Abstracts and Case Studies From the College of American Pathologists 2019 Annual Meeting (CAP19) Open Access

Context: Traditional markers for differentiating upper from lower gastrointestinal (GI) tumors (CK7, CK20, and CDX2) frequently show overlapping phenotypes. Recent studies have shown consistent expression of special AT-rich sequence-binding protein 2 (SATB2) and death decoy receptor 3 (DcR3) in colorectal neoplasms (CRCs).

Design: Immunostains for SATB2, DCR3, CDX2, CK7, and CK20 were applied to 40 CRCs, including appendiceal, right- and left-sided tumors; 40 gastric adenocarcinomas (GACs); and 40 esophageal adenocarcinomas (EACs). Intensity of expression was graded as 0 = negative, 1 = weak, 2 = moderate, and 3 = strong, relative to control cells in each preparation. Area of expression was graded as 0 = negative, 1 = 1%–5%, 2 = 6%–50%, 3 = >50%. Immunostains were analyzed as dichotomous (+/−) variables with the χ² or Fisher exact tests and as continuous variables by calculating a staining score (SS = area score + intensity score) with the Student t test to detect differences in expression.

Results: Most significant differences in expression were found for SATB2 and CK7 (P < .001). By contrast, CK20 (CRC, 100%; GAC, 82.5%; EAC, 69.2%), DCR3 (CRC, 90%; GAC, 50%; EAC, 65.4%), and CDX2 (CRC, 98%; GAC, 75%; EAC, 92%) were frequently expressed by upper and lower GI tumors. Marker combinations with the highest discriminative power were (1) CK7⁻/CK20⁺: CRC, 80%; GAC, 22.5%; EAC, 0%; (2) CK7⁻/SATB2⁺: CRC, 68%; GAC, 8%; EAC, 0%; 3) CK7⁺/SATB2⁻: CRC, 3%; GAC, 60%; EAC, 58%.

Conclusions: SATB2 and CK7 provide high discriminative power for differentiating upper from lower GI tumors; CK7⁻/SATB2⁺ is characteristic of CRC; and CK7⁺/SATB2⁻ is characteristic of GAC and EAC. CK20, DCR3, and CDX2 are frequently expressed in upper and lower GI neoplasms.

Lysosomal acid lipase deficiency (LAL-D) is a rare autosomal recessive lysosomal storage disease caused by mutations in the LIPA gene, which produces cholesteryl ester and triglyceride accumulation predominantly in hepatocytes, adrenal glands, and gastrointestinal tract. The first pediatric patient with LAL-D in Colombia was recently reported in the literature. We describe 2 additional cases of this rare pathology occurring in 2 siblings, aged 5 and 7 years, who presented with hepatomegaly, dyslipidemia, and abnormal liver function. A liver biopsy was done in both siblings, and this revealed portal infiltration by foamy macrophages and a prominent microvesicular steatosis in hepatocytes (Figure 1, A), but only the older sibling had evidence of advanced liver fibrosis. Immunostaining for lysosomal markers, including cathepsin D and LAMP-1 (Figure 1, B), reflected the lysosomal nature of the lipid vacuoles. After enzymatic confirmation, both siblings started enzyme replacement therapy with sebelipase α. Follow-up transaminase levels and lipid profile showed a notorious decrease in AST and ALT, and a slight increase in HDL cholesterol. Genetic sequence analysis of the LIPA gene was performed, and this showed the c.[894G>A]:[386A>G] mutation. It is important to increase awareness of this rare disease among pathologists. The expression of lysosomal markers (such as cathepsin D, LAMP-1, and LAPM-2) around the lipid vacuoles and the enzymatic confirmation support the diagnosis of LAL-D in pediatric patients.

Context: Benign multicystic peritoneal mesothelioma (BMPM) and well-differentiated papillary mesothelioma (WDPM) of the abdominal cavity are uncommon entities, with few cases found in the literature. It is imperative to provide additional information regarding the nature of these lesions to better guide management in these patients.

Design: All surgical pathology files were examined, and all diagnoses of BMPM and WDPM at our institution were selected from 1995 to 2017. The clinical and pathologic data were reviewed in detail. Immunohistochemical stains and cytogenetic studies were then performed in all cases.

Results: Five cases of BMPM and 1 case of WDPM were identified. The average age was 47 years. Five patients (83%) were female and 1 patient (17%) was male. The WDPM case was positive for deletion of p16 (CDKN2A) by FISH, and all cases of BMPM were negative. P53 stain was strongly positive in one BMPM case (Figure 2) and moderately positive in 2 cases. MIB-1 stain showed focal positivity on 3 BMPM cases. One case showed ER and PR staining. No cases showed BAP1 loss.

Conclusions: Three cases of BMPM showed at least moderate expression of p53 and the case of WDPM was positive for deletion of p16 by FISH, suggesting that some of these lesions may harbor true malignant potential. Additionally, the patient with WDPM was found to have MEN1 syndrome. The possibility of shared genetic pathways for these lesions should be considered. Testing these lesions for molecular aberrations and exploring the possibility of shared genetic pathways would be an interesting idea for future studies.

Context: Food material is occasionally encountered in tissue samples submitted for pathologic examination and has been sparsely evaluated in the literature. We undertook this study to record the histologic appearance of common foods and to determine whether they can indeed resemble potentially pathogenic materials sometimes encountered in the gastrointestinal tract (eg, in colon biopsies).

Design: We evaluated samples of 48 different food types, including grains, fruits, seeds, and vegetables. The raw foods underwent routine histologic processing, and we examined the resultant hematoxylineosin–stained slides for identifiable structures.

Results: Most vegetables were composed of architecturally complex but otherwise nondescript cellulose. Pulse material was distinctly identifiable, as previously described. Pigmented insoluble fiber in the pulp of dates was yellow with a fish-scale texture, as was the testa/seed coat of kiwi seed; these both mimicked sevelamer resin. Spherical okra seeds detached from their fibrous locules (Figure 3, A) resembled bile acid sequestrant granules (Figure 3, B), though smaller. Finally, the rounded shape and convoluted outer coats of some seeds (particularly tomato seeds; Figure 3, C) bore passing structural resemblances to various helminths, such as Anisakis simplex (Figure 3, D).

Conclusions: The histologic structures of commonly eaten plant foods can occasionally resemble structures of diagnostic significance in the gastrointestinal tract. Although this differential diagnosis is often quickly resolvable, awareness of the histologic appearance of certain foods may be valuable in rare situations where the identity of a foreign substance remains in doubt and a patient's clinical information (including medication list) is unavailable.

A collision tumor is an extremely rare phenomenon that consists of 2 histologically distinct neoplasms occurring within the same organ with no significant overlap. Each tumor displays a different histogenesis and tumorigenesis pathway. The occurrence of synchronous adenocarcinoma and lymphoma has been reported within a lymph node and a variety of extranodal sites, such as the gastrointestinal tract, lung, and bone marrow; however, the hepatobiliary system is seldom involved. Primary hepatic lymphoma is in itself a rare entity, with most cases displaying diffuse large B-cell lymphoma. Primary hepatic mucosa-associated lymphoid tissue (MALT) lymphoma is an even rarer event, and its collision with intrahepatic cholangiocarcinoma makes a novel finding, which, to our knowledge, has not been described in the literature. We present a case of a 78-year-old woman who underwent a partial hepatectomy for a biopsy-proven intrahepatic cholangiocarcinoma (Figure 4, A). Detailed microscopic examination identified atypical monotonous lymphoid cells intermingled with the glands and stroma within this intrahepatic cholangiocarcinoma (Figure 4, B through D). A thorough immunohistochemical panel including CD3, CD20, BCL2, BCL6, cyclin D1, Ki-67, HepPar-1, pan-keratin, arginase, CDX2, synaptophysin, chromogranin, and mismatch repair proteins uncovered an incidental MALT lymphoma colliding with this intrahepatic cholangiocarcinoma. This clinically unsuspected diagnosis subsequently led to more comprehensive systemic investigation and staging, with subsequent bone marrow examination, revealing stage IV lymphoma. This unique case highlights the importance of a thorough workup including astute histomorphologic evaluation and ancillary studies to accurately classify a clinically unsuspected neoplasm in close contact with a diagnosed tumor.

Context: Distinguishing primary cholangiocarcinoma (CC) from metastatic pancreatic ductal adenocarcinoma (PDAC) is challenging as there are no reliable markers available. Recent studies show that prostate-specific membrane antigen (PSMA) is expressed in the endothelium of neovasculature of solid malignancies and can be detected by PSMA-targeted imaging technology. Here we studied PSMA expression pattern in primary CC and metastatic adenocarcinomas.

Design: Forty-nine cases of liver mass resections were collected. Immunohistochemical stains for PSMA and CD34 were performed. The expressions of PSMA in tumor cells and neovascular endothelium were analyzed separately. The presence of vascular structures was highlighted by CD34 expression.

Results: Twenty-two cases (22 of 49; 44.9%) showed PSMA expression on the peritumoral vascular structures, 5 cases (10.2%) showed expression on tumor cells, and the rest lacked expression of either. All of the 7 cases of primary CC showed PSMA vascular expression (Figure 5, A and B) compared with none of the 8 cases of metastatic PDAC (P < .01) (Figure 5, C and D). In addition to the PDACs, none of the other metastatic adenocarcinomas were positive for PSMA. Metastatic prostate carcinoma showed PSMA expression in tumor cells (5 of 8; 62.5%), 2 of which also showed peritumoral vascular positivity. Fifty-nine percent (13 of 22) of hepatocellular carcinomas were positive for tumor vasculature.

Conclusions: Primary CCs have universal peritumoral neovascular PSMA expression, whereas most metastatic adenocarcinomas, including PDAC, do not have a similar PSMA expression pattern. Our findings suggest that evaluating PSMA expression in the peritumoral vessels may help distinguish primary CC from metastatic adenocarcinomas, especially in morphologically challenging PDACs.

Context: Treatment-related cytologic atypia (TRCA) is frequently observed in patients with esophageal/gastroesophageal junctional adenocarcinoma following neoadjuvant chemoradiation. TRCA is characterized by voluminous eosinophilic or vacuolated cytoplasm, large bizarrely shaped nuclei with coarse chromatin, and apparent mitotic inactivity. The goal of this study was to evaluate whether TRCA confers an overall survival advantage in cases with partial response to neoadjuvant chemoradiation.

Design: A total of 153 cases of esophageal/gastroesophageal junctional adenocarcinoma treated with neoadjuvant chemoradiation and esophagectomy were classified as diffuse TRCA (dTRCA; ≥90% of tumor cells with TRCA), patchy TRCA (<90% and ≥1% TRCA), and no TRCA (nTRCA; <1% TRCA). The four-tiered College of American Pathologists tumor regression score system was used to evaluate treatment effect (v4.0.0.0, 2017). Overall survival was evaluated using Kaplan-Meier curves and log-rank analysis. KI-67 immunohistochemistry was performed in 8 cases each of dTRCA and nTRCA, and more than 300 cells were scored per case.

Results: Partial response, score 2, was observed in 68 patients (44%). Of these, dTRCA was present in 14 cases (21%), patchy TRCA in 20 cases (29%), and nTRCA in 32 cases (47%). The Ki-67 index was significantly lower in cases with dTRCA (mean ± SD = 17.4% ± 14.5%) than cases with nTRCA (42.6% ± 23.2%; P = .02). However, the median overall survival of patients with dTRCA and nTRCA was similar, 25.2 and 20.6 months, respectively (P = .21, hazard ratio 0.637; 95% CI, 0.316–1.270).

Conclusions: The data suggest that treatment-related atypia does not confer a survival advantage in patients with partial response to neoadjuvant chemoradiation in esophageal/gastroesophageal junctional adenocarcinoma.

Angiomyolipoma (AML) is a rare benign mesenchymal tumor composed of vessels, smooth muscle, and adipose tissue. AML frequently occurs in the kidney, but it can occur in other organs such as the liver. AML is usually asymptomatic and incidentally identified because of its indolent growth. We report a case of spontaneous rupture of hepatic AML with collective review of 8 previously reported cases. A 52-year-old man was admitted because of sudden onset of severe abdominal pain, hypotension, and anemia. Abdominal CT revealed a 9-cm hemorrhagic heterogeneous mass in the left lobe of the liver and a significant amount of acute hemoperitoneum. Emergency embolization for the hepatic artery feeding the mass was performed. Forty-seven days later a left hepatectomy was performed. The left lobe contained a 7.5-cm ruptured cystic mass with marked necrosis and hemorrhage. Microscopically, the tumor consisted of sheets of atypical pleomorphic epithelioid and short spindle cells with pale eosinophilic and vacuolated cytoplasm, focal mature adipose tissue, and numerous thickened wall blood vessels (Figure 6, A and B). Tumor cells were positive for human melanin black (HMB) 45, smooth muscle actin, Melan-A, and caldesmon, and negative for HepPar-1 and cytokeratin 7 (Figure 6, C and D). Pathologic diagnosis was hepatic AML. Hepatic AML could cause, albeit rarely, spontaneous rupture, as in this case. Literature review shows that ruptured hepatic AML is large (average diameter 8 cm) without sex or age preference, and accurate diagnosis before surgery is challenging. This case provides important information for differential diagnosis of ruptured hepatic mass.

Malignant peritoneal mesothelioma is a rare aggressive tumor with typical growth pattern of a locally expansive mass. The most frequently reported initial symptoms are abdominal pain, abdominal swelling, anorexia, marked weight loss, ascites, and paraneoplastic syndromes (ie, hypoglycemia, venous thrombosis, and thrombocytosis). Rectal prolapse as an initial clinical manifestation of peritoneal epithelioid mesothelioma has never been reported. We report an unusual case of a 90-year-old woman with severe rectal prolapse for 1 month who underwent full-thickness rectal prolapse repair. During the surgery, upon approaching the peritoneal reflection, it was noted to be bulging with ascites and had significant nodularity on the external surface. The peritoneum was opened and ascites fluid was evacuated. Perirectal peritoneum was embedded with carcinomatosis implants. The histology of the mass revealed infiltrative nests and sheets of uniform and sharply defined epithelioid mesothelial cells with prominent nuclei, which is consistent with malignant peritoneal epithelioid mesothelioma. The tumor cells were positive for calretinin, cytokeratin 5/6 (CK5/6), and Wilms tumor 1 (WT1) but negative for B72.3, MOC31, p53, carcinoembryonic antigen (CEA), estrogen receptor (ER), and CD15. The diagnosis was further confirmed by electron microscopy that showed focal areas with numerous elongated microvilli and enlarged desmosomes. Given the rarity of malignant peritoneal mesothelioma, this case may provide added information for clinicians regarding their natural history and optimal management (Figure 7, A through D).

A 61-year-old alcoholic man with history of cholecystectomy presented with a 20-year history of recurrent bowel obstruction and 30-pound weight loss. After numerous attempts at conservative management, exploratory laparotomy was performed that showed no mechanical cause. However, the obstruction persisted and intensified. A CT scan confirmed small bowel obstruction and megacolon. A total abdominal colectomy was performed, with ileostomy. Grossly, there was intestinal dilation up to 15 cm with prominent brown discoloration of bowel wall. No strictures or other fixed obstruction were identified. Microscopic examination revealed prominent lipofuscin-like pigment deposition involving the muscularis propria, muscularis mucosae, and the vascular smooth muscle. Histochemical staining was positive for PAS, and negative for iron and calcium, consistent with lipofuscin. The gross and histologic findings fit with brown bowel syndrome (BBS). BBS is a very rare condition characterized by lipofuscin deposits predominantly within the smooth muscle of the muscularis mucosae and/or muscularis propria that imparts a brown color to the bowel. It is generally thought to be a smooth muscle mitochondrial myopathy due to chronic vitamin E deficiency secondary to fat malabsorption syndromes, resulting in free radicals causing peroxidation of unsatu-rated membrane lipids with accumulation of lipofuscin. BBS may be seen in patients with alcohol abuse, maldigestion, chronic bowel inflammation, and intestinal lymphangiectasia. Our patient's severe chronic intestinal pseudo-obstruction, low levels of certain fat-soluble vitamins (A, D, and E), significant weight loss, and history of cholecystectomy with alcohol abuse correlates with BBS clinically.

Malignant gastrointestinal neuroectodermal tumor (GNET) is a rare entity that exclusively occurs in or near the gastrointestinal tract. It is predominantly found in young adults with frequent local recurrence and metastasis. Here, we report a case of a 49-year-old man who presented with abdominal pain and weight loss. Abdominal CT scan revealed an ileal tumor with mesenteric lymphadenopathy. Lymphoma was highly suspected clinically because of his remote history of thymic B-cell lymphoma. A core needle biopsy of mesenteric node was inconclusive because of limited tumor for further study. A right hemicolectomy was performed. Grossly, an ulcerated tumor involving full thickness of ileum with multiple tumor-replaced lymph nodes was identified. Histologically, the tumor grew in diffuse sheets and nests with focal pseudoalveolar and pseudopapillary patterns. The tumor cells were large, epithelioid, and polygonal with eosinophilic or clear cytoplasm and vesicular chromatin. Abundant multinucleated osteoclast-like giant cells were present. The tumor cells showed diffuse strong positivity for S100 and Sox10 but were negative for melanocytic markers. EWSR1-ATF1 gene fusion was identified by FISH analysis. Histologically, GNET can mimic many epithelial and nonepithelial gastrointestinal tumors. It is extremely challenging to make a diagnosis from previous core biopsy, especially with a past medical history of lymphoma. Awareness and recognizing this entity and its diagnostic criteria are necessary for pathologists to avoid misdiagnosis.

Intussusception is the telescoping of a proximal segment of the gastrointestinal tract into an adjacent distal segment. It is a rare cause of obstruction in adults. Malignant pleural mesothelioma is an uncommon neoplasm of mesothelial origin that can be difficult to diagnose. Here, we report an unusual case of small bowel intussusception in an adult due to metastatic pleural mesothelioma. A 62-year-old woman presented with abdominal pain, constipation, and emesis. Computerized tomography revealed jejunal obstruction secondary to intussusception. She underwent segmental resection, which revealed a 2.7-cm, well-circumscribed mass involving the muscularis propria and abutting the serosa. Microscopically, the tumor was composed of sheets of large epithelioid and spindle cells with prominent nucleoli, areas of necrosis, frequent mitosis, and lymphovascular invasion. The patient was previously diagnosed with pleural mesothelioma 15 months prior. She had metastasis to an aortocaval lymph node and was receiving chemotherapy. Pleural biopsy showed mesothelioma with epithelioid cells diffusely positive for WT-1, calretinin, D2-40, and CK5/6. However, the jejunal tumor cells were positive for WT-1 but faintly positive for calretinin (Figure 8), D2-40, and CK5/6. Stains were negative for CK20, villin, and CDX-2. These findings were consistent with metastatic pleural mesothelioma. Small bowel high-grade malignancies with minimal mucosal involvement and extensive lymphovascular invasion are more commonly metastasis than primary. If the history of prior malignancy is remote or unknown, it is important to include mesothelioma in differential diagnoses with carcinoma, sarcoma, lymphoma, and melanoma. Moreover, performing multiple mesothelial markers can be beneficial, as patchy and faint staining makes the diagnosis challenging.

Context: Phospho-histone H3 is associated with mitotic chromatin condensation in late G2 and M phase of the cell cycle. This study aims to confirm the reliability of a manual count of phospho-histone H3–positive cells on immunohistochemical stained slides (MC-PHH3) in neuroendocrine tumors of gastrointestinal tract and pancreas compared with manual mitotic counting on H&E–stained slides (MMC-HE) and manual count of the Ki-67 proliferation index (MC-Ki67).

Design: The study included 134 patients with neuroendocrine tumors of the gastrointestinal tract and the pancreas from our institution from 2011 to 2017. MC-Ki67 and MMC-HE were retrieved from the pathology report. MC-PHH3 was assessed by a board-certified pathologist as counts/5 mm².

Results: Manual counting showed 108 cases of G1, 21 of G2, and 5 of G3 tumors according to World Health Organization grading criteria. There was good spearman correlation between MC-PHH3 and MCKi67 (correlation coefficient 0.64, P < .001) and moderate correlation between MMC-HE and MC-PHH3 (correlation coefficient 0.43, P < .001). The moderate correlation may be due to overestimation of the MC-PHH3 count secondary to fixation, background lymphocytes, and edge artifact staining.

Conclusions: Given the significance of neuroendocrine tumors and neuroendocrine carcinoma grading based on mitotic count, we propose that although phospho-histone H3 may not be a sufficient replacement for MMC-HE, it may serve as a confirmatory marker when MMC-HE and MC-Ki67 are discrepant.

Focal nodular hyperplasia (FNH) is the second most common benign hepatocellular lesion with an incidence of 0.6% to 3%. Classic histologic features include nodular architecture divided by thick fibrous septa, dystrophic vessels, and bile ductular reaction. There is a paucity of literature regarding FNH with fatty change/steatohepatitis-like change, which can be confused with steatohepatitic variant of hepatocellular carcinoma. We report an unusual case of FNH with steatohepatitis-like changes. A 44-year-old woman presented with a few days' history of right abdominal pain. Computed tomography showed a 3.0-cm solitary mass on liver segment 5, for which hepatic segmentectomy was performed. The resection specimen showed a 3.0-cm pale-yellowish nodule (Figure 9, A). Microscopy showed nodules of hepatocytes separated by thick fibrous septa with thick-walled vessels (Figure 9, B). Lesional hepatocytes showed moderate steatohepatitic changes (ballooned hepatocytes, and lobular inflammation) with moderate macro-vesicular steatosis (about 40%) (Figure 9, C). There was focal mild pericellular fibrosis. Thick hepatocellular plates/cords >3 cells wide were focally present. Interface showed ductular reaction (highlighted by CK 7) (Figure 9, D). Thin rim of background liver was histologically unremarkable, without significant steatosis or steatohepatitis. We present this case of FNH to highlight the unusual occurrence of steatohepatitis-like changes within the lesional hepatocytes, which should not be confused with steatohepatitic variant of hepatocellular carcinoma. Common classical features of FNH including thick-walled vessels within the fibrous septa, ductular reaction, and thick fibrous bands are helpful in differentiating FNH from hepatocellular carcinoma.

Fibrous obliteration of the appendix is common and found in ~10% of appendices. It is usually an incidental finding in appendices removed for other reasons (such as acute appendicitis) and is not by itself an indication for surgery. We present a case of a 50-year-old woman who underwent an elective hysterectomy and salpingo-oophorectomies for chronic pelvic pain. Intraoperatively, serosal nodules of the appendix raised concern for carcinoma, prompting appendectomy. Grossly, 8 firm, tan nodules studded the appendiceal serosa. The nodules ranged from 2 to 10 mm maximally and appeared to randomly involve the entire length of the appendix. Cross-sectioning showed mushroom-shaped lesions comprising transmural growths (“stems”) herniating through the wall to form serosal surface implants (“caps”). Microscopy confirmed transmural extrusion of intra-appendiceal fibro-obliterative tissue causing serosal nodule formation. Additionally, the tip of the appendix contained a 3-mm well-differentiated neuroendocrine tumor and 1 microscopic focus of intramural endometriosis; both were distant from the foci of herniating fibro-obliterative tissue. Immunohistochemical staining showed the protrusions of fibro-obliterative tissue contained the typical mix of cells seen in fibrous obliteration of the appendix including neural cells, myofibroblasts, fibroblasts, endothelium, and smooth muscle cells. Features of diverticulosis, appendicitis, neuroma, and fibrous adhesions were absent. In summary, we present a novel, previously unreported variant of fibrous obliteration remarkable for transmural and serosal nodular involvement of the appendix. The condition mimicked invasive carcinoma intraoperatively prompting appendectomy (Figure 10).

