal bleeding and was subsequently diagnosed with a UML after a hysterectomy. Histologically, the tumor was composed of abundant aggressive, malignant, spindled cells in a myxoid background with extensive lymphovascular invasion (Figure 219). Further analysis of the tumor proved it was positive for desmin and smooth muscle actin and negative for CD10, supporting UML. In an effort to further characterize this neoplasm, c-Kit and Dog1 were found to be positive, and a JAK3 P132T missense germline mutation was found via next-generation sequencing. A literature review revealed no previous reports of a UML found to be positive for c-Kit or in the setting of a JAK3 mutation. It has been suggested that UML occurs in 4 of 1 000 000 women; although the more conventional variant is more common, this mesenchymal tumor has not been extensively studied. The therapeutic options of chemotherapy and radiotherapy have been shown to be ineffective at this time. Given the highly aggressive nature of this tumor and the lack of therapeutic options, c-Kit–targeted therapy should be pursued. This JAK3 mutation may prove to be a prognostic marker (as recently found in clear cell renal cell carcinoma) or to be just a bystander, but further case study is needed.
Metastatic Prostate Cancer Diagnosed in a Colon Polyp: (Poster No. 148)
Adenocarcinoma of the prostate is the second most-common cause of cancer-related deaths among men in the United States. Metastatic disease commonly involves the bones, lymph nodes, lungs, liver, and brain. Rarely, colonic involvement is seen, and it is generally due to direct extension to the rectum. It is exceedingly uncommon for distant metastasis to occur in the right colon and small bowel. We present a case of prostatic adenocarcinoma metastasizing to the appendiceal orifice in a 78-year-old man. Our patient had a history of adenocarcinoma of the prostate (Gleason score 4 + 4 = 8) diagnosed 4 years before presentation (Figure 220, A). He also had a history of adenocarcinoma of the distal colon 30 years prior, which resulted in a partial colectomy and permanent diverting colostomy. Before his presentation, follow-up colonoscopy findings had been negative. During routine colonoscopy, he was found to have a 0.4-cm polyp near the appendiceal orifice. Histologically, the polyp demonstrated colonic mucosa with an infiltration of the lamina propria by individual cells with abundant cytoplasm and round nuclei with prominent nucleoli (Figure 220, B). The neoplastic cells were strongly positive for PSA (Figure 220, D) and negative for CK7, CK20, and CDX2 (Figure 220, C) supporting a diagnosis of metastatic prostatic adenocarcinoma. Metastatic disease of extracolonic origin arising in a polyp is extremely uncommon, but metastases have been reported to involve breast, ovary, stomach, esophagus, and kidney. This is one of the first cases of metastatic prostate cancer diagnosed in a colon polyp described in the English literature.
Immunophenotypic Characterization of Fetal Testis and Associated Excretory Duct System: (Poster No. 152)
Context: The immunophenotype of testis and associated excretory ducts has not been fully characterized in fetal or pediatric patients. Testis and excretory structures may be involved by diverse neoplastic processes, and knowledge of normal immunophenotype may aid in clinical diagnosis and advance understanding of tumor histogenesis.
Design: Sections of 18 testicles from fetal/pediatric autopsies of 14 patients without known syndromic affliction or genitourinary disease were stained with a panel of relevant immunomarkers (AR, ER, PR, PSA, PSMA, PAX8, WT1, calretinin, CK7, CK20, OCT4, SALL4, and CD117). Intensity (strong, 3; moderate, 2; weak, 1; or none, 0) and percentage of cells staining were multiplied to give a product score (scale, 0–300; positive staining >50).
Results: Germ cells frequently expressed OCT4 (10 of 18), SALL4 (15 of 18), and CD117 (11 of 18), and OCT4 expression positively correlated with CD117 expression. Sertoli cells expressed WT1 (15 of 18) and calretinin (15 of 18). Leydig cells were assessed in only one case (with Leydig cell hyperplasia) and expressed calretinin. The tunica vaginalis frequently expressed PR (6 of 14), WT1 (14 of 14), calretinin (14 of 14), CK7 (14 of 14), and CK20 (6 of 14). Excretory structure immunophenotypes are summarized in the Table; AR, PAX8, and CK7 were expressed throughout the excretory system, and only the ductuli efferentes expressed ER and PR.
Conclusions: Fetal testis and excretory structures demonstrate specific immunophenotypes and are similar to adult testis and excretory structures (data not shown). Knowledge of these immunophenotypes may aid the surgical pathologist in accurate diagnosis of fetal and adult testicular and paratesticular neoplasms.
A Rare Case of Isolated Testicular Myeloid Sarcoma in a Nonleukemic Infant: (Poster No. 153)
Myeloid sarcoma (MS) is a neoplasm composed of immature and mature myelomonocytic cells in extramedullary locations. We present a case of isolated testicular MS in a 4-month-old infant. He presented with an incidentally noted, 2-cm, left testicular mass. He underwent left orchiectomy with a clinical preoperative differential diagnosis of yolk sac tumor, teratoma, and epidermoid cyst. Grossly, the tumor was a tan, well-circumscribed mass within the testicular parenchyma. The tumor was composed of infiltrative, intermediate-sized cells with moderate, pale-pink, agranular cytoplasm, with oval to irregular nuclei, and inconspicuous nucleoli. Mitoses were rare, and there was no necrosis. The atypical cells were positive for monocytic markers CD4, CD68, and lysozyme, and were negative for lymphocytic markers. Flow cytometry demonstrated that the cells were positive for monocytic markers CD4 and CD14, and stem cell markers HLA-DR and CD123; the myeloid marker CD117 was negative. There was no definitive evidence of concurrent leukemia. Eighteen months after diagnosis and chemotherapy, he had no evidence of disease recurrence. Myeloid sarcoma most commonly affects the skin, bone, and central nervous system; to date, only 4 cases have been reported in the testicle in infants. Myeloid sarcoma is associated with acute myeloid leukemia and can precede the disease or may herald a leukemic relapse. It is paramount to accurately diagnose MS on initial analysis, as prompt initiation of chemotherapy may confer a prognosis similar to children with acute myeloid leukemia, rather than the more dismal prognosis of MS (Figure 221).
Concurrence of Prostatic Adenocarcinoma and Lymphoma—Clinical and Pathologic Characteristics: A Single Institutional Experience: (Poster No. 159)
Context: Prostatic adenocarcinoma (PA) is the most common type of cancer in men, with newly diagnosed cases in almost 150 per 100 000 men in America each year. Primary or secondary lymphoma involving the genitourinary system, on the other hand, is very rare, particularly in the prostate. The clinical and pathologic nature of lymphoma coexisting with PA may be an underinvestigated topic.
Design: Data from our institutional files of patients with concurrent lymphoma and PA between 2001 and 2013 was retrieved after obtaining institutional review board approval. Each case was reviewed and diagnoses confirmed by a GU pathologist and a hematopathologist.
Results: Approximately 3500 prostatic biopsies and radical prostatectomies were performed between 2001 and 2013. A total of 34 patients (0.9%) were found to have both PA and lymphoma (median age, 69 years). Nine of 34 cases of lymphoma were discovered incidentally during staging or follow-up of patients with PA. Three of those 34 cases transformed to aggressive types of lymphoma. Of the 16 patients with completed follow-up data, 7 died of disease (5 of lymphoma and 2 of PA). The 5-year survival for PA alone is expected to be 100%; however, the median overall survival of those 7 patients was 51 months after diagnosis of lymphoma (Table).
Conclusions: A thorough investigation of atypical lymphoid infiltrates within prostatic tissue is warranted in patients with or without a history of lymphoma as the subtypes of lymphoma may coexist and be more aggressive than PA. The appropriate diagnosis may significantly affect clinical management.
A Case of Adult-Onset Collagenofibrotic Glomerulopathy: An Extremely Rare Glomerular Disease: (Poster No. 161)
Collagenofibrotic glomerulopathy (CFG) is an extremely rare glomerular disease, characterized by massive accumulation of collagen type-III fibrils in the mesangium and subendothelial aspect of the glomerular basement membrane. Being rarified, the cause and pathogenesis of the CFG is still uncertain. Scarce case reports and small series are reported from Japan, with sporadic cases from Europe and Brazil. We report a case of CFG in a 56-year-old Middle Eastern woman who had a long standing history of hypertension, type II diabetes, and chronic kidney disease. She presented with progressively declining renal function and nephrotic range proteinuria. Her serum creatinine rose from 1.2 mg/dL to 2.2 mg/dL during the period of 1 year. The family history and serologic workup was not contributory. The renal biopsy showed global and marked expansion of glomerular tufts by deposits of pale, eosinophilic material without significant increase in mesangial cellularity (Figure 222, A). The deposits were weakly PAS+ (Figure 222, B) but completely negative for Congo red and immunofluorescence. By electron microscopy, the deposits were located in the mesangium and subendothelial aspect of the glomerular basement membrane (Figure 222, C) and demonstrated curved and spiral fibers with distinct transverse striation every 60 nm, characteristic of type-III collagen (Figure 222, D). The lamina densa of the basement membrane was unremarkable, the most differentiating feature to distinguish CFG from the morphologically related entity nail-patella syndrome. In conclusion, we report a case of an adult-onset CFG, which is an extremely rare glomerular disease and are seeking analysis of more cases to understand the pathogenesis.
Melanocytic Neuroectodermal Tumor of Infancy Involving the Testis and Paratesticular Region: An Unusual Presentation of a Rare Neoplasm: (Poster No. 163)
Paratesticular melanocytic neuroectodermal tumor of infancy involving testis is an extremely rare entity with only a few cases described in the literature. Although technically benign, locally aggressive growth, recurrences, and metastases have all been reported, highlighting the need for early diagnosis and therapy. We report a case of a 7-month-old, male infant who presented in our institution after unsuccessful treatment with antibiotics for swelling and discoloration of left scrotum. Ultrasound showed a hypervascular, 16 × 12-mm, paratesticular mass with subsequent mass effect on the testis. A left inguinal orchiectomy was performed. Gross examination revealed a firm, 2.0-cm, tan/white mass with ill-defined borders abutting the tunica albuginea but sparing the epididymis and spermatic cord. Microscopically, small blue tumor cells were arranged in nests, cords, and papillary tufts within alveolar spaces involving both testis and epididymis (Figure 223, A). Scattered large tumor cells were also present, often containing chunky melanin pigment (Figure 223, B). Within the background, there was abundant fibrous tissue. Other features included a few scattered apoptotic cells, infrequent mitosis, minimal necrosis, and rare intratumoral lymph vascular invasion. Immunohistochemistry showed positivity for neuroendocrine markers (Figure 223, C; synaptophysin+) and HMB-45 (Figure 223, D). One year clinical follow-up revealed no evidence of recurrent or metastatic disease. Although a rare diagnosis, this entity should be considered when dealing with a small blue cell tumor of the aratesticular/testicular region.
Pediatric Renal Malignancies Other Than Wilms Tumor: Ten Years of Experience From a Single Institute: (Poster No. 166)
Context: Renal malignancies other than Wilms tumors are rare in childhood. Wilms tumor accounts for 6%–7% of childhood cancers, whereas the remaining renal malignancies account for less than 1%. To gain more knowledge about this rare tumor, we collected all the cases from our institute during the past 10 years and analyzed the clinical and pathologic characteristics of those cases.
Design: Our archive for kidney specimens comes from patients younger than 18 years. Pathology reports were reviewed; cases other than Wilms tumor were identified. All clinical information and ancillary study results were analyzed. For one case, additional IHC stains (CK7, AE1/3, TFE3), and TFE3 break-apart fluorescence in situ hybridization assay (FISH) assay were performed.
Results: A total of 83 cases of renal malignancies, with only 5 cases other than Wilms tumors identified. The clinical and pathologic features of these cases are summarized in the Table. Interestingly, case 1, which was previously diagnosed as papillary RCC with oncocytic change and osteoid metaplasia, was reclassified as TFE3-translocation RCC, supported by IHC stains and FISH.
Conclusions: Pediatric renal malignancies other than Wilms tumor are rare, about 6% of all renal malignancies in this age group. These are extremely heterogeneous, including TFE3-translocation RCC, unclassified RCC, mesenchymal chondrosarcoma, rhabdoid tumor, and undifferentiated sarcoma. These tumors present with wide age distribution (3 month to 17 years) and are usually associated with aggressive clinical behavior. Some of them had characteristic changes at the molecular genetic level. Further clinical and basic research of these tumors is warranted to better understanding and treatment of these rare malignancies.
Concordant Clear Cell “Mesonephric” Carcinoma of the Bladder and Lung Adenocarcinoma With Clear Cell Features—Multiple Primaries Versus Metastatic Neoplasms: Clinical and Pathologic Challenges: (Poster No. 167)
Clear cell carcinoma of the bladder (CCCB) is a rare variant of urinary bladder adenocarcinoma. We report a patient with CCCB with a concordant right upper lobe pulmonary adenocarcinoma with clear cell features and address the important immunohistochemical distinctions between the two primary tumors. The patient was a 59-year-old woman who presented with hematuria. Her past medical history included invasive mammary carcinoma and end-stage renal disease on hemodialysis. A computed tomography (CT) urogram revealed a 3-cm polypoid bladder mass. The CT chest scan showed a 1-cm right upper lobe nodule. The patient underwent transurethral biopsy and open radical cystectomy of the bladder mass, and a transthoracic core needle biopsy of the lung nodule. Histologically, the bladder tumor consisted of flat, cuboidal to columnar cells with clear or eosinophilic cytoplasm, and a hobnail appearance, organized in tubulocystic and blunt papillary patterns. The neoplastic cells were diffusely positive for racemase, CA 125, CK7, and focally positive for CK20, p53, and CEA. The lung tumor demonstrated a glandular architecture with mucin production (positive mucin and PAS). The neoplastic cells were diffusely positive for CK7, Napsin-A, and TTF1 and negative for CK20 and CA 125. The presence of clear cell features in both neoplasms raised the possibility of lung metastasis from the primary bladder tumor. However, the glandular architecture of the lung neoplasm, along with its distinctive immunoprofile, confirmed the presence of separate primaries (Figure 224, A through D).
Medullary Renal Cell Carcinoma—Tumor Associated With Sickle Cell Trait: Case Report and Review of Literature: (Poster No. 168)
Medullary renal cell carcinoma is a malignant epithelial tumor that arises from the collecting duct epithelium. It is extremely rare and almost exclusively associated with the sickle cell trait and young, black, male patients. This highly aggressive and chemoresistant neoplasm constitutes 2% of all kidney tumors in young adults, and because 95% are diagnosed with metastatic disease at presentation, the prognosis is dismal. We report the case of a Hispanic 42-year-old man with unknown sickle cell trait status presenting with a 3-month history of unintended weight loss and malaise. He was found to have a renal mass by imaging studies and was sent for urologic intervention to undergo a left nephrectomy. Gross examination of the kidney revealed a 13-cm, ill-defined, white-tan mass with yellowish, rubbery areas involving the hilar area. Histologically, it was a poorly differentiated neoplasm with immunoreactivity for CK7 and pankeratin and characteristic loss of INI1, which is consistent with the diagnosis of medullary renal cell carcinoma. This tumor is an extremely rare type of kidney cancer with a very poor prognosis that is minimally improved with chemotherapy regimens. It is important to differentiate it from the clinicopathologically similar but INI1+ collecting-duct carcinoma. Most of the cases are diagnosed in late stages; therefore, avid recognition and clinical suspicion, especially in high-risk populations (sickle cell trait in young, black, male patients), may be the first step to improving survival rates. The case presented here posed a diagnostic challenge because of its unusual demographic characteristics (Figure 225, A and B).
A Comparison Study of GATA3, S100P, and Uroplakin II in Genitourinary Cancers: (Poster No. 169)
Context: Immunohistochemical markers specific for urothelial carcinoma (UC) have been inadequate. Recently, new markers, S100P and uroplakin II (UII), have been identified and commercialized. We compared these antibodies, along with GATA3, using histologically similar carcinomas to derive sensitivity for detecting bladder UC and specificity for ruling out diagnostic confounders, prostate carcinoma (PC) and renal cell carcinoma (RCC).
Design: Using antibodies to GATA3 (clone HG3-31), S100P (Cell Marque, polyclonal), and UII (clone BC21), we immunohistochemically stained tissue microarrays containing 56 UC cases, 46 PC cases, 76 clear cell RCC (CRCC) cases, and 63 papillary RCC (PRCC) cases. Tumors in which less than 5% of cells stained were scored as positive; staining intensity (weak versus strong) and extent (focal versus diffuse) were also recorded.
Results: GATA3 and S100P showed equivalent sensitivity for detecting UC (86%). UII was less sensitive (61%). The fraction of UC cases that stained intensely was greatest for GATA3, followed by UII, then S100P. The specificities of GATA3, S100P, and UII for UC versus other GU cancers were 99%, 88%, and 98%, respectively. Background staining with S100P antibody was significant with intense staining of smooth muscle. Figure 226 shows a Venn diagram of the stain overlap in UC.
Conclusions: A combination of GATA3 and UII, but not S100P because of lower specificity and staining quality, is most useful in the differential diagnosis of UC. GATA3 and UII antibodies are directed to nonrelated proteins and appear to sort independently, explaining different staining percentages and justifying their combined use for reliable detection of UC.
Are Intracystic Papillary Proliferations the Precursor Lesion of Clear Cell Papillary Renal Cell Carcinoma in Patients With Acquired Cystic Kidney Disease?: (Poster No. 170)
Context: The association between renal epithelial neoplasms and acquired cystic kidney disease (ACKD) has long attracted the attention of pathologists. However, the pathogenesis and molecular links are still not well established. In our practice, intracystic papillary proliferations are frequently observed in ACKD specimens. We aimed to examine the expression profile of proteins of interest in the intracystic papillary proliferations in ACKD specimens with coexisting clear cell papillary renal cell carcinoma (CCPRCC), one of the most common neoplasms associated with ACKD.
Design: The nephrectomy cases of ACKD from 2000 to 2014 were retrieved from our archives. Cases of CCPRCC accompanied by spatially separate intracystic papillary proliferations were included in our study. Tissue microarray was created using the corresponding formalin-fixed, paraffin-embedded tissue blocks. Immunostains for CAIX, CK7, AMACR, and CD10 were carried out with appropriate controls.
Results: Histomorphologic study revealed small foci of intracystic papillary proliferations protruding from the cyst epithelium, composed of epithelial cells with eosinophilic to clear cytoplasms, round to oval nuclei, and inconspicuous nucleoli (Figure 227, A and B). The nuclei were arranged away from the basement membrane, resembling the neoplastic cells of CCPRCC. Immunohistochemical studies demonstrated the diffuse, intense membranous immunoreactivities of CAIX (Figure 227, C) and CK7 (Figure 227, D) in the epithelial cells of the papillary proliferations, and the negative immunostains for AMACR and CD10, an immunoprofile matching that of CCPRCC.
Conclusions: Our histologic and immunohistochemical findings support the concept that intracystic papillary proliferations represent the precursor lesion of CCPRCC in patients with ACKD.
Unusual Collision Tumor Composed of Renal Angiomyolipoma With Epithelial Cysts and a Low-Grade Clear Cell Renal Epithelial Tumor: (Poster No. 171)
Renal angiomyolipoma is a benign, typically solid neoplasm containing varying amounts of fat, vessels, and smooth muscle. A rare cystic variant termed angiomyolipoma with epithelial cysts (AMLEC) was described in 2006, and fewer than 25 cases have been reported in the literature. We report a case of a 47-year-old man with an incidental 6-cm cystic renal mass treated by partial nephrectomy. The grossly and radiographically solitary, multicystic tumor appeared to be a collision tumor of 2 microscopically distinguishable lesions: (Figure 228): (1) an AMLEC consisting of epithelial cysts lined by cuboidal to hobnail cells and surrounded by a compact subepithelial layer of cellular stroma composed predominantly of epithelioid cells with glassy eosinophilic cytoplasm; and (2) a multiloculated collection of cysts lined by clear cells and surrounded by relatively acellular fibrous stroma. The clear cells had small, uniform nuclei and were occasionally multilayered. The renal parenchyma surrounding the cystic tumors contained 2 papillary adenomas. Immunohistochemical stains showed that the AMLEC stromal components were positive for HMB-45, Melan-A, estrogen receptor, progesterone receptor, and desmin, whereas the AMLEC epithelial component was positive for pancytokeratin, CK7, and PAX8. The multiloculated clear cell tumor showed positive staining for CK7, PAX8, and CAIX. To our knowledge, this is the first reported case of an incidentally found AMLEC juxtaposed to a multiloculated clear cell renal cell proliferation. Molecular characterization of these 2 tumors is currently underway.
Monophasic Synovial Sarcoma of the Extratesticular Soft Tissue: Report of a Rare Occurrence: (Poster No. 174)
Tumors arising from extratesticular soft tissue are rare, and most represent sarcomas arising from different components of hilar and spermatic cord soft tissue. Because of the proximity to testis and its appendages, it is often challenging to accurately diagnose these lesions. Moreover, metastasis from other sites is always a consideration. We report a case of a 53-year-old man with a right spermatic cord mass with extension into the testicular appendages. Grossly, the tumor measured 8 cm with a homogenous, tan cut surface. Histologically, the mass consisted of a highly cellular, monotonous organoid and a nested proliferation of medium-sized, round to oval cells with clumped nuclear chromatin, small nucleoli, and minimal cytoplasm. Mitotic activity was brisk. A prominent hemangiopericytoma-like vasculature and hypocellular edematous areas alternating with highly cellular foci, with the latter predominating, were noted. Adjacent testicular parenchyma and epididymis were microscopically uninvolved and otherwise displayed no pathologic changes. Initially, differential diagnosis included sex cord-stromal tumor, neuroendocrine tumor, and round blue cell tumor. The immunostains showed the tumor cells to express cytokeratin AE1/AE3, vimentin, TLE1, bcl2, CD99, CD56, and synaptophysin (focal, weak). Calretinin, inhibin, WT1, and CD34 stains were negative. Staining for β-catenin was positive in a cytoplasmic distribution. Overall, tumor morphology and immunohistochemical profile were consistent with a monophasic synovial sarcoma. To our knowledge, this is the second case reported in extratesticular soft tissue, and pathologists should consider this in the differential diagnosis (Figure 229, A [tumor and epididymis], B [tumor], C [TLE1], and D [bcl2]).
Epididymal Papillary Cystadenocarcinoma: (Poster No. 175)
Neoplasms arising from the epididymis are extremely rare, making characterization and diagnosis difficult. We report a case of epididymal papillary cystadenocarcinoma in a 64-year-old man. The patient, with a past history of orchiopexy for an undescended testis, presented with a progressively enlarging right scrotal mass with drainage from skin for more than 3 years. Multiple urologists advised him to have the mass excised, and the patient finally agreed after it had doubled in size during the prior 6 months. The resected specimen measured 12.5 × 10 × 8.5 cm with ulceration through the scrotal skin. Grossly, the tumor appeared to arise from the hilar structures. Microscopic examination revealed columnar cells in a papillary architecture with tubular and cystic areas as well as foci of necrosis (Figure 230, A and B). Cells showed eosinophilic to clear cytoplasm with moderately pleomorphic nuclei. Prominent mitotic activity with invasion into the surrounding stroma, soft tissue, and scrotal wall was present. Differential diagnosis including metastasis. and origin from adjacent structures was considered. Immunostains revealed the tumor to be positive for CDX2, CK20, AMACR, AE1/AE3, with apical positivity for CD10, focally positive for EMA, and scattered positivity for PLAP and MART1 (Figure 230, C and D). It was negative for CK7, calretinin, WT1, and PAS, PAX8, PAX2, glypican 3, PSA, and PSAP. These findings, along with location, morphology, and absence of tumor elsewhere, are consistent with epididymal origin, leading to the diagnosis of epididymal papillary cystadenocarcinoma, a rare case arising in a maldeveloped testis.
The Highest Level of Serum β-HCG With Atypical Syncytiotrophoblasts: A Distinct Entity of Seminoma: (Poster No. 179)
Approximately 30% of seminomas have syncytiotrophoblastic cells with increased serum human chorionic gonadotropin (β-HCG). In this scenario, it is important to differentiate between seminoma with syncytiotrophoblastic cells and choriocarcinoma because the clinical management would be different. The levels of serum β-HCG in seminoma with syncytiotrophoblast cells are usually less than 500 mIU/mL. We present a case of stage I seminoma with abundant giant cells and HCG levels of 16 562 mIU/mL, creating a diagnostic dilemma. A 39-year-old Hispanic man presented with a 2-month history of scrotal pain and swelling. Ultrasound showed a 9.6 × 7.2 × 5.6-cm vascular mass suspicious for malignancy. Serum β-HCG was 16 562 mIU/mL, and lactate dehydrogenase was 1567, whereas α-fetoprotein level was within reference range. He underwent a right radical orchiectomy. On gross examination, there was a pink-tan, lobulated mass replacing the entire testis with scattered areas of necrosis and hemorrhage. Microscopic examination showed features of classical seminoma with rete testis involvement and lymphovascular invasion. However, there were also scattered giant cells of 2 types noted, a foreign body type and syncytiotrophoblastic cells, which stained for pancytokeratin. Prominent clusters of atypical syncytiotrophoblastic cells, associated with large blood-containing lacunae (Figure 231), raised the possibility choriocarcinoma, especially with high serum HCG level. Extensive sampling was performed, and no cytotrophoblastic cells or any other germ cell component were identified. To conclude, this is the highest level of serum HCG reported in a case of pure seminoma to our knowledge. The clusters of atypical syncytiotrophoblast cells lining the blood spaces should be carefully evaluated for cytotrophoblastic cells to exclude choriocarcinoma.
Primary Renal Ewing Sarcoma/Primitive Neuroectodermal Tumor in a 65-Year-Old Patient With a History of Bilateral Breast Cancer: (Poster No. 180)
Primary renal Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET) is a rare tumor characterized by genetic translocation t(11;22) and is typically seen in young adults. It is often difficult to diagnose in older patients, especially when there is a history of malignancy. We describe a case of primary renal ES/PNET in a 65-year-old woman with treated bilateral breast cancer. On a computed tomographic scan, a heterogeneous mass was discovered incidentally in the upper pole of the kidney. Grossly, the tumor was unifocal, 11 × 8 × 4 cm, and white to pink with soft and fleshy cut surfaces. Microscopically, it consisted of sheets and large, irregular nests of uniform, small blue round cells with high nuclear to cytoplasmic ratios. No geographic necrosis was identified, and the tumor was mitotically active (Figure 232, A and B). No significant glycogen was identified with PAS and PAS-D stains. Immunohistochemical stains revealed that the tumor cells were diffusely positive for CD99 (Figure 232, C) and focally positive for CD56 and synaptophysin. Rare stromal, but no tumor cells, were positive for S100. No expression of cytokeratin AE1/AE3, cytokeratin 5, cytokeratin 7, cytokeratin 20, cytokeratin CAM 5.2, chromogranin, myogenin, p63, GATA3, TTF1, PAX8, desmin, WT1, CD3, CD20, CD45, and CD138 was identified. κ and λ by chromogenic in situ hybridization were also negative. The morphologic features and immunostaining results of this tumor were most consistent with ET/PNET. The diagnosis was further confirmed by fluorescence in situ hybridization, which identified the presence of a EWSR1 gene rearrangement (Figure 232, D).
Concurrent Renal Cell Carcinoma and Follicular Lymphoma Involving Renal Parenchyma and Ureter: A Rare Presentation: (Poster No. 183)
Although renal cell carcinoma is the most common renal cancer, concurrent renal cell carcinoma and lymphoma involving kidney parenchyma and ureter is very rare. This report describes a case of an 82-year-old man who presented with hydronephrosis. Imaging study revealed a 4.1-cm renal parenchyma lesion and a paranephric mass. Needle biopsy of the renal parenchymal lesion demonstrated renal cell carcinoma. The patient had previously undergone a nondiagnostic needle biopsy of the paranephric mass 3.5 years before the diagnosis of renal cell carcinoma. Radical nephrectomy was performed. Enlarged periaortic lymph nodes were noted at surgery, and lymphadenectomy was performed. Intraoperative frozen section on one of the periaortic lymph nodes was reported as negative for renal cell carcinoma, but the possibility of lymphoma was raised. Histopathology and flow cytometry revealed follicular lymphoma. The ureter was diffusely infiltrated by lymphoma, which was the cause of hydronephrosis in this patient. Final pathologic evaluation confirmed the presence of renal cell carcinoma. In addition, renal parenchyma and perirenal soft tissues were infiltrated by lymphoma. The concurrence of renal cell carcinoma and follicular lymphoma involving kidney parenchyma and ureter is rare. Accurate diagnosis of both entities was necessary for proper patient care. Figure 233 shows ureter involved by lymphoma (A) and transitional area between renal cell carcinoma (upper left) and follicular lymphoma (lower right) in kidney (B through D; B, hematoxylin-eosin; C, pancytokeratin AE1/3 highlights renal cell carcinoma cells (upper left); and D, BCL2 immunohistochemistry staining of both follicular lymphoma (lower right) and renal cell carcinoma (upper left).
Incidentally Discovered Basal Cell Carcinoma of the Prostate: Morphologic and Immunohistologic Review of 3 Cases: (Poster No. 184)
Context: Basal cell carcinoma of the prostate is a rare and poorly characterized neoplasm of the prostate, with an estimated 68 reported cases in the literature. The morphologic spectrum of prostatic basal cell carcinoma includes the more-indolent adenoid cystic subtype and the more-aggressive basaloid pattern subtype.
Design: We identified 3 cases of basal cell carcinoma at our institution during the past 40 years. Clinical, morphologic, and immunohistologic data were reviewed.
Results: All 3 cases (age range, 73–93 years) were diagnosed incidentally on transurethral resection of prostate performed for symptomatic relief of benign prostatic hyperplasia. Two cases demonstrated adenoid cystic histologic features (nests and clusters of basaloid cells with cribriform architecture) (Figure 234, left). One case demonstrated basaloid histologic features (solid nests of pleomorphic cells exhibiting central necrosis and desmoplastic stromal response) (Figure 234, right). Necrosis, lymphovascular invasion, perineural invasion, and Ki-67 mitotic rate were more pronounced in the basaloid carcinoma than they were in the adenoid cystic carcinomas. By immunohistochemistry, neoplastic cells stained variably for p63 (positive in 2 of 3), 34βE12 (patchy positive in 3 of 3, ranging from 5%–60% of neoplastic cells), p40 (positive in 1 of 3), and bcl2 (positive in 2 of 3). Additionally, results for the following immunohistochemical stains have not, to our knowledge, been previously reported in the literature: GATA3 (positive in 1 of 3); p501S (negative); and NKX3.1 (negative).
Conclusions: We present the morphologic and immunohistologic spectrum of a rare prostatic tumor entity. Recognition of the unique clinical presentation (incidental discovery on transurethral curettage for obstructive symptomatology) is essential.
Adult Pleomorphic Juxtaglomerular Cell Tumor: (Poster No. 188)
A 40-year-old man with chronic hypertension of unknown etiology since his teens presented to our emergency department following a motor vehicle collision. Computerized tomographic scan demonstrated an incidental finding of a 1.9-cm, enhancing, solid, interpolar renal mass inferior to the hilum of the right kidney. The patient underwent a right partial nephrectomy. Gross examination revealed an encapsulated, well-circumscribed, tan-grey mass. Histology showed a vascular tumor with capillaries and scattered muscular arterioles. Tumor cells were epithelioid with abundant eosinophilic, granular cytoplasm arranged in sheets and trabeculae. Some areas had a fibromyxoid background. The cells were predominantly monomorphic; however, some areas showed marked pleomorphism with large nuclei and prominent nucleoli (Figure 235). Mitotic activity was absent. Tumor cells were positive for vimentin, CD34, and c-KIT. Cytokeratin, chromogranin, synaptophysin, SMA, CAM 5.2, and HMB-45 were negative. CD31 and ERG highlighted delicate vascular channels within the tumor. The tumor's morphology, immunohistochemical profile, and clinical history supported the diagnosis of juxtaglomerular cell tumor (JCT). The JCT is an extremely rare, benign, renal neoplasm that causes hypertension, hyperaldosteronism, and hypokalemia secondary to renin secretion. Unlike our case, JCT is typically found in young adults. The differential diagnosis for JCT includes renal cell carcinoma, hemangiopericytoma, solitary fibrous tumor, and glomus tumor. Pleomorphism is a rare finding in JCT and, in combination with an older age at diagnosis, can lead to an inaccurate malignant diagnosis. Immunohistochemical stains are helpful in correctly diagnosing this benign entity.
Impact of Tissue Decalcification on Immunohistochemical Detection of Germ Cell Tumor Markers: (Poster No. 195)
Context: We investigated the impact of decalcification on the detection of commonly used germ cell tumor markers using germ cell tumor cell lines.
Design: Three germ cell tumor cell lines were obtained from American Type Culture Collection. Cell blocks were constructed from each cell line. A set of IHC markers as listed in the Table was tested on each cell line. Three cell lines collectively expressed all target markers. The cell pellets containing a mixture of the 3 cell lines were first fixed in 10% neutral-buffered formalin for 8 hours and then decalcified in Decalcifier B (Fisher Healthcare, item 23245683) for the durations indicated in the Table. The aforementioned IHC markers were tested on the tissue microarray sections. The staining intensity and percentage were recorded.
Results: The results are summarized in the Table.
Conclusions: These data demonstrate that tissue decalcification has (1) a significant negative impact on OCT4, Nanog, SOX2, and SALL4 detection; PLAP and CD30 detection; and D2-40 detection after 30 minutes, 60 minutes, and 6 hours of decalcification, respectively; and (2) has a limited impact on the detection of glypican-3, β-HCG, and CD10 following 1 week's decalcification.
Urachal Mucinous Tumor of Low Malignant Potential: An Incidental Finding in the Bladder of a Patient With Chronic Kidney Disease: (Poster No. 196)
The rare entity described as urachal mucinous tumor of low malignant potential is often an incidental finding and can present a diagnostic dilemma. We present a 75-year-old woman with hypertension and chronic kidney disease with an incidentally discovered bladder mass on a follow-up ultrasound for bilateral renal cysts. Previously, no imaging had been used to evaluate her bladder. This worrisome finding prompted a computed tomography scan, which detected a multi-septated, midline cystic lesion associated with the anterior-superior aspect of the bladder, suspicious for a tumor arising from an urachal remnant. A partial cystectomy was performed. Microscopic examination showed a multiloculated cystic lesion with abundant mucin involving the muscularis propria and perivesical adipose tissue without involvement of the overlying urothelium. The lining of the cystic spaces was composed of flat to columnar as well as pseudostratified cells with mild to moderate nuclear atypia (Figure 236, A). No features suggestive of a malignant process were present. Therefore, the diagnosis was “low-grade mucinous epithelial neoplasm (mucinous tumor of low malignant potential).” Helping identify the origin of this tumor were foci of urothelium-lined glandular structures with eosinophilic secretions in the muscularis propria adjacent to the neoplasm, representing urachal remnants (Figure 236, B). Also, immunohistochemistry stains showed the lining of the cystic spaces were positive for CK20 and CDX2 but negative for CK7, consistent with previous reports of this entity. This unusual case shows how certain ancillary findings can help point to an urachal origin as opposed to other primary sites.
TGR5 Is a Marker of the Distal Tubules and Not Expressed in Clear Cell Carcinoma: (Poster No. 197)
Context: The G protein–coupled bile acid receptor (TGR5) is a cell surface receptor that induces the production of intracellular cAMP and activation of a MAP kinase signaling pathway. Whether TGR5 expresses in normal kidney or renal neoplasms is not known.
Design: Fifty-eight renal cortical neoplasms were retrieved between 2000 and 2014. Immunostain was performed using TGR5 antibody (1:1000, Sigma). Cells with a membranous and cytoplasmic staining were considered as positive. A combined score of intensity and extent was calculated and categorized as negative, weak, moderate, and strong staining.
Results: In nontumoral kidney, TGR5 was strongly positive in distal convoluted tubules and thin loop of Henle, whereas the proximal convoluted tubules showed absent or focal weak staining, suggesting TGR5 may act as a selective marker for the distal tubular cells. Twenty-five of 27 clear cell renal cell carcinomas (CCRCC) cases (92.6%) were negative for TGR5 staining (P < .001) and 2 CCRCCs (2 of 27) had TGR5 focal staining in the area of papillary features. All papillary RCCs (11 of 11) and all urothelial carcinomas of the renal pelvis (8 of 8) expressed TGR5. All oncocytomas (5 of 5) showed weak TGR5 staining. All chromophobe RCC (6 of 6) showed weak to moderate TGR5 staining. Two clear cell papillary RCCs (2 of 2) showed strong TGR5 staining. One metanephric adenoma (1 of 1) and one poorly differentiated RCC (1 of 1) were negative for TGR5 (Table).
Conclusions: TGR5 may be a selective marker for the distal tubular cells. All papillary RCCs, chromophobe RCCs, and oncocytomas showed various degrees of TGR5 expression, whereas most CCRCCs were negative. TGR5 would be helpful in differentiating CCRCC from other renal carcinomas.
Clinical, Histologic, Immunohistochemical, and Molecular Features of Melanotic Xp11 Translocation Renal Cell Cancer: (Poster No. 198)
Context: Melanotic Xp11 translocation renal cancer (TRC) is an extremely rare renal cancer with only 6 reported cases, categorized under the family of microphthalmia-associated transcription factor (MiTF) neoplasms that harbor TFE3 gene fusion. Morphologic features of the reported cases have similar characteristics. These tumors express melanocytic markers but are negative or focally positive for epithelial markers. Critical to the diagnosis is that all cases have nuclear TFE3 protein expression that reflects TFE3 gene rearrangement. To date, all cases confirmed by molecular methods have been identified in the pediatric population or adult women.
Design: Here, we describe the clinical, histologic, immunohistochemical, and molecular findings of melanotic Xp11 TRCs. In addition, we report the first case, to our knowledge, of melanotic Xp11 TRC in an adult man.
Results: Melanotic Xp11 TRCs shared similar clinical, histologic, immunohistochemical and molecular features, including solid nested architecture; clear to granular eosinophilic cytoplasm; melanin cytoplasmic pigment; negative epithelial markers, smooth muscle markers and renal cell markers; positive melanocytic markers with exception of S100; and gene rearrangement involving TFE3 gene (Table).
Conclusions: The purpose of this study was to increase the awareness of the general surgical pathologist regarding the melanotic Xp11 TRC as a newly described malignant cell neoplasm, which occurs in a wide age range, is more commonly found in women, and can be misinterpreted as metastatic melanoma and perivascular epithelioid cell tumor (PEComa). Our report includes the first reported case with a confirmed diagnosis of melanotic Xp11 TRC in an adult man and highlights the importance of awareness of this entity.
Malignant Perivascular Epithelioid Cell Neoplasm (PEComa) of the Kidney With TFE3 Rearrangement: (Poster No. 199)
We report the case of a 28-year-old man with a large renal neoplasm (21 cm), adrenal involvement, multiple positive lymph nodes, and lung metastases. At 3 month follow-up after radical nephrectomy, patient had developed hepatic metastases, peritoneal metastases, and invasion of the superior vena cava with mass extending into the right atrium, despite chemotherapy. Histologically, the original tumor was composed of cells with clear to focally eosinophilic or vacuolated cytoplasm arranged in nests, sheets, and papillary or pseudopapillary structures. Areas of necrosis and hemorrhage were prominent. Some areas showed hyalinized fibrous bands with focal psammoma-like calcifications. Occasional foci showed smaller cells with scant cytoplasm. Occasional cells showed cytoplasmic pigment. Immunostains showed that most of the neoplastic cells were strongly positive for TFE3 protein, cathepsin K, HMB-45, and negative for Melan-A, AE1/AE3, CK7, EMA, PAX8, vimentin, and CD10. Recently, a subgroup of PEComas was recognized to harbor rearrangements involving the TFE3 gene, similar to translocation-associated renal cell carcinomas and alveolar soft part sarcomas. These TFE3 rearrangement-associated PEComas, like the tumor in this case, have shown a unique constellation of features that contrasts to PEComas in general, including nested and alveolar architecture with epithelioid morphology. These tumors appear to occur in young patients and, thus far, have not been associated with tuberous sclerosis. A closely related entity is the so-called melanotic Xp11 2 translocation renal cancer. These tumors show overlapping features of carcinoma, melanoma, and PEComa but are thought to be most closely related to PEComa (Figure 237).
Malignant Triton Tumor—A Rare Somatic Malignant Transformation in Testicular Mixed Germ Cell Tumor: Case Report and Prognostic Implication: (Poster No. 202)
Testicular teratoma is frequently mixed with other germ cell tumors (GCTs). Somatic-type malignancy (STM) is a rare phenomenon in testicular teratoma with histology similar to somatic cell malignancy elsewhere in the body. The few cases reported in literature showed sarcomatous component (SC) more frequent than carcinoma. The SC appeared in the primary tumor or in the recurrence/metastases and was resistant to the usual chemotherapy for GCTs. Embryonal rhabdomyosarcoma and malignant peripheral nerve sheath tumors (MPNSTs) were the most and least frequent, respectively. Only one case of malignant triton tumor (MTT) was reported in a mediastinal mature teratoma (MT). We report a case of testicular MT showing prominent SC of MTT and minor seminomatous component. A 24-year-old African American man presented with sudden left testicular pain and swelling. Ultrasound revealed enlarged left testis with heterogeneous parenchyma. Grossly, the testis was replaced by a well-defined mass (210 g, 8 × 7 × 7.5 cm). The cut surface revealed white fibrotic, soft pink, and cartilaginous areas (Figure 238, A). Tumor histology revealed a MT (Figure 238, B) intermixed with a large component of MPNST with rhabdomyosarcomatous differentiation consistent with MTT (Figure 238, C and D). A microfocus of seminoma was present in about 2% of the tumor. The SMT in testicular GCTs is a rare event. Our case may be the second MTT-STM reported in the literature. The STM in GCTs carries a poor prognosis, especially when present in metastases and may cause treatment failure because chemotherapy for GCTs will not be effective for the SC. This emphasizes the importance of identification of STM in teratoma for prognosis and proper treatment.
Chondroid Syringoma of the Scrotum: Case Report of a Rare Presentation and Literature Review: (Poster No. 205)
Chondroid syringoma is a rare, benign adnexal skin tumor that shares morphologic similarities with pleomorphic adenoma (benign mixed tumor) of the salivary gland. Most of these tumors (>95%) arise in the head and neck region; literature review reveals only 10 published cases of chondroid syringoma arising in the scrotum. Significantly, only 1 of these cases was diagnosed in the United States, and most (7 of 10) were found in patients of Japanese ethnicity. Herein, we report the second case of scrotal chondroid syringoma in a patient presenting in the United States. The patient was a 56-year-old white man who presented with a nontender, unilateral scrotal mass. On clinical exam, the mass was felt to be located in the subcutaneous tissue and not in the testicle itself, and he underwent excisional biopsy with sparing of the testicle. Grossly, the ovoid mass was 1.3 cm in greatest dimension, firm, tan-pink, and well-circumscribed. The cut surface was gray-white to yellow-white and glistening. There was a small ellipse of overlying unremarkable skin. Microscopically, there was a well-encapsulated, intraductal proliferation composed of lobules of mature hyaline cartilage and intervening bland ductal structures (Figure 239, A through C). There was no significant nuclear atypia or mitotic activity. Immunohistochemically, the tumor was diffusely positive for CK5/6, patchy positive for p63 (Figure 239, D), and negative for SALL4. It is essential to differentiate scrotal-based lesions, including chondroid syringoma, from testicular lesions in the workup of a solitary mass to avoid potential over management with orchiectomy.
Unilateral Amyloidosis of the Lacrimal Gland: A Case Report and Review of Literature: (Poster No. 207)
Amyloidosis is a disorder of protein metabolism characterized by extracellular deposition of misfolded proteins. It can occur in isolation affecting only one tissue type or as part of a systemic disease causing organ damage and serious morbidity. Localized deposits of amyloid are most often encountered in the lung, larynx, skin, urinary bladder, tongue, and the region about the eye. Unilateral amyloidosis of the lacrimal gland is a rare occurrence; to our knowledge, only 19 cases have been reported in the literature. We report a case of primarily localized amyloidosis of the right lacrimal gland in a 47-year-old woman who presented with subacute painless proptosis of the right eye. The patient had no associated systemic illness and was otherwise asymptomatic. Computed tomography of the orbits revealed calcification and uniform enlargement of the right lacrimal gland. Magnetic resonance imaging was performed to further assess whether the bone matrix on the affected orbit was involved. A unilateral lacrimal gland excision was performed. The diagnosis of primary localized amyloidosis of the lacrimal gland was made based on histology. Hematoxylin-eosin stain showed islands of pink, amorphous material with calcifications, whereas polarization of Congo red stain demonstrated apple green birefringence of amyloid. Lacrimal gland amyloidosis, although rare, should be considered as a differential diagnosis for a calcific lacrimal gland mass. Review of published cases indicates they presented with a similar clinical picture: eyelid ptosis with subacute onset of proptosis in a middle-age female (Figure 240, A through C).
Mesenteric Paraganglioma Presenting as a Small-Bowel Volvulus: (Poster No. 4)
Paragangliomas are rare tumors of the neural crest cell that arise from sympathetic and parasympathetic neural paraganglia and adrenal medulla. The most common location is adrenal medulla (pheochromocytoma). Intra-abdominal extra-adrenal paragangliomas and those arising outside of known paraganglia locations are associated with more aggressive behavior. A 92-year-old-woman presented with excruciating abdominal pain of 1 day duration, associated with nausea and diarrhea. Physical examination revealed a distended abdomen, bilateral lower quadrant tenderness, and absent bowel sounds. Computed tomography (CT) of the abdomen showed a closed loop small-bowel obstruction (CLSBO). An emergent laparotomy was performed and revealed a distended, deep red, and thickened small bowel with CLSBO secondary to volvulus. The volvulus was reduced. While running the bowel, a mass was identified in the mid-ileal mesentery. The mass was 3 × 2.8 × 2 cm, well circumscribed, and rubbery with red-tan, solid, and homogeneous cut surfaces. Microscopically, tumor cells were arranged in a characteristic trabecular or “Zellballen” (nest of cells) pattern. Immunohistochemistry demonstrated reactivity with chromogranin and synaptophysin. S100 stained in a sustentacular pattern. The remaining stains, including pancytokeratin, CD20, CD138, inhibin, and PAX-8, were negative. The mesentery is an extremely rare location for paraganglioma. So far, 12 cases have been reported. Most cases were nonfunctional, and an incidental finding on CT, hence preoperative diagnosis, is difficult. Paragangliomas should be included in the differential diagnosis of solid tumors of the mesentery. Metastases have not been reported in the 13 mesenteric paragangliomas. However, patients should be closely followed up even after complete resection.
A Unique Case of Mediastinal Teratoma With Mature Pancreatic Tissue, Nesidioblastosis, and Aberrant Islet Differentiation: A Case Report and Literature Review: (Poster No. 7)
Mediastinal teratomas with elements of mature pancreatic tissue are rare. Only a very few cases of pancreatic tissue with nesidioblastosis in teratoma have been reported. Here we report a case of a 12-year-old boy who presented with pleural effusion and was revealed to have a large anterior mediastinal mass. Biopsy of the mass revealed a benign mature teratoma. After biopsy the teratoma ruptured into the right thoracic cavity. It was then excised and sent to pathology for further evaluation. Preoperatively there was no evidence of hyperinsulinemia or hypoglycemia. Postoperatively there was no change in blood glucose levels. Histologically, the mass showed large areas of mature pancreatic tissue flanking a small intestine–like structure. Numerous endocrine cell islets, poorly defined groups of neuroendocrine cells, and ductular-insular complexes characteristic of nesidioblastosis were dispersed in the exocrine pancreatic parenchyma. In addition, other parts of the tumor containing keratinizing squamous epithelium with cutaneous adnexal glands, small intestine, and bronchus including cartilage and respiratory epithelium were observed. Some islets contained 2 or more cell types while others were monophenotypic. Immunohistochemical staining showed pronounced expression of pancreatic polypeptide, moderate expression of somatostatin and insulin, and complete absence of glucagon-containing cells. The selective deletion of glucagon might hold clues to an important regulatory mechanism in pancreatic development.
Fine-Needle Aspiration Cytology of Metastatic Anaplastic Thyroid Carcinoma: (Poster No. 8)
Anaplastic thyroid carcinoma (ATC) is an undifferentiated form of thyroid cancer with a mean survival of 4 months. It is more common in females and presents at an average age of 70 years. Anaplastic thyroid carcinomas may exist simultaneously or in concert with well-differentiated thyroid carcinoma in 7% to 89% of all cases. Molecular studies of BRAF somatic mutations in tumors with ATC and papillary thyroid carcinoma (PTC) show similar profiles, suggesting that both components arise from a single clone. A 60-year-old man presented with an enlarging right neck mass, cough, and hoarseness. Computed tomography (CT) of the neck and chest showed an 11.7-cm right thyroid lesion, bilateral upper lobe lung nodules, and enlarged regional lymph nodes. A fine-needle aspiration (FNA) of the neck mass demonstrated PTC. A CT-guided FNA of a right lung nodule was positive for malignancy, showing discohesive, plasmacytoid, highly atypical cells. A concurrent needle core biopsy with immunohistochemical stains supported a diagnosis of metastatic ATC. To determine if an anaplastic component was present in the PTC, a repeated FNA of the neck mass was performed. The FNA showed PTC with anaplastic features, confirming that the lesion in the lung represented metastatic disease. Although PTC with anaplastic features is known to metastasize to the lung, this has been infrequently reported in the cytologic literature. This report documents the important role of FNA biopsies for confirming the presence of metastatic disease, obviating the need for surgical intervention for diagnostic purposes.
Advanced Endoscopic Resections at the Gastroesophageal Junction: A 10-Year Institutional Review: (Poster No. 11)
Context: Endoscopic mucosal resections (EMRs) and endoscopic submucosal dissections (ESDs) are frequently used for therapy of premalignant and early-stage malignant lesions of the gastrointestinal tract. EMR and ESD are increasingly used at our institution for the management of Barrett esophagus (BE) with high-grade dysplasia (HGD) and intramucosal adenocarcinoma. Given the incidence of positive margins seen on recent EMRs and ESDs, an institutional review was performed to examine the correlation between clinicopathologic variables and margin status.
Design: A 10-year retrospective review of all EMRs and ESDs was performed by searching our pathology database. Thirty-one patients who underwent EMR or ESD for BE with HGD or intramucosal adenocarcinoma were identified. The following clinicopathologic variables were recorded: age, procedure type, tumor histology, degree of tumor differentiation, depth of invasion/tumor stage, margin status, and presence or absence of lymphovascular invasion.
Results: ESDs were significantly less likely than EMRs to have positive margins (30.8% versus 72.2%, respectively; P = .03). Tumor stage correlated with positive margin status (pT1a [23.1%], pT1b [75%], pT2 [100%]; P = .006) as did the degree of tumor differentiation (well [20%], moderately [52.4%], poorly [100%]; P = .05).
Conclusions: ESD was superior to EMR for the management of BE with HGD and/or intramucosal adenocarcinoma in our patient series. There was a significant association between the positive margins and tumor stage and degree of differentiation. Our results suggest that biopsy demonstration of a poorly differentiated tumor or submucosal invasion should prompt discussion of clinical management, as it is very unlikely that EMR/ESD will provide negative margins.
Features of Autoimmune Gastritis Are Distinct From Those of Helicobacter pylori Infection, Even in Early Stages of Disease: (Poster No. 13)
Context: Autoimmune gastritis (AIG) is a T-cell mediated disorder characterized by destruction of oxyntic glands. In the absence of intestinal metaplasia, the inflammatory pattern of AIG may resemble that of Helicobacter pylori–related gastritis in oxyntic mucosal samples. Cases of AIG with extensive pyloric metaplasia may mimic H pylori–related antral gastritis. We performed this study to characterize the early histologic features of AIG and identify helpful clues that distinguish it from H pylori–mediated gastric injury.
Design: Fifty-three cases of AIG, including 25 without intestinal metaplasia, were evaluated for multiple morphologic features. These cases were compared to H pylori gastritis involving body (n = 16) and antrum (n = 18).
Results: Compared to H pylori infection of the body, cases of AIG with intestinal metaplasia (n =28) showed a significantly greater degree of oxyntic gland atrophy (96% versus 50%). In the absence of intestinal metaplasia, cases of AIG showed a greater degree of endocrine cell hyperplasia (76% versus 31%), diffuse and/or deep lamina propria chronic inflammation (96% versus 63%), with more abundant eosinophils (mean/high-power field [HPF]: 25 versus 14) and apoptotic bodies (mean/HPF: 3 versus 1.5), but fewer neutrophils (28% versus 69%). Significant features that distinguished AIG with pyloric metaplasia (n = 48) from H pylori–related antral injury included endocrine cell hyperplasia (90% versus 50%), inspissated eosinophilic material in glands (40% versus 11%), eosinophils (mean/HPF: 28 versus 15), apoptotic bodies (mean/HPF: 3 versus 1.5), and fewer neutrophils (31% versus 61%).
Conclusions: The inflammatory pattern of AIG is distinct from that of H pylori infection of the body and from H pylori–related antral gastritis.
Cronkhite-Canada Polyposis Associated With Multifocal Dysplasia: Report of a Rare Case: (Poster No. 14)
Cronkhite-Canada (CC) syndrome is a rare noninherited hamartomatous polyposis that can involve any part of the gastrointestinal tract except the esophagus, with associated ectodermal changes. Because the histopathologic features overlap with juvenile polyposis (JP), CC represents a diagnostic challenge if there are no significant ectodermal manifestations. It is generally believed that in contrast to JP, CC polyps are rarely associated with dysplasia and its association with malignancy is controversial. We present a case of CC with associated multifocal dysplasia of the colon. A 74-year-old Korean woman presented with epigastric pain, vomiting, diarrhea, and weight loss. Physical examination showed hair loss, nail dystrophy, and hand hyperpigmentation. Endoscopy examination showed carpetlike polyposis involving the entire stomach and colon. Biopsy of the nonpolypoid background mucosa showed edematous lamina propria, cystically dilated glands filled with mucin, and active chronic inflammation resembling inflammatory bowel disease (IBD). Multiple foci of complete and incomplete intestinal metaplasia were noted in gastric mucosa. Biopsy of some colon polyps showed multiple areas of low-grade dysplasia. In the largest polyp, there was an abrupt transition from the background mucosa to the dysplastic area. Immunohistochemistry showed retained SMAD4 expression and focal IgG4-positive plasma cells in the lamina propria. Her symptoms were partially relieved by steroids, and colectomy is planned. In summary, we present a rare case of CC syndrome clinically mimicking IBD and histopathologically associated with multifocal dysplasia of the colon, highlighting the importance of careful clinicopathologic correlation in the differential diagnosis of JP and CC.
Colonic Biopsies in Pediatric Microscopic Colitis: The More the Better?: (Poster No. 17)
Context: Microscopic colitis (MC) is an entity that presents with chronic diarrhea and a normal or near normal gross appearance of colonic mucosa. Studies and data of MC are limited since it is a rare entity in the pediatric population. Performing more biopsies may increase the sensitivity of colonoscopy. However, this practice leads to a higher health care cost. We investigated the correlation between the number of colonic biopsies and the diagnosis of MC in children.
Design: Pathology reports of colonoscopy performed by 2 pediatric gastroenterologists at different institutions from 2013–2014 were reviewed. Clinician A submitted random colon biopsies as a single-part biopsy. Meanwhile, clinician B submitted separate biopsies from ascending, transverse, descending, and rectosigmoid colon into a multiple-part biopsy. The results between the 2 groups were compared.
Results: Fifty-four and 34 consecutive biopsies performed by clinician A and clinician B were designated as group A and group B, respectively. The predominant clinical symptoms for both groups were chronic diarrhea and vomiting. The average number of biopsies for group A patients was 4 biopsies (submitted as 1-part colonic biopsy). In comparison, each group B patient had an average of 13 biopsies (ranging from 3- to 5-part colonic biopsies). No MC diagnosis was made in group A patients, and 2 patients from group B were diagnosed with lymphocytic colitis (P = .15).
Conclusions: There was no significant difference of MC diagnosis in groups with 1-part and multiple-part colonic biopsies. In this cost-conscious era, clear guidelines for performing biopsies in children with normal colonoscopy are necessary.
Bile-Related Reactive Gastropathy Is Associated With an Increased Risk of Barrett Esophagus: (Poster No. 19)
Context: There is limited evidence that reflux of bile plays a significant role in the pathogenesis of Barrett esophagus (BE). This study aims to compare the prevalence of indirect evidence of reactive gastropathy (RG) in patients with and without BE.
Design: A retrospective review was performed on gastric biopsy specimens from 59 patients with histologically proven BE, and 59 without it were evaluated. Patients with Helicobacter pylori gastritis or history of recent nonsteroidal anti-inflammatory drug administration were excluded. RG is graded on a scale from 0 to 3 on the basis of severity.
Results: Among 59 patients with BE (mean age 56 ± 5 years), 23 had no RG; 17 had grade 1; 9 had grade 2; and 10 had grade 3. In contrast, among the 59 patients without BE (mean age 55 ± 3 years), 42 had no RG; 1 had grade 1; 1 had grade 2; and 3 had grade 3. The P for the sum of amalgamated scores 1, 2, and 3 was <.01.
Conclusions: Compared to the control group, a significantly higher incidence of RG in patients with BE suggests that duodenogastroesophageal reflux plays a significant role in the development and progression of BE. Our results confirm previously reported limited studies of a close association of BE with RG.
Histopathologic and Immunohistochemical Comparative Study of Strictures in Crohn Disease: (Poster No. 21)
Context: Fibrostenosing lesions commonly complicate Crohn disease (CD). However, detailed pathologic studies describing their features are lacking. The current study was performed to characterize submucosal remodeling in stenotic lesions of CD and compare them with features of healed ulcers in colectomy specimens from patients with severe ulcerative colitis (UC) and failed pouch resection specimens.
Design: The study group consisted of small-bowel resection specimens from 31 patients with stricturing CD. Controls included 20 UC colectomy specimens and 12 resected ileal pouches with severe pouchitis. Each case was assessed for inflammation, repair, pyloric metaplasia, and muscularis mucosae hyperplasia (MMH). Immunostains for MUC6, smoothelin, and muscle-specific actin were also performed.
Results: Thirty CD cases (97%) showed MMH confined to strictures and often occupying at least two-thirds of the submucosal thickness. These impressions were confirmed by smoothelin and smooth muscle actin stains. All CD cases with MMH also showed pyloric metaplasia (95%) confirmed by MUC6 immunostains. In contrast, MMH and pyloric metaplasia were significantly less frequent in UC (15% and 15%, P < .001 and P < .001, respectively). Ileal pouches also showed MMH (50%) and pyloric metaplasia (75%) at rates comparable to CD, but more frequently than UC (P = .03 and P < .001, respectively).
Conclusions: Fibrostenosing lesions of CD mostly reflect MMH rather than submucosal fibrosis and are almost always associated with pyloric metaplasia. Contraction of this neomuscular layer may contribute to functional stenosis. Future studies evaluating the relationship between pyloric metaplasia and stricture development may be warranted.
Esophageal Lipoma: An Uncommon Neoplasm: (Poster No. 26)
Lipomas account for 16% of all soft tissue neoplasms. However, they are uncommon within the gastrointestinal tract especially within the esophagus, with an incidence of only 0.4%. We report a case of an 80-year-old white man with a history of reflux disease of more than 10 years who had complaints of persistent severe reflux symptoms and dysphagia. An upper gastointestinal examination revealed a 5×3-cm mass that was removed laparoscopically. Grossly, the mass appeared as an oval, predominantly encapsulated, yellow-red glistening adipose tissue measuring 5.5 × 3.5 × 2.0 cm. Microscopic examination revealed mature, lobulated fibroadipose tissue consistent with lipoma. The postoperative course of the patient was uneventful and his symptoms improved considerably. Dysphagia is the most common symptom of esophageal lipomas. Other symptoms may include odynophagia, melena, and compression of the upper respiratory tract. Lipomas of the esophagus are commonly pedunculated and located within the cervical region of the esophagus; they can assume a huge size, causing death by suffocation. Other complications include ulceration and malignant transformation. Diagnosis is aided by evaluating the characteristics of the mass by endoscopic examination and computed tomography. Surgical enucleation is the treatment of choice, which can be performed endoscopically or via cervical esophagotomy. Thoracotomy is the preferred option for a thoracic location. Esophagotomy and esophagogastrostomy are performed if the esophageal lumen is opened surgically, as primary repair can be complicated by obstruction, leakage, and mediastinitis. Thus appropriate workup leads to the correct diagnosis and can prevent complications of this rare entity.
Reevaluation of Hyperplastic Polyps of Colon at Ben Taub General Hospital: (Poster No. 28)
Context: Colonic serrated polyps are the most common polyps of the large bowel. In the past 10 years, the focus on sessile serrated polyp (SSP) has increased, as it has premalignant risk. The most recent edition of the World Health Organization classification of gastrointestinal tumors indicates that untreated SSP is associated with substantial increased risk of developing colon cancer.
Design: The purpose of this study is to reevaluate hyperplastic polyps that were diagnosed at our tertiary hospital in the past year to determine if some of these polyps should be reclassified as SSP.
Results: We reviewed 174 hyperplastic polyps from 144 patients (74 women, 70 men). Twenty-one patients had more than 1 polyp. The patients were 26 to 91 years old (average, 57 years old). The polyp size ranged from 0.1 to 2.5 cm. Most hyperplastic polyps were resected from rectosigmoid (59%) followed by ascending (14%) and transverse colon (12%). After reevaluation of hematoxylin-eosin–stained slides, 29 polyps were determined to be SSP. Twenty-one (71%) of the SSPs were in the proximal colon; 4 were less than 0.4 cm in diameter, while 25 polyps (86%) were 0.5 cm in diameter or larger.
Conclusions: We plan to inform the gastroenterologists of the change of diagnosis to facilitate the appropriate follow-up. Furthermore, education of practicing pathologists should be considered to increase the knowledge about this relatively new entity.
Microsatellite Instable Adenocarcinoma of Pancreatobiliary Tract: How Many Were Missed?: (Poster No. 31)
Microsatellite instability (MSI) adenocarcinoma involving pancreat-obiliary tract has been underrecognized owing to its rarity and incompletely defined histopathology. Recognition of MSI status, however, could have major patient impact owing to its clinical implication. Here we illustrate 2 such tumors, 1 hilar adenocarcinoma (Klatskin tumor) and 1 pancreatic, focusing on the morphology, immunoprofile, and molecular studies, aiming to raise pathologists' awareness and to enrich our knowledge about MSI pancreatobiliary tumors. Our first case involves a 67-year-old woman who underwent Klatskin tumor resection. Tumor cells contained vesicular nuclei with prominent nucleoli, forming nests and nodules with pushing borders; perineural and lymphovascular invasion were multifocal. Immunohistochemistry showed loss of MLH-1 and PMS-2, and intact MSH-2 and MSH-6. Our second case involves a 77-year-old man who underwent Whipple resection for pancreatic adenocarcinoma, which was composed of oncocytic cells with vesicular nuclei and prominent nucleoli; signet ring cells and mucin were appreciated. Intratumoral lymphocytes and peritumoral banding were present. MSH-2 and MSH-6 were absent. Notably, the patient underwent colectomy at another hospital 11 years prior; the requested case showed medullary histology and loss of MSH 2 and MSH6, confirmed by added immunohistochemistry. In both cases, next-generation sequencing showed no mutation for BRAF and RAS oncogenes; patients' management was updated accordingly. We conclude that MSI adenocarcinoma involving pancreatobiliary tract displays subtle and focal MSI histopathologic features, which might be overlooked if unaware of them. We believe that astute morphologic examination, aided by ancillary and molecular studies, will facilitate in reaching an accurate diagnosis and improving patient care.
Expression of HER2/neu in Extrahepatic Cholangiocarcinoma: (Poster No. 32)
Context: Human epidermal growth factor receptor-2 (HER2/neu) is a tyrosine kinase receptor that has been overexpressed in various human cancers. The aim of this pilot study was to explore the frequency of HER2/neu expression in extrahepatic cholangiocarcinoma.
Design: This is a retrospective study using 89 tissue samples (median age, 66 years; 23 females and 22 males) including 45 samples from nonneoplastic biliary tissue (NNB) and 43 samples of extrahepatic cholangiocarcinoma (EHBC). A tissue microarray including NNB and EHBC was constructed and analyzed by immunohistochemistry (IHC) and dual in situ hybridization for HER2/neu expression. The HER2/neu expression was scored by following the guidelines used for the ToGA study.
Results: All NNB samples and all but 1 EHBC sample showed no expression of HER2/neu by IHC. The 1 EHBC case positive for HER2/neu had an IHC score of 6 (3 + 3). Similarly, HER2/neu gene amplification was only present in 2 EHBC samples.
Conclusions: Our findings are similar to those reported in the literature. Although HER2/neu overexpression has been documented in many types of cancer, HER2/neu overexpression tends to have no role in the development and/or progression of EHBC.
A Unique Case of Simultaneous Pancreatic and Gastric Heterotopias Within An Ileal Lipoma Forming a 7-cm Obstructive Tumor: (Poster No. 34)
Pancreatic and gastric heterotopias are ectopic pancreatic and gastric tissue without anatomic continuity of the pancreas proper or stomach. Simultaneous pancreatic and gastric heterotopias are rare; their coexistence within a third entity forming an obstructive mass has not been reported in gastrointestinal pathology. A diagnosis of malignancy or a missed diagnosis could derail the clinical course. We report a novel case of “colliding” pancreatic and gastric heterotopias residing within an obstructive ileal lipoma in a 53-year-old woman who has had episodes of worsening abdominal pain for decades. Endoscopically, a large terminal ileal tumor was seen, which was subsequently resected. Gross examination of the resected tumor showed a 7-cm, white-yellow fatty tumor with a 1.6-cm firm central area. Microscopic examination revealed benign submucosal lipoma occupying 70% of the lesion. Interestingly, the firm area showed pancreatic type acini, ducts, and islets of Langerhans. Furthermore, gastric heterotopia was identified within the same mass. No architectural or cytologic atypia was identified. Patient follow-up has been unremarkable. This is the first report of 3 coexisting entities forming an obstructive lesion mimicking malignant neoplasm in the gastrointestinal tract, with a clinical impression of adenocarcinoma leading to abrupt resection. Pancreatic heterotopia is less frequent than gastric heterotopia, commonly seen in stomach and rarely in duodenum or jejunum. Coexisting heterotopias within a third entity are extremely rare in the gastrointestinal and hepatobiliary tract and ampulla of Vater. Awareness of these coexisting processes and astute histologic evaluation are key to prevent overdiagnosis and to properly manage a patient.
Spectrum of Clinicopathologic Deviations in Long-Segment Hirschsprung Disease Compared to Short-Segment Hirschsprung Disease: (Poster No. 35)
Context: Hirschsprung disease (HD), a congenital disorder with male preponderance, is characterized by rectal or rectosigmoid aganglionosis coupled with neural hyperplasia. When HD affects a longer segment (“long-segment HD” [LHD]), there are many deviations from the classic profile.
Design: All HD cases were retrieved from our pathology database from the past 21 years (1993–2014) and reviewed for clinical and histologic findings.
Results: Nine LHD cases were diagnosed from a total of 48 HD cases (19%). There were 6 females and 3 males (male to female ratio, 1:2) and average age at diagnosis was 12 days. Symptoms included abdominal distention (8), failure to pass meconium (4), and emesis (4). Two cases were associated with congenital heart disease and 1 with neonatal hypothyroidism. Only 3 of 9 patients underwent rectal suction biopsy, while others were diagnosed operatively. Complications included dumping syndrome (2), septicemia (2), failure to thrive (2), and enterocolitis (1). The aganglionosis extended at least to the terminal ileum (total colonic aganglionosis) in 7 of 9 cases and to the splenic flexure in 2 of 9 cases. Neural hyperplasia was variable: limited to rectum (2 of 9), limited to rectum and sigmoid colon (4 of 9), and completely absent (3 of 9).
Conclusions: LHD lacks male preponderance and is in contrast more common in females. Diagnosis is often delayed since most cases deviate from common HD presentation. LHD is more often diagnosed operatively rather than on rectal suction biopsy, likely due to atypical presentation as well as significant complications. Additionally, rectal neural hyperplasia and aganglionosis can be present in both conditions.
