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Abstract
Infantile haemangiomas are common vascular tumours of infancy. They typically present shortly after birth, undergo a period of rapid proliferation, and then slowly involute over many years. Although most patients require no intervention, appropriate investigation and treatment may be necessary in a minority of cases. Identifying which patients require further investigation or intervention can be difficult due to the heterogeneity of clinical presentation. This is compounded by a lack of rigorous randomised controlled trials on haemangioma management. Therefore, the rationale for treatment is not always straightforward. Haemangiomas occur anywhere on the body, have superficial, deep or mixed morphology, and depending on anatomic location, size and subtype, can be associated with underlying structural anomalies and many other potential complications. Generally, the management of difficult haemangiomas is best approached on a case-by-case basis. Over the last few years, there have been several advances in our understanding of haemangiomas, together with some exciting new therapeutic options. In the following review, the authors discuss the various possible complications of infantile haemangiomas, the rationale for treatment and appropriate possible interventions.
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Introduction
Many exciting advances in the management of complicated infantile haemangiomas (IH) have occurred over the past decade. Historically, oral corticosteroids and a small number of other systemic agents have been the mainstay of treatment, however new systemic and topical treatments have now been added to this armamentarium. Although the majority of IH involute spontaneously, requiring no intervention, treatment is necessary in certain patients. Because new treatments are available, it is increasingly important to recognise which haemangiomas have clinical features requiring further evaluation or treatment. Unfortunately, this is not always easy due to the wide heterogeneity of haemangiomas in terms of size, location and growth, all of which can make assessment and intervention difficult and time-sensitive, especially in the first few weeks to months of life. Unfortunately, there is severe lack of randomised controlled trials (RCT) to guide treatment decisions,1 which still rely on a thorough understanding of the natural history of haemangiomas combined with expert opinions and clinical experience.
Background
IH occur in up to 4–5% of neonates.2 IH are unique vascular tumours which differ in both clinical behaviour and immunohistochemical markers from other vascular tumours and malformations with which they are sometimes confused.3 IH are typically absent or present as a precursor lesion at birth, becoming noticeable in the first few weeks of life, and often proliferate rapidly during the first few weeks to months of life. Their early growth is highlighted in a study by Chang et al, which showed that by 3 months of age, 80% of superficial haemangioma growth has been achieved.4 This growth is followed by a period of slow involution, often over many years. But ‘involution’ does not necessarily imply resolution with normal appearing skin. In addition to permanent skin changes, certain anatomic locations and patterns may prompt further investigation or medical intervention.
Whether treatment is needed, and if needed which treatment should be chosen, depends on the particular clinical situation. Such decisions are usually clear-cut if there is a primarily medical rationale for treatment, for example a threat to vision or airway, but may be less straightforward if the concern is the threat of tissue distortion or scarring potentially leading to permanent disfigurement. Factors to consider in such cases include the age of the patient as well as the specific location and size of the haemangioma. Lacking RCTs or broad consensus on IH treatment, each patient must be managed on a case-by-case basis. However, there are certain common scenarios indicating when and why treatment may be necessary. It is also important to anticipate which patients may require additional evaluation for associated localised or extra-cutaneous morbidities. Generally, difficult IH are observed in the following types of clinical presentations:
Those that ulcerate
Those which can result in permanent disfigurement
Those leading to functional impairment
Those with associated structural anomalies
Those posing life-threatening complications.
In scenarios 1 and 2, intervention is almost always required. In scenarios 3, 4 and 5, further evaluations as well as intervention are needed.
Ulceration
Ulceration is the most common complication of IH, occurring in 15–25% of IH in a referral setting.5 6 Risk factors include large size, a superficial component, and location on mucosal or intertriginous surfaces. Large IH in such high risk locations, and those with early white or grey surface discoloration are very likely to proceed to ulceration.7 Unfortunately, specific interventions to prevent ulceration are not well established, but identifying at-risk patients is very helpful in planning prompt and frequent follow-up. In addition, conservative measures such as the avoidance of friction, liberal use of emollients on at-risk sites and possible systemic treatment aimed at halting proliferation may help minimise ulceration. Pain and scarring are the major causes of morbidity secondary to ulceration. Other complications such as bleeding or infection are uncommon.
