Publications by authors named "Dhanpat Jain"

169 Publications

An Expert, Multidisciplinary Perspective on Best Practices in Biomarker Testing in Intrahepatic Cholangiocarcinoma.

Oncologist 2022 Aug 4. Epub 2022 Aug 4.

City of Hope, Duarte, CA, USA.

Intrahepatic cholangiocarcinoma (iCCA) is a rare and aggressive malignancy that arises from the intrahepatic biliary tree and is associated with a poor prognosis. Until recently, the treatment landscape of advanced/metastatic iCCA has been limited primarily to chemotherapy. In recent years, the advent of biomarker testing has identified actionable genetic alterations in 40%-50% of patients with iCCA, heralding an era of precision medicine for these patients. Biomarker testing using next-generation sequencing (NGS) has since become increasingly relevant in iCCA; however, several challenges and gaps in standard image-guided liver biopsy and processing have been identified. These include variability in tissue acquisition relating to the imaging modality used for biopsy guidance, the biopsy method used, number of passes, needle choice, specimen preparation methods, the desmoplastic nature of the tumor, as well as the lack of communication among the multidisciplinary team. Recognizing these challenges and the lack of evidence-based guidelines for biomarker testing in iCCA, a multidisciplinary team of experts including interventional oncologists, a gastroenterologist, medical oncologists, and pathologists suggest best practices for optimizing tissue collection and biomarker testing in iCCA.
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http://dx.doi.org/10.1093/oncolo/oyac139DOI Listing
August 2022

An update on ductal plate malformations and fibropolycystic diseases of the liver.

Hum Pathol 2022 Jun 28. Epub 2022 Jun 28.

Department of Pathology, Yale School of Medicine, New Haven CT 06520, USA. Electronic address:

A variety of cystic and fibrocystic lesions can occur in the liver, which may be single or multiple and etiologically can be acquired or have genetic underpinnings. Although the morphology of ductal plate development and various associated malformations has been well described, the genetic etiologies of many of these disorders are still poorly understood. Multiple clinical phenotypes in the liver are proposed to originate from ductal plate malformations: congenital hepatic fibrosis, Caroli's disease, Von Meyenburg complex, and the liver cysts of autosomal dominant polycystic kidney and liver diseases. Although many of the patients with these disorders, particularly with isolated liver involvement remain asymptomatic, some develop portal hypertension or symptoms from cyst enlargement. Development of hepatocellular malignancy is a risk in a small subset. Recent advances have made it now possible for some of these phenotypes to be genetically defined, and intriguingly animal models of adult polycystic liver disease suggest that abnormal organ development is not required. This review describes the current understanding, genetic underpinning, and key clinicopathologic and imaging features of these fibropolycystic liver diseases.
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http://dx.doi.org/10.1016/j.humpath.2022.06.022DOI Listing
June 2022

The many faces and pathologic diagnostic challenges of autoimmune hepatitis.

Hum Pathol 2022 Jun 23. Epub 2022 Jun 23.

Department of Pathology, Yale School of Medicine, New Haven, CT, 06520, United States. Electronic address:

Autoimmune hepatitis (AIH) is an immune-mediated chronic inflammatory liver disease, characterized by hypergammaglobulinemia, the presence of specific autoantibodies, and typical abnormalities in liver histology. Prompt diagnosis and initiation of immunosuppressive treatment are necessary for both chronic and acute onset AIH to prevent progression to end-stage liver disease or fatal liver failure. However, the diagnosis of AIH is challenging mainly because of its heterogeneous clinical, serological and pathological features. Although portal lymphoplasmacytosis and interface hepatitis are the most typical histological features of AIH, many other histological features can be observed in AIH, including emperipolesis, hepatocyte rosettes, and Kupffer cell hyaline globules. Recent studies have questioned emperipolesis and hepatocyte rosette formation as typical features of AIH, and atypical clinical and histological presentations have also been recognized. This led an international working group to propose the modified AIH diagnostic criteria. However, it is well recognized that there are no pathognomonic characteristics that can be used to diagnose AIH and careful clinicopathological correlation is required to arrive at the correct diagnosis. The aim of this review is to summarize the histological features of AIH, its varied histopathologic spectrum, recent updates and major differential diagnoses in routine clinical practice.
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http://dx.doi.org/10.1016/j.humpath.2022.06.019DOI Listing
June 2022

Prominent Pseudoacini in Focal Nodular Hyperplasia: A Potential Diagnostic Pitfall.

Am J Surg Pathol 2022 Jun 22. Epub 2022 Jun 22.

Department of Pathology, Yale School of Medicine, New Haven, CT.

Pseudoacini are generally a morphologic feature of hepatocellular carcinoma (HCC), being absent or rare in benign hepatocytic tumors, such as hepatocellular adenoma. However, rarely these can be seen in focal nodular hyperplasia (FNH) and may pose diagnostic challenges, especially when prominent. The study was aimed to evaluate the occurrence of pseudoacini in FNH and their clinicopathologic correlations. A total of 95 FNH cases diagnosed from 2005 to 2020 were included in the study. A pseudoacinus was defined as a circular arrangement of hepatocytes around a central dilated lumen present within the lobular parenchyma of the lesion with or without inspissated bile. Among the 95 FNH cases, 28 (29.5%) showed pseudoacini, which were prominent in 12 (12.6%) cases. Of these 3 occurred in patients above 50 years old. The pseudoacini were numerous in 3 cases, leading to an initial consideration of HCC in the differential diagnosis, and 1 case was diagnosed as well-differentiated hepatocellular neoplasm on initial biopsy. All 12 cases showed map-like staining pattern for glutamine synthetase. The hepatocytes forming the pseudoacini were positive for CK7 and HepPar1, while the inner lumina were highlighted by CD10 and bile salt export pump immunostains similar to adjacent canaliculi. The presence of prominent pseudoacini was not significantly associated with any clinical or pathologic features. The findings suggest that pseudoacini are likely manifestation of hepatocyte biliary transdifferentiation associated with chronic cholestasis in the lesion. This feature may pose a potential diagnostic pitfall especially on needle biopsies and awareness is needed to avoid misdiagnosing this as HCC.
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http://dx.doi.org/10.1097/PAS.0000000000001931DOI Listing
June 2022

Microangiopathic Hemolytic Anemia Is a Late and Fatal Complication of Gastric Signet Ring Cell Carcinoma: A Systematic Review and Case-Control Study.