The Role of Ki-67 and PHH-3 in Grading and Prognostication of Pancreatic Neuroendocrine Tumors: A Comparison Study: (Poster No. 37)
Context: The current histologic grading of pancreatic neuroendocrine tumors (PNETs) is based on mitosis and/or Ki-67 index. Phosphohistone-3 (PHH-3) is an effective marker for quantification of mitosis. It remains unclear which method more accurately predicts grade and clinical outcome. Additionally, it is unknown if necrosis, perineural invasion (PNI), and lymphovascular invasion (LVI) correlate with clinical outcome.
Design: PNET cases diagnosed at UAB on the basis of World Health Organization criteria were included. Clinicopathologic data were collected and immunohistochemical staining for Ki-67 and PHH-3 was performed. Additionally, necrosis, LVI, and PNI were evaluated for each case. R project statistical analysis was performed for correlations.
Results: The study included 51 cases with a male to female ratio of 0.82. The median age was 61 years (range, 34–84 years). Disease-free survival rate was 84%. Histologic grade differed in 22% of the cases (n = 11), using PHH-3 versus Ki-67, with most discrepancies (55%) between grades 1 and 2. Neither method was superior in predicting disease recurrence. Both significantly predicted lymph node metastasis, with slightly greater significance for PHH-3 (P = .01). Necrosis and PNI correlated with stage (P = .003 and P = .049), while LVI status did not. Recurrence was not associated with necrosis, PNI, or LVI.
Conclusions: PHH-3 produces similar grading to Ki-67 and is not more effective at predicting recurrence in PNET. PHH-3 significantly predicted the presence of lymph node metastases, but with a similar value to Ki-67. Tumor stage is significantly associated with necrosis and PNI, but not LVI. These features may be helpful for predicting the clinical course of PNET.
Isolated Lymphocytic Gastritis in Family Members: (Poster No. 38)
Lymphocytic gastritis is an uncommon disease most frequently associated with celiac disease or Helicobacter pylori infection and occasionally with other entities. Isolated lymphocytic gastritis is very rare. We describe the case of a 21-year-old man who was examined for symptoms of upper gastrointestinal discomfort and weight loss, but no lower gastrointestinal concerns. On endoscopic examination, there was severe erosive gastritis diffusely involving the antrum and body; the duodenum was normal. Microscopically, gastric mucosa showed marked chronic inflammatory infiltrate, nonactive, and the duodenum showed normal villous architecture. Immunostains for CD3, CD20, and H pylori were performed, with controls in working condition. Frequent intraepithelial T lymphocytes were observed, similarly in antrum and body, with an average count of 37 per 100 gastric epithelial cells, performed by 2 pathologists. There was also an aggregate of B lymphocytes in gastric mucosal stroma. No H pylori microorganisms were found. No significant intraepithelial lymphocytosis was observed in the duodenal mucosa, with average count of 5 intraepithelial lymphocytes per 100 duodenal epithelial cells. Review of the patient's family history revealed that his mother had similar symptoms at a young age and underwent upper gastrointestinal endoscopy. The rendered diagnosis was chronic gastritis; however, the microscopic description of pathology in her biopsy tissue, including special stains, represented findings of lymphocytic gastritis. She did not have H pylori or evidence of celiac disease. HLA haplotypes of these 2 persons were not examined. Coincidence of isolated lymphocytic gastritis in related individuals, without any other clinically detectable associated disease, supports the notion that it is a genetically restricted disease.
FGFR2 Translocations in a Subset of Combined Cholangiocarcinoma–Hepatocellular Carcinoma: (Poster No. 41)
Context: Combined cholangiocarcinoma–hepatocellular carcinoma (CCA-HCC) is rare. CCA-HCC shows features of both cholangiocarcinoma and hepatocellular carcinoma and is thought to arise from intrahepatic stem cell progenitors similar to intrahepatic cholangiocarcinomas. Intrahepatic cholangiocarcinomas are known to harbor oncogenic FGFR2 translocations. These translocations represent a target for therapy by clinically available FGFR2 inhibitors. We studied a series of CCA-HCCs to determine if FGFR2 translocations were present in these tumors.
Design: We retrieved cases of CCA-HCC from the institutional files from 1994–2013. The histologic diagnosis was confirmed and the subtype of CCA-HCC determined. A block with both cholangiocarcinoma and hepatocellular components was selected for immunohistochemistry, using hepatocellular and biliary markers and FGFR2 break-apart fluorescence in situ hybridization with a previously validated probe (Abbott). Cases without morphologic or immunohistochemical evidence of both hepatocellular and biliary phenotypes were excluded. Clinical follow-up was obtained.
Results: Seven cases of CCA-HCC were identified; affected patients had a median age of 60 years. FGFR2 rearrangement was detected in both hepatocellular and biliary components of 1 CCA-HCC, stem cell type 1, including virtually all cells. The remaining 6 cases, all of classical type, were negative. Clinical follow-up was available for 6 patients; each died of disease after a median of 21 months from resection.
Conclusions: FGFR-targeted therapy may be of benefit in the stem cell type of CCA-HCC. Additional study of more cases will help to determine the frequency of FGFR2 rearrangement in CCA-HCC and the potential scope for targeted therapy.
The Prognostic Value of Blood Neutrophil to Lymphocyte Ratio in Patients With Gastrointestinal Stromal Tumor: (Poster No. 46)
Context: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal tract. Currently, tumor size, location, and mitotic count are used to assess the risk for tumor recurrence. Recently, neutrophil to lymphocyte ratio (NLR) has been shown to have prognostic value in some solid tumors. In this study, we investigated the prognostic significance of NLR in patients with GISTs.
Design: We identified 26 patients with previously untreated localized GIST who were operated on between 2010 and 2014. Peripheral blood samples were collected within 10 days before surgery, and none had clinical signs of infection at the time of blood sampling. Blood NLR was calculated as neutrophils per lymphocytes (count). Tumor histology including size, location, morphology (spindle, epithelioid, and mixed), mitotic count per 50 high-power fields (HPFs), and stage were recorded. t test, ANOVA, and 1-tailed Pearson test were used for statistical analysis.
Results: Among all 26 patients, the NLR ranged from 0.96 to 5.62 with an average of 2.45 ± 1.07. There was no significant correlation between the blood NLR and phenotypic subtypes (P > .05), tumor stage (Pearson correlation coefficient [r] =0.164, P > .05), tumor size (r = 0.173, P > .05), or location (P > .05). Mitosis count showed 18 patients with low mitotic rate (≤5/50 HPFs) and 8 patients with high mitotic rate (>5/50 HPFs). There was no significant difference between the NLR of these 2 patient groups (P > .05).
Conclusions: NLR represents an easily assessable parameter of systemic inflammatory response. Based on our current findings, however, its prognostic value remains questionable in GIST. Further studies are needed.
Apoptotic Body Counts in Normal Ileal Biopsies Overlap With Acute Cellular Rejection of Small-Bowel Allografts: (Poster No. 50)
Context: Acute cellular rejection, a major complication following small intestinal transplant, is diagnosed by biopsy. An important feature is the number of apoptotic bodies present in 10 consecutive crypts. The presence of 2 or fewer bodies is considered normal, whereas the presence of 6 is considered mild acute cellular rejection. The presence of 3 to 5 apoptoses is problematic for pathologists, and is often classified as indeterminate for acute cellular rejection. We investigated how many crypt apoptotic bodies could be identified in normal ileal biopsies from outpatients with a negative screening colonoscopy.
Design: A retrospective search identified ileal biopsies taken to document complete colonoscopy during screening colonoscopy in outpatients with native intestines. We recorded the number of biopsy pieces per specimen and the maximum apoptotic body count (ABC) in 10 consecutive crypts after examining 6 levels per case.
Results: Four patients had an ABC ≤ 2. Two patients had an ABC of 6, while 4 patients had 3 to 5.
Conclusions: Sixty percent of normal ileal biopsies from non-transplanted individuals could conceivably be diagnosed as indeterminate or positive for acute small-bowel allograft rejection solely on the basis of ABC. This suggests that the diagnostic specificity will be low if the diagnosis is based only on ABC and ignores other acute cellular rejection features.
Strongyloides Colitis as a Harmful Mimicker of Inflammatory Bowel Disease: (Poster No. 51)
Autoinfection characteristic of Strongyloides stercoralis frequently makes the infection a lifelong disease unless it is effectively treated. There is an overlapping histomorphology between inflammatory bowel disease and Strongyloides colitis. Low index of suspicious can lead to misdiagnosis and fatal consequences. We present a case of Strongyloides colitis mimicking the clinical and pathologic features of inflammatory bowel disease. A 64-year-old woman presented to the emergency department with a chief complaint of abdominal pain, diarrhea, and red blood per rectum that started 4 days before admission. Past medical history included rheumatoid arthritis and recent diagnosis of inflammatory bowel disease (ulcerative colitis) 3 months before presentation. She was subsequently admitted for evaluation of gastrointestinal bleed. Endoscopy revealed diffuse inflammation suggestive of inflammatory bowel disease, which led to initiation of Mesalamine and IV Solumedrol therapy. Biopsies revealed increased lymphoplasmacytic infiltrate of lamina propria with eosinophilic microabcesses, mild architectural distortion, and presence of larvae within the crypt lumina and lamina propria, consistent with S stercoralis. Subsequently, immunosuppressive medication was halted. The patient ultimately died a few days later. This case emphasizes the importance of identifying the overlapping clinical and pathologic features of Strongyloides colitis and inflammatory bowel disease. A high index of suspicion and recognition of particular histologic findings, including eosinophilic microabcesses, aids in the correct diagnosis. Definitive diagnosis is crucial as each carries distinct therapeutic implications and outcome.
Interobserver Agreement Study on Diagnosing Serrated Polyps With Stromal Changes: (Poster No. 52)
Context: Prolapse-related changes are a confounding factor leading to misdiagnosis of serrated polyps. Interobserver agreement studies on the diagnosis of serrated polyps with stromal changes have not been reported.
Design: Fifty-four consecutive serrated polyps with stromal changes were collected by 1 pathologist during a 2-month period. Twenty additional cases of serrated polyps with perineurial-like stromal proliferation were also included. The polyps were rereviewed by 3 gastrointestinal pathologists and the consensus interpretation was correlated with the clinicopathologic features.
Results: Among 74 polyps, a consensus diagnosis of hyperplastic polyp (HP) and sessile serrated polyp (SSP) was reached in 39 and 11 polyps, respectively. The overall interobserver agreement among 3 pathologists was moderate (paired κ values: 0.42, 0.50, and 0.56). The SSP polyps were larger, were more often located in the right colon, and occurred more often in women (7.3 ± 5.3 versus 4.5 ± 2.7 mm, P =.02; 72.7% versus 7.7%, P < .001; and 77.7% versus 30.7%, P =.02). The SSP polyps were associated with concurrent SSP in other parts of the colon (27.3% versus 0%, P = .008). A consensus diagnosis could not be reached in the remaining 24 polyps (32.4%). Among the 24 serrated polyps that were unclassifiable, 11 were interpreted by 2 reviewers as SSP and 13 were interpreted by 2 reviewers as HP.
Conclusions: Approximately 67.7% of serrated polyps with stromal changes could be accurately classified as SSP or HP. The remaining serrated polyps, unclassifiable with stromal changes, may represent a heterogeneous group.
Sevelamer Use Associated With Anemia and Melena in a 65-Year-Old Man With End-Stage Renal Failure: (Poster No. 53)
Sevelamer is an anion exchange resin used to treat hyperphosphatemia in patients with end-stage renal disease (ESRD) who are undergoing renal dialysis. To our knowledge few reports discuss the histologic findings related to sevelamer use in the gastrointestinal mucosa. We demonstrate the clinical and histologic outcomes related to the use of sevelamer. A 65-year-old African American diabetic man with a history of ESRD, requiring chronic hemodialysis, presented to our hospital for evaluation of anemia and melena. Among his medications was sevelamer. An endoscopy showed ulcerations in the gastric and colonic mucosa. Multiple biopsies were taken, and formalin-fixed, paraffin-embedded tissue blocks were examined by light microscopy with polarized lensed property. Sections from both the stomach and transverse colon demonstrated fibrinopurulent exudate, consistent with ulceration. Both biopsies demonstrated fragments of crystalline material varying in color from yellow to red to purple and focally had a fish-scale–like appearance. This material was refractile but not polarizable, and was consistent with sevelamer crystals. Sevelamer crystals have a nonpolarized property and when deposited in the mucosa, they cause direct toxic effects. Reviewing patients' medication history is necessary specifically in patients with ESRD. With the growing use of sevelamer, it is important to recognize the potential clinical impact of its pathophysiology in relation to gastrointestinal mucosa. The lack of literature mandates further evidence in defining the mechanism of injury.
Heterogenous Polyps Are Present in Patients With SMAD4-Mutated Juvenile Polyposis–Hereditary Hemorrhagic Telangiectasia Syndrome: (Poster No. 56)
Context: Juvenile polyposis syndrome (JPS) is an autosomal dominant disorder associated with gastrointestinal hamartomatous polyps. Since the first characterization of classical juvenile polyp by Hellwig it has been discovered that JPS contains a spectrum of morphologies that uniquely relate to the underlying genetic alteration in SMAD4 with an epithelial phenotype or BMP1a with a classic phenotype. A significant number of patients with SMAD4 JPS have concurrent hereditary hemorrhagic telangiectasia (HHT) syndrome. The aim of this study is to uniquely identify the spectrum of gastrointestinal polyp morphologies within a single family cohort with SMAD4-mutated JPS-HHT syndrome.
Design: Sixty-seven gastrointestinal polyps (18 gastric, 5 duodenal, 44 colonic) from 2 brothers with SMAD4-mutated JPS-HHT syndrome were reviewed independently by 3 observers (1 attending pathologist with expertise in familial polyposis and 2 fourth-year residents). A consensus diagnosis was rendered for each polyp by following the World Health Organization 2010 criteria and criteria set forth by Hattem et al.
Results: Morphologic heterogeneity was identified; however, most were juvenile polyps (44% epithelial, 31% classic), 9% goblet cell–rich hyperplastic polyps, 6% benign lymphoid aggregates, 6% gastric hyperplastic polyps, and 3% colonic inflammatory polyps.
Conclusions: In these patients with SMAD4-mutated JPS-HHT syndrome, epithelial juvenile polyps were the most predominant; however, a wide spectrum of polyps were observed including classic juvenile polyps, hyperplastic polyps, and benign lymphoid aggregates, highlighting the variable phenotypes in patients with SMAD4-mutated JPS-HHT syndrome. Future correlative studies of these polyps with SMAD4 immunohistochemistry and molecular analysis will help to further characterize these polyps.
Unexpected Microsatellite Instability Frequently Identified in Colorectal Adenocarcinoma Without Characteristic Medullary Histology—How Often Should We Order Confirmatory Tests: An Institutional Experience in an NCI-Designated Cancer Center: (Poster No. 57)
Context: Microsatellite instability (MSI) status impacts clinical course in colorectal adenocarcinoma, as conventional chemotherapy adversely affects these patients. MSI tumors display certain histopathologic characteristics including right colon, mucin production, signet ring, and lymphocytic infiltrate. However, we frequently encounter MSI tumors without these “diagnostic” features; MSI could be missed if confirmatory tests are not considered. Needless to say such a miss could hamper patient care.
Design: A total of 279 cases of resected colorectal adenocarcinoma (2012–2015) were reviewed. The electronic chart, histopathology, immunohistochemistry, and molecular studies were reviewed and compared to those described for MSI in the literature.
Results: Forty-three of 279 adenocarcinoma cases (15%) were MSI, identified by immunohistochemistry. Average age was 69.8 years and male to female ratio was 0.7. Interestingly, 11 of 43 tumors (26%) were at non–right colon locations. Notably, only 26 of 43 (60%) showed “typical” MSI features (mucinous, signet ring, or medullary morphology). The remaining 17 MSI tumors (40%) were histologically indistinguishable from microsatellite-stable counterparts. Specifically, 12 of these 17 tumors (70.6%) lost MLH1 and PMS2; 3 (17.6%) lost MSH2 and MSH6; 1 (5.9%) lost PMS2; and 1 (5.9%) lost MLH1, PMS2, and MSH6. Subsequently, patients were managed appropriately after MSI clarification.
Conclusions: Forty percent of MSI colorectal tumors do not display classic morphologic features of MSI; an absence of these features does not exclude MSI. MSI adenocarcinoma and its microsatellite-stable counterparts share a spectrum of histopathology. This investigation suggests that routine immunohistochemistry and/or molecular tests should be performed with minimal reservation to optimize clinical intervention and patient care.
Loss of Microfibril-Associated Protein 5 Expression Is Helpful in Identifying Invasion in Intraductal Papillary Mucinous Neoplasm: (Poster No. 61)
Context: The identification of invasion in intraductal papillary mucinous neoplasm (IPMN) can be challenging but is vital for prognosis and treatment. Microfibril-associated protein 5 (MFAP5) is a small extracellular protein involved in elastic microfibril assembly and angiogenesis. We evaluated stromal expression of MFAP5 in IPMNs with and without invasion to determine its utility in their distinction.
Design: Sixty-three IPMN cases without invasion, including cases with low (15), intermediate (15), and high-grade (13) dysplasia, as well as 20 IPMN cases with invasive adenocarcinoma, were stained for MFAP5. MFAP5 staining intensity was graded as 0 to 3. A staining score was calculated as intensity multiplied by percentage positivity. Statistical analysis was performed by using unpaired Student t test.
Results: In IPMN with and without invasion, the average patient age was 70 and 64 years, respectively, with male to female ratio 1:1.5 and 1:1.3, respectively. In IPMN with invasion, the average MFAP5 score of invasive tumor stroma was 0.27 ± 0.37, significantly lower than that of nearby noninvasive area (2.06 ± 0.91, P < .001) and that of IPMN cases (2.44 ± 0.65, P < .001). IPMNs with low and intermediate-grade dysplasia show similar MFAP5 scores (average, 2.52 and 2.54), and high-grade dysplasia cases show mildly decreased MFAP5 expression (average, 2.24; P = .19).
Conclusions: IPMN with invasive adenocarcinoma shows significantly decreased MFAP5 expression in tumor stroma, when compared to noninvasive area and to fibrotic stroma in IPMN (without invasion); thus, MFAP5 may be helpful in identifying invasive areas within IPMN. MFAP5 immunostain is not helpful in distinguishing IPMN with different degrees of dysplasia.
Adenocarcinoma Ex–Goblet Cell Carcinoid: A Series of 6 Cases: (Poster No. 65)
Context: Adenocarcinoma ex–goblet cell carcinoid (ex-GCC) is a rare mixed glandular-neuroendocrine neoplasm that represents a distinct entity that occurs almost exclusively in the appendix. The aim of this study is to examine the clinical and pathologic characteristics of this tumor.
Design: Search of pathology database at University of Miami from 2003–2014 identified 6 adenocarcinoma ex-GCC cases. The demographics, histologic features, and immunohistochemical pattern were reviewed.
Results: Of the 6 adenocarcinoma ex-GCC cases, 3 involved women and 3 involved men, with a mean age of 53.8 years (range, 37–67 years). Three of the 6 patients had an appendectomy followed by additional surgery including hemicolectomy with or without omentectomy and the remaining 3 patients had initial hemicolectomy. The tumor size ranged from 2 to 10 cm and in 1 of the cases the tumor size could not be determined. Metastases were identified in 5 cases (83%). By immunohistochemistry, the tumor cells were positive for CK20 (4 of 4), CDX2 (3 of 3), synaptophysin (patchy, 3 of 5; and rare cells, 2 of 5), and negative for chromogranin. The patients presented with metastasis (5 of 6) to omentum (3 of 5), sigmoid colon (3 of 5), small intestine (1 of 5), stomach (1 of 5), ovaries (1 of 5), and liver (1 of 5). The primary tumor stage was T3 (2 of 4) and T4 (2 of 4). One patient died owing to recurrent cancer 2 years after diagnosis.
Conclusions: Adenocarcinoma ex-GCC is a rare tumor that presents in advanced stage with metastasis at the time of diagnosis. A meticulous histologic evaluation to identify the preexisting goblet cell carcinoid is of critical importance to diagnose this aggressive tumor and determine patient prognosis.
A Rare Case of Concomitant Multifocal Gastrinoma and Adenocarcinoma in the Stomach: (Poster No. 67)
Stomach is an uncommon location for gastrinoma. Here we report a rare case of multifocal gastrinoma in the antrum, with concomitant gastric adenocarcinoma and neuroendocrine cell hyperplasia. The patient is a 35-year-old man presenting with mild upper abdominal discomfort for 3 months. The blood gastrin level was elevated to 542 pg/ mL (normal, <100 pg/mL). Endoscopic examination found multiple polyps in the antrum, and biopsy showed carcinoid tumors. Antrectomy was performed. In the surgical specimen, multiple pedunculated polyps measuring up to 2 cm and many small sessile polyps with central umbilication were present in the antrum and pylorus. Pathologic study showed that the polyps had nests of low-grade tumor cells that were positive for gastrin, confirming a diagnosis of multiple gastrinomas. Incidentally, 1 large polyp was found to harbor a focus of poorly differentiated adenocarcinoma with signet ring cell features, invading into submucosa. In the body of the stomach, diffuse enterochromaffin-like cell hyperplasia and small carcinoid tumors were identified. Regional lymph nodes were positive for both adenocarcinoma and gastrinoma. In addition, Helicobacter pylori–like organisms were detected in the antral mucosa. Postoperatively, the patient recovered uneventfully and his gastrin level dropped to 30 pg/mL. The patient is currently receiving chemotherapy. This is a rare case of multifocal gastrinoma at an unusual location. The concomitant presence of a poorly differentiated gastric adenocarcinoma suggests that gastrin may play a role in the pathogenesis of the adenocarcinoma. This case suggests that stomach specimens from patients with gastrinoma should be thoroughly examined to look for any unsuspected adenocarcinoma.
Ezetimibe-Induced Autoimmune Hepatitis in a 75-Year-Old Woman: (Poster No. 69)
Ezetimibe was introduced as a first member of a new class of cholesterol-lowering drugs that inhibits uptake of dietary and biliary cholesterol. Approved by the US Food and Drug Administration in 2002, it is considered a safe drug with its usage spreading rapidly during the last few years. Rarely causing severe hepatic side effects, liver abnormalities produced by ezetimibe are mostly asymptomatic and reversible. Though it does not induce or inhibit enzyme systems in the liver it undergoes enterohepatic circulation and is exposed to liver and bile. There are very few reported cases of significant liver injury associated with ezetimibe in the literature, 2 of them being acute autoimmune hepatitis type caused by ezetimibe alone and another in combination with statin. We report a case of drug-induced autoimmune hepatitis in a 75-year-old woman after intake of ezetimibe. Our patient had a history of asthma, hyperlipidemia, hypertension, and eczema accompanied with elevated transaminases, γ-glutamyl transferase, and alkaline phosphatase. Smooth muscle antibody titer was positive. Liver biopsy revealed mixed chronic hepatocellular and cholestatic injury with bridging fibrosis consistent with drug-induced autoimmune hepatitis. The cause of ezetimibe toxicity is unclear. Our case is unusual as it is a second case of drug-induced autoimmune hepatitis caused by ezetimibe alone. Our case also emphasizes the importance of monitoring patients taking ezetimibe and its cautious use, especially in individuals with prior hepatic disease.
Serous Cystadenocarcinoma Arising in Vitelline Duct Remnant: (Poster No. 70)
Malignant neoplasms arising in vitelline duct remnants are rare, yet well documented. Most examples comprise gastric-type adenocarcinoma and carcinoid tumors. Herein we report, to the best of our knowledge, the first case of adenocarcinoma arising from the anterior abdominal wall from presumed vitelline duct remnant, with histologic and immunophenotypic features of serous cystadenocarcinoma of pancreatic origin. The patient was a 53-year-old woman who presented with an enlarging midline abdominal wall mass during the past year. Computed tomography showed a 6.0-cm mass involving linea alba, rectus abdominis, and subcutaneous fat, with regional lymphadenopathy. No other lesions were seen on extensive clinical workup. Histopathologic examination demonstrated a spectrum of serous neoplasia, with serous cystadenocarcinoma representing the better differentiated component, papillary serous carcinoma with numerous psammoma bodies representing the areas of higher grade, and solid sheets of poorly differentiated tumor cells representing poorly differentiated component. These morphologic features were those of serous neoplasia with dedifferentiation. Immunohistochemically, the tumor was diffusely and strongly positive for CK7, CK19, CA 19.9, and MUC1, but was largely negative for CK20, MUC2, TTF-1, thyroglobulin, GCDFP15, mammaglobin, ER, WT1, calretinin, S100, synaptophysin, p63, HBME, CEA, p53, and SALL4. CDX-2 highlighted occasional tumor cells. The features were those of serous cystadenocarcinoma, with immunophenotypic features of pancreaticobiliary differentiation. The tumor was most likely of vitelline duct origin, given the midline anterior abdominal wall localization and the lack of pancreatic or hepatobiliary lesions on imaging. The prognostic implications and presumed embryologic derivation of this unusual tumor are discussed.
Herpes Simplex Virus Colitis With Positive In Situ Hybridization and Negative Immunohistochemistry of Herpes Simplex Virus in a Posttransplant Patient: (Poster No. 71)
Herpes simplex virus (HSV) infection is common with a worldwide prevalence up to 98% by the fourth decade. However, HSV colitis is rare. So far, few cases have been reported that are associated with inflammatory bowel disease (IBD). Immunocompromised patients are at increased risk of recurrent, disseminated, or even life-threatening systemic infection from latent HSV, which persists in sensory nerve ganglia. Early detection allows prompt treatment with antiviral agents. Detection of HSV can be performed by immunohistochemistry (IHC), in situ hybridization (ISH), or polymerase chain reaction in affected tissue/biopsies, although some think IHC is possibly more sensitive than ISH. Here we report a case of HSV colitis in a 35-year-old patient status 3 months post kidney and pancreas transplants. Our patient reported 1 week of nausea/vomiting and watery diarrhea; cytomegalovirus and Clostridium difficile workups were negative. Colonoscopy examination results were normal. Biopsy showed few mucosal epithelia with typical HSV morphology: nuclear molding, multinucleation, and margination of chromatin; however, HSV immunohistochemistry was negative. Subsequent ISH confirmed the existence of HSV. The patient subsequently received 2 weeks of Valtrex, and gastrointestinal symptoms resolved thereafter. A study showed ISH can detect early HSV infection and distinguish HSV-1 and HSV-2, while IHC can pick up more signals from both cell nuclei and cytoplasm, appearing more sensitive than ISH, which only shows nuclear staining. Additionally, IHC can stain necrotic areas. This case demonstrates the value of in situ hybridization for early detection of HSV colitis, which is particularly helpful in cases suggestive but not diagnostic of this condition.
Small Cell Carcinoma of Colon in a Young Man: (Poster No. 77)
Small cell carcinomas of the colon are uncommon tumors, largely reported in elderly men and women. We report a case of a young man who developed small cell carcinoma in ascending colon with metastasis to liver. This 24-year-old man with past medical history of autosomal recessive polycystic kidney disease, end-stage renal disease (status post renal transplant in 2009, for second time) presented with iron deficiency anemia and diarrhea. He noticed bright red blood per rectum. Imaging study suggested right hepatic flexure mass and multiple hepatic nodules concerning for metastatic disease. No pulmonary nodules were noted. We received a right hemicolectomy specimen with an annular, fungating mass in the ascending colon, measuring 4.5 × 3.5 × 1.5 cm and a central induration/puckering on the serosal side. On sectioning, the mass was firm in consistency, tan, and homogeneous. Microscopy showed small cell carcinoma of colon that infiltrated through the muscularis propria to the pericolonic fat with lymphovascular invasion. Eight of 16 lymph nodes were positive for metastatic carcinoma. Immunophenotypically, the tumor cells were positive for cytokeratin, chromogranin, CD56, and TTF-1 and were negative for synaptophysin. Three polyps ranging from 0.3 to 0.5 cm were identified, which were 1 cm away from the mass and later microscopically diagnosed as tubular adenomas. The remaining mucosa was tan and smooth with no other abnormalities identified. Corresponding liver nodule biopsy showed metastasis. This is an unusual case of small cell carcinoma, as it is very uncommon in a young patient.
Intrahepatic Sarcomatoid Cholangiocarcinoma in a 60-Year-Old Woman: (Poster No. 78)
Intrahepatic sarcomatoid cholangiocarcinoma (IHSCC) is a rare and aggressive variant of cholangiocarcinoma with a poor prognosis. In the liver, sarcomatoid transformation has been reported in 3.9% to 9.4% of hepatocellular carcinomas at autopsy and in 4.5% of cholangiocarcinomas. It has been reported that prognosis for IHSCC is worse than that of conventional intrahepatic cholangiocarcinoma. We report the case of a 60-year-old African American woman with a history of hepatitis C with worsening right upper quadrant pain. Her evaluation confirmed a 10-cm, mostly solid mass with a cystic component in the right hepatic lobe. A computed tomography–guided biopsy was performed; 4 needle core biopsies were processed and a panel of immunohistochemical staining was performed. The tumor was characterized by cells with plump, spindled to markedly atypical hyperchromatic nuclei with some entrapped hepatocytes. The tumor infiltrated hepatic parenchyma with a focally prominent component of immature lymphocytes. The cytokeratin AE1/AE3 stain was positive, and there was an equivocal staining for cytokeratin 7, CD68, and smooth muscle actin. The HepPar-1 stain appeared to be negative in the tumor. Negative stains included the following: cytokeratin 20, p63, cytokeratin 5/6, epithelial membrane antigen, CDX-2, BRST-2, CD117, CD31, CD45, and S100 protein. A mucicarmine stain was also negative. IHSCC has an aggressive course. Clinically, one should keep it as a possibility in a presentation mimicking hepatocellular carcinoma and intrahepatic cholangiocarcinoma, when there is rapidity in the tumor growth and normal serum AFP marker. The rarity of this condition warrants reporting.
E-Cadherin as a Potential Marker for Differential Diagnosis of Goblet Cell Carcinoid and Signet Ring Cell Carcinoma in Vermiform Appendix: (Poster No. 79)
Context: Goblet cell carcinoid (GCC) in vermiform appendix is a rare neoplasm. Owing to its histopathologic similarity to signet ring cell carcinoma (SRCC), it is invariably difficult to distinguish the two by hematoxylineosin stain. Therefore, we investigated expression of E-cadherin and other IHC markers in GCC and SRCC, and compared them with typical appendiceal carcinoid (CT) and poorly differentiated adenocarcinoma of colon with signet ring cell features.
Design: The cases were collected at Rowan University-SOM/ Kennedy Health System and Geisinger Health System between 2009 and 2011. Histopathologic examination of the resected appendices, occasionally with adjacent cecum, revealed CT (n =3), GCC (n =3), and SRCC (n = 1). Poorly differentiated adenocarcinomas of colon with signet ring cell features (n = 3) and SRCC in stomach (n = 2) were included in this study as controls.
Results: The expression of β-catenin and E-cadherin was compared in all the cases. β-Catenin was expressed on the plasma membrane of GCC and SRCC, a pattern similar to that of CT and adenocarcinomas of colon. However, E-cadherin stain showed clear difference between GCC and SRCC. E-cadherin stain was negative on the plasma membrane of the signet ring cells in appendiceal and gastric SRCC but positive in GCC, CT, and colonic poorly differentiated adenocarcinomas with signet ring cell features.
Conclusions: The findings suggest that signet ring cells in pure SRCC are different from those of CT and GCC. Our findings also indicate that E-cadherin could potentially be a useful immunomarker in the differential diagnosis between goblet cell carcinoid and signet ring cell carcinoma.
Barrett Esophagus and Its Associated Dysplasia: (Poster No. 81)
Context: Barrett esophagus (BE) is at risk of developing dysplasia (BE-D) and carcinoma (CA). Interobserver variation in interpretation of BE-D necessitates markers to complement histologic diagnosis.
Design: Esophageal biopsies (129) obtained from 39 BE patients during 11 years were reviewed for any histologic progression and tested for p53, Ki-67, Mcm2, β-catenin, cyclin D1, and p16, and compared with histology. Strong nuclear (N) or cytoplasm (C) staining in contiguity (not scattered) was considered positive.
Results: BE progressed to BE-D in 58.9% of cases (LGD in 51.2%, HGD in 7.7%). Progression time ranged from 1 to 11 years. p53, cyclin D1, and Mcm2 colocalized in LGD and HGD/CA, clearly delineating from the adjacent normal epithelium. Strong staining was in 83.3% (5 of 6) of HGD/CA cases and 68.6% (24 of 35) of LGD cases and was distinct from that of BE or BE with indefinite dysplasia (ID). BE/BE-ID that eventually progressed to LGD showed positive staining in groups of cells in previous biopsies. No p53 stain was seen in 1 of 7 HGD/CA cases (14.3%). β-Catenin was mostly cytoplasmic in LGD but lost or C/ N in HGD/CA. p16 staining (C/N) was present in 60% of HGD/CA cases and spotty in LGD.
Conclusions: BE progressed to BE-D in 58.9% of cases in this study. p53, cyclin D1, Mcm2, and β-catenin staining was significantly associated with the degree of dysplasia. A panel of marker testing is complementary to histology in BE, BE-ID, LGD, and HGD in the risk stratification.
Mast Cells, but Not Microfibril-Associated Protein 5, Are Associated With Microvascular Density in Pancreatic Adenocarcinoma: (Poster No. 82)
Context: Both mast cells and microfibril-associated protein 5 (MFAP5), an extracellular protein, have been shown to promote angiogenesis. We evaluated mast cell density (MCD) and MFAP5 expression, in relation to CD34+ microvessel density (MVD), to assess angiogenesis in pancreatic adenocarcinoma and analyzed their association with clinicopathologic features and outcome.
Design: Eighty-seven cases of pancreatic adenocarcinoma (2004–2009) were identified. Tissue microarrays were constructed with 2 cores/ case and immunostained with MFAP5, CD34, and CD117. Clinicopathologic features including age, sex, tumor grade, stage, and overall survival were reviewed. Average follow-up was 15 months. Staining intensity of MFAP5 in tumor stroma was graded 0 to 3. MFAP5 staining score was calculated as intensity multiplied by percentage positivity. MVD is the average number of CD34+ microvessels in three ×200 high-power fields (HPFs). MCD is the average number of CD117+ cells in three ×200 HPFs. Statistical analysis was performed by using χ2 tests (comparison studies) and Kaplan-Meier curve (survival studies).
Results: Patient mean age was 66 years, with male to female ratio of 1.6:1. MCD and MFAP5 score were positively and negatively correlated with MVD (P < .001), respectively. Higher MFAP5 score was associated with more advanced stage (P = .01). MFAP5 score, MVD, and MCD were not associated with overall survival, age, sex, tumor grade, or tumor size.
Conclusions: Mast cells, but not MFAP5, appear to correlate with intratumoral angiogenesis in pancreatic adenocarcinoma. Increased MFAP5 expression is correlated with more advanced stage but not outcome. Since MFAP5 is inversely correlated with MVD, it does not appear to act through a proangiogenic mechanism.
Clinical Significance of Yap Protein in Patients With Pancreatic Ductal Adenocarcinoma: (Poster No. 85)
Context: Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer death in the United States. Patients with PDA frequently carry oncogenic KRAS mutation. Yes-associated protein (YAP) is a critical factor downstream of KRAS–mitogen-activated protein kinase. It is overexpressed in liver, lung, skin, prostate, and ovarian cancers. This study aims to investigate YAP protein expression in PDA and its relationship to clinical outcomes.
Design: We examined nuclear and cytoplasmic staining of YAP protein by immunohistochemistry by using tissue microarrays from formalin-fixed, paraffin-embedded blocks in patients with PDA, neuroendocrine tumor (NET), and control benign tissues. Sections of duplicate tissue cores from 31 samples of 17 patients with PDA, 30 samples of 13 patients with NET, and 24 samples of benign tissues were examined with YAP antibody (Santa Cruz Biotechnology, Inc., Dallas, Texas). YAP expression of each subject was quantified by using a 4-value intensity score (0, negative; 1, weak; 2, moderate; and 3, strong). The results were correlated with clinical outcomes. Mann-Whitney and Kruskal-Wallis tests were used. Survival probability was calculated by Kaplan-Meier method.
Results: Nuclear and cytoplasmic staining of YAP protein from patients with PDA was significantly higher than that from patients with NET and the normal controls (P < .05). High YAP expression was correlated with overall poor survival (P < .01).
Conclusions: YAP protein may be a potential biomarker in the development of effective diagnosis and treatment strategies in patients with PDA.
Clinicopathologic Evaluation and Follow-up of Patients With Small Intestinal and Multivisceral Transplant in a Tertiary Care Hospital: (Poster No. 86)
Context: Small intestinal and multivisceral transplant (SI/MVT) is uncommon and posttransplant heavy immunosuppression and close clinical follow-up are required. We report our experience with all SI/ MVTs with transplant indications, clinicopathologic correlation, rejection episodes, opportunistic infections, and complications in these patients.
Design: From January 2009 to March 2015, all cases of SI/MVT were retrieved. The slides were reviewed and the clinical course was followed through electronic medical records.
Results: Of a total of 14 patients, 12 were SI transplant and 2 were multivisceral transplant cases. Age range was 22 to 59 years (mean, 45.9 years). Male to female ratio was 1:1.8. Indications for transplant included short gut syndrome (4), malignancy (3), Crohn disease (2), and others (5). Three patients experienced rejection episodes, while infections were identified in 4 patients, including 2 cytomegalovirus, 1 mucormycosis, and 1 Klebsiella infection. Of 14 patients, 13 are alive. Complications seen were bowel obstruction (1), diarrhea (1), fluid retention (1), abdominal pain and distention (1), and chylous ascites (1).
Conclusions: In our experience, the SI/MVT outcome is excellent, with only 1 patient who needed retransplant and 1 death reported outside the hospital due to unknown cause.
Elevated Fecal Calprotectin Levels Predict Active Inflammation on Lower Gastrointestinal Tract Biopsies: (Poster No. 87)
Context: Calprotectin is a calcium and zinc protein found in neutrophils. The presence of calprotectin in feces has been shown to be a strong surrogate marker for fecal neutrophils. It has also been used to differentiate inflammatory bowel disease and irritable bowel syndrome, as well as monitor inflammatory bowel disease activity.
Design: We examined all fecal calprotectin levels ordered at our institution from January 2013 to March 2015 and correlated them with terminal ileum, colon, and rectal biopsies to evaluate if elevated (>105 μg/g) calprotectin levels predicted the presence of active neutrophilic inflammation in biopsies.
Results: Of the 107 patients who had fecal calprotectin levels during the study period, 36 had biopsies. Of the 36 patients, 19 had elevated fecal calprotectin and 17 did not. Eighteen of the 19 patients with elevated fecal calprotectin had evidence of active neutrophilic inflammation on biopsy. Only 3 of 17 patients with low levels of fecal calprotectin had evidence of active neutrophilic inflammation on biopsy. The sensitivity and specificity of fecal calprotectin to predict active inflammation were 85.7% and 93.3%, respectively. Pathologic diagnosis on biopsies included chronic active colitis consistent with active inflammatory bowel disease (n = 14), active colitis (n = 2), collagenous colitis with focal activity (n = 2), ischemic colitis (n = 1), ulcer (n =1), and invasive adenocarcinoma with ulceration (n =1). The remaining cases (n = 15) showed no evidence of active inflammation.
Conclusions: Fecal calprotectin is a sensitive and specific marker for the detection of active inflammation on biopsies of the lower gastrointestinal tract.
Interobserver Variability in the Morphologic Classification of Gastrointestinal Polyps in a Kindred With SMAD4-Mutated Juvenile Polyposis–Hereditary Hemorrhagic Telangiectasia Syndrome: (Poster No. 88)
Context: Juvenile polyposis syndrome (JPS) is an autosomal dominant disorder leading to the development of hamartomatous polyps in the gastrointestinal tract. A significant number of patients with JPS with the SMAD4 mutation develop concurrent hereditary hemorrhagic telangiectasia (HHT) syndrome. A recent classification as either classical or epithelial juvenile polyp, based on histopathologic parameters in patients with JPS, has been proposed. However, recently it has been questioned whether gastrointestinal hamartomatous polyps can be reproducibly classified. The aim of this study is to evaluate the interobserver variability of gastrointestinal polyps within a kindred with SMAD4-mutated JPS-HHT syndrome.
Design: Sixty-seven gastrointestinal polyps (18 gastric, 5 duodenal, 44 colonic) from 2 brothers with SMAD4-mutated JPS-HHT syndrome were reviewed independently by 3 observers (1 attending pathologist with expertise in familial polyposis and 2 fourth-year residents). Classification of each polyp was done by following the World Health Organization 2010 criteria and criteria set forth by Hattem et al. Unweighted κ was calculated for interobserver agreement.
Results: The overall interobserver agreement for all polyps in patients with SMAD4-mutated JPS-HHT syndrome was moderate (κ = 0.5846). Interobserver agreement for gastric polyps was fair (κ = 0.218), duodenal polyps was moderate (κ =0.444), and colorectal polyps was moderate (κ = 0.5706).
Conclusions: Overall interobserver agreement was moderate for gastrointestinal polyps in patients with SMAD4-mutated JPS-HHT syndrome, but was only fair for gastric polyps. The classification was particularly difficult for smaller lesions. Future correlative studies of these polyps with SMAD4 immunohistochemistry and molecular analysis, and additional educational experiences such as Internet-based teaching, may help to improve interobserver agreement.
Colonic Diverticulitis With an Incidental Finding of Prototheca zopfii Organisms: A Case Report and Review of the Literature: (Poster No. 89)
Clinical infection with Prototheca species can present in many ways including cutaneous, bursal, or disseminated forms. Of these clinical forms, protothecal intestinal infections are a very rare occurrence, and there have only been a few documented cases within the medical literature. We present a case of a 67-year-old African American man who presented to our veterans hospital with bowel obstruction. The patient has a pertinent medical history of end-stage renal disease status post cadaveric renal transplant (on immunosuppressive therapy), diverticulosis, Clostridium difficile infection, and herpetic perirectal ulcer. Clinically, the patient presented with symptoms of weight loss, left lower quadrant pain, and pencil-thin stool. Colonoscopic and barium studies confirmed a complete obstruction at the level of the distal descending colon. Carcinoembryonic levels were within normal limits. The patient underwent a left hemicolectomy, and gross examination of the specimen revealed a markedly thickened bowel wall with multiple diverticula. Histologic examination revealed diverticular disease with associated transmural inflammation and numerous associated dark round structures. The basophilic round structures appeared to contain cell walls and stained positively for fungal stains. Overall, the diagnosis of Prototheca zopfii was made from the characteristic histopathologic features and the results of the fungal staining pattern. To our knowledge, this is the first reported case of a colonic diverticulitis with involvement by P zopfii. We present an overview of the biology, epidemiology, histopathologic features, clinical manifestations, and treatment options of Prototheca as it relates to our patient.
Metastatic Colorectal Adenocarcinoma Exhibits Overlapping Histologic Features With Extrahepatic Cholangiocarcinoma: (Poster No. 94)
Colorectal liver metastases with intrabiliary growth occur in approximately 10% of all colorectal metastasis. We present the case of a young male patient previously operated on for rectal cancer who developed an isolated extrahepatic bile duct lesion. A 48-year-old man underwent a low anterior resection surgery in January 2013 after neoadjuvant chemoradiation for invasive, poorly differentiated adenocarcinoma of the rectum with bilobar liver and lung metastases (ypT3, N0, M1). Circumferential resection margins were positive for tumor with foci of lymphovascular invasion. An extended left hepatic lobectomy was performed in August 2013 that showed 4 nodules consistent with metastatic moderately differentiated adenocarcinoma. In October 2014 our patient presented with abnormal liver function test results, and a positron emission tomography/computed tomography performed showed a hypermetabolic focus in the common bile duct and no abnormal uptake in the liver. Endoscopic retrograde cholangiopancreatography confirmed an intraductal polypoid mass within the distal common bile duct with biopsies showing moderately differentiated intestinal-type adenocarcinoma. The bile duct tumor was positive for CK20, CDX2, β-catenin, and CK19 while negative for CK7 and hepatocytes, similar to the previous liver metastasis, consistent with a colorectal primary. The use of clinical history allied with a small panel of immunomarkers enables distinction of secondary from primary bile duct tumors.
The Gist of Sleeve Gastrectomies: A Retrospective Analysis of Pathologic Findings: (Poster No. 95)
Context: Examination of surgical specimens by pathology is determined by the expected presence or absence of clinically significant findings. Institutional discretion is used when microscopic examination is unlikely to yield valuable clinical information. While various histopathologic changes have been described in vertical sleeve gastrectomies, the decision for pathology review varies between institutions. Our institution has opted to microscopically review all sleeve gastrectomy specimens. We provide an institutional review of pathologic findings in sleeve gastrectomy specimens and explore the necessity of routine examination.
Design: A retrospective review of pathology reports was completed for 720 consecutive morbidly obese patients who underwent vertical sleeve gastrectomy between January 2012 and December 2013 at a single institution.
Results: Findings included 6 gastrointestinal stromal tumors (0.83%); size ranged from 0.2 to 1 cm (average, 0.43 cm). Immunohistochemistry was positive for CD117 (6 of 6) and CD34 (1 of 1), and negative for smooth muscle actin (0 of 6), desmin (0 of 1), and S100 (0 of 1). Also found were 466 instances of chronic gastritis (64.7%); 53 fundic gland polyps (7.4%); 17 positive for Helicobacter pylori (2.36%); 24 active gastritis (3.33%); 14 intestinal metaplasia (1.94%); 6 hyperplastic polyps (0.83%), 1 with low-grade dysplasia; 4 parietal cell hyperplasia (0.56%); 4 submucosal lipomatosis (0.56%); and 1 to 2 patients each with the following: nonnecrotizing granuloma, microneuroendocrine tumor, foveolar hyperplasia, “rare” goblet cells, hypertrophic gastropathy, pancreatic heterotopia, hamartomatous polyp, and calcific arteriosclerosis.
Conclusions: Many of the histopathologic findings have clinical implications and their frequency supports the routine examination of sleeve gastrectomy specimens by pathology.
Colonic Tuberculosis Disguising as Colonic Carcinoma: (Poster No. 96)
Extrapulmonary tuberculosis is becoming increasingly more common in developed countries owing to the rise in prevalence of immunocompromised individuals, increasing immigrant population, and decreased access of the public to proper health care. We present a case of colonic tuberculosis mimicking the clinical features of primary colonic malignancy. A 48-year-old Hispanic man with no significant past medical history presented with diffuse abdominal pain and distension with nausea and vomiting for 2 days. He had experienced an approximately 20-lb weight loss during the previous 2 months. Family history was significant for colorectal cancer. Upon admission, computed tomography revealed a colonic mass with diffuse mesenteric lymphadenopathy and small-bowel obstruction. Based on these findings, the working diagnosis was a colonic malignancy and referral for surgical hemicolectomy was warranted. An urgent colonoscopy was performed. The biopsy of the mass revealed an ulcerated colonic mucosa with cryptitis, crypt abscesses, and necrotizing granulomatous inflammation with mycobacteria by acid-fast stain. Therefore, antitu-bercular therapy was initiated and the hemicolectomy was canceled. Our present case illustrates the need to keep a high clinical suspicion for primary colonic tuberculosis when encountering patients presenting with masslike lesions that may mimic solid tumors. Owing to the increasing prevalence of extrapulmonary tuberculosis, it is therefore imperative to consider primary colonic tuberculosis owing to obvious therapeutic implications and outcome.
Incidental Metastatic Medullary Carcinoma of the Colon Involving an Extraterritorial Adenoma: Diagnostic Pitfall and Impact on Patient Care: (Poster No. 98)
Microsatellite instability–associated colorectal medullary carcinoma (MC) has been gaining attention recently owing to its impact on clinical management and prognostication. Usually, MC is composed of sheets of tumor cells with pushing borders and lymphoplasmacytic banding. Rarely does MC present as a mucinous adenocarcinoma or a pure signet ring cell carcinoma. It is believed that MC possesses less aggressive properties than microsatellite-stable tumors; however, we recently encountered an opposite example, with lymphovascular invasion and distant metastasis in an MC. We present a unique case of metastatic signet ring cell MC, which was incidentally identified as involving a noncontiguous distant adenoma after screening colonoscopy, so as to emphasize these unique and essential histologic features and to caution diagnostic pitfalls. A 58-year-old man presented for a routine colonoscopy. A 2-cm adenoma was removed from hepatic flexure, which showed signet ring cell carcinoma, with loss of MLH1/PMS2 and retained MSH2/MSH6 immunohistochemically. Next-generation sequencing showed no mutation in B-Raf, EGFR, and Ras. The cauterized margin was benign. Significantly, biopsy of a noncontiguous 0.5-cm adenoma (35 cm distal) showed rare signet ring cells within lymphovascular spaces, with identical morphology and immunopheno-type as seen in MC. Owing to this unexpected finding, the patient received chemotherapy, awaiting resection. MC could present as signet ring call carcinoma, with multifocal lymphovascular invasion and aggressive clinical behavior; understanding the molecular basis of MC and awareness of its histologic features and clinical impact are pivotal for reaching the correct diagnosis and for improving patient management.
Lymphoepithelial-like Carcinoma Involving a Rectal Tonsil: (Poster No. 99)
Prominent, localized, reactive lymphoid rectal tissue, “rectal tonsil,” is an unusual entity that may be mistaken for lymphoma. We report a case of poorly differentiated, nonkeratinizing squamous cell carcinoma (lymphoepithelioma-like carcinoma) arising in a rectal tonsil. A 45-year-old white woman admitted for rectal bleeding was found to have a 1.3-cm submucosal, posterior, midline, mobile rectal mass just proximal to the dentate line. The findings were suggestive of a neuroendocrine tumor, and transanal local excision was performed. Histopathologic examination revealed a well-circumscribed nodule confined within the submucosa, composed of lymphoid tissue with lymphoid follicles containing distinct germinal centers. Syncytial nests of malignant cells with eosinophilic cytoplasm and moderately pleomorphic nuclei with irregular contours and prominent nucleoli infiltrated between the lymphoid aggregates. The neoplastic cells expressed cytokeratin AE1/ AE3 and p63 with diffuse and strong nuclear and cytoplasmic expression of p16. Neuroendocrine markers, S100 protein, and CD45 stains were negative. The Ki-67 labeling index was estimated at 95%. In situ hybridization for Epstein-Barr virus–encoded small RNAs, and human papillomavirus 6, 11, 16, and 18 were negative. The patient lacked any significant past medical history and results of a gynecologic examination were unremarkable. Imaging studies were negative except for a salivary gland lesion that is being evaluated. While most cases of rectal tonsil in the literature are nonneoplastic in nature, the potential for malignant epithelial neoplasms to present in this setting should be considered when these specimens are encountered.
Intrahepatic Biliary Lymphoepithelioma-like Carcinoma With Neuroendocrine Features: (Poster No. 103)
Lymphoepithelioma is a form of undifferentiated carcinoma, characterized by a prominent lymphoid stroma. Originally described in the nasopharynx, lymphoid stroma-rich carcinomas arising elsewhere are termed lymphoepithelioma-like carcinoma (LELC). In the liver, primary LELC is rare; most of these tumors have been identified as cholangiocarcinomas, most of which are also associated with Epstein-Barr virus (EBV). Here we report a unique case of LELC (cholangiocarcinoma) with neuroendocrine features, without EBV infection. A 77-year-old Asian man with past medical history of nonalcoholic fatty liver disease and steatohepatitis, diabetes, and stroke was incidentally found to have a 3.5-cm liver mass in the right lobe on computed tomography scan. Right liver lobectomy was performed. Histology showed cords of moderately differentiated, polygonal, malignant epithelial cells intersected by prominent lymphoplasmacytic infiltrates. Hepatocellular differentiation was not appreciated by histomorphology, nor were there distinct glands by routine stains. Immunohistochemically, the tumor epithelial cells were positive for keratin 7, keratin 19, MUC-1, and carcinoembryonic antigen (CEA; membranous and cytoplasmic) and negative for HepPar1, arginase 1, canalicular pCEA, and CD10. The surrounding infiltrating inflammatory cells were positive for CD45. This panel of staining results is typical for LELC (cholangiocarcinoma); however, there was focal staining for synaptophysin and rare cells also showed chromogranin positivity indicative of neuroendocrine differentiation. Fluorescence in situ hybridization for EBV was negative. Based on all these results, the diagnosis of lymphoepithelioma-like carcinoma (cholangiocarcinoma) with neuroendocrine features, non-EBV associated, was rendered. This case, to the best of our knowledge, is the first lymphoepithelioma-like carcinoma (cholangiocarcinoma) with neuro-endocrine features.
Analysis of Yes-Associated Protein 1 Expression in Hepatoblastoma: (Poster No. 104)
Context: Hepatoblastoma is the most common pediatric liver malignancy, occurring most often in preterm infants. Patients often present with an abdominal mass and early lung metastases. Total resection of the tumor is crucial; however, 60% of tumors are unresectable at the time of diagnosis. Irregular activation of Yes-associated protein (YAP) 1 has been linked to the development of several childhood tumors and hepatic neoplasms in adults. However, detailed analysis of precursor YAP signaling in hepatoblastoma has yet to be studied. In this study, we will explore whether YAP is expressed in hepatoblastomas and its potential therapeutic impact.
Design: Upon internal review board approval, we researched our files for hepatoblastoma cases from 1992–2014. Slides from those patients were stained for H&E and YAP to identify the expression of this protein in this experimental group. The control group consisted of age-matched patients with normal liver. The correlation of the presence of YAP and the clinical outcome was examined.
Results: We reviewed the cases of 62 patients with hepatoblastoma. Patient ages ranged from 0 to 21 years. All tumors stained positively for YAP protein, while age-matched controls and adjacent hepatocytes were negative for YAP. Embryonal variant showed a stronger staining pattern than the fetal subtype.
Conclusions: YAP expression can be a helpful diagnostic marker for hepatoblastoma and for differentiating embryonal from fetal pattern. A better understanding of YAP overexpression, and its association with tumor formation in hepatoblastoma, may provide researchers with information to develop a targeted pharmacogenetic treatment with subsequent improvement of patient outcomes.
Misplacement of Dysplastic Epithelium (Pseudoinvasion) and Transmural Mucin Invasion in Duodenal Puetz-Jeghers Polyposis: An Unusual Case With Duodenal Mass: (Poster No. 106)
Misplacement of dysplastic epithelium accompanied with transmural mucin invasion in Puetz-Jeghers polyposis (PJP) is a major diagnostic pitfall and a mimicker of invasive mucinous adenocarcinoma. We present a challenging case of a 43-year-old man with PJ syndrome and symptoms of gastrointestinal obstruction due to a mass in the distal duodenum. Colonoscopy additionally revealed multiple 12- to 26-mm polyps in the rectum, entire colon, and cecum. A Whipple procedure was performed. Gross examination revealed a large firm mass measuring 5.2 cm in the duodenum, 1.3 cm away from the ampulla, along with numerous tan-brown pedunculated polyps ranging from 0.2 to 3.8 cm throughout the segment of the duodenum. Microscopic evaluation revealed hamartomatous polyps with arborizing network of smooth muscle and extensive epithelial misplacement through the muscularis propria up to the serosa. The misplaced epithelial islands had a lobular configuration with areas of low-grade and focal high-grade dysplasia accompanying nonneoplastic epithelium, and absence of stromal desmoplastic reaction. In addition, there was a transmural pattern of mucin invasion and mucin cysts, not associated with dysplastic epithelium (enteritis cystica profunda). While histopathologic interpretation is difficult in such cases of PJP, overdiagnosis of mucinous adenocarcinoma should be avoided. Similar findings have been described in association with PJP of the small intestine. Our case represents an extreme spectrum of this process with mass formation and dissecting mucin extending up to the serosal surface. Close clinical surveillance is recommended in these cases, in view of their associated increased prevalence of malignancy.
Large B-Cell Lymphoma in Small Intestine: (Poster No. 107)
Primary small-intestine lymphoma represents approximately 1% of all small-intestine tumors. The most common type is mucosa-associated lymphoid tissue (MALT) lymphoma. Large B-cell lymphoma type is rather a rare entity. Here we report a case of large B-cell lymphoma arising from duodenum. A 32-year-old man with past medical history of gastroesophageal reflux disease and gastric ulcer presented with hematemesis and melena. Esophagogastroduodenoscopy found a large circumferential infiltrative process between duodenal bulb and second portion of the duodenum that was suggestive of malignancy. Histologically, the biopsy specimen showed a cellular infiltrate within the lamina propria. The cellular infiltrate was composed of a population of large lymphocytes with scant cytoplasm, markedly enlarged nuclear, and variable prominent nucleoli. There were increased mitoses but no necrosis. Immunohistochemically, the atypical lymphocytes were immunoreactive with CD20, Pax-5, BCL-6, BCL-2, and MUM-1. They were occasionally positive with CD30, but negative with CD10, CD23, and AE1/AE3. Stains for HSV-1, HSV-2, and CMV were all negative. Ki-67 labeling was high, approximately 60%. Diagnosis of large B-cell lymphoma of duodenum with postgerminal center phenotype was rendered. Fluorescence in situ hybridization for c-MYC or BCL-6 rearrangement and BCL-2/IGH translocation were all negative.
Plasma Cell Granuloma: An Entity Within the Spectrum of IgG4-Related Disease: (Poster No. 110)
Plasma cell granuloma (PCG), often referred to as inflammatory pseudotumor, is a relatively rare, mass-forming lesion composed of polyclonal plasma cells set in a background of storiform fibrosis and spindle cell proliferation. This lesion may occur within any site and should be included in the differential diagnosis of plasma cell neoplasms. Recent literature and immunohistochemical stains performed on our cases suggest that PCG falls within the spectrum of IgG4-related diseases. Two patients diagnosed with PCG at a tertiary care center were identified, retrospectively. The median age of presentation was 53 years. Both tumors were mass-forming lesions in the head and neck. Case 1 presented as a 3.2-cm soft tissue mass centered in the left nasopharynx extending into the middle ear and auditory canal. Case 2 presented as a 3.0-cm expansile mass within the clivus. Both patients received a subtotal resection given the location. Histologically, both cases demonstrated a diffuse population of morphologically unremarkable plasma cells with scattered mixed inflammatory cell infiltrate, set in a background of storiform fibrosis. In each case, immunohistochemical stains and in situ hybridization studies demonstrated a polyclonal population of CD138+ plasma cells. IgG4 immunohistochemical staining revealed 20 and more than 50 positive plasma cells per high-power field, respectively. We present 2 cases of PCG with morphologic and immunohistochemical evidence to suggest their inclusion within the IgG4-related disease spectrum, which would have significant impact on treatment and the possibility of metachronous lesions and progressive disease.
Therapy-Related MLL and RUNX1 Amplification in Ring Chromosomes: (Poster No. 113)
Context: Ring chromosomes are circular structural abnormalities formed by fusion of broken short or long arms of 1 or more chromosomes. Inherently unstable, they are found in less than 1% of hematologic malignancies as a single ring usually accompanying other abnormalities in a complex karyotype. Recently, additional anomalies such as multiple rings and gene amplification within rings were observed in therapy-related cases.
Design: To further characterize ring chromosomes, they were searched in a database containing approximately 20 000 hematologic malignancies studied with conventional cytogenetics.
Results: Among 38 patients showing ring chromosomes, 12 therapy-related cases (31.5%) were identified, 3 of which had 2 or 3 copies of ring chromosomes. Only 1 newly diagnosed patient had multiple ring chromosomes. Thirteen cases were further elucidated with fluorescence in situ hybridization, identifying 2 therapy-related gene amplifications of MLL in acute myeloid leukemia and RUNX1 in hairy cell leukemia. In contrast, 2 de novo cases had gene amplification of BCL2 in acute myeloid leukemia and FGFR1 in acute lymphoblastic leukemia.
Conclusions: In our cohort, the incidence of multiple ring chromosomes is 25% in therapy-related hematologic malignancies and less than 5% in newly diagnosed patients despite similar frequencies of complex karyotypes, 91.6% and 80.7%, respectively. Genes for transcriptional regulatory nuclear proteins with histone methyltransferase activity (MLL) and promoter activation (RUNX1) were amplified in therapy-related cases, while de novo cases had amplification of genes directly influencing cell proliferation via antiapoptotic (BCL2) and tyrosine kinase activity (FGFR1). Therapy may be related to the class of genes participating in hematologic malignancies with ring chromosomes.
Nonamyloid Proteinaceous Lymphadenopathy in a Patient With Marfan Syndrome and Seronegative Arthritis: (Poster No. 114)
Proteinaceous lymphadenopathy (PL) occurs in enlarged lymph nodes with replacement of the normal architecture by deposition of acellular amorphous material, usually amyloid. Rare reports in the literature describe PL in patients with other diseases such as Marfan syndrome and rheumatoid arthritis. A 47-year-old African American woman with a complicated past medical history, including Marfan syndrome and seronegative arthritis, presented with bilateral axillary lymphadenopathy. A lymph node excision was performed. Histologic examination of the lymph nodes revealed deposition of acellular eosinophilic material within the lymph node parenchyma. A Congo red stain performed on the tissue was negative, excluding amyloidosis. A trichrome stain also highlighted the acellular eosinophilic material. Additionally, stains for periodic acid–Schiff with and without diastase, AFB, and GMS revealed no evidence of infectious microorganisms. Overall, the findings were compatible with nonamyloid PL. PL is an exceedingly rare benign disease of the lymph nodes. Most often, it is due to deposition of amyloid. There are infrequent reports in the literature of PL arising in patients with Marfan syndrome or rheumatoid arthritis, but not both concurrently. Furthermore, no patients with seronegative arthritis and PL have been reported. To the best of our knowledge, PL has never previously been described in a patient with both Marfan syndrome and seronegative arthritis.
“Double-Hit” B-Cell Lymphoma With MYC and CCND1 Rearrangement: A Rare, Aggressive Lymphoma Presenting a Diagnostic and Classificatory Challenge: (Poster No. 115)
Cases of B-cell lymphoma with dual MYC and cyclin D1 rearrangements are rare, and have been reported sporadically in the literature. The classification of these lymphomas is challenging and controversial, as they have intermediate features between a blastoid mantle cell lymphoma and diffuse large B-cell lymphoma. A 73-year-old man presented with fatigue, weight loss, peripheral leukocytosis, anemia, and thrombocytopenia. Radiography revealed mediastinal, intrapulmonary, and periportal lymphadenopathy with splenomegaly. He underwent bone marrow biopsy, flow cytometric analysis, and cytogenetic studies (fluorescence in situ hybridization [FISH]). The bone marrow showed virtual marrow replacement by monotonous, medium-sized to large lymphoma cells with a high proliferation index, cytomorphologically reminiscent of Burkitt lymphoma. The neoplastic cells were immunohistochemically positive for CD20, c-Myc, MUM1, and cyclin D1; SOX11, CD5, and CD10 were negative. These findings were replicated by flow cytometry. FISH showed an atypical CCND1/IGH gene rearrangement, without BCL-2 or BCL-6 rearrangement. The differential diagnosis included blastoid mantle cell lymphoma with additional MYC gene rearrangement, or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and mantle cell lymphoma with MYC and cyclin D1 dual-gene rearrangements. While the latter diagnosis is not yet listed in the 2008 World Health Organization classification scheme, this diagnosis was favored in light of the cytomorphology, lack of CD5, CD10, and SOX11, and atypical cyclin D1 gene rearrangement. This is a critical therapy branch point and appropriate classification is essential.
Secondary Hemophagocytic Lymphohistiocytosis Associated With Granulomatosis With Polyangiitis (Wegener Granulomatosis): A Case Report With Review of the Literature: (Poster No. 116)
Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome that is potentially fatal despite treatment. It is caused by a dysregulation in natural killer T-cell function, resulting in activation and proliferation of histiocytes with uncontrolled hemophagocytosis and cytokine overproduction. HLH can be either primary, with a genetic etiology, or secondary, associated with malignancies, autoimmune diseases, or infections. Autoimmune diseases are an important cause of HLH. Among rheumatic disorders, HLH occurs most frequently in systemic juvenile idiopathic arthritis. There is sparse literature on cytopenia and HLH cases associated with granulomatosis with polyangiitis (GP), and thus hematologic and bone marrow findings of Wegener granulomatosis have not been studied well. Here, we report a case of GP associated with HLH, a clinicopathologic entity involving the proliferation of hemophagocytic histiocytes in the bone marrow, resulting in fever, hepatosplenomegaly, lymphadenopathy, pancytopenia, liver dysfunction, and coagulopathy. The authors report this case to draw attention to this severe syndrome that may often go undiagnosed in patients with rheumatic diseases, especially granulomatosis with polyangiitis, and can affect prognosis.
A Rare Case of Mantle Cell Lymphoma Involving the Thyroid Gland in the Background of Hashimoto Thyroiditis: (Poster No. 117)
Thyroid lymphomas are a rare entity accounting for 5% of all thyroid malignancies and comprising 2% of all malignant extranodal lymphomas. Most thyroid lymphomas are non-Hodgkin lymphomas of B-cell origin, with diffuse large B-cell lymphoma being the most common (50%–70%) followed by mucosa-associated lymphoid tissue lymphoma (23%–30%). Mantle cell lymphoma of the thyroid is a very rare occurrence. We present a case of a 64-year-old woman with a history of Hashimoto thyroiditis. A total thyroidectomy was performed secondary to a recent increase in the size of her thyroid nodules and to alleviate her compressive symptoms. On gross examination a large cystic nodule (4.2 cm) was identified in the right lobe with multiple smaller nodules in the left lobe of the thyroid. Sections from the right thyroid nodule revealed marked lymphocytic infiltrate mostly in the form of variably sized follicles with germinal centers with marked expansion of the mantle zones. Immunoperoxidase stains revealed that the expanded mantle zone cells were positive for CD20, CD5, CD43, cyclin D1, and SOX11. Cyclin D1 and SOX11 also highlighted scattered interfollicular neoplastic B cells. Concurrent flow cytometric analysis identified CD5+, CD10− monoclonal B cells with λ light-chain restriction. These findings were consistent with mantle cell lymphoma involving thyroid with predominantly mantle zone growth pattern. Fluorescence in situ hybridization analysis showed a CCND1-IGH rearrangement. The patient was clinically staged IEA by the Ann Arbor staging system. She is currently under close clinical observation and is doing well without any additional treatment.
Epstein-Barr Virus–Positive Diffuse Large B-Cell Lymphoma of the Young: Case Reports and Literature Review: (Poster No. 118)
Diffuse large B-cell lymphoma (DLBCL) is the most common variant of non-Hodgkin lymphoma (NHL) accounting for approximately 30% of the NHL cases worldwide. The 2008 World Health Organization (WHO) classification of lymphoid neoplasms uses morphologic, immunophenotypic, genetic, and clinical criteria to further subclassification. Epstein-Barr virus (EBV)–positive DLBCL of the elderly is a newly described entity in the 2008 WHO classification of lymphomas. This entity occurs in immunocompetent patients who are older than 50 years and is accompanied by an EBV-associated clonal B-cell proliferation. More than 90% of humans are infected with EBV, which persists for life. EBV-positive DLBCL of the elderly is believed to be related to the senescence of the immune system. However, most of the data that led to the introduction of this entity were derived from East Asian patient populations, yet little is known about Western populations. This review describes 2 immunocompetent patients, younger than 50 years, with EBV-positive DLBCL. The occurrence of these cases illustrate that EBV-positive DLBCL should not have an age criterion and the designation of this disease must be modified in the next version of the WHO classification.
Histiocytic Sarcoma With a BRAF V600E Mutation Arising From Hairy Cell Leukemia: Possible Role for Targeted Therapy?: (Poster No. 119)
Histiocytic sarcoma (HS) is a rare malignancy of mature histiocytes and can be primary or secondary. Secondary HS often shares the same molecular or cytogenetic abnormality as the primary malignancy. We describe the first case of HS with a BRAF V600E mutation arising within months of a diagnosis of hairy cell leukemia (HCL). The only other case described of HS arising from HCL involved a case of longstanding treated HCL. Our patient was a 69-year-old man with a history of factor V Leiden deficiency and untreated HCL. He presented with severe back pain radiating to his leg. Workup revealed an L5 vertebral mass, which was biopsied. Sections revealed large irregular cells with abundant eosinophilic cytoplasm, irregular folded nuclei, and prominent nucleoli. Frequent mitoses, necrosis, and neutrophils were also present. The tumor cells were positive for S100, CD68, CD163, CD45, weak CD4, and BCL-2. CD1a, CD34, CD21, and CD23 were negative. All epithelial, melanoma, and lymphoid markers were negative. His results were considered consistent with a histiocytic sarcoma. Polymerase chain reaction testing was positive for BRAF V600E mutation. Owing to his comorbidities, the patient only received radiation to the L5 region. He was deemed stable for discharge and is currently following up with his radiation oncologist. Histiocytic sarcoma is a rare aggressive malignancy with few treatment options. From the results of our case, targeted therapy could play a role in treatment. Further investigation is needed to understand the molecular biology and help improve the overall outlook of this disease.
