Vascular malformations of the head and neck and a molecularly guided precision therapy framework

Vascular malformations of the head and neck carry high morbidity because of their proximity to the airway, cranial nerves, sensory organs, and cerebral vasculature. Although the ISSVA classification of vascular anomalies has standardized diagnostic terminology, therapeutic decisions for malformations have remained largely phenotype-driven and procedure-centered. Recent advances in genomics reveal that many vascular malformations are genetically driven disorders of endothelial signaling, enabling a transition toward etiological, mechanism-based therapy. This review presents a molecularly guided precision framework for the management of head and neck vascular malformations, focusing specifically on etiological medications that modify underlying disease biology. We synthesize evidence supporting three principal therapeutic classes: mTOR inhibition for PI3K-AKT-mTOR-driven disease, direct PI3Kα inhibition for PIK3CA-mediated pathology, and MEK inhibition for RAS/MAPK-driven lesions. We summarize translational and clinical evidence and provide practical guidance on indications, expected responses, toxicity monitoring, and sequencing for head and neck lesions. By reframing treatment selection around molecular drivers rather than descriptive phenotype, this review introduces a clinically actionable paradigm that advances care for vascular malformations from lesion control toward durable, mechanism-based disease modification.