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Background Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are the leading causes of hepatocellular carcinoma (HCC) worldwide. Limited data exist on surgical outcomes for NAFLD/NASH-related HCC compared with other HCC etiologies. We evaluated differences in clinicopathological characteristics and outcomes of patients undergoing surgical resection for NAFLD/NASH-associated HCC compared with other HCC etiologies. Methods Demographic, clinicopathological features, and survival outcomes of patients with surgically resected HCC were collected. NAFLD activity score (NAS) and fibrosis score were assessed by focused pathologic review in a subset of patients. Results Among 492 patients screened, 260 met eligibility (NAFLD/NASH [n = 110], and other etiologies [n = 150]). Median age at diagnosis was higher in the NAFLD/NASH HCC cohort compared with the other etiologies cohort (66.7 vs. 63.4 years, respectively, P = .005), with an increased percentage of female patients (36% vs. 18%, P = .001). NAFLD/NASH-related tumors were more commonly >5 cm (66.0% vs. 45%, P = .001). There were no significant differences in rates of lymphovascular or perineural invasion, histologic grade, or serum AFP levels. The NAFLD/NASH cohort had lower rates of background liver fibrosis, lower AST and ALT levels, and higher platelet counts (P Conclusions Patients with NAFLD/NASH-related HCC more commonly lacked liver fibrosis and presented with larger HCCs compared with patients with HCC from other etiologies. No differences were seen in rates of other high-risk features or survival. With the caveat of sample size and retrospective analysis, this supports a similar decision-making approach regarding surgical resection for NAFLD/NASH and other etiology-related HCCs.

Myeloid cells are key regulators of cirrhosis, a major cause of mortality worldwide. Because stromal cells can modulate the functionality of myeloid cells in vitro, targeting stromal-myeloid interactions has become an attractive potential therapeutic strategy. We aimed to investigate how human liver stromal cells impact myeloid cell properties and to understand the utility of a stromal-myeloid coculture system to study these interactions in the context of cirrhosis.Single-cell RNA-sequencing analyses of non-cirrhotic (n = 7) and cirrhotic (n = 5) human liver tissue were correlated to the bulk RNA-sequencing results of in vitro cocultured human CD14We found that stromal-myeloid coculture reduces the frequency CD14Our work reveals an unanticipated role for liver stromal cells in impeding the maturation and altering the differentiation of macrophages and should prompt investigations into the role of local IL-6 production in the pathogenesis of liver disease. These studies provide a framework for investigating macrophage-stromal interactions during cirrhosis.The impact of human liver stromal cells on myeloid cell maturation and differentiation in liver disease is incompletely understood. In this study, we present a mechanistic analysis using a primary in vitro human liver stromal-myeloid coculture system that is translated to liver disease using single-cell RNA sequencing analysis of cirrhotic and non-cirrhotic human liver tissue. Our work supports a role for stromal cell contact in restricting macrophage maturation and for stromal-derived IL-6 in limiting the differentiation of a cirrhotic macrophage subset.

Context.— High-grade appendiceal mucinous neoplasm (HAMN) is a relatively recently introduced term describing a rare epithelial neoplasm of the appendix that demonstrates pushing-type invasion but high-grade cytologic atypia. It remains understudied. Objective.— To describe clinicopathologic features of HAMNs. Design.— We identified 35 HAMNs in a multi-institutional retrospective study. Clinical and histologic features were reviewed in all cases, as well as molecular features in 8 cases. Results.— Patients were 57 years of age on average and most commonly presented with abdominal/pelvic pain. Histologically, 57% of the tumors showed widespread high-grade features. Architectural patterns in high-grade areas included flat, undulating, or villous growth, and occasionally micropapillary, cribriform, or multilayered growth. Thirteen cases had intact serosa, and the remaining 22 perforated the serosa, including 7 with peritoneal acellular mucin beyond appendiceal serosa and 10 with grade 2 pseudomyxoma peritonei. Molecular abnormalities included KRAS mutations in 7 cases and TP53 mutations in 4. No tumor confined to the appendix recurred. Two patients without pseudomyxoma peritonei at initial presentation developed pseudomyxoma on follow-up. Among 11 patients who presented with pseudomyxoma peritonei, 5 died of disease and 3 were alive with disease at last follow-up. Conclusions.— HAMNs have a similar presentation to low-grade appendiceal mucinous neoplasm, and similar stage-based prognosis. When they spread to the peritoneum, they typically produce grade 2 pseudomyxoma peritonei, which may be associated with a worse prognosis than classical grade 1 pseudomyxoma peritonei.

Risk stratification of gastrointestinal stromal tumors (GISTs) is based on experience with tumors of the stomach, small bowel, and rectum, which are far more common than GISTs of other sites. In this study from 47 institutions, we analyzed GISTs of the esophagus (n = 102), colon (n = 136), and appendix (n = 27) for their size, mitotic rate, morphology, and outcome to determine which criteria predict their behavior. Esophageal GISTs were small (median: 2.5 cm) with spindle cell morphology and a low mitotic rate (mean: 3.6/5 mm2). Twelve (12%) tumors progressed, including 11 with a mitotic rate >5/5 mm2 and one large (6.8 cm) GIST with a mitotic rate of 2/5 mm2. Colonic GISTs were smaller (median: 1.4 cm) and presented with abdominal pain or bleeding in 29% of cases. Most (92%) were composed of spindle cells with a mean mitotic rate of 4.6/5 mm2. Sixteen (12%) tumors progressed: 14 had mitotic rates >5/5 mm2, and two were >5.0 cm with a mitotic rate 5/5 mm2) and size >5.0 cm. These findings support the use of size and mitotic rate for prognostication of GISTs in these locations, similar to tumors of the stomach, small bowel, and rectum.