Oncologist 2022 May 19. Epub 2022 May 19.

Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA.

Background: Microangiopathic hemolytic anemia (MAHA) is a rare paraneoplastic syndrome that has been reported in patients with gastric signet ring cell carcinoma (SRCC). Clinical and prognostic features of MAHA in this setting have been poorly described.

Materials And Methods: We conducted a systematic review in 8 databases of gastric SRCC complicated by MAHA and performed a case-control study assessing factors associated with survival in patients with gastric SRCC and MAHA in our pooled cohort compared with age-, sex-, and stage-matched cases of gastric SRCC from the Surveillance, Epidemiology, and End Results (SEER) database. Descriptive analyses were performed and multivariable Cox-proportional hazards regression modeling was used to determine factors associated with overall survival.

Results: All identified patients (n = 47) were symptomatic at index presentation, commonly with back/bone pain, and dyspnea. Microangiopathic hemolytic anemia was the first manifestation of gastric SRCC in 94% of patients. Laboratory studies were notable for anemia (median 7.7 g/dL), thrombocytopenia (median 45.5 × 103/μL), and hyperbilirubinemia (median 2.3 mg/dL). All patients with MAHA had metastatic disease at presentation, most often to the bone, bone marrow, and lymph nodes. Median survival in patients with gastric SRCC and MAHA was significantly shorter than a matched SEER-derived cohort with metastatic gastric SRCC (7 weeks vs 28 weeks, P < .01). In multivariate analysis, patients with MAHA were at significantly increased risk of mortality (HR 3.28, 95% CI 2.11-5.12).

Conclusion: Microangiopathic hemolytic anemia is a rare, late-stage complication of metastatic gastric SRCC and is associated with significantly decreased survival compared with metastatic gastric SRCC alone.
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http://dx.doi.org/10.1093/oncolo/oyac093DOI Listing
May 2022

An Appraisal of Immunohistochemical Stain Use in Hepatic Metastasis Highlights the Effectiveness of the Individualized, Case-Based Approach.

Arch Pathol Lab Med 2022 May 5. Epub 2022 May 5.

From the Department of Pathology (Wang, Sebastian, Walther, Zhang, Jain), Yale University School of Medicine, New Haven, Connecticut.

Context.—: Liver biopsy plays an important role in the clinical management of metastases and often requires workup using immunohistochemical (IHC) markers, but the approach varies among institutions.

Objective.—: To evaluate the utility of a morphologic pattern-based, individualized approach in the workup of hepatic metastases.

Design.—: All liver biopsies with metastasis between 2015 and 2018 were identified from our institutional database and were reviewed. The morphologic pattern of the metastasis and IHC markers used in each case were recorded. The final identification of primary site of the tumor was assessed based on all the available clinicopathologic data. The academic ranking and practice pattern of the pathologist signing out the case were also recorded.

Results.—: A total of 406 liver biopsies with metastasis were identified, and the cases were classified as adenocarcinoma (253 of 406; 62%), carcinoma not otherwise specified (12 of 406; 3%), neuroendocrine neoplasm (54 of 406; 13%), poorly differentiated carcinoma (43 of 406; 11%), nonepithelial tumor (24 of 406; 6%), and squamous cell carcinoma (20 of 406; 5%). The primary site was unknown in 39% (158 of 406) at the time of liver biopsy. A primary site was determined in 97% (395 of 406) of all cases, and only 3% (11 of 406) remained true carcinoma of unknown primary. The average IHC markers/case in patients with known primary was 2.6, compared with 5.9 with an initial unknown primary and 9.5 in cases of true carcinoma of unknown primary.

Conclusions.—: An individualized, case-based approach seems to be highly cost-effective and uses fewer IHC markers compared with preset panels that often comprise 10 or more IHC markers.
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http://dx.doi.org/10.5858/arpa.2021-0457-OADOI Listing
May 2022

Hepatic Adenomas in Patients 60 and Older Are Enriched for HNF1A Inactivation and Malignant Transformation.

Am J Surg Pathol 2022 06 6;46(6):786-792. Epub 2022 Apr 6.

Division of Anatomic Pathology, Mayo Clinic, Rochester, MN.

Hepatic adenomas occur most commonly in women between the ages of 20 and 40 years, but rarely they occur in older aged persons, including those 60 years of age or older. This group of adenomas, however, has not been systemically examined. Twenty-six hepatic adenomas in persons 60 years of age or older were studied, along with a control group of 50 hepatic adenomas in persons aged 30 to 39. Hepatic adenomas in persons 60 or more years of age were found in 21 women and 5 men, while the control group had 44 women and 6 men. Subtyping the adenomas in persons 60 years or older showed the following results: 18 HNF1A-inactivated adenomas (69%), 4 inflammatory adenomas (15%), and 4 unclassified adenomas (15%). In contrast, the control group showed a significantly different pattern (P=0.003), with a greater percentage of inflammatory adenomas (28, 56%), fewer HNF1A-inactivated adenomas (8, 16%), and more unclassified adenomas (14, 28%). Atypia and malignant transformation within the hepatic adenomas was studied next. Of the hepatic adenomas in persons age 60 or greater, 3 (12%) showed atypical histologic features, and 6 (23%) had a malignant transformation. In contrast, for hepatic adenomas in the control group, only 4 (8%) adenomas showed atypical histologic features, and 3 (6%) had undergone malignant transformation. In addition, the hepatic adenomas that were atypical or showed early malignant transformation were less likely to have beta-catenin activation in patients over 60 (2/9 cases) compared with those between 30 and 39 years (5/7 cases). Myxoid change and heavy lipofuscin deposition were also more common in adenomas in older aged persons. In conclusion, hepatic adenomas in persons 60 years of age or older are enriched for HNF1A-inactivated adenomas and have a higher frequency of malignant transformation. Malignant transformation, however, is less likely to develop through activation of the beta-catenin pathway.
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http://dx.doi.org/10.1097/PAS.0000000000001892DOI Listing
June 2022

Consensus recommendations for histological criteria of autoimmune hepatitis from the International AIH Pathology Group: Results of a workshop on AIH histology hosted by the European Reference Network on Hepatological Diseases and the European Society of Pathology: Results of a workshop on AIH histology hosted by the European Reference Network on Hepatological Diseases and the European Society of Pathology.