Adenocarcinoma is the most common type of esophageal cancer in the United States. We present a report of an esophageal cancer with adenocarcinoma, neuroendocrine, and squamous cell differentiation. Thepatient was a58-year-old man with aremotehistory of orthotopic heart transplantation for ischemic cardiomyopathy who presented with intractable nausea, vomiting, abdominal pain, and watery diarrhea. A computed tomography scan revealed a solitary lung nodule and multiple hypoattenuated liver lesions. On endoscopy, a large ulcerated gastroesophageal junction mass was identified with submucosal extension into the gastric cardia. Biopsies of the liver and gastroesophageal lesions revealed a poorly differentiated neoplasm with patchy myxoid stroma and dyskeratosis (Figure 11, A). The background esophageal epithelium demonstrated focal goblet cell metaplasia. By immunohistochemistry, the neoplastic cells were variably positive for MOC-31 (Figure 11, B) and p63 (Figure 11, C) and strongly positive for synaptophysin (Figure 11, D), consistent with multidirectional differentiation. Clinical laboratory tests found elevated chromogranin A levels. The patient's condition deteriorated rapidly within 2 weeks of the diagnosis with progressive somnolence and confusion. Here we present an exceptionally rare case of an aggressive esophageal carcinoma with multilineage differentiation.

Primary biliary tract neuroendocrine tumors are extremely rare and account for 0.2%–2% of all gastrointestinal neuroendocrine tumors. Paucity of enterochromaffin cells in the biliary tract is the reason for paucity of these tumors at this location. Chronic inflammation of bile duct epithelium is responsible for metaplasia of enterochromaffin cells and formation of neuroendocrine tumors. We report a case of an 83-year-old woman who presented with epigastric pain, nausea, heart-burn, fatigue, and weight loss and later developed jaundice. Results of her liver function tests were elevated. She had a remote history of malignant melanoma of skin. Computed tomographic scan and endoscopic ultrasound showed biliary distension with a 2.6 × 2.1 × 2.0-cm mass in the distal common bile duct. She underwent a pancreatoduodenectomy, cholecystectomy, and retroperitoneal lymph-adenectomy. Distal common bile duct revealed a 4.5 × 2.2 × 1.5-cm tan-red polypoid mass close to the ampulla of Vater (Figure 12, A) composed of sheets of ovoid cells, slightly spindled-shaped with fine granular chromatin and frequent mitoses (Figure 12, B, C). Immunohistochemical stain for CD56 was diffusely positive (Figure 12, D) and CAM5.2, CK18, CK-WSS, and synaptophysin were focally positive. Chromogranin, CD99, EMA, AE1/AE3, CK-19, villin, CEA-polyclonal, melanoma cocktail, and CD45 were negative. MIB-1 showed an 80% proliferation index. Morphology and immunoprofile supported diagnosis of high-grade (small cell) neuroendocrine carcinoma of the distal bile duct (pT1). Later she had metastasis of the carcinoma to the lung and cervical spine. This case highlights an unusual rare presentation of neuroendocrine tumors in the biliary tract.

Context: During upper endoscopy, routine biopsies are often taken from endoscopically normal duodenums. To our knowledge, there has not been a recent assessment of the diagnostic yield or influence on management of routine biopsy of endoscopically normal duodenums.

Design: The laboratory information system was searched for patients who had duodenal biopsies between January and June 2018. The upper-endoscopy reports were reviewed and only biopsies from 500 endoscopically normal duodenums were included. The pathologic findings in the duodenal biopsies and the patient indications for upper endoscopy were recorded. Cost saving analysis was performed.

Results: Twenty-seven of 500 patients (5.4%) with endoscopically normal duodenums had abnormal histopathology. The most common histopathologic findings were peptic duodenitis (51.9%), increased intraepithelial lymphocytes (25.9%), and gastric heterotopia (11.1%). One patient with increased intraepithelial lymphocytes had subsequent positive celiac serology, 1 patient had subsequent negative celiac serology, and the remaining 5 patients had no celiac serology. The most common clinical presentation in these patients was epigastric pain, nausea, vomiting, and heartburn. The most common clinical presentation in patients with peptic duodenitis was dysphagia and heartburn. The patient charge for 1 duodenal biopsy was $601. The laboratory cost to process 1 duodenal biopsy was $55.

Conclusions: The yield of biopsying endoscopically normal duodenal mucosa is very low (5.4%) and it is unlikely to find a treatable diagnosis unless there is a concern for celiac disease. More selective biopsying would result in significant cost savings to patients and have minimal clinical impact.

Context: Cirrhotic-like hepatocellular carcinoma (CL-HCC) is a rare distinct variant of carcinoma (HCC). It is clinically/radiologically unsuspected but discovered incidentally during microscopic examination of an explanted “cirrhotic” liver. Published literature on CL-HCC is sparse and prognosis is not well known because of its rarity. We seek to increase awareness among general pathologists of this rare entity, which requires careful attention while examining “cirrhotic” liver.

Design: CL-HCCs were discovered incidentally during microscopic examination of “cirrhotic” liver explant in 3 patients. H&E and immunohistochemical stains were examined. Fibrosis, serum α fetoprotein (AFP) detectability of a mass on imaging, underlying liver disease, and posttransplantation outcomes, including the recurrence, metastasis, and death, were all reordered.

Results: All 3 patients were men with age of 50–58 years; 2 were African American and 1 was white. No lesions were noted on preoperative radiology. Grossly, they were bilaterally involved (~25%–75%) by neoplastic nodules, which ranged in size from 0.5 to 1.7 cm (Figure 13, A). Microscopically they often showed a pseudo-glandular pattern with steatotic features, perinodular sclerotic rims, and small vessel invasion (Figure 13, B and C). Relative to HCCs, CL-HCCs immunophenotypically show frequent ubiquitin and CD10 (cytoplasmic and membranous) positivity, strong glypican-3, and low Ki-67 proliferative index, but are negative for α-fetoprotein. The demographics of our patient population suggests a male predominance as there is only 1 published case of CL-HCC in a female, albeit a small sample size.

Conclusions: CL-HCC is a cryptic variant of HCC and often evades pretransplant detection. The etiology of CL-HCC remains diverse. Further research is necessary to determine the carcinogenesis and to improve methods of detection.

Amyloidosis is improper deposition of insoluble protein in tissue that impairs its function and architecture. The liver is commonly affected and manifests with hepatomegaly and abnormal function tests. We report a case of hepatic failure initially attributed to acute chronic liver failure (ACLF) in a 59-year-old African American woman. She was encephalopathic with stable vitals: bilirubin, 24.3; INR, 2; creatinine, 4.2; and MELD score of 40 with rapidly declining renal function. Results of magnetic resonance cholangiopancreatography were negative. Her workup was unrevealing, and she was deemed to have decompensated cryptogenic cirrhosis. She received simultaneous liver and kidney transplant. Explanted liver revealed extensive amyloidosis, AL amyloid κ type. Bone marrow biopsy and flow cytometry were negative without plasma cell dyscrasia. Further workup suggested no systemic involvement. AL amyloidosis is a rare disease. Liver involvement occurs in 62%–90% of cases but is usually limited to hepatomegaly with elevated alkaline phosphatase and occurs in the setting of systemic amyloidosis. Stigmata of chronic liver disease are rare: hyperbilirubinemia is seen in 5% of patients and suggests poor prognosis. Our patient's explanted liver revealed extensive amyloid deposition within portal, periportal, and focally in septa (Figure 14, A). Congo red was positive (Figure 14, B and C). Trichrome confirmed cirrhosis (Figure 14, D). Her hepatic amyloidosis was unique in the severity of symptoms and level of organ involvement that led to ACLF and ultimately transplantation. Hepatic amyloidosis is usually limited to hepatomegaly and abnormal laboratory values but can present as hepatic failure and should be considered in patients with otherwise unclear etiology of liver disease.

An 88-year-old man presented for gastrectomy for gastric adenocarcinoma after receiving neoadjuvant chemotherapy. Gross examination revealed multiple firm serosal nodules (Figure 15, A) ranging from 0.1 to 0.5 cm overlying a palpable 5.5-cm luminal mass (Figure 15, C). They were presumed to be extension or metastatic spread of the gastric adenocarcinoma. Microscopically, the luminal mass was confirmed to be gastric adenocarcinoma (Figure 15, D; intestinal type, [y] pT1bpN0). The serosal nodules were composed of spindled cells in a hyalinized and partially calcified stroma and were CD117 (Ventana Medical Systems, Tucson, Arizona) and DOG1 (Figure 15, B; Cell Marque, Rockland, California) immunoreactive consistent with multifocal gastrointestinal stromal tumor (GIST) ([m] pT1pN0). Small GISTs are often asymptomatic and not infrequently incidentally identified during operation or pathologic examination for another pathologic process—neoplastic or otherwise. This case is unusual as the GISTs were multifocal in a patient without a known GIST-associated syndrome. However, his past medical history was notable for a neurofibroma, congenital hypertrophy of the retinal epithelium, and a sister who died from a nonspecified gastric cancer in her early 50s. Although the occurrence of multifocal GISTs outside the setting of a syndrome is more common than previously thought, the combined diagnosis of a multifocal GIST and gastric adenocarcinoma is rare. This patient's concurrent neoplasms and medical history hint at an underlying genetic cause, which may provide further evidence for a shared neoplastic driving mechanism.

Isolated ischemic necrosis of the cecum (ISNC) is a rare condition that occurs in patients with low-flow state. Right lower abdominal pain is the most common symptom and clinically resembles acute appendicitis. We report herein a case of ISNC presenting as a distinct mass-forming lesion mimicking malignancy in an 87-year-old man with hypertension and chronic heart disease who presented to the emergency room with right abdominal pain. CT imaging showed focal wall thickening and contour bulge along the medial aspect of the ascending colon suspicious for colonic neoplasm. Laparoscopic right hemicolectomy was performed and a mass lesion in the cecum was identified intraoperatively. Gross examination revealed a 5.0 × 3.7-cm tan-brown, well-demarcated mass with scalloped border and necrotic surface. Histologic examination demonstrated acute ischemic necrosis with transmural hemorrhage and abscess consistent with perforation. At the periphery of the lesion, there were relatively normal-appearing arteries juxtaposed by abnormal ones exhibiting intimal thickening consisting of finely granular amphophilic material morphologically resembling amyloid. Yet Congo red stain was negative, whereas elastin stain was positive, confirming segmental vascular elastosis likely causing ischemia. There was no evidence of epithelial dysplasia or carcinoma. The patient survived surgery and recovered well clinically. Cecal ischemia has been described in association with a variety of clinical entities; however, this is the first case report where it presents as a mass-forming lesion mimicking malignancy. In patients with long-standing history of hypertension and heart disease, ISNC should be considered in the differential diagnosis of right lower quadrant pain (Figure 16).

Context: There is growing evidence of the role of immune therapy in colorectal cancers. We have investigated the expression of PD-L1 in colorectal carcinoma and in its microenvironment and correlated expression with clinicopathologic parameters, microsatellite instability, and BRAF mutation status.

Design: The study group comprised 110 resection specimens of colorectal carcinoma. Tissue microarrays were made using an automated tissue microarray system (TMA Grandmaster, 3DHistotech) and stained with immunohistochemistry using antibodies to PD-L1 (SP263) and assessed at cutoffs >5%, 5%–50%, >50%, BRAF 600VE (VE1 mouse monoclonal), and MMR protein antibodies MLH-1 (M1), PMS2 (EPR3947), MSH2 (G219-1129), and anti-MSH6 (44). All immunohistochemistry assays were performed on a Ventana BenchMark XT automated staining instrument according to manufacturer's instructions (Ventana Medical Systems, Inc, Tucson, Arizona).

Results: PD-L1 in tumor cells was seen in 40% of cases, in tumor-infiltrating lymphocytes in 45.5%, BRAF 600VE in 11%, MLH1/PMS2 loss in 9%, and MSH2/MSH6 loss in 12.7%. PD-L1 was expressed in >5% of cells in 17.3% of cases, 5%–50% in 15.5%, and >50% in 7.2%. Correlates of PD-L1 expression are shown in the Table. Further PD-L1 expression was analyzed in synchronous primary and metastatic lymph node (n = 37). Concordant expression was evident in 65% of cases, whereas 35% of cases showed discordance.

Conclusions: PD-L1 was expressed in a fair number of colorectal cancers. BRAF was significantly coexpressed with PD-L1.

Sarcomatoid renal cell carcinoma is a rare form of dedifferentiated renal cell carcinoma with high metastatic rate and adverse prognosis. Common metastatic sites include lymph node, lung, liver, and bone. We report herein a case of sarcomatoid renal cell carcinoma with unusual metastasis to the small bowel in a 65-year-old woman with a history of clear cell renal cell carcinoma with focal sarcomatoid transformation. She presented in the emergency department with worsening abdominal pain. Imaging showed ruptured acute appendicitis; however, diagnostic laparoscopy found no evidence of appendicitis but a small punctate perforation in the small bowel. Gross examination showed a 2-cm tan-white lobular firm lesion at the perforation site involving the full thickness of the small bowel. Histology revealed a high-grade spindle cell neoplasm with hyperchromatic and pleomorphic nuclei, frequent mitotic figures, and necrosis. Immunohistochemistry confirmed tumor cells to be positive for CD10 and CA-IX, but negative for pan-cytokeratin, EMA, PAX-8, RCC, desmin, smooth muscle actin, C-kit, DOG-1, CD34, and S100. Molecular studies showed that the tumor cells were microsatellite stable but harbored mutations in PBRM1, TERT, and VHL genes, supporting renal cell carcinoma in nature. The patient received radiation therapy but unfortunately expired in 1 month because of rapid disease progression. In summary, this is a rare and challenging case of metastatic sarcomatoid renal cell carcinoma to the small bowel with loss of renal cell carcinoma markers, reinforcing the aggressive nature of this entity and the importance of correlating with the prior history for reaching correct diagnosis.

Primary pancreatic adenosquamous carcinoma (PASC) is an extremely rare clinical entity with an incidence of approximately 4% in all pancreatic malignancies. We report a case of PASC presenting as duodenal diverticulum. A 79-year-old white man was referred to the hospital. Computerized tomography revealed a large duodenal diver-ticulum at the third portion of the duodenum associated with a 4.3-cm mass at the pancreatic head. No additional mass was identified. Serum carcinoembryonic antigen (CEA 0.8 ng/mL) and CA19-9 (19 U/mL) were within normal limits. Peritoneal amylase level was significantly high (6298 U/L). Fine-needle aspiration and EUS-guided biopsy confirmed malignant cell present. Subsequently pancreaticoduodenectomy was performed. Gross examination revealed a large well-defined, pale tan-yellow, firm mass (5.1 × 3.5 × 3.1 cm) with a central cavity and necrosis. The cavity opened to the duodenal mucosal surface. Microscopically, the mass showed large nests of tumor cells with marked central necrosis. The tumor predominantly exhibited squamous differentiation with focally vague glandular features. No neuroendocrine differentiation was noted. The tumor cells showed enlarged, irregular nuclei with vacuolated chromatin. An increased mitotic figure (16/10 per high-power field) and Ki-67 (85%) was identified. Immunohistochemical studies revealed tumor cells were strongly positive for p63, p40, and CK8/18 and negative for synaptophysin, chromogranin, CK19, CK20, and CDX2. A literature review was performed. The PASC presented as a large mass with central necrosis, which may be a pathologic feature for PASC. Pancreaticoduodenectomy is the common treatment of choice. Close follow-up should be applied to detect possible early recurrence and distal metastasis (Figure 17).

Congenital epidermoid cysts of the liver are an uncommon finding, with only 14 previously reported cases. Their pathogenesis is poorly understood. Aside from a recent report documenting pancytokeratin staining, no other descriptions of this entity have included immunohistochemical findings. We report 2 rare cases of hepatic epidermoid cysts, the first evaluated with a broad panel of immunohistochemistry with the aim of elucidating histogenesis. Both cases were detected on second-trimester antenatal ultrasound in otherwise developmentally unremarkable females. The cysts enlarged slowly after birth and were resected at ages 2 and 6 months, both for the indication of avoiding potentially more difficult surgery in the future. Grossly, the cysts were unilocular (4.8 cm) and multilocular (7.0 cm). Microscopically, both were lined by stratified nonkeratinizing squamous to focally transitional-like epithelium and surrounded by a paucicellular fibrous stroma (Figure 18, A). In the multilocular cyst, hepatocytes as well as fibrous stroma populated the septa (Figure 18, B). Epithelial cells were positive for HBME-1 (Figure 18, C), p63, CK19, CEA, Cam5.2, and CK7 in the luminal 1–2 layers only (Figure 18, D) and EMA. D2-40, WT-1, calretinin, and Ca19-9 were negative. Interestingly, similar immunohistochemical staining is seen in splenic epidermoid cysts. Similar to our cases, these entities stain with p63 as well as CEA, CK7 (luminal 1–2 layers only), and HBME-1; they are negative for calretinin and WT-1. Immunohistochemical overlap with splenic epidermoid cysts suggests a shared pathogenesis and immunoreactivity for HBME-1 and p63 detracts from the hypothesis that hepatic epidermoid cysts derive from underlying hepatobiliary elements.

Adenocarcinoma of the esophagus is the most common tumor in the distal esophagus. Distant metastasis to skeletal muscle is extremely rare. Here we report a case of esophageal adenocarcinoma metastasizing to the thigh skeletal muscle and presenting as a mass. The patient is a 60-year-old man with no significant past medical history who was experiencing dysphagia with 30-pound weight loss during 3 months. Endoscopy showed a mass at the gastroesophageal junction. A biopsy demonstrated crowded glands with pleomorphism and luminal necrosis, infiltrating into the lamina propria mixed with scattered single cells. The epithelial cells are hyperchromatic with angulated nuclei, vesicular chromatin, and a high nuclear to cytoplasm ratio. A final pathologic diagnosis of at least intramucosal adenocarcinoma was made (Figure 19, A and B). PET images showed a nonspecific hypermetabolic nodule between muscles of the right distal lateral thigh. An ultrasound-guided fine-needle aspiration of the nodule was performed. Cytology smears showed a hypercellular specimen composed of cohesive, crowded groups, mixed with single malignant cells demonstrating nuclear hyperchromasia and pleomorphism, occasional prominent nucleoli, and fine, vacuolated cytoplasm (Figure 19, C). Immunohisto-chemical staining for AE1/AE3 is diffusely strong, supporting the diagnosis of metastatic adenocarcinoma from the patient's known esophageal primary (Figure 19, D). PD-L1 immunostaining was negative. Molecular studies revealed no reportable alteration with companion diagnostic including microsatellite status, FGFR3 amplification, TP53 R273C, and TP53 R282W. A literature search shows our study is the first case report of an esophageal adenocarcinoma with distant metastasis to the thigh.

Fibroelastosis is characterized by proliferation of fibroelastic tissue. Although elastosis is commonly seen in sun-exposed areas such as the skin, fibroelastosis of visceral organs is rarely reported. Here we present an unusual case of fibroelastosis of the gallbladder with masslike features. A 62-year-old man with a past medical history of intermittent abdominal pain underwent laparoscopic cholecystectomy for cholelithiasis and recurrent cholecystitis at time of concurrent sleeve gastrectomy. Grossly the gallbladder lumen was filled with green sludge and 4 green-yellow choleliths. There was a 1.4 × 1.0-cm area of firm white-gray mural thickening (up to 0.6 cm in thickness) of the fundus, with associated serosal puckering. Histologically the gallbladder was characterized by chronic cholecystitis. The area of mural thickening demonstrated nodular aggregates of homogenous amorphous eosinophilic refractile nonpolarizable material in the submucosa and surrounding the blood vessels (Figure 20, A and B). Within the eosinophilic material, thick and haphazardly oriented fibers were identified. Congo red staining was negative for amyloid (Figure 20, C). Verhoeff–van Gieson stain highlighted the elastin fibers within the nodular areas (Figure 20, D). There was no dysplasia or malignancy. Fibroelastosis of the gallbladder is an underrecognized entity, with only rare reported cases. It has been postulated to be the result of bile leakage into the interstitium with local tissue response to cytokines. As seen in this case, fibroelastosis of the gallbladder bears close resemblance to amyloidosis and mass-forming lesions; the diagnosis can be aided by histochemical studies and pathologists should be aware of this interesting diagnosis to avoid misinterpretation.

Context: The histologic diagnosis of autoimmune gastritis (AIG) depends on separate antral and body biopsy specimens. However, in actual practice, pathologists often receive few biopsy samples from undesignated locations. In addition, determining site of origin is further complicated by the characteristic antralization of oxyntic mucosa or intestinal metaplasia seen in AIG. Given the distinct distribution of gastrin-producing neuroendocrine cells (G cells) in the stomach, we hypothesize that dual-color, double immunohistochemical (IHC) staining of gastrin and synaptophysin is a simple, quick, and reliable method to evaluate biopsy specimen for AIG in a single slide.

Design: We included 30 cases of AIG and 80 cases of normal control, Helicobacter-associated gastritis (HPG), reactive gastritis (RG), and chronic gastritis without defined cause (CG) collected between 2010 and 2018. The specimens were subjected to sequential IHC staining of gastrin and synaptophysin.

Results: Thirty cases showed oxyntic antralization mucosa with marked chronic inflammation/intestinal metaplasia and some separate fragments of unremarkable antral mucosa in random gastric biopsy. Double IHC staining demonstrated enterochromaffin-like cell (ELC) hyperplasia (highlighted by synaptophysin with brown chromogen) and sparing gastrin staining (negative for red chromogen) in the same fragment of tissue. This IHC pattern was not present in all other non-AIG cases, including normal, HPG, RG, and CG.

Conclusions: Our results demonstrated that this double IHC stain is sensitive and specific for AIG. Compared with traditional single, separate IHC staining, this dual-color, double IHC staining is much easier to interpret. This technique will be especially useful for specific cases where minimal tissue is available.

Intra-abdominal desmoid tumors are slow-growing, locally aggressive spindle cell neoplasms. They exhibit a slight female predominance and can be either sporadic or associated with familial adenosis polyposis (FAP). FAP is caused by mutations in the APC gene, a tumor suppressor gene. Patients with FAP have an increased risk of developing colorectal carcinoma, gastric and small bowel adenomatous polyps, bone osteomas, intra-abdominal desmoid tumors, and other neoplasms. The lifetime risk of colorectal cancer is essentially 100%, usually in the third decade of life. A 24-year-old woman presented to the trauma bay in extremis and was emergently taken to the operating room. Exploratory laparotomy revealed a greater than 20-cm abdominal tumor adherent to multiple organs and perforating the stomach. She underwent tumor resection, subtotal gastrectomy, splenectomy, distal pancreatectomy, adrenalectomy, and partial transverse colectomy. Gross examination of the en bloc resection revealed a large, firm, white mass invading and adherent to the colon, pancreas (Figure 21, A), stomach, and spleen. The stomach was completely carpeted with small polyps (Figure 21, B), and additional polyps were noted in the transverse colon. Microscopic examination of the tumor revealed a bland spindle cell neoplasm with myxoid stroma (Figure 21, C). The tumor demonstrated nuclear reactivity with β-catenin, consistent with intra-abdominal desmoid tumor. The stomach (Figure 21, D) and colon polyps represented tubular adenomas. Genetic testing revealed a pathologic mutation (c.5803delC) in the APC gene, consistent with classic FAP. This case highlights the importance of awareness of the association between desmoid tumors and FAP to ensure appropriate genetic counseling and clinical follow-up is obtained.

