Unravelling switch/sucrose non-fermentable (SWI-SNF) complex-deficient thoracic tumours: a clinicopathological comparative on undifferentiated tumours and non-small cell lung carcinomas with BRG1 and BRM deficiency.

Abstract

Aims: This study was undertaken to compare and expand the clinicopathological characteristics of SMARCA4-deficient thoracic undifferentiated tumour (SMARCA4-dUT) and switch/sucrose non-fermentable-deficient non-small cell lung carcinomas (SWI/SNF-dNSCLC) and to address cases with intermediate features.

Methods: The pathology department archive was searched for all primary mediastinal, pleural and lung-based malignancies that showed aberrant expression of two SWI/SNF proteins the Brahma (BRM) aka SMARCA2 and/or (Brahma-related gene 1 (BRG1) aka SMARCA4. Patient demographics, treatment and clinical outcomes were collected from records and telephonic interviews. Differences in histopathological features and immunohistochemical stains were analysed. Cases with characteristics intermediate between both tumour entities were sequenced to advance our understanding of their biology and to assign them a more accurate classification.

Results: We identified 50 tumours with SMARCA4 and/or SMARCA2 deficiencies, including 23 (46%) SMARCA4-dUT, 18 (36%) SMARCA4-dNSCLC and 2 (4%) SMARCA2-dNSCLC. Dyscohesive or undifferentiated cellular morphology versus frank gland formation along with keratin, claudin-4 and expression of >1 stem cell marker helped classify the SWI/SNF deficient tumours as SMARCA4-dUT or SWI/SNF-dNSCLC (p<0.05). Seven (14%) cases with BRG1 deficiency displayed 'intermediate' features of both SMARCA4-dNSCLC and SMARCA4-dUT and had the shortest overall survival. The smoking-related gene signature was observed on sequencing in all four cases examined.

Conclusion: Tumours with intermediate features between SMARCA4-dUT and SWI/SNF-dNSCLC exist and portend an equally poor prognoses. Immunostains, including keratin, claudin-4, TTF1, HepPar1, stem cell markers, along with BRG1 and BRM testing, are essential adjuncts to morphology, while molecular studies can offer supplementary evidence in challenging cases.