Is Hemoglobin Variant Analysis Helpful in the Diagnostic Workup of Patients Revealing Microcytic Erythrocytosis on Complete Blood Count?: (Poster No. 121)
Context: Complete blood count studies can reveal hidden pathology through indices such as hemoglobin, mean corpuscular volume (MCV), and red blood cell (RBC) count.
Design: We focused our analysis on patients with microcytic erythrocytosis with or without anemia. Data from all complete blood cell count (CBC) studies within a 2-year period at Thomas Jefferson University Hospital were reviewed, and patients meeting the inclusion criteria of microcytosis (MCV < 80 fL) and erythrocytosis (RBC count > 5.2 T/L [female] and > 6 T/L [male]) were selected (n = 138). With the premise that potential hemoglobinopathies underlie these 2 laboratory abnormalities, results of hemoglobin variant analysis performed by high-performance liquid chromatography on these patients were reviewed. Hemoglobin values for the patients ranged from 7.2 to 16.1 g/dL, MCVs ranged from 54.5 to 79 fL, and RBC count ranged from 5.2 to 7.5 T/L. Seventy-three patients had mild anemia, while 65 patients had hemoglobin levels within the sex-specified reference range.
Results: Sixty-seven patients were discovered to have elevated A2 levels (>3.5%), supporting a diagnosis of β-thalassemia minor. Forty-six patients had normal hemoglobin A and A2 with no documented iron studies. The underlying etiology for these patients could include a myriad of conditions such as iron deficiency, α-thalassemia, or anemia of chronic disease. Twenty patients had an underlying hemoglobinopathy and the remaining 5 had iron deficiency, based on documented iron studies.
Conclusions: Our study of these 138 patients showed that at least 87 patients (63%) had either a hemoglobinopathy or thalassemia. We therefore recommend that hemoglobin variant analysis be reflexively performed on CBC specimens that are found to have microcytic erythrocytosis without a known underlying etiology.
Cell Population Data—A Window Into the Diagnosis of Dengue Fever: A Tertiary Care Center Experience in Southern India: (Poster No. 122)
Context: Dengue fever is rapidly emerging as the most prevalent vector-borne viral disease in India. Patients are at risk of developing complications such as dengue hemorrhagic fever and disseminated intravascular coagulation, associated with high mortality rates. It still remains a diagnostic challenge, as there are no specific symptoms to distinguish it from other common viral febrile illnesses. The VCS data (volume, conductivity, and scatter) and cell population data available in automated hematology analyzers are capable of quantifying and reflecting subtle, yet decisive changes in the morphology of leukocytes. Thus, we decided to explore the role of this technology in rendering a diagnosis of dengue fever.
Design: A cross-sectional study was conducted between June and October 2014 in the hematology laboratory. Two hundred twenty IgM-positive cases of dengue fever were involved. Two level controls were also exercised: (1) acute febrile illness with thrombocytopenia, which was negative for both dengue IgM status and malaria (n =200); and (2) normal healthy subjects (n = 150). The VCS data for neutrophils, lymphocytes, and monocytes were retrieved from a Beckman Coulter LH780 series analyzer. Mann-Whitney test was applied for statistical analysis.
Results: The standard deviation (SD) of neutrophil volume and scatter, the SD of lymphocyte volume, scatter, and mean lymphocyte scatter, along with SD of monocyte volume and scatter, showed statistically significant differences between the cases and controls (P < .001).
Conclusions: Cell population data were found to be effective in distinguishing dengue fever from other acute febrile illnesses. Further studies in this vein along with discriminant factors could be the way ahead.
Characterization of CD19+ Plasma Cell Neoplasms: (Poster No. 123)
Context: Most neoplastic plasma cells expresses CD38, CD138, and cytoplasmic light chain; aberrantly express CD56, CD117, CD28, and CD20; and are usually negative for CD45 and the pan-B cell marker CD19. However, a subset of plasma cell neoplasms (PCNs) expresses CD19 and is believed to be associated with monoclonal gammopathy of undetermined significance and thought to show an aggressive behavior pattern.
Design: We retrospectively evaluated CD19 expression on PCNs by using flow cytometry–based diagnostic assays performed on bone marrow aspirates of patients from January 2013 to August 2014. We then compared patient demographics, pathologic features, and clinical outcome.
Results: A total of 18 cases of CD19+ PCNs were identified that represented 4.7% of all PCNs (n = 384). CD19+ PCNs occur more frequently in white persons and young males (median age, 57.5 years). On the basis of World Health Organization diagnostic criteria, most patients had multiple myeloma (72%) versus monoclonal gammopathy of undetermined significance (28%). Serum immunoglobulin distribution was similar to CD19− multiple myeloma. Bone marrow plasma cells infiltrate ranged from 10% to 80% with interstitial/obliterative/mixed patterns and had low-grade morphologic features. Flow cytometric analysis revealed bright (38%), heterogeneous (52%), or bimodal CD19 expression (3%). Coexpression of CD27 and/or CD81 was observed in 88% of cases. Most of these patients received treatment and are alive with minimal residual disease.
Conclusions: Our findings suggest that CD19+ PCNs are more commonly associated with multiple myeloma than monoclonal gammopathy of undetermined significance. Moreover, most of these tumors exhibit low-grade tumor morphology and are associated with better prognosis.
Pediatric Acute Megakaryoblastic Leukemia With Novel MLL Gene Fusion Partner: (Poster No. 125)
Acute megakaryoblastic leukemia (AMKL, FAB-M7) is a rare leukemia, with slightly higher pediatric incidence due to association with Down syndrome. MLL gene (11q23)–rearranged acute myeloid leukemia (AML), traditionally associated with monocytic differentiation (FAB-M4/5), has rarely been reported in AMKL. To our knowledge, AMKL with t(10;11)(p11.2;q23) has never been previously reported. We document the first case of AMKL with t(10;11)(p11.2;q23) rearrangement. A 15-month-old, previously healthy girl presented with easy bruising, pallor, and fever. Physical examination revealed hepatosplenomegaly and lower extremity papular rash. Complete blood cell count showed anemia, severe thrombocytopenia, and leukocytosis with 7.7% circulating blasts. Bone marrow examination showed 40% blasts with occasional cytoplasmic blebs, which stained positively for CD31, CD61, and factor VIII (weak) by immunohistochemistry. By flow cytometry, the blasts were positive for CD42, CD61, CD7 (dim), CD71, CD99, and CD58, and negative for myeloperoxidase, TdT, cytoplasmic CD3, and CD79a. Cytogenetic analysis revealed markedly complex karyotype including t(10;11)(p11.2;q23), confirmed by fluorescence in situ hybridization for MLL rearrangement. The patient was enrolled in chemotherapy protocol AAML1031 and is currently in remission 5 months post treatment, awaiting bone marrow transplant. MLL-rearranged AML has poor but widely variable prognosis based on the specific partner gene. Translocation with 10p11.2 has been shown to have unfavorable prognosis, with 5-year event-free survival of only 17%. However, prognosis is difficult to extrapolate owing to disease rarity and short follow-up. In summary, we describe an extremely rare case of MLL-rearranged AMKL, which highlights the importance of morphologic-cytogenetic correlation for appropriate AML risk categorization and disease monitoring.
Extraoral Plasmablastic Lymphoma: Study of 4 Cases: (Poster No. 126)
Context: Plasmablastic lymphoma is uncommon, with most cases occurring in the oral cavity of HIV patients. Here we present 4 extraoral cases with various clinical presentations.
Design: Case 1 involves a 40-year-old man with a skin mass on the left thigh. Case 2 involves a 58-year-old man with a nasal mass followed by a back mass. Case 3 involves a 60-year-old man with an abdominal mass. Case 4 involves a 63-year-old woman with a retroperitoneal mass. Immunohistochemistry, flow cytometry, and in situ hybridization were performed to characterize biopsies from these 4 patients.
Results: In all cases, the infiltrates consisted of atypical cells with variable plasmacytic differentiation. Immunohistochemistry showed that they were positive for CD138; Ki-67 index was greater than 70%. The tumor cells in the skin biopsy (case 1) were positive for CD138 and negative for other T and B markers, CD117, CD56, and cyclin D1. Clinical workup found a bladder mass, which showed similar histology and immunophenotypic profile. For case 4, the tumor cells were negative for pan T and B lymphocyte markers, CD45, CD56, CD117, CD123, and ALK1, but positive for CD138 and epithelial membrane antigen (subset). Flow cytometry showed κ-chain restriction. Two cases were negative for EBER. The differential diagnosis of anaplastic plasmacytoma was considered and ruled out by the absence of CD56 expression, a high proliferative index, and absence of plasma cell neoplasm.
Conclusions: These cases were diagnosed as extraoral plasmablastic lymphoma. Awareness of this rare entity is necessary to establish a correct diagnosis in cases with unconventional clinical presentations.
A Case of Solitary Plasmacytoma, With Unusual Erythrophagocytosis and Iron Accumulation in Plasma Cells: (Poster No. 127)
Erythrophagocytosis by plasma cells is a rare finding in patients with plasma cell dyscrasias. Accumulation of iron inclusions in neoplastic plasma cells is also uncommonly observed and has been described in a few cases of alcoholism, megaloblastic anemia, frequent red blood cell transfusions, and hemochromatosis. We report a case of a 67-year-old man with a longstanding history of monoclonal gammopathy of undetermined significance and alcoholism who presented with pathologic rib fracture. Complete skeletal survey showed no evidence of other bony lesions. Additionally, hemoglobin, calcium, blood urea nitrogen, and creatinine levels were within normal limits. A bone marrow biopsy of the posterior iliac crest revealed a mildly hypercellular bone marrow (40%) with erythroid hyperplasia and plasma cell dyscrasia (5% plasma cells). Subsequently, the rib lesion was biopsied, which revealed findings diagnostic of a plasmacytoma. Interestingly, the plasma cells in the rib biopsy displayed erythrophagocytosis and cytoplasmic eosinophilic granules. A Prussian blue iron stain revealed the presence of multiple intracytoplasmic iron granules within the neoplastic plasma cells. In addition, touch preparations demonstrated occasional intact red cells within the cytoplasm of plasma cells. Of note, these unusual findings were not identified in the plasma cells in the bone marrow biopsy. To our knowledge, this is the first case of plasma cell dyscrasia in which accumulation of iron in the cytoplasm of plasma cells and plasma cell erythrophagocytosis are simultaneously described. These findings may provide insight into the mechanisms that cause iron accumulation in neoplastic plasma cells and warrant further investigations.
Unclassifiable Splenic B-Cell Lymphoma/Leukemia With BRAF Mutation: (Poster No. 129)
We report a case of splenic B-cell lymphoma/leukemia with BRAF V600E mutation that does not have the characteristic features of hairy cell leukemia or any other defined splenic B-cell lymphoma/leukemia. The BRAF mutation is highly sensitive and specific for hairy cell leukemia with no reports seen in “splenic diffuse red pulp small B-cell lymphoma” or “hairy cell leukemia variant.” The patient is a 68-year-old woman with new onset fatigue and dyspnea on exertion. She had pancytopenia and IgM-κ paraprotein. Bone marrow examination with flow cytometry showed hypercellular marrow with few interstitial lymphoid aggregates with no demonstrable lymphoma or plasma cell neoplasm. She developed left upper quadrant abdominal pain and computed tomography scan showed splenomegaly measuring 14.5 cm with 2 infarcted regions with no lymphadenopathy or hepatomegaly. She underwent splenectomy with gross examination showing red pulp hyperplasia and an infarct. Microscopic evaluation showed red pulp hyperplasia due to cords of Billroth expanded by a lymphoid infiltrate and dilated sinusoids. The white pulp showed atrophy. There were also nonnecrotizing granulomas throughout the spleen. Flow cytometry showed a monotypic B-cell population (accounting for 33.8% of all nucleated cells) that was CD45+ (dim), CD19+, CD20+, FMC7+, CD5−, CD10−, CD11c+, CD23−, CD25−, CD43+, CD103−/+, and κ+. Immunohistochemistry showed these lymphocytes were annexin-A1 negative with a 20% to 30% proliferation index. Extracted DNA from the residual flow cytometry specimen showed a weak signal for BRAF V600E mutation by AS–polymerase chain reaction assay. We propose that BRAF mutation is not exclusive to hairy cell leukemia and further studies are needed.
Plasmablastic Lymphoma Centered in the Epididymis: A Rare Presentation With Excellent Treatment Effect: (Poster No. 130)
Plasmablastic lymphoma (PBL) is a rare and aggressive variant of diffuse large B-cell lymphoma. It was initially described and is usually found in the oral cavity of patients with human immunodeficiency virus (HIV). More recently, extraoral PBL has been reported in both HIV-positive and HIV-negative patients. We report a rare case of PBL centered within the epididymis of a 37-year-old HIV-positive man with excellent response to treatment. Our patient presented with pain and swelling of the left testicle. Imaging studies demonstrated an enlarged left testicle with heterogeneous echo pattern. Extensive bilateral retroperitoneal lymphadenopathy was also noted but no focal testicular mass was seen. The patient underwent an orchiectomy. Grossly, a 7.0-cm well-defined mass was identified, centered within the epididymis. Microscopically, the mass showed a large cell lymphoma with plasmacytic differentiation. The malignant cells were positive for CD138 and negative for CD20, calretinin, epithelial markers, and HHV-8. In situ hybridization detected the presence of Epstein-Barr virus within the tumor cells. More than 90% of the tumor cells were positive for Ki-67. Molecular studies revealed positivity for MYC-IGH (t 8:14) translocation. The patient received 6 cycles of DA-EPOCH (dose-adjusted etoposide/prednisone/vincristine/cyclophamide/doxorubicin) in addition to intrathecal chemotherapy for CNS prophylaxis. Literature review shows poor prognosis associated with MYC/IGH gene rearrangement; however, our patient is responding well to the treatment. This case illustrates that PBL should be included in the differential diagnosis for masses of the epididymis, and contrary to the previous reports, more aggressive treatment may provide patients with greater survival.
Marked Lymphocytosis in Hairy Cell Leukemia: Need for Caution When Diagnosing Variant Hairy Cell Leukemia: (Poster No. 131)
Hairy cell leukemia (HCL) is an uncommon B-cell neoplasm usually presenting with pancytopenia, splenomegaly, and rare circulating neoplastic cells with cytoplasmic projections. These cells express CD103, CD25, and CD11c and show a BRAF V600E mutation. An infrequent subtype of HCL termed variant hairy cell leukemia (HCLv) presents with lymphocytosis, unmutated BRAF, poor prognosis, and is resistant to conventional therapy. Differentiating between the two is essential for effective treatment and predicting disease outcome. We present an unusual case of a 33-year-old man with left upper quadrant pain who was diagnosed with classical HCL with lymphocytosis. Workup revealed a white count of 91 000/μL, hemoglobin of 7.3 g/dL, and platelets were 39 000/μL. Imaging revealed splenomegaly, and peripheral blood flow showed CD11c, CD25, and CD103-positive cells. This led to a diagnosis of HCL, and a subsequent bone marrow biopsy showed 90% marrow involvement by HCL. Owing to his atypical presentation with lymphocytosis, HCLv was suspected and rituximab was started. However, a BRAF mutational analysis came back positive for V600E mutation, leading to a diagnosis of classic HCL. Subsequent treatment with cladribine led to a dramatic response. Currently, the patient is following up on an outpatient basis, had a recent WBC count of 4.3/μL, and his splenomegaly has resolved. With sparse reports of such an atypical presentation of classic HCL, our case highlights the need for caution while diagnosing HCLv and lays the case for faster turnaround time for BRAF mutational analysis for effective treatment of classic and variant HCL.
Epstein-Barr Virus–Associated Mucocutaneous Ulcer: (Poster No. 135)
Epstein-Barr virus (EBV) is known to be associated with B-cell lymphoproliferative disorders. However, EBV-positive mucocutaneous ulcer (EBV-MUS) is a recently described entity observed in immunocompromised individuals. EBV-MUS are aggressive-appearing ulcerated lesions seen in the skin, oral cavity, and gastrointestinal tract. They have Hodgkin-like features with a self-limited, indolent course, generally responding well to conservative management. We present a case of EBV-MUS recently encountered in a 53-year-old renal transplant recipient. She had persistent rectal pain and bleeding for 2 years after hemorroidectomy. An anodermal large ulcer with excoriation and granular margins was noted on examination, and an initial biopsy from the lesion was inconclusive. A repeated biopsy demonstrated ulcerated squamous and colonic mucosa with a polymorphic lymphoid infiltrate in the submucosa that contained large atypical cells. The large atypical cells were positive for PAX-5, CD30, and weakly positive for CD20 by immunoperoxidase stains and demonstrated EBV-encoded small RNA by in situ hybridization. EBV-MUS is a recently described occurrence in transplant patients, and awareness of this entity is necessary for appropriate diagnosis and treatment.
Primary Splenic Follicular Lymphoma With Unusual Presentation: Case Report and Review of the Literature: (Poster No. 136)
Primary splenic lymphoma (defined as restricted to the spleen and hilar lymph nodes) is a rare malignancy accounting for less than 1% of non-Hodgkin lymphomas. Primary follicular lymphoma comprises only 5% of all primary splenic lymphomas. Its classic macroscopic appearance consists of uniformly expanded white pulp nodules throughout the whole parenchyma, causing marked splenomegaly. This case report highlights a case of primary splenic follicular lymphoma in an elderly gentleman, presenting as a solitary mass. A 72-year-old otherwise healthy man had a close follow-up of a splenic mass, incidentally found on imaging. The last computed tomography of the abdomen demonstrated a normally sized spleen with a non-enhancing, low-density mass measuring 3.4 cm that significantly enlarged during the previous 6 months. An additional lesion in the left kidney was also noticed. The patient had mild normocytic anemia without any peripheral lymphadenopathy or other extranodal sites of involvement. The splenectomy showed a well-demarcated mass composed of expanded back-to-back follicles. By immunohistochemical analysis, the neoplastic germinal centers were uniformly positive for CD10, CD20, bcl-2, and bcl-6. A κ-restricted CD10+ B-cell population was found by flow cytometry. Histologically, the mass was predominantly low grade with 25% of high-grade 3A follicular lymphoma. No diffuse areas of large cell lymphoma were present. Primary splenic lymphoma is a rare condition for which classification is frequently challenging. Review of the literature revealed that fewer than 100 cases of primary follicular lymphoma have been reported, with just a few cases presenting as a single lesion. Splenectomy offers both definitive histologic diagnosis and therapeutic resolution.
Transient Monosomy 7 in a Chronic Myelogenous Leukemia Patient During Nilotinib Therapy: (Poster No. 137)
Withdrawn.
Therapy-Related Acute T Lymphoblastic Leukemia: Report of 2 Cases: (Poster No. 138)
Acute leukemia arising as the result of prior cytotoxic therapy is considered therapy related and includes therapy-related acute myeloid (t-AML) and lymphoblastic leukemia (t-ALL). t-AML, the most common form, is well characterized clinicopathologically and cytoge-netically; however, t-ALL remains poorly understood owing to rarity of this disease. Moreover, t-ALL with T-cell phenotype (t-T-ALL) is much rarer than t-ALL with B-cell phenotype (t-B-ALL) with only sporadic cases reported. Here we describe clinical, cytogenetic, and immuno-phenotypic characteristics of 2 cases of t-T-ALL. Patient 1 was a 37-year-old woman who developed t-T-ALL with central nervous system (CNS) involvement 1 year after chemotherapy and radiation for breast cancer. Flow cytometry revealed lymphoblasts that were CD45+, CD2+, CD3 dim+, CD7+, CD8+, CD5 dim+, CD10+, CD117+, CD34−, and nTdT–. Cytogenetically, lymphoblasts harbored t(4:14)(q35;q24). She was treated with CALGB 19802 followed by maintenance therapy. She had a relapse after a year and died despite hyper-CVAD treatment. Patient 2 was a 69-year-old man who developed t-T-ALL with CNS involvement 8 years after adjuvant chemotherapy for colon cancer. Lymphoblasts were positive for CD3, CD10, and CD99 without expression of TdT, CD34, CD4, or CD8. Cytogenetics revealed a complex karyotype with hypoploidy. He was treated with hyper-CVAD with no response and died within 10 months. t-T-ALL is an extremely rare entity with a potentially inferior outcome compared to that of de novo T-ALL. Although recurrent cytogenetic abnormalities have been identified in t-AML and t-B-ALL (ie, MLL gene rearrangement), more case reports and larger scale studies are warranted to understand the molecular background of t-T-ALL.
Variability of Mean Corpuscular Hemoglobin Content in Hemoglobin SC Disease: (Poster No. 146)
Context: Contradictory reports indicate the mean corpuscular hemoglobin content (MCHC) is within the reference range or is elevated in hemoglobin SC disease.
Design: We interpreted high-performance liquid chromatograms from the Bio-Rad Variant II to identify patients with hemoglobin SC and included only those with simultaneous complete blood cell counts (CBCs), using the Bayer Advia 2120, an analyzer that measures the MCHC directly. We also reviewed medical literature for widely used MCHC reference ranges and excluded those patients with recent transfusions, those who were younger than 12 years, or those who were treated with hydroxyurea. If patients had repeated procedures, we used the first chromatogram and CBC results during the 12 study years.
Results: Of 471 SC chromatograms examined, 285 were excluded as 18 indicated recent transfusions; 12 had hemoglobin F > 5.2; 42 were from children younger than 12 years; 74 were not associated with a simultaneous CBC; and 139 were repeated studies. The 186 SC patients included ranged in age from 14 to 80 years, consisted of 79 males and 107 females, and their MCHC varied from 30.6 to 37.2 pg. Based on our reference range cutoff of 35.5 pg, 10.8% had elevated MCHC values. Other widely used MCHC cutoffs of 35.0, 35.7, and 36.0 pg resulted in 24.7%, 8.6%, and 5.4%, respectively, of values that were elevated.
Conclusions: MCHC is elevated in a small percentage of patients when meticulous exclusion of patients for influences on CBC results occurs. Hemoglobin SC is a valuable CBC parameter and should be considered along with hereditary spherocytosis as a cause of elevated MCHC.
Flow Cytometric Characteristics of Thymocytes in Adenoid Tissue: Comparison to Normal Thymus and Thymoma: (Poster No. 149)
Flow cytometric analysis of secondary lymphoid tissue is a common approach to rapid diagnosis in suspected cases of lymphoproliferative disorders. In the absence of histomorphology, flow cytometric analysis of lymphoid tissue can be challenging, especially for the inexperienced pathologist. The presence of normal thymocyte precursors in adenoid tissue of children has previously been described. In evaluation of these tissues, a clear understanding of normal thymocyte differentiation is key to recognizing these normal cells when present. We report the case of a 3-year-old child who had a cardiac transplant and subsequent adenoidectomy owing to suspicion of posttransplant lymphoproliferative disease. The analyzed sample consisted predominantly of mature T- and B-cell subsets typical for secondary lymphoid tissue and without evidence of PTLD. A small population of CD45-dim cells was also noted. On further analysis, the CD45-dim population consisted of a CD7-bright, CD10+, CD34+ cell population showing acquisition of CD4 followed by CD8. Within the brighter CD45+ lymphocytes, a second population of CD3−, CD4+, CD8+, CD10+thymocytes and a similarly sized population exhibiting dual CD4 and CD8 expression with acquisition of low-density CD3 were identified. By comparison to normal thymic tissue and thymoma, the pattern of differentiation observed was characteristic for normal, early thymocyte maturation. We demonstrate here the normal phenotypic patterns of early thymocyte maturation observed in thymus, thymoma, and adenoid tissue to facilitate correct flow cytometric interpretation in the evaluation of these tissue types.
ZAP70-Related Severe Combined Immunodeficiency Initially Diagnosed as Incomplete (Atypical) Kawasaki Disease: (Poster No. 153)
ZAP70-related severe combined immunodeficiency (ZAP70-related SCID) is a cell-mediated immunodeficiency characterized by absent or extremely low CD8+ T-cell counts and abnormal T-cell receptor signaling. This form of SCID is relatively rare with fewer than 30 cases currently described in the literature and typically presents in infancy with recurrent opportunistic infections, failure to thrive, and diarrhea. This report describes a case of ZAP70-related SCID that was initially diagnosed as incomplete (atypical) Kawasaki disease. A 7-month-old infant presented with 2 weeks of fever, leukocytosis (33.5 K/μL), and anemia. No infectious etiology was identified and clinical presentation along with laboratory workup suggested incomplete Kawasaki disease. The patient was treated with a single infusion of IVIG and 72 hours of high-dose aspirin with resolution of fever. Seven months later, the patient presented again with 3 weeks of fever, persistent leukocytosis, failure to thrive, and varicella infection following vaccination. During his hospital evaluation, flow cytometric analysis conducted to evaluate for the presence of hematologic malignancy revealed nearly absent CD8+ T cells with a CD4+/CD8+ ratio of 40:1. Subsequent testing demonstrated the absence of ZAP70 expression on CD3+ and CD56+ cell populations. Additionally, CD45+ total lymphocyte proliferative response to mitogens and antigens was absent to markedly decreased. The patient was diagnosed with ZAP70-related SCID and referred for further evaluation and potential bone marrow transplant.
A Unique Case of Myeloid Sarcoma Presenting as Multiple Lesions in the Lung: (Poster No. 155)
Myeloid sarcoma is a rare hematopoietic neoplasm of immature myeloid cells that occurs in extramedullary sites, most frequently the bone, skin, and lymph node. We report a case of a 65-year-white man with multiple comorbidities who presented to an outpatient clinic with concerns of shortness of breath, night sweats, and malaise for the last month. After an initial trial of antibiotics, he returned to the clinic with no improvement. A chest radiograph revealed significant tumor burden in his right chest. A follow-up computed tomography revealed numerous pleural and parenchymal-based lung nodules, including a large nodule in the right base. In addition, a large right renal mass was identified. The lung lesions were believed to be metastatic disease. The pleural lesions were biopsied transbronchially and after a series of stains were reviewed, it was signed out as poorly differentiated carcinoma. A week later, the renal mass was removed and a right thoracotomy was performed. The renal mass was a renal cell carcinoma. The thoracotomy specimen was received as multiple specimens each showing a poorly differentiated malignant neoplasm. Flow cytometry was performed that revealed a phenotypically unusual myelomonocytic population, suggestive of myeloid neoplasm. A subsequent panel of stains revealed positivity for CD68, focal pancytokeratin staining, and other negative stains. The case was signed out as a myeloid sarcoma. This is an unusual presentation of myeloid sarcoma as multiple lung lesions with aberrant staining for pancytokeratin, presenting in a man with a second unrelated primary.
Relapsed Acute Megakaryocytic Leukemia Presenting as a Dural Mass: (Poster No. 159)
Acute megakaryocytic leukemia is a rare subtype of acute myeloid leukemia evolving from primitive megakaryoblast. Acute megakaryocytic leukemia can be curable with a combination of chemotherapy and stem cell transplant. We report an unusual case of acute megakaryocytic leukemia relapsing as an isolated dural mass with no evidence of bone marrow and/or peripheral blood involvement. A 64-year-old woman with a history of acute myeloid leukemia presented with headache and concerns of progressive right-sided facial pain. The patient was initially diagnosed with acute myeloid leukemia with megakaryoblastic features in 2012 on the basis of bone marrow biopsy. She received multiple cycles of chemotherapy followed by a matched unrelated donor allogenic stem cell transplant in October 2013. Recently, the patient began experiencing progressive headache and right-sided facial pain. Radiologic studies were performed that revealed a dural mass along the right petrous apex and extension into the region of Meckel cave. She subsequently had a craniotomy, and a debulking surgery was performed. Histologic examination demonstrated diffuse infiltration of malignant cells with enlarged nucleus, open chromatin, and medium amount of cytoplasm in association with area of crushed artifact. Immunohistochemical stains revealed positive staining of malignant cells for CD45, CD34, CD117, CD33, and CD61. The stain for Ki-67 showed high proliferation rate (60%–70%). The malignant cells were negative for PAX-5, CD20, CD3, pankeratin, and HMB-45. The stain for vimentin was positive in stromal cells and fibrosis. These immunostains supported the above-stated final diagnosis. This case report suggests dural metastasis should be considered in hematologic malignancies.
Primary Adrenal Diffuse Large B-Cell Lymphoma: (Poster No. 161)
An 86-year-old man with a past medical history of hepatocellular carcinoma, clear cell type (2013) was found to have bilateral adrenal masses (left: 9.3 cm; right: 3.3 cm) on computed tomography (CT) scan concerning for metastatic disease. A CT-guided core-needle biopsy of the left adrenal mass showed sheets of tumor composed of large cells with prominent nucleoli. Immunohistochemistry revealed the tumor cells were positive for CD20, MUM-1, and Bcl-6 (30%), while negative for S100, AE1/AE3, CD3, Hep Par, Bcl-1, CD10, synaptophysin, chromogranin, and inhibin. The Ki-67 labeling index was approximately 90%. In situ hybridization for EBER was negative. Fluorescence in situ hybridization cytogenetic studies for IGH/BCL2 fusion, rearrangement of the BCL6 (3q27) locus, and rearrangement of the MYC (8q24) locus were negative. A whole-body positron emission tomography/CT scan revealed hypermetabolic bilateral adrenal masses with no lymphadenopathy. The radiographic imaging, histologic features, immunoprofile, and molecular findings were consistent with primary adrenal diffuse large B-cell lymphoma. Primary adrenal lymphoma (PAL) is an extremely rare subtype of extranodal non-Hodgkin lymphoma with fewer than 100 cases reported in the last 40 years. PAL presents with bilateral adrenal masses in 70% of the documented cases and can result in adrenal insufficiency. Although rare, in the setting of bilateral adrenal masses, primary extranodal B-cell lymphoma should be considered in the differential diagnosis owing to the dramatic change in treatment.
A Fatal Case of Hemophagocytosis Associated With Still Disease: (Poster No. 162)
We report the case of a 34-year-old woman with a prolonged history of vague arthralgia associated with fever and recurrent lymphadenopathy for which a lymph node excisional biopsy is described below. Within a couple of months, she developed systemic illness associated with fever of unknown origin that at the time was diagnosed as Still disease. She ultimately died of her disease 1 year later. Her autopsy showed widespread evidence of hemophagocytosis along with skin ulceration resembling Stevens-Johnson syndrome. Microscopically, the enlarged sampled lymph node showed a paracortical and interfollicular expansion composed of small lymphocytes, interdigitating dendritic cells, and pigment-laden macrophages. CD3 and CD5 highlighted a predominant T-cell population consisting of mostly CD8+ T cells. CD20 and CD21 highlighted the compressed follicles with BCL-6–positive and BCL-2–negative germinal centers. A CD34+ nonarborizing vascular proliferation was seen. Epstein-Barr virus by in situ hybridization was negative. Flow cytometry showed a predominant T-cell population with an inversed CD4 to CD8 ratio; no other immunophenotypic aberrancies were noted. Molecular studies were negative for B- and T-cell rearrangement. At the time, this was described as an atypical reactive lymphoid proliferation. In retrospect, the findings may represent an early immunoproliferative disorder due to chronic inflammation or alternatively, early systemic hemophagocytosis.
De Novo Isolated Splenic Myeloid Sarcoma Masquerading as Mesenteric Artery Occlusion–Associated Acute Abdomen: (Poster No. 163)
Myeloid sarcoma is a tumor mass composed of immature myeloid cells occurring at extramedullary sites. Myeloid sarcoma is a rare disease and is unique as an isolated de novo splenic process. We report the case of a 41-year-old man with a past medical history of pancreatitis who was admitted for acute abdominal pain. Radiologic studies revealed acute mesenteric ischemia with splenic infarct. He underwent a thrombectomy and splenectomy. At that time, the patient's complete blood count revealed minimal leukocytosis with increased monocytes and normal complete biochemical tests. Histologic examination of the submitted tissue (spleen, accessory spleen, and clot section of the mesenteric artery) identified an atypical myelomonocytic infiltrate expressing lysozyme, CD68, CD163, CD4, CD14 (variably dim to positive), and myeloperoxidase (subset population). Concurrent bone marrow examinations revealed a normocellular bone marrow with trilineage maturation. Cytogenetic studies performed on bone marrow aspirate revealed a normal male karyotype with no evidence of an acquired clonal abnormality, and fluorescence in situ hybridization analysis showed no evidence of t(8;21) or inv(16) or aberrations associated with chromosome 5, 7, or 13. Therefore, we present a unique case and, to the best of our knowledge, this is the first reported case in the literature of an isolated splenic myeloid sarcoma with associated mesenteric artery occlusion without bone marrow involvement. This case highlights the rarity, diagnostic challenges, and vague clinical symptoms that a myeloid sarcoma can present within its vast repertoire of pathogenesis.
Developing Best Practice Guidelines Improves Utilization and Decreases Expense of Immunophenotyping of Lymphoproliferative Disorders in Peripheral Blood: (Poster No. 166)
Context: Because many peripheral blood (PB) requests were deemed poor choices for flow cytometry (FC), we explored whether the recommendation of best practice guidelines (BPGs) would improve the selection of cases submitted for FC studies.
Design: As baseline, 2 months of consecutive cases of PBFC (n = 105) were reviewed by a staff pathologist for clinical appropriateness. Fifty-six (53%) of the outcomes were negative for lymphoproliferative disorders (LPDs) and occurred with absolute lymphocyte count (ALC) < 5.0 K/μL, age <50 years, or no history of LPDs. We developed BPGs that included the following: (1) PBFC is indicated if ALC > 5 K/μL in patients >50 years old, with history of LPD regardless of age, or presence of abnormal lymphocytes; (2) PBFC is not indicated if ALC < 5K/μl, or age <50 years, unless either abnormal lymphocytes or history of LPD is present. The BPG memo was sent to ordering providers by e-mail and mail in mid-November. Subsequently, 2 months of consecutive cases (n = 73) were collected to study the BPG impact on utilization.
Results: These data showed a 46% reduction of total samples submitted and 25% reduction of improper orders.
Conclusions: Dissemination of BPG influenced provider behavior to both (1) reduce the number of PBFC orders and (2) shift the case selection in the direction of proper clinical indications. We estimate that this could save more than $120K of expenses annually.
Histiocytic Sarcoma of the Adrenal Gland: (Poster No. 167)
Histiocytic sarcoma (HS) is an exceedingly rare hematopoietic malignancy that shows morphologic and immunophenotypic features similar to those of mature tissue histiocytes. Extranodal presentation is frequent, most commonly gastrointestinal tract, skin, and soft tissue. Here we report a case of HS involving the adrenal gland and scalp. The patient was a 77-year-old man whose past medical history was significant for radiation therapy to the scalp for treatment of pruritus associated with a burn at the age of 18 months. He presented with a 4.0-cm scalp lesion at the site of radiation. Imaging studies revealed a rapidly enlarging left adrenal mass that increased from 1.2 to 8.0 cm in 2 months. He underwent excision of the scalp lesion and computed tomography–guided biopsy of the adrenal mass. Microscopically, both lesions were similar and composed of sheets of polygonal cells with pale, glassy, pink cytoplasm with marked nuclear pleomorphism and prominent nucleoli. Immunophenotypically, these cells expressed histiocytic markers CD68, CD163, and CD14, and also were positive for CD45 and CD4, but negative for a battery of markers of other origins. Given his poor performance status, the patient was given the options of medical oncology evaluation and hospice, and was then lost to follow-up. To our knowledge, this was the second reported case of adrenal HS, and HS has not been recorded at the site of radiation in the literature. This case raises the possibility of radiation as the inducement of HS, as is the case with other radiation-induced sarcomas that typically have a prolonged latency period.
Thrombocytosis in a Patient With Acute Promyelocytic Leukemia During All-Trans Retinoic Acid Treatment: (Poster No. 170)
A patient with acute promyelocytic leukemia treated with all-trans retinoic acid, arsenic trioxide, and idarubicin developed marked thrombocytosis starting treatment day 28 (700 × 109/L). Bone marrow biopsy showed marked megakaryocytic hyperplasia with clustering and sheeting, as well as focal reticulin fibrosis. The thrombocytosis was transient, recovered after day 45 and without complication. Transient thrombocytosis has been previously reported in patients with all-trans retinoic acid treatment. The mechanism is not well understood. All-trans retinoic acid has been recently shown to directly upregulate thrombopoietin transcription in human bone marrow stromal cells, and elevated thrombopoietin level has been reported in some patients. Our case supports the concept that thrombocytosis in all-trans retinoic acid–treated patients is reactive and results from enhanced megakaryopoiesis.
Monotypic B-Cell Population and Chromosomal Aberration in Histologically Benign Lymph Node: (Poster No. 171)
A light-chain–restricted B-cell population historically has been considered a marker of malignancy. However, it can be seen in nonneoplastic B-cell proliferations. Our case demonstrates an association of lymphoid hyperplasia with a monotypic B-cell population and gain of chromosome 18q21. A 14-year-old boy presented with a 3-cm submandibular lymph node 6 weeks after an upper respiratory tract infection. Computed tomography/positron emission tomography scan revealed cervical lymphadenopathy of nonneoplastic-range uptake. The lymph node showed prominent follicular hyperplasia. Follicles varied in size and shape, and were composed of variously sized lymphocytes with admixed tingible body macrophages, typical of reactive germinal centers. Rare follicles showed a more monotonous population of larger cells with round to slightly irregular nuclei. Flow cytometry detected a minor population (13%) of λ light-chain–restricted, medium to large B-cells coexpressing CD10 and negative for CD5/CD23. Fluorescence in situ hybridization analysis revealed a gain of chromosome 18q21, targeted by a BCL2 probe, in 11% of nuclei. Although the monotypic population raised the possibility of pediatric follicular lymphoma, the limited size of this population, combined with typical reactive morphology in the bulk of the lymph node, was not supportive of such an entity. A diagnosis of atypical hyperplasia with progressive transformation of germinal centers was confirmed by an outside consultant. Cases of benign clonal B-cell proliferation have been described. They commonly occur in boys and do not progress to a frank lymphoma. This phenomenon may reflect the emergence of a restricted B-cell clone due to exaggerated normal oligoclonal germinal center response.
Mantle Cell Lymphoma Involving the Pituitary Gland: (Poster No. 173)
A 71-year-old woman with history of carotid stenosis, hypertension, hyperlipidemia, aortic stenosis, and hypothyroidism was transferred from an outside hospital for further management of newly diagnosed pituitary macroadenoma. The patient noticed vision changes 2 month before admission. She had a history of mantle cell lymphoma originally diagnosed in 2009 with recurrence in 2012, status post chemotherapy. As magnetic resonance imaging revealed a sellar mass involving the pituitary gland and infundibular stalk, the patient underwent an immediate transsphenoidal decompression surgery. Surgical biopsy from the pituitary lesion showed proliferation of atypical lymphocytes in diffuse sheets with areas of crush artifacts involving the pituitary gland. The atypical lymphocytes were small with scant cytoplasm, irregular nuclear contour, clumped chromatin, and occasional inconspicuous nuclei. The atypical lymphocytes were positive for CD20 (diffuse and strong), CD5, CD23, and BCL-1 while negative for CD3. Ki-67 showed an average nuclear proliferation index in the range of 10% to 20%. Corresponding flow cytometry revealed a surface λ clonal B-cell population (~27% of total) expressing CD19, CD20 (bright), and CD22, coexpressing CD5 with heterogenous expression of CD23. Cells were negative for CD10 and TdT. The present report describes an extremely rare case of mantle cell lymphoma with involvement of the pituitary gland. Lymphoma infiltration to the pituitary is difficult to differentiate from pituitary adenoma, meningioma, and other sellar lesions. Hypopituitarism may be the presenting symptom of lymphoma in the absence of associated overt symptoms or signs of a hematologic malignancy, resulting in delay in diagnosis and prompt initiation of definitive therapy.
Enteropathy-Associated Lymphoma With NK-Cell Immunophenotype: (Poster No. 174)
NK-cell lymphomas are a heterogeneous group of tumors, many of which occur in the nasopharyngeal region and are associated with the Epstein-Barr virus (EBV). However, they can also appear in nonnasal sites such as gastrointestinal tract, skin, and testis. Here we report a rare case of EBV-negative enteropathy-associated NK-cell lymphoma (CD5−/CD56+ T-cell receptor silent peripheral T-cell lymphoma) of the gastrointestinal tract proven by immunophenotype and gene rearrangement studies. The patient is a 24-year-old man who presented at an outside hospital with progressively worsening diarrhea, nausea, and vomiting and was diagnosed there as having enteropathy-associated T-cell lymphoma (based on immunohistochemistry and morphology) and given CHOEP chemotherapy regimen without significant resolution of his symptoms. He came to our institution for a reevaluation. Esophagogastroduodenoscopy with biopsies were repeated. Immunophenotypic analysis by flow cytometry demonstrated a predominant neoplastic population with NK-cell immunophenotype: surface CD3−, CD56+, CD103+, CD2−, CD5−, CD7+, CD4−, and CD8−. The results of T-cell γ and β gene rearrangement studies were negative. The patient's treatment was switched to SMILE and GELOX chemotherapy regimens with significant resolution of symptoms. This case demonstrates that T-cell gene rearrangement studies and flow cytometry are extremely critical to differentiate rare enteropathy-associated NK-cell lymphoma from T-cell lymphoma. Relying on immunohistochemistry can lead to misdiagnosis and mistreatment.
Transient Monosomy 7 in a Chronic Myelogenous Leukemia Patient During Nilotinib Therapy: (Poster No. 176)
Monosomy 7 is a common chromosome abnormality in myeloid malignancies, particularly myelodysplastic syndrome and acute myeloid leukemia. Monosomy 7 has been described in Philadelphia-negative cells in chronic myelogenous leukemia (CML) patients taking tyrosine kinase inhibitors (TKIs) with variable outcomes. We report the case of a CML patient receiving nilotinib who achieved complete remission and was found to have a transient monosomy 7 clone. A 54-year-old man who initially presented with splenomegaly was diagnosed with CML. The conventional karyotype showed t(9;22;19)(q34;q11.2;q13.1) in all 20 metaphases. Fluorescence in situ hybridization revealed BCR/ABL1 fusion in 94.2% of nuclei. No other cytogenetic abnormalities were found at that time. He was given nilotinib. His course was complicated by severe pancytopenia, thus the nilotinib dose was decreased. After 25 months of treatment, he achieved complete hematologic and cytogenetic remission. However, monosomy 7 was found in 15 of 20 metaphases without any evidence of his known CML clone, suggesting the emergence of an unrelated clone. No overt dysplasia was identified in the bone marrow biopsy except for the presence of occasional small megakaryocytes. The patient continued to receive nilotinib with close follow-up. Repeated bone marrow biopsy 5 months later showed no significant morphologic changes, with monosomy 7 detected in only 6 of 20 metaphases. One year later, the monosomy 7 clone had completely disappeared. This case illustrates that monosomy 7 can be a transient finding in CML patients receiving TKI treatment, and that it is not an absolute indication of the emergence of a new myeloid malignancy.
A Case of Pre–B Acute Lymphoblastic Leukemia With Marked Eosinophilia: (Poster No. 178)
Acute lymphoblastic leukemia (ALL) with eosinophilia is extremely rare. A 30-year-old man presented with shortness of breath, night sweats, and 20-lb weight loss. Complete blood cell count (CBC) showed severe eosinophilia (white blood cell count [WBC], 77 000/μL; 80% eosinophils). The subsequent bone marrow biopsy revealed hypercellular marrow (cellularity 90%), M:E ratio of 7:1, marked increase in eosinophils, and no increase in blasts. Flow cytometry and chromosomal analysis of peripheral blood and bone marrow were unremarkable. The patient was treated with steroids and imatinib with good response but was lost to follow-up. Three months later, the patient was hospitalized owing to increased shortness of breath, sore throat, and joint pain. CBC showed WBC of 274 000/μL with 97% eosinophils. Repeated bone marrow biopsy showed blasts infiltrating 50% of marrow. The blasts expressed TdT, CD10, CD20, and CD79a, but were negative for MPO and lysozyme, indicating pre–B ALL. Cytogenetic studies failed to reveal any abnormalities by FISH and karyotyping. The patient developed respiratory failure and died. Autopsy revealed widespread dissemination of leukemia with eosinophilic infiltration involving heart, lung, and kidneys. The cause of death was announced as sepsis. FISH studies with 5q and 14q probes performed on infiltrative blast in kidney showed only unbalanced translocation of 14q. ALL presenting with severe eosinophilia is a rare entity. Eosinophilia can precede the diagnosis of ALL by 1 to 9 months. Absence of reactive eosinophilia should prompt evaluation of primary eosinophilia with recurrent molecular abnormalities including rearrangement of 4q12 (PDGFRA), 5q31-q33 (PDGFRB), and 8p11-13 (FGFR1). Early recognition of ALL with eosinophilia will lead to prompt treatment and alleviate the complications of eosinophil toxicity.
Mixed Phenotype Acute Leukemia, T/Myeloid: Bilineal or Unilineal?: (Poster No. 179)
A 51-year-old man presented with sore throat, anemia, thrombocytopenia, and leukocytosis with increased blasts. Bone marrow examination revealed 84% blasts with heterogenous morphology (ranging from small blasts with high nuclear to cytoplasmic ratio to large blasts with prominent nucleoli and generous cytoplasm). Immunophenotyping by flow cytometry demonstrated 2 blast populations. Both populations were positive for the following surface markers: CD34, HLA-DR, CD13, CD33 (partial and weak), CD71, CD117, CD2, CD7, and CD11b. Approximately 85% of these blasts expressed cytoplasmic CD3 and 15% expressed cytoplasmic MPO. B-lineage markers were negative. This leukemia met World Health Organization criteria for mixed phenotype acute leukemia (MPAL), T/myeloid. The WHO describes MPAL as “bilineal” because 2 subpopulations of blasts are recognized by flow cytometry. Cytogenetic testing revealed normal male karyotype. Next-generation sequencing identified WT1 and FLT3 ITD mutations both associated with acute myeloid leukemia (AML) and MPAL. Other common AML and T–acute lymphoblastic leukemia (TALL)–associated mutations were negative. The patient underwent TALL induction chemotherapy. There is growing evidence supporting the relationship between T-cell and myeloid development, suggesting either a common precursor or a lymphoid precursor with reactivation of a myeloid differentiation program. The flow cytometric findings and the AML-associated genetic abnormalities support the aforementioned hypothesis. This brings into question the traditional treatment of these patients with ALL regimens followed by allogeneic stem cell transplant. Given the unique biology and poor prognosis associated with the MPAL T/myeloid group, there is an urgent need for new tailored therapeutic strategies for the treatment of this disease.
Angioimmunoblastic T-Cell Lymphoma Presenting With Skin Rashes With Associated Monoclonal Plasmacytic Proliferation: (Poster No. 180)
A 54-year-old man presented with skin rashes. Physical examination found generalized lymphadenopathy. Peripheral blood showed atypical lymphocytosis. Immunohistochemistry, in situ hybridization, flow cytometry, and polymerase chain reaction (PCR) gene rearrangement studies were performed to characterize the skin, lymph node, and bone marrow biopsies. Skin biopsy showed prominent perivascular lymphoplasmacytic infiltration extending to the dermis and deep subcutaneous adipose tissue without epidermotropism. The lymphoid cells were small to medium sized with irregular nuclei, inconspicuous nucleoli, and moderate clear cytoplasm. By immunohistochemistry, more than 90% lymphoid cells were CD3+ T cells. The prominent plasma cells were highlighted by CD138 with κ light-chain restriction. Both T-cell and B-cell receptor gene rearrangements were demonstrated by PCR. A lymph node biopsy showed architecture effacement. Blood vessels were focally associated with sheets of atypical small to medium lymphoid cells, similar to the skin. They were positive for CD3, CD4, CD7, PD-1, and CXCL-13; a subset was positive for CD10. Occasional EBER-positive cells were revealed by in situ hybridization. CD21 highlights accentuated follicular dendritic networks encasing postcapillary venules. Flow cytometry showed CD4+T lymphocytosis. No bone marrow involvement was identified by immunohistochemistry and gene rearrangement study. The morphologic and immunopathologic findings were diagnostic for angioimmunoblastic T-cell lymphoma. When evaluating lymphoid infiltrate with plasma cells, angioimmunoblastic T-cell lymphoma should be included in the differential diagnosis even when light-chain restriction is present.
Green Neutrophilic Inclusions and Acute Hepatic Failure: (Poster No. 187)
Acute hepatic failure demonstrates rapid increases in serum aminotransferases and marked depression of albumin and total protein. Subsequently, serum ammonia, lactate dehydrogenase, alkaline phosphatase, and bilirubin levels dramatically increase. Peripheral blood findings include acanthocytic, spur cell anemia secondary to the marked increase in red blood cell cholesterol content and splenic destruction. Coarse, bright-green cytoplasmic neutrophilic inclusions have been previously described in the literature to have an association with acute hepatic failure. The exact nature of these inclusions has yet to be determined; it has been postulated they may be derived from biliverdin. These inclusions have been associated with impending death, usually within 24 to 48 hours. Here we describe 2 cases of acute hepatic failure, with associated bright-green neutrophilic inclusions, where both patients survived beyond the ominous 48-hour period. Our first patient is a 48-year-old woman with subacute febrile respiratory illness and mild hepatitis who developed multiorgan failure. Liver enzymes became acutely elevated; peripheral blood findings included leukocytosis with neutrophilia, granulocytic left shift with toxic granulation, and occasional green neutrophilic inclusions. The patient rapidly deteriorated and died 8 days later. Our second patient is a 67-year-old woman who presented with portal vein thrombosis and mesenteric ischemia requiring small-bowel resection. Her liver enzymes became acutely elevated, and the peripheral blood showed neutrophilia with toxic changes and rare bright-green inclusions. The patient's condition stabilized and she is still alive. To our knowledge this is the first report of patients surviving beyond 48 hours after discovery of these inclusions.
Utility of Bilateral Bone Marrow Biopsy Examination in Evaluation of Plasma Cell Myeloma: (Poster No. 190)
Context: Bilateral bone marrow biopsies are useful in staging of lymphoma and metastatic disease. There are limited data on its utility in evaluation of plasma cell myeloma. The aim of this study was to analyze bilateral biopsies from myeloma patients.
Design: Pathology reports for bilateral biopsies performed on patients with a myeloma diagnosis at our institution in 2013 were reviewed. All patients had concurrent marrow flow cytometry. Degree of marrow plasma cell involvement on each side, clinical characteristics, and treatment history were noted.
Results: Ninety-eight bilateral biopsies were performed for myeloma evaluation, of which 17 were from patients after hematopoietic stem cell transplant. Seventy-five cases (76.5%) had abnormal plasma cells by flow cytometry, while 67 cases (89.3%) included CD138 immuno-histochemistry. All cases with myeloma by morphology and/or CD138 stain had abnormal flow immunophenotype. Of cases with flow documentation of disease involvement, 7 cases (9.3%) had a discrepancy in plasma cell percentage of at least 10% between the right and left sides. Discrepancies were identified by morphology in 2 cases and by CD138 stains in 5 cases. The degree of discrepancy ranged from 10% to 65%.
Conclusions: Bilateral bone marrow biopsy evaluation identified a higher degree of myeloma involvement in one side in a subset of cases. The discrepancy rate of 9.3% is comparable to published studies on the utility of bilateral biopsies for non-Hodgkin lymphoma. Similarly, bilateral biopsies can contribute additional information to the evaluation of patients with plasma cell myeloma.
Peripheral T-Cell Lymphoma, Not Otherwise Specified, and Angioimmunoblastic T-Cell Lymphoma: A Rare Case of Concurrent T-Cell Neoplasms in a 53-Year-Old Man: (Poster No. 191)
Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), and angioimmunoblastic T-cell lymphoma (AITL) are distinct lymphoid neoplasms as classified in the 2008 World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissues. We present the case of a 53-year-old man diagnosed with both PTCL-NOS with a leukemic phase and AITL within lymph nodes. The patient presented with abdominal distension, weakness, and fatigue; he was found to have splenomegaly and lymphadenopathy. Lymph node biopsy revealed architectural effacement by small to intermediate-sized lymphocytes with interspersed large cells with prominent nucleoli and vesicular chromatin. Increased numbers of arborizing high endothelial venules were noted. Immunohistochemical stains were performed on paraffin-embedded tissue with the following positive results: CD2, CD3, CD4, CD5, and CD10. The scattered large cells were highlighted by CD30 and CD20. Decreased staining was noted with CD7 and CD8. Dim, partial PD-1 staining was also identified. Lymph node findings were compatible with involvement by AITL. Further evaluation revealed a peripheral blood leukocytosis composed of atypical lymphocytes with basophilic cytoplasm and condensed nuclear chromatin. The staging bone marrow biopsy was hypercellular, consisting primarily of atypical lymphocytes. Flow cytometric evaluation revealed the following immunophenotype: CD45, CD5, CD2, CD4, CD52, and partial CD25, CD3, CD7, and HLA-DR. The cells were negative for CD8 and CD10. The immunophenotypic and morphologic findings in the peripheral blood and bone marrow were not compatible with the concurrent lymph node diagnosis of AITL and fit more closely with PTCL-NOS. A review of the literature revealed no documented cases of concurrent PTCL-NOS and AITL.
ALK-Positive Large Cell Lymphoma With Unusual Morphology and Immunophenotype: (Poster No. 192)
Anaplastic lymphoma kinase–positive large B-cell lymphoma (ALK+ LBCL) is a rare entity. The tumor cells usually have monomorphic immunoblastic/plasmablastic morphology, are strongly positive for ALK, EMA, and CD138 but negative for lineage-associated markers and CD45. A 45-year-old man presented with 2 large paraspinal masses involving the L3–L4 and L4–L5 region, measuring up to 8.4 cm in largest dimension. Biopsy of the L4 mass showed a lymphoma composed of sheets of large anaplastic and pleomorphic cells with abundant cytoplasm and prominent nucleoli. The morphology of tumor cells varied, including immunoblast-like, centroblast-like cells and large multinucleated forms. The tumor cells were strongly positive for CD45 and positive for ALK (cytoplasmic, granular), MUM1, EMA, CD20 (subset, dim), BCL-6 (dim), PAX 5 (faintly positive, small subset), and negative for CD79a, CD138, CD10, CD30, CD3, CD4, CD5, CD68, and CD163. Corresponding 8-color flow cytometric analysis did not detect a clonal B-cell population or population of large cells. ALK fluorescence in situ hybridization analysis using LSI ALK dual-color, break-apart probe revealed loss of ALK gene region, and no ALK rearrangement. B-cell clonality study by polymerase chain reaction demonstrated IgH and IgK rearrangements. The patient received 2 cycles of RCHOP and a follow-up positron emission tomography/computed tomography showed near resolution of all sites of disease. Unusual features of this lymphoma include pleomorphic tumor cell morphology, CD138 negativity, strong positivity for CD45, and partial positivity for CD20, PAX 5, and bcl-6. Our case suggests that ALK+ LBCL may be a heterogeneous group of diseases with diverse morphology and immunophenotype.
Epstein-Barr Virus–Positive Mucocutaneous Ulcer Involving the Colon: Hodgkin or Hodgkin-like?: (Poster No. 194)
A 25-year-old woman with a longstanding history of Crohn disease treated with varying doses of prednisone and 6-mercaptopurine presented with fever, severe rectal pain, cramping, and diarrhea. A sigmoid colectomy was performed for pelvic sepsis. Histologic examination revealed chronic active colitis with deep necrotizing ulcers, granulomas, and sinus/fistula formation supporting involvement by Crohn disease. Additionally, a transmural “atypical lymphoid infiltrate” consisting of large atypical cells with “Hodgkin cell–like” morphology in a background of mixed inflammatory cells was identified. The atypical cells were positive for EBER, CD30, CD15, PAX5 (weak), OCT2, and CD25 and negative for CD19, BOB1, and CD79a. The morphology and immunophenotype were characteristic of classical Hodgkin lymphoma. In context of prior immunosuppression, localized nature of the disease process, and absence of nodal disease, this patient's Epstein-Barr virus (EBV)–positive lymphoproliferative disorder was diagnosed as “Hodgkin-like EBV+ mucocutaneous ulcer.” After 2 months of observation, the patient had complaints of severe rectal pain and her positon emission tomography scan showed activity in the rectal area. Repeated biopsy showed continued involvement. The patient was treated with local radiation. A 6-month follow-up biopsy showed resolution of the lymphoproliferative process. EBV-positive mucocutaneous ulcer involving the colon is a recently described, extremely rare entity seen in patients with inflammatory bowel disease treated with immunosuppressive therapy. The proposed etiology is a localized lapse in EBV immunosurveillance. Although this entity immunohistologically mimics classical Hodgkin lymphoma, the clinical course is indolent and most patients respond favorably to a change in immunosuppressive regimen and/or local radiation.
Concomitant Bone Marrow Involvement by Plasma Cell Myeloma and CD5+ B-Cell Lymphoproliferative Disorders: A Series of 16 Cases: (Poster No. 195)
Context: Concomitant presence of plasma cell myeloma (PCM) and CD5+ B-cell lymphoproliferative disorders (LPDs) creates diagnostic challenges, especially with shared immunoglobulin light-chain restrictions.
Design: We describe cases with simultaneous marrow involvement by PCM and CD5+ LPDs. A retrospective chart review from January 2005 to July 2014 identified 16 cases meeting these criteria. We reviewed clinical, laboratory, radiology, and pathologic findings.
Results: Most patients were older white men (median age, 72.2 years). Seventy-five percent presented with anemia, and an M protein including IgG (88%) and IgM (12%) subtypes. Lytic bone lesions were identified in 68.7%. Plasma cell infiltrates in the marrow ranged from <5% to 96% of cellularity and peripheral monotypic B-cell lymphocytosis (MBL) was identified in 56.2%. By flow cytometry, monotypic B cells aberrantly coexpressed CD5 in 87.5% of cases. Criteria for CLL/ SLL and MBL were met in 37.5% and 62.5% of cases, respectively. Most patients with CLL/SLL had lymphadenopathy with >5% marrow involvement (83.3%). Marrow involvement was <5% for PCM/MBL cases. In all cases PCM and CLL/SLL infiltrates were morphologically and immunohistochemically distinct. In 15 of 16 patients, PCM shared an immunoglobulin light-chain restriction with CLL/MBL. Cytogenetically, 50% of cases showed normal karyotypes; the remainder had PCM-associated karyotypes.
Conclusions: Concomitant presence of PCM and CD5+ B-cell LPDs creates diagnostic challenges. Stringent marrow examination and use of ancillary studies rendered accurate diagnoses in all cases. Appropriate clinical assessment remains pivotal.
Antiphospholipid Syndrome: Analysis of Dilute Russell Viper Venom Time Titer: (Poster No. 196)
Context: Antiphospholipid syndrome can be diagnosed by a persistently positive lupus anticoagulant test, such as the dilute Russell viper venom time (DRVVT), in the context of thrombosis or pregnancy morbidity. The characteristic features of the DRVVT titer are unknown.
Design: The medical record of 3660 consecutive patients with DRVVT orders were examined for criteria satisfying the diagnosis of antiphospholipid syndrome. DRVVT titer was examined for distribution of values, change in magnitude over time, and relationship with clinicopathologic features.
Results: Twenty-six patients were diagnosed with antiphospholipid syndrome on the basis of a persistently positive DRVVT and thrombosis. DRVVT titer was predominantly low magnitude (71% of specimens), of similar magnitude between initial and repeated testing (mean DRVVT titer: 1.40 versus 1.38; P = .81), and associated with the presence of anti-cardiolipin antibodies (IgG and IgM) and anti–β-2-glycoprotein I antibodies (IgG and IgM) (P =.004, P =.02, respectively). Titer was not associated with age, sex, type of thrombosis, number of thromboses, or a positive hexagonal phase phospholipid neutralization test.
Conclusions: DRVVT titer was predominantly of low magnitude, stable over time, and associated with the presence of specific types of antiphospholipid antibodies.
ABO Typing Discrepancy in a Patient With Pure Red Cell Aplasia: (Poster No. 198)
ABO typing is a 2-part test that consists of typing red cells for the presence of A and B antigens (forward type), and screening of serum or plasma for the presence of anti-A and anti-B antibodies (reverse type). An ABO discrepancy exists when the results of the forward type are incongruent with the reverse type. ABO discrepancies occur for many reasons including problems inherent to the red cells or serum or from technical errors. We report a unique case of an ABO-typing discrepancy involving a 48-year-old woman with known AB Rh-positive blood type. She was referred to our institution for evaluation and management of her pure red cell aplasia. On initial presentation she had a marked reticulocytopenic anemia with hemoglobin of 8.7 g/dL, hematocrit of 25.2%, and absolute reticulocyte number of 0.01 × 10E6/μL. Her bone marrow demonstrated erythroid maturation arrest in the marrow. During her ABO typing, the forward type showed group O red cells but the reverse type indicated group AB blood type. Investigation into the discrepancy revealed that despite the known AB Rh-positive blood type, the patient had only been transfused with group O red cells. Because of her pure red cell aplasia none of her native AB red cells were serologically detected. Pure red cell aplasia is a rare form of severe anemia caused by a severely reduced number of reticulocytes and nearly absent erythroid precursors in the bone marrow.
Early Manifestation of Coagulopathy in Pregnancy: (Poster No. 199)
Pulmonary embolism in the first trimester of pregnancy is a rare event. Although active protein S decreases in pregnancy, the intrapartum period is uneventful in most cases owing to other anticoagulant mechanisms that compensate for the decrease in this anticoagulant cofactor. We herein describe a case of a 21-year-old woman who was asthmatic and a former cigarette smoker. She presented in the 11th week of pregnancy with left-sided, nonradiating chest pressure of 2 to 3 hours' duration. She did not have a previous history of venous thrombosis. Her D-dimer at presentation was 2.6 μg/ mL. Computed tomography of the chest demonstrated a left lower lobe subsegmental pulmonary embolus. The patient was given enoxaparin 60 mg twice daily. Coagulation workup after the event revealed low protein S activity of 37% and elevated factor VIII level of 254.6%, while her postpregnancy testing demonstrated borderline low protein S activity of 60%, and normal factor VIII level of 108.5%. The present case demonstrates that a more comprehensive clinical risk assessment and prepregnancy coagulation workup may be useful in identifying women at risk for intrapartum thrombophilia, such as individuals with high factor VIII levels, both hereditary and nonhereditary protein S deficiency, as well as borderline low levels of this cofactor. The preventive strategy would allow prophylaxis and careful monitoring of similar patients during pregnancy, as well as counseling on contributing risk factors such as smoking and oral contraceptive use.
Development of Anti-e After Platelet Concentrate Transfusion: (Poster No. 202)
Platelet concentrates (PCs) are prepared from donated whole blood units by centrifugation and subsequent pooling of 4 to 6 units. Thus, PCs may contain a small amount of donor RBCs. We report a case of a 60-year-old man with a past medical history of coronary artery disease who presented to our emergency department with shortness of breath. Previous medical history indicated a recent admission, 1 month prior, to another local hospital for shock and respiratory failure. Type and screen (T/S) done at that time revealed an O+blood type with negative antibody screen. During that admission, the patient received only 5 doses of PCs (2-group O+, 2-group O−, and 1-group A−). He reported no other recent blood product transfusions at any other facility. Our current T/S, and before any transfusions, showed a positive antibody screen. A panel for antibody identification was performed. The antibody reacted with 9 of 10 reagent cells. The reactivity was predominately at room temperature and 37°C phases, indicating an IgM class antibody. Some reactivity was also seen at AHG (anti-human globulin) phase, indicating an IgG class antibody. The autocontrol was negative. Testing additional cells revealed an anti-e specificity. The patient's “e” antigen typing was performed and found to be negative, indicating that this is a true allo-antibody. Since anti-e antibody predominantly exists as an IgG immunoglobulin class antibody, the presence of IgM class reactivity suggests that this may be a newly developed antibody. This case illustrates that antibodies to RBC antigens can develop after platelet transfusion.
Neutropenia in a Newborn With Maternal-Fetal ABO Incompatibility: (Poster No. 204)
Maternal-fetal ABO incompatibility occurs in 15%–20% of all pregnancies and typically manifests as asymptomatic to mild hemolytic disease. Rarely, examination of these patients may reveal additional disease. We report the case of a 34-year-old gravida 2, para 1 mother with O–blood type who gave birth to a boy at full term with A+blood type. Although the mother was given prenatal Rhogam, the infant's Coombs test was weakly positive with maternal anti-A antibodies. Although newborns do not undergo routine blood testing at our institution, the positive Coombs test led to a complete blood cell count that demonstrated mild thrombocytopenia and severe neutropenia. A follow-up bone marrow biopsy at 18 weeks of age demonstrated decreased granulopoiesis with maturation arrest at the promyelocyte stage, consistent with severe congenital neutropenia. Genetic testing was positive for a heterozygous ELANE mutation. The patient was started on daily G-CSF treatment at 4 months of age, and has done well during the past 2 years. To the best of our knowledge, this is the second published case in which maternal-fetal ABO incompatibility prompted workup leading to the early identification of severe congenital neutropenia. When untreated, patients with severe congenital neutropenia present by 2 years of age with oral ulcerations and painful gingivitis. Other presenting symptoms include staphylococcal or streptococcal infections involving the mouth, lungs, skin, or soft tissue. Awareness of the multiple causes of neutropenia in a neonate is critical to differentiate severe congenital neutropenia from more common causes of neutropenia, including neutropenia directly related to maternal-fetal ABO incompatibility.
Massive Hemorrhage Transfusion Protocol Review: (Poster No. 207)
Context: Massive transfusion is described in trauma. However, gastrointestinal (GI), postoperative, and postpartum bleeding can all be massive. To streamline component delivery, massive hemorrhage transfusion protocols (MHTPs) are used. Continuous assessment ensures optimal care. At our center, MHTP was introduced in 2003 using an RBC:plasma of 2.5:1. It was modified in 2011 to 2:1 in response to provider requests. We report MHTP use and modification impact.
Design: Activations between September 25, 2011, and March 15, 2015, were reviewed. Analyzed data were age; sex; diagnosis; service; RBC, plasma, and platelets transfused; HCT; platelet count; INR; patient ABO/Rh; antibody screen; RBC ABO/Rh; and whether emergency release was required. Beginning May 19 , 2014, data were collected on protocol discontinuation and complaints.
Results: MHTP was activated 354 times. Median age was 60 years with 42% women. Median product use was RBC 5 U, plasma 3 U, 1 apheresis platelet. Mean RBC:plasma was 1.8:1. The most common diagnoses were GI bleed 42%, trauma 18%, AAA 9%, and obstetric bleeds 7%. Mean RBC:plasma by diagnosis: GI bleed 2.2:1, trauma 1.9:1, AAA 1.7:1, obstetric bleeds 1.2:1. In 27% of cases, no discontinuation call occurred. There was 1 delay complaint; it was determined that failure on the part of the clinicians to provide a dedicated runner of products resulted in this delay.
Conclusions: Continuous assessment of protocol effectiveness is essential to ensure optimal patient care. We will continue to solicit clinician comments on the effectiveness of activations and address concerns in a timely manner. As indicated by poor performance on protocol discontinuation, education is needed regarding discontinuing the MHTP after stabilization preventing wastage and optimizing personnel.
Patients With Platelet-Dense Granule Storage Pool Deficiency Often Have Abnormal Responses to Epinephrine in Platelet Aggregation Assays: (Poster No. 208)
Context: Platelet delta granule storage pool deficiency (δ-SPD) is an underdiagnosed condition that manifests clinically as easy bruising, mucosal bleeding, epistaxis, and, in women, menorrhagia. This is related to a decreased number of delta (dense) granules in their platelets causing platelet dysfunction. Platelet δ-SPD is considered to have a decreased response to low levels of the agonist ADP. Previous studies have demonstrated normal platelet response to ADP in aggregation studies for 20%–23% of patients known to have δ-SPD; however, other commonly used agonists used in aggregation assays to diagnose platelet dysfunction have not been reported for patients with this disorder.