Liver Int 2022 05 12;42(5):1058-1069. Epub 2022 Mar 12.

Department of Pathology, Aretaieion Hospital, National and Kapodistrian University of Athens, Athens, Greece.

Background & Aims: Diagnostic histological criteria for autoimmune hepatitis (AIH) have not been clearly established. Previously published criteria focused mainly on chronic AIH, in which inflammatory changes mainly occur in portal/periportal regions and may not be applicable to acute presentation of AIH, in which inflammatory changes are typically predominantly lobular in location. International consensus criteria for the diagnosis and assessment of disease severity in both acute and chronic AIH are thus urgently needed.

Methods: Seventeen expert liver pathologists convened at an international workshop and subsequently used a modified Delphi panel approach to establish consensus criteria for the histopathological diagnosis of AIH.

Results: The consensus view is that liver biopsy should remain standard for diagnosing AIH. AIH is considered likely, if there is a predominantly portal lymphoplasmacytic hepatitis with more than mild interface activity and/or more than mild lobular hepatitis in the absence of histological features suggestive of another liver disease. AIH is also considered likely if there is predominantly lobular hepatitis with or without centrilobular necroinflammation and at least one of the following features: portal lymphoplasmacytic hepatitis, interface hepatitis or portal-based fibrosis, in the absence of histological features suggestive of another liver disease. Emperipolesis and hepatocellular rosettes are not regarded as being specific for AIH.

Conclusions: The criteria proposed in this consensus statement provide a uniform approach to the histological diagnosis of AIH, which is relevant for patients with an acute as well as a chronic presentation and to more accurately reflect the current understanding of liver pathology in AIH.
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http://dx.doi.org/10.1111/liv.15217DOI Listing
May 2022

Subtyping intestinal metaplasia in patients with chronic atrophic gastritis: an interobserver variability study.

Pathology 2022 Apr 25;54(3):262-268. Epub 2022 Feb 25.

Diagnostic and Research Institute of Pathology, Diagnostic and Research Center for Molecular BioMedicine, Medical University of Graz, Graz, Austria. Electronic address:

Incomplete gastric intestinal metaplasia (GIM) is associated with an increased risk of gastric cancer. We aimed to examine the interobserver variability of GIM subtyping (incomplete vs complete) in histological diagnosis of patients with chronic atrophic gastritis and to identify factors with potential impact on agreement. Nine international gastrointestinal expert pathologists assessed 46 cases with complete, incomplete or mixed-type GIM on scanned haematoxylin and eosin (H&E)-stained slides. Results were compared with the consensus diagnosis driven by two experts. Interobserver variability was evaluated by kappa statistics. Focusing on the predominant pattern, the agreement between each observer and the consensus diagnosis ranged from 78% to 98%. The level of agreement was moderate to almost perfect (weighted kappa=0.464-0.984). The participating pathologists reached substantial overall agreement (Fleiss' kappa=0.716, 95% confidence interval 0.677-0.755). Misclassification with potential impact on clinical decision making occurred in 5.7% of case ratings. The pattern of GIM (pure GIM versus mixed-type GIM) differed significantly between cases with high and low agreement (p=0.010), while the number of biopsy pieces per sample and the portion of mucosal surface involved by GIM did not. Pathologists who apply subtyping in daily routine performed better than those who do not (p=0.040). In conclusion, subtyping GIM on H&E-stained slides can be achieved satisfactorily with high interobserver agreement. The implementation of GIM subtyping as a risk stratifying tool in current practice guidelines by the European Society of Gastrointestinal Endoscopy (ESGE) and the American Gastroenterological Association (AGA) carries a low rate of misclassification, at least among gastrointestinal expert pathologists.
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http://dx.doi.org/10.1016/j.pathol.2021.12.288DOI Listing
April 2022

TCF7L2 transcriptionally regulates Fgf15 to maintain bile acid and lipid homeostasis through gut-liver crosstalk.

FASEB J 2022 03;36(3):e22185

Department of Internal Medicine, Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut, USA.

FGF19/FGF15 is an endocrine regulator of hepatic bile salt and lipid metabolism, which has shown promising effects in the treatment of NASH in clinical trials. FGF19/15 is transcribed and released from enterocytes of the small intestine into enterohepatic circulation in response to bile-induced FXR activation. Previously, the TSS of FGF19 was identified to bind Wnt-regulated TCF7L2/encoded transcription factor TCF4 in colorectal cancer cells. Impaired Wnt signaling and specifical loss of function of its coreceptor LRP6 have been associated with NASH. We, therefore, examined if TCF7L2/TCF4 upregulates Fgf19 in the small intestine and restrains NASH through gut-liver crosstalk. We examined the mice globally overexpressing, haploinsufficient, and conditional knockout models of TCF7L2 in the intestinal epithelium. The TCF7L2 mice exhibited increased plasma bile salts and lipids and developed diet-induced fatty liver disease while mice globally overexpressing TCF7L2 were protected against these traits. Comprehensive in vivo analysis revealed that TCF7L2 transcriptionally upregulates FGF15 in the gut, leading to reduced bile synthesis and diminished intestinal lipid uptake. Accordingly, Vilin ; Tcf7L2 mice showed reduced Fgf19 in the ileum, and increased plasma bile. The global overexpression of TCF7L2 in mice with metabolic syndrome-linked LRP6 substitution rescued the fatty liver and fibrosis in the latter. Strikingly, the hepatic levels of TCF4 were reduced and CYP7a1 was increased in human NASH, indicating the relevance of TCF4-dependent regulation of bile synthesis to human disease. These studies identify the critical role of TCF4 as an upstream regulator of the FGF15-mediated gut-liver crosstalk that maintains bile and liver triglyceride homeostasis.
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http://dx.doi.org/10.1096/fj.202101607RDOI Listing
March 2022

Interobserver agreement of estimating the extent of intestinal metaplasia in patients with chronic atrophic gastritis.

Virchows Arch 2022 Jun 13;480(6):1277-1281. Epub 2021 Dec 13.

Diagnostic and Research Institute of Pathology, Diagnostic and Research Center for Molecular BioMedicine, Medical University of Graz, Neue Stiftingtalstraße 6, 8010, Graz, Austria.

