Abstracts and Case Studies From the College of American Pathologists 2018 Annual Meeting (CAP18)

Hepatobiliary cystadenocarcinoma is an uncommon neoplasm. We report on an unusual hepatobiliary cystadenoma with cystadenocarcinoma transformation. To the best of our knowledge, this is the first case to illustrate the transformation process from benign to malignant within the single mass lesion in liver. A 72-year-old asymptomatic man presented with a liver mass on November 9, 2017, which was 4.5 × 4.5 cm on computed tomography. Fine-needle aspiration was performed on January 9, 2015, and showed no overtly malignant cells; however, the specimen was of limited cellularity. Positron emission tomography scan on September 9, 2015, displayed no significant difference in hypermetabolic activity. Follow-up examination on October 4, 2017, showed increase in mass size to 7.3 × 6.5 cm. The patient underwent hepatic segmentectomy on November 9, 2017, for definitive diagnosis. The resection specimen showed a single pale-tan, firm mass with focally irregular borders. Microscopic examination showed a single mass composed of benign hepatobiliary serous cystadenoma with a transitional zone and small area of carcinoma. Histologically, the tumor showed the typical features of a hepatocystadenoma, which consists of multilocular cysts with a single layer of flattened or cuboidal epithelial cells without underlying ovarian stroma. The malignant area displayed more solid architecture with nests and trabecular or organoid well-differentiated tumor cells. Immunohistochemical studies were supportive of the biliary origin with positive immunohistochemical stains for CK7, CK19, and CEA. Synaptophysin, chromogranin, CD56, and mucicarmine were negative, which excluded neuroendocrine and mucinous neoplasm. Molecular profile analysis showed ARID1A positivity. Follow-up data during 3-month duration showed no evidence of recurrence or metastases (Figure 1).

Ménétrièr disease (MD) is a rare hypertrophic gastropathy characterized by thickening of the gastric mucosa in the form of giant rugal folds, hypochlorhydria, and protein loss. It occurs in 2 forms, depending on the patient's age: (1) adults have progressive disease with insidious onset and significant morbidity and mortality; (2) children usually have sudden onset and the disease is often self-limited. The etiology of MD is still unknown, but the association with cytomegalovirus infection in children has been well documented in previous studies. The risk of malignancy in MD is not yet entirely elucidated. Clinical evidence supports that MD is a disorder involving excess EGFR signaling. Cetuximab, an epidermal growth factor receptor inhibitor, became the first-line therapy for MD and it has been successful in some patients. Our patient was a 48-year-old woman with progressive gastrointestinal symptoms related to MD and transfusion-dependent iron-deficiency anemia for 8 years. Total gastrectomy was performed because she did not have good response to cetuximab and was found to have a 3-cm mass endoscopically. Total gastrectomy specimen showed large torturous gastric folds in gastric fundus and body (Figure 2, A and B). Microscopically, invasive moderately differentiated adenocarcinoma with focal invasion into the submucosa was noted (Figure 2, C). This case nicely illustrates the importance of endoscopic surveillance for detection of early gastric cancer in MD patients.

Context: An important genetic change in pancreatic cancer is the SMAD4 mutation, which leads to the loss of SMAD4 protein expression. Many studies have shown that the loss of SMAD4 expression is associated with poor prognosis. However, other studies have found no correlation between the loss of SMAD4 expression and poor outcome. The goal of the current study was to evaluate SMAD4 expression in the different T, N, and overall tumor stages with the new AJCC 8th edition staging.

Design: Pathology and clinical follow-up database was retrospectively queried for patients who had undergone surgical resection for pancreatic ductal adenocarcinoma between 2014 and 2017. Tumors were restaged according to the new definitions described in the 8th edition AJCC manual.

Results: A total of 110 patients with resected pancreatic ductal adenocarcinomas were included in this study. Overall, 37.3% of cases were positive for SMAD4 expression (Table). Lower-staged tumors had a greater proportion of SMAD4 expression. Among the T1-, T2-, and T3-staged tumors, 60%, 36.8%, and 18.2% of cases showed positive SMAD4 expression, respectively. A higher proportion of tumors with no lymph node metastasis was positive for SMAD4 expression (53.3%); however, there did not appear to be a significant SMAD4 expression difference between cases with N1 and N2 diseases. On average, SMAD4-negative tumors were 0.7 cm larger than SMAD4-positive tumors and were associated with an overall shorter patient survival.

Conclusions: In the present study, preserved SMAD4 expression is associated with lower-staged tumors, smaller tumor size, and higher survival rates compared with tumors showing loss of SMAD4 expression.

Context: We perform immunohistochemistry (IHC) on metastatic neuroendocrine tumors of occult origin to assign primary site, including the pancreas-specific transcription factor islet 1 (ISL1). ISL1-stained liver metastases demonstrate pericentrivenular cytoplasmic hepatocyte staining (Figure 3, A), reminiscent of that seen with glutamine synthetase (GS). GS is diffusely expressed by β-catenin–activated hepatic adenomas (HAs) and some hepatocellular carcinomas (HCCs) and demonstrates maplike/anastomosing staining in focal nodular hyperplasia (FNH).

Design: ISL1 (clone 40.3A4; 1:200) and GS (clone 6/GS; 1:500) IHC were performed on tissue microarrays: 159 HCCs, 45 HAs, 31 FNHs. Staining was diffuse, maplike/anastomosing, or negative (pericentrivenular or absent). For diffuse staining, intensity (0–3+) and extent (0%–100%) were evaluated with an H-score (intensity × extent) calculated. Western blots were performed on mouse liver tissue lysates; GS should react as a 42-kDa band.

Results: Diffuse staining was noted in 77% (mean H-score 126) and 29% (mean H-score 142) of HCCs and 7% (mean H-score 157) and 2% (mean H-score 270) of HAs with GS and ISL1, respectively. Maplike/anastomosing staining was seen in 97% (with GS) and 90% (with ISL1) of FNHs. All ISL1-positive HCCs were GS positive, and ISL1 positivity predominated in tumors with stronger GS positivity. Western blots revealed a prominent 42-kDa band with the GS but not the ISL1 antibody. A less prominent 50-kDa band was detected with both (Figure 3, B).

Conclusions: ISL1 IHC reacts with liver tissue/tumors similarly to GS, though it is less sensitive. Although ISL1 did not react with the major 42-kDa protein in a Western blot of liver tissue, both GS and ISL1 reacted with a minor 50-kDa protein.

Yolk sac tumor (YST) initially presenting as an extragonadal mass is a diagnostic challenge because of histologic variability and tendency to mimic somatic tumors. We present a case of a 27-year-old woman who presented with phlegmon at the ileocecum with a history of ulcerative colitis for more than 10 years. Gross examination showed a large mass in the cecum extending to the ileocecal valve. Histologically, the tumor consisted of sheets of high-grade malignant cells and malignant glands with prominent cytoplasmic clearing and supranuclear and subnuclear vacuolization. Typical colorectal adenocarcinoma–type morphology was not seen. Tumor was positive for AE1/AE3, CDX2, SALL-4, glypican-3, AFP (patchy), CD117 (patchy, weak), and EMA (patchy). The tumor was also focally positive for CK7 and CK20 and negative for PAX8, OCT3/4, arginase, and CD30. Molecular CancerTYPE ID was nonseminomatous germ cell tumor with 90% probability. The morphology, immunoprofile, and molecular features were consistent with YST. The background colon was consistent with ulcerative colitis with no dysplasia. Investigation showed that the right ovary could not be visualized on CT scan, an absence of mediastinal mass, and markedly elevated serum AFP. The patient developed 2 new liver lesions, which were biopsied and showed metastatic YST. YST and colon adenocarcinoma can have histologic and immunohistochemical features that can contribute to diagnostic pitfalls. Recognition of various morphologies of YST and absence of features typical for colorectal adenocarcinoma will lead to correct panel and interpretation of immunohistochemical studies.

Context: CMV infection poses serious risks in immunocompromised patients. The yield for testing lower gastrointestinal (GI) specimens from this group is consistently low. We evaluate features increasing the yield of immunohistochemistry (IHC) and its effect on clinical outcome.

Design: We reviewed all positive lower GI cases during 10 years. Data collected included primary disease, biopsy indication, serologic results, clinical suspicion, treatment, and outcome. We also recorded endoscopic and histologic inflammation grade, virocytes (H&E and IHC), unique histology, and biopsy site and number. Control cases included 51 IHC-negative cases and IHC-negative internal controls from the study group.

Results: Fifty patients were eligible for study. The distribution of underlying disease was similar between study and control patients. Clinical features predicting CMV IHC positivity included positive serology and clinical concern (both P < .001). Uninflamed or mildly inflamed mucosa was more common in CMV-negative biopsies (P = .04). Amongst patients with proven CMV infection, positive biopsy sites tended to have higher levels of eosinophils and more severe inflammation than negative sites. Sixteen of 34 treated patients had adverse outcomes in the test group compared with 8 out of 51 in the control group. Patients with greater than 5 positive cells on CMV IHC were more likely to require colonic resection or suffer mortality compared with those with fewer inclusions.

Conclusions: CMV colitis in immunocompromised patients carries an increased risk of adverse outcomes, which varies by virocyte count. Clinical concern, positive serology, and severe histologic activity help predict which biopsies are most likely to have positive IHC results.

Context: Biliary atresia is the most common pediatric cholestatic disease. It is the most common indication for liver transplant in children. The usual reason for transplant is failure of the Kasai procedure due to repeated episodes of cholangitis and progressive liver fibrosis. Hepatocellular carcinoma (HCC) is an uncommon tumor in the first decade but can be seen in older children in the setting of a metabolic condition. There have been a few case reports of biliary atresia livers developing HCC. The aim of this study was to illustrate these unusual, incidental, and early tumors.

Design: Retrospective review of 3 cases that were received as consults. Clinical information was collected and immunohistochemistry was done for a panel of β-catenin, glutamine synthetase, glypican 3, MOC31 (EPCAM), Prox-1, and SALL4 where possible.

Results: The findings of the cases are summarized in the Table.

Conclusions: The 3 cases of HCC occurred in cirrhotic livers because of failed Kasai for BA. The presence of adenomatous and dysplastic nodules in case 2 and an incipient HCC in case 3 suggests hepatic regeneration may be the initial point in tumorigenesis. The second case illustrates an unusual and unique combination of 2 distinct nodules that suggests coexistent hepatoblastoma (HB) and HCC, which has not been reported before. The β-catenin activation noted only in the HB is interesting, suggesting the possibility of an acquired mutation. The cases illustrate the importance of grossing liver explants in all fibrotic livers with the aim of detecting small (<1 cm) nodules that may not be detected by imaging techniques prior to transplant.

Context: In the United States there are more than 130 000 new cases of colorectal cancer annually. Characterizing mutations involved in the pathogenesis of colorectal adenocarcinoma is an important step toward developing gene-based therapies. Next-generation sequencing (NGS) enables screening for variants in large panels of genes in tissues.

Design: We collected formalin-fixed, paraffin-embedded tissue from rectal adenocarcinoma cases, including biopsy and surgical resection specimens. Patients came from 2 groups: those with a complete response (CR) to preoperative therapy (n = 8), and those who responded poorly (NR, n = 8). NGS using the Human Comprehensive Cancer GeneRead DNAseq Targeted Panel, which screens for variants in 160 genes, was performed.

Results: In both groups we found mutations in genes previously implicated in colorectal cancer, including PTEN and NF1. Mutations in genes that have not been described in colorectal cancer, such as GNAQ (3 of 8 CR and 5 of 8 NR) and ATM (5 of 8 CR and 5 of 8 NR), were also identified.

Conclusions: GNAQ codes for a guanine nucleotide-binding protein that couples transmembrane receptors to intracellular pathways. Mutations have been reported in melanoma and ocular neoplasms. ATM is involved in cell division and repairing damaged DNA. ATM mutations have been described in several cancers, including breast and pancreatic. GNAQ and ATM mutations are novel findings in rectal carcinoma, present in 50% and 62.5% of specimens, respectively. Interestingly, all patients with the GNAQ mutation harbored the same variant. Going forward, we will confirm these mutations in additional specimens, and compare the mutation profile between NR and CR to identify mutations that predict response to therapy.

Epithelioid angiomyolipoma (EAML) of the liver is a rare neoplasm and is often misdiagnosed as a malignant neoplasm, such as hepatocellular carcinoma, because of nonspecific clinical and radiologic features. The histomorphology and immunohistochemical staining profile are important in the diagnosis of EAML. We report a case of a 46-year-old woman with a 6-month history of abdominal pain who was found to have a 2.4-cm liver mass on CT scan corresponding to a LI-RADS (Liver Reporting and Data System) category LR5 lesion (ie, highly suspicious for hepatocellular carcinoma). Liver biopsy was performed and a diagnosis of EAML was made. Later, the patient underwent liver segmentectomy (Figure 4, A). Microscopically (Figure 4, B) the tumor was composed of epithelioid cells in nests and sheets with vacuolated and pink granular cytoplasm. Nuclei were oval to round with a few prominent nucleoli. No cytologic atypia, necrosis, or mitosis was present. The tumor showed focal fatty component and few abnormal thick-walled blood vessels. Immunohistochemically, the neoplastic cells were positive for Melan-A, HMB-45 (Figure 4, C), and SMA (Figure 4, D), and negative for S100, HEPAR1 arginase, CAM 5.2, and AE1/AE3. The final diagnosis was EAML. This uncommon tumor with clinical and radiologic features that mimic hepatocellular carcinoma presents a diagnostic challenge to clinicians and radiologists. Moreover, the epithelioid variant of angiomyolipoma usually lacks or shows minimal fatty component and abnormal thick-walled blood vessels, which further presents a diagnostic challenge to pathologists. Careful histologic examination and appropriate immunohistochemical staining are essential to reach the correct diagnosis.

Context: Drug-induced liver injury (DILI) and herbal/dietary supplement (HDS)–related liver injury is a rare idiosyncratic reaction with potentially devastating clinical outcomes. It may present unique diagnostic challenges and require a close collaboration between the clinician and the pathologist for an accurate diagnosis.

Design: A retrospective review of all clinically proven patients with DILI/HDS who presented to our institution from January 2013 through December 2017 was performed. In each case, slides were rereviewed for assessment of the histopathologic pattern of injury and correlated with the causative agent.

Results: Thirty-five cases of DILI/HDS were identified (male to female ratio = 1:1.7; age range, 18–79 years; median age, 52 years). Histopathologic patterns of injury and corresponding causative drugs/HDSs are summarized in the Table. Acute hepatitis (45.7%) was the most common histopathologic pattern of injury and nonnecrotizing granulomatous hepatitis (2.9%) was the least common. The majority of the histopathologic patterns of injury were consistent with those previously reported in the literature; however, 2 unusual cases of cholestatic hepatitis with bile duct injury and steatosis due to dronedarone and hydroxycut and 1 case of steatohepatitis due to trimethoprim-sulfamethoxazole were identified. Furthermore, we report 2 cases of cholestatic hepatitis due to the use of trimethobenzamide hydrochloride and rizatriptan that have not been previously reported.

Conclusions: In our study, most cases displayed “typical” histopathologic patterns of DILI/HDS. However, some new patterns of hepatic injury were also observed, reaffirming the pivotal role of the clinician and hepatopathologist in the care of patients with DILI/HDS.

Context: Practices have used reflexive ancillary testing to aid in the detection of intestinal metaplasia (IM) in gastric biopsies; however, this system has been increasingly questioned. We assessed the impact cessation of reflex Alcian blue (AB) histochemical staining had on rates of gastric IM detection and correlated these findings with the background gastric histologic findings.

Design: Gastric biopsy reports for 6 months preceding (reflex period) and 6 months immediately following the cessation of upfront AB staining (selective period) were reviewed. Reports were assessed for the presence or absence of IM, if AB was performed, and the existence of background mucosal disease.

Results: A total of 2411 reports were reviewed, with 1145 during the reflex period and 1266 during the selective period. IM was diagnosed in 191 (7.9%), with 109 of 1145 (9.5%) in the reflex period and 82 of 1266 (6.5%) in the selective period, a difference that proved significant (P = .006). There was no statistical difference between the rates of IM detection between the periods in chronic inactive gastritis (10.3% versus 9.9%, P = .91) or reactive gastropathy (5.7% versus 4.1%, P = .50). However, examination of the rates of IM diagnoses in cases of active gastritis revealed a decrease of approximately 45% in the selective period during the reflex period (21.8% versus 11.9%, P = .01).

Conclusions: Cessation of upfront AB staining may be associated with an overall decrease of IM detection in gastric biopsy material; however, it is largely isolated to cases of active gastritis. Attention must be given when evaluating cases with this finding as robust inflammation may mask subtle IM.

Context: Diagnosing pancreatic ductal adenocarcinoma (PDAC) in the setting of metastasis with an unknown primary remains very challenging because of the lack of specific biomarkers.

Design: Using tissue microarray and immunohistochemistry, we investigated the protein expression pattern of transcriptional factor HNF-1B in 127 primary PDACs, 17 metastatic PDACs, and 278 nonpancreatic carcinomas.

Results: HNF-1B was expressed in all nonneoplastic pancreaticobiliary epithelium of the primary pancreaticobiliary carcinomas. HNF-1B was immunoreactive in 84.3% of PDACs, 81% of cholangiocarcinomas, 72% of ampullary carcinomas, and 92.9% of gallbladder adenocarcinomas. Notably, HNF-1B expression was expressed in 94.1% of metastatic PDACs. Among nonpancreaticobiliary cancers, HNF-1B was immunoreactive less frequently in clear cell carcinomas of the kidney and Müllerian origins. Gastroesophageal, lung, and prostate adenocarcinomas occasionally expressed HNF-1B in up to 37% of cases. HNF-1B was completely negative in hepatocellular, colorectal, breast, and lung squamous cell carcinomas. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of HNF-1B for primary pancreaticobiliary carcinoma are 84%, 68%, 66%, 85%, and 75%, respectively. The overall survival of PDAC patients was significantly associated with tumor size ≥2 cm and high tumor grade by multivariate analysis.

Conclusions: In conclusion, HNF-1B may have a utility to aid in the diagnosis of metastatic pancreaticobiliary carcinoma with a panel of other markers to exclude lung, kidney, prostate, and Müllerian origins.

Context: Cellular senescence is one mechanism of cell-cycle arrest regulating proliferation. Key cell-cycle regulators (CCRs) such as p16, p21, and p27 are thought to be involved in tumor senescence (TS) through initiation and maintenance. TS has been shown to have possible links to chemotherapy resistance and tumor progression. In archival tissue CCRs may be used as surrogate markers for senescence. There is a paucity of data determining the significance of TS in the setting of pancreatic ductal adenocarcinoma (PDA). We evaluate key CCRs involved in TS and their prognostic value in PDA.

Design: Tissue microarrays (TMAs) were created using formalin-fixed, paraffin-embedded tissue from PDA cases identified in pancreatectomies performed at our institution from 2005 to 2016. Cases lacking complete clinical information were excluded. The TMAs were then stained for p16, p21, p27, and p53 using standard immunohisto-chemistry. Two independent reviewers used the Allred scoring method to score each case. Statistical analysis included Kendall coefficient of concordance (KC) between reviewers, adjusted Cox proportional hazard models, and ANOVA models using tumor grade, gender, and race.

Results: This study included 69 cases of PDA. p27 expression was found to be a significant predictor of outcome with an unadjusted HR of 1.23 (1.05–1.44; P = .01), and an adjusted hazard ratio of 1.30 (1.09–1.54; P = .003). KC between reviewers was >0.800 for p16, p21, and p53; KC for p27 was 0.653.

