Benign Cutaneous Vascular Tumors of Infancy: Title and subTitle BreakWhen to Worry, What to Do FREE

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).

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

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.

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

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}

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}

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}

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, 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 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}

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}

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

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}

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 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 BFGF and vascular endothelial growth factor, while raised in proliferating hemangiomas, are generally low in KHE.⁵¹ Heparin, which mobilizes BFGF and induces tumor angiogenesis, has been shown to incite KHE growth and worsen the clinical course.⁵²

Early in its course, KHE may appear deceivingly similar to the common hemangioma. However, mature lesions have a distinctive violaceous color, with an infiltrative, nodular growth pattern that closely mimics a malignant tumor (Figure 6). Further examination of the skin may reveal the presence of telangiectasias and/or ecchymoses, clues to underlying KMS. An association of KHE with lymphangiomatosis has also been reported.⁵³

Further evaluation of a suspected KHE requires magnetic resonance imaging and tissue for pathologic examination. Characteristic magnetic resonance imaging findings include ill-defined tumor margins with the involvement of multiple tissue layers. The feeding or draining vessels within a KHE tend to be small and few, in contrast with the common hemangioma. Another distinguishing feature is the presence of signal voids without flow-related enhancement, indicative of hemosiderin, other blood products, or fibrosis.^{54 - 55}

Histologically, KHE appears as a lobular infiltrate of benign endothelial cells. Thrombosed capillaries, slitlike vascular spaces, and scattered epithelioid cells are frequently seen. The pathology is similar to that of Kaposi sarcoma, thus the term "kaposiform."⁵⁶ The evaluation of an infant with a suspected or confirmed KHE should also include a complete blood cell count and coagulation studies to detect coexisting KMS.

Tufted angioma, also known as "progressive capillary hemangioma" or "Nakagawa's angioblastoma," is a rare, histologically benign vascular tumor, which was first described in 1949.⁵⁷ Distinguishing clinical features include a slow rate of growth, truncal location, and lack of tendency toward spontaneous involution. The TA may also be complicated by KMS, although less commonly than KHE.

Most TAs are not present at birth, but develop within the first year of life. The thorax is the most frequently affected site, particularly the neck, shoulders, proximal extremities, and upper trunk. Larger lesions are at greater risk for underlying KMS.⁵⁸ Clinically, a TA manifests as a dusky red to blue, subcutaneous plaque or nodule. Often annular with a wide, palpable border and central depression, the lesion is said to resemble a "doughnut" in the skin. One third of TAs are tender to palpation.^{57 ,59 - 66} Increased vellus hair growth and hyperhidrosis of the surrounding skin have also been described.^{61 - 62 ,64}

On low microscopic power, numerous lobules or "tufts" of capillaries are present within the middle to lower dermis. Higher magnification reveals that the capillary tufts are composed of benign spindle cells, which may show protrusion into neighboring vessels. The histologic features of TA may overlap with those of KHE, suggesting that these 2 entities lie within the same neoplastic spectrum.^{57 ,67}

The typical TA growth phase consists of slow, lateral extension, which continues for a few months to several years.⁵⁹ In contrast with the common hemangioma, spontaneous regression is uncommon.^{59 ,64 ,68} However, a rare, clinical variant of TA has been described, characterized by very early presentation (congenital or within the first month of life), preferential localization to the lower limbs, and progression toward sclerosis.^{59 ,69} Comparative clinical features of the common hemangioma, KHE, and TA are listed in Table 3.

