What are infantile hemangiomas?

Infantile hemangiomas are benign vascular tumors that are characterized by a rapid growth phase followed by a spontaneous involution phase. Most infantile hemangiomas are found in the skin, and they occur rarely in the liver, spleen, gastrointestinal tract, airway and central nervous system. A precursor lesion may appear at birth as a pink or red macule or patch that resembles a bruise or telangectasia at the hemangioma site. Single lesions predominate, but there also can be multiple lesions in up to 20 percent of infants, with the head, neck and trunk being the areas most often affected. Clinical appearance of infantile hemangiomas depends on their location within the skin. A superficial hemangioma is a well-demarcated, elevated, bright red mass or plaque that blanches incompletely with pressure. Sometimes a hemangioma can have a deep component that is a soft, flesh-colored, rubbery, ill-defined subcutaneous mass with a bluish hue.

What is their pathogenesis and who is at risk?

Most cases of hemangiomas are sporadic, but a recent study showed a third of the patients had a first-degree relative with a vascular anomaly and 12 percent had a first-degree relative with a hemangioma. The mechanisms for the development of infantile hemagiomas are not completely understood and their pathogenesis is just now being elucidated. The current theory is that endothelial precursor cells in circulation respond to hypoxic stimuli and undergo vasculogenesis (the formation of primitive blood vessels from angioblasts), leading to the formation of infantile hemangiomas. Several risk factors for the development of infantile hemangiomas exist, including female sex, Caucasian race and preterm birth. Increased maternal age, multiple gestation, pre-eclampsia, placenta previa, maternal history of infertility, chorionic villus sampling, assisted reproductive technologies and ovulation promotion also have been suggested as additional risk factors. Many of these factors, such as increased maternal age and multiple births via reproductive technologies, are related rather than independent variables. Our case-control study utilized multivariate regression models to demonstrate that the most significant risk factor is low birth weight (less than 2,500 gm).

Is the incidence of infantile hemangiomas increasing?

Infantile hemangiomas are among the most common birthmarks, however, their exact incidence is not known. Unlike most congenital anomalies of the skin, infantile hemangiomas are not noted at birth but become evident within the first few weeks of life as they begin to proliferate. They are therefore less amenable to tracking via traditional birth-defect registries. Most practitioners believe the number of infants with infantile hemangiomas has been increasing. We have observed an increase in the number of infants with infantile hemangiomas presenting for care. The Birthmarks and Vascular Anomalies Center at Children's Hospital of Wisconsin has seen an 800 percent increase in hemangioma-related visits over the past 15 years. With the results of our recent study, we now believe we have an explanation for this emerging disease of childhood. The rate of preterm and low-birth-weight infants in the U.S. continues to rise. In 2005, 8.2 percent of infants born in the U.S. were less than 2,500 gm, the highest percentage recorded since 1968 and higher than the rate in most industrialized countries. This rise is highest in white, non-Hispanic infants, the group at greatest demographic risk for developing infantile hemangiomas – an increase of 38 percent since 1990. Our study demonstrated that for every 500 gm decrease in birth weight, the risk of infantile hemagiomas increased by 40 percent. Assuming a 15 percent incidence of hemangiomas in preterm infants, the number of hemangiomas in preterm infants on the basis of low birth weight alone would be expected to more than double, from 20,000 in 1985 to 50,000 in 2005. While the use of assisted reproduction per se was not found to be an independent risk factor in this study, most experts agree that it has contributed significantly to the overall rise in premature and low birth weight infants in the U.S., especially in white, non-Hispanic infants.

What are the complications of hemangiomas?

Figure 2a Localized hemangioma.

Although hemangiomas spontaneously resolve, up to 24 percent of infants will have complications. Outcome depends on the size, location and subtype of hemangiomas, with the single most important factor being hemangioma subtype. Larger hemangiomas carry a higher risk for complications and those that compromise a vital structure can be life threatening despite their size. (See Table 1.) There are two subtypes of hemangiomas: localized (focal) and segmental. Localized hemangiomas appear to arise from a single focus and demonstrate clear, well-defined spatial confinement. (See Figure 2a.) Segmental hemangiomas arise multifocally from what appears to be an embryologic "segment" and display linear or geographic patterns. (See Figure 2b.) Segmental hemangiomas are more common in female infants and have an increased risk of complications and an overall poorer outcome than localized hemangiomas. Potential complications of hemangiomas can be divided into three categories:

Figure 2b Segmental hemangiomas.

Functional impairment:

Permanent disfigurement: The location, rate of growth and depth within the skin of the hemangioma, the age of the patient and presence of complications govern the likelihood that hemangiomas will cause permanent damage. Hemangiomas with prominent dermal components, particularly those involving the lips, nose, ears and forehead, and those with deep ulceration, are at greatest risk for scarring. In these locations large or rapidly growing lesions will leave residual fibrofatty tissue, even after the hemangioma has involuted. In some instances the fibrofatty tissue is relatively easy to surgically remove (nasal tip), whereas in others the surgical scar may be quite conspicuous (upper lip).

