CARATTERISTICHE CLINICO-PATOLOGICHE, PROFILO MOLECOLARE E BERSAGLI PER L’IMMUNOTERAPIA NEI CARCINOMI INDIFFERENZIATI DEL PANCREAS CON CELLULE GIGANTI SIMIL-OSTEOCLASTICHE

Pancreatic carcinoma is a malignant neoplasm with a high mortality rate. The study of conventional pancreatic ductal adenocarcinoma (PDAC) and its variants can improve the comprehension of its biology. The aim of this thesis is a comprehensive study of a PDAC variant, the undifferentiated carcinoma of the pancreas with osteoclast-like giant cells (UCOGC). After collecting a significant number of UCOGC (23 pancreatic and 5 extra-pancreatic), we recorded clinic-pathological data. Then we performed whole-exome sequencing for comprehensive molecular analysis. Tumor samples were also tested with immunohistochemistry (IHC) for immunotherapy biomarkers PD-1, PD-L1 and CD163. The prognostic role of clinic-pathological, molecular and IHC results was evaluated with ad-hoc survival analysis. We found that UCOGC could present in a “pure” form or associated with a differentiated neoplasia (usually PDAC). The “pure” form of UCOGC has a better prognosis. At molecular level, UCOGC shares the same somatic mutations with PDAC, involving the four most important driver genes KRAS, TP53, SMAD4 and CDKN2A. This demonstrates definitively that UCOGC is a real PDAC variant. No typical UCOGC genes were found but, interestingly, SERPINA3, a driver gene in some gynecological malignancies never found in association with pancreatic carcinoma, presented the same mutation in two distinct UCOGC. The IHC for the immunological targets revealed that PD-L1 is more expressed in UCOGC associated with PDAC; its expression has a negative prognostic role. PD-1, if present, was expressed by peri-tumor lymphocytes. CD163 was significantly and diffusely expressed in all the histiocytes of all UCOGC. We demonstrated an important role of morphology, having the “pure” form a better prognosis. Molecular results have clarified that UCOGC is a PDAC variant. IHC of PD-1, PD-L1 and CD163 showed that UCOGC may represent a potential target for new immunotherapy strategies. In particular, data concerning PD-L1 appear very promising, demonstrating its expression in above all cases associated with PDAC and its negative prognostic value. Furthermore, CD163 is expressed diffusely and strongly in all cases, with possible implications for future immunotherapies.