The rate of syphilis in the United States has been increasing steadily in the past decade, but it remains an uncommon diagnosis in tissue biopsies. Most of the pathology literature on hepatic syphilis consists of older series or case reports. This study aimed to systematically characterize the histologic spectrum of hepatic syphilis in a contemporary cohort. Clinicopathologic features of 14 hepatic syphilis cases between 2012 and 2018 were analyzed to characterize the broad spectrum of histologic changes. Thirteen patients were men (age range: 19 to 59 y); 6 had known human immunodeficiency virus, 7 were men known to have sex with men, and no patient had known prior syphilis. Hepatic syphilis was the primary clinical suspicion in only 1 patient. Common symptoms included jaundice, rash, and abdominal pain. Thirteen had elevated transaminases, and 12 had elevated alkaline phosphatase. Pathologic changes were grouped into 5 histologic patterns: biliary-pattern injury (n=5), acute hepatitis (n=4), autoimmune hepatitis-like (n=1), fibroinflammatory mass-forming lesion (n=2), and no particular pattern (n=2). Nearly all showed portal and lobular lymphocytes and plasma cells; 12 had prominent histiocytes/Kupffer cells, 9 had ductular reaction, and 7 had duct inflammation. Occasional focal findings included dropout (n=7), phlebitis (n=7), and loose granulomata (n=5). Treponeme immunohistochemistry was positive in 10 and negative in 4, though treatment was given before biopsy in 3 of those 4. Thirteen patients had rapid plasma reagin testing either before or after biopsy, with 1:64 or higher titer. All patients who received treatment recovered. Hepatic syphilis is rare but likely underrecognized. It exhibits a variety of histologic appearances and therefore should be considered in several hepatic differential diagnoses, especially in men who have sex with men. Kupffer cells, granulomata, and phlebitis may suggest the diagnosis regardless of predominant histologic pattern. Negative treponeme immunohistochemical staining does not exclude the diagnosis, including in untreated patients.

Background Primary sclerosing cholangitis (PSC) is a well-described risk factor for the development of cholangiocarcinoma (CCA). Early detection of CCA in these patients is of great importance because it expands options for therapeutic interventions, including liver transplantation. Current diagnostic tests for the evaluation of biliary strictures are limited to biliary brushing (BB) cytology and fluorescence in situ hybridization (FISH). Next-generation sequencing (NGS) has become an important diagnostic tool in oncology and may be a useful tool for diagnosing CCA on BBs. It is not clear how NGS performs when it is added to BB cytology and FISH in patients with PSC. Methods This study reports the authors' experience with NGS performed as a prospective cotest with cytology and FISH on BBs obtained from 60 patients with PSC followed at Massachusetts General Hospital. A duct with malignancy was defined as a high-risk (HR) stricture with either high-grade dysplasia or CCA. Results NGS was better than FISH and cytology in detecting HR strictures, which showed multiple genetic mutations in all cases. NGS provided specific mutational information, and NGS results were reproducible in longitudinal samples. Conclusions Adding NGS to BB cytology and FISH in the evaluation of biliary strictures for patients with PSC may provide additional information that could help to inform clinical management.

AIMS: Coronavirus disease 2019 (COVID-19) has been recognised as a predominantly respiratory tract infection, but some patients manifest severe systemic symptoms/coagulation abnormalities. The aim of this study was to evaluate the impact of severe COVID-19 infection on the gastrointestinal tract. METHODS AND RESULTS: We examined clinicopathological findings in 28 resected ischaemic bowels from 22 patients with severe COVID-19. Most patients required intubation preoperatively and presented with acute decompensation shortly before surgery. D-dimer levels were markedly elevated in all measured cases (mean, 5394 ng/ml). Histologically, 25 cases (19 patients) showed evidence of acute ischaemia with necrosis. In this group, the most characteristic finding was the presence of small vessel fibrin thrombi (24 of 25 cases, 96%), which were numerous in 64% of cases. Patients with COVID-19 were significantly more likely than a control cohort of 35 non-COVID-19-associated acute ischaemic bowels to show isolated small intestine involvement (32% versus 6%, P

SARS-CoV-2 is the viral agent of COVID-19, a pandemic that surfaced in 2019. Although predominantly a respiratory ailment, patients with COVID-19 can have gastrointestinal (GI) and hepatobiliary manifestations. These manifestations are often mild and transient, but they can be severe and consequential. In the GI tract, ischemic enterocolitis is the most common and significant consequence of COVID-19. In the liver, the reported pathologic findings may often be related to consequences of severe systemic viral infection, but reports of hepatitis presumed to be due to SARS-CoV-2 suggest that direct viral infection of the liver may be a rare complication of COVID-19. In both the GI tract and liver, lingering symptoms of GI or hepatic injury after resolution of pulmonary infection may be part of the evolving spectrum of long COVID.

Context.— COVID-19 has been associated with liver injury, and a small subset of patients recovering from severe disease have shown persistent markedly elevated liver biochemistries for months after infection. Objective.— To characterize persistent biliary injury after COVID-19. Design.— A search of the pathology archives identified 7 post–COVID-19 patients with persistent biliary injury, and the clinical, radiologic, and pathologic features were assessed. Results.— All patients in this cohort presented with respiratory symptoms and had a complicated clinical course with acute elevation of liver biochemistries. Alkaline phosphatase (ALP) was markedly and persistently elevated after discharge (median peak ALP, 1498 IU/L, at a median of 84 days from diagnosis). Magnetic resonance cholangiopancreatography showed 3 patients with irregularity, stricturing, and dilatation of intrahepatic ducts; no radiographic abnormalities were identified in the remaining 4 patients. Liver biopsies showed mild portal changes with features of cholestatic injury in 4 patients (bile duct injury and canalicular cholestasis) and marked biliary obstruction in 2 patients (profound cholestasis, ductular reaction, and bile infarcts), but no SARS-CoV-2 RNA was identified on in situ hybridization. On follow-up, most patients had minimal intervention and showed marked improvement of liver biochemistries but with mild persistent elevation of ALP. Conclusions.— A subset of critically ill COVID-19 patients demonstrates marked and persistent cholestatic injury, with radiographic and histologic evidence of secondary sclerosing cholangitis, suggesting that cholestatic liver disease and secondary sclerosing cholangitis may be long-term sequelae of COVID-19 acute illness as a longstanding manifestation of critical illness.

