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Benign Cutaneous Vascular Tumors of Infancy
When to Worry, What to Do
Denise Walker Metry, MD;
Adelaide A. Hebert, MD
Arch Dermatol. 2000;136:905-914.
ABSTRACT
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Objectives To discuss the current knowledge regarding complicated hemangiomas (cervicofacial, periorbital, lumbosacral, and parotid), including the associated syndromes of diffuse neonatal hemangiomatosis and PHACES (posterior fossa malformations, most commonly of the Dandy-Walker variant; hemangiomas [especially large, plaquelike, facial lesions]; arterial anomalies; cardiac anomalies and coarctation of the aorta; eye abnormalities; and sternal cleft and/or supraumbilical raphe). To discuss 2 newly recognized entities that may be a source of diagnostic confusion with the common hemangioma, the kaposiform hemangioendothelioma and tufted angioma. To discuss the risks and benefits of current treatment options, including the use of systemic corticosteroids and interferon in necessary situations.
Data Sources The pertinent world literature was reviewed and incorporated into experience from our pediatric dermatology practice at the University of Texas Medical School at Houston.
Conclusions The common hemangioma, kaposiform hemangioendothelioma, and tufted angioma, though benign histologically, may cause serious consequences for children. Dermatologists should be able to recognize unique clinical presentations of these lesions and obtain further diagnostic evaluation accordingly. Dermatologists should also be aware of available treatment options, including the use of systemic chemotherapy in life-threatening situations.
INTRODUCTION
THE MOST common tumors of infancy are benign vascular lesions. Before 1982, the term "hemangioma" was used to encompass a wide range of vascular growths, independent of clinical manifestations, natural history, or embryological origin. Subsequently, Mulliken and Glowacki1 proposed the first biological classification for vascular birthmarks. Their landmark article was the first to distinguish a hemangioma, characterized by a growth and involutional phase, from a vascular malformation, a structural anomaly derived from arteries, veins, or lymphatics.1 In 1997, this classification was broadened to include 2 additional vascular entities—the kaposiform hemangioendothelioma (KHE) and tufted angioma (TA).2
Though histologically benign, certain unique presentations of vascular tumors may cause serious, even life-threatening, consequences for the newborn. When should the evaluating physician be concerned? When is intervention necessary, and what options are available? In this review we discuss the anatomical locations of the common hemangioma that may warrant further evaluation and therapy. We also review the rare syndromes associated with the common hemangioma: diffuse neonatal hemangiomatosis and PHACES (posterior fossa malformations, most commonly of the Dandy-Walker variant; hemangiomas [especially large, plaquelike, facial lesions]; arterial anomalies; cardiac anomalies and coarctation of the aorta; eye abnormalities; and sternal cleft and/or supraumbilical raphe). Lastly, we discuss the distinguishing features of the 2 vascular entities now recognized to be complicated by the Kasabach-Merritt syndrome (KMS)—KHE and TA (Table 1).
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Table 1. Congenital Vascular Neoplasms and Associated Conditions
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HEMANGIOMAS
Hemangiomas are the most common tumors of infancy. The incidence in the general newborn population is between 1.0% and 2.6%, but as high as 10% among whites. Hemangiomas occur 4 times more frequently in females than males, and are especially common among those infants born prematurely.3-8 The incidence seems to be directly related to birth weight, as almost 1 of every 4 newborns weighing less than 1000 g will develop a hemangioma.7 Gestational age may also be correlated, but has not been specifically studied. While most hemangiomas occur sporadically, familial transmission in an autosomal dominant fashion was recently reported.9
Approximately half of hemangiomas are present at birth; the remainder become evident within the first month of life.8 Early lesions are clinically subtle and may resemble a scratch or bruise. Hemangiomas may also manifest as a small patch of telangiectasias or hypopigmentation (Figure 1). Following the initial presentation, a characteristic growth (proliferative) phase continues for an average of 6 to 12 months. Rarely, hemangiomas will be fully developed at birth. Such lesions tend to involute rapidly within the first few months of life.10
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Figure 1. Annular, hypopigmented patch with central telangiectasias characteristic of an early hemangioma.
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Most hemangiomas are solitary, ranging from a few millimeters to several centimeters in diameter. The head and neck are the most commonly affected locations. Lesions may be superficial, deep, or combined (compound hemangiomas). Superficial hemangiomas are well-defined, bright red, nodules or plaques located above clinically normal skin. In contrast, deep hemangiomas are raised, flesh-colored nodules, which often have a bluish hue or overlying telangiectatic patch. Though less common, a hemangioma may initially be seen as a bright red macule or patch, resembling a port-wine stain.
