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

## TL;DR

This paper introduces a new approach to treating head and neck vascular malformations by using molecular insights to guide precision therapy.

## Contribution

The paper proposes a precision therapy framework based on molecular drivers rather than traditional phenotype-based treatment decisions.

## Key findings

- Three principal therapeutic classes are supported by translational and clinical evidence: mTOR inhibition, PI3Kα inhibition, and MEK inhibition.
- Treatment decisions can now be guided by molecular drivers of vascular malformations, leading to mechanism-based disease modification.
- The framework provides practical guidance on indications, responses, toxicity monitoring, and sequencing for head and neck lesions.

## Abstract

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.