Chapter 126. Vascular Tumors

Vascular anomalies are common birthmarks.1 Their classification has often been problematic, with contradictory and confusing descriptive nomenclature. A classification system first proposed by Mulliken and Glowacki was revised in 1996 by the International Society for the Study of Vascular Anomalies based on clinical, radiologic, and hemodynamic characteristics, into vascular malformations and vascular tumors.2 Vascular malformations (see Chapter 172) are errors of morphogenesis whereas hemangiomas and other vascular tumors grow by cellular proliferation.

There are several types of vascular tumors, many of which occur in childhood. These tumors have also had confusing nosology,3 with descriptive but imprecise terminology such as strawberry, capillary, and cavernous. Several types of hemangiomas have been described (infantile, rapidly involuting congenital, lobular capillary, etc.), so whenever possible, hemangioma should not be used as a stand-alone noun but rather qualified by an adjective based on the specific condition.

Epidemiology

Infantile hemangiomas (IH) are the most common benign tumors of childhood, occurring in approximately 4% of children by 1 year of age.4,5 In contrast to other types of hemangiomas and vascular malformations, IH have a characteristic proliferative phase followed by a slower involution phase. They are more common in females (2–5:1 ratio) and in premature infants, especially those weighing less than 2,500 g.6,7 Other risk factors are Caucasian race, multiple gestation pregnancy, and maternal age greater than 30 years. Preterm infants are more likely to have multiple tumors, and the sex ratio is less skewed toward females.8 Contrary to prior observations, newer prospective studies do not support chorionic villus sampling as a risk factor.7,8

Etiology and Pathogenesis

IH are primarily composed of endothelial cells but also contain fibroblasts, pericytes, interstitial cells, and mast cells. Although the precise pathophysiologic mechanisms of the growth and involution of endothelial cells remains unknown, several recent discoveries have advanced our understanding of IH.9–13 The patterns found in segmental hemangiomas suggest at least some hemangiomas occur via developmental error as early as 4–6 weeks of gestation.14 IH only occur in humans, and adequate animal or laboratory models have been difficult to develop.

The recognition that a glucose transporter protein, GLUT1, is expressed in all stages of hemangioma maturation spurred new hypotheses on the pathogenesis of IH.15,16 GLUT1 expression in absent in the normal cutaneous vasculature but is found in placental blood vessels as well as in other so-called barrier tissues such as the blood–brain barrier. This, together with other immunohistochemical markers shared by IH and human placenta (FcγRII, merosin, and LeY), and the similar gene expression profiles found on DNA-based microarrays led to speculation that these tumors are of placental origin from either embolized placental cells or invading angioblasts that have differentiated toward a placental phenotype.16,17 IH lack a villous architecture and do not express known placental trophoblastic markers suggesting that they are not placental emboli.18 In addition, a recent study determined that hemangioma endothelial cells are of fetal, not maternal origin.19 Further investigations into the cellular origin of hemangioma endothelial cells have demonstrated that these cells have features of immature mesenchymal cells. They have features similar to an early embryologic vessel, the cardinal vein20 and express CD133, a primitive cell marker, during proliferation.21,22 Implantation into immunodeficient mice of CD133+ cells isolated from IH gives rise to GLUT1+ vessels that later diminish and are replaced by adipocytes.23 While not a perfect replica of IH growth, this model merits attention and additional study.

Additionally, while previous work suggested that IH arise because of aberrations in angiogenesis, recent investigations show that IH are not simply cutaneous capillaries with excessive growth, but more likely represent de novo vasculogenesis in the skin and other sites. Alterations in pathways that negatively control vascular endothelial growth factor receptor 2 (VEGFR2) signaling in vascular endothelial cells appear to play an important role in IH development and their rapid growth. In some patients germline mutations in VEGFR2 or tumor endothelial marker 8 (TEM8) lead to these signaling abnormalities.24,25 In vitro studies indicate that hypoxia and estrogen synergistically enhance hemangioma proliferation.21 Some studies have demonstrated evidence of clonality in hemangiomas, but further research is needed to demonstrate whether these tumors, particularly when in segmental patterns, are truly clonal.26,27

Clinical Findings

History

The clinical history is one of the most important keys to diagnosing an IH (Box 126-1).28 Absence at birth or presence as a premonitory mark, usually an area of pallor, telangiectasias, or duskiness is characteristic, whereas a fully formed soft-tissue mass at the time of birth is most likely not an IH, but another vascular anomaly or other disease process.

