Background
Penile squamous cell carcinoma (PSCC) is a rare but aggressive malignancy associated with HPV infection, affecting men worldwide.1,2 By 2023, PSCC is estimated to affect >2,000 men in the United States and >50,000 globally, with survival rates showing limited improvement over the past 3 decades.1,3
High-risk HPV DNA infection accounts for more than half of PSCC cases, which exhibit distinct molecular and clinical features.2,4,5 Although HPV DNA–mediated oropharyngeal cancer (OPC) has demonstrated prognostic advantages and has been incorporated into WHO staging and therapy deintensification protocols,6 the prognostic significance of HPV DNA infection in PSCC remains uncertain.7–10
The limited sample sizes in previous prospective cohort studies, methodological variations in assessing HPV DNA status, and the absence of large-scale meta-analyses contribute to the current gaps in knowledge. However, leveraging p16INK4a detection via immunohistochemistry (IHC) as a cost-effective surrogate marker for HPV—a method that has been a gold standard in recent decades—allows for broader studies and longitudinal population analyses of HPV infections. This is because the HPV E6 and E7 oncoproteins cause degradation of the tumor suppressor protein pRb, which releases p16 production from its negative feedback control, resulting in elevated levels of p16INK4a. Thus, p16 overexpression becomes a reliable marker for identifying HPV-associated lesions.11 Previous research has validated the acceptable sensitivity comparability between HPV DNA and p16INK4a IHC biopsies in OPC and other HPV-associated squamous cell carcinomas.12 Understanding the role of HPV DNA and p16INK4a in PSCC offers the potential to refine disease risk stratification and craft tailored treatment approaches for this rare HPV-associated cancer.13–15 However, despite the recognized prognostic value of HPV DNA presence and p16INK4a protein overexpression in OPC, studies exploring these markers in PSCC have yielded conflicting results.2,16,17
The only prior meta-analysis, conducted by Sand et al,16 pooled results from 20 studies evaluating clinical outcomes in PSCC. Their findings revealing conflicting results, precluding definitive clinical conclusions. Although they reported improved disease-specific survival (DSS) in patients with PSCC positive for HPV DNA or exhibiting high p16INK4a expression,16 no significant associations were observed with disease-free survival (DFS) and overall survival (OS). Since its publication in 2018, there has been a substantial increase in observational studies documenting the impact of HPV DNA and p16INK4a status on PSCC outcomes. This meta-analysis aims to comprehensively analyze the current literature to better define the prognostic role of HPV DNA and p16INK4a testing in PSCC clinical outcomes.
Methods
Search Strategy and Selection Criteria
We performed a systematic literature search in PubMed and Embase, covering articles published between March 1992 and January 2023. The database search was filtered for articles written in English. For both searches, we included the following terms: “Prognosis” OR ”Prevalence” AND “HPV” OR “Human Papillomavirus” OR ”Human Papillomaviruses” OR “Papillomaviridae” OR “human papillomavirus” OR ”Cyclin-Dependent Kinase Inhibitor p16” OR “Cyclin-Dependent Kinase Inhibitor p16” OR “p16INK4a” OR “Cyclin-Dependent Kinase Inhibitor-2A” OR “p16INK4a Protein” OR “CDKN2A Protein” OR “CDKN2 Protein” AND “Penile Neoplasms” OR “Penile Neoplasms” OR “Penis Neoplasms” OR “Penis Neoplasm” OR “Penile Neoplasm” OR “Penis Cancer” OR “PSCC” OR “Penile Carcinoma” OR “Penis Carcinoma” OR ”Penis Tumor" OR “PSCCs.”
The search was independently conducted by authors A. Mustasam and K. Parza and verified by J. Chahoud. In cases of disagreement, a joint dialog was initiated until consensus was reached. A fourth author, R. Sandstrom, resolved any unresolved conflicts. In both searches, we verified all supplementary information using reference lists to ensure completeness.
The study was organized following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and the protocol is registered on the PROSPERO platform for meta-analysis (CRD42019131355).18 Eligibility was restricted to studies with human participants only, examining the prognostic association between HPV DNA or p16INK4a and clinical outcomes in PSCC. Studies were excluded if their outcome of interest was the development of other squamous cell carcinomas. To be eligible for inclusion, studies needed a cohort size of at least 20 patients. Abstracts, letters to the editor, case reports, review articles, case-control studies with <20 cases and <20 controls, and cohort studies with <20 patients were excluded; studies including <20 patients were excluded due to insufficient statistical power. Additionally, studies were excluded if they did not report the associated risk for at least HPV or p16INK4a with progression-free survival, DFS, OS, or DSS. No restrictions were placed on the methods used for HPV detection or p16INK4a IHC detection.