The extent of gastric intestinal metaplasia (GIM) can be used to determine the risk of gastric cancer. Eleven international gastrointestinal expert pathologists estimated the extent of GIM on haematoxylin and eosin (H&E)- and Alcian blue-Periodic acid Schiff (AB-PAS)-stained slides of 46 antrum biopsies in 5% increments. Interobserver agreement was tested with the intraclass correlation coefficient (ICC). Correlation between standard deviation and extent of GIM was evaluated with the Spearman correlation. The interobserver agreement was very good (ICC = 0.983, 95% confidence interval (CI) 0.975-0.990). The use of AB-PAS did not increase the agreement (ICC = 0.975, 95% CI 0.961-0.985). Cases with a higher amount of metaplastic epithelium demonstrated a higher standard deviation (rs = 0.644; p < 0.01), suggesting lower diagnostic accuracy in cases with extensive GIM. In conclusion, estimating the extent of GIM on H&E-stained slides in patients with chronic atrophic gastritis can be achieved satisfactorily with high interobserver agreement, at least among international expert gastrointestinal pathologists.
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http://dx.doi.org/10.1007/s00428-021-03245-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9184363PMC
June 2022

Dyrk1b promotes hepatic lipogenesis by bypassing canonical insulin signaling and directly activating mTORC2 in mice.

J Clin Invest 2022 02;132(3)

Cardiovascular Research Center, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA.

Mutations in Dyrk1b are associated with metabolic syndrome and nonalcoholic fatty liver disease in humans. Our investigations showed that DYRK1B levels are increased in the liver of patients with nonalcoholic steatohepatitis (NASH) and in mice fed with a high-fat, high-sucrose diet. Increasing Dyrk1b levels in the mouse liver enhanced de novo lipogenesis (DNL), fatty acid uptake, and triacylglycerol secretion and caused NASH and hyperlipidemia. Conversely, knockdown of Dyrk1b was protective against high-calorie-induced hepatic steatosis and fibrosis and hyperlipidemia. Mechanistically, Dyrk1b increased DNL by activating mTORC2 in a kinase-independent fashion. Accordingly, the Dyrk1b-induced NASH was fully rescued when mTORC2 was genetically disrupted. The elevated DNL was associated with increased plasma membrane sn-1,2-diacylglyerol levels and increased PKCε-mediated IRKT1150 phosphorylation, which resulted in impaired activation of hepatic insulin signaling and reduced hepatic glycogen storage. These findings provide insights into the mechanisms that underlie Dyrk1b-induced hepatic lipogenesis and hepatic insulin resistance and identify Dyrk1b as a therapeutic target for NASH and insulin resistance in the liver.
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http://dx.doi.org/10.1172/JCI153724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8803348PMC
February 2022

Pathogenic BRCA2 germline variants in combined hepatocellular-cholangiocarcinoma.

Pathol Int 2022 Feb 22;72(2):138-140. Epub 2021 Nov 22.

Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.

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http://dx.doi.org/10.1111/pin.13188DOI Listing
February 2022

Hepatocellular Carcinoma: Does the Background Liver With or Without Cirrhosis Matter?

Am J Clin Pathol 2022 Feb;157(2):305-313

Department of Pathology, New Haven, CT, USA.

Objectives: The pathologic differences between hepatocellular carcinoma (HCC) arising in noncirrhotic and cirrhotic livers have not been well studied.

Methods: We performed a retrospective analysis of 378 HCC cases (95 in noncirrhotic, 283 in cirrhotic livers) from pathology archives (2010-2017).

Results: Patients without cirrhosis were more likely to have hepatitis B (13.68% vs 2.83%, P < .001) or no known liver disease (30.53% vs 4.24%, P < .001), while hepatitis C was more common in patients with cirrhosis (65.72% vs 30.53%, P < .001). HCCs in noncirrhotic livers were larger in size (P < .001); were more likely to have a macrotrabecular histologic pattern (13.68% vs 4.95%, P < .01); were more likely to have fibrolamellar (3.16% vs 0%, P = .02), macrotrabecular-massive (13.68% vs 6.01%, P = .03), and clear cell (16.84% vs 6.71%, P < .01) subtypes; have a higher histologic grade (P < .01); be anaplastic tumor cells (P < .001); have a higher rate of vascular invasion (P < .01); and have a higher tumor stage (P = .04).

Conclusions: The findings indicate that HCCs in noncirrhotic livers demonstrate a larger tumor size; have a more macrotrabecular histologic pattern; have fibrolamellar, macrotrabecular-massive, and clear cell subtypes; have a higher tumor grade and stage; have a higher rate of vascular invasion; and have more anaplastic tumor cells compared with cirrhotic livers. Further studies to explore different pathways that promote oncogenesis in noncirrhotic livers are needed to better understand the pathogenesis of HCC.
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http://dx.doi.org/10.1093/ajcp/aqab125DOI Listing
February 2022

Obeticholic Acid Decreases Intestinal Content of Enterococcus in Rats With Cirrhosis and Ascites.

Hepatol Commun 2021 Sep 10;5(9):1507-1517. Epub 2021 Jun 10.

Digestive Diseases Section, Yale University, New Haven, CT, USA.

The intestinal microbiome and bacterial translocation (BT), the passage of microorganisms from the gut lumen to mesenteric lymph nodes and other extra-intestinal sites, are main mechanisms implicated in liver injury and further decompensation in patients with cirrhosis. We hypothesized that obeticholic acid (OCA), a semisynthetic bile acid, would change the microbiome composition and reduce bacterial translocation in experimental cirrhosis. Rats with cirrhosis induced by carbon tetrachloride inhalation (a nonseptic model) with ascites present for at least 7 days were randomized to receive a 14-day course of OCA at a dose of 5 mg/kg/day (n = 34) or placebo (n = 34). Stool was collected at days 1 (randomization), 8, and 14 (sacrifice) for analysis of intestinal microbiome using the V4 hypervariable region of the bacterial 16S gene amplified by polymerase chain reaction. Bacteriological cultures of mesenteric lymph nodes, blood, and ascites were performed at end of study. Twenty-four animals in each group reached the end of study. Compared with placebo, rats treated with OCA had decreased relative abundance of Enterococcus in both ileum content (P = 0.02) and in stool (P < 0.001). BT from pathogenic bacteria was not different between groups. At end of treatment, rats on OCA had a significantly lower aspartate aminotransferase (AST) (266 vs. 369 IU/L; P < 0.01) and higher serum albumin (0.9 vs. 0.7 g/dL; P < 0.01) than rats on placebo. Conclusion: Although OCA did not appear to reduce BT by pathogenic bacteria, the reduction in intestinal content of Enterococcus, which has been associated with hepatocyte death, in OCA-treated animals is consistent with our observed improvements in AST and in liver function, as evidenced by higher serum albumin.
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http://dx.doi.org/10.1002/hep4.1740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435275PMC
September 2021

Clinicopathological significance of neutrophil-rich colorectal carcinoma.