Cutaneous Lesions

Growth Characteristics

Though IH are not present at birth as fully formed tumors, superficial IH almost always become apparent within the first month of life. The period of most rapid growth typically occurs within the first 5 months of life, with 80% of growth being completed by 5 months of age.29 Deep hemangiomas may be noted at a somewhat later age, on average 1 month later than superficial IH and uncommonly are not appreciated until a few months of life. Large, segmental, deep, and parotid gland hemangiomas may continue to enlarge slowly for months to years longer.30 This growth phase is followed by a slower involution phase which is more variable in length, lasting for months to years (Fig. 126-1). Evidence of involution (change to a dull red, then gray or milky-white color, followed by flattening and softening) is usually apparent by 1 year of age.29 Smaller hemangiomas typically involute sooner than very large ones, but there are exceptions. Most IH complete their course by the age of 7–10 years. Some children have normal skin after involution whereas the remainder has telangiectasias, atrophy, fibrofatty residuum, or scarring.

Classification.14

Hemangiomas which involve the upper dermis (so-called superficial hemangiomas) have a bright strawberry red color; whereas those with deep dermal and subcutaneous location are skin color to blue in color. Those involving both superficial and deeper skin structures, so-called mixed hemangiomas, have both features. In addition to this clinical appearance, IH can be classified as localized, segmental, or indeterminate.31,32 Localized hemangiomas exhibit clear spatial containment as if arising from one central focus (Fig. 126-2). Segmental hemangiomas (similar to other segmental dermatologic disease such as vitiligo and neurofibromatosis) correspond to a portion of a developmental segment or broad anatomic territory (Fig. 126-3).33 They are often plaque-like in nature with a linear or geographic configuration. Those hemangiomas not clearly identifiable as localized or segmental are termed indeterminate (see Fig. 126-3). The patterns of facial segmental IH have been found to correspond to neural-crest-derived facial prominences, and a new map for them has recently been proposed.14 Multifocal hemangiomas are usually multiple localized hemangiomas. Though the exact number is somewhat arbitrary, the presence of more than five hemangiomas confers a risk of extracutaneous hemangiomas.

Classification of hemangiomas by subtype not only facilitates communication but also helps predict risk of complications and need for treatment. A prospective study of 1,058 children with IH showed that segmental hemangiomas are 11 times more likely to experience complications and eight times more likely to receive treatment than localized hemangiomas even when controlled for size.34

Atypical Presentations

Atypical presentations of IH include deep hemangiomas and those with minimal to no proliferation. Deep IH proliferate in the lower dermis and subcutaneous tissue without penetration of the papillary dermis (Fig. 126-4). They present as a localized, firm, rubbery subcutaneous mass that can be slightly raised with a bluish color or with telangiectasias involving the overlying skin, or they may be deep enough that the overlying skin is completely flat and of normal hue. If there is involvement of the papillary dermis, the cutaneous surface is often bright red and thus classified as a superficial and deep IH. IH with minimal to absent proliferation often have fine telangiectasias with a minimal to absent proliferative component thus resembling persistent premonitory IH (Fig. 126-5). They have recently been shown to be GLUT-1 positive indicating that they are indeed IH, but for unknown reasons, have not had a rapid proliferative phase. For unknown reasons, they are more common in the lower body.35,36

Medical and Extracutaneous Risks

Certain hemangiomas have known associated risks. Anatomic location is one of the most important factors affecting risk. Hemangiomas involving the central face (including the nose and perioral skin), periocular area, neck, mandibular region, and perineum should alert clinicians to possible increased risk of complications. In addition, the presence of multiple or segmental hemangiomas is associated with greater risk of extracutaneous disease.28

PHACE

Facial segmental IH are associated with PHACE (Online Mendelian Inheritance in Man #606519), a neurocutaneous syndrome that consists of the following features: posterior fossa brain malformations, segmental cervicofacial hemangioma, arterial anomalies, cardiac defects or coarctation of the aorta, eye anomalies, and sternal defects, such as sternal clefting or supraumbilical raphe.37 A recent workshop reviewed knowledge about PHACE and consensus criteria for diagnosis have been proposed (see Table 126-1).38,39 Up to one third of patients with large facial hemangiomas will be found to have PHACE when studied thoroughly.38 While initial reports emphasized structural brain abnormalities, particularly Dandy–Walker malformation, recent reports have found that arterial anomalies of the head and neck are more common than structural brain abnormalities.37–40 These intracranial arterial defects can lead to a Moyamoya phenomenon, ischemia, and stroke.41,42 Other complications including seizure disorders and developmental delay are sometimes present in the setting of these CNS abnormalities.40 The most common cardiac anomaly is coarctation of the aorta, most often involving the transverse aorta. Brain imaging [magnetic resonance imaging (MRI) and magnetic resonance angiography] should be considered in all infants with a large segmental hemangioma of the face.43 In addition, formal ophthalmologic examination and echocardiogram may be performed, given the relative frequency of anomalies in these sites. Periodic developmental and neurologic assessments should be performed.

