Propranolol has replaced corticosteroids as preferred first-line therapy for the management of infantile hemangiomas (IH). The topical β-blocker timolol is now an alternative to oral propranolol and watchful waiting for smaller IH. Research in the last decade has provided evidence-based data about natural history, epidemiology, and syndromes associated with IH. The most pressing issue for the clinician treating children with IH is to understand current data to develop an individualized risk stratification for each patient and determine the likelihood of complications and need for treatment. This article emphasizes the nuances of complicated clinical presentations and current treatment recommendations.
Key points
- •
Infantile hemangiomas (IH) show great heterogeneity in size, morphology, growth, residua remaining after involution, and in degree of response to therapy.
- •
Propranolol is now preferred first-line therapy, given that its efficacy, tolerability, and safety are superior to that of oral corticosteroids.
- •
The period of most rapid proliferation is complete by 8 weeks after birth, suggesting that referral to specialists should occur early, within the first month of life for concerning IH.
- •
More infants are now treated with propranolol than were previously treated with oral corticosteroids, and the full implications of this shift in practice are not yet clear.
Introduction
Infantile hemangiomas (IH) are both the most common benign vascular tumors and the most common soft tissue tumors in children, characterized by a unique tripartite growth cycle of proliferation, plateau, and involution. Although most involute without intervention, many require medical or surgical treatment. They are marked by a great heterogeneity in morphology, size, growth, residua remaining after involution, and in degree of response to therapy. The treatment algorithm and approach to the management of IH have undergone a dramatic shift since 2008, with the advent of propranolol as a treatment option. After an initial report published in the New England Journal of Medicine , physicians worldwide rapidly changed decades of practice, seemingly within months. Despite the initial recommendation for caution from some circles, physicians from multiple specialties proceeded in treating many thousands of infants, despite lack of randomized controlled trials or large prospective studies. Propranolol has definitively unseated corticosteroids as preferred first-line therapy, for reasons of both efficacy and safety. Consensus guidelines for its use now exist, but there are many lessons to be learned by the medical community from the haphazard manner in which the primacy of propranolol was established. More recently, the topical β-blocker timolol, which is available as an ophthalmic preparation, has been proposed as an alternative to oral propranolol for smaller IH. The last decade has provided evidence-based data about natural history, epidemiology, and syndromes associated with IH. Information continues to emerge about the as yet not fully understood pathogenesis of IH and mechanism of action for therapeutics. The most pressing issue for the clinician treating children with IH is to understand current data to develop an individualized risk stratification for each patient and determine the likelihood of complications and need for treatment.
Introduction
Infantile hemangiomas (IH) are both the most common benign vascular tumors and the most common soft tissue tumors in children, characterized by a unique tripartite growth cycle of proliferation, plateau, and involution. Although most involute without intervention, many require medical or surgical treatment. They are marked by a great heterogeneity in morphology, size, growth, residua remaining after involution, and in degree of response to therapy. The treatment algorithm and approach to the management of IH have undergone a dramatic shift since 2008, with the advent of propranolol as a treatment option. After an initial report published in the New England Journal of Medicine , physicians worldwide rapidly changed decades of practice, seemingly within months. Despite the initial recommendation for caution from some circles, physicians from multiple specialties proceeded in treating many thousands of infants, despite lack of randomized controlled trials or large prospective studies. Propranolol has definitively unseated corticosteroids as preferred first-line therapy, for reasons of both efficacy and safety. Consensus guidelines for its use now exist, but there are many lessons to be learned by the medical community from the haphazard manner in which the primacy of propranolol was established. More recently, the topical β-blocker timolol, which is available as an ophthalmic preparation, has been proposed as an alternative to oral propranolol for smaller IH. The last decade has provided evidence-based data about natural history, epidemiology, and syndromes associated with IH. Information continues to emerge about the as yet not fully understood pathogenesis of IH and mechanism of action for therapeutics. The most pressing issue for the clinician treating children with IH is to understand current data to develop an individualized risk stratification for each patient and determine the likelihood of complications and need for treatment.
