de Freitas Daniela, Aguiar Fernando Nalesso, Anton Cristina, de Almeida Danielle Cristina, Bacchi Carlos Eduardo, Carvalho Jesus Paula, Carvalho Filomena Marino
Instituto do Cancer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo, 251, ZIP code 01246-000, Sao Paulo, SP, Brazil.
Department of Pathology, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo, 455, room 1465, ZIP code 01246-903, Sao Paulo, SP, Brazil.
Heliyon. 2023 Jun 22;9(6):e17495. doi: 10.1016/j.heliyon.2023.e17495. eCollection 2023 Jun.
DNA mismatch repair protein deficiency (MMRd) in endometrial carcinoma is associated with the risk of Lynch syndrome and response to immune checkpoint inhibitors. It is also related to microsatellite instability and corresponds to a molecular subtype of endometrial tumor with an unclear prognosis. Here, we evaluated the clinicopathological characteristics and prognosis of 312 consecutive endometrial carcinoma cases submitted to complete surgical staging at a single institution. We compared MMRd and mismatch repair protein-proficient (MMRp) tumors and examined the effects of the MMR protein loss type (MLH1/PMS2 vs. MSH2/MSH6) and influence of L1CAM and p53 expression. The median follow-up period was 54.5 (range, 0-120.5) months. No difference was observed between MMRd [ = 166 (37.2%)] and MMRp [ = 196 (62.8%)] cases in terms of age, body mass index, FIGO stage, tumor grade, tumor size, depth of myometrial infiltration, or lymph node metastasis. More MMRd than MMRp tumors had endometrioid histology (87.9% vs. 75.5%) and despite MMRd had more lymphovascular space invasion (LVSI; 27.2% vs. 16.9%), they presented fewer recurrences and no difference in lymph node metastasis and disease-related death. Relative to those with MLH1/MSH6 loss, tumors with MSH2/MSH6 loss were diagnosed at earlier FIGO stages, were smaller, and had less ≥50% myometrial invasion, LVSI and lymph node metastasis. Outcomes, however, did not differ between these groups. L1CAM positivity and mutation-type p53 expression were more common in MMRp than in MMRd tumors and did not differ between the MLH1/PMS2 and MSH2/MSH6 loss groups. In the entire cohort, L1CAM and mutation p53 expression were associated with worse prognosis, but only non-endometrioid histology, FIGO stage III/IV, and deep myometrial infiltration were significant predictors. In the subgroup of endometrioid carcinomas, only FIGO stage III/IV was associated with poor outcomes. The risk of lymph node metastasis was associated with tumor size, non-endometrioid histology, and multifocal LVSI. For MMRd tumors, only tumor size and myometrial invasion depth were predictive of lymph node involvement. In our cohort, MMRd tumors were associated with greater recurrence-free, but not overall, survival. The precise identification of MMRd status, present in a substantial proportion of endometrial cancer cases, is a challenge to be overcome for proper patient management. MMRd status serves as a marker for Lynch syndrome, and a significant number of these tumors are high risk and candidate to immunotherapy.
子宫内膜癌中的DNA错配修复蛋白缺陷（MMRd）与林奇综合征风险及免疫检查点抑制剂反应相关。它还与微卫星不稳定性有关，对应于预后不明的子宫内膜肿瘤分子亚型。在此，我们评估了在单一机构接受完整手术分期的312例连续子宫内膜癌病例的临床病理特征和预后。我们比较了MMRd和错配修复蛋白 proficient（MMRp）肿瘤，并研究了MMR蛋白缺失类型（MLH1/PMS2与MSH2/MSH6）的影响以及L1CAM和p53表达的影响。中位随访期为54.5（范围0 - 120.5）个月。在年龄、体重指数、国际妇产科联盟（FIGO）分期、肿瘤分级、肿瘤大小、肌层浸润深度或淋巴结转移方面，MMRd组[ = 166例（37.2%）]和MMRp组[ = 196例（62.8%）]之间未观察到差异。MMRd肿瘤比MMRp肿瘤具有更多的子宫内膜样组织学类型（87.9%对75.5%），尽管MMRd有更多的淋巴管间隙浸润（LVSI；27.2%对16.9%），但它们的复发较少，且在淋巴结转移和疾病相关死亡方面无差异。相对于MLH1/MSH6缺失的肿瘤，MSH2/MSH6缺失的肿瘤在较早的FIGO分期被诊断出来，体积较小，且≥50%肌层浸润、LVSI和淋巴结转移较少。然而，这些组之间的结局并无差异。L1CAM阳性和突变型p53表达在MMRp肿瘤中比在MMRd肿瘤中更常见，且在MLH1/PMS2和MSH2/MSH6缺失组之间无差异。在整个队列中，L1CAM和突变型p53表达与较差的预后相关，但只有非子宫内膜样组织学、FIGO III/IV期和深层肌层浸润是显著的预测因素。在子宫内膜样癌亚组中，只有FIGO III/IV期与不良结局相关。淋巴结转移风险与肿瘤大小、非子宫内膜样组织学和多灶性LVSI相关。对于MMRd肿瘤，只有肿瘤大小和肌层浸润深度可预测淋巴结受累情况。在我们的队列中，MMRd肿瘤与更高的无复发生存率相关，但与总生存率无关。准确识别大量子宫内膜癌病例中存在的MMRd状态是患者合理管理中有待克服的一项挑战。MMRd状态是林奇综合征的一个标志物，并且这些肿瘤中有相当数量是高危的且是免疫治疗的候选对象。