Conclusions: The association of increased expression of p27 with a higher risk of mortality suggests that p27 expression may have prognostic value in PDA. A larger cohort would be useful in confirming this association.

Azathioprine is an immunosuppressant commonly prescribed to patients who underwent organ transplant to prevent transplant rejection. Patients on this medication can potentially experience different types of adverse effects, including myelosuppression, malignancy, and hepatitis. Acute cholestatic injury, one of the forms of hepatotoxicity, is often a self-limiting disease that occurs at a rate of 1 in 1000 patients taking this medication. We present a rare case of acute cholestatic injury in a patient taking azathioprine that eventually led to failed transplanted liver. Our patient is a 60-year-old man with a history of orthotopic liver transplant several years prior to presentation because of cirrhosis from hepatitis C virus. The patient had been doing well until he started looking “yellow” while asymptomatic otherwise. A complete metabolic panel ordered by his primary care physician showed significant transaminitis, and his liver biopsy at admission showed moderate to severe acute cellular rejection. Throughout his hospital course, the patient kept deteriorating despite clinical care from multiple specialties and eventually had to undergo a repeat liver transplant. Examination of the transplanted liver showed marked zone 2 and 3 ischemic changes, mild periportal inflammation, and an extensive, marked panlobular cholestatsis. Review of the literature confirms that such findings are consistent with findings of azathioprine-induced liver injury. We present this rare case of drug-induced liver injury to highlight the importance of keeping azathioprine as a differential diagnosis when encountering liver specimens with the aforementioned histomorphology, as early detection is a key to successful patient care.

Context: Not infrequently, an incidental pT1 adenocarcinoma is completely removed by polypectomy. Despite considerable literature on the subject, the parameters that determine whether or not subsequent surgery is indicated are still uncertain. Our aim was to address this issue by comprehensively analyzing various histologic factors in these tumors that could indicate a risk for nodal disease.

Design: Our study included a retrospective cohort of all polypectomies harboring an incidental adenocarcinoma that had subsequent segmental resection for nodal staging and no residual primary tumor. Various histologic parameters were assessed, namely, size of polyp, size of invasive focus, distance from deep margin, deep margin positivity, tumor differentiation, tumor budding, lymphovascular invasion, peritumoral chronic inflammation, and type of desmoplastic reaction. These features were compared with the binary outcome variable of lymph node positivity at resection using Excel 2013 (Microsoft, Redmond, Washington).

Results: There were a total of 57 cases identified in this cohort, with all slides available for review. Although polyp size correlated with size of invasive tumor (P < .001), none of the histopathologic factors examined (Table) showed any correlation with lymph node status other than the presence of myxoid, immature desmoplastic stroma (as opposed to collagenous, mature desmoplastic stroma) with a 12.75 odds ratio (95% CI, 1.41–115).

Conclusions: Recent studies have shown the prognostic significance of the type of stromal response in colorectal adenocarcinomas, but this is the first study to show the significance in pT1 adenocarcinomas arising in a polyp. This is an interesting and unexpected finding, and needs studies on larger cohorts for further validity.

Context: Gastrointestinal granular cell tumors (GCTs) are rare; the most common site is esophagus (eGCT). Recent literature suggests a link between eosinophilic esophagitis (EOE) and eGCT. The aim of our study was to determine if EOE or other disorders associated with eosinophilia are consistently associated with eGCT.

Design: We retrospectively searched our pathology database from 1999 to 2018 for eGCTs. Archived slides and medical records were reviewed.

Results: Twenty-two patients (12 men and 10 women; age range, 33–66 years; median age, 48 years) had eGCT (size range, 0.04–2.0 cm; median, 0.6 cm). Thirteen had a history of gastroesophageal reflux disease, 4 had Barrett esophagus, and 1 had EOE. Fifteen eGCTs had intralesional eosinophils (6 with peak >10 eosinophils/×400 high-power field [hpf]); of these, 12 also had eosinophils in lamina propria (5 with peak >10 eosinophils/hpf). eGCTs with atypical features (including nuclear enlargement and prominent nucleoli) were more likely to have increased eosinophils in nonepithelial compartments than those without atypia. Pleomorphism and spindled cells were seen in 5 eGCTs (mean peak intralesional eosinophils, 27.2 per hpf); 2 of these had Barrett esophagus. The single eGCT in EOE had only 2 intralesional eosinophils/hpf.

Conclusions: We found no association between EOE and eGCT. Instead, most patients had gastroesophageal reflux disease or Barrett esophagus. eGCT patients with significant eosinophilic infiltrates (peak >10/hpf) in esophageal lamina propria also had significant intralesional eosinophils. Eosinophilia, common in eGCT and adjacent stroma, likely drives atypical/reactive histologic features, but a pathogenetic relationship between eosinophil-rich inflammatory conditions and eGCT has not yet been established.

Context: Cytomegalovirus (CMV) is a globally prevalent virus that infects immunocompromised and immunocompetent patients. CMV colitis is a common manifestation in immunocompromised patients and mimics other diseases. This leads to delayed diagnosis and adverse outcomes. This study aims to assess clinicopathologic predictors of CMV colitis including associated diseases, gastrointestinal symptoms, endoscopic findings, and histologic findings.

Design: We searched our electronic pathology database for patients diagnosed with CMV colitis and identified 117 cases between 2003 and 2017. Clinical features, endoscopic findings, and histologic findings were reviewed.

Results: Patients ranged from 17 to 80 years old (median, 53 years) with a male to female ratio of 1.3:1. At diagnosis, 115 patients (98%) were immunocompromised and 2 (2%) were immunocompetent. Immunocompromised patients' histories included solid organ transplant (57%), bone marrow transplant (20%), IBD (9%), HIV (9%), recent chemotherapy (3%), and concurrent autoimmune disease (2%). These patients presented with diarrhea (87%), bloody diarrhea (8%), hematochezia (3%), severe anemia (1%), and rectal pain (1%). Endoscopic findings included erythema, edema, ulceration, friability, exudate, and mass formation. CMV viral inclusions were present on H&E in 72 patients (61%), and 45 (39%) required immunohistochemistry. Characteristic histologic findings included minimal to severe active colitis with cryptitis, crypt abscesses, and increased crypt epithelial apoptosis. Four patients showed evidence of concurrent graft-versus-host disease. Immunocompetent patients' histories included end-stage renal disease and a history of unprotected anal sex.

Conclusions: To predict CMV colitis risk, assessment of associated diseases and clinical symptoms is crucial. The pathologist should be vigilant about CMV colitis in immunocompromised patients with diarrhea and a history of solid organ/bone marrow transplant.

Microsatellite instability (MSI) contributes to carcinogenesis, tumor behavior, therapeutic efficacy, and prognosis. Sporadic MSI and Lynch syndrome cancers are histologically indistinguishable. Generally, MSI tumors are less aggressive, associated with earlier stages and devoid of lymphovascular invasion. However, we have encountered MSI tumors demonstrating highly invasive behavior, lymphovascular involvement, and distant metastasis. It is pivotal to recognize these ominous features and uncover the molecular alteration when investigating MSI; such information would significantly impact clinical decision making and patient outcome. Two resected MSI tumors were analyzed. The histomorphology, immunoprofile, and next-generation sequencing (NGS) findings were investigated and discussed. The first case was a hepatic flexure colonic adenocarcinoma in a 69-year-old woman; the tumor perforated the colon and invaded into duodenum and omentum despite concurrent FOLFOX chemotherapy. Further tests revealed that MLH1 and PMS2 were absent in tumor, whereas NGS identified BRAF V600E mutation. The second case was a left colon adenocarcinoma in a 76-year-old man. The tumor perforated the colon and stomach and metastasized to the liver. Immunostains showed loss of MLH1 and PMS2 (Figure 5, A through D); NGS identified KRAS and TP53 mutations. Based on these findings, the patients received modified postsurgery chemotherapy, with no evidence of recurrence 1.5 years later. MSI does not necessarily mean a less-aggressive clinical course. Comprehensive approaches should be taken to identify the culprit(s) underlying/in addition to MSI. Such testing should be uniformly performed to best guide effective and targeted therapeutic strategies. These efforts will fine-tune and improve the treatment regimens and influence the genetic counseling of patients' families.

There are minimal reports on microsatellite instability in unresectable gastrointestinal squamous cell carcinomas (SCCs), which are clinically challenging to manage; less than one-third of such tumors showed responses to conventional chemoradiation therapy. In light of the development of immunotherapy for combating a spectrum of malignancies, impeding immune inhibitory mechanisms in gastrointestinal SCCs targeting programmed cell death protein 1 and its ligand should be considered as a novel strategy. We report herein a novel case of microsatellite-instable anal SCC that showed dramatic clinical response to pembrolizumab following initial ineffective chemoradiation therapy. An 81-year-old man presented to our institute because of a history of hypertension, hyperlipidemia, stroke, and advanced anal SCC. He was not a surgical candidate because of his comorbidities; his SCC progressed after 6 cycles of cisplatin chemotherapy and radiation at an outside hospital. His biopsy was reviewed and confirmed at our institute to be a P16- and HPV-negative moderately differentiated SCC. Of note, additional immunostains demonstrated loss of mismatch repair proteins MLH1 and PMS2 and retained MSH2 and MSH6 in his tumor; molecular studies indicated microsatellite instability. Subsequently, cisplatin was switched to pembrolizumab. After 3 cycles, both the tumor and originally prominent lymphadenopathy showed significant responses. Currently the patient has finished 4 cycles of pembrolizumab, with clinical evidence of disease regression. Microsatellite instability and immunotherapy should be considered for optimizing management of advanced gastrointestinal SCCs, especially for those challenging cases that failed chemoradiation therapies or when patents are not surgical candidates.

Context: In transplant patients, the gastrointestinal (GI) tract is affected by the immunocompromised state, therapies, and underlying diseases. We studied the spectrum of GI pathologies in hematopoietic stem cell transplant recipients.

Design: In a retrospective chart review, 27 years of departmental archives in pathology were searched for pediatric GI biopsies with clinical history of hematopoietic stem cell transplant.

Results: Of 82 patients, comprising 70 (85.4%) bone marrow and 12 stem cell transplants, 38 biopsies (46.3%) were performed within 100 days of transplant. Among 43 esophageal biopsies, 13 (30.1%) showed esophagitis, including 1 herpetic infection, and 9 (20.9%) represented graft-versus-host disease (GVHD). Of 64 gastric biopsies, 28 (43.8%) showed GVHD (mostly grade I), 1 (1.5%) had EBV⁺ posttransplant lymphoproliferative disorder, and 1 expressed recurrent Hodgkin lymphoma. Among 69 duodenal and 22 terminal ileum biopsies, 29 (42.0%, mostly grade II) and 8 (36.3%) represented GVHD, respectively. Eighty-two colon biopsies showed 43 with GVHD (52.4%): of 8 right colon biopsies, 4 (50%) had cryptitis and 1 (12.5%) had GVHD, and 5 (41.7%) GVHD, 3 (25%) cryptitis, and 1 EBV⁺ posttransplant lymphoproliferative disorder were appreciated in 12 left-colon biopsies. Also, 6 (35.2%) GVHD including 1 CMV⁺ subject and 5 (29.4%) cryptitis were identified in rectosigmoid colon (n = 17). There were 45 nonspecified colon biopsies, representing most frequently 28 GVHD (62.2%) and 5 (11.1%) active colitis with cryptitis. Posttransplant lymphoproliferative disorder was seen in the same patient.

Conclusions: A broad variety of GI pathology has been observed. The incidence of GVHD was from 20.9% to 52.4% at different locations, with more severity in duodenum. Posttransplant lymphoproliferative disorder was seen in 1 patient (1.2%) at 2 different sites.

Primary synovial sarcomas of the gastrointestinal tract are extremely rare, and within that group, a majority are reported in the upper gastrointestinal tract (eg, esophagus and stomach). We present the second reported case (to our knowledge) of primary synovial sarcoma of the rectum. A 48-year-old woman presented with hematochezia and was found on initial colonoscopy to have an exophytic rectal tumor. Biopsy showed a high-grade, poorly differentiated tumor that was positive for CKAE1-3 (focal), EMA (focal), vimentin (diffuse, strong), CD99 (diffuse, strong cytoplasmic with membrane accentuation), and BCL-2 (diffuse, strong). The tumor was negative for CAM5.2, neuron-specific enolase, S100, CD10, CD34, CD117, muscle-specific actin, smooth muscle actin, and desmin. The MiB-1 value was 15%. Molecular studies for the SYT-SSX1 and SYT-SSX2 fusion transcripts via reverse transcription polymerase chain reaction were done and were positive for the SYT-SSX1 fusion transcript. The patient underwent a low anterior resection and there was a 6.3 × 4.1 × 4.0-cm mass that extended through the muscular layer into the perirectal adipose tissue with 4 of 18 lymph nodes positive for malignancy. Recurrence occurred approximately 1.5 years after resection and despite systemic chemotherapy, the patient died 46 months after her first tissue diagnosis. This case is important because not only does it add to the literature and provides a stark contrast to the other case of synovial sarcoma of the rectum, it also highlights the importance of immunohistochemistry and molecular studies when approaching synovial sarcoma of unusual location.

Gangliocytic paraganglioma (GP) is a benign mixed neuroendocrine tumor, typically seen in the second part of duodenum. Here we present a rare case of GP in the duodenum with a spindled morphology and diffuse positivity for CD117, mimicking gastrointestinal stromal tumor (GIST). A 66-year-old man had an upper gastrointestinal endoscopic ultrasound revealing a 22-mm submucosal mass in the second part of the duodenum near the ampulla. The biopsy showed a spindle cell lesion that was diffusely positive for CD117 and interpreted as consistent with GIST. CT imaging showed a 3.3-cm mass without extramural extension. Partial duodenectomy showed a well-circumscribed tumor centered in the submucosa. The tumor was composed of cellular proliferation of epithelioid to spindle cells arranged in nests and trabeculae separated by delicate fibrovascular septae. The tumor cells were diffusely and strongly positive for CD117, synaptophysin, chromogranin, and CD56 but negative for DOG1 and CD34. S100 highlighted the spindle cells adjacent to the fibrous septa. Rare ganglion cells were identified within the tumor, confirming the diagnosis of GP. CD117 positivity in GP is rarely described. In small biopsies this diagnosis is very difficult, as not all 3 components may be sampled. Moreover, it may be misdiagnosed as a GIST. Distinguishing between these tumors is critical because the treatment is markedly different. The use of multiple immunohistochemical markers may assist in arriving at the correct diagnosis. This case highlights the importance of considering GP in the differential diagnosis of mesenchymal submucosal lesions in the second part of duodenum.

Drug-induced liver injury (DILI) occurs frequently and accounts for more than 40% of all fulminant hepatic failure (FHF) patients in the United States. Most of the DILI cases that result in FHF are secondary to acetaminophen. Here we present a case of FHF in a female patient who was started on levetiracetam for 2 weeks (500 mg/6 h) to manage seizure following an ischemic stroke. The patient presented to the emergency room with hypotension, delirium, and markedly elevated liver enzymes (baseline: ALK, 106 U/L; ALT, 51 U/L; and AST, 91 U/L; presentation: ALK, 217 U/L; ALT, 692 U/L; AST, 1532 U/L). All other laboratory study results, including viral hepatitis panel, CMV, EBV, HIV, HSV, acetaminophen level, α₁-antitrypsin, anti–smooth-muscle antibody, ceruloplasmin, and immunoglobulin level, were unremarkable. The patient's serum levetiracetam level was notably elevated at 80 μg/mL (normal range, 12–46 μg/mL). Levetiracetam and atorvastatin were stopped upon consideration of drug-induced liver injury. However, within 48 hours of admission, the patient's condition deteriorated and she passed away. At autopsy, findings consistent with a toxic liver injury were identified. Histologic findings include the diffuse centrilobular pattern of necrosis, cholestasis, and mild lymphocytic inflammation in a background of steatosis (Figure 6, A and B). No histologic findings of portal vein obliteration or advanced fibrosis were identified, confirming acute medication injury as the cause of her liver injury. The few previously published case reports describing this association are reviewed, and the importance of liver function test in patients on levetiracetam should be kept in mind.

Solid pseudopapillary neoplasm (SPN) is a rare low-grade neoplasm that accounts for 1% to 2% of all pancreatic exocrine neoplasms. More than 90% of reported cases have occurred in young women, with a higher prevalence in black and Asian populations. Herein we report an unusual case of a 78-year-old white man who presented with SPN metastasis in the liver. The patient was diagnosed with an SPN 15 years ago, for which he underwent distal pancreatectomy. He was found to have adrenal metastases 11 years later, and underwent adrenalectomy. The patient underwent partial hepatectomy without neoadjuvant therapy. Grossly, the 4.5 × 4.5 × 2.3-cm resected mass was well circumscribed with tan-yellow cut surfaces. The majority of the mass was necrotic, but it did demonstrate a focal area of viable tumor cells at the periphery. Microscopically, the tumor exhibited pseudopapillary architecture due to cuffing of the small blood vessels by neoplastic cells, which had moderate amounts of eosinophilic cytoplasm. The nuclei were small, round, and uniform, with some demonstrating focal longitudinal grooving. Immunostaining demonstrated absence of AE1/AE3, chromogranin, and synaptophysin expression. Staining for β-catenin revealed aberrant nuclear localization, confirming the diagnosis of SPN (Figure 7, A through D). Although SPN often follows an indolent clinical course with low malignant potential, metastases can present even a decade after complete resection. Furthermore, prior case series have suggested SPNs in males behave more aggressively than the traditional indolent course that is seen in females with SPNs. Therefore, SPN should continue to be entertained as a possibility even years after definitive surgery, especially in male patients.

Mixed acinar-neuroendocrine tumors (ACCNETs) of pancreas are extremely rare and introduce a diagnostic challenge because of heterogeneous chymotrypsin immunoreactivity and overlapping morphologic features. We report a 64-year-old woman who initially presented with abdominal pain and was found to have a pancreatic body/tail mass measuring 11 × 10.6 cm. Fine-needle aspiration showed a neuroendocrine carcinoma with a high proliferative index (Ki67 = 90%) (Figure 8, A and B). Subsequently, she underwent distal pancreatectomy and splenectomy, which revealed metastatic pancreatic neuroendocrine carcinoma positive for chromogranin, synaptophysin, and CD56 (Figure 8, C) and negative for chymotrypsin. Resection was followed by chemoradiation; however, disease recurred. Microsatellite instability (MSI) testing showed an MSI-high tumor. Whole-exome sequencing revealed multiple alterations with no approved targeted therapy, including somatic mutations in MLH1, MEN1, and NF1. These variants were not seen in germline DNA. Interestingly, transcriptome analysis showed high expression of trypsinogen and chromogranin A and moderate expression of pancreatic lipase, synaptophysin, and chymotrypsinogen, raising the possibility of an ACCNET. Repeat chymotrypsin stain (Figure 8, D) on several tumor blocks showed focal positivity, supporting the diagnosis of ACCNET. The patient's disease progressed despite chemotherapy and immunotherapy. She died with widespread metastatic disease 18 months after diagnosis. ACCNET is a diagnostic challenge, requiring combination of different diagnostic modalities. Our understanding of the long-term, postoperative course of the disease and effective treatment options is limited because of the rarity of this entity and no established consensus.

