EP1.15-03 SMARCA4-Deficient Thoracic Malignancies: A Unifying Genetic Aberration Across Tumors of Divergent Differentiation

Abstract

Mutations in ATPase-dependant chromatin remodelling units are one of the most common genetic alterations observed in human cancer. Germline mutations in SMARCA4 encoding for Brg-1 protein, a subunit of the SWI/SNF chromatin modifier unit, are well recognised as the causative genetic event in rhabdoid tumor predisposition syndromes that occur in infants and young children. In recent years, somatic mutations in SMARCA4 have been increasingly identified in many adult-onset malignancies ranging from well differentiated carcinomas to poorly differentiated high grade sarcomas in a variety of anatomical sites, including thorax. Documentation of such tumors is essential to our understanding of the pathogenesis and possible mechanisms of therapeutic targetting. Case 1: A 60-year-old male smoker presented with chronic emphyema thoracis of non-tubercular etiology which was treated by intercostal drainage. He had repeated episodes of blockade of chest drain over the next 6 months and eventually a thoracic window was surgically created. Five months following thoracotomy, patient presented with a mass growing at the site of the thoracic window. No other masses in the lung parenchyma or mediastinal lymphadenopathy was seen. Patient underwent an excision of the granulation tissue-like mass. Formalin fixed paraffin embedded sections were subject to microscopy and immunohistochemistry for vimentin, CD34, MIC2, p53, SALL4, pan-cytokeratin (AE1/AE3), EMA, p40, TTF-1, cytokeratin-7, Hepar-1, desmin, myogenin, CD31, S100, Melan-A, HMB-45, GATA-3, calretinin, WT1, INI-1, brg-1 and hematolymphoid markers. Case 2: A 58-year old male smoker presented with hemoptysis and cough. On evaluation, an endobronchial mass was identified and was excised. Formalin fixed paraffin embedded sections from excised tumor mass was subject to microscopy and immunohistochemistry for cytokeratin 7, cytokeratin 19, epithelial membrane antigen, chromogranin, synaptophysin, cytokeratin 20, CD117, TTF-1, NUT1, Her2neu, GATA3, p40, S100, INI-1 and brg-1. Case 1: Microscopy revealed a tumor centred in the soft tissue of the chest wall ulcerating the overlying skin. No lung parenchymal involvement was seen. The tumor was arranged in sheets composed of monomorphic large tumor cells with abundant eosinophilic cytoplasm and prominent nucleoli showing frequent mitoses and foci of necrosis. No squamous or glandular differentiation was seen. Tumor cells were only immunopositive for vimentin, CD34, MIC2, p53, and SALL4, very focally immunopositive for CK (AE1/AE3) and showed retained INI-1 protein expression. Brg-1 expression was lost in tumor cells leading to a diagnosis of SMARCA4-deficient thoracic sarcoma. Case 2: Microscopy revealed a high grade tumor arising from the main bronchi with parenchymal and tracheal extension ulcerating the overlying squamous epithelium. Tumor cells were arranged in lobules with peripheral palisading and central necrosis. The tumor cells were large with frequent cytoplasmic clearing and frequent mitoses. Tumor cells were immunopositive for CK-7, CK-19, EMA, CG while were negative for others. INI-1 was retained while brg-1 was lost leading to a diagnosis of SMARCA4-deficient carcinoma. Two independant studies have delineated SMARCA4-deficient thoracic sarcomas and SMARCA4-deficient lung carcinomas as distinct clinicopathological entities. Despite a unifying genetic alteration, these tumors appear to show varied histomorphology and immunoprofiles. Long term follow-up and molecular analysis of such tumors is necessary.