Tissue Factor Expression in Penile Squamous Cell Carcinoma: A Potential Marker of HPV-Independent Disease

Background/Objectives: In a series of 33 patients with advanced penile squamous cell carcinoma (PSCC), we evaluated tissue factor (TF), TROP2, and nectin-4 protein expression as potential therapeutic targets. Expression levels of these proteins were also correlated to clinicopathological characteristics, including high-risk human papillomavirus (HPV), CDKN2A (p16) status, and aberrant p53 expression. Methods: A tissue microarray (TMA) was constructed with three cores per patient tumor (99 total cores). Anti-TF antibody staining was performed by immunohistochemistry, and H-scores for membrane and cytoplasm staining were assessed (range 0-300). The percentage of cores and patient tumors staining positive for TF (≥10% of tumor cells with at least 1+ intensity in cytoplasm and/or membrane) and H-scores were described and compared with HPV and p16 status. The association of TF expression with tumor grade, presence of metastatic disease, lymphovascular invasion (LVI), perineural invasion (PNI), aberrant p53 expression, recurrence-free survival (RFS), and cancer-specific survival (CSS) was assessed. Nectin-4 and TROP2 staining and their association with clinical/pathological data were determined in a similar manner. Results: TF staining was evident in 26 (81.3%) of the cohort and was more prominent in HPV-negative tumors in both the membrane (H-score 69.6 vs. 18.8; p = 0.003) and cytoplasm (H-score 59.2 vs. 17.7, p = 0.007). Cytoplasmic (H-score 61.7 vs. 11.7, p < 0.001) and membrane TF staining (H-score 71.7 vs. 15.0, p < 0.001) favored p16-negative tumors. The p53 status was more likely to be aberrant in the higher TF staining samples (cytoplasm H-score 61.7 vs. 18.3, p = 0.012; membrane H-score 67.5 vs. 20.3, p = 0.006). We observed an association with TROP2 staining and positive p16 status (membrane H-score 120.3 vs. 85, p = 0.052; cytoplasmic H-score 135 vs. 107.5, p = 0.041). We observed an association of TROP2 staining with positive LVI (membrane H-score 136.7 vs. 66.7, p = 0.014; cytoplasmic H-score 110 vs. 93.3, p = 0.04). We found no association between TF, TROP2, or nectin-4 staining with CSS or RFS; however, we suspect that this was due to our small sample size. Conclusions: Our results indicate that TF was expressed in the majority of advanced PSCC with enhanced expression among HPV-independent, p53-aberrant tumors and may represent a novel therapy target in advanced PSCC.