Hepatic epithelioid hemangioendothelioma (HEHE) is a rare vascular neoplasm with uncertain risk factors. HEHE may be multifocal and bilobar, necessitating transplantation. Extrahepatic disease is often present and not a contraindication to transplant. We report a case of HEHE with recurrence 10 years posttransplant. A 42-year-old woman with pruritus and right upper quadrant pain presented for liver transplantation. Medical history included primary biliary cirrhosis treated with ursodiol. Ascites and hepatosplenomegaly were present. Laboratory findings included elevated alkaline phosphatase (281 U/L), total bilirubin (2.3 mg/dL), AST (49 U/L), and ALT (39 U/L). Antinuclear antibodies were present (titer 1:1280; homogenous pattern). Imaging demonstrated liver and lung masses with epithelioid hemangioendothelioma confirmed on biopsy. Histologic examination of the explanted liver demonstrated CD34-positive epithelioid cells in fibromyxoid stroma with intracytoplasmic lumina, some containing erythrocytes (Figure 9, A and B). A cirrhotic background was present. Features of primary biliary cirrhosis were not identified. Posttransplant imaging demonstrated liver masses in the first 2 years after transplant, which subsequently resolved. Fibrosis was identified on imaging after 1 year. At 9 years, the liver appeared to be macronodular with bandlike fibrosis. Histologic examination of core biopsies did not demonstrate recurrence. Ten years after transplant, the patient developed ascites, abdominal pain, and fever. Biopsy demonstrated recurrent HEHE with bands of CD31-positive and CD34-positive elongate cells and intracytoplasmic lumina in fibrous stroma (Figure 9, C and D). HEHE is a malignant tumor with an incidence of 1 per million. Awareness of this disease is important as transplantation may allow long-term survival even in metastatic disease.

Context: Colorectal adenocarcinoma (CRA) is the fourth most common cancer in the United States. Immunohistochemical (IHC) assessment of mismatch repair status can identify CRAs that are MMR deficient (dMMR), which may impact prognosis and treatment. Carbonic anhydrase IX (CAIX) is a transmembrane glycoprotein that is expressed with tumor hypoxia. CAIX expression has been associated with adverse prognostic factors in other cancers. In our study, we examined CAIX expression in dMMR CRAs, which is not well documented in the literature.

Design: Sixty-three CRAs were included in a tissue microarray. CAIX IHC was performed and graded based on staining intensity (0–3+) and percentage of epithelial tumor staining.

Results: CAIX IHC expression was identified in 50 of 61 cases (82.0%), without statistically significant difference among tumor grades. There was increased expression of CAIX in the deep leading edge of the tumor in 44% of cases, whereas 56% of cases demonstrated decreased or no difference in CAIX expression. Necrotic tumors demonstrated CAIX expression in 18 of 23 cases (78.26%) versus 25 of 36 nonnecrotic tumors (69.4%, P = .46). CAIX expression was present in 61.9% of lymph nodes/tumor deposits.

Conclusions: Although high CAIX expression was not associated with morphologic features or nodal status, it was identified in a majority of the dMMR CRAs in this study. Prior studies have demonstrated high CAIX expression in tumors from patients with Lynch syndrome. The tumor hypoxia and acidic tumor environment may contribute to genomic instability in these tumors. More studies are needed, but high CAIX expression may have future therapeutic implications.

Multiple endocrine neoplasia type 2B (MEN2B) is a rare, aggressive autosomal dominant hereditary syndrome characterized by medullary thyroid carcinoma, pheochromocytoma, mucosal neuroma, intestinal ganglioneuroma, and marfanoid habitus. Patients may variably present with nonspecific symptoms, including deceased muscle tone and constipation. MEN2B is caused by RET mutation located on chromosome 10q11.2. The majority of the patients carry a de novo mutation. All patients with MEN2B will develop early-onset medullary thyroid carcinoma, which determines overall clinical prognosis. The American Thyroid Association recommends prophylactic thyroidectomy before the age of 1 year. Given the typical delay in diagnosis because of high rate of de novo RET mutation and lack of family history, improved knowledge of the nonendocrine manifestation is crucial in early diagnosis and optimizing clinical management. We report a case where an 8-year-old boy with a history of severe constipation was hospitalized for abdominal distension, fecal impaction, and sepsis. Endoscopic biopsy revealed gastrointestinal submucosal microscopic ganglioneuromatosis without mass-forming lesions. Together with his marfanoid appearance and “blubbery lips” with multiple mucosal neuromas on clinical examination, suspicion for MEN2B was raised. Workup revealed moderately elevated serum calcitonin and bilateral small thyroid nodules on ultrasound. Subsequent genetic testing confirmed RET codon M918T mutation and the diagnosis of MEN2B was established. Total thyroidectomy and pretracheal lymph node excision were performed. Pathology demonstrated bilateral multifocal medullary thyroid carcinoma and metastasis to the pretracheal lymph node. This case demonstrates that gastrointestinal submucosal microscopic ganglioneuromatosis is an important pathologic finding that should raise the suspicion for MEN2B.

Primary liver neoplasms comprise <2% of all pediatric tumors. Because up to 75% of pediatric liver tumors are malignant, it is crucial to differentiate malignant lesions from benign tumors to avoid unnecessary surgery. The most common benign hepatic mass lesions include hemangioma and focal nodular hyperplasia (FNH). FNH accounts for <2% of all pediatric liver tumors, and the median age at diagnosis is 8.6 years. Here, we report a rare case of FNH at an unusually young age of 16 months. A previously healthy boy presented with a newly identified palpable abdominal mass, decreased appetite, and weight loss. Elevated AFP and normal β-hCG were found on laboratory studies. Abdominal MRI showed a large left hepatic lobe mass (7.3 × 5.9 × 4.9 cm). An IR-guided biopsy revealed hyperplastic hepatocyte nodules separated by thick fibrous septa with embedded bile ductules and thick-walled blood vessels, reminiscent of cirrhosis (Figure 10, A). Nonclonal deletion of the long arm of chromosome 1 was detected by chromosomal analysis. Immunohistochemistry studies revealed geographic staining for Glutamine synthetase and cytoplasmic staining of β-catenin (Figure 10, B and C). These histomorphologic features and immunohistochemistry staining results were consistent with FNH. A lateral segmentectomy (segments 2, 3) was performed. Grossly, a bulging subcapsular mass with patchy tan-white areas on cross section was observed (Figure 10, D through F). The patient's postoperative course and follow-up has remained uneventful. The pathogenesis of FNH is presumed to involve a congenital vascular anomaly with localized interruption of blood flow, which results in hyperplasia of the remaining hepatic parenchyma.

Context: Recent studies identified HOXB13 (G84E) mutation is the most common germline mutation associated with prostate cancer. Men with this mutation have a 10- to 20-fold increased risk of prostate cancer. HOXB13 maintains a high expression level into adulthood in normal prostate and distal colon. We recently found that HOXB13 is down-regulated in ductal adenocarcinoma of prostate. Thus, we would like to investigate the expression of HOXB13 in rectum/sigmoid adenocarcinoma.

Design: We collected 53 cases of colon adenocarcinoma: 5 from cecum and 48 from rectum/sigmoid. The blocks containing both normal mucosa and carcinoma were subjected to HOXB13 immunostaining. Immunostaining was carefully examined to determine presence or absence of nuclear staining of HOXB13.

Results: For all 5 cases of cecum adenocarcinoma, both normal mucosa and carcinoma were negative for HOXB13. For rectum/sigmoid adenocarcinoma cases, all 48 (100%) normal mucosa was positive for HOXB13. However, only 6 of 48 (12.5%) cases of rectum/sigmoid adenocarcinoma were positive for HOXB13; a majority of them (42 of 48 cases; 87.5%) showed loss of HOXB13 expression (Figure 11, A through D).

Conclusions: This is the first study of HOXB13 expression in colonic adenocarcinoma. Compared with benign colonic glands, a majority of rectum/sigmoid adenocarcinoma showed loss or decrease of HOXB13 expression. Our data suggest that down-regulation of HOXB13 is important for rectum/sigmoid adenocarcinoma carcinogenesis. Further studies including sequencing of HOXB13 in rectum/sigmoid adenocarcinoma are warranted.

Context: Schwann cell hamartoma, formerly known as mucosal neurofibroma, is frequently found in the form of small polyps in the large intestine. These lesions are positive for S100, perhaps with more intensity than neurofibroma.

Design: To investigate the expression of SOX-10 and calretinin in Schwann cell hamartoma, 3 lesions from appendix and ascending and sigmoid colon were identified. Immunohistochemistry with antibodies for SOX-10, calretinin, S-100, Mart-1, and HMB-45 was performed.

Results: All lesions were strongly and diffusely positive for S-100 (cytoplasmic and nuclear), SOX-10 (nuclear), and calretinin (mainly dotlike cytoplasmic and in some cells, especially the lesion of appendix, both cytoplasmic and nuclear) (Figure 12). No staining with Mart-1 and HMB-45 was identified.

Conclusions: SOX-10 is a transcription factor playing a role in the development and maintenance of Schwann cells and melanocytes. In soft tissue tumors, Schwann cells can be detected with SOX-10 in schwannoma and neurofibroma. Granular cell tumors also express SOX-10, supporting their possible Schwann cell origin. The expression of SOX-10 by Schwann cell hamartoma is a strong proof for the Schwann cell origin of those lesions. Calretinin is a vitamin D–dependent calcium-binding protein structurally related to S100 and inhibin. That S100 protein–positive cells ensheathed calretinin-positive axons is an indication of Schwann cell origin (Human Pathol. 2009;40[8]:1159–1167). Accordingly, calretinin is expressed in schwannomas and granular cell tumors, whereas it is not expressed in neurofibromas or has weak and focal expression. The expression of SOX-10 and calretinin in Schwann cell hamartomas is strong proof for the Schwann cell origin of those lesions.

A 75-year-old man underwent a low anterior resection for a moderately differentiated sigmoid adenocarcinoma, with 2 of 17 positive lymph nodes. An umbilical hernia repair performed simultaneously also showed microscopic adenocarcinoma. The morphology of the adenocarcinoma in the umbilical hernia and 1 lymph node (Figure 13, A) was similar, and different from the sigmoid adenocarcinoma and a second lymph node (Figure 13, B). The glands were without necrosis and more rounded with vesicular nuclei. On immunohistochemistry, this was CK20⁻, PSA⁺ (Figure 13, C), and CDX2⁺ (Figure 13, D). The other positive lymph node was morphologically similar to the sigmoid adenocarcinoma, which was CK20⁺, CDX2⁺, and PSA⁻. The patient was diagnosed with metastatic prostate carcinoma in the umbilical hernia and in 1 lymph node. The sigmoid tumor was pT2 N1a MX instead of pT2 N1b M1c. At the time of surgery, the existence of prostate cancer was not known. Subsequent investigations revealed prostate cancer 17 years earlier, treated with brachytherapy; the patient had been lost to follow-up. After surgery, the serum PSA level was 18.5 and 19.75 the following month. Metastatic adenocarcinoma in lymph nodes of colorectal resections may arise from different primary malignancies, affecting stage and management; a remote malignancy may be brought to light or a new malignancy discovered. Genitourinary carcinomas in particular may metastasize to the same lymph nodes as distal colorectal carcinomas; the morphology of the tumors may be more similar than different. A low threshold for immunohistochemical workup is recommended and CDX2 positivity may be misleading.

Context: Collagenous colitis (CC) is a type of microscopic colitis without distinct endoscopic changes. Microscopically, CC is characterized by preservation of crypt architecture and an increase in inflammatory cells within the lamina propria. The pathognomonic finding is the presence of a thickened subepithelial collagen layer, thicker than 10 μm. The collagen band in CC is composed of type VI collagen, tenascin, and a minor amount of types I and III collagen. Trichrome stains highlight collagen type I and IV whereas reticulin stain stains collagen type III. We sought to apply reticulin stain in diagnosing CC.

Design: Thirty-nine cases of CC diagnosed by H&E ± trichrome stains from 2009 to 2014 at our institute were retrieved and 40 cases of lymphocytic colitis (LC) from the same time period served as negative control. Reticulin and trichrome stains were performed and the results were compared.

Results: Both trichrome and reticulin stains show irregular and ragged collagen layer with entrapment of inflammatory cells, stromal cells, and small capillaries in all CCs; therefore, the sensitivity is 100% for both stains. Surprisingly, reticulin stain displays a better basket-weave pattern that is diagnostic for CC. In comparison with LC, 7 of them showed false positivity by trichrome stain (specificity = 82.5%) whereas only 1 of them was focally positive by reticulin stain (specificity = 97.5%).

Conclusions: Compared with trichrome stain when diagnosing CC, reticulin stain has equal sensitivity but better specificity and the staining pattern is easier to interpret. When H&E features are not convincing, reticulin stain can function as a complementary diagnostic tool.

Context: An association between lymphocytic esophagitis (LyE) and gastroesophageal reflux disease (GERD) has not been established. GERD frequently overlaps with primary esophageal motility abnormalities. Considering that motility abnormalities have a known association with LyE, the goal of this study was to elucidate whether LyE is associated with GERD in patients with normal esophageal motility.

Design: The study group was derived from 246 patients with severe GERD evaluated for Nissen fundoplication. One hundred sixty-two patients had adequate biopsies and no evidence of motility abnormalities by manometry. A control group consisted of 142 cases of Candida esophagitis. LyE was defined as increased peripapillary intraepithelial lymphocytes (IELs) with absent or rare granulocytes and no other features of esophagitis. The cutoffs for normal IEL were based on previously reported values. IELs were counted in the most affected field of view (×400). IELs were typed using CD4/CD8 immunohistochemistry.

Results: Twenty-four patients (14.8%) had biopsies with increased IEL. Two major patterns of lymphocytic inflammation emerged: LyE in 11 patients (6.8%) (mean ± SD age 49 ± 12 years, M:F = 5:6), and haphazardly dispersed IEL within an area of reflux esophagitis in 11 patients (6.8%) (age 47 ± 11 years, M:F = 8:3). All LyE cases showed CD8 T-cell predominance (CD4:CD8 = 0.27 ± 0.25). In contrast, only 2 Candida esophagitis cases (1.6%) had LyE with CD8 T-cell predominance (P < .02). The odds of having CD8-predominant LyE were significantly elevated in GERD as compared with the Candida group (odds ratio, 5.13; CI, 1.12–23.6).

Conclusions: The data suggest that LyE with CD8 T-cell predominance is associated with GERD.

Context: In situ hybridization (ISH) for albumin is reportedly highly sensitive and specific for primary hepatobiliary (pHB) tumors. This study evaluated clinical utility of albumin ISH in diagnosing poorly differentiated pHB tumors that are negative for conventional markers and differentiating them from metastatic adenocarcinomas.

Design: ISH for albumin was performed using RNA scope detection kit (Leica Biosystems, Buffalo Grove, Illinois) with Bond III autostainer, using probe Hs-ALB-01 (ACD, Newark, California), on 60 cases including 21 hepatocellular carcinomas (HCCs); 4 poorly differentiated pHB tumors difficult to classify; 16 cholangiocarcinomas (CCs), including 6 hilar/extrahepatic, 10 intrahepatic CCs (ICCs); 4 combined HCC-CCs; and 15 metastatic tumors.

Results: Albumin ISH was positive in 18 of 21 HCCs, specifically 5 of 7 poorly differentiated HCCs with strong, diffuse dotlike cytoplasmic staining. Of these, 2 were only focally positive for Hepar-1 and Arginase-1. All 4 pHB tumors unclassifiable on histology were strongly positive for albumin ISH. Only 2 of 10 ICCs showed scattered positivity. Combined HCC-CCs were positive in CC component (n = 2 of 4) and in HCC component (n = 4 of 4). All 6 hilar/extrahepatic CCs and 14 of 15 metastatic tumors were negative. One metastatic hepatoid gastric adenocarcinoma was positive. Entrapped hepatocytes and bile ductules within ICCs and metastatic tumors were positive for albumin ISH and interpreted as negative.

Conclusions: ISH for albumin is a useful marker for identifying poorly differentiated pHB tumors, particularly poorly differentiated HCCs that are negative or only focally positive for other hepatocellular markers. ISH for albumin may be helpful in differentiating ICC from extrahepatic CC and metastatic adenocarcinoma if metastatic hepatoid adenocarcinoma is not in the differential diagnosis.

Primary squamous cell carcinoma (SCC) of the pancreas is a very rare entity. It accounts for up to 0.7% of pancreatic carcinomas. The tumor is associated with extremely poor survival, with a median survival period of 6 months. It has been suggested that it originates from the pancreatic ductal cells. Because native pancreatic tissue lacks squamous epithelium, diagnosis of a primary pancreatic SCC is made only after metastatic disease and adenosquamous carcinoma, another rare primary tumor of the pancreas, have been excluded. Here, we report a case of squamous cell carcinoma of the pancreas with a distinct origin. The patient was a 61-year-old woman with a history of pancreatic cystic mass since 2006. An EUS in October 2014 showed a perigastric/pancreatic 9.3 × 6.8-cm anechoic lesion with irregular, hyperechoic walls. Cytology from the procedure demonstrated abundant anucleate squamous cells and keratinous debris, and sheets of hypercellular squamous epithelium with atypia that were suspicious for squamous cell carcinoma. Distal pancreatectomy and splenectomy were then performed. Grossly, a large and ruptured 6.5 × 4.0 × 2.5-cm cystic lesion was identified. Inside the cystic lesion, there were multiple firm tan-white nodules. Histologically, some areas showed benign lymphoepithelial (squamous epithelia) cysts from which in situ and invasive squamous cell carcinoma arose. To our knowledge, this is the first report that a squamous carcinoma originated from a benign squamous lymphoepithelial lesion in the pancreas.

Context: Autoimmune gastritis (AIG) is a body-predominant gastritis characterized by presence of anti–parietal cell and/or anti–intrinsic factor antibodies and destruction of oxyntic glands. It is difficult to distinguish atrophic body mucosa from antral mucosa on H&E stains, especially with pseudopyloric gland metaplasia. Gastrin immunostains identifying G cells are useful for this purpose because G cells are normally present only in the antrum. However, it is not uncommon to encounter positive gastrin staining in the body. This study aimed to interpret the results of gastrin immunostains in AIG.

Design: Fifty-seven cases of AIG diagnosed between 2015 and 2017 in our institute were retrieved, including 55 biopsies and 2 sleeve gastrectomies. Slides were reviewed and gastrin immunostains were analyzed for G-cell number, distribution, and their association with intestinal metaplasia.

Results: G cells were identified in the body of 38 cases (67%). Intestinal metaplasia was noted in 45 (79%) of the gastric bodies. All 38 cases had G cells in rare single-cell pattern at the areas with intestinal metaplasia. Fourteen cases had randomly scattered distribution, 15 cases had crypt distribution, and 9 cases had both a random and a crypt pattern. In contrast, G cells in the antrum demonstrated an evenly glandular pattern at neck areas.

Conclusions: It is not uncommon to encounter G cells in the gastric body of AIG, particularly with intestinal metaplasia. However, the number and pattern of these cells are different from those in the antrum. This observation can potentially aid the pathologist in avoiding the misinterpretation of body-type mucosa as antrum.

