Mimickers of Infantile Hemangiomas

Infantile hemangiomas (IHs) are the most common tumors of infancy and usually follow a typical course of growth and involution. We report four soft tissue tumors that were referred to the pediatric dermatology clinic as IHs and the process by which they were diagnosed and treated. Clinicians should be aware of presentations of these uncommon, but serious soft tissue tumors. Many of these mimickers have a vastly different clinical prognosis, and early intervention to limit sequelae is crucial. Biopsy of atypical lesions should be considered early in the diagnostic process since they have varied prognosis and treatment strategies.     

Propranolol for Preoperative Management of a Large Infantile Hemangioma

Infantile hemangiomas (IHs) are common vascular tumors that typically follow a predictable pattern of rapid proliferation followed by gradual involution. Although most do not require treatment, some large or difficult IHs do, with medical and surgical options available. Prior reports indicate the success of using propranolol, a nonselective β‐blocker, to treat these lesions. This report will demonstrate the use of propranolol preoperatively to manage a large IH followed by surgical excision of the lesion in a collaborative medical and surgical approach.     

Growth Hormone Replacement in Patients with PHACE Association and Hypopituitarism

Partially empty sella with growth hormone (GH) deficiency is rarely reported in association with PHACE (posterior fossa anomalies, cervicofacial infantile hemangiomas [IHs], arterial anomalies, cardiac defects, eye anomalies, and midline/ventral defects). Consequently, little is known about the effect of GH replacement on the proliferation and involution of IHs in children with PHACE. We describe two children with PHACE and partially empty sella, both of whom received GH replacement for treatment of hypopituitarism. In our first patient we observed erythema and prominence of the vasculature in the hemangioma shortly after initiation of therapy at age 20 months, although after 4 weeks of treatment the appearance of the hemangioma stabilized and little change was seen during eight additional years of therapy. In our second patient we noted enlargement of the hemangioma after starting low‐dose GH at age 5 years, prompting discontinuation of GH replacement after 3 months of therapy. The hemangiomas continued to grow after discontinuation of GH treatment. GH administration in our patients was associated with erythema and prominence of IHs. Our findings suggest that GH replacement therapy may promote transient or more prolonged proliferation of IHs and should be administered with close clinical monitoring.     

Treatment of Infantile Hemangiomas with Sirolimus in a Patient with PHACE Syndrome

Infantile hemangiomas (IHs) are common benign tumors of childhood. IHs often regress satisfactorily without intervention, but a subset of IHs may lead to functional or cosmetic morbidity necessitating therapy. PHACE syndrome is characterized by a variety of neurocutaneous and vascular anomalies that typically include segmental hemangiomas. We present an infant with PHACE syndrome and segmental IH that failed conventional first‐line therapies. Treatment with sirolimus provided benefit with regression of the cutaneous IH. As an inhibitor of the mammalian target of rapamycin (mTOR) pathway, the effective use of sirolimus may shed light on the emerging role of mTOR signaling in the development and pathogenesis of IHs.     

Hemangiomas: new insight and medical treatment

Infantile hemangiomas (IHs) are the most common tumors of infancy and are usually characterized by a pattern of rapid proliferation, followed by a slower period of involution. In most cases, IHs do not require any treatment because they spontaneously regress over the years. However, in a minority of patients, a therapy is mandatory and should be started early to avoid functional and esthetic impairment or even severe systemic complications. Currently, no medications exist that are specifically labeled to treat his; however, because the serendipitous discovery of the efficacy of propranolol in the treatment of IHs at the Dermatologic Department of the University of Bologna, β-blocker therapy has become the first-line therapy in severe and/or complicated hemangiomas. This is a practical review reporting our approach to IHs in our daily practice.     

Infantile Hemangiomas with Minimal and Arrested Growth: Clinical Features and Treatment Outcomes with 0.5% Topical Timolol Maleate

BackgroundA minority of infantile hemangiomas showing minimal or arrested growth (IH-MAGs) have been recognized in the literature. Nevertheless, the clinical features and treatment outcomes of IH-MAGs have not been well investigated.ObjectiveThis study aimed to understand the clinical characteristics of IH-MAGs better and their response to treatment with topical timolol maleate.MethodsWe retrospectively reviewed medical records and clinical images of patients with IH-MAGs. Treatment response with topical timolol was assessed in both IH-MAGs and classic infantile hemangiomas (IHs) groups.ResultsOf the 1,038 patients with IHs, only 31 (3.0%) were diagnosed with IH-MAGs. Lesions with non-proliferative components were more frequently distributed in the lower half of the body (61.5%) than those with proliferative components (16.7%). In 14 patients treated with topical timolol, the global assessment scale showed more significant and rapid improvement than in those with classic IHs.ConclusionAlthough the prevalence of IH-MAGs may be relatively low, understanding their clinical features will help in differential diagnosis. Furthermore, these type of lesions might be more responsive to topical timolol than classic IHs.     

