By Gary M. White, MD
The infantile hemangioma is a vascular proliferation occurring in infancy. Lesions typically regress spontaneously during childhood. Females and preterm infants are preferentially affected. There are rare families where hemangiomas are more common, with an autosomal dominant inheritance pattern being seen. Occasionally, hemangiomas may be associated with other malformations, e.g. a large facial hemangioma with the Dandy-Walker malformation, a plaque-like hemangioma spanning the midline of the sacrum with a tethered cord, or a hemangioma over the neck and airway involvement.
Hemangiomas usually present during the first month of life. They may be present at birth, but more commonly the skin at birth shows a mild abnormality (e.g. a barely visible, white, anemic stain, a faint, telangiectatic lesion, a blue spot mimicking a bruise). Over the ensuing weeks and months, the lesion enlarges. One study showed that 80% of the growth occurs in the first 3 months with the greatest in the second month of life [Frieden]. Lesions may ulcerate. Although the hemangiomas usually decrease in size between ages 2 and 10 years, a single study found that most of these tumors do not regress after age 3.5 years.
In general terms, hemangiomas may be divided into superficial, deep or mixed.
Many parents worry that the IH will “pop like a balloon” resulting in uncontrolled bleeding. Thankfully, most hemangioma bleeding is slow, minor, and can be controlled with 10 to 15 minutes of direct pressure.
See vascular lesions congenital/newbown. A hemangioma differs from a vascular malformation in that the former proliferates, typically for the first 3-9 months of life and rarely beyond a year and a half. Congenital hemangiomas include RICH and NICH. Rhabdomyosarcomas, infantile myofibromatosis, etc. can resemble hemangiomas but are more firm. Any hemangioma that seems excessively firm deserves careful evaluation and biopsy if necessary. Rarely, a hemangioma may be so flat at birth as to resemble a port wine stain. Deep hemangiomas can be a challenge diagnostically and imaging may be very helpful.
Vascular lesions full size at birth may represent RICH, NICH, partially involuting hemangiomas and vascular malformations.
Glucose transporter 1 (GLUT-1) is found normally in placental blood vessels and blood-brain barrier blood vessels. 97% of Hemangiomas test positive for GLUT-1. RICH and NICH area glut-1 negative.
In the perfect situation, all patients with an IH or suspected IH would be evaluated as early as possible by a pediatric dermatologist or other clinician familiar with the use of topical timolol, oral propranolol and pulsed dye laser (PDL). Clearly, these therapies are more efficacious the sooner they are employed. Waiting until the IH has undergone the "growth spurt" (usually at 5-7 weeks of life) makes both topical timolol and laser less effective. Topical timolol is readily available, efficacious and with few side effects than PDL. It may be employed for most uncomplicated IH. In selected cases, PDL therapy can be very beneficial, but side effect and logistics are issues (e.g. will general anesthesia be needed? Pain control during the procedure, etc.) Lesions on the face may require close follow up (weekly?) to assess response to therapy, growth and any potential complications.
Referral to a pediatric dermatologist may be considered for the "alarming" hemangiomas (those that interfere with vital functions such as eating, breathing, seeing), and those larger ones on the face, perianal area or lumbosacral area or those associated with other congenital abnormalities. Nasal hemangiomas develop the most complications, e.g., airway obstruction, ulceration, visual obstruction, ocular compression and infection. Involvement of the beard area and neck should prompt airway evaluation to exclude subglottic infantile hemangiomas which can cause life-threatening airway obstruction [JEADV 2016;30;2056]. Systemic propranolol may be indicated. Sometimes, infants are seen too late, e.g. at 12 weeks of age, when most of the growth has already occurred. In that case, a short course e.g. 2-3 months of propranolol, may considered to see if there is any effect.
Two studies have found that 92% of IHs completely involute by age 4. Even though the IH may have involuted, that does not mean that normal skin remains. In one study of 184 hemangiomas [JAMA Derm 2016;152;1239], resolution to normal skin only occurred in 45%. Common sequelae included telangiectasias (84%), fibrofatty tissue (47%), and anetodermic skin (33%). Combined hemangiomas with a superficial component and a step border were associated with more sequelae. Once resolution has occurred, the skin should be evaluated for cosmesis, and redundant skin excised if needed. Active treatment with propranolol in various studies has shown complete regression without sequelae after 6 months of treatment in 60% of cases. Thus, consideration of propranolol or other active therapy should be considered, especially in larger lesions.
One drop of topical timolol 0.5% liquid (eyedrops) or gel forming solution may be applied BID. Starting as early as possible is key. Both the liquid and gel are equally efficacious [PD 2017;34;492], but the liquid is not as convenient as it tends to run off the hemangioma onto normal skin. Measured blood levels of timolol are either undetectable or very low in most cases [Sheila Fallon-Friedlander, MD].
