Intraductal Tubulopapillary Neoplasm of the Pancreas: An Update From a Pathologist's Perspective

Abstract

Context.-Intraductal tubulopapillary neoplasm (ITPN)is a rare intraductal epithelial neoplasm of the pancreas recently recognized as a distinct entity by the World Health Organization classification in 2010. It is defined as an intraductal, grossly visible, tubule-forming epithelial neoplasm with high-grade dysplasia and ductal differentiation without overt production of mucin. The diagnosis can be challenging owing to morphologic overlap with other intraductal lesions and its rarity. While recent advances in molecular genetic studies of ITPN have provided new tools to facilitate clinical diagnosis, the limited number of cases has yielded limited follow-up data to guide management.Objective.-To provide a clinical, pathologic, and molecular update on ITPN with respect to clinical presentation, imaging findings, histopathologic features, differential diagnosis, biological behavior, molecular characteristics, and treatment options.Data Sources.-Analysis of the pertinent literature (PubMed) and authors' research and clinical practice experience based on institutional and consultation materials.Conclusions.-Clinical presentation, imaging findings, histopathology, immunohistochemistry studies, molecular characteristics, prognosis, and treatment options of ITPN are reviewed. Important differential diagnoses with other intraductal neoplasms of the pancreas-especially intraductal papillary mucinous neoplasm-using histopathologic, molecular, and immunohistochemical studies, are discussed. Despite the recent progress, more studies are necessary to assess the biology and genetics of ITPN for a better understanding of the prognostic factors and treatment options.(Arch Pathol Lab Med. 2016;140:1068-1073; doi: 10.5858/arpa.2016-0207-RA) T he intraductal neoplasms of the pancreas are defined by the current 4th edition of the World Health Organization (WHO) classification as macroscopic epithelial neoplasms with ductal differentiation that grow in the pancreatic ductal system. The 2 entities included in this category are intraductal papillary mucinous neoplasm (IPMN) and intraductal tubulopapillary neoplasm (ITPN). Note that intraductal lesions with nonductal differentiation, such as acinar cell carcinoma, are not included in this category. Interestingly, before the current WHO classification, intraductal neoplasms of the pancreas were classified into 3 groups: IPMN, pancreatic intraepithelial neoplasia (PanIN), and intraductal tubular neoplasm.1,2 Intraductal tubular neoplasm was then further classified into intraductal tubular adenoma and intraductal tubular carcinoma, with intraductal tubular adenoma considered as the precursor of intraductal tubular carcinoma.3 Both IPMN and ITPN can be either cystic or solid-mass forming. The distinction between the intraductal neoplasms and PanIN is that PanIN is microscopic. On the contrary, by definition, both IPMN and ITPN are grossly and radiographically detectable lesions with an arbitrary minimal size criterion of 1 cm. Intraductal tubulopapillary neoplasms can have variable componen...

Pancreatic Ductal Adenocarcinoma and Its Precursor Lesions

“…Clear cell changes, stromal osseous, and cartilaginous metaplasia have been reported in ITPN. 33 The neoplastic cells of ITPN are positive for cytokeratin 7, cytokeratin 19, MUC1, and MUC6; and they are negative for MUC2, MUC5AC, trypsin, and b-catenin. 30 MUC6 and MUC5AC are useful in differentiating ITPNs from IPMNs because most IPMNs are MUC5A þ /MUC6 À , whereas ITPNs are MUC6 þ /MUC5A À .…”

“…30 Postoperative recurrence and liver metastasis of ITPN have been reported. 33 The 5-year survival rate of patients with ITPN-associated invasive carcinoma is >30%, which is better than conventional PDAC. 21 ITPN shares overlapping morphologic features with pancreatobiliary IPMN and IOPN.…”

Precursor Lesions of Pancreatic Cancer

“…ITPN is a grossly detectable (> 1 cm) epithelial neoplasm characterized by an intraductal solid nodular mass within a distended pancreatic duct with minimal cyst formation and consisting of tumor cells with a tubular architecture without accompanying overt mucin production [65,66]. ITPN is rare, comprising < 1% of exocrine tumors of the pancreas [67].…”

“…The tumor cells are predominantly cuboidal cells with enlarged nuclei, moderate to severe atypia, and eosinophilic or amphophilic cytoplasm (fig. 1K) [65,69,70]. Intracytoplasmic mucin is usually absent or minimally present [68].…”

“…The majority of ITPN cases show comedo-type intraluminal necrosis. ITPNs are usually positive for MUC1 and MUC6, but negative for MUC2 and MUC5AC [65,68,71], differentiating them from IPMN, especially the pancreatobiliary type (MUC1+, MUC5AC+, and MUC6−/+some; table 1) [43,65,69]. p53 overexpression is observed in a third of ITPNs, but SMAD4 expression is retained [66].…”