CONGENITAL ANOMALIES AND PEDIATRIC PLASTIC SURGERY
CHAPTER 21 VASCULAR ANOMALIES
HARVEY CHIM AND ARUN K. GOSAIN
Vascular anomalies come in all shapes and sizes. They may be flat or raised and purple, red, or pink. They have been the subject of superstition and folklore for eons. Early attempts at classification of vascular lesions were hampered by the use of confusing, often eponymous nomenclature, based variably on clinical, pathologic, biological, embryological, or descriptive factors. An early pathologic classification by Virchow1 divided vascular anomalies into angiomas (simplex, cavernosum, and racemosum) and lymphangiomas (simplex, cavernosum, and cystoids). Conversely, a capillary malformation (CM) was variably described as a “port-wine stain,” “nevus flammus,” or “capillary hemangioma.”
Mulliken and Glowacki2 further defined the nature of vascular anomalies in a seminal work and classified these into hemangiomas and vascular malformations, distinguishing them based on clinical course, biologic behavior, and histopathological features. This laid the groundwork for our current understanding of these lesions. In 1993, Jackson et al.3 further divided vascular anomalies into hemangiomas, vascular malformations, and lymphatic malformations (LMs).
Most recently in 1996, the International Society for the Study of Vascular Anomalies (ISSVA) proposed a classification (Table 21.1) based on that originally published by Mulliken and Glowacki, which divides vascular anomalies into vascular tumors and malformations.4 This is now the most widely accepted classification system and forms the basis for diagnosing and treating vascular anomalies.Vascular tumors include hemangiomas and other proliferative lesions. Vascular malformations are subdivided based on vascular components into simple and combined malformations. Integral variants of vascular malformations include capillary, venous, arteriovenous, and lymphatic malformations. Tumors and malformations are distinguished based on biological behavior, clinical appearance, and radiological and pathological features.
Vascular tumors proliferate largely by endothelial cell hyperplasia. The prototypical lesion is the infantile hemangioma (IH), which demonstrates rapid postnatal growth and slow regression during childhood. Vascular malformations, in contrast, have a quiescent endothelium and are thought to be caused by local defects of vascular morphogenesis and remodeling. Vascular malformations never regress and often persist or enlarge throughout life. Vascular malformations have been further categorized based on flow characteristics into fast-flow and slow-flow lesions. Fast-flow lesions include lesions with an arterial component (AM [arterial malformation], AVM [arteriovenous malformation], AVF [arteriovenous fistula], C-AVM [capillary arteriovenous malformation], and L-AVM [lymphatic arteriovenous malformation]). Slow-flow lesions would encompass all other lesions.
IH is a vascular tumor that affects from 5% to 10% of Caucasian infants by 1 year of age. It is more common in females than in males (3 to 5:1) and in preterm infants (23%). Around 80% of hemangiomas are solitary, while 20% are multifocal. IH is characterized by a three-stage life cycle, consisting of the proliferating phase, involuting phase, and involuted phase (Figure 21.1).
The cellular origin of IH has been shown to be related to clonal expansion of a hemangioma-initiating multipotent stem cell,5 which expresses the marker CD133 and has the capacity to form human blood vessels expressing erythrocyte-type glucose transporter protein-1 (GLUT-1) and merosin. This vasculogenic activity appears to be confined to hemangioma-derived stem cells only. Hemangioma endothelial cells also appear to be fundamentally different from normal endothelial cells, with constitutive low expression of vascular endothelial growth factor receptor (VEGFR)1 and missense mutations in genes encoding VEGFR2 and TEM8 (tumor endothelial marker 8), suggesting a germline mutation leading to variant downstream signaling in the vascular endothelial growth factor (VEGF) pathway.6 The unique cellular nature of hemangioma cells suggests that the etiology of IH relates to a mutation of endothelial cells at the stem cell level instead of embolized placental cells, as previously postulated.
FIGURE 21.1. Hemangioma. This girl with a right facial hemangioma demonstrates the three-stage life cycle of IH, consisting of the proliferating phase ((A) age 3 months), involuting phase ((B) age 18 months), and involuted phase ((C) age 7 years).