In one dBPCT of infants aged 5-24 weeks, timolol appeared most effective in the management of infantile hemangiomas with a volume of 100 mm3 or less. No episodes of bradycardia nor hypotension were seen. A key point is that the effect may not visible for 4 months especially for thicker lesions. The mean duration of therapy in one study was 9.5 months. Make sure to follow closely to make sure not proliferating rapidly (and might need oral propranolol). Initiation of therapy within 3 months of life and superficial lesions respond best.
In preterm infants, those with ulceration, large surface area or mucosal lesions, the concern of systemic effect similar to oral propranolol has been raised. Close monitoring of temperature, blood pressure, and heart rate in premature and low-birthweight infants with IHs at initiation of and during therapy with topical timolol is recommended [PD 2016;33;405].
Timolol is particularly useful for periorbital hemangiomas. There is little concern if it smears into the eye as it has been used for treatment of glaucoma in infants for decades.
If PHACES is a possibility, timolol treatment should not be initiated because of concern about cardiovascular effects.
The FDA approved the first and only beta-blocker formulation in March 2014 for the treatment of proliferating infantile hemangioma requiring systemic therapy. Hemangeol™, was studied in infants aged 5 weeks to 5 months. In a RDBPCT, propranolol 3 mg/kg/day for 6 months demonstrated a 60.4% success rate (complete or near complete resolution) vs. 3.6% in the placebo group. Side effects include drop in blood pressure (usually mild), sleep disturbances, and hypoglycemia. Treatment may need 10-12 months. Many experts in clinical practice use 2-2.5 mg/kg/day and that is sufficient. Premies are more likely to have issues with hypotension, so for them a lower dose is preferred, e.g. 1-1.5 mg/kg/day. A question was asked of pediatric experts, "Do you admit the patient to start propranolol?" Most only for specific situations, e.g. parents not reliable, very complicated/severe case.
Hypoglycemia, though rare, can induce seizures. Temporarily suspending treatment with propranolol may be considered in infants with restricted oral intake, e.g. during a respiratory illness.
Rebound of hemangiomas treated with propranolol occurred in 25% of cases in one review of nearly 1000 [Pediatrics online March 7 2016].
Concern has been raised about potential CNS side effects and the use of propranolol [Br J Dermatol 2015 Jan 01;172(1)13-23]. Unfortunately, studies in infants are lacking.
IL propranolol in one small study of 6 children had no effect (PD March 2014). A comparative study of atenolol vs propranolol in 23 patients, no significant difference was seen in results or side effects [JAAD 2014 :70:1045]. In a comparative study against captopril, propranolol was found superior [JAAD 2016;74;499].
Nadolol is a nonselective beta-blocker with no intrinsic sympathomimetic activity, and in contrast to propranolol, it has little myocardial depressant activity, wider therapeutic uses in childhood, and a longer half-life of 12–24 hours. A twice daily dosage is recommended in children younger than 22 months. The longer half-life improves adherence and decreases rebound. In contrast to propranolol, nadolol cannot cross the blood–brain barrier, decreasing adverse events such as nightmares and concerns about longterm memory loss. Patients with proliferative IH, treated with oral nadolol for 6 months, experienced almost complete involution of their tumor, which was significantly different from patients treated with propranolol. [Br J Dermatol. 2013 Jan;168(1):222-4].
The initial article [J Dermatol. 2015;42:202] and subsequent communication from the author [Dermatology News Jan 2016;p. 24] shows that about 70% (12/17) of infants experienced 80-100% improvement in their IH with oral itraconazole 5 mg/kg/day given for an average of 8.8 weeks. Liver tests should be monitored but in his series they have been normal. 30% of patients have mild diarrhea.
One study showed a high clearance rate with just one treatment using the 650 microsecond, pulsed 1064-nm Nd:YAG laser, spot size 2-3 mm and fluence of 42-64 joules [Dermatology News June 2016, p. 31]. The best results were in patients treated in the first 6 weeks of life. Over 75% of hemangiomas were either completely or almost completely cleared over the 1-year follow up period.
Imiquimod has been used for infantile hemangiomas [Clin Exp Dermatol. 2013 Dec;38(8):845-50]. In a comparison study of imiquimod 5% every other day vs timolol TID [Dermatology. 2015;230(2):150-5], timolol was superior, especially in terms of earlier onset and fewer side effects.
See ulcerated hemangioma.
Small lower lip. If not bleeding nor interfering with eating, topical timolol.
Systemic steroids were the old treatment before propranolol. IL steroids don't work.
Initial look of hemangioma and several weeks later.
A very large, extensive hemangioma. MRI is in order. Courtesy Michael O. Murphy, MD
Mixed type of infantile hemangioma with red superficial portion and a deep nodular component. Courtesy Michael O. Murphy, MD
Redundant skin on the abdomen of an adult who had an IH there as a child.
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