Diagnosis
Proper diagnosis of IH hinges on a solid understanding of the classification structure for vascular anomalies, and the most comprehensive and widely accepted classification schema is put forth by the International Society for the Study of Vascular Anomalies (ISSVA). The classification rests primarily on distinguishing vascular tumors, of which IH are the most common, from vascular malformations ( Fig. 1 , Table 1 ). In all but a few cases, the diagnosis of IH can be determined by good history taking and physical examination.
| Vascular Tumors and Malformations | |||
|---|---|---|---|
| KHE | Congenital to infancy or later | Firm, reddish brown to violaceous, plaque or nodule | May be associated with Kasabach Merritt phenomenon: increased D-dimer, low fibrinogen, low or very low platelets |
| TA | As for KHE | Similar to KHE ± associated hair | Similar to KHE, although considered less severe on spectrum |
| RICH | Congenital; full size at birth | Often symmetric blue nodule with coarse telangiectasia; rim of pallor | High flow |
| Noninvoluting congenital hemangiomas | Congenital; full size at birth or minimal postnatal growth | Similar to RICH | High flow |
| Pyogenic granuloma | Infancy or childhood (more commonly) | Friable vascular papule with brisk intermittent bleeding | Rarely may be multiple and congenital |
| Multifocal lymphangioendotheliomatosis | Congenital | Varied appearance of papules, plaques, or nodules | Thrombocytopenia (waxing and waning), potentially severe gastrointestinal bleeding |
| Blue rubber bleb nevus syndrome | Congenital, infancy or later | Small compressible blue to purple papulonodules | May be confused for multifocal IH. Associated with gastrointestinal bleeding ± larger venous malformation, often in thigh or pelvis |
| Capillary malformation (PWS) | Congenital | Confluent pink to dusky pink; reticulated possible | Reticulated may appear similar to minimal growth IH |
| Venous malformation | Congenital but may not be noted until later | Blue-purple compressible; growth gradual and progressive | Low flow; may be confused with deep IH |
| Glomuvenous malformation | Congenital in segmental plaque presentation; multifocal lesions present later | Segmental thin plaque pink to violaceous; papules/nodules firm ± tender | Autosomal dominant; limited to skin and soft tissue |
| Lymphatic malformation | Macrocystic head and neck present at birth; microcystic often noted later | Deep skin-colored nodule ± vascular appearing pink to purple blebs | Low flow; may be confused with deep IH |
| Verrucous hemangioma | Congenital | Plaque, papule, or nodule with keratotic change over time | Are subtype of lymphatic malformation |
| Cutis marmorata telangiectatica congenita | Congenital | Reticulated, marbled pink to dusky purple ± ulceration ± limb undergrowth | May be confused with minimal growth IH or reticulated PWS |
| Nonvascular Lesions | |||
|---|---|---|---|
| Myofibroma | Congenital to infancy | Small to large plaques and nodules | May be ulcerated, mimicking ulcerated IH |
| Spitz nevus | Infancy rarely; childhood commonly | Pink to red-brown papule | Typically solitary, although may have agminated presentation |
| Juvenile xanthogranuloma | Congenital to infancy | Pink to red-brown papules or nodules | Become yellow with time; central ulceration possible in larger lesions |
| Dermoid cyst | Congenital | Skin-colored to slightly bluish, firm, typically mobile nodule face and scalp at sites of suture closure/embryonic fusion | May be confused with deep IH |
| Encephalocele | Congenital | Bluish nodule, may transilluminate in midline frontal or occipital scalp | Consider with midline deep blue nodule |
| Rhadomyosarcoma | Congenital to first year for most | Firm tumoral nodule with overlying telangiectasias; embryonal rhabdomyosarcoma is multifocal and congenital | May be confused with deep or mixed IH |
| Infantile fibrosarcoma | Congenital to first 2 y | Red to blue, firm and fixed to underlying tissue | May be confused with mixed IH, but more often KHE/TA or RICH/NICH |
| Langerhans cell histiocytosis | Congenital, infancy or later | Seborrheic distribution in scalp and diaper area especially; red to brown papules, nodules, petechial papules | Congenital presentation more favorable prognosis than presentation in infancy or later. Presentation with larger nodule, often on scalp, possible |
| Neuroblastoma | Congenital to early infancy | Blue to violaceous nodule | Increased urine homovanillic ± vanillylmandelic acid |
| Congenital leukemia cutis | Congenital to neonatal | Pink, blue, or violaceous firm plaques and nodules | May be confused with multifocal IH |
Epidemiology
The incidence of IH has remained unclear, because they are not often present at the time of hospital discharge after birth (when most registries for birth defects are completed.) Current evidence from a prospective study that followed nearly 600 pregnant women and their infants until the infants were 9 months of age suggests an overall incidence of IH of 4.5%, and up to 9.8% in premature infants. Although the cause of IH is not yet fully known, there are several important risk factors for development of IH that have been elucidated and corroborated among multiple studies. The most important risk factor is that of low birth weight, which, although often associated with prematurity, is a risk factor exclusive of gestational age at birth. For every 500-g decrease in birth weight, Drolet and colleagues showed that the risk of developing an IH increases by 40%, which is in line with previous data showing that hemangiomas occur in nearly 1 in 4 infants weighing less than 1000 g at birth. IH are significantly more common in female infants, with most studies showing a female predominance of 1.8 to 2.4:1. White (non-Hispanic) race is another well-established risk factor; additional reported risk factors include multiple gestation pregnancy, advanced maternal age, placenta previa, preeclampsia, chorionic villus sampling, and antenatal vaginal bleeding. Although IH have traditionally been discussed as a sporadic disorder, there is mounting evidence of IH occurring in kindreds, suggesting there is a role for genetic predisposition in the pathogenesis of IH.