A characteristic marker of IH is GLUT-1. IH immunostains positively for GLUT-1 throughout its life cycle and is negative in most other vascular lesions. In the proliferative phase, IH consists of plump, rapidly dividing endothelial cells, and pericytes that form tightly packed sinusoidal channels. A characteristic ultrastructural feature of this phase is the presence of multilaminated basement membranes. Increased angiogenesis is seen in this phase as documented by the expression of VEGF, matrix metalloproteinase (MMP)-2, proliferating cell nuclear antigen, and basic fibroblast growth factor. These markers of angiogenesis and cell proliferation are not seen in vascular malformations.
In the involuting phase, there is gradually decreasing endothelial activity and luminal enlargement. Apoptosis is seen in endothelial cells before 1 year and peaks in 2-year-old specimens. Increasing fibrosis, stromal cells (such as mast cells, fibroblasts, and macrophages), and expression of tissue inhibitor of metalloproteinase-1, a suppressor of new blood vessel formation, is seen.7 Finally, in theinvoluted phase, the previously highly cellular lesion has been largely replaced by loose fibrofatty tissue mixed with dense collagen and reticular fibers.
Hemangiomas typically appear at birth or within the first 2 weeks of life. Most of these are innocuous, with only about 10% being locally invasive, disfiguring, or life-threatening. The clinical appearance depends on depth, location, and stage of evolution. Around 30% to 40% are quiescent at birth, appearing only as a cutaneous mark, such as a pale area, macular stain, telangiectatic macule, or ecchymotic spot or scratch.
The current morphological classification system for hemangiomas separates them as localized, segmental, or multiple. Localized hemangiomas present as focal, tumor-like growths that are contained to one defined cutaneous region and fail to demonstrate a linear or geometric pattern. Segmental hemangiomas are less common than the localized lesions and are generally more plaquelike in presentation. Segmental lesions also demonstrate a geographic distribution over a specific cutaneous region and are more likely to be associated with various complications, require more aggressive therapy, and have a poorer overall outcome.
Proliferative Phase. In typical hemangiomas, the majority of proliferation occurs during a rapid growth phase in the first 6 to 8 months with cessation of growth by 1 year of age. At this stage, the tumor is typically in its most florid presentation. The composition of the tumor becomes more apparent as it proliferates, demonstrating a superficial and/or deep component. The clinical presentation of the superficial component includes a bright red, well-demarcated, slightly elevated noncompressible plaque. Hemangiomas deeper in the dermis and subcutaneous tissue are usually soft, warm, ill-defined subcutaneous masses that have a slightly bluish hue. Often, hemangiomas have both superficial and deep components.
Involuting Phase. In the involuting phase, the florid crimson color of IH fades to a dull purplish hue, with increased pallor of the skin and decreased turgor of the tumor. This phase marks the regression of the tumor, and typically lasts anywhere from 2 to 10 years. In many children the involuting phase results in virtually normal skin, but in a number of cases children with hemangiomas will exhibit residual telangiectasias, pallor, atrophy, textural changes, and sometimes residual fibrofatty tissue.
Involuted Phase. Regression is complete in 50% of children by 5 years and in 70% of children by 7 years, with continued improvement up to 10 to 12 years of age. Bulky and large lesions may regress completely, while a flat superficial hemangioma may lead to permanent alteration in the texture of the skin.
While most hemangiomas resolve without complication, a considerable number result in functional impairment or permanent disfigurement. Ulceration is the most frequent complication,8 occurring in 5% of all cutaneous hemangiomas, and results in pain with the risk of infection, hemorrhage, and scarring. Those at greatest risk are large, segmental lesions of the lip, perineum, or intertriginous regions. Ulceration results from necrosis and usually occurs during a period of rapid growth. In addition to rapidly enlarging hemangiomas, ulceration has a high risk of occurrence in the anogenital region due to moisture and frictional stress, which results in extreme pain on urination and defecation.
Location also plays a major role in determining the likelihood of complications. Hemangiomas of the eyelid or in the periocular region can cause astigmatism, strabismus, and, in severe cases, amblyopia. Large hemangiomas on the pinna of the ear can cause deformation of the external ear or temporary conductive hearing loss. Hemangiomas with a distribution over the mandible, chin, and upper neck (“beard” distribution) have a greater risk of association with airway hemangiomas. Hemangiomas of the airway may be life-threatening because of their potential for proliferation and eventual airway obstruction. Infants with subglottic hemangiomas often present with hoarseness and stridor. These lesions in infants 6 to 12 weeks old are of particular concern as they may progress rapidly to respiratory failure.
