Orbital Lymphatic Malformations Are Associated With Intracranial Vascular Anomalies

Orbital lymphatic malformations (OLMs) are a rare type of lymphatic malformation involving the soft tissues within the bony orbit. OLMs present specific treatment challenges and cause significant morbidity. The contribution of pathologic genetic variants and potential association of intracranial vascular anomalies with OLMs has yet to be described. We hypothesized that (1) OLMs are indicators of underlying cerebrofacial venous metameric syndrome (CVMS) and are associated with intracranial vascular anomalies, and (2) OLMs are caused by PIK3CA variants and are candidates for targeted medical therapy.

Retrospective case review was performed for patients with OLMs treated at a single institution from 2000 to 2025. Diagnosis of CVMS was made via magnetic resonance imaging (MRI) based on established criteria of segmental distribution of ocular, facial, and cerebral vascular malformations. Symptoms, MRI and genetic findings, and management are described.

Seven of 412 patients with head and neck lymphatic malformations had OLM. Common symptoms included eye swelling (n = 7), ptosis (n = 3), and headache (n = 5). All patients were diagnosed with CVMS on MRI. All patients underwent surgical resection and were candidates for targeted medical therapy after tissue-based DNA sequencing revealed "hotspot" PIK3CA variants p.E542K (n = 4) and p.H1047R (n = 3). Five patients were started on alpelisib, resulting in symptom improvement at 6 months of treatment.

OLMs were associated with intracranial vascular anomalies, meeting radiographic criteria for CVMS. All patients had "hotspot" PIK3CA variants on tissue-based genetic testing. Screening for intracranial vascular anomalies and targeted medical therapy with PI3K/AKT/mTOR pathway inhibitors should be considered in OLM management.