Background Precision oncology relies on molecular diagnostics, and the value-proposition of modern healthcare networks promises a higher standard of care across partner sites. We present the results of a clinical pilot to standardize precision oncology workflows. Methods Workflows are defined as the development, roll-out, and updating of disease-specific molecular order sets. We tracked the timeline, composition, and effort of consensus meetings to define the combination of molecular tests. To assess clinical impact, we examined order set adoption over a two-year period (before and after roll-out) across all gastrointestinal and hepatopancreatobiliary (GI) malignancies, and by provider location within the network. Results Development of 12 disease center-specific order sets took ~9 months, and the average number of tests per indication changed from 2.9 to 2.8 (P = .74). After roll-out, we identified significant increases in requests for GI patients (17%; P < .001), compliance with testing recommendations (9%; P < .001), and the fraction of “abnormal” results (6%; P < .001). Of 1088 GI patients, only 3 received targeted agents based on findings derived from non-recommended orders (1 before and 2 after roll-out); indicating that our practice did not negatively affect patient treatments. Preliminary analysis showed 99% compliance by providers in network sites, confirming the adoption of the order sets across the network. Conclusion Our study details the effort of establishing precision oncology workflows, the adoption pattern, and the absence of harm from the reduction of non-recommended orders. Establishing a modifiable communication tool for molecular testing is an essential component to optimize patient care via precision oncology.

Context.— Cytomegalovirus (CMV) hepatitis in allograft livers is an important infectious complication, with histology that historically has been described to overlap with that of acute cellular rejection (ACR), a diagnosis that compels a different treatment regimen. Objective.— To update the clinicopathologic features of CMV hepatitis and explore its clinical and histologic relationship with ACR. Design.— A retrospective analysis of 26 patients with a diagnosis of CMV hepatitis across 4 institutions was performed, including clinical, histologic, and immunohistochemical features. Results.— Patients were predominantly CMV donor positive/recipient negative (D+/R−; n = 9 of 15) and received a diagnosis of CMV hepatitis at a mean age of 52 years (SD, 17 years), at a mean interval of 184 days (SD, 165 days) from transplantation. Mean CMV viral load at diagnosis was 241 000 IU/mL (SD, 516 000 IU/mL), and liver biochemical enzymes were elevated (mean alanine aminotransferase, 212 U/L [SD, 180 U/L]; mean aspartate aminotransferase, 188 U/L [SD, 151 U/L]; mean alkaline phosphatase, 222 U/L [SD, 153 U/L]). Ten cases did not show histologic features of ACR, and 16 cases demonstrated features of ACR (including marked bile duct injury and endotheliitis). Viral cytopathic change was found in all cases. All patients were treated with a combination of antiviral therapy and CMV intravenous immunoglobulin, with near resolution of biochemical enzymes in all patients with undetectable serum CMV viral titers. Conclusions.— CMV hepatitis and ACR are complex processes with interlinking mechanisms that are important to distinguish. A subset of transplantation patients with CMV hepatitis show histologic changes that mimic ACR but were treated successfully with antiviral therapy alone.

Smooth muscle tumors represent the second most common mural mesenchymal neoplasm in the gastrointestinal tract, but established criteria for prognostic assessment of these tumors are lacking. A large cohort of surgically resected intramural gastrointestinal smooth muscle tumors from 31 institutions was analyzed to identify potential prognostic features. Pathologic features were assessed by expert gastrointestinal and/or soft tissue pathologists at each center. Immunohistochemical confirmation was required. A total of 407 cases from the esophagus (n = 97, 24%), stomach (n = 180, 44%), small bowel (n = 74, 18%), and colorectum (n = 56, 14%) were identified. Patients ranged in age from 19 to 92 years (mean 55 years), with a slight female predominance (57%). Mean tumor size was 5.4 cm, with the largest tumor measuring 29 cm. Disease progression following surgery, defined as local recurrence, metastasis, or disease-related death, occurred in 56 patients (14%). Colorectal tumors were most likely to progress, followed by small bowel and gastric tumors. None of the esophageal tumors in this series progressed. Receiver operator characteristic analysis identified optimal cutoffs of 9.8 cm and 3 mitoses/5 mm2 for discriminating between progressive and non-progressive tumors. Histologic features strongly associated with progression by univariate analysis included moderate-to-severe atypia, high cellularity, abnormal differentiation (defined as differentiation not closely resembling that of normal smooth muscle), tumor necrosis, mucosal ulceration, lamina propria involvement, and serosal involvement (P 10 cm and/or showing ≥3 mitoses/5 mm2 may behave aggressively, and therefore close clinical follow-up is recommended in these cases.

Background Angiotensin-converting enzyme 2, a target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), demonstrates its highest surface expression in the lung, small bowel, and vasculature, suggesting abdominal viscera may be susceptible to injury. Purpose To report abdominal imaging findings in patients with coronavirus disease 2019. Materials and Methods In this retrospective cross-sectional study, patients consecutively admitted to a single quaternary care center from March 27 to April 10, 2020, who tested positive for SARS-CoV-2 were included. Abdominal imaging studies performed in these patients were reviewed, and salient findings were recorded. Medical records were reviewed for clinical data. Univariable analysis and logistic regression were performed. Results A total of 412 patients (average age, 57 years; range, 18 to >90 years; 241 men, 171 women) were evaluated. A total of 224 abdominal imaging studies were performed (radiography, n = 137; US, n = 44; CT, n = 42; MRI, n = 1) in 134 patients (33%). Abdominal imaging was associated with age (odds ratio [OR], 1.03 per year of increase; P = .001) and intensive care unit (ICU) admission (OR, 17.3; P < .001). Bowel-wall abnormalities were seen on 31% of CT images (13 of 42) and were associated with ICU admission (OR, 15.5; P = .01). Bowel findings included pneumatosis or portal venous gas, seen on 20% of CT images obtained in patients in the ICU (four of 20). Surgical correlation (n = 4) revealed unusual yellow discoloration of the bowel (n = 3) and bowel infarction (n = 2). Pathologic findings revealed ischemic enteritis with patchy necrosis and fibrin thrombi in arterioles (n = 2). Right upper quadrant US examinations were mostly performed because of liver laboratory findings (87%, 32 of 37), and 54% (20 of 37) revealed a dilated sludge-filled gallbladder, suggestive of bile stasis. Patients with a cholecystostomy tube placed (n = 4) had negative bacterial cultures. Conclusion Bowel abnormalities and gallbladder bile stasis were common findings on abdominal images of patients with coronavirus disease 2019. Patients who underwent laparotomy often had ischemia, possibly due to small-vessel thrombosis. © RSNA, 2020.

