Original ArticlesA Novel NIPBL-NACC1 Gene Fusion Is Characteristic of the Cholangioblastic Variant of Intrahepatic CholangiocarcinomaArgani, Pedram MD*; Palsgrove, Doreen N. MD†; Anders, Robert A. MD, PhD*; Smith, Steven C. MD, PhD‡; Saoud, Carla MD*; Kwon, Regina MD, MPH*; Voltaggio, Lysandra MD*; Assarzadegan, Naziheh MD*; Oshima, Kiyoko MD*; Rooper, Lisa MD*; Matoso, Andres MD*; Zhang, Lei MD§; Cantarel, Brandi L. PhD∥; Gagan, Jeffrey MD, PhD†; Antonescu, Cristina R. MD§Author Information *Departments of Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD †Department of Pathology ∥Bioinformatics Core Facility, Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX ‡Department of Pathology, Virginia Commonwealth University, Richmond, VI §Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY P.A. and D.N.P. contributed equally. Conflicts of Interest and Source of Funding: Supported in part by Biliary Cancer Research Fund at Johns Hopkins (P.A.). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Pedram Argani, MD, Department of Surgical Pathology, The Johns Hopkins Hospital, Weinberg Building, Room 2242, 401 North Broadway, Baltimore, MD 21231-2410 (e-mail: [email protected]). The American Journal of Surgical Pathology: November 2021 - Volume 45 - Issue 11 - p 1550-1560 doi: 10.1097/PAS.0000000000001729 Buy SDC Metrics Abstract We report a novel NIPBL-NACC1 gene fusion in a rare primary hepatic neoplasm previously described as the “cholangioblastic variant of intrahepatic cholangiocarcinoma.” The 2 index cases were identified within our consultation files as morphologically distinctive primary hepatic neoplasms in a 24-year-old female and a 54-year-old male. The neoplasms each demonstrated varied architecture, including trabecular, organoid, microcystic/follicular, and infiltrative glandular patterns, and biphasic cytology with large, polygonal eosinophilic cells and smaller basophilic cells. The neoplasms had a distinctive immunoprofile characterized by diffuse labeling for inhibin, and patchy labeling for neuroendocrine markers (chromogranin and synaptophysin) and biliary marker cytokeratin 19. RNA sequencing of both cases demonstrated an identical fusion of NIBPL exon 8 to NACC1 exon 2, which was further confirmed by break-apart fluorescence in situ hybridization assay for each gene. Review of a tissue microarray including 123 cases originally diagnosed as well-differentiated neuroendocrine neoplasm at one of our hospitals resulted in identification of a third case with similar morphology and immunophenotype in a 52-year-old male, and break-apart fluorescence in situ hybridization probes confirmed rearrangement of both NIPBL and NACC1. Review of The Cancer Genome Atlas (TCGA) sequencing data and digital images from 36 intrahepatic cholangiocarcinomas (www.cbioportal.org) revealed one additional case with the same gene fusion and the same characteristic solid, trabecular, and follicular/microcystic architectures and biphasic cytology as seen in our genetically confirmed cases. The NIPBL-NACC1 fusion represents the third type of gene fusion identified in intrahepatic cholangiocarcinoma, and correlates with a distinctive morphology described herein. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.