Marcela Salomao

Steatohepatitic hepatocellular carcinoma (SH-HCC): a distinctive histological variant of HCC in hepatitis C virus-related cirrhosis with associated NAFLD/NASH.

In explant livers with chronic hepatitis C (HCV-C) we have noted a distinctive histologic variant that we have termed steatohepatitic hepatocellular carcinoma (SH-HCC) with features resembling non-neoplastic steatohepatitis, including large droplet steatosis, ballooning of malignant hepatocytes, Mallory-Denk bodies, inflammation, and pericellular fibrosis. This study was undertaken to further describe the characteristics and prevalence of this histologic variant in HCV-C and any possible association with underlying risk factors for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). We selected two 2-year periods (mid-2003 to mid-2005 and 2007 to 2008), from which selected explant livers with HCV-C and HCC were examined to determine the characteristics and frequency of SH-HCC. The underlying cirrhotic liver was also reassessed for steatosis and evidence of steatohepatitis. Clinical records were consulted for concomitant NAFLD and NASH risk factors. The SH-HCC variant was found in a total of 22 of 62 HCC cases (35.5%). Fourteen of the 22 patients with SH-HCC (63.6%) had at least one known risk factor for NAFLD/NASH including diabetes (6 of 22, 27.3%), obesity (6 of 22, 27.3%), hypertension (11 of 22, 50%), and hyperlipidemia (5 of 22, 27.8%). In 14 of the 22 cases (63.6%) of SH-HCC, the non-neoplastic liver showed changes of NAFLD/NASH superimposed on otherwise typical features of HCV-C. In conclusion, in our series of HCV-C explants, approximately one-third of HCCs show a distinctive histological variant termed SH-HCC. Underlying risk factors for NAFLD and for NASH were identified in 63.6% of our cases. Moreover, non-neoplastic tissue in HCV-C explants showed changes of NAFLD/NASH in 63.6% of cases. These results suggest a possible NAFLD/NASH pathway leading to SH-HCC in the setting of HCV-C which requires further investigation in the future.

Utility of an immunohistochemical panel consisting of glypican-3, heat-shock protein-70, and glutamine synthetase in the distinction of low-grade hepatocellular carcinoma from hepatocellular adenoma.

Background:The pathologic distinction between hepatocellular carcinoma (HCC) and hepatocellular adenoma (HCA) is sometimes problematic due to histologic overlap between the 2 entities, a problem amplified on small biopsy specimens. Several recently characterized immunohistochemical markers such as glypican-3 (GPC-3), heat-shock protein-70 (HSP-70), and glutamine synthetase (GS) help distinguish dysplastic nodules from HCC. The utility of this panel in the distinction of low-grade hepatocellular carcinoma (LG-HCC) from HCA has not been fully described. Objective:To determine whether the above markers are useful in the distinction of HCCs from HCAs. Design:Tissue microarrays were constructed with 30 LG-HCCs and 18 HCAs. The arrays were stained with the above markers and analyzed with respect to amount and pattern of staining. GPC-3 and HSP-70 were considered positive when 10% of tumor cells showed immunoreactivity. GS was considered positive when 50% of tumor cells showed immunoreactivity. Results:GPC-3 was positive in 13 of 30 LG-HCCs and 0 of 18 adenomas. The sensitivity was 43% and the specificity was 100%. HSP-70 was positive in 14 of 30 LG-HCCs and 0 of 18 adenomas. The sensitivity was 46% and the specificity was 100%. GS was positive in 24 of 30 LG-HCCs and 9 of 18 adenomas. The sensitivity was 80% and the specificity was 50%. Conclusions:GPC-3 and HSP-70 are helpful in separating carcinomas from adenomas. GS is not useful in this clinical context.

Fine‐needle aspirations of pancreatic serous cystadenomas: Improving diagnostic yield with cell blocks and α‐inhibin immunohistochemistry

The diagnosis of serous cystadenoma (SCA), a rare benign pancreatic neoplasm, can alter the management of patients with pancreatic masses. Although characteristic imaging findings and fluid chemical analysis have been described, SCAs are not always recognized preoperatively. Furthermore, scant cellular yield on fine‐needle aspiration (FNA) often leads to a nondiagnostic or nonspecific benign diagnosis. α‐Inhibin (AI), a sensitive marker for SCA, is infrequently required for diagnosis in surgical specimens due to their characteristic histologic appearance. The objective of the current study was to determine whether AI staining can improve SCA diagnosis on FNA specimens.