In rare cases, multiple (usually greater than five) cutaneous hemangiomas (diffuse hemangiomatosis) and large facial hemangiomas are associated with visceral hemangiomas. These infants present from birth to 16 weeks of age with a triad consisting of congestive heart failure, hepatomegaly, and anemia, resulting in higher morbidity and mortality rates. An association between hepatic hemangiomas and hypothyroidism has also been reported, due to the production of type 3 iodothyronine deiodinase by the tumor. Hence, thyroid-stimulating hormone levels should be monitored in these infants. While the liver is the most common internal organ involved, the gastrointestinal tract, brain, and lung are also common sites.
These lesions are a unique subset of vascular tumors, distinct from IHs. Unlike IH, these rare lesions present fully grown at birth and do not demonstrate the rapid neonatal proliferation characteristic of IH. These can be classified into rapidly involuting congenital hemangioma (RICH) and noninvoluting congenital hemangioma (NICH).
These lesions do not stain for GLUT-1, but have similar location, size, appearance, gender ratio, and histological and radiological features as IH.9 RICH manifests as a solitary raised gray or violaceous tumor with ectasia, radial veins, central telangiectasias, and a pale surrounding halo. It can result in sufficient shunting to cause high-output congestive cardiac failure. RICH’s defining feature is accelerated regression, usually obvious within a few weeks after birth and complete by 6 to 14 months of age. NICH presents as a well-circumscribed, plaquelike tumor with a pink, blue, or purple hue, central coarse telangiectasia, and a pale rim (21.2). In contrast to RICH, NICH grows proportionately to the child and remains unchanged, demonstrating a fast-flow signal by Doppler examination. There are rare instances of coexistence of either RICH or NICH in a child with IH and also instances in which RICH ceases to regress and assumes the likeness of NICH.
While the clinical phases of proliferation and involution usually make the diagnosis clear, a deep lesion in the neck or trunk may cause confusion with an LM. Similarly, a superficial hemangioma in an extremity may resemble a CM. In these cases, ultrasonography or magnetic resonance imaging (MRI) may be useful to confirm a diagnosis. RICH and NICH can also be mistaken for AVMs due to a prominent fast-flow signal. Another differential is pyogenic granuloma, which unlike hemangiomas rarely appears before 6 months of age (mean age 6.7 years). These lesions grow rapidly and may form a stalk or pedicle with epidermal breakdown. Other infantile tumors that may cause confusion include kaposiform hemangioendothelioma, tufted angioma, (“angioblastoma of Nakagawa”), myofibromatosis (“infantile hemangiopericytoma”), and fibrosarcoma.
Ultrasonography of a proliferating-phase hemangioma demonstrates a distinct shunting pattern, consisting of decreased arterial resistance and increased venous velocity. Even an experienced ultrasonographer can have difficulty distinguishing a young hemangioma from an AVM because both are rheologically fast flow. An MRI with contrast is the gold standard imaging modality, but it requires sedation or general anesthesia if the child is younger than 6 years old. MRI reveals parenchymatous (solid) tissue of intermediate intensity on T1-weighted spin-echo images and moderate hyperintensity on T2-weighted spin-echo images. Prominent flow-voids are located around and within the tumor, indicating rapid flow in feeding arteries and dilated draining veins. At some time in the late involuting phase, hemangiomas become slow-flow lesions, often with prominent fatty parenchyma.
FIGURE 21.2. Non-involuting congenital hemangioma. A. A 1 year-old boy with noninvoluting congenital hemangioma (NICH) involving the right thigh diagnosed at birth. B. Characteristic morphology is that of a well-circumscribed, plaquelike tumor with a pink, blue, or purple hue, central coarse telangiectasia, and a pale rim. C. MRI demonstrates lesion to involve the skin and subcutaneous tissues superficial to the muscle fascia.
