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.
背景/目的：在一组33例晚期阴茎鳞状细胞癌（PSCC）患者中，我们评估了组织因子（TF）、TROP2和nectin-4蛋白表达作为潜在治疗靶点的价值。这些蛋白的表达水平还与临床病理特征相关联，包括高危型人乳头瘤病毒（HPV）、CDKN2A（p16）状态以及异常p53表达。方法：构建了组织微阵列（TMA），每例患者肿瘤取三个核心（共99个核心）。通过免疫组织化学进行抗TF抗体染色，评估膜和细胞质染色的H评分（范围0-300）。描述TF阳性染色（≥10%的肿瘤细胞在细胞质和/或膜上染色强度≥1+）的核心和患者肿瘤百分比及H评分，并与HPV和p16状态进行比较。评估了TF表达与肿瘤分级、转移性疾病的存在、淋巴血管侵犯（LVI）、神经周围侵犯（PNI）、异常p53表达、无复发生存期（RFS）和癌症特异性生存期（CSS）的关联。以类似方式确定了nectin-4和TROP2染色及其与临床/病理数据的关联。结果：该队列中26例（81.3%）患者显示明显的TF染色，且在HPV阴性肿瘤中，膜（H评分69.6 vs. 18.8；p=0.003）和细胞质（H评分59.2 vs. 17.7；p=0.007）的TF表达更为显著。细胞质（H评分61.7 vs. 11.7；p<0.001）和膜TF染色（H评分71.7 vs. 15.0；p<0.001）在p16阴性肿瘤中更明显。在TF染色较高的样本中，p53状态更可能异常（细胞质H评分61.7 vs. 18.3，p=0.012；膜H评分67.5 vs. 20.3，p=0.006）。我们观察到TROP2染色与p16阳性状态相关（膜H评分120.3 vs. 85，p=0.052；细胞质H评分135 vs. 107.5，p=0.041）。我们还观察到TROP2染色与LVI阳性相关（膜H评分136.7 vs. 66.7，p=0.014；细胞质H评分110 vs. 93.3，p=0.04）。我们发现TF、TROP2或nectin-4染色与CSS或RFS之间没有关联；然而，我们怀疑这是由于我们的样本量较小所致。结论：我们的结果表明，TF在大多数晚期PSCC中表达，且在HPV非依赖性、p53异常肿瘤中表达增强，可能代表晚期PSCC的一个新治疗靶点。
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