Strategies for improving diagnostic accuracy of biliary strictures

Brush cytology is the initial intervention when evaluating biliary strictures. Biliary brush cytology is known for its low sensitivity (but high specificity) and may be accompanied by biopsies and/or fluorescent in situ hybridization (FISH) to improve diagnostic yield. This study aimed to identify features to enhance cytological sensitivity, and assess which sampling method(s) improve identification of pancreatobiliary adenocarcinomas (PBCa).

Histopathologic distinction between fibrosing cholestatic hepatitis C and biliary obstruction.

The histopathologic distinction between posttransplantation fibrosing cholestatic hepatitis C (FCH-C) and biliary obstruction (BO) is challenging. We sought to identify histopathologic features that could be useful in the differential diagnosis between these 2 entities. A total of 38 cases of hepatitis C virus (HCV)-negative, cholangiography-proven BO (including 16 posttransplant and 22 nontransplant patients) and 13 patients with posttransplantation FCH-C were included. FCH-C patients were characterized by cholestatic disease, high HCV viral load, no evidence of biliary tract obstruction on imaging, and typical histopathologic findings (≥3 of the following: 1, prominent ductular reaction; 2, hepatocyte swelling with lobular disarray; 3, periportal sinusoidal fibrosis, and 4, cholestasis). Biopsies were evaluated with hematoxylin and eosin, Masson trichrome, Victoria blue, and rhodanine stains. Cytokeratin 7 (CK7) immunohistochemistry was used to assess for the presence of CK7+ intermediate hepatobiliary cells. We found that portal edema (63.1% vs. 7.6%; P<0.0001), bile duct dilatation (26.3% vs. 0%; P=0.0003), acute cholangitis (15.7% vs. 0%; P=0.008), bile infarcts (10.5% vs. 0%; P=0.03), periductal fibrosis (23.6% vs. 0%; P=0.0007), and periportal copper deposition (60.5% vs. 15.3%; P=0.0006) are significantly more common in BO, whereas hepatocellular swelling with lobular disarray (84.6% vs. 5.2%; P<0.0001) and periportal sinusoidal fibrosis (34.2% vs. 100%; P<0.0001) are seen more frequently in FCH-C. Furthermore, marked ductular reaction with rare or absent CK7+ intermediate cells is highly suggestive of FCH-C in this context (73.6% vs. 7.6%; P<0.0001). In summary, this study offers a comprehensive characterization of the histologic features discriminating FCH-C from BO.

Bile salt export pump: a sensitive and specific immunohistochemical marker of hepatocellular carcinoma.

Bile salt export pump (BSEP) is a transporter expressed exclusively at hepatic canaliculi and drives bile‐salt efflux. Minimal data exist about BSEP expression in tumours. We hypothesized that BSEP immunohistochemistry would be specific for hepatocellular carcinoma (HCC).

The Hepatitis Aggressiveness Score (HAS): a novel classification system for post-liver transplantation recurrent hepatitis C.

Several histopathologic features have been described in cases of fibrosing cholestatic hepatitis C (FCH-C). We investigated whether FCH-associated features can be utilized as the basis of a novel grading system for the entire population of post–liver transplantation (LT) recurrent hepatitis C virus (HCV) infection. Liver biopsies obtained at a median (interquartile range) of 12.3 (10.4-13.8) months post-LT from 170 patients with recurrent HCV were included. Biopsies were assessed for the following FCH features: (1) ductular reaction, (2) cholestasis, (3) hepatocyte ballooning, and (4) periportal sinusoidal fibrosis. A Hepatitis Aggressiveness Score (HAS) was assigned on the basis of the number of FCH features as follows: 0 features=HAS 1; 1 to 2 features=HAS 2; and 3 to 4 features=HAS 3. We analyzed the performance of this novel system in predicting clinicopathologic outcomes compared with conventional grading systems after a median (interquartile range) follow-up of 24 (13-45.5) months. The HAS classification was highly predictive of fibrosis progression (P<0.001) and was the best predictor of graft loss in a multivariable analysis model, which included all conventional hepatitis grading systems (adjusted hazard ratio=5.5, confidence interval 2.9-10.7, P<0.001 for HAS 3 vs. HAS 1 and 2, compared with adjusted hazard ratio=1.0, confidence interval 0.5-1.9, P=0.94 for the presence of moderate to severe necroinflammation by at least 1 conventional grading system). Presence of at least 3 of 4 FCH features (HAS 3 group) characterized a subset of patients with distinctly worse prognosis and severe cholestatic disease (ie, FCH-C). We propose a novel approach to the histologic grading of post-LT recurrent HCV based exclusively on FCH features. This system allows accurate identification of FCH-C cases and stratification of all recurrent HCV patients into distinct prognostic categories.