Association with Dysmorphic Features
There are instances in which hemangiomas appear to be associated with certain dysmorphic conditions. Large facial hemangiomas of the neck and face, for instance, may be associated with a syndrome referred to as PHACES: posterior fossa malformations, hemangiomas of the cervicofacial region, arterial anomalies, cardiac anomalies, eye abnormalities, and occasionally sternal defects (Table 21.2). The large facial hemangioma is usually plaquelike and segmental in nature. There is a marked female predominance (ratio of affected girls to boys, 9:1), which is significantly greater than the 3:1 ratio of girls to boys reported for typical hemangiomas. Figure 21.3 shows a patient with PHACES who presents with the characteristic facial hemangioma accompanied by significant abnormalities in the cerebrovascular circulation.
Dandy-Walker malformation is the most common structural brain abnormality associated with PHACES. However, other central nervous system lesions have been shown. Common arterial abnormalities of the head and neck include agenesis, hypoplasia, stenosis, dysplasia, aneurysms, and anomalous branches of the major cerebral arteries. Incidence is unknown but potential neurologic defects such as developmental delay or seizure disorder, Horner syndrome, stroke, and progressive neurologic disease have been reported. Cardiac abnormalities include coarctation of the transverse aorta, but congenital heart defects such as ventricular septal defects and patent ductus arteriosus may also be seen. Eye abnormalities include optic nerve hypoplasia, persistent retinal vessels, and microphthalmia. Sporadic reports of endocrinopathies, including hypothyroidism and hypopituitarism, and intracranial hemangiomas associated with PHACE can also be found in the literature.
Hemangiomas located over the lumbosacral spine appear to also be a component of abnormal morphogenesis as they may be associated with occult spinal dysraphism or genitourinary anomalies. Of greatest concern are those lumbosacral hemangiomas that appear segmental, span the midline, and are flat or telangiectatic. Early detection and therapeutic or surgical intervention are important to prevent permanent neurologic sequelae.
The management of hemangiomas remains controversial, with a large and growing number of medical and surgical modalities. Due to the wide spectrum of clinical presentation and the potential for rapid change in early infancy, it can be challenging to predict which hemangiomas will be innocuous and which will be problematic. While the decision to treat hemangiomas that impair function or are life-threatening, such as those occurring in the periocular region, airway, liver or gastrointestinal tract, is obvious, the decision to treat less-threatening hemangiomas often depends on the location of the hemangioma, size, and growth phase as well as the age of the patient at the time of evaluation.
Observation. The majority of IH will involute with time, leaving normal or slightly blemished skin only. Reassurance of the parents and regular follow-up visits are essential to monitor for local complications and progression of the hemangioma.
Local Wound Care. Management and treatment of ulcerated hemangiomas should focus on healing the open wound, preventing secondary infections, and alleviating pain. Local wound care may include compresses for gentle debridement of thick crust and exudate reduction, barrier creams, such as zinc oxide or hydrophilic petroleum, applied to the surface of the hemangioma, and occlusive dressings to serve as barriers and prevent desiccation. Viscous lidocaine may help control pain. Topical antibiotics may be efficacious for superficial ulcerations, whereas oral antibiotics may be necessary if overt secondary infection is present and oral pain medicines may be required for pain.
FIGURE 21.3. PHACES with facial hemangioma. Top row: A 6-month-old girl who presents with left facial hemangiomas with secondary ptosis of the left upper eyelid. Bottom row: MRI demonstrates an intracranial aneurysm involving the left internal carotid artery extending into the middle cranial fossa (arrows).
Medical Management. Pharmacologic therapy is indicated for hemangiomas that threaten function or result in local complications. Around 10% of hemangiomas cause complications such as major ulceration/destruction, distortion of tissues, and obstruction of the visual axis or airway. Approximately 1% of hemangiomas cause life-threatening complications, such as high-output cardiac failure from an intrahepatic hemangioma. There has been a recent trend toward early pharmacologic treatment of hemangiomas in aesthetically prominent regions that do not threaten function but result in cosmetic disfigurement. The nasal tip is a representative area where patients may be best served with early pharmacologic treatment and possible laser therapy (Chapter 19) to speed involution and to prevent permanent skin changes, thereby providing the optimal skin quality for subsequent surgical debulking of the residual fibrofatty changes and correction of the splayed alar cartilages (Figure 21.4).10
Corticosteroids The role of steroids as a mainstay in treatment of hemangiomas is well defined, with an overall response rate of approximately 85%.7 The mechanism of action has been found to be related to the inhibition of vasculogenic potential in hemangioma-derived stem cells, together with downregulation of expression of VEGF-A and other angiogenic proteins inclusive of urokinase plasminogen activator receptor, monocyte chemoattractant protein-1, interleukin-6, and MMP-1.11
Steroids can be administered intralesionally or topically for small, well-localized tumors or orally for large and/or aggressive hemangiomas that may impair function, cause severe disfigurement, or are life-threatening. For intralesional injections, usually three to five injections are administered at 6- to 8-week intervals. Systemic corticosteroids remain first-line therapy for large or life-threatening hemangiomas; however, this may change with the recent advent of propranolol in treating severe hemangiomas of infancy. A recommended dose of 2 to 3 mg/kg of oral prednisolone is given as a single morning dose for 4 to 6 weeks, and subsequently tapered over several months and discontinued by 10 to 11 months of age. A responsive hemangioma typically responds within several days to 1 week. In an acute situation such as threatened upper airway or visual field compromise, intravenous corticosteroid at the same dose results in a more rapid response.