A 6-year-old boy with POLG mutation and history of global development delay, temperature dysregulation, epilepsy, and cardiac arrest presented with reduced bowel movements, abdominal distension, and severe constipation. He had multiple admissions since birth for fever, diarrhea, respiratory distress, and hypothermia. He was tracheostomy and G-tube dependent and status post Nissen fundoplication. Imaging studies revealed dilated cecum, ascending and proximal transverse colon, and collapsed distal colon with impacted stools at the hepatic flexure, suspicious for Hirschsprung disease. A rectal biopsy was performed. Many ganglion cells were identified in the submucosa showing multiple eosinophilic refractile cytoplasmic inclusions. Calretinin immunohistochemical stain revealed scanty immunoreactive nerve twigs in the lamina propria. The mucosa showed aggregates of foamy macrophages, possibly reflecting the effects of chronic constipation. The abnormal cytoplasmic inclusions within the ganglion cells along with gastrointestinal and oculo-neurologic symptoms suggested a mitochondrial cytopathy, consistent with mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE). MNGIE is a multisytemic autosomal recessive disorder caused by mutation in TYMP gene encoding for thymidine phosphorylase. MNGIE was first described by Okamura et al in 1976, with an onset before 30 years. Common presentations include gastrointestinal dysmotility, cahexia, ptosis, ophthalmoparesis, sensory loss, wasting, peripheral neuropathy, and leukoencephalopathy. Reduced thymine phosphorylase activity in the buffy coat and TYMP gene sequencing can aid in diagnosis of MNGIE. Biopsy is rarely required. Hirschsprung disease is a differential diagnosis that shows the absence of ganglion cells in submucosa. There is no definite therapy for the treatment of MNGIE. Death results because of infections or metabolic complications.

Context: Cirrhosis remains the strongest risk factor for hepatocellular carcinoma (HCC); however, incidence of HCC in noncirrhotic livers is increasing. Differences between cirrhotic and noncirrhotic HCC have not been recently studied in light of changing disease etiologies in the developed world.

Design: HCC biopsies and resections (2010–2014) were studied. History and slides were reviewed to assess background liver disease, including fibrosis and etiology. Histologic features of HCC were assessed, including grade, subtype, histologic patterns, steatosis, and cytoplasmic and nuclear features. Histologic pattern, clear cell change, and steatosis were scored at 10% intervals. Other histologic features were recorded dichotomously. Comparisons in pathologic features were made between noncirrhotic (stages 0–3) versus cirrhotic livers (stage 4).

Results: A total of 231 HCC cases (60 noncirrhotic, 171 cirrhotic) were identified. Noncirrhotic patients were more likely to have hepatitis B or liver disease of unknown etiology, whereas hepatitis C was more common in cirrhotic patients. HCCs in noncirrhotic livers were larger (mean, 5.7 cm) compared with cirrhotic livers (mean, 3.1 cm) (P < .001). HCCs in noncirrhotic livers were more likely to have macrotrabecular pattern (P = .03), higher nuclear grade (P < .001), greater proportion of clear cells (P = .01), and presence of anaplastic tumor cells (P < .001). There was no difference in the amount of steatosis in the HCC or background between cirrhotic and noncirrhotic patients.

Conclusions: Macrotrabecular and clear cell HCC patterns were more common in noncirrhotic livers. Most other features did not differ in noncirrhotic HCCs. Contrary to common belief, there was no difference in steatosis in HCC or background liver between the 2 groups.

Myelolipomas are rare benign tumors of mature hematopoietic tissue and fat that most commonly arise in the adrenal glands. Extra-adrenal myelolipomas are exceedingly rare and have been reported in the presacral region, liver, mediastinum, perirenal region, stomach, and spleen. The etiology is unknown; however, it is hypothesized that they arise because of embolization of bone marrow tissue and/or reactivation of peritoneal embryonic connective tissue in response to a triggered stimulus. To date, no cases of multiple myelolipomas in a posttransplant liver have been reported in the literature. We report the case of a 58-year-old white man who had an orthotopic liver transplant in 1998 secondary to chronic hepatitis C infection. He presented in February 2018 with nausea, vomiting, and body aches. His laboratory results showed elevated bilirubin, alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase levels. Ultrasound of the liver showed multiple echogenic liver lesions. Magnetic resonance cholangiopancreatography was performed and revealed multiple variably sized lesions in the liver with the largest measuring 6.0 cm. These lesions demonstrated a fat signature on the MRI. A liver biopsy was performed. Diff-Quik–stained touch imprints showed myeloid and erythroid hematopoietic cells as well as scattered benign hepatocytes. The H&E stained sections of the liver biopsy revealed trilineage bone marrow hematopoietic elements mixed with mature adipose tissue diagnostic of a myelolipoma. No atypia, bone, or cartilaginous tissue was identified. The radiologic differential diagnosis of this rare hepatic lesion includes angiomyolipoma, lipoma, and liposarcoma. Therefore, a biopsy is required for accurate diagnosis and subsequent management (Figure 14).

Context: Mycophenolic acid (MPA) is an immunosuppressant drug known to induce injury in the lower gastrointestinal (GI) tract. Only limited cases of injury pattern in the upper GI tract (UGIT) associated with MPA have been studied. This study aims to further study morphologic pattern of UGIT injury in symptomatic patients taking MPA.

Design: Twenty-three patients (12 solid organ transplant, 11 lupus nephritis) who were taking MPA with GI symptoms and had concurrent UGIT biopsies were identified. Eighteen duodenal, 17 gastric, and 8 esophageal biopsies were examined. Apoptosis and patterns of injuries were evaluated. The apoptotic body (AP) counts in duodenal, gastric, and esophageal biopsies from 30 normal cases were standardized for comparison. The cutoff values for apoptosis were ≥2/100 crypts for duodenum, ≥3/100 glands for stomach, and ≥2/10 high-power fields for esophagus.

Results: Among the 23 cases, increased AP counts were present in 11 duodenal biopsies (61%), 6 gastric biopsies (35%), and 4 esophageal biopsies (50%). Additional findings included chronic duodenitis (6 of 18; 33%) and active duodenitis (3 of 18; 17%); reactive gastropathy (4 of 17; 24%); and chronic active gastritis (3 of 18; 17%), reactive esophageal epithelial change (5 of 8; 63%) and active esophagitis (3 of 8; 38%).

Conclusions: Our results are consistent with and support previously reported findings of MPA-associated injury pattern of UGIT. Our data further provide a diagnostic tool to recognize the injury pattern induced by MPA in UGIT biopsies.

Clear cell variant of epithelioid mesothelioma is an extremely rare tumor with only isolated cases reported so far in the peritoneum. Here, we report a case of peritoneal epithelioid mesothelioma, clear cell variant, in a 63-year-old woman with an unusual indolent clinical course. The patient presented with a 27.2-cm upper abdominal mass and a 5.5-cm liver lesion, which on imaging appeared to involve the anterior wall of the stomach and transverse colon. Retrospective review of the patient's abdominal CT scan 4 years prior showed a small stomach wall lesion. This was subsequently considered to have grown in size and represented the current abdominal mass. Both the abdominal and liver masses were subsequently biopsied and showed a proliferation of monomorphic epithelioid cells with distinct cell membranes, fine chromatin, and clear to finely vacuolated pale eosinophilic cytoplasm arranged in nests and solid sheets. The tumor cells were immunoreactive for calretinin, D2-40, HBME, CK5/6, CK19, CK7, and WT-1. PAS and PAS-D highlighted the intracytoplasmic glycogen deposits. The tumor cells were negative for GATA-3, CK20, inhibin, arginase, HMB45, p63, glypican-3, CD117, DOG1, CDX2, Pax8, TTF-1, chromogranin, synaptophysin, and albumin in situ. Based on the immunophenotype and morphology, the tumor was diagnosed as epithelioid mesothelioma, clear cell variant. Clear cell variant of peritoneal epithelioid mesothelioma should always be considered in patients with an abdominal or pelvic mass with clear cell features regardless of the clinical course. Given the rarity of such an entity, its clinical course and prognosis remains unclear.

Context: Angiolipofibromas represent rare mesenchymal polyps that have been described in the gastrointestinal tract. Reported sites include the colon, small bowel, and esophagus. These polyps are usually submucosal and patients may present with bleeding. As there are only a few case reports of this entity in the gastrointestinal tract we undertook this study to further characterize these lesions clinicopathologically.

Design: Six cases of angiolipofibromas were identified from our departmental archives from January 1, 2009, to January 1, 2018. The slides were reviewed and the histologic characteristics were analyzed along with various clinical parameters.

Results: The average age at diagnosis was 52 years (range, 45–57 years) with an equal representation of men and women. Most patients presented for colonoscopy for routine screening (including 1 patient with Crohn colitis). The majority of polyps identified on colonoscopy were small (7–12 mm) aside from one case that had a 3- to 4-cm mass that was concerning for malignancy. All cases showed a varied mixture of submucosal fat, variably sized vessels, and fibrous tissue, with half of the cases showing extension into the mucosa, expanding the lamina propria (Figure 15).

Conclusions: Angiolipofibromas are benign mesenchymal gastrointestinal polyps that are most likely hamartomatous in etiology and are seen in middle-aged adults. There is no apparent predilection with respect to sex or anatomic site within the colon. Importantly, this lesion may mimic malignancy clinically, as seen in one of our cases, although they are completely benign. Pathologists should be aware of this entity when approached with a mesenchymal polyp in the colon.

A 30-year-old woman at 28 weeks' gestation presented to the emergency department with acute right lower abdominal pain and vomiting. Physical examination revealed abdominal rigidity and rebound tenderness. Laboratory values were significant for leukocytosis. Magnetic resonance imaging demonstrated a 5-cm inflammatory mass medial to the cecum, concerning for appendicitis. During an exploratory laparotomy, a large phlegmon was identified in the right lower abdomen, and the appendix was adherent to the terminal ileum and cecum. An appendectomy was performed. Gross examination revealed a diffusely hemorrhagic, edematous appendix with purulent exudate on the mucosal and serosal surfaces. A perforation was identified, communicating with a peri-appendiceal abscess. Histopathology confirmed gangrenous appendicitis; however, in addition a masslike formation of stromal and glandular elements was identified (Figure 16, A and B). The mass was embedded within the appendiceal wall and protruded into the lumen. The stromal component was characterized by large, polygonal cells with eosinophilic cytoplasm, well-defined cell borders, and round nuclei. The glandular element exhibited intraglandular tufting, hobnailing, cytoplasmic vacuolation, and clear nuclei. Our diagnosis was decidualized appendiceal endometriosis with perforation. Although endometriosis is common in women of childbearing age, appendiceal endometriosis is uncommon and affects less than 1% of the general population. Perforated appendicitis secondary to endometriosis during pregnancy is extremely rare, with only 5 reported cases. Our patient did not have a known history or symptoms of endometriosis. Currently, no consensus exists on whether elective appendectomy is indicated for suspected appendiceal endometriosis. In women, the differential diagnosis for an appendiceal mass should include endometriosis.

Withdrawn.

Primary intestinal leiomyosarcoma is a rare gastrointestinal malignancy with only 27 reported cases in the literature. These malignant smooth muscle tumors pose diagnostic difficulties secondary to their location, nonspecific symptoms, and relative infrequency. A 78-year-old man was referred to our institution by his primary care physician for an anemia workup. Initial endoscopy and colonoscopy were negative. Subsequent evaluation by video capsule endoscopy showed bleeding in the distal jejunum. An upper balloon-assisted endoscopy was performed, showing an ulcerated proximal jejunal mass. Biopsies were difficult to obtain secondary to poor visualization and were ultimately superficial and unrevealing. Computed tomography scan of the abdomen and pelvis showed a 4-cm mass with no evidence of metastatic disease. An exploratory laparotomy was performed with resection of the small bowel mass and primary anastomosis. Pathology demonstrated a smooth muscle actin–positive, caldesmon-positive spindle cell neoplasm consistent with an epithelioid leiomyosarcoma. Primary malignancies of the small bowel are rare and consist predominately of adenocarcinomas and carcinoids. Sarcomas account for approximately 10% of small bowel neoplasms, with the vast majority being gastrointestinal stromal tumors. Leiomyosarcomas and gastrointestinal stromal tumors share morphologic features and must be differentiated based upon immunohistochemistry, specifically the expression of c-Kit, a component of the KIT tyrosine kinase receptor, which allows for proper subclassification.

Pembrolizumab is an immune checkpoint inhibitor offering improved outcomes for patients with advanced malignancies. Despite the successful therapeutic responses, many patients will develop immune-related adverse events involving any organ. Pembrolizumab-associated hepatitis has been described clinically; however, to our knowledge, there is scant literature describing the histopathologic features associated with this entity. A 60-year-old woman with metastatic thymoma status post 2 cycles of pembrolizumab presented with dyspnea, weakness, and elevated liver chemistries (AST 198, ALT 112, ALK-P 648, and total bilirubin 9.1). A liver biopsy was performed. The portal tracts were expanded by marked dense inflammatory cells consisting mostly of lymphocytes and histiocytes. Severe bile duct injury with bile duct loss was highlighted by cytokeratin 7 immunolabeling. Focal mild central venulitis, mild cholestasis, and macrovesicular steatosis were also present. The lobules showed mild chronic inflammation with focal parenchymal granuloma along with rare single-cell hepatocyte and confluent necrosis. CD3 and CD20 immunostains highlighted the dense portal inflammation to be predominantly of T lymphocytes. Trichrome and reticulin stains confirmed mild portal fibrosis. No stainable iron and no granules positive for periodic acid–Schiff with diastase were present. CMV immunostain and EBER in situ hybridization did not highlight any viral organisms. The overall features were compatible with pembrolizumab-associated liver injury in this clinical context. With the increasingly widespread use of immune checkpoint inhibitors, recognition of the histopathologic features consistent with immune-mediated adverse events is important for establishing the diagnosis.

Context: Epiploic appendages are fatty peritoneal structures on the external surface of the colon. If infarcted, they either become necrotic in situ or auto-amputate and float freely in the abdomen. They often show an “egglike” appearance, with a smooth, glistening, ovoid outer shell and central fat necrosis. Infarcted epiploic appendages (IEAs) have received little pathologic scrutiny.

Design: We reviewed 52 IEAs from 49 patients, recording patient age, sex, and body mass index (BMI); indication for surgery; surgical impression of the IEA; and lesion size, gross appearance, central fibrosis, rind thickness, necrosis, hemorrhage, inflammation, calcification, and ossification. Characteristics were compared across attached and loose IEAs using Fisher exact text and the unpaired t test.

Results: Average age was 54 years, male ro female ratio was 13:36, and average BMI was 31.4. Twenty-eight IEAs were attached and 22 were loose; location was unclear in 2. Most were incidental; 3 attached cases caused “appendagitis.” Most (31; 60%) had the classic egglike appearance. Rind thickness averaged 0.84 mm. Common histologic findings included fat necrosis (84%), calcification (67%), and fibrosis (58%). Attached cases had a larger mean size (1.8 versus 1.3 cm, P = .048), but the rinds were similar in thickness. Loose cases were more often necrotic (100% versus 75%, P = .01); attached cases were more often hemorrhagic (36% versus 5%, P = .01) and inflamed (64% versus 14%, P < .001).

Conclusions: IEAs have different morphology whether they remain attached to peritoneum (where they increase in size and cause local hemorrhage/inflammation) or become necrotic and detached. Loose cases are usually incidental; attached cases may cause symptoms.

Extragastrointestinal stromal tumors (EGISTs) are very uncommon and account for less than 5% in a large series of stromal tumors. Although EGISTs seem to have morphologic and immunohistochemical similarities with GISTs, their pathogenesis, incidence, genetic background, and prognosis are not completely known. Here we report an interesting case of EGISTs with ultrastructual features of neuronal differentiation that have been characterized in gastrointestinal autonomic nerve tumors. A 71-year-old man was incidentally found to have a mesenteric mass in 2013 on CT. Recently, the patient presented for evaluation of progression of mesentery mass and CT revealed one 4.5 × 4.1-cm rounded mass within the upper abdominal mesentery. Histologic examination revealed spindle cells arranged in small fascicles, low mitotic rate, and focal necrosis. Immunohistochemically, the tumor cells showed strong positivity for c-kit, DOG-1, and CD34; focal positivity for S100; occasional positivity for synaptophysin; and negativity for CD56 and chromogranin. Electronic microscopy showed elongated cytoplasmic processes devoid of basement membrane material (*), rare neurosecretory granules (arrow), immature junction (circle), and skenoid fibers (S) (Figure 18). c-Kit mutation analysis revealed a duplication of Ala502-Tyr503 in exon 9 associated with intermediate response to imatinib. Thus, double dosing of imatinib 800 mg was suggested to clinicians. EGISTs tend to have a more aggressive biological behavior than their gastrointestinal counterparts. Complete surgical resection is the most effective treatment associated with the use of imatinib in the presence of adverse prognostic factors. In any case, a strict follow-up is necessary because of high recurrence rates.

Good syndrome (GS), combined thymoma and hypogammaglobulinemia, was first reported in 1954. It is a rare adult-onset immunodeficiency, predisposing to various infections. We report the case of a 61-year-old woman who was diagnosed with GS 4 years after the first serious clinical manifestations (colon perforation and sepsis) in 2013. She underwent partial left hemicolectomy and subsequently developed multiple episodes of Clostridium difficile infection. She presented to our center on 3 occasions with significant diarrhea. Initially in 2015, sigmoidoscopy revealed erythematous mucosa and pathology reported active colitis with ulceration, negative for CMV and HSV. Subsequently in 2016, colonoscopy was normal. However, biopsies showed paucity of plasma cells, so common variable immunodeficiency was considered. Follow-up tests revealed extremely low levels of immunoglobulins and she was put on intravenous immunoglobulin. In 2017, a thymoma was resected, leading to the diagnosis of GS. In 2017, colonoscopy and pathology were similar to those of 2016 and further workup did not identify B lymphocytes by CD20 immunostain. T-cell ratio and distribution appeared normal. Considering immune dysfunction and infection as possible etiologies of diarrhea, budesonide was added and symptoms improved. The slides of 2015 were reviewed and no plasma cells were noted. This case alerts pathologists to keep immunodeficiency diseases in mind because lack of plasma cells can be easily missed. Imaging studies looking for thymoma are suggested in patients lacking plasma cells to differentiate GS from common variable immunodeficiency. On the other hand, the finding of a thymoma should prompt immunodeficiency-related tests for possible GS.

Intraductal oncocytic papillary neoplasm, the rarest of the 4 histologic subtypes of intraductal papillae mucinous neoplasms, is characterized by complex arborizing papillae, oncocytic cells, and intraepithelial lumina formation. Because there are limited reports on pathologic characteristics and management of the intraductal oncocytic papillary neoplasm, we present a case of microinvasive intraductal oncocytic papillary neoplasm with positive nodal metastasis and its management. A 57-year-old man presented with acute pancreatitis and was found to have a necrotic cystic lesion in pancreatic tail on CT imaging (Figure 19, A). Magnetic resonance cholangiopancreatography was suggestive of a mixed-type (main and branch ducts) intraductal papillary mucinous neoplasm with a 4-cm cystic lesion in the tail of the pancreas and dilatation of the proximal pancreatic duct. Upper endoscopic ultrasound showed frondlike projections in the cystic cavity and pancreatic duct with nodular formation. Histologic examination of the distal pancreatectomy demonstrated a 4.5-cm high-grade intraductal oncocytic papillary neoplasm with microscopic invasion involving the main duct (Figure 19, B). In addition, 2 of 19 lymph nodes were involved by metastatic carcinoma. The immunostaining results showed the neo-plastic cells were positive for Hep Par 1 (Figure 19, C) and MUC5A (Figure 19, D), focally positive for MUC1, and negative for MUC2 and CDX2, which supports the diagnosis. The patient received chemotherapy with gemcitabine and abraxane and adjuvant radiation therapy. Seventeen months postresection there is no clinical evidence of recurrence and metastasis.