Periocular Hemangiomas

Infants with periocular hemangiomas are at risk for anisometropia and amblyopia, which if untreated, can lead to permanent visual loss (Fig. 126-6).44,45 Direct pressure on the cornea can produce astigmatism or myopia, and the mass effect of the tumor itself can cause ptosis, proptosis, visual axis occlusion, or strabismus. Any patient with a hemangioma in the periocular area should have a prompt formal ophthalmologic evaluation with repeat visits during the proliferative phase (typically the first 3–4 months of life). Imaging studies may be needed to assess whether retrobulbar involvement is present.

“Beard Area” Hemangiomas

Segmental hemangiomas involving the preauricular, mandibular, chin, and neck skin (or so-called beard area) have a 60% risk of having symptomatic airway disease.46 Airway hemangiomas often present with the insidious onset of biphasic stridor between weeks 4 and 12 of life and are often mistakenly diagnosed as tracheomalacia, upper respiratory infection, or croup. If the hemangioma continues to enlarge, respiratory distress can ensue and become life-threatening. Prompt evaluation by a pediatric otolaryngologist and treatment is essential.47 Hemangiomas can also involve the parotid gland, and may require treatment due to massive growth, deformity of adjacent structures, and, in rare cases, high-output congestive heart failure.48,49

Lumbosacral and Perineal Hemangiomas

Segmental hemangiomas overlying the lumbosacral or perineal area can have associated spinal, bony, and genitourinary anomalies. Two acronyms have been proposed for this constellation of findings: PELVIS syndrome for perineal hemangioma, external genitalia malformations, lipomyelomeningocele, vesicorenal abnormalities, imperforate anus, and skin tag, and SACRAL syndrome, denoting spinal dysraphism, anogenital anomalies, cutaneous anomalies, renal and urologic anomalies, associated with angioma of lumbosacral localization.50,51 Segmental hemangiomas overlying the lumbosacral spine have a significant risk of spinal dysraphism and tethered spinal cord. MRI is strongly recommended in this setting.52 Other evaluations such as renal ultrasound should be based on clinical findings.

Multifocal Hemangiomas

Approximately 15% of infants will have more than one hemangioma, and premature infants have an even higher risk of multiple lesions (Fig. 126-7). In rare cases, infants can have hundreds of lesions. Until Glut-1 staining was recognized as a specific marker for IH, many infants with multifocal vascular tumors and extracutaneous disease were described as having diffuse neonatal hemangiomatosis. Many of these infants however actually have other vascular tumors. Infants with 5 or more IH are known to have an increased risk of having hepatic hemangiomas. Other sites of visceral involvement are exceeding rare in true IH. Visceral hemangiomas including those affecting the liver, gastrointestinal tract, and brain, have also been reported with solitary segmental hemangiomas.53

Hepatic Hemangiomas

The liver is the most common extracutaneous site of IH, Infants with >5 IH should be evaluated for the possibility of liver hemangiomas with liver ultrasound.54 Even if present, hepatic hemangiomas are often asymptomatic, however a minority cause morbidity, and in rare cases are life threatening. A classification for liver hemangiomas has been proposed by Christison-Lagay et al including three types of hepatic hemangiomas, two of which are true IH.55 The most common type (the presence of a few or multifocal liver hemangiomas) is often asymptomatic but can cause high-output congestive heart failure. A much rarer condition where the liver is virtually replaced by hemangiomas is termed “diffuse” disease. This life-threatening condition can result in abdominal compartment syndrome and a severe form of hypothyroidism due to tumor-related deiodination of thyroid hormone (see Section “Laboratory Tests”). A third type of hepatic hemangioma, wherein large solitary vascular tumors are typically present at birth is associated with arteriovenous shunting. In most cases these are not true infantile hemangioma but more likely analogous to rapidly involuting congenital hemangioma (RICH) occurring in the liver.