The most common complication of rapidly proliferating hemangiomas is ulceration, which may result in secondary infection, pain, and/or scarring. Unlike their nonulcerated counterparts, ulcerated hemangiomas are also more likely to bleed, either spontaneously or following minor trauma. However, bleeding is rarely profuse and can generally be controlled by applying local pressure.11-12 Large, plaquelike lesions on the lip or perineum are the most likely to ulcerate (Figure 2). While the exact origin of ulcer formation is unknown, maceration and frictional stress are probable contributing factors.
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Figure 2. Sacral hemangioma complicated by ulceration.
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Hemangiomas generally cease growing by the time the infant is 18 months old. A period of slow, spontaneous involution then occurs for an average of 2 to 6 years. The first clinical sign of involution is grayish discoloration, which begins centrally as the tumor softens and flattens. Regression of deeper lesions is more difficult to visualize; however, the timing and progression are equivalent. The rate and extent of hemangioma involution varies greatly between children and is independent of lesion size or appearance. However, location may be a factor, as lesions over the lip, parotid gland, or distal nose ("Cyrano" nose) appear more likely to persist or involute only partially. Most hemangiomas have completed their involutional phase by the time a child reaches 10 years of age. However, up to 40% of children are left with residual skin changes such as scarring, atrophy, redundant skin, discoloration, and/or telangiectasias. Large, nodular, superficial hemangiomas of the face are at particular risk for scarring, which may be disfiguring.13-15
Although the exact mechanism for hemangioma development remains unknown, vascular growth factors seem to play a role in the pathogenesis. Proliferation most likely results from an imbalance between positive and negative angiogenic factors expressed by the hemangioma and adjacent normal tissue.16 Increased apoptosis during the second year of life has been shown to offset cellular proliferation and may be involved in initiating hemangioma regression.17
Immunohistochemical studies have documented an overexpression of basic fibroblast growth factor (BFGF), vascular endothelial growth factor, proliferating cell nuclear antigen, and type IV collagenase within proliferating hemangiomas. In vitro, BFGF has been shown to stimulate endothelial cell hyperplasia, as well as the proliferation and migration of vascular smooth muscle cells and fibroblasts. In vivo, BFGF stimulates angiogenesis. Furthermore, increased quantities of BFGF have been found in the urine of patients with proliferating hemangiomas. Urinary BFGF levels may offer a future means of monitoring treatment efficacy.18-22 During the involution phase, the level of tissue inhibitor of metalloproteinase, an inhibitor of new blood vessel formation, is increased and mast cells are more numerous. Urinary levels of BFGF tend to decrease with hemangioma regression.22
CERVICOFACIAL HEMANGIOMAS
In 1997, Orlow et al23 recognized a strong association between hemangiomas in a cervicofacial location and symptomatic hemangiomas of the upper airway. The risk seems to be directly related to the extent of cutaneous involvement in a "beard"distribution, which includes the preauricular skin, chin, anterior neck, and/or lower lip.23 Characteristically, the airway hemangioma is superficial, unilateral, and subglottic.24 Affected infants are most likely to become symptomatic between 6 and 12 weeks of life, usually with progressively worsening inspiratory and/or expiratory stridor, which is particularly evident during feeding or crying. Cough, cyanosis, and hoarseness are other common manifestations. Almost 40% of the affected children eventually require tracheotomy. Airway involvement may be confirmed using endoscopic visualization.23, 25
PERIORBITAL HEMANGIOMAS
The development of a hemangioma in a periorbital location, particularly the upper eyelid, may lead to visual compromise. Astigmatism, the most common complication, results from direct compression of the optic globe or hemangioma expansion into the retrobulbar space. Other potential problems include ptosis, proptosis with corneal damage, strabismus, and stimulus deprivation amblyopia, one of the leading causes of preventable blindness.26 Immediate intervention is crucial, as visual compromise need only be present a short time ( 2 weeks) to result in permanent damage to the visual system. Therapy may be as simple as patching the normal eye to ensure use of the partially obstructed eye; however, more aggressive treatment may be necessary. Early examination by an ophthalmologist familiar with periorbital hemangiomas and their potential complications is mandatory.14, 27-28
LUMBOSACRAL HEMANGIOMAS
Hemangiomas located over the lumbosacral spine may be associated with spinal dysraphism or other underlying congenital anomalies. Lesions of greatest concern are those that span the midline and are plaquelike and/or telangiectatic in appearance (Figure 3). Reported underlying anomalies include tethered cord, imperforate anus with fistula formation, bony anomalies of the sacrum, abnormal genitalia, renal abnormalities, and lipomeningomyelocele.29-32
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Figure 3. Lumbosacral hemangioma with supragluteal cleft deviation, associated with underlying spinal dysraphism. (Courtesy of Ilona J. Frieden, MD, San Francisco, Calif).
