Peripheral Vascular Anomalies, Malformations, and Vascular Tumors

Chapter 64 Peripheral Vascular Anomalies, Malformations, and Vascular Tumors

Nonmalignant vascular anomalies can be functionally divided into two groups: proliferative vascular lesions and static vascular malformations. Unfortunately, this distinction is not universally appreciated, and diagnoses are often incorrect in the literature and clinical practice because of knowledge gaps and lack of clarity. Box 64-1A delineates a classification initially proposed by Mulliken and Glowaki,1 and Box 64-1B is an updated version published by the International Society for the Study of Vascular Anomalies (access at Functional classification helps guide management and prognosis. This chapter discusses peripheral (i.e., not central nervous system [CNS] or cardiac) vascular anomalies, including vascular tumors and syndromic vascular disorders, and offers new genetic information and insights into putative signaling pathways implicated in their development.

Proliferative Vascular Anomalies and Tumors

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 coagulopathy4,5 (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

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).1720PHACE(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

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 case2,29 and is currently being studied in a clinical trial (; see Table 64-4).

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

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

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

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

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
RASA-1 (RAS p21 protein activator 1) loss of function
Multifocal small macular CMs + AVM 608354
Venous malformations, multiple cutaneous and mucosal; VMCM
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
Collagen and calcium-binding EGF domain–containing protein 1
Intestinal lymphangiectasia, severe lymphedema, mental retardation 235510
Hypotrichosis-lymphedema-telangiectasia syndrome
Alopecia and/or areas of sparse hair, transparent skin, lymphedema, telangiectasia 607823
Lymphedema-distichiasis syndrome
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
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
16p13.3, 9q34
Pulmonary (and extrapulmonary) lymphangiomyomatosis; female predominance, adult onset 606690
Loss of function
HHT type I 9q34.1
Endoglin (131195)
Part of TGF-β receptor complex
HHT type 2 12q11-q14
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
Cutis marmorata telangiectatica congenita
Macrocephaly-cutis marmorata telangiectatica congenita
Cutaneous reticulated mottling, telangiectasia, and phlebectasia, undergrowth or overgrowth of an involved extremity ± other anomalies 219250
Glomovenous malformation
Glomulin (601749)
FKBP (FK506 binding proteins)-associated protein, 48-KD; FAP48
Glomovenous malformations
Cutaneous venous malformations with glomus cells surrounding distended vein-like channels
PHACES Association Posterior fossa brain malformations
Segmental facial hemangiomas
Arterial anomalies
Cardiac anomalies
Eye abnormalities
Sternal or midline anomalies
Phosphatase and tensin homolog; tumor suppressor
Macrocephaly, multiple lipomas, vascular anomalies, pigmented macules of the penis 153480
Cowden’s syndrome
Phosphatase and tensin homolog; tumor suppressor
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

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.23,4045

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.

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.5255

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.5760 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.6466 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

In addition, proapoptotic factors and appearance of adipocytes during the involution phase support a role for inflammation and immunoregulation in this process71 (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.

Jul 1, 2016 | Posted by in CARDIOLOGY | Comments Off on Peripheral Vascular Anomalies, Malformations, and Vascular Tumors

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