Department of Pathology & Immunology, Washington University at St. Louis School of Medicine, St. Louis, MO, 63110, USA.
Department of Pathology & Immunology, Washington University at St. Louis School of Medicine, St. Louis, MO, 63110, USA.
Hum Pathol. 2020 Jun;100:15-23. doi: 10.1016/j.humpath.2020.04.007. Epub 2020 May 5.
Synovial sarcoma (SS) is a soft-tissue malignancy that most often affects patients aged between 15 and 40 years, and the prognosis for patients with metastatic disease is generally poor. This study was performed to evaluate checkpoint blockade immunotherapy markers in SS, including tumor mutational burden (TMB), DNA mismatch repair (MMR) status, and PDL-1 (programmed cell death ligand 1), PD1 (programmed cell death 1), and CD8 expression by normal-tumor paired whole-exome sequencing (WES) and immunohistochemistry (IHC). Outcomes evaluated included event-free and overall survival. Twenty one (21) FISH (Fluorescence In Situ Hybridization)-confirmed SS cases (11 F, 10 M) were studied, with age ranging from 8 to 89 years at diagnosis and follow-up ranging from 1 to 16 years. TMB (n = 16) ranged from 0.83 to 212/Mb (median, 1.7). Only one case showed a high TMB of 212/Mb and missense variants of MMR genes in the primary tumor, while the other 15 cases had a low TMB of less than 5/Mb. IHC was performed on all 21 tumor samples for PD-L1, PD1, CD8, and MMR proteins. PD-L1 membranous staining was detected in 3 of 21 cases (14.3%), ranging from 1 to 5% for tumor proportion score and 1-10 for combined positive score. PD1 was detected in 15 of 21 cases (71.4%), ranging from 1 to 25/HPF (high power field) (median, 2). CD8 stain was seen in all cases, ranging from 2 to 60/HPF (median, 5). PD1 staining results correlated with CD8 staining results (P < 0.0001). No correlation of TMB or IHC markers was found with survival. No fixed pattern of TMB or IHCs between primary and metastatic tumors was observed; there was no correlation between TMB or IHCs and age, location, or diagnosis subtype. All of the cases tested showed retained expression of MMR proteins. The results show that for SS, a tumor with strong driver translocation, most cases have a low TMB, but occasionally a high TMB may be present, as observed in 1 of the 16 (6.25%) cases. The demonstration of a subgroup of SS cases with high TMB might explain the 10% response rate to checkpoint immunotherapy observed in clinical trials in patients with SS.
滑膜肉瘤（SS）是一种软组织恶性肿瘤，最常影响 15 至 40 岁之间的患者，而转移性疾病患者的预后通常较差。本研究旨在评估 SS 中的检查点阻断免疫治疗标志物，包括肿瘤突变负担（TMB）、DNA 错配修复（MMR）状态以及通过正常肿瘤配对全外显子测序（WES）和免疫组织化学（IHC）检测的程序性细胞死亡配体 1（PDL-1）、程序性细胞死亡 1（PD1）和 CD8 表达。评估的结果包括无事件生存和总生存。研究了 21 例经 FISH（荧光原位杂交）证实的 SS 病例（11 例女性，10 例男性），诊断时年龄为 8 至 89 岁，随访时间为 1 至 16 年。TMB（n=16）范围为 0.83 至 212/Mb（中位数为 1.7）。只有 1 例原发性肿瘤中显示 TMB 高（212/Mb）且 MMR 基因有意义变异，而其他 15 例 TMB 低（小于 5/Mb）。对所有 21 例肿瘤样本进行了 PD-L1、PD1、CD8 和 MMR 蛋白的 IHC 检测。在 21 例病例中有 3 例（14.3%）检测到 PD-L1 膜染色，肿瘤比例评分范围为 1 至 5%，联合阳性评分范围为 1-10。在 21 例中有 15 例（71.4%）检测到 PD1，范围为 1 至 25/HPF（高倍视野）（中位数，2）。所有病例均可见 CD8 染色，范围为 2 至 60/HPF（中位数，5）。PD1 染色结果与 CD8 染色结果相关（P<0.0001）。TMB 或 IHC 标志物与生存无相关性。在原发性和转移性肿瘤之间未观察到 TMB 或 IHC 之间存在固定模式；TMB 或 IHC 与年龄、位置或诊断亚型之间无相关性。所有检测的病例均显示 MMR 蛋白表达保留。结果表明，对于具有强烈驱动易位的 SS，大多数病例的 TMB 较低，但偶尔可能存在高 TMB，如 16 例中的 1 例（6.25%）。SS 亚组病例中高 TMB 的存在可能解释了临床试验中观察到的 SS 患者对检查点免疫治疗的 10%反应率。