Tumor necrosis factor inhibitors are used for a range of nonmalignant diseases and are associated with a variety of opportunistic infections. We present a diagnostically challenging case of disseminated histoplasmosis presenting with liver failure as a complication of immuno-suppression from methotrexate therapy for psoriasis. A 47-year-old man was admitted with fever, joint pain, right upper quadrant discomfort, and jaundice, and was diagnosed with acute hepatitis. Eight months earlier, he was diagnosed with psoriatic arthritis and was started on adalimumab and methotrexate. Viral and fungal etiologies were ruled out on blood samples, and he was discharged after psoriatic arthritis medications were discontinued. Two days later he returned with nonbilious emesis and high bilirubin and liver enzymes. Broad spectrum antibiotics and antifungal agents were initiated. He subsequently developed respiratory failure, fever, tachycardia, and altered mental status, requiring intubation. Liver biopsy revealed portal chronic inflammation, Kupffer cell hyperplasia, and poorly formed granulomas. GMS fungal stains were negative. Within 2 days he became acidotic, anuric, and hypotensive. He expired 18 days after the initial presentation. Autopsy revealed bilateral pneumonia, severe congestion, and hepatomegaly with extensive necrosis. GMS stain demonstrated yeast forms consistent with histoplasma. Results from urinary histoplasma antigen test were reported positive (after his death). This case illustrates the risk of missing opportunistic fungal infections in patients receiving methotrexate therapy for nonmalignant diseases. The diagnosis of histoplasmosis was only made at postmortem examination and highlights the importance of keeping histoplasma in the differential diagnosis in similar clinical scenarios (Figure 22).

Context: Helicobacter pylori gastritis has been reported to be associated with obesity. We aimed to study the prevalence of H pylori gastritis in sleeve gastrectomy specimens.

Design: We retrospectively reviewed sleeve gastrectomy specimens from our institution during the past 5 years. The rate of diagnosis of H pylori gastritis was assessed.

Results: A total of 284 sleeve gastrectomy specimens were evaluated during the past 5 years. Ancillary studies were performed in 61 cases (21.5%). Nineteen cases (6.7%) were diagnosed with H pylori gastritis, all of which were first-time diagnoses. Of these, H pylori gastritis was diagnosed based on H&E sections in 7 cases; an immunostain or special stain was performed in 12 cases (see Table). Histologic features that prompted ancillary studies include active chronic gastritis (9 cases), inactive chronic gastritis (7 cases), and prominent lymphoid follicles (4 cases). Treatment was initiated promptly in 14 cases. Additionally, hematopathology consultations were obtained for 3 cases because of the presence of prominent lymphoid aggregates in the absence of H pylori. Further workup revealed incidental monoclonal B-cell lymphoproliferative process in 2 of the cases, confirmed by B-cell receptor gene rearrangement by polymerase chain reaction.

Conclusions: Incidental findings on sleeve gastrectomy specimens can have important clinical implications. Proper treatment for H pylori gastritis may prevent complications such as peptic ulcer disease, gastric cancer, and gastric lymphoma. Histologic evaluation has a high sensitivity and specificity for detecting H pylori when combined with special or immunostains. Atypical patterns of inflammation should prompt the pathologist to pursue further workup such that proper treatment may be initiated.

Context: Biopsy diagnosis of gastric signet ring cell carcinoma can be challenging because of poorly cohesive cancer cells dispersing in benign tissue. This study aimed to identify clinicopathologic features to help avoid misdiagnosis.

Design: Twenty-five signet ring cell carcinomas diagnosed on gastric biopsy were identified in our database (2004–2018). The slides were reviewed for pathologic features. The clinical presentations and endoscopic features were evaluated.

Results: Clinical presentations were pain (33%), nausea/vomiting (17%), dysphagia (13%), stenosis/obstruction (9%), metastasis including ascites or Krukenberg tumor (8%), bleeding (8%), incidental finding (4%), diarrhea (4%), and anorexia (4%). Endoscopic features included mass (35%), thickened gastric wall (27%), ulceration/hemorrhage (23%), stenosis (8%), and friable mucosa (7%). The pathologic findings in nonneoplastic tissue were as follows: chronic inflammation (92%), lamina propria expansion (84%), glandular withering (76%), acute inflammation (48%), intestinal metaplasia (40%), and foveolar hyper-plasia (36%). Three patients (10%) underwent more than 1 biopsy before a definitive diagnosis. Clinical presentations were small bowel obstruction, ascites, and dysphagia. Endoscopy in all 3 patients revealed thickened gastric wall without mass. The initial biopsy from the 3 patients showed chronic inflammation, glandular withering, intestinal metaplasia, lamina propria expansion, and foveolar hyperplasia; only 1 case had a few atypical cells.

Conclusions: Firm diagnoses were not reached on initial biopsy in 12% of patients with signet ring cell carcinoma. Main endoscopic findings were mass, thickened gastric wall, and ulceration. In cases with few tumor cells, pathologic features including chronic inflammation, lamina propria expansion, and glandular withering may provide clues to malignancies.

Context: We investigated the prevalence of Helicobacter pylori infections in sleeve gastrectomy (SG) patients, as studies remain controversial in determining the necessity for histopathologic evaluation of all SG specimens. We also present a case of a 53-year-old woman with morbid obesity and complaints of regurgitation/heartburn whose SG specimen showed a 1.3-cm polyp, microscopically consistent with ectopic pancreatic polyp (see Figure 23, arrow), with an additional 36 juvenile/retention polyps. H pylori immune stain was negative in her acute inflamed gastric tissue.

Design: A retrospective analysis was performed on SG cases signed out by 4 pathologists from 2017 to 2018. We calculated the percentage of H pylori positive cases out of the total number of SG cases.

Results: A total of 223 cases were reviewed, of which 7.62% (n = 17) were confirmed to be positive for H pylori infection based on immunohistochemical staining (detecting rate from 0% to 15% among 4 pathologists).

Conclusions: Our data show a total of 7.62% positive cases for H pylori infection with a wide range of detecting rate among pathologists, indicating that SG specimens should be submitted for histopathologic evaluation, similar to other investigations. The acute inflammation most likely resulted from irritation of the large ectopic pancreatic polyp rather than H pylori infection in this case report.

Metastatic colorectal cancer to the orbit and paranasal sinuses is rare. There have only been 5 previously published reports describing the involvement of sinonasal tract secondary to metastatic colorectal cancer. We report a case of a 54-year-old woman who was diagnosed with rectal adenocarcinoma in 2017, status post chemoradiation therapy (2017) and surgical resection (2018), with pathologic staging of ypT3ypN2b with acute onset of facial pain and numbness. Patient initially developed numbness of right face (approximately 2 months postsurgery), at which time computed tomography (CT) scan of head was unremarkable. She was reportedly symptom free until approximately 8 months postsurgery when she had pain of right face and jaw. CT scan of sinuses showed soft tissue infiltration (2.25 cm in greatest dimension; Figure 24, A, with arrow) surrounding right pterygoid bone with extension into pterygopalatine fossa, sphenopalatine foramen, and Vidian canal with surrounding demineralization of the sphenoid bone. She underwent right endoscopic sphenoidotomy with biopsy of the mass that was microscopically consistent with moderately differentiated adenocarcinoma with mucin production, with immunohistochemistry consistent with colorectal origin. She underwent radiation therapy to the right skull base without any further reported complications or any other metastatic lesions thus far. The 5 previously published reports present cases with varying signs and symptoms including isolated vision loss, exophthalmos, and as incidental findings with metastatic colon cancer to other organs. To our knowledge this is the first case presentation with symptoms of unilateral facial numbness and pain secondary to metastatic colon cancer to the sphenoid wing.

Muir-Torre syndrome (MTS), a variant of autosomal dominant Lynch syndrome, is characterized by at least 1 visceral malignancy and 1 cutaneous neoplasm of sebaceous differentiation, with or without keratoacanthomas. The gene mutated in MTS is 90% MSH-2 and 10% MLH-1. A 48-year-old African American woman was diagnosed with sebaceous adenoma of the scalp. The patient provided a family history of scalp lesions and colon cancer at age 45 in her mother and colon cancer in 4 maternal relatives before the age of 50. This patient's sebaceous neoplasm showed loss of expression of MSH-2 and MSH-6 by immunohistochemistry, raising suspicion for MTS. Two years later, the patient underwent colonoscopy for hematochezia, constipation, and weight loss, which discovered a circumferential fungating sigmoid colon mass. Biopsies were consistent with adenocarcinoma with patchy loss of MSH-2 and MSH-6 by immunohistochemistry. Given the patient's history of sebaceous neoplasm and colon cancer with a pathogenic mutation in MSH-2 c.2047G>A (p.Gly683Arg), the diagnosis of MTS was confirmed. Sigmoidectomy revealed invasive colorectal adenocarcinoma with mucinous features. Additionally, prophylactic total hysterectomy and bilateral salpingo-oophorectomy was performed, and endometrial endometrioid adenocarcinoma FIGO grade 2 was diagnosed. Current guidelines recommend patients diagnosed with colon cancer or endometrial cancer undergo mismatch repair testing to screen for Lynch syndrome. For MTS, sebaceous neoplasms typically precede visceral malignancies. Sebaceous neoplasms, especially in patients less than 60 years old, should be tested for microsatellite instability, and if testing is positive the patient should undergo screening for visceral malignancies.

Withdrawn.

Pancreatic adenosquamous carcinoma is rare and accounts for only 1%–2% of exocrine pancreatic malignancies. This variant shows squamous and glandular differentiation, and the former should represent at least 30% of the entire tumor for diagnosis. This tumor is associated with poorer prognosis than the conventional pure ductal adenocarcinomas. We present a case of this rare entity in a 53-year-old woman who presented with severe abdominal pain. Computed tomography scan of the abdomen showed a hypodense lesion in the neck/proximal body of the pancreas. Fine-needle aspiration cytology of the lesion showed few atypical cells suspicious for carcinoma. The patient underwent a distal pancreatectomy. Grossly, a poorly circumscribed yellow-white firm mass (5.0 × 5.0 × 4.2 cm) was identified within the pancreas. Microscopically, the tumor showed a poorly differentiated carcinoma composed of areas showing squamous differentiation admixed with conventional ductal adenocarcinoma (Figure 25, A). Immunostains and special stains confirmed the squamous component by positivity of p63 and CK5/6 (Figure 25, B) and the adenocarcinoma component by positivity of CDX2 (Figure 25, C) and mucicarmine (Figure 25, D). The tumor was negative for chromogranin and synaptophysin. Multiple regional lymph nodes were negative for tumor (0/16). The patient received adjuvant chemotherapy and was alive at 3-month follow-up. In summary, we present this rare case of pancreatic adenosquamous carcinoma. It is important to recognize and distinguish it from conventional pancreatic adenocarcinoma, as the metastatic lesions may show only squamous or glandular component, and treatment may include additional modalities directed at the squamous component.

There was a 4-fold increase in prevalence of syphilis between 2002 and 2015. In 2017 alone, there were 30 644 cases of primary and secondary syphilis reported in the United States. Here, we report a case of syphilitic proctitis in a 34-year-old man with an unusual presentation. He presented with left lower quadrant pain that was unrelieved by lactulose. A palpable rectal mass was found during digital rectal examination. A CT scan of the abdomen and pelvis revealed multiple enlarged pelvic lymph nodes and thickening of the rectal wall. Colonoscopic examination revealed a nonobstructing, ulcerated, 1.5-cm submucosal mass in the rectum. Clinically, the differential diagnosis included a mass-forming rectal lymphoma or adenocarcinoma. Microscopically, colonic mucosa showed marked expansion of lamina propria with a mixed inflammatory infiltrate of lymphocytes, histocytes, and occasional plasma cells. Frequent nonnecrotizing granulomas were identified in the lamina propria and submucosa. There was focal mild active colitis with cryptitis and rare crypt abscesses. Crypt architectural distortion was not present. PAS, GMS, and AFB stains did not highlight any microorganisms. A molecular and immunohistochemical workup was negative for lymphoma. Treponema pallidum immunohistochemistry demonstrated abundant spirochetes consistent with syphilitic proctitis. Syphilis continues to present a clinical and pathologic diagnostic challenge. The pathologist is often the first to suspect the diagnosis of syphilis proctitis on the basis of histomorphology. The presence of numerous granulomas and the relative paucity of plasma cells in the inflammatory infiltrate were unusual findings in this case.

Context: Pancreatic neuroendocrine microadenoma (<0.5 cm in diameter) is a precursor lesion for pancreatic neuroendocrine tumor (PNET) in MEN syndromic patients or sporadic cases. It has been rarely reported in literature as an incidental finding in pancreatectomy specimens resected for other conditions such as cystic pancreatic disease. We herein report 10 cases of incidentally identified microadenomas to characterize the clinicopathologic features.

Design: A retrospective search for “pancreas” and “microadenoma” was performed in our institution's pathology database for years 2003–2019. Relevant clinical information, including survival data, was collected from electronic medical records.

Results: Ten cases were identified, consisting of 7 women and 3 men, with an average age of 68 years (range, 36–75 years). Among them, 5 patients (50%) were diagnosed with diabetes mellitus, 3 (30%) with morbid obesity, and 1 (10%) with MEN syndrome. Microadenoma(s) occurred more frequently in the tail of pancreas (n = 6; 60%). The majority were single focus of tumor (n = 6; 60%). The associated pancreatic pathologic findings included intraductal papillary mucinous neoplasm (n = 3), PNET (n = 2, 1 MEN patient), solid pseudopapillary neoplasm (n = 1), mucinous cystic neoplasm (n = 1), pancreatic ductal adenocarcinoma status post neoadjuvant therapy (n = 1), chronic pancreatitis (n = 1), and gunshot wound debridement (n = 1). Immunostains revealed negative insulin, positive glucagon, and low Ki-67 labeling index (<1%) in all tumors. All patients survived after an average of 28 months on follow-up.

Conclusions: This case series, the largest reported so far, establishes pancreatic neuroendocrine microadenoma, a biologically benign tumor, as an incidental finding associated with a variety of benign and malignant conditions.

A 76-year-old woman presented to the emergency room with chief complaint of abdominal pain. Laboratory workup confirmed the diagnosis of gallstone pancreatitis. Computerized tomography scan showed masslike intraluminal filling defect within the gallbladder and patient subsequently underwent cholecystectomy procedure. On gross examination, the gallbladder showed an exophytic mass near the fundus that measured 2.5 cm. Microscopic sections revealed a tubulopapillary lesion with multiple lineages of neoplastic epithelium including biliary (Figure 26, A) (40%) with eosinophilic cytoplasm, vesicular nuclei, prominent nucleoli, and positive staining with MUC1 (Figure 26, B); gastric foveolar (40%) with apical mucin and basally located nuclei; intestinal (Figure 26, C) (20%) with goblet cells; and positive staining with MUC2 (Figure 26, D) and CDX2. Focal high-grade dysplasia was also identified without invasive carcinoma. Intracholecystic papillary-tubular neoplasm (ICPN) is a rare lesion with a reported incidence of <0.5% in cholecystectomies. ICPN has a predilection for females (female to male ratio of 2:1), and the mean age of presentation is 64 years. This lesion was previously classified as adenomas (both intestinal and pyloric types), papillary carcinoma in situ, and papillomatosis. ICPN is a unique neoplasm that can show variable cellular lineages, a spectrum of dysplasia, and a combination of papillary and tubular growth patterns. It is important to recognize this tumor because ICPN is a relatively indolent neoplasm and should be distinguished from a more aggressive pancreatobiliary-type gallbladder carcinoma, which has a less favorable prognosis.

Hepatitis E virus (HEV) is now increasingly recognized as an emerging infection in developed countries. The histopathologic features of acute HEV infection are variable but have overlapping features with other acute viral hepatitides, including lobular disarray, lobular and portal inflammation, prominent Kupffer cells, and hepatocyte necrosis and regeneration. We report a case of HEV infection with unique histopathologic features. A 70-year-old man with a history of hypertension and skin cancer presented from an outside hospital with a 2-week history of progressive malaise, anorexia, dark urine, and jaundice after eating a buffalo burger while on vacation in South Dakota. His liver enzymes were elevated (AST 4796 U/L, ALT 6358 U/L, ALK-P 300 U/L, total bilirubin 8.6 mg/dL). Hepatitis A, B, and C and EBV and CMV serologies were nonreactive. A liver biopsy showed a dense sinusoidal lymphohistiocytic infiltrate (CD68⁺, CD163⁺) with focal hepatocyte necrosis (Figure 27). The lymphocytes were composed of mainly T cells with a mixture of CD4 and CD8 cells. Occasional B cells were seen but no large B cells were identified. Plasma cells, eosinophils, and neutrophils were present but not prominent. AFB, GMS, CMV, adenovirus, treponemal stains, and EBER in situ hybridization did not highlight any microorganisms. The overall histopathologic features led to the broad etiologic consideration of infectious agents, hematologic process, and medication-associated injury. Hepatitis E serology testing later revealed increased immunoglobulin M (IgM) and IgG antibodies. This case highlights the importance of considering HEV infection in the differential diagnosis of acute liver injury pattern with prominent lymphohistiocytosis.

Ixabepilone is a chemotherapeutic agent approved by the food and drug administration in 2007 for use in metastatic and locally advanced breast cancer. Its main indication is when anthracycline and taxane are no longer effective because of progressive disease or resistance, or when they are contraindicated because of toxicity. Ixabepilone is a semisynthetic analogue of the epothilone B class that stabilizes microtubules, resulting in mitotic arrest and apoptosis. To the best of our knowledge, this is the first report describing the histologic effect of ixabepilone on the gastrointestinal tract mucosa. An 80-year-old woman with a history of metastatic ductal breast carcinoma presented 6 months after the initiation of ixabepilone with worsening dysphagia and regurgitation. An upper endoscopy was performed, which showed mild mucosal erythema involving the gastroesophageal junction and the stomach. Histologically, numerous apoptotic bodies and ring mitoses were identified in the gastroesophageal junction and stomach epithelium, highly suggestive of mitotic arrest and medication-induced injury. The histologic changes with ixabepilone are reminiscent of taxane and colchicine effects on the gastrointestinal tract mucosa and have been associated with colchicine, but not taxane, toxicity. Although these 3 medications belong to different drug classes and have different binding sites, they are all microtubule-stabilizing agents, blocking mitosis and resulting in cell death. Whether these histologic findings represent clinical toxicity from ixabepilone is not entirely clear; however, the symptoms along with the endoscopic and histologic findings suggest mucosal injury. Awareness of this possible medication-induced injury is essential to avoid missing potential toxicity.

Leiomyomas are benign smooth muscle neoplasms commonly originating in the uterus. Primary hepatic leiomyoma is very rare. It is an isolated pathology occurring in the liver without any coexisting leiomyomas. It has been reported to occur in immunocompromised individuals or those with Epstein-Barr virus, but may also occur in healthy individuals. However, sometimes leiomyomas occur in unusual locations, making the diagnosis clinically and radiologically very challenging. We report a case of a 54-year-old healthy woman with abdominal pain and discomfort for a year. On CT scan there was a 2-cm lesion in the liver, and MRI done a year later confirmed the findings with an increase in the size of the lesion. Biopsy of the lesion demonstrated low-grade spindle cell proliferation with low-grade cytologic features. No atypia, mitotic activity, or necrosis was identified. Immunohistochemical stains showed positivity for actin, calponin, and caldesmon (focally) and were negative for desmin, keratin, p63, estrogen receptor, progesterone receptor, WT-l, CD117, Dog1, HMB45, and S-100. Vascular markers CD31 and CD34 were only expressed in vessels and were negative in lesional cells. The overall morphologic features were not of GIST, solitary fibrous tumor, neurofibroma, PEComa, vascular, adipocytic, or epithelial neoplasms. The lesion was most compatible with a low-grade, myxoid, spindle cell lesion with muscle differentiation consistent with leiomyoma. Hepatic leiomyoma is assumed to arise from smooth muscle cells that line the biliary tree or blood vessels of the liver parenchyma. Our patient underwent a partial hepatectomy along with microwave ablation of a liver tumor (Figure 28).

Primary hepatic adenosquamous carcinoma is a rare variant of hepatic carcinoma with aggressive clinical behavior. To our knowledge, 75 cases have been reported in the English literature. Herein we report a case of 63-year-old white woman who presented with dull abdominal pain. CT scan revealed a “liver abscess.” She was treated with antibiotics for 5 weeks without significant clinical improvement. Both MRI and repeated CT scan were consistent with an abscess that had increased in size. Laboratory results showed leukocyte count of 7100 / μL and alkaline phosphatase of 149 U/L, whereas tumor markers (CA 19-9 and AFP) were within normal range. The patient underwent partial hepatectomy. An intraoperative examination revealed a 7.5-cm ill-defined mass (Figure 29, A). Frozen section analysis was consistent with carcinoma. Final pathologic diagnosis was adenosquamous carcinoma of the liver. Microscopically, the tumor showed abundant central necrosis with a rim of squamous cell carcinoma constituting 95% of the tumor (Figure 29, B) intermixed with adenocarcinoma and focal intrahepatic high-grade biliary intraepithelial neoplasia (Figure 29, C). A transitional zone between the 2 histologic patterns was identified (Figure 29, D). The squamous component was strongly positive for p40 and the glandular component showed strong positivity for CK19. Postoperative course was uneventful. The patient underwent 5 cycles of 5-fluorouracil and oxaliplatin. In the following 8 months, the patient developed hepatic-colocutaneous fistula and small bowel obstruction. Because of the rarity of this cancer, no therapeutic strategies have been established. Hence it becomes important to report all individual experience–based information.

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-associated death. Liver transplant is one treatment modality for patients with HCC who are amenable to surgical resection. However, the recurrence rate of HCC after liver transplant is up to 11% at 3 years. The newly developed HCC/hepatic neoplasms in the transplanted liver could be de novo or recurrence from original liver. Knowing the origin of the new tumor in transplanted liver is important for the understanding of the pathogenesis and clinical management of hepatic neoplasms in liver transplant patients. A new hepatic neoplasm was identified in a 74-year-old man 4.7 years posttransplant. Histochemical studies (H&E, trichrome, reticulin stains) and immunohistochemistry studies (CK7, CD34, etc) were used to compare the morphology and molecular changes of the original HCC and the newly developed neoplasm in the transplant. Also, tissue blocks of explanted liver and the recent liver mass biopsies were sent to Mayo Clinic Laboratories for specimen source identification. A panel of 12 DNA markers that recognize highly variable regions of human DNA were used in a polymerase chain reaction–based assay to compare the DNA isolated from the 2 tissue resources. The morphology, histology, and immunohistochemistry studies showed that the newly developed neoplasm was different from the original HCC. Genetic results indicated that the newly identified neoplasm was derived from donor tissue, rather than being a recurrence of his prior HCC. Thus, a de novo new hepatocellular neoplasm was identified in transplanted liver.

Context: Paired box protein 8 (PAX8) is a transcription factor expressed in benign and malignant tissues of thyroid, kidney, and the Müllerian system. Expression of PAX8 is regarded as uncommon in biliary tract carcinomas but has not been well studied.

Design: Forty-two primary cholangiocarcinomas with both a clinical and pathologic diagnosis were identified from 2002 to 2017. PAX8 immunohistochemistry with a polyclonal antibody (1:1000; 10336-1-AP, Proteintech) was performed and the results were interpreted by 2 pathologists using the 4-tier system: strong diffuse (>75% of the tumor cells), strong focal (<75%), weak diffuse, and weak focal. The association of PAX8 expression with clinical outcomes including the disease-free rate and the overall survival was evaluated.

Results: Overall 14 of 42 cholangiocarcinomas (33%) showed PAX8 expression: strong diffuse staining in 3 cases (7%); strong focal staining in 7 cases (17%); and weak focal staining in 4 cases (10%). Relative to weak PAX8 expression or no staining, high levels of PAX8 expression were associated with significantly worse overall survival (P = .04; Figure 30). The median overall survival was 8.5 months for patients with strong PAX8 staining and 21.6 months for patients with weak/negative expression.

