Intraductal tubulopapillary neoplasms of the bile ducts: clinicopathologic, immunohistochemical, and molecular analysis of 20 cases

Abstract

Intraductal tubulopapillary neoplasm is a well-established entity in the pancreas. A similar, if not identical, tumor occurs also in the biliary tract. We conducted a multicenter study of 20 such lesions, focusing on their clinicopathologic characteristics and molecular profile. Biliary intraductal tubulopapillary neoplasms were seen in patients in their 60s (mean 62 years). The tumors were intrahepatic 70%, extrahepatic 10%, and perihilar 20%; mean tumor size was 6.9 cm. Histologically, all intraductal tubulopapillary neoplasms showed, in addition to their typical tubular pattern, solid areas (70%) or abortive papillae (50%). Necrosis was common (85%), predominantly focal (40%), and with 'comedocarcinoma-like pattern' in 40%. Immunohistochemically, these neoplasms were characterized by the expression of MUC1 (80%) and MUC6 (30%) and by the absence of MUC2 and MUC5AC. Associated invasive carcinomas were present in 16 (80%), mainly conventional tubular adenocarcinoma (50%). The molecular alterations observed included CDKN2A/p16 (intraductal components 44%, invasive 33%) and TP53 (intraductal components 17%, invasive 9%). Mutations in KRAS (intraductal 6%, invasive 0%), PIK3CA (intraductal 6%, invasive 0%), and loss of SMAD4/DPC4 (intraductal 7%, invasive 0%) were rare. No alterations/mutations were identified in IDH1/2, BRAF, GNAS, EGFR, HER2, and β-catenin. Follow-up information was available for 17 patients (85%) with mean follow-up 44 months. Overall combined survival rates showed favorable prognosis: 1 year 100%, 3 years 90%, and 5 years 90%. In conclusion, despite the relatively high incidence of invasive carcinoma (80%), available follow-up suggests that biliary intraductal tubulopapillary neoplasms have an indolent behavior. Molecular analyses highlight the low prevalence of alterations of common oncogenic signaling pathways in intraductal tubulopapillary neoplasm. Further studies using whole-exome sequencing are required to discover yet unknown molecular changes and to understand the carcinogenesis of intraductal tubulopapillary neoplasms.

Neoplastic precursors (dysplasia, intraepithelial neoplasia) of the gallbladder and biliary tract: terminology, classification, pathologic diagnosis, and clinical significance

“…The term "intraductal tubular neoplasms of the biliary ducts" was also proposed for this group, 6 and indeed, these tumours are characterized, and in fact delineated from IPNBs, by their tubular growth pattern with only minimal, if any, papilla formation. 7 However, due to the analogy with their pancreatic counterpart and the name already in use (also acknowledged by the WHO-2010), the preferred name has become ITPN. Another important defining characteristic of ITPN is the mucin-poor nature of the cells.…”

“…They are predominantly intrahepatic but can be seen in the extrahepatic bile ducts as well. 7 Pathologic features: on gross examination, the bile ducts are filled with nodules. Foci of invasion are typically represented by firm, white scirrhous lesions with irregular borders, but they are well demarcated from the hepatic parenchyma.…”

Tumoral Versus Flat Intraepithelial Neoplasia of Pancreatobiliary Tract, Gallbladder, and Ampulla of Vater

“…66,67 However, ITPN of the bile duct has a different genetic-alteration pathway than IPNB. 68 Like the pancreas, the bile duct shows a similar spectrum of intraductal neoplasms of IPNB and ITPN, which corresponds to tumoral IN of the bile duct.…”

Updates on Precancerous Lesions of the Biliary Tract: Biliary Precancerous Lesion

“…3 A recent multicenter study of ITN showed that 14 of 20 cases (70%) were intrahepatic, and 16 (80%) were associated with invasive component, with an indolent behavior. 19 Distinctive from IPN-B, ITN lacks unequivocal papilla formation and mucin production. However, both IPN-B and ITN share overlapping features, such as intraductal growth, cyst formation, dysplasia, and an association with invasive carcinoma.…”

“…However, both IPN-B and ITN share overlapping features, such as intraductal growth, cyst formation, dysplasia, and an association with invasive carcinoma. 3,19 Mucinous cystic neoplasm is another rare precursor lesion that can give rise to invasive adenocarcinoma. This tumor occurs predominantly in perimenopausal women.…”