New and Emerging Targeted Therapies for Vascular Malformations

An Van Damme; Emmanuel Seront; Valérie Dekeuleneer; Laurence M. Boon; Miikka Vikkula


Am J Clin Dermatol. 2020;21(5):657-668. 

In This Article

Vascular Malformations

Vascular malformations are described by the main affected vascular component (lymphatic, venous, capillary, arteriovenous) and subdivided as 'simple', 'combined', or 'associated with other anomalies'.[2,4,5] Additionally, vascular malformations are further described as 'slow-flow' or 'fast-flow', depending on the absence or presence of an arterial component.

Vascular malformations are, by definition, present at birth and grow proportionally with the child. Nevertheless, appearance and symptoms are not static, with possible expansion or dilation of the affected vessels during growth spurts and puberty.[6] They do not regress or disappear spontaneously. They can be localized or diffuse, and appearance and symptoms depend on location, extension, and the involved anatomical structures. Common symptoms include pain, deformation, esthetic issues, and functional impairment.

Capillary malformations (CMs) represent the most prevalent vascular malformation and mainly occur in the skin as pink or red macules ("port wine" stains).[7] They are present at birth and persist throughout life if left untreated. They can become thicker and darker with time.

Lymphatic malformations (LMs) consist of dilated lymphatic channels or cysts, lined with endothelial cells with a lymphatic phenotype. They can be subdivided into microcystic, macrocystic, and mixed subtypes. Generalized lymphatic anomaly (GLA) is a rare condition characterized by multifocally occurring LMs in the skin and soft tissue, as well as abdominal and thoracic organs and bone.[8] In Gorham-Stout Disease (GSD), LMs affect a single or multiple contiguous bones, leading to progressive osteolysis. Both entities can lead to pathologic fractures and abdominal and thoracic effusions.

Common venous malformations (VMs) represent the most frequent vascular malformation treated in expert centers.[9,10] They are usually unifocal lesions. The overall incidence is estimated at 1/5000. They are soft compressible subcutaneous masses with bluish skin discoloration without bruit, pulsation, or redness. Recurrent thrombophlebitis in the slow-flow enlarged vessels is a typical feature, which can lead to the presence of phleboliths. More than 90% of VMs occur sporadically but familial forms exist.[2,4,5,9] These are caused by germ-line mutations in the tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domain 2 (Tie2) gene, whereas most sporadic forms harbor somatic mutations in the same gene (see below).

Arteriovenous malformations (AVMs) are rare fast-flow vascular anomalies, composed of malformed arteries, veins, and capillaries.[2,7] They are present as a warm painful pulsating lesion and can cause ulceration. Arteriovenous shunting can lead to cardiac overload and eventually decompensated heart failure. They may be associated with other vascular and non-vascular abnormalities and overgrowth.