Treatment of ulceration
Conservative wound care with topical modalities such as barrier emollients like Aquaphor (petrolatum) in conjunction with non-adherent dressings such as thin hydrocolloid dressings or petrolatum impregnated gauze, are typically used as first-line treatment for ulceration. When crusting is present, it must be debrided with dilute hydrogen peroxide or saline soaks 2–3 times daily, as crusting can prevent re-epithelialisation and can become a source of infection. To help with pain control, topical lidocaine 2–5% ointment can be applied directly to the ulcer in small (pea-sized) amounts up to 3–4 times daily. Other topical treatments often used in the setting of ulceration include topical metronidazole gel or cream, while becaplermin gel (a topical platelet derived growth factor) is sometimes used as a second-line topical agent.8
Another physical modality used with some success in the treatment of ulcerated haemangiomas is the flashlamp-pumped pulsed dye laser, which has been reported to be effective in both pain relief and expediting healing.9 Early surgical excision can also be helpful in ulcerated IH where a scar is anticipated. In addition, oral propranolol has recently been described in the management of ulcerated haemangiomas; however, further studies are needed to evaluate the efficacy and safety of propranolol in this setting.10
Haemangiomas leading to permanent disfigurement
The recognition that IH can lead to permanent disfigurement has increased greatly in the past 2 decades. Indeed, in a large cohort study, prevention of disfigurement was the most common reason, apart from ulceration, for active treatment.11 There are numerous scenarios where the location, size or shape of an IH may lead to significant aesthetic compromise. In general, haemangiomas that are large and occupy a territory or region (ie, those that are segmental) are more commonly associated with complications including potential disfigurement. Large, segmental haemangiomas with a prominent superficial component may leave significant textural changes or scarring in their wake. Paediatricians may wish to consider early referral of such patients to a subspecialist, as possible complications and/or associated structural anomalies are significantly higher with this presentation (see PHACE association below).
Localised haemangiomas in specific anatomic locations (particularly those on the central face or involving contoured surfaces, for example the nasal tip, lip, etc) may also cause significant aesthetic concern. Nasal tip haemangiomas may cause splaying of the alar cartilage during the proliferative phase, resulting in the so-called ‘Cyrano’ nose deformity.12 13 Early intervention with intralesional corticosteroid or systemic therapy is often warranted in affected patients. In cases where the deformity persists, surgical debulking prior to school age can be helpful.14 Similarly, haemangiomas of the lip may become bulky or ulcerated, and permanently distort the normal lip anatomy. IH with a very prominent superficial component, particularly if sessile or pedunculated, can lead to excessive stretching of the overlying skin, resulting in permanent atrophy, textural change and persistent fibrofatty residuum. When located on the head and neck or in a prominent location, these sequellae can lead to significant disfigurement, and while the goal is to prevent such changes, if they have already ensued, early surgical correction is quite reasonable. Use of a purse-string closure technique has been reported to help minimise the size of the resultant scar.15
Haemangiomas leading to functional impairment
Haemangiomas can lead to functional impairment in a variety of clinical scenarios. The most common pertains to periorbital haemangiomas that can threaten developing vision. Obstruction of vision from periorbital IH can lead to strabismus and amblyopia.16 Astigmatism is another frequent complication of periobital haemangiomas. Infants with periorbital haemangiomas should be referred very early on (4–8 weeks of age) for frequent, regular eye examinations by an ophthalmologist during the proliferative phase. If visual compromise is suspected or detected, systemic therapy or surgical debulking is usually indicated.17,–,22 Other examples where functional impairment is a significant concern include large or ulcerated haemangiomas located on the lip/perioral area which interfere with feeding. In addition, bulky IH located on the head and neck, or ears, may lead to positional torticollis and/or plagiocephaly.