Medical intervention is often required for large, ulcerative hemangiomas, or those impinging on vital structures. Local wound care is the mainstay of ulcer therapy, and is especially important for lesions in locations subject to trauma and infection, such as the perineum. Commonly employed topical therapies include antibiotics, barrier creams, and bio-occlusive dressings. Local wound care not only provides a barrier against secondary infection, but also serves to substantially reduce pain.¹²

Ulcerated, perineal hemangiomas are particularly challenging to manage. Parents should be instructed to use only superabsorbant diapers with frequent diaper changes to minimize exposure to urine and stool. Barrier pastes, such as zinc oxide, may be applied in a thick coating and covered with petroleum jelly (Vaseline)–impregnated gauze. Gentle removal of the paste may be achieved by using a mineral oil–moistened gauze, and should be performed with each diaper change. Alternatively, a hydrocolloid dressing (eg, Ultrathin Duoderm; Conva Tec, Bristol Meyers Squibb, Skillman, NJ) may be left in place for several days and is especially well suited for the perineum. Topical metronidazole gel has also been found to be safe and efficacious, especially in intertriginous or moist areas such as the lip and perineum.¹²

The pain associated with ulceration is often severe. Affected infants commonly suffer from sleep disturbance and increased irritability. The use of oral acetaminophen (with or without codeine) or a topical anesthetic agent (ie, 2.5% lidocaine hydrochloride ointment) is often warranted. When using lidocaine, parents should be instructed to apply only a pea-sized amount, no more than 4 times daily, to avoid the potential risks of lidocaine toxicity. An EMLA (a eutectic mixture of local anesthetics) cream has been approved for use only on intact skin and should be avoided. Moreover, it contains prilocaine, which has been associated with infantile methemoglobinemia. This risk is increased when EMLA is used concomitantly with other methemoglobinemia-associated drugs, such as acetaminophen.⁶⁹ If available, pulsed dye laser therapy has been shown to both relieve pain and promote reepithelialization of ulcerated hemangiomas.^{12 ,70}

Systemic corticosteroids remain the first-line therapy for complicated hemangiomas, although their exact mechanism of action is still not well understood. When used during the proliferative phase, systemic corticosteroids often arrest hemangioma growth and induce regression, with response rates of 30% to 90%. Although controversial, steroid use may also help prevent ulcer development and promote healing.^{71 - 73} Intralesional steroid injections may be beneficial for small (<2 to 3-cm diameter), well-defined hemangiomas. Generally, 3 to 5 injections are given at 6-week intervals; individual doses should not exceed 3 mg/kg of body weight. However, intralesional therapy should be performed cautiously, especially when treating periocular hemangiomas. Although rare, serious side effects including eyelid necrosis, central retinal artery occlusion, and adrenal suppression have been reported.^{74 - 77} A safer alternative for periocular hemangiomas may be the topical application of clobetasol propionate (Temovate) cream; however, large confirmatory studies are lacking.^{78 - 79} Intralesional photocoagulation treatment with the potassium-dianyl-phosphate and Nd:YAG lasers has also been used for periorbital hemangiomas.⁸⁰

Systemic corticosteroids alter hypothalamic-pituitary-adrenal function within a few days following therapy initiation, especially if administered twice daily.⁸¹ Thus, single-morning dosing is preferred. The usual starting dose is 2 to 3 mg/kg of body weight, which is then continued for 4 to 8 weeks. Some authors have advocated even higher doses of 5 to 6 mg/kg per day.⁸² The drug should then be slowly tapered to physiologic doses (2 mg/m²per day of prednisone or equivalent) for 1 to 2 months, and slowly decreased over another 1 to 2 months before therapy is terminated.⁸³ Abrupt discontinuation or rapid tapering of corticosteroids while a hemangioma is still in its active growth phase often results in rebound proliferation.

Corticosteroid use for infantile hemangiomas often results in minor, transient side effects, but long-term complications are rare. Short-term effects are more likely to develop with steroid courses of 6 months or longer, and resolve with drug tapering. The most common of such complications is the development of a cushingoid facies, which usually begins within the first 1 to 2 months of treatment. Personality changes such as depressed mood, agitation, insomnia, or restlessness occur in approximately one third of infants, usually in the first 2 weeks of therapy. Delayed skeletal growth, which is often readily apparent since a child grows more rapidly in the first year of life than at any other time, results from a temporary inhibition of collagen synthesis. However, almost all children catch up to their normal growth curve by 2 years of age. Gastric upset occurs in approximately 20% of infants and resolves with histamine₁-blockers such as ranitidine or cimetidine. Hypertension, though less common in children, has also been reported. Blood pressure monitoring should be performed in those infants undergoing systemic corticosteroid therapy.⁸³

