Comparative Analysis of Genetic Alterations, HPV-Status, and PD-L1 Expression in Neuroendocrine Carcinomas of the Cervix

SIMPLE SUMMARY: Patients with neuroendocrine carcinoma of the cervix (NECC) have limited treatment options due to its rarity and aggressiveness. In this study, we performed a comparative genetic analysis between 25 NECC and other cervical cancer types (180 squamous cell carcinoma, 53 adenocarcinoma, and 14 adenosquamous carcinoma). Furthermore, the expression of programmed cell death-ligand 1 (PD-L1) was assessed by immunohistochemistry. PIK3CA and TP53 were commonly altered genes in cervical cancer, while SMAD4, RET, EGFR, and APC were NECC-specific altered genes. Of note, 11 NECC cases showed at least one actionable mutation linked to molecular targeted therapies, and 14 cases showed more than one combined positive score for PD-L1 expression. These results may boost the generation of effective treatment strategies for NECC in the future. ABSTRACT: Neuroendocrine carcinoma of the cervix (NECC) is a rare and highly aggressive tumor with no efficient treatment. We examined genetic features of NECC and identified potential therapeutic targets. A total of 272 patients with cervical cancer (25 NECC, 180 squamous cell carcinoma, 53 adenocarcinoma, and 14 adenosquamous carcinoma) were enrolled. Somatic hotspot mutations in 50 cancer-related genes were detected using the Ion AmpliSeq Cancer Hotspot Panel v2. Human papillomavirus (HPV)-positivity was examined by polymerase chain reaction (PCR)-based testing and in situ hybridization assays. Programmed cell death-ligand 1 (PD-L1) expression was examined using immunohistochemistry. Somatic mutation data for 320 cases of cervical cancer from the Project GENIE database were also analyzed. NECC showed similar (PIK3CA, 32%; TP53, 24%) and distinct (SMAD4, 20%; RET, 16%; EGFR, 12%; APC, 12%) alterations compared with other histological types. The GENIE cohort had similar profiles and RB1 mutations in 27.6% of NECC cases. Eleven (44%) cases had at least one actionable mutation linked to molecular targeted therapies and 14 (56%) cases showed more than one combined positive score for PD-L1 expression. HPV-positivity was observed in all NECC cases with a predominance of HPV-18. We report specific gene mutation profiles for NECC, which can provide a basis for the development of novel therapeutic strategies.