Vascular malformations

Vascular malformations arise from defects during early vascular development and lead to the formation of abnormally structured vessels. These malformations can significantly impact the quality of life of patients and their expansion often induces chronic pain, deformities, functional limitations, infections, bleeding, and, in severe cases even death. During EADV 2024, Prof Dr Miikka Vikkula from the UC Louvain and the de Duve institute in Brussels discussed the pathogenesis of vascular malformations and illustrated how these pathogenic insights can inspire new therapeutic strategies.

Molecular and genetic research into vascular malformations have revealed that a complex set of transduction pathways or involved in the development of these disorders. In this, fast-flow anomalies often seem to involve the RAS/MAP signaling pathway, whereas slow-flow lesions are predominantly characterized by aberrant PI3K-AKT signaling. Interestingly, many of the pathways that are involved in the development of vascular malformations are also involved in the pathogenesis of cancer.1 As a result, several studies have evaluated the potential of oncogenic drugs that target these pathways in patients with vascular malformations. For the moment, the most promising data with this strategy have been generated using mTOR inhibitors. For example, in the prospective, phase III VASE trial, the mTOR inhibitor sirolimus was evaluated in 31 pediatric and 101 adult patients with slow-flow vascular malformations.2 In this trial, 2 years of sirolimus resulted in a clinical improvement in 85% of patients, with a low rate of grade ≥3 adverse events. After a median follow-up of 13 months after stopping sirolimus, 54% of patients suffered a recurrence.2 

In addition to mTOR inhibitors, also anti-angiogenic agents are being evaluated in patients with vascular malformations. In this respect, Prof Vikkula mentioned some spectacular results that he obtained with thalidomide in patients with severe, ulcerating vascular malformations. While our understanding of vascular malformations has increased dramatically following the introduction of next generation sequencing, there is still a lot of work to do. One of the more pressing medical needs in this light consists of lymphoedema. In fact, in more than 70% of patients the cause of this lymphoedema is unknown and for the moment there are no effective therapies to address this complication.