Is the morphological subtype of Extra-Pulmonary Neuroendocrine Carcinoma clinically relevant?

Extra-pulmonary neuroendocrine carcinomas (EP-NECs) are lethal cancers with limited treatment options. Identification of contributing factors to the observed heterogeneity of clinical outcomes within the EP-NEC family is warranted, to enable identification of effective treatments. A multicentre retrospective study investigated potential differences in ‘real-world’ treatment/survival outcomes between small cell (SC) versus (vs.) non-SC EP-NECs. One-hundred-seventy patients were included; 77 (45.3%) had SC and 93 (54.7%) had non-SC EP-NEC. Compared to the SC subgroup, the non-SC subgroup had; 1) a lower mean Ki-67 (69.3% vs. 78.7%, p=0.002); 2) a lower proportion of cases with a Ki-67≥55% (73.9% vs. 88.7%, p=0.025); 3) reduced sensitivity to first-line platinum/etoposide (objective response rate; 31.6% vs. 55.1%, p=0.015, and disease control rate; 59.7% vs. 79.6%, p=0.027); 4) worse progression-free survival (PFS) (adjusted-HR=1.615, p=0.016) and overall survival (OS) (adjusted-HR=1.640, p=0.015) in the advanced setting. Within the advanced EP-NEC cohort, subgroups according to morphological subtype and Ki-67 (< vs. ≥55%) had significantly different PFS (adjusted-p=0.021) and OS (adjusted-p=0.051), with the non-SC/Ki-67<55% and non-SC/Ki-67≥55% subgroups showing the best and worst outcomes, respectively. To conclude, the morphological subtype of EP-NEC provides complementary information to Ki-67 and may aid identification of patients who could benefit from alternative first-line treatment strategies to platinum/etoposide.