J Clin Pathol 2021 Jul 26. Epub 2021 Jul 26.

Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA

Aims: The importance of the interaction between tumour cells and neutrophils has recently begun to emerge. However, the significance of tumour-infiltrating neutrophil (TIN) in colorectal carcinomas (CRCs) remains unclear. The aim of this study was to investigate the prognostic significance of TIN in CRCs.

Methods: CRCs were evaluated for TIN and were classified as neutrophil-rich (NR), neutrophil-intermediate (NI) and neutrophil-poor (NP) based on the presence of >15, 5-15 and <5 TIN per 100 tumour cells, respectively. Various clinicopathological parameters were recorded in each case including age, gender, histological grade, tumour, node, metastasis (TNM) stage, tumour location and DNA mismatch repair (MMR) status.

Results: Among the 348 CRC cases reviewed, 38 cases were NR, 43 cases were NI and 267 cases were NP. High TIN was associated with higher histological grade (p=0.0222), right-sided tumour location (p=0.0025), advanced TNM stage (p=0.0346) and higher rate of MMR-deficient CRCs (p=0.0027). Patients with NR CRCs had significantly poorer 5-year recurrence-free survival comparing to patients with NI or NP CRCs on Kaplan-Meier analysis (p=0.0001) and high TIN remained an independent risk factor with multivariate analysis (p=0.0137; HR: 1.930, 95% CI: 1.144 to 3.255). NR CRCs are more commonly seen in MMR-deficient than in MMR-proficient CRCs (p=0.0006). Patients with MMR-deficient NR CRCs showed similar 5-year recurrence-free survival compared with MMR-proficient NR CRCs.

Conclusions: Our findings reveal that high TIN confers poorer patient prognosis in both MMR-proficient and MMR-deficient CRCs.
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http://dx.doi.org/10.1136/jclinpath-2021-207702DOI Listing
July 2021

Inhibin-positive hepatic carcinoma: proposal for a solid-tubulocystic variant of intrahepatic cholangiocarcinoma.

Hum Pathol 2021 10 20;116:82-93. Epub 2021 Jul 20.

Department of Pathology, University of California, San Francisco, San Francisco, CA 91343, United States. Electronic address:

Inhibin-positive hepatic carcinoma is a rare primary liver neoplasm that resembles sex cord-stromal tumor and thyroid follicular tumors. The term "cholangioblastic variant of intrahepatic cholangiocarcinoma" has been proposed. This study describes the clinicopathologic, immunophenotypic, and molecular features of a small series (n = 6) of this rare tumor. Albumin in situ hybridization (ISH) and capture-based next-generation sequencing (NGS) were also performed. All tumors occurred in young women (mean age 32.5 years, range 19-44 years) as a solitary large mass (mean 15.8 cm, range 6.9-23.5 cm). All tumors showed a highly distinctive morphology with sheets and large nests of tumor cells alternating with tubular and cystic areas imparting a sex cord-like or thyroid follicle-like morphology. Cytologic atypia was mild, and mitotic activity was low. All cases were positive for inhibin, as well as pancytokeratin, CK7, CK19, and albumin ISH. Synaptophysin and chromogranin showed focal or patchy staining, whereas INSM1 was negative. Markers for hepatocellular differentiation, thyroid origin, and sex cord-stromal tumor were negative. There were no recurrent genomic changes based on capture-based NGS of ∼500 cancer genes. Recurrence and/or metastasis was seen in three (50%) cases (follow-up time range for all cases: 5 months to 2 years). In conclusion, this series describes the distinctive morphology, immunophenotypic features, and diffuse albumin staining in six cases of a rare inhibin-positive primary liver carcinoma that runs an aggressive course similar to intrahepatic cholangiocarcinoma. Genomic changes typical of cholangiocarcinoma or hepatocellular carcinoma were not identified, and there were no recurrent genetic abnormalities. We propose the term "solid-tubulocystic variant of intrahepatic cholangiocarcinoma" to reflect the spectrum of morphologic patterns observed in this tumor.
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http://dx.doi.org/10.1016/j.humpath.2021.07.004DOI Listing
October 2021

Pediatric Hepatocellular Adenomas: The Influence of Age and Syndrome on Subtype.

Am J Surg Pathol 2021 12;45(12):1641-1647

Departments of Laboratory Medicine and Pathology.

Hepatocellular adenomas are rare in children. A large study focused on pediatric patients has not been undertaken. A natural language search was performed at 5 institutions for hepatocellular adenomas in patients younger than 21 years old. Clinical characteristics as well as immunohistochemical staining profile was reviewed and adenomas subtyped per standard classification. Patients were divided into prepubescent and postpubescent age group. Thirty-one patients were included. Eleven (35%) were male and 10 (32%) were prepubescent. Fifteen (54%) of 28 patients with known clinical histories had adenomas associated with a syndrome. The percentage of the different adenoma subtypes was: 16% β-catenin activated, 10% combined inflammatory and β-catenin activated, 29% HFN1α-inactivated, 35% inflammatory, and 10% unclassified subtype by immunohistochemical staining. Interestingly 53% of patients with syndromes were male, while 85% of patients in the nonsyndromic group were female. The total number of β-catenin activated tumors was greater in the syndromic group (5/15, 33%) and prepubescent group (5/10, 50%) than in the nonsyndromic group (2/13, 16%) and postpubescent group (3/21, 14%), P=0.4 and 0.07, respectively. Inflammatory type adenoma was more frequent in the postpubescent (10/21, 48%) than in the prepubescent group (1/10, 10%), P=0.06, trending toward significance. Pediatric patients with hepatocellular adenomas frequently have syndromes, especially in the prepubescent group. In patients with syndromes a greater percentage of adenomas were β-catenin activated. In patients without a known syndrome the distribution of hepatocellular adenoma subtypes appears similar to adults.
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http://dx.doi.org/10.1097/PAS.0000000000001763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8608351PMC
December 2021

An update on subtypes of hepatocellular carcinoma: From morphology to molecular.

