High-risk human papillomavirus infection and immunohistochemical expression patterns of p16 and Rb in primary and metastatic squamous cell carcinoma of the lung.

The prevalence of high-risk human papillomavirus (HR-HPV) infection in lung squamous cell carcinoma (SCC) remains controversial. Moreover, distinguishing primary lung SCC from metastatic SCC is challenging. HPV-associated cancers, including oropharyngeal and cervical carcinomas, exhibit typical p16 overexpression and Rb partial loss pattern in both primary sites and lymph node metastases. However, their diagnostic utility in pulmonary lesions remains unclear. The clinicopathological features of 114 cases of primary lung SCC and 11 of pulmonary metastatic SCC were analyzed. HR-HPV infection was assessed using RNA in situ hybridization and immunohistochemistry for p16 and Rb. HR-HPV was not detected in any primary lung SCC cases, whereas it was detected in 9 of 11 metastatic SCC cases. All nine cases of HPV-positive metastatic SCCs showed p16 positivity and Rb loss (partial loss, n = 8; complete loss, n = 1). Among the primary lung SCC cases, 31 (27.2%) cases were positive for p16, and 48.4% showed preserved Rb expression and 51.6% showed complete loss of Rb expression. The p16 or Rb expression status did not influence the prognostic difference in primary SCCs. HR-HPV infection was not observed in primary lung SCC, suggesting a lower prevalence than previously reported. The p16+/Rb partial loss pattern was exclusively associated with metastatic HPV-related SCC, whereas primary lung SCC demonstrated distinct p16 and Rb expression profiles. However, cases with a p16+/Rb complete loss pattern require HPV-specific testing. The combination of p16 and Rb IHC with HPV-specific testing may help differentiate primary lung SCC from metastatic SCC.