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

In a series of 33-patients, we evaluated tissue factor (TF) expression in penile squamous cell carcinoma (PSCC). A tissue microarray (TMA) was constructed with 3 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). 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. 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) were assessed. Nectin-4 and TROP2 staining and their association with clinical/pathological data was determined in a similar manner. TF staining 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 is due to our small sample size. Our results indicate that TF expression could be positive biomarker for HPV-independent, p53-aberrant PSCC, while TROP2 could be associated with HPV-associated PSCC.