Penile squamous cell carcinoma (pSCC) is a rare tumour with a variable prognosis. More prognostic markers linked to mutational signatures and the tumour immune microenvironment are needed. A cohort made up of 165 invasive pSCC was retrospectively analysed using formalin-fixed, paraffin-embedded tumour tissue, focusing on tumour mutational burden (TMB), programmed death ligand 1 (PD-L1) expression, microsatellite instability (MSI), the number of tumour infiltrating lymphocytes (TILs) expressing cytotoxic T-lymphocyte-associated protein 4 (CTLA4), HPV status determined by p16 immunohistochemistry, and several traditional histopathological variables. High TMB (>10 mut/Mb) was associated with high PD-L1 expression (TPS 50-100%), and HPV-negative status. High PD-L1 expression was linked to HPV negativity, a high number of intratumoural CTLA4+ cells, and brisk lymphocytic infiltrate. High TMB was a significant predictor of shorter overall survival (OS) in both univariate and multivariate analysis when using a median cut-off value of 4.3 mut/Mb, but not when using an arbitrary cut-off of 10 mut/Mb. Low CTLA4+ cell infiltration at the tumour invasion front was a marker of shorter OS and cancer-specific survival in both univariate and multivariate analysis. PD-L1 expression had no significant impact on prognosis. Only two cases were MSI high. The results support the hypothesis of two aetiological pathways in pSCC cancerogenesis: (1) SCC linked to HPV infection characterised by low TMB, less common PD-L1 expression, and a lower number of TILs; and (2) SCC linked to chronic inflammation leading to a high number of acquired mutations (high TMB), HPV negativity, increased neoantigen production (i.e., PD-L1), and high immune cell infiltration.
Pathology. 2023 Dec 01 [Epub ahead of print]
Jan Hrudka, Jan Hojný, Zuzana Prouzová, Michaela Kendall Bártů, David Čapka, Nicolette Zavillová, Radoslav Matěj, Petr Waldauf
Department of Pathology, 3rd Faculty of Medicine, Charles University, University Hospital Kralovske Vinohrady, Prague, Czech Republic. Electronic address: ., Department of Pathology, 1st Faculty of Medicine, Charles University, General University Hospital, Prague, Czech Republic., Department of Pathology, 3rd Faculty of Medicine, Charles University, University Hospital Kralovske Vinohrady, Prague, Czech Republic; Department of Pathology, 1st Faculty of Medicine, Charles University, General University Hospital, Prague, Czech Republic., Department of Urology, 3rd Faculty of Medicine, Charles University, University Hospital Kralovske Vinohrady, Prague, Czech Republic., Department of Urology, 3rd Faculty of Medicine of Charles University, Thomayer University Hospital, Prague, Czech Republic., Department of Pathology, 3rd Faculty of Medicine, Charles University, University Hospital Kralovske Vinohrady, Prague, Czech Republic; Department of Pathology, 1st Faculty of Medicine, Charles University, General University Hospital, Prague, Czech Republic; Department of Pathology and Molecular Medicine, 3rd Faculty of Medicine, Charles University, Thomayer University Hospital, Prague, Czech Republic., Department of Anaesthesia and Intensive Care Medicine, 3rd Faculty of Medicine, Charles University, University Hospital Kralovske Vinohrady, Prague, Czech Republic.