Natural history
The growth cycle of IH is unique among vascular tumors and malformations, showing proliferation and preprogrammed involution. IH start with a nascent phase as either an area of pallor, a telangiectatic patch, or something mistaken for an ecchymosis or birth trauma. They may present anywhere on the body surface but are present most commonly on the head and neck, a finding which is also true of vascular malformations. Typically, most begin to proliferate to a noticeable degree at between 2 and 4 weeks of life, although IH that are located primarily in the subcutis, known as deep IH, presenting as bluish or skin-colored nodules ( Fig. 2 ), may not be noted until even a few months of age.
IH morphology can be described by the following 2 complementary concepts ( Fig. 3 ). First, the concept of depth of involvement in the dermis, fat, and soft tissue is informative not only in establishing the diagnosis but can help to predict concern for future deformity and residua. In addition to deep lesions, IH can present as superficial, with bright pink, fuchsia, or red on the surface of a papule, plaque, or nodule ( Fig. 4 ). Most IH present as mixed morphology, with both superficial and deep components, with a pink surface overlying a soft tissue swelling with a pink to bluish hue ( Fig. 5 ). Second, the outline and distribution of IH on the body surface, in addition to the anatomic depth, provide valuable prognostic information about the possible need for treatment and potential associated complications. In this schema, IH are regarded as localized when they seem to arise from an isolated focal point as with a solitary nodule; these are the most common presentation (see Fig. 5 ). IH are deemed segmental when they occupy a subunit of a body part such as the forearm ( Fig. 6 ) or a broad region on the face ( Fig. 7 ). Segmental IH are more often, but not always, plaques as opposed to nodules.
Significant work has elucidated the segments of the face through reproducible mapping of photographs of affected children. The segments are labeled 1 (frontotemporal), 2 (maxillary), 3 (mandibular), and 4 (frontonasal). Segments 2, 3, and 4 correlate with established embryologic placodes ; however, segment 1 is similar but not identical to distribution of the first branch of the trigeminal nerve (V1.) The reason for this lack of conformity with known facial planes on the upper face is not fully understood. The concept of facial segments for IH is important, because it relates to associated syndromes, complications, and necessity of therapeutic intervention. The category of indeterminate IH encompasses those lesions that appear more geographic in morphology than localized lesions but that do not clearly occupy a known mapped segment ( Fig. 8 ). Multifocal IH ( Fig. 9 ) are defined differently by different investigators, but are generally held to be small, relatively monomorphic lesions, at least 5 to 10 in number, distributed over the skin surface.
During the first 2 months of life, nearly all hemangiomas double in size, and newer evidence suggests that the most rapid period of growth occurs between 5.5 and 7.5 weeks of age, with most rapid proliferation complete in the first 8 weeks of life. Most reach 80% of maximum size at between 3 and 5 months of age, although segmental and deep IH have a more prolonged growth phase. Maximum size is generally fulfilled at 9 months and almost always by 12 months of age, although rare reports exist of growth extending beyond age 2 years. Plateau in growth then occurs and is followed by involution, which occurs over several years, with the most rapid phase of involution occurring between ages 1 and 4 years. The growth cycle is dynamic, and within the same lesion, central graying and regression may begin to occur as the periphery is still proliferating. This improved understanding of the growth cycle informs the clinician’s ability to offer anticipatory guidance to families about expected future growth and to plan for the likelihood of need for, and duration of, intervention and workup based on age at presentation, size, and morphology of IH.
Although radiologic imaging is not necessary in most cases of IH, IH are high-flow lesions that show the features presented in Table 2 , which can help to confirm diagnosis in challenging cases and with presurgical planning, most often during involution.