Context: Invasive micropapillary adenocarcinoma is a rare variant of colonic adenocarcinomas with poor prognosis. Categorization of molecular alterations in micropapillary predominant colorectal tumors may help further characterize signaling pathway alterations seen in these lesions and predict response to treatment.

Design: We reviewed colon resections with colonic adenocarcinoma at our institution for the last 2 years and identified 9 cases that were micropapillary predominant (9 of 108 cases; 7%). The expression of hMLH1, hMSH2, hMSH6, and hPMS2 mismatch repair proteins was reported. Ion AmpliSeq second generation sequencing was performed on the 9 tumors for analysis of mutations in KRAS, EGFR, BRAF, PIK3CA, AKT1, ERBB2, PTEN, NRAS, STK11, MAP2K1, ALK, DDR2, CTNNB1, MET, TP53, SMAD4, FBX7, FGFR3, NOTCH1, ERBB4, FGFR1, and FGFR2.

Results: Patient demographics included median age of 50 years (range, 34–61 years), with female to male ratio of 2:1. In this cohort of micropapillary adenocarcinomas, all cases (9 of 9; 100%) occurred in the sigmoid or rectum and were lymph node positive. All cases (9 of 9; 100%) had intact expression mismatch repair proteins. However, 8 cases (8 of 9; 89%) were found to harbor a mutation involving TP53, and 1 of those 8 cases additionally harbored a mutation involving KRAS.

Conclusions: This study suggests that micropapillary colonic adenocarcinomas are characterized by classic chromosomal instability with TP53 mutation. Research concerning the spectrum of TP53 mutations, some of which may be amenable to targeted drug therapy, is still ongoing. Meanwhile, categorization of tumor types that show repeated alterations in TP53 may help guide continued research in the field of targeted drug therapy.

Context: Once a liver is cirrhotic, it can be difficult to establish the cause based on histology. This study assessed pathologic findings in cirrhotic livers and correlated them with established clinical diagnoses.

Design: For 258 cirrhotic liver biopsy/resection specimens, we searched medical records for clinical diagnosis and disease-associated laboratory values (including iron studies, serologic testing, and genotyping) and evaluated slides for >5% macrovesicular steatosis, Mallory hyaline, more than rare plasma cells or eosinophils, ductular/lobular cholestasis, glycogenated nuclei, iron, and PAS-D–positive globules within hepatocytes. Histologic findings suggestive of a diagnosis were compared between patients with and without that diagnosis using Fisher exact test.

Results: Across all cases, 36% had macrovesicular steatosis, 27% had Mallory hyaline, 18% had plasma cells, 10% had eosinophils, 38% had lobular cholestasis, 29% had ductular cholestasis, 37% had glycogenated nuclei, 24% had iron (≥grade 2), and 13% had PAS-D–positive globules. Most findings were not significantly related to a commonly associated diagnosis (steatosis and alcoholic/nonalcoholic steatohepatitis [P = .09]; plasma cells and autoimmune hepatitis [P = .40]; lobular cholestasis and primary sclerosing cholangitis/primary biliary cirrhosis [P = .06]; iron and hemochromatosis [P = .24]; PAS-D–positive globules and α₁-antitrypsin [A1A] deficiency [P = .13]; glycogenated nuclei and Wilson disease [P = .65]). However, Mallory hyaline was more often seen in patients with than without clinical steatohepatitis (35% versus 20%, respectively; P = .008).

Conclusions: Macrovesicular steatosis, plasma cells, lobular cholestasis, iron, and glycogenated nuclei should not be relied upon in isolation to establish a causative diagnosis in cirrhosis. PAS-D–positive globules are not definitive evidence of A1A deficiency, and ductular cholestasis doesn't necessarily imply sepsis. Only Mallory hyaline appears to have utility in suggesting a diagnosis in cirrhosis.

Paraneoplastic leukemoid reaction (PLR) is an extremely rare presentation of solid tumors. To our knowledge, this is the first English-literature report of isolated primary colon cancer presenting with PLR. A 70-year-old presenting with watery diarrhea was found to have a white blood cell count (WBCC) of 105.4 K/mm³. Results of extensive infectious and hematologic investigations, including bone marrow examination with flow cytometric, cytogenetic, and molecular analysis, were negative. Five weeks after initial presentation, CT scan of the abdomen showed a large ascending colon mass. Surgical resection demonstrated an undifferentiated, MLH-1–deficient colon cancer, which was notable for a marked intratumoral neutrophilic infiltration (Figure 20). Resection, without additional intervention, led to a dramatic decrease of WBCC from 162.5 K/mm³ (day of the surgery) to 42.2 K/mm³ (following day) to 11.7 K/mm³ (1 week later). Systematic English-literature review revealed 53 patients presenting with PLR from 1976 to 2017: mean age 61 years, 2.5:1 male to female ratio, mean peak WBCC 67.6 K/mm³ (predominantly neutrophilic). The most common primary site was lung (n = 13; 25%). In the digestive system (n = 20), the following primary sites were encountered in descending order: liver (35%), gallbladder (25%), pancreas (15%), stomach (15%), esophagus (5%), and concurrent liver/colon (5%). Most of the liver tumors were poorly differentiated hepatocellular carcinoma with a sarcomatous element. Intratumoral neutrophilic infiltration was reported in 7 cases. Eighty-five percent (26 cases tested) showed elevated serum and/or body fluid granulocyte colony-stimulating factor (G-CSF) or granulocyte/macrophage colony-stimulating factor and all 15 tumors tested showed G-CSF immunopositivity, making tumor secretion of G-CSF a plausible mechanism for PLR.

Context: Hyaluronic acid (HA) is a linear glycosaminoglycan composed of repeating disaccharide units of glucuronate and N-acetylglucosamine. Recent literature has shown that the extracellular matrix or stroma of tumors contains highly expressed noncellular elements such as HA, which creates an environment favoring tumor invasiveness and persistence. As such, HA is considered a potential diagnostic target. However, HA detection has been challenging because it is highly conserved across species and ubiquitously present in nearly all the tissues. A sensitive and specific assay is needed.

Design: Recombinant protein technology can overcome limitations of the traditional methods that rely on an endogenous HA binding protein (HABP). A novel recombinant HABP was generated, consisting of TSG-6 (a member of the HA binding protein family) bound to a rabbit Fc receptor, known as rec-HABP, with its intended use being detection of HA in tissues. Ten percent NBF–fixed gastric, breast, pancreatic, and cholangiocarcinoma tumor tissues stained by the rec-HABP were used to evaluate the overall performance of this novel assay.

Results: It was observed that the Ventana assay using rec-HABP shows high specificity and sensitivity compared with the existing immunohistochemistry assays. An automated procedure using Opti-View DAB immunohistochemistry detection on BenchMark advanced staining instruments provides reproducible staining results using several tumor indications. A practical interpretation method is proposed and presented.

Conclusions: It was demonstrated that this novel HA assay is highly specific for HA in a clinical setting. An ease-of-use automated staining procedure for human FFPE tissues can also reduce the entry barriers in clinical practice.

All authors are employees of Roche/Ventana. Dr Liu is a shareholder of Illumina stock. Drs Portier and Delgado are shareholders of Roche stock.

Mucinous adenocarcinoma of gallbladder is defined as tumor with >50% of extracellular mucin component. It constitutes 2.5% of gallbladder carcinomas. Pure mucinous (colloid) carcinoma is a distinct subtype with mucin component comprising >90% and it is exceedingly rare. An 88-year-old Asian man presented with a 1-week history of right upper quadrant pain with fever. Ultrasound showed gallstones with thickened wall, with findings suggestive of emphysematous cholecystitis. CT scan further showed possible fistulization to small bowel. The patient underwent urgent open cholecystectomy for complicated acute perforated cholecystitis. Grossly, the gallbladder wall was disrupted, tan-white, thickened up to 2 cm, and >90% granular and gritty on sectioning. Microscopic examination showed a mucinous adenocarcinoma predominantly composed of pools of extracellular mucin containing clusters of tumor cells forming glandular architecture with surface dysplasia. The tumor cells were positive for CK7, CDX-2, and (patchy) CK20. Mismatch repair proteins were intact. Cystic duct and liver bed margins were involved by carcinoma. The patient decided not to pursue any medical treatment. Five-month follow-up CT scan showed partially calcified nodule in the cholecystectomy bed, with calcified porta hepatis and portacaval lymph nodes suggestive of locally advancing disease without distant metastasis. Pure mucinous carcinoma is discussed because of its extreme rarity, acute presentation, nonspecific clinical and radiologic features altered by excessive mucin, advanced stage of presentation, and uncertain prognosis. A meticulous gross examination of the gallbladder wall in older patients is crucial for appropriate diagnosis and staging.

Goblet cell carcinoid (GCC) tumors account for less than 5% of primary appendiceal tumors. Here we report a case of rectal tumor in a 65-year-old man with morphologic features reminiscent of adenocarcinoma ex–goblet cell carcinoid. The patient underwent a low anterior resection, and the specimen showed a large, fungating, friable mass in the rectum straddling the peritoneal reflection. Microscopy showed mucinous adenocarcinoma with features of signet ring cells. Fifteen percent of the tumor also showed areas reminiscent of GCC, appearing as tubules and cryptlike structures composed of gobletlike cells distended with mucin and occasional granular eosinophilic cytoplasm. Synaptophysin immunostain was predominantly positive in areas with signet ring cell and GCC-like morphology. Additionally, the conventional and mucinous components of the tumor demonstrated patchy positivity for synaptophysin. Nine lymph nodes contained metastatic tumor with morphologic features of mucinous adenocarcinoma, conventional adenocarcinoma, signet ring cells, and GCC-like cells. There is no high-grade neuroendocrine component morphologically. On imaging, the appendix appeared unremarkable. However, diagnosis of GCC of the appendix is seldom made preoperatively because most appendiceal tumors are not mass-forming lesions. Pathologists should be aware of this and raise a consideration of a metastasis from an appendiceal primary. Primary GCC outside the appendix is extremely rare, and the literature is conflicting if it does occur outside of the appendix.

Epidermoid cysts of the cecum are extremely rare. They are typically cutaneous lesions with limited reports of internal organ involvement. There are only 9 cases reporting epidermoid cysts of the cecum. The etiology is classified as either acquired or congenital. Acquired lesions are considered a result of implantation of epidermal fragments during abdominal trauma or surgery. Congenital lesions lack history of intraabdominal trauma/surgery and are thought to be a result of aberrant embryogenic ectodermal implantation into the gut. We report a case of a cecal epidermoid cyst in a 74-year-old man with no history of lower abdominal surgery or trauma and explore the possible histogenesis of this lesion in abdominal viscera. Our patient underwent a laparoscopic resection of a 10-cm intramuscular cystic mass of the cecum. On microscopy, the cyst was lined by stratified squamous epithelium with a granular layer. The lumen of the cyst was filled with flaky keratin. These findings are consistent with an epidermoid inclusion cyst. We further hypothesize a possible histogenesis derived from the relationship of the respective embryologic structures during development. Between weeks 6 and 12, there is a physiologic umbilical herniation of the cecum, the periderm undergoes keratinization and desquamation to be replaced by cells arising from the basal layer, and then the midgut reenters the abdominal cavity. Encasing of an epidermal structure in the muscularis propria that includes the basal layer may result in later development of a cecal epidermoid cyst.

Collagenous gastritis is a rare disease characterized by the subepithelial deposition of collagen bands thicker than 10 μm with a lamina propria inflammatory infiltrate. Collagenous colitis and collagenous sprue have similar histologic characteristics to collagenous gastritis and are thought to be part of the same disease entity. Collagenous gastritis is particularly rare, with fewer than 20 cases reported in the literature since the first description by Colletti and Trainer in 1989. We report an 11-year-old boy who presented with abdominal pain, nausea, vomiting, and weight loss. Result of colonoscopy with biopsies was normal. Esophagogastroduodenoscopy showed thickened white-tan areas and patchy erythematous mucosa in body. Antral mucosa was nodular. Gastric biopsies showed antral and fundic gastric mucosa with patchy thickened subepithelial collagen with superficial bandlike areas that frequently merged with irregular deeper patches, few foci of increased intraepithelial lymphocytes, capillaries, and moderate infiltrates of mixed inflammatory cells. Helicobacter pylori infection was not detected by Diff-Quik stain or urease test. No other clinical explanation was identified and the endoscopic and histopathologic findings were deemed diagnostic of collagenous gastritis. Follow-up endoscopy after 3–4 months showed similar findings after symptomatic treatment. Collagenous gastritis is diagnostically challenging and recognition requires awareness of its existence and histologic pattern. The cause of collagenous gastritis is unknown and no effective treatment has been established. Better understanding of the disease will require study of a larger number of patients to establish diagnostic criteria and therapeutic strategies.

Context: β₂-Microglobulin (B2M) is a component of major histo-compatibility (MHC) class I molecules that is present on all nucleated cells. Truncating mutations of B2M have been reported to be associated with impaired human leukocyte antigen (HLA) class I antigen presentation in MMR-deficient (dMMR) tumors, leading to the development of immune escape variants and more aggressive tumors. We evaluated the clinicopathologic effect of loss of expression of B2M on dMMR colorectal adenocarcinomas (CRAs).

Design: Sixty-four dMMR CRAs were included in a tissue micro-array. Based on their B2M immunohistochemical staining, they were classified as positive (any positive staining, >0%) or negative (complete loss, 0%). B2M status was correlated with clinicopathologic features.

Results: Loss of B2M expression by immunohistochemistry was identified in 19 cases (29.7%). Of these, 13 (68.4%) were well to moderately differentiated, 7 (36.8%) demonstrated lymphovascular invasion, and 8 (42.1%) had lymph node metastases. Positive B2M expression was identified in 45 cases (70.3%). Of these, 26 (57.8%) were poorly differentiated, 26 (57.8%) showed lymphovascular invasion, 23 (51.1%) had lymph node metastases, 9 (20%) had perineural invasion, and 40 (88.9%) were AJCC pathologic stage T3 or greater (Table).

Conclusions: Loss of B2M expression, by immunohistochemistry, in dMMR CRAs is associated with lower-grade tumors, lower rates of lymphovascular invasion, perineural invasion, lymph node metastases, and lower tumor stage. This is in contrast to what is expected based on the mechanism of B2M in regard to antigen presentation and warrants additional investigation.

Gastric colonization with Helicobacter pylori is a known risk factor for peptic ulcers (10%), gastric carcinoma (1%–3%), and mucosa-associated lymphoid tissue (MALT) lymphomas (<0.1%). We report a unique case of a 70-year-old woman with a remote history of bleeding gastric ulcers found to have an incidental large gastric diffuse large B-cell lymphoma (DLBCL), non–germinal center (nGC) phenotype. Upper gastrointestinal endoscopy and ultrasound demonstrated a large, infiltrative and ulcerative submucosal mass (10.3 cm) at the lesser curvature of the stomach. CT and PET scans were concordant with a hypermetabolic mass without additional disease. Separate additional biopsies were remarkable for a gastric adenoma, in a background of H pylori gastritis and intestinal metaplasia. A diffuse infiltration of large atypical lymphocytes with irregular nuclei, vesicular chromatin, distinct nucleoli, and numerous apoptotic figures was noted. Flow cytometry analysis highlighted the aberrant B lymphocytes coexpressing CD45, CD20, CD79a, and negative for CD5, CD19, CD10, CD23, CD38, and restricted for surface κ immunoglobulin. Immunohistochemically the neoplastic cells were positive for CD20, CD79a and co expressed MUM-1 (40%) and were negative for CD3, CD10, BCL2 and BCL6 (10%) with brisk mitotic activity (60%–80%), compatible with non–GC-immune–phenotype DLBCL (Han algorithm). Molecular studies were positive for clonal immunoglobulin gene rearrangement. FISH studies were negative for BCL6, BCL2, and MYC. The patient was scheduled to be treated with 6 cycles of R-CHOP followed by radiotherapy with substitution of etoposide for vincristine to avoid peripheral neuropathy for occupational reasons.

Boerhaave syndrome is a longitudinal transmural disruption of the esophagus due to an acute increase in esophageal pressure after forceful vomiting and blunt abdominal trauma. There are cases reported secondary to bowel obstructions such as incarcerated hernias and gallstone ileus. Here we describe an unusual case of Boerhaave syndrome due to biliary cancer. The patient was an 87-year-old man without known history of cancer who presented with nausea, vomiting, and severe epigastric pain. X-ray revealed left pneumothorax and bowel-gas pattern. Computed tomography showed pneumomediastinum, fluid-filled esophagus, gastric distention, and ill-defined mass within the liver. The patient underwent chest tube insertion and flexible esophagogastroduodenoscopy, which revealed esophageal rupture at the left esophagogastric junction. The patient became too unstable for thoracotomy and expired within 20 hours of admission. On autopsy, the decedent was found to have a 6-cm esophageal perforation, with spillage of gastric content into pleural and mediastinal cavities, and an inferior hepatic mass adhering to the duodenum and hepatic flexure of the colon. Grossly, the liver lesion was a 7 × 4.5 × 3.5-cm tan-white, fibrotic mass completely encasing the gallbladder. Microscopic examination revealed poorly differentiated adenocarcinoma involving the liver, duodenum, and pericolonic adipose tissue, which was immunohistochemically positive for CK7, CK19, and CK20 and negative for CDX2, supporting a diagnosis of poorly differentiated biliary adeno-carcinoma. Boerhaave syndrome accounts for 15% of esophageal perforations and is associated with high morbidity and mortality, and is fatal in the absence of prompt treatment. We report this case to increase awareness of this entity.

Context: Gastrointestinal stromal tumors (GISTs) constitute up to 90% of mesenchymal neoplasms of the gastrointestinal tract that are managed surgically. Endoscopic submucosal dissection (ESD) is an effective modality to resect mucosal and submucosal lesions of the gastrointestinal tract including GISTs. In January 2014, we implemented pathology synoptic reporting for GISTs removed by ESD. We evaluated the effect of standardization on the completeness of pathology reports.

Design: After obtaining internal review board approval, electronic medical records were searched for cases of GIST treated by ESD from January 1, 2008, to December 31, 2017. Fifty-two cases were found and allocated into 2 groups: prestandardization (24 cases) and poststandardization (28 cases). Pathology reports from both groups were reviewed to compare prestandardization and poststandardization completeness of reports for essential variables, including size of lesion, histologic type, mucosal involvement, depth of invasion, margins, ulcer, mitotic rate, immunohistochemistry for CD117, Miettinen risk of progression, and pT staging. The collected data were analyzed using χ² test to evaluate difference for reporting of each variable. P < .05 represented a statistically significant difference in this study.

Results: We noted improvement in reporting of 5 variables: size of lesion, mucosal involvement, depth of invasion, Miettinen risk of progression, and pT staging. Three of those variables showed statistically significant improvement: mucosal involvement (57.1% versus 20.8%; P = .01); pT (42.9% versus 12.5%; P = .03); and Miettinen risk of progression (85.7% versus 56.5%; P = .02).

Conclusions: Our study supports that a standardized synoptic summary can improve the quality and completeness of pathology reports.

Context: The Lerner system is the most commonly used histologic grading system for gastrointestinal (GI) graft-versus-host disease (GVHD), but fails to provide prognostic stratification. The aim of this study was to develop a histologic grading system for GI GVHD that incorporates apoptotic counts and assess its prognostic significance.

Design: Colon biopsies taken to assess for GVHD from 2008 to 2014 were retrospectively reviewed for the maximum number of apoptotic bodies per 10 contiguous crypts (ap/10), crypt dropout, and ulceration. A novel histologic scoring system was developed combining scoring of mucosal irregularities (no crypt dropout or ulceration = 0; crypt dropout without ulceration = 1; ulceration = 2) and crypt apoptotic counts (no apoptosis = 0; 1–6 ap/10 = 1; >6 ap/10 = 2). Clinical information was collected from chart review.

