Department of Pathology, The University of Hong Kong, Hong Kong SAR, China.
Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong SAR, China.
Mod Pathol. 2020 Jan;33(1):138-152. doi: 10.1038/s41379-019-0345-2. Epub 2019 Aug 5.
Female genital melanomas are rare. At diagnosis, most affected patients have advanced disease. Surgery remains the primary treatment, and adjuvant therapy is largely ineffective. Recently, immune checkpoints and the mitogen-activated protein kinase pathway have been explored as treatment targets. However, evaluation of these biomarkers in genital melanomas is limited. We evaluated the clinicopathological features of 20 vulvar, 32 vaginal, and three cervical melanomas and assessed programmed cell death ligand 1 (PD-L1) expression, CD8 tumor-infiltrating lymphocyte density, mismatch repair proteins, VE1 immunohistochemistry, and KIT and BRAF mutations. The median age of the patients was 66 years, and median tumor sizes were 25, 30, and 20 mm for vulvar, vaginal, and cervical tumors, respectively. Mean mitotic figures were 18, 19, and 30 per mm. Thirty-seven patients (67%) had operable tumors. After a median follow-up of 15 months, only nine patients (16%) were alive. Eight of the nine survivors did not have lymph node metastasis. Using 5% as the threshold, PD-L1 expression was observed in 55%, 50%, and 33% of vulvar, vaginal, and cervical tumors, respectively, when the Roche SP263 antibody was used and 20%, 53%, and 0%, respectively, when the Dako 28-8 antibody was used. The median CD8 tumor-infiltrating lymphocyte density was significantly higher in vulvar/vaginal than cervical melanomas and correlated with PD-L1 expression. No cases exhibited loss of mismatch repair proteins. Five cases harbored KIT mutations, three of which were hotspots. BRAF V600E mutation was not detected. Univariable analysis showed that tumor size greater than or equal to 33 mm, mitotic figures of greater than or equal to 10 per mm, lymph node metastasis, and low CD8+ tumor-infiltrating lymphocyte density were adverse prognostic factors. Thus, patients with genital melanomas have a poor prognosis, and evaluation of multiple biomarkers is necessary to identify patients who may benefit from immunotherapy or targeted therapy.
女性生殖器黑色素瘤较为罕见。在诊断时，大多数受影响的患者已处于疾病晚期。手术仍是主要的治疗方法，而辅助治疗效果往往不佳。近年来，免疫检查点和丝裂原活化蛋白激酶途径已被探索作为治疗靶点。然而，这些生物标志物在生殖器黑色素瘤中的评估有限。我们评估了 20 例外阴、32 例阴道和 3 例宫颈黑色素瘤的临床病理特征，并评估了程序性细胞死亡配体 1（PD-L1）表达、CD8 肿瘤浸润淋巴细胞密度、错配修复蛋白、VE1 免疫组化以及 KIT 和 BRAF 突变。患者的中位年龄为 66 岁，外阴、阴道和宫颈肿瘤的中位肿瘤大小分别为 25、30 和 20mm。平均有丝分裂数分别为 18、19 和 30 个/mm。37 例（67%）患者的肿瘤具有可操作性。中位随访 15 个月后，仅 9 例（16%）患者存活。9 例存活者中，8 例无淋巴结转移。当使用罗氏 SP263 抗体时，PD-L1 表达分别在 55%、50%和 33%的外阴、阴道和宫颈肿瘤中观察到，而当使用 Dako 28-8 抗体时，PD-L1 表达分别在 20%、53%和 0%的外阴、阴道和宫颈肿瘤中观察到。CD8 肿瘤浸润淋巴细胞密度在外阴/阴道黑色素瘤中明显高于宫颈黑色素瘤，且与 PD-L1 表达相关。无病例显示错配修复蛋白缺失。5 例存在 KIT 突变，其中 3 例为热点突变。未检测到 BRAF V600E 突变。单变量分析显示，肿瘤大小≥33mm、有丝分裂数≥10 个/mm、淋巴结转移和低 CD8+肿瘤浸润淋巴细胞密度是不良预后因素。因此，生殖器黑色素瘤患者预后较差，需要评估多种生物标志物，以确定可能受益于免疫治疗或靶向治疗的患者。
