Infantile hemangiomas (IHs) are the most common soft tissue tumors of childhood. The wide spectrum of disease has made it difficult to predict need for treatment and has made it challenging to establish a standardized approach to management. This article provides the reader with an up-to-date discussion of IH, identifying features of this condition which predict need for treatment as well as associated complications and reviewing management.
Infantile hemangiomas (IHs), also known as hemangiomas of infancy, are the most common soft tissue tumors of childhood. Despite their frequency, much remains to be learned about the pathogenesis, and management often is based on anecdote rather than evidence-based data. While most IHs are uncomplicated and do not require intervention, they can be a significant source of parental distress, cosmetic disfigurement, and morbidity. The wide spectrum of disease, both in the morphology of these lesions, but more importantly in their behavior, has made it difficult to predict need for treatment and has made it challenging to establish a standardized approach to management.
The nomenclature surrounding hemangiomas is confusing, as several entities recognized today as distinct vascular tumors or malformations historically have been referred to as hemangiomas. This article focuses on IH, which must be differentiated from congenital hemangioma. Unlike IHs, congenital hemangiomas are well formed at birth, tend to be bulky tumors, and do not undergo proliferation. Similar to IH, a halo of pallor may be present surrounding the lesion, and central ulceration may occur. Some of these lesions undergo rapid involution within the first several months of life (rapidly involuting congenital hemangiomas or RICH), whereas others remain unchanged (noninvoluting congenital hemangiomas or NICH). As congenital hemangiomas are well developed by birth, they may be detected in utero by prenatal ultrasound. Immunohistochemical markers also help distinguish congenital hemangiomas from IH, as they do not stain with GLUT-1.
Epidemiology
There have been few prospective studies performed assessing the exact incidence of IHs. Incidence has been difficult to ascertain, because IHs may not appear until after the immediate newborn period. In addition, the confusing nomenclature and often misuse of the term hemangioma make interpretation of older studies difficult. The incidence of IH has been estimated to be 1% to 5%. Risk factors for development of IH include Caucasian ethnicity, low birth weight, and female sex (female to male ratio of 2.4:1). Infants who are products of a multiple gestation pregnancy have a higher risk of developing a hemangioma. The incidence of multiple gestation in a large hemangioma population was three times greater compared with that of the general population reported by the National Center for Health Statistics; this finding may be confounded by low birth weight, which is an established independent risk factor. IHs previously were considered sporadic; however, clinicians have noted a familial tendency, often caring for multiple siblings with hemangiomas. A recent study observed that 32% of patients with IH had a vascular anomaly in a first-degree relative; familial IH was specifically reported in 12% of patients. Walter and colleagues studied five families (22 individuals) with hemangiomas and vascular malformations and found a linkage to a locus on chromosome 5q31-33. This suggests that genes are located on this part of the chromosome, which contributes to the development of hemangiomas. While these data provide compelling evidence that genetic factors contribute significantly to the development of hemangiomas, to the authors’ knowledge, none of these studies have led to identification of a specific gene.
Pathogenesis
The pathogenesis of infantile hemangiomas is poorly understood, but is generally believed to be multifactorial. Many studies have analyzed hemangioma tissue from surgical specimens. North and colleagues were first to note that the endothelial-like cells of the hemangioma expressed GLUT-1, the erythrocyte-type glucose transporter protein. This appears to be an exclusive marker for IH and is an invaluable tool used to distinguish hemangiomas from other vascular lesions. GLUT-1 is also expressed on the chorionic villus cells of the placenta, and several studies have pointed out the molecular similarities between placenta and IH. A relationship to the placenta as the possible source of hemangioma endothelial cells also has been suggested given the presence of overlapping markers in both hemangioma and placental vessels.
The rapid proliferation of endothelial-like cells has led many investigators to focus on angiogenesis, in which new vessels develop from local endothelial cells. Alternatively, there is evidence that IHs may develop through vasculogenesis, in which new vessels arise from circulating endothelial progenitor cells recruited to hypoxic tissue. Children with proliferating IHs have increased levels of circulating endothelial progenitor cells and surgical specimens of hemangiomas are positive for the coexpression of progenitor specific markers such as CD34, CD133, and vascular endothelial growth factor (VEGF) receptor-2.
Molecular and cellular mediators have been implicated in the proliferative and involutive phases of hemangiomas VEGF, basic fibroblast growth factor, insulin-like growth factor-2, tissue inhibitor of metalloproteinase (TIMP) type 1, type 4 collagenase, urokinase, hypoxia-inducible growth factor (HIF1alpha), and mast cells. It recently was noted that the VEGF signaling pathway may play an important role in the development of IHs. Recent studies suggest that a shift in the balance of VEGF to VEGF receptor binding results in endothelial proliferation within IHs.