The use of propranolol in the treatment of infantile haemangiomas: an update on potential mechanisms of action

Currently, propranolol is the preferred treatment for problematic proliferating infantile haemangiomas (IHs). The rapid action of propranolol has been shown to be especially dramatic in IHs involving dyspnoea, haemodynamic compromise, palpebral occlusion or ulceration. Another remarkable aspect of propranolol treatment revealed that the growth of the IHs was not only stabilized, but also that the improvement continued until complete involution was achieved, leading to a considerable shortening of the natural course of IH. However, the mechanisms underlying the effects of propranolol have not been fully elucidated. Recent studies have offered evidence of a variety of mechanisms. These include the promotion of pericyte‐mediated vasoconstriction, the inhibition of vasculogenesis and catecholamine‐induced angiogenesis, the disruption of haemodynamic force‐induced cell survival, and the inactivation of the renin–angiotensin system. This review summarizes these mechanisms and the new concepts that are emerging in this area of research. Moreover, several molecular mechanisms by which propranolol may modify neovascularization in IH have also been proposed. The antihaemangioma effect of propranolol may not be attributable to a single mechanism, but rather to a combination of events that have not yet been elucidated or understood. Further studies are needed to evaluate and verify these mechanisms to gain a greater understanding of the effects of the intake of propranolol on haemangioma involution.     

Infantile hemangioma research: looking backward and forward

This is a remarkable time to be a student of infantile hemangiomas (IHs). IH is a common tumor, estimated to occur in approximately 4% of infants. Studied for many decades, the acquisition of knowledge and pace of IH research are accelerating. The article by Greenberger et al. in this issue is a welcome addition to the literature. It examines rapamycin as a possible treatment for IH that could potentially be curative because suppression of self-renewal of stem cells might deplete hemangiomas of the stem cells from which they originate. However, before we get too enthusiastic about using rapamycin for IHs, it is important to reflect on lessons learned from previous hemangioma therapies.     

Propranolol and Infantile Hemangiomas Four Years Later: A Systematic Review

To systematically review the literature evaluating efficacy and adverse events of propranolol treatment for infantile hemangiomas, we searched the MEDLINE and Cochrane databases for all studies examining the response of infantile hemangiomas (IHs) to propranolol published between June 12, 2008, and June 15, 2012. Forty‐one studies with 1,264 patients were included; 74% of patients were female and approximately 30% had received other treatments before propranolol. Propranolol was initiated at a mean age of 6.6 months at a mean dose of 2.1 mg/kg/day and for a mean treatment duration of 6.4 months. The response rate for patients with IHs treated with propranolol was 98% (range 82%–100%), with response rate defined as any improvement with propranolol. Treatment response rates were comparable for studies evaluating IHs at specific sites, such as periorbital IHs. Studies that followed patients after treatment completion reported IH rebound growth in 17% of patients. There were 371 adverse events reported in 1,189 patients. The most common adverse events were changes in sleep (n = 136) and acrocyanosis (n = 61). Serious adverse events were rare, with reports of symptomatic hypotension in five patients, hypoglycemia in four, and symptomatic bradycardia in one. This systematic review of 1,264 patients treated with propranolol for IHs showed a high rate of efficacy and a low rate of serious adverse events.     

Dramatic Shift in the Infantile Hemangioma Treatment Paradigm at a Single Institution

Historically the first line of treatment for infantile hemangiomas (IHs) has been oral corticosteroids, but because of recent discoveries recognizing the effectiveness of oral and topical beta‐blockers, IH management is dynamically changing. With these new treatment options, some physicians are altering the way they manage IHs despite having little evidence‐based data on the treatment methods. Highlighting treatment changes at a single large tertiary pediatric referral center, we conclude that despite the numerous studies already published on this topic, more reliable prospective studies are needed to determine the safety, efficacy, and best treatment algorithms for the use of topical and oral beta‐blockers for the treatment of IHs.     

Comparison of Two Formulations of Topical Timolol for the Treatment of Infantile Hemangiomas

This report compares the efficacy of timolol maleate 0.5% eyedrops (TM) with that of timolol maleate 0.5% ophthalmic gel‐forming solution in the treatment of infantile hemangiomas (IHs). Sixty‐six patients undergoing treatment with topical timolol were retrospectively reviewed; our results revealed similar therapeutic efficacies for both types of timolol formulations. Early treatment initiation (<3 mos) and superficial lesions correlated with better treatment response. TM eyedrops may be a more cost effective, equally efficacious modality of treatment for IHs.     

