Abstracts and Case Studies From the College of American Pathologists 2015 Annual Meeting (CAP '15)

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.

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.

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).

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 (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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 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.

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).

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.

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.

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.

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.

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.

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).

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.

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.

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 (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).

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).

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.

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 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).

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 (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.

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 (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.

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.

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 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.

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 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).

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.

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.

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).

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.

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.

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.

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 (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.

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.

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).

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.

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).

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).

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.

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 (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).

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.

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 (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.

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 (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 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.

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.

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.

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.

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.

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.

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.

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.

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.

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 (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.

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.

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.

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.

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 (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.

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.