Indian J Pathol Microbiol 2021 Jun;64(Supplement):S112-S120

Department of Pathology, Yale School of Medicine, New Haven, CT, USA.

The morphologic spectrum of hepatocellular carcinoma (HCC) is quite broad. While in about one-third of cases, the neoplasms can be categorized into meaningful subtypes based on morphology, a vast majority of these neoplasms are morphologically heterogeneous. With extensive tumor profiling, data has begun to emerge which can correlate specific morphologic features with underlying molecular signatures. A true morphologic subtype not only has reproducible H & E features, further supported by specific immunohistochemical or molecular signatures, but also has specific clinical implications and prognostic associations. Eight such morphologic subtypes are recognized by the 2019 WHO classification of tumors with a few more additional subtypes described in the literature. The goal of this review is to familiarize the reader with the morphologic subtypes and elaborate on the clinical and molecular associations of these neoplasms.
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http://dx.doi.org/10.4103/IJPM.IJPM_751_20DOI Listing
June 2021

HNF-1β is a More Sensitive and Specific Marker Than C-Reactive Protein for Identifying Biliary Differentiation in Primary Hepatic Carcinomas.

Arch Pathol Lab Med 2022 01;146(2):220-226

From the Department of Pathology (Patil, Jain, Zhang).

Context.—: Intrahepatic cholangiocarcinoma (iCCA) needs to be distinguished from hepatocellular carcinoma (HCC) and metastasis, and in the absence of any specific biliary markers, is often a diagnosis of exclusion. Hepatocyte nuclear factor (HNF)-1β is a transcription factor that plays a critical role in bile duct system morphogenesis.

Objective.—: To investigate the diagnostic value of HNF-1β to differentiate iCCA from HCC by immunohistochemistry and compare HNF-1β with C-reactive protein (CRP), a previously identified marker for iCCA.

Design.—: Cases of iCCA (n = 75), combined hepatocellular-cholangiocarcinoma (cHCC-CCA) (n = 13) and HCC (n = 65) were included in the study.

Results.—: All cases of iCCA (74 of 74, 100%) expressed HNF-1β compared with CRP expressed in 72.60% (53 of 73). The sensitivity and specificity of HNF-1β to differentiate iCCA from HCC was 100% and 92.31%, whereas the sensitivity and specificity for CRP was 75.58% and 7.79%. The expression of HNF-1β was greater in iCCA and the CCA component of cHCC-CCA compared with CRP (87 of 87, 100% versus 65 of 86, 75.58%; P < .001). On the contrary, CRP was more frequently expressed compared with HNF-1β in HCC and HCC component of cHCC-CCA (71 of 77, 92.21% versus 6 of 78, 7.69%; P < .001).

Conclusions.—: Our data indicate that HNF-1β is a more sensitive and specific marker than CRP for the diagnosis of iCCA and to identify the CCA component in cHCC-CCA. Lack of HNF-1β expression may be used to exclude iCCA from consideration in cases of adenocarcinomas of unknown primary.
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http://dx.doi.org/10.5858/arpa.2020-0725-OADOI Listing
January 2022

GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension.

J Exp Med 2021 07 6;218(7). Epub 2021 May 6.

Department of Internal Medicine (Digestive Diseases), Yale School of Medicine, New Haven, CT.

Portal hypertension is a major contributor to decompensation and death from liver disease, a global health problem. Here, we demonstrate homozygous damaging mutations in GIMAP5, a small organellar GTPase, in four families with unexplained portal hypertension. We show that GIMAP5 is expressed in hepatic endothelial cells and that its loss in both humans and mice results in capillarization of liver sinusoidal endothelial cells (LSECs); this effect is also seen when GIMAP5 is selectively deleted in endothelial cells. Single-cell RNA-sequencing analysis in a GIMAP5-deficient mouse model reveals replacement of LSECs with capillarized endothelial cells, a reduction of macrovascular hepatic endothelial cells, and places GIMAP5 upstream of GATA4, a transcription factor required for LSEC specification. Thus, GIMAP5 is a critical regulator of liver endothelial cell homeostasis and, when absent, produces portal hypertension. These findings provide new insight into the pathogenesis of portal hypertension, a major contributor to morbidity and mortality from liver disease.
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http://dx.doi.org/10.1084/jem.20201745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105721PMC
July 2021

Thick Fibrous Septa on Liver Biopsy Specimens Predict the Development of Decompensation in Patients With Compensated Cirrhosis.

Am J Clin Pathol 2021 Oct;156(5):802-809

Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA.

Objectives: In compensated cirrhosis, thick fibrous septa and small nodules on liver biopsy specimens correlate with the presence of clinically significant portal hypertension (CSPH). In turn, CSPH is the strongest predictor of cirrhosis decompensation. The aim of the study was to correlate liver biopsy specimen characteristics with the development of decompensation in patients with compensated cirrhosis.

Methods: Patients with compensated cirrhosis and a concurrent liver biopsy specimen were reviewed. Semiquantitative grading of septal thickness and nodule size was performed. Primary end point was development of clinical decompensation. In total, 168 patients (median age, 49 years; 76% men) were included in the study; the most common etiology was viral.

Results: In a median follow-up of 50 months, 43 (26%) patients developed clinical decompensation (60% ascites, 16% encephalopathy, 12% variceal hemorrhage, 7% jaundice, and 5% mixed). On univariate analysis, septal width was significantly associated with decompensation, but nodule size was not. On multivariate analysis including model for end-stage liver disease score, serum albumin, and septal width, albumin and septal width were independent predictors of decompensation.

Conclusions: Histologic cirrhosis in compensated patients can be subclassified by severity based on septal thickness, with thick septa denoting worse prognosis.
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http://dx.doi.org/10.1093/ajcp/aqab024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8512277PMC
October 2021

Cutaneous and hepatic vascular lesions due to a recurrent somatic mutation reveal a pathway for vascular malformation.

