Molecular and morphologic characterization of intraductal tubulopapillary neoplasms of pancreas with novel potentially targetable fusions

Intraductal tubulopapillary neoplasms (ITPNs) are rare pancreatic tumors with distinct histological and molecular features. Distinction of ITPN from other pancreatic neoplasms is crucial given the known favorable prognosis and the high frequency and diversity of potentially targetable fusions in ITPN. While the histological features of ITPN are well documented, there are few reports on the cytological features, and molecular characterization of ITPN. The authors reported three cases diagnosed in their laboratory between 2016 and 2021. Clinical data, cytomorphological and histological features, with immunophenotypic and molecular characterizations of these cases are described and compared with those reported in the literature. All 3 cases were diagnosed as ITPN based on the microscopic presence of intraductal nodules composed of tightly packed small tubular glands lined by cuboidal cells lacking apparent mucin. On molecular profiling KRAS and TP53 variants were found in Case 1, FGFR2-INA fusion in Case 2, and STARD3NL-BRAF fusion was detected in Case 3. Immunohistochemistry (IHC) revealed that the neoplastic cells in Case 1 were MUC2 positive and MUC6 negative, but in Cases 2 and 3, were negative for MUC2 and positive for MUC6. These results demonstrate the immunophenotypic and molecular variabilities of histologically similar pancreatic neoplasms. The absence of alterations characteristic of more common pancreatic neoplasms should prompt the consideration of fusion studies in morphologically relevant cases. The combination of morphological, IHC, and molecular analyses is important for reliable identification of ITPN given its potential clinical management implications.