SMARCA4-Deficient Thoracic Sarcoma: A Case Report and Review of Literature

Abstract

SMARCA4-deficient thoracic sarcoma (SMARCA4-DTS) is a recently described entity with a poor prognosis that is defined by certain genetic alterations in the BAF chromatin remodeling complex, specifically SMARCA4 and SMARCA2. We present a case of a SMARCA4-DTS in a 59 year-old male with a heavy smoking history who was found to have an unexpected right upper lobe lung mass on routine chest radiograph after a visit to his primary care physician. This led to a biopsy with a diagnosis of poorly differentiated carcinoma at an outside institution. The patient was subsequently seen at our facility for surgical intervention. The right upper lobectomy contained a 7.2-cm poorly differentiated malignancy with slightly discohesive cells arranged in sheets and nests, abundant geographic necrosis, and with many areas showing rhabdoid morphology. The tumor was focally reactive for CK7, AE1/3, Cam5.2, and SALL4 and showed scattered reactivity for CD34 and SOX2. There was complete loss of reactivity for both SMARCA4 and SMARCA2. The histology and immunophenotype were all consistent with the diagnosis of a SMARCA4-DTS. Next-generation sequencing showed a frameshift mutation in the SMARCA4 gene and no abnormality with the SMARCA2 gene. Interestingly, this tumor was confined to the pulmonary parenchyma with no invasion of the visceral pleura nor the mediastinum and with no clinically apparent metastases at the time of presentation. This case is presented to add to the cohort of cases described to date and to discuss the immunohistochemical and molecular findings with regard to SMARCA2.

Ipilimumab and Pembrolizumab Mixed Response in a 41-Year-Old Patient with SMARCA4-Deficient Thoracic Sarcoma: An Interdisciplinary Case Study

“…The patient was a 41-year-old man with a history of smoking and a survival time of 2 years after initial diagnosis, in compliance with the typical epidemiology of SMARCA4-deficient thoracic sarcoma [1,4]. Along with the SMARCA4 mutation, the rhabdoid morphology as well as immunohistochemical profile of the described tumor corresponded to observations from previously conducted studies, histomorphologically and molecularly setting this subgroup apart from non-sarcomatoid SMARCA4-deficient NSCLC.…”

“…It predominantly affects males with a median age of 48 with a history of smoking. The prognosis is poor, with a median survival of 6-7 months; direct comparison with prognostic data of thymic carcinoma patients reveals a considerably shorter 2-year survival rate (12.5 vs. 64.4%) [1][2][3][4][5]. Since then several case studies reporting this entity have been described in the literature [1,[6][7][8][9].…”

“…Histologically, the tumors consist of poorly differentiated epithelioid to rhabdoid cells with high mitotic rates, and present an immunohistochemical loss of the proteins BRG1 (Brahma-related gene-1; the protein encoded by the SMARCA4 gene) and BRM (Brahma), with an intact expression of INI-1 (integrase interactor 1) [2,4,10].…”

“…Due to its direct influence on chromatin accessibility and remodeling, both inactivation as well as overexpression of SWI/ SNF subunits may have carcinogenic potential [10]. BRG1 and BRM are encoded by the genes SMARCA4 and SMARCA2 [4]. Inactivation of SMARCA4 as well as SMARCA2 co-deficiency are characteristic for the tumor profile of SMARCA4-deficient thoracic sarcoma [4].…”

“…Inactivation of SMARCA4 as well as SMARCA2 co-deficiency are characteristic for the tumor profile of SMARCA4-deficient thoracic sarcoma [4]. Generally, mutations in SWI/SNF subunits or associated proteins have been found to be present in approximately 20% of all human cancers, among them non-small cell lung cancer (NSCLC), medulloblastoma, Burkitt's lymphoma, small cell ovarian carcinoma, hypercalcemic type (SCCOHT), dedifferentiated endometrial carcinoma, sinonasal undifferentiated carcinoma, pediatric rhabdoid tumors, and other cancers [4,10,11]. SMARCA4 mutations specifically have also been found in cases of thymic carcinoma, NSCLC, and SCCOHT [3,[12][13][14].…”