A Subset of Thoracic SMARCA4-Deficient Undifferentiated Tumors Express GATA3

Abstract

Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a rare and highly aggressive malignant neoplasm characterized by high-grade undifferentiated morphologic features and recurrent inactivating mutations of SMARCA4. These tumors consistently exhibit loss of SMARCA4 (BRG1) while displaying variable expression of other nonspecific markers. Recently, we encountered a SMARCA4-UT demonstrating immunoreactivity for GATA3, and we sought to characterize this phenomenon in a larger series. A total of nine SMARCA4-UTs were examined from 3 large academic institutions. The clinicopathologic and molecular characteristics were studied and GATA3 immunohistochemistry was performed. The cohort included 5 male and 4 female patients, with a median age of 54 years and a median smoking history of 37 pack-years. At initial diagnosis, mediastinal lymph node involvement was observed in 5 patients (56%) while distant metastases were present in 7 patients (78%). The median survival was 6 months. Histologically, the tumors were characterized by sheets of undifferentiated epithelioid and/or rhabdoid cells, accompanied by frequent mitotic figures and necrosis. Immunohistochemically, all tumors displayed a complete loss of BRG1 expression. Notably, 4 of 9 tumors (44%) were positive for GATA3 expression, including one tumor that exhibited strong and diffuse immunoreactivity. GATA3 expression in SMARCA4-UT may pose diagnostic challenges, requiring differentiation from other GATA3-positive tumors. This distinction is crucial for accurate prognostication and treatment decisions.

Molecularly Defined Thoracic Neoplasms

“…14,49 SMARCA4-DUT has been described in patients with a median age of 39 to 59 years old and a wide age range. [50][51][52] There is a strong male predominance. [51][52][53] The vast majority of patients are smokers.…”

“…[50][51][52] There is a strong male predominance. [51][52][53] The vast majority of patients are smokers. 51,52 Patients present with a rapidly progressing tumor that, at the time of presentation, has already metastasized to various sites in 77% to 83% of patients.…”

“…[51][52][53] The vast majority of patients are smokers. 51,52 Patients present with a rapidly progressing tumor that, at the time of presentation, has already metastasized to various sites in 77% to 83% of patients. 50,52 The tumors most commonly occur in the mediastinum, followed by the pleura and lung.…”

“…51,52 Patients present with a rapidly progressing tumor that, at the time of presentation, has already metastasized to various sites in 77% to 83% of patients. 50,52 The tumors most commonly occur in the mediastinum, followed by the pleura and lung. 51,53 SMARCA4-DUT have been included in the 2021 WHO classification of lung tumors.…”

“…4B) expression of BRG1 is the hallmark of SMARCA4-DUT. [50][51][52][53][54] Attention must be paid to the presence of a positive internal control in the form of benign cells such as endothelial cells or inflammatory cells expressing BRG1. These tumors usually also show a loss of expression of BRM (encoded by SMARCA2).…”