Hemangiomas are considered the most common tumors of childhood. They are benign growths of endothelial cells (ECs), with a unique natural history characterized by a rapid growth phase usually beginning in the first weeks of life and continuing until 9 to 12 months of age (Fig. 64-1). The majority of hemangiomas subsequently undergo spontaneous gradual (but extensive) involution. Histological correlation with the growth phase demonstrates involution and is characterized by increased connective tissue in the dermis and fat in the subcutaneous tissues.² An important exception to this growth/regression pattern is the group of rapidly involuting congenital hemangiomas (RICH), which are generally present in full at birth (or even detected prenatally), and noninvoluting congenital hemangiomas (NICH), which do not change size postnatally.³ Growth curves for these hemangiomas are illustrated in Figure 64-2. A subset of patients with RICH may have high-flow lesions with prenatal or postnatal high-flow characteristics and/or transient coagulopathy^4,⁵ (Fig. 64-3). Congenital nonprogressive hemangiomas have been shown by North et al. to be histologically and immunophenotypically distinct from classical hemangiomas of infancy and are speculated to have a differing pathogenesis.⁶ NICH-type lesions were found to have high flow clinically (as assessed by Doppler), and inferred histologically, in that small arteries were seen shunting into lobular vessels or abnormal veins.⁷ Another subtype of hemangiomas are those with minimal or arrested growth, presenting as areas of telangiectasia with peripheral bulkiness. In one series, the majority of this type of hemangioma was present on the lower extremities.⁸

Figure 64-1 Hemangioma of infancy.

A-B, Sequential photos of infant who developed aggressive proliferative hemangioma with ophthalmological as well as cosmetic issues. In early phases (A), this lesion is not easily differentiated from a capillary malformation.

Figure 64-2 Growth curves for infantile hemangioma, rapidly involuting congenital hemangioma (RICH), and noninvoluting congenital hemangioma (NICH).

(From Mulliken J, Enjolras O: Congenital hemangiomas and infantile hemangioma: missing links. J Am Acad Dermatol 50:875–882, 2004; used with permission.)³

Figure 64-3 Rapidly involuting congenital hemangioma (RICH).

RICH of thigh with ulceration (A) and during natural involution (B). C. RICH of chest wall will high-flow component necessitating inotropic agents, intubation, and embolization. Infant had transient coagulopathy. Notice circumferential halo in both cases.

Typical hemangiomas are known to be most common in females, premature infants, and in the facial region. Results of the multicenter Hemangioma of Infancy Study of over 1000 children with hemangiomas showed an increased incidence in white non-Hispanic infants, multiple gestations, infants born to older mothers, and in association with placenta previa and/or preeclampsia.⁹ Other studies have shown (1) a threefold increased risk of hemangiomas in infants born to mothers who had transcervical chorionic villous sampling compared to amniocentesis (the incidence of hemangiomas in the amniocentesis group was equivalent to the incidence of hemangiomas in the general population)^10,¹¹ and (2) a correlation with placental anomalies with abnormal uteroplacental circulation.^12,¹³ Waner et al. noted a nonrandom distribution of facial hemangiomas and found two patterns of growth: focal lesions (in 76.3% of the 205 patients assessed) and diffuse lesions (in 23.7%). The focal hemangiomas correlated to 22 sites of occurrence, all near lines of mesenchymal or mesenchymal-ectodermal embryonic fusion. The diffuse hemangiomas were in a segmental distribution and were specified as frontonasal (27%), maxillary (35%), or mandibular (38%). There was a threefold increased incidence of ulceration in patients with diffuse hemangiomas compared to that in patients with focal hemangiomas.¹⁴ Haggstrom et al. expanded the observation of nonrandom distribution, designating four primary segments (Seg1-Seg4) to correspond with cutaneous location¹⁵ (Fig. 64-4). Large hemangioma size, facial location, and/or segmental hemangiomas were more likely to require medical intervention.¹⁶ Segmental hemangiomas can be associated with a higher incidence of PHACE(S) syndrome, visceral hemangiomas, and underlying lumbosacral anomalies (e.g., occult spinal dysraphism, including lipomyelomeningocele with tethered cord).¹⁷^–²⁰PHACE(S) Association is an acronym for posterior fossa structural malformations, hemangiomas (segmental), arterial anomalies, cardiac defects, eye abnormalities, (and sternal and other midline deformities)²¹ (Fig. 64-5). A patient with a segmental hemangioma and one or more of these criteria has PHACES. In one series, approximately one third of patients with facial segmental hemangiomas were found to have PHACES, those at higher risk having large hemangiomas involving more than one anatomical segment, and in the frontonasal or frontotemporal distribution. Of those with PHACES, most (90%) had more than one extracutaneous finding (most commonly CNS arteriopathy or cardiac anomaly).²² Similarly, Oza et al. observed that patients with large facial segmental cutaneous (Seg1-Seg4) hemangiomas were especially at risk of CNS structural and cerebrovascular anomalies, those with Seg1 distribution hemangiomas had a higher incidence of ocular anomalies, and those with Seg3 distribution had airway, ventral, and cardiac anomalies. In this series, all patients with CNS structural anomalies had concomitant CNS arteriopathies. Also identified were supratentorial CNS anomalies (cortical dysgenesis and migration abnormalities). Arteriopathies are most commonly dysplastic vessels with an aberrant course involving the internal cerebral artery and its embryonic branches ipsilateral to the side of the cutaneous hemangioma.²³ Hypoplasia, agenesis, or absence of normal arteries can also occur. In one review, some 20% of patients had arterial occlusions and stenoses.²⁴ Progressive changes can lead to aneurysm formation.²³

