Molecular and clinicopathological characterisation of SMARCA4-deficient uterine tumours: distinguishing features between dedifferentiated/undifferentiated endometrial carcinoma and undifferentiated uterine sarcoma.

内容摘要

SMARCA4-deficient uterine tumours encompass two distinct entities: SMARCA4-deficient undifferentiated/dedifferentiated endometrial carcinoma (SDUDEC) and SMARCA4-deficient uterine sarcoma (SDUS). Despite their divergent classifications, these tumours share overlapping clinicopathological and molecular features that complicate diagnosis. This study characterises their distinguishing features and clinical significance through analysis of 34 SDUDEC and 14 SDUS cases, integrating clinicopathological, immunohistochemical [BRG1 (encoded by SMARCA4), BRM (encoded by SMARCA2), INI1 (encoded by SMARCB1), ARID1A, ARID1B, SOX2, claudin-4, CK8/18, Chromogranin, synaptophysin, INSM1, p53, and MMR proteins], and next-generation sequencing (NGS; 14 SDUDEC and 14 SDUS) data. SDUDEC patients were significantly older than SDUS patients, with a median age of 54 years (range 28-63) compared to 37 years (range 24-58) (p<0.01). SDUDEC exhibited marked immunohistochemical heterogeneity, whereas SDUS showed uniform profiles: all SDUS cases (10/10) demonstrated dual BRG1/BRM loss with preserved expression of other SWI/SNF complex proteins, absent claudin-4 (0/12) and SOX2 (0/8) expression, and no MMR deficiency (0/14) or mutant-type p53 (0/13). NGS revealed frequent endometrial carcinoma-associated alterations in SDUDEC but rarely in SDUS. Prognostic outcomes did not differ significantly (p>0.05). These findings highlight distinct molecular landscapes: SDUDEC aligns with endometrial carcinogenesis, while SDUS may arise via alternative SMARCA4-dependent mechanisms. A diagnostic algorithm combining endometrial carcinoma molecular classification, SWI/SNF protein testing, and thorough sampling is proposed. This study expands the clinicopathological and molecular spectrum of SMARCA4-deficient uterine tumours, underscoring the need for entity-specific management strategies.