Table 1: Hemangiomas high risk location

When are hemangiomas associated with congenital malformations?

Large facial segmental hemangiomas are associated with PHACE (Posterior fossa malformations, Hemangiomas, Arterial anomalies, Coarctation of the aorta and cardiac anomalies, Eye anomalies and Sternal cleft) syndrome. Preliminary results from a study by the Hemangioma Investigator Group revealed 30 percent of infants with large (greater than 22 cm²) hemangiomas of the head or neck had at least one associated finding. Infants with large infantile hemangiomas of the face, neck and scalp should be referred to a pediatric dermatologist given the high risk of complications, need for treatment and associated malformations. Spinal dysraphic conditions have been described in infants with hemangiomas overlying the lumbosacral spine. Our multi-institutional HIG study evaluating patients with midline hemangiomas greater than 2.5 cm in the lumbosacral region had a positive predictive value for occult spinal dysraphism in asymptomatic patients. Radiological imaging is indicated in infants with hemangiomas over the lumbosacral region, particularly along the midline.

When and how should hemangiomas be treated?

Treatment of infantile hemangiomas is challenging given the wide spectrum of disease, unpredictable biologic behavior and natural tendency for involution. Aggressive treatment is necessary for infants at highest risk for complications. Treatment of infantile hemangiomas is designed to control growth, minimize deformity, preserve function and limit the amount of psychological and emotional stress on the patient and parents. Systemic pharmacotherapy is used to treat large lesions, lesions that present a surgical challenge or those causing functional or life-threatening problems. Much of the treatment for infants and children with vascular anomalies is based on expert opinion and observational studies. There are no FDA-approved agents for treatment of infantile hemangiomas. Agents with reported activity in treating infantile hemangioma include steroids, interferon alpha, vinca alkaloids and propranolol. Prospective data addressing the efficacy and safety of accepted pharmacologic interventions for the treatment of infantile hemangioma have not been generated. As such, physicians must rely on anecdotal reports and clinical judgment to determine the optimal treatment for infants with complicated lesions.

Since the initial report of propranolol use for treatment of infantile hemangiomas in 2008, there has been a flurry of publications describing its efficacy and potential side effects. These publications were not subjected to the usual stringency of Phase I and II clinical trials. Although these results are encouraging, further studies need to be completed for this indication to collect toxicity data. Based on case reports and case series in the literature, oral propranolol appears to have a favorable safety profile in children akin to the well-established profile in adults. The most common serious adverse effects of oral propranolol include bradycardia and hypotension. Bronchospasm can be seen in patients with reactive airway disease or during an acute respiratory illness. Hypoglycemia is a recognized adverse effect of propranolol therapy that usually is related to poor oral intake, such as might occur with an intercurrent illness or prior to general anesthesia. Hypoglycemia has emerged as the most common serious adverse event for use of propranolol for infantile hemangioma. To date, there are 10 cases of severe hypoglycemia secondary to propranolol for use in infantile hemangioma. Clinical manifestations of hypoglycemia in infants can vary widely. Mild hypoglycemia produces symptoms associated with counter-regulatory epinephrine action, including sweating, shakiness, tachycardia, anxiety and hunger. With propranolol-induced Beta-adrenergic blockade, early symptoms may be masked; as sweating is not typically blocked by Beta-blockers, this may be the more reliable symptom for diagnosis. More severe hypoglycemia produces symptoms of neuroglycopenia, including lethargy, stupor, poor feeding, seizures, apnea, loss of consciousness and hypothermia. Symptomatic hypoglycemia and hypoglycemic seizures have been reported in infants with hemangiomas treated with oral propranolol. These cases occurred in both newborns and toddlers, but often were associated with poor oral intake or concomitant infection. Most of the reported patients who developed hypoglycemia were prescribed relatively low doses (1.25-2 mg/kg/day), suggesting that hypoglycemia associated with propranolol may not be dose dependent. Other milder adverse effects include gastrointestinal symptoms, sleep disturbances and mood changes with depression in older treated patients.

While oral propranolol rapidly has been adopted and has now become first-line therapy for many physicians, there is significant uncertainty and divergence of opinion regarding drug initiation, safety monitoring, dose escalation and its use in PHACE syndrome. A recent survey of providers demonstrated that significant variability in propranolol treatment protocols exists between institutions. Some centers hospitalize all patients for initiation of treatment, whereas others rarely do. Some experts recommend intensive outpatient monitoring of patients, whereas others do little to no monitoring. Our group has obtained a National Institutes of Health grant to develop consensus-derived "best practices" for use of propranolol for infantile hemangioma. An international, multinational phase II and III clinical trial is being conducted, which is likely to provide additional safety and efficacy data in the near future. Until more safety data is available, optimal care of infants with complicated infantile hemangioma requiring systemic pharmacologic therapy should be provided by physicians with expertise in both infantile hemangioma and the use of propranolol in infants. Other treatment options include topical and intralesional corticosteroids, topical timolol, laser therapy, wound care for ulcerated lesions and surgical excision.

Table 2: Hemangioma therapeutic considerations

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