Figure 64-4 Distribution patterns of facial segmental hemangiomas.

(From Haggstrom AN, Lammer EJ, Schneider RA, et al: Patterns of infantile hemangiomas: new clues to hemangioma pathogenesis and embryonic facial development. Pediatrics 117:698–703, 2006.) Reproduced with permission, copyright by the AAP.

Figure 64-5 Segmental hemangiomas.

Note beard distribution and Seg3 distribution (A). Patient also had subglottic hemangioma. B, Partial Seg1&2 hemangioma that extended to neck and back. Patient was also found to have PHACE (posterior fossa structural malformations, hemangiomas [segmental], arterial anomalies, cardiac defects, eye abnormalities) arteriopathy.

Most hemangiomas are asymptomatic and require no therapy. Despite this clinical course, hemangiomas nonetheless may be the source of significant psychosocial morbidity (although this has not been well studied). Early intervention may be considered to prevent morbidity and/or preclude the need for future surgery. Hemangiomas may cause complications requiring medical therapy to catalyze the involution phase. These complications may include obstruction of the upper airway, ophthalmological disturbances, ulceration or bleeding, persistent soft-tissue deformity, cerebral vasculopathy, and/or high-output congestive heart failure (CHF); all are discussed below.

Kasabach-Merritt Phenomenon, Kaposiform Hemangioendothelioma, and Tufted Angioma

Trapping of platelets and other blood elements (Kasabach-Merritt phenomenon) has been known to occur in association with a subset of vascular anomalies since it was first described in 1940.²⁵ This is an extremely important diagnosis because early detection and rapid evaluation and treatment (if clinically symptomatic) are essential. Kasabach-Merritt phenomenon is not associated with common hemangiomas of infancy, but with kaposiform hemangioendothelioma (KHE) or tufted angiomas.^26,²⁷ On examination, the lesion is often edematous, boggy, and ecchymotic (Fig. 64-6). Anatomical predilection is for the chest wall and shoulder, groin extending down the leg, retroperitoneum, or face. Gender distribution tends to be equal. Hematological features of Kasabach-Merritt phenomenon include thrombocytopenia, hypofibrinogenemia, elevated fibrin degradation products, and D-dimers. Radiological hallmarks of KHE are cutaneous thickening, diffuse enhancement with ill-defined margins, small feeding/draining vessels, stranding, and hemosiderin deposits. The histological features of KHE are spindled ECs resembling Kaposi sarcoma (but not associated with human immunodeficiency virus [HIV] infection), abnormal lymphatic-like vessels, microthrombi, hemosiderin, and decreased mast cells and pericytes (which are often seen in hemangiomas). There may be residual tumor after resolution of hematological abnormalities, and radiological studies often demonstrate persistent vascular tumors. Residua of KHE-associated tumors may be dormant vascular tumors rather than scars. Clinically as well as histologically, they differ considerably from involuted hemangiomas. A subset of patients with KHE do not have an associated coagulopathy.²⁸ Treatment of KHE is not standardized but depends on the morbidity, location, and radiological features. Multimodal therapy may include steroids, chemotherapy (most commonly vincristine), interferon (IFN), antifibrinolytic agents, antiplatelet agents, and/or embolization. Diffuse intramuscular involvement often makes surgery not an option. Treatment with Rapamune (sirolimus) has been reported in one case^2,²⁹ and is currently being studied in a clinical trial (http://clinicaltrials.gov/ct2/show/NCT00975819?term=sirolimus&rank=82; see Table 64-4).

