Infantile Hemangiomas: A Review and Future Opportunities

Abstract

Infantile hemangiomas (IHs) are identified in about 5–12% of infants, making them the most common benign tumor of childhood (Figure 1). IHs are vascular growths characterized by an abnormal proliferation of endothelial cells and aberrant blood vessel architecture.¹ IHs commonly involute after proliferation, traditionally leading to a non-interventional or “wait and see” management approach. However, a large subset of these growths can become problematic causing morbidities such as ulceration and scarring, disfigurement, or functional impairment. Another subset of these cutaneous hemangiomas may also be markers for visceral involvement or other underlying abnormalities. Historically, treatment options were often rife with unwanted side effects and modest results. However, with newer established treatments which are both safe and effective, there is a time-sensitive need for early identification of high-risk hemangiomas to ensure prompt delivery of treatment for best outcomes. Despite a more recent dissemination of awareness of IHs and these newer treatments, there remains a large subset of infants who still experience a delay in care and poor outcomes which are likely avoidable. There may be some avenues in Missouri to help mitigate these delays.

Introduction

The pathogenesis of IHs has yet to be fully defined. A leading hypothesis is that circulating endothelial progenitor cells migrate to locations in which conditions (eg, hypoxia and developmental field disturbances) are favorable for growth.² IHs grow in a relatively expected trajectory, with 80% of growth in the first five months of life, and growth which is typically complete by nine months.³ In 2019 the American Academy of Pediatrics put forth the first Clinical Practice Guidelines for the Management of Infantile Hemangiomas. The guideline helps to stratify infantile hemangiomas which may be more problematic, prompting increased vigilance in monitoring or referral for early treatment. The ability to identify IHs which are more likely to cause morbidity or unfavorable outcomes allows primary care practitioners to decide whether IHs should be characterized as “High Risk” or “Low Risk.” Making this distinction as “High Risk” then allows for increased monitoring in the primary care setting and/or early referral to an IH specialist for assessment and treatment.

Classification of Hemangiomas: “High Risk” or “Low Risk”

Clinicians should classify an IH as “High Risk” if there is evidence of or potential for the following: 1) life-threatening complications; 2) functional impairment; 3) ulceration; 4) associated structural anomalies (eg, in PHACE syndrome or SACRAL syndrome); or 5) permanent disfigurement, ² as outlined in Figure 2.

Figure 2.

IH Clinical Findings and Possible Risks

Life threatening complications include IHs of the airway, which most commonly occur in the subglottis, already the narrowest part of the pediatric airway, and present with biphasic stridor. Hepatic hemangiomas, when occurring in a multifocal or diffuse pattern, can in rare circumstances lead to hepatomegaly, hypothyroidism and cardiac failure.⁴

Functional impairment may occur from IHs located around the eyes or mouth. IHs around the eyes, particularly > 1cm, may cause mechanical distortion which ultimately may lead to amblyopia.⁵ IHs around the mouth, particularly those which also ulcerate, may leading to feeding difficulties.

Ulceration of the skin or mucosal surfaces, which occurs up to 21% of the time, leads to pain, bleeding, often secondary infection, and always scarring.⁶ Ulceration typically occurs by four months of age, and during the proliferative phase of IHs. Certain types of IHs are at higher risk, including superficial, mixed types, segmental IHs, and those involving the scalp, neck, and perioral, perineal, perianal, and intertriginous sites.

In rare circumstances, some infants may have associated structural anomalies with their segmental IHs. PHACE syndrome may be considered in an infant with a large (>5cm) segmental IH on the face, scalp or neck. Cerebrovascular anomalies, present in more than 90% of patients with PHACE syndrome, are the most common extracutaneous feature of the syndrome, followed by cardiac anomalies (67%) and structural brain anomalies (52%).² The risk of PHACE syndrome in an infant presenting with a large segmental IH of the head or neck is approximately 30%. LUMBAR syndrome, which should be considered for large segmental IHs of the lumbosacral or perineal areas which extend onto a leg, present with myelopathy as the most common anomaly.