Haemangiomas with associated structural anomalies
There are at least two distinct clinical scenarios where IH can indicate a possible underlying structural anomaly: large facial haemangiomas (typically 5 cm in size or greater) and medium to large haemangiomas involving the lumbosacral or perineal regions. Patients with large, segmental facial IH are at risk for both adverse aesthetic outcomes (see above) and associated structural anomalies. PHACE association (posterior fossae abnormalities, haemangioma, arterial/aortic anomalies, cardiac anomalies, eye abnormalities and sternal/supraumbilical raphe) is an uncommon but not rare neurocutaneous disorder for which diagnostic criteria have been proposed.23 24 Prospective studies have demonstrated that patients with facial IH greater than 5 cm in diameter have an approximately 30% risk of PHACE, with cerebrovascular anomalies being the most common extra-cutaneous association.25 26 Particular facial segments appear to correlate with an increased risk of this association, principally haemangiomas affecting the frontal and temporal skin and those overlying the mandibular skin (so-called segments 1 and 3).23 Optimal evaluation for PHACE includes MRI and MR angiogram of the head and neck, echocardiogram (particularly to detect aortic arch anomalies), ophthalmological examination for structural anomalies and thyroid function studies. Patients with segmental facial IH often require systemic therapy to prevent other possible complications (ie, ulceration, visual compromise, airway disease) and to preserve normal facial anatomy.
IH overlying the lumbosacral skin or perineum can be associated with underlying structural anomalies including lipomyelomeningocele and tethered spinal cord. The structural anomalies in this region have been referred to by different acronyms that highlight similar associations: SACRAL (spinal dysraphism, anogenital, cutaneous, renal and urological anomalies, associated with an angioma of lumbosacral localisation) syndrome,27 PELVIS (perineal haemangioma, external genitalia malformations, lipomyelomeningocele, vesico-renal abnormalities, imperforate anus and skin tag) syndrome28 and LUMBAR (lower body haemangioma and other cutaneous defects, urogenital anomalies, ulceration, myelopathy, bony deformities, anorectal malformations, arterial anomalies and renal anomalies).29 Infants with large or segmental IH in the lumbosacral area require further evaluation including MRI of the spine. In one recent prospective study, ∼50% of infants with IH overlying the lumbosacral area were found to have an associated intraspinal abnormality and ultrasound was not as sensitive as MRI in detecting these anomalies.30 Moreover, in very young infants (<3 months old), MRI may not be sensitive enough to detect tethered spinal cord, so if no sinus tracts or symptoms are present, MRI may be best deferred to approximately 6 months of age, or repeat imaging may be considered in patients where there is a high index of suspicion.
Haemangiomas associated with potentially life-threatening complications
IH affecting the liver or the airway can lead to life-threatening emergencies. The liver is the most common extra-cutaneous site of IH involvement. Liver haemangiomas are found in approximately one-quarter of patients with five or more cutaneous haemangiomas, which percentage increases with increasing numbers of haemangiomas. Liver ultrasound, with Doppler flow assessment of the hepatic blood flow, is helpful to evaluate underlying hepatic involvement. The presence of liver haemangiomas, however, does not necessarily mandate treatment as most, similar to cutaneous haemangiomas, remain asymptomatic. If liver haemangiomas are present, but are small, asymptomatic and not replacing large areas of liver parenchyma, serial ultrasound (most often monthly) can be helpful in following patients to ensure that the haemangiomas stabilise rather than continue to grow.31 Much less commonly, liver haemangiomas can cause high-output heart failure or severe liver enlargement with consumptive hypothyroidism can ensue.32,–,34 In these clinical situations, systemic therapy aimed at shrinking the intrahepatic lesions may be necessary. Many different therapeutic agents have been used in this setting with reported benefit including systemic corticosteroids, interferon α (IFN α) and vincristine, but propranolol has emerged as a particularly useful medication for severe hepatic haemangiomas.35 In rare severe cases, surgical intervention and even hepatic transplantation have been carried out.36 37