Figure 64-6 A, Kaposiform heman- gioendothelioma presenting with boggy diffuse mass, thrombocytopenia, and coagulopathy. B, After several courses of vincristine therapy.

Tufted angioma, first described in the late 1980s, is a benign vascular tumor typified by tufts of capillaries in the dermis. The clinical appearance ranges from erythematous indurated annular nodules to plaques, with or without hypertrichosis (Fig. 64-7). They commonly occur on the trunk and extremities, and they may be associated with Kasabach-Merritt phenomenon. Chu et al. suggest that KHE and tufted angioma may represent a continuum; they report a case of transformation between both tumors within a single patient.³⁰

Figure 64-7 Tufted angioma on abdominal surface.

Patient had Kasabach-Merritt phenomenon. Note site that was biopsied.

Pyogenic Granuloma

Pyogenic granuloma (also termed lobular capillary hemangioma) is an acquired vascular lesion of the skin and mucous membranes seen in pediatric patients (Fig. 64-8). The lesions have a cervicofacial propensity but can also be located on the trunk or extremities. The majority occur on the skin, and less frequently the mucous membranes (oral cavity and conjunctivae). These lesions are small and papular and tend to bleed. Treatment includes: (1) excision and linear closure, (2) shave excision, (3) cauterization, (4) cryotherapy, (5) carbon dioxide (CO₂) or pulsed dye laser, or (6) sclerotherapy.³¹

Figure 64-8 Pyogenic granuloma, an acquired vascular lesion often seen in children.

Lesions are prone to bleeding.

Kaposi Sarcoma

Kaposi sarcoma is a neoplasm commonly but not exclusively seen in patients with acquired immunodeficiency syndrome (AIDS).^32,³³ It is an unusual vascular neoplasm originally described in 1872. The clinical appearance begins as violaceous macules that progress to plaques and papules and then nodules. Kaposi sarcoma is thought to be multifocal rather than metastatic, with multiple lesions occurring simultaneously at different anatomical locations. Histological features include spindle cells and ECs with rare mitotic figures. Evidence indicates that Kaposi sarcoma is monoclonal, although these data are conflicting. A novel human herpesvirus known as Kaposi sarcoma–associated herpesvirus (KSHV), or human herpesvirus type 8 (HHV8), has been identified in Kaposi sarcoma tissue, supporting a viral etiology. Growth factors and cytokines are also believed to be involved in Kaposi sarcoma development. Therapies directed against Kaposi sarcoma include antiviral agents, antiangiogenic drugs, and immunosuppressive agents. Recent studies show the effectiveness of antiretroviral therapy suppressing HIV/AIDS-associated Kaposi sarcoma growth.³⁴

Vascular Malformations

Vascular malformations are present at birth and grow in parallel with the rate of growth of the child, with no propensity to spontaneous involution. They are due to developmental anomalies of the vasculature and may involve one or several types of vessels (arteries, veins, capillaries, or lymphatics). Vascular malformations are properly described according to the affected anomalous vascular channel. They can range from capillary malformations (commonly referred to as port-wine stains; Fig. 64-9) to large bulky growths that can distort the normal structures of the body and potentially lead to a high-output cardiac state (arterial malformations). Studies suggest that capillary malformations may be a result of abnormal innervation of discrete capillary beds causing chronic focal vascular ectasia.^35,³⁶ In one study, nerve density was significantly decreased in biopsies of capillary malformations, as compared to uninvolved skin.³⁷

Figure 64-9 Capillary malformations.

