Vascular anomalies are a heterogenous group of conditions that can be classified into two broad categories, namely vascular tumours and vascular malformations. The International Society of the Study of Vascular Anomalies (ISSVA) classification¹ has led to standardisation of the nomenclature of vascular anomalies, especially among physicians managing these conditions. This is important as there now exists a variety of different treatment options targeted at the various vascular tumours and malformations. Inaccurate diagnoses may lead to inappropriate treatments with suboptimal outcomes. Vascular anomalies that are more complex, such as Klippel-Trenaunay Syndrome (KTS), should be managed under the care of a multidisciplinary team, as a combination of various treatments may be required for optimal results.

Vascular tumours can be sub-classified into benign, locally aggressive/borderline or malignant. The commonest benign vascular tumours in infants and children are infantile haemangiomas (IHs). Locally aggressive vascular tumours, such as kaposiform haemangioendothelioma (KHE) or tufted angioma (TA), are rare in children but can be associated with severe complications which include Kasabach-Merritt syndrome (KMS). Malignant vascular tumours are extremely rare in children, but can occur in older patients, such as angiosarcoma.

Vascular malformations can be sub-classified into simple, combined or syndromic. Simple malformations can be slow-flow (capillary, venous or lymphatic malformations) or high-flow (arteriovenous malformations). Combined malformations can be a combination of the various simple malformations, such as veno-lymphatic. Syndronic malformations (malformations that are part of a syndrome) are rare. More common examples include KTS and Parkes Weber syndrome. Somatic mosaic mutations, such as the mutation of the PIK3CA gene, have been detected in many of these malformations and malformation syndromes.

VASCULAR TUMOURS

Infantile Haemangiomas

Infantile haemangiomas (IHs), the most common vascular tumour in children, affect two to four per cent of infants. It is more common in females, premature infants and twins.

IHs most commonly present in the first three to four weeks of life as enlarging red or bluish papules or nodules. IHs grow in breadth and depth over four to five months, thereafter slowing in the rate of growth until the child is about one year of age, before it begins to involute (decrease in size).

The rate of involution is estimated at about 10 per cent per year, with smaller lesions resolving faster than larger ones. Although small IHs can involute to near-normal skin, large IHs, if left untreated, may involute with residual fibrofatty change and telangiectasias.

Most IHs are uncomplicated with minimal cosmetic concern, and can be observed for spontaneous resolution. A handful of IHs may lead to life-threatening or function-threatening complications, or have a potential to cause severe cosmetic disfigurement. Early identification of these IHs is important, as early treatment within the first six months of life can reduce these complications.

More common on the head and neck region, IHs can occur on almost any part of the skin. Superficial IHs (Figure 1) usually appear as bright or deep red papules, nodules or plaques. Deeper lesions (Figure 2) can be skin-coloured or have a bluish hue. Many IHs can have a mixed appearance, with both superficial and deep components. All forms of IHs have a soft consistency on palpation.

Diagnosis

A doppler ultrasound placed over an IH will reveal fast-flow components. Large IHs on the head and neck region may be associated with eye, brain and heart abnormalities (PHACES syndrome); while those in the groin, perineal or sacral region may be associated with spinal and genito-urinary abnormalities (PELVIS syndrome). IHs at certain sites, such as the lip, groin, neck and ear, may ulcerate and lead to pain, infection and scarring. Multiple IHs (> 5) may be associated with visceral involvement, such as that of the liver or spleen.associated with visceral involvement, such as that of the liver or spleen. Complicated IHs require prompt referral to a paediatric dermatology unit for urgent investigations and treatment.

Treatment

The treatment of IHs has revolutionised over the past decade with the use of beta blockers. Systemic beta-blockers such as propranolol have been shown to be very effective in the treatment of complicated IHs if started within the first year. Topical beta-blockers such as timolol have also been found to be efficacious in the treatment of more superficial IHs. Lasers, such as the pulsed dye laser (PDL), can also be used to treat IHs.

Kasabach-Merritt Syndrome, Kaposiform Haemangioendothelioma and Tufted Angioma

Kasabach-Merritt syndrome (KMS) is characterised by thrombocytopenia, coagulopathy and microangiopathic haemolytic anaemia, associated with an underlying rapidly expanding vascular tumour, most commonly kaposiform haemangioendothelioma (KHE) (Figure 3) and tufted angioma (TA).

The vascular lesion commonly becomes enlarged and indurated, and infants can present with bleeding manifestations such as ecchymoses, epistaxis, haematochezia and haematuria. Although both KHE and TA can be locally aggressive, they may also undergo spontaneous involution.

Diagnosis

Diagnosis is usually clinical and confirmed with radiology through a doppler ultrasound, magnetic resonance imaging (MRI) or histology.

