Penile squamous cell carcinoma (PSCC) is a rare disease with limited systemic therapy strategies in advanced stages. To gain a better understanding about tumor and immune-related factors in PSCC with potential implications for future therapeutic options, we assessed T-lymphocytic tumor immune microenvironment (TIME), human papillomavirus (HPV) status, and p16 expression in a retrospective, multi-institutional cohort of 115 PSCC patients. We constructed a tissue microarray (TMA) containing cores from the tumor front (TF) and tumor center (TC) and performed immunohistochemistry (IHC) using antibodies against p16INK4A, CD3, CD8, and PD-L1. Cluster analysis based on CD3, CD8, and PD-L1 expression revealed two distinct immunophenotypic subgroups. The non-inflamed cluster with low expression of CD3, CD8, and PD-L1, and the inflamed cluster with high expression of these markers. Specific clustering configurations involving IHC assessments from TC highlighted a significantly shorter overall survival and cancer-specific survival for the inflamed cluster compared to the non-inflamed cluster. PD-L1 tumor proportion score (TPS) was higher in cases with vascular and lymphatic invasion, whereas combined positive score (CPS) was higher in samples with lymphatic invasion and lymph node metastasis. p16INK4A negative cases showed higher PD-L1 TPS/CPS and reduced metastasis free survival compared to p16INK4A positive samples. Taken together, this study demonstrates the prognostic value of the TIME using the three widely available markers CD3, CD8, and PD-L1 in PSCC. Furthermore, it provides additional evidence for a survival benefit of p16INK4A positive cases, compared to p16INK4A negative cases.
Virchows Archiv : an international journal of pathology. 2026 Apr 08 [Epub ahead of print]
August Fiegl, Miriam Angeloni, Jan Mink, Alexey Pryalukhin, Oybek Khalmurzaev, Stefan Lohse, João Lobo, Rui Henrique, Carmen Jerónimo, Hagen Loertzer, Joachim Steffens, Heiko Wunderlich, Rainer M Bohle, Michael Stöckle, Vsevolod Matveev, Carol Geppert, Kerstin Junker, Fulvia Ferrazzi, Arndt Hartmann
Institute of Pathology, University Erlangen-Nuremberg, Erlangen, Germany. ., Institute of Pathology, University Erlangen-Nuremberg, Erlangen, Germany., Department of Urology and Pediatric Urology, Saarland University, Homburg, Germany., Institute of Clinical Pathology and Molecular Pathology, Wiener Neustadt State Hospital, Wiener Neustadt, Austria., Institute of Virology, Saarland University, Homburg, Germany., Portuguese Oncology Institute of Porto/Porto Comprehensive Cancer Center Raquel Seruca, & School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Porto, Portugal., Clinic of Urology and Paediatric Urology, Westpfalz-Klinikum, Kaiserslautern, Germany., Department of Urology and Paediatric Urology, Sankt-Antonius-Hospital, Eschweiler, Germany., Clinic of Urology and Paediatric Urology Georg Klinikum, Eisenach, Germany., Institute of Pathology, Saarland University Medical Center, Homburg, Germany., Department of Urology, Federal State Budgetary Institution "N.N. Blokhin National Medical Research Center of Oncology", Ministry of Health of the Russian Federation, Moscow, Russian Federation.