Int J Gynecol Pathol. 2021 Mar 1;40(2):148-155. doi: 10.1097/PGP.0000000000000682.
Ovarian clear cell carcinoma (OCCC) is an aggressive chemotherapy-resistant cancer with limited treatment options, and some OCCCs have mismatch repair (MMR) deficiency (MMRD). Emerging evidence has revealed that various cancers with MMRD are susceptible to anti-programmed death-1/programmed death ligand-1 (anti-PD-1/PD-L1) immunotherapy, and certain histologic features are associated with MMRD. However, few studies have addressed this in OCCC. We reviewed 76 OCCCs for tumor-associated inflammation (intratumoral stromal inflammation and peritumoral lymphocytes) and performed immunohistochemistry for 4 MMR proteins and PD-L1. MMR-deficient OCCCs were analyzed for microsatellite instability (MSI), and those with MLH1 loss were tested for MLH1 promoter methylation. No patients fulfilled the Amsterdam II criteria for the diagnosis of Lynch syndrome. Four (5.3%) tumors showed diffuse intratumoral stromal inflammation obliterating the tumor-stroma interfaces, and none had peritumoral lymphoid aggregates. MMRD was found in 2 (2.6%) tumors; one had MLH1/PMS2 loss (MSI-high and MLH1 promoter methylation was detected) and the other had MSH2/MSH6 loss (MSI-low). Twenty (26.3%) tumors showed tumoral PD-L1 expression ≥1%. Both MMR-deficient tumors showed diffuse intratumoral stromal inflammation and tumoral PD-L1 expression ≥50%. Three of the 4 (75%) tumors with diffuse intratumoral stromal inflammation also showed tumoral PD-L1 expression ≥50%. None of the tumors without diffuse intratumoral stromal inflammation showed MMRD (P=0.021) or tumoral PD-L1 expression ≥50% (P=0.0001). We identified a strong correlation among diffuse intratumoral stromal inflammation, MMRD, and high tumoral PD-L1 expression in a small but significant subset of OCCCs. Histologic evaluation can facilitate patient selection for subsequent anti-PD-1/PD-L1 immunotherapy.
卵巢透明细胞癌（OCCC）是一种侵袭性、化疗耐药的癌症，治疗选择有限，部分 OCCC 存在错配修复（MMR）缺陷（MMRD）。新出现的证据表明，各种存在 MMRD 的癌症易受抗程序性死亡-1/程序性死亡配体-1（抗 PD-1/PD-L1）免疫治疗的影响，并且某些组织学特征与 MMRD 相关。然而，在 OCCC 中很少有研究涉及这一点。我们回顾了 76 例 OCCC 的肿瘤相关炎症（肿瘤内间质炎症和肿瘤周围淋巴细胞），并对 4 种 MMR 蛋白和 PD-L1 进行了免疫组化染色。对 MMR 缺陷的 OCCC 进行微卫星不稳定性（MSI）分析，对 MLH1 缺失的病例进行 MLH1 启动子甲基化检测。没有患者符合林奇综合征的阿姆斯特丹 II 标准诊断。4 例（5.3%）肿瘤显示弥漫性肿瘤内间质炎症，破坏肿瘤-间质界面，均无肿瘤周围淋巴细胞聚集。发现 2 例（2.6%）肿瘤存在 MMRD；1 例 MLH1/PMS2 缺失（MSI-高，检测到 MLH1 启动子甲基化），另 1 例 MSH2/MSH6 缺失（MSI-低）。20 例（26.3%）肿瘤表现为肿瘤 PD-L1 表达≥1%。2 例 MMR 缺陷肿瘤均显示弥漫性肿瘤内间质炎症和肿瘤 PD-L1 表达≥50%。4 例弥漫性肿瘤内间质炎症的肿瘤中有 3 例（75%）肿瘤 PD-L1 表达≥50%。无弥漫性肿瘤内间质炎症的肿瘤均未出现 MMRD（P=0.021）或肿瘤 PD-L1 表达≥50%（P=0.0001）。在一小部分具有显著意义的 OCCC 中，我们发现弥漫性肿瘤内间质炎症、MMRD 和肿瘤 PD-L1 高表达之间存在很强的相关性。组织学评估有助于选择随后进行抗 PD-1/PD-L1 免疫治疗的患者。