Design: This retrospective study was designed to review the results of light transmittance aggregometry assays using 4 different agonists: ADP (2 concentrations), epinephrine, collagen, and ristocetin for patients diagnosed with δ-SPD.
Results: Patients included in the study (n=120) had a mean of 2.90 ± 0.15 dense granules/platelet (normal =4–6 granules/platelet). A total of 27.5% of our patients were found to have normal aggregation assays for all 4 agonists. Response to epinephrine was abnormal in 58.3% of our patients, and abnormal response to low levels of ADP was less frequent at 31.7%. Ristocetin was abnormal in 15.8%; collagen and arachidonic acid abnormalities were less frequent at 10% and 11.7%, respectively.
Conclusions: Abnormal platelet response to epinephrine in aggregation studies is more common than abnormal response to ADP in patients with δ-SPD.
Acute Liver Failure Secondary to Neonatal Hemochromatosis: (Poster No. 209)
Neonatal hemochromatosis is the most common cause of acute liver failure in the neonatal period. It is associated with high morbidity and mortality due to iron overload in hepatic and extrahepatic tissues. We report an unusual case of neonatal hemochromatosis, which was confirmed on autopsy in a 31-week-old premature baby boy who presented with progressive liver dysfunction and respiratory distress. He was born to a 38-year-old woman who had no relevant past medical or family history. Sonogram showed anhydramnios and enlarged multi-cystic dysplastic kidneys in neonate. Immediately after birth he started bleeding from intravenous sites and developed germinal matrix hemorrhage and intrapulmonary hemorrhage. Workup revealed normal WBC count with low platelet count, and increased PTT, PT, direct bilirubin, and low factor VII levels. Genetic chromosomal analysis and metabolic evaluation results were negative. The patient was started on fresh frozen plasma, cryoprecipitate, recombinant human coagulation factor VIIa, platelets, and packed red blood cells. Further laboratory workup revealed markedly elevated ferritin and α-fetoprotein levels. Magnetic resonance imaging showed signal abnormality in liver and pancreas compatible with iron deposition. He was started on intravenous immunoglobulins and exchange transfusion and liver biopsy was scheduled. Despite all medical efforts the baby did not survive. Histology examination showed marked iron deposition in multiple organs including liver, pancreas, myocardium, respiratory secretory glands, thyroid, kidneys, and adrenal glands. Neonatal hemochromatosis is a rare and severe condition of unknown etiology with extremely poor prognosis. Here, we describe a rare case of neonatal hemochromatosis with progressive liver failure and coagulopathy.
Constellation of Cardiac Anomalies in a Neonate That Hindered Proper Extracorporeal Membranous Oxygenation Cannulation: (Poster No. 3)
Congenital cardiovascular defects are the most common of birth defects and affect nearly 40 000 infants in the United States yearly. Neonates present the highest mortality rate. The patient is a 16-day-old female infant delivered at 36 weeks gestation because of nonreassuring fetal heart tones requiring resuscitation and extracorporeal membranous oxygenation (ECMO). A venous-arterial ECMO was applied. Her status did not improve, and she was pronounced dead 2 weeks later. At autopsy, the pulmonary trunk was seen to exit the right ventricle and give off small-caliber right and left pulmonary arteries, and continue with its original large caliber to meet the arch of the aorta. Its lumen at this wide ductus lies in direct continuity with the descending aorta, which assumes the same caliber. The aorta exits the left ventricle and branches normally. After exit of the left common carotid artery, the aortic arch becomes severely stenotic, and is soon joined by the pulmonary trunk. Distal to this, the left subclavian artery exits from the arch. Where the pulmonary artery/trunk enters the aorta the arch returns to large caliber and turns, to become the descending aorta. The arterial ECMO catheter tip was in the brachiocephalic trunk. The venous catheter was intended to end in the right atrium through the superior vena cava. Because of the abnormal angulation of the superior vena cava, the cannula was misplaced into the azygous vein. We report this case because the existence of anomalous vasculature posed a challenge to natural oxygenation and ECMO procedures.
Associations of Pregnancy-Associated Plasma Protein-A (PAPP-A) Levels With Essential Hypertension (EH) and Hypertensive Disorders in Pregnancy (HPD) in Chinese Population: A Meta-Analysis of 20 Research Studies Involving 3332 Individuals: (Poster No. 6)
Withdrawn.
Primary Cardiac Interatrial Leiomyoma: (Poster No. 7)
Leiomyomas are benign tumors that are hormonally responsive and commonly occur in the genitourinary and gastrointestinal tract of women of reproductive age. They are extremely rare in the heart. Here we describe an incidental finding of an interatrial leiomyoma in an autopsy of a 48-year-old obese man who presented with a 4-month history of symptoms of decompensated right and left heart failure secondary to idiopathic dilated cardiomyopathy. Transesophageal echocardiogram, chest x-ray, and left and right heart catheterization revealed no mass. Histopathologic examination demonstrated a primary intracardiac leiomyoma. Immunohistologically, the mass stained positively for vimentin and actin and negatively for S-100, CD34, and CD117. To the author's knowledge, this is the first known report of a primary interatrial leiomyoma.
Analytical Performance of the Catachem Methanol Enzymatic Assay Using a Beckman Au5810 Chemistry Analyzer: (Poster No. 9)
Context: A rapid serum methanol (MeOH) quantification assay is desirable in a hospital setting to aid with rapid diagnosis and immediate medical treatment of acute MeOH ingestion. However, such assays are not widely available in the hospital setting, due in large part to the lack of an automated platform. The CATACHEM methanol enzymatic assay is capable of screening and quantifying methanol using an automated chemistry analyzer (AU5810).
Design: The MeOH enzymatic assay by CATACHEM, a 2-step kinetic procedure read at 340 nm where the increase in absorbance is directly proportional to the concentration of methanol, was evaluated after implementing method parameters for the AU5810.
Results: Precision was determined from 3 levels during 5 days (n = 15) with all CV% less than 8%. Linearity was evaluated from 3 samples prepared within the claimed analytical range of the assay of 0 to 100 IU/ L. The lower limit of quantitation of 3.4 mg/dL was the lowest concentration at which all samples were accurate to 15% of the target concentration. Twenty-nine samples were correlated with GC-FID, with 15 samples giving greater than 5 mg/dL results, yielding a Deming Regression Equation of y = 0.899x – 2.66, r = 0.982, standard error = 8.38. Interference was performed with 18 compounds structurally similar to methanol, with only 1,4 butanediol and urine methanol yielding a false-positive result. No carryover was identified.
Conclusions: The CATACHEM enzymatic assay demonstrates acceptable performance for quantifying MeOH in serum. This assay can be performed within a 1-hour turnaround time, allowing for immediate diagnosis and treatment of methanol ingestion in an emergency setting.
Repeatedly Indeterminate QuantiFERON Gold In-Tube Test Results in a Child With Kikuchi Disease: A Case Report and Review of Literature: (Poster No. 10)
Kikuchi disease, or histiocytic necrotizing lymphadenitis, is a rare, benign, self-limited condition of unknown etiology. We present a case of a 9-year-old African American girl who presented with fevers of unknown origin, diffuse maculopapular pruritic rash, lymphadenopathy, and vague abdominal and joint pain. An extensive workup for autoimmune and infectious etiologies was undertaken, including 3 QuantiFERON Gold In-Tube tests (Cellestis Limited, Carnegie, Victoria, Australia, QTF-GIT) to rule out tuberculosis. These results were persistently indeterminate. Concurrently, a lymph node biopsy was performed and hematopathology revealed histiocytic necrotizing lymphadenitis and the patient was ultimately diagnosed with Kikuchi disease. The indeterminate QTF-GIT results were subsequently found to be a consequence of high interferon-γ (IFN-γ) levels in the Nil tube. The QTF-GIT test involves 2 control tubes, a Nil, which measures IFN-γ levels in the absence of tuberculosis-specific antigens, and a Mitogen, which ensures cells are capable of IFN-γ production. The literature is scarce on indeterminate QTF-GIT test results due to patient-specific causes of high Nil tube IFN-γ levels, with the majority of the literature focusing on indeterminate results due to low Mitogen tube levels. Multiple case reports have shown that Kikuchi disease is associated with elevated serum IFN-γ levels, though a case of an indeterminate QFT-GIT test due to intrinsic IFN-γ secretion in Kikuchi disease has never been reported in the literature to the best of our knowledge. This case report represents the first report of a complication in tuberculosis testing using QTF-GIT in patients with Kikuchi disease.
Detection of Prenatal Exposure to Illicit Substances by Meconium Analysis: Results of a Retrospective Study at a Tertiary Care Center: (Poster No. 11)
Context: The exposure of newborns to illicit substances during pregnancy is a serious social problem. Exposure to illicit substances not only has ill effects on maternal and newborn health, but also maternal dependence compromises child care and enhances the prospect of child neglect. Meconium testing is a noninvasive method for identifying exposure to illicit substances used during pregnancy from about the 12th week of gestation.
Design: A retrospective analysis of meconium specimen testing for illicit substances was performed as a part of the clinical workup at the Tufts Medical Center between January 1, 2013, and July 8, 2014. The specimens were submitted to a reference laboratory, where they were initially screened by immunoassay for amphetamines, cocaine metabolite, marijuana, opiates, and PCP. Specimens with positive screening results were confirmed by tandem mass spectrometry within the same reference laboratory.
Results: Screening results were positive in 28 out of 192 (14.6%) tested meconium specimens. Marijuana was positive in 13 specimens (46.4%), followed by opiates (10; 35.7%), amphetamines (5; 17.8%), and cocaine metabolite (2; 7.1%). Two specimens were positive for 2 substances. All positively screened specimens were confirmed by more specific and sensitive methods.
Conclusions: The data from this pilot study suggest that a significant number of neonates are exposed to illicit substances in utero among obstetric population at this hospital. Meconium analysis can be a very useful tool for identifying in utero illicit substance exposure in newborns primarily those whose mothers appear normal at birth and denied use of illicit substances.
Hypoglycemia in Geriatric Patients With Diabetes: (Poster No. 13)
Context: More than 25% of people age 65 and older in the United States have diabetes, and almost one-third are unaware that they have the disease. The first step in diabetes care is glycemic control to prevent the acute complications and reduce the risk of long-term complications; the American Diabetes Association has recommended A1c <7% as an indicator for tight glycemic control.
Design: Specimens from 13 974 patients resident in long-term care facilities for A1c and glucose were collected. Glucose and A1c were done using Roche Integra 800 (Roche Diagnostic, Indianapolis, Indiana); A1c assay was standardized according to IFCC transferable to DCCT/NGSP. Patients' data were separated into 6 age groups: <50, 51–60, 61–70, 71–80, 81–90, and >90 years old. The prevalence of glucose <75 mg/dL was calculated at A1c <7.0%, <7.5%, and <8% for all age groups. Statistical analysis was done using Analyse-it.
Results: Of the patients 66.0% had A1c <7% and 16.3% had A1c >8%. There was a negative correlation between A1c and glucose <75 mg/dL across all ages; the groups with lower A1c have the highest percentage of patients with hypoglycemia.
Conclusions: This study suggests that diabetes is well monitored in LTCF; two-thirds of the patients have met the recommended goal for geriatric glycemic control. Hypoglycemia is more common in patients with A1c <7%; physicians should follow the American Diabetes Association and the American Geriatric Association recommendation and endorsement for higher glycemic target for the older diabetic patients to avoid hypoglycemia and its consequences.
Hemoglobin Sickle-Lepore: Series of 4 Cases in the Past 30 Years at East Carolina University and Literature Review: (Poster No. 14)
The doubly heterozygous condition sickle with Lepore hemoglobin is rare, previously described in only 16 patients. Documented cases have occurred primarily in those of Mediterranean descent. The Hb Lepore gene is a crossover fusion product of the δ- and β-globin genes. Peripheral smears show microcytosis, hypochromia, and irreversibly sickled cells. Vaso-occlusive complications occur. Splenomegaly is common. We report a series of 4 cases diagnosed at East Carolina University during the past 30 years. All 4 African American patients were referred to East Carolina University. The most recent 2 diagnoses were made by HPLC and confirmed by acid and alkaline gel electrophoresis at ECU. The 3 most recent cases are still followed at the ECU sickle cell clinic. The most recent patient, in 2012, is the youngest diagnosed of the 4 cases, a 4-month-old female infant, referred for sickle cell disease identified on newborn screen. She was given penicillin 125 mg prophylaxis. Hydroxyurea was begun at 2 years 10 months. The previous 2 patients were diagnosed at ages 12 and 26. Both are African American males diagnosed after sickle cell crises in 1991 and 2003. Both have had numerous hospital admissions and considerable morbidities. The original case (an African American female) was diagnosed in 1987 by the Centers for Disease Control and Prevention. The combination of predominantly HbS with microcytosis suggests sickle cell β-thalassemia, but diagnosis of HbS Lepore is suggested by the low to low-normal HbA2 levels resulting from incapacitation of one delta globin gene by the crossover. HbF levels vary.
Analysis of Indeterminate QuantiFERON-TB Gold In-Tube Test Results in an Academic Medical Center: (Poster No. 15)
Context: The QuantiFERON-TB Gold In-Tube test (Cellestis Limited, Carnegie, Victoria, Australia) is an in vitro assay that evaluates interferon-γ production in response to tuberculosis-specific antigens. A number of patient-specific conditions can cause indeterminate results in this assay. The impact of these conditions on test performance in clinical practice was evaluated.
Design: We reviewed 1615 QuantiFERON-TB Gold In-Tube results from 1564 patients in hospital clinics, private ambulatory clinics, and inpatients from July 21 to December 5, 2014. Positive, negative, and indeterminate results were calculated based on the manufacturer's protocol. Medical records of patients with indeterminate test results were reviewed.
Results: The positive, negative, and indeterminate rates were 6%, 83%, and 11%, respectively. There were 179 indeterminate test results in 160 patients. The indeterminate rate in inpatients was 36% versus 6% in the private ambulatory and hospital clinics (P < .001). Of indeterminate results 82% were in immunocompromised patients. Of the indeterminate results that were not in immunocompromised patients, 44% were in conditions known to cause intrinsic interferon-γ release, such as autoimmune conditions and acute viral infections. Indeterminate results in immunocompromised patients were due to low mitogen tube levels, whereas those in patients with autoimmune conditions and viral infections were due to high nil tube values.
Conclusions: Underlying conditions such as being immunocompromised or having intrinsic interferon-γ secretion results in high rates of indeterminate results with the QuantiFERON-TB Gold In-Tube test. Although indeterminate results in immunocompromised patients are well supported in the literature, literature regarding indeterminate results due to high nil tube values is scarce.
Pleomorphic Lipoma of the Face: (Poster No. 18)
Pleomorphic lipoma is an uncommon lipoma variant, which often occurs in the subcutaneous tissue of shoulders, backs, and posterior necks (up to 70% of cases). Microscopically, it may resemble a liposarcoma; however, it is a slow-growing and well-circumscribed benign lesion. To our knowledge, there are only 33 cases reported in the English-language literature of pleomorphic lipoma of the face. We report a 44-year-old man with a left facial mass. Imaging studies showed that the mass appeared to be separate from the parotid gland and was an enlarging posterior zygomatic arch superficial soft tissue lesion measuring 1.9 × 1.9 × 2.7 cm. The mass was clinically suspicious for pleomorphic adenoma or nerve sheath tumor. Fine-needle aspiration was performed, which showed adipose tissue with atypical cell clusters and rosette/floret–like formation suggesting a lipoma variant. An excision of the mass was performed and pathology revealed a spindle cell neoplasm with a myxoid background and containing numerous floretlike multinucleated cells. The background nuclei were small, mildly pleomorphic, and homogenous. There was a chicken wire–like background of collagen fibers, but not of blood vessels. Immunostains for vimentin and CD34 were strongly and diffusely positive, whereas S100, desmin, and AE1/3 were negative. All of these morphologic and immunohistochemical findings were consistent with pleomorphic lipoma. This case emphasizes the cytologic features of pleomorphic lipoma and illustrates that because of its unusual anatomic location, pleomorphic lipoma of the face can be a difficult diagnosis and increased awareness of its clinicopathologic features should allow for accurate classification.
Folate Receptor α Immunohistochemistry in Cytology Specimens of Metastatic Breast Carcinoma: (Poster No. 28)
Withdrawn.
Can Risk Stratification for Aggressive Behavior Be Performed on Fine-Needle Aspirations or Core Biopsies From Gastrointestinal Stromal Tumors?: (Poster No. 29)
Context: The Gastrointestinal Stromal Tumor (GIST) workshop sponsored by the National Institute of Health in 2001 proposed the list of histologic criteria to define risk of aggressive behavior in GISTs. Risk stratification is based on mitotic count (MC) and tumor size from resection specimens. However, histologic criteria for aggressive behavior have not been evaluated on core biopsy or fine-needle aspiration (FNA), which are often the primary diagnostic modalities in these tumors. The purpose of our study was to assess if MC and therefore risk of aggressive behavior could be predicted on FNA or core biopsy.
Design: Fourteen cases of GISTs were selected (5 high risk, 4 intermediate risk, and 7 low and very low risk based on the resection specimens). All tumors were initially diagnosed by FNA or core biopsy. MC in 50 high-power fields (HPFs) was assessed in all biopsy and surgical specimens and the results were compared. Biopsies in which 50 HPFs could not be counted were excluded.
Results: Prediction of aggressive behavior was concordant between biopsy and surgical resection in 10 of 14 cases. From the remaining 4 cases, 2 were downgraded from intermediate to low risk on the resection specimen, and 2 were upgraded to high risk from intermediate risk on the biopsy.
Conclusions: Although our case numbers are low, our data show that in around 70% of cases, MC can predict aggressive behavior in GIST when compared with resection specimen. However in 28.5% of cases, the MC was discordant. Additional studies are being conducted on larger cohorts to further validate the utility of MC on biopsies.
Metastatic Renal Cell Carcinoma on Pericardial Effusion Cytology: Detection of a Rare Presentation: (Poster No. 33)
Because renal cell carcinoma (RCC) is known for presenting in unusual anatomic sites, the low-grade appearance of some clear cell RCCs can present further diagnostic difficulty. We report a case of clear cell RCC in a pericardial effusion in a 76-year-old woman without prior history of malignancy. She presented with chest discomfort, dyspnea, and weight loss. Workup revealed pleural and pericardial effusions, as well as multiple lung nodules. The pericardial fluid demonstrated rare small groups of cohesive cells with clear vacuolated cytoplasm and bland nuclei with nucleoli. Further imaging revealed a right renal mass and pulmonary metastasis. Tissue biopsy and immunohistochemical profile from the metastatic lung lesion demonstrated neoplastic cells immunoreactive for AE1/AE3, CD10, and RCC. The diagnostic challenge in fluid cytology is to differentiate metastatic clear cell RCC from reactive mesothelial cells or histiocytes. Additional sampling and cell block material for immunohistochemical stains can help to differentiate these tumor cells from normal components of effusions, especially when clinical suspicion of malignancy is high.
BRAF V600e Mutation–Positive Papillary Thyroid Microcarcinoma Presenting as Mediastinal Lymphadenopathy: A Challenging Cytopathologic Diagnosis: (Poster No. 34)
We report a case of an 84-year-old man with dyspnea but an otherwise unremarkable physical examination. Radiologic imaging demonstrated mediastinal lymphadenopathy. Endobronchial ultrasound-guided fine-needle aspiration biopsy of the mediastinal lymph nodes showed tumor cells arranged in papillae with fibrovascular cores. The tumor cells had enlarged, overlapping nuclei with irregular contours, and pale, powdery chromatin. Tumor cells with optically clear nuclei were seen in the cell block. Immunohistochemistry was positive for TTF-1 and PAX-8. These findings were consistent with papillary thyroid carcinoma. BRAF V600E (T1799A) mutation testing performed on the cell block was positive. An encapsulated papillary microcarcinoma, classical variant (0.4 cm in greatest dimension), was identified in the right lobe following total thyroidectomy. Papillary thyroid microcarcinoma is an indolent cancer that rarely metastasizes, and the encapsulated well-differentiated variant generally has a better prognosis. However, the presence of BRAF V600E (T1799A) mutation, as in the present case, is associated with a more aggressive biologic behavior. The cytopathologic diagnosis of papillary carcinoma is frequently straightforward. However, this becomes challenging in instances where the initial presentation is metastasis to distant sites/ lymph node groups without an apparent thyroid mass. The differential diagnosis for mediastinal lymphadenopathy often includes metastatic carcinoma (usually from the lungs), lymphoma, and granulomatous disease like sarcoidosis. The finding of tumor cells with cytomorphologic features suspicious for papillary carcinoma even in the absence of an obvious thyroid mass should warrant consideration of this entity, and immunohistochemical workup with thyroid markers such as TTF-1, PAX-8, and thyroglobulin.
Primary Large B-Cell Lymphoma of the Uterine Cervix: Presentation in Papanicolaou Test Slide and Cervical Biopsy: (Poster No. 40)
About 25% of lymphomas arise extranodally and primary lymphoma of the uterine cervix and corpus is very rare, accounting for only 0.5% of extranodal lymphomas. Among all cervical malignancies, the overall incidence of primary cervical lymphoma is less than 1%, and the most common initial presentation is vaginal bleeding. A 69-year-old woman presented with irritative urinary voiding. Imaging studies showed an 18-cm uterine mass centering on the cervix and extending into the bladder. The Papanicolaou test slide demonstrated a necrotic background and degenerative changes in single and grouped atypical small round blue cells with high nuclear to cytoplasm ratio, scant cytoplasm, hyperchromatic focally cleaved nuclei with occasional snout projections. Cervical biopsies showed necrotic tissue with marked cautery artifact, single and grouped atypical small round blue cells with significant degeneration amongst crushed cellular debris. The tumor cells were positive for CD45 and CD20, and negative with epithelial, neuroendocrine, and muscle markers. A PAX-5 highlighted both crushed and rare intact tumor cells. A Ki-67 immunostain showed a markedly elevated proliferative index and the MUM1 stain was diffusely positive. Comprehensive B-cell gene rearrangement studies detected clonal immunoglobulin heavy-chain gene rearrangement. Because of its rarity, cervical lymphoma may sometimes be confused with other types of malignant neoplasms or inflammatory processes. Therefore, it is important to recognize the cytologic features of cervical lymphomas and be aware of the potential diagnostic pitfalls for timely diagnosis and therapy.
Fine-Needle Aspiration, Flow Cytometry, and Molecular Features of Precursor B-Cell Lymphoblastic Lymphoma Presenting as a Vertebral Fracture: A Diagnostic Dilemma: (Poster No. 41)
Precursor B-cell lymphoblastic lymphoma (B-LBL) is an aggressive neoplasm, usually presenting in children and young adults. It is uncommon in the elderly, and extranodal presentation is even rarer. The skin is the most common site of extranodal involvement, followed by bone, and its manifestation as primary vertebral lytic lesion is very rare. Here, we report a case of B-LBL diagnosed on fine-needle aspiration (FNA) who initially presented with back pain, vertebral fracture, and osteolytic lesions but without peripheral blood or bone marrow involvement. FNA smears were hypercellular, comprising small round cells with scant cytoplasm. Nuclei were round with fine chromatin. Biopsy from vertebral body was highly cellular and consists of small lymphoid cells. The cells were uniformly and strongly positive for both TdT and CD34. CD3 stains scattered small cells and CD20 stains scattered aggregates representing 10%–15% of the cells. CD56 and cyclin D1 were negative. Determination of B-cell lineage was based on the flow cytometry. Flow cytometric immunophenotyping of vertebral body lesion showed approximately 11% of total cells negative for CD45 and express CD19, CD10, CD22 (dim), and CD34 with no CD20 or surface light-chain immunoglobulin expression. This immunophenotype was consistent with B-lymphoblasts, likely B-ALL. PCR analysis showed BCR/ABL translocation. This case is unique as it presents in an elderly patient with primary vertebral lesion and thus poses diagnostic challenge. However, FNA with the aid of flow cytometry and molecular studies was instrumental in reaching this unusual diagnosis and helped to start chemotherapy without any delay.
Glypican-3, Heat Shock Protein 70, and Glutamine Synthetase Immunohistochemistry Expression in Hepatocellular Lesions in Fine-Needle Aspiration Cell Blocks: A Review of 32 Cases: (Poster No. 42)
Context: Recently, the role of heat shock protein 70 (HSP70), glypican-3 (GPC3), and glutamine synthetase (GS) immunohistochemistry (IHC) panel to aid in the morphologic diagnosis of hepatocellular carcinoma (HCC) has been described in liver resection and biopsy specimens; however, to the authors' knowledge, application of this panel has not been investigated on fine-needle aspiration (FNA) cell blocks. Here, we examine the utility of these 3 markers and validate their use on formalin-fixed, paraffin-embedded FNA cell blocks.
Design: Thirty-two archival, formalin-fixed, paraffin-embedded cell blocks representing 10 cases of benign hepatic lesions, 12 cases of HCC, and 10 cases of metastatic neoplasms (MET) were retrieved. IHC for GPC3, HSP70, and GS was applied to all cases. The patients' final diagnoses were confirmed by histology, diagnostic imaging, or therapeutic intervention.
Results: In the differentiation of HCC from benign hepatic lesions, the overall accuracy was 77.3% (3 positive markers) and 95.5% (at least 2 positive markers) with 100% specificity for both combinations. However, in MET, the 3 and 2 positive marker combinations were expressed in 10.0% and 70.0%, respectively.
Conclusions: Although this IHC panel proved useful in differentiating benign hepatocellular lesions from HCC, caution should be used in applying it to differentiate HCC from MET, as immunoreactivity of 2 markers, most commonly GS and HSP70, is typically expressed in MET.
Minimal Uterine Serous Carcinoma Presenting as a Malignant Pleural Effusion on Initial Diagnosis: Reemphasizing the Role of Effusion Cytology in Tumor Workup: (Poster No. 43)
Body fluid cytology plays an important role in the diagnosis and staging of malignancies. Most malignant effusions are associated with a clinically apparent primary tumor. Occasionally, a malignant effusion is the first clinical presentation of an underlying occult neoplasm. We present a case of a 63-year-old woman who presented with a malignant pleural effusion and no obvious primary tumor on imaging in which the workup of the cytology material was integral in her medical and surgical management. The patient presented to the emergency room with shortness of breath and dry cough. Computed tomography scan showed a large right-sided pleural effusion. No other masses or lesions were identified on further imaging. Pleural fluid cytology revealed adenocarcinoma. Immunohistochemistry showed the tumor cells to be positive for AE1/AE3, Ber-Ep4, PAX8, p53, CK7, CA125, ER, WT1, and TTF1 and negative for napsin A, CK20, CDX2, and mammaglobin. This was interpreted as suggestive of a gynecologic primary. A subsequent hysterectomy was performed and examination of the endometrium revealed a 1.8-cm polyp showing mixed serous and endometrioid carcinoma with superficial invasion into the myometrium (<0.1 cm). The background endometrium demonstrated extensive endometrial intraepithelial carcinoma (EIC). Our case is unique in that the initial clinical presentation of malignant pleural effusion with carcinoma arising from a diminutive endometrial polyp in a background of extensive EIC has not previously been reported. Workup of cytologic material can be integral to the diagnosis and clinical management of these patients.
Fine-Needle Aspiration Cytology of Granulomatous Lesions of the Breast: An Institutional Experience in a Developing Country: (Poster No. 44)
Context: Various nonneoplastic lesions of the breast including granulomatous mastitis can mimic malignancy clinically and on radiology. The present study was carried out to analyze the cytologic features of granulomatous lesions of the breast.
Design: In a 4-year retrospective study, 17 patients with a histopathologic diagnosis of granulomatous mastitis were evaluated. Their cytomorphologic features were correlated with clinical, radiologic, and microbiological findings.
Results: All patients in our study were in the age range of 22 to 62 years and presented with breast lump. Peau d'orange appearance, erythema of the skin, and axillary lymphadenopathy were seen in some cases. Most of the lesions appeared hypoechoic on mammo-gram. Histology showed well-formed granulomas and negative Ziehl-Neelsen stain in all cases. On cytology, 9 showed well-formed granulomas along with scattered histiocytes, giant cells, numerous neutrophils, and cell debris. Further, no caseous necrosis was seen. One case each of Mycobacterium tuberculosis and Burkholderia pseudomallei was identified by culture subsequently. Among the cases without granulomas on cytology, scattered histiocytes and giant cells were commonly seen.
Conclusions: In the developing world, tuberculosis and melioidosis can present with granuloma formation. In the breast, these entities can have overlapping features with idiopathic granulomatous mastitis. In the absence of well-formed granulomas, the latter may be mislabeled as breast abscess on cytology. In such a scenario, the presence of scattered histiocytes and giant cells may serve as useful clues suggestive of granulomatous mastitis in corroboration with clinicoradiologic findings.
Getting More From Less: Recovery of Dissociated Cells for Ancillary Testing by Washing Core Needle Biopsies: (Poster No. 46)
Context: An emerging problem for pathologists is the triaging of core needle biopsies for both pathologic diagnosis and molecular testing. These innately diminutive specimens are easily exhausted during routine microtomy, additional sectioning, and immunohistochemistry, often resulting in insufficient tissue remaining for molecular-based, therapy-guiding assays. As part of an investigation on a new paradigm involving microfluidics, we sought to determine the optimal reagent for the recovery of cells from core needle biopsy washings that would neither deplete the core of diagnostic cells nor damage its morphology.
Design: Core needle biopsies were procured from 21 different tumor specimens and either (1) immediately fixed in formalin; or washed in (2) 1× phosphate-buffered saline (1×PBS); (3) a nonen-zymatic cell dissociation reagent, or (4) graded dilutions of collagenase IV. The washed cores were subsequently fixed in formalin for paraffin embedding and histology. Cytospin slides were prepared from the washes and the qualitative and quantitative characteristics of the cells examined. The matching core needle tissues were similarly examined.
Results: The optimal reagent for the recovery of cells with preserved cytologic and core morphology was 1×PBS.
Conclusions: Cytologic and histologic preservation was optimal with cores washed in 1×PBS. Reagents that dissociated more cells damaged either the cells recovered for cytology or the tissue itself.
A Rare Case of Metastatic Cervical Squamous Cell Carcinoma Causing Biliary Obstruction: (Poster No. 47)
Squamous cell carcinoma is the most common malignancy of the cervix with worldwide incidences ranging from 5 to 100/100 000. The risk of distant metastasis increases with depth of invasion and can spread both hematogenously and through the lymphatics. Common sites of metastasis include the lungs, bone, and para-aortic and supraclavicular lymph nodes. Here we report a rare case of metastatic squamous cell carcinoma of the cervix to the bile duct presenting as painless obstructive jaundice. A 40-year-old woman with vaginal bleeding was found to have a 6-cm mass obliterating the cervix with right-sided vaginal involvement. A subsequent biopsy revealed grade 2 squamous cell carcinoma with lymphovascular space involvement. Imaging revealed the presence of the mass with parametrial involvement and was staged FIGO IIB with no evidence of distant metastasis. The patient underwent radiation and cisplatin-based chemotherapy but was noncompliant. Seven months later the patient developed gradually progressive icterus, with elevated direct, indirect, and total bilirubin levels. Imaging demonstrated biliary obstruction secondary to strictures and a mass in the region of the porta hepatis. An endoscopic biopsy was undertaken that was noncontributory. One week later an endoscopic fine-needle aspiration was done that demonstrated the presence of malignant squamous cells that were immunoreactive with cytokeratin 5/6, P40, and P16, establishing the diagnosis; no other primary was detected. This case demonstrates although extremely rare, squamous cell carcinoma can metastasis to the biliary hilar region causing painless obstructive jaundice; fine-needle aspiration is a valuable diagnostic tool in such situations.
Will High-Risk HPV Test as a Primary Screening Method for Cervical Cancer Affect AGC (AGUS) Cases?: (Poster No. 48)
Context: The current management guideline for AGC is colposcopy. Recently, the FDA has approved HR-HPV DNA test for primary cervical cancer screening. How will this affect AGC cases? We reviewed AGC cases in a 4-year period in our files and will present results here.
Design: There were 58 AGC cases of 33 505 Papanicolaou (Pap) tests between 2010 and 2014. HR-HPV test using FDA-approved Cervista HPV-HR System was performed on 54 out of the 58 cases. Among the 54 cases, 45 had adequate histology follow-up including cervical/vaginal biopsy, endocervical curettage, cervical LEEP, endo-metrial biopsy/curettage, and hysterectomy within 1 year after Pap test.
Results: Of 45 AGC cases with both HR-HPV test and adequate histology follow-up, 10 (22.3%) were positive and 35 (77.7%) were negative for HR-HPV. Histology diagnoses in the HR-HPV positive group were 1 invasive cervical neuroendocrine carcinoma, 2 low-grade intraepithelial lesions (CIN1/HPV), and 7 negative results. Histology diagnoses in the HR-HPV negative group were 5 endometrial adenocarcinoma, 1 high-grade squamous intraepithelial lesion (CIN2), 2 LSIL, and 27 negative results. All 5 adenocarcinoma cases had concurrent tissue biopsies with Pap tests.
Conclusions: HR-HPV test picked up cervical dysplasia/malignancy due to HR-HPV infection whereas the other CIN1-2 cases in HR-HPV negative group were probably not due to HR-HPV. The AGC cases with endometrial adenocarcinoma had concurrent tissue biopsies because of clinical presentation regardless of HR-HPV tests status. The findings indicate no adverse effect on AGC cases when HR-HPV testing is used as a primary screening tool. Large series of studies are warranted.
Perifolliculitis Capitis Abscedens et Suffodiens With Remarkable Scalp Lesions With Histologic Findings Mimicking Pilonidal Sinus: (Poster No. 50)
Perifolliculitis capitis abscedens et suffodiens is a rare inflammatory skin condition with multiple treatment modalities. In the US, it affects African American adult males most commonly and is rarely found in whites or women. Our aim is to evaluate the histologic and bacteriologic findings to understand its impact on the clinical outcome. Biopsies from scalp lesion were received fresh from a 36-year-old white man with multiple nodular scalp lesions. A sterile technique was performed to send samples for microbiologic analysis. Formalin-fixed paraffin blocks were histologically examined. Special stains on tissue blocks were performed. Histologic examination revealed a diffuse dermal inflammatory process with granulomas and active chronic inflammation. Rare bacteria consistent with proprianibacterium species were found focally within hair follicles and deep dermis with a Brown & Brenn stain. The findings were most consistent with perifolliculitis capitis abscedens. The patient was started on a course of antibiotics for a period of time with no response. Using special stains for microbiologic identification that guide different treatment modalities may have a major impact on the management protocol of this condition.
Utility of Frozen Section Analysis for Fungal Organisms in Skin/Soft Tissue Wound Debridement Margin Determination: (Poster No. 52)
Context: Zygomycetes cause different patterns of infection in immunosuppressed individuals, including sino-orbito-cerebral, pulmonary, skin/soft tissue infection, and disseminated disease. Infections with zygomycetes have a high mortality rate, even with prompt treatment. Early treatment is critical, and includes antifungal agents and surgical debridement. In some centers, clear margins are monitored by serial frozen sections, but there are no specific guidelines for the use of frozen sections during surgical debridement. Studies in fungal rhinosinusitis found 62.5%–85% sensitivity of frozen section analysis in margin assessment. However, the utility of frozen section analysis for margin evaluation in debridement of skin/soft tissue infection has not been published.
Design: We present a case of zygomycosis of decubitus ulcers in which we assessed statistical measures of performance of frozen section analysis for presence of fungal organisms on the margin, compared with formalin-fixed, paraffin-embedded (FFPE) sections as gold standard. A total of 33 specimens (94 tissue blocks) were sectioned, stained with H&E, and evaluated. Negative interpretations were confirmed by Gomori methenamine silver stain on FFPE sections.
Results: Hematoxylin and eosin staining of frozen sections had 63.2% sensitivity and 100% specificity for assessing margins clear of fungal organisms. The negative and positive predictive values were 66.7% and 100%, respectively. Using the presence of acute inflammation and necrosis as markers of fungal infection improved sensitivity (100%) at the expense of specificity (42.9%).
Conclusions: Use of intraoperative assessment of skin and soft tissue margins for fungal infection is a valuable tool in the management of skin and soft tissue fungal infection treatment.
Cutaneous Microsporidiosis: A Rare Infectious Disease in a Leukemia Patient: (Poster No. 53)
Microsporidia are obligate intracellular spore-forming parasites that cause opportunistic infections in immunocompromised hosts. Most cases of microsporidiosis are documented in patients with HIV/ AIDS. Infection mainly affects the gastrointestinal tract; in contrast, cutaneous lesions are a very rare manifestation of microsporidial infection. Transmission is usually caused by inhalation or ingestion of spores. Infection of host cells is achieved by injection micro-sporidial sporoplasm through the polar tubule apparatus of the organism. Here, we report a rare case of microsporidiosis in a 65-year-old patient with acute lymphocytic leukemia and myositis presenting with painless nonpruritic skin lesions. Skin biopsy showed multiple small, ovoid, intracellular organisms in the follicular epithelial cells, dermal and perivascular interstitial cells, and presumed endothelial cells of small vessels associated with a perivascular and periadnexal mixed inflammatory dermal infiltrate. Various infections were considered, including toxoplasmosis, histo-plasmosis, and candidiasis; further testing for toxoplasmosis and histoplasmosis was negative. Thereafter, the case was sent to Centers for Disease Control and Prevention for further workup. Most organisms stained positive by Giemsa and Lillie-Twort Gram stain, a few stained by Ziehl-Neelsen and GMS stain, and punctate polar staining was appreciated by PAS staining. Electron microscopy showed characteristic features of diplokaryotic organisms with up to 11 coils of polar tubule in an anisofillar arrangement. Final diagnosis was rendered after PCR diagnosis of the microsporidial species Annacaliia algerae. In summary, microsporidiosis, although very rare, should be considered in the differential diagnoses of asymptomatic cutaneous lesions in immunocompromised patients.
Dermatofibrosarcoma Protuberans With Coexisting Fibrosarcomatous and Giant Cell Fibroblastoma-Like Components in the Breast of a Woman: (Poster No. 54)
Dermatofibrosarcoma protuberans (DFSP) is a rare, slow-growing, locally aggressive tumor that constitutes 1% of all soft tissue sarcomas. Metastases are rare. Fibrosarcomatous changes have been identified in up to 20% of all cases of DFSP. When these changes make up >5% of the tumor, a diagnosis of fibrosarcomatous DFSP (DFSP-FS) is made. Multiple studies report more aggressive behavior, higher local recurrence rate, and increased risk of distant metastases in DFSP-FS. Giant cell fibroblastoma (GCF), a childhood tumor, is thought to be a variant of DFSP, as both tumors have the same clinical appearance and immunohistochemical and molecular features. Herein, we present a case of a 48-year-old woman presenting with a 6.4-cm breast mass. Upon excision, microscopic examination showed a spindle cell neoplasm with areas of delicate fibroblast-like cells arranged in a storiform pattern, as seen in classic DFSP. These areas were strongly and diffusely positive for CD34. However, distributed throughout the tumor, there were multiple fibrosarcomatous areas showing fascicular architecture, hypercellularity, increased mitotic rate, and near-complete loss of CD34 expression. These fibrosarcomatous areas constituted approximately 70% of the lesion. In addition, a GCF-like component consisting of large, atypical multinucleated cells adjacent to irregular, vessellike spaces was seen. To our knowledge, this is the first case report of a DFSP-FS with a GCF-like component in an adult. This finding further supports the notion that GCF and DFSP may be variants of the same entity.
Precocious Acrometastasis to the Digits of the Hand: Case Series and Review of Literature: (Poster No. 58)
Case reports of metastases from the gastrointestinal tract account for less than 0.007% of reported precocious acrometastases. After extensive literature review, this is the first reported case of adenocarcinoma of the right fifth digit of the hand, consistent with a colonic primary. A 75-year-old white man presented with a painful lesion at the tip of the right fifth digit following trauma. The lesion was biopsied and diagnosed as adenocarcinoma, metastatic, gastrointestinal origin, for which the patient underwent an amputation of the right fifth digit of the hand. Tumor invaded the distal phalanx with diffuse involvement of the deep soft tissue and bone. Immunohistochemical stains for CK20, CDX-2, and CEA were positive in the tumor cells, findings compatible with metastatic adenocarcinoma from the colon. Similarly, a 64-year-old man presented with pain, swelling and bleeding of his left index finger, with a history of a spider bite. Post–digit amputation, the lesion was positive for HepPar, glypican3, and CD10 and he was diagnosed with metastatic hepatocellular carcinoma. We present a unique case series of precocious acrometastasis from the colon and liver to the digit of the hand and postulate that trauma may have played a role in the acrometastasis. Moreover, we stress the importance of early microscopic evaluation and pathologic diagnosis as a determinant of prognosis for these patients.
Nipple Eczema: Further Characterization of an Uncommon Clinicopathologic Entity: (Poster No. 60)
Context: Nipple eczema, a mimic of Paget disease, remains clinically and pathologically poorly characterized.
Design: An electronic search of our pathology archives for “nipple eczema” during an 11-year period (2004–2014) was conducted. Only cases with available histopathologic material and clinical data were included.
Results: Ten cases of nipple eczema (female: 8, male: 2; age range: 16–77, mean: 50; all unilateral) were studied. All 10 patients, presented with pruritic and scaly nipple, of a “few” days to 30-month duration. No patient at presentation was pregnant or lactating, and all were otherwise asymptomatic. Clinical differential diagnosis included Paget disease (in all cases), eczema, and lichen sclerosus et atrophicus. Physical examination showed either xerotic or erythematous plaques. Histologically, overlapping features of eczematous and psoriasiform dermatitis including acanthosis, parakeratosis, spongiosis, intraepithelial inflammatory cell infiltrate, and alteration of granular cell layer were present. Eosinophilic spongiosis and entrapment of serum in stratum corneum distinguished nipple eczema from psoriasis. Neither fungi nor carcinoma was identified. No contact etiology could be established in any case. Clinical resolution was achieved with topical steroids.
Conclusions: Nipple eczema, a clinical mimic of Paget disease, displays concurrent histopathologic features of eczematous and psoriasiform dermatitis, and typically occurs in an adult of either sex with unilateral nipple involvement.
Clinical and Pathologic Features of Extramammary Perianal Paget Disease and Its Occult Connection With an Underlying Anal Adenocarcinoma: An Institutional Experience With 12 Cases: (Poster No. 61)
Context: Extramammary perianal Paget diseases (EMPPDs) are intraepithelial forms of adenocarcinoma, being either primary skin entities or secondary to an underlying invasive adenocarcinoma; in the latter cases the identified culprits were predominantly colorectal adenocarcinoma. Unfortunately, in most EMPPD cases the underlying etiology remains undetermined. At an NCI-designated comprehensive cancer center, our institutional experience indicates that anal adeno-carcinoma, instead of colorectal primary, is an important underrecognized source leading to EMPPD.
Design: Twelve EMPPD cases were retrieved from institutional pathology archives. Endoscopic, radiologic, and histopathologic findings were reviewed. An immunophenotyping panel (cytokeratin 7 and 20, GCDFP, GATA3, CDX2, and P40) was analyzed and all synchronous or metachronous malignancies were inspected.
Results: The ages at diagnosis ranged from 50 to 83 years (median 68). Follow-up ranged from 3 months to 10 years. Diagnoses of skin-only EMPPD were made in 11 cases after extensive biopsies (20–61 biopsies per case). The potential connection with any contributing malignancy was excluded. Of notice, in one case, coexisting extra-luminal invasive anal adenocarcinoma was uncovered. Tumor cells showed signet ring morphology, immunoprofile of CK7+/CK20+/ CDX2+/GCDFP–/GATA3–, identical to the intraepithelial EMPPD component. Concurrent colonoscopy and imaging studies were negative for any colorectal primaries. The patient underwent neo-adjuvant chemoradiation for anal adenocarcinoma prior to resection.
Conclusions: EMPPD is frequently a skin primary entity; however, anal adenocarcinoma should be excluded when facing any EMPPD considering its association with the latter, insidious presentation, and, most important, its underrecognized malignant potential. Identification of an underlying anal adenocarcinoma significantly impacts the patient's management and prognosis.
A Rare Case of Primary Cutaneous Osteosarcoma: (Poster No. 63)
Primary cutaneous osteosarcoma is an exceedingly rare malignant mesenchymal neoplasm of the skin that produces bone, osteoid, or chondroid material and does not involve the underlying bone. The most common site for extraskeletal osteosarcoma is in the deep soft tissues of the thigh, upper extremities, and retroperitoneum; however, it may occur anywhere in the body. Involvement of the skin is rare and when it does occur it is more commonly due to metastatic disease rather than a primary malignancy. We report an uncommon case of primary cutaneous osteosarcoma. Our patient is an 84-year-old man with an unremarkable medical history who presented to the dermatology clinic complaining of a 0.5 × 0.4-cm pink flesh to translucent-appearing, shiny papule on the right superior jawline that was not connected to the underlying bone. Clinically the differential diagnosis included basal cell carcinoma, trichoepithelioma, and other adnexal tumors. An excisional biopsy was performed that demonstrated an unremarkable epidermis with a hypercellular reticular dermis with occasional large spindled cells with amphophilic cytoplasm. The deep dermis was involved by mature osteoid formation and infiltration of highly mitotically active, atypical epithelioid, and spindled cells with abundant nuclear pleomorphism, amphophilic cytoplasm, and poorly defined cell borders. Occasional multinucleate forms were seen. Immunohistochemistry was performed that showed strong positive staining with vimentin. Based on these histomorphologic findings, a diagnosis of primary cutaneous osteosarcoma was made. Our case adds to the dearth of literature regarding primary cutaneous osteosarcoma and provides pathologists and dermatologists much-needed insight into this rare condition.
Extravascular Papillary Endothelial Hyperplasia Presenting as a Left Elbow Mass: (Poster No. 64)
Papillary endothelial hyperplasia (PEH), also known as Masson tumor, is a benign lesion caused by a reactive proliferation of endothelial cells. PEH most commonly occurs within the lumen of thrombosed vessels or preexisting vascular tumors. Extravascular PEH accounts for approximately 5% of all cases. We report a case of PEH with an uncommon presentation and location. A 52-year-old white man with a past medical history significant for rheumatoid arthritis presented with a painful left elbow mass. Surgical removal was performed and revealed a tan-pink mass measuring 5.7 × 4.5 × 3.0 cm. On cut section, the mass had a partly cystic appearance. Histology revealed organizing thrombus with associated endothelial hyperplasia with frondlike papillary architecture and cytologically bland CD34 positive endothelial cells. No evidence of a vessel wall surrounding the tumor was observed. A diagnosis of extravascular PEH was made. PEH was first described in a hemorrhoidal vein by Pierre Masson in 1923, and accounts for approximately 2% of all vascular tumors of the skin and subcutaneous tissues. PEH most commonly occurs in areas subjected to trauma such as the digits, head, neck, lower extremities, and trunk. Age distribution ranges from 9 months to 80 years. Extravascular PEH is the least common form and may be difficult to distinguish from angiosarcoma. Bland endothelial cytology and lack of adjacent tissue infiltration help establish the diagnosis of PEH. This case report serves to raise awareness of this clinicopathologic entity and emphasizes the importance of differentiating PEH from angiosarcoma.
Giant Solitary Trichoblastoma of the Groin: First Reported Case: (Poster No. 65)
Trichoblastomas and basal cell carcinomas (BCCs) both originate from infundibular stem cells and may be challenging to differentiate, especially in a limited biopsy of a giant lesion. Trichoblastoma is a benign neoplasm commonly found in the face as a solitary papule. It uncommonly occurs at other locations and can present as an exceedingly rare giant variant, but to our knowledge this has never been described in the groin. Hereby, we present a case of a 64-year-old man who presented with a nonpainful right groin mass. It remained pea size for 4 years but grew to reach golf ball size during the previous 5 months. The core biopsy showed a dermal lesion composed of numerous islands of basaloid cells exhibiting peripheral palisading and papillary mesenchymal bodies within a cellular stroma. Although the absence of epidermis precluded the evaluation of an epidermal connection, based on the presence of mesenchymal bodies and the intratumoral preserved cytokeratin 20–positive Merkel cell population, trichoblastoma was favored over BCC. The subsequent resection of the mass revealed a 5-cm well-circumscribed, lobulated, solid mass and confirmed the absence of epidermal connection, separation artifact, or perineural invasion. The final diagnosis of giant solitary trichoblastoma (GST) was rendered. This case demonstrates that GST should be included in the differential diagnosis of basaloid follicular germinal cell tumors of the groin and has to be differentiated from giant basal cell carcinoma, which has been reported in this region and is clinically with poorer prognosis.
Two Unexpected Findings in Malignant Melanoma Node Dissections: (Poster No. 68)
A 64-year-old woman presented for a rapidly growing mass of the scalp and a painful lump in the neck. Biopsy of the scalp mass revealed malignant melanoma, spindle cell type, and an ultrasound revealed left neck and supraclavicular lymphadenopathy. In January 2015 the patient underwent resection of the scalp mass and left neck dissection. Microscopic examination revealed malignant melanoma, spindle cell type, Clark level V, and one level of 5 out of 25 lymph nodes with metastatic melanoma. In addition, there were minute foci of metastatic follicular papillary thyroid carcinoma in one level 2 lymph node. In March 2015 the patient underwent total thyroidectomy. Pathology revealed a microscopic focus of papillary thyroid carcinoma in the right lobe, and one lymph node metastasis. A 70-year-old man presented with a rapidly growing “nevus” of his right arm, and a palpable axillary nodule. Biopsies revealed malignant melanoma with metastasis to an axillary lymph node. In December 2014 the patient underwent a wide local resection with axillary dissection. Microscopic examination revealed an ulcerated malignant melanoma, Clark level IV, and 2 of 11 lymph nodes with metastatic melanoma. Incidentally, one node contained numerous plasma cells with κ restriction. Workup to rule out multiple myeloma was performed, and a diagnosis of primary lymph node plasmacytoma was made. In both patients presented here, significant additional malignancies were diagnosed at an early stage during lymph node dissection for malignant melanoma. This emphasizes the importance of meticulous microscopic examination in lymph node dissections.
Pachydermodactyly: Report of 2 Cases: (Poster No. 69)
Pachydermodactyly is a rare form of superficial digital fibromatosis resulting in asymptomatic firm swelling of the lateral sides of the proximal interphalangeal joints of the fingers and is seen mainly in young men. The etiology of pachydermodactyly is still unclear, but exogenic factors may be the main cause. This abnormality frequently involves the second, third, and fifth fingers. We report 2 cases of pachydermodactyly; case 1 was a 17-year-old adolescent boy with a 3-year history of progressive, asymptomatic swelling of the lateral aspects of the PIP joints of all fingers of both hands. He reported no history of trauma. The second case was an 18-year-old woman with a history of asymptomatic, bulbous, firm swelling of the PIP joint of middle finger of her right hand. She was a carpet weaver and had a history of mild, repetitive mechanical trauma on her finger during her work. Histopathologic examination of both biopsy specimens from the lesions revealed marked hyperkeratosis and acanthosis of the epidermis and significant thickened dermis composed of eosinophilic collagen bundles and slight increase in number of fibroblasts.
MAML2 Translocation Has the Last Word on Diagnosing an Oncocytic Mucoepidermoid Carcinoma: (Poster No. 70)
Mucoepidermoid carcinoma is the most common malignant tumor of the salivary gland. The oncocytic variant of mucoepidermoid carcinoma (OMEC) is rare and some OMEC show exclusive oncocytic morphology. Here we report an OMEC case of the parotid gland in a 73-year-old woman with exclusive oncocytes and rare mucocytes. The case was initially misdiagnosed as oncocytic carcinoma by a pathology consultant based on morphology only. Further workup revealed that the neoplastic cells had diffuse nuclear positivity with p63 immunostaining and the presence of the MAML2 translocation, supporting the diagnosis of OMEC. Distinguishing OMEC of exclusive oncocytes from oncocytoma and oncocytic carcinoma can be very challenging for pathologists and is critical for proper clinical management. The observation of mucocytes in an oncocytic salivary neoplasm should raise the suspicion of OMEC. Our experience suggests that appropriate ancillary studies, especially the MAML2 translocation, may provide the essential evidence in difficult cases.
Giant Cell Tumor of Skull Base With Extensive Local Invasion: (Poster No. 71)
Giant cell tumor constitutes 1%–2% of all head and neck tumors. The most common sites are sphenoid and temporal bone. We present a case of primary skull-base giant cell tumor with widespread local extension. A 58-year-old African American man presented with difficulty in swallowing and swelling in the head and neck, 1 month after partial resection. On imaging, the large heterogeneously enhancing soft tissue mass centered within the skull base and sella extended to sphenoid sinus, left middle ear, nasopharynx, oropharynx, and around bilateral carotid arteries. The patient progressed to acute airway compromise requiring tracheostomy. The patient underwent debulking through extended endoscopic endonasal approach and received postoperative radiotherapy. On histopathology, mitotically active, round. mononuclear stromal cells interspersed with numerous osteoclastic giant cells were seen. The nuclei of the 2 cell types appeared very similar. Spindle cells were not seen. Immunostain for CD68 is positive in giant cells, whereas cytokeratin, synaptophysin, S100, CD30, CD31, and PLAP immunostains were uniformly negative. Diagnosis of conventional giant cell tumor of bone was rendered. Because of local invasion, recurrent nature and the rarity in the head and neck region with difficulties resecting the tumor completely prolongs the morbidity. This uncommon lesion should be considered in differential diagnosis in any extensively involved skull-base mass and requires long-term follow-up.
Squamous Cell Carcinoma With Myxoid Stroma: (Poster No. 76)
Although many variants of squamous cell carcinoma exist, squamous cell carcinomas with myxoid stroma have only rarely been described in the literature. Herein we describe a case of a 52-year-old man with a 1.4-cm posterior right nasopharynx mass, with metastases to bilateral cervical lymph nodes and diffuse bony metastases. On biopsy, the nasopharyngeal mass demonstrated a poorly differentiated carcinoma with rare foci of identifiable squamous differentiation, including squamous pearl formation, set within abundant myxoid stroma. There was no evidence of peripheral palisading of tumor cells, mucus cells, glandular formation, or reduplicated basement membrane material. A biopsy of a sacral metastasis and resection of a humeral metastasis demonstrated similar morphologic features. Immunohistochemical workup of the nasopharyngeal mass showed that the tumor was strongly and diffusely positive for cytokeratin AE1/AE3 and squamous markers P40 and P63. Focal positivity for EMA was noted, whereas the tumor was negative for S-100 and CD117. When combined with the morphologic findings, the immunohistochemical stains helped to confirm the diagnosis and exclude other important entities in the differential (including adenoid cystic carcinoma, sarcoma, and melanoma). The patient has responded well to chemoradiation therapy for nasopharyngeal carcinoma, including resolution of his nasopharyngeal mass and marked interval decrease in size of his osseous and cervical metastases. To our knowledge, this is the first report of a keratinizing squamous cell carcinoma of the nasopharynx with myxoid stroma.
Primary Mucosal Melanoma in the Nasopharynx, Clinically and Histologically Mimicking a Highly Vascularized Tumor and Sinonasal Undifferentiated Carcinoma, Respectively: (Poster No. 78)
Primary mucosal melanoma of the head and neck is a rare and aggressive neoplasm, accounting for 0.7%–3.8% of all melanomas, involving the sinonasal cavity, pharynx, and larynx. Features such as pseudopapillary architecture and pigmentation are associated with worse outcome. Because of its rarity in the sinonasal cavity, mucosal melanoma is difficult to diagnose. We report the case of a 68-year-old man with an impression of sinonasal polyposis on a computed tomography scan. Paraffin-embedded and formalin-fixed tissue blocks were microscopically examined. Based on the location, a list of differential diagnosis was formulated and a panel of different immunohistochemical stains was applied. The histopathologic examination showed interspersed sheets of atypical cells with moderate amount of cytoplasm and prominent nucleoli, negative for pancytokeratin, cytokeratin 5/6, synaptophysin, chromogranin, myogenin, CD99, and CD20. Although CD3 highlights the lymphocytes in the background, tumor cells were strongly positive for Melan A, S100, and HMB45, confirming the diagnosis of malignant melanoma. Primary malignant melanoma in the nasal cavity is a very rare condition. Histologically, it can mimic other neoplasms more frequent in that location, such as sinonasal undifferentiated carcinoma, high-grade lymphoma, or nasopharyngeal carcinoma (undifferentiated type). Thus, malignant melanoma should always be in the differential diagnosis, especially when reporting frozen.
Morphology and Immunohistochemical Study of Oncocytoma Arising From Salivary Gland and Kidney: (Poster No. 82)
Context: The oncocytomas of salivary gland and kidney have similar, if not identical, histomorphology. With new concepts and availability of new immunohistochemical (IHC) markers, we systemically studied these 2 tumors based on morphology and IHC stains.
Design: Cases of oncocytomas of salivary gland and kidney were retrieved from our department archive. All cases were reviewed and diagnosis was confirmed. Tissue microarray (TMA) was constructed. IHC stains PAX8, P63, CK5/6, keratin, and epithelial membrane antigen (EMA) were performed on TMA slides.
Results: Totals of 30 and 25 cases of oncocytomas from kidney and salivary gland, respectively, are included in this study. Microscopically, kidney oncocytomas show solid/nested growth pattern with uniform cell population, whereas salivary gland oncocytomas have focal vaguely glandular formation and 2 cell populations. In addition, kidney oncocytomas showed diffuse positivity of PAX8, keratin, and EMA. On the other hand, salivary gland oncocytomas present with 2 cell staining patterns: one cell population is strongly positive for P63 and CK5/6; another cell population is strongly positive for keratin and EMA.
Conclusions: Oncocytomas from salivary gland and kidney are morphologically similar with subtle difference that can be confirmed by IHC stains: kidney oncocytomas with uniform cells that are positive for PAX8; salivary gland oncocytomas present with morphologically and immunophenotypically distinct 2 cell populations: epithelium and myoepithelium. Oncocytomas from salivary gland and kidney are originating from different cells and presumably have different tumorigenesis.
Keratocystic Odontogenic Tumor With Human Papillomavirus Infection and Mild Dysplasia: (Poster No. 84)
Keratocystic odontogenic tumor (KCOT) is an odontogenic cystic neoplasm with a potential for locally aggressive behavior and high recurrence rate. Here we report the case of a recurrent KCOT that was associated with human papillomavirus (HPV) infection and mild dysplasia. The patient is a 68-year-old man who underwent a cyst excision from his left mandible with extraction of tooth #18. Microscopically, a typical KCOT was present. Approximately 20% of its squamous lining showed features of mild dysplasia, including koilocytic changes and binucleation. p16 and p53 stains were positive in the dysplastic area. A HPV typing assay revealed HPV subtype 16. The case was diagnosed as KCOT with HPV-associated mild dysplasia. Two years later, the patient had a recurrent tumor removed from the same area, which showed no residual features of HPV infection or dysplasia. The association of KCOT and HPV infection has been only rarely reported in the literature. Whether HPV could be involved in pathogenesis, aggressiveness, or risk of recurrence of KCOT remains to be fully elucidated.
Hemangioma Presenting as a Hypopharyngeal Mass in an Adult: (Poster No. 88)
Hemangiomas are very common tumors characterized by increased number of normal or abnormal vessels filled with blood and constitute 7% of all benign tumors of infancy and childhood; most are present from birth and eventually regress spontaneously. Although hemangiomas typically are localized lesions confined to the head and neck, they can occasionally be more extensive and can occur internally. Nearly one-third of these internal lesions are found in the liver. Hemangiomas in the postcricoid region have almost exclusively been reported in infants and young children. Here, we are reporting a case of hypopharyngeal hemangioma in a 64-year-old man who presented with recurrent dysphagia. Laryngoscopy showed a 5-mm, granular-appearing, pedunculated mass in the postcricoid region. It was excised by suspension microlaryngoscopy with KTP laser. Microscopic examination showed closely packed spindle cells with scant fibrous stroma and spaces containing blood. Immunohistochemical staining with CD34 and SM-actin showed that the lesion was composed of numerous small blood vessels. The spindle cells were focally positive for S-100 and CD117. These morphologic features and immunohistochemical staining pattern confirmed the diagnosis of hemangioma. The postcricoid region is a very uncommon location for hemangioma. There have been few cases of hypopharyngeal hemangioma reported in the literature in the adult population. This case study emphasizes the importance of recognizing hemangioma in an adult patient presenting with a hypopharyngeal mass. Clinicians and pathologists should be aware of this unusual location and presentation of hemangioma.
Basaloid Squamous Cell Carcinoma Involving the Salivary Gland: A Pitfall on Fine-Needle Aspiration: (Poster No. 89)
We present an unusual case of a 59-year-old woman with basaloid squamous cell carcinoma involving the parotid gland. The patient presented with a right parotid mass for 1.5 months. An ultrasound demonstrated a 2.7 × 1.7 × 1.6-cm lobulated, hypoechoic mass with minimal internal vascularity in the right parotid gland. Smears on fine-needle aspiration of the mass showed basaloid epithelial cells arranged in cohesive groups and clusters with nuclear crowding/ overlap. Occasional groups displayed nested to trabecular architecture with adjacent globular and linear arrays of hyalinized, basement membrane–like material. The cells had moderately to markedly atypical, round to oval nuclei with high nuclear to cytoplasmic ratios, occasional prominent nucleoli, coarse chromatin, and scant cytoplasm. The differential diagnosis on fine-needle aspiration included basaloid salivary gland neoplasms such as adenoid cystic carcinoma, basal cell adenocarcinoma, or carcinoma ex pleomorphic adenoma. Total parotidectomy was performed, with a final diagnosis of basaloid squamous cell carcinoma. Histology showed predominantly basaloid tumor cells displaying only focal areas with abrupt keratinization and entrapped hyalinized material. Immunohistochemical stains were positive for CK7, CK5/6, p63, and EMA. Tumor cells were negative for CK20, CEA, calponin, and CD117. This case illustrates the pitfall of salivary gland neoplasms with basaloid cells and hyalinized material on aspiration cytology. Consideration must be given for the possibility of involvement by basaloid squamous cell carcinoma, a non–salivary gland neoplasm with cytologic features that mimic those of basaloid salivary gland neoplasms.
Granular Cell Tumor of the Orbit: (Poster No. 92)
Granular cell tumor (GCT), previously referred to as granular cell myoblastoma, is a rare benign soft tissue tumor that may involve the orbit, periocular skin, lacrimal sac, optic nerve, ciliary body, conjunctiva, and caruncle, in addition to nonocular tissues such as the skin, gastrointestinal, respiratory, and genital tracts, and peripheral nerves. Recent ultrastructural and immunohistochemical studies suggest Schwann cells as the probable origin of the tumor. This is a case of a 53-year-old woman who presented with history of paresthesia and diplopia during the last few weeks. Magnetic resonance imaging of brain revealed a relatively well-circumscribed, hypotense mass measuring 1.6 × 1.3 × 1.0 cm on expected location of superior oblique muscle that was in close proximity to optic nerve. The tumor was approached via cul-de-sac orbitotomy. We received one tan to gray, well-demarcated, encapsulated mass measuring 1.6 × 1.3 × 1.0 cm. Microscopic examination showed the tumor consisted of nests of polygonal cells with prominent round to oval nuclei in a collagenized stroma with a fascicular development pattern, with surrounding muscle. Immunohistochemical staining showed significant positivity for S-100 protein and PAS diastase resistant. These morphologic features and immunohistochemical staining pattern confirmed the diagnosis of granular cell tumor. The orbit is a very uncommon location for granular cell tumor. This case study emphasizes the importance of recognizing granular cell tumor in orbit. Clinicians and pathologists should be aware of this rare tumor while diagnosing orbital tumors.
Metastatic Neoplasms to the Thyroid Gland: A Report of 31 Cases From a Single Medical Center: (Poster No. 93)
Context: Although metastatic neoplasms to the thyroid gland are uncommon, the incidence appears to have increased in recent years.
Design: Cases of metastatic neoplasms to the thyroid gland were retrospectively retrieved from the surgical pathology archives at Barnes-Jewish Hospital from Jaunary 1, 1989, to September 15, 2014.
Results: Among 1415 cases of thyroid malignant neoplasms, 31 cases represented metastasis to the thyroid gland, with 12 cases occurring in the last 4 years. The median age was 62 years (range 35–80 years), with a female predominance (61%). Renal cell carcinoma (RCC), clear cell type, was the most common metastasis (12 cases), followed by squamous cell carcinoma of the head and neck (6 cases: 3 tongue primaries and 3 larynx primaries), adenocarcinoma of the colon (5 cases), lung (4 cases: 2 squamous cell carcinoma and 2 small cell carcinoma), adenocarcinoma of the breast (2 cases), and soft tissue sarcoma (2 cases). The average time period from primary tumor diagnosis to metastasis to the thyroid was 30 months (0 to 158 months), and 2 cases of metastatic RCC were detected before the primary tumor. Among 12 patients with RCC, 3 had concurrent papillary thyroid carcinomas.
Conclusions: The thyroid gland was an uncommon site of metastasis as judged by the past literature. At least in our recent experience, we have seen an increase in the number of cases, which may reflect a true increase in incidence or a more aggressive diagnostic approach. Metastatic RCC was the most common category, and can be the initial presentation. Both papillary thyroid carcinoma and metastatic RCC can coexist.
Discovering the Face of a Mammary Analogue Secretory Carcinoma in an 11-Year-Old Boy: A Case Report and Review of the Literature: (Poster No. 95)
Salivary gland malignancies are rare in the pediatric population, with mucoepidermoid and acinic cell carcinomas being more frequent. The recently described mammary analogue secretory carcinoma (MASC) has emerged as a veritable diagnosis of exclusion. The few cases of MASC described in adolescents occurred in 13- to 17-year-old patients with equal sex distribution. The morphologic overlap among MASC, acinic cell, and mucoepidermoid carcinomas requires use of immunohistochemical stains and molecular testing. We present a case of an 11-year-old boy who was diagnosed with a MASC in the right parotid. He presented with a slowly enlarging 3.2-cm parotid mass that was biopsied by fine-needle aspiration and mucoepidermoid carcinoma was the favored diagnosis. Resection showed a well-circumscribed lesion with central hemorrhage. Histologic examination showed a lobulated neoplasm separated by thick fibrous bands with microcystic, papillary, and follicular architecture containing eosinophilic secretions. The tumor cells were uniform with conspicuous nucleoli and patchy vacuolated cytoplasm. Focal necrosis was present. PAS-positive luminal secretions and scattered cytoplasmic granules were identified. Iron stain identified prominent hemosiderin-laden macrophages within the fibrous bands. The tumor cells were positive for CAM5.2, CEA, and mammaglobin; weakly positive for GATA-3, DOG-1, and S-100; and negative for p63. The main diagnostic considerations were MASC or zymogen-poor acinic cell carcinoma. ETV6-NRK rearrangement was identified by FISH, confirming the diagnosis. To our knowledge, this is the youngest pediatric patient diagnosed with MASC. It is becoming increasingly important to exclude MASC in pediatric patients when acinic cell carcinoma is a main diagnostic consideration.
Medullary (Thyroid)-Like Carcinoid Tumor (Neuroendocrine Carcinoma) of the Larynx: Does a Medullary Carcinoma of Larynx Exist and Is a Distinction From Carcinoid Tumor Important?: (Poster No. 97)
Larynx carcinoids may express calcitonin. Medullary (thyroid)-like carcinoid tumor (MLCT; medullary-like moderately differentiated neuroendocrine carcinoma) has been previously described. These tumors secrete and express calcitonin similarly to medullary thyroid carcinoma (MTC). We report an unusual case of MLCT that presented as mass in the right arytenoid fold with increased serum calcitonin level (SCL) and TTF-1 expression. A 57-year-old man presented with a 4-year history of right-sided pharyngeal pain and tenderness. A supraglottic (right arytenoid fold) lesion was found and resected. The tumor was present in the submucosa and was characterized by sheets and nests of cells with round to oval nuclei with finely granular chromatin and eosinophilic cytoplasm. A Congo red stain was positive for amyloid. The tumor was strongly positive for AE1/AE3, chromogranin, synaptophysin, PTH, and calcitonin, and was focally positive for TTF-1. These cells were weakly positive for CEA and S-100, and negative for HMB-45, somatostatin, and serotonin. These features were consistent with MLCT. After resection, SCL was 8 pg/mL. After 43 months, the patient presented with metastasis on his neck lymph nodes. His SCL was 14 pg/mL. A total thyroidectomy showed multifocal C-cell hyperplasia. Eight years later, a right false vocal cord and neck recurrence were found and resected. At 11 years, a well-differentiated (grade 1) pancreatic neuroendocrine tumor was found. At 12 years, an additional neck recurrence was found. Before making a diagnosis of MLCT, a diagnosis of MTC should be excluded; however, the origin of MLCT from ectopic C-cell–like cells is entertained.