Conclusions: Variable PAX8 expression is detected in one-third of primary cholangiocarcinomas, with strong staining seen in about 5%–15%. Therefore, PAX8 staining in hepatobiliary tumors is not invariably indicative of metastatic disease. High PAX8 expression in biliary tract carcinoma is associated with worse overall survival, may indicate a more aggressive tumor phenotype, and may be a useful prognostic biomarker for cholangiocarcinoma.

Context: Barrett esophagus (BE) is a premalignant condition characterized by replacement of normal esophageal squamous mucosa with columnar epithelium. BE is traditionally monitored via endoscopy and forceps biopsies for the presence of dysplasia; however, the sensitivity of this method is limited because of sampling error. Recently, adjunctive sampling via wide-area transepithelial sampling with 3D analysis (WATS), an abrasive brushing technique that renders full thickness sampling of the epithelium with analysis aided by computer imaging systems, has been shown to increase detection of BE and dysplasia. The order of WATS to traditional targeted and random biopsies has not been shown to significantly affect the detection of dysplasia; however, the effect of WATS on the quality of post-WATS biopsies has not been reported.

Design: Cases having undergone WATS with subsequent biopsy and cases without WATS using forceps biopsy alone were provided by a participating gastroenterologist. Following internal review board approval, the slides were deidentified, randomized, and evaluated by 2 pathologists for quality, as graded by overall intactness of the surface epithelium. Cases were assigned a score from 1 to 3, with score 1 being none/minimal intact surface epithelium and 3 being near-complete intactness.

Results: The average quality score for cases having undergone WATS was 2.24 compared with cases without prior WATS having an average score of 2.54 (P = .049).

Conclusions: WATS significantly adversely impacts the quality of subsequent biopsies by disrupting the surface epithelium. Although this may not affect the interpretability of the biopsies overall, we recommend the collection of biopsies prior to brushing.

Context: Total mesorectal excision (TME) is the standard of care for patients with rectal cancer. The assessment of TME adequacy is a quality assurance measure as it predicts local recurrence risk. There are 3 grades of TME: complete (3), nearly complete (2), and incomplete (1). We sought to compare the assessment of TME grade among surgeons (Ss), pathologists (Ps), and pathologists' assistants (PAs).

Design: Prospective, blinded grading of TME specimens was performed between November 1, 2017 and February 1, 2019, by the S performing the procedure (CC, FF, LT, JS), at least one pathologist (CWM, ARH), and at least one PA (EAS, LAK). Grades were submitted to one PA who maintained the data. Weighted κ (WK) values were used so that a difference between grades 1 and 3 would be weighted as a greater disagreement than between grades 2 and 3.

Results: Thirty-one specimens were examined by the S, at least one P, and one PA. Interobserver variability for all specimens was moderate agreement (WK=0.525) between PAs, moderate agreement (WK=0.489) between Ps, slight agreement (WK = 0.199) between Ss and PAs (WK = 0.199), moderate agreement (WK = 0.545) between Ps and PAs, and fair agreement (WK = 0.369) between Ss and Ps (summarized in Table).

Conclusions: There are only a few prior studies comparing interobserver variability of grading TME specimens. Most recently, a Canadian group demonstrated interrater reliability between 0.85 and 0.92 among Ps, PAs, pathology residents, and Ss. The worst agreement occurred between Ss and Ps, similar to our study. In the future, the best approach to TME grading may be multidisciplinary consensus.

Multiple endocrine neoplasia (MEN), type I, is a hereditary condition associated with tumors of the parathyroid, pituitary, and pancreatic islet cells. Pancreatic neuroendocrine tumor is a common presentation. A few cases of neuroendocrine tumors with ossification have been reported in lung and stomach; however, to our knowledge, there are no known cases of pancreatic neuroendocrine tumors with ossification reported in literature so far. We report a case of a 34-year-old woman with a medical history of multiple endocrine neoplasia type I who presented with a 1.8-cm pancreatic mass that was discovered during screening MRI. Distal pancreatectomy was performed. The specimen was thoroughly and meticulously sectioned. Grossly, a well-circumscribed mass (size 1.3 cm) with tan-yellow homogenous cut surface was identified in pancreatic tail and body. Histologically, the tumor showed features of well-differentiated neuroendocrine tumor, grade 2, supported by cytokeratin AE1/AE3, synaptophysin, chromogranin, and Ki-67 immunostains (Ki-67 proliferative index, 4%). A fragment of mineralized bony tissue (size 0.25 cm) was identified embedded in the tumor, consistent with tumor ossification. In addition, tumor cells diffusely expressed glucagon but were negative for β-catenin, somatostatin, and gastrin immunostains. Figure 31, A, H&E; Figure 31, B, ossification within the tumor; Figure 31, C, Ki-67 immunostain; Figure 31, D, glucagon positivity. Ossification in panNET is a rare finding. The significance is not well known, and it probably denotes an acquisition of osteoblastic phenotype.

A 54-year-old man underwent a laparoscopic sleeve gastrectomy for morbid obesity. Preoperative physical examination, review of systems, and peripheral blood work did not hint at any evidence of a hematolymphoid malignancy. On gross examination of his gastrectomy specimen, the serosa had a focal area of hemorrhage but there were no masses, ulcers, or other abnormalities (Figure 32, A). Representative sections were taken of the hemorrhagic region, along with several routine random areas of normal mucosa. Other than the focal area of hemorrhage, there was little evidence to indicate an underlying pathologic process or malignancy, as small hemorrhagic areas are common findings in surgical specimens. On histologic examination, sections taken from the hemorrhagic areas showed a diffuse atypical lymphoid infiltrate extending into the lamina propria and submucosa, with nodular pattern and focal germinal centers (Figure 32, B). In addition, there was an associated architectural distortion with gastric glandular atrophy. The lymphoid cells were positive for CD43, BCL-2, and CD20 (Figure 32, C), with κ restriction (Figure 32, D). They were negative for CD5, CD23, CD138, BCL-6, and cyclin D1. The proliferation index by Ki-67 was low at 1%–5%. Helicobacter pylori stains on 3 of the blocks were negative. With these histologic findings, the patient was diagnosed with an incidental mucosal-associated lymphoid tissue (MALT) lymphoma. In conclusion, our case emphasizes the importance of examining surgical specimens both macroscopically and microscopically for the identification of incidental malignant findings in asymptomatic patients. In addition, it is imperative to perform representative sampling on these specimens.

Context: Less than 3% of pancreatic ductal adenocarcinoma (PDA) patients are ≤45 years old (very-early-onset pancreatic cancer [VEOPC]) and rarely carry germline mutations. Limited data exist on the underlying molecular pathways and its potential impact in management and survival. This study aims to characterize clinicopathologic features and molecular alterations in VEOPC.

Design: Cases were identified through retrospective pathology database search. Patients ≤45 years old (VEOPC) with available clinical data, H&E-stained slides, and paraffin blocks were included. A matched population of PDA in older patients (>45 years) was selected. Molecular profiles were available in a subset of cases; additional molecular characterization of the remaining cases is being completed.

Results: Summarized findings are shown in the Table. There were no definitive associations between known risk factors, histopathologic features, and VEOPC, except poor differentiation of the tumors. VEOPC showed a greater diversity of molecular alterations in all 4 cases tested in comparison with the known TP53 and KRAS mutations in the matched control. VEOPC was associated with a reduced number of living patients and had a worse overall survival.

Conclusions: Known risk factors and histopathologic parameters were not different among the cases studied and matched controls with the exception of histologic tumor grade. VEOPC cases revealed greater diversity of molecular alterations and shorter survival. The study suggests that perhaps the greater complexity of the underlying molecular alterations in VEOPC may explain worse tumor differentiation and may have an impact on overall survival.

Context: Helicobacter pylori (HP) is a class I carcinogen responsible for gastrointestinal ulcers and malignancies. Although many American laboratories performed upfront staining for detection, we have ceased this practice secondary to CMS reimbursement changes and practice recommendations put forth by the Rodger C. Haggitt Gastrointestinal Pathology Society. We studied the effect of this change on our H pylori detection rate.

Design: We retrospectively analyzed the rate of HP detection before and after the practice change (2011–2013 and 2016–2018, respectively). The first 500 patients from each time frame were analyzed to assure adequate power. Data were collected on detection rate, symptoms, indication for biopsy, endoscopic findings, prior infection, and use of proton pump inhibitors. Histology was reviewed for all positive cases.

Results: Patients with positive testing in the postimplementation group were older (mean 64.9 versus 47.9 years). There were no significant differences in M:F ratio or race (p = 1, P = .6). The HP detection rate dropped by 53.8% during the study period (10.4% to 4.8%; P = .003). Available histology demonstrated postimplementation cases to more frequently have moderate to marked neutrophils and atrophy, intestinal metaplasia, and plasma cell–predominant inflammation. The pretherapeutic group had more cases with lymphocyte-predominant inflammation (31.9% versus 11%).

Conclusions: Reimbursement and practice changes negatively affected our practice. The HP detection rate decreased by more than half postimplementation, suggesting an increased risk of undetected infection. Postimplementation cases demonstrate more typical histology patterns, including more plasmacytic and neutrophilic inflammation and intestinal metaplasia, whereas other patterns (lymphocyte predominant) are likely underrecognized.

Immunotherapy targeting programmed cell death-1 has expanded rapidly for managing advanced malignancies. Of note, immunotherapy is associated with immunity modulation that potentially can affect various organs/functions, especially the gastrointestinal tract, with manifestations ranging from self-limited diarrhea to colitis. Steroids are the first-line remedy for immunotherapy-related adverse events. However, steroids are associated with reactivation of opportunistic pathogens and complicated clinical courses. A 65-year-old man was managed with nivolumab for stage 4 small cell carcinoma of the lung and developed immunotherapy-induced diarrhea. Subsequently steroids were administrated with partial symptom resolution. However, 3 weeks later the patient returned with worsening diarrhea and abdominal cramping refractory to medical management. Imaging, endoscopy, and pathology investigations were conducted. Radiology and colonic endoscopy findings were unremarkable; random colon biopsies were performed. The differential diagnosis was vast given the worsening gastrointestinal symptoms and preceding immunotherapy-related diarrhea. Though difficult, it is crucial to distinguish the etiologies as the management differs. Microscopic examination revealed architecturally intact colonic mucosa with peculiar apical basophilic epithelial fringe, the so-called false brush border, highlighted by Warthin-Starry stain, with minimal inflammation identified. These findings were highly consistent with enterocolonic spirochetosis. Metronidazole was administered, followed by quick resolution of the patient's symptoms. This case highlights the novel presentation of symptomatic spirochetosis, manifested by spirochete-colonizing gastrointestinal epithelium, and the importance of a timely diagnosis in minimizing patient morbidity/mortality. Steroid administration–associated spirochetosis and immunotherapy-related gastrointestinal adverse events share similar clinical pictures, yet the involved mechanisms are different. Therefore, the implicated diagnostic workup, therapeutic strategies, and corresponding clinical courses are distinct.

Foregut cysts are benign congenital malformations that originate from the primitive foregut. They are commonly seen in the mediastinum and can occur anywhere along the gastrointestinal tract. However, pancreatic foregut cysts are very rare, with only a few cases reported in the literature. We report a case of a 44-year-old woman who presented with intermittent abdominal pain for 2 weeks. Abdominal CT scans revealed a fluid attenuation focus in the pancreas measuring 7.1 cm and demonstrating septations with calcifications (Figure 33, A). The mass was resected along with a splenectomy (Figure 33, B). Histopathologic examination of the mass showed a multicystic lesion with surrounding atrophic pancreatic tissue and calcifications (Figure 33, C). The cysts had a ciliated epithelial lining that was cuboidal to columnar with areas showing stratification, and the cyst walls consisted of spindled smooth muscle (Figure 33, D). These findings were consistent with a foregut cyst. Pancreatic foregut cysts have nonspecific clinical presentations, mimicking true cysts of the pancreas, pancreatic pseudocysts, or even pancreatic cystic neoplasms. Distinguishing them from other cystic lesions can be difficult because they have very similar clinical and radiologic features. Fine-needle aspiration demonstrating ciliated epithelium is said to be sufficient for preoperative diagnosis. However, definitive diagnosis is usually made based on histopathologic examination after resection. This case highlights the importance of considering ciliated foregut cysts in the differential diagnosis of cystic lesions occurring in the pancreas.

Follicular pancreatitis is a rare entity of the pancreas, which is characterized histologically by prominent lymphoid follicles with reactive germinal centers. Herein we report a case of follicular pancreatitis presenting in a 69-year-old woman who had been followed since 2016 for a slowly enlarging cystic mass of the pancreatic tail without communication to the main pancreatic duct. CT scan showed a 29 × 21-mm single-compartment lesion without septa and a thin outer wall. Endoscopic ultrasound was performed in January 2019. At that time CEA and amylase levels of the cyst were drawn, which were 517 and 5, respectively. Because of this, a diagnosis of mucinous cystic neoplasm was made, and the patient had a distal pancreatectomy performed. Sectioning demonstrated a 3.0-cm unilocular cyst filled with clear fluid, lined by a smooth surface (Figure 34, A). The cyst did not communicate with the main pancreatic duct. The entire cyst was submitted for microscopic examination. Histologically the cyst was lined by simple cuboidal epithelium that was a biliary type without atypia (Figure 34, B). The background pancreas was characterized by chronic inflammatory infiltrate and marked follicular-type lymphoid hyperplasia with prominent germinal centers (Figure 34, B). Bcl-2 stain was negative in the germinal centers (Figure 34, C). CD21 showed intact follicular dendritic network within the germinal centers (inset, Figure 34, C). Immunoglobulin G4 showed very low count (Figure 34, D). No storiform fibrosis, obliterative phlebitis, or granulocytic/neutrophilic epithelial lesions were noted. We report this case to increase the awareness of follicular pancreatitis as a distinct form that mimics cystic pancreatic neoplasms.

Context: Biliary tract carcinomas, including gallbladder carcinoma and cholangiocarcinoma, are aggressive malignancies needing more effective treatment. Receptor tyrosine kinase–like orphan receptor 1 (ROR1) is highly expressed in various malignancies with minimal expression in normal adult tissues, making it an attractive immuno-therapy option. In this study, we analyzed expression of ROR1 by immunohistochemistry in this subset of tumors and compared it with various clinicopathologic features.

Design: A total of 110 cases of biliary tract carcinomas resected between 2000 and 2014 were identified at our institution. Tissue microarrays were constructed using 1-mm duplicate cores, immuno-stained for ROR1 (dilution 1:7; cat# 564464,5BD Biosciences), and scored for staining intensity (0–3) and percentage tumor cell staining. H-scores were calculated (intensity × percentage: low 0–1; moderate >1–2; high >2–3) and compared with clinicopathologic features available for 73 cases. Statistical analysis was performed using Fisher exact test and Student t test.

Results: Moderate to high expression was seen in 94.5% (69 of 73) of cases. All well-differentiated carcinomas (4 of 4) showed moderate to high expression. Seventy-five percent of cases with low expression (3 of 4) were poorly differentiated carcinomas. There were no significant differences between moderate- and high-staining groups with regard to origin, tumor size, age, gender, grade, or prevalence of lymphovascular invasion, perineural invasion, or nodal metastasis at the time of resection (P = .07 to >.99).

Conclusions: Moderate to strong ROR1 expression by immunohistochemistry was present in most biliary tract carcinomas, suggesting ROR1 could be a potential target for therapy in these malignancies. There was no significant correlation between ROR1 expression and other clinicopathologic data analyzed.

Primary pancreatic gastrointestinal stromal tumor (GIST) is exceedingly rare. A 52-year-old woman presented with abdominal pain and a 7-cm mass was seen in the pancreatic head (Figure 35, A). Subsequent endoscopic ultrasound-guided fine-needle aspiration biopsy showed a spindle cell neoplasm (Figure 35, B) diffusely positive for CD117, consistent with GIST. Tumor size remained the same despite treatment with imatinib, and a pancreaticoduodenectomy was performed. The resection specimen showed a pancreatic GIST with low mitotic count (2/5 mm²). Foci of necrosis consistent with treatment effect were also identified (Figure 35, C). CD117 (Figure 35, D) and DOG1 were diffusely positive within the tumor. During 3 months of follow-up, the patient has been doing well. Primary pancreatic GIST is extremely rare, with only around 20 reported cases. Patient ages range between 30 and 84 years, without gender predilection. It can occur anywhere within the pancreas as a mass lesion. Mitotic count correlates with the risk of metastasis, but pancreatic GISTs tend to have an aggressive behavior. Surgical resection appears to be the treatment of choice, even in cases with recurrent disease. Some cases also receive adjuvant imatinib therapy. In summary, we report a rare case of primary pancreatic GIST. Despite its rarity, GIST should be kept in the differential diagnosis of primary pancreatic tumors.

Context: We previously identified mutations of SRC in gallbladder carcinomas (GBCs) and cholangiocarcinomas (CCs). We sought to characterize expression of SRC in these tumors by immunohistochemistry, in addition to CDH17 and c-MYC, and correlate with clinicopathologic data.

Design: A total of 110 resections were identified at our institution (2000–2014). Tissue microarrays were constructed; immunostained for SRC (1:600; Abcam), CDH17 (1:450; Novus Biologicals), and c-MYC (1:100; Cell Marque); graded by H score (staining intensity × percentage tumor staining); and correlated with data available for 73 cases. Statistical analysis was performed using Fisher exact test and Student t test.

Results: For SRC, 77% had moderate to high H scores; 91% of poorly differentiated tumors had low to moderate H-scores. Low to moderate H scores were associated with poor prognostic factors: 83% lymphovascular invasion (LVI+); 80% perineural invasion (PNI+); 81% lymph node metastases (LN+). For CDH17, low H scores were associated with poorly differentiated tumors (73%; P = .02) and poor prognostic factors (79% LVI+, 72% PNI+, 73% LN+). High H scores were associated with smaller tumor size compared with low H scores (18 versus 33 mm, P = .02). For c-MYC, 68% had low H scores. Ten percent had high H scores, with 71% of these showing LVI. Low H scores were seen in 73% of LVI+, 68% of PNI+, and 73% of LN+ cases. No differences in marker expression were seen in GBCs versus CCs.

Conclusions: Low CDH17 expression was associated with poorly differentiated tumors whereas high CDH17 expression was associated with smaller tumor size, suggesting utility as a prognostic marker. Low to moderate SRC expression appeared to be an adverse factor, whereas overexpression of c-MYC was not significant. No markers were useful to distinguish GBCs from CCs.

Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare entity with low-grade malignant potential and accounts for less than 3% of all pancreatic exocrine tumors. Most cases occur in young females and notably rarely in men. A 46-year-old man presented with left abdominal pain for a year. Computerized tomography scan revealed a 5.7-cm solid and cystic pancreatic mass. Endoscopic ultrasound-guided fine-needle aspiration revealed clusters of uniform small cells in a hemorrhagic background. These cells had little pleomorphism, fine chromatin, and pale cytoplasm. Cell block displayed loosely cohesive, round to oval uniform cells with inconspicuous nucleoli, surrounding rare thin delicate vascular cores (Figure 36, A). The neoplastic cells were positive for β-catenin, vimentin, CD56, and CD10, and negative for CK7, CK20, progesterone receptor, S-100, trypsin, and chymotrypsin. Microscopic examination of the subsequent distal pancreatectomy showed solid and pseudopapillary growth patterns (Figure 36, B). Degenerative changes with extensive necrosis and hemorrhage were seen, along with areas of pleomorphic and atypical multinucleated giant cells (Figure 36, C). β-catenin showed aberrant nuclear immunoreactivity (Figure 36, D). The presence of atypical or multinucleated giant cells appears to have no prognostic significance and is considered a degenerative change. Our case highlights the importance of including SPN in the differential diagnosis in a male patient with complex pancreatic lesion and incorporating immune studies to achieve an accurate diagnosis. It was previously suggested that SPN in males can behave more aggressively. It is worthwhile to have interval follow-up on this patient population because ~15% of SPNs have the potential for malignant transformation.

Context: Gastric mixed adenoneuroendocrine carcinoma (MANEC) is a rare entity associated with aggressive clinical course and ominous patient outcome. Histomorphologically, MANEC tumors mimic “simple” carcinomas frequently, posing significant diagnostic challenges. A missed MANEC diagnosis is detrimental to patient management and prognosis.

Design: Until now only limited gastric MANEC cases were reported, with a spectrum of histopathologic heterogeneity. To determine the main diagnostic challenges, the histomorphologic and immunopheno-typical profiles of gastric MANECs in our institute during a 5-year span were reviewed.

Results: A total of 8 gastric MANECs were retrieved, including 2 originally misclassified. The first missed MANEC was diagnosed adenocarcinoma without essential immunohistochemical investigation; this tumor was composed of small or intermediate-sized cells with scant cytoplasm and fusiform nuclei with granular chromatin and inconspicuous nucleoli. The second missed MANEC was called poorly differentiated neuroendocrine carcinoma; however, the glandular structures and mucin component were overlooked. Immunostains showed positive synaptophysin (7 of 8), chromogranin (4 of 6), and CD56 (7 of 7) in neuroendocrine components, whereas the adenocarcinoma portions were positive for CEA (3 of 5), pan-cytokeratin (5 of 5), and CK7 (5 of 5) but negative for neuroendocrine markers.

Conclusions: MANECs are defined as containing at least 30% of both neuroendocrine and adenocarcinoma components. The proportions and behavior of both components influence the management and patient outcome, and deserve close attention, as MANECs are aggressive tumors with rapid progression. It is pivotal to carefully inspect the histopathologic features in each individual case. An accurate diagnosis and systemic evaluation allow one to subclassify MANECs into different prognostic categories, which will likely help patient stratification and improve therapeutic efficacy.

We describe a case of a 31-year-old man presenting with acute cholestatic liver injury attributable to whey protein supplements. He did not use recreational drugs or alcohol. His diagnosed ulcerative colitis had been in remission for more than 4 years. Laboratory tests revealed total bilirubin of up to 10.6 mg/dL (conjugated bilirubin: 5.7 mg/dL), and mildly elevated transaminases. Viral hepatitis and autoimmune antibodies were negative. Results of magnetic resonance cholangiopancreatogram were unremarkable. A liver biopsy taken 4 weeks following discontinuation of supplements showed marked canalicular cholestasis with a lesser degree of hepatocellular cholestasis, with accentuation in perivenular zones. CK7 immunostain showed no definite bile duct loss; however, ductular proliferation and biliary metaplasia were noted. There was mild mixed portal tract inflammation in addition to central venulitis and hepatocytic injury. The patient showed a slow recovery after the discharge. Whey protein supplementation is an uncommon cause of liver injury but should be considered in the differential diagnosis of unexplained liver injury, particularly in young men. A study of dietary whey protein in rats showed strong elevation of inflammatory mediators in perivenular hepatocytes, hepatic degeneration, and monocyte accumulation. Similarly, injuries reported in human liver include centrilobular hepatocellular and canalicular cholestasis, increased stellate cells, vacuolization in hepatocyte cytoplasm, and portal inflammatory cell infiltration. In contrast to most idiosyncratic drug-induced hepatocytic injuries that are immunoallergic reaction in nature, drug-induced cholestatic injury results from a blockage in the hepatobiliary transporter system. The damaging metabolite in cholestatic injury decreases canalicular transporter function on the apical hepatocyte membrane and eventually leads to intracellular accumulation of bile constituents and hepatocytic toxic damage (Figure 37).

