Original ArticlesIntracholecystic Papillary Neoplasms Are Distinct From Papillary Gallbladder Cancers A Clinicopathologic and Exome-sequencing StudyAkita, Masayuki MD*,†; Fujikura, Kohei MD, PhD*; Ajiki, Tetsuo MD, PhD†; Fukumoto, Takumi MD, PhD†; Otani, Kyoko MD, PhD*; Hirose, Takanori MD, PhD‡; Tominaga, Masahiro MD, PhD§; Itoh, Tomoo MD, PhD*; Zen, Yoh MD, PhD, FRCPath*,∥Author Information Departments of *Diagnostic Pathology †Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe Departments of ‡Pathology §Gastroenterological Surgery, Hyogo Cancer Center, Akashi, Japan ∥Institute of Liver Studies, King’s College Hospital, London, UK Conflicts of Interest and Source of Funding: Supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Yoh Zen, MD, PhD, FRCPath, Institute of Liver Studies, King’s College Hospital, London SE5 9RS, UK (e-mail: [email protected]). The American Journal of Surgical Pathology: June 2019 - Volume 43 - Issue 6 - p 783-791 doi: 10.1097/PAS.0000000000001237 Buy SDC Metrics Abstract Although intracholecystic papillary neoplasms (ICPNs) have been increasingly recognized, their features remain unclear because of the lack of standardized definition. This study aimed to elucidate clinicopathologic and genetic features of ICPNs using stringent diagnostic criteria. On the basis of the recently proposed criteria, gallbladder neoplasms showing delicate papillary growth were diagnosed as ICPNs, while polypoid papillary adenocarcinomas arranged in a complex architecture were categorized as papillary gallbladder cancers (GBCs). Clinicopathologic features were compared among ICPNs (n=7), papillary GBCs (n=24), and nonpapillary GBCs (n=44). Whole-exome and validation Sanger sequencing was also conducted. Gross mucin hypersecretion was detected in 3/7 ICPNs (43%), 1/24 papillary GBCs (4%), and 1/44 nonpapillary GBCs (2%) (P<0.001). All patients with ICPN lacked lymphovascular invasion and nodal metastasis, while these features were occasionally observed in patients with papillary or nonpapillary GBC (13% to 59%). ICPNs were less advanced than papillary and nonpapillary GBCs (P<0.001) with all cases of ICPNs being recurrence-free. Whole-exome and Sanger sequencing identified somatic mutations in STK11 (a causative gene of Peutz-Jegher syndrome; n=3), CTNNB1 (n=2), and APC (a gene of familial adenomatous polyposis; n=1) in ICPNs, while those alterations were exceptional in papillary and nonpapillary GBCs. ICPNs more commonly showed cytoplasmic and/or nuclear expressions of β-catenin than papillary and nonpapillary GBCs. In conclusion, the histology-based classification of gallbladder papillary neoplasms is useful for identifying ICPNs that share clinicopathologic features with the pancreatic counterpart. ICPNs meeting the criteria were genetically distinct from papillary and nonpapillary GBCs, with STK11, CTNNB1, and APC being identified as major driver genes for ICPNs. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.