HGG Adv 2021 Apr 1;2(2). Epub 2021 Mar 1.

Department of Dermatology, School of Medicine, Yale University, New Haven, CT 06510, USA.

The term "cavernous hemangioma" has been used to describe vascular anomalies with histology featuring dilated vascular spaces, vessel walls consisting mainly of fibrous stromal bands lined by a layer of flattened endothelial cells, and an irregular outer rim of interrupted smooth muscle cells. Hepatic hemangiomas (HHs) and cutaneous venous malformations (VMs) share this histologic pattern, and we examined lesions in both tissues to identify genetic drivers. Paired whole-exome sequencing (WES) of lesional tissue and normal liver in HH subjects revealed a recurrent c.121G>T (p.Gly41Cys) somatic mutation in four of five unrelated individuals, and targeted sequencing in paired tissue from 9 additional HH individuals identified the same mutation in 8. In cutaneous lesions, paired targeted sequencing in 5 VMs and normal epidermis found the same c.121G>T (p.Gly41Cys) somatic mutation in three. encodes gap junction protein alpha 4, also called connexin 37 (Cx37), and the p.Gly41Cys mutation falls within the first transmembrane domain at a residue highly conserved among vertebrates. We interrogated the impact of the Cx37 mutant via lentiviral transduction of primary human endothelial cells. We found that the mutant induced changes in cell morphology and activated serum/glucocorticoid-regulated kinase 1 (SGK1), a serine/threonine kinase known to regulate cell proliferation and apoptosis, via non-canonical activation. Treatment with spironolactone, an inhibitor of angiogenesis, suppressed mutant SGK1 activation and reversed changes in cell morphology. These findings identify a recurrent somatic c.121G>T mutation as a driver of hepatic and cutaneous VMs, revealing a new pathway for vascular anomalies, with spironolactone a potential pathogenesis-based therapy.
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http://dx.doi.org/10.1016/j.xhgg.2021.100028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078848PMC
April 2021

Can primary hepatocellular carcinoma histomorphology predict extrahepatic metastasis?

Hum Pathol 2021 07 24;113:39-46. Epub 2021 Apr 24.

Department of Pathology, Yale School of Medicine, New Haven, CT, 06520, United States. Electronic address:

Studies comparing the histomorphologic features and phenotypic heterogeneity between primary and its corresponding metastatic hepatocellular carcinoma (HCC) are lacking. The aim of this study was to assess and compare the histomorphologic features and heterogeneity between primary and metastatic HCC. A total of 39 cases with both primary and metastatic tissues were identified from pathology archives (2000-2019). The common sites of metastasis included lung (28.21%), abdominal cavity (25.64%), lymph nodes (20.51%), bone (17.95%), soft tissue (15.38%), and adrenal gland (10.26%). Both the primary and metastatic tumors showed heterogeneity in intratumoral histologic patterns (87.18% and 76.92%, respectively). The most common histologic pattern was solid in both primary (61.54%) and metastases (56.41%), followed by macrotrabecular in primary (17.95%) and metastases (10.26%). Among HCC-subtypes, macrotrabecular-massive HCC was the most common subtype in both primary and metastases (28.21% each). Primary tumors in noncirrhotic livers were more likely to have larger size and microvascular invasion than those in cirrhotic livers. The histomorphology (histologic pattern, subtype, and grade) between the primary and metastases was discordant in about 50% cases (48.72%, 48.72%, and 51.28%, respectively). Our findings exhibit significant intratumoral heterogeneity and histomorphologic discordance between primary and metastatic HCCs. The solid and macrotrabecular histologic patterns and the macrotrabecular-massive subtype were the most common histomorphologic features seen in primary tumors associated with metastasis. Further studies to identify and explore different pathways that promote HCC metastasis and to compare the differences between primary and metastatic tumors on a larger cohort are needed to better understand the pathogenesis of metastasis.
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http://dx.doi.org/10.1016/j.humpath.2021.04.008DOI Listing
July 2021

Evolution of the liver biopsy and its future.

Transl Gastroenterol Hepatol 2021 5;6:20. Epub 2021 Apr 5.

Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA.

Liver biopsies are commonly used to evaluate a wide variety of medical disorders, including neoplasms and post-transplant complications. However, its use is being impacted by improved clinical diagnosis of disorders, and non-invasive methods for evaluating liver tissue and as a result the indications of a liver biopsy have undergone major changes in the last decade. The evolution of highly effective treatments for some of the common indications for liver biopsy in the last decade (e.g., viral hepatitis B and C) has led to a decline in the number of liver biopsies in recent years. At the same time, the emergence of better technologies for histologic evaluation, tissue content analysis and genomics are among the many new and exciting developments in the field that hold great promise for the future and are going to shape the indications for a liver biopsy in the future. Recent advances in slide scanners now allow creation of "digital/virtual" slides that have image of the entire tissue section present in a slide [whole slide imaging (WSI)]. WSI can now be done very rapidly and at very high resolution, allowing its use in routine clinical practice. In addition, a variety of technologies have been developed in recent years that use different light sources and/or microscopes allowing visualization of tissues in a completely different way. One such technique that is applicable to liver specimens combines multiphoton microscopy (MPM) with advanced clearing and fluorescent stains known as Clearing Histology with MultiPhoton Microscopy (CHiMP). Although it has not yet been extensively validated, the technique has the potential to decrease inefficiency, reduce artifacts, and increase data while being readily integrable into clinical workflows. Another technology that can provide rapid and in-depth characterization of thousands of molecules in a tissue sample, including liver tissues, is matrix assisted laser desorption/ionization (MALDI) mass spectrometry. MALDI has already been applied in a clinical research setting with promising diagnostic and prognostic capabilities, as well as being able to elucidate mechanisms of liver diseases that may be targeted for the development of new therapies. The logical next step in huge data sets obtained from such advanced analysis of liver tissues is the application of machine learning (ML) algorithms and application of artificial intelligence (AI), for automated generation of diagnoses and prognoses. This review discusses the evolving role of liver biopsies in clinical practice over the decades, and describes newer technologies that are likely to have a significant impact on how they will be used in the future.
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http://dx.doi.org/10.21037/tgh.2020.04.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829074PMC
April 2021

α-Fetoprotein mRNA in situ hybridisation is a highly specific marker of hepatocellular carcinoma: a multi-centre study.