Most patients with Cowden syndrome have lesions in the gastrointestinal tract, characterized by multiple polyps of various histologic types in the large bowel, polyps in the upper gastrointestinal tract, and esophageal glycogenic acanthosis. However, pathologists are often unaware of the distinctive polyposis phenotype of Cowden syndrome. In this multicenter study, we report the spectrum of gastrointestinal manifestations in a series of 43 Cowden syndrome patients who had at least one endoscopy. The median age at the first endoscopy was 46 years and 58% were women. In 24 of 29 (83%) tested patients, a pathogenic germline mutation in PTEN was identified. The histology from 199 endoscopy procedures (67 upper gastrointestinal endoscopy and 132 colonoscopies) was reviewed. Hamartomatous polyps of the large bowel were the most common lesions, present in 85% of patients. Hamartomatous polyps showed varied histology, including lymphoid aggregates in 55% of patients, a lipomatous component in 52%, a ganglioneuromatous component in 52%, and a fibrous-rich component in 14%. Polyps with at least two different stromal components were found in 55% of patients. Inflammatory polyps were present in 21% of patients. Conventional adenomas and serrated polyps were identified in 48% and 62% of patients, respectively. In the upper gastrointestinal tract, the most common lesions were esophageal glycogenic acanthosis (37%), gastric hamartomatous polyps (47%), and duodenal hamartomatous polyps (20%). All patients with glycogenic acanthosis who had a colonoscopy had hamartomatous polyps of the large bowel. In five patients, the diagnosis of Cowden syndrome was established after the pathology report raised suspicion for the diagnosis. Pathologists who are aware of the characteristic admixture of lesions in Cowden syndrome can play an essential role in recommending referral to genetic counseling and gene testing. Early diagnosis of Cowden syndrome is important, as these patients and their relatives are at increased risk for developing multiple cancers.

Background COVID-19 is a deadly multisystemic disease, and bowel ischemia, the most consequential gastrointestinal manifestation, remains poorly described. Our goal is to describe our institution’s surgical experience with management of bowel ischemia due to COVID-19 infection over a one-year period. Methods All patients admitted to our institution between March 2020 and March 2021 for treatment of COVID-19 infection and who underwent exploratory laparotomy with intra-operative confirmation of bowel ischemia were included. Data from the medical records were analyzed. Results Twenty patients were included. Eighty percent had a new or increasing vasopressor requirement, 70% had abdominal distension, and 50% had increased gastric residuals. Intra-operatively, ischemia affected the large bowel in 80% of cases, the small bowel in 60%, and both in 40%. Sixty five percent had an initial damage control laparotomy. Most of the resected bowel specimens had a characteristic appearance at the time of surgery, with a yellow discoloration, small areas of antimesenteric necrosis, and very sharp borders. Histologically, the bowel specimens frequently have fibrin thrombi in the small submucosal and mucosal blood vessels in areas of mucosal necrosis. Overall mortality in this cohort was 33%. Forty percent of patients had a thromboembolic complication overall with 88% of these developing a thromboembolic phenomenon despite being on prophylactic pre-operative anticoagulation. Conclusion Bowel ischemia is a potentially lethal complication of COVID-19 infection with typical gross and histologic characteristics. Suspicious clinical features that should trigger surgical evaluation include a new or increasing vasopressor requirement, abdominal distension, and intolerance of gastric feeds.

A Man with Fatigue and Leg Swelling A 48-year-old man with alcohol use disorder was admitted because of weight gain, fatigue, and swelling in both legs. Sixteen months earlier, he had been hospital...

AimsThe histological distinction of intrahepatic cholangiocarcinoma (ICC) from metastatic adenocarcinoma remains a challenge. The primary goal was to evaluate the diagnostic value of morphology and albumin expression in the diagnosis of ICC.MethodsWe evaluated morphological patterns in 120 ICCs and 677 non-hepatic adenocarcinomas and performed in situ hybridisation (ISH) stain for albumin in the former cohort (retrospective cohort). We also identified 119 samples from primary and metastatic lesions, the validation cohort, in which albumin ISH was performed as part of the diagnostic workup. Targeted sequencing was performed on selected cases. We also mined existing expression profiling data including cases from The Cancer Genome Atlas (TCGA) (41 760 unique samples).ResultsIn the retrospective cohort, 45% of ICCs and IDH mutations and FGFR2 fusions) were identified in 31% of ICCs (10 of 32). An analysis of the TCGA data validated the specificity of the albumin assay.ConclusionsThe cholangiolar pattern and albumin RNA ISH distinguishes ICC from metastatic adenocarcinoma with high specificity. Given the high prevalence of targetable mutations in ICC, albumin RNA ISH is an essential component in the workup of tumours of uncertain origin. A specific diagnosis of ICC could trigger molecular testing and uncover targetable genetic alterations.

BACKGROUND: There is considerable interest in a neoadjuvant approach for resectable pancreatic ductal adenocarcinoma (PDAC). This study evaluated perioperative gemcitabine + erlotinib (G+E) for resectable PDAC. METHODS: A multicenter, cooperative group, single-arm phase II trial was conducted between April 2009 and November 2013 (ACOSOG Z5041). Patients with biopsy-confirmed PDAC in the pancreatic head without evidence of involvement of major mesenteric vessels (resectable) were eligible. Patients (n=123) received an eight-week cycle of G+E before and after surgery. The primary endpoint was two-year overall survival (OS), and secondary endpoints included toxicity, response, resection rate, and time to progression. Resectability was assessed retrospectively by central review. The study closed early due to slow accrual; no formal hypothesis testing was performed. RESULTS: One hundred fourteen patients were eligible, consented, and initiated protocol treatment. By central radiologic review, 97 (85%) of the 114 patients met protocol resectability criteria. Grade 3+ toxicity was reported in 60% and 79% of patients during the neoadjuvant phase and overall, respectively. Twenty-two of 114 (19%) patients did not proceed to surgery, 83 patients (73%) were successfully resected. R0 and R1 margins were obtained in 67 (81%) and 16 (19%) resected patients, respectively. Fifty-four patients completed postoperative G+E (65%). The two-year OS rate for the entire cohort (n=114) was 40% (95%CI 31–50) with a median OS of 21.3 months (95%CI 17.2–25.9). The two-year OS for resected patients (n=83) was 52% (95%CI 41–63) with a median OS of 25.4 months (95%CI 21.8–29.6). CONCLUSIONS: For resectable PDAC, perioperative G+E is feasible. Further evaluation of neoadjuvant strategies in resectable PDAC is warranted with more active systemic regimens.

