The Prognostic Role of HPV or p16INK4a Status in Penile Squamous Cell Carcinoma: A Meta-Analysis
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Background: HPV infection is implicated in approximately half of global penile squamous cell carcinoma (PSCC) cases. Previous studies on HPV DNA and p16INK4a status in PSCC have yielded inconclusive prognostic findings. This meta-analysis aims to elucidate the prognostic role of HPV in PSCC by pooling data on disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS). Methods: We systematically searched Medline and Embase up to January 2023 for relevant human studies. Data from eligible publications reporting HPV DNA or p16INK4a status, along with and DFS, DSS, or OS outcomes, were extracted. A random-effects meta-analysis model was used to synthesize data, with study weights based on size and significance. The study protocol was registered with PROSPERO (CRD42019131355). Results: Out of 544 studies screened, 34 publications were included, comprising a pooled sample size of 3,944 patients. p16INK4a-positive status was associated with improved OS (hazard ratio [HR], 0.54; 95% CI, 0.39–0.75; I2=31%), DFS (HR, 0.52; 95% CI, 0.29–0.94; I2=20%), and DSS (HR, 0.34; 95% CI, 0.23–0.50; I2=18%). HPV DNA positivity was significantly associated with improved DFS (HR, 0.63; 95% CI, 0.46–0.87; I2=13%) and DSS (HR, 0.46; 95% CI, 0.29–0.75; I2=47%) but not OS (HR, 0.92; 95% CI, 0.74–1.11; I2=0%). Conclusions: This meta-analysis, comprising the largest number of patients with PSCC to date, shows a notable correlation between p16INK4a immunohistochemistry positivity and survival outcomes. These findings support the understanding that penile cancer cases not associated with HPV tend to behave more aggressively. We support p16INK4a immunohistochemistry testing as part of the initial diagnostic evaluation of patients with PSCC.
Submitted June 21, 2024; final revision received October 4, 2024; accepted for publication October 9, 2024. Published online January 3, 2025.
A. Mustasam and K. Parza contributed equally to this work.
Author contributions: Conceptualization: Semaan, Chahoud. Study design: Chahoud. Literature search: Mustasam, Parza, Sandstrom, Chahoud. Risk of bias assessment: Mustasam, Parza, Sandstrom, Chahoud. Data extraction: Mustasam, Parza, Sandstrom. Data verification: Mustasam, Parza, Sandstrom, Kim, Chahoud. Formal analysis: Mustasam, Parza, Kim. Investigation: Mustasam, Parza, Ionescu, Gullapalli, Paravathaneni, Kim, Sandstrom, Grass, Johnstone, Eschrich, Safa, Chadha, Roman Souza, David, Semaan, Zacharias, Pettaway, Giuliano, Spiess, Chahoud. Writing—original draft: Ionescu, Mustasam, Parza, Sandstrom, Al Assaad, Semaan, Spiess, Chahoud. Writing—review & editing: Mustasam, Parza, Ionescu, Gullapalli, Paravathaneni, Kim, Sandstrom, Grass, Johnstone, Eschrich, Safa, Chadha, Roman Souza, David, Semaan, Zacharias, Pettaway, Giuliano, Spiess, Chahoud.
Data availability statement: All data collected, including the search strategy, the review protocol, and data extraction sheets, are available immediately after publication and are either published as supplementary material or can be accessed through the corresponding author. Protocol link: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=131355
Disclosures: Dr. Chahoud has disclosed receiving grant/research funding from Allogene, Astellas, Bristol Myers Squibb, Eisai, Eli Lilly, Exelixis, Genentech, Merck, and Pfizer; and serving as a scientific advisor for Merck, Pfizer, Exelixis, Aveo, Eisai, and Mycaregorythm. Dr. Giuliano has disclosed receiving grant/research support from and serving as a scientific advisor for Merck. The remaining authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.
Supplementary material: Supplementary material associated with this article is available online at https://doi.org/10.6004/jnccn.2024.7078. The supplementary material has been supplied by the author(s) and appears in its originally submitted form. It has not been edited or vetted by JNCCN. All contents and opinions are solely those of the author. Any comments or questions related to the supplementary materials should be directed to the corresponding author.
Supplementary Materials
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