Pediatric Dermatology: Infantile Hemangiomas

Sheila Freidlander, MD

Ilona Frieden, MD

In this presentation, Drs Frieden and Friedlander discuss infantile hemagiomas, coxsackie and beyond, and nail disease.

Infantile Hemangiomas (IH): What We’ve Learned

At USC, Dr Friedlander and her colleagues followed 500 babies in a prospective study looking at the incidence and risk factors for IH.  They found that overall 4.5 percent of infants were affected. The risk factors included placental anomalies (35 percent of IH deliveries) and gestational age (extreme prematurity). One of the unexpected findings was that of location (53 percent were located on trunk, only 12 percent on the head and neck), this would make sense with what one would expect as the trunk is a larger body surface area. They also found that 91 percent of the hemangiomas were focal and 23 percent were abortive/telangiectatic.  The most important thing that was discovered was that only one of the 34 lesions discovered on the 500 babies needed intervention. This is reassuring information and can help guide clinicians to “worry less” about small truncal lesions:  however facial and larger lesions should be evaluated early to determine if intervention would be appropriate.  .

IH: Where do they come?

Dr Friedlander comments that the worrisome cases are those where the potential for  functional deformity or cosmetic disfigurement exist.  There are three major theories that most experts are comfortable with regarding the pathogenesis of IH. The first  is placental embolization; supporting evidence for this includes the following:  IH share surface characteristics with placental tissue (glut-1, HPL). In addition, placental markers (hCG and hPL) are  expressed on endothelium of proliferating, but not involuting IH tissue. Other similarities between placental and IH tissue have been  identified through DNA profile clustering analysis.

The second theory concerns a somatic mutation in a gene mediating endothelial cell proliferation (VEGF receptor). VGEF (vascular endothelial growth factor) can be likened to a  stimulus package for endothelial cells. Most of the time VEGF will complex  with an inhibitory receptor. If there is not enough of the inhibitory receptor (VEGF 1) around,  then VEGF will complex  with other “more stimulatory type” VEGF receptors and  proliferation then results. Angiogenesis is a tightly regulated balance of promoting and inhibitory factors.  In the simplified model below, complexing of VEGFR2 with VEGF activates EC proliferation.

 

The third theory, which is the most popular right now, is that IH may result from a combination of factors, including the presence of an area of localized hypoxia  Vascular cells in this area of low oxygen tension produce  hypoxia inducible factor (HIF). HIF sends a message to endothelial progenitor cells in the bone marrow, which then “home” to the hypoxic area and proliferate there.

Why do the endothelial progenitor cells (EPCs) misbehave in the first place?  Perhaps they possess a mutation such as mentioned in theory 2, perhaps it is just the hypoxic endothelial cells, in a particular area, expressing  “recruitment” factor for EPCs. . It has been found that infants with IH have an increased number of circulating EPCs, supporting this latter theory.

The general belief is that all of these theories could be involved with IH.

Therapy for IH

Dr Frieden comments that extrapolating from the data from Dr. Friedlander’s study,  about one in every thousand infants will need an intervention for a hemangioma.  For several years, beta-blockers have been studied as a treatment for IH. There are more than 240 articles published. Dr Frieden and her colleagues conducted a systematic review of 41 case series, with greater than ten patients, looked at a total of 1264 patients. 28 percent of the patients received prior treatment, most commonly oral prednisolone. Propranolol was initiated at the mean age of 6.6 months at a mean dose of 2.1 mg/kg/day. The mean duration of treatment was 6.4 months.  The results of this systematic review demonstrated a response rate of 98 percent (range 82-100 percent). The response rates were comparable irrespective of anatomic sites. There was rebound growth in 17 percent. Adverse events occurred in about three to five percent, with sleep changes and acrocyanosis being the most common. Serious AEs were rare. (Marqueling et al. Pediatr Dermatol. 2013; 30(2):182-91.

In Dr Frieden’s experience, this response rate really parallels that of isotretinoin, i.e. it works so well that  you don’t really need statistics to prove that it works. Dr Frieden also comments that in her practice, they have been treating IH with propranolol for several years and have seen remarkable results.

