Intraductal tubulopapillary neoplasm (ITPN) of the pancreas: A distinct entity among pancreatic tumors

Aims: Intraductal tubulopapillary neoplasm (ITPN) of the pancreas is a recently recognized pancreatic tumor entity. Here, we aimed to determine the most important features with a systematic review coupled with an integrated statistical approach. Methods and results: PubMed, SCOPUS and Embase were searched for studies reporting data on pancreatic ITPN. The clinicopathological, immunohistochemical, and molecular data were summarized. Then, a comprehensive survival analysis and a comparative analysis of the molecular alterations of ITPN with those of pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasm (IPMN) from reference cohorts (including the International Cancer Genome Consortium- ICGC dataset and The Cancer Genome Atlas- TCGA program) were conducted. The core findings of 128 patients were as follows - 1) Clinicopathological parameters: pancreatic head is the most common site; presence of an associated adenocarcinoma was reported in 60% of cases, but with rare nodal metastasis. 2) Immunohistochemistry: MUC1 (>90%) and MUC6 (70%) were the most frequently expressed mucins. ITPN lacked the intestinal marker MUC2; unlike IPMN, it did not express MUC5AC. 3) Molecular landscape: Compared with PDAC/IPMN, the classic pancreatic drivers KRAS, TP53, CDKN2A, SMAD4, GNAS, and RNF43 were less altered in ITPN (p<0.001), whereas MCL amplifications, FGFR2 fusions, and PI3KCA mutations were commonly altered (p<0.001). 4) Survival analysis: ITPN with a "pure" branch duct involvement showed the lowest risk of recurrence. Conclusions: ITPN is a distinct pancreatic neoplasm with specific clinicopathological and molecular characteristics. Its recognition is fundamental for its clinical/prognostic implications and for the enrichment of potential targets for precision oncology.