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

Abstract

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: (i) 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. (ii) 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. (iii) 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). (iv) Survival analysis: ITPN with a "pure" branch duct involvement showed the lowest risk of recurrence.

Conclusion: 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.

Keywords: IPMN; ITPN; PDAC; intraductal; pancreas; pancreatic ductal adenocarcinoma; tubulopapillary.

Figure 1

Typical histology of pancreatic ITPN with an associated invasive adenocarcinoma. (A) Low‐magnification image for appreciating the different types of architecture that can be encountered in ITPN: the black arrow indicates the tubular architecture, which is generally predominant, the black triangle indicates the papillary component, which is not a constant presence in this type of lesion, and the asterisk indicates the infiltrative component (hematoxylin–eosin, 4× original magnification). (B,C,D) Higher magnification of the tubular (B), of the papillary (C), and of the infiltrative (D) components (hematoxylin–eosin, 10 × original magnification). [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 2

Classical immunohistochemical patterns of mucins expression in pancreatic ITPN (10× original magnification). (A) MUC1: this is the mucin more often expressed by pancreatic ITPN. (B) MUC6: this is another mucin very often expressed by pancreatic ITPN, sometimes it appears more focal. (C) MUC5AC: it is usually negative in ITPN, different from IPMN. (D) MUC2: it is usually negative in ITPN, different from intestinal IPMN. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 3

Kaplan–Meier curve regarding disease‐free survival of patients with pancreatic ITPN based on the different pattern of ductal tree involvement. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 4

Typical appearance of a case of pancreatic ITPN, showing solid and solid/cystic areas (A: solid/cystic appearance at gross sampling, B: solid and solid/cystic appearance at imaging: CT scan, where the lesion is indicated by a yellow arrow). [Colour figure can be viewed at wileyonlinelibrary.com]