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We investigated the impact of pathologic differentiation (well or poorly differentiated) in metastatic grade 3 GEP-NEC patients receiving etoposide and platinum (EP)-based therapy, and evaluated a more exact Ki67 index cut-off point to select patients with grade 3 GEP-NEC who might benefit from EP-based therapy. A total of 31 patients with metastatic grade 3 GEP-NECs receiving EP-based therapy were included in this study. Primary sites included 13 foregut-derived GEP-NECs [stomach ( n = 4), duodenum ( n = 4), and pancreas ( n = 5)] and 2 hindgut-derived GEP-NECs of the rectum. 14 patients had well differentiated (WD) and 17 had poorly differentiated (PD). Between WD and PD grade 3 GEP-NECs, there was a significant difference in the distribution of Ki67 index. There was no significant difference of treatment efficacy between WD and PD grade 3 GEP-NECs (RR; 35.7% vs. 41.2%, p = 0.525). Tumor response to EP occurred in 5 of 7 patients with Ki67 &gt; 60% and 7 of 24 with Ki67 ≤ 60%, which was significantly different (RR; 71.4% vs. 29.2%, P = 0.043). Among grade 3 GEP-NECs, there was a significant difference in ranges of Ki67 index between WD and PD NECs. Higher levels (&gt; 60%) of Ki67 index might be a predictive marker for efficacy of EP as a standard regimen in grade 3 GEP-NECs.

The impact of pathologic differentiation (well/poorly) and the degree of Ki-67 index in patients with metastatic WHO grade 3 GEP-NECs