Distinct Rb expression pattern in HPV-associated neuroendocrine carcinomas of the uterine cervix

This study aimed to characterize high-risk human papillomavirus (HR-HPV) infection and the expression patterns of p16, Rb, p53 and cyclin D1 in uterine cervical neuroendocrine carcinomas (UCNECs). We also aimed to clarify the similarities and differences between UCNECs and pulmonary neuroendocrine carcinomas (NECs).

We examined the expression patterns of p16, Rb, p53, and cyclin D1 by immunohistochemistry (IHC) and HR-HPV infection by mRNA in situ hybridization (ISH) in 29 UCNEC cases, along with histological review. Ten pulmonary small cell neuroendocrine carcinomas (SCNECs) were included for comparison. Histologically, most UCNECs were SCNECs combined with adenocarcinoma or squamous cell carcinoma. HR-HPV ISH was performed in 28 UCNEC cases; 27 (96%) were HPV-positive and 1 (4%) was HPV-negative. All HPV-positive cases (n = 27) showed p16 overexpression, partial Rb loss, a wildtype p53 pattern, and negative cyclin D1 expression. The single HPV-negative case showed focal p16 positivity, retained Rb expression, a wildtype p53 pattern and positive cyclin D1 expression. In contrast, all 10 pulmonary SCNEC cases were negative for HR-HPV and positive for p16, showing complete loss (n = 9) or retained (n = 1) Rb expression, and often aberrant p53 expression (n = 8; 5 diffuse and 3 null).

Most UCNECs are associated with HPV infection and characterized by p16 overexpression as well as partial loss of Rb. The Rb expression pattern differs between HPV-positive UCNECs and HPV-negative pulmonary NECs, suggesting the potential diagnostic utility of Rb as well as p16.