Background Evidence suggests that early-onset gastric cancers are distinct from traditional gastric cancers; however, detailed genomic and morphologic characterization of these cancers has not been performed. Methods Genomic analysis was performed for 81 patients with gastric cancer who were 50 years old or younger; pathology slides were available for 53 of these patients, and they were re-reviewed to perform a morphologic-molecular correlation analysis. The results were compared with corresponding cBioPortal data and The Cancer Genome Atlas (TCGA) analysis, which represent traditional gastric cancers. The TP53 molecular signature was established to determine the pattern of somatic mutational damage. Variants of potential germline origin were also identified from next-generation sequencing data. Results A higher rate of CDH1 mutations (22.2% of early-onset gastric cancers vs 11.4% of traditional gastric cancers; P = .0042) but a similar rate of TP53 mutations (63% of early-onset gastric cancers vs 56.6% of traditional gastric cancers; P = .2674) were seen in early-onset cancers in comparison with traditional gastric cancers. The diffuse/mixed types correlated with the TCGA genomically stable type, and the remaining Lauren types correlated with the TCGA chromosomal instability type. Diffuse and indeterminate histologic types (overall survival, 26.25 months for the intestinal type, 20.5 months for the mixed type, 12.62 months for the diffuse type, and 9 months for the indeterminate type; P = .027) and the presence of a CDH1 gene mutation (overall survival, 9 months for mutant CDH1 and 22 months for wild-type CDH1; P = .013) significantly correlated with worse survival. The TP53 gene frequently showed transition mutations (65.5%) involving the CpG sites (49%). Variants of potential germline origin were seen in high-penetrance genes (CDH1 and APC) and moderate-penetrance genes (ATM, NBN, and MUTYH) in 9.9% of cancers. Conclusions Early-onset gastric cancer has distinct genomic alterations, such as CDH1 mutations, but shares with traditional gastric cancers a high frequency of TP53 mutations and the TP53 mutagenic signature. Diffuse and indeterminate histologic types and the presence of a CDH1 mutation are associated with worse overall survival. Endogenous factors leading to cytosine deamination and potential germline alterations in moderate-penetrance cancer susceptibility genes may be implicated in the pathogenesis of these cancers.

BackgroundRare cases of immune checkpoint inhibitor (ICI)-associated celiac disease (ICI-CeD) have been reported, suggesting that disruption of tolerance mechanisms by ICIs can unmask celiac disease (CeD). This study aims to characterize the clinicopathological and immunophenotypic features of ICI-CeD in comparison to ICI-associated duodenitis (ICI-Duo) and usual CeD.MethodsA medical and pathological records search between 2015 and 2019 identified eight cases of ICI-CeD, confirmed by tTG-IgA. Nine cases of ICI-Duo, 28 cases of moderate CeD, as well as 5 normal controls were used as comparison groups. Clinical information was collected from the electronic medical records. Immunohistochemistry for CD3, CD8, T-cell receptor gamma/delta (γδ), programmed death ligand 1 (PD-L1), and programmed death 1 (PD-1) were performed, with quantification of intraepithelial lymphocyte (IEL) subsets in three well-oriented villi. CD68, PD-L1, and PD-1 were assessed as a percentage of lamina propria surface area infiltrated by positive cells. Statistical significance was calculated by the Student’s t-test and Fisher’s exact test.ResultsThe eight patients with ICI-CeD (F:M=1:3) and nine patients with ICI-Duo (F:M=5:4) presented similarly with diarrhea (13/17) and abdominal pain (11/17) after a median of 1.6 months on ICI therapy. In patients with ICI-CeD, tTG-IgA ranged from 104 to >300 IU/mL. Histological findings in ICI-CeD and ICI-Duo were similar and included expansion of the lamina propria, active neutrophilic duodenitis, variably increased IELs, and villous blunting. Immunohistochemistry showed that the average number of IELs per 100 enterocytes is comparable between ICI-CeD and ICI-Duo, with increased CD3+CD8+T cells compared with normal duodenum but decreased γδ T cells compared with CeD. Average PD-L1 percentage was 9% in ICI-CeD and 18% in ICI-Duo, in comparison to ConclusionsICI-CeD resembles ICI-Duo clinically and histologically but shares the serological features and response to gluten withdrawal with classic CeD. Immunophenotyping of IELs in ICI-CeD and ICI-Duo also shows similar CD3, CD8, γδ T cell subsets, and PD-L1 populations, all of which differed quantitatively from usual CeD. We conclude that ICI-CeD is biologically similar to ICI-Duo and is likely a variant of ICI-Duo, but treatment strategies differ, with ICI-CeD often improving with GFD alone, whereas ICI-Duo requires systemic immunosuppression.

Immune checkpoint inhibitors can induce a durable response against a wide range of malignancies but may cause immune related adverse events. Immune checkpoint inhibitor (ICI) related hepatitis commonly shows lobular inflammation with histiocytes, vague to well-formed granulomas, fibrin ring granulomas, and endothelialitis. ICI cholangitis has also been reported and these patients may have bile duct dilatation or obstructive changes on imaging, and portal-based inflammation with duct injury. ICI related cholangitis is reportedly less responsive to steroids. The purpose of this study was to evaluate whether the pattern of inflammation on liver biopsy correlates with the pattern of LFT abnormalities, imaging findings, and responsiveness to steroids. Patient who developed elevated LFTs and underwent liver biopsy were identified. Clinical data was obtained from the electronic records. Liver biopsies were reviewed, and the pattern of inflammation was recorded as hepatitis, cholangitis, steatotic, or mild non-specific changes. Thirty-six liver biopsies had a hepatitis pattern of inflammation, including 16 patients with granulomas and 14 patients with endothelialitis. Sixteen patients had a cholangitic pattern, with portal-based inflammation. Four patients each had a pattern resembling fatty liver or mild nonspecific changes. The two commonest histologic patterns correlated with the pattern of LFT abnormalities. The cholangitic pattern was more likely to have bile duct dilatation or narrowing on liver imaging, and two patients were eventually diagnosed with bile duct obstruction from tumor. The pattern of inflammation, presence of granulomas, or presence of endothelialitis on liver biopsy did not predict response to steroids or the need for secondary immunosuppression. In conclusion, we found that a liver biopsy in patients on immune checkpoint inhibitors might not predict the need for steroids, the length of time that steroids is required, or the need for secondary immunosuppression. A cholangitic pattern may be seen when the pattern of LFTs is cholestatic, but this pattern can also be seen in competing drug reactions or bile duct obstruction from tumor.