Treatment

Treatment of KMS, KHE and TA may require different regimens and a multidisciplinary approach. Options include systemic high-dose corticosteroids, anti-fibrinolytics, interferon, vincristine and anti-thrombotics. More recently, the use of sirolimus has proven to be very effective in reducing both the KMS, as well as the size of the underlying tumour. Surgery, embolisation and radiation are used less often in recent years. Sirolimus, also known as rapamycin, was first isolated from the bacterium, Streptomyces hygroscopicus, and its anti-proliferative properties is due to inhibition of mTOR. It has been used for the treatment of various vascular anomalies, including vascular tumours, such as KHE, and vascular malformations, such as lymphatic malformations and venous malformations. It also has immunosuppressive properties and has been used extensively in the prevention of transplant rejection. Common side effects include stomatitis, peripheral oedema, abdominal pain and headache.

VASCULAR MALFORMATIONS

Capillary Malformations

The commonest vascular malformations are capillary malformations or port-wine stains (PWS). These are usually present at birth and grow in proportion to the child. Although initially flat, they may thicken during puberty and adulthood. Although asymptomatic, they may cause significant cosmetic and psychological distress in patients and their caregivers. Large PWS affecting the forehead or eyelids (Figure 4) may be associated with Sturge-Weber syndrome (SWS), with cranial and ophthalmological associations.   

These patients require brain imaging and thorough eye examinations. Seizures and developmental delay are common neurological manifestations of SWS. PWS that are not of cosmetic concern may be left alone.

Treatment

Those that have the potential to lead to cosmetic or psychological impairment may be treated with lasers. The pulsed dye laser (PDL) is the commonest laser used in the treatment of PWS. Treatment can begin within the first few months of life, and the child will require multiple treatments, usually one to two months apart.

Venous and Lymphatic Malformations

Venous and lymphatic malformations are the next most common forms of vascular malformations. They usually present within the first few years of life, with soft, bluishto- purplish swellings (Figure 5). Most common on the head and neck, they may occur anywhere on the body. Although mostly asymptomatic, they can present with pain, bleeding and secondary infection.

Diagnosis

Radiological investigations, such as a doppler ultrasound or MRI, can aid in diagnosis and should be performed in all lesions undergoing treatment.

Treatment

Small, asymptomatic lesions may be left alone, while treatment is recommended for larger lesions, especially if symptomatic. Various treatment modalities may be employed, and thorough discussion of the benefits and side effects of each treatment is essential for patients and caregivers to make an informed choice. Treatment options include sclerotherapy, lasers, surgery, and systemic medications such as sirolimus. Some lesions may require more than one modality for optimal results. Recently, an increasing number of somatic genetic mutations have been discovered in vascular anomalies, such as in the PIK3CA gene. Genetic testing may be offered in some cases, which may guide management decisions.

Vascular Malformations Syndromes

Some vascular malformations may be associated with other anomalies, such as tissue overgrowth. These “vascular malformations syndromes” are rare but have the potential to lead to severe physical and psychosocial impairment. Somatic mosaic mutations in the PIK3CA gene have been found in the PIK3CA-related overgrowth syndromes (PROS). These include KTS and CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis /spinal) syndrome.

Patients with PROS present with asymmetric limb overgrowth associated with various slow-flow vascular malformations (Figure 6). Multidisciplinary and multi-modality treatment is required for these patients, including sclerotherapy, embolisation, systemic medications such as sirolimus, lasers and surgery.

Other genetic mutations that have been discovered to underlie other vascular malformation syndromes include that of the GNAQ gene (SWS), AKT1 gene (Proteus syndrome), RASA1 gene (Parkes Weber syndrome) and PTEN gene (Bannayan-Riley Ruvalcaba syndrome). More specific treatments targeting these mutations may be available in the near future.

CONCLUSION

Vascular tumours and malformations range from mild to severe conditions that can lead to significant physical, psychological and emotional impairment. Many of these conditions have been well classified under the latest ISSVA classification. Specific treatments are now available for the management of many of these conditions. However, complex and more severe cases will require multidisciplinary treatment in centres specialising in the management of complex vascular anomalies.​

REFERENCES

1. ISSVA classification for vascular anomalies (2018). Retrieved from https://www.issva.org/UserFiles/file/ISSVA-Classification-2018.pdf
2. Harter N, Mancini AJ. Diagnosis and management of infantile hemangiomas in the neonate. Pediatr Clin North Am2019;66:437-459
3. Hammill AM, et al. Sirolimus for the treatment of complicated vascular anomalies in children. Pediatr Blood Cancer 2011;57:1018 1024
4. Zuniga-Castillo M, Teng CL, Teng JMC. Genetics of vascular malformation and therapeutic implications. Curr Opin Pediatr 2019;31:498-508
5. Martinez-Lopez A, et al. Vascular malformations syndromes: an update. Curr Opin Pediatr 2019; Jul 29. doi: 10.1097/MOP.0000000000000812. (Epub ahead of print)