title: Molecular and cytogenomic profiling of hepatic adenocarcinoma expressing inhibinA, a mimicker of neuroendocrine tumors: proposal to reclassify as "cholangioblastic variant of intrahepatic cholangiocarcinoma".
abstract: Only a single case report exists in the literature of hepatic adenocarcinoma expressing InhibinA in a young woman, in which the authors proposed it to be a rare variant of intrahepatic cholangiocarcinoma (iCCA). We present novel molecular and histologic findings in our series of three cases occurring in young women and show these tumors may mimic well-differentiated neuroendocrine tumors (NET). Immunohistochemical (IHC) profiling was performed along with a next-generation sequencing (NGS) 47-gene solid tumor panel, and cytogenomic profiling via single-nucleotide polypmorphism microarray. IHC for inhibinA, chromogranin A (ChrA), and synaptophysin (Syn) was surveyed in liver tumors and in fetal liver. Two of the three patients recurred with metastatic disease with two confirmed deaths. Histological patterns present in the tumors included solid, trabecular, organoid, microcystic, and blastemal-like. IHC was positive for cytokeratin 7 in 3/3, cytokeratin 19 in 3/3, inhibinA in 3/3, ChrA in 3/3, Syn in 3/3, Sox9 in 2/3 and HepPar1 in 0/3. NGS was negative for pathogenic mutations. Recurrent cytogenomic abnormalities included gain of 17q, and loss of 6q. InhibinA was strong and diffusely expressed in 0/10 (0%) iCCA, 0/15 (0%) hepatocellular carcinomas (HCC), in the biliary component of 1/4 (25%) combined HCC-iCCA, 0/4 hepatoblastomas, 1/8 (13%) metastatic NET, and in 1/8 fetal liver tissues. We propose a classification of "cholangioblastic variant of intrahepatic cholangiocarcinoma" and molecular pathogenesis for this rare malignancy. Accurate identification on core biopsy is crucial for clinical management as it may mimic neuroendocrine neoplasms.
authors.affiliation: Department of Pathology and Laboratory Medicine at the Hospital of the University of Pennsylvania, Philadelphia, PA 19104; Current affiliation: Molecular Diagnostics Laboratory and Clinical Genomics Center, Pathology and Laboratory Medicine, University of California Los Angeles Medical Center, Los Angeles, CA 90095.
authors.forename: David R
authors.initials: DR
authors.lastname: Braxton
authors.affiliation: Laboratory of Oncology Cytogenetics, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Debra
authors.initials: D
authors.lastname: Saxe
authors.affiliation: Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Nevena
authors.initials: N
authors.lastname: Damjanov
authors.affiliation: Department of Pathology and Laboratory Medicine at the Hospital of the University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Kristen
authors.initials: K
authors.lastname: Stashek
authors.affiliation: Department of Pathology and Laboratory Medicine at the Hospital of the University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Stuti
authors.initials: S
authors.lastname: Shroff
authors.affiliation: Center for Personalized Diagnostics, Perelman School of Medicine, University of Pennsylvania Philadelphia, PA 19104.
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Morrissette
authors.affiliation: Department of Pathology and Laboratory Medicine at the Hospital of the University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Tondon
authors.affiliation: Department of Pathology and Laboratory Medicine at the Hospital of the University of Pennsylvania, Philadelphia, PA 19104. Electronic address: Eef@Mail.Med.Upenn.edu.
authors.forename: Emma E
authors.initials: EE
authors.lastname: Furth
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry / Q000175:diagnosis* / Q000235:genetics / Q000556:secondary; D000293:Adolescent; D000328:Adult; D001650:Bile Duct Neoplasms / Q000737:chemistry / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics*; D018281:Cholangiocarcinoma / Q000737:chemistry / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D020732:Cytogenetic Analysis; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D007265:Inhibins / Q000032:analysis*; D008113:Liver Neoplasms / Q000737:chemistry / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D025202:Molecular Diagnostic Techniques; D018358:Neuroendocrine Tumors / Q000737:chemistry / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D009626:Terminology as Topic; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; C422362:inhibin A; D007265:Inhibins
keywords: Cholangioblastic; Cholangiocarcinoma; Cytogenomics; InhibinA; Neuroendocrine; SNP array; TGF-β signaling