Poorly differentiated gastric adenocarcinomas (PDGACs) possess clinicopathologic diversity. Here we describe an unusual case of PDGAC associated with an intense and accentuated lymphocytic infiltrate, features characteristically seen in lymphoepithelioma-like gastric carcinoma (LLGC), in a young woman. A 21-year-old woman presented to our hospital for second opinion because of worsening epigastric pain and anemia, with an original outside diagnosis of erosive hemorrhagic gastritis. Linitis plastica with malignant ascites and nodal metastasis was suspected upon endoscopy- and ultrasonography-guided rebiopsy. Microscopically, the rebiopsy showed sheets of round to polygonal neoplastic cells with poorly defined cell borders, high nucleus to cytoplasm ratio, and hyperchromatic nuclei intermingled with but not obscured by a dense lymphocytic population. Immunohistochemistry labeled these cells with pankeratin, EMA, and intact mismatch repair proteins, whereas EBV in situ hybridization was negative. The intratumoral lymphocytes were labeled by CD3 and CD20. These findings in this PDGAC case mimic features typically seen in LLGC. Our patient was not a surgical candidate because of advanced disease stage; modified chemotherapy was initiated following next-generation sequencing. In contrast to LLGC, PDGAC is associated with an ominous clinical course and survival rate; a misclassification of these 2 could bring detrimental consequences to patients. Indeed, a definitive diagnosis of LLGC was not established in this biopsy based on these intriguing histology and aggressive disease progression. An accurate diagnosis should rest on systemic histomorphology and ancillary testing, combined with clinical and laboratory evidence. The mismatch repair proteins status and molecular profile of the tumor essentially play key roles in clinical decision making.

Context: Perineural invasion (PNI) is an independent adverse prognostic factor in colon cancer and may be an indication for chemotherapy. This study investigated the utility of AE1/3/S100 dual immunohistochemical (IHC) staining in the assessment of PNI in low-grade stage IIA colon adenocarcinoma.

Design: The pathology database (2001–2016) was queried for low-grade stage IIA colon carcinoma. A total of 134 cases were identified with a mean age of 69.8 years (33–88), 43 from the left and 91 from the right colon. Dual AE1/3/S100 IHC was performed. H&E and IHC slides were independently reviewed by 3 pathologists to assess PNI and interobserver variability.

Results: In the original pathology reports, PNI was identified in 9 cases (6.7%), indeterminate in 2 (1.5%), negative in 106 (79%), and not mentioned in 17 (12.8%). Upon independent H&E slide review, complete agreement was reached among 3 pathologists in 101 cases (75.3%): 99 cases (98.0%) negative and 2 (2.0%) positive for PNI. At least one observer called indeterminate and positive in 12 (9.0%) and 24 cases (17.9%), respectively. The Fleiss κ for interobserver agreement on H&E was fair (κ = 0.33). By AE1/3/S100 IHC, the 3 pathologists had complete agreement in 120 cases (89.5%): 73 (60.8%) negative, 46 (38.3%) positive, and 1 (0.9%) indeterminate for PNI. At least one observer called indeterminate and positive in 3 (2.2%) and 59 cases (44.0%), respectively. The Fleiss κ for interobserver agreement on IHC was almost perfect (κ = 0.86) (Figure 38).

Conclusions: Compared with H&E, AE1/3/S100 IHC increased the number of cases considered positive for LVI. The dual IHC showed markedly improved interobserver reproducibility.

Context: Lymphovascular invasion (LVI) in stage IIA colon cancer is associated with a worse prognosis and is an indication for chemotherapy. This study investigated the utility of CDX2/CD31 dual immunohistochemical staining (IHC) in LVI assessment in low-grade stage IIA colon adenocarcinoma.

Design: The pathology database (2001–2016) was queried for low-grade stage IIA colon carcinoma. A total of 115 cases were identified with a mean age of 69.5 years (33–88); 43 were from the left and 72 from the right colon. CDX2/CD31 IHC was performed. H&E and IHC slides were independently reviewed by 3 pathologists to assess LVI and interobserver variability.

Results: In the original report, LVI was identified in 21 (18.3%), indeterminate in 12 (10.4%), negative in 80 (69.6%), and not mentioned in 2 cases. Upon independent review of H&E slides, complete agreement among 3 pathologists was reached in 79 cases (68.7%): 4 (3.5%) positive and 75 (65.2%) negative for LVI. At least one observer called indeterminate and positive in 21 (18.3%) and 22 cases (19.1%), respectively. The Fleiss κ for interobserver agreement on H&E was fair (κ = 0.25). By CDX2/CD31 dual IHC, the 3 pathologists had complete agreement in 105 cases (91.3%): 5 (4.3%) positive and 100 (87%) negative. At least one observer called indeterminate and positive for LVI in 7 (6.1%) and 10 cases (8.7%), respectively. The Fleiss κ for interobserver agreement on IHC was moderate (κ = 0.59) (Figure 39).

Conclusions: Compared with H&E, CDX2/CD31 IHC reduced the number of cases considered indeterminate or positive for LVI. The IHC showed improved interobserver reproducibility, with only 4.3% cases being considered positive for LVI.

Intraductal extension of pancreatic neuroendocrine tumors (PNETs) is a rare growth pattern. Only 9 PNETs with this growth pattern have been reported. We recently identified 2 cases of PNETs invading into the main pancreatic duct (MPD). Two cases were obtained with imaging finding of distal pancreatic lesions. Fine-needle aspiration confirmed diagnosis of PNETs, which led to distal pancreatectomies. Case 1 involves a 78-year-old man who presented with abdominal pain and elevated lipase (>600 UL). Endoscopic ultrasound showed a hypoechoic mass in the distal pancreatic body and hyperechoic walls in the MPD. Grossly, the pancreatic mass (4.1 cm) filled and obstructed the MPD. Microscopically, the tumor showed invasion into the MPD, and intrapancreatic and extrapancreatic large veins. Case 2 involves a 51-year-old woman who presented with abdominal pain. Endoscopic ultrasound showed a hypoechoic mass in the tail of the pancreas. Grossly, the pancreatic mass (6.3 cm) extended into the MPD. Microscopically, both cases were confirmed by Ki-67, synaptophysin, and chromogranin immunostains to be well-differentiated PNETs, grade 2, showing invasion into the MPD (Figure 40, A and B). Both tumors were negative for glucagon, gastrin, and somatostatin. There is no evidence of recurrence and metastatic disease after 3-month postsurgical follow-up in either case. It is noted that well-differentiated PNETs can have MPD and large vein invasion. However, the clinical outcome of patients with this presentation is yet to be determined.

Primary retroperitoneal mucinous cystic neoplasm (PRMCN) is extremely rare, and its etiology, pathogenesis, and prognosis remain unclear, with histology being similar to that of ovarian or pancreatic counterparts. We herein report an unusual case of PRMCN with malignant transformation leading to multifocal invasive adenocarcinoma from our institution. The patient was a 23-year-old overweight woman presenting with fever, nausea, vomiting, and abdominal pain who on imaging was found to have a 17-cm cystic lesion in the right midabdomen exerting mass effect on the liver and right ureter. She underwent right hemicolectomy and en bloc resection of a retroperitoneal mass with a subsequent pathologic diagnosis of multifocal invasive moderately to poorly differentiated adenocarcinoma arising in a primary mucinous cystic neoplasm with low- and high-grade dysplasia of retroperitoneum. The adenocarcinoma was invading through the mucinous cyst wall with fistula tract formation and intestinal serosa and into muscularis propria of small and large intestine. Immunohistochemically tumor cells were positive for CK7, pankeratin, and MOC-31 with high Ki-67 proliferative index, and negative for CK20, CDX-2, PAX-8, TTF-1, calretinin, and WT1. Subsequent thorough oncologic, radiologic, and tumor-marker workup failed to identify any primary tumors in our patient with 12 months' surveillance after surgery being recurrence free. There are no pathognomonic clinical or radiologic findings for primary retroperito-neal mucinous cystic neoplasm, making the preoperative diagnosis challenging. Delay in diagnosis and treatment may lead to complications such as rupture, infection, and malignant transformation, as in our case. Surgical resection and pathology report are crucial to facilitate accurate diagnosis and treatment.

Primary well-differentiated neuroendocrine tumors (WD-NET) of the liver are exceedingly rare, and liver metastasis in a young patient is also rarely reported. We present a case of probable metastatic WDNET, World Health Organization grade II, in the liver of an otherwise healthy 26-year-old Ethiopian woman. The patient complained of vague right upper quadrant abdominal pain and was found to have a 20 × 16 × 9-cm, well-delineated, partially cystic and solid mass in the right lobe of the liver by CT scan. The lesion was an assumed hepatic adenoma given her history of taking oral contraceptives. The mass was resected and the tissue was histologically examined by hematoxylin and eosin staining. Morphologically, the tumor appeared as sheets of crowded cells with areas of pseudopapillary configuration with occasional pseudorosette formation and areas of necrosis. The cells appeared to have ample pink cytoplasm without definitive cell borders and low-grade nuclei with a vesiculated and “salt-and-pepper” chromatin pattern (Figure 41, A and B). Immunohistochemistry revealed the tumor was strongly positive for chromogranin (Figure 41, C) and synaptophysin. CDX-2 showed weak positivity (Figure 41, D) and Ki-67 was approximately 5%. Because of the limited ancillary testing methods available at the Ethiopian laboratory, 2 US-based pathology institutions worked with the laboratory to make a diagnosis. Because of this multi-institutional and international collaboration, the patient will receive further workup to determine if this lesion represents a primary or metastatic tumor.

Intracholecystic papillary-tubular neoplasm (ICPN) is a rare neoplasm of the gallbladder. The association of ICPN and primary sclerosing cholangitis (PSC) is extremely rare. Herein, we report such a case of a patient with long-standing PSC and ICPN, pyloric gland subtype with various metaplastic features. A 48-year-old man with history of ulcerative colitis and PSC cirrhosis was incidentally found to have a 0.5-cm polyp in the gallbladder during routine endoscopic retrograde cholangiopancreatography that remained stable for 6 years until a recent MRI showed a new indeterminate 1.5-cm gallbladder lesion. Follow-up ultrasound revealed a hypoechoic, multilobulated vascular lesion with infoldings. A cholecystectomy was performed. On gross examination, a 0.8-cm polyp on the gallbladder fundus along with multiple detached friable fragments in the lumen was identified. Histologically, the lesion showed a papillary-tubular architecture with a fibrovascular core, findings consistent with ICPN. No invasive carcinoma was identified. The background showed chronic cholecystitis with pyloric gland metaplasia demonstrating mixed classic, inverted nuclei and Paneth cell types (Figure 42, A through D). Immunohisto-chemistry showed the ICPN and background pyloric gland metaplastic epithelium to be strongly positive for MUC-6, whereas MUC5AC was weakly positive and MUC-1 and MUC-2 were negative, ruling out biliary and intestinal subtypes. Among the different ICPN phenotypes, the pyloric gland type has the lowest risk for malignant transformation. This unique case of an ICPN arising in a patient with UC and PSC cirrhosis confirms the importance of close clinical follow-up with imaging followed by surgery when needed and appropriate immunohistochemical studies to guide patient management.

Context: Small cell carcinoma of the prostate makes up approximately 0.5% to 2% of all prostate carcinomas. It is an aggressive subtype with a poor prognosis and overall decreased survival. Neuroendocrine differentiation within prostatic adenocarcinoma has been demonstrated to be hormone independent; thus, most small cell carcinomas occur in patients with conventional prostate adenocarcinoma following androgen deprivation therapy.

Design: Four patients with prostate adenocarcinoma treated with androgen deprivation therapy, which evolved to small cell carcinoma with liver metastasis, were identified from departmental archives for 2018. Slides were reviewed and clinicopathologic variables were analyzed.

Results: The average age at liver metastasis was 73 years (range, 68–76 years). Two patients developed liver metastasis more than a decade following initial diagnosis, whereas 2 presented with advanced prostate cancer shortly prior to liver metastasis. Histologically, all liver lesions were composed of nests of cells with high nuclear to cytoplasmic ratios, granular chromatin, and frequent mitoses. All cases were synaptophysin, chromogranin, and AE1/AE3 positive and had a Ki-67 labeling index of ≥70% of neoplastic cells. NKX3.1 was negative in all but one case, which demonstrated only weak positivity. Prostate-specific antigen (PSA) levels were normal to near normal in all patients. Three of 4 patients died after the diagnosis of liver metastasis.

Conclusions: Our case series highlights the importance of considering a prostate primary, even in the setting of normal PSA levels and loss of prostate immunohistochemical markers, when diagnosing a metastatic neuroendocrine lesion in the liver. Additionally, when small cell carcinoma of the prostate metastasizes to the liver, it portends a particularly dismal prognosis.

Context: Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by the destruction of interlobular bile ducts leading to the development of cholestasis and progressive liver damage. Elevated alkaline phosphatase, positive antimitochondrial antibodies (AMA), and histologic evidence of PBC are diagnostic features of PBC seen in patients without extrahepatic biliary obstruction or comorbidities affecting the liver. This series aims to describe clinicopathologic features of rare patients who present with positive AMA but without histologic features of PBC.

Design: Five liver biopsies obtained from patients with positive AMA that showed no histologic evidence of PBC were reviewed (August 2017–February 2019) and clinicopathologic characteristics were analyzed.

Results: All patients underwent liver biopsy to exclude the presence of PBC due to positive AMA serology (Table). All 5 had comorbidities that affect the liver, none known to cause positive AMA. A male-predominant patient series (4:1) ranged in age from 19 to 79 years. Histologic features of PBC, such as nonsuppurative destructive cholangitis, florid-duct lesion, or destruction of interlobular bile ducts/ductopenia, were not seen. Biopsies from all patients displayed nonalcoholic fatty liver disease (steatosis/steatohepatitis) accompanied with varying degrees of fibrosis.

Conclusions: Although highly suspicious for PBC, positive AMA serology may be seen in patients who show no histologic evidence of PBC, as seen in our patient series. Exclusion of false-positive results and rare conditions that may cause positive AMA serology other than PBC is necessary. Because sole AMA positivity reportedly may indicate significant risk of developing active PBC in succeeding years, clinical follow-up of these rare patients is warranted.

Gastrointestinal bleeding is a clinical manifestation that often requires intervention with biopsy and histologic examination because of the possibility of an underlying malignancy. However, metastasis to the stomach is uncommon, with an occurrence of up to 0.7% in various neoplasms. We present a case of a 91-year-old man who presented with gastrointestinal bleeding and underwent esophagogastroduodenoscopy that revealed a 0.9 × 0.6 × 0.5-cm gastric polyp. It consisted of malignant tumor cells with nested growth patterns of clear cells with areas of hemorrhage (Figure 43, A and B). Typical morphology for a gastric neoplasm was not seen. Tumor cells within tissue were positive for vimentin, PAX-8 (nuclear) (Figure 43, C), and AE1/3. Tumor cells were negative for CK7 (D), CK20, CD10, and CD68. The morphology and immunohistochemical findings supported the diagnosis of metastatic renal cell carcinoma to the stomach. It was later confirmed during a phone discussion with the clinician that the patient had a remote history of a renal cell carcinoma. The incidence of renal cell carcinoma in the United States is reported to be 15.3 per 100 000 people per year. Gastric metastasis occurs in 0.2% of cases with renal cell carcinoma. Metastasis of renal cell carcinoma to the stomach is a rare occurrence that can present as gastrointestinal bleeding. Recognition of the clinical presentation, medical history, risk factors for cancer, or a history of renal cell carcinoma will lead to the proper clinical diagnosis that can be supported with tissue examination and immunostaining.

Gastric adenosquamous carcinoma (GASC) is a challenging entity that accounts for less than 1% of all gastric malignancies. Frequently diagnosed at advanced stages, patients are unable to achieve surgical management because of the large disease burden present. Although limited literature has been published regarding management of advanced cases, we present a case of microsatellite instability (MSI) in gastric adenosquamous cell carcinoma to help guide patient treatment. We report a novel finding of MSI-GASC in an 82-year-old woman who presented with gastric outlet obstruction and a prior diagnosis of poorly differentiated carcinoma. Despite multilineage chemoradiation therapy, the tumor continued to progress. Given the tumor growth, a gastrectomy was performed to reveal a 7.0-cm tumor involving the full thickness of the gastric wall, extending into serosa (pT4a). Histopathologic examination revealed a tumor demonstrating poorly differentiated adenocarcinoma intermingled with squamous islands/nests and frequent infiltrating lymphocytes. Immunohistochemistry highlighted 45% of tumor cells that were positive for P40 and CK5/6. MSI analysis showed a loss of MLH-1/PMS-2 and retention of MSH-2/MSH-6; PD-L1 expression was positive. Next-generation sequencing confirmed MSI findings and identified EGFR, PIK3CA, and TP53 mutations. The novel finding of MSI-GASC, taken in combination with the tumor PD-L1 expression and unique mutational profile, led providers to change therapy from 5-fluorouracil chemotherapy to pembrolizumab-based immunotherapy. The patient remained disease free at 22 months. Assessment for MSI status should be considered for the management of gastric cancers, as the prognostic factors and clinicopathologic features are unique. Timely recognition of MSI status can significantly improve a patient's outcome and clinical response.

Dubin-Johnson syndrome is an autosomal-recessive disorder that typically presents as jaundice in young adulthood. Mutations in the ABCC2 gene that encodes the MRP2 transporter lead to impaired hepatic biliary excretion, conjugated hyperbilirubinemia, and black discoloration of the liver. We report an unusual case presenting as neonatal cholestasis with paucity of interlobular bile ducts. Following an uncomplicated pregnancy and delivery, a newborn female was noted to have conjugated hyperbilirubinemia since birth. On the seventh day of life, her total bilirubin was 17.36 mg/dL (reference range, 0.1–1.3 mg/dL) with a direct bilirubin of 6.38 mg/dL (reference range, 0.0–0.3 mg/dL); γ-glutamyltransferase was 1333 U/L (reference range, 2–151 U/L), and serum aminotransferase levels were within normal limits. At 6 weeks of age, a liver biopsy was performed and revealed cholestasis with ductular proliferation and a paucity of interlobular bile ducts. Endoscopic retrograde cholangiopancreatography demonstrated an intact intrahepatic and extrahepatic biliary tree, ruling out biliary atresia. Molecular genetic testing was negative for Alagille syndrome but showed heterozygous mutations in the ABCC2 gene: c.2302 C>T, a pathogenic variant reported in patients with Dubin-Johnson syndrome, and c.1586 G>A, a variant of unknown significance. Immunohisto-chemistry for MRP2 showed absent canalicular staining, supporting the diagnosis of Dubin-Johnson syndrome. Paucity of interlobular bile ducts is seen in Alagille syndrome, biliary atresia, and certain infections, metabolic diseases, and chromosomal disorders, but is not typically seen in Dubin-Johnson syndrome. This case illustrates an unusual presentation of Dubin-Johnson syndrome occurring in a neonate with the unexpected histologic finding of paucity of interlobular bile ducts.

Colonic leiomyomas (LM) are relatively common lesions discovered incidentally during colonoscopy, particularly in the distal sigmoid colon and rectum. Patients are diagnosed at an average age of 62 years and there is a slight male predominance (2.5:1). Histologically, LMs are well-circumscribed lesions that arise from the muscularis mucosae and occupy the submucosa. They are composed of well-differentiated smooth muscle cells characterized by cigar-shaped nuclei and abundant eosinophilic cytoplasm. LMs stain positively for desmin and actin and are negative for CD34, CD117, S-100, and cytokeratin. Here, we present a case of a 53-year-old woman with a past medical history significant for irritable bowel syndrome and gastroesophageal reflux disease who presented for screening colonoscopy. Colonoscopy revealed a 3-mm polyp in the ascending colon. Histopathologic analysis revealed normal colonic mucosa overlying a well-circumscribed, submucosal-based nodule (Figure 44). The nodule was composed of epithelioid cells, some with intracytoplasmic vacuoles, in a matrix reminiscent of chondroid. The epithelioid cells stained positively for ERG, and the stroma stained positively for smooth muscle actin. Additional immunohistochemical stains, including desmin, DOG1, c-Kit, CD31, cytokeratin AE1/AE3, CD34, and S-100, were negative. Given the morphologic and immunophenotypic findings, in addition to reported ERG expression in tumors with cartilaginous differentiation, this mesenchymal polyp was most compatible with a benign epithelioid leiomyoma with chondroid-type matrix, and to our knowledge, this is the first description of this type of colon polyp. Lastly, we demonstrate the importance of recognizing ERG positivity in cartilaginous lesions so as to not render a misdiagnosis of epithelioid hemangioendothelioma.

Context: Microsatellite instability (MSI) is prognostic for survival in many cancers and has been reported inconsistently in esophageal adenocarcinoma (EAC) and rarely reported in Barrett esophagus (BE) with low- and high-grade dysplasia.

Design: Immunohistochemical stains for PMS2, MSH6, PD-1, and PD-L1 were performed on 50 cases of BE, 48 cases of BE with low-grade dysplasia (LGD), 50 cases of BE with high-grade dysplasia (HGD), and 50 cases of EAC.

Results: All cases of BE (50), LGD (48), and HGD (50) had intact nuclear expression of PMS2. One case of EAC out of 50 (2%) had a loss of nuclear expression of PMS2. All cases of BE (50), LGD (48), HGD (50), and EAC (50) had an intact nuclear expression of MSH6. All cases of BE (50) and LGD (48) were negative for PD-1. One case of HGD (2%) and 2 cases of EAC (4%) were PD-1 positive. Similarly, all cases of BE (50), LGD (48), and HGD (50) had a PD-L1 CPS score <1 except 1 case of EAC (2%) that had a CPS score >1.

Conclusions: In our study we found 2% of EACs to be MSI-H, which was lower than in other studies. MSI tumors usually have an increased mutational burden with increased PD-L1 expression due to increased tumor-infiltrating lymphocytes. However, the MSI-H EAC in this study has low PD-L1 expression (CPS score <1). We conclude that MSI pathway is not very common in esophageal adenocarcinoma (EAC) and its precursors. PD-1 and PD-L1 are similarly seldom expressed in these tumors.

Schistosomiasis is the second most prevalent parasitic disease globally. The worms causing schistosomiasis are not found in North America, but the disease should be suspected in patients emigrating from endemic areas. The intestinal involvement in schistosomiasis is relatively common, with the 2 major species, Schistosoma japonicum, primarily involving the small intestine, and Schistosoma mansoni, principally involving the large intestine. We report an unusual case of S mansoni present in the duodenum, as well as the large bowel. An 11-year-old boy presented with fatigue, dizziness, and abdominal pain. Results of laboratory tests showed severe microcytic hypochromic anemia. He recently emigrated from Tanzania with a positive serology test for Schistosoma spp. at the time of immigration. He was prescribed praziquantel but compliance was poor. No improvement was seen despite adequate doses of iron prescribed, and no source of blood loss was identified. The upper and lower gastrointestinal scopes were unremarkable, and biopsies were obtained to rule out eosinophilic/collagenous gastritis, duodenitis, or colitis. Histopathologic examination of the duodenal biopsies revealed multiple granulomata in sub/mucosa, with viable and calcified parasitic eggs (125 by 50 μm). The eggs showed a thin transparent shell and a typical lateral spine, consistent with S mansoni (Figure 45). There was also diffuse involvement of the colon, supporting a diagnosis of chronic recurrent/residual diffuse intestinal schistosomiasis. The microscopic examination of excreta remains the gold standard for diagnosis of schistosomiasis. Serologic tests are indicated for travelers or immigrants from endemic areas. Pathology remains a powerful tool for elucidating long-standing residual/recurrent cases manifested with severe or untreatable symptoms.