Electronic Atlas of Epithelioid Soft Tissue Tumors: Pathology “App” Development Made Easy: (Poster No. 100)
Context: An electronic atlas “app” for handheld devices can correlate clinical and histologic features quickly. The Atlas of Pancreatic Pathology and Cytopathology apps developed by Johns Hopkins Pathology (itunes.apple.com, 2012) allow for accessible, rapid review of pancreatic histology. Digital distribution of textbooks for cytopathology teaching has also been effective. However, pathology, as a specialty, is lagging in integrating handheld devices into training and daily practice. Time, funding, and lack of programming knowledge can be attributed to the scarcity of pathology apps. To address this gap, we developed a proof-of-concept atlas app encompassing soft tissue tumors with epithelioid morphology.
Design: A free video game development platform (GameMaker Studio v1.4, YoYo Games Ltd, Dundee, Scotland) was selected because it is export platform agnostic, has a robust graphical back end, and requires minimal programming knowledge. Static digital images were retrieved from our institution's whole slide image database.
Results: The app runs natively, using touch controls, on Apple and Android handhelds or Web browsers. Diagnoses can be filtered by immunohistochemical staining patterns, histologic keywords, and clinical features. It includes 11 diagnoses spanning 170 images, each with a brief description along with expected immunohistochemical staining patterns. To the best of our knowledge there are no other apps covering this material.
Conclusions: With minimal programming knowledge, a multiplatform pathology app can be developed. This may provide boundless opportunities to enhance pathology education in the absence of resources.
An Account of EPIC 2014 Beaker Implementation at Stanford Medical Center: (Poster No. 102)
Context: This presentation reviews Stanford University Medical Center's experience in implementation of the EPIC 2014 Beaker laboratory information system.
Design: The presentation will be chronological, beginning with the rationale for changing the laboratory information system and selection of Beaker. The majority of the presentation will review the implementation process at Stanford, including the overall scope, key aspects of system design, activities and timeline for execution of scope, and cutover plan. Review of the implementation will occur with references to EPIC phases 0 through 5 (planning, phase 0; design, phases 1 and 2; build, phase 3; testing, phase 4; training, phase 4; go live, phase 5). This review will also highlight the process followed at Stanford, and they varied from recommendations by the vendor EPIC, in particular testing and training. Throughout the presentation, managerial points, specifically what was done well and what could have improved upon, will be highlighted.
Results: Pre– versus post–go-live turnaround times and other key performance indicators will be revealed. In summary, turnaround times showed a slight bump in the receive-to-verify time interval within the first week of go-live, which normalized to pre–go-live levels within 5 days. The number of mislabeled specimens was reduced, which we attribute to implementation of positive patient identification.
Conclusions: EPIC Beaker is a viable laboratory information system, and its strengths include positive patient identification and vertical integration with the electronic medical record. Weaknesses include lack of component level final resulting, critical call workflow, aliquoting/ specimen sharing, and quality control functionality.
A Computer Model for Semiautomatic Differentiation of Benign and Malignant Breast Lesions: (Poster No. 104)
Context: We have developed a computer model to differentiate between benign and malignant breast lesions.
Design: A series of 20 benign sclerosing adenosis and 20 malignant (high-grade infiltrating ductal carcinomas) breast lesions was chosen. For each slide 5 images of lesions with diagnostic features were captured at ×400 magnification. Each image was divided into multiple 1000 × 1000-pixel images; these images were then binarized and segmented. The computer model then extracted cell graphs to identify the matrix of adjacent cells; the network properties were determined for each image and these variables were evaluated using a multilayer perceptron model. The model was trained to analyzing test images.
Results: A total of 200 lesions with diagnostic features were captured and 800 binarized images extracted from them. To train the model, 320 images (40%) were used, and the remaining 480 images (60%) were used for testing. To estimate the initial weights for the model, 4 training sessions were performed and the initial weights were selected from training weights that had the smallest sum of squared errors. The model was used to test the remaining images with a single binary outcome: benign versus malignant. The model was 99% accurate.
Conclusions: A computer model using multilayer perceptron neural network that extracts the cell graphs of breast images is highly accurate and precise for differentiating benign and malignant lesions. Currently the model is optimized for differentiating benign and malignant breast lesions but it can potentially be used for other organs and lesions as well.
Enhancing Laboratory Medicine Using “Big Data”: (Poster No. 105)
Context: Historically, laboratory has been the major analytical area providing a rich source of data for patient care. With the advent of “Big Data” the laboratory still is the major driver; however, the complexity of acquisition, analysis, display, and summarization makes additional resources and expertise necessary.
Design: The James A. Haley Veterans Hospital (JAHVH) created a Data Acquisition and Analytics Service (DAAS) to address the administrative and clinical needs of JAHVH. DAAS consists of experts that understand the structure, relationships, and location of data within both our Electronic Medical Record and the Corporate Data Warehouse (CDW). They work together with content experts from clinical and administrative services to improve efficiency, safety, accurate data capture, and overall patient care.
Results: The advantages of Big Data and a CDW are severalfold. We are able to analyze comparative data not just from our facility but in our instance 7 other hospitals. In addition to laboratory data, other clinical patient information is available. We investigated diabetic patients by geographic location including their medications, progress notes, comorbid conditions, ambulatory care visits, home-health visits, prosthetic items, and hospitalizations. Although extremely complex, DAAS can easily acquire and stage the information.
Conclusions: The facility and specifically the laboratory have already seen changes in our clinical practice and efficiencies gained though Big Data and the DAAS. We improved workload capture, appropriate PSA testing, and patient placement by acuity for appropriate and optimal care.
HCV Patient Warehousing Increased Between November 2013 and February 2014, and Patient Age Influences Warehousing Decision: (Poster No. 106)
Context: Sofosbuvir was approved in December 2013. We analyzed rates of patients with hepatitis C (HCV) in the Medivo Lab Exchange Database tested for HCV, having genotype 1 (G1), and proceeding to treatment versus those “warehoused” (delayed treatment initiation), during the period before versus after approval of sofosbuvir.
Design: We included all patients with HCV who had at least 1 viral load or genotype test between December 2010 and September 2014, and counted those who had only 1 test of either type during this period as being warehoused. We studied all HCV G1 patients (N =161 953) by age group to see if age was a factor in warehousing. Differences between age groups were tested using t test.
Results: We found a 75% increase in the number of HCV patients tested between November 2013 and January 2014, and the percentage of HCV G1 warehoused patients increased by 3.1% between November 2013 and February 2014, a significant increase (P < .001). Looking at age groups, we found that those in their 20s were 15% more likely to be warehoused than those in their 40s and 50s. This difference in mean warehousing rate is significant. We also found that patients in their 70s had the highest variability in their warehouse status.
Conclusions: The number of warehoused HCV patients increased around the time of the approval of sofosbuvir at the end of 2013. Patient age appeared to be a factor in warehousing decisions, with patients <40 years more likely to be warehoused than those ≥40 years.
Elizabethkingia meningoseptica as an Unusual Cause of a Community Acquired Infection With a Fatal Outcome: (Poster No. 107)
Elizabethkingia meningoseptica is an oxidase- and catalase-positive, nonfermentative gram-negative environmental saprophytic rod that can colonize medical devices and equipment, predictably because of its ability to form biofilms and resist mechanical and chemical disinfection. This organism is associated with multidrug-resistant nosocomial infections. Here, we present a case of community-acquired E meningoseptica. A 73-year-old man with history of diabetes mellitus, decubitus ulcer, chronic obstructive pulmonary disease, and laryngeal cancer in the remote past, presented with symptoms, signs, and laboratory data consistent with sepsis and multiorgan dysfunction syndrome. An initial set of blood and pleural fluid cultures demonstrated gram-negative rods. Following overnight incubation on solid media in a CO2-enriched atmosphere at 35°C, pale yellow colonies grew on 5% sheep blood agar and chocolate agar, but no growth was observed on MacConkey agar. The isolates were identified by VITEK2 (bioMérieux, Inc., Durham, North Carolina) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry as E meningoseptica. Automated antimicrobial susceptibility tests demonstrated resistance to numerous drugs, except for fluoroquinolones. The patient's antibiotic regimen was switched from broad spectrum to levofloxacin with nafcillin on day 5 of his hospital stay. Although the patient cleared E meningoseptica infection, he remained in critical condition and shortly developed nosocomial infections involving the urinary tract with Candida albicans and the respiratory tract with Stenotrophomonas maltophila that led to death. In patients who present with severe sepsis caused by nonfermenting gram-negative bacteria, E meningoseptica should be considered, noting its resistance to broad-spectrum antibiotics and the potential for a devastating outcome.
Cross-Reactivity of Treponema pallidum Immunohistochemistry With Intestinal Spirochetes: (Poster No. 109)
Context: A commercially available polyclonal antibody for immunohistochemistry for Treponema pallidum (Biocare/PP153AA) is available, and has been found diagnostically useful in cutaneous biopsies from patients with secondary syphilis. We were concerned that non-Treponema spirochetes may cross-react, if this stain was used in the oropharynx or gastrointestinal tract. We used biopsies from patients with intestinal spirochetosis to assess potential cross-reactivity.
Design: We searched in the Institute's electronic archives from January 2005 to December 2014 for “Intestinal Spirochetosis.” Hematoxylin and eosin stains, as well as Warthin-Starry stains, were reviewed in all cases to confirm the diagnosis. Immunohistochemistry for T pallidum (Biocare/PP153AA) was performed on 2-μm-thick sections of the paraffin-embedded tissues for all the biopsies. Demographic information was obtained from the electronic medical records.
Results: Eight patients with intestinal spirochetosis involving the colorectal mucosa were identified and the diagnosis was microscopically confirmed. The ages of the patients ranged from 24 to 72 years (mean = 43 years). In all biopsies, there was strong reactivity (ie, positivity) with the polyclonal antibody for T pallidum.
Conclusions: Although this immunohistochemical stain for T pallidum has proven extremely helpful in cutaneous biopsies of patients with secondary syphilis and superior to the Warthin-Starry stain, caution is warranted when using this stain in anatomic locations wherein non-Treponema spirochetes are part of the normal microbiota.
BCG Lymphadenitis Following Immunotherapy for Bladder Cancer: (Poster No. 112)
This case is that of a 79-year-old man with a history diabetes mellitus, and recurrent urothelial carcinoma. He initially presented with severe intraepithelial atypia (carcinoma in situ), for which he received bacillus Calmette-Guérin (BCG) treatment. He was referred for a possible radical cystectomy, and presurgical staging computed tomography scan showed retroperitoneal and bilateral iliac chain lymphadenopathy. A computed tomography scan of the chest showed mediastinal and hilar adenopathy. He underwent mediastinoscopy with biopsy, and was found to have necrotizing granulomata. Stains for acid-fast bacilli were positive, but cultures failed to show growth. Lymphadenopathy is a well-recognized complication of the BCG vaccine, but diffuse lymphadenopathy following BCG immunotherapy for bladder cancer is uncommon, with isolated case reports in the literature. Different BCG strains used for vaccines have been shown to have different clinical outcomes, and it has been hypothesized that there might be a similar difference in outcomes among different BCG strains used for immunotherapy.
Mycobacterium neoaurum Septicemia in an Immunocompromised Patient Who Has a Central Venous Catheter: (Poster No. 115)
Mycobacterium neoaurum, a member of the Mycobacterium parafortuitum complex, is one of the rapidly growing mycobacteria species that are responsible for a variety of clinical syndromes in humans, including catheter-related bloodstream infection. Infections due to M neoaurum are rare; most M neoaurum bloodstream infections occur in immunocompromised patients. Diagnosis by conventional methods is challenging because its staining and morphologic characteristics overlap with other pathogens including Nocardia, Tsukamurella, Gordonia, and Rothia. We present a case of 36-year-old woman with a complicated medical history including diabetes mellitus, systemic lupus erythematosus, methicillin-resistant Staphylococcus epidermidis bacteremia, multiple drug–resistant urinary tract infections, seizure, neurogenic bladder with a suprapubic catheter, with a peripherally inserted central catheter line in place for several months, and on several medications including prednisone, who presented to our hospital complaining of weakness and abdominal pain. She had purulent urine and foul-smelling odor coming from her catheter, and was found to be septic. Urine culture grew extended-spectrum β-lactamase–producing Escherichia coli. Blood culture was positive for gram-positive beaded bacilli, acid fast partially positive in 3 blood culture sets; aerobic bottles. Colonies on chocolate agar were shiny orange colored. Sequence-based identification confirmed the diagnosis of M neoaurum. The catheter line was removed, and the patient was placed on different antibiotics based on the bacterial identification including doxycycline, ertapenem, and linezolid and Meropenem. Three weeks later, the patient improved significantly and was discharged.
Validation of Next-Generation Sequencing Technology in a CAP-Accredited Laboratory: (Poster No. 118)
Context: Next-generation sequencing (NGS) technologies are being introduced and used in the clinical laboratory arena. This is transforming the landscape of medicine in various diseases. Clinical validation of this methodology remains the challenge. We report our experience with the validation of Trusight One panel (Illumina) panel in a College of American Pathologists–accredited laboratory.
Design: Twenty-five blinded specimens from various laboratories were used for the validation in our laboratory for the Febrile Seizure Panel and the Autism Spectrum Panel. The Trusight One Sequencing (TSO) panel was used that provides comprehensive coverage of >4800 clinically relevant genes. The sequencing was performed on Miseq instrument using the v3 kit. The variant calling was done using Illumina Miseq Reporter (v2.4) and analyzed for sequence variant by Illumina Variant Studio (v2.2).
Results: There was a 100% correlation of the results, based on variants detected by our method and other laboratories using NGS and/ or Sanger sequencing technology. We noted dropouts in GC-rich region of the genes. Reducing the number of samples multiplex didn't overcome the problem. Sanger sequencing was needed for complete data of the GC-rich genes.
Conclusions: All the variants were identified and confirmed. The TSO is a robust NGS technology that can be used for various disorders in the clinical laboratory arena. Sanger sequencing is still needed to fill in the gap produced by NGS for complete analysis. NGS using TSO results in faster turnaround time for better patient management.
Effect of Noninvasive Prenatal Testing on Prenatal Aneuploidy Screening Uptake in a Rural Health Care System: (Poster No. 119)
Context: We examined the contribution of noninvasive prenatal testing (NIPT) screening for chromosomal abnormalities with cell-free fetal DNA (cffDNA) on use of prenatal screening options for Down syndrome and other aneuploidies in the Geisinger Health System, where the overall screening uptake rate has historically been lower than for urban populations. Screening is offered in a variety of general obstetric and specialty clinics.
Design: Recent performance rates for maternal serum and NIPT screening were calculated in the context of total system pregnancies. Midtrimester quad screen (AFP, hCG, uE3, and DIA) and first trimester combined screening (FTS) with hCG, PAPP-A and nuchal thickness were performed in house. NIPT with cffDNA analysis was sent to a referral laboratory. Serum alpha fetoprotein (AFP), human chorionic gonadotropin (hCG), unconjugated estriol (uE3), and pregnancy-associated plasma protein a (PAPP-A) were performed with the Immulite 2000 system (Siemens, Malvern, Pennsylvania). DIA was measured with a DSL ELISA system. Positivity rates were consistent with published values.
Results: Since 2010, the uptake rate for quad screen declined from 42.5% to 26.9%, FTS increased from 13.5% to 16.1%, and, during the past 2 years, NIPT accounted for 8.6% and 10.6%. Overall screening uptake increased incrementally from 48.5% to 53.6% during that period.
Conclusions: The addition of FTS and NIPT yielded progressive shifting of screening to earlier gestation samples. The NIPT screening captures an additional 5% of pregnancies that would not have otherwise had screening. We are honing efforts to understand the gap in pregnancies for which screening is not performed in order to improve efficiency of the prenatal testing program.
A Phase I Study of AZD9291 in Patients With EGFR-TKI–Resistant Advanced Non–Small Cell Lung Cancer: Safety, Efficacy, and EGFR T790M Mutation Testing: (Poster No. 120)
Context: AZD9291 (AstraZeneca) is an irreversible EGFR-TKI, selective for EGFR-TKI–sensitizing (EGFRm) and T790M resistance mutations. We report data from the global phase I study (AURA; NCT01802632) of AZD9291 in patients with EGFRm advanced non–small cell lung cancer (NSCLC).
Design: Patients with acquired resistance to EGFR-TKIs received oral AZD9291 20–240 mg once daily. Prospective T790M testing was required for inclusion in the expansion cohorts. Testing was performed at local laboratories where feasible, and centrally (Cobas EGFR mutation test) where tumor material was available. The primary objective was to investigate safety, tolerability, and efficacy (objective response rate [ORR]).
Results: As of December 2, 2014, 283 patients (female 62%, median age 60, Asian/white 61%/31%, immediate prior EGFR-TKI therapy 62%) were enrolled: dose escalation, 31 patients; dose expansion, 252 patients. A total of 91% (222 of 244) of samples submitted for central testing were analyzed successfully; 163 were T790M positive by central testing. One hundred sixty-one patients had both local and central T790M results, either positive or negative (concordance 89%; 143 of 161). Adverse events (AEs) in all patients were mostly mild (CTCAE Gr 1/2), with diarrhea (50%) and rash (grouped terms; 46%) most commonly reported. Investigator-determined treatment-related Gr ≥3 AEs occurred in 17% of patients. Investigator-assessed confirmed ORR: T790M positive, 59% (92 of 157; 95% CI, 51%–66%); T790M negative, 23% (16 of 69; 95% CI, 14%–35%). At the recommended Phase II dose of 80 mg, investigator-assessed confirmed ORR was 66% (95% CI, 52%–77%) in T790M-positive disease.
Conclusions: In this Phase I study, AZD9291 demonstrates clinical activity with a manageable tolerability profile. Central and local T790M results showed high concordance in expansion cohorts.
Dr Jänne is a consultant to AstraZeneca, Chugai, Pfizer, Merrimack Pharmaceuticals, Clovis Oncology, Genentech, and Roche; is a shareholder in Gatekeeper Pharmaceuticals; has received grant or research support from Astellas and AstraZeneca; and has received royalties from LabCorp. Mr Frewer, Dr Cantarini, Mr Dearden, Dr Jenkins, and Dr Ghiorghiu are employees and shareholders of AstraZeneca. Dr Yang is a consultant to AstraZeneca, Roche/ Genentech, Boehringer Ingelheim, MSD, Merck Serono, Novartis, Clovis Oncology, Eli Lilly, Bayer, Celgene, Astellas, Innopharma, and Ono Pharmaceutical, and has received honoraria from AstraZeneca, Roche/Genentech, Boehringer Ingelheim, MSD, Merck Serono, No-vartis, Clovis Oncology, Eli Lilly, Bayer, Celgene, Astellas, Innopharma, and Ono Pharmeceutical.
JAK2V617F Mutation Detection in Essential Thrombocythemia Revisited by Combined Allele-Specific Polymerase Chain Reaction and Pyrosequencing: (Poster No. 122)
Context: JAK2V617F mutation is a World Health Organization diagnostic criterion for essential thrombocythemia (ET) with detected frequency of 40%–50%. Infrequently low mutant allele burdens (<1%) are seen, and detection is discrepant because of varying sensitivities of testing methods used. This study combines allele-specific polymerase chain reaction (ASPCR) with pyrosequencing to improve sensitivity of detecting low-level mutant alleles.
Design: DNA from 85 patients with suspected chronic myeloproliferative neoplasms was tested with ASPCR. Positive cases underwent pyrosequencing, performed on both regular and ASPCR products. A 2% positive control was made using a wild-type blood DNA sample spiked with HEL cell line DNA homozygous for JAK2V617F mutation. The spiked HEL cell line DNA was serially titrated with wild-type blood DNA to 1% and 0.1% to assess sensitivity.
Results: Of the 85 cases tested with ASPCR, 9 were positive for JAK2V617F mutation and 5 were diagnosed with ET. Signal intensities varied, with the lowest weaker than 2% control. Mutant allele loads of the 5 ET cases by pyrosequencing on regular PCR products ranged from 8% to 27%. Pyrosequencing on ASPCR products improved detection of the lowest mutant allele load from borderline level of 8% to definitive level of 22%. Sensitivity assay of pyrosequencing on ASPCR revealed 13% mutant allele on 1% spiked DNA. In comparison, the sensitivity of regular PCR and pyrosequencing was 5%.
Conclusions: We conclude that our more sensitive method of combining ASPCR and pyrosequencing compared with ASPCR alone allows for detection of lower levels of mutant allele burden, allowing for more definitive diagnosis of challenging ET cases.
Development and Validation of Ion Torrent–Based Comprehensive Panel for Characterization of Single-Nucleotide Polymorphisms in Multiple Genes Implicated in Susceptibility and Severity of Graft-vs-Host Disease, Cytomegalovirus, and Epstein-Barr Virus Infections: (Poster No. 124)
Context: Graft-vs-host disease, which is modulated by immuno-suppression, is associated with high morbidity and mortality in patients treated by hematopoietic stem cell transplant. Cytomegalovirus and Epstein-Barr virus infections cause significant morbidity and mortality among immunosuppressed patients. Multiple single-nucleotide polymorphisms (SNPs) impact the susceptibility and severity of graft-vs-host disease as well as cytomegalovirus and Epstein-Barr virus infections.
Design: Based on literature review, a comprehensive 222-SNP panel representing 94 genes important in the development of graft-vs-host disease and the susceptibility of cytomegalovirus and Epstein-Barr virus infection was developed using the AmpliSeq website with in silico coverage of 99.35%. Libraries were prepared in 2 pools using 10 ng of DNA derived from a healthy individual. Following standard processing, samples were run on the Ion Torrent using 318v2 chips. The raw data, variant calls, and coverage analysis were analyzed by Ion Torrent Suite v.4.2.1.
Results: Two hundred nineteen of the 222 SNPs representing 94 genes were analyzed, with an average depth of coverage of 11 823 (range, 129–59 178). Comparison of in silico and analytical runs showed a high concordance for the target coverage (99.35% and 98.65%, respectively). Common SNPs were observed with expected frequencies consistent with those reported in the literature and SNP databases.
Conclusions: This panel represents a new, powerful tool for future correlative studies of multiple polymorphisms that impact the susceptibility to graft-vs-host disease in patients treated with stem cell transplant and other populations of immunosuppressed patients that are at risk for cytomegalovirus and Epstein-Barr virus infections.
Utility of Next-Generation Sequencing in Rectal Cancer Personalized Medicine: (Poster No. 125)
Context: Next-generation sequencing (NGS) has become a reliable technology in the routine clinical setting. Identification of KRAS mutation in colorectal cancer (seen in 35%–40% of patients) predicts the lack of response to epidermal growth factor receptor inhibitors. In this observational study, we summarized our experience identifying somatic mutations in rectal cancer patients using NGS technology.
Design: Nineteen rectal cancer cases were tested using the 50-gene Ion Torrent Cancer Hotspot Panel v2. DNA was extracted from unstained formalin-fixed, paraffin-embedded tissue sections. Barcoded libraries were prepared using 10 ng of DNA and multiplexed on Ion Torrent 318v2 chips. Variants were identified and annotated using the Torrent Suite Variant Caller Plugin (v.4.0.2). Quality and functional predictions were assessed using Golden Helix SVS (v.7.7.8, Bozeman, Montana).
Results: Nineteen patients (18 adenocarcinoma; 1 undifferentiated carcinoma) were predominantly older men (M:F =1.7:1; mean age, 61.5 years). Nearly one-third (31.6%) of them had metastatic disease (3 liver, 2 lung, 1 liver and lung). Actionable mutations were identified in 10 of 19 (52.6%) patients. These mutations were located in KRAS (8 cases), NRAS (1 case), and BRAF (1 case). KRAS mutation was most frequently seen at codon 12 (5 cases) and 13 (2 cases). In addition, we identified a single case with an uncommon KRAS mutation (c.436G>A, p.A146T).
Conclusions: NGS is a robust technology that can identify genetic variants in multiple genes simultaneously. More than half of our rectal cancer patients had actionable genes, suggesting that this technology may have clinical implications.
Liquid Biopsy Technique Reveals Cancer-Associated Genomic Signatures in Pregnant Women: (Poster No. 128)
Context: Neoplasms can shed detectable levels of cell-free DNA (cfDNA) into plasma. Noninvasive prenatal testing uses next-generation sequencing of cfDNA in maternal plasma for evaluation of fetal aneuploidies. Analysis of this sequencing data may also provide insights regarding the use of cfDNA to monitor neoplasm development, expansion, or recurrence.
Design: Following IRB approval, 84 846 cases were assessed for deviation from the normal diploid state using a quantitative metric. Cases with the most extreme deviation from expected diploid coverage were de-identified and reviewed for patterns of chromosomal variation by visual inspection of the whole genome. With this approach, trisomies or segmental copy number variations (CNVs) could be detected over any chromosome.
Results: Of the 149 (0.18%) cases selected for review, 106 were associated a single trisomy and 43 had CNVs on more than 2 chromosomes. in the latter group, 16 cases showed multiple large-amplitude CNVs affecting several chromosomes (oncoploidy). Five of these cases were from women with known cancers. The remaining 11 cases could indicate occult neoplasms that were present at the time of testing.
Conclusions: These data suggest that multiple CNVs in plasma cfDNA could reflect the presence of an occult neoplasm. The workup of patients with these secondary findings remains unclear. More studies are needed to determine the clinical significance of multiple CNVs and to provide guidance for the clinical follow-up of patients thought to be at high risk for an occult neoplasm based on analysis of “liquid biopsy” data.
Drs Halks-Miller, Chudova, and Barbarcioru are employees and shareholders of Illumina. Dr Halks-Miller is a consultant to Crescendo Biosciences.
Epstein-Barr Virus Viral Load as a Potential Predictor of Development of Posttransplant Lymphoproliferative Disorder in Pediatric Solid-Organ Transplant Recipients: (Poster No. 129)
Context: Posttransplant lymphoproliferative disorder (PTLD) is a well-recognized and potentially life-threatening complication after organ transplantation. Although the incidence of PTLD is higher in children than in adults, the correlation between Epstein-Barr virus (EBV) viral load and PTLD has not been well studied in children.
Design: One hundred thirty-five solid-organ transplant pediatric patients (mean age 5.3 years) whose highest EBV viral load in the peripheral blood was greater than 1000 (copy number/105 lymphocytes, measured by real-time polymerase chain reaction) between 2004 and 2013 in our institution were reviewed retrospectively. The patients were separated into 4 groups based on the EBV viral load: group 1 (>30 000, n = 15), group 2 (5000–30 000, n = 42), group 3 (2000–4999, n = 32), and group 4 (1000–1999, n = 46). The correlation of EBV viral load with pretransplant EBV serostatus, incidence, and duration of PTLD development was determined.
Results: Thirty-four of the 135 patients (25.2%) developed PTLD, including patients with liver (20 of 83; 24.1%), kidney (3 of 31; 9.7%), heart (7 of 16; 43.8%), and small intestine transplant (4 of 5; 80.0%). The incidence of PTLD was 60.0% in group 1, 26.2% in group 2, 25.0% in group 3, and 13.0% in group 4. Twenty-five of 34 PTLD patients (73.5%) were seronegative prior to transplantation and had higher EBV viral load. EBV-seronegative recipients developed PTLD faster (24.7 ± 28.47 months) than EBV-seropositive recipients (62.7 ± 67.93 months) (P =.02).
Conclusions: PTLD frequently occurred after solid-organ transplantation in EBV-naive pediatric patients with high EBV viral load. EBV viral load is a valuable predictor for the development of PTLD. Seronegative recipients with high EBV viral load should be monitored closely for the development of PTLD.
Targeted Genomic Profiling in Colon Cancer: Experience in a Large Community-Based Pathology Practice: (Poster No. 130)
Context: National Comprehensive Cancer Network (NCCN) guidelines recommend screening for Lynch syndrome and assessing for mutations in KRAS, NRAS, and BRAF genes to guide clinical management decisions in the setting of colon cancer. Additional biomarkers have been implicated that could potentially refine diagnosis, prognosis, and/or therapy selection.
Design: Based on NCCN guidelines and literature review, we designed a focused (7 gene) next-generation sequencing assay to complement our Lynch syndrome screening strategy. Our initial 3-month experience using this testing strategy in community practice is presented herein.
Results: An actionable alteration was detected in 92% of 183 total cases profiled. KRAS or NRAS mutation was detected in 81 patients (44%) who would not benefit from anti-EGFR therapies. BRAF mutation was detected in 16% and was informative to exclude Lynch syndrome in microsatellite unstable tumors and identify patients with a grim prognosis for which promising targeted therapies are in active clinical development. Thirty-six percent of cases that were wild type for KRAS, NRAS, or BRAF showed mutations in additional genes including PIK3CA, CTNNB1, TP53, and PTEN. Fifty-nine percent of mutated cases showed more than 1 mutation. CTNNB1 mutations were detected in 2% of cases and associated with clinical, morphologic, and pathologic findings highly suggestive of Lynch syndrome.
Conclusions: A focused next-generation sequencing panel composed of highly actionable genes provides additional information to existing screening assays and is feasible for implementation in community practice. CTNNB1 alterations need to be evaluated in larger studies as a potential complement to existing colon cancer testing strategies and a therapeutic target using WNT-pathway inhibitors.
All authors are employees of PathGroup. Dr Welch is also a shareholder of PathGroup.
Analytical Validation of a Proliferation-Based Molecular Signature Used as a Prognostic Marker in Early-Stage Lung Adenocarcinoma: (Poster No. 131)
Context: We have developed a gene expression signature that provides prognostic information for patients with early-stage lung adenocarcinoma that would benefit from adjuvant chemotherapy. This signature uses quantitative reverse transcription polymerase chain reaction to measure RNA expression of 31 cell-cycle progression (CCP) genes normalized to 15 housekeeping genes to provide a quantitative CCP score. The signature can identify aggressive early-stage tumors that might be suitable for postsurgical therapy. The aim of these studies was to validate the analytical performance of the CCP gene signature.
Design: The analytical performance of the CCP gene signature was evaluated using formalin-fixed, paraffin-embedded lung resections by assessing parameters such as precision, dynamic range, and RNA input requirements.
Results: The signature had a standard deviation (SD) of 0.06 score units, which is 1% of the clinical range of scores. The dynamic range of CCP scores in this signature was from –13 and 14 score units. The average amplicon efficiencies for target and housekeeper genes were comparable at 107% and 105%, respectively. All but one amplicon had a SD <0.5 CT. The gene signature reproducibly generated a consistent CCP score with RNA input concentrations between 0.12 and 62.5 ng/ μL, which is considerably larger than the concentration ranges used for clinical testing (2–40 ng/μL).
Conclusions: These studies demonstrate that the gene signature is robust and reproducible, making it suitable for use in a clinical setting.
Hepatitis C Virus (HCV) Genotype and Subtype Distribution of Patient Samples Tested at University of Texas Medical Branch in Galveston Between 2011 and 2014: (Poster No. 132)
Context: Hepatitis C virus (HCV) genotype data are routinely generated in clinical laboratories to guide treatment and predict prognosis. The aim of this study was to determine the distribution of HCV geno/subtypes and their association with demographic characteristic among the patients tested in the Molecular Diagnostics Laboratory at the University of Texas Medical Branch in Galveston between January 2011 and November 2014.
Design: Genotypes and subtypes were determined from a 240-bp fragment of the 5′ untranslated region and a 270-bp fragment of core region of HCV. The data were analyzed using statistical analysis software version 9.1.3.
Results: Among the 6573 patients with their HCV geno/subtype tested, the most frequent HCV geno/subtype was 1a (65.3%), followed by 3a (11.5%), 1b (10.4%), and 2b (8.8%). The HCV geno/subtype distribution has not varied over time. Race/ethnicity and sex were independently associated with genotype 1 infection when compared with types 2 and 3. African Americans and Hispanic Americans were 11.3- and 1.4-fold more likely to be infected with genotype 1 than whites, respectively. Men were 1.2-fold more likely to be infected with genotype 1 than women. When only genotype 1 infection was considered, African Americans were 1.9-fold more likely to be infected with 1b than whites. Patients older than 40 years old were 1.8-fold more likely to be infected with 1b than younger patients.
Conclusions: The most frequent HCV subtype in our patient population was 1a, followed by 3a, 1b, and 2b. This could serve as a starting point for testing association of HCV subtypes with hepatic steatosis and cirrhosis.
Use of SNP Microarray Technology for Block Identity Testing: (Poster No. 134)
Rarely, concern for specimen mix-up may require tissue identity testing against a known sample. Usually this is performed through analysis of short tandem repeat markers, which often requires sending the sample to a reference laboratory. We describe the novel application of in-house single-nucleotide polymorphism (SNP) microarray technology to confirm the identity of 2 sets of renal transplant biopsies with clinical concern for preanalytic specimen mix-up. Tissue identity testing was complicated by the presence of patient lymphocytes within donor renal tissue, resulting in chimeric specimens. Two sets of renal transplant biopsies with concern for specimen mix-up and a corresponding previous biopsy of known identity were obtained. Care was taken to confirm that the known biopsy was from the same renal transplant, as one patient was status post second cadaveric renal transplant. Genomic DNA was extracted from the formalin-fixed, paraffin-embedded blocks and analyzed using the Infinium CytoSNP-850K BeadChip and Genome-Studio (Illumina, San Diego, California). Genotypes were filtered to include SNPs with a minor allele frequency of 0.5 (approximately 750 SNPs); homozygous variants were identified in the sample with known identity and genotypes from the unknown samples were compared. Through use of this method, we were easily able to confirm that the specimens were correctly labeled. We present 2 cases in which microarray technology and SNPs were used to confirm tissue identity within formalin-fixed, paraffin-embedded blocks of chimeric samples, a previously undescribed technique. This method could be easily replicated at other institutions that already use microarray technology.
Anaplastic Supratentorial Cortical Ependymoma in a 62-Year-Old Man: (Poster No. 140)
Supratentorial cortical ependymomas are rare lesions that occur in the superficial cortex of young adults and are associated with a history of seizures. We report a case of a 62-year-old man who presented with altered mental status, left-sided weakness, and seizures. Magnetic resonance imaging revealed a 1.0 × 0.7 × 0.6-cm rim-enhancing mass in the right medial frontal lobe with associated diffuse gliomatosis suspicious for infection versus tumor. The patient underwent a bifrontal craniotomy with open interhemispheric resection of the mass. Histologic examination of hematoxylin and eosin–stained sections demonstrated markedly pleomorphic tumor cells with brisk mitotic activity that formed perivascular pseudorosettes. Immunohistochemical studies revealed that the tumor cells were immunoreactive for GFAP and S100 and focally immunoreactive for EMA and CD99. MIB-1 and Ki-67 labeled approximately 10% of tumor cells. The morphology and immunophenotype of the tumor cells are consistent with an anaplastic ependymoma, WHO grade III. The patient completed a 2-month regimen of radiotherapy. Subsequent imaging studies have failed to reveal progression of neoplasia 8 months after resection. Although the body of literature for supratentorial cortical ependymomas is growing (at least 45 reported cases), to date there are only 3 reported cases in patients 60 years of age or older, all of whom are female. Continued follow-up of the oldest reported case of supratentorial cortical ependymoma in a man to date will provide useful prognostic data for this rare patient demographic.
Suprasellar Anaplastic Hemangiopericytoma in a 34-Year-Old Man: (Poster No. 143)
A 34-year-old man with a 7-year history of a pituitary tumor treated with radiation therapy and 2 transsphenoidal resections at another institution presented with bitemporal hemianopsia. Magnetic resonance imaging revealed a 3.7×3.5×2.2-cm enhancing bilobed sellar/suprasellar mass causing significant mass effect, radiologically consistent with a pituitary macroadenoma. The patient underwent a left frontotemporal craniotomy with microsurgical excision of the sellar/suprasellar tumor. Hematoxylin and eosin–stained sections revealed a highly cellular, monomorphic spindle cell neoplasm with mild atypia, abundant microvasculature with occasional branching vessels, focal hemorrhage, and up to 7 mitoses per 10 high-power fields. Tumor cells were immunoreactive for CD34, STAT6, and EMA (focally and weak). Tumor cells were nonimmunoreactive for progesterone receptor, synaptophysin, chromogranin, S-100 protein, GFAP, and TTF-1. MIB-1 and Ki-67 labeled approximately 15% of tumor cells. Histology and immunohistochemistry were consistent with an anaplastic hemangiopericytoma, World Health Organization (WHO) grade III. The patient subsequently underwent radiotherapy and 2 reresections, both of which were positive for hemangiopericytoma. He died 7 months later after experiencing a pulmonary saddle embolus, but no autopsy was performed. Central nervous system hemangiopericytomas are rare, representing approximately 0.4% of all primary central nervous system tumors. Hemangiopericytomas of the sellar region are exceptionally rare, with only 12 reported cases in the world literature. Furthermore, only 2 of those cases were WHO grade III. Central nervous system hemangiopericytomas have a clinical and radiologic presentation that is strikingly similar to pituitary adenomas but have a differing biology and treatment, thereby meriting inclusion in the differential diagnosis of pituitary tumors.
Intracranial Solitary Fibrous Tumor With Pseudopapillary Architecture: Case Report of an Uncommon Tumor With Unusual Histopathology: (Poster No. 144)
Solitary fibrous tumor (SFT) is an uncommon soft tissue neoplasm first described in the pleura in 1931, and later recognized in other anatomical locations. Involvement of the central nervous system is rare; there are approximately 200 cases of central nervous system SFT in the English literature. To the best of our knowledge, this is the first report of an intracranial SFT showing areas of pseudopapillary architecture. This case involved a 73-year-old man who presented with recent onset altered mental status. Imaging studies showed a large left posterior parietooccipital region intradural, extra-axial mass with significant mass effect in the adjacent brain. Neuropathologic examination demonstrated a spindled mesenchymal neoplasm with variable cellularity and prominent collagen deposition. In areas, the tumor was discohesive, imparting a prominent pseudopapillary architecture. Entrapped brain parenchyma was present, indicating brain infiltration. The tumor cells were positive for CD34, CD99, vimentin, and BCL-2; EMA was negative. Both the Ki-67 and mitotic indices were low, and anaplastic nuclear features were absent. To the best of our knowledge, this is the first example of an intracranial SFT with pseudopapillary architecture. Occasional extracranial SFTs showing papillary features have been reported. The significance of this architectural pattern is unclear; it may be elucidated by future studies.
Primary Atypical Epithelioid Hemangioendothelioma of the Clivus: (Poster No. 146)
Epithelioid hemangioendothelioma, first characterized by Weiss and Enzinger in 1982, is an endothelial malignancy categorized as an intermediate entity between hemangioma and angiosarcoma. Epithelioid hemangioendotheliomas have an indolent course, are very rare (0.01% of cancer population), and can be found in multiple anatomical sites. More commonly, it presents as a painful, poorly circumscribed mass in the extremities, but has also been reported in the liver, bone, and lung. We report a case of a 60-year-old man with a 3.5-cm petroclival mass, with new onset diplopia and sixth cranial nerve palsy. Imaging showed a heterogeneous, expansile mass at the petroclival junction extending into the petrous bone to the left lateral C1 arch and into the posterior fossa. The mass was excised and showed clusters and rows of cells with medium-sized, atypical nuclei, large nucleoli, and eosinophilic cytoplasm imparting an epithelioid appearance. The cells were occasionally vacuolated and lined small vascular channels, supporting an endothelial origin. In addition to the nuclear atypia and large nucleoli, increased mitoses were seen (up to 4 per 10 high-power fields). The tumor cells were immunoreactive for CD31 and CD34 vascular markers as well as for vimentin. They were negative for S-100, HMB45, MART-1, CAM 5.2, and EMA. While several cases of intracranial epithelioid hemangioendotheliomas have been reported, this case had frank atypia (increased mitosis, large nucleoli, and nuclear atypia) and therefore may have different prognostic implications compared with epithelial hemangioendotheliomas without atypia.
Invasive Meningothelial Meningioma Involving Bone and Soft Tissue: (Poster No. 147)
Meningiomas constitute a histologically diverse group of tumors that arise from meningothelial cells. With the exception of a few observed variants, these tumors are slow growing and often remain asymptomatic or mildly symptomatic. Here, we present the case of a 37-year-old woman with a 6-month history of worsening exophthalmos and epiphora of the left orbit. Initial imaging studies were consistent with a large, malignant-appearing primary bone lesion with blastic and lytic features. In addition, there was a sunburst periosteal reaction involving the greater wing of the sphenoid bone with intracranial and surrounding soft tissue involvement. The tumor created a mass effect on the intraconal structures of the left orbit, resulting in exophthalmos of the globe. A biopsy of the involved soft tissues revealed scant tumor resembling meningioma in sheetlike cell clusters interspersed in reactive bone and fibrous tissue. An excision was subsequently performed of the affected bone and dura. Microscopic evaluation of the dura revealed nests of meningothelial cells diffusely infiltrating the dura without forming a nodular mass. In the resected bone specimen, the meningioma could be seen infiltrating the marrow spaces. No necrosis, mitosis, hypercellularity, or other atypical features were identified. A final diagnosis of meningothelial meningioma, WHO grade I, was made. This case demonstrates that meningiomas can mimic malignant processes on imaging and should remain a consideration in select ENT cases.
Pontocerebellar Hypoplasia (PCH1) With EXOSC3 Gene Mutation: Case Report and Review of the Literature: (Poster No. 149)
Pontocerebellar hypoplasia type 1 (PCH1) is a rare autosomal recessive disorder characterized by diffuse muscle wasting secondary to spinal cord anterior horn cell loss and cerebellar hypoplasia with global developmental and cognitive delay. Recent whole-exome sequencing studies have identified mutations in the exosome component 3 (EXOSC3) gene in approximately half of families with PCH1. In this report, we describe the autopsy findings of a dysmorphic and globally delayed 18-year-old man with PCH1 and EXOSC3 gene mutation, as well as a family history of 3 similarly affected brothers. The immediate cause of death was acute cardiorespiratory insufficiency with subacute pulmonary emboli and organizing bronchopneumonia. Gross neuropathology was remarkable for cerebellar atrophy and a pale substantia nigra. Microscopic neuropathology of the cerebellum demonstrated a hypocellular internal granule layer with atrophic and disorganized Purkinje cells, while the midbrain (substantia nigra) showed paucity of intracellular and extracellular pigmentation within dopaminergic neurons. The spinal cord showed relative reduction of anterior horn neurons, as previously described in the literature. In this case report, we review our current understanding of the genetic landscape of PCH1. Additionally, the presence of a pale substantia nigra has not been reported in these patients. While the clinical significance of a pale substantia nigra is unknown, this case suggests that the EXOSC3 gene may affect other neurologic structures in addition to the spinal cord anterior horn and cerebellum.
Giant Choroid Plexus Calcification in the Posterior Fossa of the Brain: (Poster No. 153)
We report here a case of a calcified mass in the posterior fossa in a 62-year-old man. This patient has a known history of a benign brain mass for at least 10 years. He presented with recent episodes of dizziness, poor balance, and significant headache. Computed tomography of the head without contrast and MRI found a 2.4 × 2.3 × 2.3-cm calcified mass in the posterior fossa arising from the region of left posterior medulla extending into the fourth ventricle with associated dilatation of the fourth, third, and lateral ventricles. A craniotomy was performed to completely remove the mass. The specimen appeared rock hard on gross examination. After decalcification microscopic examination showed extensive calcifications of different shapes and sizes intermixed with small foci of benign epithelium with focal papillary formation. The epithelium was focally positive for cytokeratin (CAM5.2 and AE1/AE3), weakly positive for GFAP, and negative for S-100, and was consistent with choroid plexus cells by immunohistochemical staining profile. The final diagnosis was rendered by a neuropathologist at the Mayo Clinic as a calcified mass consistent with giant choroid plexus calcification. This patient is doing well status post craniotomy.
Metastatic Glioblastoma: A Case Report of Pulmonary Metastases From Primary Glioblastoma: (Poster No. 154)
Glioblastoma, the most common and aggressive primary glial tumor, has a median survival time of approximately 3 months without medical treatment. Surgical resection, radiotherapy, and chemotherapy are the main forms of treatment and have been shown to increase life expectancy to 1 to 2 years. The tumor has an infiltrative growth pattern that distorts the normal anatomy and can extend to distant parts of the brain along white matter tracts. While glioblastoma commonly infiltrates surrounding brain tissue, extracranial metastases are extremely rare. This is most directly due to the lack of lymphatic vessels in the brain and the decreased ability of the malignant cells to invade blood vessels. We present a case of a 56-year-old woman with a history of a right temporal glioblastoma, who was found to have biopsy-proven metastases to the lung. The patient presented for a chest x-ray, as part of a requirement for a clinical trial, and was found to have bilateral lung nodules; a subsequent chest computed tomography scan showed numerous pulmonary nodules and a low-density lesion in the liver. The patient underwent surgery and a frozen section consultation was performed that showed infiltrative pleomorphic cells with pseudopalisading necrosis concerning for metastatic glioblastoma. The permanent section histology demonstrated similar histologic findings. Strong, diffuse staining for glial fibrillary acid protein and S-100 and negative staining for cytokeratin supported the diagnosis.
Dermoid Cyst in the Fourth Ventricle Complicated With Hydrocephalus and Herniation: (Poster No. 155)
Dermoid cysts in the fourth ventricle are rare and are often underdiagnosed and their complications may be fatal. We present such a case and hope to bring an attention to the clinicians and pathologists. A 14-year-old adolescent girl presented to the ED with subjective fever, headache, emesis, and neck pain. She was found unresponsive a few hours later and did not respond to resuscitation. Computed tomography scan showed a cystic mass in the fourth ventricle resulting in hydrocephalus and cerebellar tonsillar herniation. A brain-only autopsy demonstrated a 4.0-cm in diameter cystic lesion in the fourth ventricle adjacent to the cerebellar leptomeninges and brain stem. The cyst is lined by thin squamous epithelium with a few hair shafts seen focally and contains squamous debris, which is positive to pancytokeratin immunostain and negative for glial fibrillary acidic protein. Patient previous history is significant for polysplenia syndrome, situs inversus with levocardia, and nonrotation of intestine. Dermoid cysts in the posterior fossa possibly arise from epithelial cells retained during closure of the neural tube. Coincidence with other congenital malformations is all the more rare. These cysts usually cling tightly to the midline, and favor the posterior fossa, especially cerebellar vermis and fourth ventricle. The cystic wall may contain hair follicles and sebaceous and sweat glands, and the contents usually are desquamated products of the epithelial cells and secretions of the glands. Clinical manifestations are principally referable to the local mass effects, mostly headache and seizures. Chemical meningitis due to spontaneous rupture is rare but can be fatal.
Milestones-Based Curriculum Design: (Poster No. 159)
Context: As of July 1, 2014, pathology training programs are required to use Milestones to evaluate residents and fellows. Although the 6 core competencies remain the framework under which the Milestones are organized, application of individual Milestones can be difficult and models for the incorporation of Milestones into new and existing resident curriculum are lacking.
Design: A new outcomes-based microbiology curriculum designed around the Milestones was developed for residents at the University of Washington in Seattle. An Entrustable Professional Activity statement was developed to describe what the resident should be capable of doing at the end of the rotation (ie, function as a consultant and medical director). The individual experiences and skills necessary to prepare the resident to perform the Entrustable Professional Activity formed the basis of the goals and objectives for the rotation and were referenced against pertinent areas of the American Board of Pathology examination blueprints. Milestones were applied as evaluation criteria for the rotation.
Results: Use of the Entrustable Professional Activity as a framework simplified identification of relevant Milestones as evaluation criteria for the rotation. Use of Milestones in resident evaluation provides objective data for the Clinical Competency Committee and the Accreditation Data System, thereby reducing administrative burden.
Conclusions: Incorporation of the Milestones into resident and fellow curriculum can be accomplished through articulation of Entrustable Professional Activities. Although it was applied prospectively in this case, this methodology can also be applied to existing curriculum.
Understanding Educational Gaps in the Diagnosis of T-Cell Lymphoma via an Online Survey: (Poster No. 160)
Context: T-cell lymphomas (TCLs) are rare diseases whose accurate diagnosis poses significant challenges to pathologists. To understand these challenges and the role of CD30 immunohistochemistry (IHC) testing in lymphoma, an online survey was conducted among pathologists and hematopathologists who diagnose TCLs.
Design: A fieldwork agency invited 340 pathologists who diagnose lymphoma to participate in the survey. Participants met the following criteria: board-certified/eligible, noncommercial pathologist, 3–40 years in practice, and made a TCL diagnosis in the last 6 months. The 49-question survey required approximately 20 minutes to complete and was conducted online June 13 to July 18, 2014.
Results: One hundred fifty pathologists (100 pathologists, 50 hematopathologists), completed the survey. Fifty-one percent practiced in a community setting. Eighty-four percent of pathologists and 68% of hematopathologists indicated TCLs are the most challenging lymphomas to diagnose. Fifty-seven percent of pathologists and 46% of hematopathologists did not report using standard IHC panels for diagnosing TCL. Fifty-five percent of pathologists and 58% of hematopathologists did not identify CD30 as an important IHC stain for classifying TCLs. Overall, 48% of surveyed pathologists did not recognize the importance of differentiating TCL subtypes for determining patient treatment. Thirty-eight percent were unaware of an FDA-approved agent that targets CD30, with pathologists (26%) less likely to be aware than hematopathologists (62%).
Conclusions: Pathologists find diagnosing TCLs challenging and there is variation amongst pathologists in their workup. There is an underappreciation of the therapeutic impact of distinguishing TCL subtypes; there is an increased need to educate pathologists about the utility in performing CD30 IHC and the therapeutic significance of CD30 expression in lymphoma.
Mr Levak is an employee and shareholder of Seattle Genetics, Inc. Dr Slack is a consultant with Seattle Genetics, Inc.
Pathology Residency Quality Improvement Curriculum in a Large Academic Center: (Poster No. 161)
Context: Formal training in quality improvement and leadership is essential for success of future pathologists. The Accreditation Council for Graduate Medical Education (ACGME) Pathology Milestones emphasize participation in quality, risk management, and laboratory safety activities. Updated ACGME program requirements include participation in quality improvement projects. To merge the pathology-specific educational focus with recently adopted university-wide residency quality and safety requirements, a curriculum that provides pathology residents education and leadership opportunities in laboratory quality and safety was developed.
Design: Objectives and lesson plans were established, drawing from personal experiences and content borrowed from Clinical Quality Improvement courses, instruction by the College of American Pathologists, Lean/Six Sigma training, and the university required Institute for Healthcare Improvement Open School modules in quality improvement, cost of quality, root cause analysis, and leadership.
Results: Ten monthly 1-hour lessons touching 10 different pathology milestone subcompetencies are established for second-year pathology residents. Lesson formats include formal lectures, role playing, and hands-on learning. Topics include data collection, leading a team, project tools, Lean/Six Sigma, root cause analysis, and cost of quality. A resident-led quality improvement project under the mentorship of faculty will illustrate competency. Open discussion of project progress and challenges is incorporated into each session. Successful completion of the curriculum includes formal presentation of the project.
Conclusions: This curriculum meets pathology residency and institutional requirements in quality and safety. It engages residents early in training in developing professional relationships with faculty and laboratory staff, leading a team, and improving patient care, which are activities often reserved for those in practice.
Histology Laboratory Paraffin Waste Disposal: A Cost Reduction Opportunity: (Poster No. 165)
Context: Paraffin is the most popular histologic wax used in the processing of pathologic specimens for microscopy. A mixture of saturated hydrocarbon chains, it is used to infiltrate and then embed tissue. Excess paraffin disposal is a state-regulated activity. Disposal of excess paraffin as biohazardous waste may be an unnecessary expense. We investigated the most appropriate disposal method of paraffin waste, including both economic and regulatory considerations.
Design: Investigatory methods included review of relevant published literature, meeting with our histology laboratory manager, and speaking with Ohio State Environmental Protection Agency infectious and hazardous waste experts. Practices at other hospitals were determined by e-mail inquiry. The amount of paraffin waste in our histology laboratory was monitored, and disposal costs were determined.
Results: Per the Ohio State Environmental Protection Agency, paraffin wax containing minimal residual embedded tissue is neither an infectious nor a hazardous waste and thus can be disposed of in regular landfill trash. Our histology laboratory generates an average of 56 pounds of paraffin waste per day, which is currently disposed of as biohazardous waste. Savings of 87% is estimated if disposed of as regular landfill trash. Paraffin contaminated by hazardous laboratory chemicals would preclude landfill disposal.
Conclusions: Landfill disposal of paraffin at our institution is cost-effective and would meet state regulations regarding environmentally safe practices. This may be applicable to hospitals in other states depending on local regulations.
“Inflammatory Myofibroblastic Tumor”–Like Dedifferentiation of ALK-Rearranged Lung Adenocarcinoma: (Poster No. 167)
Anaplastic lymphoma kinase (ALK) functions as an oncogenic driver in a subset of hematopoietic, epithelial, and mesenchymal neoplasms. Activation of ALK most commonly occurs through gene fusion events, the presence of which predicts response to ALK-targeted inhibitors in some tumor types. Echinoderm microtubule-associated protein-like 4-ALK (EML4-ALK) fusions represent the majority of ALK rearrangements in lung adenocarcinomas and were, until recently, thought to be exclusive to that tumor type. However, recent work has identified EML4-ALK fusions in approximately 20% of inflammatory myofibroblastic tumors (IMTs), particularly in those arising in the lung. Here, we present a patient with an ALK-rearranged poorly differentiated lung adenocarcinoma with a predominant sarcomatoid component that was morphologically indistinguishable from IMT. The IMT-like component comprised the majority of the tumor and demonstrated positive immunohistochemical staining for ALK but negative staining for keratins and TTF-1. The adenocarcinoma component, which infiltrated adjacent tissue, was positive for keratins, TTF-1 and ALK. Macrodissection followed by targeted next-generation sequencing of the adenocarcinoma and IMT-like components revealed EML4-ALK rearrangements in both components with identical fusion sequences. No differences were identified in the mutational profiles of the 2 areas. Copy number analysis demonstrated focal gain of the MYC gene in the IMT-like component. The presence of identical EML4-ALK rearrangements in the adenocar-cinoma and IMT-like areas supports a diagnosis of ALK-rearranged lung adenocarcinoma with IMT-like dedifferentiation. Our findings suggest that ALK-driven epithelial and mesenchymal neoplasms exist on a morphologic spectrum and emphasize the need to consider translocation testing in pulmonary tumors with unusual sarcomatoid morphology.
Epithelial Cells Within Pleura—Not Always a Malignancy: (Poster No. 168)
Normal lung visceral and parietal pleura consist of collagen and elastin fibers lined by a monolayer of mesothelium. Epithelium is not a normal pleural component. We report a case of a 76-year-old African American woman who presented with rectal bleeding. The computed tomography scan of the abdomen and pelvis showed rectosigmoid wall thickening, a large, fluid-attenuated pelvic mass, and a right middle lobe lung nodule. Image guided drainage of the pelvic mass revealed neutrophils and gram-negative rods but no evidence of malignancy. Antibiotics were started. Colonoscopy with sigmoid mass biopsy revealed invasive moderately differentiated colonic adenocarcinoma. Computed tomography guided fine-needle aspiration and biopsy of the lung nodule were performed. Fine-needle aspiration showed clusters of malignant cells with rare acinar configuration and intracytoplasmic mucin. The tumor cells were positive for TTF-1 and CK7 and negative for CK20, consistent with primary lung adenocarcinoma. The biopsy of the lung nodule did not show carcinoma in multiple levels. A well-defined cluster of benign epithelial cells with glandular configuration and a separate gland lined by ciliated columnar epithelium were identified in pleura; they expressed CK7 and TTF-1. The benign mesothelial cells lining the pleura were positive for CK5 and CK7. Rare cases of benign pulmonary epithelial inclusions within pleura have been reported. This case study highlights the importance of recognizing this benign condition, especially in patients with coexisting malignancy, in order to avoid a false-positive diagnosis of malignancy involving pleura.
Undifferentiated Pleomorphic Sarcoma With Osteoclast-Like Giant Cells of Lung: (Poster No. 171)
Malignant fibrous histiocytoma, now known as undifferentiated pleomorphic sarcoma, is a relatively common malignant soft tissue tumor but a rare primary neoplasm of lung. We report a case of undifferentiated pleomorphic sarcoma with osteoclast-like giant cells originating within lung parenchyma. An 82-year-old African American man, a nonsmoker, presented with complaints of shortness of breath, hemoptysis, and mild cough. On computed tomography image, a right lower lobe mass was identified. A chest x-ray 18 months prior was unremarkable. No other significant mass/lesion was identified in full-body imaging. A biopsy of the mass was nondiagnostic. Subsequently, a right lower lobectomy was performed revealing an irregular mass (9.4 × 6.3 cm). The cut surfaces of the mass were white-yellow with firm/soft areas. On light microscopy the neoplasm was composed of spindle cells with pleomorphic osteoclast-like giant cells; mitoses were 17/10 high-power fields. Levels 7 and 10 and peribronchial lymph nodes were negative for metastasis. Multiple immunohistochemical stains were performed: pancytokeratin (–), S100 (–), desmin (rare focal positive), and CD68 (positive). The above stains with routine stained sections support a diagnosis of undifferentiated pleomorphic sarcoma, giant cell type. Three months later, he had a soft tissue metastasis on the back of his neck. This tumor is rare in lung, but should be considered following exclusion of other primary sites. The tumor has tendency for local and distant metastasis. Surgical resection is diagnostic and therapeutic.
A Correlation Analysis of Positron Emission Tomography Scan and Mediastinal Lymph Node Biopsy: (Poster No. 174)
Context: Positron emission tomography (PET) has improved advances in the detection of malignant nodes over the conventional computed tomography scan in patients with lung cancer, especially because it integrates morphologic images with metabolic information. However, false-negative and false-positive findings do occur in the PET scan of mediastinal lymph nodes.
Design: To examine the efficacy of PET scan in detecting mediastinal metastatic lymph nodes in lung cancer, we reviewed and compared the PET results with the corresponding biopsy pathologic results in the patients who had both examinations done during the years of 2010–2014 at our institution.
Results: One hundred twenty cases were collected for this study. PET scan showed a sensitivity of 82.35% (14 of 17), specificity of 79.61% (82 of 103), positive predictive value of 40% (14 of 35), and negative predictive value of 96.47% (82 of 85). No specific histologic patterns were identified in the negative lymph nodes to account for the positive PET results.
Conclusions: PET scan shows high sensitivity and specificity for detecting mediastinal lymph node metastasis, which is proven to be a useful imaging tool in evaluation for lung cancer patients. A negative PET result is relatively more powerful (high negative predictive value) than a positive PET result (low positive predictive value). The use of PET scan in staging the lymph node for the mediastinum must take into account the significance of false-positive and false-negative results. Mediastinal lymph node biopsy is still necessary to determine whether hypermetabolic mediastinal lymph nodes are positive for lung cancer metastasis.
High Yield of Oncogenic Drivers in Lung Adenocarcinomas With Psammoma Bodies: Comprehensive Molecular Profiling of 10 Resected Cases Using Next-Generation Sequencing: (Poster No. 175)
Context: Recent studies suggest a high incidence of psammoma bodies in adenocarcinomas with fusions of ALK, ROS1, and RET, especially in Asian populations. Our aim was to determine whether psammoma bodies in lung adenocarcinomas from a Western population are associated with oncogenic drivers, especially fusions.
Design: We reviewed 364 resected lung adenocarcinomas for psammoma bodies. Prior molecular testing was reviewed, and 10 cases lacking known genomic alterations were submitted for comprehensive genomic profiling via targeted next-generation sequencing that identifies 4 classes of genomic alterations within 236 genes (Foundation Medicine, Cambridge, Massachusetts).
Results: There were 27 lung adenocarcinomas with psammoma bodies, 3 of which harbored known oncogenic drivers (1 ALK fusion, 1 EGFR-L858R, 1 exon 20 insertion). Of the 10 submitted cases (52–83 years, 6 female/4 male, 2 never smokers), 3 had no prior molecular testing, and 7 were negative for EGFR, ALK, or both. Psammoma bodies per case ranged from 1 to >100 (mean 40). Oncogenic drivers were found in 9 of 10 psammomatous lung adenocarcinomas (90%), including 1 EML4/ALK fusion (ex-smoker/female), 1 complex ALK rearrangement (never smoker/female), 1 EGFR-L858R mutation (ex-smoker/male), 3 KRAS-G12V mutations (ex-smokers/2 male/1 female), and 3 ERBB2 mutations (2 ex-smokers/1 never smoker/2 female/1 male). A TP53 truncation was identified in the single case without an oncogenic driver (ex-smoker/female).
Conclusions: In this small sampling, a high percentage of lung adenocarcinomas with psammoma bodies have an oncogenic driver demonstrated by comprehensive genomic profiling, with a relatively high rate of ALK rearrangements and ERBB2 mutations. The absence of ROS1 or RET fusions in this small series likely reflects their low incidence in Western populations.
A Rare Case of Pulmonary Malignant Inflammatory Myofibroblastic Tumor With Rapid Progression Mimicking IgG4-Related Disease: (Poster No. 176)
Inflammatory myofibroblastic tumor (IMT) is a rare lesion, described in numerous organ systems. The diagnosis of IMT relies on the presence of characteristic morphology, including a fascicular arrangement of myofibroblasts with admixed lymphoplasmacytic infiltrate and slitlike vessels. We report a case of pulmonary malignant IMT with rapid progression and features of IgG4-related disease in a previously healthy 20-year-old woman. The patient presented with cough and hemoptysis and underwent a chest radiography, which showed a 6-cm nodular-appearing right upper lobe mass. Lobectomy specimen demonstrated a well-circumscribed lesion with a yellow-white fibrous and mucoid cut surface. Microscopic examination revealed storiform fibrosis with alternating zones of bland and atypical spindled cells in the lymphoplasmacytic well-vascularized background. Zones with atypical cells demonstrated necrosis, nuclear pleomorphism, and abnormal mitotic figures. One out of 4 regional lymph nodes was positive for metastatic disease. The spindle cells showed cytoplasmic positivity with antibody to smooth muscle actin and anaplastic lymphoma kinase 1 and no reactivity with antibodies to AE1/AE3, S-100, CD34, and desmin. Fluorescent in situ hybridization study detected rearrangement of the ALK gene at 2p23.2. In addition to a storiform fibrosis, lymphoplasmacytic infiltrate demonstrated an increase in IgG4 plasma cells, averaging 58 cells per high-power field in 3 fields, with a ration of IgG4 to IgG of 49%, satisfying minimal histopathologic criteria of IgG4-related disease. Two months postresection, the patient returned with multiple pulmonary nodules and mediastinal lymphadenopathy, prompting initiation of chemotherapy with crizotinib. Further studies are necessary to elucidate the relationship between pulmonary malignant IMT and IgG4-related disease.
A Rare Case of Primary Pleural Epithelioid Angiosarcoma: (Poster No. 179)
Primary pleural angiosarcoma is extremely rare. We report a case of this entity in a 79-year-old nonsmoking woman patient who presented with dyspnea and recurrent left hemothorax. A chest computed tomography scan showed markedly elevated left hemidiaphragm, patchy consolidation of the left lower lobe with underlying mass lesion not fully excluded. Because of persistent hemothorax, a thoracoscopic decortication of left pleura and wedge biopsy of the left lung were performed. During the procedure, a much-thickened pleura with ingrowth was noted, and excessive bleeding was encountered. Pathologic examination of the pleural tissue and lung wedge biopsy revealed tumor cells diffusely involving the pleura and extending into the subpleural lung, with glandlike alveolated structure, solid nest, and strands. The tumor cells have prominent nucleoli and eosinophilic cytoplasm, compatible with epithelioid features. By morphology, the tumor is extremely similar to epithelioid mesothelioma. The immunohistochemical stains demonstrated that the tumor is negative for epithelial and mesothelial markers, such as CK5/6, CK 7, CK20, pan-CK, EMA, and calretinin, but is positive for vimentin and most vascular-endothelial–associated markers, such as CD31, CD34, D2-40, and factor VIII. The results support the diagnosis of epithelioid angiosarcoma. Primary pleural angiosarcoma is clinically and histologically very similar to mesothelioma. However, the clinical history of no exposure to asbestos and prominent hemothorax prompts the consideration of angiosarcoma over mesothelioma. The immunohistochemical stains play an important role in differentiating these 2 entities and confirming the final diagnosis.
Differential Liver Kinase B1 Immunohistochemical Staining Characteristics in Normal Lung Tissue and Primary Lung Adenocarcinomas According to Histologic Classification: (Poster No. 180)
Context: Germline mutations in the liver kinase B1 (LKB1) tumor suppressor gene lead to Peutz-Jeghers syndrome, a cancer-predisposing condition. Subsets of lung adenocarcinomas harbor sporadic mutations. Studies have demonstrated that LKB1 protein expression correlates with the presence of biallelic gene inactivation, making immunohistochemistry a potential surrogate marker. No study has evaluated the differential LKB1 immunohistochemical patterns in the histologic subtypes of lung adenocarcinomas before.
Design: Sixty primary lung adenocarcinomas cases were included, and were subjected to immunohistochemistry using a LKB1 antibody. Adenocarcinomas were histologically subtyped using the 2011 International Association for the Study of Lung Cancer classification. Extent, intensity, and pattern of cytoplasmic staining were noted. Immunore-activity in neoplastic cells was compared with normal respiratory epithelium as an internal control and graded as follows: negative, 0; mild, 1; moderate, 2; and strong, 3.
Results: Fifty-nine tumors were invasive adenocarcinomas and of the following histology: acinar predominant (46), invasive mucinous (5), solid predominant (4), papillary predominant (3), and lepidic predominant (1), and the remaining tumor was nonmucinous carcinoma in situ. Nuclear grading was as follows: 1 (12), 2 (31), and 3 (17). Negative immunore-activity was observed in 2 cases, both of the mucinous subtype. All positive cases demonstrated diffuse cytoplasmic staining, of the following intensities: 1 (6), 2 (16) and 3 (36); no nuclear staining was observed. Normal bronchial epithelium demonstrated diffuse cytoplasmic staining.
Conclusions: Our preliminary results demonstrate variable LKB1 immunoreactivity among the histologic subtypes of lung adenocarcinomas including a lack of expression in some mucinous tumors and could be of further discriminatory value.
Unique Presentation of a Large, Rapidly Growing Pulmonary Granular Cell Tumor: (Poster No. 185)
We present a 51-year-old woman with past medical history of smoking, human immunodeficiency virus 1, and a history of intravenous drug abuse presenting with productive cough, fever, chest pain, and cachexia. Chest computerized tomography revealed a well-demarcated right upper lobe mass measuring 6.9 cm in diameter. Bronchoscopy showed an endobronchial polypoid lesion. Biopsy showed sheets of polygonal cells with bland, ovoid nuclei and abundant cytoplasm containing coarse, eosinophilic granules. No necrosis, mitoses, or atypia were present. The tumor cells were positive for S-100, CD68, and CD56. The diagnosis of granular cell tumor (GCT) was given. Upon follow-up 2 months after diagnosis, chest computerized tomography scan revealed that the mass was infiltrative, involving all 3 lobes in the right lung and having increased in size from 6.9 to 13.7 cm. Four smaller, new lesions presented within the right lung. A new pathologic fracture was present in the right fifth rib because of tumor permeation. GCT is an uncommon neoplasm in the lungs. No benign pulmonary GCT has been reported to be larger than 5 cm, to have rapid growth, or to cause a pathologic bone fracture in the rib. The clinically aggressive behavior of this tumor may be due to coexistence with another malignant neoplasm or due to presence of a malignant GCT component not biopsied. In conclusion, this case of a clinically aggressive, large pulmonary GCT questions the presumed benign nature of such neoplasms and emphasizes clinical correlation to predict their behavior.
Correlation of C4d Staining With Donor-Specific Antibodies in the Diagnosis of Antibody-Mediated Rejection in Lung Allographs: (Poster No. 186)
Withdrawn.