Pathogenesis
The pathogenesis of infantile hemangiomas is poorly understood, but is generally believed to be multifactorial. Many studies have analyzed hemangioma tissue from surgical specimens. North and colleagues were first to note that the endothelial-like cells of the hemangioma expressed GLUT-1, the erythrocyte-type glucose transporter protein. This appears to be an exclusive marker for IH and is an invaluable tool used to distinguish hemangiomas from other vascular lesions. GLUT-1 is also expressed on the chorionic villus cells of the placenta, and several studies have pointed out the molecular similarities between placenta and IH. A relationship to the placenta as the possible source of hemangioma endothelial cells also has been suggested given the presence of overlapping markers in both hemangioma and placental vessels.
The rapid proliferation of endothelial-like cells has led many investigators to focus on angiogenesis, in which new vessels develop from local endothelial cells. Alternatively, there is evidence that IHs may develop through vasculogenesis, in which new vessels arise from circulating endothelial progenitor cells recruited to hypoxic tissue. Children with proliferating IHs have increased levels of circulating endothelial progenitor cells and surgical specimens of hemangiomas are positive for the coexpression of progenitor specific markers such as CD34, CD133, and vascular endothelial growth factor (VEGF) receptor-2.
Molecular and cellular mediators have been implicated in the proliferative and involutive phases of hemangiomas VEGF, basic fibroblast growth factor, insulin-like growth factor-2, tissue inhibitor of metalloproteinase (TIMP) type 1, type 4 collagenase, urokinase, hypoxia-inducible growth factor (HIF1alpha), and mast cells. It recently was noted that the VEGF signaling pathway may play an important role in the development of IHs. Recent studies suggest that a shift in the balance of VEGF to VEGF receptor binding results in endothelial proliferation within IHs.
Clinical
IHs have tremendous clinical heterogeneity in their appearance and behavior. These lesions vary in presentation from small, red lesions to large and bulky tumors that place individuals at risk for functional impairment or permanent disfigurement. Although IHs are considered to be birthmarks, they are often not recognized until a few weeks of age. Unlike traditional birthmarks whose appearance remains relatively stable throughout life, IH demonstrate change over the first months of life. Early on, they can appear as a telangiectatic patch or an area of pallor ( Fig. 1 ). Historically, IHs have been classified by their depth of soft tissue involvement (superficial, deep, and mixed). Superficial hemangiomas involve the superficial dermis and appear as bright red lesions ( Fig. 2 ). These lesions may be plaque-like or more rounded papules or nodules. Deep hemangiomas involve the deep dermis and subcutis, and present as bluish to skin-colored nodules ( Fig. 3 ). Mixed hemangiomas have both superficial and deep components, and therefore have features of both ( Fig. 4 ). However, another classification based on morphology has proven to be more predictive of risk of complications or need for treatment. Under this classification system, hemangiomas have been described as localized or segmental or indeterminate. Localized hemangiomas are discrete and usually oval or round, whereas the term segmental has been used to describe hemangiomas that demonstrate a geographic shape and involve a broad anatomic region or a recognized developmental unit ( Fig. 5 ). As segmental hemangiomas are at higher risk of complications and associated anomalies, the distinction is an important one. The concept of a segmental distribution may not be readily familiar to some physicians; however, these lesions can be recognized by their larger size as they have been shown to cover four times greater surface area than localized lesions.
The natural history of IH is characterized by an initial proliferative or growth phase followed by a plateau phase, and finally the involution phase. However, the transition from the growth phase to involution may be more dynamic than previously thought, reflecting a balance between local proliferative factors and factors involved in apoptosis. Most hemangioma growth occurs in the first 5 months, at which point 80% of the final size has often been reached. However, some IHs exhibit minimal proliferation, remain flat, and may be reticular or network-like in appearance. On average, IHs typically reach their maximum size by 9 months, but deep hemangiomas may proliferate longer. Prolonged growth for 2 years has been rarely observed. Hemangiomas with an extended growth phase tend to be larger lesions and more often segmental or indeterminate rather than localized. A subset of hemangiomas (23 IHs) evaluated from a large prospective study of 1530 IHs that demonstrated prolonged growth were all of the deep or combined subtype, and it was the deep component that was subjectively felt to have the continued growth in most. In the proliferative phase, IHs tend to be firm and noncompressible, becoming softer and more compressible as they begin to involute ( Fig. 6 ). A change in color from bright red to purple or gray can often signal transition to the involution phase. Involution takes place over several years.
IHs may occur anywhere on the skin, but are most common on the head and neck. Reproducible patterns of segmental hemangiomas on the face have been demonstrated and mapped. Segmental involvement of the lower face corresponds to known embryologic facial prominences (maxillary, mandibular, and frontonasal), whereas involvement of the upper face (forehead) does not.