Goblet cell carcinoid tumors are amphicrine tumors whose biological behavior ranges from indolent to highly aggressive, depending on tumor grade. Current grading systems for these tumors are based on identifying an adenocarcinoma arising in the setting of a goblet cell carcinoid tumor, which distinguishes this tumor from other gastrointestinal tract adenocarcinomas. Because goblet cell tumors are predominantly tumors of mucin secreting cells, we propose that they be classified as goblet cell adenocarcinomas, and graded using a methodology that has parallels in colorectal adenocarcinoma grading. We graded a large series of goblet cell adenocarcinomas by assessing the proportion of the tumor that demonstrates tubular or clustered growth. Histologic grade correlated with overall survival independent of stage, with median overall survival of 204, 86, and 29 months for low-grade, intermediate-grade, and high-grade goblet cell adenocarcinomas, respectively. Tumor stage also correlated with overall survival. We also graded the tumors according to previously proposed grading systems, and found that these systems are valid, in that they segregate patients according to prognosis.

There is limited data on the spectrum of molecular alterations in goblet cell carcinoids and adenocarcinoma ex goblet cell carcinoids of the appendix. We used next generation sequencing to determine mutations of potential pathogenetic and therapeutic significance in this rare group of tumors. Adequate DNA was successfully extracted in 34/46 cases and the final group included 18 goblet cell carcinoids and 16 adenocarcinoma ex goblet cell carcinoids. Illumina TruSeq™ was used for sequencing exons of a custom 282 gene panel using an Illumina HiSeq 2000. All cases had a minimum coverage depth of at least 50 reads. After filtering through the Exome Sequencing Project, the number of mutations per case ranged from 0–9 (mean:3). The mutational burden in adenocarcinoma ex goblet cell carcinoids was significantly higher than goblet cell carcinoids (mean 5 vs. 3; p

AIMS There is limited information regarding the clinicopathological and immunohistochemical characteristics of gastric pyloric gland adenomas (PGAs). METHODS AND RESULTS Sixty-seven cases of gastric PGA from 57 patients were analysed. PGAs occurred with similar frequency in men and women (47.4 and 52.6%, respectively), with a mean age of 66 years. Most presented in the gastric body/fundus (67.2%). Fifteen cases (22.4%) developed against a background of autoimmune gastritis (AIG), whereas normal mucosa was seen in 35.8%. Only 16.4% (11 cases) developed in patients with a genetic predisposition, most commonly familial adenomatous polyposis. Low-grade lesions had a mean size of 1.5 cm, while PGAs with high-grade dysplasia (HGD) or adenocarcinoma had a mean size of 3.5 cm (P < 0.001) and more commonly showed tubulovillous architecture (50.0 versus 25.6% in low-grade dysplasia; P = 0.040). Most PGAs (61.2%) co-expressed mucin (MUC)5AC and MUC6 (mixed type), which was associated significantly with HGD or adenocarcinoma (P = 0.013). AIG was also associated with HGD (P = 0.027), but genetic predisposition did not correlate with the grade of dysplasia (P = 0.793). The recurrence rate of PGA was similar for high- (11.8%) and low-grade lesions (7.4%) (P = 0.624). CONCLUSIONS The risk of HGD increases with the size of PGA, tubulovillous architecture and the presence of AIG as well as mixed immunophenotype. As the overall local recurrence rate is less than 10%, PGAs may be treated conservatively, but they should be excised completely if possible, particularly if they are large or show high-grade features.

Aims Lanthanum carbonate is used an alternative to calcium-based phosphate binders to manage hyperphosphatemia in patients with renal failure. The deposition of lanthanum within gastroduodenal mucosa of patients treated with the medication has been described, but given the relative novelty of this entity, the histiocytic deposits in the gastroduodenal mucosa can be confused with a variety of other processes, including infections and other drug-induced forms of injury. Methods and Results We describe 5 cases of lanthanum phosphate deposition in upper gastrointestinal tract biopsies. Three cases were confirmed with scanning electron microscopy and energy dispersive x-ray analysis, including one unique patient, status post renal transplant for polycystic kidney disease, who had last taken lanthanum 7 years prior to biopsy. Conclusion Lanthanum deposition in the upper GI tract is a mimic of other drug related forms of gastrointestinal injury, including iron pill related gastropathy. The key to making this diagnosis is a thorough drug history and awareness of the histologic features. This article is protected by copyright. All rights reserved.

Doxycycline is an oral tetracycline antibiotic that has been associated with upper gastrointestinal (GI) mucosal injury. Recently, characteristic vascular degeneration has been reported in the stomach and duodenum in patients with doxycycline-induced injury. Fourteen patients who underwent upper GI endoscopy for nonspecific symptoms and were found to have doxycycline-induced gastric and esophageal injury are described. Most patients showed characteristic vascular injury. A control group of gastric erosions and esophageal ulcers showed no cases with the characteristic vascular changes. Clinical, endoscopic, and pathologic features of doxycycline-induced upper GI tract injury are reviewed, with an emphasis on vascular injury.

An 18-year-old woman presented with acute liver failure. The total bilirubin was 19.7 mg per deciliter. Three days earlier, she had received a diagnosis of bronchitis and was treated with azithromycin. A diagnosis was made.

Fibrin ring granulomas are an uncommon finding in liver biopsies although they have been described in liver injury secondary to several infectious and noninfectious entities, most notably Q fever. Immune checkpoint inhibitors are recent advances in cancer therapy, and stimulate the immune system to cause antitumoral effects but may also lead to adverse immune events such as hepatitis and colitis. We report 2 patients on combination ipilimumab/nivolumab who developed hepatitis and had fibrin ring granulomas in their liver biopsies.

International audience; The vermiform appendix is the primary site of several distinctive benign and malignant neoplasms. Some can produce the clinical syndrome of pseudomyxoma peritonei (PMP). A consensus on their terminology was reached by an international panel of pathologists and clinicians working under the auspices of the Peritoneal Surface Oncology Group International (PSOGI), and this review discusses the application of the PSOGI classification to routine reporting. We discuss diagnosis and differential diagnosis together with implications for patient management, covering low-grade appendiceal mucinous neoplasms, high-grade appendiceal mucinous neoplasms, serrated polyps, adenomas and adenocarcinomas. We do not cover goblet cell tumours or neuroendocrine neoplasms in this paper.