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Of all the complications underlying lumbosacral hemangiomas, tethered cord may be the most devastating. Deviation of the supragluteal cleft is a particularly concerning clinical sign (Figure 3). Symptoms of spinal dysraphism, which may not arise until a child reaches 3 years of age or older, include lower extremity paresis, muscle atrophy, and incontinence. Early recognition and surgical repair is imperative, as failure to do so may result in permanent neurologic sequelae. Magnetic resonance imaging is the most sensitive means of diagnosis.29-32
PAROTID HEMANGIOMAS
Parotid hemangiomas, which almost always involve the gland in its entirety, tend to involute slowly, be more resistant to medical therapy, and are surgically challenging because of the risks of damage to the facial nerve. Uncommonly, parotid hemangiomas may cause obstruction of the external auditory canal, leading to a mild conductive hearing loss. However, except in the rare case of bilateral obstruction, normal auditory development usually remains unaffected. Parotid hemangiomas are also a potential cause of mandibular bone distortion, which occurs secondarily to the effects of mass displacement. Similar bony changes have also been reported for the skull and orbit, depending on hemangioma location.33-34
NEONATAL HEMANGIOMATOSIS
Neonatal hemangiomatosis is defined by the presence of multiple congenital hemangiomas. The disorder most commonly presents as a benign condition strictly limited to the skin. However, infants may present with a severe, life-threatening disorder, defined as hemangioma involvement of at least 3 separate organ systems. This rare condition is known as disseminated neonatal hemangiomatosis. Benign neonatal hemangiomatosis and disseminated neonatal hemangiomatosis most likely represent the 2 extremes of a disease continuum. Infants with benign neonatal hemangiomatosis experience rapid involution of their skin lesions, usually within the first 2 years of life, and have an excellent prognosis. In contrast, infants with disseminated neonatal hemangiomatosis have much higher morbidity and mortality rates.
Clinically, the hemangiomas in disseminated neonatal hemangiomatosis tend to be small (2 mm to 2 cm) and may be few or hundreds in number (Figure 4). The liver is the most commonly involved internal organ, followed by lung, brain, and intestine. Hepatic hemangiomas eventually involute, just as they do in the skin, but potentially serious complications may occur during the proliferative phase.35-36 Most infants with significant liver involvement manifest a triad of hepatomegaly, congestive heart failure, and anemia, which generally develops between 1 and 16 weeks of age. Congestive heart failure is the most common cause of death from disseminated neonatal hemangiomatosis. Other potential complications, dependent on specific organ involvement, include gastrointestinal hemorrhage, obstructive jaundice, and central nervous system sequelae caused by mass effects.37-38
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Figure 4. Multiple, small cutaneous hemangiomas characteristic of diffuse neonatal hemangiomatosis.
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Approximately 15% of infants who develop hemangiomas will have 2 or more lesions. Thus, further diagnostic evaluation should be based on physical examination and clinical symptoms. However, infants younger than 3 months with numerous, small, cutaneous hemangiomas should be carefully monitored. In this select group of patients, a screening abdominal ultrasonography with Doppler studies may be considered to rule out the possibility of hepatic involvement. Hepatic ultrasonography is also useful for distinguishing a hemangioma from an arteriovenous malformation, documenting solitary vs multiple hemangiomas, and monitoring therapy. Computed tomographic imaging provides a better assessment of lesion extent and overall liver size, and may also be used to demonstrate tumor regression during therapy.39-40
PHACES SYNDROME
An association between large facial hemangiomas and underlying cervicocranial arterial anomalies was first recognized by Pascual-Castroviejo41 in 1978. Subsequently, underlying posterior fossa brain abnormalities, particularly Dandy-Walker type malformations, were also found to be strongly associated.42 In 1995, a retrospective study additionally noted an above-average incidence of cardiac, ocular, and ventral developmental anomalies among children who are seen with large facial hemangiomas. The syndrome was thus coined "PHACES" (Table 2).43-44
The PHACES syndrome represents a spectrum of disease, and most of the affected infants manifest only one extracutaneous manifestation. The pathogenesis is unknown, but is thought to represent a developmental field defect occurring during early gestation.42-43 Female infants are predominantly affected.45 The hallmark of the syndrome is the presence of a large facial hemangioma, which is usually plaquelike and segmental, often involving one or more facial dermatomes (Figure 5). The initial presentation is often mistaken for the port-wine stain associated with the Sturge-Weber syndrome. When the hemangioma involves the ear, nose, or lip, ulceration frequently occurs, resulting in soft tissue loss. Rarely, intracranial hemangiomas may occur on the same side as the cutaneous hemangioma. Though these lesions demonstrate parallel changes in growth with their cutaneous counterparts, they tend to be neurologically silent.46
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Figure 5. Large, plaquelike facial hemangioma of the PHACES syndrome.