Use of Elastic Stain to Enhance Detection of Visceral Pleura Invasion in Surgically Resected Lung Carcinomas at Danbury Hospital: (Poster No. 189)
Context: The seventh edition of the American Joint Committee on Cancer staging system assigns lung cancers that are less than or equal to 3 cm with or without visceral pleura invasion to a pT2a or pT1 category, respectively. Evaluation of visceral pleural invasion (VPI) by H&E stain may be difficult. The objective of this study is to prospectively evaluate the routine use of elastic stain for the evaluation of VPI in surgically resected peripheral lung cancers.
Design: Elastic stains were performed on sections of 2 separate paraffin blocks of all lung carcinomas surgically resected during a 12-month period, in which the tumor most closely approaches the visceral pleura. The corresponding H&E-stained slides were evaluated for tumor invasion of visceral pleura prior to assessment of the elastic stains. These 2 results are compared.
Results: There were 12 lung carcinomas, 10 (83.3%) of which were adenocarcinomas, 1 (8.3%) squamous cell carcinoma, and 1 (8.3%) small cell carcinoma. Elastic stains identified VPI in 4 cases (33.3%). H&E-stained slides were considered positive for VPI in 3 of these 4 cases, and negative for VPI in the remaining case. Thus, elastic staining resulted in a change of tumor stage from pT1 to pT2a in 1 case (8.3%). None of the 12 cases had a falsely positive H&E stain assessment for VPI.
Conclusions: Our results confirm that pleural invasion status is difficult to assess with certainty on H&E-stained sections alone. Therefore, we recommend the routine use of elastic stain in the evaluation of pleural invasion in all peripheral lung cancers.
Metastatic Melanoma Mimicking Primary Pulmonary Sarcoma: (Poster No. 192)
Malignant melanoma is an aggressive tumor with highly variable cytomorphology that occasionally presents as metastatic disease with unknown primary. We describe a case of malignant melanoma presenting as a solitary lung mass morphologically mimicking primary pulmonary sarcoma. A 66-year-old man with a history of facial lentigo maligna presented to the clinic with nonproductive cough and unintended weight loss. Imaging showed a solitary 10.6 × 8.9-cm right lower lobe lung mass. Bronchoscopy demonstrated no evidence of endobronchial lesions. Fine-needle aspiration of the lung mass revealed a high-grade spindle cell neoplasm strongly positive for vimentin and SOX10, and negative for AE1/AE3, OSCAR, SMA, calretinin, TTF-1, S100, tyrosinase, Mart-1, MITF, and HMB-45. The differential diagnosis included primary lung sarcoma, sarcomatoid carcinoma, and malignant melanoma. Subsequent core biopsies demonstrated a malignant spindle cell tumor containing coarse cytoplasmic vacuoles arranged in intersecting fascicles with brisk mitotic activity and foci of necrosis, suggestive of a leiomyosarcoma. The tumor cells were strongly positive for SOX10 and S100, with patchy staining for SMA, SMMHC, and actin HHF35. They were negative for cytokeratins, Mart-1, MITF, tyrosinase, D2-40, CD34, p40, p63, and TTF-1. These findings were consistent with malignant spindle cell melanoma, likely metastatic. Subsequent evaluation showed no evidence of primary cutaneous disease, and review of prior lentigo maligna showed no obvious evidence of regression. Malignant melanoma is a great mimicker of other neoplasms and it must be considered in the differential diagnosis in the workup of a solitary malignant spindle cell lung tumor.
Biohazard Waste Reduction in the Cytopathology Laboratory: (Poster No. 194)
Context: Biohazardous waste is not only an environmental burden, it is costly. We investigated the feasibility of biohazard waste reduction in the cytopathology laboratory by disinfecting urine specimen containers with bleach. Containers could be disposed of in regular landfill instead of biohazardous waste.
Design: On 5 separate days, all urine containers received in the cytopathology laboratory were emptied, cleared of protected health information, and submerged for 20 minutes in a 10% bleach solution for 20 minutes. The entire process was timed, and the types of containers were quantified. An estimated whole cost comparison was performed.
Results: All of the containers were composed of hard plastic, and most had hard plastic caps, although some had metal caps. On average, 26 containers were analyzed per day. The 3 most common types of containers were 100-mL white top, 120-mL container, and 10-mL yellow-top tube. The average total time for the process was 48 minutes and 1 second, including an average active technician time of 28 minutes and 1 second. The estimated cost per year is 190% more for the bleach method than for the biohazard method.
Conclusions: The disposal of hospital biohazardous waste has a considerable impact on the environment and on the hospital budget. We describe a method where urine containers could be diverted from the regulated medical waste stream; however, the current design is not cost-effective. Automation of the bleach method, development of alternative methods, and recycling could be a future opportunity to reduce disposal costs.
Implementation of a Self-Audit in Point-of-Care Testing as a Tool to Improve Laboratory Oversight: (Poster No. 196)
Context: With the growth of point-of-care testing (POCT), patient outcomes and clinical workflows have improved. The delivery of fast and reliable results has enhanced patient care. Ensuring quality results and compliance with regulatory guidelines, however, has proved challenging for laboratory management. The purpose of this project is to implement a self-audit in POCT areas and to assess the effectiveness of a self-audit as a tool to improve laboratory oversight.
Design: A self-audit was developed and distributed to on-site and off-site POCT areas. The questions included in the self-audit are categorized into 5 domains: competency, instrument, storage, quality control, and documentation. Each question is based on regulatory and manufacturer requirements for each POCT instrument used at our institution. A post–self-audit survey was also conducted.
Results: Out of 36 POCT areas, the self-audit has been distributed to 24. All of the 24 POCT areas returned the completed form to the POCT coordinator in a timely fashion. All 24 areas showed 100% compliance across all 5 domains. A 3-question post–self-audit survey was distributed to POCT nurse managers. Out of 12 post–self-audit surveys completed, 83.3% of respondents felt that the self-audit enhanced awareness of regulatory requirements, 91.6% of respondents felt that the self-audit increased accountability, and 91.6% of respondents felt that the self-audit improved patient care.
Conclusions: A self-audit is a valuable tool for enhancing awareness and accountability among POCT operators. In addition, a self-audit can improve laboratory oversight, especially in a decentralized POCT program. Future research will correlate self-audit results with oversight audit findings.
Approach and Challenges in Determining Measurement Uncertainty at an ISO 15189:2012–Accredited Medical Laboratory: (Poster No. 197)
Context: ISO15189:2012 is a global accreditation standard for medical laboratories and is now being offered in the United States. Clause 5.5.1.4 requires determination of measurement of uncertainty (MU) of individual tests and making this information available to laboratory's users, if requested. For qualitative tests, MU represents the sensitivity and/or specificity of the test, and for quantitative tests, MU represents the expected variability in the result value. Globally, laboratories have struggled in grasping this novel concept, and we describe our approach in an outpatient laboratory setting in India.
Design: MU was determined through collation of quality control (QC) data. For routine quantitative parameters, we collated 6 months of internal QC and determined standard deviation (SD) and coefficient of variation (CV) using online statistical software (Unity Realtime, Bio-Rad, Irvine, California). Other quantitative parameters were analyzed using MS Excel (Microsoft Corporation, Redmond, Washington). Qualitative parameters were excluded.
Results: MU was calculated for individual tests in chemistry (n =95), hematology (n =17), and microbiology (n =19). CV in chemistry ranged from 1.5% (Na) to 12.4% (androstenedione). CV in hematology ranged from 1.3% (hemoglobin) to 7.7% (absolute eosinophil count). CV in microbiology ranged from 4.4% (toxoplasma IgG) to 7.8% (cytomegalo-virus IgG). A MU informational sheet was created for the laboratory users.
Conclusions: MU remains a novel concept—while laboratories face difficulties in finding consensus-driven approach, the laboratory users are not yet clear on what MU really implies for patient care. Automated methods demonstrate better MU characteristics. Future opportunities may include a consensus on how MU should be determined for qualitative parameters.
Design and Implementation of Pathology Summary Reports: Acute Leukemia Cases as Prototype: (Poster No. 199)
Context: Acute leukemia requires multiple testing modalities for diagnosis, prognosis, and potential therapeutic options. Automated integration of data from multiple reports is not currently feasible, yet results must be synthesized to produce an accurate final diagnosis upon which clinical decisions can be based.
Design: In consultation with hematology/oncology colleagues, we devised a one page pathology summary report (PSR) integrating results of morphologic examination, flow cytometry, karyotyping, fluorescence in situ hybridization, and molecular analyses in concordance with information recommended by the College of American Pathologists biomarker reporting templates. The attending pathologist reviews the data, establishes a final diagnosis, composes an interpretive comment, and generates the PSR using the anatomic pathology laboratory information system. Clinicians were anonymously surveyed to establish the clinical value of the PSR.
Results: Between June 2013 and February 2014, 39 PSRs for adult acute leukemia cases were generated. On average, 7.7 data elements (range, 5–11) appeared in each PSR. In 21 of 39 cases (54%), the PSR Final Diagnosis represented a modification of the original morphologic diagnosis because of incorporation of data not available at sign-out (eg, mutation testing results). Interpretive comments included discussions of the prognostic implications based on integrated test results. The PSRs proved useful at our multidisciplinary conferences and for data entry by oncology study coordinators and referrals to other institutions. Preliminary clinician survey results support that PSRs provided useful, convenient, and comprehensive documentation of leukemia-related laboratory findings.
Conclusions: The PSRs are an effective means by which pathologists can integrate test results into cogent consultation reports that are in alignment with current recommendations and are of high value to clinicians.
Value of Consistent Reporting of the Presence of Muscularis Propria in Urinary Bladder Biopsy Specimens: (Poster No. 200)
Context: For bladder tumors, the determination of invasion of muscularis propria is the most important prognostic information; therefore, reporting the presence of muscularis propria (adequacy) is recommended. The aim of this study was to assess the effect of consistent reporting of adequacy in all bladder biopsies on our institution's quality of bladder biopsies.
Design: All bladder biopsy reports from the years 2004 and 2013–2014 were reviewed for adequacy statements (presence of muscularis propria). The pathologic diagnoses, presence or absence of malignancy, and level of invasion were also recorded; 2003 and 2013–2014 biopsies were compared using the 2-tailed Fisher test; P < .05 was considered significant.
Results: We report on 358 bladder biopsies from 173 patients (67% male), aged 12–93 (mean, 65.4 ± 13.4) in 2004; all contained an adequacy statement. A total of 677 bladder biopsies from 297 patients, aged 9–94 (mean, 71 ± 11.9) were reported in 2013–2014; all contained an adequacy statement. The rate of “positive” biopsies containing urothelial carcinoma (in situ, papillary, or invasive) was similar in the 2 time periods (113 of 358, 31.6% versus 190 of 676, 28.1%, P = .25). However, the reported rate of presence of muscularis propria was higher in the second period (65 of 358, 18.2% versus 275 of 676, 40.7%, P < .001). No significant differences between the reported rates of lamina propria invasion (39 of 113, 34.5% versus 52 of 190, 27.3%, P = .20) or muscularis propria invasion (7 of 113, 6.2% versus 7 of 190, 3.7%, P = .41) were found.
Conclusions: Our results suggest that the consistent reporting of adequacy of bladder biopsies, even in the absence of a tumor, gives urologists feedback that can lead to improvement of the quality of biopsies.
Analysis and Solutions for Misidentified Paraffin Blocks in a Tertiary Care Academic Center: (Poster No. 202)
Context: Specimen identification is addressed through the information system (IS). However, a stand-alone cassette label printer with manual input is vulnerable to misidentification. This can negatively affect laboratory workflow and patient safety. We set to analyze the scope of the misidentified blocks and the potential causes.
Design: The IS-generated data in our medical center include block counts and daily misidentified blocks. We reviewed this error from January to June 2014. The misidentification was classified into (1) unentered blocks in the IS, (2) missing blocks, (3) mislabeled blocks, (4) surplus blocks, (4) names of the residents for the case, and (5) the station where the error originated.
Results: The monthly total number of blocks ranged from 9139 to 10 635, and the monthly number of misidentified blocks ranged from 190 to 432 (2%–4%). The “unentered in IS” comprised most of the misidentified blocks (67%), followed by “mislabeled blocks” (21%). Both errors occurred most often (95%) when multiple stations were visited by the specimen or when the specimen was handled by multiple people. Monthly trends showed a reduction in the error rate through enforcing correction by the responsible person and from circulating a monthly list.
Conclusions: Misidentified blocks comprise a significant volume of total blocks (up to 4%). The most common errors are blocks unentered in the IS (67%) and mislabeled blocks (21%). Complex cases (frozen sections, multiple parts, and cases handled by multiple people) are most prone to errors. Until the cassette labeler is incorporated into the IS, measures that may reduce the error include calling attention through a circulated list and enforcing correction.
Discrepancy in Renal Tumor Measurement: Challenges in Quality Improvement: (Poster No. 204)
Context: Pathologic staging and grading of renal tumors are important to determine prognosis and for further management of patients. The American Joint Committee on Cancer (7th edition) classifies primary tumor staging (pT) of renal tumors based on size. Therefore, accurate tumor-size measurement is an essential step during gross examination.
Design: At our institution, renal tumor measurements are performed before fixation of the specimen and during submission of the tissue for histology sections (postfixation), usually by 2 different individuals (residents and/or pathologist assistants). We observed a discrepancy in the measurement in 6 cases (Δ, 0.33 cm), which was significant enough to upstage 2 of these cases (33.3%). Using a cause and effect diagram, we identified nonstandardized measurement method as a possible explanation. We implemented a change, marking the largest tumor measurement by inking the tumor edges (largest diameter) at the time a specimen is received, which is used as the site for postfixation measurement.
Results: There was no improvement in the measurement of renal tumor using the new method. Measurement discrepancy was still observed in 6 new cases (Δ, 0.316 cm).
Conclusions: Standardization of renal tumor measurement prefixation and postfixation is challenging because it is influenced by multiple factors, is not beneficial, and could potentially be misleading. We propose a one-time measurement for renal tumors soon after receiving the specimen, as an accurate measurement is critical for staging.
Quality of Meta-Analyses in Diagnostic Pathology: (Poster No. 206)
Context: The quality of meta-analyses varies significantly, despite its importance in evidence-based medicine/pathology. To our knowledge, no study has evaluated the quality of meta-analyses in diagnostic pathology (DP). We, therefore, aimed to examine the quality of DP meta-analyses and determine whether highly cited DP meta-analyses had better quality.
Design: A literature search for meta-analyses in 7 major DP journals was conducted using PubMed. The quality of each study was assessed by awarding points based on the 27-item PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist. Higher scores indicate better quality, with possible ranges of 0–32 points. Wilcoxon rank-sum (nonparametric) test was used to compare the scores of meta-analyses.
Results: Forty-one DP meta-analyses between 2000 and 2014 were identified in PubMed. The overall quality of included meta-analyses in American DP journals was similar to that in non-American DP journals (median [interquartile range], 19 [15, 24] versus 25 [16, 26]; P =.12). The studies published in American and non-American DP journals had similar frequencies of structured abstracts (44.8% versus 72.7%, P = .11). The score/quality of the studies published in or after 2010 was significantly higher than those published before 2010 (median [inter-quartile range], 24 [16.5, 26] versus 15 [10, 19]; P = .002). Interestingly, the score/quality of included meta-analyses did not correlate with their adjusted citation ratios (correlation coefficient, –0.04; P = .81).
Conclusions: The quality of meta-analyses in DP has improved significantly in recent years, but highly cited DP meta-analyses did not have better quality. Our findings suggest more-rigorous quality assessment of submitted and cited meta-analyses is needed.
Correlation Between Original and Consultation Diagnosis Between 2010 and 2014 for the Department of Pathology at University of Florida Health, Jacksonville: (Poster No. 207)
Context: The University of Florida Jacksonville, Department of Pathology and Laboratory Medicine, regularly assesses its efficiency and effectiveness and currently has a quality assurance and improvement plan in place. Our study aimed to review cases that have been sent to other institutions for review and to analyze the correlation between the diagnoses after consultation and the original diagnoses to determine accuracy/agreement.
Design: This retrospective study analyzed all cases in anatomic pathology that were sent for consultation in 2010–2014. The data were extracted from our CoPath database. The original diagnosis was then compared with the consultation diagnosis for each case. Cases were classified as being in agreement if both diagnoses were essentially the same, or not in agreement if the diagnoses differed significantly enough to be considered as different diagnoses.
Results: Of 65 721 total cases, 295 (0.44%) were sent out for review, consisting of surgical and cytology material. Twelve cases had varying degrees of differences in diagnosis after consultation. Eight of the 12 cases were sent for expert opinion consultation. Four cases were discordant for an overall discordant rate of 1.4%. Of these discordant cases, 3 were classified as having minor discrepancies, and 1 had a major discrepancy
Conclusions: There was a high rate of agreement between original diagnoses and consultation diagnoses. Challenging cases that were not able to be classified by in-house testing were sent for second opinions. These cases were usually resolved with ancillary testing that was not available at our laboratory.
Addenda in Surgical Pathology Reports: An Institutional Experience: (Poster No. 208)
Context: The purpose of the surgical pathology report is to include all diagnostic information needed to clinically manage the patient. Reports may contain a “primary” diagnosis, whereas additional information is reported as an addendum; rarely, addenda may be generated to convey results that conflict with the primary report. We investigated addenda reporting trends at our institution.
Design: All addenda generated in the surgical pathology department at our institution January 2012–December 2013) were catalogued as follows (as previously reported in the literature): specimen defects, report defects, misinterpretation, and ancillary studies.
Results: During this period, 6404 addenda were generated (~10% of total cases). Most were issued to report the results of ancillary studies (5976; 93%), whereas a smaller percentage were issued to clarify specimen defects (4%) and report defects (1%). Misinterpretation was identified in 155 cases (2%), with 28 addenda resulting in a major change in diagnosis that would affect clinical management, and 25 addenda issuing a final diagnosis or change in diagnosis after additional review. For those cases in which a change in the diagnosis was reported in an addendum, 71% contained documentation of notifying the clinician.
Conclusions: Overall, most addenda were issued appropriately. Our rate of report and specimen defects is acceptably low. The addendum allows rapid release of clinically important and accurate diagnostic information in the form of a primary report; few cases resulted in significant alterations in diagnosis. Monitoring institutional addenda trends is a useful quality-improvement tool.
Coronary Artery Ectasia: Autopsy Case Exemplifies an Underrecognized Vascular Disorder: (Poster No. 3)
Coronary artery ectasia (CAE) is a form of coronary arteriosclerosis characterized by segmental or diffuse ectasia of the coronary arteries, which has an increased incidence in persons with abdominal aortic aneurysm, hypertension, and familial coronary arteriosclerosis. We present an autopsy case with the hallmark features of CAE. Sections of coronary and other arteries demonstrated marked necrosis of the media, with destruction of the internal and external elastic lamina, and a thickened and fibrotic intima, and histopathologic changes of CAE. Discussion of this case includes the pathogenesis of CAE, the gross and microscopic morphology, and its associated increased risk for death compared with nonocclusive coronary arteriosclerosis.
Acute Myeloid Leukemia With Fatal Pulmonary Emboli and Clinically Unrecognized, Large Intracranial Hemorrhage: An Autopsy Case Report: (Poster No. 4)
Patients with acute myeloid leukemia can present with a complex coagulopathy that may be difficult to fully characterize clinically. Autopsy can be valuable in the final evaluation of complex cases and may reveal serious, clinically unrecognized sequelae of coagulopathy. We report a case of a previously healthy, 42-year-old woman presenting with respiratory symptoms from multiple pulmonary emboli (PE), who was subsequently diagnosed with acute myeloid leukemia. Anticoagulation was a major focus of treatment because of the PE, but clinical concern regarding its safety was raised when she began to develop thrombocytopenia. Unfortunately, the patient's condition rapidly deteriorated despite aggressive therapies, and evidence of multiorgan system failure and possible early, disseminated, intravascular coagulation began to emerge. Immediately preceding death, she developed increasing tachypnea, decreased oxygen saturation, and new evidence of right ventricular dilation on ultrasound examination. These findings pointed to multiple, progressive PE as a mechanism of death. She died within 96 hours of admission, and an autopsy was performed. Autopsy confirmed multiple PEs as well as a clinically unsuspected intracerebral hematoma with associated uncal herniation and related temporal lobe contusion. Additionally, there were subcortical hemorrhages associated with fibrin thrombi, consistent with disseminated intravascular coagulation. This case highlights the role of autopsy in guiding future clinical decision making. Although the hypercoagulopathy was apparent clinically, the potentially fatal hypocoagulopathy was only revealed by autopsy. Presentation of these autopsy findings in a multidisciplinary conference heightens awareness of the complex coagulopathy that can develop in cases of newly diagnosed acute myeloid leukemia.
Pulmonary Capillary Hemangiomatosis in the Setting of Juvenile Systemic Lupus Erythematosus: (Poster No. 5)
Pulmonary arterial hypertension (PAH) in the setting of systemic lupus erythematosus (SLE) and other connective tissue disorders has been well-documented, with prevalence rates ranging from 0.5% to 17.5% of those affected. Pathophysiologically, PAH arising in the setting of connective tissue disease is characterized by vasculitis, thrombotic events, and complications of interstitial fibrosis. Although these associations have been thoroughly examined and reported in the literature, the association between SLE and pulmonary capillary hemangiomatosis (PCH) has not been exhaustively investigated. Pulmonary capillary hemangiomatosis is a very rare disorder of the pulmonary vasculature, which mainly affects adults. This disease entity is characterized by extensive proliferation of capillary-sized vessels along and within alveolar walls, which extend from pulmonary interstitial tissues to vessels and the airways, ultimately leading to luminal narrowing, obliteration, and pulmonary hypertension. The diagnosis requires histologic evaluation as clinical and radiographic findings fail to differentiate this entity from PAH and pulmonary venoocclusive disease (PVOD). We present an autopsy case of a 14-year-old girl with juvenile SLE, juvenile idiopathic arthritis (JIA), and severe PAH who succumbed to what was initially believed to be seizure activity and infection. Postmortem examination revealed extensive PCH, PVOD, and severe PAH (grade 3). The association between PCH and SLE has not been thoroughly investigated in the literature, and we hypothesize that the identification of similar lesions early in the course of disease may ameliorate adequate treatment, including possible pulmonary transplantation.
Acute Splenic Sequestration With Multiorgan Failure in an Adult With Sickle Cell β-Thalassemia: (Poster No. 6)
Acute splenic sequestration crisis is a major cause of morbidity and mortality in children with sickle cell disease. Sickle cell β-thalassemia has been associated with the development of splenic sequestration crisis in rare reports, and its natural history in these patients has not been well studied. We describe here clinicopathologic features and autopsy findings in a case of fatal splenic sequestration crisis together with multiorgan failure in a patient with sickle cell β-thalassemia syndrome. Patient was a 35-year-old woman with a past medical history of hypertension who presented initially to an outside hospital with progressive alteration of mental status and hypotension. She suffered upper respiratory infection–like symptoms 1 week earlier and soon developed right thigh and back pain with progressive weakness and alteration of mental status. Laboratory results showed hemolysis, anemia, low platelets, liver failure, renal failure and acidosis, and newly diagnosed sickle cell β-thalassemia. The patient progressed to multiorgan failure and died 2 days after admission. Autopsy and histologic examination revealed massive splenomegaly with subtotal acute splenic necrosis, systemic organ congestion, small blood vessel occlusion by sickle cells, and severe organ parenchymal injuries. The congestion by sickle cells was particularly severe in splenic sinusoids. The patient's illness was consistent with acute splenic sequestration and hemolytic crisis with induced multiorgan failure. Combining the results of our case with literature review indicates acute splenic sequestration crisis in adults with sickle cell β-thalassemia is a potentially life-threatening complication with a high risk of mortality.
Neuropathologic Findings in 2 Cases of Sudden Death in Childhood Associated With Congenital Hydrocephalus: (Poster No. 8)
Sudden unexplained death in childhood (SUDC) is defined as the death of a child older than 1 year in which the cause of death remains unclear even after a thorough clinical history review and autopsy, including postmortem toxicology testing. The authors report cases of SUDC in 2 girls with congenital hydrocephalus managed with ventriculoperitoneal shunts shortly after birth. Both children had a history of seizures and developmental delay, as well as nausea and vomiting the day before their deaths. Both children were delivered prematurely via cesarean section at 36 weeks of gestation. The first case involved a 20-month-old girl with congenital hydrocephalus secondary to cerebral aquaductal stenosis, who was found unresponsive on an adult bed approximately 4 hours after she was last known alive. The second case involves a 10-year-old girl with a history of DiGeorge syndrome (22q11.2 deletion), who was found unresponsive only 10 minutes after she was last known alive. Postmortem examination revealed that these 2 cases had neuropathologic features in common: intact and unobstructed ventriculoperitoneal shunts, generalized brain edema, temporal lobe structural abnormalities, and cerebral polymicrogyria. Because SUDC is extremely rare, the literature on the subject is sparse. In light of this, the authors provide a review of risk factors predisposing children to SUDC and propose possible mechanisms of death applicable to these cases, such as the role of childhood epilepsy in cardiac arrhythmias, gastrointestinal pathology and ventriculoperitoneal shunt malfunction, and the relationship between serum levels of antiepileptic drugs and SUDC.
Panhypopituitarism and Meningitis Complicating Transsphenoidal Resection of a Pituitary Mass in a Postpartum Woman: An Unusual Cause of Death: (Poster No. 10)
Transsphenoidal resection of pituitary tumors carries known risk of postsurgical complications, including cerebrospinal fluid leakage, meningitis, and endocrinologic, ophthalmologic, and rhinologic dysfunction. We present the clinical course and autopsy findings of a postpartum, 30-year-old woman after transsphenoidal resection of a 6-mm sellar mass discovered during pregnancy because of visual changes and headaches. Three months after an uncomplicated childbirth, the patient underwent transsphenoidal resection and rapidly developed panhypopituitarism (diabetes insipidus, hypocortisolism, and hypothyroidism) and was treated with replacement therapy. Final pathology revealed tissue consistent with a Rathke cleft cyst. One month later, following a course of levofloxacin for presumed sinusitis, the patient began to develop symptoms of meningitis (neck stiffness and headaches). This presentation was complicated by recent cessation of hydrocortisone and desmopressin replacement after running out of her supply. She was hospitalized, and baseline hydrocortisone replacement was reinitiated with intravenous antibiotics. Without improvement, the patient soon experienced sudden refractory cardiac failure with rapid neurologic decline. Pupils became fixed during transit to a tertiary care facility, and she died shortly thereafter. Autopsy confirmed cerebral edema with acute cerebellar tonsillar herniation, transsphenoidal tract and pituitary abscess, and evolving acute meningitis. Adrenal cortices were atrophic. Adrenocorticotropic hormone-deficient adrenal crisis was determined to be an integral cause of this patient's rapid clinical decline. Although the pathophysiology is poorly understood, this case report provides further evidence that secondary acute adrenal insufficiency may lead to catastrophic consequences in the face of physiologic stress (eg, meningitis), even in a young, healthy individual. Clinicopathologic findings are reviewed.
Arthrogryposis Multiplex Congenita With Unexpected Etiology: Congenital Cytomegalovirus Infection: (Poster No. 12)
Arthrogryposis multiplex congenita (AMC) describes a diverse group of disorders including multiple congenital contractures. Most cases are neurogenic in origin, with the others caused by primary muscle disorders, and there is often associated fetal akinesia sequence. Neurologic disease in infants with congenital cytomegalovirus (CMV) may be diverse in presentation. We report a case of clinically unexplained, intrauterine fetal akinesia and AMC in a live-born male at 37 weeks gestation. Prenatal ultrasounds showed upper and lower extremity contractures, abdominal echogenic foci, and clubbed feet. Fetal growth and fluid were normal. The infant was intubated at birth for apnea, had progressive respiratory failure, and lived 17 hours. Autopsy identified contractures of elbows, wrists, fingers, hips, and knees and bilateral clubfoot; micrognathia; enlarged anterior fontanelle; undescended testes; and severe pulmonary hypoplasia. Histologically identified disseminated CMV infection included viral cytopathy in liver, thyroid, kidneys, pancreas, pituitary, and brain. Cerebral histology included perivascular microcalcifications, periventricular gliosis, and multifocal microglial nodules. Subtle placental histologic findings included occasional chronic villitis with plasma cells, hemosiderin pigment deposition, and focal villous calcifications. Postnatal chromosomal microarray was normal. Although rarely described in the literature, fetal kinesia and multiple contractures can be caused by congenital CMV infection. Placental findings in congenital CMV can be subtle, and in the absence of clinical suspicion for CMV, pathologic examination of the placenta may not be diagnostically sensitive. Diagnosis of congenital CMV can be difficult, especially with atypical presentation and absence of maternal illness during pregnancy, but is important for counseling for future pregnancies.
Congenital Cytomegalovirus Infection—A Cause of Nonimmune Hydrops Fetalis: (Poster No. 13)
Hydrops fetalis (HF) may be caused by a variety of immune-mediated and nonimmune-mediated mechanisms. Rh-incompatibility, the main cause of immune-mediated HF, is rare today. Nonimmune HF can be caused by heart and lung diseases, anemia, and infections. A variety of infectious agents, including parvovirus B19, cytomegalovirus (CMV), herpes simplex virus, Toxoplasma gondii, adenovirus, enterovirus, and Treponema pallidum have all been implicated in nonimmune HF. In up to one-third of HF cases, the etiology is unknown. We report an autopsy case of fatal congenital CMV disease in a 1700-g, 30-weeks estimated gestational age, premature infant. A prenatal fetal echocardiogram showed moderate cardiomegaly with pericardial effusion, and mitral and pulmonary valves insufficiency. The newborn presented with anasarca, severe cardiomegaly, and blueberry muffin rashes. Autopsy findings revealed the presence of widespread CMV disease involving bilateral lungs and kidney, which was confirmed by immunohisto-chemistry. Although congenital CMV infection is common, affecting up to 2% of all newborns, fetal hydrops as a complication of congenital CMV infection is rare. Congenital infections with CMV may occur either in woman with primary infection during pregnancy or in women with preconceptual immunity with either reactivation or a latent infection or reinfection with a heterologous strain of virus. Because our infant's mother was CMV immunoglobulin (Ig) G+ but CMV IgM−, CMV infection occurred most likely in the infant because of reactivation of the virus or reinfection with a new strain. In summary, congenital CMV infection should be considered in the differential diagnosis of HF.
Walthard Cell Nests of the Abdomen in a Case of Elephantiasis Nostra Vera: An Unusual Autopsy Finding: (Poster No. 14)
A 44-year-old, morbidly obese woman with multiple medical problems, including elephantiasis nostra vera of the extremities secondary to chronic lymphedema died because of acute aortic dissection. She had been admitted for treatment of uncontrolled hypertension, and, 48 hours after admission, became hypotensive with associated back and chest pain. An autopsy revealed hemopericardium and rupture of the aortic root. Within the abdomen, there was a multiloculated, 17-cm cystic mass and tan-white plaques studding the serosal surface of the small and large intestine. Mucinlike globules were present in the pleural and peritoneal fluid. Both ovaries were enlarged with irregular, tan-white cut surfaces. Microscopic sections of the multiloculated, intra-abdominal mass were diagnostic of peritoneal inclusion cyst. In addition, there were transitional cell nests within the wall of the inclusion cyst. The tan-white plaques on the bowel wall were also transitional cell nests, some of which showed cystic change. The transitional epithelium stained positively with p63 and, focally, WT1. Calretinin staining was negative in the transitional cell nests but stained the lining of the peritoneal inclusion cyst. In the pelvis, there were bilateral ovarian adenofibromas. The fallopian tubes had cystic transitional cell nests, bilaterally. Nests of transitional epithelium, known as Walthard cell nests, are commonly present on the pelvic peritoneum of women of all ages and typically involve the serosal surface of the fallopian tube. To our knowledge, this is the first reported case of Walthard cell nests in the mesentery and serosal surface of the intestine.
The Postmortem Skin Examination: Frequency of Dermatologic Findings at Autopsy: (Poster No. 16)
Context: A complete academic autopsy includes a thorough external examination with gross dermatologic findings as a key part in this inspection. At our institution, the postmortem examination also includes a standard skin biopsy. We sought to determine the microscopic yield of these biopsies and the overall frequency of dermatologic diagnoses in an effort to improve diagnostic accuracy.
Design: Between 2012 and 2014, 776 complete autopsies were conducted. Postmortem microscopic skin examination was included in 389. Both microscopic and macroscopic dermatologic diagnoses were analyzed, and the original slides were reviewed.
Results: A macroscopic dermatologic diagnosis was made in 31% of autopsies. However, many of these diagnoses were vague and uninformative, such as “skin defect” and “macule.” A microscopic abnormality was recorded in 8% of cases. Dermatologic diagnoses were directly related to cause of death in 4% of autopsies. Sepsis from an infected ulcer or wound and systemic sclerosis were most common. An additional 3% of cases represented major findings contributing to cause of death. Seventeen percent of skin findings were minor and related to the decedent's medical history.
Conclusions: The discrepancy between the frequency of microscopic and macroscopic diagnoses specific to skin was higher than expected, most likely, because the lesions of interest were not sampled. This finding suggests that systematic sampling of both skin lesions and grossly normal skin may be beneficial, especially because dermatologic diagnoses contributed or were directly related to death in at least 7% of autopsies. Better training in the gross dermatologic examination may also improve diagnostic accuracy.
Fatal Strongyloides stercoralis Infection in Urban America: Two Autopsy Cases: (Poster No. 18)
Fatal Strongyloides stercoralis infection is rare in developed countries, particularly in urban populations. However, increased international travel, an increase in immigrant population, and the tendency of these nematodes to remain dormant for years has resulted in cases of fatal, disseminated Strongyloides stercoralis infection in urban hospitals. Two recent autopsy cases in our inner city, urban, teaching hospital illustrate this. The first was a 59-year-old man, a recent heart-transplant recipient, who presented with sepsis and decompensated cardiac failure. The donor was a 24-year-old man from Puerto Rico. Autopsy showed numerous Strongyloides larvae in the lungs, heart, liver, and lymph nodes. Several other organ recipients from the same donor were also documented to develop strongyloidiasis. The second case was a 70-year-old man, also from Puerto Rico, with chronic obstructive pulmonary disease on oral methylprednisolone. He was initially admitted for hypoxic respiratory failure, which was later complicated by abdominal distension and pneumatosis coli affecting the cecum and ascending colon. Both the colectomy specimens and the subsequent autopsy demonstrated numerous Strongyloides stercoralis larvae in the gastrointestinal tract, liver, bladder, skin, spleen, and brain. Both of these cases underscore the high mortality of disseminated Strongyloides stercoralis infection and the invariably associated sepsis. Strongyloides hyperinfection with sepsis should be considered in any immunosuppressed patient from a high-prevalence area. In the context of organ transplantation, a donor from such high-prevalence areas should be screened for Strongyloides stercoralis.
Non–Small Cell Carcinoma Involving the Heart: An Unusual Presentation: (Poster No. 20)
Non–small cell carcinoma of the lung involving the heart is not uncommon, yet nearly 90% remain undiscovered before postmortem examination. Here, we discuss the case of a 58-year-old man with previously diagnosed stage IV squamous cell carcinoma (SQC) of the lung after chemoradiation, presenting with acute cerebral infarct. Imaging demonstrated occlusion of the distal internal carotid artery and middle cerebral artery. Subsequent echocardiography revealed direct tumoral invasion of the posterior left atrium with bilateral intra-atrial mass. At autopsy, residual tumor directly involving the posterior atrial walls, intra-atrial septum, superior vena cava, outer muscular layer of esophagus, and aortic adventitia was identified. Histologic sections revealed occlusions of the left internal carotid, middle cerebral artery, left circumflex artery, and left anterior descending coronary artery. The SQC immunohistochemical staining of the tumor emboli was positive for CK5 and negative for p40. Lesions of this type are unusual, and although embolic stroke is often seen in association with cancer, it is typically due to hypercoagulability or embolic occlusion. Coronary artery involvement as a cause of death is rare and, in this case, points to the likelihood of direct invasion via endocardium. Surgical intervention is not an option for cases of this severity, with treatment consisting mostly of radiation and chemotherapy with response limited by cardiac toxicity and patient stability. This case illustrates an unusual presentation and pathogenesis of cardiac involvement and tumor thromboembolism, which were refractory to standard treatment, highlighting the importance of early recognition and timely intervention as it relates to prognosis.
A Hydropic, Male Fetus With Retrograde Blood Flow Through the Heart: (Poster No. 23)
Hydrops fetalis is a fetal condition characterized by edema in at least 2 fetal compartments during gestation. Although the most common etiology of hydrops is fetal anemia, congenital abnormalities can lead to physiologic dysfunction and fluid accumulation. We present a case of a stillborn, male, 34 weeks gestation fetus examined postmortem because of abnormal premortem ultrasound findings. Doppler ultrasound at 26 weeks gestation demonstrated retrograde blood flow though the aortic valve with severe regurgitation of both atrioventricular valves. External postmortem examination of the fetus showed significant hydrocephaly, low birth weight, and moderate maceration. Internal evaluation demonstrated fluid accumulation in the pericardial and pleural spaces, with a markedly enlarged heart. Examination of the heart revealed a patent dysplastic aortic valve, thickened bilateral atrioventricular valves and thickened left ventricular outflow tract. Histologic evaluation showed marked fibrin and elastin deposition in the ventricular endocardium, left greater than right. These findings are consistent with premortem ultrasound; the dysplastic aortic valve and stiffened left ventricle could not overcome systemic vascular resistance, leading to retrograde flow through the incompetent valve. The increased pressure in the left ventricle was transmitted to left atrium via the incompetent mitral valve, leading to congestion of the pulmonary circuit and pulmonary edema. The left-sided heart failure led to right-sided heart failure, with incompetence of the tricuspid valve and congestion of the coronary circuit resulting in pericardial edema. This case was a unique presentation of hydrops fetalis secondary to congenital heart disease, not to our knowledge, previously described in the literature.
Late, Intrauterine Fetal Demise: Clinical Findings Among Different Age Groups in an Inner-City Hospital: (Poster No. 27)
Context: From 1990–2003, the rate of stillbirth in the United States had steadily declined by an average of 1.4% per year. In the past decade, that decline has ceased. Targeting modifiable risk factors of specific populations may serve to further decrease the incidence of late, intrauterine fetal demise.
Design: We analyzed a cohort of 150 women (n =150) at an inner-city hospital with late, intrauterine fetal demise (defined as any fetal death at more than 20 weeks gestation). The patients were stratified into 3 age groups: younger than 21 years (n =33; 22%), 21 to 34 years (n = 98; 65%), and older than 35 years (n = 19; 13%). Modifiable risk factors were identified from chart review.
Results: The most commonly reported risk factor in women age younger than 21 years was HIV or sexually transmitted disease (24%) followed by hypertension or preeclampsia (18%). The prevalence of HIV and sexually transmitted disease in each age group decreased with age. The most commonly reported risk factor for women age 21 to 34 years was hypertension or preeclampsia (22%). Aside from advanced maternal age, the most commonly reported risk factor in women older than 35 years was also hypertension or preeclampsia (32%).
Conclusions: Given these results, we recommend that more-robust screening for HIV and sexually transmitted diseases be implemented in younger women, particularly in an inner-city setting, in an effort to further reduce the percentage of stillbirths in this population.
Necroendoscopy: (Poster No. 28)
Context: Minimally invasive, laparoscopy and thoracoscopy techniques have dramatically improved surgical procedures. The application of these innovative methods and instruments may decrease social and religious barriers to postmortem examinations because there is no significant anatomic alteration.
Design: Laparoscopy and bilateral thoracoscopy examinations were performed, after insufflation with carbon dioxide. A total of 23 consecutive, nontrauma, medical examiner cases were examined. There were 16 men and 7 women. The age range was 20 to 56 years. Instruments were placed on a single cart and consisted of 0-angle, 10-mm endoscope; xenon light source; digital signal processor; surgical carbon dioxide insufflator with pressure gauge and flow meter; and a television monitor.
Results: Visibility of the pleural surfaces and lungs was readily obtained. The parietal pericardium and size and shape of the heart were seen. Visualization of the peritoneal surfaces, liver, spleen, and intestines was improved after the experience of doing 5–10 cases. Pelvic contents were seen better after the experience of 3–5 cases. Median time of the procedure, beginning with external examination, was 42 minutes, with a range of ±8–15 minutes.
Conclusions: The performance of postmortem laparoscopy and bilateral thoracoscopy can be offered as an alternative to an autopsy. For those families that prefer necroendoscopy, we can offer collection of tissue, with minimal cold ischemic time, for tissue repositories; document the effects of therapeutic interventions; and identify structural changes that explain unusual clinical signs and symptoms.
Discordant Vaso-occlusive Sickle Cell Pathology in Twin Placenta With Single Fetal Loss Associated With Sickle Cell Trait: (Poster No. 29)
Severe vaso-occlusive sickle cell crises are less common in pregnant women with the sickle cell trait when compared with sickle cell anemia. However, in the presence of vascular/circulatory compromise induced by other pregnancy complications, extensive sickling resulting in placental insufficiency and fetal loss can occur. We report a 30-year-old woman (gravida 1, para 0000) who became pregnant assisted by intrauterine insemination followed by twin pregnancy. The pregnancy was complicated by chronic hypertension with severe preeclampsia and a history of sickle cell trait. A routine ultrasound at 34 weeks revealed intrauterine death of baby B; after which, a caesarian section was performed with delivery of deceased, male baby B and a live, male baby A. Significant findings in the diamnionic/dichorionic fused placenta were limited to the B side and included thrombosis of surface vessels; a peripheral organizing infarct; a large, central organizing thromboinfarct; abundant, nucleated red blood cells within villous vasculature; and involutional villous vascular changes consistent with intrauterine demise. Extensive sickling of maternal red cells was present within intervillous spaces and within the infarcts and thrombi. The A side was unremarkable except for a 2-vessel cord. Postmortem examination of the fetus was limited to external examination and revealed severe maceration. Sickle cell trait is generally not associated with severe sickle cell crisis during pregnancy. In this case, however, the presence of chronic hypertension and severe preeclampsia likely led to extensive sickling, vascular compromise, and fetal hypoxia and death in 1 of the 2 fetuses.
Bilateral Cerebral Infarction as a Consequence of Pituitary Apoplexy: (Poster No. 31)
Bilateral strokes are extremely rare complications of pituitary apoplexy, and their pathogenesis is not well understood. Previous studies have concentrated on 2 potential mechanisms of bilateral, internal carotid artery compromise following pituitary apoplexy: vasospasm of the internal carotid arteries from subarachnoid hemorrhage associated with pituitary adenoma hemorrhage, or direct compression of the internal carotid arteries by rapidly expanding, infarcted pituitary adenoma. To better understand the pathogenesis of bilateral strokes following pituitary apoplexy, we report autopsy findings in a case of pituitary adenoma with apoplexy that resulted in bilateral strokes and eventual global, ischemic brain death. A 56-year-old woman with a history of pituitary adenoma presented with headache, vomiting, and change in mental status. Imaging showed an increase in size of the adenoma, followed by bilateral cerebral ischemia in the territories supplied by the middle and anterior cerebral arteries. Subsequent cerebral edema, global cerebral ischemic changes, and herniation caused death. Autopsy revealed a 2.8×2.7 ×2.2-cm pituitary adenoma with recent apoplexy compressing the internal carotid arteries, bilaterally. This case indicates that direct compression of the internal carotid arteries by rapidly expanding, infarcted pituitary adenoma is a possible mechanism by which pituitary apoplexy can cause bilateral strokes.
Acute Gastric Volvulus—A Deadly But Commonly Forgotten Complication of Hiatal Hernia: An Autopsy Case Report: (Poster No. 33)
Gastric volvulus is a rare condition resulting from rotation of the stomach beyond 180°. Gastric volvulus is a difficult diagnosis, mostly because it is rarely considered. Furthermore, the imaging findings are often subtle, resulting in many cases being diagnosed at the time of surgery or, as in our case, at autopsy. We present a case of a 76-year-old man with an extensive medical history, including coronary artery disease with multiple bypass grafts, who became diaphoretic and nauseated while eating. His presumptive diagnosis at arrival to the hospital was an acute coronary event; however, findings from his initial cardiac workup were negative. A chest computed tomography scan revealed a type III sliding hiatal hernia. The following day, after consistent complaints of nausea and episodes of nonbloody emesis, he suddenly became hypotensive, tachycardic, and had an episode of coffee ground emesis. Subsequently, the patient suffered cardiac arrest, and resuscitation attempts were unsuccessful. Autopsy revealed a partially sliding hiatal hernia, consistent with the radiologic impression. Additionally, a gastric volvulus was present with extensive, focally transmural necrosis involving the body/fundus. Gastric volvulus is a rare entity with variable, nonspecific clinical presentations, which require a high level of suspicion for radiologic diagnosis. Acute cases have a high mortality rate and require emergent surgery. This case highlights the value of autopsy in the diagnosis of unsuspected cases of gastric volvulus when death occurs before surgical intervention.
Glomus Tumors and Neurofibromatosis Type 1: Does an Association Truly Exist?: (Poster No. 35)
Context: Glomus tumors are painful, benign lesions, usually arising in the subungual region from modified smooth muscle cells of the glomus body. Recently, there has been an interest in whether there is an association between type I neurofibromatosis and glomus tumors of the extremities. The purpose of this study was to investigate an association between type 1 neurofibromatosis and glomus tumors, especially of the hand.
Design: Surgical pathology archives were reviewed from 1990–2015 for cases of glomus tumors.
Results: There were 17 patients with a diagnosis of glomus tumors (male to female ratio, 1:3.3; mean age, 51 years). Most of the cases were in the hands (12 of 17 cases), but there were also some cases reported in unusual locations, such as the breast and stomach. All the tumors were unifocal with mostly a left-sided laterality. Chart review revealed other tumors for these patients (2 leiomyomata, 1 fibroadenoma, and 1 tubulovillous adenoma); however, we failed to find any association with neurofibromatosis and any glomus tumor.
Conclusions: Glomus tumors are rare mesenchymal neoplasm, arising from the glomus body. Although a few studies have shown an association between neurofibromatosis and glomus tumors, our study failed to show any association. We feel that more investigation needs to be conducted before a definitive association is confirmed.
A High-Grade, Dedifferentiated Liposarcoma With Chondrosarcomatous Element Presenting as a 22-cm Retroperitoneal Mass in a 60-Year-Old Man: (Poster No. 36)
Dedifferentiated liposarcoma (DL) occurs most frequently in the retroperitoneum, where it carries the worst prognosis. The pathologic diagnosis of DL requires the identification of well-differentiated liposarcoma and a cellular nonlipogenic sarcoma. The most-common histologic pattern of dedifferentiation is malignant, fibrous histiocytoma. We report a case of DL with foci of chondrosarcomatous features. The patient was a 60-year-old man who presented with a 22-cm retroperitoneal mass. The mass had a firm, white cut surface. The tumor consisted of a pleomorphic spindle cell sarcoma with abundant collagenous stroma, areas of chondrosarcomatous differentiation, necrosis, and foci of well-differentiated liposarcoma consisting of adipose tissue with large hyperchromatic cells. The lipogenic areas were positive for S100. The spindle cell areas were focally positive for actin and desmin, consistent with myofibroblastic differentiation. The diagnosis of DL was based on the histologic findings in conjunction with the size and location. Adequate sampling is imperative to identify heterologous components of DL and areas of well-differentiated liposarcoma. Chondrosarcomatous differentiation is a rare histologic finding in DL. Thus, the rarity of this histologic variant warrants documentation.
Intracortical Lipoma of the Tibia in an Adult: (Poster No. 37)
Intracortical lipoma is a rare entity. The actual incidence rate is not known, but a literature search revealed only 5 case reports. To our knowledge, only 1 case of intracortical lipoma in an adult tibia is described in literature. The current case report was a bone biopsy from a 70-year-old woman who had lower-limb pain from previous few months, x-ray revealed multiple well-defined, bony, lytic lesions with sclerotic margins and central translucent areas present on the metaphysis of the tibia. We received multiple bony, hard nodules with smooth surfaces. Histologic evaluation after decalcification revealed mature adipose tissue without any evidence of hematopoiesis present within the mature cortical bone. No atypia or necrosis was seen in adipocyte histologically. Radiology was correlated, and a diagnosis of intracortical lipoma was made based on classic morphologic and radiologic findings. Intracortical lipoma is a benign neoplasm, which accounts for less than 0.1% of primary bone tumors. Conservative surgery is curative and is needed in symptomatic cases only. No recurrences or evidence of malignancy has been reported so far in any of the cases. In conclusion, the current report presents the second case of an adult woman with an intracortical lipoma in the tibia. Biopsy is the gold standard. This tumor should be kept in the differential diagnosis of intracortical, osteolytic lesions of long bones.
A Rare Case of Hydatid Cyst in the Thigh of a 28-Year-Old Man: (Poster No. 39)
Hydatid cyst is a benign tumorlike growth caused by the Echinococcus tapeworm, which can cause high morbidity and mortality. Hydatid cysts are rare in the United States, with about 200 annual cases. Up to 90% of hydatid cysts develop in the liver or lungs. We present the case of a 28-year-old Eastern European man, who complained of an indurated, growing mass on his left medial thigh for 1 year. Physical examination demonstrated a 20-cm, firm, nontender, nonmoveable mass that clinically was presumed to be a sarcoma. Magnetic resonance imaging demonstrated a large, intramuscular cystic mass with multiple intralesional cystic lesions. A biopsy showed fragments of fibromuscular tissue with granulation tissue, lymphohistiocytic infiltrates, granulomas, and detached lamellar material and hooklets, suggestive of cystic echinococcus. The mass was resected, and surgical pathology received a 29.5-cm muscle fragment with an exposed necrotic sac on one aspect and a multiloculated cystic cut surface with abundant, yellow-tan, hemorrhagic, purulent material with multiple translucent, saccular structures within up to 5.0 cm. The cyst lining was roughened and granular. Hydatid cyst can occur in almost any part of the body; however, a 2005–2009 survey of 244 patients at Sheri Kashmir Institute of Medical Sciences in India demonstrated that 92% of the cases involved either the liver or lungs or both. A survey of 1802 patients with hydatid cyst in Australia in 1976 found that just 5% involve muscles. Nonetheless, this unusual case shows how it can mimic sarcoma and should be in the differential in large soft tissue masses.
Malignant Fat-Forming Solitary Fibrous Tumor With Metastatic Epithelioid Cytokeratin-Positive Dedifferentiation: (Poster No. 41)
In 2012, a 75-year-old man presented with a 9.5 ×7.0 ×2.0-cm mass in the left proximal thigh. Microscopically, the tumor was well demarcated, and a patternless distribution of spindle cells (CD34+) with intervening collagenous stroma and staghornlike, branching, thin-walled vessels; areas admixed with mature adipose tissue; and areas of marked increase in cellularity (CD34−) with moderate nuclear atypia, some epithelioid features, brisk mitotic activity, and no definite lipoblasts, consistent with a diagnosis of malignant fat-forming solitary fibrous tumor. Within 2 years, he developed pulmonary and multiple bone metastases. He was being treated with chemotherapy and radiation therapy and presented with low-back pain. Magnetic resonance imaging of the spine revealed bone metastases along T9–T12 with right anterior epidural tumoral disease at T12 resulting in severe spinal canal stenosis. The mass was removed and a T11–T12 laminectomy was performed. Multiple fragments of dense, white tissue admixed with bone was received in the pathology department. Microscopy revealed a malignant, high-grade epithelioid neoplasm with cells staining positive for cytokeratin cocktail, CAM 5.2, CK7, EMA, vimentin, and CD99; and negative for BCl2, CD34, TTF1. The MIB-1 proliferation index was 40%. A review of the prior resection showed that high-grade epithelioid component was focally positive for EMA and negative for cytokeratin. Although scattered cytokeratin positivity has been described in occasional dedifferentiated solitary fibrous tumors, extensive cytokeratin staining, including CK7 has not, to our knowledge, been described.
Solitary Lymphangioma of Spleen Presenting in an Adult as a Solid Mass: (Poster No. 42)
Splenic lymphangiomas are uncommon, benign tumors. Lymphangiomas are most commonly located in the neck and axilla and are an entity usually seen in childhood. In some patients, the lymphangiomas involve multiple sites, resulting in a lymphangiomatosis syndrome. Isolated lymphangiomas are a much rarer entity with only 9 cases reported between 1999 and 2010. We report a 48-year-old woman who was found to have a large, incidental splenic mass on magnetic resonance imaging. A computed tomography scan showed that the mass demonstrated heterogeneous enhancement and internal septation. A fine-needle core biopsy showed a lesion composed of channels containing proteinaceous material and red blood cells imbedded in a fibrous stroma. The cells lining the vascular channels stained positive for CD31, CD8, D2-40, and factor VIII. Based on the histologic and immunohistochemical findings, the differential diagnosis included hemangioma, lymphangioma, and hamartoma of the spleen. A subsequent laparoscopic splenectomy was performed. The resected spleen was 402 g and measured 16 ×11 ×6.5 cm. On sectioning, a 10 × 8.5 × 6.5-cm, solid, red-purple, firm, well-circumscribed mass, with intervening tan septa was identified. No cysts were grossly identified. Histologically, the lesion was composed of capillary- to vein-sized cystic structures with luminal, amorphous, eosinophilic proteinaceous material. The cystic structures were lined by attenuated endothelial cells that stained positive for immunohistochemical stains CD31 and D2-40. There were multiple foci of papillary protections emerging from the cyst lining. The histologic appearance and immunohistochemical profile were consistent with the rare entity of isolated splenic lymphangioma.
Intra-articular Leiomyoma of the Ankle: (Poster No. 43)
Leiomyomas are benign soft tissue tumors arising from the smooth muscle and are subclassified as superficial, vascular, and deep soft tissue subtypes. Among deep soft tissue leiomyomas, intra-articular leiomyoma is exceptionally rare, and only one pediatric case of popliteal fossa was found in the English literature. Here, we describe an intra-articular leiomyoma within the anterior ankle joint of an 83-year-old man. The patient presented with a 2-year history of right ankle pain. The pain progressively worsened for a 6-month period with the development of a large effusion. Plain radiography demonstrated no evidence of bony abnormalities. However, magnetic resonance imaging revealed a 4.8 × 2.6 × 1.4-cm intra-articular, heterogeneous mass within the right anterior talocrural joint with anteromedial osseous erosion. During surgical excision, the lesion was an intra-articular, well-circumscribed, firm tumor located deep to the extensor retinaculum. Although erosions of the tibia and talus were visible, the tumor did not appear to be growing into the bone. Microscopic examination of the mass showed hyalinized fascicles of smooth muscle cells with bland, cigar-shaped nuclei with blunt ends. No significant atypia, mitosis, or necrosis was identified. No vascular proliferation was appreciated. The smooth muscle nature of the neoplasm was confirmed by strong immunore-activity with anti–smooth muscle actin and anti–smooth muscle myosin heavy-chain antibodies. Ki-67 immunostaining showed a very low proliferation index (<1%). This is the first case, to our knowledge, of intra-articular leiomyoma of the talocrural joint. This case demonstrates the need to include leiomyoma in the differential diagnosis of a soft tissue mass in the ankle joint.
Vascular Tumor Presenting as a Duodenal Mass: (Poster No. 44)
Leiomyosarcoma of the inferior vena cava (IVC), although rare, is the most-common primary malignancy of the IVC. It is a slow-growing, aggressive neoplasm, more common in females. A 47-year-old woman presented with sharp, intermittent, and nonradiating right lower quadrant pain for 2 weeks. There was no palpable abdominal mass. Computed tomography revealed a mass (5 × 3 × 3 cm) below the superior mesenteric artery. Computed tomography 4 years earlier had shown a mass in the same location but smaller. An endoscopic ultrasound-guided fine-needle aspiration was performed, which revealed a discrete, rounded, homogeneous, and hypoechoic mass at the level of the second part of the duodenum. The cytologic diagnosis was a spindle cell neoplasm. The immunohistochemical profile (desmin+, smooth muscle actin+, CD117−, S100−, and CD 34−) was consistent with a smooth muscle neoplasm. Exploratory laparotomy was performed, and the tumor was found originating from the anterior wall of the infrarenal IVC, protruding into the lumen of the blood vessel, and externally adherent to the serosa of the duodenum. The tumor was completely excised, and the IVC was repaired by patch venoplasty. Microscopically, the tumor arose from the muscular layer and pushed against the serosa of the blood vessel. The intima of the IVC was intact. The tumor was composed of interlacing bundles and fascicles with nuclear pleomorphism, anaplasia, and rare mitoses, consistent with leiomyosarcoma. Two years after the surgery, the patient has no signs of recurrence or metastasis.
Unclassified Myxoid Sarcoma in the Carotid Body Area: A Unique Presentation: (Poster No. 45)
Tumors arising in the carotid body are rare, and, to date, a myxoid sarcoma has not, to our knowledge, been documented in this location. We report a 62-year-old woman with a low-grade myxoid sarcoma presenting as a carotid body mass. Clinical suspicion was for a recurrent paraganglioma, given the findings from an excision performed 6 years earlier in this region; however, histopathologic examination demonstrated a 6.8-cm, encapsulated, nodular, and cellular neoplasm composed of bland, monomorphic spindled cells within an extensively myxoid stroma, and delicate capillaries. The tumor cells had small, oval nuclei; stippled chromatin; and eosinophilic cytoplasm. There were no mitotic figures or necrosis. Immunohistochemically, tumor cells were only positive for vimentin and BCL2 and were negative for markers covering neuroendocrine, epithelial, mesenchymal, myoepithelial, and melanoma antigens. Ki-67 proliferative indices were low. Electron microscopy revealed mesenchymal features without a specific line of differentiation. This lesion was finally diagnosed as unclassified myxoid sarcoma, low grade. No recurrences have been documented after a year. The morphology and immunohistochemistry combined with ultrastruc-tural features demonstrated in this case are unique. A solitary fibrous tumor was considered in the differential, but in the absence of CD34 reactivity, and other markers, this was thought to be less likely. Myxoid liposarcoma was also ruled out in the wake of a fluorescence in situ hybridization study, which was negative for DDIT3 gene rearrangement. Further molecular studies may reveal genetic alterations and clues to its cell of origin and help further classification if more such cases can be identified and analyzed.
Atypical Fibroxanthoma With Unusual Morphologic Features Involving Lower Extremity: (Poster No. 47)
Atypical fibroxanthoma (AFX) is a rare tumor that typically occurs in the sun-damaged skin of the head and neck in elderly patients. Typical histologic features consist of admixed pleomorphic spindle, epithelioid, and multinucleated cells with brisk mitotic activity. We present a case of AFX with atypical morphology occurring in an unusual location. A 91-year-old man presented to the clinic with a 6 months history of a bleeding lesion on the right calf. Physical examination revealed a 15-mm, ulcerated, and friable, black papule with symmetric borders and surrounding erythema. Shave biopsy demonstrated an ulcerated, markedly hemorrhagic, and vascular-appearing tumor involving the dermis. There were many ectatic, fibrin-lined vessels with foci of organizing thrombi and endothelial papillary hyperplasia. The stroma had atypical spindle and scattered hyperchromatic pleomorphic cells with occasional intranuclear inclusions. Scattered mitoses were present, including atypical forms. The morphologic differential diagnosis included pleomorphic hyalinizing angiectatic tumor, angiosarcoma, malignant melanoma, and malignant fibrous histiocytoma. By immunohistochemistry, the atypical cells were focally positive for CD10 and negative for CK5, p63, SMA, CD31, CD34, S100, AE1/AE3, and HHV8. The patient underwent wide, local excision, which revealed no residual tumor. The histologic and immunohistochemical findings were most consistent with AFX. This case illustrates AFX with unusual vascular pattern occurring in an atypical site. Diagnosis of AFX requires exclusion of other malignant tumors. Despite its highly pleomorphic features, AFX tends to follow a benign clinical course. Local recurrence can occur, and treatment with wide, local excision is considered curative.
Subcutaneous Leiomyosarcoma of the Shoulder: (Poster No. 50)
Leiomyosarcomas (LMSs) are rare, aggressive mesenchymal neoplasms of smooth muscle origin and are divided into deep and superficial LMSs. Superficial LMSs arise from the dermis or the subcutis; the ones arising from the dermis are referred to as cutaneous LMSs, whereas those arising from the subcutis are termed subcutaneous LMSs. Cutaneous LMSs are thought to arise from the arrector pili, whereas their subcutaneous counterparts are from small- to medium-sized blood vessels. Subcutaneous LMSs are associated with higher rates of local recurrence, metastasis, and death from disease compared with lesions arising from cutaneous structures. Here, we are reporting a case of subcutaneous LMS in a 68-year-old male who presented with a mass on the posterior aspect of the right shoulder for 2 years' duration with recent increase in size; metastatic workup findings were negative. He underwent an incisional biopsy followed by wide surgical resection. Histologic examination revealed a well-delineated 2.8 × 2.6 × 2.0-cm cellular spindle cell neoplasm arising in the subcutaneous fat and arranged in fascicles with significant nuclear pleomorphism, nuclear multilobation, prominent nucleoli, and frequent mitosis (20 mitosis per 10 high-power fields) with abnormal mitosis. Immunohistochemically, the tumor cells were positive for muscle markers (smooth muscle actin, actin, caldesmon, and desmin) and negative for S100 protein. Based on morphology and immunohistochemical findings, the diagnosis of subcutaneous LMS was established. It is very important to differentiate subcutaneous LMS from cutaneous LMS because subcutaneous LMSs have a high tendency to recur locally and metastasize. Long-term follow up of these patients is mandatory.
Malignant Perivascular Epithelioid Cell Tumor of Pelvis: (Poster No. 53)
Perivascular epithelioid cell tumors (PEComas) are a family of rare mesenchymal neoplasms, characterized by their predominant perivascular location and both melanocytic and smooth muscle differentiation. The PEComa most-commonly involves the uterus, with only 5 cases of pelvic PEComa reported in the literature. We present a case of pelvic PEComa in a 70-year-old woman who presented with complaints of pain in the pelvis and suprapubic region of 1 month duration. Abdominopelvic ultrasound revealed a multiloculated cystic mass in the lower abdomen and pelvis. Grossly, the mass was multicystic, 24 × 16 × 10 cm in size with hemorrhage and necrosis. Histologically, it showed pleomorphic tumor with spindle and epithelioid cells attached to paravesical fibroadipose tissue. The tumor cells were positive for desmin, HMB-45, MITF, and TFE3 and were negative for Melan-A, myogenin, CD117, DOG1, AE1/AE3, and PAX8. Transcription factor E3–rearranged PEComas are biologically distinct, and their presence can affect the management of patient because they are known to lack tuberous sclerosis complex 2 (TSC2) alterations characteristic of conventional PEComas. This newly emerging concept has clinical and therapeutic importance in that mammalian target of rapamycin (mTORC1) inhibitors have been shown to be effective in some cases of PEComa with TSC alterations; however, very few cases are studied for TFE3. Our case was TFE3+ by immunohistochemistry but negative by fluorescence in situ hybridization (FISH) and did not have the biological characteristics of TFE3+ cases. Our case emphasizes the importance of studying TFE3 with confirmation by FISH for biologic classification and for its role as a potential prognostic indicator.
Histologically Distinct Variants in a Recurrent, Low-Grade Fibromyxoid Sarcoma for 27 Years: (Poster No. 59)
Low-grade fibromyxoid sarcoma (LGFMS) is an uncommon sarcoma that was first described in 1987. Prone to local recurrence, LGFMS has metastatic potential despite its low-grade histologic appearance. Histologically, the classic LGFMS is composed of a bland spindle cell proliferation in a myxoid stroma. In 1997, the hyalinizing spindle cell tumor with giant rosettes was first delineated. This entity is characterized by giant rosettes composed of hyalinized collagen with surrounding spindle cells. The LGFMS and the hyalinizing spindle cell tumor with giant rosettes are now recognized as the same neoplastic process. We report a case of a 47-year-old woman with a previously resected neck mass in 1987, which was originally diagnosed as a leiomyoma. In 2014, magnetic resonance imaging revealed a recurrent 3-cm mass in the right paraspinal musculature at the level of C2–C3. Histologically, the tumor was consistent with the classic pattern of LGFMS and stained positive for vimentin and MUC4. The tumor was negative for desmin, S100, SMA, NFP, EMA, and CD34. Fluorescent in situ hybridization revealed a rearrangement of the FUS gene in the region of chromosome band 16p11, which supports the diagnosis of LGFMS. This prompted the review of the previously resected tumor in 1987, which revealed a histologic pattern diagnostic of the hyalinizing spindle cell tumor with giant rosettes. This case reports the extraordinary presentation of histologically distinct variants of a recurrent LGFMS for 27 years. The patient is clinically stable.
Benign Multicystic Peritoneal Mesothelioma Presenting as an Intra-Abdominal Cystic Disease in a Man: (Poster No. 61)
Benign multicystic peritoneal mesothelioma (BMPM) is a rare cystic neoplasm that arises from the abdominal peritoneum, with less than 150 cases reported to date. They are usually found in women of reproductive age and are extremely rare in men. We report a case of BMPM in a 68-year-old man found incidentally during for workup of inguinal hernia repair. Computed tomography scan of the abdomen and pelvis was remarkable for a large, loculated cystic mass with internal septations, filling the abdomen and pelvis. The initial biopsy from the peritoneal lesion showed portions of soft tissue with numerous variably sized cystic spaces, lined by a single layer of flattened to cuboidal mesothelial cells. The subsequent excision of the tumor showed the same histologic features with no features of malignancy. Immunohistochemical stains showed the cells lining the cystic spaces to be diffusely positive for calretinin, cytokeratin AE1/AE3, and EMA. These histologic and immunohistochemical features confirm the diagnosis. The BMPMs have a broad differential diagnoses that require a high index of suspicion and awareness of their histology. Multiple treatment modalities have been tried with variable outcome; some of these modalities are still being evaluated.
Sclerosing Rhabdomyosarcoma Presenting in an Adult as a Thigh Mass: (Poster No. 62)
A 39-year-old, healthy man presented with a well-circumscribed, right thigh mass (10 × 7.8 × 3.6 cm). Following resection, the mass demonstrated a tan-yellow, “fish-flesh” cut surface. Histologic examination revealed a cellular neoplasm composed of round to oval epithelioid and focally spindled cells with scant cytoplasm and minimal pleomorphism, arranged in nests and sheets in a background of extensive hyalinized/sclerosing collagen matrix. In areas, a pseudovascular growth pattern was also present. Tumor giant cells were not noted. Mitotic figures were less than 2 per 10 high-power fields, and necrosis was focal (<5%). Immunohistochemical stains were focally strongly positive for both desmin and myogenin, and focally positive for smooth muscle actin and calponin. The tumor is a sclerosing rhabdomyosarcoma, high grade (FNCLCC [Fédération Nationale des Centres de Lutte Contre le Cancer], 2 of 3), AJCC [American Joint Committee on Cancer], pT2b). Rhabdomyosarcomas are rare in adulthood but is the most common sarcoma diagnosed in children and adolescents. Traditionally, rhabdomyosarcomas have been composed of 3 major subtypes: embryonal, alveolar, and pleomorphic variants. In recent years, a fourth category, spindle cell/sclerosing rhabdomyosarcoma, was introduced and comprises 5%–10% of diagnosed rhabdomyosarcomas. Currently, there are approximately 50 cases of sclerosing rhabdomyosarcoma in the literature, demonstrating preferential involvement of the head and neck and extremities. Recently recurrent MYO-D1 mutations have been described in these lesions. The complex histology and rarity of the tumor can pose great diagnostic difficulty, especially when encountered in adult patients.
Extramedullary Hematopoietic Tissue in a Subdural Hematoma: (Poster No. 65)
Extramedullary hematopoiesis (EMH) is the process by which red blood cells form and develop outside of the medullary spaces of the bone marrow. The EMH sites in adults most commonly involve the liver, spleen, and lymph nodes. It is rare to have EMH occur in cases of subdural hematomas. We present a case of a nonsmoking, 54-year-old, African American man, who presented to the Emergency Department with a subdural hematoma. The patient had a history of diabetes, hypertension, and lower extremity cellulitis. Because EMH in subdural hematomas is a rare phenomenon, only a few cases have been mentioned in the literature. This article will briefly review published information on EMH, as well as discuss possible mechanisms for pathogenesis. The aim of this article is to highlight a process rarely seen in subdural hematomas and to gain a better understanding of EMH's unique pathogenesis.