Results: The study group consisted of 122 colonic biopsies from 84 patients and 97 endoscopy procedures (M:F 1:1.3; mean age 53.6 years). Patients with Lerner grade 4 (ulceration) had significantly worse GVHD-specific survival compared with patients with GVHD Lerner grades 1–3 (HR 2.7; 95% CI, 1.1–14.6; P = .03). Patients with >6 ap/10 also had significantly worse GVHD-specific survival compared with patients with 1–6 ap/10 (HR 4.6; 95% CI, 2.0–13.1; P = .004). Using our newly proposed scoring system, patients with an overall histologic score of 3–4 had significantly worse GVHD-specific survival compared with patients with a score of 0–2 (HR 6.2; 95% CI, 4.4–36.1; P < .001) (Figure 21, A through D).

Conclusions: Our proposed histologic scoring system using apoptotic count and mucosal irregularities provides prognostic stratification. Further studies are necessary to validate this scoring system.

Hepatoblastoma is a rare malignant tumor accounting for less than 1% of all pediatric cancers. The morphology is varied, with numerous histologic subtypes. Some hepatoblastomas demonstrate cholangocytic differentiation and have been termed cholangioblastic hepatoblastoma. We present a case of hepatoblastoma with a cholangioblastic pattern. A 12-month-old girl with no significant medical history presented with increased crankiness and abdominal distension for 2–3 weeks. Laboratory test results were remarkable for marked elevated AFP (17 280 ng/mL). Abdominal CT showed a 13.7-cm well-circumscribed heterogenous mass with central necrosis and calcifications in the right hepatic lobe. Biopsy was performed showing a mixed epithelialmesenchymal hepatoblastoma with fetal and teratoid features, including pigmented melanocytes, squamous epithelium, and ganglion cells. Within the fetal epithelial component, foci of glandular structures with complete or incomplete lumina were identified. These structures resembled biliary ducts, but were clearly distinct from preexisting small bile ducts entrapped in the tumor. Immunohistochemically, the glandular component was diffusely positive for CK19, focally positive for CK7 and BCL-2, and negative for glypican-3. Interestingly, CK19 also stained single cells within fetal epithelial components, which might represent its multifocal differentiation pathway. The morphology and immunohistochemical findings are consistent with cholangioblastic pattern of hepatoblastoma. The patient underwent right extended hepatectomy followed by 6 cycles of chemotherapy. She is free of disease 6 months postsurgery. As more cases of cholangioblastic hepatoblastoma are identified, future studies can better characterize the clinical behavior of this rare tumor (Figure 22).

We report a 25-year-old woman presenting with right-sided abdominal pain who was found to have an appendiceal mass on imaging. Appendectomy showed involvement by diffuse ganglioneuromatosis (DG) with a transmural proliferation of loose spindled neural cells with interspersed ganglion cell clusters. Immunohistochemical stains for S100 protein, synaptophysin, and neurofilament highlighted the neural and ganglion cell hyperplasia in various layers of the appendix. DG is a benign hamartomatous proliferation of neural tissue and appendiceal involvement has been reported in <5 cases in the English literature. Knowledge of DG and its syndromic association could help detect patients with a variety of germ-line mutations including neurofibromatosis type 1 and multiple endocrine neoplasia 2b. No genetic testing guidelines exist for DG. However, given the high correlation of DG with hereditary cancer syndromes, genetic testing was recommended and pursued. Our patient was found to have a pathogenic variant, c.1541_1542delAG (p.Gln514Argfs*43), in NF1 gene. This sequence change deletes 2 nucleotides from exon 14 of the NF1 mRNA (c.1541_1542delAG), causing a frame shift at codon 51, creating a premature translational stop signal (p.Gln514Argfs*43), and resulting in an absent or disrupted protein product. Loss-of-function variants in NF1 are pathogenic and particular variant has been reported in many individuals affected with neurofibromatosis type 1. Half of neurofibromatosis type 1 cases are inherited and the remainder are the result of de novo mutations. In view of clinical outcomes and associated risk of developing malignancy, pathologic recognition with ancillary genetic testing is warranted in cases with DG lesions (Figure 23).

Immunocompromised patients are at higher risk to develop concomitant opportunistic infections or neoplasms. Their assessment can be challenging because of the number of pathologies that can arise from the gastrointestinal tract. Kaposi sarcoma and malakoplakia are 2 distinct entities commonly reported in patients receiving immunosuppressive protocols, reflecting a dependence of host immune system. We report a case of a 64-year-old man status post kidney transplant because of diabetes mellitus and hypertension who presented with recurrent epigastric pain, nausea, and vomiting and was on treatment with tacrolimus and prednisone. During hospitalization, he was found to have cytomegalovirus viremia. An upper endoscopy and colonoscopy procedures were performed. The findings included an 8-mm raised gastric lesion with umbilicated center and three 5-mm cecal nodules. Biopsies were taken from both lesions. The histologic evaluation of the gastric lesion biopsy revealed neoplastic spindle cells with mild to moderate atypia arranged in fascicles and separated by slitlike vessels, consistent with Kaposi sarcoma (Figure 24, A). HHV-8 immunostain was positive in the spindle cells (Figure 24, B). The biopsy of cecal nodules revealed a collection of enlarged histiocytes with abundant, granular pale cytoplasm and small basophilic calcified inclusions, and neutrophilic infiltrate, consistent with malakoplakia (Figure 24, C). Von Kossa stain highlighted the Michaelis-Gutmann bodies. None of the biopsies showed cytomegalovirus infection (Figure 24, D). Immuno-compromised hosts are prone to develop different concurrent neoplastic and infectious lesions, which usually have no specific clinical presentation. The pathologist should have a high index of suspicion for opportunistic infections and virus-related neoplasms.

Context: Appendicular foreign bodies are a rare cause of appendicitis. We performed this study to determine the varied causes and consequences of foreign-body appendicitis.

Design: On retrospective review of the pathology archives of 6 institutions, we identified 49 appendix specimens containing a foreign body (defined as ingested, nondigestible material). We recorded the type of foreign body, patient age and sex, symptoms, imaging findings, surgical findings, gross findings, and microscopic findings, as available.

Results: Median patient age was 8 years (range, 1 day–18 years). The foreign bodies included hair (23), plant material (9), BB pellets (2), magnets (2), foreign material not otherwise specified (8), and 1 each of the following: bead, bone, metal necklace, pencil lead, and splinter. Of 43 cases with available clinical information, 31 patients presented with abdominal pain and 18 were preoperatively diagnosed as having appendicitis or appendicular inflammation. Imaging identified only the 5 metallic objects. Five cases had clinical or gross appendiceal perforation, 3 with hair and 2 with plant material. The foreign body was grossly identified in 27 of 40 cases with available gross descriptions. Of the 27 cases with an identifiable foreign body microscopically, 10 were associated with foreign-body giant cell reaction.

Conclusions: Hair and plant material appear to be the most common foreign objects found in the appendix; they can cause mucosal damage and a foreign-body giant cell reaction. Metallic objects were uncommon. Although appendicular foreign bodies in children are rare and sometimes asymptomatic, they may lead to perforation, which occurred in 10% of cases in this series.

Context: 5-hydroxymethylcytosine (5hmC) is a marker of active demethylation and has been shown to be reduced in a variety of cancers. The aim of our study was to investigate 5hmC protein expression in colorectal carcinoma and to explore its relation to the CpG island methylator phenotype including MSI and BRAF mutations.

Design: 5hmC immunohistochemistry (IHC) was performed on 19 cases of colorectal carcinoma. MSI and BRAF mutation status had been determined previously by IHC. 5hmC staining was scored by intensity (0, negative; 1, weak; 2, moderate; 3, strong) and percentage of tumor cells staining (0, negative; 1, 1%–10%; 2, 11%–50%; 3, >50%). A combined score (0–9) was calculated from multiplying intensity by percentage scores. Loss of 5hmC staining was considered combined score <4. Stromal cells were used as a positive control. P values were estimated by Fisher exact test.

Results: Loss of 5hmC staining was present in 10 of 19 cases (53%), including 6 of 10 cases with MSI and 4 of 9 cases without MSI (P = .66). Loss of 5hmC expression was observed in 4 of 5 cases with BRAF mutation and 3 of 6 BRAF wild-type cases (P = .55).

Conclusions: Our study demonstrates that 5hmC expression is decreased in a significant proportion of colorectal carcinomas, with no association to MSI or BRAF mutation. These findings suggest that aberrant DNA methylation is a common event contributing to the pathogenesis of colorectal carcinoma. Loss of 5hmC does not appear to be more frequent in colorectal cancers of the CpG island methylator phenotype.

Teduglutide is approved for the treatment of parenteral nutrition–dependent adult patients with short bowel syndrome. Its use has been theorized to lead to the development of certain cancers. De novo development of hepatocellular carcinoma in a patient during teduglutide treatment has never been documented in the literature. A 48-year-old man with long-standing Crohn disease had short bowel syndrome due to partial enterectomy and colectomy. Because of his parenteral nutrition dependency, teduglutide was given and had enabled him to achieve nutritional autonomy off parenteral nutrition and his liver enzymes had normalized. But 3 years later, he presented with upper abdominal pain and elevated liver enzymes. Abdominal PET/CT revealed a noncirrhotic liver with 2 large hypermetabolic masses in bilateral lobes. Radiologic findings were suspicious for bilobar hepatic malignancy with lymph node metastasis. Biopsies demonstrated poorly differentiated hepatocellular carcinoma with extensive tumor necrosis in the right hepatic lobe and well-differentiated hepatocellular carcinoma, steatohepatitic subtype, in the left hepatic lobe. Immunostains were performed and confirmed the diagnosis of hepatocellular carcinoma. The background liver showed stage II nonalcoholic steatohepatitis. The patient underwent locoregional therapy and teduglutide had been discontinued. This is the first documented case of long-term teduglutide use leading to the development of hepatocellular carcinoma from noncirrhotic liver in a patient during teduglutide therapy. There is no current recommendation for the surveillance of hepatic malignancies in patients on teduglutide therapy. Regular medical and radiologic examinations are recommended based on this case report (Figure 25).

Overlap syndrome between primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) is extremely rare and only 10 cases have been reported. None were associated with inflammatory bowel disease (IBD). Here we report a unique presentation of overlap of PBC and PSC. The diagnoses were made based on clinical, biochemical, serologic, histologic, and radiologic findings. A 45-year-old woman with remote history of cholecystectomy was initially diagnosed with PBC. She had elevated alkaline phosphatase levels (645 U/L) for >6 months and positive anti-mitochondrial antibody (titer of 1:1280). On her liver biopsy, florid-duct lesions and noncaseating granulomas were identified. Both clinical and pathologic features supported the diagnosis of PBC. She was prescribed with ursodeoxycholic acid. A year later, she was discovered to have Crohn disease and was given maintenance therapy. Eleven years after being diagnosed with PBC and IBD, her alkaline phosphatase level was again noted to be elevated. Cholangiography revealed beading appearance of the intrahepatic ducts typical for PSC. Repeat biopsy showed periductal onion-skin fibrosis and ductular reaction in addition to florid-duct lesions and granulomas, findings consistent with an overlap syndrome of PBC and PSC. Unlike the other reported overlap cases of PBC and PSC, this case is the first one that arose in the setting of IBD with the diagnosis presenting in a metachronous form. This case highlights the importance of recognizing that a diagnosis of overlap syndrome can occur years after an initial diagnosis of one entity so that better clinical care and treatment optimization can be given (Figure 26).

Primary anorectal melanoma is a rare and aggressive malignancy. Patients commonly present with advanced, even metastatic, disease. Unlike cutaneous melanoma, anorectal melanoma has no known risk factors. A 74-year-old man with history of prostate cancer presented with rectal bleeding. Colonoscopy revealed a rectal mass. The mass itself was about 4 cm in size, located in the anterior left lateral wall. The tumor started from about 2 cm from anoderm and extended to 5 cm toward the proximal rectum. The low portion of the tumor involved internal sphincter. Biopsy of the rectal mass was performed and submitted for intraoperative consultation. The sections showed a high-grade malignant neoplasm of spindled and epithelioid cells with numerous mitoses and apoptosis infiltrating among benign colorectal mucosa, undermining benign squamous epithelium, and extending into muscle fibers. By immunohistochemistry, the tumor cells were positive for S100, Melan-A, HMB45, and MITF and were negative for AE1/AE3, CK7, CK20, CD56, CD117, P63, PSA, and LCA. No BRAF V600E or V600K mutations were detected. No c-KIT mutation was identified. Radiologic studies did not show any metastases. He underwent an abdomino-perineal resection (APR). He is still alive 2 years after APR with a metastatic to left groin lymph node. This entity can be easily misdiagnosed as poorly differentiated carcinoma and sarcoma. We should always perform a S-100 stain when colorectal poorly differentiated carcinoma and sarcoma are suspected. A positive S-100 stain suggests the tumor to most likely be a melanoma.

Context: The most common manifestation of cytomegalovirus (CMV) infection of the gastrointestinal (GI) tract is CMV colitis; however, upper GI tract can also be involved. This study investigates the clinical, endoscopic, and histologic features of upper GI tract CMV infection.

Design: We searched our pathology database for cases diagnosed with only upper GI tract CMV infection and identified 47 patients. The clinical features and endoscopic and histologic findings of all cases were reviewed.

Results: The patients' ages ranged from 24 to 85 years. Forty-four patients (94%) were immunocompromised whereas 3 patients (6%) were immunocompetent. Immunocompromised patients had associated diseases including transplant (55%), HIV (13%), inflammatory bowel disease (6%), and hematologic malignancy (4%). CMV esophagitis was the most common, followed by CMV gastritis, ileitis, and duodenitis, respectively. The most common presenting symptom was diarrhea (30%), followed by abdominal pain (25%), dysphagia (13%), GI bleeding (11%), odynophagia (11%), vomiting (6%), and systemic malaise (4%). Endoscopic findings ranged from ulceration (51%), erythema (19%), erosion (11%), and mass formation (2%) to normal (6%). Histologic findings consisted of focal active inflammation with or without ulceration and mild increase in crypt epithelial apoptosis. The 3 immunocompetent patients were a 25-year-old Hispanic man with abdominal pain, a 25-year-old white woman with odynophagia, and an 85-year-old woman with GI bleeding, none of whom had any underlying diseases.

Conclusions: Upper GI tract CMV infection more commonly affects immunocompromised patients. However, immunocompetent patients can also acquire CMV infection. Careful histologic examination can prevent delayed diagnosis and adverse health outcomes.

Myxomas are benign mesenchymal neoplasms with unknown etiology. The most common location for these lesions is the atrium. However, they can also occur in the skin, joints, muscles, mandible, maxilla, and sinonasal tract. There are very few published reports of myxoma in the gastrointestinal (GI) tract, and these are limited to the stomach and small intestines. We are presenting, to our knowledge, the first case report of a myxoma in the colon presenting as a polyp. A 49-year-old woman with a family history of colon cancer underwent a screening colonoscopy and was found to have a 0.2-cm sessile polyp in the cecum. Microscopically the polyp was hypocellular, was well demarcated from the surrounding mucosa, and consisted exclusively of myxoid stroma and bland spindle cells in the lamina propria without cytologic atypia. The overlying colonic epithelium showed no dysplasia. S-100 immunohistochemical stain showed only focal positivity. Myxomas in the GI tract are very rare, with this being the first reported case of a polypoid colonic myxoma. Previous reports of GI myxomas are limited, with only 1 case report of a gastric myxoma and limited reports of small intestinal myxoma, all of which were submucosal lesions. Synchronous presence of a cardiac myxoma was reported in some of these cases. This represents a newly identified mesenchymal polyp of the colon and pathologists should be aware of this diagnostic entity to avoid misinterpretation.

Paired box 8 (PAX8) is a transcription factor critical in the development of the thyroid, Müllerian system, and renal/upper urinary tracts, and thus is a highly sensitive marker for carcinomas originating from these sites. Although weak/focal PAX8 expression has been described in tumors from other sites, many, including lung adenocarcinomas, colon cancers, and breast and adrenal neoplasms, are consistently negative for PAX8. Here we describe a case of metastatic colorectal adenocarcinoma with aberrant positive nuclear staining for PAX8, the first such case to be reported in the literature. The patient, a 47-year-old woman, had a 10-cm obstructing rectal mass, a biopsy of which showed invasive moderately differentiated adenocarcinoma. Concurrently, the patient was also noted to have liver and lung metastases and a 15-cm ovarian mass. Total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed to exclude an ovarian primary. Histology of the large ovarian mass showed variably sized cribriformed glands composed of pseudostratified columnar cells with moderate cytologic atypia (Figure 27, A). The tumor also involved the contralateral ovary and uterine serosa. Immunohistochemically, the tumor was positive for CK20 (Figure 27, B) and CDX2 (Figure 27, C) and negative for CK7. The majority of tumor cells showed PAX8 positivity (Figure 27, D). A diagnosis of metastatic colorectal adenocarcinoma with aberrant PAX8 expression was rendered. Although PAX8 is a sensitive and relatively specific immunomarker, its expression in adenocarcinomas should be interpreted with caution. It should be used in conjunction with clinical history, histomorphology, and other immunostains to determine the tumor site of origin.

Context: Gastric adenocarcinoma has poor prognosis and is diagnosed at advanced stage when the treatment is usually proven ineffective. Therefore, it is very important to search for novel immunohistochemical markers that help in both early detection and effective treatment of this disease. The loss of E-cadherin, a cell adhesion protein in gastric epithelium, leads to cell invasion and distant metastasis. There is a significant correlation of its loss with histologic type and grade of gastric adenocarcinoma. The objective of this study is to determine the expression of E-cadherin in histologic types and grades of gastric adenocarcinomas that has both prognostic and therapeutic roles in gastric adenocarcinoma.

Design: Immunohistochemical expression of E-cadherin was analyzed in different types and grades of gastric adenocarcinoma according to Lauren classification.

Results: Of the selected 81 cases, 53 (65%) had intestinal-type adenocarcinoma and 28 (35%) were patients with diffuse type of adenocarcinoma. There was a significant statistical correlation of loss of E-cadherin with histologic type of adenocarcinoma. Of the 28 cases of diffuse-type gastric adenocarcinoma, 10 cases, along with 4 cases out of 53 cases of intestinal adenocarcinoma (all of which were poorly differentiated adenocarcinoma), showed complete loss of E-cadherin. All well-differentiated cases showed high expression of E-cadherin.

Conclusions: There is correlation of E-cadherin expression with the histologic type and grade of gastric adenocarcinoma. It was observed that as the grade of the adenocarcinoma gets higher there is more loss of E-cadherin expression, which proves its prognostic significance.

Context: The AJCC 7 staging system defined tumor deposits (TDs) as discrete tumor nodules separate from the main tumor mass within the lymph drainage area of the tumor without identifiable lymph node (LN) tissue. It elevated TDs to “LN metastasis equivalency” (constituting stage III disease). The 2010 SEER data (cited in AJCC 8 system) reported TD and N1c frequencies of 10% and 3%, respectively, which seemed lower than our clinical impression.

Design: We performed chart review of all in-house colon cancer resections from January 1, 2010, to July 20, 2017, recording age; sex; tumor site, size, and grade; presence of lymph-vascular invasion (LVI), perineural invasion (PNI), TDs, and LNs; AJCC 7 T, N, M; vital status; and general versus gastrointestinal (GI) pathologist. Fisher exact test was used with P < .05 considered significant.