A. Mustasam and K. Parza independently reviewed the titles and abstracts from the previously searched databases. Based on the prespecified selection criteria, both authors identified eligible studies independently. Disagreements were resolved through discussion, with a prior agreement that any unresolved conflicts would be decided by a third author (J. Chahoud). A. Mustasam and K. Parza used data collection forms to extract the required data from the eligible studies. Subsequently, both authors checked for duplicate studies by comparing authors’ names, publication dates, and population sizes. When multiple studies from the same authors covered the same population, only the most recent publication with the most complete data was selected. Both authors remained unblinded to the studies’ authors’ names, population sizes, journals of publication, and locations.
Data Extraction
Our primary focus was to examine the correlation between HPV or p16INK4a and survival outcomes (OS, DSS, DFS) in PSCC cases. This involved gathering study-specific hazard ratios (HRs) adjusted for potential confounding factors. Studies reporting recurrence-free survival were categorized under DFS due to their alignment with its definition. Data collection involved study specifics: first author’s name, publication year, country, year of sample collection, age at diagnosis (mean, median, range), follow-up duration, tissue type, cancer histology, tumor stage/grade, lymph node status, treatment modalities, HPV and p16 testing methods, definition of p16 positivity (overexpression), evaluators for p16 staining, sample sizes, and counts of positive/negative cases for HPV and p16INK4 (Supplementary Table S1, available online in the supplementary materials). For consistency and accuracy, A. Mustasam and K. Parza independently reviewed titles, abstracts, and full-text articles to extract data. A third author (J. Chahoud) verified this process, resolving discrepancies through discussion. Duplicate studies from the same authors on the same population were streamlined to the most recent publication with the most comprehensive data. Efforts were made to obtain missing data through emailing the corresponding authors of the studies. Reminders were sent after 2 weeks for nonresponses. Data that remained unobtained were marked as unavailable.
Statistical Analysis
Two reviewers (A. Mustasam and K. Parza) independently assess the quality of each study using the Newcastle-Ottawa Scale (NOS) (Supplementary Table S2). Due to the rarity of the disease, we approximated relative risk (RR) using HRs, using Cox regression to estimate HRs. Our meta-analysis focused on eligible studies reporting covariate-adjusted HRs concerning the relationship between HPV DNA and p16INK4a IHC with PSCC survival outcomes. We extracted covariate-adjusted HRs and their corresponding standard errors from these studies. In cases where adjusted HR data were unavailable, we used the Kaplan-Meier (KM) reconstruction technique to estimate survival outcomes.19 Using a random-effects meta-analysis model, we combined the HRs. Heterogeneity among study-specific HRs was assessed using both Cochran’s Q test and the I2 statistic. To address publication bias, we used funnel plots, Egger’s regression test,20 and the trim-and-fill method for correction.21 Sensitivity analyses were crucial; thus, we performed a leave-one-out analysis to evaluate the influence of individual studies on our conclusions, calculating pooled estimates by omitting one study at a time. All statistical analyses were conducted using the R meta and metafor packages.22
Results
Search Results
Figure 1 presents the PRISMA flow diagram, outlining how the meta-analysis reviewed the literature process and included a total of 34 studies23–56 involving 3,994 men. A search of the Medline and Embase databases yielded 544 articles. After removing 118 duplicates, 426 articles remained. Of these, 345 were excluded for not meeting inclusion criteria. We then thoroughly reviewed the full text of the remaining 81 articles and their reference lists, identifying 1 additional relevant publication. Following this review, we excluded an additional 48 studies: 27 for not meeting inclusion criteria, 3 due to data overlap with another study (we included the 1 with the most comprehensive data and the largest population for HR in the meta-analysis), and 18 for not providing the clinical outcome associated with HPV DNA or p16INK4a, even after corresponding with the authors.
Study selection.