Corticosteroids also depress the immune system by reducing neutrophil migration to sites of inflammation, and vaccines composed of live virus should not be administered while infants are receiving supraphysiologic steroid doses. Children should also avoid exposure to individuals with varicella infection. The varicella vaccine is available but is not given until 1 year of age, when most treated infants will have been tapered off the drug. So-called stress doses of steroids may be required if a child undergoes medical or surgical hospitalization while being given supraphysiologic corticosteroid doses. Serious corticosteroid complications, such as aseptic necrosis of the femoral head, osteoporosis, and the formation of cataracts are extremely rare in children.⁸³

Interferon alfa, given at an initial dose of 3 × 10⁶ U/m² per day, is an effective alternative for children with life-threatening hemangiomas that have not responded to corticosteroid therapy.^{84 - 86} The interferons alfa-2a (Roferon-A) and alfa-2b (Intron-A) are protein chains of 165 amino acids produced by a recombinant DNA process involving genetically engineered Escherichia coli. The 2 subtypes differ by the amino acid at position 23, where interferon alfa-2a has a lysine group and interferon alfa-2b has an arginine group. The mechanism of action useful for treating vascular tumors involves a negative effect on endothelial cell proliferation. Specifically, interferon down-regulates the expression of fibroblast growth factor that, along with other angiogenic factors, directly acts on relevant endothelial cells.⁸⁷ Though controversial, the simultaneous use of corticosteroids and interferon may be countereffective.⁸³

Interferon use in children has been limited by reports of neurotoxicity in the form of spastic diplegia. This is a crippling side effect clinically analogous to cerebral palsy, which has proven irreversible in some children despite drug withdrawal. Although the 2a form of interferon was initially implicated in the development of spastic diplegia, similar toxicity has been reported with the 2b form as well.⁸⁶ The risk, which may be as high as 20% in treated patients, seems to be dose- and duration-dependent, but the cause of this toxic effect remains unknown. Infants should receive close neurologic follow-up while undergoing treatment with interferon.

More commonly reported interferon side effects, usually transient in nature, include flulike symptoms, neutropenia, anemia, and leukocytosis.^{86 ,88 - 91} Almost 100% of infants will also develop increased transaminases (up to 5-fold the normal range), which are reversible and not an indication for discontinuation of therapy. The development of hypothyroidism, caused by autoantibody formation, has also been reported as a possible consequence of interferon use.⁴³

Severe hepatic involvement with hemangiomas requires immediate therapeutic intervention. Hepatic artery embolization, in conjunction with corticosteroid or interferon therapy, can temporarily control life-threatening congestive heart failure. However, embolization may be complicated by cirrhosis, sepsis, and hepatic infarction. Furthermore, the effectiveness of this procedure is often limited by contributing portal veins or collateral arteries. Hepatic artery ligation, hepatic resection, and transplantation have also been attempted in life-threatening cases.^{83 ,92 - 93}

When a hemangioma poses primarily cosmetic concerns, therapeutic intervention must be tailored on an individual basis. Although the final outcome of most hemangiomas cannot be predicted, lesions in certain locations are at greater risk for significant scarring. Such hemangiomas include pedunculated or superficial, nodular lesions, and/or those involving the lips, nose, ears, and glabella. In selected cases, early consultation with an experienced plastic surgeon is reasonable. However, the benefits and risks of surgical intervention must be carefully considered, since the surgical scar may be worse than the results of spontaneous involution.

"Active nonintervention" continues to be the mainstay of therapy for most uncomplicated hemangiomas, as spontaneous involution is the rule. However, a physician's decision not to medically or surgically intervene is hardly a passive one. Children and their parents need frequent follow-up for emotional support and reassurance. Photographs of former patients before and after involution are often helpful. In addition, serial photographs are often a useful way to document patient progress.