Patient has facial capillary malformation and Sturge-Weber’s syndrome.

Lymphatic malformations may cause focal or generalized lymphedema, depending on the magnitude of aberrant lymphatics (Fig. 64-10). Abnormal growth of lymphatic circulation encompasses overdevelopment (in lymphangiodysplasias, lymphangiomas, and lymphangiomatosis), underdevelopment of lymphatic vasculature, or both. Disorders of the lymphatic circulation are common, diverse, and often devastating in their functional consequences. Clinical issues common to lymphatic anomalies reflect the tendency of these malformations to develop: (1) local and systemic infections/cellulitis (infectious and aseptic); (2) leakage (e.g., superficial blebs, chylous ascites, chylothorax, peritonitis, pleural effusions); (3) malabsorption syndromes with significant metabolic consequences; (4) craniofacial distortion interfering with swallowing, airway, or causing significant visceral dysfunction; (5) recurrences or complications after surgery; and (6) swelling of the affected anatomy, with functional limitation.³⁸

Figure 64-10 Lymphatic malformations of chest wall (A), tongue (B), and buttocks/leg (C).

Syndromic Vascular Anomalies

There is a spectrum of vascular malformations with dysregulated skeletal/adipose/soft-tissue growth (Table 64-1). Klippel-Trénaunay’s syndrome (capillary-lymphatic-venous malformation with ipsilateral limb enlargement or hypoplasia, venous varicosities or developmental anomalies, or both ) is one of the most common peripheral vascular malformation syndromes (Fig. 64-11). Males and females are affected in equal proportion, and the lower limb is the most frequent site of the anomaly. In severe cases, there may be an accompanying bleeding diathesis characterized by a normal to slightly decreased platelet count, decrease in fibrinogen, and increased D-dimers and fibrin degradation products³⁹ (Fig. 64-12).