Citation: Journal of the National Comprehensive Cancer Network 2025; 10.6004/jnccn.2024.7078
Study Characteristics
Our comprehensive meta-analysis included 33 cohort studies and 1 cross-sectional study (Supplementary Table S1), spanning publications from 1992 to 2023. These studies encompass data from 13 countries across 4 continents. In total, 3,994 male adults from various age groups were included, with a mean age of 62.3 years. Throughout our investigation, we encountered research that reported the median age with the IQR or range, rather than the mean and standard deviation. To estimate the mean age, we applied the methodology introduced by Wan et al57 in 2014, which provides equations for estimating the sample mean and standard deviation based on parameters such as sample size, median, and either the IQR or range.57 Using these equations, we estimated the mean age of patients in the studies and calculated the overall mean for our sample size. For p16INK4a, our analysis included 19 studies (n=1,542), of which 5, 8, and 11 reported on DFS, DSS, and OS, respectively. We also included 29 studies (n=3,646) that employed HPV DNA testing, with 9, 10, and 11 reporting on DFS, DSS, and OS, respectively.
Among men with PSCC, 3,646 underwent HPV DNA testing, with 1452 testing positive, resulting in a prevalence of 39.8% (95% CI, 38.2%–41.4%). Moreover, p16INK4a expression by IHC was evaluated in 1,542 men, of whom 674 tested positive, yielding a prevalence of 43.7% (95% CI, 41.2%–46.2%). All included studies primarily assessed survival outcomes in patients with PSCC, focusing on DFS, DSS, or OS in relation to HPV DNA or p16INK4a status, which were determined using various methods.
HPV DNA and P16INK4a Detection Methods
In our analysis, 29 studies reported HPV DNA status. Among these, 18 utilized the PCR method for HPV DNA detection,23–28,32,33,35–37,40–43,49–51 6 employed in situ hybridization (ISH).31,34,39,44,53,55 and 4 did not specify the method used.46,47,52,54 Additionally, 1 study used a Quantus fluorometer to detect HPV DNA nucleic acid56 (Supplementary Table S1).
The 29 studies in our analysis used IHC staining to assess samples for p16INK4a-positive status. Two different methodologies were used to grade p16INK4a on IHC. A quantitative measurement approach was employed in 6 studies28,39,45,49,53,55 used, where the cutoff for p16INK4a positivity ranged from >10% to >75% of cells exhibiting positive staining. Conversely, 12 studies26,29,34,36–38,40,43,47,48,51,56 used subjective criteria to define p16INK4a positivity, using descriptions such as strong and diffuse staining, vital staining of proliferative cells, continuous and complete cytoplasmic staining, intense confluent staining, or focal scattering of staining in the cytoplasm and nucleus of cells. Bethune et al30 adopted a mixed methodology, using a qualitative cutoff of >30% staining with nuclear and cytoplasmic staining, moderate sample staining with at least 30% of cells staining, or strong cytoplasmic and nuclear staining to define p16INK4a positivity. One study50 did not specify the criteria used for determining p16INK4a positivity (Supplementary Table S1).
Study Quality Assessment
We conducted a quality assessment using the NOS, a tool specifically designed for nonrandomized studies and endorsed by the Cochrane Collaboration. We applied the appropriate version of NOS, tailored for either case-control studies or cohort studies, considering subject selection, study comparability, and outcome or exposure assessment. NOS scores ranged from 5 to 9, with 9 being the highest possible score. The median score was 7 (IQR, 7–8.25). A summary of the study evaluations using the NOS is provided in Supplementary Table S2.
Association of p16INK4a Status With Outcomes
Disease-Specific Survival
In 8 studies29,30,34,37,39,51,53,55 encompassing 795 patients, individuals who tested positive for p16INK4a demonstrated significantly prolonged DSS (HR, 0.34; 95% CI, 0.23–0.50; I2=18%) (Figure 2). To ensure the robustness of our findings, we conducted a leave-one-out meta-analysis, which consistently confirmed the significance of the results across all scenarios (Supplementary Figures S1 and S2), even when excluding one study at a time. Moreover, the Egger regression test yielded a P value of .83, indicating a lack of significant evidence for funnel plot asymmetry and suggesting that there was not enough evidence to support the presence of publication bias. (Supplementary Figures S1 and S2).
Pooled effect size for disease-specific survival in patients with p16INK4a-positive penile squamous cell carcinoma.
Abbreviation: HR, hazard ratio.