Results: TD status was reported in 86% of 515 resections, with TDs present in 28% (124 of 441). Completeness of reporting and TD frequency did not differ between general and GI pathologists (P = .52 and .74, respectively). Seventy-five percent occurred with and 25% without LN metastasis, for an N1c rate of 7%. TDs were associated with greater risk of death and more frequent LVI, PNI, T3/4, LN positivity (N+), and metastatic disease (M+)(all P < .001) (Table). Patients with TDs were less likely to be alive (57%) than those with LVI (68%; P = .06), PNI (66%; P = .19), T3/4 (71%; P = .007), and N+ disease (65%; P = .23).

Conclusions: TDs were 3 times more frequent than previously reported, though the proportion with/without concurrent LN metastasis was the same. Completeness of reporting and frequency did not differ between general and GI pathologists. TDs correlated with adverse histologic features and reduced survival.

Context: Historically, clear cell hepatocellular carcinoma (ccHCC) has been vaguely defined, leading to conflicting reports on its clinicopathologic features. However, more precise definitions have been proposed in recent literature. We sought to apply these new criteria to a series of ccHCC, determine the rate of each subtype at our institution, and elucidate any clinicopathologic patterns.

Design: Institutional archives were searched for ccHCC, identifying 66 cases. Applying published criteria, tumors were divided into early HCC (n = 4; E-HCC), steatotic HCC (n = 11; S-HCC), steatohepatitic HCC (n = 34; SH-HCC), chromophobe HCC (n = 2; C-HCC), and ccHCC, not otherwise specified (n = 15; ccHCC-NOS). Tumor, background liver, and clinical features were obtained from reviewed slides and clinical records.

Results: Although cytoplasmic macrovesicular steatosis was common in E-HCC/S-HCC/SH-HCC (n = 49 of 66, 74.2%), many had an admixture of steatotic and flocculent cytoplasm (n = 44 of 49; 89.7%). CHCC and ccHCC-NOS had variably flocculent and/or optically clear cytoplasm without steatosis (n = 17). Although ccHCC-NOS exhibited the highest lymphovascular invasion rate (66.7% versus 43.1%), this trend did not reach statistical significance (P = .1). Steatohepatitis in background liver was significantly more common in S-HCC and SHHCC than in ccHCC-NOS (P = .006). No other significant differences were noted in clinicopathologic features of tumor or background liver.

Conclusions: New definitions left only 22.7% of ccHCC as ccHCCNOS, which did have macrovesicular steatosis in tumor cell cytoplasm like the other subtypes. S-HCC, SH-HCC, and E-HCC frequently arose in the background of steatohepatitis, suggesting an etiologic difference between these subtypes and nonsteatotic subtypes of ccHCC-NOS and C-HCC, though few other etiologic or pathologic features appeared different between the subtypes.

Traditional serrated adenomas (TSAs) pose challenges both in diagnosis and management. The histomorphology and molecular underpinnings resulting in TSAs have not been fully defined. TSAs have been identified predominantly within the left colon and described to have slitlike serrations and ectopic crypts. A diagnosis of TSA in the upper gastrointestinal tract is exceedingly rare, especially in the esophagus; further association with invasive adenocarcinoma is even rarer. A 49-year-old woman presented for a second opinion regarding worsening dysphagia, anorexia, and a midesophageal mass. Two prior biopsies of the mass were diagnosed as “prolapse polyp with no dysplasia.” Rebiopsy and subsequent resection of the mass were performed. Rebiopsy showed fragments of classic TSA with characteristic slitlike serrations, ectopic crypts, and multifocal high-grade dysplasia. The esophagogastrectomy specimen revealed a TSA associated with a 5.0-cm poorly differentiated adenocarcinoma with mucin and signet ring cells. The adenocarcinoma invaded the submucosa and muscularis propria and abutted the serosa. Immunostains showed intact mismatch repair proteins and positive CDX2 and CK20 staining in tumor. Next-generation sequencing detected KRAS (G12D) mutation in both the TSA and adenocarcinoma; BRAF mutation was not identified. This is the first case of an unequivocal esophageal TSA associated with an invasive high-grade adenocarcinoma with constitutively active KRAS. Esophageal TSA is extremely rare, with only a few cases reported involving stomach and upper gastrointestinal tract. It is important to recognize the role of KRAS mutations in these entities to determine the possible roles of targeted therapy to improve patient outcomes.

Context: Colorectal cancer is the most common cancer and a leading cause of cancer-related deaths. Development of sporadic disease takes an average of 15–20 years, so establishing preventive measures is possible. We are interested in a dietary compound, withaferin A (WA), which possesses chemotherapeutic and chemopreventive properties.

Design: We used 2 animal models to study the chemopreventive effect of WA. In intestinal tumorigenesis model C57BL/6-Apc^Min/+, mice at 6 weeks of age were fed with the vehicle or WA (4 mg/kg body weight of mice) for 5 d/wk for 12–14 weeks. The other model was azoxymethane/dextran sulfate sodium, which induces gut inflammation and tumorigenesis. Intraperitoneal injection of azoxymethane (8 mg/kg) was followed by 3 cycles of dextran sulfate sodium. WA (3 mg/kg body weight of mice) was administered 5 times/wk for 8–10 weeks. After completion, the tumor tissues underwent histopathologic and molecular analysis. An unpaired Student t test was used for statistical analysis.

Results: Oral administration of WA to Apc^Min/+ mice lead to a significant decrease in the number of polyps and colon tumors (colon: 42%, P = .02; proximal: 53%, P = .006; middle: 27.84%, P = .28; distal: 32.8, P = .001) when compared with vehicle-treated mice. Similarly, in azoxymethane/dextran sulfate sodium, oral administration of WA reduced polyp multiplicity by 40% (P = .02) compared with controls. The treatment group of both models showed inhibition of prosurvival signaling markers (Notch1, PAKT, and NFKB) and a decrease in proliferative markers.

Conclusions: Our results suggest that WA effectively suppresses intestinal polyp development and colitis-mediated colon carcinogenesis, suggesting a preventive and therapeutic role in colon cancer models.

Ischemic colitis (IC) results from reduced vascular perfusion causing mucosal injury. Although there are occlusive and nonocclusive etiologies, all show similar histologic features. In rare instances, IC may form a masslike lesion, mimicking malignancy. A 55-year-old woman presented with hematochezia and diarrhea and underwent colonoscopy. Three months prior she was treated with steroids for autoimmune hepatitis following an admission for jaundice. On colonoscopy, a masslike lesion was identified at the ileocecal valve (Figure 28, A). Notably, on previous imaging studies, no mass was detected within the abdomen. The biopsies demonstrated hyalinized lamina propria, atrophic crypts, ulceration, and active inflammation, indicative of IC (Figure 28, B and C). A repeat colonoscopy in 2 months revealed complete resolution of the masslike lesion at the ileocecal valve (Figure 28, D). IC may rarely demonstrate endoscopic findings of a colonic mass, giving the clinical impression of malignancy. Of the few patients in the literature who have undergone colectomy, submucosal and/or mural edema or submucosal fibrosis were the only histologic findings. Clues to the diagnosis of this clinicopathologic variant of IC include acute onset, rapidly changing course, elderly female patient, location in the right colon, ischemic colitis on histology after thorough sampling, and discordant imaging and colonoscopy findings. As in our case, these patients can usually be managed conservatively with resolution of the masslike lesion on follow-up endoscopy. It is important for both pathologists and gastroenterologists to be aware of this variant of IC to avoid unnecessary surgery.

Context: Hepatic venous outflow tract obstruction (HVOTO) may be caused by various etiologies. The centrizonal pattern of liver injury and fibrosis observed in HVOTO is unique and standard grading and staging systems are not available. The goal of this project was to evaluate common histopathologic features seen in various etiologies of HVOTO and determine if a recently developed fibrosis staging system was applicable.

Design: We identified HVOTO caused by different underlying etiologies. Liver biopsy slides were stained with H&E, Masson trichrome, periodic acid-Schiff–diastase, reticulin, and cytokeratin 7.

Results: We identified 4 distinct etiologies: systolic dysfunction/congestive heart failure (ie, congestive hepatopathy), Budd-Chiari syndrome, veno-occlusive disease from chemotherapy associated liver injury, and an unusual case of right-sided heart failure due to underlying pericarditis. Common histopathologic findings were identified and we graded 3 features: (1) sinusoidal dilatation (Figure 29, A), (2) nodular regenerative hyperplasia changes, and (3) amount of centrizonal fibrosis (Figure 29, B). In addition, a fibrosis staging system that was recently developed for liver biopsies with congestive hepatopathy was easily applied to all causes of HVOTO. As previously reported in HVOTO, aberrant perivenular staining with CK7 was observed in all cases (Figure 29, C). We also observed unexpected findings: 2 cases of congestive hepatopathy showed perivenular, PASD-positive intracytoplasmic globules (Figure 29, D).

Conclusions: A grading system that includes 3 easily identifiable features (sinusoidal dilatation, NRH, and amount of centrizonal fibrosis) can facilitate diagnosis of HVOTO and a recently developed fibrosis staging system for congestive hepatopathy can be successfully implemented. This approach will increase consistency in pathology reporting among centers.

A 75-year-old man with end-stage renal disease (ESRD), hemo-dialysis, and administration of phosphate-binding agent calcium acetate (PhosLo) presented with anemia and weakness. Upper endoscopy showed an erythematous duodenal mucosa; a biopsy revealed prominent aggregates of macrophages in the lamina propria with granular cytoplasm (Figure 30, A and B) and PAS/D positivity (Figure 30, C). No organisms were identified on the AFB stain. The findings were suggestive of Whipple disease. However, the confirmatory polymerase chain reaction (PCR) assay for Tropheryma whippelii was negative. On closer examination, several macrophages were noted to have intracytoplasmic, refractile, crystalline material that was faintly positive on the iron stain (Figure 30, D). Our case report aims to alert pathologists of a medication-induced histologic mimic of Whipple disease in the duodenum that was observed in the clinical setting of ESRD, hemodialysis, and administration of phosphate-binding agents. Although the aggregates of PAS/D–positive macrophages in the duodenum were suggestive of Whipple disease by light microscopy, the confirmatory PCR assay was negative. The refractile material is likely medication associated, given the clinical setting of ESRD and dialysis. Phosphate-binding agents such as lanthanum have been reported to elicit a histiocytic response with macrophages containing finely granular basophilic foreign material. This patient was not on lanthanum, but had been prescribed a different phosphate-binding agent, calcium acetate (PhosLo). We suggest that there are other drugs used in ESRD that may produce changes similar to lanthanum, and may be a mimic for Whipple disease.

Follicular lymphoma is a relatively indolent lymphoma of germinal center B cells characterized by overexpression of BCL-2. We present a case of follicular lymphoma that accompanied a colonic tubular adenoma found during routine colonoscopy in a 59-year-old woman. A 1.0-cm polyp was identified and excised at colonoscopy via hot snare. Low-power histologic examination demonstrated a typical colonic tubular adenoma with low-grade dysplasia (including loss of mucin, pencillate hyperchromatic nuclei, and loss of maturity) as well as apparent underlying chronic inflammation that expanded the lamina propria (Figure 31, A). However, further investigation of the lamina propria revealed a vaguely nodular proliferation of lymphocytes that lacked polarization found in typical reactive germinal centers. High-power views showed poorly formed nodules of a monotonous proliferation of centrocyte-like cells that lacked tingible body macrophages and mitotic activity (Figure 31, B). Immunohistochemical analysis revealed the nodules, as well as diffuse areas, strongly expressed BCL2 (Figure 31, C) and coexpressed CD20, CD10, and BCL6 (Figure 31, D), supporting a diagnosis of a low-grade follicular lymphoma. A follow-up bone marrow biopsy was consistent with follicular lymphoma involvement. Tubular adenomas are often associated with increased lamina propria inflammation, including reactive lymphoid aggregates. Our case highlights that an underlying lymphoma may be easily missed if typical features of reactive germinal centers, to include polarization, cellular polymorphism, and the presence of tingible body macrophages, are not routinely evaluated. A brief inspection of underlying inflammation in a tubular adenoma should be performed to rule out an occult lymphomatous process.

Context: Pancreatic endoscopic ultrasound fine-needle biopsy (EUSFNB) is an emerging technology for the diagnosis of solid pancreatic lesions. At our institution, EUS-FNB has become the first-line procedure for rendering such a diagnosis. In this study, we examined the diagnostic yield of the first FNB obtained in our patients, as well as explored histologic barriers to definitive diagnoses.

Design: Following a search of our pathology laboratory information system, 450 first-time FNBs were identified during the period between 2013 and 2017. Reports were evaluated for the presence of definitive neoplastic diagnoses versus those yielding categorical diagnoses of atypical, negative, or benign. All cases with available slides lacking definitive diagnoses (n = 133) or with a benign diagnosis (n = 20) were rereviewed. These cases were graded with respect to tissue integrity, measurement of the largest intact tissue fragment, and a semiquantitative assessment of blood contamination.

Results: A total of 301 cases (66.9%) yielded definitive neoplastic diagnoses. In nondiagnostic samples, the average and median intact sizes of tissue were 0.10 and 0.06 cm (0.00–0.15 cm), respectively, compared with 0.20 and 0.20 (0.05–0.40) for benign diagnoses. In nondiagnostic samples, the tissue was considered satisfactory, suboptimal, and unsatisfactory in 36%, 5%, and 59% of the cases, respectively. Blood contamination was mild in 16% of cases, moderate in 7% of cases, and significant in 77% of cases.

Conclusions: Our results show that EUS-FNB has a high rate of diagnostic success as the first-line procedure for diagnosis. In cases that do not yield a definitive diagnosis on the initial biopsy, blood contamination is a significant hindrance in obtaining diagnostic FNB samples.

Context: The pathogenesis of eosinophilic esophagitis (EoE), although known to be allergy driven, is poorly understood. Studies have shown that EoE is associated with elevated serum IgG4 levels, increased epithelial IgG4 deposits, and subepithelial IgG4-positive plasma cells. This suggests that EoE may be an IgG4-mediated process and that IgG4 staining may be useful in differentiating EoE from gastroesophageal reflux disease.

Design: We performed a retrospective study of 31 patients with EoE (clinical and endoscopic findings suspicious for EoE, confirmed diagnosis based on the presence of ≥15 eosinophils/high-power field in distal and proximal biopsies). Exclusion criteria included preexisting diagnosis of EoE or treatment prior to endoscopy. Four cases of gastroesophageal reflux disease and 4 normal controls were included for comparison. Histopathologic review and IgG4 immunohistochemical staining were performed.

Results: EoE patients were significantly more likely to have positive IgG4 staining compared with controls (15 of 29 EoE cases versus 0 of 8 control cases; P = .01). Of the 15 positive cases, 6 cases had IgG4-positive plasma cells within the lamina propria, 2 of the cases had epithelial staining only, and 7 cases had positive staining in both. Twelve of 15 positive cases showed positivity in both distal and proximal biopsies. No significant clinical, endoscopic, or histologic differences were identified.

Conclusions: EoE patients were significantly more likely to stain for IgG4 compared with controls. Although positive IgG4 staining was specific for EoE (100%), it had a poor sensitivity (48%). Our study suggests that although IgG4 may play a role in the pathogenesis of EoE, it is not a reliable marker of disease diagnosis.

α-Fetoprotein (AFP)–secreting adenocarcinoma of the esophagus arising de novo from the esophageal mucosa is a rare entity. This report describes a patient with AFP-producing adenocarcinoma with no previous history of dysplasia or adenoma. The patient is a 64-year-old man who presented with increased α-fetoprotein levels with a previous history of treated chronic hepatitis C. Computed tomography scan of the abdomen showed circumferential wall thickening of the distal esophagus/gastroesophageal junction. There were streak artifacts through the liver without cirrhosis or focal hepatic mass identified. Endoscopy and biopsy of the gastroesophageal junctional mass revealed invasive poorly differentiated adenocarcinoma. AFP immunohistochemical stain was performed, which was negative. For staging, an upper endoscopic ultrasound was performed that revealed the lesion extending endoscopically to the proximal stomach on the lesser curvature. Biopsy of the proximal stomach mass showed invasive poorly differentiated adenocarcinoma, histologically similar to the previously biopsied GE junction mass. The exact origin of the tumor (distal esophagus versus gastric) could not be determined on a histologic basis. There were no findings of a malignant precursor-like adenoma or dysplasia. The serum AFP levels responded extremely well to chemotherapy and radiotherapy and dropped from 593.3 ng/mL to 2.2 ng/mL posttreatment. Although the AFP-secreting esophageal adenocarcinoma had a negative AFP immunohistochemical stain, the drop in the AFP level after treatment supports our diagnosis. Thus, careful monitoring of the serum AFP levels at regular intervals could be a useful marker to indicate recurrence of esophageal carcinoma despite negative immunohistochemical staining for AFP.

Hepatocellular carcinomas (HCCs) with uncommon differentiations have been reported in the literature. However, HCCs with multiple differentiations are rare. We report a case of a 65-year-old man with cirrhosis secondary to nonalcoholic fatty liver disease, chronic lymphocytic leukemia (CLL), and clear cell renal cell carcinoma. During routine HCC screening, a slowly enlarging liver lesion (1.9 cm) was detected by imaging and ablated. Several enlarged lymph nodes, attributed to CLL, were also detected. During the next year, 2 additional suspicious liver lesions (0.6–2.0 cm) were found on imaging, but no intervention was performed until liver transplantation. The patient's explanted liver contained multiple masses (0.8–3.5 cm) within background cirrhosis. All of the masses had areas of traditional HCC, which were Hep-Par 1 and Arginase 1 positive. One mass had areas of cholangiocarcinomatous differentiation that were CK7 positive. A second mass had a focus of neuroendocrine carcinoma that was synaptophysin-, chromogranin A–, and CD56-positive. A third mass had clear cell differentiation. The patient's liver function improved after transplant, but a few months later, several enlarging lymph nodes were identified on imaging. Cytology of a peripancreatic node and biopsy of a supraclavicular node showed metastatic neuroendocrine carcinoma. Given the nodal metastases, he was treated conservatively. Despite treatment, his disease progressed with new metastases to his transplanted liver, as well as spine and pelvis. At this point, he began hospice care and died 2 months later. To our knowledge, this is the first case report of multiple HCCs with 4 differentiations simultaneously occurring in a patient with cirrhosis.

Intrahepatic bile duct cystadenoma is an uncommon neoplasm of the biliary duct and accounts for less than 5% of nonparasitic cysts of liver. The average age of presentation is 45 years and 95% occur in women. It may occur in association with polycystic liver disease, abnormal hepatobiliary anatomy. Grossly, the cystadenoma usually presents as an encapsulated, solitary, usually mucinous, multilocular cyst. The inner surface is smooth with few trabeculations. Complications include intracystic hemorrhage, bacterial infection, spontaneous rupture, recurrence, and malignant transformation. Treatment is complete excision with clear margins. We present a case of a 33-year-old woman who presented with abdominal distension and difficulty breathing for the past 6 months. She had nausea, vomiting, and unintentional 10-pound weight loss during the past few months. Physical examination showed moderate abdominal distension and mild tenderness in right hypochondrium. Laboratory studies showed a mildly elevated γ-glutamyl transferase at 72 U/L (normal, 9–36 U/L). Abdominal CT scans revealed hepatomegaly (35 cm) with a huge multiloculated, multiseptated, predominantly fluid attenuating lesion occupying all the right lobe of liver with few internal calcifications and a small associated nodular component (Figure 32, A). The resected specimen weighed 7.25 kg and serial sectioning revealed multiloculated cystic mass with tan-green color and gelatinous cystic material. Microscopic sections showed cyst wall lined by columnar to cuboidal mucinous epithelium overlying the fibrocollagenous stroma (Figure 32, B). Adipose tissue and smooth muscles were also seen in the wall (Figure 32, C).