Summary The molecular alterations identified among pyloric gland adenomas (PGAs) in the published literature are based on polymerase chain reaction of targeted genes, and next-generation sequencing (NGS) has not been performed. In this study, we performed NGS and correlated the molecular alterations with the histologic grade of dysplasia and immunohistochemical findings in a cohort of PGAs. Successful DNA extraction and sequencing were performed in 15 pyloric gland adenomas/adenocarcinoma from 12 patients. Additionally, 4 specimens of autoimmune gastritis were selected to serve as the control group. Ten PGAs with low-grade dysplasia were seen to have mutations in the triad of APC, KRAS, and GNAS genes. Five PGAs with high-grade dysplasia/adenocarcinoma exhibited mutations in several genes including APC, CTNNB1, KRAS, GNAS, TP53, CDKN2A, PIK3CA, and EPHA5 genes but did not exhibit mutations in the triad of APC, KRAS, and GNAS genes. The median tumor mutational burden was higher in PGAs with high-grade dysplasia/adenocarcinoma when compared with PGAs with low-grade dysplasia (5.25 and 4.38, respectively). PGAs with high-grade dysplasia/adenocarcinoma had more chromosomal gains and losses than PGAs with low-grade dysplasia. The molecular findings suggest that there are 2 separate mutator pathways of dysplasia development in PGAs.

Several types of nonconventional dysplasia have been recently described in inflammatory bowel disease (IBD). However, strict morphologic criteria are lacking, and their clinicopathologic features (including potential association with conventional dysplasia and/or colorectal cancer [CRC]) are poorly understood. A total of 106 dysplastic or serrated lesions in 58 IBD patients with CRC were retrospectively identified from five institutions. Thirty-six cases of nonconventional dysplasia were identified in 26 (45%) of the 58 patients and occurred with similar frequency in men and women (58% and 42%, respectively), with a mean age of 54 years (range: 24–73) and a long history of IBD (mean: 17 years, range: 2–43). Six morphologic patterns were recognized. Hypermucinous dysplasia (n = 15; 42%) presented as either a ‘pure type’ (n = 5; 14%) or a ‘mixed type’ with either conventional or another nonconventional subtype (n = 10; 28%). Serrated lesions, as a group, were equally common (n = 15; 42%) and included three variants: traditional serrated adenoma-like (n = 10; 28%), sessile serrated lesion-like (n = 1; 3%), and serrated lesion, not otherwise specified (n = 4; 11%). Dysplastic lesions with increased Paneth cell differentiation (n = 4; 11%) and goblet cell deficient dysplasia (n = 2; 6%) were rare. Twelve (46%) of the 26 patients had only nonconventional dysplasia, whereas the remaining 14 patients (54%) had both nonconventional and conventional dysplasias. Nonconventional dysplasia was most often graded as low-grade dysplasia (81%), which was less common in conventional dysplasia (37%) (p = 0.003). When present alone, nonconventional dysplasia was predominantly found in the left colon (81%, p = 0.006) as a polypoid or raised lesion (75%, p

IntroductionAcellular intra-abdominal mucin is associated with a favourable prognosis in pseudomyxoma peritonei. There are no current guidelines on how many blocks are needed to classify the mucin as acellular with confidence.MethodsSpecimens from cytoreductive surgery for mucinous appendiceal neoplasia, in which acellular mucin was found on initial histopathological examination, were prospectively identified. Additional tissue blocks were then taken to include either all residual visible intra-abdominal mucin or a maximum of 30 blocks. We also sent a questionnaire to pathologists in other centres.ResultsTwelve patients were identified. In two cases, neoplastic epithelial cells were found on taking additional blocks. The questionnaire results suggested considerable variation in block-taking practice.ConclusionTaking additional tissue identified neoplastic cells in 2 of 12 cases. We recommend that sampling additional material should be considered when only acellular mucin is found on initial histology. Further work to determine the optimum sampling protocol is indicated.

AIMS Dysplasia in colonic sessile serrated adenomas (SSAs)/sessile serrated polyps often shows loss of MLH1 expression as determined with immunohistochemistry, but the significance of loss of MLH1 expression in non-dysplastic crypts in these polyps is less well studied. The purpose of this study was to evaluate the prevalence of loss of MLH1 expression in non-dysplastic crypts in SSAs, and to evaluate its significance with regard to progression of these polyps. METHODS AND RESULTS Four hundred SSAs, including 158 SSAs without dysplasia, 219 SSAs with dysplasia (SSAD), and 23 SSAs with invasive adenocarcinoma (SSAC), were evaluated immunohistochemically for loss of MLH1 expression in both non-dysplastic and dysplastic portions of the polyps. Seventy-one of 400 (18%) SSAs showed loss of MLH1 expression in non-dysplastic crypts. The prevalence of MLH1-deficient non-dysplastic crypts was higher in polyps with dysplasia or carcinoma (7%, 22%, and 52% in SSAs, SSADs, and SSACs, respectively; P

Aims Appendicitis with a Crohn's-like histological appearance generally raises concern for Crohn's disease, Yersinia infection, and interval appendectomy. Actinomyces infection is a recognised cause of chronic appendicitis that can histologically mimic Crohn's disease. Methods and results We report on 20 cases of appendicitis with Crohn's-like histological features that were due to Actinomyces. Most patients presented with acute or chronic abdominal pain. Imaging studies suggested a mass in five cases. Two patients had interval appendectomy. Histological features showed Crohn's-like appendicitis in 16 cases, with moderate to marked fibrosis and granulomas in seven cases. The other four cases had less consistent histological findings. None of the patients developed Crohn's disease during the follow-up interval (median, 37 months). Conclusions Actinomyces can be associated with Crohn's-like appendicitis with marked fibrosis, transmural inflammation, lymphoid hyperplasia, and granulomas.

Autoimmune enteropathy (AIE) is a rare autoimmune disorder that has been described both in pediatric and adult patients and usually causes intractable watery diarrhea. The management of AIE is not standardized because the disease shows variable response to different immunosuppressive regimens including corticosteroids, azathioprine, cyclophosphamide, 6-mercaptopurine, tacrolimus, cyclosporine-A, infliximab, vedolizumab, and abatacept. We present a patient with adult-onset AIE and intractable high-volume diarrhea resulting in numerous hospitalizations and temporary parenteral nutrition, who is now successfully maintained on ustekinumab. Therefore, ustekinumab should be considered for further evaluation as a therapeutic option in cases of refractory AIE.

