Infantile hemangiomas (IHs) are benign vascular tumors. Clinical history and physical examination are the most important factors for diagnosis, with most IHs having a typical presentation. Treatment is required for some IHs that cause significant cosmetic deformity or functional compromise. Propranolol is the first-line treatment of most IHs. Ongoing research is increasing our understanding of the pathophysiology of these tumors and should help to identify future potential therapeutic targets.
Key points
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Hemangiomas are the most common benign tumor of childhood, and 60% occur in the head and neck.
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Most hemangiomas do not require intervention.
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Patients with complex hemangiomas benefit from a multidisciplinary approach.
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Propranolol is now first-line therapy for many hemangiomas requiring treatment.
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Ongoing multi-institutional clinical trials should help to identify future potential therapies.
Introduction
Infantile hemangiomas (IHs) are the most common benign tumor in children. They are vascular tumors consisting of immature cells and disorganized blood vessels. IHs are diagnosed in approximately 4% to 10% of children, usually before the age of 1 year. The incidence is higher in premature infants, babies from multiple gestation pregnancies, babies from in vitro fertilization, White race, and females.
Although IHs can be diagnosed on any cutaneous surface, more than 60% of lesions present in the head and neck and may have significant aesthetic and functional consequence ( Fig. 1 ). Ulceration during rapid growth and subsequent scar formation can result in permanent cosmetic deformities. High-risk areas include the nasal tip and periorbital region. Subglottic hemangiomas are associated with stridor and airway distress.
Historically, hemangiomas were referred to as stork bites or angel’s kisses. They usually are not noticed at birth but present within a few weeks of life. Unlike vascular malformations, IHs undergo 3 distinct phases of growth: a rapid proliferative phase, a quiescent phase, and a slow involutional phase.
Most IHs require no intervention and result in minimal cosmetic deformity after involution. Educating parents about the natural history of IH is an important component of care. High-risk features of IH include facial location, segmental distribution, and large size. Management of high-risk IHs is often best performed in the context of a multidisciplinary vascular anomalies center because of the complex therapeutic decisions involved. Specialties most commonly involved in managing and treating IHs of the head and neck include general pediatricians, pediatric dermatologists, plastic and reconstructive surgeons, and pediatric otolaryngologists.
Introduction
Infantile hemangiomas (IHs) are the most common benign tumor in children. They are vascular tumors consisting of immature cells and disorganized blood vessels. IHs are diagnosed in approximately 4% to 10% of children, usually before the age of 1 year. The incidence is higher in premature infants, babies from multiple gestation pregnancies, babies from in vitro fertilization, White race, and females.
Although IHs can be diagnosed on any cutaneous surface, more than 60% of lesions present in the head and neck and may have significant aesthetic and functional consequence ( Fig. 1 ). Ulceration during rapid growth and subsequent scar formation can result in permanent cosmetic deformities. High-risk areas include the nasal tip and periorbital region. Subglottic hemangiomas are associated with stridor and airway distress.
Historically, hemangiomas were referred to as stork bites or angel’s kisses. They usually are not noticed at birth but present within a few weeks of life. Unlike vascular malformations, IHs undergo 3 distinct phases of growth: a rapid proliferative phase, a quiescent phase, and a slow involutional phase.
Most IHs require no intervention and result in minimal cosmetic deformity after involution. Educating parents about the natural history of IH is an important component of care. High-risk features of IH include facial location, segmental distribution, and large size. Management of high-risk IHs is often best performed in the context of a multidisciplinary vascular anomalies center because of the complex therapeutic decisions involved. Specialties most commonly involved in managing and treating IHs of the head and neck include general pediatricians, pediatric dermatologists, plastic and reconstructive surgeons, and pediatric otolaryngologists.
Pathophysiology
IHs are vascular tumors comprised primarily of endothelial cells. Although the exact molecular mechanisms for the proliferation and involution of IHs are not fully understood, the cellular development of the tumors has been described. Evidence suggests that some may arise from developmental errors occurring as early as 4 to 6 weeks’ gestation. IHs are believed to arise from aberrant angiogenesis (formation of blood vessels from preexisting vasculature) and vasculogenesis (formation of new blood vessels from progenitor cells). Several molecular receptor pathways associated with the development of the vascular system have been identified in the lesions. These pathways include the vascular endothelial growth factor (VEGF) pathway and the β-adrenergic receptor pathway.
The VEGF receptor pathway is a common mechanism of angiogenesis in both benign and malignant tumors. Drugs designed to counter the VEGF pathway such as bevacizumab have found success in the treatment of malignancies as well as benign vascular conditions.
Endothelial cells in IHs are derived from hemangioma stem cells. During proliferation, these hemangioma stem cells produce VEGF-A, which binds to VEGF receptors and stimulates angiogenesis and differentiation of stem cells into aberrant endothelial cells. In vitro studies have found that hypoxia and estrogen synergistically enhance hemangioma proliferation.