Citation: Journal of the National Comprehensive Cancer Network 2025; 10.6004/jnccn.2024.7078
Overall Survival
A total of 11 studies26,28,30,34,45,49,50,53–56 provided data on OS in relation to p16INK4a expression, encompassing 688 men diagnosed with PSCC (244 [35%] tested positive for p16INK4a and 333 [48%] tested negative). In 3 of these studies,28,49,54 we used the KM reconstruction method to estimate HRs. A random-effects meta-analysis revealed that patients who tested positive for p16INK4a had significantly improved OS (HR, 0.54; 95% CI, 0.39–0.75; I2=31%) (Figure 3). Our leave-one-out meta-analysis confirmed that the results remained significant across all scenarios (Supplementary Figures S3 and S4). The Egger regression test yielded a P value of .059, indicating a lack of significant evidence for funnel plot asymmetry and suggesting that there was not enough evidence to support the presence of publication bias (Supplementary Figures S3 and S4). Furthermore, even after conducting a sensitivity analysis that excluded studies using the KM reconstruction method, the results remained statistically significant (HR, 0.50; 95% CI, 0.34–0.74; I2=36%) (Supplementary Figures S3 and S4).
Pooled effect size for overall survival in patients with p16INK4a-positive penile squamous cell carcinoma.
Abbreviation: HR, hazard ratio.
Citation: Journal of the National Comprehensive Cancer Network 2025; 10.6004/jnccn.2024.7078
During the publication bias analysis, the funnel plot highlighted an outlier study,53 and Egger’s test suggested borderline significance for potential publication bias (P=.059). After removing the outlier study and imputing 2 additional studies in the trim-and-fill analysis, the revised pooled HR was 0.46 (95% CI, 0.34–0.62). This adjusted HR continued to demonstrate a significant association between p16 expression and OS (Supplementary Figure S5).
Disease-Free Survival
A total of 5 studies26,38,47,48,54 provided data on DFS in relation to p16INK4a status, encompassing 396 patients with PSCC. In 3 of these studies,31,47,54 we used the KM reconstruction method. A random-effects meta-analysis demonstrated a significantly beneficial effect of p16INK4a status on DFS (HR, 0.52; 95% CI, 0.29–0.94; I2=20%) (Figure 4). Our leave-one-out meta-analysis confirmed that the results remained significant across all scenarios, except when we excluded the study by Ashley et al47 (Supplementary Figures S6 and S7). The Egger regression test yielded a P value of .04, indicating a lack of significant evidence for funnel plot asymmetry and suggesting that there was not enough evidence to support the presence of publication bias (Supplementary Figures S6 and S7). In a sensitivity analysis excluding studies analyzed using the KM reconstruction method,47 the results became nonsignificant (HR, 0.29; 95% CI, 0.02–3.76; I2=76%). This outcome is likely due to the small sample sizes in the 2 studies by Guerrero et al26 (n=24) and Tang et al38 (n=119).
Pooled effect size for disease-free survival in patients with p16INK4a-positive penile squamous cell carcinoma.
Abbreviation: HR, hazard ratio.
Citation: Journal of the National Comprehensive Cancer Network 2025; 10.6004/jnccn.2024.7078
Association of HPV DNA Status With Outcomes
Disease-Specific Survival
A total of 10 studies23–25,28,34,35,37,44,51,55 were included in the meta-analysis of DSS, encompassing 1,100 men assessed for DSS based on HPV DNA–positive status. We contacted the authors of 4 studies23,24,34,37 for additional information. The KM reconstruction method was used in 2 studies.44,55 Our pooled hazard ratios consistently favored patients who were HPV DNA–positive PSCC over those who were HPV DNA–negative (HR, 0.46; 95% CI, 0.29–0.75; I2=47%) (Figure 5). Leave-one-out meta-analysis confirmed the sustained significance of the results across all scenarios (Supplementary Figures S8 and S9). Egger regression test results yielded a P value of .84, indicating a lack of significant evidence for funnel plot asymmetry and suggesting that there was not enough evidence to support the presence of publication bias (Supplementary Figures S8 and S9). Even after excluding studies that used the KM reconstruction method,44,55 the results remained statistically significant (HR, 0.43; 95% CI, 0.24–0.78; I2=56%).
Pooled effect size for disease-specific survival in patients with HPV DNA–positive penile squamous cell carcinoma.
Abbreviation: HR, hazard ratio.
