Probes for INS

Background and Aims Bile duct invasion (BDI) by hepatocellular carcinoma (HCC) is rare and poorly characterized. Our aim was to elucidate clinical, cholangioscopic, and pathologic features of HCC with BDI and to compare them with features of cholangiocarcinoma (CC). Methods Seven cases of HCC with BDI (6 HCC and 1 combined HCC-CC) and 7 cases of CC diagnosed by cholangioscopic biopsy sampling between 2016 and 2020 were compared. Results The median age of HCC patients was 64 years (range, 49-77), and 6 patients were men. The median age of CC patients was 73 years (range, 58-75), and 4 patients were men. Obstructive jaundice was the presenting sign in 86% of HCC and 100% of CC cases. Cirrhosis was present in 77% of HCC cases but only 28% of CC cases. α-Fetoprotein was elevated in 57% of HCC cases and none of the CC cases. Both groups had biliary strictures; however, cholangioscopic features of HCC were more likely to show noncircumferential strictures with a mass and were less likely to include ulceration. Villiform formation and frond-like projections were more common in CC. Both showed increased vascularity and friability. Imaging showed a mass in 100% of HCC and in 57% of CC cases. The histopathology of HCC with BDI included trabecular or pseudoglandular architecture, granular eosinophilic cytoplasm, absence of mucin, and atypical nuclear features. Immunohistochemical staining in all HCC cases confirmed a hepatocyte phenotype. Immunohistochemical markers were required to distinguish cases of BDI caused by poorly differentiated HCC or CC because of overlapping clinicopathologic features between the 2 groups. Conclusions Cholangioscopic findings of a noncircumferential stricture with a luminal mass are indicative of HCC with BDI. Pathologists should routinely use a panel of hepatocyte and cholangiocyte biomarkers to differentiate BDI by HCC from CC and metastases in poorly differentiated carcinoma that lack mucin.

Objective: To investigate the utility of albumin RNAscope in situ hybridization in the diagnosis and differential diagnosis of hepatocellular carcinoma and its mimics. Methods: One hundred and fifty-two cases of hepatocellular carcinoma and its mimics and 33 cases of normal tissue were selected from the pathology database of the Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine from January 2013 to December 2019. Tissue microarrays were constructed and RNAscope in situ hybridization was performed to detect the expression of albumin mRNA. Results: No albumin mRNA expression was detected in normal tissues except for the liver. All hepatocellular carcinoma regardless of its degree of differentiation and primary or metastatic nature had detectable albumin mRNA, with strong and diffuse staining in 90.7% (49/54) of cases. While the positive rate of HepPar-1, Arg-1 or one of them by immunohistochemistry was 87.0% (47/54), 85.2% (46/54) and 92.6% (50/54) respectively. The positive rates of albumin mRNA in intrahepatic cholangiocarcinoma and biphenotypic hepatocellular carcinoma were 7/15 and 9/10, respectively. The former showed focal or heterogeneous staining, while the latter showed strong and diffuse staining. The positive rate of hepatoid adenocarcinoma was 8/19, and the albumin expression could be diffuse or focal. Sporadic cases of poorly differentiated gastric adenocarcinoma and metastatic colon adenocarcinoma showed focal staining of albumin mRNA. Conclusions: Detection of albumin mRNA by RNAscope in situ hybridization is of great value for the diagnosis and differential diagnosis of HCC, and the sensitivity may be improved by combining with HepPar-1 and Arg-1. It also offers different diagnostic clues according to different expression patterns.

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 in situ hybridization. Synaptophysin and chromogranin showed focal or patchy staining, while 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 next-generation sequencing (NGS) of ∼ 500 cancer genes. Recurrence and/or metastasis was seen in 3 (50%) cases (follow-up time range for all cases: 5 months-2 years). In conclusion, this series describes the distinctive morphology, immunophenotypic features and diffuse albumin staining in 6 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.

The differential diagnosis of intrahepatic cholangiocarcinomas (iCCAs) from metastatic adenocarcinomas from organs adjacent to the liver (gallbladder, pancreas, and stomach) is difficult due to histopathological similarity and a lack of specific markers. This study aimed to develop a method to differentiate iCCA and adenocarcinomas originated from extrahepatic organs adjacent to the liver.We retrospectively enrolled surgically resected iCCA (n = 181) and adenocarcinomas from extrahepatic organs (n = 30, n = 28, and n = 38 from gallbladder, pancreas, and stomach, respectively) between 2007 and 2013. The albumin mRNA in situ hybridization (ISH) and immunohistochemistry (IHC) of filamin-A and cytokeratin 19 (CK19) were performed using tissue microarray. Using logistic regression analysis of three markers, iCCA-score was developed, and its diagnostic performance was evaluated.The iCCAs were more frequently positive for albumin ISH (23.2% vs. 0%), filamin-A IHC (47.5% vs. 12.5%) and CK19 (68.5% vs. 40.6%) than extrahepatic adenocarcinomas (p < 0.001 for all). The iCCA-score consisting of these three markers was developed, and it showed higher diagnostic performance (area under the curve [AUC], 0.798 vs. 0.616, p < 0.001). Taking an iCCA-score of 2 or higher as the threshold for iCCA, the sensitivity was substantially higher than albumin ISH alone (45.9% and 23.2%, respectively; p < 0.001), but maintained high specificity (94.8% and 100%, respectively).Albumin ISH and IHC staining for filamin-A and CK19 showed distinct expression patterns between iCCA and extrahepatic adenocarcinomas from gallbladder, pancreas, and stomach. We developed iCCA-score that consisted of those three markers, and it showed better diagnostic performance than albumin ISH alone.