As of this writing, no consistently effective treatment exists for KHE. Smaller lesions may be surgically excised, although many tumors can only be treated medically because of their size or location.⁵³ Systemic corticosteroids alone have been beneficial in some patients, though most reports cite steroid use in combination with other therapeutic modalities.^{94 - 95} Interferon alfa is useful for treating both the tumor and associated KMS, and is effective in about 50% of children.^{96 - 98} Multimodal intervention has also been successful using embolization, interferon, cyclophosphamide, ϵ-aminocaproic acid, and compression therapy.⁹⁹ Isolated cases of improvement with vincristine therapy, either alone or in combination with other chemotherapeutic agents, have also been reported.^{55 ,100 - 101}

Therapeutic guidelines for the treatment of TAs have also yet to be established. Like KHE, smaller lesions may be amenable to surgery and treatment of larger lesions with systemic corticosteroids and/or interferon alfa has shown mixed results.^{59 ,65 ,102} Inconsistent results have been achieved with laser therapy (argon tunable-dye and pulsed-dye).⁶⁰ Similar to KHE, successful therapy of TA-associated KMS has been reported using vincristine.⁶⁷

The psychosocial implications of vascular tumors, especially those involving the face, deserve special mention. Parents are commonly victim to inappropriate comments by strangers, including accusations of child abuse. Infants and children may also be indirectly affected when they sense a parent's emotion of embarrassment, fear, or depression. Addressing the psychosocial aspects of care and providing the parents anticipatory guidance are essential for the effective management of benign vascular tumors.^{103 - 105}

Recent years have brought new insight into the benign vascular tumors of infancy. While most hemangiomas remain uncomplicated, certain unique presentations may be cause for concern. Periorbital hemangiomas may lead to permanent visual sequelae, including blindness. A significant proportion of infants with cervicofacial lesions in a beard distribution are at risk for simultaneous upper airway involvement, often requiring tracheostomy. Lumbosacral hemangiomas may be associated with underlying congenital anomalies, including spinal dysraphism.

Hemangiomas may also be associated with rare, often life-threatening syndromes. Infants with large, plaquelike facial hemangiomas should be evaluated for PHACES syndrome, which is most commonly associated with cerebrovascular arterial anomalies and posterior fossa brain malformations. Infants younger than 3 months who are seen with multiple, small cutaneous hemangiomas are at risk for the internal organ involvement characteristic of diffuse neonatal hemangiomatosis.

Lastly, KMS, once thought to be a complication of the common hemangioma, is now known to be associated with histologically benign, but aggressive tumors known as KHE and TA. Though these tumors may cause diagnostic confusion with the common hemangioma, they are clinically and histologically distinct entities.

Many treatment options are available for complicated vascular lesions. The mainstay of treatment for ulcerated hemangiomas involves local wound care, which protects against secondary infection and helps to relieve pain. Corticosteroids, the time-honored therapy of complicated hemangiomas, may be used topically, intralesionally, or systemically. Caution must be used when employing intralesional corticosteroids, especially when treating periocular lesions, as central retinal artery occlusion has been reported. Most side effects related to systemic steroid use for infantile hemangiomas are medically insignificant and short lived. However, immunosuppression remains a potentially serious complication, and children should not receive live virus vaccines while undergoing therapy. Furthermore, systemic steroids are not always effective. The interferons are a viable alternative for life-threatening situations. However, their use has been limited by the complication of spastic diplegia. No uniformly effective therapy is available for KHE or TA. Multimodal therapies are often necessary for these tumors. Future studies will determine whether the use of vincristine becomes a more promising treatment.

Addressing the psychosocial implications of vascular tumors, especially when located on the face, is an essential part of providing complete care for patients and their families. Treatment must be individualized on a case-by-case basis. The treating physician must bear in mind the risk benefit ratio when treating any child for a benign vascular lesion.

Accepted for publication February 11, 2000.

We acknowledge Ilona J. Frieden, MD, for review of the manuscript.

Corresponding author: Denise Walker Metry, MD, Department of Pediatric Dermatology, Baylor College of Medicine, 6621 Fannin, MC 3-3315, Houston, TX 77039.