The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.

Hepatitis C virus (HCV) infection is accelerated following liver transplantation (LT). Single nucleotide polymorphisms (SNPs) near the epidermal growth factor (EGF) (rs4444903), IL28B (rs12979860), and PNPLA3 (rs738409) loci are associated with treatment response, fibrosis, and hepatocellular carcinoma in non-transplant hepatitis C, but allograft population data are limited. We sought to determine the role of these SNPs in 264 patients with HCV who underwent LT between 1990 and 2008. Genotypes were determined from donor wedge/allograft biopsies and recipient explants. Cox proportional hazards model was used to assess time to cirrhosis, liver-related death, and retransplantation, adjusting for donor age and sustained virological response (SVR). Over a median follow-up of 6.3 yr, a trend toward increased progression to graft cirrhosis was observed among recipients of an EGF non-AA vs. AA donor liver (adjusted HR 2.01; 95% CI 0.93–4.34; p = 0.08). No other genotypes predicted cirrhosis development or graft survival. The CC IL28B variant in both recipients and donors was associated with increased rate of SVR (R-CC/D-CC 8/12[67%], R-non-CC/D-CC or R-CC/D-non-CC 23/52[44%], R-non-CC/D-non-CC 12/45[27%], p linear trend = 0.009). Recipient EGF, IL28B, and PNPLA3, and donor IL28B and PNPLA3 genotypes do not predict adverse outcomes in HCV LT recipients. A potential association exists between donor EGF genotype and cirrhosis.

e16675 Background: NAFLD associated HCC is rapidly increasing in frequency worldwide. In this study, we evaluated potential differences in clinical characteristics and outcomes of patients who underwent surgery or liver transplant for NAFLD-associated HCC compared to HCC from other etiologies. Methods: Demographic, clinicopathological features and outcomes of patients with HCC who underwent liver resection or liver transplant at Massachusetts General Hospital and Brigham and Women’s Hospital were collected (January 2004 - April 2018). Of 713 patients screened, 481were eligible: 260 underwent resection [NAFLD (n = 61), viral (n = 150), cryptogenic (CC) (n = 49)]. 221 underwent transplant [(NAFLD (n = 14), viral (n = 201), CC (n = 6)]. Results: In the Resected cohort, NAFLD patients presented with median age of (71.5 years) compared with Viral (63.4) and Cryptogenic (68.4). NAFLD patients had significantly higher Body Mass Index (BMI) > 28.8 39(66%) p = < 0.001, while patients with cryptogenic HCC presented with large tumor size (>5cm) 37(75%) p = 0.001. In multivariate analysis, tumor size 5cm (HR1.78,p = 0.002), R1 or R2 resection (HR 2.48, p = < 0.001and 2.8,p = 0.007), low platelet count (HR 2.8,p = 0.002) and diabetes (HR 1.5,p = 0.025) were poor prognostic factors in resection cohort. Median overall survival (OS) was not significantly different between NAFLD, Cryptogenic and Viral (47.2, 69.7 and 69.0 months, p = 0.18) etiologies, respectively. In the Transplant cohort, NAFLD patients had a median age of 65.5 and cryptogenic, viral (61.3 and 58.5 years) respectively. NAFLD and Cryptogenic HCC patients compared with viral HCC patients had low AFP median 3.7, 3.9 and 7.5 ng/mL(p = 0.012) respectively. In multivariate analysis patients with perineural invasion (HR 20.7,p = 0.009), disease recurrence (HR 2.5,p = 0.001) and high AFP (HR 2.1,p = 0.001) were at higher risk of death among transplant patients. No significant difference in median OS was seen between NAFLD, cryptogenic and viral (69.1,92.3 and 88.0 months, p = 0.38). Conclusions: NAFLD patients had higher BMI and had a lower AFP than viral and CC. NAFLD had similar median OS following resection and transplant when compared to those with Viral and CC.

4547 Background: The incidence of early-onset gastroesophageal adenocarcinomas (EO-GEA) is increasing, and these tumors now constitute > 30% of all gastroesophageal cancers. Besides hereditary gastric cancer syndromes, which form ~3% of EO-GEA, the morphologic and molecular spectrum of these tumors is not well-studied. Methods: Next-generation sequencing (NGS) data obtained from routine clinical care from patients with EO-GEA, defined as age ≤50 years, from 3 tertiary care centers was evaluated and compared with tumor profiles of 2,081 patients with GEA from cBioPortal for Cancer Genomics. Available histologic slides were reviewed, and the tumors were classified into Lauren and WHO subtypes. Tumor-detected pathogenic variants of potential germline origin were identified from the NGS data. Results: The study cohort was formed by 79 patients with gastroesophageal (42%) and gastric (58%) adenocarcinoma. The most commonly mutated genes included TP53 (28.5%), CDH1 (10%), ARID1A (5%), KRAS (3.9%) and PIK3CA (3.9%). EO-GEA were less likely to harbor TP53 (28.5% vs. 57.5%, p 0.003) and ARID1A (5% vs. 20.6%, p 0.002) mutations when compared with cBioPortal data. Based on the Lauren scheme, the tumors were classified into intestinal (40%), diffuse (24%), mixed (12%), and indeterminate (15%) subtypes. Driver mutations in CDH1, TP53, FBXW7, BAP1 genes were seen in diffuse/mixed subtype, and TP53, ARID1A, KRAS, PIK3CA, APC, ATM, NBN, MUTYH genes in intestinal subtype. The indeterminate subtype showed TP53 mutations and additional alterations, including SMARCB1/ SMARCA4 loss leading to rhabdoid/undifferentiated morphology. ERBB2 amplification was more likely to be present in intestinal and indeterminate subtypes (p = 0.003). CD274 amplification/PD-L1 expression was more likely to be present in indeterminate subtype (p < 0.0001). Potential germline variants included mutations in gastric cancer susceptibility genes such as CDH1 (2.5%) and APC (1%), and other cancer susceptibility genes such as ATM (4%), NBN (1%), MUTYH (1%) and POLD1 (1%). Conclusions: The molecular profile of EO-GEA is distinct from traditional gastric cancers. Histologic subtypes of EO-GEA correlate with distinct genomic alterations. Our findings also support multigene germline panel testing in parallel for patients with EO-GEA.