Complications
Although most IHs are uncomplicated and do not require treatment, 24% of those referred to tertiary institutions had complications. Providers should be aware of risk factors predictive of complications or need for treatment to facilitate early referral to a physician with expertise in the management of IH. Size, location, and subtype (localized vs segmental) are major factors to consider in evaluating an infant’s risk. Specifically, for every 10 cm 2 increase in size, a 5% increase in likelihood of complications and a 4% increase in likelihood of treatment have been reported. Although segmental hemangiomas tend to be larger lesions, this subtype has been shown to be an independent risk factor for the development of complications. Complications of IH include ulceration, functional impairment (visual compromise, airway obstruction, auditory canal obstruction, feeding difficulty), and cardiac compromise. High-risk locations for specific complications, permanent disfigurement, and associated anomalies are outlined in Table 1 .
| Location | Associated Risk |
|---|---|
| Periorbital and retrobulbar | Visual axis occlusion, astigmatism, amblyopia |
| Nasal tip, ear, large facial | Cosmetic disfigurement, scarring |
| Perioral, lip | Ulceration, feeding difficulties, cosmetic disfigurement |
| Perineal, axilla, neck | Ulceration |
| Beard distribution, central neck | Airway hemangioma |
| Liver, large | High-output heart failure |
| Large facial (“segmental”) | PHACE syndrome (see text) |
| Multiple hemangiomas | Visceral involvement (liver, gastrointestinal tract most common) |
| Midline lumbosacral | Tethered spinal cord, intraspinal hemangioma, intraspinal lipoma, genitourinary anomalies |
Ulceration
Ulceration is the most common complication (16%), and can result in pain, infection, bleeding, and permanent scarring ( Fig. 7 ). Associated pain can interfere with sleep and feeding. Locations at high risk for ulceration and the associated frequency of this complication include anogenital (50%), lower lip (30%), and neck (25%). IHs that are larger in size or of the segmental subtype are more likely to develop ulceration. Of the clinical subtypes (ie, superficial, mixed, and deep), the mixed subtype (having both superficial and deep components) has most frequently been associated with ulceration and is another independent risk factor. The cause of ulceration is not well understood, but maceration and friction are likely contributing factors given the higher frequency in locations prone to this. While ulceration can be complicated by bleeding, clinically significant bleeding (ie, requiring hospitalization/transfusion) is rare.
Visual Compromise
Complications of periorbital hemangiomas include visual axis obstruction, refractive error (astigmatism or myopia), retrobulbar involvement, amblyopia, and tear duct obstruction. Lesions that involve the posterior orbit result in proptosis or displacement of the globe. Given the threat of permanent visual impairment, patients with periorbital hemangiomas should be referred early to a physician with expertise in the treatment of IH and should be closely monitored by the ophthalmology department; monitoring should include a retinal examination.
Visceral Involvement and Complications
While solitary lesions are most common, multiple cutaneous hemangiomas may occur in 30% of patients, although only 3% of patients have greater than six. Historically patients with numerous lesions have been placed into at least two categories: disseminated neonatal hemangiomatosis and benign neonatal hemangiomatosis, with the former considered to be at the severe end of the spectrum, with multiple sites of potential extracutaneous disease and a mortality rate as high as 60%. However, in the past, all multifocal vascular lesions were considered to be hemangiomas, and with advances in histopathologic and radiologic diagnosis (ie, GLUT-1 stain), it is recognized that some of these severe cases represent other multifocal vascular anomalies rather than true IH. Many of these other multifocal vascular lesions have a more aggressive course, often with coagulopathy and bleeding, and account for the high mortality historically reported with disseminated neonatal hemangiomatosis. In some cases, this has led to overly aggressive intervention in infants with asymptomatic multifocal IH.
Patients with true multifocal cutaneous IH are recognized to have a higher risk of visceral hemangiomas, with liver and gastrointestinal (GI) involvement being most common. Ultrasound of the liver has been recommended in those patients with greater than five cutaneous hemangiomas. A recent prospective study investigated the incidence of hepatic involvement in patients with more than five cutaneous IHs compared with those with one to four cutaneous lesions, and demonstrated a significantly increased risk in patients with greater than five cutaneous lesions. In this study, 24 (16%) of the infants with five or more cutaneous IHs had hepatic hemangiomas, whereas none of the infants with less than five had hepatic hemangiomas ( P <.003), substantiating the recommendation for liver ultrasound in patients with greater than five cutaneous IHs. Reported complications of liver hemangiomas include high-output heart failure if there is significant arteriovenous shunting (typically large liver lesions), abdominal compartment syndrome, and hypothyroidism. It should be noted that isolated liver involvement without skin lesions also can occur.
Associated Anomalies
The presence of IH in particular locations can be a marker for underlying or associated anomalies. The beard distribution of an IH in which preauricular areas, chin, anterior neck, and lower lip are involved has been associated with airway hemangiomas ( Fig. 8 ). In two retrospective studies, 29% to 63% of patients with large IHs on the lower lip, chin, neck, and preauricular region (beard) had airway involvement. Airway hemangiomas typically present between 6 and 12 weeks of age with biphasic inspiratory and expiratory stridor and retractions. Cough may be associated and may mimic croup. Infants with IH in the beard distribution should be monitored closely for respiratory difficulties and referred to an ear, nose, and throat specialist for evaluation. Serial evaluations may be required in young infants, since the skin hemangioma may precede the development of symptomatic airway IH.