FIGURE 21.4. Hemangioma. Top row: A 6-month-old boy presented with a bulbous hemangioma of the nasal tip during the proliferative phase. Middle row: The patient is seen at age 3 years following completion of treatment with intralesional steroids and pulsed dye laser therapy. Cutaneous manifestations have resolved, but the nasal tip remains bulbous due to residual fibrofatty changes secondary to the hemangioma. Bottom row: Surgical correction using an open rhinoplasty approach was undertaken at 5 years of age to refine the nasal tip. The patient is seen 1 year postoperatively. (From Arneja JS, Chim H, Drolet BA, Gosain AK. The Cyrano nose: refinements in surgical technique and treatment approaches to hemangiomas of the nasal tip. Plast Reconstr Surg. 2010;126:1291, with permission.)
Common adverse effects include Cushingoid facies, which occurs in virtually all treated infants, and temporary growth retardation in around one-third of infants. However, most patients tolerate treatment well and respond with either hemangioma shrinkage or stabilization in size, with catch-up growth occurring after treatments have stopped. Other potential side effects include irritability, hypertension, immunosuppression, hirsutism, myopathy, cardiomyopathy, and premature thelarche.
Propranolol The remarkable effects of propranolol on regression of IH were discovered serendipitously and published in 2008.12 In many centers, propranolol has now become the first choice of therapy for complicated IH, even though we do not have a complete understanding of its mechanism of action. The effective dosage used most commonly is 2 mg/kg daily in three divided doses, with treatment continued until the end of the proliferative phase, and weaning of propranolol over a 2-month period. Propranolol has been found to be effective in the treatment of large facial hemangiomas following failure of oral corticosteroid therapy. It has also been found to be highly effective in the treatment of hemangiomas in dangerous or life-threatening locations, such as in the airway, periocular, and even hepatic hemangiomas with diffuse neonatal hemangiomatosis,13 with dramatic results often seen within a week of treatment.
Typically, the surface of the hemangioma exhibits whitening, followed by rapid involution. Adverse effects reported in a number of studies include symptomatic hypoglycemia, bradycardia, and hypotension.14 Key to propranolol’s mechanism of action on hemangiomas is inhibition of the hypoxia-inducible factor 1 alpha–VEGF signaling pathway, resulting in downstream inhibition of angiogenesis mediators and a direct cytotoxic effect, decreased tubulogenesis, and decreased endothelial cell migration with subsequent apoptosis.15.
