Ricci Costantino, Ambrosi Francesca, Franceschini Tania, Grillini Alessia, Franchini Eugenia, Vasuri Francesco, Orsatti Agnese, Di Sciascio Luisa, Massari Francesco, Mollica Veronica, Marchetti Andrea, Bianchi Federico Mineo, Colecchia Maurizio, Acosta Andres Martin, Lobo João, Fiorentino Michelangelo
Pathology Unit, DIAP-Dipartimento Interaziendale Anatomia Patologica, Maggiore Hospital-AUSL Bologna, Bologna, Italy.
Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy.
Virchows Arch. 2025 Sep 11. doi: 10.1007/s00428-025-04243-x.
A subset of germ cell tumors of the testis (GCTT) shows an aggressive clinical behavior, with chemo-resistance, metastases, and recurrences. Recently, enfortumab vedotin (EV), an antibody-drug conjugate (ADC) targeting Nectin-4, has been shown to improve the survival in urothelial carcinoma and has been approved for the locally advanced or metastatic cases. We stained for Nectin-4 (EPR15613-68 rb, Abcam) 46 cases (42 chemo-naive primary testicular tumors and 4 post-chemotherapy metastatic recurrences) and adopted the H-score and the specific Nectin-4 score (negative (H-score 0-14), weak (H-score 15-99), moderate (H-score 100-199), and strong (H-score 200-300)) for both the cytoplasm and the membrane. The expression of Nectin-4 was compared between different histotypes by adopting the specific Nectin-4 score and Fisher's exact test. Nectin-4 membrane expression was positive in 14/89 (15.7%) GCTT components, with median H-score of 0 (range 0-120; IQR 0-10). Choriocarcinoma (CHC) (median H-score 29 (range 20-40, IQR 21.25-38.25)) and isolated syncytiotrophoblast cells (iSTCs) [median H-score 65 (range 0-90; IQR 10-147.5)) showed statistically significant higher Nectin-4 membrane expression than the other GCTT components (p < 0.001), with staining mostly observed in syncytiotrophoblasts in CHC and thus mirroring what found in "normal" syncytiotrophoblasts of placental tissue (adopted as positive control). Additionally, 2/4 (50%) post-chemotherapy metastatic recurrences (one Tpt and one YSTpt) and 3/25 (12%) EC showed positive weak Nectin-4 membrane expression. To summarize, our study reveals that only a small minority of GCTT exhibit positive weak Nectin-4 membrane expression. However, a subgroup of potentially aggressive GCTT (especially CHC and post-chemotherapy metastatic recurrences) more frequently exhibits Nectin-4 membrane expression, thus prompting future studies to assess whether these patients may be potentially eligible for EV therapy.
睾丸生殖细胞肿瘤（GCTT）的一个亚组表现出侵袭性的临床行为，具有化疗耐药、转移和复发的特点。最近，恩杂鲁胺（EV），一种靶向Nectin-4的抗体药物偶联物（ADC），已被证明可提高尿路上皮癌的生存率，并已被批准用于局部晚期或转移性病例。我们对46例病例（42例未经化疗的原发性睾丸肿瘤和4例化疗后转移性复发肿瘤）进行了Nectin-4（EPR15613-68 rb，Abcam）染色，并对细胞质和细胞膜采用H评分和特定的Nectin-4评分（阴性（H评分0-14）、弱阳性（H评分15-99）、中度阳性（H评分100-199）和强阳性（H评分200-300））。通过采用特定的Nectin-4评分和Fisher精确检验比较不同组织学类型之间Nectin-4的表达。在89个GCTT成分中，14个（15.7%）的Nectin-4膜表达呈阳性，H评分中位数为0（范围0-120；四分位距0-10）。绒毛膜癌（CHC）（H评分中位数29（范围20-40，四分位距21.25-38.25））和孤立的合体滋养层细胞（iSTC）[H评分中位数65（范围0-90；四分位距10-147.5）]的Nectin-4膜表达在统计学上显著高于其他GCTT成分（p<0.001），染色主要见于CHC的合体滋养层细胞，因此与胎盘组织“正常”合体滋养层细胞中发现的情况一致（用作阳性对照）。此外，2/4（50%）化疗后转移性复发肿瘤（1例卵黄囊瘤和1例卵黄囊瘤型绒毛膜癌）和3/25（12%）的胚胎性癌显示Nectin-4膜表达呈弱阳性。总之，我们的研究表明，只有一小部分GCTT表现出Nectin-4膜弱阳性表达。然而，一组潜在侵袭性的GCTT（特别是CHC和化疗后转移性复发肿瘤）更频繁地表现出Nectin-4膜表达，因此促使未来的研究评估这些患者是否可能有资格接受EV治疗。
