Vascular anomalies are changes in vascularization that usually appear in the foetal stage, at birth or in early childhood. They can cause chronic pain, motor impairment, cosmetic changes or coagulopathy and may be fatal in some cases, but in every case they have a negative impact on the quality of life of the child and the family. Up to 150 different subtypes have been described. They can involve arteries, capillaries, veins, lymphatic vessels or a combination thereof. They may be associated with additional malformations and frequently cause musculoskeletal and soft tissue hypertrophy or hypotrophy. They can develop anywhere in the body, invade any tissue and affect the function of various organs. The prevalence of the different subtypes varies widely, from 1/20 to 1/1 000 000. Subtypes considered rare diseases (incidence <1/2000) continue to affect more than 500 000 individuals in the European Union (Figs. 1 and 2).

Figure 1.

Infantile haemangioma: ulcerated infantile haemangioma in elbow, congenital haemangioma in knee, kaposiform haemangioendothelioma in trunk.

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Figure 2.

Isolated arteriovenous malformation in left buttock and thigh. Patient with Sturge-Weber syndrome.

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There is a long history of attempts to diagnose and classify AVs that started with the indiscriminate use of eponyms and descriptive terms such as “port wine stain”, “strawberry birthmark” or “cavernous angioma”, among others.

The rapid proliferation of this rather unscientific nomenclature brought attention to the need to develop a biological classification of VAs. One such classification was introduced by John Mulliken in 1982,1 setting the foundations for the subsequent classification of the International Society for the Study of Vascular Anomalies (ISSVA2,3 (Tables 1 and 2).

Future knowledge in the field will be chiefly based on genetic discoveries and therapeutic innovations. Nearly 50 genetic variants have already been identified in different Vas, and the application of whole genome sequencing (WES) to affected tissues will expand this catalogue exponentially (Figs. 3–5).

Figure 3.

Venous malformations: spongiform in forehead, truncal in scalp, and sinus pericranii in midface.

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Figure 4.

Lymphatic malformations: microcystic in arm, macrocystic in neck, and kaposiform lymphangiomatosis in the back.

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Figure 5.

Capillary malformations in Sturge Weber, CLAPO and Cobb syndromes, respectively.

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Age is considered a key factor in the clinical assessment of VAs, as they may manifest with different signs and symptoms in the foetus, infant, child and adult in close association with the stage of life.

The diagnostic algorithm used in the clinical evaluation of VAs must be based on a thorough history-taking and detailed physical examination. The most important aspects to explore in the anamnesis are whether the lesion was present at birth (vascular malformations) and its growth rate (proportional or disproportional to the child’s growth). The exception is found in congenital haemangiomas: rapidly involuting congenital haemangioma (RICH) and non-involuting congenital haemangioma (NICH). Both proliferate exclusively in the foetal period.

Differentiating between haemangioma and congenital vascular malformations is critical, especially in paediatric patients. They are completely different diseases, although they are grouped under the umbrella term of vascular anomalies. Malformations are errors of vascular morphogenesis in the context of somatic mosaicism and, more rarely, germline mutations. Vascular tumours may be benign (the majority), locally aggressive or malignant (angiosarcoma and epithelioid haemangioendothelioma).

Traditionally, the treatment of VAs consisted in pressotherapy, laser, embolization and radical or palliative surgery. These treatments achieved partial control of symptoms but could not halt progression and, in many instances, did not improve the quality of life of patients.31

The true breakthrough in the management of vascular anomalies in the past 10 years was the development of targeted treatment for inhibition of the mutations present in each tumour or malformation subtype.32 Sirolimus or rapamycin is an mTOR (mammalian target of Rapamicyn) protein inhibitor that, before its use in VAs, was chiefly used to prevent allograft rejection in kidney transplant recipients. In addition to its immunomodulatory activity, sirolimus has antiangiogenic and antiproliferative effects that make it a more than appropriate tool for the management of symptomatic VAs.33 Initially it was tried in compassionate use for management of anomalies refractory to other treatments, but the good outcomes achieved, especially in patients with lymphatic malformations, expanded its indications and it is currently used, even as first-line treatment, in multitude conditions. In common LMs, sirolimus reduces the size of the lesion, eliminates lymph leakage and reduces the number of cysts and the frequency of intralesional bleeding episodes and infection. In complex LMs, sirolimus stabilises osteolysis, halting its progression, and reduces the severity of pericardial or pleural effusion and ascites. In addition, as we already mentioned in relation to KHE, sirolimus can also correct coagulopathy. Although it is usually administered orally at a dose of 0.8 mg/m2 every 12 h, there is also evidence of improvement of superficial microcystic LMs with topical administration of sirolimus.34