Infantile Hemangiomas

Infantile hemangioma (IH) is a common vascular tumor of infancy. Although benign, infants with IH can experience complications including ulceration, visual and airway impairment, and residual scarring and disfigurement. It is often challenging for clinicians to predict which tumors are in need of systemic treatment. However, data from various demographic and other studies have revealed further insights into this tumor. This article reviews the identification, evaluation, and management of high-risk IHs, including the indications for treatment and the use of systemic treatments such as corticosteroids, β-blockers, and vincristine.     

Fractional Carbon Dioxide Laser–Assisted Drug Delivery of Topical Timolol Solution for the Treatment of Deep Infantile Hemangioma: A Pilot Study

Infantile hemangiomas (IHs) are benign vascular tumors of infancy. Topical timolol has recently been reported to be an effective treatment for superficial IHs, although it failed to have an effect on deep IHs. This prospective study was aimed at evaluating the feasibility of ablative fractional laser–assisted drug delivery for enhancing topical timolol permeation into deep IHs. Nine patients ages 1 to 6 months with deep IHs were enrolled. A fractional carbon dioxide (CO₂) laser system was applied to the skin surface of deep IHs using the DeepFx mode (25–30 mJ/pulse, 5% density, single pulse) at 1‐week intervals. Topical timolol maleate 0.5% ophthalmic solution was applied under occlusion for 30 minutes four to five times per day for an average treatment duration of 14.2 weeks. Clinical improvement was evaluated according to a global score and the Hemangioma Activity Score (HAS). Four patients (44.4%) demonstrated excellent regression, four (44.4%) showed good response, and one (11.1%) experienced moderate regression. The HAS declined from 4.1 ± 0.7 at baseline to 1.7 ± 0.7 at 1 week (p < 0.001) and 1.4 ± 0.7 at 3 months (p = 0.03) after the last treatment procedure. Plasma timolol concentration was not detected in any of the patients after the first administration of topical timolol. No systemic complication or skin side effects were observed in any of the patients. Ablative fractional laser–assisted transdermal delivery of topical timolol is a safe and effective method for the treatment of deep IHs.     

Topical Timolol Solution Versus Laser in Treatment of Infantile Hemangioma: A Comparative Study

Lasers, 595‐nm pulsed dye and 1,064‐nm neodymium‐doped yttrium aluminum garnet (Nd:YAG), have been used successfully for the treatment of infantile hemangiomas (IHs). Recently the use of a topical β‐blocker, specifically timolol maleate, has been promising in the treatment of IHs. The objective of this study was to compare the effectiveness of topical timolol 5 mg/mL solution with that of combined sequential dual‐wavelength laser in the treatment of IHs. Sixty children with IHs were divided randomly into two equal groups. Group 1 was treated with applications of timolol drops (5 mg/mL) twice daily. Group 2 was treated with sequential pulsed dye and Nd:Yag laser. Treatments were performed every month for a maximum of six sessions. Efficacy was evaluated clinically and by measuring the average hemoglobin level. A significant decrease in the average hemoglobin level was determined in both groups and a dramatic response was observed in superficial hemangiomas in the timolol group. The timolol group received treatment for an average of 4.0 ± 1.1 months and the laser group for 5.5 ± 0.9 months. The degree of improvement of mixed hemangiomas to laser treatment was greater than that of the timolol group. During 3 months of follow‐up, no further improvement or relapse was reported in either group. Timolol solution is a safe and effective alternative to laser treatment in superficial hemangiomas. In mixed hemangiomas, the combined sequential 595‐nm and 1,064‐nm dual‐wavelength laser provided better results than timolol solution because it penetrated deeply so that deep dermal blood vessels were reached.     

Propranolol in the Treatment of Infantile Hemangiomas: A Meta‐Analysis in Chinese Patients

A meta‐analysis was conducted to evaluate the efficacy of propranolol in the treatment of infantile hemangiomas (IHs) in Chinese infants. A statistically significant difference was found between infants treated using propranolol and those treated using corticosteroids (p < 0.001). The total effect pooled from 26 single‐arm studies using meta‐analysis of propranolol on IHs in Chinese infants was 93% (95% confidence interval 0.88, 0.96).     

Failure of Intralesional Propranolol in Infantile Hemangiomas

The purpose of this study was to evaluate the use of intralesional propranolol injection in the management of small, noncomplicated infantile hemangiomas (IHs) located in areas of cosmetic concern. A prospective study was performed in six female infants with small, non‐complicated IHs in areas of cosmetic concern. The parents had refused oral propranolol or the patients had no response to topical timolol or had relapsed after oral propranolol and the parents refused further systemic treatment. All six patients were treated with 1 mg/mL propranolol solution at a dose of 0.2 mL/cm². The size, color, and growth of the hemangiomas were monitored and recorded every 4 weeks. Treatment response was evaluated using a 5‐point scale: much better (+2), better (+1), same (0), worse (?1), and much worse (?2). Heart rate and blood pressure were measured before and 1 hour after each injection. Adverse effects after medication were evaluated and managed accordingly. All hemangiomas stopped growing during therapy, but no significant changes in size or color were observed, even after repeated injections, and all patients were evaluated as 0 (same). One patient whose hemangioma stopped growing during treatment presented rebound growth after therapy cessation. No changes in heart rate or blood pressure were observed after intralesional propranolol injection. Adverse effects observed were pain and redness after injection. Intralesional propranolol seems safe but is not effective for the treatment of IH.     