Hepatobiliary cystadenocarcinoma is a rare malignancy associated with ovarian-like stroma and overtly malignant glands that has a favorable prognosis if completely resected, analogous to minimally invasive adenocarcinoma arising in mucinous cystic neoplasms of the pancreas. Ovarian mucinous neoplasms may have a similar histologic appearance and are known to occasionally contain mural nodules of anaplastic carcinoma. We report a case of hepatobiliary cystadenocarcinoma that subsequently presented as metastatic disease mimicking a primary gynecologic malignancy. The 30-year-old patient had a history of completely resected hepatobiliary cystadenocarcinoma 2 years prior to presentation without adjuvant therapy. She presented to her gynecologist with pelvic pain and vaginal bleeding. Physical examination revealed diffuse nodularity along the anterior vaginal wall and imaging showed a 5.8 × 4.1-cm pelvic mass with diffuse metastatic disease. Biopsies of the vaginal wall and an inguinal lymph node showed nests of pleomorphic cells with squamoid and glandular features concerning for metastatic ovarian carcinoma (Figure 46, A); however, immunohistochemistry was negative for PAX8 and ER but positive for CDX2. Subsequent review of the patient's prior resection revealed a cystic mucinous neoplasm with mural nodules of adenosquamous and anaplastic carcinoma (Figure 46, B through D), the latter previously reported only rarely in hepatobiliary cystadenocarcinoma. This case highlights the histologic overlap between hepatobiliary and ovarian neoplasms, which may present a diagnostic challenge, particularly in the setting of incomplete history. Additionally, the unusual presence of an anaplastic component in the patient's original tumor portends a worse prognosis; therefore, additional therapy should be considered in these patients.

Follicular dendritic cell sarcoma (FDCS) is a rare neoplasm occurring in both lymph nodes and extranodal sites. We report an unusual case of FDCS involving ileocecal valve. A 34-year-old man was admitted with blood in his stool for 1 month. MRI showed a 4.1-cm mass in cecum close to the ileocecal valve (Figure 47, A). He underwent right hemicolectomy with a preoperative diagnosis of gastrointestinal stromal tumor (GIST). Grossly, there was a tan ulcerated polypoid mass at the ileocecal valve measuring 4.5 × 3.7 × 2.8-cm (Figure 47, B). Microscopy revealed a multilobulated mass centered in the muscularis propria with extension into subserosa and focally extending into colonic mucosa, consisting of ovoid to spindle cells arranged in fascicles, storiform, and whorled architecture in a background of prominent lymphocytic infiltrates (Figure 47, C). The neoplastic cells had eosinophilic fibrillary cytoplasm, ovoid to spindled nuclei, vesicular chromatin, and small nucleoli. There was mild cytologic atypia without necrosis. Mitotic rate was up to 10/10 per high-power field. Immunostaining showed tumor cells were positive for CD21 (Figure 47, D), CD23, and CD35, and negative for C-kit, DOG1, SMA, AE1/3, S100, SOX10, CD34, ALK, and EBER. A diagnosis of extranodal FDCS, French Federation of Cancer Centers Sarcoma Group grade 1, was entertained. No postoperative chemoradiation was administered, in expectation of a favorable clinical outcome. We present this unusual case to highlight the importance of having a wide differential diagnosis for spindle cell tumors of the GI tract. Attention to morphologic details and judicious use of immuno-stains can help arrive at the correct diagnosis.

Head and neck squamous cell carcinoma metastasizing to the small bowel is extremely rare, whereas malignant melanoma and carcinomas from lung, breast, and ovary are noted to be the more common tumor types associated with small bowel metastasis. We present a case of a 64-year-old man with history of oropharyngeal carcinoma diagnosed 2 years prior and treated with radiation therapy who presented with abdominal pain, melena, weight loss, and anemia. Capsule endoscopy revealed an ulcerated jejunal mass with bleeding. Small bowel segment resection revealed 3 polypoid tan mucosal lesions ranging in size from 1.6 to 2.8 cm with central ulceration. Microscopic examination revealed a poorly differentiated malignancy with transmural involvement, lymphovascular invasion, and involvement of 5 of 12 mesenteric lymph nodes. Immunohistochemical evaluation demonstrated tumor cell positivity for p16 (diffuse), p63 (focal), Cam 5.2 (focal, perinuclear dotlike pattern), CD56 (focal), and synaptophysin (focal) and tumor cell negativity for Melan-A, S100, HMB45, CD45, and MCPyV. Additionally, polymerase chain reaction–based testing detected human papillomavirus (HPV) type 16 within the tumor. Overall, in view of the clinical setting, a diagnosis of metastatic HPV-mediated oropharyngeal squamous cell carcinoma was rendered. This case not only highlights an extremely rare tumor type metastasizing to the small bowel, but also may reflect a component of neuroendocrine differentiation and tumor progression as the patient's diagnostic material from a right neck lymph node metastasis 2 years earlier was negative for CD56 and synaptophysin, which may have therapeutic and prognostic implications.

Budd-Chiari syndrome (BCS) refers to the broad clinical spectrum associated with hepatic venous outflow obstruction, regardless of the etiology and level of obstruction. Liver specimens with BCS are uncommonly seen by pathologists given the rarity of the disease and the sensitivity and specificity of radiologic studies. We present 2 cases of a 36-year-old African American woman and a 50-year-old white man who presented to our institution with symptoms of fever, abdominal pain, nausea, vomiting, and jaundice. Imaging studies revealed thrombosis within the inferior vena cava and hepatic veins in the former and within the intrahepatic portion of portal vein in the latter. Both patients underwent orthotopic liver transplantation. Gross examination showed swollen, congested explanted livers with reddish purple, “nutmeg-appearing” cut surfaces and multiple venous thrombi causing near-complete luminal occlusion (Figure 48, A). Histologic sections revealed sinusoidal dilatation and congestion with extensive centrilobular hemorrhagic necrosis (Figure 48, B). Hepatic veins showed numerous occlusive thrombi (Figure 48, C) and marked intimal thickening and luminal narrowing. Diffuse nodular regenerative hyperplasia was also seen (Figure 48, D). BCS should be differentiated from hepatic sinusoidal obstruction syndrome and cardiac congestive hepatopathy. Both conditions can present with similar clinical and histologic findings as BCS; however, clinical history and radiologic findings can help make the distinction. Surgery is almost always mandatory in BCS, and prognosis generally depends upon the underlying cause and the severity of outflow obstruction. Our first patient died 3 months following her liver transplantation, whereas our second patient continues follow-up and is recovering well 10 months following surgery.

Immunotherapy agents such as cytotoxic T-lymphocyte antigen 4 and programed cell death protein-1 inhibitors show significant efficacy in treating advanced malignancies but are associated with numerous immune-related adverse events. These can manifest as severe gastroenteritis and colitis mimicking inflammatory bowel disease. This case represents a potentially rare presentation of a patient on nivolumab therapy who developed new-onset inflammation of the upper and lower gastrointestinal tract. Although colitis and gastritis are less common with nivolumab monotherapy, concurrent involvement of the upper and lower GI tract has not previously been reported. A 78-year-old man was diagnosed with metastatic lung adenocarcinoma in 2015 and treated with nivolumab immunotherapy. In 2016, he developed increased bloating, diarrhea, and loss of appetite. Upper and lower endoscopy showed Barrett esophagitis, gastritis, grade II intestinal hemorrhage, multiple clean based ulcers in the terminal ileum, and colon polyps. Esophageal biopsy revealed extensive squamous repair reaction and keratin pearl formation, which was considered suspicious for squamous cell carcinoma, microabscesses, and squamous metaplasia. Stomach biopsy showed marked intraepithelial chronic active inflammation with cryptitis and intestinal metaplasia, with negative Helicobacter pylori immunostaining and gastric dysplasia in some areas. Colon biopsy revealed areas of normal colonic mucosa with areas of cryptitis and crypt abscesses and transmural inflammation. Although these histologic findings are consistent with inflammatory bowel disease, this patient had no evidence of bowel inflammation on colonoscopy in 2014 and no known history of GERD or gastritis. Nivolumab was withheld temporarily and prednisone was given to the patient, which improved his symptoms.

Context: Atrophic gastritis (AG) has 2 defined etiologies: autoimmune atrophic gastritis (AAG), and chronic Helicobacter pylori infection. AG is defined as destruction of gastric glands followed by fibrosis and/or metaplasia and is thus nonspecific. The aim of our study was to identify cases with parietal cell atrophy (PCA) of oxyntic mucosa specifically, and to define its associations.

Design: A retrospective data search from January 2014 through November 2018 retrieved 111 biopsies with the diagnosis of AG. The pertinent clinical data and follow-up biopsies were reviewed.

Results: AG was diagnosed in 2.2% (111 of 4947) of total stomach biopsies, comprising 86 patients (male to female ratio of 1:3.4) with mean age of 56 years (range, 29–77 years). All cases showed PCA in oxyntic mucosa. H pylori was positive on histology in 8%. Serologically, in tested patients, 59% had positive antiparietal antibody and 80% had positive intrinsic factor. Gastrin was elevated in 83% of tested patients. Histologically, intestinal metaplasia was identified in 84%. In those in which synaptophysin was done, ECL-cell hyperplasia was identified in 87%. Concurrent neuroendocrine tumors were identified in 12%.

Conclusions: In our study, PCA showed a higher association with AAG than H pylori. Histologic AG is a nonspecific diagnosis and may not prompt adequate autoimmune workup by the gastroenterologist, leading to potential delays in diagnosis and treatment. This fact, and the recognition that AG is a challenging diagnosis in random gastric sampling, led us to develop an algorithmic approach (Figure 49) for the workup and diagnosis of parietal cell atrophy, with the goal of providing early and accurate diagnosis.

Anal ductal carcinoma is a rare entity. Here we report an interesting case of a 57-year-old woman who presented with hematochezia 18 months prior to presentation. Her initial anorectal examination showed mass at the left aspect of the anal verge that was mobile and quite firm. Biopsy of the mass showed adenocarcinoma originating from the rectum. A subsequent colonoscopy was done that showed the mass originating above the pectinate line with no other lesions elsewhere in the colon. No metastatic lesions were found on CT scan and a bulky lesion involving the perianal skin was found on MRI. During this presentation the patient finally underwent an abdominoperineal resection. The specimen revealed a moderately differentiated tumor, characterized by scattered solitary glands, undermining the squamous mucosa of the anal canal and perianal skin (Figure 50, A) and extending into the sphincter muscle. Focal glands showed mucinous patterns. Immunohistochemical staining showed the adenocarcinoma to be strongly immunoreactive for CK7 (Figure 50, C), with only scattered focal immunoreactivity for CK20 (Figure 50, B). The adenocarcinoma was nonimmunoreactive for CDX2, and many of the tumor cells were strongly reactive for p16 (nuclear and cytoplasmic; Figure 50, D). This immunoprofile is consistent with anal gland ductal adenocarcinoma, and with the positive p16 suggests a relationship with HPV-related dysplasia, as the patient had a history of condyloma acuminatum.

Context: MicroRNAs (miRNAs) are globally dysregulated in many tumors and play an integral role in tumorigenesis. In liver, miRNAs are abundant, modulate many cellular functions, and play an important role in pathogenesis of liver diseases. Growing evidence suggests that miRNAs can be used as potential diagnostic and therapeutic markers in various tumors including liver neoplasms. We aimed to identify differentially expressed miRNAs in liver neoplasms and use the findings as novel diagnostic tools to differentiate them.

Design: We profiled 17 candidate miRNAs on 41 samples; 9 hepatic adenomas (HAs), 4 well-differentiated hepatocellular carcinomas (HCCs), 6 moderately differentiated HCCs, 5 poorly differentiated HCCs, 10 focal nodular hyperplasias, and 7 normal liver samples. Total RNA was isolated from formalin-fixed, paraffin-embedded tissue. Complementary DNA and real-time polymerase chain reaction were performed using ABI TaqMan microRNA kits and Roche Light-Cycler480. Moderated t test was used to identify differentially expressed miRNAs.

Results: Our analysis showed that 8 miRNAs (miR221, miR222, miR223, miR200, miR375, miR126, miR301, and miR422) were significantly down-regulated in HA compared with WD-HCC. We further explored these 8 miRNAs with Ingenuity's IPA pathway analysis to gain functional interpretation of them and their predicted mRNA targets (showing 867 targets). These miRNAs are associated with hepatocellular carcinoma based on the IPA knowledge base. In addition, causal network analysis revealed top master regulators (network corrected P value <.001) were 3 miRNAs (miR221, miR200, and miR301/130) from the signature that act on these mRNA targets.

Conclusions: The targets of these miRNAs are attractive potential diagnostic and therapeutic markers. We are currently analyzing miRNA signatures in a larger cohort of patients to isolate specific genes dysregulated in liver neoplasms.

Paragangliomas are extra-adrenal neuroendocrine tumors derived from embryonic neural crest cells that arise from many sites, including the head and neck, mediastinum, retroperitoneum, and multiple organs. They may be sporadic or occur in various hereditary tumor syndromes. It is extremely rare for paragangliomas to arise from biliary sites, such as the gallbladder. As of late 2018, only 10 cases of gallbladder paraganglioma were reported in the literature. We present the case of an asymptomatic 68-year old man who presented with an incidentally discovered 3.0-cm mass between the liver and gallbladder. Imaging showed tortuous arterial flow passing through the mass. Histologically, the lesion was encapsulated with nested and trabecular epithelioid and spindled cells within a vascular stroma. The tumor was abutting the muscularis propria and several medium-sized vessels near the body of the gallbladder (Figure 51). The cells had centralized nuclei with stippled chromatin, occasional prominent nucleoli, focal nuclear pleomorphism, and rare mitotic figures. The lesional cells were positive for synaptophysin and negative for cytokeratin AE1/AE3. S-100 highlighted the surrounding sustentacular cells. These features are diagnostic of a paraganglioma. Based on radiologic and histologic correlation, we concluded that the tumor was likely arising from branches of the cystic artery, which, to the best of our knowledge, has not been previously reported in the literature. Our case highlights the importance of considering paraganglioma in the differential diagnosis of biliary tumors, even in the absence of signs and symptoms of catecholamine excess and syndromic disease.

Bowel pseudo-obstruction, also known as Ogilvie syndrome, is an abnormality of intestinal motility severe enough to produce the clinical features of intestinal obstruction. It is characterized by a functional obstruction of the colon in which the mechanism is poorly understood. Normal intestinal motility relies on the interaction between nerves and hormones that causes rhythmical contraction of smooth muscle subunits. The most common cause of acute pseudo-obstruction are drugs that decrease intestinal motility. Potassium chloride tablets may cause gastrointestinal ulceration, bleeding, and obstruction. A 66-year-old man presented with abdominal pain and distention. He had a history of hypertension, diabetes, schizophrenia, and seizure disorder. He was on aripiprazole, potassium chloride, Prolixin, and insulin. He was found to have intestinal pseudo-obstruction complicated by intestinal perforation. He underwent exploratory laparotomy and transverse loop colostomy. The resection specimen consisted of a 17-cm right hemicolectomy with attached terminal ileum and appendix, which had prolapsed through the colostomy site. No fibrous adhesions were identified on the serosal surface. The diagnosis was Ogilvie syndrome. Ileus is a common side effect related to treatment. Potassium chloride and aripiprazole and Prolixin can cause ileus with potentially fatal consequences. The new guidelines for patients with multiple comorbidities treated with medications should include recommendations about monitoring and interventions to avoid ileus among them.

Hepatocellular adenoma (HCA) is a heterogeneous entity. Four subtypes can be discerned with the application of immunohistochemistry: HNF1α-mutated subtype, inflammatory subtype, β-catenin–activated subtype, and a subset of adenomas that are unclassified with currently available tools in anatomic pathology. Although malignant transformation of HCA is more frequent in β-catenin–activated adenomas, extremely rare cases of malignant transformation of HNF1α-mutated HCA have been reported in patients with MODY3 and liver adenomatosis. Here we present a case of an 80-year-old woman without a history of MODY3 or liver adenomatosis who presented with abdominal discomfort. An abdominal CT with contrast revealed a heterogeneously enhancing mass replacing the left hepatic lobe. Left trisegmentectomy revealed a 13.5 × 12.2 × 6.5-cm yellow to tan, well-circumscribed, multilobulated tumor with a fleshy, hemorrhagic area. On microscopic examination, the fleshy and hemorrhagic area of the tumor had markedly thickened cell plates, aberrant architecture, and nuclear atypia, consistent with hepatocellular carcinoma. The remainder of the tumor was composed of a hepatocellular proliferation without portal structures and with prominent unpaired arterioles; the cells showed diffuse steatosis without significant cytologic atypia, consistent with the diagnosis of HCA. Immunohisto-chemical stains showed that fatty acid–binding protein was lost in both the adenoma and the carcinoma components and β-catenin staining demonstrated retained membranous staining. Our case describes malignant transformation of HNF1α-mutated HCA in a patient without MODY3 and adenomatosis, and provides a detailed immunohisto-chemical characterization of an otherwise rarely described entity (Figure 52).

Undifferentiated carcinomas of the pancreas are rare neoplasms and have a much poorer prognosis than the typical ductal adenocarcinomas. We herein report a case of an incidental intraductal polypoid undifferentiated carcinoma with pleomorphic giant cells (sarcomatoid carcinoma) in a 92-year-old man diagnosed during evaluation of worsening chronic constipation. Upper endoscopic ultrasound revealed a well-defined mass in the periampullary region that extended within the pancreatic duct, with upstream duct dilation. Fine-needle aspiration of the lesion was consistent with an adenocarcinoma. Subsequently, the patient underwent Whipple procedure and a 4.5 × 1.5 × 1.2-cm tan-pink, polypoid mass (Figure 53, A, B) was identified within the pancreatic duct. The pathologic examination showed an undifferentiated carcinoma composed of spindle cells with marked pleomorphism and giant cells and a focal area of conventional ductal carcinoma (Figure 53, C). The tumor showed minimal invasion into the pancreatic parenchyma (Figure 53, D) and 22 lymph nodes were negative for metastasis. Immunostains showed the spindle cells to be positive for vimentin and focally positive for EMA and AE1/3. Most of the undifferentiated carcinomas presented as large cystic tumors involving the pancreatic parenchyma. Only a few cases have been reported in the literature to show predominantly intraductal growth and those were subcentimeter in size. In spite of the known aggressive nature of these tumors, in our case the tumor was large and confined to a polyp with minimal invasion into the underlying pancreatic parenchyma. This is suggestive of early-stage tumor with favorable clinical outcome and postsurgical chemotherapy is probably not warranted.

Ampullectomy is usually a safe, effective, and minimally invasive endoscopic procedure for early ampullary neoplasms. However, there are rare reports of intrapancreatic ductal dissemination of neoplasms secondary to prior ampullectomy. We herein present a case of ampullary mucinous adenocarcinoma recurring as a multifocal tumor in the remnant pancreas suggestive of intraductal retrograde seeding of tumor cells. A 48-year-old woman underwent ampullectomy for an ampullary adenoma with minimally invasive carcinoma (Figure 54, A). Tumor cells showed loss of SMAD4 and overexpression of p53. Subsequent ampullary surveillance biopsies were negative for tumor. Ten years later, she had Whipple resection for recurrent invasive ampullary mucinous adenocarcinoma, with negative margins and no lymph node metastasis. Now 5 years after Whipple resection, she had recurrent tumors in distal pancreas and underwent completion pancreatectomy, which showed 4 separate foci of adenocarcinoma in the main pancreatic duct (Figure 54, B and C). The initial ampullary adenoma, the recurrent ampullary cancer, and the current multifocal tumors all shared similar histology and loss of SMAD4 with overexpression of p53 on immunostains (Figure 54, D). Molecular next-generation sequencing was performed on 2 of the tumors in distal pancreas and detected identical TP53 mutation at c.817C>T (p.Arg273Cys, p.R273C). The overall profile was thus suggestive of recurrence of the prior ampullary lesion in the distal pancreas, most likely secondary to ampullectomy. Intraductal tumor seeding secondary to ampullectomy has been rarely reported, and this is important to distinguish from a new primary tumor in the remnant pancreas because of its potential effect on treatment modality.

Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive cholestatic disorders of mainly pediatric population resulting in types 1, 2, and 3. Liver biopsy in type 1 shows cholestasis, whereas type 2 is associated with giant cell hepatitis and type 3 with mainly ductular proliferation. We report 2 patients, aged 12 and 2 years, who harbored mutations consistent with PFIC1/2 and PFIC3, respectively, and presented for orthotopic liver transplant. Liver biopsies revealed an autoimmune/viral hepatitis–like picture, the significance of which has not been well characterized in PFIC patients. The first patient reported a 14-kg weight loss with pruritus, hepatosplenomegaly, and abnormal laboratory findings as follows: total bilirubin 1.9 mg/dL, alkaline phosphatase 364 U/L, AST 44 U/L, immunoglobulin G (IgG) 2020 mg/dL, and IgM 253 mg/dL. No specific serologic autoimmune-related antibodies were found. Liver biopsy showed moderately active hepatitis with occasional plasma cells and bridging fibrosis, raising a consideration of autoimmune hepatitis (Figure 55, left). The patient received immunosuppressive treatment with prednisone with complete clinical response. The second patient presented with elevated liver function test results. Liver biopsy showed significant active hepatitis with interface and lobular activity, cholestasis, and bile duct proliferation (Figure 55, right), raising a differential diagnosis of viral hepatitis. Hepatitis-like features are generally absent in PFIC type 1 whereas giant cell hepatitis can be seen in PFIC type 2. Autoimmune hepatitis and primary sclerosing cholangitis have been rarely reported in PFIC patients. These features may be within the spectrum of PFIC-related changes or represent a concomitant etiology, warranting awareness and further investigations given the therapeutic implications.

In the United States, Clostridium difficile infection (CDI) affects up to 3 million patients per year. Up to 8% of hospitalized patients can develop CDI. Twenty-five percent of patients with CDI may develop CD-associated diarrhea; 1%–3% may progress to fulminant CD colitis (FCDC), which has a high mortality rate (35%–80%) and requires prompt operative intervention. A 23-year-old man, a nursing home resident with a history of anoxic brain injury secondary to ventricular fibrillation arrest, was hospitalized for evaluation of fever associated with cough productive of greenish sputum. He had developed abdominal distention with diarrhea and vomiting immediately prior to admission. He had a 3-day history of antibiotic (linezolid and piperacillin and tazobactam) use. CT scan of the abdomen showed severe thickening in the wall of the ascending colon and he underwent total colectomy. The colon was grossly dilated with maximum 11-cm dilation in the cecum and ascending colon. The mucosa was edematous with maximum bowel thickness of 1.2 cm in the ascending colon. Yellow pseudomembranes were observed throughout the colon but primarily clustered in the cecum and ascending colon. The histologic changes were consistent with type I lesion, characterized by superficial mucosal necrosis with erupting spray of fibrinopurulent exudate. Clostridium difficile toxin B gene was detected in the stool sample by qualitative polymerase chain reaction. Fulminant colitis in a young patient is most often associated with inflammatory bowel disease. However, the differential diagnosis should include FCDC even though length of antibiotic therapy may be short (3 days in our case).

Sessile serrated adenomas (SSA) of the appendix have been associated with acute appendicitis. One report in the literature shows that when entirely submitted, SSAs can be found in up to 20% of appendices sent for acute appendicitis in patients 30 years or older. However, most cases of SSAs of the appendix appear to be small, appearing in 3 or fewer cross sections when the entire appendix is submitted. We report a case of an SSA entirely replacing the appendix with resulting rupture. A 68-year-old man presented with a 1-week history of shortness of breath, fatigue, and generalized weakness. Shortly after admission he reported increasing shortness of breath and abdominal pain. A CT of the abdomen at that time was consistent with acute appendicitis complicated by rupture. Because of a rapid decline in status, definitive surgery was delayed until a month later. The specimen consisted of a distorted appendix with a fungating, polypoid mass near the tip of the appendix. The entire appendix was submitted, with every section showing SSA. A small area from the tip of appendix showed high-grade dysplasia. No invasive carcinoma or dissecting mucin was identified. We hypothesize the rupture was secondary to mass effect of the SSA. This case highlights a rare example of extensive SSA replacement of the appendix. Although there is little literature about peritoneal seeding in SSAs, because of the long interval between perforation and surgery as well as the high-grade dysplasia, close follow-up with the patient is necessary.

