Clinicopathological and molecular profile of grade 3 gastroenteropancreatic neuroendocrine neoplasms.

Abstract

The 2019Word Health Organization (WHO) subclassified grade 3 (G3) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) into neuroendocrine carcinoma (NEC) or tumours (G3NET) based on morphology and proliferation. Yet, few data exist on molecular profiles for G3NEN. We compared clinicopathological and molecular characteristics of these two groups. We retrospectively reviewed consecutive G3 GEP NEN patients and had their tumour tissues reviewed, reclassified as per the WHO 2019, and analyzed by a next-generation sequencing (NGS) panel. Between 2000 and 2019, 43 patients had pathology revision: 29 (67%) were NEC and 14 (33%) were G3NET, with a 23% change in diagnosis. Median overal survival for G3NET and NEC patients was 55.6 and 11.9months, respectively (hazard ratio=2.78 [95% confidence interval=1.09-7.11], p=.042), which was confirmed by an adjusted analysis (hazard ratio=2.90NEC vs. G3NET; p=.03). NGS was performed in 32 cases: 21NEC and 11 G3NET. Mutations in RB1 and PTEN were exclusively encountered in NEC. Median tumour mutational burden was 5 (0-67) mutations per megabase in NEC and 4.5 (0-9) among G3NET. Microsatellite instability was found in 3 (14.3%) NEC cases. In conclusion, pathology revision is essential to estimate prognosis and therapeutic plan. G3 GEP NEN generally harbour low tumor mutation burden and fewer actionable mutations, but 14% of NEC cases were microsatellite unstable and could benefit from immune checkpoint inhibitors.