Perihilar Intraductal Papillary Neoplasm of the Bile Ducts: A Clinicopathologic and Molecular Genetic Study of 27 Cases.

The College of American Pathologists recognizes "intraductal papillary neoplasm of the bile ducts (IPNB) with an associated invasive carcinoma" in its protocols for the pancreas and intrahepatic bile ducts, but not for the perihilar or distal bile ducts. We aimed to investigate the clinicopathologic and molecular features of 27 surgically resected perihilar IPNB cases. The cohort included 14 males and 13 females, with a median age of 70 years. Six IPNBs were noninvasive, while 21 had associated invasive carcinoma. The median overall tumor size was 2.8 cm, and the median invasive tumor size was 1.2 cm. Eight of 16 patients had elevated CA19-9. Immunohistochemistry as a surrogate of molecular analysis was performed in 19 cases with invasive carcinoma. Among them, positive PD-L1 expression was found in 3 cases (15.8%, all had low expression, CPS<5). DNA mismatch repair deficiency (loss of MSH2 and MSH6) and p53 overexpression were each identified in 1 case (5.3%). All cases were negative for HER2 and pan-TRK. After a median follow-up of 38 months, 11 patients died of disease. Next-generation sequencing revealed genetic alterations impacting multiple signaling pathways, including MAPK/ERK, WNT/β-catenin, TGF-β, DNA damage response, and PI3K/AKT. Our case series suggests that IPNB with associated invasive carcinoma may be included in CAP protocols as one of the carcinoma types of perihilar bile ducts. Future studies are warranted to compare perihilar IPNB with those originating in other biliary tract sites. We expect our molecular findings to help guide the selection of potential therapeutic targets.