Outpatient Use of Oral Propranolol and Topical Timolol for Infantile Hemangiomas: Survey Results and Comparison with Propranolol Consensus Statement Guidelines

Oral and topical β‐blockers are used to treat infantile hemangiomas (IHs). Although a recent consensus report provided guidelines for the treatment of IH with propranolol, there are no standard guidelines for the use of topical timolol. The objectives of this study were to determine the current use of oral propranolol and topical timolol by pediatric dermatologists in an outpatient setting and to compare current propranolol use with published propranolol consensus guidelines. An electronic survey was sent to pediatric dermatologists in May and June 2013. One hundred forty‐nine pediatric dermatologists responded to the survey, a 79% response rate. Of the respondents, 96% prescribed oral propranolol, but 75% did not follow consensus guidelines exactly; recommended history, physical examination, initial dose, and frequency varied. The dose of propranolol was usually titrated up to goal dose as recommended (89%). Fifty‐six percent monitored vital signs in patients after the initial dose and 49% continued to monitor vital signs in their clinic after each dose escalation, which did not meet consensus guideline recommendations. Ninety‐one percent reported using topical timolol for the treatment of IH and 66% responded they had used topical timolol in conjunction with oral propranolol to treat IH. The most common indication was superficial hemangiomas (97%). Most practitioners (74%) did not routinely monitor heart rate or blood pressure in infants treated with topical timolol. This study highlights the variability in prescribing and monitoring practices of physicians using propranolol for the treatment of IHs and demonstrates that topical timolol is commonly used alone and in conjunction with oral propranolol to treat IHs.     

Eighteen Cases of Soft Tissue Atrophy After Intralesional Bleomycin A5 Injections for the Treatment of Infantile Hemangiomas: A Long‐Term Follow‐Up

Pingyangmycin is a commonly used drug in China for the treatment of infantile hemangiomas (IHs) and vascular malformations. Also known as bleomycin A5, it has a similar chemical structure to bleomycin. The side effects of bleomycin include swelling, erythema, fever, headache, hyperpigmentation, ulceration, allergic reactions, and pulmonary fibrosis. We conducted this retrospective study to identify the correlation between bleomycin A5 injections and soft tissue atrophy. We performed a retrospective chart review of all patients with IHs who had this treatment and presented with soft tissue atrophy in our department from January 2011 through July 2013. Eighteen children with IHs (14 girls, 4 boys) were included in this study. The average age was 8.6 ± 3.8 years. All of the atrophied deformities were located at the injection site. Thirteen (72.2%) were located on the upper lip, three (16.7%) on the nose, and two (11.1%) on the cheeks. Seventeen (94.5%) received their first injection at the age of 1 or 2 months. The mean number of injections was 3.5 ± 1.6. The mean interval between injections was 1.2 ± 0.3 months. Eight of 18 patients (44.4%) had ulceration after injection. Intralesional bleomycin A5 injection is not safe for the treatment of IHs because it may lead to soft tissue atrophy. Other safer treatments, such as oral propranolol, should replace this treatment.     

Effectiveness of Propranolol in the Treatment of Infantile Hemangioma Beyond the Proliferation Phase

During the last 5 years, many studies have shown the efficacy of propranolol as first‐line treatment for infantile hemangiomas (IHs), but not much has been written about the role of propranolol beyond the proliferation phase of IH (>1 year). Our aim was to assess propranolol efficacy and safety in the treatment of patients older than 1 year. A retrospective study of patients older than 1 year diagnosed with IH and treated in our vascular anomalies clinic between 2009 and 2013 was performed. Eighteen patients older than 1 year with a diagnosis of IH (15 girls, 3 boys) were identified. The mean age at the time of initiation of treatment was 25.7 months (range 13–72 mos). Single lesions were observed in 13 patients and multiple lesions in 5. Fifteen patients had focal lesions and three had segmental. The median duration of treatment with oral propranolol was 11.8 months (range 2–33 mos). Complete response was observed in 72.2% of the patients and partial response in 27.8%. Recurrence was observed in three patients 4.7 months after completion of therapy (range 0.3–8 mos). These patients required further therapy with propranolol for 6 more months. Bradycardia was documented in two patients and night terrors in one patient, which led to discontinuation of treatment. In our experience, propranolol may be useful in the treatment of IHs beyond the proliferation phase (>1 year old), but more studies are needed to support this observation.