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

作者：Adele Busico, Patrick Maisonneuve, Natalie Prinzi, Sara Pusceddu, Giovanni Centonze, Giovanna Garzone, Alessio Pellegrinelli, Luca Giacomelli, Alessandro Mangogna, Cinzia Paolino, Antonino Belfiore, Ketevani Kankava, Federica Perrone, Elena Tamborini, Giancarlo Pruneri, Nicola Fazio, Massimo Milione · 发表于：Neuroendocrinology · 年份：2019 · DOI：10.1159/000503722 · 被引用次数：68 · 研究领域：Neuroendocrine Tumor Research Advances、Pancreatic and Hepatic Oncology Research、Lung Cancer Research Studies

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....