SMARCA4-Deficient Undifferentiated Thoracic Tumor: A Case Report

Abstract

The patient is a 63-year-old man, a chronic smoker, who presented with cervical masses and a decline in general health. Imaging revealed an invasive mediastinal-hilar process with cervical, mediastinal, and axillary lymphadenopathy. Lymph node biopsy showed a largely necrotic malignant tumor consisting of large, epithelioid-appearing but undifferentiated cells. Initial immunohistochemical testing was negative for epithelial (AE1/AE3, CK7, P40), lymphoid, and melanocytic markers. Positivity for SALL4 and SOX2 subsequently raised suspicion of a germ cell tumor, but negativity for OCT3/4 and weak, focal positivity for synaptophysin and CD34, coupled with complete loss of BRG1 expression, led to a diagnosis of SMARCA4-UT. Despite oncological management, the course was marked by rapid metastatic progression and the patient’s death. SMARCA4-UT is an aggressive malignant tumor that occurs primarily in adult males with a history of chronic smoking. Its definitive diagnosis is histopathological and is based on the loss of BRG1 as detected by immunohistochemistry (IHC). The phenotypic profile is often misleading due to the expression of synaptophysin and “stemness” markers (SALL4 and SOX2), leading to confusion with neuroendocrine or germ cell tumors. This entity must be distinguished from SMARCA4-deficient non-small cell lung carcinoma (NSCLC), which retains an epithelial morphology and phenotype. Awareness of this entity is crucial for the pathologist. The pathologist must systematically consider it in the presence of any undifferentiated thoracic tumor with a “negative” or atypical IHC profile in order to guide prompt therapeutic decisions. To report on and describe a rare and aggressive entity “SMARCA4-deficient undifferentiated thoracic tumor (SMARCA4-UT),” newly included in the 5th edition of the WHO Classification of Thoracic Tumors with the aim of highlighting the diagnostic challenges and pitfalls encountered by pathologists.