Incidence of Monophasic Epithelial Synovial Sarcoma in Poorly Differentiated Soft Tissue Carcinomas: (Poster No. 67)
Context: Poorly differentiated soft tissue carcinomas (PDSTC) in patients without a known primary carcinoma are uncommon. The differential diagnosis in this setting includes metastasis from occult carcinoma and primary monophasic epithelial synovial sarcoma (MESS). By definition, MESS harbors t(X;18), which is characteristic of synovial sarcoma and is readily identified by fluorescence in situ hybridization (FISH). In contrast to biphasic/conventional synovial sarcoma, MESS is composed exclusively of epithelial elements, making its recognition as a form of synovial sarcoma difficult. This study was conducted to determine the incidence of MESS by FISH in cases previously diagnosed as PDSTC.
Design: Institutional archives between 1990 and 2014 were searched for PDSTC and yielded 416 results. With extensive review of medical records, histology, and immunostains, 410 cases with current/prior diagnosis of visceral carcinoma were excluded. The FISH was performed using an SS18 (18q11.2) dual-color, break-apart probe (Abbott Molecular, Downers Grove, Illinois).
Results: Six cases of primary PDSTC were identified (33–61 years; 5 females, 1 male). One case was positive for SS18 rearrangement by FISH. It was a well-circumscribed thigh mass in a 41-year-old woman, composed of irregular nests of pankeratin and CK7+epithelial cells with enlarged nuclei and prominent nucleoli. No conspicuous spindle cell component was seen. CD34 was negative.
Conclusions: Primary PDSTC is very uncommon. A FISH study for SS18 rearrangement is useful in identifying the subset of PDSTCs that represent MESS, which may have therapeutic implications. The origin of primary PDSTC that do not represent MESS remains uncertain.
ERG Immunoreactivity in Fibrohistiocytic Lesions: A Diagnostic Pitfall: (Poster No. 69)
Withdrawn.
Solitary Fibrous Tumor of the Omentum: Report of a Rare Case: (Poster No. 70)
Solitary fibrous tumor (SFT) is a rare spindle cell neoplasm that most commonly involves the thoracic cavity, including the pleura and lung, and less frequently the extrapulmonary soft tissues. Here, we discuss an extremely rare case of SFT arising in the omentum. A 54-year-old man presented with right lower quadrant abdominal pain with rebound and guarding and 25 pound weight loss. Abdominal computed tomography scan showed a 4.5 × 3.0-cm heterogeneously enhancing mass adjacent to the ascending colon. Ultrasound-guided biopsy was nondiagnostic but indicated a mobile and fibrous mass. The patient underwent a diagnostic laparoscopy and resection of a 4.5-cm, firm, well-encapsulated omental mass. To rule out the clinical question of lymphoma, a touch preparation was performed revealing a mixture of spindle and moderately pleomorphic epithelioid cells. Histologic examination demonstrated a well-circumscribed, predominately hypocellular spindle cell neoplasm with areas of increased cellularity, intervening thick collagen bundles, and scattered staghorn vessels. Immunohistochemistry revealed spindle cells positive for CD99, BCL2, CD34, and β-catenin and negative for CD117, AE1/AE3, CD117, and S100. The morphologic and immunohistochemical features supported the diagnosis of SFT. Although most SFTs are benign, malignant transformation can occur. Malignant histologic features include tumor size larger than 5 cm, increased mitotic activity, hypercellularity, and necrosis. Treatment of SFTs includes surgical resection and chemoradiation. Previously reported cases of SFT suggest a close, long-term follow-up because of risk of local recurrence.
Fibrocartilaginous Mesenchymoma of the Distal Femur: Case Report of an Unusual Presentation in a 68-Year-Old Man: (Poster No. 72)
Fibrocartilaginous mesenchymoma (FCM) is a rare primary bone tumor that usually occurs in the long bones of children and adolescents. There have been 23 cases reported in the literature previously, and the pathologic diagnosis of FCM may be challenging. We report a FCM in a 68-year-old man presenting with local pain in the right distal thigh. Magnetic resonance imaging showed a 4.8-cm lesion extending into the cortex with an aggressive periosteal reaction within the distal femoral metadiaphysis. Microscopically, this neoplasm was composed of bland, variably cellular spindle cells in fibrous stroma with deposits of cartilage resembling epiphyseal platelike growth. The nodules of chondroid matrix were somewhat cellular but lacked obvious malignancy. Destruction of the surrounding cortical bone was present; no significant cytologic atypia or mitotic activity was identified. Overall, the histologic and radiographic features of this neoplasm most closely resembled those of FCM. This is the first case report, to our knowledge, of FCM happening in this age group. The treatment for FCM is complete excision, with close clinical follow-up because of the high incidence of recurrence.
Malignant Mesothelioma of the Spermatic Cord: (Poster No. 73)
Malignant mesothelioma (MM) is an uncommon, aggressive neoplasm that develops from cells of the mesothelium, the protective lining that covers many internal organs in the body. As of 2013, only 10 spermatic cord cases were reported in the English literature. A 66-year-old man presented with a 3-month history of an enlarging mass in the left inguinal area, and associated pain with straining and physical exertion. Radiologic studies revealed an oval mass in the left inguinal canal, as well as a left inguinal hernia. After surgical resection, the mass was found to be 9 × 5 × 5-cm, firm, fusiform, pink-tan, and surrounded by an ill-defined tan capsule. Sectioning revealed tan cut surfaces with variegated pale yellow and hemorrhagic regions. Microscopic sections showed a partially necrotic, high-grade malignant neoplasm, which infiltrated fat, muscle, and perineural spaces. It abutted the vas deferens but did not invade. The neoplasm had a biphasic appearance and was composed of spindled and epithelioid cells. Mitotic figures were abundant. Immunostaining showed expression of calretinin and positivity for multikeratins in the epithelioid areas. We present an exceptionally rare case of spermatic cord MM. These tumors are usually diagnosed at advanced stages and have a poor prognosis. Radical excision is the primary therapy in localized disease cases. Spermatic cord MMs show recurrence rates of up to 57% within 2 years. The most important prognostic indicator is the age of the patient.
Mammary Myofibroblastoma: A Case Report and Literature Review: (Poster No. 76)
A 57-year-old, otherwise healthy woman presented with a single, firm-to-rubbery mass in the left breast. Radiologic examination showed a 5.1-cm, lobulated, mixed echogenic mass. Gross examination showed a solid, firm-to-rubbery mass with well-defined borders. Histopathologic examination showed expansion of the stroma by a cytologically bland spindle cell proliferation with focal hyalinization and myxoid change. High-power examination of hematoxylin-eosin–stained sections showed round, eosinophilic, intracytoplasmic, as well as extracellular, hyaline globules. Immunohistochemically, the hyaline globules were strongly reactive with smooth muscle actin, desmin, CD34, and caldesmon. However, it was negative for S100, p63, and cytokeratin. Differential diagnosis includes any benign spindle cell lesions, such as leiomyoma, fibromatosis, schwannoma, and neuroma.
High-Grade, Triple-Negative Breast Ductal Cancers in African American Women Strongly Express p16: (Poster No. 79)
Context: p16, a tumor suppressor protein encoded by CDKN2A gene on chromosome band 9p, inhibits progression of cell cycle from G1 to S phase. p16 mutation leads to cell cycle dysregulation. Our study objective was to correlate immunohistochemical expression of p16 in 4 major subtypes of breast carcinoma (luminal A, luminal B, HER2, and triple negative) in 202 African-American women with other clinicopathologic factors.
Design: Tissue microarrays (TMAs) were constructed from forma-lin-fixed, paraffin-embedded tumor blocks from primary ductal breast carcinomas in 202 African-American women. Two separate 1-mm cores represented each case. Using Polymer-HRP system, 5-μm sections were stained with a mouse monoclonal antibody against CINtec p16. Cases with nuclear and cytoplasmic staining intensity of 3+ and expression greater than 75% were interpreted as positive. Bivariate analysis was done via χ2 analysis and survivability data were calculated via Kaplan-Meier curves (SPSS v19). Statistical significance was assumed if P < .05.
Results: p16 expression was associated with ER−(P < .001), PR−(P < .001), triple negative (P < .001), and grade 3 (P < .001) but not with survival.
Conclusions: A statistically significant association between p16 expression and triple-negative subtype cancers lacking hormone expression, and tumors with high histologic grade was found. Expression of mutant p16 detected by immunohistochemistry indicates loss of pRb phosphorylation control and dysregulated cell cycle leading to cellular proliferation. Targeting the p16-induced inhibition of the CDK4 pathway with the development of CDK4 inhibitors may prove effective in treating triple-negative and hormonally unresponsive breast carcinomas, occurring more frequently in African American women.
High-Grade, Advanced-Stage, Triple-Negative Breast Ductal Cancers in African American Women Strongly Associated With p53 Expression: (Poster No. 80)
Context: p53 has a critical role in cell cycle regulation and induces apoptosis of irreversibly damaged cells. The significance of p53 mutations and their impact on prognosis of breast cancer is not well established. The objective of this study was to correlate immunohistochemical expression of p53 in the major subtypes of breast carcinoma (luminal A, luminal B, HER2, and triple negative) in a population of 202 African-American women with clinicopathologic factors.
Design: Tissue microarrays were constructed from formalin-fixed, paraffin-embedded tumor blocks from primary ductal breast carcinomas in 202 African-American woman, using 2, 1-mm cores. Using a Polymer-HRP system, 5-μm sections were stained with a mouse monoclonal antibody against p53 (Bp53-11). Cases were categorized as positive if nuclear intensity was 3+ and extent of expression was greater than 75%. Bivariate analysis was done via χ2 analysis, and survivability data were calculated via Kaplan-Meier curves (SPSS v19). Statistical significance was assumed if P < .05.
Results: p53 expression was associated with ER−(P < .001), PR− (P < .001), triple negative (P < .001), stage IV (P = .001), grade 3 (P < .001), and distant metastases (P = .01).
Conclusions: A statistically significant association between p53 expression and triple-negative, high-grade cancers was found. The cell cycle progression from G1 to S phase was no longer blocked by p53. Our study found that p53 overexpression has an important role in the pathogenesis of advanced-stage, triple-negative breast cancer in African American women. Targeting the p53 activity by promoting the activity of cell cycle inhibitors (p16, p21, p27) may be effective in the treatment of triple-negative breast carcinomas.
Breast Adenomyoepithelioma and Malignant Adenomyoepithelioma: A Case Series Emphasizing Histologic, Radiologic, and Clinical Correlation: (Poster No. 82)
Context: Breast adenomyoepitheliomas (AMEs) are rare tumors with proliferating epithelial and myoepithelial components. The literature correlating imaging, histology, and clinical outcomes is limited. We conducted a retrospective review of AMEs to include histologic features, immunohistochemistry, radiology, and clinical follow-up.
Design: A review of our institutional database identified 20 possible cases. Thirteen of 20 cases were confirmed as AME and 1 of 20 as malignant AMEs by 2 separate pathologists. Ten of these 14 cases were stained with p63 or had archival immunostains supporting myoepithelial proliferation. Imaging was reviewed by a breast-imaging radiologist.
Results: All cases were from women aged 26–81 years. Imaging in AME was nonspecific. Nearly all were BIRADS 4. The malignant AME was larger and had more heterogenous echogenicity on ultrasound. Clinical follow-up was available for all but 2 patients and ranged from 1 to 237 months. No patients had documented recurrence or subsequent breast malignancy. In addition to the malignant AME, 3 patients had synchronous or previous malignancies: 1 with prior invasive ductal carcinoma, and 2 with synchronous ductal carcinoma in situ. Three exhibited the tubular histologic variant of AME, and 1 had predominantly lobular pattern
Conclusions: Our findings confirm nonspecific radiographic features of AME. Our rate of synchronous breast cancers was high, which is concerning for a possible increased inherent risk to breast cancer that may not be entirely explained by malignant transformation. Tubular pattern of AME was found more frequently in cases with associated malignancy. Future research should be directed toward the molecular pathogenesis of AME. Excision of this lesion with negative margins appears prudent.
Impact of the 2013 ASCO/CAP HER2 Revised Guidelines on HER2 Results in Invasive Breast Carcinoma: A Retrospective Study: (Poster No. 83)
Context: Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase that is routinely tested in breast cancer. We conducted a retrospective review to assess the impact of the 2013 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) revised guidelines on the reporting of HER2 at our institution.
Design: A consecutive series of breast core biopsies with invasive carcinoma were compared from the prerevision (December 2008–June 2012; n = 928) and postrevision (December 2013–December 2014; n = 322) intervals. Both HER2 immunohistochemistry (Ventana, clone 4B5) and fluorescent in situ hybridization (FISH) (PathVysion) were performed on each case. HER2 results were compared using Pearson χ2 test and the t test.
Results: HER2 FISH+ (from 14.3% to 17.5%, P = .18) and equivocal (from 0.9% to 9.9%, P < .001) rates increased, whereas the HER2 FISH− rate decreased (from 84.8% to 72.6%, P < .001). No significant changes were detected in HER2 immunohistochemistry reporting. HER2 double-equivocal rates increased (from 0.5% to 6.5%, P < .001). The discordance rate increased (from 0.3% to 0.9%, P = .24). The revised guidelines reclassified 10% of HER2 FISH cases by the HER2 copy number/cell criterion, with most (30 of 32) changing from negative to equivocal. HER2 double-equivocal cancers were more commonly hormone positive compared with HER2+ cancers (90.4% versus 61%, P < .001), and the mean grade (2.4) was higher than hormone-positive/HER2− cancers (1.8, P < .001).
Conclusions: HER2 FISH-equivocal rates significantly increased because of guideline revisions and thus the reporting of breast cancer cases that are double-equivocal using both FISH and immunohistochemistry have increased. The clinical management of patients that are double HER2 equivocal is unclear and requires further investigation.
Histopathologic Features Predicting Pathologic Complete Response in Breast Carcinoma Treated With Neoadjuvant Chemotherapy: (Poster No. 84)
Context: In breast carcinoma, achieving pathologic complete response (pCR) in the neoadjuvant chemotherapy (NAC) setting has prognostic importance, yet not all patients respond. Therefore, core biopsy-based factors predictive of response are necessary. We assessed biopsy histopathologic features predicting pCR.
Design: The pathology database was searched for NAC cases (2010–2015). Core biopsies were examined for tumor infiltrating lymphocytes (TILs, prominent stromal lymphocytes ± intratumoral infiltrates), extensive tumor necrosis, subtype, and receptor status (ER, PR, HER2). pCR was defined no residual invasive tumor in the breast, lymphatic emboli, and lymph node metastasis.
Results: Patient age ranged from 25 to 87 years. Available pre-NAC clinical stage (n = 93 cases) was T2N1 (35%), T2N0 (24%), T1cN1 (12%), T1bN0, T1bN1, T3N1 (each 8%), T1cN0, T3N0, and T4aN1 (each ≤ 5%). Of 101 NAC cases, 29 patients achieved pCR (29%). The TILs were found in 27 cases, 18 with pCR (67%). Extensive tumor necrosis was found in 23 cases, 9 with pCR (39%); 20 cases were invasive lobular carcinoma or mixed ductal and lobular, with only 1 demonstrating pCR (5%). Five were cases of metaplastic carcinoma, none showing pCR. Receptor status was available for 90 core biopsies; 27 cases were triple negative, 8 showing pCR (30%), and 30 cases were HER2+, 15 with pCR (50%). Of 33 ER+/HER2− cases, 2 had pCR (6%).
Conclusions: The TILs help predict response to NAC with a 2-fold increase in pCR, whereas necrosis is somewhat predictive. Invasive lobular or metaplastic histology predicts for much less response. Receptor negativity or HER2 positivity predicts the highest pCR rates.
“Random” Colon Biopsy Should Never Be Triaged Randomly: Incidental Metastatic Breast Lobular Carcinoma Identified in Endoscopically Unremarkable Colon: (Poster No. 85)
Breast cancer is one of the most devastating cancers afflicting women throughout the world. Nearly 50% of such patients have regional or distant metastases at initial presentation. Reports of colonic involvement by metastatic breast cancer have largely been limited to those with clinical or endoscopically suspicious findings. Identifying small foci of metastatic disease in otherwise routine colon biopsies is challenging. In these instances, high levels of suspicion together with careful histologic assessment are critical in identifying occult metastatic carcinoma. This is a case report of metastatic breast cancer identified within an endoscopically unremarkable colon biopsy in a patient presenting with abdominal pain and diarrhea. Colonoscopy was performed with normal findings reported. Microscopic evaluation of the “random” colon biopsy revealed rare signet ringlike carcinoma cells involving minute foci of lamina propria, which was morphologically and immunophenotypically consistent with metastatic disease from a breast primary. Review of the medical records revealed a history of breast lobular carcinoma, resected at an outside institute 1 year earlier. This was the first presentation of metastatic disease in patient's gastrointestinal tract. Following this incidental diagnosis, patient was managed accordingly, with modification of chemotherapy regimen. Identifying metastatic disease in routine gastrointestinal biopsies is difficult histologically. Careful microscopic assessment along with detailed review of patient's history is essential in detecting any metastatic disease. Such efforts are crucial for identifying an occult malignancy and for improving overall patient care. A “random” biopsy from the gastrointestinal tract should never be dealt with randomly.
Radial Scars in Breast Core Biopsies Are Infrequently Associated With Carcinoma and May Not Require Excision: (Poster No. 86)
Context: The risk of finding carcinoma in excisions for a core needle biopsy (CNB) diagnosis of a radial scar (RS) is not well defined and clinical management is variable. We report the frequency of high-risk lesions (HRLs), ductal carcinoma in situ (DCIS), and invasive carcinoma in excisions of RS diagnosed on CNB. Postexcision, clinical follow-up and chemoprevention data were also collected.
Design: Seventy-nine patients with RS on CNB between 2000 and 2014 were identified. The presence of HRL (atypical ductal or atypical lobular hyperplasia, lobular carcinoma in situ) and invasive carcinoma or DCIS in CNBs and excisions were recorded. Pathology data were reviewed by dedicated breast pathologists. The RS was categorized as targeted or incidental by a dedicated breast radiologist.
Results: Indications for CNB were a mass in 45 cases (57%), calcifications in 22 cases (28%), and magnetic resonance imaging findings in 12 cases (15%). The RS was the targeted lesion in 64 cases (81%). Forty-four cases had complete slide review of CNB and excision. Of 30 benign RSs, none was upgraded to invasive carcinoma or DCIS on excision, and 5 (17%) were upgraded to HRL. One patient with a benign RS on CNB developed ipsilateral DCIS 72 months after excision. Two patients were placed on chemoprevention for HRL found on excision.
Conclusions: None of the benign RSs on CNB was upgraded to carcinoma. The RS was the targeted lesion in 17% of cases upgraded to HRL. Excision may not be mandatory for patients with benign RSs on CNB, especially for incidental RSs.
Clinicopathologic Features of Neurofibromas of the Breast and Its Association With Breast Carcinoma: (Poster No. 87)
Context: Neurofibromas (NFs) are commonly associated with neurofibromatosis type 1. Rare cases of neurofibromas occur in the breast and nipple area. We undertook a retrospective study of breast NFs to evaluate its association with breast carcinomas (BCs).
Design: We investigated 22 cases of breast NFs for age, sex, location in the breast, presentation, occurrence of synchronous or metachronous BC, grade, tumor size, and ER, PR, Her2/neu, and p16 immunostaining.
Results: There was a female predominance (90%) and a mean age of 52 years. Six cases (27%) involved the breast parenchyma, whereas 16/22 (73%) were superficial. All cases were solitary, except for one case associated with NF1. Six cases (27%) were associated with BCs. All 6 cases of BC were associated with solitary, sporadic NFs; 4 of these 6 were synchronous. Two cases were metachronous in which NF preceded BC by 5 and 9 years. Four of 6 BCs showed parenchymal NFs. Four cases of BCs were grade 3, and 2 were grade 1–2. Four of 5 cases were ER+and PR+, and 1 of 4 was HER2+. Three of 3 cases showed abnormal p16 cytoplasmic staining in the BCs and focal nuclear staining in the NFs.
Conclusions: Most of the NFs were solitary, sporadic tumors. Our study revealed an association of synchronous/metachronous breast carcinoma with solitary and sporadic NFs. The BC was more commonly associated with parenchymal rather than superficial NF. Patients with parenchymal NF should have close clinical follow-up for breast carcinoma.
The Prognostic Significance of Tumor Infiltrating Lymphocytes in Metaplastic Breast Carcinomas: (Poster No. 89)
Context: The presence of lymphocytes within tumor cells has become a prominent area of research because of their active participation in tumoral immune response. In breast cancer specifically, tumor infiltrating lymphocytes (TILs) have a pivotal role in chemotherapy sensitivity and prognosis. This study investigated the prognostic significance of TILs in metaplastic breast carcinomas (MBCs).
Design: A total of 31 cases from the Thomas Jefferson database were reviewed. The diagnosis of MBC was confirmed, and TILs were assessed based on the International TILs Working Group 2014 recommendations. The TILs were assessed as a percentage of lymphocytes and plasma cells based on morphology on representative hematoxylin-eosin slides. They were then subdivided into 3 categories (<5%, 5%–40%, >40%) and correlated with outcomes at 5 and 10 years and histologic subtypes.
Results: Five of 31 patients had TILs less than 5%, with 80% overall mortality and 60% mortality within 5 years. Eleven patients had TILs between 5% and 40%, with 31% overall mortality and 23% mortality within 5 years. Tumors with TILs of 40% or greater comprised the remainder of the group, with only 10% overall mortality. More than one-half of the patients with more than 40% TILs had disease-free survival for longer than 5 years. Among the subtypes of MBCs, spindle cell variants were associated with the most TILs (50%), whereas osseous and sarcomatoid variants were associated with the least amount of TILs (10% and 15%, respectively).
Conclusions: Even though there is heterogeneity in the percentage of TILs present in MBCs, they can be used as an adjunct prognostic marker at extremes of below 5% and above 40%.
High SIRT1 Expression Associated With Epithelial-Mesenchymal Transformation in Breast Cancers: (Poster No. 90)
Context: Cancer cells undergoing epithelial mesenchymal transformation (EMT) are associated with cancer metastasis, cancer recurrence, and cancer resistance to chemotherapy. Cancer cell EMT can be demonstrated by expression of vimentin and loss of E-cadherin. SIRT1, a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase, has recently been linked to cancer stem cells and cancer cell EMT. The goal of this study was to evaluate the association between SIRT1 expression and breast cancer EMT.
Design: Immunohistochemistry for SIRT1, vimentin, and E-cadherin was performed on 33 cases of breast cancer specimens. The immunohistochemical staining was blindly scored for intensity 0–3 and percentage 0–100, and the total scores were calculated as intensity × percentage. Student t test and Pearson correlation coefficient were used for statistical analysis.
Results: SIRT1 and vimentin expression were significantly associated with breast cancer grade (G1/G2 versus G3, P =.046 for SIRT1 and P = .003 for vimentin). Vimentin expression was negatively associated with E-cadherin expression (R = –0.3398, P = .07), consistent with the gain of vimentin and loss of E-cadherin in cancer EMT. Vimentin expression showed strong positive correlation with SIRT1 expression (R = 0.6155, P < .001), indicating high SIRT1 expression was associated with breast cancer EMT.
Conclusions: Our study showed SIRT1 expression was significantly high in grade 3 breast cancers, and high SIRT1 expression was significantly associated with gain of vimentin in breast cancer. So, SIRT1 may be an important EMT regulator in breast cancers and could be used as a therapeutic target in high grade, metastatic, or therapy-resistant breast cancers.
X-ray of Breast Carcinoma Does Not Affect Expression of Clinically Relevant Biomarkers: (Poster No. 92)
Context: The College of American Pathologists (CAP) and the American Society of Clinical Oncology (ASCO) have emphasized the need to reduce preanalytic variables for evaluating predictive biomarker expression in breast cancer. At our institution, some surgeons perform x-ray lumpectomies to detect clips or calcifications; this is a preanalytic variable that has not been previously investigated. We asked whether such radiation affects expression of relevant biomarkers in breast cancer.
Design: A previous study at our institution found that human breast cancers grown in mice demonstrate the same immunohistochemical and molecular profiles as the original tumors. Thirteen human breast-tumor grafts with different immunoprofiles were harvested fresh from mice. A portion of each tumor received an autocalculated dose of radiation from our x-ray system (Faxitron, Tucson, Arizona). The CAP/ASCO guidelines for cold ischemia time and fixation were followed. Irradiated and control samples were then processed in duplicate onto a tissue microarray for immunohistochemistry. A blinded pathologist evaluated ER, PR, p53, and Ki-67 by the H-score method. HER2 was evaluated using the CAP/ASCO 2013 protocol. Staining was also evaluated using an optimized scoring algorithm performed on digitally scanned slides. Histologic scores for irradiated and control samples were compared by Wilcoxon signed-rank test.
Results: There was no significant difference in quantity or intensity of staining between irradiated and nonirradiated samples by manual or digital analysis: ER (P =.38), PR (P =.08), p53 (P =1.0), and Ki-67 (P = .64). Her2 staining was similarly unchanged in the one tumor exhibiting 3+ staining.
Conclusions: Our study demonstrates an important negative result—that radiation does not significantly affect the expression of predictive biomarkers in breast cancer.
Genomic Alteration Analysis in Stage 4 Breast Cancer Using 2 Types of Next-Generation Sequencing: (Poster No. 94)
Context: The aim of this study was to characterize the genomic alterations of advance stage breast cancer by reviewing next generation sequencing results to identify pathways that may be commonly altered in advance stage breast cancer.
Design: The study included 8 patients with stage-4 breast cancer. Data were collected from patients who had 2 types of targeted next-generation sequencing done on formalin-fixed, paraffin-embedded tissue and circulating tumor DNA in blood plasma. The data were analyzed for gene alteration type, hormone receptor status, and molecular pathway.
Results: A total of 75 unique alterations were found in 8 patients using both methods of next-generation sequencing. On the tumor tissue samples, 87.5% of the patients had an alteration in the p53 pathway and 75% of patients had an alteration in the MTOR pathway. Using circulating tumor DNA, 50% of patients had an alteration in the MTOR pathway, 57% of which were mutations in PIK3CA. Thirty-eight percent of patients had a mutation in p53 in circulating tumor DNA. Using both methods combined, 75% of patients had an alteration in the MTOR pathway, 50% of which were alterations in PIK3CA, and 88% of patients had an alteration in the p53 pathway, 90% of which were mutations in p53. Three patients had a change of therapy because of the results of their genomic analysis.
Conclusions: MTOR and p53 are upregulated in both tumor tissue and circulating DNA in advanced breast cancers, which provide valuable insight for drug research and targeted therapy.
In Situ mRNA Detection of Progesterone Receptor in Invasive Breast Cancer: (Poster No. 95)
Context: In situ, chromogenic, bright-field messenger RNA (mRNA), progesterone receptor (PR) transcript enumeration has not, to our knowledge, been explored.
Design: Thirty-six formalin-fixed, paraffin-embedded breast samples are used to construct 2mm tissue microarray for evaluation of total PR (PRt) protein expression by immunohistochemistry (IHC) and PRt and PRb isoform in situ mRNA detection by RNAScope (Advanced Cell Diagnostics).
Results: The PRt transcript copy number in benign luminal epithelial cells was 1. Baseline PRt transcript density was very low (1:8) compared with reference housekeeping gene (POLR2A) transcript number. The PRt transcript copy number in invasive breast cancer ranged from 0 to 3. Average percentage of PR expression by IHC, normalized to PRt transcript copy number, was as follows: 0 (4%), 1 (21%), 2 (29%), and 3 (30%). Pearson correlation coefficient (r) of PRt by IHC and RNAScope (continuous variable) was 0.37 (P = .04). Average PR (IHC) expression reduced significantly in high tumor grade, invasive breast cancer. Of 30 invasive breast cancer cases, 15 were PR−ve based on IHC expression. Out of 15, PRt mRNA transcripts were present (>1 copy) in 6 cases. Of these 6 cases, 3 had high (>2) copy numbers. Interestingly, PRb isoform transcripts were also highly expressed among the respective subset. Based on PRt mRNA expression, copy number of 2 or greater may be termed as positive expression among breast cancers. Correlative concordance between PRt and PRb isoform by RNAScope is 0.77(r) (P < .001).
Conclusions: Dynamic range of PRt mRNA compared with benign and invasive breast cancer is narrow. In situ mRNA PR detection could be a valuable tool to screen for false-negative PR performed through IHC.
Discordance in the Diagnosis of Metaplastic Breast Carcinoma on Core Biopsy and Surgical Excision: (Poster No. 96)
Context: Metaplastic breast cancer (MBC) is an uncommon, aggressive variant of invasive mammary carcinoma (IMC). The extent of metaplastic component required to diagnose MBC is not well defined. The goal of this study was to determine the diagnostic concordance rate for MBC in a series of core needle biopsies (CNB) with corresponding excisions.
Design: A total of 122 cases of MBC were identified from 2002 and 2013 and 28 cases without CNB slides or radiology were excluded. Pathology slides and reports were reviewed by dedicated breast pathologists. Clinical and imaging information were obtained from the electronic medical record.
Results: Of the 94 cases with material available for review, 63 (67%) were diagnosed as MBC, and 31 (33%) were diagnosed as IMC–no special type (NST) on CNB. Of the 31 cases not diagnosed as MBC on CNB, 16 (52%) showed squamous differentiation, and 15 (48%) showed matrix production or heterologous elements on excision. On review of CNB slides, no IMC-NST were reclassified as MBC, and necrosis was prominent in 9 (29%). The tumors presented as palpable masses in 15 discordant cases (48%) and 46 concordant cases (73%) (P = .02). Cases diagnosed as IMC-NST on CNB presented with smaller tumor size (P = .008) on imaging studies or gross examination.
Conclusions: Up to one-third of patients with MBC may be diagnosed with IMC-NST on CNB, potentially affecting selection of patients for neoadjuvant therapy. The metaplastic component may be more extensive in larger tumors, leading to higher concordance for CNB and excisions.
High-Grade Transformation of a Low-Grade Adenosquamous Carcinoma of the Breast: (Poster No. 97)
Low-grade adenosquamous carcinoma (LGASC) is a rare form of metaplastic breast carcinoma that has a markedly better prognosis than typical metaplastic carcinomas. Although there has been one documented incidence each of lymph node and lung metastasis, the most common concern is for local recurrence. Transition from LGASC to another higher-grade lesion has only been unequivocally reported once. That change was to a high-grade spindle cell metaplastic carcinoma. We present a 73-year-old, otherwise healthy woman who presented with a solitary, painless, 0.8-cm, subareolar mass found on screening mammogram. Ultrasound-guided biopsy and subsequent needle-localized lumpectomy were performed, which showed poorly differentiated invasive ductal carcinoma arising from an LGASC. The bland ductal epithelial cells with squamous differentiation and infiltrating tubules comprising the LGASC were partially overrun by solid proliferations of epithelial cells with high-grade nuclei and abundant pale cytoplasm. These high-grade areas did not exhibit squamous differentiation, and the bland spindle cells retained their low-grade morphology. A vast panel of immunohistochemical (IHC) stains confirmed the triple-negative phenotype of both tumor populations and the loss of peripheral p63 staining highlighted the transition from LGASC to a higher-grade carcinoma. The IHC supported the lack of squamous or myoepithelial differentiation, supporting the transformation to a nonmetaplastic, high-grade carcinoma. This case reports the first known incidence, to our knowledge, of poorly differentiated ductal carcinoma arising out of an LGASC. Awareness of this entity is paramount because it drastically changes prognosis and management.
Histologic Changes Associated With Radioactive Seed Placement in Breast Specimens: (Poster No. 98)
Context: Use of radioactive seed (RS) is becoming increasingly popular over wire localization (WL) for localizing breast lesions. Although RS has gained popularity in use, to our knowledge, no studies have assessed for histologic changes in RS specimens compared with WL specimens.
Design: Reports and slides from patients who underwent breast surgery or excisional biopsy with RS localization were retrieved and compared with patients who underwent excisional biopsy with WL (control group). Slides were reviewed to assess histologic changes associated with RS and WL. Histologic diagnosis, margin status, and time interval between seed placement and day of surgery were recorded. Location of RS was correlated with gross identification of placement site, as recorded in the cassette summary key.
Results: Forty RS cases were identified and compared with 41 WL cases from the same period. Histologic changes in RS cases consisted of a fixed polygonal defect with a thin peripheral fibrin rim without histiocytic change. Histologic change in WL cases consisted of a linear disruption of the tissue filled with fresh hemorrhage. The RS defect juxtaposed near each healing biopsy site in most cases (34 of 40, 85%), whereas WL disruption varied in location. No significant difference between the two groups in margin status (RS, 12.5%; WL, 13%) was appreciated.
Conclusions: We describe the characteristic histologic changes as well as margin status corresponding to the RS placement. Recognition and knowledge of RS changes may be helpful in identifying the site of radiographically detected lesions excised in the absence of a previous biopsy.
Examination of Thermal Injury at the Surgical Margin of Breast Carcinomas: A Randomized, Controlled Trial of 2 Electrosurgical Devices: (Poster No. 99)
Context: Recent guidelines of “no ink on tumor” in the pathologic assessment of breast carcinomas have highlighted the importance of visualization and assessment of the surgical margin for proper diagnosis and treatment. We examined by histology the thermal effects of 2 electrosurgical devices on margin assessment following breast lumpectomy and propose an assessment methodology.
Design: Fifty women undergoing lumpectomy were equally randomized to excision with a traditional electrosurgery pencil (SOC, 65 ± 11 years old) or a low thermal injury device, PEAK PlasmaBlade (LTI, 63± 13 years old). Fixed tissue specimens were used to measure the depth of fused and distressed zones of thermal injury laterally and perpendicularly from the center of the injured area. Charring, epithelial damage, and effect on diagnosis were semiquantitatively scored on a 0–3 point scale. Specimen quality on diagnosis was determined by the addition of these scores.
Results: Depth of fused and distressed injury zones in malignant tissue margins demonstrated a 43%–50% reduction with the LTI device versus SOC; combined depth was 1774 ± 1062 μm versus 3389 ± 1915 μm (P < .001), respectively. Margins without tumor demonstrated LTI versus SOC combined depth of 2101 ± 1173 μm versus 3408 ± 1659 μm (P < .001). Charring and epithelial cell damage were minimal to none in 40%–50% of LTI specimens versus equivalent SOC amount as minimal to moderate, with 5% being severe (0.8% in LTI). Overall, higher cumulative scores were demonstrated in the LTI device group.
Conclusions: Lumpectomy specimens excised with the LTI device demonstrated significantly lower thermal injury artifact and higher histologic quality scores compared with traditional electrosurgical pencil devices. Future studies should examine downstream outcomes of these results.
Dr Sangoi is a consultant to Medtronic. Both Drs Sangoi and Naruns have received grant or research support from Medtronic.
Evaluation of NPAS2 as a Novel Expression Marker for Breast Cancer: (Poster No. 102)
Context: The neuronal PAS domain protein 2 (NPAS2) is one of the essential circadian genes that regulates the 24-hour oscillation of many biologic and physiologic processes. Emerging data have demonstrated that it has a substantial impact on tumor-related biologic pathways. Our previous research provided the first evidence that the polymorphism and the RNA expression level of NAPS2 were strongly associated with breast cancer survival.
Design: Currently, there is no published data on NPAS2 protein expression in human tissue. Therefore, we conducted the first translational study to determine whether the in situ NPAS2 protein expression was also strongly associated with breast cancer risk and survival.
Results: We stained 40 T1 and T2 stage invasive ductal carcinomas with a polyclonal antibody of NPAS2. Benign breast parenchyma presented on the same slide was used as an internal control, which showed a low to medium level of NPAS2 expression. The result showed that by immunostaining, in 55% of the cases, NPAS2 expression was decreased in the tumor compared with benign tumors (χ2, P = .09).
Conclusions: These preliminary results show that the NPAS2 protein level was borderline decreased in breast cancer. However, our previous research by real-time polymerase chain reaction (PCR) using RNA extracted from tumor tissue demonstrated a stronger association. It is highly likely that the real-time PCR technique is much more sensitive than IHC for detecting changes in expression level. We will continue this study with increased sample size and using an alternative antibody before we reach a final conclusion.
Bilateral Cystic Hypersecretory Ductal Carcinoma In Situ of the Breast in a 47-Year-Old Woman: (Poster No. 103)
Cystic hypersecretory ductal carcinoma in situ (DCIS) is a rare pathologic entity that comprises dilated, cystic ducts lined by micropapillary tufts of cells with nuclear atypia. Dense, eosinophilic intraluminal contents resembling thyroid colloid are seen. A background of cystic hypersecretory change is usually seen, with similarly dilated ducts, eosinophilic luminal contents and a bland, flat to cuboidal epithelial lining. Additional associated findings may include lactational change and, in rare cases, invasive carcinoma. This constellation of findings, especially in the absence of conventional DCIS or invasive carcinoma, may present significant diagnostic difficulty for the pathologist and may be overlooked or dismissed. Approximately 65 cases have been reported in the literature, and all have been unilateral. We report the case of a 47-year-old woman with bilateral cystic hypersecretory DCIS diagnosed on mastectomy. The patient's initial diagnosis of left-sided intermediate-grade, solid DCIS followed stereotactic biopsy for microcalcifications. A bilateral total mastectomy revealed left-sided, solid, intermediate-grade DCIS as well as foci of dilated, cystic ducts with eosinophilic intraluminal material, atypical micropapillary epithelial lining, and lactational change. Cystic hypersecretory DCIS was also present in the prophylactic right mastectomy. Biomarkers performed on the tissue showed weak, scattered positivity for both estrogen receptor and progesterone receptor. To our knowledge, this is the first reported case of bilateral cystic hypersecretory DCIS and represents an exceptionally rare manifestation of this diagnostically challenging lesion.
Prognostic Marker Expression of Female Breast Carcinoma With Brain and Bone Metastasis: (Poster No. 104)
Context: In primary breast cancer, prognostic markers are important for making effective treatment decisions. A challenge in the management of breast cancer is the development of systemic metastasis. We performed a retrospective study of female breast carcinoma with brain (BRM) or bone (BOM) metastases to identify whether histology or prognostic markers predict site of metastasis and also to identify marker concordance between primary tumor and metastasis.
Design: We identified 76 patients with primary breast cancer who developed BOM (n =53) or BRM (n =23) between 1997 and 2014; only cases with ER and PR by immunohistochemistry (IHC), and HER2 by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) were included.
Results: Of cases with BOM, 83% were ER+ and 62% were PR+. HER2 was positive 13%, and FISH showed amplification in 10%. Triple-negative cases accounted for 10%. Discordant staining between the primary tumor and the metastasis was seen in 48%. Ductal carcinoma accounted for 61% of cases, lobular 32%, and mixed 7%. Of cases with BRM, 30% were ER+and 13% were PR+. HER2 was positive in 48%, and FISH showed amplification in 47%. Triple-negative cases accounted for 35%. Discordant staining was seen in 45%. Ductal carcinoma accounted for 91% of cases, and mixed accounted for 9%.
Conclusions: Cases with BRM were more likely to be ER−, PR−, overexpress HER2, triple negative, and of ductal type. Lobular histology was associated with the development of bone but not brain metastases. Discordant prognostic markers were seen in both brain and bone metastases, indicating the importance of marker testing of metastasis before medical treatment.
Rare Case of Intracystic Papillary Carcinoma of the Breast in a Male Patient: (Poster No. 106)
Intracystic papillary carcinoma (IPC) is an extremely rare subtype of breast carcinoma and accounts for 0.5%–1% of all breast cancers. We report a rare case of IPC in a 56-year-old man who presented with a 6-month history of a right breast mass. He also has a history of papillary renal cell carcinoma (PRCC), which was incidentally discovered during renal transplant for end-stage kidney disease because of recurrent urinary tract infections in 2008. A fine-needle aspiration of the breast mass revealed only marked acute inflammation, histiocytes, and blood. Excisional biopsy revealed a 3.0-cm, well-encapsulated, cystic tumor. Histologically, the tumor consisted of atypical cells arranged in papillary and cribriform patterns within a large cystic duct surrounded by a thick, fibrous capsule. The cells were monotonous and had round, vesicular nuclei, prominent nucleoli, and abundant cytoplasm. By immunohistochemistry, the tumor cells were negative for CK5, calponin, and p63. Estrogen receptor and progesterone receptor were strongly positive. The overall findings were consistent with IPC. Because IPC in men is extremely rare, there are few reported cases in the literature. To our knowledge, this is the first described case of IPC and PRCC in a male patient. It has been reported that IPC differentially expresses genes involved in papillary carcinomas of other organs, such as the thyroid and kidney. Intracystic papillary carcinoma has an excellent prognosis in the absence of concomitant in situ or invasive carcinoma. Thorough sampling for the presence of in situ or invasive carcinoma is crucial for future risk stratification and management.
Carcinomasarcoma of Ovary: (Poster No. 108)
Primary ovarian carcinosarcoma is a rare, biphasic tumor also known as malignant mixed mesodermal tumors or malignant mixed müllerian tumors (MMMTs). By definition, this is variable admixture of both malignant epithelial (carcinomatous) and stromal component. It accounts for 1%–3% of ovarian malignancies, and so far, 400 cases have been reported in literature. In most cases, extraovarian, intra-abdominal spread occurred at the time of diagnosis. There is collision theory about MMMTOS that 2 different cellular lines with mutations generate the tumor. Here, we report case of a 53-year-old, postmenopausal woman who presented with abdominal pain and vaginal bleeding of 3 months duration. Computed tomography scan showed cystic solid right ovarian mass. The CA 125 was elevated (156 IU/mL). Total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed. We received an ovarian mass weighing 550 g and measuring 19 cm at greatest dimension with cystic and solid component and fibrosis, hemorrhage, and necrosis. Microscopically, there were irregular gland-lined pleomorphic cells with hyperchromatic nuclei. The stroma showed the presence of oval- to spindle-shaped fusiform cells with pleomorphic hyperchromatic nuclei, rhabdoid cells, and chondroid cells in myxoid background. Mitotic activity was frequent (8–9 per 10 high-power fields) with the presence of tumor necrosis. Immunohistochemistry showed the epithelial component was positive for AE1/AE3, CK7, ER, PR, vimentin, and PAX8.The sarcomatous component were positive for INI-1 and vimentin. There is no consensus on the optimal therapy, and uniform agreement does not exist about the optimal treatment of MMTOs, except that achieving optimal debulking at the time of initial surgery significantly improves overall survival. Principal prognosis factor is heterologous sarcomal component.
Ciliated Low-Grade Papillary Serous Carcinoma of the Ovary: (Poster No. 109)
This case is that of a 56-year-old woman who presented with bilateral cystic pelvic masses. A hysterectomy, bilateral salpingo-oophorectomy, and removal of peritoneal implants were performed. Histopathologic exam revealed low-grade papillary serous carcinoma with cilia and psammomatous calcifications involving the right and left ovaries, and focally invading the serosa of the lower uterine segment. Metastatic papillary serous carcinoma was seen in the sigmoid, omentum, and peritoneum. Serous carcinomas of the ovary are presumed to be a malignancy resulting from a clonal expansion of fallopian tube secretory cells resulting in a decreased ratio of ciliated cells to secretory cells. The amount of ciliated conversion in secretory cells is thought to be correlated with the degree to which mutations affect normal differentiation. Cilia are frequently found in borderline serous tumors, with low- and high-grade serous carcinoma of the ovary usually demonstrating only rare cilia. As such, there is a potential pitfall of underdiagnosing a low-grade papillary serous carcinoma with ciliated conversion as a borderline tumor. Therefore, the presence of numerous cilia in the tumor should not by itself exclude the possibility of a low-grade papillary serous carcinoma, and adequate sampling with careful inspection for invasion is warranted.
Adenoidcystic Carcinoma of the Bartholin Gland: Incidental Metastatic Disease 16 Years Later on Chest X-ray: (Poster No. 113)
A 61-year-old woman being followed at Montefiore Medical Center presented for urgent care with viral bronchitis. A chest x-ray revealed several right-sided lung nodules not seen on prior 2010 imaging. At age 46 years, our patient was treated for a 2.8-cm Bartholin gland adenoid cystic carcinoma (BGACC) following resection with positive margins and perineural invasion. At the time, she was treated with adjuvant radiation therapy, cisplatin, and 5-fluorouracil. Wedge resections of the current lung nodules revealed metastatic ACC in the right upper, middle, and lower lobes with negative margins. To date, she had no other identifiable metastatic disease. Because BGACC is a very rare disease, there are fewer than 100 cases reported in the literature. With any rare disease, treatment and follow-up guidelines can be very difficult to create. In the case of BGACC, early surgical intervention can be curative. Because BGACC is a slow growing tumor, it has excellent long-term survival but a 10-year disease-free interval of approximately 33%. The tumor recurs locally or distant with the most-common site being the lungs. With this high rate of recurrence, regular radiographic screening may help identify early recurrence, which can subsequently be treated with surgical intervention. In our patient, lung wedge resections were able to completely excise all identifiable disease recurrence, which was seen incidentally on imaging for bronchitis.
Ovarian Calcified Thecoma With Extensive Adipose Metaplasia: A Rare Entity in a Young Patient: (Poster No. 114)
Ovarian thecoma usually occurs in postmenopausal women with a peak incidence in the sixth decade. Ovarian thecoma with extensive calcification and adipose metaplasia is very rare. In this report, we describe the case of a 35-year-old woman with a clinical history of a left ovarian mass. On gross examination, the tumor was a 7.5 × 6.5 × 5.5-cm, yellow nodule with calcification involving 99% of the cut surfaces. Microscopic examination revealed cellular and paucicellular areas with bland ovoid stromal cells, merging with numerous foci of dystrophic calcification and extensive adipose metaplasia. The differential diagnosis included fibroma/fibrothecoma, thecoma, and teratoma. Immunohistochemical staining of the tumor was positive for calretinin and inhibin. These results supported the diagnosis of calcified thecoma. A total of 6 extensively calcified thecomas have been previously reported as case reports, and 10 of 70 cases of thecoma demonstrated pronounced calcification in a recent study. Among the calcified thecoma cases reported, only 2 were also reported to exhibit extensive adipose metaplasia, as was seen in our case. It is important to consider this uncommon benign entity in a young female patient because the tumor may be estrogenic and cause the patient to present with abnormal uterine bleeding. If imaging demonstrates an adnexal mass with extensive calcification, calcified thecoma should be included in the differential diagnosis.
Pancytokeratin Expression in Ulcerated Decidual Reaction of the Cervix: A Potential Diagnostic Pitfall: (Poster No. 115)
This report describes the case of a 35-year-old woman (gravida 1, para 0), whose pregnancy was complicated by an abnormal Papanico-laou test showing atypical squamous cells of undetermined significance, with a positive human papillomavirus test (HPV high-risk genotype 16), discovered at 18 weeks gestation. Upon colposcopic examination, a 3.0-mm friable and exophytic cervical lesion was found and biopsied. Histologic exam revealed mitotically inactive, large, and polygonal cells with abundant granular eosinophilic cytoplasm and round to oval nuclei with dispersed chromatin and occasional conspicuous nucleoli that underlie the ulcerated epithelium. These cells displayed patchy expression of pancytokeratin and p16 immunostains, and a low MIB-1 proliferative index. There was no expression of GATA3, CD10, p63, and CK5/6 immunostains. The masslike configuration, ulceration, abnormal Papanicolaou test, and other initial morphologic findings prompted some consideration of an invasive squamous cell carcinoma, but that possibility was excluded by additional studies. Short-term clinical follow-up has been unremarkable. The potential expression of pancytokeratin in decidual reactions is an underemphasized phenomenon that may represent a diagnostic pitfall in their differential diagnosis with squamous cell carcinoma, especially in the setting exemplified by the current case (mass lesion, ulceration, HPV positivity, p16 coexpression).
Somatic Mutation Profiling of Benign Brenner Tumors of the Ovary and Associated Mucinous Neoplasms: (Poster No. 117)
Context: Benign ovarian Brenner tumors (BTs) are often associated with mucinous cystadenomas (MCAs) or mucinous borderline tumors (MBTs) and are hypothesized to share a histogenic origin and progression, yet limited molecular characterization has been conducted to support this. Our goal was to identify molecular mechanisms linking these tumors.
Design: DNA from 6 BTs and associated ipsilateral MCAs (4) or MBTs (2) was extracted from tumor formalin-fixed, paraffin-embedded samples and sequenced using a 358-gene next-generation sequencing assay. Sequenced samples were subjected to an in-house bioinformatic pipeline for variant calling and annotation with a manually curated clinical knowledgebase. Variant calls were compared within tumor groups to assess somatic mutation profiles.
Results: A total of 220 different high/medium impact variants were detected across all samples with high concordance (59.5%–94.7%, P = .86) between BT and MCA-MBT samples. Exon-coding mutations detected in highest frequency in benign BT and MCA-MBT, respectively, were in GLI1 (7.5% and 6.1%), BRCA1 (6.4% and 7.6%), and AURKB (4.6% and 4.1%). Twenty variants were common to all (6 of 6) BTs, whereas 24 variants were found in all (6 of 6) MCA-MBTs. Mutations in RAS were noted in 4 of 6 MCA-MBT samples. MYC amplification was detected in 2 paired BT-MCA, in one of the Brenner cases, and both of the MCA components.
Conclusions: The high degree of overlap in gene variants between BT and mucinous (MCA-MBT) tumors observed supports the idea of a shared origin or progression. Differences observed in affected genes and pathways, particularly involving RAS and MYC, may point to molecular drivers that support the divergent phenotype and progression of these tumors.
Loss of PAX2 Expression Is Common in Both Endometrioid and Serous-Type Endometrial Carcinoma: (Poster No. 118)
Context: Recently published data suggest that loss of expression of PAX2 (a potential tumor suppressor) is an early event in endometrial carcinogenesis. Similarly, PAX2 loss has been described as a putative precursor for tubo-ovarian serous carcinoma in the absence of p53 alteration. In this study, we compared PAX2 expression and its relationship to p53 expression in endometrioid and serous endometrial carcinomas.
Design: Endometrial carcinomas (n =103) were divided into grades 1–2 endometrioid (n =42), grade 3 endometrioid (n =26), and serous (n = 35). PAX2 and p53 expression was determined in each case by immunohistochemistry. PAX2 was classified as negative, heterogeneous, or positive. p53 expression was classified as “mutated” when exhibiting strong, diffuse staining, or completely absence of staining (p53 null phenotype). Results were then compared by appropriate statistical analysis.
Results: PAX2 loss occurred commonly and at similar frequencies in both endometrioid and serous carcinomas (grades 1–2, 69.1%; grade 3, 61.5%; serous: 60.0%; P =.17). Twenty-one of 25 cases (84%) of serous carcinoma showed coincident p53 mutation and predominant PAX2 loss (>80% negative). Mutated p53 was more common in grade 3 endometrioid tumors than it was in grade 1–2 (26.9% versus 2.4%, P < .001) and did not appear to correlate with predominant PAX2 loss, which was common in both tumor grades (69.2% and 81.0%).
Conclusions: The high frequency of PAX2 loss in both endometrioid and serous endometrial carcinomas suggests a relevant role for this tumor suppressor in more than one pathway of endometrial carcinogenesis. Overall, PAX2 loss correlated with altered p53 expression in serous carcinoma but not in endometrioid carcinomas.
The Invasive Mole: Defining Characteristics of Molar Pregnancy: (Poster No. 120)
Invasive mole is an uncommon sequela of persistent or metastatic gestational trophoblastic disease that manifests clinically as persistent elevated levels of β-hCG following a molar pregnancy. Gestational trophoblastic disease is composed of complete or partial hydatidiform molar lesions. The pathogenesis of molar pregnancy is related to aberrant fertilization with resultant overexpression of paternal genes. The reported incidence of molar pregnancies is primarily confined to the uterus with distant spread occurring in a small percentage of cases. We describe a 36-year-old woman with a past medical history of endometriosis who presented with vaginal bleeding at 6 weeks of pregnancy with markedly elevated β-hCG levels and symptomatic hyperthyroidism. Before admission, the patient had passed “tissuelike clusters” from the vagina with symptoms of tachycardia, abdominal pain, emesis, and severe nausea for several weeks. A transabdominal ultrasound demonstrated an enlarged uterus, estimated at 23 weeks, with no intrauterine pregnancy identified. An endometrial curettage was consistent with complete hydatidiform mole, and weekly methotrexate therapy was initiated. Because of persistently elevated β-hCG levels after more than 20 weeks of methotrexate therapy, repeat pelvic ultrasound was performed that was notable for a residual invasive mass within the fundus. In addition, several subcentimeter bilateral pulmonary lesions were identified on chest CT scan. Six months after the initial diagnosis, she underwent a hysterectomy. Histopathologic examination was notable for an invasive complete hydatidiform mole with lymphovascular involvement. This case illustrates an uncommon finding of invasive mole confirmed by histologic findings from a hysterectomy specimen.
Leiomyosarcoma Arising in Diffuse Uterine Leiomyomatosis With Extra Uterine Dissemination: (Poster No. 122)
Diffuse uterine leiomyomatosis (DUL) is a rare condition characterized by extensive myometrial involvement by leiomyomatous growth. It has been reported less than 40 times in the literature. Only 2 cases of extrauterine extension have ever been reported with DUL. Leiomyosarcoma arising within DUL has never, to our knowledge, been reported. Our patient has all 3. Our case involves a 48-year-old woman with a several year history of heavy bleeding, pelvic pain, and an enlarging uterine mass. Radiologic images demonstrated an apparent bilobed mass within the uterus. A hysterectomy was performed, and the uterus was removed in 2 parts. The superior segment had subserosal and myometrial nodules too numerous to count. The inferior portion was a 12-cm mass with hemorrhage and necrosis, protruding from the cervical os. The superior segment was positive for smooth muscle actin (SMA) and negative for p53 with a low Ki-67 index. Gross exam, histology, and immunohistochemistry led to a diagnosis of DUL. The inferior segment was positive for SMA and p53 with a high Ki-67 index. This mass was diagnosed as a leiomyosarcoma. In addition, several nodules were discovered on the adnexa and regional lymph nodes. These nodules were positive for SMA and negative for p53 with a low Ki-67 index. They represent benign, metastasizing leiomyomas. The patient has been treated with 6 rounds of chemotherapy. Additional nodules have been discovered in the lungs and para-aortic lymph nodes. To date, these are all consistent with benign, metastasizing leiomyomas. This is an extremely rare case of DUL with leiomyosar-coma and benign metastases.
High-Risk Human Papillomavirus (HPV) Genotype 39+ Cervical Cancer in a 32-Year-Old Woman: Rationale for HPV Genotyping Beyond Types 16 and 18: (Poster No. 124)
High-risk human papillomavirus (HR-HPV) is a known etiologic factor in the development of cervical cancer. We report a case of a 32-year-old woman with an indurated pelvic mass who presented with lower back pain and vaginal bleeding for 10 months. Computed tomography (CT) scan demonstrated an enhancing 7.2 × 6.3 × 6.1-cm heterogeneous mass apparently originating from the posterior cervix and displacing the lower uterine segment. Histologic examination of the initial cervical biopsy demonstrated high-grade squamous intraepithelial lesion with glandular involvement, and the subsequent biopsy displayed coalescing sheets and islands of high-grade squamous carcinoma with foci of mucinous differentiation. Immunohistochemical staining demonstrated positivity for p16, CK7, p63, and CK5/6, and p53. Tumor cells were negative for PAX8 and synaptophysin and predominantly negative for vimentin. The HR-HPV genotyping analysis with the Linear Array HPV genotyping assay (Roche Molecular Diagnostics, Pleasanton, California) revealed the presence of HR-HPV 39. In the literature, HR-HPV 39 has rarely been identified in invasive cervical cancers. Recent guidelines recommend genotyping for 16 and 18 in cervical cytology specimens and pooling additional HR-HPV subtypes into an “other” category. This case illustrates the pathogenicity of some “other” HR-HPV subtypes, and we suggest there may be a need for HR-HPV genotyping beyond 16 and 18 when evaluating the risk of developing cervical cancer.
Endometrial and Cervical Involvement in Pseudomyxoma Peritonei: A Case Report and Review of Literature: (Poster No. 125)
Pseudomyxoma peritonei (PMP) is an infrequent and poorly understood condition characterized by the presence of mucinous ascites with variable amounts of enteric-type neoplastic mucinous epithelium. Most commonly, PMP is secondary to rupture of a low-grade appendiceal mucinous neoplasm. In women, ovaries are often secondarily involved, mimicking a primary ovarian mucinous neoplasm. However, involvement of endometrium and cervix by PMP is exceptionally rare. Here, we report a case of a 64-year-old woman who presented with postmenopausal bleeding. Endometrial biopsy showed abundant necrotic debris with mucinous materials and few atypical cells. Preoperative computed tomography scan of the abdomen and pelvis revealed a 2.1-cm endometrial strip with heterogeneous appearance, bilateral complex adnexal masses, abnormal diffuse thickening of the appendix without significant periappendiceal inflammation, and ascites. She underwent modified radical hysterectomy with bilateral salpingo-oophorectomy, appendectomy, small bowel resection, and omentectomy. Grossly enlarged uterus was filled with abundant mucinous material in the cavity. Frozen section showed dissecting mucin involving the full thickness of the myometrium. Few atypical mucinous epithelium were present in the myometrium and endometrium. The appendix was diffusely thickened to 0.7 cm, and entirely involved by signet ring adenocarcinoma on microscopic examination. Both enlarged ovaries and fallopian tubes were involved by metastatic signet ring carcinoma, which was also seen in cervical stroma, omentum, serosa of the small bowel, and mesenteric lymph nodes. Tumor cells were strongly positive for CK20 and negative for CK7, WT1, and ER, consistent with an appendiceal origin. Only 4 similar cases have been reported previously in the English literature.
Umbilical Metastasis—Unusual Presentation of Grade 1 Endometrioid Adenocarcinoma: First Reported Cases: (Poster No. 127)
Well-differentiated endometrial adenocarcinomas are prognostically correlated with stage and depth of myometrial invasion, and are often associated with an indolent course. We present 2 cases wherein umbilical metastasis was the initial presentation of a well-differentiated endometrial adenocarcinoma. Two women (case 1, gravida 0, aged 51 years; case 2, gravida 0, aged 46 years) presented to the emergency department with complaints of abdominal pain. Imaging studies in both cases confirmed a soft tissue mass in the umbilical area, along with an enlarged uterus and dilated endometrial cavity. In case 1, an excised 4.5-cm umbilical mass showed metastatic endometrial adenocarcinoma. A subsequent total abdominal hysterectomy revealed FIGO grade 1 endometrioid adenocarcinoma. In case 2, similar to case 1, the biopsy of a 4.2-cm umbilical mass showed metastatic endometrial adenocarcinoma; a subsequent endometrial biopsy revealed well-differentiated endometrioid adenocar-cinoma. In the literature, reports of “Sister Mary Joseph” nodule associated with endometrial adenocarcinoma had high-grade histology. To our knowledge, these are the first reported cases of Sister Mary Joseph nodules secondary to a primary, well-differentiated endometrial adenocarcinoma. Such occurrences may reflect the consequences of the delay in seeking treatment by patients presenting at a county hospital. The findings of microsatellite instability (MSI-high) in one patient (case 1) may also be a contributing factor, despite the apparent low-grade histology. In summary, we present 2 unusual cases of aggressive behavior of well-differentiated endometrial adenocarcinoma.
Squamous Cell Carcinoma In Situ Involving Fallopian Tube: (Poster No. 129)
Squamous cell carcinoma in situ involving the fallopian tube is rare. What is more commonly observed is extension of cervical squamous cell carcinoma into the vagina and rare case studies of involvement of the lower uterine segment. We present a case of 63-year old postmeno-pausal woman (gravida 6, para 4-0-2-4) with a past history of left partial salpingectomy for ectopic gestation and Papanicolaou smear with subsequent conization positive for squamous cell carcinoma in situ with focal microinvasion. A total abdominal hysterectomy and bilateral salpingo-oophorectomy was performed. On gross examination, the ectocervix and endocervical canal at the 7 o'clock position revealed a 1.7-cm, raised, tan-white, firm lesion, extending into the lower uterine segment on the posterior side. The endometrium, 0.1 cm in thickness, was unremarkable. The left fallopian tube was dilated with purulent luminal material. Microscopic examination revealed well-differentiated squamous cell carcinoma involving the cervix and extending in situ to the endometrium, as has been previously described in the literature. In addition, sections of the left fallopian tube showed squamous cell carcinoma in situ. The residual endometrium underlying the squamous carcinoma in situ was atrophic. p16 immunostain was strongly and uniformly positive in the cervical squamous cell carcinoma, the squamous cell carcinoma in situ component lining the endometrial cavity, and the focus within the left fallopian tube. The clinical significance of this presentation is not known at this time; it is possible that this may be identified more often as the more thorough examination of fallopian tubes has become routine practice.
Two Synchronous Primary Cancers in a Patient After Transplant: (Poster No. 130)
Posttransplantation- and immunosuppression-associated malignancies are recognized complications. The increased risk makes surveillance and clinical suspicion high priorities, even for rarely occurring tumors. We report a case of a patient with a history of bilateral lung transplant on chronic immunosuppressants who subsequently developed synchronous primary gastrointestinal and gynecologic tumors, with the cecal tumor metastasizing to the gynecologic primary. A 66-year-old woman with no known family history of cancer presented with worsening abdominal pain, postmenopausal bleeding, and unintentional weight loss. She was found to have a positive fecal occult test. Colonoscopy identified a single, 7-cm, polypoid cecal mass that was histologically consistent with a colonic adenocarcinoma on biopsy, with invasion into the muscularis propria on the resection specimen. Endometrial curettings found the presence of a spindle cell neoplasm, identified as a malignant mixed Müllerian tumor with the carcinoma element present in the subsequent hysterectomy. These 2 tumors were morphologically and immunohistochemically distinct. On further studies, there were foci of metastatic cecal adenocarcinoma to the malignant mixed Müllerian tumor showing different morphologies and immunophenotypes. The presence of these 2 tumors simultaneously with tumor-to-tumor metastasis is extremely rare and likely linked to the patient's history of immunosuppression.
A Case of High-Grade Ovarian Serous Carcinoma Evolving From Low-Grade Serous Carcinoma: (Poster No. 131)
Molecular characterization has helped define 2 broad categories of serous ovarian carcinoma based on their clinical behavior and molecular changes. Low-grade serous carcinoma is most frequently associated with mutations in KRAS and BRAF and may arise from borderline serous neoplasms in the ovary. In contrast, high-grade serous carcinoma is frequently associated with mutations in TP53 as well BRCA1/2 and may arise from fallopian tube epithelium. However, the exact molecular-morphologic correlation of these 2 entities remains unclear. We report a case of serous ovarian carcinoma with both high-and low-grade morphologic and immunohistochemical characteristics and the results of molecular testing on both components. The neoplasm contained distinct regions of high-grade serous morphology and diffuse strong p53 and estrogen receptor immunoreactivity, whereas the low-grade component was labeled with estrogen receptor and was negative for p53. Using laser-capture microdissection, we identified pure low-and high-grade cell populations and sequenced each using targeted capture and massively parallel sequencing with BROCA for 45 ovarian cancer susceptibility/DNA repair genes. The high-grade component of the serous carcinoma had a p53 mutation (R248W) without loss of heterozygosity, whereas the low-grade component lacked p53 mutations. Loss of heterozygosity at 17q was identified in the high-grade, but not low-grade, components, consistent with the expectation for high-grade ovarian carcinoma. No tubal intraepithelial neoplasia was identified on complete serial sectioning. These results are most consistent with transformation of a low-grade primary ovarian serous carcinoma into high-grade serous carcinoma at least partly driven by development of a pathogenic mutation in TP53.
An Unusual Presentation of a Partial Hydatidiform Mole: (Poster No. 132)
Partial hydatidiform mole is a type of gestational trophoblastic disease that results from fertilization of an apparently normal ovum by 2 sperm, or, less frequently, by a single diploid sperm, leading to a triploid genotype. Placental maternal surface shows patchy hydropic villi in a background of normal-appearing villous tissue. A fetus may be present; however, there is usually severe intrauterine growth restriction, hydrocephaly, syndactyly, midline facial clefting, and cardiovascular and renal anomalies. We report an unusual presentation of a partial hydatidiform mole diagnosed by umbilical cord tissue triploidy and placental histology in a 24-year-old woman (gravida 1, para 0) with preterm premature placental rupture of membranes at 18 weeks and 4 days of gestation. Multiple fetal anomalies were diagnosed by ultrasound, including omphalocele, Dandy Walker variant, polyhydramnios, and a suspected cardiac defect. Gross examination of the placenta revealed marked placentomegaly at 342 g (reference mean, 80 g). Fetal examination revealed a female fetus with macrosomia of 320 g (reference mean, 195 grams), omphalocele, and bilateral overlapping toes. Of note, gross and microscopic examinations of thoracic and abdominal internal organs were unremarkable with the exception of bilateral renal enlargement. The discovery of triploidy and characteristic placental histology led to a diagnosis of a partial hydatidiform mole; however, several unexpected findings were also present, namely marked placentomegaly, fetal macrosomia, and the presence of fewer than expected fetal anomalies.
Nongestational Choriocarcinoma With Widespread Metastases Presenting in a Placenta: (Poster No. 133)
Choriocarcinoma (CC) is a rare tumor with an incidence estimated to be between 1 in 25 000–40 000 pregnancies. It can occur after term pregnancies, preterm pregnancies, abortions, ectopic pregnancies, or a hydatidiform mole. The exact cause is unknown and CC can develop months to years after an antecedent pregnancy. We present a case of a 42-year-old woman (gravida 10, para 9) who went into preterm labor at 33 weeks and delivered a healthy female neonate. On gross examination of the placenta pale infarctlike areas were present on the maternal surface. Microscopically, these pale areas showed increased intervillous mononuclear cells of unclear origin and rare multinucleated cells, which stained positive for β-hCG, leading to a diagnosis of CC. The patient was started on multiagent chemotherapy and was noted to have lesions in the lung, adrenal, and breast, suspicious for metastases. After the patient failed multiple rounds of chemotherapy, a biopsy of her breast lesion was performed, and it was morphologically and immunohistochemically identical to her placental lesion. Choriocarcinoma can occur in 3 forms, gestational, intraplacental, and nongestational, which cannot be differentiated based on gross and microscopic features. DNA analysis can be used to identify the genetic origin of CC. Gestational CC developing after a complete molar pregnancy would show only paternal allelic contributions. Gestational CC that develops after a normal pregnancy would show allelic contributions from both maternal and paternal DNA. In our case, the CC showed only maternal DNA, thus the diagnosis for our patient was nongestational CC with widespread metastases, initially presenting in the placenta.
The Expression Pattern of Insulin-Like Growth Factor 1 in Granulosa Cell Tumors of the Ovary: (Poster No. 134)
Context: Ovarian granulosa cell tumors (GCTs) are relatively uncommon with propensity for extraovarian spread and recurrence. Accurate diagnosis and staging is crucial for management. Immunohistochemistry (IHC) is often used in initial diagnosis and recurrence. Inhibin A (InA) is classically positive in GCT; however, the staining pattern can be focal. Insulin-like growth factor 1 (IGF1) is expressed in developing follicles. Here, we investigated the utility of IGF1 IHC in GCT and potential implications.
Design: Twenty-one GCT cases from institutional archives were included (19 primary and 2 recurrent cases). Eighteen cases had available staging: stage IA (n = 12), IC (n = 2), IIC (n = 3), IIIA (n = 1). All cases were initially reviewed with hematoxylin-eosin stains and InA IHC. InA staining pattern was graded as follows: 1+ (<60% staining), 2+ (60%–99%), 3+ (100%). All cases were then stained with IGF1 for relative strength (weak/strong) and pattern (focal/diffuse) analyzed.
Results: All cases showed diffuse IGF1 positivity. The IGF1 was weakly positive in all cases with little to no variation in strength. The InA was moderate to strongly positive in all cases but with a more variable pattern: 1+(n =2 cases), 2+(n =12), and 3+(n =6). The stage of disease did not affect the pattern or strength of IGF1 staining.
Conclusions: IGF1 is a reliable and sensitive stain for GCT. Although weak, its pattern is diffuse, whereas InA is stronger but with a widely variable pattern. IGF1 may thus be useful to identify GCTs in small biopsies for initial diagnosis as well as to monitor for recurrence.