Steroids versus Propranolol

Another systematic review compared steroids to propranolol. The review of literature was conducted from studies from 1965-2012; 16 studies (2,629 patients) versus 25 studies (795 patients). The overall efficacy rate for systemic steroids was 71 percent compared to 97 percent for propranolol.  AEs for steroids were 17.6 percent versus 13.7 percent in propranolol. This review concluded that propranolol has greater efficacy and acceptable AEs for the treatment of IH. (Izadpanah A, et al. Plast Reconstr Surg. 2013;131(3):601-613.)

Propranolol Consensus Guidelines

Dr Frieden and her colleagues developed guidelines in order to come up with best practices for treating these patients. It is important that dermatologists understand whether patients should be treated inpatient or outpatient. Inpatient hospitalization is suggested for infants younger than eight weeks of age including  gestationally-corrected age for preterm infants, any infant with inadequate social support, and any age infant with comorbid conditions affecting the cardiovascular or respiratory systems. Outpatient treatment with monitoring can be considered for infants/toddlers over eight weeks of age with adequate social support and no significant comorbid conditions.

Regarding monitoring, the peak effect of oral propranolol on HR and BP is one to three hours after administration. Patients should be monitored with HR and BP measurement at baseline and at one and two hours after receiving the initial dose. This should be repeated with significant dose increases, i.e., greater than 0.5 mg/kg/day, including at least one set of measurements after the target dose has been achieved. If HR and BP are abnormal, then the child should be monitored until the vitals signs normalize and if necessary the dosage adjusted. The cardiovascular effects are usually most pronounced  after the first dose so there is no need to repeat monitoring  for the same dose again unless the patient is very young or has comorbid conditions. Of note, HR is usually easier to accurately obtain than BP.

With regards to hypoglycemia, routine glucose testing is not recommended. The risk of hypoglycemia is age-dependent and is related to the effects of propranolol on gluconeogenesis and glycogenolysis.  Hypoglycemia ia more likely to occur if a child has had a prolonged period of time without oral intake and is age dependent. Infants less than six weeks of age should be fed at least every four hours, infants six weeks to four months should be fed every five hours and infants greater than four months every six to eight hours. Propranolol should be temporarily discontinued during intercurrent illness, especially in the setting of restricted oral intake.

Providers must remember that these guidelines are based on current knowledge and should be considered provisional. Martin. et al have written an article providing written instructions re: propranolol therapyr  for parents and caregivers.  It is a  useful educational tool and resource for these parents and includes extremely helpful information. (Martin K, et al. Pediatr Dermatol. 2013;30(1):155-159.

How do beta blockers work?

Both speakers agree that  we don’t fully understand how this class of medications works for IH. One of the theories is that they decrease rennin production. The second theory is the regression via HIF-1-alpha-mediated inhibitor of VEGF-A and the third theory is the inhibition of “homing” of endothelieal progenitor cells to hemangioma sites, as Dr Friedlander previously discussed.

Topical Beta Blockers

Sometimes the risk-benefit ratio of propranolol is of concern. We now have an option with the  topical beta blocker, timolol, which has been  previously approved  for adult and pediatric glaucoma. There have been at least twenty articles since February 2010 with approximately 175 patients evaluated. Nearly all of these studies were retrospective with the largest series being of 73 patients. Most of the studies utilized timolol ophthalmic solution but two reports used compounded propranolol. There were varied concentrations and frequency, however timolol 0.5% gel-forming solution is most commonly used, typically with a – duration of three months or more.

Collectively, reports in the past two and a half years have shown encouraging results with topical beta blockers. Lesions on the eyelid tend to do particularly well, as do hemangiomas which are more superficial and smaller in size. Preliminary reports suggest that timolol is well tolerated, in that there have been no significant toxicity reports to date. The drug is also relatively inexpensive. It is important; however, to remember that timolol has a relatively higher potency and there is a risk of achieving significant blood levels, particularly in small premature infants. The quantity used should be limited; some healthcare providers use a maximum of one drop two times per day.

Multimodal Therapy

We have seen beneficial effects of early pulsed dye laser (PDL) therapy in individuals with infantile hemangiomas. (Admani S et al. Dermatologic Surgery. 2012;1-7)  Multiple cases have demonstrated that in some cases you can do better with combination therapy, such as steroid use and PDL or beta blockers and PDL. Mixing and matching with regards to treating IH is a reasonable approach.