When cardiac compromise or severe hypothyroidism is a complication of hepatic hemangioma, systemic intervention is necessary. Embolization may be helpful if high-output congestive heart failure is present.56,57 Aggressive thyroid hormone replacement is needed in cases with hypothyroidism.58 In life-threatening cases liver transplant may be considered as a therapeutic option.

Laboratory Tests

Thyroid Function Tests

Hypothyroidism is a rare complication in infants with massive hemangiomas of the liver.59,60 First reported by Huang et al, hemangioma tissue demonstrates high levels of type 3 iodothyronine deiodinase activity, which accelerates the degradation of thyroid hormone.58,61 Infants with significant hepatic hemangiomas should have thyroid function evaluated, including T3 (the hormone consumed) and thyroid-stimulating hormone, because T4 levels may initially remain normal. Conversely, screening liver ultrasound looking for hemangiomas should be performed in infants with hypothyroidism of unknown etiology even in the absence of cutaneous hemangiomas. Hypothyroidism and other endocrine abnormalities have also been reported with PHACE syndrome. Infants with PHACE syndrome, large cutaneous hemangiomas, or extensive hepatic haemangiomas should have thyroid function [specifically thyroid-stimulating hormone, triiodothyronine (T3), and thyroxine (T4)] checked routinely.62

Platelet Studies

Platelet studies are not indicated in IH as the Kasabach-Merritt phenomenon (KMP) is not associated with IH but rather with kaposiform hemangioendothelioma (KHE) and tufted angioma (TA) (see Section “Pharmacologic Therapy”).

Recommended tests and imaging studies are included in Section “Cutaneous Lesions” with discussion on specific IH and their related physical findings.

Complications

Ulceration is the most common complication of IH, occurring in approximately 15% of patients usually during the proliferative phase with a median age of onset of 4 months.63 It occurs most frequently with segmental IH and at sites that are exposed to moisture and friction such as the perioral, perianal, and other intertriginous sites.64 Secondary infection can occur but its frequency is debatable. Cultures usually show polymicrobial growth and are likely the result of colonization.65 Localized infection will often improve with the use of topical mupirocin or metronidazole. However, if deeper or persistent infection is suspected, systemic antibiotics should be prescribed.

Local wound care, barrier protection, and pain control are essential for treatment. Bio-occlusive dressings may be helpful but those intended to stick to the skin may be limited by location because they do not adhere well near orifices.66,67 In these areas, thick applications of petrolatum-based ointments can be helpful. Pain can be a major issue in management. It can be minimized with an occlusive dressing, oral acetaminophen with or without codeine, and the use of very small amounts of topical lidocaine ointment no more than a few times a day.64 Ulcerations generally heal with scarring within 2–3 weeks with topical care. For refractory cases, other treatment modalities including pulsed dye laser (PDL) or Becaplermin 0.01% gel, a synthetic platelet-derived growth factor, have anecdotally been reported to be effective.68,69 Therapies aimed at halting hemangioma growth, such as intralesional and systemic steroids or excision, may be useful in some cases.

Other serious complications such as hypothyroidism, internal organ involvement, or vital structure compromise due to the location of IH in certain anatomic sites have been discussed in Section “Cutaneous Lesions.”

Prognosis and Clinical Course

The prognosis of most IH is excellent, with spontaneous involution and little to no sequelae, but a significant minority of IH result in permanent disfigurement or medical sequelae. Certain characteristics are associated with an increased risk of complications and need for treatment (Table 126-2).29,70 Consideration of early treatment should be given to hemangiomas with these characteristics, depending on the specific clinical setting.

Treatment

The decision to initiate treatment is based on many factors, including size and location, psychosocial implications, and risks and benefits of the proposed therapy. For the majority of small hemangiomas, close observation and follow up is the most appropriate approach. This does not mean doing nothing. The infant should be seen frequently, especially during the first few months (corresponding to the proliferative phase). During these visits, education about the natural course of IH and discussions about the psychosocial impact on the child and/or the family should occur.71 Photographs of the likely outcome for a similar lesion are often helpful. Many parents experience anxiety and may find themselves subject to comments from complete strangers about their child's hemangioma.72 Most parents of young children do not think their child is deeply affected by these reactions, but facial hemangiomas, in particular, can cause psychological suffering once the child reaches school age.73,74 Potential treatment options should be discussed well ahead of entrance to elementary school.

If it is decided that treatment is necessary, options include pharmacologic, laser, or surgical interventions (see Table 126-3). However, management remains controversial with few double-blind controlled studies and no Food and Drug Administration-approved labeled indications for medical treatments.