Haemangiomas involving the airway can be potentially life-threatening. Cutaneous IH in the mandibular distribution (facial segment S3), particularly bilateral skin disease, is a marker for a high risk of airway haemangiomas, but occasionally infants with IH at other sites or even without cutaneous haemangiomas may be affected.11 Many infants with this anatomical distribution of cutaneous haemangiomas also require therapy to prevent disfigurement. Those with bilateral mandibular haemangiomas, even in the absence of airway signs or symptoms, should ideally be referred to paediatric otolaryngology for airway evaluation. Clinicians should also be aware of the signs and symptoms of airway haemangiomas, principally hoarse cry, stridor or noisy breathing, with onset most often occurring between 4 and 12 weeks of age. Prompt referral to paediatric otolaryngology is important to directly evaluate the airway and systemic therapy should be started promptly or medication dosages increased as severe proliferation of IH in the airway can be life-threatening. Tracheostomy, which used to be a relatively frequent outcome, is rarely necessary now that effective systemic therapy is given early in the course of disease. While oral corticosteroids at high doses (3–5 mg/kg/day) can be beneficial,38 oral propranolol is gaining favour as a first-line treatment.39,–,41 Adjunctive laser therapy can also be helpful, particularly in cases where there is a relatively circumscribed area of bulky disease.
Treatment modalities
Topical therapies
There are no large randomised studies supporting the use of any topical agent in the treatment of IH. However, there are reports of several topical agents which show some efficacy when used during the early proliferative stages. These include potent topical steroids, imiquimod cream and topical timolol maleate gel. In general, topical therapies are most useful for early superficial lesions as deep or large IH are unlikely to respond to topically applied agents. Recently, in response to the initial promise of oral propranolol in the treatment of IH, topical timolol maleate 0.5% gel has been reported to be effective in treating small, superficial IH.42 43 Theoretical complications include systemic absorption leading to hypoglycaemia, hypotension or bradycardia. Topical timolol has been gaining favour with paediatric dermatologists as it appears to be safe and effective for small, superficial IH despite the potential for the side effects mentioned above. Superpotent topical steroids, particularly clobetasol, have shown some benefit in treating small superficial IH and may have some limited efficacy in periorbital lesions.19 Potential side effects include possible systemic absorption, cutaneous atrophy and striae, so close follow-up is necessary. Topical imiquimod cream has also been reported to be effective in treating some small superficial lesions44,–,47 and may be considered as a treatment option in early IH of the head and neck area. Crusting, irritation and theoretically, ulceration, are possible complications.
Intralesional therapies
Intralesional steroids for the treatment of IH were originally administered by ophthalmologists for periorbital lesions.48 However, this treatment is now less popular due to the risk of retinal artery damage and blindness.49 Intralesional steroids for IH on other sites such as the lip and nasal tip, can be helpful in stabilising growth or decreasing the bulk of the haemangioma, and if successful, may obviate the need for systemic therapy and/or surgery. Several treatments are usually undertaken about 3–4 weeks apart. Usually, triamcinolone 10 mg/ml is used and doses typically do not exceed 1–2 mg/kg per injection. Possible side effects include bleeding, skin atrophy, infection and adrenal suppression.
