Gastroenteropancreatic High-Grade Neuroendocrine Neoplasms: Histology and Molecular Analysis, Two Sides of the Same Coin

Background:In gastroenteropancreatic (GEP) high-grade neuroendocrine neoplasms (H-NENs), Ki-67 threshold of 55% defines three prognosis subclasses: neuroendocrine tumor (NET) G3, neuroendocrine carcinoma (NEC) <55%, and NEC >= 55%. We investigated whether the molecular profiling of H-NENs differs among these subcategories and evaluated potential therapeutic targets, including PD-L1.Methods:In GEP-NEN patients, we evaluated: (i) 55% threshold for Ki-67 labeling index for further stratifying NEC and (ii) immunoreactivity and gene mutations by immunohistochemistry and targeted next-generation sequencing (T-NGS).Results:Fifteen NETs G3 and 39 NECs were identified. Ki-67 labeling index was <55% in 9 NECs and >= 55% in 30 NECs. Gene mutations by NGS (TP53, 32.9%;KRAS, 5.5%;BRAF, 4.1%) were detected in 46.6% NENs, significantly enriched in NEC >= 55% (76.7%) compared to NEC <55% (55.6%) or NET (20.0%). PD-L1 staining in tumor-infiltrating lymphocytes was observed in NEC >= 55% (36.7%;p= 0.03). Median OS was 4.3 years in NET G3, 1.8 years in NEC <55%, and 0.7 years in NEC >= 55% (p <0.0001); it was 2.3 years with NGS wild-type, 0.7 years with >= 1 mutation (p <0.0001), 0.8 years in PD-L1-positive patients, and 1.7 years in PD-L1-negative subjects (p= 0.0004). In multivariate analysis, only the proposed subclassification approach yielded statistically significant differences between groups (NEC <55% vs. NET G3, HR 14.1, 95% CI 2.2-89.8,p= 0.005; NEC >= 55% vs. NET G3, HR 25.8, 95% CI 3.9-169,p= 0.0007).Conclusions:These findings identify NEC >= 55% as a biologically and prognostically distinct subtype and pave the way for more personalized treatment.