Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA.
Division of Anatomic Pathology, Mayo Clinic, Scottsdale, AZ, USA.
Mod Pathol. 2017 Oct;30(10):1422-1432. doi: 10.1038/modpathol.2017.61. Epub 2017 Jun 23.
A distinct subset of thoracic sarcomas with undifferentiated rhabdoid morphology and SMARCA4 inactivation has recently been described, and potential targeted therapy for SMARC-deficient tumors is emerging. We sought to validate the clinicopathological features of SMARCA4-deficient thoracic sarcomas. Clinicopathological information was gathered for 40 undifferentiated thoracic tumors with rhabdoid morphology (mediastinum (n=18), lung (n=14), pleura (n=8)). Thymic carcinomas (n=11) were used as a comparison group. Immunohistochemistry included BRG1 (SMARCA4), BRM (SMARCA2), INI-1 (SMARCB1), pan-cytokeratin, desmin, NUT, S-100 protein, TTF1, CD34, and SOX2. BRG1 loss was present in 12 of 40 rhabdoid thoracic tumors (30%): 7 of 18 in mediastinum (39%), 2 of 8 in pleura (25%), and 3 of 14 in lung (21%). All BRG1-deficient tumors tested for BRM (n=8) showed concomitant loss. All thymic carcinomas showed retained BRG1 and INI-1. Morphologically, tumors with BRG1 loss showed sheets of monotonous ovoid cells with indistinct cell borders, abundant eosinophilic cytoplasm, and prominent nucleoli. Scattered areas with rhabdoid morphology (ie, eccentric nuclei, dense eosinophilic cytoplasm, discohesion) were present in all the cases. SMARCA4/BRG1-deficient sarcomas showed rare cells positive for cytokeratin in 10 cases (83%). One showed rare TTF1-positive cells. All were negative for desmin, NUT, and S-100 protein. CD34 was positive in three of five (60%) BRG1-deficient tumors tested. SOX2 was positive in all four BRG1-deficient tumors tested, and negative in all seven tested cases with retained BRG1. SMARCA4/BRG1-deficient sarcomas occurred at median age of 59 years (range 44-76) with male predominance (9:3) and had worse 2-year survival compared with BRG1-retained tumors (12.5% vs 64.4%, P=0.02). SMARCA4-deficient thoracic sarcomas can be identified based on their distinctive high-grade rhabdoid morphology, and the diagnosis can be confirmed by immunohistochemistry. Identification of these tumors is clinically relevant due to their aggressive behavior, poor prognosis, and potential targeted therapy.
一种具有未分化横纹肌样形态和 SMARCA4 失活的独特胸肉瘤亚群最近被描述，并且针对 SMARC 缺陷肿瘤的潜在靶向治疗正在出现。我们试图验证 SMARCA4 缺陷性胸肉瘤的临床病理特征。为 40 例具有横纹肌样形态的未分化胸肿瘤（纵隔（n=18），肺（n=14），胸膜（n=8））收集临床病理信息。胸腺癌（n=11）用作比较组。免疫组化包括 BRG1（SMARCA4），BRM（SMARCA2），INI-1（SMARCB1），泛细胞角蛋白，结蛋白，NUT，S-100 蛋白，TTF1，CD34 和 SOX2。BRG1 缺失存在于 40 例横纹肌样胸肿瘤中的 12 例（30％）：纵隔 18 例中的 7 例（39％），胸膜 8 例中的 2 例（25％），肺 14 例中的 3 例（21％）。所有 BRG1 缺陷肿瘤均检测到 BRM（n=8），均显示同时缺失。所有胸腺癌均保留 BRG1 和 INI-1。形态上，BRG1 缺失的肿瘤表现为具有不明显细胞边界，丰富嗜酸性细胞质和明显核仁的单调卵圆形细胞片。所有病例均存在具有横纹肌样形态的散在区域（即偏心核，密集的嗜酸性细胞质，脱粘）。在 10 例（83％）SMARCA4/BRG1 缺陷肉瘤中罕见细胞阳性表达细胞角蛋白。一例罕见 TTF1 阳性细胞。所有均为结蛋白，NUT 和 S-100 蛋白阴性。CD34 在 5 例 BRG1 缺陷肿瘤中的 3 例（60％）阳性。SOX2 在所有 4 例 BRG1 缺陷肿瘤中均为阳性，而在 7 例保留 BRG1 的肿瘤中均为阴性。SMARCA4/BRG1 缺陷性胸肉瘤的中位年龄为 59 岁（范围 44-76），男性为主（9：3），与保留 BRG1 的肿瘤相比，2 年生存率更差（12.5％对 64.4％，P=0.02）。基于其独特的高级横纹肌样形态，可以识别 SMARCA4 缺陷性胸肉瘤，并且可以通过免疫组织化学来确认诊断。由于其侵袭性行为，不良预后和潜在的靶向治疗，这些肿瘤的鉴定具有临床意义。
