Infrequent HPV Infection in Colorectal Neuroendocrine Carcinoma: Molecular and Histologic Characteristics.

Background/

Objectives

Colorectal neuroendocrine carcinomas (NECs) are rare, aggressive tumors with poorly defined clinicopathologic and molecular features. Their biological behavior and optimal treatment strategies remain unclear. Additionally, a subset of anorectal NECs may be associated with high-risk human papillomavirus (HPV) infection, suggesting potential heterogeneity in pathogenesis.

Methods

We retrospectively reviewed 12 cases of colorectal NECs. Clinical outcomes, histologic morphology, immunohistochemistry, molecular profiling, including common oncogenic mutations, and HPV status were analyzed.

Results

Seven cases demonstrated small cell NECs, and five showed large cell NECs. The majority of NECs (n = 9) arose in the rectum. TP53 mutations were the most common (75%), followed by KRAS, RB1, FBXW7, and BRAF mutations. One case demonstrated mismatch repair (MMR) deficiency. High-risk HPV was detected in one rectal NEC, which lacked common oncogenic mutations and was the only long-term survivor (54 months). p16 expression did not correlate consistently with HPV in situ hybridization (ISH) status. Among small cell NECs with follow-up, platinum-based chemotherapy resulted in significantly longer survival than FOLFOX (13.5 vs. 4 months, p = 0.0209).

Conclusions

Colorectal NECs display histologic and molecular heterogeneity. The tumors of small cell NECs potentially benefit more from platinum-based chemotherapy. HPV-associated NECs may represent a distinct subset with better prognosis, but p16 is not a reliable surrogate marker. Routine subclassification into small vs. large cell types and comprehensive molecular profiling, including HPV testing, may aid clinical decision-making and prognostication.