Intraductal papillary neoplasms of the bile duct consist of two distinct types specifically associated with clinicopathological features and molecular phenotypes

Abstract

Intraductal papillary neoplasm of the bile duct (IPNB) is a grossly visible papillary biliary neoplasm with morphological variations and occasional invasion. Recently a new classification of IPNB into type 1 and type 2 was proposed in which the type 1 IPNBs consist of fine papillary neoplastic glands and the type 2 IPNBs consist of complex branching glands, seldom with foci of solid-tubular components. However, clinicopathological and molecular characteristics of these types of IPNBs are yet to be identified. We aimed to uncover clinicopathological and molecular characteristics of the types of IPNBs. Thirty-six IPNBs were studied retrospectively. Clinicopathological features as well as molecular alterations of 31 genes were evaluated by means of targeted next-generation sequencing and immunohistochemical examination of expression of mucin and cancer-associated molecules. The 36 IPNBs were classified into 22 of type 1 and 14 of type 2. The type 1 IPNBs were associated with a non-invasive phenotype, intestinal and oncocytic subtypes, development in the intrahepatic bile duct, overt mucin production, and a relatively good prognosis. The type 2 IPNBs were associated with an invasive phenotype, the pancreatobiliary subtype, development within the extrahepatic bile duct, and worse prognosis compared with the type 1 IPNBs. In the molecular analysis, recurrent mutations were found in RNF43 (5.7%). Mutations in KRAS and GNAS were enriched in the type 1 IPNBs, whereas mutations in TP53, SMAD4, and KMT2C were enriched in the type 2 IPNBs. These results indicate that IPNBs consist of two distinct types of neoplasms specifically associated with clinicopathological features and molecular phenotypes.No conflicts of interest were declared.

Pathological, molecular, and clinical characteristics of cholangiocarcinoma: A comprehensive review

“…Some patients may present with mucus hypersecretion. Like intraductal papillary mucinous neoplasm (IPMN) of the pancreas, IPNB is histologically classified into four types based on their histological and immunohistochemical features: pancreaticobiliary (Figure 6C ), intestinal, gastric and oncocytic types[ 67 ]. Pancreaticobiliary and intestinal subtypes are the most common types, although its frequency varies across geographical regions.…”

Inhibition of FGF10-ERK signal activation suppresses intraductal papillary neoplasm of the bile duct and its associated carcinomas

“…The diagnosis of IPNB must be descriptive because it is determined using the papillary morphology in both humans and mice. Two reports have identified genetic alterations in human IPNBs using next-generation sequencing analysis (Aoki et al, 2020;Yang et al, 2019). The frequently found genetic mutations included TP53, KRAS, GNAS, and RNF43; however, none exceeded 50%.…”

Whole-exome sequencing for a more accurate diagnosis of intraductal papillary neoplasms of the bile duct

“…CTNNB1 is an important constituent gene in the Wnt/β-catenin pathway. Although the Wnt pathway is known to be activated in bile-duct cancers, CTNNB1 mutation is not commonly reported in patients with cholangiocarcinoma and IPNB [ 3 , 6 ]. Moreover, genetic mutation in CTNNB1 is involved in the formation of pyloric-gland polyps in the stomach and gall bladder [ 7 ].…”

“…Although some whole-exome sequencing-based studies on bile-duct cancers have been reported, and KRAS and TP53 are listed as important gene variants, most analyses were performed in mixed patients with IPNB and bile-duct cancers [ 5 ]. Aoki et al recently performed targeted capture sequencing of cancer-driver genes in the context of IPNB [ 3 ]; however IPNB-specific gene mutations could not be identified via target gene analysis alone. In the present case, whole-exome sequencing of the tumor revealed somatic mutations in well-known cancer-driver genes such as CTNNB1 and NFE2L2 ; interestingly, mutations frequently identified in bile-duct cancers and IPNB, such as KRAS and GNAS mutations, were not found ( Table 1 ).…”

“…The IPNB diagnostic criteria are, however, often ambiguous, e.g. whether IPNB is considered a type of cancer and whether it must have mucus production are debatable [ 3 ]. Therefore, establishing new IPNB diagnostic criteria based on an alternative approach, such as whole-exome sequencing, is required.…”