^{Table 64-1} Syndromic Vascular Anomalies and Genetic Information

Name	Features	Omim
Blue rubber bleb nevus syndrome Bean syndrome	Multiple small soft venous malformations on skin, gastrointestinal tract, elsewhere	112200
CLOVES syndrome	Congenital lipomatous overgrowth, vascular malformations, and epidermal nevi, skeletal/spinal anomalies	612918
Gorham’s syndrome Gorham-Stout’s syndrome Cystic angiomatosis of bone, diffuse disappearing bone disease	Lymphangiomatosis, bony destruction	123880
Klippel-Trénaunay’s syndrome	Capillary, venous, ± lymphatic malformation, hypertrophy of the related bones and soft tissues ± atretic deep venous system of affected extremity	149000
Maffucci’s syndrome (osteochondromatosis/ dyschondroplasia with vascular lesions)	Enchondromatosis and subcutaneous spindle cell hemangioendotheliomas, risk of chondrosarcoma, other malignancies including CNS	166000
Proteus’ syndrome	Gigantism (partial) of hands and feet, nevi, asymmetrical and disproportionate overgrowth, hemihypertrophy, macrocephaly, dysregulated adipose tissue, vascular malformations	176920
CM-AVM; CMC1 5q13-22 RASA-1 (RAS p21 protein activator 1) loss of function	Multifocal small macular CMs + AVM	608354
Venous malformations, multiple cutaneous and mucosal; VMCM 9p21 TIE2/TEK gain of function AD (most are sporadic)	Focal venous dilation with sparse vascular smooth muscle cells, cutaneous, mucosal, ± underlying areas	600195
Hennekam syndrome 18q21.32 CCBE1 Collagen and calcium-binding EGF domain–containing protein 1	Intestinal lymphangiectasia, severe lymphedema, mental retardation	235510
Hypotrichosis-lymphedema-telangiectasia syndrome HLTS 20q13.33 SOX18	Alopecia and/or areas of sparse hair, transparent skin, lymphedema, telangiectasia	607823
Lymphedema-distichiasis syndrome 16q24.3 AD or de novo FOXC2 loss of function	Limb edema and double rows of eyelashes (distichiasis) ± other associated anomalies including cardiac, renal, vascular, CNS gene mutation	153400
Milroy’s disease 5q35.3 AD, AR, or de novo FLT4 vascular endothelial growth factor receptor 3; VEGFR3 loss of function	Primary congenital hereditary lymphedema type Ia	153100
Lymphedema praecox Meige’s disease Late-onset lymphedema	Hereditary lymphedema type II Peripubertal onset	153200
Lymphangioleiomyomatosis LAM 16p13.3, 9q34	Pulmonary (and extrapulmonary) lymphangiomyomatosis; female predominance, adult onset	606690
HHT Osler-Weber-Rendu AD Loss of function HHT type I 9q34.1 Endoglin (131195) Part of TGF-β receptor complex HHT type 2 12q11-q14 ALK1 Activin A receptor, type II-like kinase-1; ACVRLK1 cell surface receptor for TGF-β superfamily HHT type 3 5q31.3-q32 HHT type 4 7p14 Juvenile polyposis/HHT syndrome; JPHT 18q21.1 SMAD4 tumor suppressor; mutations affect TGF-β signaling	Cutaneous, mucosal and visceral telangiectasias and AVMs, epistaxis, and gastrointestinal bleeding, ± pulmonary AV fistulas, hepatic, CNS, spinal AVM HHT1: cerebral AVMs > pulmonary AVMs HHT2: hepatic AVMs more common	187300 600376 601101 610655 175050
Cutis marmorata telangiectatica congenita CMTC Macrocephaly-cutis marmorata telangiectatica congenita	Cutaneous reticulated mottling, telangiectasia, and phlebectasia, undergrowth or overgrowth of an involved extremity ± other anomalies	219250
Glomovenous malformation GVM AD 1p22-p21 Glomulin (601749) FKBP (FK506 binding proteins)-associated protein, 48-KD; FAP48	Glomovenous malformations Cutaneous venous malformations with glomus cells surrounding distended vein-like channels	138000
PHACES Association	Posterior fossa brain malformations Segmental facial hemangiomas Arterial anomalies Cardiac anomalies Eye abnormalities Sternal or midline anomalies	606519
Bannayan-Riley-Ruvalcaba 10q23.31 PTEN Phosphatase and tensin homolog; tumor suppressor	Macrocephaly, multiple lipomas, vascular anomalies, pigmented macules of the penis	153480
Cowden’s syndrome 10q23.31 AD PTEN Phosphatase and tensin homolog; tumor suppressor PHTS	Macrocephaly, multiple hamartomas, cutaneous verrucous lesions, gingival/buccal papules, facial trichilemmomas, risk of breast/ thyroid/renal/endometrial malignancies, cerebelloparenchymal disorder VI (Lhermitte-Duclos’ disease)	158350

Figure 64-11 A, Patient with Klippel-Trénaunay’s vascular malformation syndrome complicated by leg-length discrepancy, asymmetrical foot size requiring custom orthotics, lymphopenia, and frequent septic episodes due to abnormal lymphatic communications. B, Patient with Klippel-Trénaunay’s vascular malformation syndrome, leg length discrepancy with cutaneous capillary malformation, and blebs prone to bleeding.

Figure 64-12 Patient with venous vascular malformation of left leg (A), with leg length discrepancy and extensive involvement, as noted on magnetic resonance imaging (MR) (B).

Patient later developed knee contractures, pain, and coagulopathy.

