Clinical, pathological and molecular profiles of G3 neuroendocrine tumors and neuroendocrine carcinomas
In 2019, WHO subclassified grade 3 (G3) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) into neuroendocrine carcinoma (NEC) or tumors (G3 NET). Yet, few data exist on clinical and molecular profiles for G3 NEN. We aimed to compare the clinicopathological and molecular characteristics of G3 GEP NET and GEP NEC.
We retrospectively collected data of all G3 GEP NEN patients (pts) diagnosed and treated at our cancer center from 2000 to 2019. Cases with available tumor tissues were reviewed and reclassified according to the WHO 2019 classification. Formalin-fixed, paraffin-embedded NEN tissues had DNA extracted for genomic profiling through next-generation sequencing (NGS), which evaluated mutations profiles, tumor mutation burden (TMB) and the presence of microsatellite instability. Survival from treatment start was the primary endpoint.
Seventy-seven pts were included: median age at the diagnosis was 56 (26-91) years and 62% (48/77) were males. The most common primary sites were gastric (27%, 21/77), pancreas (23%, 18/77) and unknown primary NEN (23%, 18/77). Metastatic disease was present in 69% at diagnosis and 91% developed metastasis. Out of 77, 43 (56%) had pathology revision: 29 cases were NEC (67%) and 14 were reclassified as G3 NET (33%), with a change in diagnosis of 23%. In a median follow-up of 44 months, median OS in non-pancreatic digestive G3 NET, pancreatic G3 NET, and GEP NEC were 23.7, 55.6 and 10.8 months, respectively (non-pancreatic G3 NET vs NEC, p=0.01). Median OS in G3 NET with ki67 > 55%, NEC 55% was 19, 25 and 8 months, respectively. In Cox regression multivariate analysis, only cell differentiation sustained as a risk of death (HR 3.14 NEC vs G3 NET; P = 0.025). NGS was performed in 42% (32/77) cases: 21 NEC and 11 G3 NET. Median tumour mutational burden was 5.67 (0 – 66.82) mutations per megabase among NEC and 4.52 (0 – 8.83) among G3 NET. Tumors were microsatellite unstable in 3 (14.3%) NEC cases but zero among G3 NET pts. The most commonly mutated genes in G3 NET were TP53 (N=3; 27.3%), CDKN2A (N=3; 27.3%) and KRAS (2/11, 18.2%) and TP53 (N=15; 71.4%), Rb1 (N=7; 33.3%), PTEN (N=6; 28.6%) and APC (N=4; 19%) among NEC.
Non-pancreatic digestive G3 NET is associated with increased survival compared to NEC. Pathology revision is essential to estimate prognosis and consequently therapeutic plan, as some of G3 NET can be treated as G2 NET. While G3 GEP NEN generally harbours low TMB and fewer actionable mutations, 14% of NEC cases were microsatellite unstable and could benefit from immune checkpoint inhibitors.
Legal entity responsible for the study
Genentech Roche - funding for molecular analysis.
The presenting author has declared no conflicts of interest.