Clinicopathologic Spectrum of a Series of Melanomas of Cervix and Vagina From a Single Tertiary Cancer Referral Center in India: (Poster No. 137)
Context: Cervicovaginal melanomas are rare tumors that display a varied histopathologic spectrum and lack specific treatment guidelines.
Design: Clinicopathologic features of 23 cervicovaginal melanomas diagnosed during a 10-year period are presented. Immunohistochemical (IHC) stains were performed in 17 of 23 cases (73.9%).
Results: Age range was 22–72 years (mean, 56.8 years). Seven tumors (30.4%) occurred in cervix and 16 (69.5%) in vagina, mostly as nodular/polypoid lesions. Average T size (n = 9) was 3.7 cm. Histopathologically, most tumors displayed diffuse cell pattern (n = 19; 82.6%), followed by pseudovascular (n =3), nesting (n =3), alveolar (n = 2), and pseudoglandular (n = 1) patterns. Six tumors (26%) revealed pagetoid spread. Most tumors revealed moderate to marked pleomorphism with polygonal to spindly, “rhabdoid,” and anaplastic forms, including giant cells. Mitoses ranged from 2–3 to 40–50 per 10 high-power-fields. “Pink nucleoli” were seen in 14 (60.8%) and intranuclear inclusions in 10 tumors (43.4%). Necrosis was noted in 12 (52.2%) and pigment in 16 tumors (69.5%). Immunohistochemically, S100-P was positive in 16 of 16 (100%); HMB-45 in 14 of 16 (87.5%) and Melan-A in 7 of 8 tumors (87.5%). AE1/AE3 and EMA were positive in 1 of 5 tumors (20%). Therapeutically (n = 15), 8 patients (53.3%) underwent surgery, 3 (20%) adjuvant chemotherapy (computed tomography [CT]); 2 adjuvant CT and radiotherapy (RT); and 1 patient, each, CT and external beam RT, respectively. On follow-up (n = 13; 2–17 months), a single patient developed recurrence, and 3 developed metastasis (mostly lymph nodes). Finally, 4 patients were free of disease, 4 alive with disease, and 4 died of disease (14–15 months).
Conclusions: This is one of the largest series from Asia describing a wide histopathologic spectrum of cervicovaginal melanomas. Key histopathologic features include pleomorphic cells, pink nucleoli, and intranuclear inclusions. S100-P, Melan-A, and HMB-45 constitute an optimal diagnostic IHC panel. Surgery forms the treatment mainstay.
Worrisome Presentation of Benign Multicystic Peritoneal Mesothelioma, Mimicking Metastatic Ovarian Cancer: (Poster No. 140)
Benign multicystic peritoneal mesothelioma (BMPM) is a rare disease of unknown pathogenesis and uncertain malignancy. Here, we report a case of multifocal BMPM in a 48-year-old woman who presented with chronic abdominal pain, weight loss, and early satiety. The patient's imaging revealed diffuse multiloculated cystic lesions of varying size of uncertain etiology throughout the abdomen suggestive of pseudomyxoma peritonei. However, because of suspicious clinical presentation, the patient underwent exploratory laparotomy, total abdominal hysterectomy, cytoreduction, and tumor debulking, and the lesions were completely resected. The lesions were multiple clusters of grapelike cysts surrounded by a transparent, thin membrane and containing clear serous fluid. These lesions were present throughout the omentum, greater curvature of the stomach, gastrohepatic region, transverse colon mesentery, cecal nodule, and cul-de-sac. The patient's uterus and left ovary were free of lesion. The histologic examination revealed multiple cysts lined by single, flattened or cuboidal mesothelial cells, with a fibrous wall and filled with clear fluid, involving adipose tissue. The lining cells were immunohistochemically positive for calretinin, WT1, AE1/AE3, vimentin, and PAX8, and they were negative for CEA. The pathologic diagnosis was consistent with BMPM. The pathogenesis of BMPM is still uncertain. Some authors believe that endometriosis is an inciting factor to BMPM and that female sex hormones have a role in its pathogenesis. However, because of rarity of the disease, there is a lack of consensus on the treatment and patient management strategy. More studies are needed to better understand its etiology and to establish standard patient care.
Suggested Approach to Assess Neoadjuvant Treatment Effect in High-Grade Serous Carcinoma: (Poster No. 141)
Context: Neoadjuvant chemotherapy alters tumor morphology, histology, and cellularity in posttherapy specimens. Although strict criteria exist for grading neoadjuvant response in breast carcinoma, currently there is no standard for gynecologic tumors. Our study aimed to identify morphologic and cytologic features of treated high-grade serous carcinoma (HGSC), correlate it with outcomes, and form criteria to classify histologic response.
Design: Seventeen cases of neoadjuvant HGSC were evaluated based on nucleoli at ×10 magnification (0, not visible; 1, visible; 2, prominent in 50%), nuclear atypia (1 to 3, smudging/vacuolization), cytoplasmic atypia (0 to 3, vacuolization/eosinophilia), pleomorphism (1 to 3), fibrosis (0 to 3), calcification (0 to 3), residual tumor size, percentage of cellularity, and morphology. Pretreatment comparison was available for 11 of 17 cases. Patients were placed into 6 categories: deceased (n = 2), distant metastasis (n = 2), aggressive recurrence (n = 2), stable recurrence (n =3), clinical remission (n =5), and no follow-up data (3).
Results: Nucleoli and nuclear atypia were prominent in cases with poor outcomes (death, metastasis, and aggressive recurrence). Cytoplasmic atypia was present in all cases and was prominent in aggressive and stable recurrences. Varying amounts of fibrosis were present in all and were strongest in cases with poor outcomes. Calcifications were most variable, present in 9 of 17 cases without apparent association with outcome. Residual tumor size, percentage of cellularity, and morphology did not correlate with outcomes.
Conclusions: Assessment of treatment effect in HGSC is difficult. Our data indicate that nucleoli and nuclear atypia are most useful in predicting clinical outcome in patients with neoadjuvant HGSC. A standardized method for analyzing and reporting therapy response is necessary to better predict patient outcomes in neoadjuvant HGSC cases.
Mature Ovarian Teratomas With Tumor-Infiltrating Lymphocytes Involving Neuroglial Tissue: A Potentially Critical Histologic Finding Associated With Anti-NMDAR Encephalitis: (Poster No. 143)
Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a rare but potentially life-threatening condition associated with a variety of acute psychiatric and neurologic symptoms. Although anti-NMDAR encephalitis can occur as autoimmune phenomenon, it is often diagnosed as a paraneoplastic neurologic syndrome in the setting of an ovarian teratoma. A recent study analyzed lymphoid infiltrates in ovarian teratomas in 5 patients with anti-NMDAR encephalitis. Here, we report the ovarian pathology from 2 additional patients with suspected or confirmed anti-NMDAR encephalitis. Case 1 was a previously healthy, 29-year-old woman who presented with acute psychosis and episodic catatonia, eventually requiring intubation. An ovarian mass was resected and diagnosed as a mature cystic teratoma. The patient had mild improvement in neurologic function but died as a result of bilateral pulmonary emboli 1 month after presentation. Retrospective analysis of the ovarian teratoma during autopsy review identified dense, tumor-infiltrating lymphocytes associated with the neuroglial component of the teratoma, including germinal centers. Case 2 was a 38-year-old woman who presented with severe headache and behavioral changes. An ovarian mass was resected and diagnosed as mature teratoma. Once again, retrospective analysis identified a prominent intratumoral lymphocytic infiltrate with germinal centers associated with neuroglial tissue in the ovarian neoplasm. Pathologists need to be aware that ovarian teratomas with tumor-infiltrating lymphocytes involving neuroglial tissue have been described in some patients with anti-NMDAR encephalitis. Timely recognition of this histologic finding may affect treatment decisions and clinical laboratory testing.
Multiple Human Papilloma Virus (HPV) Genotype Infection Is the Rule in HPV First-Detected, Infected Women: (Poster No. 144)
Context: At least 20 human papilloma virus (HPV) genotypes infect human genitalia. Some are high risk (genotype 16 and 18), whereas some others are low risk (6 and 11). The list of intermediate-risk genotypes is long. Infection with one genotype does not protect against other genotypes.
Design: One hundred and eighty women positive for HPV by hybrid-capture method were examined for HPV genotyping by performing polymerase chain reaction from cervical swabs for the following genotypes: 16, 18, 30s, 50s, 45, 6, and 11.
Results: The average woman's age was 37.2 years. A single genotype was seen in 40 of 182 cases (22%); 2 genotypes were seen in 27 (15%); 3 genotypes in 46 (25%); 4 genotypes in 29 cases (16%); 5 genotypes in 28 cases (15%); 6 genotypes in 11 cases (6%); and 7 genotypes in one patient. The most frequent genotypes were as follows: genotype 50s, 120 cases (66%); genotype 16, 107 cases (59%); genotype 30s, 107 cases (59%); genotype 18, 23 cases (13%); genotype 45, 30 cases (17%); genotype 6, 76 cases (42%); and genotype 11, 94 cases (52%).
Conclusions: Most of the HPV-infected women were infected with more than one genotype (78%). The most common genotype was 50s (66%), followed by genotypes 16 and 30s (59% each). The least-frequent genotype was 18 (15%), followed by 45 (17%).
Frequency of the Coexistence of Endometrial Intraepithelial Neoplasia in Patients With Endometrial Polyps and Hyperplasia: (Poster No. 145)
Context: Endometrial intraepithelial neoplasia (EIN) is a precancer-ous lesion of endometrioid adenocarcinoma. In the 1994 World Health Organization (WHO) classification system, these lesions were included in the category of endometrial hyperplasia, and subcategorized according to architectural complexity, and cytologic atypia; however, this system failed to distinguish patients with hyperplasia from patients with developing precancerous lesions. Although the WHO classification in 2003 addressed these issues, many pathologists are still diagnosing EIN cases under the traditional WHO endometrial hyperplasia model. The purpose of this retrospective study was to evaluate the frequency of the coexistence of EIN in cases diagnosed under the traditional hyperplasia model, including polyps, at our institution.
Design: We applied the 2003 WHO criteria for the diagnosis EIN on a total of 183 cases, previously diagnosed with the traditional endometrial hyperplasia model.
Results: In patients diagnosed with simple endometrial hyperplasia without atypia, 5.8% had EIN. In patients diagnosed with complex endometrial hyperplasia with atypia, 25% had EIN, and 16.7% patients diagnosed with complex endometrial hyperplasia without atypia had EIN. In patients diagnosed with benign endometrial polyps, 5.6% had EIN, and in patients with polyps containing simple hyperplasia, none showed EIN. In addition, EIN was identified in one case diagnosed as a polyp with complex hyperplasia and atypia.
Conclusions: In this study, we identified EIN lesions among cases previously diagnosed under the traditional hyperplasia model. Based on our results, all cases of endometrial hyperplasia and polyps must be evaluated carefully to rule out the coexistence of EIN because these lesions carry an increased risk of progression to endometrioid adenocarcinoma.
Female Adnexal Tumor of Probable Wolffian Origin: (Poster No. 147)
Female adnexal tumor of probable Wolffian origin is a rare tumor with only about 80 cases documented in the literature. Our case involved a 50-year-old woman who presented with a left-sided, 14-cm adnexal mass discovered during routine examination. Magnetic resonance imaging confirmed a solid and partially cystic mass. On resection, the mass had a smooth capsule, and its cut surface was tan-white, solid to focally cystic, lobulated, and friable. Sections showed multiple architectural patterns, with sievelike, cystic, solid, and papillary areas and focal necrosis. The tumor cells had oval nuclei and clear to focally granular cytoplasm. No mitoses or cytologic atypia were seen. Immunohistochemical stains were positive for calretinin, WT1, and vimentin, with focal tumor cell positivity for AE1/AE3, inhibin, and CD10. Negative stains were EMA and chromogranin. Female adnexal tumor of probable wolffian origin is a neoplasm of uncertain malignant potential, with most cases having a benign clinical course. However, rare malignant cases seen may also have bland histology, although mitoses and atypia can also be noted. The major differential diagnosis includes Sertoli cell tumor, which is malignant and carries a vastly different prognosis. Hence, an accurate diagnosis is essential. Follow-up and therapeutic options remain unclear because of minimal data about these tumors. By addition of our case, we can attempt to develop a greater understanding of these elusive tumors to provide for better clinical care and treatment.
Clinicopathologic Features of Prostatic Epithelioid Hemangioendothelioma: A Rare Case Report: (Poster No. 149)
Epithelioid hemangioendothelioma is a rare vascular tumor mostly seen in liver, lung, and bone. Recently, it also has been reported in the adrenal gland, kidney, and bladder; however, involvement of the prostate has not been reported previously. Here, we report the first case of prostatic epithelioid hemangioendothelioma found incidentally in a 71-year-old man who presented with prostatic abscess. Our patient, who after several vascular procedures, including a graft for abdominal aortic aneurysm, presented with gross hematuria and an elevated white blood cell count of 25 000/μL. Computed tomography scan was suspicious for a 3-cm, right-sided prostatic abscess. The patient immediately underwent transurethral resection of prostate (TURP) and unroofing of a potential prostatic abscess. Microscopically, it showed nests of atypical vascular proliferation lined by papillary structures composed of epithelioid endothelial cells with moderate cytologic atypia, rare mitotic figures, and infiltration into the prostatic tissue. The proliferative vascular immunohistochemical profile was positive for CD31, CD34, and ERG; focal positive for cytokeratin AE1/AE3, cytokeratin MNF; MIB1 at 15%–20%; and negative for HHV8. Because of the invasive nature of this lesion, atypical histologic features, and immunohistochemical profile, this lesion was classified as epithelioid hemangioendothelioma (vascular lesion of intermediate malignant potential). Our case is the first report, to our knowledge, of a prostatic epithelioid hemangioendothelioma, and our aim is to call the clinician/pathologist's attention to this rare tumor that should be considered in the differential diagnosis of mass/tumors involving the prostate.
Liposarcoma-like Differentiation in Invasive High-Grade Urothelial Carcinoma: (Poster No. 150)
A 50-year-old African American woman, with a past medical history of a bladder mass, pyelonephritis, and recurrent urinary tract infection, presented with abdominal pain, fever, and suprapubic tenderness. Abdominal computed tomography (CT) scan revealed a large bladder mass, retroperitoneal lymphadenopathy, bilateral hydronephrosis, and massive ascites. A CT-guided paracentesis of ascitic fluid showed degenerated, atypical cells weakly expressing MOC31 and BerEP4 and not expressing D2-40 or WT1. One year previously, cystoscopy had revealed the bladder mass when the patient presented with hematuria. Bladder wash did not reveal malignant cells at that time. Bladder wash performed at this admission showed malignant cells consistent with high grade urothelial carcinoma. Cystoscopic biopsy of the bladder mass revealed invasive high grade urothelial carcinoma, extensive necrosis, lymphvascular invasion, and involvement of muscularis propria. Pseudolipoblasts and bizarre multinucleated giant cells characterized a pleomorphic component. GATA3, P63, CK 7, and CK 903 showed diffuse expression by tumor cells with conventional histology and displayed focal expression in the sarcomatoid component. Pseudolipoblasts were negative for S100 immunostain, which ruled against the diagnosis of pleomorphic liposarcoma. The immunohistochemical findings confirmed that pseudolipoblasts represented sarcomatoid differentiation of high-grade urothelial carcinoma. A CT-guided paracentesis of loculated perihepatic and subhepatic fluid showed malignant cells with immunohistochemistry findings consistent with a bladder origin, confirming stage IV disease. The patient died a few days later before transfer to hospice care.
Multifocal Clear Cell Papillary Renal Cell Carcinoma in a Patient With Non–End-Stage Renal Disease: (Poster No. 151)
Clear cell papillary renal cell carcinoma (CPRCC) was first described in patients with end-stage renal disease (ESRD) but is now commonly identified in those without renal impairment. Rare cases of CPRCC are reported in patients with von Hippel-Lindau, but they have an immunohistochemical and genetic profile of clear cell RCC. We present a non-ESRD patient with multiple bilateral kidney lesions who was found to have at least 10 CPRCCs on unilateral nephrectomy. A 72-year-old woman was incidentally found to have multiple bilateral renal nodules and liver cysts on imaging studies. There was no reported family history of renal disease or renal cancer. The patient underwent left radical nephrectomy, adrenalectomy, and retroperitoneal lymph node sampling. Representative sections were selected and were paraffin embedded and hematoxylin-eosin stained. Immunohistochemical studies (CK7, CD10, and AMACR) were also performed. Following surgery, 12 grossly distinct masses were identified throughout the left kidney, ranging in size from 1.0 to 4.3 cm. Histologically, 10 were CPRCC, 1 papillary oncocytic RCC, and 1 oncocytoma. Other microscopic CPRCCs were present. Six lymph nodes were negative for tumor. The CPRCCs stained positive for CK7 and negative for CD10 and AMACR. The CPRCC is most common in patients without kidney impairment where multifocality is not common and is limited to a few lesions in comparison to those with ESRD. This patient had at least 10 CPRCCs and may have additional tumors in the contralateral kidney. We are not aware of any genetic association or familial syndromes in patients with these pathologic and clinical findings.
Unusual Presentation of Papillary Renal Cell Carcinoma: (Poster No. 154)
Papillary renal cell carcinoma (PRCC) is the second most-frequent type of renal cell carcinoma. It's classically divided into type 1 and 2 tumors, comprising approximately 10% of RCC cases. Trisomy or tetrasomy 7, trisomy 17, and loss of chromosome Y are the most common karyotypic changes in PRCC. We describe a case of a 37-year-old man who presented in 2013 to our institution with pleuritic chest pain, shortness of breath, and pleural effusion, found on chest X-ray. He had no significant past medical history but his family history revealed his mother died at age 60 from clear cell renal cell carcinoma. Cytology of the effusion showed crowded groups of malignant cells with large nuclei, prominent nucleoli, and foamy cytoplasm in papillary configuration. The tumor's immunophenotype, including expression of α-methyl acyl coenzyme-A racemase (AMACR), pancytokeratin, PAX8, and vimentin, was suggestive of renal cell carcinoma. No CD10, RCC, or cytokeratin-20 expression was seen. Imaging studies revealed enlarged mediastinal lymph nodes but no lesions in the kidneys. Molecular studies on the lymph node aspirate were consistent with kidney as primary site with 96% probability of papillary renal cell carcinoma as the subtype. In 2014, new peritoneal metastases were found on computed tomography scan. Cytogenetic analysis of metastatic nodules removed from the omentum and abdominal wall revealed multiple chromosomal abnormalities including gains in 7, 12, and 20, and loss of Y. He has had several recurrent pleural and pericardial effusions, but, to date, no tumor has been found in the kidneys.
Prostatectomy Specimens Weighed With Bilateral Seminal Vesicles: (Poster No. 155)
Context: Prostate-specific antigen density (PSAD) is an important clinical measure. Prostate weight is used to calculate PSAD in retrospective studies. Seminal vesicles (SV) do not produce PSA, and their weight should not be included in PSAD calculation. Grossing recommendations from the International Society of Urological Pathologists (ISUP) began recommending weighing prostates without SV in 2010. Thus, to determine PSAD from archived radical prostatectomy specimens weighed with SV, it's necessary to adjust for SV weight. Herein, we measured the average weight of SV and calculated adjustment factors for prostate weight and PSAD for specimens weighed with SV.
Design: Weights of the prostates and bilateral submitted SV were separately recorded in 172 consecutive prostatectomies. Average weight of bilateral SV, proportion of prostate weight from combined weight, and PSAD difference calculated with total (prostate and SV) and prostate weights were calculated. Both adjustment factors were validated on databases at 2 different institutions.
Results: Average weight of SV was 6.4 g. Prostate constitutes on average 87% of the total specimen. The PSAD averaged 1.154 higher when only prostate weight was included compared with combined weight. Application of these adjustment factors allowed elimination of differences between prostate weights and PSAD in 2 other institutions for specimens measured with and without SV.
Conclusions: Prostatectomy specimens weighed without SV were on average 13% lighter than combined specimens. Therefore, PSAD is adjusted by a factor of 1.154 in SV combined specimens. Thus, unless institution-specific adjustment parameters are developed, these adjustment factors are to be implemented in retrospective cohorts or in institutions where combined weight is recorded.
Sporadic Renal Hemangioblastoma: A Rare Neoplasm and Potential Mimicker of Malignancy: (Poster No. 156)
Hemangioblastomas are slowly growing, highly vascular neoplasms that can occur sporadically or in the setting of Von Hippel Lindau syndrome. Although generally considered central nervous system tumors, hemangioblastomas may be primary to the kidney. We present a case of a 78-year-old woman with an incidental finding on CT scan of a 3.2-cm, left renal mass. Ultrasound showed a vascular, solid mass in the superior pole of the kidney “concerning for malignancy.” The patient underwent a radical nephrectomy. Gross examination revealed a circumscribed, solid, red mass measuring 3 × 3 × 2.5 cm. Microscopic examination showed an encapsulated neoplasm composed of numerous capillary-sized blood vessels intermingled with stromal cells with variable amounts of cytoplasm, some showing fine vacuolation. The neoplasm showed alternating areas of hypercellurity and hypocellularity, as well as hemosiderin deposits and foci of extramedullary hematopoiesis; mitotic figures were rare. The neoplastic cells showed immunoreactivity for inhibin and S100, and were negative for AE1/AE3, EMA, HMB-45, and Melan-A. CD34 and factor VIII highlighted the rich vascular network, whereas CD117 showed the presence of mast cells. CD10 was patchy positive, and there was a weak to moderate nuclear immunoreactivity for PAX8. This immunoprofile, together with the morphology, supported the diagnosis of hemangioblastoma. Renal hemangioblastomas are rare tumors that can be mistaken for malignancies radiologically. Additionally, they may mimic other neoplasms microscopically, such as renal cell carcinoma or epithelioid hemangiopericytoma. Wider recognition of their occurrence as primary renal tumors is warranted to avoid a malignant misdiagnosis.
Renal Translocation Carcinoma With Unusual Immunophenotype: A Case Report With Morphologic, Immunohistochemical, Fluorescence In Situ Hybridization, and Ultrastructural Analysis: (Poster No. 157)
We describe a case of translocation renal cell carcinoma (TRCC) with an unusual immunophenotype. The diagnosis was established by identifying TFE3 gene rearrangement with immunohistochemical staining and fluorescence in situ hybridization (FISH). A previously healthy, 43-year-old woman presented with a well-demarcated, 3.5-cm, left renal mass in the middle of the kidney. The pale-tan homogeneous mass was grossly limited to the kidney. Microscopic examination showed predominantly alveolar and tubular architecture. A small focus of papillary architecture was noted. No psammoma bodies or hyaline nodules were seen. Neoplastic cells had clear cytoplasm containing hyaline droplets and enlarged nuclei with irregular contours, vesicular chromatin, and nucleoli. Neoplastic cells were positive for TFE3, RCC marker, racemase, CK7, EMA, and CD10, and negative for CK20, CD117, and p63. Electron microscopy showed moderate numbers of mitochondria, lipid vacuoles, glycogen, and microvesicles. The carcinoma was initially signed out as renal cell carcinoma, unclassified. On review, the histologic features and immunostaining for TFE3 were considered to be suggestive of TRCC, which was confirmed by the presence of TFE3 gene rearrangement on FISH. The immunophenotype in this case is unusual. Positivity for CK7 and EMA is typically not present in TRCC. Morphologically, this case of TRCC showed a predominant alveolar/tubular pattern and lacked typical characteristic papillary architecture or psammoma bodies. The variation in morphologic and immunophenotypic features and the importance of TFE3 testing must be recognized to correctly classify this renal carcinoma.
Major Histocompatibility Complex Class I in Clear Cell Renal Cell Carcinoma: High Expression Is Associated With Improved Prognosis: (Poster No. 158)
Context: Approximately 30% of localized clear cell renal cell carcinomas (CCRCCs) after nephrectomy (SPN) develop metastases. There is an increasing interest for immune-mediated markers to predict outcomes. We investigated utility of MHCI expression as a potential prognostic immune marker in patients with CCRCC.
Design: Fifty-five patients with localized CCRCC SPN and at least 4 years of follow-up were included. Immunohistochemical staining (IHC) for MHCI was performed. Automated image analysis algorithm was applied to quantitate MHCI expression. It generated the positivity score, correlating to degree of MHCI expression, and allowing rapid whole slide scanning of digital slides.
Results: Mean MHCI positivity score was 0.75 (SE, ±0.20). Alive patients had increased MHCI expression (0.80 positivity score) compared with deceased (0.62 positivity score; P < .001). MHCI positivity scores greater than the mean were associated with increased cancer-specific survival (P = .002). The MHCI expression was higher among patients with no recurrence (0.80) compared with those with recurrence (0.70; P =.02), and time-to-recurrence was longer in patients with higher-than-the-mean MHCI positivity scores (P = .02). Alive patients with recurrence had increased MHCI expression (0.81) compared with those who succumbed to disease recurrence (0.62; P < .001). No correlation was detected between FNG and MHCI tumor expression (ANOVA, P = .65, F = 0.423) or between stage and MHCI tumor expression (ANOVA, P = .73, F = 0.311).
Conclusions: By using automated image analysis, we demonstrate that MHCI expression may be an important prognostic factor for recurrence-free survival and for the prognosis of patients with recurrence. In addition, MHCI has an important role in tumor-host immune system interaction in CCRCC.
Urothelial Carcinoma With Clear Cell Change: A Clinical and Immunohistochemical Analysis: (Poster No. 160)
Context: In this series, one of the largest to date, we analyzed the clinicopathologic and immunohistochemical features of urothelial carcinoma with clear cell features (UCACC).
Design: A search was made through the archives of 2 major academic institutions for cases of UCACC. Clinicopathologic data were also obtained. Immunohistochemical stains for GATA-3, CD10, napsin, CD117, B72.3, and PAX8 were performed on cases with available tissue blocks.
Results: Fifteen cases of UCACC were identified. Mean patient age was 67 years (range, 56–87 years). Eight of 15 cases (53%) involved men. Nine of 15 cases (60%) contained additional histologic subtypes, including glandular, squamous, sarcomatoid, signet-ring/plasmacytoid, and micropapillary variants. All of the cases were at least pT2. Immunohistochemical analysis revealed strong nuclear positivity for GATA-3 in 9 of 11 cases (82%). CD10 showed membranous positivity in 7 of 11 cases (64%). PAX8 was positive in 2 of 11 cases (18%). Napsin, CD117, and B72.3 were negative in all cases.
Conclusions: The UCACC is an aggressive variant of UCA, which frequently presents at an advanced stage and is associated with other histologic subtypes. The positive expression for GATA3 and negative expression for PAX8 in most cases will be useful in the distinction of UCACC from metastatic clear cell renal cell carcinoma and other metastatic clear cell tumors of unknown origin.
Aggressive Pathologic Features at Radical Nephroureterectomy Do Not Predict Intravesical Recurrence: A 5-Year Retrospective Clinicopathologic Analysis: (Poster No. 162)
Context: Biologically, urothelial carcinoma tends to have a multifocal growth pattern involving both the upper and lower urinary tracts. Prior studies have shown variable results in terms of what preoperative or perioperative clinicopathologic factors at radical nephroureterectomy (RNU) predict or are associated with an intravesical recurrence (IVR). Our study attempted to determine what whether any aggressive pathologic features at RNU predict an IVR.
Design: All radical nephroureterectomy specimens in the 5-year period between 2007 and 2012 were collected and analyzed in terms of many factors but, specifically, aggressive pathologic features (angiolymphatic invasion, carcinoma in situ, and positive margins). This was correlated with the presence of an IVR.
Results: A total of 98 cases were reviewed. Forty-seven cases (48%) either had concurrent cystectomies or had evidence of urothelial carcinoma involving the bladder before RNU. Of the remaining 51 cases, 33 had no evidence of an IVR and 18 had cystectomies for the presence of IVR at some point after RNU. Of the 33 patients without IVR, 21 (63%) also had no evidence of aggressive features on RNU, whereas 12 (36%) did have evidence of aggressive features on RNU (P = .68).
Conclusions: A higher percentage of patients without an IVR also lacked aggressive features on RNU when compared with the percentage of patients who did not have an IVR but did display aggressive features at RNU. This finding was not statistically significant, indicating that aggressive pathologic features at RNU are suggestive but not predictive of an IVR in this population of patients.
Pitfalls of PAX8 Immunostaining in Primary Tumors of Kidney: (Poster No. 164)
Context: PAX8 serves as a useful immunohistochemical marker for renal cell carcinoma (RCC). Because PAX8 is a diagnostic marker, we wanted to check its immunostaining in less-common RCCs as well as other primary (non-RCC) kidney tumors.
Design: Retrospectively, we sorted 114 kidney tumor cases and stratified them according to their histologic types into primary RCCs (with subtypes as clear cell, papillary, chromophobe, sarcomatoid, tubulocystic, TFE3-associated RCCs, and RCC associated with acquired cystic renal disease) and other primary renal tumors (non-RCCs). We included 2 uncommon RCC cases (1 TFE3-associated RCC, and 1 RCC-associated with acquired cystic renal disease) and 2 non-RCC cases (1 kidney lymphoma, and 1 urothelial carcinoma mimicking RCC) and compared their clinical and pathologic features. Finally, we performed immunostaining with PAX8.
Results: Immunostaining with PAX8 was positive in both non-RCC cases (1 kidney lymphoma and 1 urothelial carcinoma mimicking RCC) and negative in 2 uncommon RCC cases (1 TFE3-associated RCC; 1 RCC associated with acquired cystic renal disease).
Conclusions: Immunostaining with PAX8 is a very useful and widely practiced tool in diagnosing kidney tumors. Even though immunostaining with PAX8 can be a helpful tool for diagnosing RCCs because findings are commonly positive for that, one should be aware of the exceptions that have been found in our primary RCC and non-RCC cases. PAX8 positivity or negativity in immunostaining should be interpreted cautiously in diagnosing primary kidney tumors.
Observing Histologic Changes in Post-CyberKnife Prostate Biopsies: (Poster No. 165)
Context: One of the newest therapeutic options for the treatment of prostate cancer is CyberKnife therapy also known as stereotactic body radiotherapy (SBRT). Beginning in 2003, Winthrop University Hospital had developed the largest treated patient population in the United States. Currently, we have identified 11 patients with post-CyberKnife prostate biopsies because of elevated prostate-specific antigen (PSA) levels. The total radiation dose is generally higher (92 Gy versus 81 Gy) than delivered by traditional external beam therapy. This study was performed to observe potential differences in histology between post-CyberKnife biopsies and usual radiation effects.
Design: Since 2003, 3600 patients with adenocarcinoma of the prostate were treated at Winthrop-University Hospital by CyberKnife radiotherapy. The post-Cyberknife biopsies of 11 patients identified were reviewed by 2 pathologists and observed for adenocarcinoma, radiation-type changes, and unexpected histologic abnormalities, compared with their pre-Cyberknife biopsies. Patients were identified by medical record number.
Results: Out of the 11 post-CyberKnife biopsies, 8 biopsies were observed to have acinar gland atrophy, epithelial atypia, atypical fibroblastic reaction, and stromal edema with eradication of the previous cancer. The remaining 3 biopsies showed recurrence of cancer. Of those 3 biopsies, 1 did not demonstrate typical radiation effect.
Conclusions: CyberKnife therapy is a novel treatment option for prostate carcinoma demonstrating promising cure rates and infrequent postradiation side effects. Standard radiation effects are observed in post-CyberKnife biopsies, which may be due to increased radiation dose; this treatment still remains a forerunner in prostate cancer.
Liesegang Rings Mimicking Renal Malignancy: (Poster No. 172)
Liesgang rings are laminated, ringlike structures with internal radial striations that are uncommonly encountered during histopathologic review of various tissues. They are thought to be formed by alternating precipitation and diffusion of minerals and proteins. Liesgang rings have been a diagnostic pitfall for pathologists, commonly being confused with parasites, psammoma bodies, and amyloid. In the kidney, Liesgang rings are most often seen in association with renal cysts. We report a case of a 59-year-old man incidentally found to have multiple renal cysts involving the left kidney. Follow-up ultrasound revealed a solid-appearing, exophytic mass in the lower pole of the left kidney measuring 2 cm. Computed tomography performed several months later showed a complex solid and cystic mass in the lower pole of the left kidney measuring 3.7 cm. The patient subsequently underwent a partial nephrectomy. Gross examination revealed a well-encapsulated, semisolid-semicystic 2 × 1.6 × 1.8-cm hemorrhagic mass. Histologic sections showed a cystic structure entirely filled with fibrin, blood, and Liesgang rings. The cyst focally displayed a bland, attenuated lining with clear cell change. No architectural patterns of neoplasm were seen. A Congo red stain was negative for amyloid. This case demonstrates that a benign renal cyst containing Liesgang rings can mimic a malignant neoplasm of the kidney on radiologic imaging and that Liesgang rings, although uncommon, should be a diagnostic consideration in the evaluation of renal masses.
Major Histocompatibility Complex Class I in Clear Cell Renal Cell Carcinoma (CCRCC): Comparison of Expression in Primary CCRCC Versus Metastatic CCRCC: (Poster No. 173)
Context: About 30% of localized clear cell renal cell carcinomas (CCRCCs) following nephrectomy (SPN) develop metastases. Most often, RCC metastasizes to lungs (50%–60%), bone (30%–40%), liver (30%–40%), and brain. Previously, we showed that major histocompatibility complex class I (MHCI) could be an important prognostic factor in CCRCC for both recurrence-free survival and for survival of patients with recurrence. Here, we analyzed MHCI expression in primary and metastatic CCRCC.
Design: Patient with CCRCC who were SPN with lung metastases (n = 19) and bone metastases (n = 16) were selected. Immunohistochemistry for MHCI was performed on tumor sections. An automated image analysis algorithm was applied to quantitate MHCI expression. It generated the positivity score (PS) correlating to the degree of MHCI expression and allowing rapid whole-slide scanning of digital slides. MHCI expression was compared in primary versus metastases with a Kruskal-Wallis test.
Results: Mean age for both cohorts combined was 60 years. Three presented at stage T1 (8.57%), 6 at T2 (17.1%), 25 at T3 (71.4), and 1 at T4 (2.86%). Three had Fuhrman grade 1 (8.57%), 20 had grade 2 (57.1%), and 12 had grade 4 (34.3%). For lung metastases, mean MHCI (PS) of primary tumors was 0.73, whereas metastases had a score of 0.70 (not statistically significant, P = .89). For bone metastases, the mean MHCI PS of the primary tumors was 0.73 whereas metastases had a score of 0.60 (not statistically significant, P = .15).
Conclusions: By using automated image analysis, we demonstrated that MHCI expression in primary versus metastatic CCRCC is relatively similar and suggest that MHCI has an important role in tumor-host immune system interaction in patients with CCRCC.
Inflammatory Myofibroblastic Sarcoma of the Bladder: Histologic and Immunohistochemical Findings of a Mesenchymal Neoplasm With Increased Malignant Potential: (Poster No. 176)
Mesenchymal tumors of the bladder have similar appearances of spindle cells in an inflammatory background, and some neoplasms possibly represent a spectrum of one pathologic entity. However, malignant findings, including cytologic atypia and atypical mitoses, should not be present. We present the case of a 61-year-old woman with hematuria. Cystoscopy identified a 5-cm mass at the bladder dome, leading to surgery. Surgical pathology received a partial cystectomy specimen with a 4.5 × 4.5 × 5.0-cm, exophytic polypoid mass on the mucosal surface. The mass extended into the muscularis propria but not into the perivesical tissues. Hematoxylin-eosin slides and subsequent appropriate immunohistochemical stains were prepared. Histologically, the tumor consisted predominantly of bland eosinophilic spindle cells in a myxoid, inflammatory background with focal microcalcifications. However, there were foci of increased mitoses, cytologic atypia, and necrosis. Immunohistochemical stains demonstrated tumor cells positive for vimentin and ALK1, and focally positive for desmin, smooth muscle actin, and CD68. Based on these findings, this case was signed out as low-grade inflammatory myofibroblastic sarcoma. Inflammatory myofibroblastic tumor of the bladder is a tumor of intermediate malignant potential with a propensity to recur but rarely metastasize. Inflammatory myofibroblastic sarcomas are associated with increased recurrence and metastasis and have been previously reported in the head/neck, extremities, mesentery, omentum, and peritoneum, but few cases in the bladder. Although inflammatory myofibroblastic tumors have a comparatively benign clinical behavior, mesenchymal tumors of the bladder with cytologic atypia, atypical mitoses, and necrosis should raise concerns for malignant behavior and require closer clinical follow-up.
TFE3 Immunohistochemistry Pitfalls in Diagnosis of Xp11.2 Renal Cell Carcinoma: (Poster No. 177)
Context: There is increasing recognition of different morphologic patterns of TFE3 (Xp11.2) renal cell carcinoma (RCC), and TFE3 immunostaining often has inaccurate results. We validated the stain on fluorescence in situ hybridization (FISH)-proven TFE3 RCCs and analyzed staining in other types of RCC.
Design: Serial dilutions were performed on 2 FISH-proven RCCs. Highest working dilution of stain was tested on 36 RCCs followed by validation on 4 fresh cut slides of TFE3 RCCs from another institution. Then, 10 cases of TFE3 FISH-proven carcinoma from consults were used for the final validation. Lastly, TFE3 antibody was tested on 120 RCCs.
Results: Two in-house, TFE3 FISH-proven RCC cases demonstrated strong and diffuse nuclear staining at 1:2000 dilution. Mesangial cells showed comparable intensity staining. At this dilution 5 of 36 RCCs showed weak positivity. Optimal dilution of consult cases was 1:500. In 120 RCCs, the stain at 1:250 dilution showed a more-diffuse immunoreactivity in 13% clear cell, 28% chromophobe, and 25% papillary RCC. Of 28 cases stained at both 1:2000 and 1:250 dilutions, 4 chromophobe and 1 papillary RCC changed from negative to weak-patchy positive staining.
Conclusions: Weak false-positive TFE3 staining is not uncommon in RCC, and its frequency depends on RCC type and antibody dilution. Unlike in TFE3 FISH-proven RCC, the distribution of staining in clear cell, chromophobe, and papillary RCCs is patchy and less intense than mesangial cells. Staining of the tumor periphery should not be considered positive. Only cases with strong and diffuse nuclear immunoreactivity should be considered true-positive and diagnostic of Xp11.2 RCC.
Solitary Fibrous Tumor of the Prostate Gland and Pelvis: (Poster No. 178)
Context: Solitary fibrous tumor (SFT) most commonly occurs in the thoracic cavity, and less commonly at other sites, including the urogenital tract. Features of malignancy include tumor size larger than 10 cm, increased cellularity, pleomorphism, more than 4 mitotic figures per 10 high-power fields (HPFs), necrosis, and infiltrative growth.
Design: The surgical pathology files were searched from 2000 to 2015 for SFT involving the prostate gland. Immunohistochemical studies for CD34, CD99, and BCL2 were performed.
Results: Four cases were found. Patient age ranged from 61–75 years; 2 presented with obstructive urinary symptoms and 2 had a prostatic mass. Three patients had an elevated prostate-specific antigen (PSA) level (mean, 8.9 ng/mL). No patient had a history of hypoglycemia. Primary prostatic SFT was found in 3 patients, and 1 patient had a pelvic SFT that involved the bladder, prostate gland, and seminal vesicles. Two patients also had prostatic adenocarcinoma. In one case, the tumor size was larger than 10 cm and had increased cellularity and necrosis. A second case had increased cellularity and 6 mitotic figures per 10 HPFs. All cases showed strong tumor cell expression for CD34, BCL2, and CD99. Three cases were classified as benign and one, with high mitotic rate, as malignant SFT. Follow-up information was available for 3 patients, and all of them are alive and free of disease.
Conclusions: Usually, SFT, a rare neoplasm of the prostate and pelvis, exhibits favorable prognosis, even without further adjuvant therapy. Therefore, it is critical to differentiate SFT from other spindle cell neoplasms, particularly prostatic stromal tumors and gastrointestinal stromal tumors.
Pathologic Findings in Transurethral Resections of Prostate and Emerging Trends in the Management of Incidental Prostatic Carcinomas: (Poster No. 181)
Context: Transurethral resection of prostate (TURP) is a common procedure for prostatic hypertrophy and a variety of findings, including malignancy, can be encountered; incidental prostate carcinoma (PCa) is found in 4%–15% of cases. We studied patient characteristics and clinical outcomes, analyzed TURP as a diagnostic tool, and evaluated trends in treating incidental PCa.
Design: A data search of our institutional files for all TURP specimens (2003–2013) was performed. Cases with known or suspected nonprostatic pathology (ie, bladder or urethral carcinoma) were excluded. Patient demographics, clinical and follow-up information, reports, and hematoxylin-eosin slides were reviewed.
Results: Of the 751 consecutive TURP specimens reviewed, 107 prostatic carcinomas were identified (43 with previously diagnosed PCa and 63 with incidental findings; patient age range, 47–92 years). Of these, 36 had available initial prostate-specific antigen (PSA) ranging from 0.6 to 64 ng/mL (8 with PSA >10 ng/mL). Forty-seven were clinical stage T1a; 16 were T1b. Prognostic grade distribution was grade 1, 43; grade 2, 8; grade 3, 4; grade 4, 1; and grade 5, 7. Other findings included atypical adenomatous hyperplasia (n = 9), atypical basal cell hyperplasia (n = 9), high-grade prostatic intraepithelial neoplasia (n = 9), urethral atypia (n =4), and atypical small acinar proliferation (n =4). Most grade 1 or 2 patients had follow-up PSA or biopsy; patients grade 3 or greater were treated with different modalities. Of grade 5 patients, 1 died of disease, and 3 developed metastatic disease. Interestingly, 1 patient with grade 1 developed metastasis.
Conclusions: Most incidental PCas are low grade, and surveillance may be enough in most cases; however, one-third occur as grade 2 or higher, requiring a management plan. Cases of TURP should be carefully examined for malignancies as well as other pathologies.
Epithelioid Angiomyolipoma of the Kidney: A Case Report and Literature Review: (Poster No. 182)
We report a case of a 42-year-old man who was found to have a 3.0-cm, solid, enhancing right renal mass suspicious for renal cell carcinoma as well as an indeterminate 3-mm, left lower-lobe pulmonary nodule on computed tomography scan of the thorax and abdomen. Additionally, magnetic resonance imaging scan of the abdomen revealed the renal mass to have an irregular, heterogeneous T2 signal with central enhancement, concerning for renal cell carcinoma. The patient underwent a partial nephrectomy, which revealed the mass was limited to the kidney. Microscopic examination showed a triphasic tumor composed predominantly of epithelioid cells (95%) with scattered smooth muscle and blood vessels. Centrally, the tumor consisted of large, polygonal epithelioid cells with abundant eosinophilic cytoplasm, large nuclei, prominent nucleoli, and multinucleated pleomorphic forms with no necrosis. Immunohistochemistry revealed the epithelioid cells were strongly and diffusely positive for HMB-45 and negative for S100. Muscle-specific actin highlighted the scattered smooth muscle, and CD34 highlighted the dispersed blood vessels. Unlike classic angiomyolipoma, epithelioid angiomyolipoma is a potentially malignant mesenchymal neoplasm, as evidenced by local recurrence and distant metastasis. Yet, there is no universal agreement found in the literature regarding the criteria for its diagnosis. Furthermore, limited studies have been done on the potential malignant behavior. To date, biopsy of the pulmonary nodule was nondiagnostic. Although rare, recognition of this entity is needed because it can mimic a variety of neoplasms and pose diagnostic challenges.
Potential Antifibrotic Effect of Imatinib on a Kidney Graft: (Poster No. 185)
Withdrawn.
Differential Expression of PAX8 Between Normal Urothelium and Urothelial Carcinoma in Upper and Lower Urinary Tract: (Poster No. 186)
Context: PAX8 is a member of family transcription factors involved in regulation of embryonic development of thyroid gland, kidney, and müllerian organs. Nuclear expression of this cell-lineage–specific marker has been used for diagnosis of tumor in these sites. The objective of this study was to investigate expression of PAX8 in urothelial carcinoma (UC) of the urinary tract.
Design: A total of 21 cases of UC (11 from renal pelvis and 10 from ureter) together with 5 UCs and 8 cases of normal urothelial mucosa from urinary bladder were included in this study. Immunohistochemical stains of PAX8 were performed in all tissue sections, and results were confirmed by 2 independent pathologists.
Results: Although full-thickness expression of PAX8 was found in normal urothelium of both renal pelvis and ureter, no nuclear stains of PAX8 were identified in all 11 cases of UC in the renal pelvis. Focal, weak PAX8 expression was seen in only 1 case of low-grade UC of the ureter. All findings from UC and normal urothelium of bladder were completely negative for PAX8 expression.
Conclusions: We demonstrate the differential expression of PAX8 in normal urothelium between the upper and lower urinary tract. PAX8 expression is lost in most UCs from the upper urinary tract. Our data suggest a potential role of PAX8 in tumorigenesis of urothelial carcinoma in renal pelvis and ureter. PAX8 may serve as a useful marker to aid in the differential diagnoses between urothelial malignancies and benign reactive urothelium of the upper urinary tract.
Idiopathic Nodular Glomerulosclerosis: Further Pathogenic Evidence of the Role of Smoking and Obesity: (Poster No. 187)
Context: Idiopathic nodular glomerulosclerosis (ING) is a clinicopathologic entity with morphologic features similar to those of nodular diabetic glomerulosclerosis but with no evidence of abnormal glucose metabolism or other specific disease. However, ING remains a rare disease entity with an unclear pathogenesis. This study aimed to evaluate the clinicopathologic features of 13 patients with ING.
Design: Thirteen cases of ING were identified in a retrospective review of renal biopsies. Diabetic nodular glomerulosclerosis and other conditions with histologic findings of nodular glomerulosclerosis were excluded by clinical, laboratory and histopathologic investigations. Clinical data and laboratory results at the time of biopsy were analyzed in all cases. The renal biopsies were examined by light, immunofluorescence (IF), and electron microscopy (EM).
Results: The study cohort consisted predominantly of older (mean age, 63.4 years) white (72%) women (61%). Clinical findings at the time of biopsy included renal insufficiency (mean serum creatinine, 2.6 mg/dL), proteinuria (mean, 5.9 g/d), hypertension (94%), history of smoking (69%), and obesity (body mass index, >30; 59%). Histopathologic findings showed nodular glomerulosclerosis (100%), arterioarteriolosclerosis (100%), prominent hyalinosis (71%), and moderate glomerular basement membrane thickening (88%). The IF and EM had no other specific findings.
Conclusions: Our results are consistent with the conclusion of others that ING is a clinicopathologic entity closely associated with advanced age and hypertension. The overall incidence of smoking in our study is similar to that reported in similar published studies. Our data also show that ING is closely associated with obesity. Further studies are needed to elucidate the pathogenesis of ING.
Incidental Findings in Whole Mount Prostate Glands Resected for Reasons Other Than Prostate Cancer: (Poster No. 189)
Context: The incidental findings, such as prostatic adenocarcinoma, in prostate glands resected for bladder or rectal cancer are not uncommon. Whole mount of prostate glands will allow us to observe these incidental findings in greater detail.
Design: To characterize the epidemiologic and pathologic features of incidental findings, all hematoxylin-eosin–stained, whole mount slides of radical prostatectomy cases as part of definitive surgery for bladder or rectal cancers from 2011 to 2014 were retrieved from our archives. The following findings were recorded: presence or absence of prostatic adenocarcinoma, and the extent, location, and presence of inflammation, atrophy, benign prostatic hyperplasia, and prostatic intraepithelial neoplasia.
Results: Among 23 cystoprostatectomy cases retrieved, 14 patients (61%) had incidental prostatic adenocarcinomas, one-half of which were present as multifocal lesions. Twenty-six adenocarcinoma lesions (70%) were detected in the anterior aspect of the prostate, whereas 11 lesions (30%) were detected in posterior aspect. Thirty-one of the adenocarcinomas (84%) were located in the peripheral zone, 5 (14%) in the transitional zone, and 1 (3%) in the expanding peripheral and transitional zones. In terms of the Gleason score, 25 adenocarcinomas (68%) were scored as 6 (3 +3), 10 cases (26%) as 7 (3 +4), 1 case (3%) as 5 (3 +2), and 1 case (3%) as 4 (2 +2). Multifocal, high-grade prostatic intraepithelial neoplasia (12 of 14; 86%), inflammation (11 of 14; 79%), atrophy (8 of 14; 57%), benign prostatic hyperplasia (8 of 14; 57%), urothelial carcinoma involving urethra (2 of 14; 14%), and squamous metaplasia (1 of 14; 7%) were observed.
Conclusions: Our study demonstrated a greater incidence of multifocal, small prostatic adenocarcinomas, and the anterior prostate gland harbored a disproportionately higher number of silent adenocarcinomas.
Nephrotic Syndrome in a Patient With Sickle Cell Disease: An Unusual Presentation: (Poster No. 190)
Although sickle cell nephropathy is a common cause of morbidity and mortality in sickle cell disease (SCD), nephrotic range proteinuria is less common. A variety of alterations in renal morphology and function are found in SCD. Here, we report a case of a 22-year-old African-American woman, who has a history of SCD with multiple hospitalizations for vaso-occlusive crisis, spinal bifida with neurogenic bladder requiring straight catheterization, and hydrocephalus following ventriculoperitoneal shunt, who was found to have nephrotic range proteinuria and slightly increased serum complement C3 (177 mg/dL) and C4 (59 mg/dL). A renal biopsy showed the presence of glomerular intracapillary sickling and hypercellularity with coexistent, focal segmental mesangial interposition, resulting in membranoproliferative glomerulonephritis (MPGN-like changes). This pattern of glomerular changes has also been called microangiopathic glomerulopathy (MAG) and resulted from chronic thrombotic microangiopathy because immunofluorescence and electron microscopy do not detect any immune-complex deposits. Ultrastructural examination showed a glomerulus, with mainly effaced foot processes (>90% effaced) and lobular proliferation with hypercellular glomeruli. Glomerular basement membrane duplication was extensive with areas of numerous layers of basement membrane. This lesion has been attributed to an endothelial injury caused by intracapillary sickling, altered glomerular hemodynamics, and a hypercoagulable state common in these individuals. A review of the literature suggests that nephrotic syndrome in SCD is associated with a much-worse prognosis and that early identification and treatment of albuminuria may decrease mortality in patients with SCD.
Cellular Angiofibroma of the Inguinoscrotal Region With Cytologic Atypia and Abundant Adipose Tissue Simulating Liposarcoma: (Poster No. 191)
Cellular angiofibroma (CAF) is a rare, benign mesenchymal neoplasm of the vulvovaginal or inguinoscrotal regions. We report a case of CAF with abundant intralesional fat and focal cytologic atypia that raised the possibility of liposarcoma. A 60-year-old man presented with a 1-month history of a nontender, painless, and growing lesion in the inguinoscrotal area that progressively became painful before he presented for medical attention. Ultrasound revealed a heterogenous and hypervascular, 2.5-cm mass in the lower testicular pole. A scrotal exploration was performed with excision of the mass. Grossly, the lesion measured 3 cm, was gray-tan, firm, well circumscribed, and attached to the spermatic cord. Microscopically, there were predominately spindle-shaped cells in an edematous and lightly fibrous stroma interspersed with chronic inflammatory cells and numerous, thick-walled blood vessels, many with wall hyalinization. These findings are typical of CAF, but there were also scattered cells with cytologic atypia and abundant intralesional adipose tissue with focal fat necrosis. Foci of cytologic atypia were reported in less than 10% of CAF cases, and adipocytes, although rarely abundant, were reported in up to 24% of cases. Nonetheless, the presence of both cytologic atypia and abundant adipocytes with fat necrosis in the same lesion raised the possibility of a well-differentiated liposarcoma. Although rare, liposarcoma is the most common sarcoma in this region. There were no lipoblasts, and the absence of MDM2 gene amplification further supported the diagnosis of CAF. Awareness of the spectrum of changes in CAF is important to prevent misdiagnosis.
BK Virus–Associated Micropapillary Ureteral Urothelial Carcinoma in a Patient With a Combined Renal and Pancreas Transplant: (Poster No. 192)
BK polyomavirus (BKV) exposure is common, seen in at least 90% of adult populations; however, BKV-associated organ disease is essentially restricted to immunosuppressed patients, and its pathogenic role in neoplasia is controversial. Renal transplant-associated urothelial carcinoma is a rare event with the reported incidence varying from 0.4% to 4.5%. Micropapillary urothelial carcinoma is a rare, unique variant of urothelial carcinoma occurring in the genitourinary tract, with an aggressive clinical course. Recent reports suggest a higher incidence of micropapillary urothelial carcinoma occurring after renal transplantation with a possible association with BKV. We present a case of a 65-year-old man who presented with bowel obstruction 7 years after a combined pancreas and renal transplantation and a several year history of BKV nephropathy. Imaging revealed distal ureter stenosis recalcitrant to stenting, and intraoperative assessment revealed numerous intra-abdominal masses studding the peritoneum. A biopsy of a peritoneal nodule revealed diffuse micropapillary epithelial nests contained within tissue retraction spaces and composed of cells with mild to moderate cytoplasm and pleomorphic nuclei with prominent nucleoli and irregularly distributed chromatin without viral cytopathic effect. The neoplastic cells were positive for p63, CK7, CK20, p53, and SV40 and were negative for TTF and CDX2. Real-time quantitative polymerase chain reaction analysis revealed BK virus within the tumor cells, and short tandem repeat analysis revealed the tumor was of recipient origination. This case lends support for the role of BKV in the development of transplant-associated ureteral micropapillary urothelial carcinoma and highlights the importance of its recognition in helping guide therapeutic management.
Mature Retroperitoneal Cystic Teratoma Associated With Left Adrenal Gland in a 61-Year-Old Man: (Poster No. 193)
Primary, mature teratoma is an uncommon germ cell tumor and consists of somatic cells that are derived from 2 or more germinal layers. This tumor mostly occurs in children, and very few cases have been reported occurring in adults, where all tumors are considered malignant unless proven otherwise. Retroperitoneal teratomas are uncommon and only account for 4% of teratomas, and most are metastasis from other primary sites. Most cases are asymptomatic, are identified incidentally, and behave in a benign fashion; therefore, complete excision is curative. We report a 61-year-old man with appendicitis. A computed tomography (CT) scan revealed an incidental left retroperitoneal adrenal mass with multiple punctate calcifications. Laparotomy revealed an 86-g (7.5 cm) cystic mass with a 1-mm capsule attaching to the left adrenal gland. Sections from the mass showed ciliated bronchial epithelium lining the inner surface of the cyst with associated cartilage. Extensive microscopic examination revealed no immature component or malignancy. Comprehensive metastatic workup failed to reveal any other primary source; therefore, a diagnosis of mature cystic teratoma was rendered. Because of the complexity of the retroperitoneal architecture on CT and magnetic resonance imaging, it is very challenging to distinguish teratoma associated with adrenal from an adrenal tumor. Serum markers such as AFP, CEA, and CA19-9 can be of limited help in the differential diagnosis. Considering the rarity of primary retroperitoneal teratomas, frequency of retroperitoneal spread, and potential for regression in germ cell tumors, it is imperative to diligently seek a primary site before rendering the diagnosis of primary retroperitoneal teratoma.
INI1 Deletion Is Detected by Fluorescence In Situ Hybridization in Renal Medullary Carcinomas: (Poster No. 194)
Context: Renal medullary carcinomas (RMCs) and collecting duct carcinomas (CDCs) are rare, aggressive neoplasms that have significant overlapping clinical, histomorphologic, and immunohistochemical (IHC) features. Loss of INI1 expression has been reported as a consistent feature of RMC, and IHC evaluation for INI1 expression has been shown to be helpful in the diagnosis of these neoplasms. However, the mechanism underlying INI1 protein inactivation in these neoplasms has been poorly characterized. In the current study, we report our experience using fluorescence in situ hybridization (FISH) for determination of INI1 deletion status in RMC and CDC.
Design: Using an in-house institutional database, 4 cases of RMC and 2 cases of CDC were identified. Dual-color FISH was performed on formalin-fixed, paraffin-embedded sections of all cases using paired locus-specific FISH probes targeting INI1 and the telomeric region of 22q (control probe). Additionally, IHC expression of INI1 was performed, with nuclear staining indicative of retained INI1 protein status.
Results: The IHC evaluation showed that INI1 expression was universally absent in the RMC cases. Three RMC cases had successful FISH hybridization, with one case exhibiting INI1 deletion. Neither of the CDC cases had demonstrable INI1 deletion, and both showed preserved INI1 expression by IHC.
Conclusions: Although INI1 protein inactivation appears to be a consistent feature in RMC, only a proportion of these tumors harbor INI1 deletions detectable by FISH analysis. Lack of INI1 expression in the remaining RMC cases is likely due to inactivating INI1 mutations. In our small cohort, neither INI1 deletions nor loss of INI1 expression were features of CDC.
HER2 Expression in Small Cell Carcinoma of the Bladder and Renal Pelvis: Comparison With Adjacent, Invasive, High-Grade Urothelial Carcinoma: (Poster No. 200)
Context: HER2 overexpression has been characterized in lung small cell carcinoma (SCC). More recently, HER2 overexpression has been documented in invasive high-grade urothelial carcinoma (HGUCA) of the bladder and renal pelvis. In view of similar biologic behavior and treatment of lung SCC, it has been hypothesized that there would be HER2 overexpression in SCC of the bladder and renal pelvis. Although previous studies investigated HER2 expression in invasive HGUCA of the bladder and renal pelvis, this is the first study, to our knowledge, to investigate HER2 expression in SCC of the bladder and renal pelvis.
Design: Twenty-four SCC cases were identified. Clinicopathologic parameters were documented. Immunohistochemical stains for HER2 were performed with overexpression defined as 3+ staining involving more than 10% of tumor cells. Expression of HER2 in all cases of SCC was documented, including HER2 expression in the adjacent invasive HGUCA.
Results: Mean patient age was 67 years (range, 47–81 years). There was a male predominance (15 of 24; 62.5%). Adjacent HGUCA was present in 8 of 24 (33%) cases. HER2 overexpression was present in all 8 cases (100%) with adjacent HGUCA. Interestingly, all cases of SCC of the bladder and renal pelvis did not demonstrate HER2 overexpression in the SCC component.
Conclusions: HER2 overexpression does not appear to be associated with SCC of the urinary bladder and renal pelvis. However, all cases with adjacent invasive HGUCA demonstrated HER2 overexpression in the latter component. It is conceivable that cases of invasive HGUCA of the bladder and renal pelvis with HER2 overexpression may be predisposed to dedifferentiation to SCC.
BCG Epididymoorchitis Presenting as a Painless Testicular Mass: (Poster No. 201)
Intravesicular Bacille Calmette-Guérin (BCG) therapy is a well-established treatment for urinary bladder malignancies. We report a case of BCG epididymoorchitis presenting as a painless testicular mass. A 69-year-old man was diagnosed with noninvasive, low-grade papillary urothelial carcinoma and received adjuvant intravesical BCG therapy. He subsequently suffered 3 recurrences of bladder cancer that were treated with transurethral resection and intravesical BCG therapy. After the second BCG course, the patient developed epididymitis that was successfully treated with levofloxacin. Shortly after his last BCG course, he developed painless scrotal swelling without fever or chills. Ultrasound showed an enlarged epididymal head and a 2.2-cm parenchymal mass that suggested a differential diagnosis of neoplasm versus abscess. Because the mass was nontender and painless, the urologist suspected malignancy and an inguinal orchiectomy was performed. The specimen was sent for intraoperative consultation. The cut surface of the specimen showed an ill-defined, indurated area (3.8 cm) in the testicular parenchyma with partial involvement of the epididymis. Touch preparations showed mixed inflammation, and special staining demonstrated acid-fast bacilli. Histologically, there were necrotizing granulomas with associated fibrosis involving the testicular parenchyma and epididymal head. There was no evidence of malignancy. Rifampin, ethambutol, and isoniazid were prescribed for 12 months. At this time, the patient has completed approximately 8 months of therapy and is asymptomatic. Epididymoorchitis is typically painful. This case illustrates that BCG-associated epididymoorchitis can present as a painless testicular mass that may be mistaken clinically for a testicular neoplasm leading to orchiectomy.
IgG4-Related Pseudotumor in Kidney With Unusual Presentation: (Poster No. 203)
Immunoglobulin G4-related disease (IgG4-RD) is a systemic condition with multiorgan involvement. Pathogenesis is unclear but is believed to be autoimmune. Kidneys show tubulointerstitial nephritis, rarely pseudotumors, often with pancreatic disease and elevated serum IgG4. Coexistent hydronephrosis, chronic pyelonephritis, and renal impairment are not well reported. We describe a case of IgG4-related pseudotumor with bilateral hydronephrosis, chronic pyelonephritis, and elevated serum creatinine (SCr) but without elevated IgG. A 46-year-old man with sickle cell trait presented with microscopic hematuria, no proteinuria, and a stable SCr of 1.7 mg/dL. Magnetic resonance imaging revealed a multiloculated, thick-walled cystic lesion in the left kidney suspicious for malignancy. A diagnosis of IgG4-RD was not considered in view of the normal IgG finding, despite atrophic pancreas and mild bilateral hydronephrosis on imaging. A partial nephrectomy showed a 3.3 × 2.7 × 2.7-cm, gray-white, homogenous mass, mostly in renal medulla associated with cortical scars and dilated calyces. Microscopically, the medulla was replaced by storiform fibrosis and marked lymphoplasmacytic infiltrates containing abundant IgG4+ plasma cells, consistent with a diagnosis of IgG4-related pseudotumor. Cortex showed focal areas of tubular atrophy with “thyroidization,” focally markedly dilated tubules with neutrophils, necrotic debris, and lymphocytic tubulitis, suggestive of chronic pyelonephritis in conjunction with partial bilateral ureteral obstruction. The latter is possibly due to retroperitoneal fibrosis. In conclusion, a diagnosis of IgG4-RD should be considered in patients with mass lesion on imaging with bilateral hydronephrosis despite serum IgG within reference range. An association with chronic pyelonephritis has not been described previously, to our knowledge, but may be one possible pathogenesis of IgG4-RD in kidney.
Adenocarcinoma In Situ Arising in Defunctionalized Bladder: (Poster No. 204)
Malignancies are rare in defunctionalized bladders and are usually urothelial or squamous carcinomas. We report a rare case of a 54-year-old man with a defunctionalized bladder left in situ who had an ileal conduit done in early childhood for unknown reasons and who developed primary bladder adenocarcinoma. The patient had a history of bilateral ureteroileal obstructions and presented to the hospital with urosepsis. Ultrasound and a computed tomography scan of the abdomen and pelvis revealed a bladder mass. Cystoscopy showed multiple bladder wall lesions. The tumors were transurethrally resected, and 12 days later, the patient underwent radical cystoprostatectomy, pelvic lymph node dissection, bilateral ureteroileal revision of anastomoses, and stent placement. Microscopically, both resections and cystoprostatectomy were an in situ bladder adenocarcinoma. Immunohistochemistry in the tumor was positive for CDX2 and CK20 and negative for PSAP, PSA, CK 7, p63, and Gata 3. Malignancies in patients with defunctionalized bladders and urinary diversion have increased during the past few decades. The cancer incidence and mortality of patients with defunctionalized bladders is not currently known. The development of neoplasia in these patients is often associated with coexisting carcinogenic stimuli, such as prolonged tobacco use or bladder exstrophy. The exact frequency of tumor development in patients with defunctionalized bladders that is not associated with any other risk factor is still unknown. A defunctionalized bladder left in situ developing adenocarcinoma is rare, with only a few reports in the literature. Symptoms such as mucoid urethral discharge or bleeding in patients with long-term defunctionalized bladders should raise concern for malignancy.
Multicentric Penile and Scrotal Sclerosing Lipogranuloma Associated With Long-Standing Topical Application of Nonprescription Mineral Oil Therapy for Male Genital Enlargement: (Poster No. 206)
Intradermal injection of oils or human fat into the genitalia is rarely performed as part of a regimen for male genital enlargement therapy. These patients present with unifocal dermal lipogranuloma. To our knowledge, multicentric sclerosing lipogranuloma secondary to use of topical creams and oils for male genital enlargement has not been reported in the literature. The patient was a 61-year-old white male body builder with a longstanding history of topical application of mineral oils and creams onto his genitalia for purposes of genital enlargement. He gave no history of injecting any foreign material into his genitals within the previous 20 years. He presented with a swollen painful penis and a unilateral scrotal mass. Ultrasonography and magnetic resonance imaging demonstrated a large left peritesticular echogenic mass. The patient underwent left orchiectomy and excisional biopsy of a penile nodule. A 5.8-cm peritesticular mass and a 1.5-cm penile nodule were identified grossly. Both lesions were histologically identical, consisting of variably sized adipocyte-like vacuoles in a background of dense fibrosis, histiocytes, and giant cells. The histiocytes were positive for CD68 and negative for pancytokeratin and CD117 by immunohistochemistry. Additionally, lesional tissue was S100 immunostain negative, suggesting that it was not adipocyte in origin. Sclerosing lipogranuloma must be considered in the differential diagnosis of paratesticular and subcutaneous masses. The prolonged use of topical oils for genital enlargement and their application over a wide surface area may be associated with multicentric sclerosing lipogranuloma, clinically mimicking a primary or metastatic genital neoplasm.
Painless Proptosis in a 50-Year-Old Man: Orbital Schwannoma With Cystic Degeneration: (Poster No. 208)
Intraorbital schwannomas are rare, accounting for 1%–4% of all orbital neoplasms. A 50-year-old man presented with gradually progressive, right-eye proptosis and ptosis of 9 months duration. No history of vision loss or numbness was present. Noncontrast-enhancing computed tomography scan showed a round, homogenous, noncalcified right orbital mass in the superior aspect of the intraconal region; no other masses were noted. During right orbitotomy with total tumor excision and lateral bone flap, the mass had a firm posterior attachment to the frontal nerve but was not attached to the superior rectus muscle. Grossly, the 1.7-cm, tan-brown nodule had a smooth external surface and tan-yellow cystic cut surface with hemorrhage. Histopathology revealed a well-encapsulated multicystic lesion with a solid component. The hypocellular myxoid foci intermixed with the hypercellular areas, which contained interlacing fascicles of spindle cells, with focal palisading. Background showed abundant foamy macrophages, recent hemorrhage, and hyalinized blood vessels. Vimentin and S100 antibodies diffusely stained the spindle cells, whereas pancytokeratin AE1/AE3 and CD34 immunostains were negative. The diagnosis of schwannoma is typically established by histopathologic exam, unless the surgeon finds the neural tumor attachment during the surgery. Multiple schwannomas in a patient suggest neurofibromatosis-2 or schwannomatosis. In conclusion, schwannoma should be considered in the differential diagnosis of any intraorbital spindle cell lesion. If multiple, then neurofibromatosis-2 should be ruled out.
Uveal Melanoma in a 37-Year-Old Black Woman: A Rare Presentation: (Poster No. 209)
Although uveal melanoma is the most common primary intraocular tumor in adults, it is rare and generally occurs in people of European descent with light eye color and at older age. We report a case of a 37-year-old black woman with history of retinal detachment of the right eye at age 29 that became nonfunctioning and shrunken (phthisis bulbi). A computed tomography scan before ocular prosthesis procedure incidentally found a well-demarcated, lobular mass with heterogeneous enhancement, centered within the intraconal space, which predominantly involved the inferior orbit as well as the right optic nerve and lateral rectus muscle. Biopsies showed a tumor with mixed epithelioid and spindle cells that were positive for Melan-A, HMB-45, S100, MUM1, and Sox-10. The patient was diagnosed with malignant melanoma. Orbital exenteration was performed. The mass had focal heavy pigmentation and measured 3.3 × 2.9 × 2.8 cm, filling the entire globe, extending extensively outside of the sclera and involving the optic nerve. Microscopically choroid and ciliary body were involved. Additional studies revealed the tumor cells were negative for BRAF V600E (VE1) and retained expression of BAP1 (BRCA-associated protein 1). BAP1 mutation is reported to associate with uveal melanoma and lost expression of BAP1 is often seen in uveal melanoma metastasis. This rare case of uveal melanoma presented as an incidental finding in a young black woman with phthisis bulbi at an advanced stage. To date, the patient has no distant metastasis, but outcomes with this advanced stage are generally poor.