Pharmacologic Therapy

Corticosteroids

Until recently systemic corticosteroids were the first-line treatment for deforming, endangering, or life-threatening IH (see Fig. 126-6).75 They work best during the growth phase, causing slowing or cessation of growth in up to 90% of cases, with actual shrinkage in approximately one third. Although the mechanism of action is not well understood, recent studies suggest the upregulation of mitochondrial cytochrome b, clusterin/ApoJ (possible apoptotic markers), and/or interleukin-6 as markers of corticosteroid-induced cessation of hemangioma growth.76–78 Prednisone or prednisolone is given at a dose of 2–3 mg/kg/day, typically for 4–8 weeks followed by a tapering of varying length, depending on the age of the child and indication for treatment. A meta-analysis showed an 84% response rate with an average dose of 2.9 mg/kg for a mean of 1.8 months before tapering. Although 3 mg/kg/day is more effective (94% response) than 2 mg/kg/day (75% response), greater adverse events are found with the higher dose.79

Short-term complications of systemic corticosteroids include: cushingoid faces (71%), personality changes (29%), gastric irritation (21%), fungal infection (oral or perineal, 6%), and diminished gain of height (35%) and weight (42%) during treatment. More than 90% of children with diminished gain of height return to their pretreatment growth curve by 24 months of age (Table 126-3).80,81 Other complications include hypertension, steroid-induced myopathy, immunosuppression, and transient adrenal insufficiency.81,82 Blood pressure should be monitored with each visit to the dermatologist or pediatrician.83 Children taking more than 2 mg/kg/day of prednisone for longer than 14 days are considered to have a deficit in cell-mediated immunity. Live viral vaccinations should be deferred in infants receiving high-dose corticosteroids. Rare cases of Pneumocystis carinii pneumonia have been reported in this setting, leading some physicians to use trimethoprim-sulfamethoxazole prophylaxis during treatment.84,85

Intralesional corticosteroids can be an effective treatment for relatively small localized hemangiomas located in high-risk sites such as the lip, nasal tip, cheek, and ear. Injections for periocular hemangiomas are usually performed by ophthalmologists, but reports of retinal artery embolization and blindness have resulted in a reduced use of this modality.86–87 The largest published case series of intralesional steroids found that the majority showed greater than 50% reduction in volume with the best results occurring in relatively superficial hemangiomas. Adverse events occurred in 6.4% of patients and included cushingoid appearance, cutaneous atrophy, and anaphylactic shock (see Table 126-3).88

A few case series have reported on the efficacy of class 1 topical corticosteroids, especially for small, superficial hemangiomas.89–91

Propranolol

Recently, propranolol has been found to cause cessation of growth and shrinkage of IH and has replaced corticosteroids as the first line treatment for most deforming, endangering, or life-threatening IH.91 In the 3 years since 2008 when the initial series of 11 infants reported by Leaute-Labreze and colleagues, more than 150 articles have been published, most of them enthusiastically attesting to the efficacy of this treatment modality. This includes a randomized controlled trial comparing placebo to propranolol and retrospective studies comparing the effects of corticosteroids and propranolol.92,93 Most studies have used a dose range from 1.5 to 3 mg/kg/day given either 2 or 3 times per day. In most reports, patients are treated for at least 6 months with an acceptable side-effect profile. Unlike steroids which usually stabilize hemangioma growth, but do not cause involution, propranolol causes actual regression in the majority of cases. Rebound growth after cessation of therapy can occur, but usually responds well to retreatment.92,93 Side effects of propranolol include asymptomatic transient decrease in blood pressure, agitation, sleep alteration, sweating, wheezing, and cold hands. However the most concerning side effect which has emerged is hypoglycemia, which while rare, can be potentially life-threatening. Anticipatory guidance to minimize hypoglycemia in young infants includes frequent feeding and stopping the medication if oral intake is poor.94,95 Impressive results have been reported in other settings including fully proliferated cutaneous hemangiomas, airway, liver and orbital hemangiomas.92,96–98 Patients with PHACE syndrome who have central nervous system vascular anomalies may be at risk for stroke or other sequellae due to impaired arterial blood flow related to a drop in blood pressure or heart rate. Uniformly accepted standard monitoring procedures for patients on propranolol for IH have not yet been established. The mechanism of action of propranolol for hemangiomas is unknown, but it has been postulated to its effects by three different molecular mechanisms: vasoconstriction, inhibition of angiogenesis and induction of apoptosis.95,99