Most recently, the β-adrenergic receptor pathway has garnered attention in the pathophysiology of IHs because of the serendipitous discovery of propranolol as an effective therapeutic agent. Several hypotheses have been proposed to explain the powerful effects that propranolol has on IHs.
One hypothesis is that propranolol causes β-adrenergic vasoconstriction within the hemangiomas. This vasoconstriction may lead to decreased bulk and flow through the IHs. Recent studies using ultrasonography have shown a decrease in lesion volume and vessel density after initiation of propranolol therapy.
Others have proposed a direct effect on apoptosis in capillary endothelial cells. A recent study published by Chim and colleagues suggests that propranolol induces regression of IHs through a downregulation of VEGF-A and HIF-1-α, a potent master regulator of angiogenesis. In addition, downstream products of the decreased VEGF-A expression may exert a direct cytotoxic effect in the form of decreased endothelial cell migration and apoptosis.
One important distinction between the vasculature found in IHs from normal cutaneous vessels is the presence of glucose transporter 1 (GLUT1). Studies support that 97% of hemangiomas test positive for GLUT1. Normally, GLUT1 is found only in placental blood vessels and vessels at the blood-brain barrier. This has proved to be a reliable diagnostic test to differentiate IHs from other hemangiomalike lesions and has been used to confirm subglottic involvement of IH. Although this discovery has led to several theories of a placental role in the development of IHs, no definitive conclusions have been made. However, there are GLUT1 negative hemangiomas, including noninvoluting congenital hemangiomas and rapidly involuting congenital hemangiomas, but these are rare and do not follow the typical clinical course of IH.
Recent data suggest that the mammalian target of rapamycin (mTOR) (a protein kinase) pathway may also play a role in angiogenesis during IH development. Rapamycin, an mTOR inhibitor, has been found to prevent new blood vessel formation and increase regression of already formed blood vessels. Further research of the molecular triggers of the quiescent and involution phases of the natural history of IH may help identify novel treatment of IHs.
Diagnosis
IHs are best diagnosed from history and thorough physical examination. Imaging is generally not necessary for diagnosis, but if performed, magnetic resonance imaging (MRI) with gadolinium is the study of choice. IHs have a typical appearance on MRI described as a salt and pepper pattern ( Fig. 2 ). Clinically, IHs are generally not present at birth; however, an area of cutaneous abnormality can be observed in the form of pallor, duskiness, or telangiectasias. IHs are classified by their depth of penetration and location.
Superficial lesions are characterized by involvement of the upper dermis and were historically described as strawberry red lesions. Deep lesions occupy dermal and subcutaneous tissues. Their appearance is darker and may be more palpable as a soft tissue mass.
IHs can exist as focal lesions or can present as larger, widespread segmental lesions ( Fig. 3 ). Localized IHs arise from 1 central focus, whereas segmental lesions involve a developmental segment of the body or a larger anatomic territory. A third category of indeterminate hemangiomas is reserved for lesions that are not clearly either localized or segmental in nature. Patients with multiple localized lesions are classified as having multifocal disease. Extracutaneous hemangiomas, especially intra-abdominal and hepatic hemangiomas, are more commonly found in patients with multifocal disease. Patients identified with 5 or more cutaneous IHs are generally recommended to undergo abdominal MRI because of the high incidence of liver involvement.
As discussed earlier, IHs distinguish themselves from other vascular lesions in their 3 distinct intervals of development. These intervals comprise proliferative, quiescent, and involutional phases. The proliferative phase usually begins shortly after birth and continues throughout the first year of life. Most lesions achieve 80% of size by 5 months of age. This relatively active proliferative phase is then followed by a period of quiescence.
The involutional phase can take months to years to complete. Superficial lesions change from bright red to a dull red, followed by gray. Topographically, superficial IHs flatten and soften during the involutional phase. Most IHs complete their involution by the age of 10 years. Although most involuted IHs leave imperceptible scar, some patients can be left with dense fibrofatty tissue or cutaneous telangiectasias after involution.
During the proliferative phase, superficial hemangiomas close to the cutaneous surface can ulcerate. Lesions exposed to friction or chronic moist conditions are also more likely to ulcerate. Segmental IHs are also more likely to ulcerate. Ulceration can cause significant discomfort, bleeding, and scarring if not treated expeditiously. Overall, ulceration occurs in approximately 15% of patients, with a median onset of 4 months.
Within the head and neck, IHs that undergo ulceration can cause significant morbidity, with resultant scarring of sensitive structures. In particular, the ear and the nose are at significant risk of cartilage necrosis and loss with deeply ulcerative lesions.
Subglottic Hemangioma
In addition to cosmetic concerns, head and neck IHs may also pose functional concerns with respect to breathing when they occur in the subglottic region. Subglottic hemangiomas can occur in isolation or can present along with cutaneous IHs ( Fig. 4 ). Especially at risk are patients with hemangiomas in the segmental beard distribution ( Fig. 5 ). The beard pattern describes a segmental hemangioma involving the preauricular area, chin, lower lip, and neck. The coexistence of subglottic hemangioma in patients with beard lesions has been described as high as 63%.
