GJA4-Associated Cavernous Venous Malformation: A Distinct Morphologic and Molecular Subtype of Venous Malformation

The classification of superficial cavernous-pattern venous malformations (VMs) remains a subject of clinical debate due to overlapping morphologic features and a lack of defined molecular drivers, particularly for lesions traditionally termed "cavernous hemangiomas". This study aimed to delineate the molecular landscape of these lesions, focusing on the significance of GJA4 mutations. We evaluated 54 cases of superficial cavernous-pattern VMs. Molecular analysis was performed using MassARRAY and digital PCR to detect mutations in GJA4, TEK, PIK3CA, GNAQ, GNA11, and GNA14. Histologic reappraisal was conducted to correlate clinicopathologic features with molecular findings. Histologic stratification categorized the cohort into classic VM (cVM, n=7) and cavernous VM (CVM, n=47); the latter was further subdivided into classical (CL-CVM, n=32) and non-classical (nCL-CVM, n=15) subtypes. GJA4 (c.121G>T, p.Gly41Cys) mutations were identified in 94% (30/32) of CL-CVM cases but were entirely absent in all cVM and nCL-CVM cases. In contrast, cVMs frequently harbored TEK or PIK3CA mutations (71%, 5/7). The molecular drivers for nCL-CVM remained largely unknown, except for a single GNA11 mutation. Morphologically, CL-CVM was characterized by dermal localization, circumscribed margins, and "back-to-back" vascular channels with fibromyoid walls displaying circumferential SMA and h-caldesmon expression. Notably, 75% (24/32) of CL-CVM cases required a diagnostic revision from their original entries. Clinical follow-up data (n=50; range: 0.1-114 months) demonstrated that all patients with CL-CVM (n=29) and nCL-CVM (n=14) achieved no evidence of disease status. In contrast, 29% (2/7) of classic cVMs resulted in residual or recurrent disease. In conclusion, GJA4 p.Gly41Cys mutation is a highly sensitive and specific molecular marker for "classical" CVMs. Our findings support a genotype-phenotype reclassification of superficial CVMs, wherein GJA4 mutations define a distinct, non-infiltrating clinicopathologic entity, separating it from the broader spectrum of superficial cavernous-pattern vascular anomalies.