Infantile hemangiomas: Diagnosis and treatment

By Beth A. Drolet, MD, and Anna Juern, MD

Case illustration:

Figure 1 Plaque encompassing most of the patient's eyelid.

A 2-month-old preterm female was transferred to Children's Hospital of Wisconsin for a large hemangioma on her right upper eyelid. She was a product of a twin gestation, born at 26 weeks with a birth weight of 940 grams. This hemangioma was not present at birth but became apparent at 2 weeks of age and rapidly grew to the point where the patient was unable to open her right eye fully. There was concern for the development of deprivation amblyopia. The patient also had two smaller hemangiomas, one on her scapula and another on her mid lower back. On physical examination, she had a 1.5 x 1.8 cm, bright-red plaque overlying a 2.5 x 2.9 cm, subcutaneous, bluish nodule on the right upper eyelid. The plaque encompassed most of the eyelid. (See Figure 1.) Patching of the left eye was initiated to help prevent amblyopia. Oral prednisolone was given to preserve vision. This halted the proliferation of the hemangioma, however, the eye remained closed. Based on a recent case series, oral propranolol subsequently was added. Over the next six weeks the eyelid hemangioma decreased in size and the patient was able to open her right eye.

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 recent case-control study published in the Journal of Pediatrics 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 per-centage 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?

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

Figure 2a Localized hemangioma.

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:  

Ulceration: This is the most frequent complication and typically occurs in deep, rapidly enlarging hemangiomas or in those located in trauma- or pressure-prone areas of the body. These can be excruciatingly painful and carry the risk of infection, hemorrhage and scarring. When hemorrhage occurs, blood loss usually is minimal and can be controlled with direct pressure. Hemangiomas of the anogenital region are particularly at risk for ulceration and infection and are accompanied by severe pain upon urination or defecation. Superinfection may lead to

Figure 2b Segmental hemangiomas.

cellulitis, osteomyelitis, septicemia and, in some cases, has been lethal.

Functional impairment: Periorbital hemangiomas pose considerable risk to vision and should be carefully monitored with early involvement by an ophthalmologist to prevent permanent damage including blindness. Astigmatism, caused by insidious compression on the cornea by the growing hemangioma or extension of the tumor into the retrobulbar space, is the most common complication. Stimulus-deprivation amblyopia may result from physical obstruction of the visual axis by the hemangioma. Periocular hemangiomas can be subtle without cutaneous manifestations and may extend deep into the orbit causing exophthalmos or globe displacement. Hemangiomas involving the ear may obstruct the external auditory canal, resulting in otitis externa or a temporary conductive hearing loss, which ultimately may cause speech delay. Large nuchal hemangiomas may impair neck range of motion, albeit temporarily. Airway hemangiomas can be life-threatening and do not always occur in the setting of cutaneous findings. Hemangiomas of the beard distribution (preauricular region, chin, lower lip, mandibular region and anterior neck) pose the greatest risk. Subglottic hemangiomas can cause hoarseness and stridor (noisy breathing) with progression to respiratory failure, often occurring at 6 to 12 weeks of age. In these cases, direct endoscopic visualization of the airway is warranted. Close clinical observation is advised in asymptomatic patients, as 60 percent of them will develop symptomatic airway hemangiomas.

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).  

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, which was described 10 years ago. Preliminary results from a study by the Hemangioma Investigator Group revealed 65 percent of infants with large (greater than 22 cm2) hemangiomas of the head or neck had at least one associated finding. Infants with large facial hemangiomas 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. A 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 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. Table 2 shows therapeutic consideration to be taken into account when deciding whom to treat.

When treatment is indicated, the standard of care is oral corticosteroids as a result of their antiproliferative effect. Other treatment options include topical and intralesional corticosteroids, laser therapy, wound care for ulcerated lesions and surgical excision. Newer agents include vincristine and propranolol, which have been used for life- or vision-threatening hemangiomas unresponsive to oral corticosteroids. Vincristine functions by interfering with mitotic spindle microtubules and induces apoptosis in tumor cells in vitro. It is effective but has potentially serious side effects. Currently Children's Hospital is conducting a randomized clinical trial looking at the efficacy and safety of oral prednisolone versus intravenous vincristine in the treatment of infantile hemangiomas. Propranolol recently has been shown to be effective in a non-case-controlled series. Although these results are encouraging, further studies need to be completed to demonstrate superiority over existing therapeutic interventions. In addition, toxicity data needs to be collected for this indication. Many infants with hemangiomas are preterm and low birth weight and are at greater risk for hypoglycemia from propranolol. In addition, the effect of beta blockage on infants with cerebrovascular anomalies (PHACE) is not understood.