Sturge-Weber’s syndrome includes a capillary malformation in the trigeminal distribution, intracranial angiomatosis and dysplasia, seizures, and glaucoma (see Fig. 64-9). Other examples of dysmorphic syndromes associated with vascular malformation are Turner’s and Noonan’s syndromes, Parkes Weber’s syndrome, hereditary hemorrhagic telangiectasia (HHT), blue rubber bleb nevus syndrome (Fig. 64-13), Maffucci’s syndrome, CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, spinal/skeletal anomalies or scoliosis), Proteus’s syndrome, Bannayan-Riley-Ruvalcaba’s syndrome, and Cowden’s syndrome (see Table 64-1). Syndromes noted for CNS vascular anomalies include von Hippel-Lindau, ataxia-telangiectasia, Sturge-Weber, and tuberous sclerosis; however, CNS and spinal arterial or venous anomalies are now known to occur in association with a number of vascular anomalies.^23,⁴⁰^–⁴⁵

Figure 64-13 Patient with blue rubber bleb nevus syndrome.

Patient has large vascular malformation of neck and history of severe gastrointestinal bleeding due to similar vascular malformations in gastrointestinal tract.

Dysmorphic syndromes associated with hemangiomas are predominantly associated with superficial segmental hemangiomas such as PHACES Association or sacral and/or genitourinary defects, associated with hemangiomas in the lumbar area.^19,⁴⁶

PTEN-Associated Hamartoma Syndromes

PTEN (phosphatase and tensin homolog protein) is a tumor suppressor gene. Patients with a PTEN mutation are susceptible to cancers and warrant early and regular screening. Some patients with vascular anomalies (arteriovenous, lymphatic, venous) have the PTEN mutation, such as those with Cowden’s and Bannayan-Riley-Ruvalcaba’s syndromes.⁴⁷ A family history or presence of lipomas, thyroid disorders, tricholemmas, macrocephaly, and penile lentigines may point to a PTEN mutation. Consultation with a geneticist and family screening for mutations is indicated, and early screening for thyroid, breast, brain, gynecological, and other cancers should be initiated for all individuals with the PTEN mutation.^47,⁴⁸ Tan et al. recommend screening for PTEN mutations in patients with vascular malformations and the described findings and/or multiple vascular anomalies with a characteristic angiographic appearance, adipose-containing intramuscular lesions, and multiple intracranial developmental venous anomalies.⁴⁰

Patients with Cowden’s syndrome have typical skin growths that may resemble small, uniform, cutaneous and mucosal warts or skin tags, as well as macrocephaly and cognitive delay. Malignancies seen in patients with Cowden’s syndrome are usually breast, thyroid, or endometrium. Additional findings are benign tumors, thyroid nodules, breast masses, and Lhermitte-Duclos’ disease, a benign noncancerous brain tumor, which is pathognomonic. Often the suspicion of Cowden’s syndrome begins with a family history of thyroid nodules, lipomas (benign fatty lumps), and/or cancers. If the family history and clinical spectrum (macrocephaly, hamartomas, skin tag–appearing lesions) are present, the patient and family should be referred to a genetics specialist for further discussion and blood testing for the presence of the PTEN mutation. Since not all the mutations are available for testing, more sophisticated tests may be required if the initial test is negative and the patient/family fulfills the criteria for the disorder. Upon the suspicion or diagnosis of Cowden’s syndrome, individuals should be placed in a cancer surveillance program to facilitate early detection and prompt referral for further evaluation and treatment.

Bannayan-Riley-Ruvalcaba’s syndrome is characterized by macrocephaly, noncancerous fatty masses (lipomas), vascular malformations, intestinal polyps, thyroid disorders, pectus excavatum, hyperextensible joints, proximal muscle abnormalities, and predisposition to breast and thyroid cancers. Male patients have penile lentigines. Bannayan-Riley-Ruvalcaba’s syndrome, which is often diagnosed in childhood, is also associated with mutations of the PTEN gene, thus the same guidelines hold true for patients suspected of having this disorder, as well as their family members.