Topical β Blockers

Preliminary reports have demonstrated good responses with timolol 0.5% administered twice a day for superficial hemangiomas. Timolol is much more potent than propranolol, and data regarding percutaneous absorption are lacking, so using only a small amount (i.e., 1 drop BID) is currently recommended. More studies are needed to assess the results of this modality to determine its place in therapy.100,101,102

Interferon‐α

Interferon-α therapy is reserved for hemangiomas causing morbidity that are unresponsive to oral corticosteroids, or where such therapy is contraindicated. It is quite effective, but potential neurotoxicity, specifically spastic diplegia, has limited its use (see Table 126-3). A meta-analysis of 441 patients showed 11 developed irreversible spastic diplegia and 16 developed motor disturbances that were reversible on discontinuation of the drug.103 All affected patients were younger than 1 year of age at initiation of therapy, suggesting that the drug may be safer after 1 year of age. Neurologic evaluations should also be performed monthly in treated children.

Chemotherapy

Vincristine is often used in the treatment of the KMP and its associated tumors, KHE and TA.104–106 Given the potential neurotoxicity of interferon (see Section “Interferon-α”), vincristine is considered by some to be a second-line treatment for aggressive, complicated IH that do not respond to corticosteroids. However, further evaluation through prospective clinical trials is needed (see Table 126-3).

Cyclophosphamide has been reported in the pediatric hematology-oncology literature to be effective in the treatment of life-threatening diffuse neonatal hemangiomatosis.78,107

Imiquimod

A recent phase II open-label, uncontrolled study found that topical imiquimod 5% cream improved IH color, but not size, confirming that imiquimod's utility is limited superficial hemangiomas.108 Crusting and ulceration are potential side effects.109

Laser Therapy

The PDL, originally designed to treat portwine stains, has been used to treat IH with varying results.110 Several reports have shown improvement in treating hemangioma ulceration,111,112 and its use in diminishing residual telangiectasias and erythema after involution is well accepted. Its use in the treatment of proliferating hemangiomas is controversial.113 Batta et al performed the only prospective, randomized, controlled study to date regarding the treatment of IH in 121 patients aged 1–14 weeks, using 585-nm PDL without cooling compared to observation alone.110 Their results showed no difference between complete and nearly complete clearance with laser compared to observation alone at age 1 year, with a trend toward increased hypopigmentation and textural change in the laser-treated group. Other studies have shown good results with either the 585-nm PDL or 595-nm PDL, with varying fluences (total energy per unit area), but several have emphasized that treatments work best for more superficial hemangiomas and are unable to halt growth of deeper components.114–117 Severe ulceration and scarring, particularly in treating segmental hemangiomas during the proliferative phase, have been reported (see Table 126-3).118 A conservative approach is to reserve PDL primarily for treating ulceration and for hastening resolution of erythema in IH after the proliferative phase is completed.119

Surgical Therapy

Surgical excision may be indicated at any time during the life cycle of an IH (Fig. 126-8).1 In most instances, it is best to wait until regression is well under way and a more accurate assessment can be made regarding whether scarring and textural changes have occurred. Decisions regarding this can often be made at age 3–5 years, even if involution is not complete.120 Certain anatomic locations such as the nasal tip and lip often require surgery.121–126 Even earlier excision may be indicated in cases where clinical characteristics, such as pedunculated, very ulcerated, or extremely thick dermal involvement dictate that scarring will inevitably occur. A standard elliptical excision is often performed; however, circular excision followed by a purse-string closure may leave a smaller scar.127

Many other benign vascular neoplasms occur in both children and adults.128 This chapter highlights selected important vascular tumors. More comprehensive reviews of this subject can be found elsewhere.128–130

Congenital Hemangiomas

Hemangiomas that are fully formed tumors at the time of birth and do not proliferate in postnatal life are referred to as congenital hemangioma or congenital nonprogressive hemangioma. There are two major subtypes recognized on the basis of their natural history: the RICH and noninvoluting congenital hemangioma (NICH).131 Collectively, both are sometimes referred to as congenital nonprogressive hemangioma. The distinguishing pathologic features of these tumors are lobules of capillaries set within densely fibrotic stroma containing hemosiderin deposits, focal lobular thrombosis, and sclerosis.132 They are GLUT-1 negative.133 Both have similar anatomic sites of predilection, such as the extremities or postauricular skin, but they can occur elsewhere. RICH often appears as a raised, violaceous tumor with large, radiating veins or with overlying telangiectasia and a halo of pallor (Fig. 126-9). Central ulceration may be present. Most RICH involute spontaneously by age 14 months, often sooner, and usually leave residual atrophic inelastic skin in their wake.134 In one report a presumed RICH was noted on prenatal ultrasound and involuted before birth, leaving a scar tissue at the site of the lesion.135 NICH are also present at birth, but usually flatter than RICH, presenting as a well-circumscribed round to oval, slightly indurated, or raised soft-tissue mass with overlying telangiectasias and a rim of pallor (Fig. 126-10).