The risk of IHs causing permanent disfigurement is more likely than life threatening or functional problems. This can be caused via scarring or distortion of anatomical landmarks. The shift to treating IHs to prevent future skin changes stems from the development of more effective and safer treatment modalities. This is more often considered in anatomical areas which are not covered by clothing (like the face) or in emotionally sensitive areas (like the breasts).⁷

Treatment Types and Initiation of Treatment

There is good evidence that almost all high risk IHs should be treated first line with systemic beta blocker therapy, typically propranolol solution.⁸ Propranolol is a nonselective antagonist of both β-1 and β-2 adrenergic receptors. The precise mechanisms of action of propranolol on IHs are still unclear. Propranolol dose should start between 2 and 3 mg/kg per day unless there are comorbidities (eg, PHACE syndrome) or adverse effects (eg, sleep disturbance) that necessitate a lower dose.² Treatment should continue until 12–15 months of age to reduce the instance of rebound growth, which commonly occurs, particularly when stopped under nine months of age.⁹ Propranolol should be administered with or after feeding, and doses be held at times of diminished oral intake or vomiting to reduce the risk of hypoglycemia. Potential adverse effects of propranolol include sleep disturbances, bronchial irritation, and clinically symptomatic bradycardia and hypotension. It is no longer necessary to screen all infants with EKG prior to initiation of propranolol therapy, except infants with specific comorbidities or family histories.

Providers may prescribe topical timolol maleate as a therapy for thin and/or superficial IHs.² There are few risks or adverse side effects related to therapy, and this may be preferred as a possible treatment for patients of parents who have safety concerns regarding the use of oral propranolol in their young infant. Timolol is not typically used on ulcerated IHs.

Difficulties, Systemic Pitfalls in Healthcare… and Opportunities

There is a finite window within the natural history of IHs where intervention is effective. Less commonly is treatment initiated at six months of age or later given the lower likelihood of success, although in some cases with potential significant morbidity, it may be worthwhile to trial systemic medication. Additionally, there are occasionally parental concerns regarding the safety of propranolol given its typical use as a blood pressure medication, and parents may opt to monitor instead.

Given the finite window to treat IHs and thus improve outcomes, one reoccurring pitfall is the time to see an IH specialist. For instance, pediatric dermatologists view infantile hemangioma referrals as more urgent appointments and will try to accommodate patients to be seen within one week or sooner, if needed. When referrals are made, it is of particular importance that medical offices (either PCPs or other specialists) feel comfortable following up referrals with emails, messages, or phone calls to the clinic stating urgency. These appointments should not wait the standard “next available,” and the urgency may not be known to all scheduling staff.

One possibility to reduce delays in care could be the establishment of an on-call type of hotline in Missouri, potentially aptly named the “Hemangioma Hotline,” where primary care or other providers can call for more immediate triage help regarding the timing for scheduling appointments, finding an IH specialist, or instruction regarding the starting of medication prior to being seen by a specialist. Having this support and establishing this open communication may be an excellent start to decreasing the morbidity that still surrounds high risk IHs. Other possibilities include an ECHO via the MO Telehealth Network or in coordination with MOAAP that would further educate providers regarding the urgency of these tumors and help to guide through initial assessment. Ideas regarding funding or comments regarding general interest level would be welcome.

Conclusion

Despite increased dissemination of knowledge and better treatment modalities for IHs, there are still many poor outcomes, particularly in areas without IH specialists. Education regarding delineation of high risk vs. low risk IHs help to determine the urgency of referral and whether treatment should be initiated. A statewide “Hemangioma Hotline” or other educational tools may help to improve the gap in outcomes.

Figure 1.

Infantile hemangiomas (IHs) are identified in about 5–12% of infants, making them the most common benign tumor of childhood.