Pancreatic ductal adenocarcinoma (PDAC) and distal cholangiocarcinoma (dCCA) are very aggressive tumors with a high mortality rate. Pancreas and distal bile ducts share a common embryonic development. Hence, PDAC and dCCA exhibit similar histological features that make a differential diagnosis during routine diagnostic practice challenging. However, there are also significant differences, with potential clinical implications. Even if PDAC and dCCA are generally associated with poor survival, patients with dCCA seem to present a better prognosis. Moreover, although precision oncology-based approaches are still limited in both entities, their most important targets are different and include alterations affecting BRCA1/2 and related genes in PDAC, as well as HER2 amplification in dCCA. Along this line, microsatellite instability represents a potential contact point in terms of tailored treatments, but its prevalence is very low in both tumor types. This review aims at defining the most important similarities and differences in terms of clinicopathological and molecular features between these two entities, also discussing the main theranostic implications derived from this challenging differential diagnosis.

Pancreatic neuroendocrine neoplasms (PanNENs) are rare neoplasms arising from islets of the Langerhans in the pancreas. They can be divided into two groups, based on peptide hormone secretion, functioning and nonfunctioning PanNENs. The first group is characterized by different secreted peptides causing specific syndromes and is further classified into subgroups: insulinoma, gastrinoma, glucagonoma, somatostatinoma, VIPoma and tumors producing serotonin and adrenocorticotrophic hormone. Conversely, the second group does not release peptides and is usually associated with a worse prognosis. Today, although the efforts to improve the therapeutic approaches, surgery remains the only curative treatment for patients with PanNENs. The development of high-throughput techniques has increased the molecular knowledge of PanNENs, thereby allowing us to understand better the molecular biology and potential therapeutic vulnerabilities of PanNENs. Although enormous advancements in therapeutic and molecular aspects of PanNENs have been achieved, there is poor knowledge about each subgroup of functioning PanNENs.Therefore, we believe that combining high-throughput platforms with new diagnostic tools will allow for the efficient characterization of the main differences among the subgroups of functioning PanNENs. In this narrative review, we summarize the current landscape regarding diagnosis, molecular profiling and treatment, and we discuss the future perspectives of functioning PanNENs.

Intraductal oncocytic papillary neoplasm (IOPN) of the pancreas is a distinct entity from intraductal papillary mucinous neoplasms (IPMNs) and is considered one of the precursor lesions of pancreatic cancer. Through immunohistochemistry (IHC) and an artificial intelligence (AI)-based approach, this study aims at characterizing its immune microenvironment. Whole-slide IHC was performed on a cohort of 15 IOPNs, 2 of which harboring an associated adenocarcinoma. The following markers were tested: CD3, CD4, CD8, CD20, CD68, CD163, PD-1, PD-L1, MLH1, PMS2, MSH2, and MSH6. The main findings can be summarized as follows: (i) CD8+ T lymphocytes were the predominant immune cells (p < 0.01); (ii) the vast majority of macrophages were concurrently CD68+ and CD163+; (iii) all tumors showed an activated PD-1/PD-L1 axis, but none had mismatch repair deficiency; (iv) AI-based analysis revealed the presence of 2 distinct regions in each case, namely, Re1, localized at the center of the tumor, and Re2, located at tumor periphery; (v) the infiltrating component of the 2 invasive IOPNs showed a smaller extent of Re1 and a reduced rate of CD4+ cells, as well as a larger extent of Re2 and increased rate of CD8+ cells. IOPNs are lesions enriched in immune cells, with a predominance of CD8+ T lymphocytes and class 2 macrophages. Differently from IPMN-oncogenesis, the progression towards invasive carcinoma is accompanied by an increased rate of CD8+ lymphocytes. This finding may suggest the presence of an active self-immune surveillance in invasive IOPNs, potentially explaining, at least in part, the excellent survival rate of IOPN patients.

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The tumor showed extensive microcalcifications and cells with oval, nuclei and a clear perinuclear halo (A), positive immunostaining for OLIG‐2 (B), GFAP (C), and CD34 (D), and intermingled Neu‐N‐positive neurons (E). FISH revealed multiple signals for the centromere of chromosome 7 (gains) (green probe) and the EGFR locus (red probe) (F, left), and a single signal for the centromere of chromosome 10 (loss) (F, right).