Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.
Division of Cancer Immunology, Research Institute/Exploratory Oncology Research & Clinical Trial Center, National Cancer Center East, Chiba, Japan.
Mod Pathol. 2020 Sep;33(9):1660-1668. doi: 10.1038/s41379-020-0530-3. Epub 2020 Apr 1.
Synovial sarcoma (SS) is an aggressive tumor that most often affects the deep soft tissues in young adults. Intrathoracic SS is rare and is associated with poor outcome, highlighting the urgent need for a novel therapeutic strategy. In the process of clinical sequencing, we identified two patients with intrathoracic SS harboring the BRAF V600E mutation. The patients were women aged 32 and 23 years, and both presented with SS18-SSX2-positive monophasic SS in the thoracic cavity. BRAF V600E mutations were detected by next generation sequencing, and validated immunohistochemically by diffuse intense positivity to BRAF V600E mutation-specific antibodies. The phosphorylated ERK (pERK) immunohistochemistry result was also positive. One patient received a combination therapy of dabrafenib and trametinib, which led to tumor shrinkage. However, the tumor growth progressed 7.5 months later with an additional NRAS Q61K mutation. Immunohistochemical screening of 67 archival SS tumor samples failed to identify additional samples with BRAF V600E mutation. However, 32% of BRAF V600E-negative cases was positive for pERK, and one of the six tumors showing the highest pERK expression harbored an FGFR2-activating mutation. This is the first report of targetable BRAF mutation in a small subset of SS. Our study suggests involvement of the mitogen-activated protein kinase pathway and the potential clinical implication of BRAF mutation screening in SS.
滑膜肉瘤（SS）是一种侵袭性肿瘤，主要发生于年轻人的深部软组织。胸内 SS 较为罕见，预后较差，这突显了对新型治疗策略的迫切需求。在临床测序过程中，我们发现了两名胸内 SS 患者存在 BRAF V600E 突变。两名患者均为女性，年龄分别为 32 岁和 23 岁，均表现为胸内 SS18-SSX2 阳性单相 SS。通过下一代测序检测到 BRAF V600E 突变，并通过 BRAF V600E 突变特异性抗体弥漫强阳性进行免疫组织化学验证。磷酸化 ERK（pERK）免疫组化结果也是阳性的。一名患者接受了 dabrafenib 和 trametinib 的联合治疗，导致肿瘤缩小。然而，7.5 个月后肿瘤生长进展，并出现了额外的 NRAS Q61K 突变。对 67 例存档 SS 肿瘤样本进行免疫组化筛选未能发现其他 BRAF V600E 突变的样本。然而，32%的 BRAF V600E 阴性病例 pERK 阳性，在表达 pERK 最高的 6 例肿瘤中，有 1 例存在 FGFR2 激活突变。这是 SS 中存在可靶向 BRAF 突变的首例报告。我们的研究提示了丝裂原活化蛋白激酶途径的参与，以及 BRAF 突变筛查在 SS 中的潜在临床意义。