Current concepts in the immunohistochemical evaluation of liver tumors

Immunohistochemistry often plays an important role in the evaluation of liver tumors. Recent advances have established a classification system for hepatocellular adenomas (HCAs) based on morphology, molecular alterations, and immunohistochemistry. Specifically, loss of liver fatty acid binding protein is seen in HNF1α-inactivated HCA, staining with serum amyloid A is seen in inflammatory HCA, and diffuse staining with glutamine synthetase (GS) is seen in β-catenin activated HCA. A panel of immunohistochemical stains including glypican-3 (GPC-3), heat shock protein 70, and GS are useful in distinguishing HCC from non-malignant dysplastic nodules. Immunohistochemistry is also useful to determine whether a liver tumor is of primary hepatocellular or metastatic origin. Recently described markers useful for this purpose include arginase-1, GPC-3, and bile salt export pump. These newer markers may offer superior utility when compared to traditional markers of hepatocellular differentiation such as alpha-fetoprotein, hepatocyte paraffin-1, polyclonal carcinoembryonic antigen, and CD10. This paper will review recent advances in the immunohistochemical evaluation of liver tumors.

Mutational analysis by next generation sequencing of gastric type dysplasia occurring in hyperplastic polyps of the stomach: Mutations in gastric hyperplastic polyps

UNLABELLED Gastric hyperplastic polyps (GHP) are the most common type of polyps occurring in the stomach. Although GHP are broadly interpreted as benign lesions, they may progress to dysplasia and adenocarcinoma. OBJECTIVE In this study, we aimed to identify genomic mutations that characterize and may drive malignant transformation in GHP by using next-generation sequencing. Eight GHP (2 with dysplasia, 1 indefinite for dysplasia and 5 without dysplasia) were studied. Only large polyps (>1cm) with gastric differentiation were included in this study, while adenomatous polyps (intestinal-type) were excluded. Immunohistochemistry for MUC2, MUC5A, MUC6, CDX2, p53, and Ki67 was performed. DNA was extracted from formalin-fixed paraffin-embedded sections and sequenced for the detection of somatic mutations. Multiplex sequencing was done with the TrueSeq Amplicon Cancer Panel in the MiSeq platform. Variant annotation and visualization were performed using NextGENe (SoftGenetics) software. No pathogenic mutations were detected in GHP without dysplasia. TP53 gene mutations were the most common alteration in dysplastic GHP (2 of 2 dysplastic cases). PIK3CA mutation was identified in a GHP with pyloric-type dysplasia, whereas foveolar-type dysplasia carried TP53 mutations. In conclusion, TP53 gene mutations are a common alteration in the early dysplastic stage during malignant transformation of GHP. GHP with dysplasia may show dual differentiation. In our study, pyloric-type dysplasia was associated with a PIK3CA alteration whereas foveolar dysplasia carried TP53 mutations. The identification of carcinoma-associated mutations in large GHP provides additional evidence of their neoplastic potential and emphasizes the need for their complete resection and follow-up.

Histopathology of Graft-vs-Host Disease of Gastrointestinal Tract and Liver An Update

OBJECTIVES Graft-vs-host disease (GVHD) is a donor T-cell-mediated disorder affecting the recipients skin, gastrointestinal tract, lungs, and liver. It complicates up to 70% of hematopoietic cell transplantation and is associated with high morbidity and mortality rates. METHODS An extensive review of the literature has been performed to include the most current consensus on the histopathologic diagnosis of gastrointestinal and liver GVHD. RESULTS In this review, we present an overview of GVHD, with emphasis on the histopathologic evaluation of gastrointestinal and liver specimens, including the most important differential diagnoses and possible pitfalls. CONCLUSIONS Histopathologic examination remains the mainstay of diagnosis of gastrointestinal and liver GVHD and is interpreted in conjunction with clinical and laboratory data.