Systemic therapies
β Blockers
In many of the clinical scenarios outlined above, prompt administration of systemic medications maybe warranted. In the past 3 years there have been more than 120 reports regarding the efficacy of oral β blockers – principally propranolol – as a highly effective therapy for IH and its complications. A large international RCT is underway, but many are already advocating this as first-line treatment for IH both in terms of safety and efficacy.50
Propranolol is a non-selective β-adrenergic blocker which has previously been used mainly to treat cardiac conditions in infancy or neonatal hyperthyroidism. It was first reported to shrink IH by Léauté-Labrèze et al in 2008.51 Subsequent reports have emphasised that this therapy is effective not only in halting haemangioma growth but also in diminishing the size of haemangiomas, up to and even after growth has already been completed.52 Other β blockers such as acebutolol and nadolol have also shown beneficial effects, but the vast majority of reports concern the use of propranolol.39 53,–,58 Propranolol is most often administered at 1–3 mg/kg divided into twice or thrice daily doses. Protocols for dosing, initiation of therapy and monitoring vary widely. In young patients <2 months of age, many physicians initiate therapy during a brief in-patient hospitalisation, whereas in older children the medication is often administered on an outpatient basis, in some cases with a gradual titration of dosage upwards over a few days to 1–2 weeks. Propranolol has many potential side effects, including hypoglycaemia, hypotension and bradycardia, exacerbation of reactive airway disease and drug–drug interactions. Hypoglycaemia has emerged as a rare but particularly worrisome side effect; additional complications such as diarrhoea and hyperkalemia have also recently been reported.59,–,61 Until larger clinical trials are completed, awareness of potential adverse events and consultation with local specialists such as paediatric cardiologists is recommended prior to initiating treatment. Patients with PHACE syndrome and severe cerebrovascular disease are, at least in theory, at risk for demand-related brain ischaemia with even relative hypotension from β blockers. Risks and benefits in this subset of patients must be weighed carefully.
As the dose and initiation protocols for administering oral propranolol seem to vary widely, so does the duration of treatment. This is in part due to the fact that rebound growth has often been noted after discontinuing medication. Therefore, many clinicians feel most comfortable maintaining treatment with propranolol until well after the growth phase is completed, which with deep or large IH, can be up to 1 year of age. A recent small RCT of 20 patients treated with oral propranolol and 20 patients treated with placebo demonstrated the safety and efficacy of oral propranolol in a small number of patients. In this study, significant rebound growth after propranolol was discontinued was documented mainly in infants under the age of 12 months.62
Systemic corticosteroids (prednisolone, prednisone)
Corticosteroids have been the mainstay of systemic therapy for IH since the 1960s.63 Prednisolone, most typically administered at 2–3 mg/kg/day, is often given as a single daily dose. In general, systemic steroids are very effective in halting haemangioma growth during the proliferative phase (1–4 months).64 One meta-analysis showed that 3 mg/kg is likely the most effective dose, achieving stabilisation of growth in 90% of patients.65 Side effects are well known and include gastrointestinal upset and irritability, weight gain, cushingoid appearance, hypertension, growth delay, adrenal suppression and immunosuppression. In most cases, corticosteroids are very well tolerated despite potential side effects. Regular follow-up and monitoring of height, weight and blood pressure is recommended while on treatment.
Vincristine
Vincristine is a vinca alkaloid chemotherapy agent widely used by oncologists to treat haematological and solid tumour malignancies. It has been used with success in the treatment of life-threatening IH, most commonly in conjunction with systemic corticosteroids and/or other therapies.66 Vincristine is administered intravenously at a dose of 1.0–1.5 mg/m2 weekly. Like any immunosuppressive agent, vincristine has many side effects when used at high doses, however, in patients with IH, the medication seemed to be well tolerated. Collaboration with a consultant haematologist/oncologist and regular monitoring are necessary.
Interferon α
Recombinant IFN α (2a and 2b) has known antiangiogenic properties and has been used in the management of complicated IH failing other forms of medical therapy.67 Its use has been limited since the recognition of spastic diplegia in up to 20% of treated patients.68 69 Most clinicians view IFN as a third line therapy and it is not widely used in patients under 1 year of age.
Conclusion
Although most IH do not require intervention, there are many clinical situations (as described above and summarised in table 1) when prompt treatment is necessary to prevent life-threatening complications or potential disfigurement. Due to their heterogeneity, recognising which haemangiomas will require intervention and why can be quite challenging. Management of these difficult cases should be based on experience and in-depth understanding of the presentation and natural history of IH. In specific cases where the rationale for treatment might be unclear, collaboration with a paediatric dermatologist or other subspecialist is often necessary. Ideally, consultation with a multi-disciplinary vascular anomalies team can be extremely helpful in managing difficult haemangiomas.
Management of difficult infantile haemangiomas
References
Footnotes
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Competing interests None.
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Provenance and peer review Commissioned; externally peer reviewed.