Both NICH and RICH are high-flow vascular anomalies, often showing arteriovenous microfistulas on Doppler interrogation. Some cases of RICH involute only partially, and the residual tumor resembles NICH, supporting the concept that RICH and NICH may be variants of each other.

Indications for treatment of NICH or RICH are similar to those for IH, including impairment of visual function and congestive heart failure. Excision should definitely be considered for ulceration, which can lead to severe hemorrhage, and for postinvolutional skin changes if disfiguring. NICH do not go away but are often asymptomatic; decisions regarding their removal must weigh risks and benefits of the proposed treatment.

Tufted Angioma

Etiology

TA is a benign vascular tumor that has also been called angioblastoma of Nakagawa. Its etiology and pathogenesis are uncertain. Unlike IH, there are no known gender or gestational age correlates.

Clinical Findings

Most cases are acquired early in childhood and have a protracted course. Rare congenital forms also exist. TAs display various clinical patterns. They may present as a subtle stain-like area that later thickens, as a large, plaque-like, infiltrated, red or dusky blue-purple lesion, or as an exophytic, firm, violaceous, cutaneous nodule (Fig. 126-11). TA are usually solitary, but multifocal cases have been reported.136 TA must be differentiated from IH as well as other vascular tumors. They are often somewhat firmer and may be tender. Histologically, both acquired and congenital TAs demonstrate vascular tufts of tightly packed capillaries, randomly dispersed throughout the dermis in a typical “cannonball distribution” with crescentic spaces surrounding the vascular tufts, and lymphatic-like spaces within the tumor stroma.137,138 Unlike IH, TA does not stain with GLUT1,15 and D2–40, a lymphatic marker, is only partially positive in surrounding vessels, helping distinguish TA from KHE.139

Complications

KMP may develop in TA but this is more common with KHE (see Section “Kaposiform Hemangioendothelioma”).

Prognosis and Clinical Course

TA may persist unchanged or regress completely within a few years.140

Treatment

No single treatment is effective. Interferon-α and PDL have anecdotally been reported to be effective.

Kaposiform Hemangioendothelioma

KHE is a rare vascular tumor that has usually been reported in association with KMP. It may be present at birth or develop in early childhood. Rare adult cases have been reported. It may present as a brown-red stain at birth which begins to thicken and become purpuric, or as a plaque or nodule similar to TA. Regional lymph node involvement may occur, but not distant metastases. Mediastinal or retroperitoneal disease may present with hemothorax and ascites.141 Spontaneous involution is rare. Most reported cases have had associated KMP, but the KHE can occur in the absence of a coagulopathy.142,143

The histology of KHE is characterized by spindled cells with minimal atypia and infrequent mitoses lining slit-like or crescentic vessels containing hemosiderin. The tumor is GLUT-1 negative. The overlap of both clinical and histologic features has led some to suggest that TA and KHE are part of a spectrum of disease. Increased lymphatic spaces reactive with the lymphatic markers vascular endothelial growth factor receptor-3 and D2–40 suggest a lymphatic origin, similar to that of Kaposi sarcoma.144,145

The prognosis and management of KHE varies with extent and location of the tumor, in addition to the presence of KMP. Therapies for KMP are discussed below.

Kasabach-Merritt Phenomenon

The KMP refers to the presence of platelet trapping in the setting of vascular tumors (Fig. 126-12). It was long considered to be a complication of “hemangioma,” but it is now recognized to be a complication of TA and KHE, not IH.146,147

KMP must be differentiated from the coagulopathy which can arise in association with venous and mixed venous-lymphatic malformations (sometimes erroneously called KMP) due to chronic clotting and consumption of clotting factors, but not primarily by platelet trapping.148 The hallmark of KMP is a tender, expanding vascular tumor with thrombocytopenia, usually severe. Consumption of fibrinogen, elevated d-dimers, and decreased coagulation factors occurs to varying degrees. Most cases involve the skin and musculature, but deeper viscera including cervicothoracic, abdominal, and pelvic regions can be affected. Although the tumors causing KMP can persist, the coagulopathy usually abates by 1 year of age or sooner with treatment. KMP may resolve with atrophic or stain-like areas, infiltrated plaques and papules, or nodules. Residual fibrosis is not rare and can result in considerable morbidity.149

