The prognostic differences between neuroendocrine carcinoma (NEC) and mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) remain unclear.This study aimed to compare the prognostic outcomes of NEC and MiNEN by analyzing the clinicopathological features of these diseases and exploring factors affecting progression after radical surgery. Additionally, we employed whole-exome sequencing to investigate the molecular mechanisms influencing the prognosis of both conditions.Among the 252 patients followed, 163 underwent surgical treatment. The median time to tumor progression was 16 months (range: 9-56 months). Tumor pathology type (p = 0.007), lymph node metastasis (p < 0.0001), and distant metastasis (p < 0.0001) were identified as independent factors affecting disease progression in NEC and MiNEN patients. MiNEN patients without lymph node or distant metastasis generally had a better prognosis. First-line chemotherapy regimens did not show a significant impact on disease progression (p = 0.160, median progression-free survival [mPFS]: 36 vs. 13 vs. 23 vs. 15 months). However, the etoposide plus cisplatin (EP) regimen has shown good efficacy in gastric neuroendocrine neoplasms (NENs) (p = 0.048, mPFS: 45 vs. 12 vs. 32 vs. 16 months), especially in gastric MiNENs (p = 0.022, mPFS: Undefined vs. 11 vs. 52 vs. 37 months). Further investigation into the genetic mutation differences between NECs and MiNENs revealed that among previously sequenced data, rectal NECs commonly exhibited mutations in MUC16, SPTA1, ATM, PDGFB, NF1, FAT4, AR, APC, ANTXR2, and ADGRA2. In contrast, rectal MiNENs showed common mutations in NOTCH2, ZNRF3, CARD11, TP53, OBSCN, FPR1, APC, ANGPT2, ARID1A, and AR. Mutations in ANGPT2 and OBSCN were present in two rectal MiNEN cases, while NF1 and PDGFB mutations were found in two rectal NEC cases but not in MiNENs. The JAK-STAT signaling pathway appears to be specific to rectal NECs and may be involved in tumor progression.EP regimen remains the most effective chemotherapy option for neuroendocrine tumor patients. There were prognostic differences between NECs and MiNENs, as well as differences in genetic mutations and signaling pathways. This study provided new insights into the prognosis assessment and treatment strategies for NENs, particularly highlighting the importance of personalized treatments and the development of novel targeted therapies.© 2025 S. Karger AG, Basel.