Prenatal Diagnosis of Vascular Anomalies

With the availability of improved techniques in fetal ultrasound and magnetic resonance imaging (MRI), prenatally diagnosed vascular anomalies are becoming increasingly recognized. Most prenatally diagnosed vascular lesions are vascular malformations. Vascular lesions detected prenatally are generally identified by asymmetrical limbs and/or high-flow lesions (e.g., arteriovenous malformations [AVMs]or high-flow RICH-type lesions).⁴⁹ If symptomatic in utero, such as high-flow vascular lesions compromising fetal hemodynamic status, prenatal therapy with maternal steroids or digoxin can be instituted. Maternal steroid therapy may be helpful in the management of fetal hemangiomas.^50,⁵¹

Etiology of Hemangiomas and Vascular Malformations

Why do vascular anomalies occur? The simple answer is that they are due to many causes—mechanical, environmental, hormonal, and genetic—although no single etiology is thematic. Within the last several years, major research breakthroughs are unraveling potential etiological factors leading to formation of vascular anomalies, as detailed in excellent reviews.⁵²^–⁵⁵

As subtypes of hemangiomas with segmental cutaneous distribution and associated visceral anomalies became evident, researchers speculated involvement of neural crest–derived cells, further supported by identification of neural crest cell markers (neurotrophin receptor p75) in proliferating hemangioma tissue.⁵⁶ Several studies demonstrated markers for progenitor mesodermal stem cells (brachyury, GATA) or endothelial and hematopoietic cells (platelet endothelial adhesion molecule [PECAM]-1 [CD31]), intracellular adhesion molecule (ICAM)-3, bcl-2 gene expression, KDR⁺, CD133⁺, CD34⁺, endothelial precursor cells, lymphatic endothelial hyaluronan receptor-1, von Willebrand factor (vWF), and Snrk-1 in hemangioma tissue.⁵⁷^–⁶⁰ Constitutive activation of the endothelial tie-2 receptor and vascular endothelial growth factor receptor (VEGFR)-2-related signaling pathways have been identified in human hemangiomas of infancy.^52,^54,⁶¹

Clonality of ECs was demonstrated,^62,⁶³ and the potential role of ECs in hemangioma development elucidated.⁶⁴^–⁶⁶ Bischoff et al. isolated hemangioma-derived stem cells, which unlike other precursor cells, grew in vitro and differentiated in vivo into cells with properties of hemangiomas, including the eventual presence of adipocytes, as seen in involuting hemangiomas.² Hemangiomas and placental vessels express common proteins including glucose transporter (GLUT)-1.⁶⁷ This discovery is of diagnostic utility and spearheaded insights into placenta-based hypotheses. For example, Mihm and Nelson proposes a metastatic niche theory for hemangioma development, suggesting the placenta prepares hemangioma precursor cells that “home” to sites of hemangioma growth⁶⁸ (Fig. 64-14). Proliferating hemangiomas have been shown to express VEGF-A as well as genes involved with nuclear factor (NF)-κB-related pathways.^69,⁷⁰

Figure 64-14 Metastatic niche theory of hemangioma development.

(From Mihm MC, Nelson JS: Hypothesis: the metastatic niche theory can elucidate infantile hemangioma development. J Cutan Pathol 37:83–87, 2010; used with permission.)

In addition, proapoptotic factors and appearance of adipocytes during the involution phase support a role for inflammation and immunoregulation in this process ⁷¹ (Fig. 64-15). The vast majority of hemangiomas appear to be sporadic; however, familial cases harboring germline mutations of angiogenesis-related genes (VEGF2 and tumor endothelial matrix marker [TEM8]) have been identified.⁷² A secondary somatic event appears to be necessary for hemangioma development. Box 64-2 summarizes features of hemangioma endothelial cells.

Figure 64-15 Adipocytes in hemangioma involution.

Photographs and hematoxylin & eosin–stained frozen sections of resected proliferating hemangioma from 3-month-old child (A, C) and involuted hemangioma of 7-year-old child (B, D). Note presence of adipocytes in involuted hemangioma.

(From Yu Y, Fuhr, J, Boye, E, Gyorffy, S, Soker, S, Atalia, A, Mulliken, J, Bischoff. Mesenchymal Stem Cells and Adipogenesis in Hemangioma Involution. Stem Cells 2006;24:1605–1612.2 used with permission.)

Box 64-2 Summary of Properties of Hemangioma Endothelial Cells *