Interferon Alpha Recombinant interferon (IFN)-α-2a or IFN-α-2b is a second-line agent for life-threatening hemangiomas or those that threaten a vital function (e.g., vision). Indications for its use include: (a) failure to respond to corticosteroid; (b) contraindications to prolonged parenteral corticosteroid; (c) complications of corticosteroid; and (d) parental refusal of corticosteroid. Corticosteroids and IFN should not be coadministered in therapeutic dosage; corticosteroids should be tapered quickly on initiation of IFN. There is no evidence for drug synergism. The empiric dose is 2 to 3 mU/m2, injected subcutaneously daily. IFN dosage is titrated as the infant gains weight; otherwise regrowth can occur. The rate of response is >80% with 6 to 10 months of sustained therapy usually required.16
IFN is effective therapy for tumors that cause Kasabach-Merritt phenomenon. Kasabach-Merritt phenomenon is a rare, life-threatening condition, where a vascular tumor traps and destroys platelets, resulting in thrombocytopenia. This may lead to a consumptive coagulopathy, with loss of clotting factors such as fibrinogen, and subsequently disseminated intravascular coagulation and even death. Although it was initially thought that Kasabach-Merritt phenomenon was associated with IH, more recent literature associates this disorder with specialized vascular tumors to include kaposiform hemangioendothelioma and tufted angioma.17 Two caveats should be noted in managing this coagulopathy: (a) do not transfuse platelets unless there is evidence of active bleeding or unless a surgical procedure (such as placement of a long line) is indicated and (b) do not give heparin because it can stimulate tumor growth and aggravate platelet trapping.18 The infant given IFN usually has a fever for the first 1 to 2 weeks; pretreatment with acetaminophen 1 to 2 hours prior to injection dampens the febrile response. IFN causes reversible toxicoses of up to fivefold induction in liver transaminase, transient neutropenia, and anemia. Neutropenia is ascribed to “margination,” not to suppression of bone marrow, and resolves on continued treatment. Infants on IFN grow and gain weight in a normal fashion. The worst long-term adverse reaction is spastic diplegia, which usually improves following prompt cessation of therapy. Children receiving IFN require periodic neurologic and developmental assessment.
Vincristine Vincristine is a second-line therapy that has been used successfully in the treatment of infants with complicated hemangiomas that do not respond to corticosteroids or cannot be weaned off corticosteroids. It has also been effective in the treatment of diffuse neonatal hemangiomatosis, kaposiform hemangioendothelioma, and tumors that cause Kasabach-Merritt phenomenon. Vinca alkaloid must be administered through a central intravenous line. It has a response rate of >80%. Side effects include peripheral neuropathy, constipation, minor hair loss, and sepsis and other complications related to the central line.
Lasers. Lasers can be used to selectively treat hemangiomas depending on the specific indication (Chapter 19). Pulsed dye laser (PDL) can be effective in treating relatively flat, superficial hemangiomas but has limited depth of penetration and is thus ineffective at treating deeper and thicker lesions. PDL seems to be most effective in treating residual telangiectases after involution of the hemangioma. Careful consideration is necessary before using PDL as several treatments are usually necessary. In addition, there is evidence that the risk of scarring when this is used to treat hemangiomas is greater than that when treating port-wine stains. Other laser systems have also reportedly been used to treat hemangiomas, such as the neodymium:yttrium-aluminum-garnet (Nd-YAG) and the potassium titanyl phosphate (KTP) laser, but these systems are more operator-dependent and tend to have a higher risk of scarring.
Surgical Management. Surgical excision is typically used later in childhood to improve residual scarring or to remove fibrofatty tissue. However, earlier removal may be considered for lesions that are localized or pedunculated, where resulting abnormalities are virtually inevitable (Figure 21.5). Surgery may also be performed if persistent bleeding or ulceration occurs, if function- or life-threatening lesions do not respond to pharmacologic therapy, or for school-age children in an attempt to attain a more normal appearance.
Infancy (Proliferating Phase) Indications for resection of a well-localized tumor in the first year are (a) obstruction, usually a tumor in the upper eyelid or subglottis; (b) deformation, for example, periorbital tumor causing amblyopia, retroauricular hemangioma causing a prominent ear; (c) bleeding; (d) ulceration unresponsive to topical, intralesional, or systemic therapy; and (e) predictable scar or hair loss, particularly if the infant must undergo a general anesthetic for another reason.
Early Childhood (Involuting Phase) Indications for removal prior to entering school are: (a) resection is inevitable, for example, postulcerative scarring, unalterably expanded skin, or high probability of residual fibrofatty tissue; (b) same scar length/appearance if excision were postponed; (c) scar easily hidden in relaxed cutaneous tension lines or a border of a facial aesthetic unit; and (d) necessity for staged resection or reconstruction.
Late Childhood (Involuted Phase) Resection of an involuted hemangioma is usually undertaken (a) for damaged skin; (b) for abnormal contour (fibrofatty residuum); (c) for distortion or destruction of an anatomic structure; or (d) because staged removal or reconstruction is necessary.