Citation: Journal of the National Comprehensive Cancer Network 2025; 10.6004/jnccn.2024.7078
Overall Survival
A total of 11 studies23,24,26,28,33,45,49,50,52,55,56 were included in this analysis, encompassing 1,414 men evaluated for OS. We attempted to contact the authors of one study45 for additional information but were unable to obtain the detailed data. The KM reconstruction method was used in 3 studies.28,49,54 No statistically significant difference in hazard for death was observed between patients who were HPV DNA–positive and those who were HPV DNA–negative (HR, 0.91; 95% CI, 0.74–1.11; I2=0%) (Figure 6). Leave-one-out meta-analysis confirmed the sustained significance of the results across all scenarios (Supplementary Figures S10 and S11). Egger regression test results yielded a P value of .65, indicating a lack of significant evidence for funnel plot asymmetry and suggesting that there was not enough evidence to support the presence of publication bias (Supplementary Figures S10 and S11). The results remained insignificant even after excluding studies analyzed using the KM reconstruction method (HR, 0.95; 95% CI, 0.75–1.20; I2=0%) (Supplementary Figures S10 and S11).
Pooled effect size for overall survival in patients with HPV DNA–positive penile squamous cell carcinoma.
Abbreviation: HR, hazard ratio.
Citation: Journal of the National Comprehensive Cancer Network 2025; 10.6004/jnccn.2024.7078
Disease-Free Survival
In our analysis of DFS, we included 9 studies,26,27,31,32,40–43,51 and contacted the authors of 3 of the studies27,32,43 for additional data. The KM reconstruction method was applied in one study.42 For another study,41 the HR and its standard error were estimated using Cox proportional hazard regression analysis of the original individualized data. In total, we analyzed data from 1,015 men to assess DFS based on HPV DNA–positive status. A random effects meta-analysis result showed that patients who tested positive for HPV DNA had significantly better DFS (HR, 0.63; 95% CI, 0.46–0.87; I2=13%) compared with those who tested negative (Figure 7). Leave-one-out meta-analysis confirmed the sustained significance of the results across all scenarios (Supplementary Figures S12 and S13). Egger regression test results yielded a P value of .35, indicating a lack of significant evidence for funnel plot asymmetry and suggesting that there was not enough evidence to support the presence of publication bias (Supplementary Figures S12 and S13). Even after excluding the one study that used the KM reconstruction method,42 the results remained statistically significant (HR, 0.67; 95% CI, 0.50–0.90; I2=0%).42
Pooled effect size for disease-free survival in patients with HPV DNA–positive penile squamous cell carcinoma.
Abbreviation: HR, hazard ratio.
Citation: Journal of the National Comprehensive Cancer Network 2025; 10.6004/jnccn.2024.7078
Discussion
To our knowledge, this study represents the most extensive meta-analysis examining the correlation between HPV DNA and p16INK4a in PSCC, encompassing 34 studies and 3,994 patients. Notably, it is the first to explore the association between p16INK4a/HPV DNA status and disease recurrence in PSCC. Building on the analysis of Sand et al,16 we included 14 additional studies, encompassing a more contemporary and diverse cohort of patients with PSCC and resulting in a larger sample size.
Our updated meta-analysis encompassed studies from diverse regions: 13 from Europe, 8 from the United States, 8 from Brazil, 4 from Asia, and 1 from Canada. It is important to note that Cox regression was used to estimate HRs for our analysis. The findings reveal that HPV DNA presence correlates with a 54% reduction in the hazard of mortality from PSCC and a 37% reduction in the hazard of disease recurrence. Additionally, our analysis underscores that p16INK4a positivity significantly correlates with reductions in disease-specific mortality (66%), overall mortality (46%), and disease recurrence (48%). Testing for publication bias showed no significant evidence of its presence in our data.
Given the favorable prognosis for HPV-related PSCC, particularly the reduced risk of recurrence and mortality, more conservative surgical approaches, such as organ-preserving techniques, may be considered, especially in patients with lower disease burden and in appropriately selected patients. Evidence from studies on penile-conserving surgery supports this approach, showing no significant impact of local recurrence on long-term survival.58,59
This meta-analysis specifically focused on DFS, a critical factor in comprehensive clinical understanding. Our findings not only align closely with prior research but also provide robust evidence confirming the substantial prognostic significance of HPV-related markers. These findings extend beyond disease-specific mortality, considering risks associated with disease recurrence and overall mortality.
For example, Sand et al16 previously reported a favorable impact of p16INK4a positivity on DSS (pooled HR, 0.45; 95% CI, 0.30–0.69) but found no effect on OS (pooled HR, 0.88; 95% CI, 0.49–1.59).16 However, our analysis indicates significant positive influence of p16INK4a on all endpoints, including DFS (HR, 0.52; 95% CI, 0.29–0.94; I2=20%) and OS (HR, 0.54; 95% CI, 0.39–0.75; I2=31%). This stronger effect may be attributed to the larger p16INK4a sample size in our study (n=1,542) compared with the 116 cases in the prior study.