Human intestinal spirochetosis (IS) is a colonization of the intestines by spirochetes, most commonly Brachyspira spp. Histologically, IS presents as thickened blue epithelial brush border. Although this finding is usually incidental, spirochetal invasion beyond surface epithelium with associated gastrointestinal symptoms has been reported. IS is thought to be associated with oral-anal contact and is most common among immunocompromised homosexual men and populations in subsistence conditions. Here we discuss a rare case of appendiceal spirochetosis presenting as vague appendicitis in a previously healthy young woman. A 21-year-old, sexually active, afebrile, HIV-negative woman presented to the emergency department complaining of nausea, vomiting, and acute abdominal pain that migrated to the right lower quadrant within 48 hours. She also mentioned irregular menses and weight gain. Laboratory results showed neutrophilia and monocytosis without leukocytosis, elevated testosterone, and negative pregnancy test. Abdominal ultrasound was concerning for appendicitis. Laparoscopic appendectomy revealed mild hyperemia but was not definitive for acute appendicitis. Grossly, the appendix was unremarkable. Microscopic examination showed diffuse lymphoid hyperplasia with focal acute inflammation within the lamina propria. High-magnification sections showed patches of thickened, blue brush border (3–6 μm) confirmed as IS by spirochete immunostain (Figure 56). AFB and GMS were negative. The patient was successfully treated with metronidazole and discharged. Appendiceal IS is discussed because of its rarity, particularly in an HIV-negative, young adult woman with clinically and radiologically diagnosed appendicitis. Histologically, the appendix showed minimal acute inflammation and diffuse lymphoid hyperplasia. A meticulous microscopic examination of the entire luminal epithelium of the appendix is warranted for diagnosis and treatment.

Hepatocellular adenomas (HCAs) constitute a heterogeneous group of benign liver tumors with variable risk of malignant transformation. HCAs are classified into 4 major subtypes: HNF1-α inactivated (HNF1A-I), β-catenin activated, inflammatory, and unclassified. β-Catenin is part of the Wnt signaling pathway. HNF1A inactivation and β-catenin Wnt signaling activation are usually mutually exclusive in HCA, possibly because of distinct tumorigenesis pathways. We report the case of a 63-year-old woman with an incidental 18 × 13-mm enhancing liver nodule found during workup for shortness of breath. She had a 10-year history of hormone replacement therapy. The liver nodule was biopsied, and microscopic examination revealed a well-differentiated hepatocellular proliferation displaying marked steatosis and mild sinusoidal dilatation without bile ducts, inflammation, or reticulin disruption. Immunohistochemically, the neoplastic cells showed positive membranous staining for β-catenin without nuclear staining and were diffusely positive for glutamine synthetase (GS) and negative for CRP, serum amyloid A (SSA), and glypican 3, with loss of liver fatty acid binding protein (LFABP) expression. The morphologic and immunohistochemical findings were consistent with HNF1A-I HCA with β-catenin activation (B-CAT-ACT). Diffuse GS expression is thought to be reflective of Wnt signaling pathway deregulation and is considered a surrogate feature of B-CAT-ACT in HCAs, even in the absence of immunohistochemical β-catenin nuclear staining. B-CATACT is found in <1% of HNF1A-I HCA. Overall, HNF1A-I HCA has a relatively low risk of progression. However, any HCA with B-CAT-ACT should be followed up closely because of increased risk for malignant transformation.

A 46-year-old man with long-standing symptoms of gastroesophageal reflux disease and diarrhea was admitted to the endoscopy clinic. He had been followed for his irritable bowel syndrome for 4 years prior to this. The upper endoscopy showed an irregular Z line of the gastroesophageal junction, features of a short segment Barrett esophagus, and hiatus hernia. Mucosal biopsy of the gastroesophageal junction showed an increased thickness of the subepithelial collagen layer, up to 100 μm, confirmed by trichrome staining (Figure 57). The collagen fibers focally extended into the lamina propria and surrounded glands/crypts and superficial vessels. The squamous epithelium showed basal hyperplasia and spongiosis. Focal sloughing of squamous and columnar epithelial cells was present. There was mild chronic inflammation in the lamina propria. No mucosal eosinophilia, intestinal metaplasia, dysplasia, or yeast/fungus was present. There was no histomorphologic finding suggestive of scleroderma. Stomach biopsies (corpus and antrum) showed mild chronic inflammation and proton pump inhibitor effects. There was no evidence of acute inflammation or Helicobacter pylori. No increased thickness of the subepithelial collagen layer or intraepithelial lymphocytosis was found in the stomach, duodenum, terminal ileum, or colon biopsies.

Common variable immunodeficiency (CVID) is a heterogenous clinical disease secondary to impaired B-cell differentiation and defective immunoglobulin production. CVIDs are commonly diagnosed at young age because of recurrent infections. Gastrointestinal symptoms are usually malabsorption or diarrhea. The histopathology of CVID in the gastrointestinal system can demonstrate various morphologic abnormalities, including lymphocytic colitis, collagenous enterocolitis, and celiac sprue. We present a case of CVID in a 75-year-old woman with gastrointestinal involvement as celiac sprue. The patient had a history of recurrent ear infections and pneumonia and presented with weight loss and several months of severe persistent diarrhea. Her celiac serology was negative, whereas immunoglobulin levels of immunoglobulin G (IgG) and IgA were 50% lower than normal levels. Her initial endoscopy showed villous blunting at the duodenum, but symptoms were not improved on a gluten-free diet. IVIG and budesonide treatment improved diarrhea, but diarrhea recurred after being off therapy. Subsequent endoscopy showed diffuse blunted, atrophic, and nodular mucosa in the entire duodenum and proximal jejunum. Microscopic examination of the jejunum showed marked villous blunting, chronic inflammation, intraepithelial lymphocytosis, and thickened subepithelial collagen layer with presence of plasma cells (Figure 58). Budesonide and IVIG were initiated again. This study demonstrates the diagnosis of CVID can be delayed because of histologic manifestations of celiac sprue with presence of plasma cells in gastrointestinal biopsies. Microscopic features of celiac disease should prompt a differential diagnosis including CVID with consideration of serum immunoglobulin levels in older adults.

Pancreatic vasoactive intestinal polypeptide-secreting neuroendocrine tumors (VIPomas) are extremely rare occurrences. The VIPoma syndrome is also known as Verner-Morrison syndrome, which often presents as watery diarrhea, hypokalemia, and hypochlorhydria or achlorhydria (WDHA, or pancreatic cholera syndrome). VIPomas are believed to occur at an annual incidence of 0.1 to 0.2 cases per 1 million in the United States. Here we present a case of VIPoma in a 70-year-old woman who was seen in the emergency department for severe dehydration and near syncopal episode. She also complained of flushing, persistent diarrhea, and gradual weight loss (15 pounds) during the previous 4 years with unclear etiology. Abdominal CT scan showed a 3.9 × 3.7-cm mass in the distal pancreas. The serum VIP level was markedly elevated (367 pg/mL; normal, <75 pg/mL). The patient underwent a laparoscopic robot-assisted distal pancreatectomy and splenectomy. A 4.1-cm mass was identified in the distal pancreas macroscopically. Histology exhibited a well-circumscribed mass composed of epithelial cells organized in nested, trabecular, and pseudo-glandular pattern associated with fibrosis (Figure 59, A). The tumor cells had a moderate amount of eosinophilic cytoplasm and salt-and-pepper granular chromatin (Figure 59, B). Tumor cells were diffusely positive for chromogranin and synaptophysin and focally positive for VIP by immunohistochemistry (Figure 59, C). The patient's clinical symptoms were resolved after surgery. Clinical presentation, serology, and pathologic findings were consistent with a functional VIPoma, which is a rare entity among pancreatic neuroendocrine tumors.

Combined hepatocellular cholangiocarcinoma (cHCC-CC) is a rare malignant tumor of the liver, more aggressive than hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CC). Patients often present with locally advanced and/or metastatic disease. Little is known about the molecular alterations of this tumor. Here we report a case of cHCC-CC with molecular analysis by next-generation sequencing (NGS). A 57-year-old woman with no history of viral hepatitis or cirrhosis presented with masses in the liver, spleen, and lung; lytic bone lesions; and enlarged hilar lymph nodes. Ultrasound-guided core biopsy was performed on the liver mass. Numerous single and groups of pleomorphic cells with irregular, hyperchromatic nuclei and prominent nucleoli were seen on the imprints (Figure 60, A). Biopsies showed a tumor with trabecular and glandular patterns composed of malignant cells with eosinophilic cytoplasm, round to oval nuclei, and prominent nucleoli. Mucin was noted in the neoplastic glands. Focal necrosis was identified (Figure 60, B). The tumor was diffusely positive for HSA, CK7, CK19, and CEA-p, indicating combined features of HCC and CC (Figure 60, C and D). CK20, CDX2, TTF-1, napsin-A, arginase, glypican 3, CA19.9, GATA-3, and PAX-8 immunostains were negative. A diagnosis of cHCC-CC was rendered. KRAS pGly12Asp mutation was detected. PD-L1 was negative. Previously KRAS alterations in cHCC-CC have been reported only in Japanese cases. KRAS mutations are common in CC and seem to be associated with worse prognosis. They are infrequent in HCC and implications of KRAS alterations in cHCC-CC are not known. Additional molecular studies are warranted, which may improve the treatment and prognosis of this tumor by targeted therapies.

Constitutional mismatch repair deficiency is an extremely rare condition with biallelic germline mutation in one of the mismatch repair proteins. It is manifested by multiple malignancies at young age. Here we present a case of a 36-year-old woman with a clinical diagnosis of Lynch-like syndrome and biallelic germline PMS2 gene mutation. The patient had been diagnosed with colon cancer at age 24, which was treated by subtotal colectomy; subsequent bilateral breast ductal cancer with bilateral mastectomy; proximal jejunal adenocarcinoma with partial small bowel resection; and squamous cell carcinoma of the face and tongue. The recent colonoscopy revealed granular mucosa of the rectal remnant. The patient underwent endoscopic mucosal resection. Histology showed multiple tubular adenomas and multifocal intramucosal adenocarcinoma with signet ring cell differentiation (Figure 61, A and B). There was prominent peritumoral and intratumoral lymphocytic infiltration. There was no histologic evidence of submucosal invasion. PMS2 expression was completely lost in tumor cells, benign crypt epithelium, stromal cells, and inflammatory cells, consistent with biallelic homozygous germline mutation (Figure 61, C). MLH1 (Figure 61, D), MSH2, and MSH6 mismatch repair proteins were retained in tumor cells as well nontumor cells. Pathologists and clinicians should be aware of this condition in young patients developing multiple malignancies to warrant an early referral to a genetic counselor and adequate cancer surveillance.

Actinomycosis is a rare infection with variable presentation that is difficult to diagnose preoperatively. It is commonly locally infiltrative and has been reported to mimic carcinoma radiologically and clinically because of chronicity and associated inflammation. We present the case of a 42-year-old woman with bowel obstruction and outside diagnosis of colonic adenocarcinoma. CT of abdomen (Figure 62, A) showed a 5.0 × 4.7 × 3.5-cm midtransverse colon mass, a 4.0 × 3.9 × 1.9-cm peritoneal mass, and multiple implants. The patient had an intrauterine device for 16 years prior to presentation. The patient underwent an extended right hemicolectomy and en bloc small bowel resection. Gross examination did not identify tumor but revealed a segment of colon and small bowel with focal loss of mucosal folds and thickened wall up to 1.8 cm with dilated proximal bowel. Histologically, the thickened bowel wall showed extensive acute and chronic inflammation with granulation tissue and necrosis. Rare sulfur granules were identified on hematoxylin and eosin staining; gram-positive filamentous rods were highlighted by Gram stain and were also PAS-D and GMS positive (Figure 62, B through D). AFB stain was negative. Surgically, there was no connection between the uterus and colon. The intrauterine device was removed in case of indolent infection. The patient was discharged on 6–12 months of antibiotics. In conclusion, actinomycosis is a rare infection sometimes associated with intrauterine devices and can mimic malignancies within the pelvis and abdomen. Intraabdominal actinomycosis can be extremely difficult to diagnosis preoperatively because of the wide range of presentations.

Context: Assessment of fibrosis in nonalcoholic fatty liver disease (NAFLD) is important in predicting disease progression. Transient elastography (TE) is a noninvasive estimation of hepatic fibrosis and when combined with controlled attenuation parameter can assess the degree of hepatic steatosis. In this study, we compare the results of fibrosis obtained from transient elastography with those obtained from liver biopsy.

Design: We reviewed 16 NAFLD patients who underwent transient elastography followed by liver biopsy. The following parameters were recorded: steatohepatitis, steatosis in liver biopsy (mild, ≤33%; moderate–severe, >33%), fibrosis in liver biopsy (Brunt score 0–1, no or sinusoidal fibrosis; 2–3, sinusoidal fibrosis with portal fibrosis or bridging fibrosis; 4, cirrhosis), TE steatosis score (S score; S1, 11%–33%; S2–S3, >33%) and TE fibrosis result (F 0–1, n o or mild scarring; F 2–F3, moderate–severe scarring; F 4, cirrhosis).

Results: Sixteen patients were identified, and steatohepatitis was present in 88% of these patients (Table). The degree of steatosis was concordant between TE and liver biopsy in most F 0–1 and F 4 patients, but it was not concordant in more than half of the F 2–3 patients. The degree of fibrosis was concordant with liver biopsy in 55% of F 0–1 patients, 25% of F 2–3 patients, and none of the F 4 patients.

Conclusions: Discrepancy in fibrosis was noted in 62% of the patients when compared with liver biopsy. TE results are more reliable in cases with low TE fibrosis (F 0–1), whereas TE fibrosis of 4 needs to be confirmed by liver biopsy.

Context: Fecal blood–based screening has been shown to be an effective strategy in reducing colorectal cancer mortality. The goal of this project was to compare the efficacy of 2 commercial FIT tests, Polymedco (P-FIT) and Hemosure (H-FIT), in detecting premalignant and malignant colorectal lesions.

Design: This is a hospital-based prospective study. Consecutive nonselective stool samples were collected during a 3-month study period at UCLA and analyzed by P-FIT and then H-FIT tests. Follow-up data including colonoscopy for up to 3 years were obtained by reviewing the hospital electronic record.

Results: A total of 808 stool samples from individual patients were tested. P-FIT was positive in 307 samples (38%) and negative in 511 (62%). H-FIT was positive in 367 samples (45%) and negative in 451 (56%). The overall concordance of the 2 tests was 90%, and the 2 tests showed overall similar performance characteristics in detecting tubular adenoma and more advanced lesions. However, there were 8 samples that tested positive by P-FIT and negative by H-FIT, whereas 68 samples tested positive for H-FIT but negative for P-FIT. Among these 68 patients with only H-FIT positivity, 26 underwent colonoscopy, with 10 (38%) showing precancerous adenomatous lesions or malignancy. Meanwhile, among the 8 patients with only P-FIT positivity, 5 underwent colonoscopy, with 1 patient (20%) showing tubular adenoma (χ² = 2.9; P < .1).

Conclusions: Two FIT tests (P-FIT and H-FIT) showed similar test performance characteristics in detecting tubular adenomatous and above lesions. The H-FIT showed a slightly higher sensitivity than PHIT in detecting tubular adenoma and more advanced lesions.

Among pancreatic carcinomas, the World Health Organization recognizes a category with mixed differentiation, including mixed acinar-neuroendocrine carcinoma, mixed acinar-ductal, and mixed acinar-neuroendocrine-ductal carcinoma. Adenosquamous carcinoma is considered a distinct entity with bilineage differentiation whose diagnosis requires at least 30% of both components. The histopatho-logic identification of each component could be challenging in poorly differentiated tumors, especially with preceded neoadjuvant treatment; a third lineage/component in a pancreatic adenosquamous carcinoma has not been reported. A 73-year-old man presented for second opinion regarding his recently resected pancreatic tumor following neoadjuvant chemotherapy and newly identified metastatic disease involving liver. The outside diagnosis stated poorly differentiated adenocarcinoma (ypT2N0). His case was requested and reviewed. Review of the outside Whipple case identified a 2.5-cm tumor with unequivocal adenosquamous histomorphology, confirmed by positive CK5/6 and CDX2 immunostains performed at our institute. Remarkably, synaptophysin, chromogranin, and CD5/6 immunostains also highlighted most tumor cells. The histomorphology and immunophenotypes were most consistent with trilineage differentiation (Figure 63). Subsequent mutational analysis detected loss of CDKN2A and CDKN2B and mutation of SMAD4, ARID1A, and CTNNB1 genes, and stable microsatellites. Patient was originally managed with Gemzar and FOLFIRINOX. Based on these newly acquired findings and liver metastasis, Abraxane treatment was initiated and clinical trials were offered. To our knowledge this is the first pancreatic carcinoma identified with simultaneous trilineage adenosquamous and neuroendocrine differentiation. We believe that astute histomorphologic evaluation and systemic immunohistochemistry are essential in reaching an accurate diagnosis. The impact of this subclassification on the clinical management and patient outcome awaits further investigation.

Granular cell tumor (GCT) was considered a neoplasm of Schwann cell origin. GCT of gastrointestinal tract, especially of the colon, is very rare. We report a case of a patient with GCT of cecum and discuss the histopathologic and immunohistochemical features. The patient is a 32-year-old woman who was found to have a 1.5-cm subepithelial lesion distal to appendiceal orifice during screening colonoscopy because of her history of Crohn disease. The initial biopsy of cecum mucosa overlying the mass demonstrated focal active colitis, consistent with her Crohn disease. The patient subsequently underwent laparoscopic right hemicolectomy. Macroscopically, a firm, well-circumscribed mass was covered by cecal mucosa measuring 2 × 1.5 × 1.5 cm. Histologically, this submucosal tumor was composed of plump histiocyte-like cells with abundant granular eosinophilic cytoplasm and centrally located vesicular or dark pyknotic nuclei. The tumor cells were diffusely positive for S-100, CD 56, and inhibin by immunohistochemistry (IHC) and negative for synaptophysin and neurofilament. During a 3-year follow-up, she has been well without tumor recurrence. GCT in the cecum is rare, generally found incidentally, and follows a benign course. However, malignant GCTs have been described but are extremely uncommon. We must be aware of the possibility of GCT when we deal with submucosal tumors in the colon. Histologic examination and IHC stains can help guide our diagnosis.

A 62-year-old man presented with acute generalized abdominal pain and absence of bowel movements for 4 days. He denied anal pain, bloody stool, and discharge. He stated being in a long-term relationship with his male partner. Results of HIV screen were negative and no sexually transmitted disease was reported. CT of the abdomen and pelvis revealed circumferential rectal thickening with perirectal and pelvic lymphadenopathy concerning for malignancy. Colonoscopy showed multiple polyps in the sigmoid colon and rectum with inflamed distal rectal mucosa. Biopsies revealed tubular adenomas with occasional lymphocytes, plasma cells, and histiocytes within the lamina propria. Random rectal biopsies demonstrated expansion of the lamina propria and submucosa by chronic lymphoplasmacytic infiltrates, prominent lymphoid aggregates, and poorly formed granulomas (Figure 64, A and B). Acid-fast bacteria stain, Gomori methenamine silver, and Steiner modified silver did not reveal infectious microorganisms. Because of high level of suspicion, Treponema pallidum immunostaining was performed, showing spirochetes within the lamina propria of the rectosigmoid polyps and the rectum (Figure 64, C), compatible with syphilitic proctosigmoiditis. Subsequent serology revealed positive RPR and reactive confirmatory T pallidum particle agglutination test. Furthermore, rectal Chlamydia trachomatis nucleic acid amplification testing was also positive. We report a case of syphilitic proctocolitis and concurrent C trachomatis infection with unusual presentation. Tissue biopsy helped make the diagnosis, initiating prompt treatment and preventing onward transmission. Because of increases in the incidence of sexually transmitted diseases, including isolated infectious proctocolitis, caused by T pallidum and C trachomatis, a high index of suspicion is warranted for timely recognition and treatment.

Intraductal papillary mucinous neoplasm is a cystic mucin producing exocrine neoplasm of the pancreatic duct. This neoplasm can be concurrently associated with pancreatic neuroendocrine tumor (Pan-NET). We report an uncommon case of mixed intraductal papillary mucinous neoplasm (IPMN) and PanNET. Only 8 such cases have been previously reported in the literature. A 63-year-old man was found to have an incidental 2.8-cm multiseptated cyst in the tail of the pancreas. Endoscopic ultrasound with fine-needle aspiration revealed a PanNET. Distal pancreatectomy and splenectomy were performed and revealed a well-circumscribed, cystic mass filled with mucin measuring 3 × 2 × 2 cm. Microscopic examination showed the cyst wall lined by tall columnar mucinous epithelium, gastric phenotype, intermixed with subepithelial sheets of well-differentiated mildly anisomorphic cells expressing synaptophysin and chromogranin. The proliferation index was 2%. Low-grade dysplasia was noted in the IPMN. No high-grade dysplasia or carcinoma was seen. The background pancreas showed an additional focus (0.5 cm) of well-differentiated neuroendocrine tumor in a background of chronic pancreatitis. Association of pancreatic ductal lesions and PanNET is uncommon and can present in 2 patterns. The most common pattern is intraductal papillary mucinous neoplasm with PanNET occurring as concurrent yet 2 discrete lesions. The second is mixed pattern, which is very uncommon, shows intermingling of both components, and requires the presence of endocrine differentiation in at least one-third of tumor volume. This includes the rare intraductal PanNET, mixed intraductal papillary mucinous neoplasm and PanNET (our case), and mixed adenocarcinoma and neuroendocrine carcinoma.

Idiopathic myointimal hyperplasia of mesenteric veins (IMHMV) is a rare disease of unknown etiology that classically affects the rectosigmoid colon and mimics inflammatory bowel disease. We present a case of a 62-year-old man with a past medical history of hypertension, hyperlipidemia, and chronic colitis of unknown etiology. A previous biopsy performed from the rectosigmoid colon showed patchy ischemic colitis associated with vascular ectasia and intravascular fibrin thrombi with no chronicity or granuloma seen. Hence, the patient's colitis was refractory to medical management, surgical intervention with total colectomy, and end ileostomy was opted. Gross findings revealed inflammation and wall thickening affecting mainly the distal colon. On histologic examination, the distal and sigmoid colon showed ischemic colitis. The mesenteric veins, confirmed by EVG stain, were significantly thickened and tortuous and the lumens narrowed or obliterated with media-intimal hyperplasia and fragmentation of elastic lamina (Figure 65, A and B). Focal organizing thrombi with recanalization were identified, and no vasculitis was seen. The veins in the proximal portion of the mesentery were generally uninvolved. The findings rendered a diagnosis of idiopathic myointimal hyperplasia of the mesenteric veins. This entity has mainly been diagnosed after pathologic review of colectomy specimen, as the biopsy findings are usually suggestive of an ischemic etiology and nonspecific. Awareness of this disease will assist in understanding the etiology and permit adequate management for these patients who are many times misdiagnosed with inflammatory bowel disease.

