Tumoral Intraductal Neoplasms of the Bile Ducts Comprise Morphologically and Genetically Distinct Entities

Abstract

Context.— Tumoral (grossly visible) intraductal neoplasms of the bile ducts are still being characterized. Objective.— To investigate their morphologic, immunohistochemical, and molecular features. Design.— Forty-one cases were classified as gastric-, intestinal-, pancreatobiliary-type intraductal papillary neoplasm (IPN), intraductal oncocytic papillary neoplasm (IOPN), or intraductal tubulopapillary neoplasm (ITPN) on the basis of histology. All neoplasms were subjected to targeted next-generation sequencing. Results.— The mean age at diagnosis was 69 years (42–81 years); male to female ratio was 1.3. Most neoplasms (n = 23, 56%) were extrahepatic/large (mean size, 4.6 cm). The majority (n = 32, 78%) contained high-grade dysplasia, and 68% (n = 28) revealed invasion. All gastric-type IPNs (n = 9) and most ITPNs/IOPNs showed consistent colabeling for CK7/MUC6, which was less common among others (P = .004). Intestinal-type IPNs (n = 5) showed higher rates of CK20 expression than others (P < .001). Overall, the most commonly mutated genes included TP53 and APC, while copy number variants affected ELF3 and CDKN2A/B. All gastric-type IPNs contained an alteration affecting the Wnt signaling pathway; 7 of 9 (78%) showed aberrations in the MAPK pathway. Mutations in APC and KRAS were common in gastric-type IPNs as compared with others (P = .01 for both). SMAD4 was more frequently mutated in intestinal-type IPNs (P = .02). Pancreatobiliary-type IPNs (n = 14) exhibited frequent alterations in tumor suppressor genes including TP53, CDKN2A/B, and ARID2 (P = .04, P = .01 and P = .002, respectively). Of 6 IOPNs analyzed, 3 (50%) revealed ATP1B1-PRKACB fusion. ITPNs (n = 6) showed relatively few recurrent genetic aberrations. Follow-up information was available for 38 patients (median, 58.5 months). The ratio of disease-related deaths was higher for the cases with invasion (56% versus 10%). Conclusions.— Tumoral intraductal neoplasms of the bile ducts, similar to their counterparts in the pancreas, are morphologically and genetically heterogeneous.

Intraductal neoplasms of the pancreatobiliary tract: navigating the alphabet

“…50 However, even the patients with invasive carcinoma appear to have a relatively protracted clinical course. 49,50 Recently, another classification system has been proposed to classify IPNBs as Types 1 and 2. 53 Type 1 IPNBs are most found in intrahepatic bile ducts and characterised with regular villous, papillary or tubular structures, usually with low-grade dysplasia.…”

“…49,[59][60][61] Moreover, like their pancreatic counterparts, oncocytic-type IPNBs may reveal ATP1B1::PRKACB fusion and IPNBs with a tubular growth pattern have relatively few recurrent genetic aberrations. 49 Goeppert et al also reported that papillary and tubulopapillary/tubular neoplasms differ in their DNA methylation profiles. 58 These findings suggest that, just like the pancreatic ones, biliary IOPNs and ITPNs should be separated from the other mass-forming intraductal neoplasms of the bile ducts.…”

“…Intraductal papillary neoplasms of the bile duct (IPNB) are counterparts of IPMNs in the bile ducts 49 . Patients commonly present with recurrent and intermittent abdominal pain, and cholangitis‐related symptoms 50 …”

“…High‐grade IPNBs are often associated with invasive carcinoma, usually in the form of tubular adenocarcinoma, although mucinous (colloid) carcinoma is also common in eastern cohorts 50 . However, even the patients with invasive carcinoma appear to have a relatively protracted clinical course 49,50 …”

Intraductal papillary neoplasm of the bile duct: Cytomorphologic and molecular features

“…When invasion is present, the term “IPNB with associated invasive carcinoma” is used. Although it has not been officially recognized as a distinct entity in the bile duct yet, emerging studies show that, as described in the pancreas, intraductal tubulopapillary neoplasm (ITPN) is another rare premalignant lesion that can also involve the bile ducts 6–8 . Histologically, ITPN is characterized by intraductal tubulopapillary growth.…”