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Structural brain malformations, which occur in almost 50% of cases, are the most common underlying anomalies of PHACES syndrome. Most malformations are of the Dandy-Walker type, which is characterized by a hypoplastic or absent cerebellar vermis and a markedly dilated fourth ventricle, often referred to as a posterio fossa cyst. The Dandy-Walker type malformation is a developmental disorder of the midline central nervous system, which is associated with a wide spectrum of congenital and morphological defects, below average intellectual level, and early death in many patients. Other reported brain anomalies associated with PHACES syndrome include agenesis of the corpus callosum, cerebellar atrophy, and arachnoid cysts.41, 47
Cervicocranial arterial anomalies are the second most common component of the syndrome (occurring in approximately one third of the cases). Both persistent embryonic arteries and agenesis of major arteries may be seen, as well as aneurysmal dilatations and anomalous branches of the internal carotid artery.41, 48 Affected children commonly demonstrate developmental delay, and recent evidence suggests an increased risk for aneurysmal and occlusive changes. Hemiparesis and/or seizures may result from cerebral infarction.19
Less commonly reported complications of PHACES syndrome include cardiac, ocular, and ventral developmental anomalies. The most frequently reported cardiac anomaly is coarctation of the aorta. Other cardiac findings include cor triatriatum with partial anomalous pulmonary venous return, tricuspid and aortic atresia, patent ductus arteriosus, and ventricular septal defects. Unusual ophthalmologic abnormalities are found in approximately one fourth of the affected children, and include increased retinal vascularity, microphthalmia, optic nerve hypoplasia, exophthalmos, choroidal hemangiomas, strabismus, colobomas, congenital cataracts, and glaucoma. Ventral developmental defects most commonly manifest as sternal clefting or the presence of a supraumbilical raphe. The degree of sternal clefting ranges from a sternal pit, without underlying soft tissue or bony loss, to complete separation of the sternal bars. The supraumbilical raphe resembles a well-healed scar, which extends several centimeters above the umbilicus.49
The PHACES syndrome should be considered in any infant presenting with a large, plaquelike facial hemangioma. Children at risk should undergo complete neurologic examination, with brain imaging studies performed accordingly. Cranial ultrasound can be used as a screening test in infants younger than 6 months with open fontanelles. However, the posterior fossa is best viewed using magnetic resonance imaging, and the cerebrovasculature with magnetic resonance angiography. Careful cardiac examination and blood pressure measurements of all 4 extremities are indicated to exclude coarctation of the aorta and structural cardiac abnormalities. If any of the above components of PHACES syndrome are present, consultation with a pediatric ophthalmologist is also indicated. Lastly, if the hemangioma distribution is cervicofacial, infants should be closely monitored for signs of respiratory distress indicative of airway involvement.42-43
VASCULAR ENTITIES ASSOCIATED WITH KMS
Kasabach-Merritt syndrome refers to the development of life-threatening thrombocytopenia as a result of platelet trapping within a vascular tumor. Occasionally, KMS may also be complicated by the secondary consumption of fibrinogen and coagulation factors. Infants presenting with large, common hemangiomas were once closely monitored for the development of KMS. However Enjolras et al,50 in 1997, reported that KMS is not associated with the common hemangioma but with 2 other vascular entities—KHE and TA.50
KAPOSIFORM HEMANGIOENDOTHELIOMA
Kaposiform hemangioendothelioma is an uncommon, aggressive vascular tumor. Although benign histologically, this entity carries a high mortality risk if left untreated. Kaposiform hemangioendothelioma most commonly affects children younger than 2 years and is often present at birth. Unlike the common hemangioma, the incidence among male and female infants is equivalent. Kaposiform hemangioendothelioma is generally unifocal and favors the skin (particularly the trunk or extremities), or retroperitoneum. To our knowledge, hepatic involvement does not occur. The angiogenic growth factors |
