Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
Rare Cancer Center, National Cancer Center Hospital, Tokyo, Japan.
Mod Pathol. 2017 Jun;30(6):797-809. doi: 10.1038/modpathol.2017.11. Epub 2017 Mar 3.
A growing number of studies suggest critical tumor suppressor roles of the SWI/SNF chromatin remodeling complex in a variety of human cancers. The recent discovery of SMARCA4-deficient thoracic sarcomas has added to the list of tumor groups with the SMARCA4 inactivating mutation. To better characterize these tumors and establish their nosological status, we undertook a clinicopathological and molecular analysis of 12 SMARCA4-deficient thoracic sarcomas and compared them with three potentially related disease entities. Eleven men and one woman with SMARCA4-deficient thoracic sarcomas (aged 27-82 years, median 39 years) were included in the study. Most of the patients had heavy smoking exposure and pulmonary emphysema/bullae. The primary tumors were large and involved the thoracic region in all cases and simultaneously affected the abdominal cavity in 3 cases. The patients followed a rapid course, with a median survival of 7 months. Histologically, all tumors showed diffuse sheets of mildly dyscohesive, relatively monotonous, and undifferentiated epithelioid cells with prominent nucleoli. Immunohistochemically, all tumors demonstrated a complete absence (8 cases) or diffuse severe reduction (4 cases) of SMARCA4 expression. Cytokeratin, CD34, SOX2, SALL4, and p53 were expressed in 6/12, 10/12, 10/12, 10/12, and 7/10 cases, respectively. SMARCA2 expression was deficient in 11/12 cases, and none (0/8) expressed claudin-4. Targeted sequencing was performed in 5 cases and demonstrated the inactivating SMARCA4 mutation in each case and uncovered alterations in TP53 (5/5), NF1 (2/5), CDKN2A (2/5), KRAS (1/5), and KEAP1 (1/5), among others. Comparative analysis supported the distinctiveness of SMARCA4-deficient thoracic sarcomas as they were distinguishable from 13 malignant rhabdoid tumors, 15 epithelioid sarcomas, and 12 SMARCA4-deficient lung carcinomas based on clinicopathological and immunohistochemical grounds. SMARCA4-deficient thoracic sarcomas constitute a unique, highly lethal entity that requires full recognition and differentiation from other epithelioid malignancies involving the thoracic region.
越来越多的研究表明，SWI/SNF 染色质重塑复合物在多种人类癌症中具有重要的肿瘤抑制作用。最近发现的 SMARCA4 缺陷性胸肉瘤使具有 SMARCA4 失活突变的肿瘤群体增加。为了更好地描述这些肿瘤并确定其分类地位，我们对 12 例 SMARCA4 缺陷性胸肉瘤进行了临床病理和分子分析，并将其与三种可能相关的疾病实体进行了比较。纳入研究的 11 例男性和 1 例女性 SMARCA4 缺陷性胸肉瘤患者（年龄 27-82 岁，中位年龄 39 岁）。大多数患者有大量吸烟史和肺气肿/大疱。所有患者的原发肿瘤均较大，且均累及胸区，3 例同时累及腹腔。患者病程进展迅速，中位生存时间为 7 个月。组织学上，所有肿瘤均表现为弥漫性轻度黏附不良、相对单调、未分化的上皮样细胞，有明显的核仁。免疫组化染色显示，8 例完全缺失（8 例）或弥漫性严重减少（4 例）SMARCA4 表达。6/12 例肿瘤表达细胞角蛋白，10/12 例肿瘤表达 CD34，10/12 例肿瘤表达 SOX2，10/12 例肿瘤表达 SALL4，7/10 例肿瘤表达 p53。11/12 例肿瘤 SMARCA2 表达缺失，8/8 例肿瘤不表达 claudin-4。5 例进行了靶向测序，均显示每个病例存在失活的 SMARCA4 突变，并发现 TP53（5/5）、NF1（2/5）、CDKN2A（2/5）、KRAS（1/5）和 KEAP1（1/5）等基因的改变。比较分析支持 SMARCA4 缺陷性胸肉瘤的独特性，因为它们在临床病理和免疫组化基础上与 13 例恶性横纹肌样肿瘤、15 例上皮样肉瘤和 12 例 SMARCA4 缺陷性肺腺癌区分开来。SMARCA4 缺陷性胸肉瘤是一种独特的、高度致命的实体瘤，需要充分认识并与累及胸区的其他上皮样恶性肿瘤区分开来。
