Vascular anomalies

Treatment

Treatment of tumours and vascular malformations will depend on each case. We have already seen that some tumours can be treated with propranolol and rapamycin. Capillary malformations are treated with laser; venous and lymphatic malformations can be treated with sclerosis, surgery or medical treatment if the mutation has been identified. Arteriovenous malformations usually require a combination of embolisation, surgery and targeted medical treatment such as trametinib or vemurafenib , which block the altered pathways. 

For overgrowth syndromes associated to vascular malformations, the treatment will depend on the anomalies presented by the patient. It is particularly useful to try and find the mutation in this group of diseases. Therefore, if we find a mutation in the PI3K/AKT pathway, we can use PI3K inhibitors to block the pathway at its earliest stages. Inhibitors bind to the PI3K protein and do not allow its phosphorylation, so the protein does not adopt an active form.

New treatments with antibodies are now targeting AKT.

• Miransertib (ARQ 092): suppresses AKT by inhibiting the active form (binds to its receptor in the cell membrane, preventing AKT from doing so) and inactive form (prevents its phosphorylation) of AKT, which is very useful for patients with overgrowth and/or vascular anomalies with genetic alterations in AKT. Proteus syndrome is one of the diseases affected by mutations in AKT, so this new therapy would be more specific and effective than classic PI3K inhibitors. Studies show that miransertib achieves a 50% decrease in the levels of phospho-AKT (active AKT) and non-phosphorylated AKT (non-active AKT).
• Alpelisib (BYL719): recent studies carried out at the Sant Joan de Déu Children's Hospital on the use of this PIK3CA inhibitor in the treatment of overgrowth diseases related to PI3K have shown improvement of the symptoms. Patients who have taken this drug have experienced substantial improvements in the size of vascular tumors, improvement in congestive heart failure, attenuation of scoliosis, etc. The results are promising and no major adverse effects have been reported, but before it can be used in routine clinical practice, more trials and larger patient samples must be conducted for these improvements to be statistically significant.

After treatment with PI3K and AKT inhibitors, pain and other quality of life measures improve and are more stable.

It is true that there is still no cure for these syndromes but these treatments have really improved the progression of the disease, regression of the malformations and the patients’ quality of life.

Surgery may be required to remove overgrown tissue, especially if it is limiting the patient’s day-to-day life. Depending on the area affected by the overgrowth, this may not be treatable with surgery, and it may not be possible to control it effectively with antibodies. In this case the patient cannot be treated and sooner or later the body will not be able to cope with uncontrolled cell overgrowth, especially if it happens inside the brain.

Prognosis

The impact of the disease on patients and families is very strong. Vascular malformations and tumours are usually part of a larger pathological entity known as a syndrome. These syndromes are the result of mutations that lead to overgrowth and uncontrolled proliferation in any tissue in the body, but there are some tissues that are predisposed to experience this overgrowth, such as the skin and bone tissue.

These injuries can be very visible, which is an important psychological issue to deal with, and we must also work to find solutions for this. Moreover, this overgrowth, which is usually asymmetrical (one side of the body is bigger than the other), can lead to disabilities such as limping.

External overgrowth may be very visible, but the internal overgrowth of tissues (tumours) is normally benign in these syndromes. This means that the proliferation will not metastasise (will not spread to other parts of the body), but it can be life-threatening if the increased tissue compresses other important structures such as the trachea or spinal cord or blocks the blood flow to other structures causing ischaemia. Benign tumours must be followed-up closely in case they reach a considerable size or threaten nearby structures. In this case, we will need to consider removing them.