No one treatment is uniformly effective. Options include corticosteroids, vincristine, cyclophosphamide, actinomycin-d, methotrexate, interferon-α, ticlopidine plus aspirin, surgical excision, arterial embolization, and radiotherapy. Platelet transfusions should be avoided unless active bleeding occurs or before surgical procedures.150–154

Multifocal Lymphangioendotheliomatosis with Thrombocytopenia

Multifocal lymphangioendotheliomatosis with thrombocytopenia (MLT)—also known as cutaneovisceral angiomatosis with thrombocytopenia—is a rare condition, characterized by multiple cutaneous vascular papules and plaques that are usually present at birth with more developing over time. The use of GLUT1 as a specific histopathologic marker for IH has led to the recognition that these vascular growths are not a widespread variant of IH. The clinical spectrum of the disease is expanding. Some patients have prominent exophytic cutaneous vascular tumors, whereas others have subtle blueberry muffin-like papules.155 Most affected infants have intermittent thrombocytopenia and lesions in the gastrointestinal tract, leading to gastrointestinal bleeding. Other reported sites of involvement include bones, synovium, lungs, liver, spleen, and brain. Undoubtedly, many patients previously diagnosed with “diffuse neonatal hemangiomatosis” actually had MLT. Skin biopsy specimens demonstrate thin-walled vessels, some hobnailed endothelial cells, and intraluminal papillary projections similar to Dabska tumor.156,157 Some of the vessels stain with lymphatic markers such as LYVE-1 or D2–40.155 No single treatment has been effective; patients have been treated with a variety of systemic medications including corticosteroids, interferon, vincristine, and most recently bevacizumab and thalidomide.155,158 Prognosis varies based on extent of disease and bleeding complications.

Spindle Cell Hemangioendothelioma

Spindle cell hemangioendothelioma is a rare vascular tumor most often seen with Maffucci syndrome. It can occur at any age and site but the extremities are the most commonly affected. The histology is of a nodular, dense, spindle cell proliferation in association with dilated dysplastic veins. Lesions can be locally aggressive and may recur even after excision.159

Congenital Eccrine Angiomatous Hamartoma (Sudoriparous Angioma)

Congenital eccrine angiomatous hamartoma is a rare condition characterized by ill-defined plaques with increased lanugo hair and sweating at the site of the lesion. They are usually located on the extremities or abdomen. Diagnosis is established on the basis of characteristic histologic findings: closely packed eccrine sweat glands associated with dilated capillaries, a few dysplastic venous channels, and a dense collagenous matrix.160

Pyogenic Granuloma (Lobular Capillary Hemangioma)

Pyogenic granuloma (PG) is also known by its correct histopathologic description lobular capillary hemangioma. It is one of the most common vascular tumors of infants and children and can also occur in adults, particularly in pregnant women. PG usually presents as a solitary, red, rapidly growing papule or nodule, often with a subtle collarette of scale (Fig. 126-13). Typical locations include the cheek or forehead but virtually any body site including the mucous membranes may be affected. They often develop an eroded surface, with subsequent bleeding which can be profuse, resulting in the moniker the band-aid disease. In very young infants, PG is often mistaken for an infantile hemangioma.161

PG does not involute spontaneously, but simple curettage with electrocautery is usually curative. Other options include excision, laser surgery (carbon dioxide or pulsed dye), and cryotherapy. Topical imiquimod has recently been shown to be an effective treatment.162 Recurrence and even satellite lesions surrounding the original PG have been reported.163,164

Other Vascular Tumors

Targetoid hemosiderotic hemangioma is a benign lesion presenting as a violaceous papule, often surrounded by a pale rim and peripheral ecchymotic halo, which fades with time. Lesions usually present on the trunk or extremities and histologically consist of dilated vascular channels within intraluminal papillary projections dissecting into collagen bundles in the subcutis. Extravasated erythrocytes and hemosiderin are present, hence the designation.

Endovascular papillary angioendothelioma (Dabska tumor) is a dermal nodule or a diffuse swelling on the head, neck, or extremities. Dabska tumor is a low-grade angiosarcoma. Epithelioid hemangioendothelioma and retiform hemangioendothelioma are other examples of low-grade angiosarcomas. These tumors, Kaposi sarcoma, and angiosarcoma are discussed in Chapter 128. Vascular malformations are discussed in Chapter 172.