A 66-year-old woman presented with fatigue, abdominal pain, and anemia. On imaging, a 9.5-cm mass involving the pancreatic tail with direct extension into (or possibly from) the stomach was identified. Concurrent nodules in the liver, lung, spleen, adrenal glands, colon, and omentum were discovered. Endoscopic evaluation of the stomach demonstrated irregular friable mucosa in the cardia. Histologic sections of the irregular gastric mucosa revealed a biphasic malignant neoplasm composed of glandlike spaces lined by cells with abundant cytoplasmic mucin, framed by a multilayered squamous/transitional epithelium (Figure 66, A). No intestinal metaplasia or dysplasia were identified. Both mucinous and squamous components were positive for CK7 (Figure 66, B), whereas only the squamous component expressed CK5/6 (Figure 66, C) and only the glandular component expressed monoclonal CEA (Figure 66, D). Taken all together, the findings were diagnostic of adenosquamous carcinoma. Adenosquamous carcinoma is a rare tumor with extremely poor prognosis. Although it can be found in several locations, it represents only 3% of pancreatic exocrine malignancies and less than 0.5% of gastric malignancies, respectively. In both pancreas and stomach, the tumor typically presents at late stage. In this case, concurrent involvement of both organs raised concern regarding the site of origin. As immunohistochemistry is insufficient for distinguishing between tumors from these 2 sites, the combination of imaging features (major lesion in the pancreas), endoscopic observation (absence of significant mass lesion on the gastric mucosa), and microscopic findings (absence of in situ neoplasia in the stomach) supported pancreas as the primary site.

Pancreatic adenocarcinoma is the most common type of pancreatic neoplasm. It is one of the most lethal human cancers. Most tumors form a mass lesion with/without obstruction of duct. Diffuse involvement of the entire pancreas is extremely uncommon. Here we describe a case of pancreatic adenocarcinoma with extensive pancreatic intraepithelial neoplasia involving the entire pancreas without forming a mass on radiology and gross. A 63-year-old man presented with abdominal discomfort and nausea for a few months. Computer tomography revealed diffuse irregular dilatation throughout the main pancreatic duct in the body and tail without mass (Figure 67, A). A resection of distal pancreas and spleen was performed. Grossly, no definite mass lesion was identified. Histopathology revealed invasive, moderately differentiated adenocarcinoma on a background of chronic atrophic pancreatitis. Also noted was extensive pancreatic intraepithelial neoplasia 3 involving both branch and main pancreatic duct. Two months postsurgery the patient underwent fine-needle aspiration of pancreas, which showed malignant cells in papillary-tubular architecture favoring well-differentiated adenocarcinoma versus adenocarcinoma arising in an intraductal tubular-papillary neoplasm. A Whipple procedure was performed. Grossly, no mass was seen. Sections revealed similar histopathology as the previous resection (Figure 67, B through D). At 2 months postsurgery follow-up visit, the patient was doing well clinically and scheduled for future adjuvant chemotherapy. The current case highlights an unusual feature of pancreatic adenocarcinoma in the form of no mass lesion, associated with extensive pancreatic intraepithelial neoplasia involving the entire pancreas. The exact prognostic significance of this rare finding needs further exploration.

Malignant mesotheliomas are rare neoplasms of mesothelial cell origin. They can be classified based on morphology into epithelioid, sarcomatoid, or mixed types. Peritoneal epithelioid mesothelioma with clear cell features is very rare and mimics various malignancies, posing a diagnostic challenge. Here we report a rare case of primary peritoneal mesothelioma with predominantly clear cell features and a unique molecular signature. A 68-year-old man who had multiple liver nodules on imaging was admitted for worsening abdominal pain. He complained of intermittent abdominal pain for more than 10 years. Longitudinal follow-up of the patient's abdominal images during 10 years showed slowly progressive liver lesions. Microscopic examination of resected tumors revealed pleomorphic epithelioid neoplasm with clear cytoplasm, distinct cell borders, optically clear chromatin, and prominent nucleoli embedded in a vascular stroma. Immunostaining showed that the tumor cells were positive for AE1/3, vimentin, carbonic anhydrase IX, TFE1/33, and GATA3 and negative for PAX-8, arginase-1, hepatocyte-specific antigen, inhibin, S100, DOG1, CD117, CD31, TTF-1, p63, smooth muscle actin, and HMB45. CancerType ID testing favored the diagnosis of mesothelioma with 90% probability, a diagnosis that was further confirmed by calretinin and WT1 positivity. Foundation genomic testing showed VHL Y98fs*24 mutation, a unique genetic mutation that to our knowledge was never previously described in peritoneal mesotheliomas. In summary, this is a rare case of primary peritoneal mesothelioma with clear cell features presenting as liver masses. The tumor had a unique genetic mutation and behaved in an indolent manner, in contrast to what is commonly seen in mesotheliomas.

Context: Neonatal giant cell hepatitis (NGCH) is a histologic pattern of liver injury seen in a subset of infants with persistent neonatal jaundice. Although some infants recover with medical management, others develop progressive liver injury. Data on clinical follow-up are limited on prior NGCH studies. NGCH cases at our institution were retrospectively reviewed to identify histologic attributes that may predict adverse clinical outcome.

Design: Institutional archives were queried (January 1990 to April 2018) for liver biopsy reports in infants (age <1 year) with key words “giant cell” and “hepatitis.” Slides were evaluated for histologic features by 3 hepatobiliary pathologists blinded to identifying information. Clinical diagnoses and outcomes were recorded. Correlations were assessed by χ² test.

Results: Follow-up data (range, 4 weeks through 20 years) were available in 18 of 22 infants with NGCH aged 3 to 26 weeks (mean = 12 weeks) at the time of diagnosis. Eight infants (44%) developed progressive liver disease, of whom 3 were successfully transplanted but 5 (28%) died of disease. Ten patients (56%) had improving liver function at last follow-up. Etiology of NGCH was idiopathic in 8 (44%), bile duct paucity in 3 (16%), total parenteral nutrition in 4 (22%), biliary atresia in 1, perinatal asphyxia in 1, and sepsis in 1. There was a strong association of fibrosis stage ≥2 (P = .002), ductular cholestasis (P = .03), as well as patchy or confluent necrosis (P = .03), with progressive liver disease.

Conclusions: Fibrosis (stage ≥2), ductular cholestasis, and necrosis appear to predict progressive liver disease in NGCH.

Gallbladder carcinosarcoma is one of the rarest subsets of gallbladder malignancies. To date, 108 cases have been reported worldwide. To our knowledge, this case represents only the second reported patient with a primary gallbladder cancer displaying both carcinosarcoma and neuroendocrine components. Herein we report a 71-year-old man with a gallbladder mass discovered on CT scan (Figure 68, A). The patient underwent a radical cholecystectomy with regional lymphadenectomy and en bloc resection of liver segments IV and V. Macroscopically, a 3.5-cm polypoid mass near the gallbladder fundus was examined. Grossly, the lesion showed necrosis and cystic changes filled with mucin. Microscopically, the tumor demonstrated moderately differentiated adenocarcinoma with focal chondroid differentiation (Figure 68, B and C) and high-grade neuroendocrine tumor component (Figure 68, D) arising in a cystic papillary neoplasm. The neuroendocrine neoplasm was positive for chromogranin and synaptophysin. Ki-67 proliferation index was ~ 50%. The patient did not receive adjuvant chemotherapy in the setting of complete surgical resection. Surveillance CT scan taken 47 months after initial diagnosis (done at 6-month intervals) demonstrated extensive metastasis. The patient is currently receiving chemotherapy. Because of the low incidence and poor prognosis of this tumor, it is essential to gather all individual experience–based information.

Undifferentiated carcinomas of the pancreas are extremely rare nonendocrine pancreatic neoplasms accounting for 5% of all pancreatic malignant tumors. Undifferentiated carcinoma with osteoclast-like giant cells (UC-OGC) is a rare subtype. It is mainly composed of 2 cellular components including osteoclast-like giant cells (OGCs) and ovoid to spindle-shaped highly pleomorphic mononuclear tumor cells. UC-OGC is currently considered a distinct variant of pancreatic ductal adenocarcinoma (PDAC). Prognosis is poor and most patients survive less than a year. Patients with a pure UC-OGC have better prognosis than those with an UC-OGC with an associated conventional PDAC component. We report a 66-year-old man who presented with weight loss and constipation. Abdominal CT showed a pancreatic head mass with pancreatic ductal dilatation. Fine-needle aspirate of the mass was suggestive of adenocarcinoma and occasional multinucleated giant cells were also detected. The patient underwent pancreatoduodenectomy following 11 cycles of chemotherapy. On gross examination there was a 2.3 × 2.2 × 1.8-cm, well-defined, pale tan, firm mass in the pancreatic head (Figure 69, A). Microscopic examination revealed round to spindle-shaped cells, highly pleomorphic mononuclear cells, and multinucleated OGCs (Figure 69, C) adjacent to the pancreatic duct (Figure 69, B) with areas of necrosis and hemorrhage. No epithelial glandular malignant elements were recognizable. Immunohistochemical studies showed the malignant spindled and pleomorphic cells were positive for vimentin and caldesmon and negative for keratins AE1/AE3 (Figure 69, D) and CAM5.2. The multinucleated giant cells were positive for CD68. These findings were consistent with undifferentiated carcinoma with OGCs. In conclusion, we report a rare case of undifferentiated carcinoma with OGCs. Fewer than 100 cases have been reported in literature.

Context: Neuroendocrine carcinoma (NEC) of the esophagus is extremely rare. The objective of this study was to compare the tumor characteristics and overall survival (OS) between esophageal small and large cell NEC, and with adenocarcinoma (EAC).

Design: Esophageal NECs were selected from the National Cancer Database (2004–2013). Multivariable analysis and Kaplan-Meier method were performed. The prognostic factors for EAC were derived from the literature.

Results: Of 483 selected patients with esophageal NEC, 11.8% were large and 88.2% small cell. The median age was 66. NEC more commonly presented in males (68%). Most of the NECs were >4 cm (80% in large versus 68% in small cell). The rate of esophagectomy was 21% in large versus 5.9% in small cell (P < .001); 88% of NECs had chemotherapy. Multivariable analysis showed that tumor >4 cm (hazard ratio [HR], 1.53; P = .03) and stage IV (HR, 4.16; P < .001) were associated with significantly worse OS, whereas small cell type (HR, 0.51; P = .02), esophagectomy (HR, 0.18; P = .01), and chemotherapy (HR, 0.38; P < .001) were predictors of better OS in NEC. The 5-year OS was 3% for large versus 10% for small cell NEC (P = .04); this was less than 20% in EAC. The most important prognostic factors in EAC are depth of invasion and lymph node status.

Conclusions: Using the largest data set of esophageal NEC to date, the major independent predictors of OS include morphology, tumor size, stage, esophagectomy, and chemotherapy. The large cell NEC has the worst OS rate, followed by small cell NEC, and then EAC.

Rhabdomyosarcoma (RMS) is a common soft tissue sarcoma in children that can infrequently present in adulthood. Rarely RMS arises in solid organs. Although embryonal and alveolar RMS are the most common (>80% of all) histologic subtypes encountered, rare variants can occur. We report on a case of spindle cell/sclerosing variant of RMS in the liver of a 57-year-old woman. To the best of our knowledge, this is the first report of spindle cell/sclerosing variant of RMS in adult liver. The patient presented with shortness of breath, epigastric discomfort, and fatigue in May 2018. Magnetic resonance imaging revealed an 18.5-cm left hepatic lobe mass impinging on the heart and multiple nodules in the omentum. The patient underwent partial hepatectomy and left hemidiaphragm resection later in May 2018. Gross examination revealed an 18.5-cm liver mass abutting but not grossly invading the diaphragm (Figure 70, A). Histology revealed spindle cells arranged in a storiform pattern with pale eosinophilic cytoplasm, elongated nuclei, rare mitoses (up to 5/10 per high-power field), and foci of necrosis. Frequent rhabdomyoblasts with cross-striations and areas of stromal hyalinization with pseudovascular arrangement of tumor cells were noted (Figure 70, B and C). Immunohistochemically, neoplastic cells showed expression of desmin (strong and diffuse) and myogenin (patchy; Figure 70, D) but no expression of cytokeratins, HMB-45, or Melan-A. Fluorescent in situ hybridization was negative for FOXO1 gene rearrangement. Cytogenetics demonstrated hypodiploidy. The morphology, immunoprofile, and molecular features are consistent with a spindle cell/sclerosing variant of RMS. The patient is disease free 9 months post adjuvant chemotherapy.

Acinar cell carcinoma (ACC) with papillocystic growth of the pancreas is a rare variant that can mimic intraductal neoplasms. We present a case of a 75-year-old man who initially presented with 2 months of epigastric pain, nausea, and vomiting, and was found to have an epigastric cystic mass arising from the pancreatic neck. The patient underwent a complex surgery to remove a 25-cm cystic mass that was adherent to the pancreas, stomach, duodenum, and gallbladder with metastasis to the diaphragm and liver. Grossly, the mass was 40% cystic and 60% solid. The solid component contained small, cystic loculations with prominent papillary excrescences and was filled with milky fluid and grumous material (Figure 71, A). Histologic features included both cystic and papillary architecture lined by cuboidal cells with granular, eosinophilic cytoplasm and conspicuous nucleoli (Figure 71, B through D). Immunohistochemical stains demonstrated that the neoplastic cells were trypsin, BCL-10, and chymotrypsin positive, consistent with acinar cell differentiation. Papillocystic variant of ACC is a diagnostic challenge because of its rarity and morphologic overlap with the more common intraductal papillary mucinous neoplasm, which carries a more indolent course. There are only a handful of reported cases of papillocystic ACC. Previous reports suggest that this variant is less aggressive than conventional ACC. Here we present a rare, large, and relatively aggressive case. Our understanding of how this growth pattern impacts survival and management is limited. Recognizing this rare entity is essential for appropriate treatment and further study of its clinical behavior.

Context: Adenomyomatous hyperplasia (AH) of the gallbladder, reported in 1%–8.7% of cholecystectomies, is hypothesized to be an exaggerated form of chronic cholecystitis, but the exact pathogenesis of this entity is still unknown. AH consists of cystically dilated sinuses/glands with a surrounding spindle cell proliferation that is thought to be composed predominately of smooth muscle cells. Myofibroblasts are contractile and secrete a variety of biochemical modulators, influencing the microenvironment by the “field effect.” Myofibroblasts can be immunohistochemically distinguished from smooth muscle cells by their desmin negativity. The primary objective of this study is to quantify and compare the myofibroblastic proliferation in AH, chronic cholecystitis, and gallbladder carcinoma.

Design: Eighteen cases of AH and 5 cases each of chronic follicular cholecystitis, chronic cholecystitis, and gallbladder carcinoma were stained with actin and desmin. The percentage of myofibroblasts was estimated by the difference between actin and desmin staining.

Results: The percentage of actin staining was significantly higher in AH and gallbladder carcinoma as compared with chronic follicular and chronic cholecystitis (P = .04). The percentage of desmin staining did not show any significant difference between the 4 groups. The estimated myofibroblastic population was significantly higher in AH and gallbladder carcinoma as compared with chronic follicular and chronic cholecystitis (P = .005).

Conclusions: The spindle cell proliferation around cystically dilated glands in AH is composed predominantly of myofibroblasts and not smooth muscle cells as previously described. This finding suggests that a derangement in epithelial-stromal interactions is the underlying pathophysiology in AH. This in turn raises the suspicion of a possible neoplastic nature of the glandular component in this entity.

An 80-year-old man presented with weight loss and obstructive jaundice symptoms. CT scan of abdomen showed moderate intrahepatic biliary duct dilatation with mass and soft tissue thickening in the region of proximal common hepatic duct that was highly suspicious for hilar cholangiocarcinoma (ie, Klatskin tumor). He underwent percutaneous transhepatic cholangiography (PTC), which was nondiagnostic and was complicated by acute kidney injury and acute ascending cholangitis. After treatment with fluids and antibiotics, he underwent extended right hepatectomy and Roux-en-Y hepaticojejunostomy. Grossly, diffuse thickening of the hepatic hilar area, hepatic ducts, cystic duct, and common bile duct with a mucoid appearance was identified. Microscopically, the tumor was composed entirely of well-defined pools of mucin with detached clusters of malignant cells and many signet ring cells (Figure 72). Hepatic ducts showed areas of high-grade biliary intraepithelial neoplasia (BilIN III). Cystic duct demonstrated a range of precursor lesions including BilIN-3, predominantly intestinal type, and a small tubular adenoma (intestinal type). There was overt mucinous carcinoma in situ in the cystic duct, and based on these findings, invasive carcinoma likely arising from the cystic duct was favored. Pure mucinous cholangiocarcinoma is an exceedingly uncommon entity, and it is usually large and advanced at the time of diagnosis with more aggressive behavior than ordinary carcinomas. Fewer than 20 cases of pure mucinous cholangiocarcinoma have been reported in the literature, and signet ring cell carcinoma of the extrahepatic bile ducts is extremely rare, with only 5 reported cases with very poor outcomes.

Gastric tubule neck dysplasia (TND) represents a rare precursor lesion of some diffuse-type gastric carcinoma (DTGC). It is believed to originate from the neck region of the oxyntic glands. This is a rare and problematic diagnosis, especially on small gastric biopsies, because it develops deep in nonmetaplastic epithelium of the neck region and the mucosal surface is commonly spared. We present our experience with 2 such cases, highlighting the histopathologic features suggestive of TND and the utility of IMP3 in identifying the transition to DTGC. A 43-year-old man and 66-year-old woman with a friable gastric mass in the body of the stomach underwent a small gastric biopsy that was negative for malignancy. A repeat “jumbo” biopsy demonstrated gastric oxyntic mucosa with normal surface and foveolar epithelium and an abnormally elongated gastric neck region in which cords of enlarged, atypical, cuboidal cells had large vesicular nuclei, prominent nucleoli, and pale acidophilic cytoplasm suggestive of TND (Figure 73, A). An abrupt transition from TND to invasive DTGC was clearly identified and confirmed by positive immunostain for IMP3 (Figure 73, B). On gastric resection, a DTGC with positive lymph nodes was identified. The tumor was metastatic to the omentum and stage IV in the 43-year-old whereas it was restricted to the stomach and stage III in the 66-year-old. Although TND is IMP3 negative, the areas of abrupt transition to DTGC become IMP3 positive. In summary, in a small biopsy, the presence of IMP3-positive cells at the advancing front of TND is predictive of DTGC. Additional cases are needed to support our conclusion.

Sarcina ventriculi is an anaerobic gram-positive coccus found in acidic environments that has been increasingly reported in the upper gastrointestinal tract. Infection by S ventriculi has been associated with delayed gastric emptying and, in the setting of gastric ulcers, emphysematous gastritis and gastric perforation. We present 2 cases of S ventriculi infection. The first case is of a 58-year-old man with a history of esophageal adenocarcinoma who had undergone esophagectomy. Follow-up esophagogastroduodenoscopy 8 months later showed an area of erythema in his neo-esophagus and retained food material at the anastomosis. Biopsies taken from the neo-esophagus showed acute esophagitis and Sarcina organisms (Figure 74, A and B). He received no antibiotic treatment and remained asymptomatic. The second case is of a 9-year-old boy with a history of eosinophilic esophagitis and pyloric stenosis who presented with persistent emesis. Esophagogastroduodenoscopy demonstrated purulence with sloughing of the mucosa in his esophagus and an ulceration immediately distal to the gastric antrum. Biopsies of the midesophagus showed ulceration and S ventriculi (Figure 74, C) and the proximal esophagus showed eosinophilic esophagitis. Biopsies of the gastric body also showed rare Sarcina organisms in a background of mild chronic inflammation (Figure 74, D). He was placed on ciprofloxacin and metronidazole with repeat biopsy 2 months later showing no S ventriculi. To our knowledge, we report the first case of S ventriculi infection associated with eosinophilic esophagitis. Although the pathogenesis of S ventriculi is unclear, awareness of the bacteria is important as treatment in symptomatic patients may prevent complications such as gastric perforation.

Solitary fibrous tumor (SFT) is a rare mesenchymal tumor mostly located in the mediastinum and seen in middle-aged adults with no gender predilection. Hepatic SFT is a rare tumor and should be considered in the differential diagnosis of hepatic spindle cell lesions. We are presenting a case of an 88-year-old woman with mildly elevated liver enzymes. CT demonstrated numerous hypervascular liver lesions ranging from 1 to 3 cm (Figure 75, A). Ultrasound-guided liver fine-needle aspiration was performed, which consisted of rare benign hepatocytes and blood elements in the smear. Concurrent percutaneous liver biopsy revealed a bland spindle cell proliferation in a “patternless pattern” (Figure 75, B) with multiple small vessels (Figure 75, C). Tumor cells had low mitotic activity. Immunohistochemical studies were performed and tumor cells were positive for STAT-6 (Figure 75, D), CD34, and Bcl-2 and negative for C-kit, pancytokeratin, S100, SMA, desmin, arginase, and synaptophysin. The histomorphology and immunohistochemical profile were characteristic for SFT. SFT in the liver is a very rare mesenchymal tumor. As this is a mesenchymal lesion, fine-needle aspiration may not always yield a sufficiently cellular smear for definitive diagnosis. The definitive diagnosis is established by the histologic examination and immunohistochemical studies, especially STAT-6. The outcome of SFT mostly depends upon the resectability of the tumor. The patient passed away within a month after the diagnosis secondary to cardiac comorbidities.

We present a case of a 28-year-old woman with no significant medical liver history who presented with a large hepatic mass. Gross examination revealed a 15-cm well-demarcated and unencapsulated mass. Cut sections of the tumor were fleshy white with variably sized smooth-lined cysts. There was focal hemorrhage and myxoid change and no significant necrosis. H&E sections showed tumor cells arranged in glands, microcystic, and cystic patterns with focal nesting and solid growth. There was mild cytologic atypia, no necrosis, and rare mitotic figures. Focal calcifications and small vessel lymphovascular invasion were present. Immunohistochemical stains showed tumor cells stained positive for cytokeratin AE1/AE3, cytokeratin 7, MOC-31, inhibin, and synaptophysin (weak). FOXL2 was focally positive. A Ki-67 proliferation index was 10% overall. Tumor cells were negative for cytokeratin 20, HepPar-1, arginase, glypican-3, PAX-8, TTF-1, GATA-3, ER, PR, chromogranin, CD68, PLAP, SF1, Melan-A, calretinin, WT-1, D2-40, and EMA. Results of a next-generation sequencing assay analyzing mutations in 50 cancer-related genes were negative. To our knowledge, this is the fifth reported case of a hepatic adenocarcinoma expressing inhibin A in a young woman. The term “cholangioblastic variant of intrahepatic cholangiocarcinoma” has been suggested, although the histogenesis is unclear. The distinctive morphology and immunoreactivity for inhibin and neuroendocrine markers are similar to our case. The natural history of this tumor is unclear because of its rarity, although aggressive features have been described. Our patient is alive after 1 year; however, more studies are needed to understand the biology and behavior of this unique tumor.

Sarcina ventriculi is a gram-positive anaerobic organism that can rarely infect human beings. Sarcina is not generally present in the normal healthy human stomach; however, it has been reported in the setting of pyloric ulceration and/or stenosis. To our knowledge, only 19 cases of human infections by this microorganism have been described in literature to date. We present a case of S ventriculi infection in a 71-year-old white man who presented with dysphagia to solid foods. The patient had a past medical history of Helicobacter pylori–positive chronic active gastritis status post therapy eradication. Endoscopic examination revealed congested, edematous-appearing mucosa at the GE junction without frank ulcerations or erosions. Thick yellow material was noted throughout the esophageal mucosa that was difficult to clear with water spray. Gastric and duodenal mucosae were unremarkable. Multiple tissue biopsies showed structures occurring in tetrads with molding and flattening of the cell borders, suggestive of S ventriculi. An interesting highlight of our case was the prior history of H pylori–positive chronic active gastritis, for which he was treated with triple therapy resulting in the eradication of H pylori. This association between S ventriculi and H pylori has only been previously mentioned in 2 cases. The patient in our case was treated with 2 weeks of antibiotics with improvement of his dysphagia symptom. Follow-up repeated esophagogastroduodenoscopy examination revealed the eradication of the microorganism. It is important for pathologists to recognize this rare microorganism and recommend proper clinical management to the clinician (Figure 76).