Diagnostic utility of EWSR1 in hyalinizing clear cell carcinoma: a systematic review and meta-analysis

Hyalinizing clear cell carcinoma (HCCC) is a rare, low-grade salivary gland tumor that poses diagnostic challenges due to its morphological and immunohistochemical overlap with other clear cell neoplasms of the head and neck. EWSR1 gene rearrangements, particularly EWSR1-ATF1 fusion, have been identified as distinctive molecular markers; however, their diagnostic significance remains unclear. This systematic review and meta-analysis, conducted in accordance with PRISMA guidelines and registered in PROSPERO (CRD42022382551), evaluated the diagnostic role of EWSR1 rearrangements in HCCC. Comprehensive searches of PubMed, Scopus, EMBASE, Cochrane Library, and Google Scholar up to July 2024 identified 14 studies (2011-2023) encompassing 174 HCCC cases. Patients were predominantly female (F:M ratio = 2.05:1; mean age 53.3 years), with tumors commonly involving the palate, base of tongue, and nasopharynx. Immunohistochemistry showed strong positivity for Pan-CK (96.9%), p40 (100%), p63 (92.7%), and CK7 (86.4%), while myoepithelial and melanocytic markers were negative. Molecular testing revealed EWSR1 rearrangements in 86.7% (137/158) by FISH and 57.1% (8/14) by RT-PCR, with EWSR1-ATF1 fusion confirmed in 38 cases. Pooled analysis demonstrated high heterogeneity (I² = 90.98%), and subgroup analysis showed no gender-based difference. Compared with 144 controls, HCCC exhibited a 2.16-fold higher likelihood of EWSR1 positivity, though not statistically significant (p = 0.10). These findings highlight EWSR1, particularly EWSR1-ATF1 fusion, as a sensitive molecular marker that improves diagnostic accuracy when integrated with histopathology and immunohistochemistry.