Tahara Shinichiro, Kohara Masaharu, Sato Kazuaki, Morii Eiichi
Department of Pathology, Osaka University Graduate School of Medicine, Suita, 565-0871, Japan.
Department of Pathology, Osaka University Graduate School of Medicine, Suita, 565-0871, Japan.
Pathol Res Pract. 2022 Jan;229:153699. doi: 10.1016/j.prp.2021.153699. Epub 2021 Nov 20.
Endometrioid carcinoma (EC) is classified into 3 histological subtypes; Grade 1 (G1), Grade 2 (G2), and Grade 3 (G3). Although the prognosis is relatively good in G1, some G1 cases are more aggressive, which are called G1 with MELF (microcystic, elongated, and fragmented) pattern. Current therapy, such as radiotherapy and chemotherapy, is not effective in MELF, and more effective treatment is needed. The Cancer Genome Atlas (TCGA) performed an integrated genomic, transcriptomic, and proteomic analysis and classified EC into 4 groups: DNA polymerase epsilon (POLE) ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high, in which MELF was associated with microsatellite instability hypermutated. Microsatellite instability is detected in a wide variety of cancer, and PD-1 (programmed cell death 1) and PD-L1 (programmed cell death-ligand 1) are received a lot of attention as a therapeutic target. To date, no studies have been focused on PD-L1 expression in EC with MELF pattern. Then we performed immunohistochemical analysis of the distribution of PD-L1 expressing cells in G1 with MELF pattern. In cases of G1 with MELF pattern, tumor cells expressed PD-L1 significantly higher in invasive front area than in surface area. We often found lymphovascular invasion of PD-L1 expressing tumor cells. PD-L1 expressing tumor cells in MELF would be the cause of recurrence or lymph node metastasis. Moreover, in most G1 cases with MELF pattern, PD-L1 was expressed in inflammatory cells as well as tumor cells in invasive front area. PD-L1 expression in both tumor and immune cells contribute to immune suppression and both cells could be sensitive to therapeutic agents targeting the PD-L1/PD-1 axis. Therefore, significant therapeutic effect can be expected by applying PD-1/PD-L1 immunotherapy to the treatment of G1 with MELF.
子宫内膜样癌（EC）分为3种组织学亚型：1级（G1）、2级（G2）和3级（G3）。虽然G1的预后相对较好，但一些G1病例更具侵袭性，这些被称为具有微囊状、拉长状和破碎状（MELF）模式的G1。目前的治疗方法，如放疗和化疗，对MELF无效，需要更有效的治疗。癌症基因组图谱（TCGA）进行了综合基因组、转录组和蛋白质组分析，并将EC分为4组：DNA聚合酶ε（POLE）超突变型、微卫星不稳定性高突变型、拷贝数低型和拷贝数高型，其中MELF与微卫星不稳定性高突变型相关。微卫星不稳定性在多种癌症中都有检测到，程序性死亡蛋白1（PD-1）和程序性死亡配体1（PD-L1）作为治疗靶点受到了广泛关注。迄今为止，尚未有研究聚焦于具有MELF模式的EC中PD-L1的表达。然后我们对具有MELF模式的G1中表达PD-L1的细胞分布进行了免疫组化分析。在具有MELF模式的G1病例中，肿瘤细胞在浸润前沿区域的PD-L1表达明显高于表面区域。我们经常发现表达PD-L1的肿瘤细胞发生淋巴血管浸润。MELF中表达PD-L1的肿瘤细胞可能是复发或淋巴结转移的原因。此外，在大多数具有MELF模式的G1病例中，浸润前沿区域的炎症细胞以及肿瘤细胞中都表达了PD-L1。肿瘤细胞和免疫细胞中的PD-L1表达都有助于免疫抑制，并且这两种细胞可能对靶向PD-L1/PD-1轴的治疗药物敏感。因此，可以预期通过应用PD-1/PD-L1免疫疗法治疗具有MELF模式的G1会有显著的治疗效果。