Similarly, HPV DNA status showed a positive correlation with improved DFS and DSS, with most studies revealing consistent results. However, the few cases with discrepancies between these markers may indicate the possibility of poorer outcomes. This is consistent with earlier research on HPV-related OPC,13 where such discrepancies were associated with adverse results.
The findings are consistent with known differences in the carcinogenic pathways leading to HPV-positive and HPV-negative PSCC. Our previous work has established a biologic and molecular rationale supporting our epidemiologic observations that HPV DNA positivity and p16INK4a expression are associated with improved cancer-specific survival rates and reduced disease recurrence. Moreover, our research, along with others, has identified distinct molecular profiles specific to HPV DNA involvement in PSCC, differentiating it from non–HPV-associated PSCC carcinogenesis.4,5 Notably, TP53 mutation occurs exclusively in HPV DNA–negative PSCC cases, contributing to poorer clinical outcomes compared with HPV DNA–associated cases. Additionally, 9p21 loss, particularly involving CDKN2A, is more frequent in HPV-negative cases and is linked to a “cold” immune microenvironment, characterized by reduced tumor-infiltrating leukocytes. This immunosuppressive environment leads to lower response rates to immune checkpoint therapy, further worsening prognosis.60 These differences in molecular pathways and genetic alterations significantly contribute to clinical disparities observed between HPV-positive and HPV-negative PSCC, highlighting distinct prognostic factors.
Quality of the Evidence
This meta-analysis is the most comprehensive investigation on this subject to date. Although most of the studies in our analysis were cohort-based, they exhibited a high level of quality, as indicated by NOS scores ranging from 5 to 9. Notably, we addressed a significant limitation of previous research—interstudy heterogeneity.
Our approach to mitigating this issue involved several key steps. First, statistical tests revealed no significant heterogeneity or publication bias among the studies included in our various subgroup analyses. Second, to accommodate the diversity of HPV DNA detection methods employed, we conducted a subgroup analysis specifically focusing on studies using HPV DNA and those using the p16INK4a IHC surrogate marker. Third, we individually assessed the associations of HPV DNA and p16INK4a with PSCC DFS, OS, and DSS. This type-specific meta-analysis represents a substantial enhancement in the quality of evidence presented in this study.
Study Limitations
We acknowledge several limitations in our analysis. First, the retrospective nature of the study and the presence of heterogeneous treatment regimens are notable limitations. Second, in 3 of the included studies, HRs were calculated based on data extracted from KM curves.28,49,54
Additionally, for one study by Bezerra et al,34 we needed to contact the authors to obtain HRs that were not initially reported in their peer-reviewed publication. Although these situations may introduce some inaccuracies in our estimates, they nonetheless constitute the best available data to support the prognostic significance of HPV DNA and p16INK4a in this rare cancer. Furthermore, our findings align with those observed in biologically similar, more common cancers associated with HPV DNA, such as OPC.
Also, the subjectivity in assessing p16INK4a overexpression across studies reflects the variability in assessment methods, making it challenging to synchronize data for a unified analysis. Finally, it is important to note that the included studies did not report on specific HPV DNA types, which was not considered in our HPV DNA–specific analysis.
Research and Clinical Implications
The alignment between our epidemiologic finding in PSCC and those observed in OPC, coupled with the molecular plausibility of high-risk HPV DNA influencing the biology and, consequently, clinical outcomes in PSCC, provides compelling evidence for the adoption of p16INK4a IHC testing as a marker for HPV DNA viral infection. This approach may offer additional insights in the prognosis assessment of patients with PSCC.
The data presented align with the inclusion of p16INK4a IHC testing in the initial diagnostic evaluation of patients with PSCC. Such recommendations could be considered by both the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Penile Cancer61 and the European Association of Urology-American Society of Clinical Oncology Collaborative Guidelines on Penile Cancer.62
Conclusions
As we continue to strive for advancements in cancer care to enhance survival and quality of life for patients, the correlation with survival observed in HPV DNA–associated PSCC suggests a direction for future research endeavors. These efforts should be pursued with care, focusing on strategies for optimizing therapeutic approaches for HPV DNA–associated PSCC, ultimately leading to enhanced quality of life for patients with PSCC.
Acknowledgments
We would like to thank the R.S. Evans Foundation for their generous donation in support of penile cancer research at Moffitt Cancer Center.
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