Prognostic Significance of p16 and Its Relationship with Human Papillomavirus Status in Patients with Penile Squamous Cell Carcinoma: Results of 5 Years Follow-Up

Abstract

Penile Squamous Cell Carcinoma (PSCC) is associated with high-risk human papillomavirus (HR-HPV). The immunohistochemical (IHC) test for p16INK4a (p16) is highly correlated with HR-HPV expression in other SCCs. To investigate whether the expression of p16 IHC or HR-HPV is associated with survival in PSCC, we conducted a single institution analysis of 143 patients with a diagnosis of PSCC and, available tissue were tested for p16 IHC staining patterns, histological subtype, tumor grade, and lymphovascular invasion (LVI) by an experienced pathologist. HR-HPV status using the Cobas PCR Assay or the RNAScope high-risk HPV in situ hybridization kit were also assessed. Patient characteristics were summarized using descriptive statistics of clinico-pathologic variables. Kaplan–Meier was used to estimate median overall survival (OS), cancer specific survival (CSS) and correlated with HPV, p16, and other study variables. Patients with p16+ tumors had a significantly longer median CSS in comparison to the p16– group (p = 0.004), with respective 5-year CSS probability of 88% (95% CI; 0.84, 1) versus 58% (95% CI; 0.55, 0.76; p = 0.004). HPV status did not predict survival outcomes. Multivariable analysis with respect to OS and CSS, showed that p16+ status was associated with a lower risk of death (HR = 0.36, 95%CI; 0.20–0.67, p = 0.001), and improved CSS (HR = 0.20, 95% CI; 0.07–0.54, p = 0.002) after adjusting for covariates. In conclusion, tumor p16 status via IHC was an easy to perform independent prognostic factor for OS and CSS that correlates with HR-HPV expression.

Transcriptomic, Proteomic, and Genomic Mutational Fraction Differences Based on HPV Status Observed in Patient-Derived Xenograft Models of Penile Squamous Cell Carcinoma

“…Positive p16 expression was found in XPe3, XPe9, and XPe16 lysates in the immunoblot that correlated with the p16-positive assignments using our hybrid IHC-scoring method. For XPe20 and XPe821, PDX lysates had little to no p16 expression based on immunoblotting and they were considered p16-negative using our hybrid IHC-scoring method [ 10 ]. We did not observe HPV16 E6 or E7 transcripts in Pe20 patient tissue and we observed the transcripts for both proteins in XPe821.…”

“…We used our recently published hybrid system (HS) for analyzing p16 via IHC. The HS method uses both the percentage (>75%) of positive staining of the tumor section and the staining pattern [ 10 ]. In the HS method, tumor tissues with a positive staining of >75% and a pattern of 3 or 2 are considered positive for p16, whereas those with a staining pattern of <75% and a staining pattern of 2, 1, or 0 are considered negative for p16.…”

“…Overexpression of p16 can be detected by immunohistochemical (IHC) staining and has been found to be a reliable marker for HR-HPV infection in oropharyngeal SCC and PSCC [ 5 , 6 , 7 , 8 , 9 ]. PSCC patients with strong p16 expression observed via IHC have been found to have a better prognosis than PSCC patients with spotty expression or no expression [ 10 , 11 ]. Therefore, there is evidence that carcinogenesis is different in HPV-positive (HPV+) versus HPV-negative (HPV−) PSCC, and this could possibly be a therapeutic vulnerability.…”

Human Papillomavirus Infection in Penile Cancer: Multidimensional Mechanisms and Vaccine Strategies

“…Generally, p16 ink4a (a cyclin-dependent kinase inhibitor) is inhibited by Rb protein [80,81]. Thus, HPV E7-induced blocking of Rb function can increase p16 ink4a expression in PC via a feed-back control [82][83][84]. Even though up-regulation of p16 ink4a expression has been observed during HPV infection, several studies have demonstrated that the p16 ink4a gene can be methylated.…”

The Prognostic Role of Human Papillomavirus and p16 Status in Penile Squamous Cell Carcinoma—A Systematic Review

“…The development of PSCC is frequently linked to multiple risk factors, such as inadequate hygiene, absence of circumcision, tobacco smoking, specific genetic conditions, and the presence of HPV, which can be found in 30-50% of cases [8][9][10][11][12].…”