Analysis of Concurrent Intracholecystic Papillary Neoplasms and Biliary Intraepithelial Neoplasia Reveals Distinct Histologic and Molecular Profiles.

Abstract

Context.—: Intracholecystic papillary neoplasms (ICPNs) and biliary intraepithelial neoplasia (BilIN) are presumed precursors to gallbladder adenocarcinomas, but their relationship is incompletely understood.

Objective.—: To perform morphologic and molecular characterization of concurrent ICPNs, nonpolypoid mucosa, and adenocarcinomas to determine whether these lesions are related at the DNA level.

Design.—: Background mucosa and 36 ICPNs were graded by a pathologist blinded to original diagnoses. Separate areas of ICPNs, BilIN (n = 5), nondysplastic adjacent mucosa (n = 8), and invasive adenocarcinoma (n = 3) were amplified and sequenced on a next-generation sequencer. Data were manually curated to identify pathogenic somatic variants.

Results.—: High-grade ICPNs were associated with low-grade (n = 1) or high-grade (n = 3) BilIN or no dysplasia (n = 5). Fifteen were associated with invasive adenocarcinoma. Low-grade ICPNs were associated with low-grade BilIN (n = 3) or no dysplasia (n = 9). Pathogenic variants included CTNNB1 (catenin beta 1) exon 3 (7); TP53 (tumor protein p53) (6); APC (APC regulator of WNT signaling pathway) (2); RB1 (RB transcriptional corepressor 1) (1); KRAS (KRAS proto-oncogene, GTPase) (1); and PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) (1). Pathogenic variants in ICPNs were not detected in BilIN or nondysplastic mucosa. Mutations in invasive cancers included TP53, PIK3CA, and RB1, concordant with the ICPN, but not with BilIN, in all 3 cases.

Conclusions.—: BilIN in the background of ICPNs was of the same or lower grade than ICPNs. Synchronous ICPNs and BilIN lacked concordant somatic mutations. Mutations in adenocarcinomas aligned with the ICPNs. This suggests that ICPN and BilIN are independent at the DNA level and that the presence of ICPNs may not imply risk for subsequent flat dysplasia elsewhere in the biliary tree.