Solid pseudopapillary tumor of the pancreas is a rare neoplasm of low malignant potential and excellent prognosis after complete surgical resection. IgG4-related pancreatitis (type 1 autoimmune pancreatitis) is a mass-forming lesion that can radiographically mimic pancreatic cancer but is treated with steroid therapy. Coexisting pancreatic neoplasm with autoimmune pancreatitis is exceedingly rare. We report a case of a 47-year-old woman who presented with acute pancreatitis and worsening abdominal pain. Imaging showed a large cystic and solid mass involving the pancreatic body and tail with progressive mass enlargement and splenic vein occlusion with development of collateral circulation. The mass was diagnosed as a solid pseudopapillary tumor by fine-needle aspiration. En bloc resection included distal pancreas, spleen, distal stomach, distal duodenum, and superior mesenteric vein. On gross examination, the 9-cm mass involved the pancreas and invaded peripancreatic soft tissue and stomach wall. Histologic examination demonstrated small discontinuous foci of classical solid pseudopapillary tumor characterized by pseudopapillae formed by delicate blood vessels lined by monotonous cells (Figure 33, A). The tumor was positive for β-catenin (Figure 33, A, inset). The majority of the 9-cm mass was composed of lymphoplasmacytic inflammation and spindle cell proliferation (Figure 33, B) with associated destruction of pancreatic ducts and obliterative phlebitis (Figure 33, C), consistent with autoimmune pancreatitis. Immunohistochemical stain for IgG4 showed more than 50 plasma cells per high-power field (Figure 33, B, inset). The autoimmune pancreatitis invaded the gastric wall (Figure 33, D) and peripancreatic soft tissues, giving the clinical impression of a locally aggressive solid pseudopapillary tumor.

Appendiceal intussusception is an extremely rare condition with a reported incidence of 0.01% and was first described by McKidd in 1858. Clinical presentation varies with different cases, with some patients being completely asymptomatic and some presenting with acute appendicitis or chronic nonspecific abdominal pain. We report a case of a 37-year-old woman with a history of recurrent hospitalizations for intractable nausea, vomiting, and right lower quadrant abdominal pain. She presented again with the aforementioned symptoms. Physical examination showed right lower quadrant tenderness with no rebound tenderness or guarding. CT scan revealed an indefinite cecal mass and subsequent colonoscopy showed a soft and mobile polypoidal lesion in the cecal wall with an intact overlying mucosa. She underwent robotic ileocecectomy. Intraoperative consultation showed a 2.0 × 1.0 × 1.0-cm luminal protrusion of the appendix into the cecum. Microscopic examination of the lesion disclosed a polypoidal lesion composed of unremarkable fibromuscular stroma admixed with a few adipose tissue and scattered ganglion cells. The lesion was lined by normal-looking colonic mucosa with prominent lymphoid follicles (Figure 34). The overall findings were compatible with those of an inverted appendix. Appendiceal intussusception is classified into 5 types based on the site and degree of intussusception. Our case represents an example of complete invagination/inversion of the appendix into the cecum (Type V). In conclusion, we present this case because of its rarity. Appendiceal intussusception often constitutes a diagnostic challenge and increasing the awareness of this condition will facilitate earlier diagnosis and appropriate management.

Context: The stepwise progression from gastroesophageal reflux disease (GERD) to Barrett esophagus (NDBE) and dysplasia/esophageal adenocarcinoma (EAC) is a multistep neoplastic process associated with several genetic abnormalities. Limitation of histologic diagnoses demands reliable objective indispensable biomarker testing.

Design: This study consisted of (1) review of 303 histology biopsies from 97 patients undergoing endoscopic surveillance up to 14 years' duratio; (2) biomarker testing of p16, p53, cyclin D1, MCM2, Ki-67, and MUC2 by immunohistochemistry on FFPES; and (3) fluorescence in situ hybridization (FISH) testing on CytoBrush samples using 4 probes (8q24 [MYC], 9p21 [CDKN2A], 7q12 [ERBB2], and 20q13.2 [ZNF217]).

Results: Most of the NDBE showed stepwise morphologic changes, ultimately to dysplasia/EAC in long-term follow-up, with progression rate ranging from 2 to 10 years, and coexistence of multigrade dysplasia. Aberrant P53⁺/P16⁺ expression was detectable in NDBE (6.2%), NDBE with indefinite dysplasia (NDBE-IND; 11.1%), and GERD. P16 expression was an early event in neoplastic progression. P53 alteration in NDBE/NDBE-IND was greater among patients who progressed to low-grade dysplasia (LGD)/high-grade dysplasia (HGD). Strong Ki-67, cyclin D1, and MCM2 expression was seen in LGD and HGD. FISH testing with homozygous loss of p16 (43%–67%) in NDBE-IND and tetrasomy in LGD was associated with aberrant p53 expression.

Conclusions: Homozygous loss of p16 and tetrasomy on FISH, aberrant p53 and P16 expression, and overexpression of Ki-67, MCM2, and cyclin D1 in NDBE and NDBE-IND are predictable to neoplastic progression. Thus, the combination of protein biomarkers and FISH testing could improve early risk stratification and foster a cost-effective surveillance program.

Patients with mutated mismatch repair genes face an increased risk of developing a spectrum of malignancies. Pathologists need to be aware that these patients are prone to develop gastrointestinal carcinomas with unusual “noncarcinomatous” histomorphology that does not resemble the recognized Lynch syndrome spectrum. One should keep microsatellite instability in mind when classifying a tumor biopsy for the first time, as this is the key step in initiating the clinical course. Here we introduce an initially missed microsatellite instable carcinoma from our consultation service. The patient was a 51-year-old woman without any cancer history who presented to an outside institution because of jaundice and fever. Endoscopy identified a 4-cm ampulla mass. A diagnosis of sarcomatous malignancy with rhabdoid features was originally rendered. The patient presented to our institution for a second opinion and to initiate chemoradiation targeting the “sarcoma.” Ancillary tests were performed on the acquired outside material. The tumor cells were labeled by CAM5.2 and CDX2 despite the “sarcomatous” and focally solid/nested histomorphology. A mucicarmine stain highlighted intracellular mucin. Immunostaining showed loss of MSH6 with retained MLH1, MSH2, and PMS2. The MSH6 gene germline mutation was later confirmed. The management plan of chemoradiation/resection was switched to a Whipple procedure, with a “PT2N0M0” microsatellite instable adenocarcinoma being resected. The patient remains disease free 2 years later. This novel microsatellite instable carcinoma indicates that such tumors may present with noncarcinomatous histomorphology and essential ancillary analyses should be performed with minimal reservation to determine microsatellite status and to optimize patient management/outcomes (Figure 35).

A 3-year-old girl with a past medical history of autism spectrum disorder and global developmental delay presented with a several-month history of decreased appetite, fatigue, and abdominal distension. An abdominal X-ray showed striking hepatomegaly. Ultrasound demonstrated a large multicystic mass in the right upper quadrant with thick septations and internal debris. MRI revealed mass effect on adjacent structures, including displacement of the right hemidiaphragm and compression of the right kidney (Figure 36, A). Serum AFP, CEA, and β-hCG results were within normal limits. The patient underwent partial liver resection and gross examination showed an 18 × 17 × 5-cm, pink-purple cystic lesion with gray-white to pink-yellow cut surfaces and numerous cystic spaces up to 13.5 cm in greatest dimension (Figure 36, B). Microscopic examination (Figure 36, C) revealed a lesion composed of bland spindle cells within a variably loose, edematous/myxoid stroma with scattered ectatic thin-walled vessels, and occasional entrapped large biliary structures, the latter surrounded by dense concentric fibrosis. Grossly appreciated cystic structures were not lined by epithelium and contained degenerated blood or bile, the latter often with xanthomatous reaction at the periphery (Figure 36, D). Hepatic mesenchymal hamartoma represents 8% of primary liver tumors in children, and is the second most common benign pediatric liver tumor. Approximately 80% present within the first 2 years of life as an asymptomatic, enlarging abdominal mass. Radiologic studies show variable solid and cystic components and complete resection is curative. We discuss recent developments in our understanding of the biology of this unusual, likely neoplastic, process.

A 55-year-old man presented for evaluation of ulcers in his left inguinal and intergluteal folds progressing during several months. During a screening colonoscopy for workup of worsening anemia 1 month prior, a polyp was excised and pathology revealed an unusual histiocytic infiltration seen on pathology. PET-CT revealed hypermetabolic cutaneous foci involving the left inguinal and perianal regions corresponding to sites of cutaneous ulceration. The patient described the ulcers as asymptomatic and gradually enlarging in size. He denied drainage or pain from the affected areas. He also denied sexual activity, nausea, vomiting, abdominal pain, blood in stool, fevers, weight loss, or other constitutional symptoms. On examination, in the patient's left inguinal fold and intergluteal cleft were well-demarcated ulcerations with rolled cobblestoned borders and fibrinous granulation tissue at the ulcer base. Results of a complete blood count with differential analysis, basic metabolic panel, and rapid plasma reagin were unremarkable. On histopathology, both skin and colon biopsies showed a dense proliferation of histiocytes and lymphocytes. Immunostaining was positive for S100, CD1a, and CD4 and weakly positive for CD45 and CD68. CD20 and CD3 were negative. Electron microscopy of the skin biopsy showed Birbeck granules within the cytoplasm of a Langerhans cell. The skin lesion was negative for BRAF V600 mutation. A bone marrow biopsy was negative for CD1a and S100. We report an unusual case of Langerhans cell histiocytosis occurring in an adult male with gastrointestinal involvement showing negative BRAF mutation.

Context: Gastric intestinal metaplasia (GIM) and associated atrophic gastritis are considered preneoplastic conditions that confer an up to 6-fold increase for gastric cancer, the second leading cause of cancer death worldwide. Multifocality of GIM and an incomplete type of intestinal metaplasia have also been linked to increased gastric cancer risk. Proposed algorithms for optimal endoscopic surveillance in GIM patients based on such risk factors and histologic findings on initial biopsies exist, yet uniform pathologic reporting criteria are not well established.

Design: A review of 150 cases of GIM from 2013 to 2015 in a single institution was performed to investigate the reporting of this finding. Histopathologic assessment included identification of GIM type (complete, incomplete), presence and grade of dysplasia, and associated gastritides, including H pylori gastritis. Pathology reports were reviewed for biopsy indication, mention of GIM type, presence and type of dysplasia, and presence and type of associated gastritis.

Results: Complete-type and incomplete-type GIM were seen in 126 (84%) and 19 (12.7%) cases, respectively. The antrum was the predominant site (84%), with multifocal GIM seen in 11.3% of cases. Nearly 25% (24.8%) of patients had associated histologic H pylori infection. Atrophic gastritis was demonstrated in 8.7% of patients. Surprisingly, in the presence of GIM, 23% of patient reports failed to mention the presence/absence of dysplasia, and none mentioned GIM type.

Conclusions: There is considerable variability and lack of standardization in GIM pathology reporting. Mandatory inclusion of GIM type and dysplasia status may aid in clinical decision making to establishing appropriate surveillance in GIM patients, especially those at increased risk for gastric cancer.

Primary lung adenocarcinomas are classically thyroid transcription factor 1 (TTF-1) positive, whereas secondary carcinomas are negative for TTF-1. Nevertheless, it has been described that metastatic colorectal cancer carcinomas to lung could show TTF-1 positivity, which creates a critical diagnostic pitfall. Our case involves a 52-year-old woman with a lung nodule found during metastatic workup for a recently diagnosed and resected stage I adenocarcinoma of colon. Biopsy of the lung nodule confirmed a metastatic colonic adenocarcinoma. A wedge resection of the metastatic lesion was performed. The tumor was histologically similar to the previously diagnosed colonic adenocarcinoma. Immunohistochemical staining showed strong positivity for CDX2 (clone EPR2764Y, rabbit, monoclonal) and TTF1 (SP141, rabbit, monoclonal); tumor cells were focally positive for CK20 and negative for CK7 and napsin A (clone MRQ-60, mouse, monoclonal). Representative block and H&E slides from the previously diagnosed colonic carcinoma were requested from an outside institution. The colonic adenocarcinoma and the adenocarcinoma in the lung were morphologically identical. Immunostains were performed on 1 representative block of colonic adenocarcinoma. The tumor was strongly positive for CDX-2 and TTF-1, focally positive for CK20, and negative for CK7 (Ventana Ultra). Our case highlights that nuclear TTF-1 expression should be interpreted with caution during immunohistochemical workup for adenocarcinoma of unknown origin. To avoid potential pitfalls, TTF-1 should be interpreted in conjunction with the clinical setting, histologic features, and a panel of other IHC markers.

Context: Pancreatic neuroendocrine tumors (PanNETs) constitute 3%–5% of pancreatic malignancies and have increasing incidence. Although worse prognosis is associated with larger size, high mitotic rate, and vascular and perineural invasion, little is known about tumor growth and metastasis in PanNETs. OR51E1 is an olfactory receptor protein that plays a role in transducing odorant signals through neurotransmitter pathways. OR51E1 is normally expressed in cells with neuroendocrine functions. It is also a potential marker for prostate carcinoma and small intestinal neuroendocrine carcinomas (SI-NETs). We examine expression of OR51E1 in PanNETs and SI-NETs and its correlation with prognostic indicators.

Design: Thirty-nine PanNET (12 females, 27 males) and 11 SI-NET (3 females, 8 males) specimens were analyzed for OR51E1 expression. H-scoring was used to evaluate staining intensity (0–3+) and percentage of positive cells. One-way analysis of variance or Student t test correlated mean H-score with clinical and histopathologic parameters.

Results: Nonneoplastic acinar, duct, and islet cells displayed OR51E1 staining. Seven of 11 SI-NETs (63.6%) and 26 of 39 PanNETs (66.7%) displayed cytoplasmic staining. Seven of 38 (18.4%) PanNETs had strong patchy staining. In PanNETs, H-scores of OR51E1 staining do not correlate with tumor size, Ki-67, mitotic rate, or stage. Interestingly, decreased OR51E1 expression correlates with perineural invasion (H-score 113.7 ± 9.9 versus 67.0 ± 15.1; P = .01).

Conclusions: This is the first demonstration of OR51E1 expression in PanNETs and pancreatic tissue. The association between OR52E1 expression and perineural invasion in PanNETs implicates the role of OR51E1 in tumor spread. OR51E1 has potential use as a prognostic indicator for PanNETs.

The association between microscopic colitis and inflammatory bowel disease is unclear. There are case reports of symptomatic microscopic colitis in patients with quiescent inflammatory bowel disease. Here we present a case of concomitant presentation of new-onset microscopic colitis in a patient with active inflammatory bowel disease. The patient was a 75-year-old man with history of hypertension, myocardial infarction, Type II diabetes mellitus, psoriasis on adalimumab, and distal ulcerative colitis. Despite mesalamine treatment, he had chronic diarrhea for years and weight loss. The patient underwent esophagogastroduodenoscopy and colonoscopy for persistent nonbloody diarrhea. On endoscopy, the esophagus and duodenum were normal and the stomach showed patchy mucosal erythema. There was moderate to severe inflammation with granular ground-glass appearance of the mucosa, involving the rectum up to 25 cm from the anus, and the remaining bowel was normal. The microscopic examination of the second and third portion of the duodenum showed no pathologic diagnosis. The colon biopsies from the ascending, transverse, and descending colon showed increased intraepithelial lymphocytes, consistent with lymphocytic colitis. The biopsy from the rectosigmoid area showed moderate chronic active colitis with architectural distortion, basal lymphoplasmacytosis, cryptitis, and crypt abscess, consistent with chronic active colitis and the patient's history of inflammatory bowel disease. There was no evidence of infection by histology and microbiology culture studies. This case highlights the recognition of microscopic colitis in inflammatory bowel disease patients and the clinical significance of performing biopsies from all anatomical segments of colon to increase the diagnostic yield.

Lymphangiomas are benign lymphatic malformations with a poorly understood pathogenesis. Lymphangiomas are most commonly a disease of children, with nearly 50% presenting at birth and up to 90% presenting before 2 years of age. These lymphatic malformations are subdivided into 3 classes; microcytic, macrocytic (including cystic hygroma), and combined, with all 3 subtypes showing a predilection for the head and neck. According to Sumner B et al, lymphangiomas in 61 patients were examined, revealing the head to be the most common site (n = 35), followed by the neck (n = 25), then trunk and extremities (n = 43), and finally 6 cases of the internal organs (n = 1 of abdomen). Of note, the rare intra-abdominal lymphangiomas present prior to the age of 5 years in 60% of cases. We describe an interesting case of an 82-year-old woman who presented with multiple episodes of abdominal pain requiring 2 hospitalizations during 6 months. She ultimately presented with signs and symptoms of small bowel obstruction. Partial small bowel excision with mesentery revealed a segment of bowel, with a tan, vascularized, fluctuating, lobulated mass measuring 6.1 × 4.2 × 3.9 cm attached within the mesentery of the specimen. Sectioning of the mass revealed milky-white contents admixed with thickened gelatinous contents contained within the thin, tan septate mucosa of the mass. Immunohistochemistry analysis revealed CD31, CD34, and D2-40 positivity in the cells lining the mucosa. The correlation of clinical, macroscopic, and microscopic findings supports the diagnosis of macrocytic lymphangioma.

Gastric heterotopia has been described at various locations including rectum. In the gastrointestinal tract, it commonly presents as a polyp, but the presentation as a mass lesion is very rare. Here we report a 54-year-old man who underwent his first screening colonoscopy, which showed a nonobstructing, noncircumferential, and nonbleeding 2.5-cm mass in the upper rectum. Histologic examination of the biopsy material, however, showed almost unremarkable gastric oxyntic mucosa. There was no colorectal mucosa. Although the histologic identification was not challenging, the pathologic interpretation was difficult. It led to the confusion of specimen mix-up, and the patient had to undergo another procedure in a different hospital, with the same outcome. The consideration of gastric heterotopia did not occur, especially because there was no normal tissue native to the biopsy site, compounded by the confusing endoscopic presentation. He was finally referred to our institution, and the outside pathology material was submitted for in-house consultation. In retrospect, with 2 similar biopsy findings, a diagnosis of gastric heterotopia was rendered. The patient then underwent an endoscopic mucosal resection (representative image in Figure 37) with clear margins. It is important to be aware that specimen mix-up may occur at any level of specimen processing, from collection to preparation of slides; however, this case report illustrates the caveat that a wrong assumption in this regard may lead to unnecessary invasive procedures for the patient. A conscious awareness of heterotopias in general is important to avoid this pitfall.

Context: Conventional dysplasia can develop in sessile serrated adenoma (SSA). The 4th edition of the World Health Organization Tumours of the Digestive System recommends the term “SSA/P with cytologic dysplasia.” Grading of dysplasia and diagnosis of “mixed SSA/P-tubular adenoma” are discouraged. Accordingly, guidelines for postpolypectomy surveillance have recommendations for SSA/P with or without dysplasia, regardless of grading of dysplasia. We designed a survey to determine how effectively this terminology is being implemented by pathologists and gastrointestinal (GI) specialists.