Br J Cancer 2021 06 6;124(12):1988-1996. Epub 2021 Apr 6.

Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

Background: Pathologic diagnosis of hepatocellular carcinoma (HCC) can be challenging in differentiating from benign and non-hepatocytic malignancy lesions. The aim of this study was to investigate the potential utility of α-fetoprotein (AFP) mRNA RNAscope, a sensitive and specific method, in the diagnosis of HCC.

Methods: Three independent retrospective cohorts containing 2216 patients with HCC, benign liver lesions, and non-hepatocytic tumours were examined. AFP was detected using ELISA, IHC (Immunohistochemistry), and RNAscope. Glypican3 (GPC3), hepatocyte paraffin-1 (HepPar-1), and arginase-1 (Arg-1) proteins were detected using IHC.

Results: AFP RNAscope improved the HCC detection sensitivity by 24.7-32.7% compared with IHC. In two surgical cohorts, a panel of AFP RNAscope and GPC3 provided the best diagnostic value in differentiating HCC from benign hepatocytic lesions (AUC = 0.905 and 0.811), and a panel including AFP RNAscope, GPC3, HepPar-1, and Arg-1 yielded the best AUC (0.971 and 0.977) when distinguishing HCC from non-hepatocytic malignancies. The results from the liver biopsy cohort were similar, and additional application of AFP RNAscope improved the sensitivity by 18% when distinguishing HCC from benign hepatocytic lesions.

Conclusions: AFP mRNA detected by RNAscope is highly specific for hepatocytic malignancy and may serve as a novel diagnostic biomarker for HCC.
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http://dx.doi.org/10.1038/s41416-021-01363-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184895PMC
June 2021

Hepatocellular neoplasms arising in genetic metabolic disorders: steatosis is common in both the tumor and background liver.

Hum Pathol 2021 02 24;108:93-99. Epub 2020 Nov 24.

University of Washington, Department of Laboratory Medicine and Pathology, Seattle, WA 98195, United States; University of Washington, Department of Medicine, Seattle, WA 98195, United States. Electronic address:

Hepatocellular neoplasms can develop in multiple genetic metabolic disorders. While there have been rare case reports, clinical and pathological characterizations have not been systematically performed. We conducted a retrospective study in 9 patients with these rare genetic metabolic disorders, including glycogen storage disease type 1, ornithine carbamyl transferase deficiency, hereditary tyrosinemia type 1, and Navajo neurohepatopathy, who developed hepatocellular neoplasms. Our results show that steatosis is a common finding in both tumor (6/9 cases, 67%) and background liver parenchyma (8/9 cases, 89%), underlying a possible role for steatosis in tumorigenesis in these genetic metabolic disorders. Our findings also raise a consideration of underlying genetic metabolic disorder when young patients with hepatocellular neoplasm show steatosis in both the tumor and background liver.
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http://dx.doi.org/10.1016/j.humpath.2020.11.012DOI Listing
February 2021

Intestinal metaplasia around the gastroesophageal junction is frequently associated with antral reactive gastropathy: implications for carcinoma at the gastroesophageal junction.

Hum Pathol 2020 11 14;105:67-73. Epub 2020 Sep 14.

Department of Surgical Pathology, Yale University School of Medicine, New Haven, CT, USA. Electronic address:

Increasing evidence suggests that bile reflux (BR) plays a major role in mucosal injury, leading to adenocarcinoma of the proximal stomach and distal esophagus. However, gastric BR is difficult to diagnose and investigate. Reactive gastropathy (RG), in the absence of nonsteroidal anti-inflammatory drugs (NSAIDs) and other known causes, likely represents bile-mediated injury to the gastric mucosa. The goal of this study is to explore the association between antral RG and gastroesophageal junction (GEJ) mucosal inflammation and intestinal metaplasia (IM). The pathology database was searched for patients who had gastric biopsies with a diagnosis of antral RG and concurrent gastric cardia/GEJ/distal esophagus biopsies from 2013 to 2015. Age- and sex-matched patients with normal gastric antral biopsies served as controls. Biopsies from the GEJ region were evaluated for histological changes, including inflammation, antral and pancreatic metaplasia, RG, the type of gastric glands, proton pump inhibitor (PPI) changes, and IM. Detailed clinical history and medication use (including PPIs and NSAIDs) were recorded. IM in the GEJ region was more frequent in patients with antral RG than in controls (33.0% vs. 5.2%, 95% confidence interval [18.3-37.3%]). In addition, inflammation, other mucosal changes around the GEJ (RG and foveolar hyperplasia), antral IM, and PPI-associated mucosal changes were also more frequently seen in patients with antral RG. Our results show that antral RG is associated with mucosal injury and IM around GEJ, suggesting a role of BR. Further studies are needed to study duodenogastric-esophageal BR and its role in development of proximal gastric and distal esophageal adenocarcinoma.
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http://dx.doi.org/10.1016/j.humpath.2020.08.007DOI Listing
November 2020

Updates in staging and pathologic evaluation of esophageal carcinoma following neoadjuvant therapy.

Ann N Y Acad Sci 2020 12 6;1482(1):163-176. Epub 2020 Sep 6.

Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.

Esophageal carcinoma comprises two major subtypes-squamous cell carcinoma and adenocarcinoma, the incidences of which vary widely across the world and also depend on the location within the esophagus. The staging of esophageal cancer (EC) also remains unique among various gastrointestinal carcinomas, as it takes into account the location, histologic type, and grade. Its management has been evolving over the years and the recent American Joint Committee on Cancer staging system has been updated to reflect the changing practice and new data. It is clear that preoperative neoadjuvant therapy is increasingly being used for the treatment of locally advanced esophageal carcinomas, followed by surgical resection that improves survival. A variety of histologic changes can be seen after neoadjuvant therapy, which can be challenging for the pathologists. The presence of residual tumor in the surgically resected specimen and lymph node following neoadjuvant therapy is associated with poor prognosis. Hence, a thorough pathologic assessment of tumor regression grade and accurate tumor staging is required by pathologists to provide valuable prognostic information to guide further management. Tumor regression grading in ECs needs to be improved and standardized.
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http://dx.doi.org/10.1111/nyas.14462DOI Listing
December 2020
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