4MO p53 and p16ink4a as predictive and prognostic biomarkers for nodal metastasis and survival in a contemporary cohort of penile squamous cell carcinoma

Abstract

Human papilloma virus (HPV) infection is implicated in a proportion of invasive squamous cell carcinoma of the penis (PC). A subset of PC involves dysregulation of the p53 pathway. HPV in situ hybridization (ISH) and p16 ink4a positivity are surrogate markers for HPV infection, and p53 immunohistochemistry (IHC) denotes abnormality in the p53 pathway. Clinicopathologic characteristics of a cohort of Indian PC patients with respect to p16 and p53 expression were analyzed. 123 PC patients were studied for p16 and p53 IHC and HPV ISH and the results were correlated with various clinicopathologic parameters. p16 and HPV ISH were positive in 47% and 53% of the tumors, respectively. The proportion of warty, basaloid, or mixed warty-basaloid tumor subtypes showed significant p16 positivity (p < 0.0001) compared to other subtypes. In patients where p16 was negative, a p53-positive phenotype had a higher propensity for lymph node metastases (OR, 5.4; 95% CI, 1.7 to16.8; p=0.003). Similarly, p53 positivity dictates nodal involvement in the p16-positive subset of tumors (OR, 5; 95% CI, 1.2 to 20.1; p=0.024). On multivariate analyses, pathologic subtypes (warty, warty-basaloid, and basaloid) (p<0.0001), p16 expression (p<0.0001), and absence of nodal metastasis (p<0.0001) were significant predictors of improved overall (OS) and cancer specific survival (CSS). The OS was significantly longer in patients with p16+ tumors (p<0.0001), as was the CSS (p<0.0001). Patients with dual positive tumors had a significantly higher OS (p<0.001) and CSS (p=0.01), in the entire cohort. In the node positive patients, dual positivity was associated with significantly higher OS (p<0.0001); however, the median CSS for p53+/p16+tumors was not significantly different compared to p53- /p16- tumors (p=0.064), although there was a trend towards improved CSS. There is a strong concordance between p16 IHC and HPV ISH results. p16 status is an independent predictor of survival (OS and CSS) in our cohort of PCs. p53 is a predictor of nodal metastasis irrespective of p16 status. Dual positive tumors have a significantly better outcome in comparison to dual negative tumors.