The effectiveness and safety of treatment with sirolimus has been confirmed, as it has proven to be harmless with minimal adverse effects, even in neonates. However, the optimal dose, serum drug concentration and duration of treatment have yet to be established. The current evidence suggests that treatment with sirolimus should be individualised and that doses and target drug concentrations should be tailored in each patient based on the phenotype and clinical manifestations.35

To alleviate pain associated with thrombi or phleboliths, aspirin may be given at a dose of 50 mg/day, although there is insufficient evidence on its efficacy.36 If this is not effective, the administration of low molecular weight heparin via the subcutaneous route is effective from the first dose, with a recommended treatment duration of at least 2 weeks.37 Oral factor Xa inhibitors such as rivaroxaban, approved for use in children, or factor IIa inhibitors, such as dabigatran, are anticoagulants whose use is increasing in these patients, allowing for prolonged treatment in very severe cases, and their combination with rapamycin seems to be effective in reducing the size of these lesions.38–40

The discovery of PIK3CA variants in patients with VAs has led to the incipient use of PIK3CA inhibitors, initially developed for treatment of cancer, in these patients, with promising results.

Alpelisib is an oral inhibitor of the p110α subunit of class I phosphatidylinositol 3-kinase (PI3KCA) in the 2-aminothiazole derivative group. In vitro, alpelisib exhibits potent inhibition of the p110α subunit of PI3K with a good safety profile. Alpelisib had only been authorised for use in combination with fulvestrant for PIK3CA-mutated, hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced or metastatic breast cancer, but the United States Food and Drug Administration (FDA) recently authorised its use in patients with congenital VAs carrying this variant. In 2018, Canaud described a murine model of VAs with overgrowth similar to the disease in humans.41,42 The model demonstrated the efficacy of alpelisib in preventing and improving organ dysfunction. The article also described the compassionate use of alpelisib in 19 patients (adult and paediatric) with PROS, which achieved improvement of symptoms in every patient. The treatment achieved a decrease in size in previously intractable vascular tumours, with improvement of congestive heart failure, reduction of hemihypertrophy and attenuation of scoliosis. The treatment was not associated with any significant adverse events. This case series was the first to provide direct evidence in support of the use of PIK3CA inhibitors as a promising treatment option for PROS.

At present, treatment with alpelisib in patients with PROS is provided through expanded access and in the framework of 4 clinical trials. Since there is already a significant number of patients in treatment with alpelisib for this rare indication, a retrospective review is being conducted to analyse clinical and functional outcomes and the safety profile of this treatment.

The data available to date indicate that 75% of patients respond to treatment and 25% show a very significant reduction in lipomatous masses, and no patient has dropped out of treatment due to serious adverse events.42

As we already discussed, changes in KRAS, NRAS, BRAF and MAP2K1 have been identified in patients with arteriovenous and lymphatic malformations that may yield targeted treatments in the future. MEK1 inhibitors, which are already used in cancer and neurofibromatosis type 1, may be tried in compassionate use in these patients, for whom few non-invasive treatment options are currently available. Trametinib and, more recently, selumetinib have already been established as treatment options in patients with high-flow malformations, malformations with osteolysis and kaposiform lymphangiomatosis caused by KRAS variants.43

New molecules and indications are being investigated with the aim of reducing the aggressiveness of previous treatments and to give hope and improve quality of life in patients who do not respond to conventional treatment.

The authors have no conflicts of interest to declare.