Bergonie Institute, Department of Pathology, Bordeaux, France.
Hospices civils de Lyon, Groupement Hospitalier Est, Department of Pathology, Lyon, France.
Am J Surg Pathol. 2019 Apr;43(4):455-465. doi: 10.1097/PAS.0000000000001188.
SMARCA4-deficient thoracic sarcoma (SMARCA4-DTS) is a recently described entity with an aggressive clinical course and specific genetic alterations of the BAF chromatin remodeling complex. In the present study, we reviewed the clinical and pathologic features of 30 cases of SMARCA4-DTS, discussed its main differential diagnoses and the challenging diagnostic scenarios that the average pathologist may face. In addition, we tested the specificity of the "SMARCA4-DTS immunohistochemical signature" (co-loss of SMARCA4 and SMARCA2 with overexpression of SOX2) in a large cohort of intrathoracic malignancies. Patients ranged from 28 to 90 years of age (median: 48 y), with a marked male predominance (male:female=9:1) and they were usually smokers. Tumors were generally large compressive masses located in the mediastinum (n=13), pleura (n=5), lung (n=2) or in 2 or more of these topographies (n=10). Treatment strategies were varied, including 1 case treated with EZH2 inhibitors. Median overall survival was 6 months. Histologically, tumors were poorly differentiated frequently showing rhabdoid features. A subset of cases showed a focal myxoid stroma (7%, n=2/30) and rare cases displayed a previously unreported pattern simulating desmoplastic small round cell tumors (7%, n=2/30). Making a diagnosis was challenging when dealing with biopsy material from massively necrotic tumors and in this setting the expression of SOX2, CD34, and SALL4 proved useful. All tested cases displayed concomitant loss of SMARCA4 and SMARCA2 and most tumors expressed epithelial markers (Pan-keratin or EMA) (n=29/30), SOX2 (n=26/27), and CD34 (n=17/27). SMARCB1 expression was retained in all cases (23/23). SALL4 and Claudin-4 were expressed in a subset of cases (n=7/21 and 2/19, respectively). TTF-1 and P63 were focally expressed in 1 case each. P40 and NUT were not expressed (0/23 and 0/20, respectively) The SMARCA4-DTS immunohistochemical signature was both sensitive and specific, with only a subset of small cell carcinoma of the ovary hypercalcemic type showing overlapping phenotypes. Our study confirms and expands the specific features of SMARCA4-DTS, emphasizing the fact that they can be straightforwardly identified by pathologists.
SMARCA4 缺陷性胸肉瘤（SMARCA4-DTS）是一种最近描述的实体瘤，具有侵袭性的临床病程和特定的 BAF 染色质重塑复合物的基因改变。在本研究中，我们回顾了 30 例 SMARCA4-DTS 的临床和病理特征，讨论了其主要的鉴别诊断和普通病理学家可能面临的具有挑战性的诊断情况。此外，我们还在一组大型的胸内恶性肿瘤中测试了“SMARCA4-DTS 免疫组织化学特征”（SMARCA4 和 SMARCA2 共同缺失，SOX2 过表达）的特异性。患者年龄 28-90 岁（中位年龄：48 岁），男性明显多于女性（男性：女性=9:1），且多为吸烟者。肿瘤通常是位于纵隔（n=13）、胸膜（n=5）、肺（n=2）或 2 个以上这些部位的大的压迫性肿块（n=10）。治疗策略多种多样，包括 1 例接受 EZH2 抑制剂治疗。中位总生存期为 6 个月。组织学上，肿瘤通常分化差，常表现出横纹肌样特征。一部分病例显示局灶性黏液样基质（7%，n=2/30），少数病例显示一种以前未报道的模拟促结缔组织增生小圆细胞肿瘤的模式（7%，n=2/30）。在处理大量坏死性肿瘤的活检材料时，做出诊断具有挑战性，在此情况下，SOX2、CD34 和 SALL4 的表达证明是有用的。所有测试的病例均显示同时缺失 SMARCA4 和 SMARCA2，并且大多数肿瘤表达上皮标志物（Pan-keratin 或 EMA）（n=29/30）、SOX2（n=26/27）和 CD34（n=17/27）。所有病例均保留 SMARCB1 表达（n=23/23）。SALL4 和 Claudin-4 在一部分病例中表达（n=7/21 和 2/19）。TTF-1 和 P63 分别在 1 例中局灶性表达。P40 和 NUT 不表达（0/23 和 0/20）。SMARCA4-DTS 免疫组织化学特征既敏感又特异，仅有一小部分卵巢小细胞癌伴高钙血症型表现出重叠表型。我们的研究证实并扩展了 SMARCA4-DTS 的特定特征，强调了病理学家可以直接识别它们的事实。
