An Aggressive Case of Thoracic Undifferentiated SMARCA4-Deficient Tumor With Extensive Pleural Involvement

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INTRODUCTION: SMARCA4-deficient undifferentiated thoracic tumors (SMARCA4-UT) result from an inactivating mutation of SMARCA4, which encodes the tumor suppressor protein brahma-related gene 1 (BRG1) – a part of a larger complex involved in chromatin remodeling. Tumors are most commonly found in the anterior mediastinum (61%) followed by pleura and lung (29%). The majority are metastatic at the time of diagnosis, with a predilection for young male smokers. We present a case of newly diagnosed SMARCA4-UT with extensive pleural involvement. CASE PRESENTATION: A 40-year-old male with a 20 pack-year history of tobacco and marijuana use was admitted with a 2 week history of severe exertional dyspnea and pleuritic chest pain. He is employed in a factory and has exposure to metal dust and melted nickel. He had no history of vaping or inhalation of other substances, and no known family history of lung disease or lung cancer. CT chest revealed numerous right sided pleural based masses and soft tissue plaques, a right pleural effusion, diffuse thoracic adenopathy and bilateral giant bullous paraseptal emphysema (Figure 1 & 2). Following discussion between pulmonology and thoracic surgery, thoracentesis was not performed due to the increased risk of bleeding from the multiple pleural masses, as well as the degree of paraseptal bullous emphysema. A CT-guided needle biopsy was performed of the pleural mass, and histopathological analysis revealed sheets of poorly differentiated epithelioid cells, tumor cell immunopositivity for synaptophysin and loss of SMARCA4 expression within tumor cells. A diagnosis of thoracic SMARCA4-deficient undifferentiated tumor was established. PET/CT showed innumerable FDG-avid right pleural based lesions with a max SUV of 14.3, as well as FDG-avid right hilar and bilateral mediastinal adenopathy (Figure 3). No convincing evidence of metastasis was noted in the abdomen/pelvis, or on MRI brain. The patient had a mediport placed, and was urgently started on chemotherapy with carboplatin and paclitaxel. Initiation of immunotherapy was planned on an outpatient basis, pending the results of next generation sequencing. DISCUSSION: SMARCA4-UT is an aggressive malignancy, with a reported median survival of only 4 - 7 months. There has been a limited response to chemotherapy and surgery, and only a partial response to immunotherapy with the anti-PD-1 antibody pembrolizumab when used in select patients, either as first-line therapy or after failed chemotherapy. To date, there exists no definitive therapy for SMARCA4-UT. Preclinical and early clinical trials are currently underway using the histone methyltransferase EZH2 inhibitor Tazemetostat. CONCLUSIONS: Further investigation into the pathogenesis and natural history of SMARCA4-UT is needed to identify additional treatment options for this highly fatal entity




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Chest Annual Meeting 2023, October 8-11, 2023, Honolulu, HI