Clinical and Pathological Features
In contrast to hemangiomas, which have a defined natural history, vascular malformations might not present clinically until early childhood and tend to grow proportionately with the child, often becoming more prominent at puberty. They do not regress, and typically persist throughout life. They have been reported to occur in approximately 0.3% to 0.5% of the population, with no gender predilection. They are classified both by the predominant channel type (Table 21.1) and by flow characteristics into fast-flow and slow-flow lesions.
Each of the four major categories of vascular malformation has a unique histopathologic appearance and all are lined by quiescent endothelium. CMs comprise regular, ectatic, thin-walled capillary-to-venular–sized channels located in the papillary and upper reticular dermis (see Figure 21.6). There is a deficiency of perivascular neural elements, which might account for altered neural modulation of vascular tone and progressive ectasia. Of note is that CMs may appear similar to tufted angioma on clinical examination (see Figure 21.7), and an incisional biopsy is indicated if the diagnosis is in question since the natural history and treatment for tufted angioma differ markedly from those of CM. LMs have walls of variable thickness comprised of both striated and smooth muscle and nodular collections of lymphocytes in the connective tissue stroma. Venous malformations (VM) are characterized histologically by thin-walled vascular spaces surrounded by abnormally formed layers of smooth muscle, often in clumps. The dysplastic venous networks drain to adjacent veins, many of which are varicose and lack valves. Pale acidophilic fluid is typically seen within the channels and sacs of an LM, whereas blood, fresh and organizing thrombi, and phleboliths characterize a VM. AVMs comprise thickened fibromuscular walls, fragmented elastic lamina, and fibrotic stroma. The veins in an immature AVM are “arterialized” (reactive muscular hyperplasia), whereas in a mature AVM, the veins evidence degenerative fibrosis and muscular atrophy.
FIGURE 21.5. Hemangioma. A. A 9-month-old girl presented with hemangioma of the upper lip. This was resected early due to aesthetic concerns, as the prominent location and extent of skin disfigurement would have resulted in an inevitable residual deformity. B. Early postoperative image demonstrating restoration of the philtral architecture of the upper lip.
Evaluation of Vascular Malformations
Treatment by multidisciplinary teams remains key in the optimal management of patients.19 The development of vascular anomalies clinics and conferences allows evaluation by physicians in other specialties such as dermatology, radiology, and pathology to determine the best treatment for the patient. A large number of imaging modalities are available for evaluation of vascular malformations, with some more suited to each type of lesion. As first-line techniques, plain radiographs are useful in imaging skeletal growth disturbances and phleboliths in VMs, while color Doppler ultrasound is useful for real-time assessment of superficial lesions and assessment of blood flow velocity, to distinguish fast-flow from slow-flow anomalies. However, Doppler ultrasound is very operator dependent and may not delineate the anomaly well from adjacent structures. Use of computed tomography (CT) is limited by lack of soft-tissue detail and exposure to ionizing radiation. However, it has a place in the evaluation of intraosseous vascular malformations and secondary bony changes.
MRI is probably the best imaging technique, being noninvasive and nonionizing, and also providing superb detail of soft tissues. It demonstrates flow characteristics, abnormal channels, and extent of involvement in tissue planes. The use of magnetic resonance angiography (MRA) and magnetic resonance venography (MRV) allows differentiation between slow-flow and fast-flow malformations.
CM is not seen by MRI, except as minor cutaneous thickening. VM gives high-signal intensity on T2-weighted images, brighter than fatty tissue. Phleboliths are pathognomonic for a venous anomaly and seen as discrete round signal voids on T1- and T2-weighted spin-echo and gradient images. It is difficult to distinguish LM from VM or LVM. These are better delineated by the administration of intravenous gadolinium and repetition of the T1-weighted sequences. VMs enhance inhomogeneously, whereas LM shows either rim enhancement or no enhancement. AVM demonstrates a myriad of flow-voids in all sequences, high-flow vessels on gradient sequences, contrast enhancement with gadolinium sequences, and usually no discrete parenchymatous signal abnormality. Other more invasive techniques that are less used nowadays include angiography and venography. Angiography is used for therapeutic embolization, either preoperatively or in an elective setting.
FIGURE 21.6. Venous malformation. Left: A 6-year-old boy presents with a superficial venulocapillary malformation involving the left side of the face. Middle: Photomicrograph shows numerous small isolated branching vessels present in the superficial dermis (H&E, 4 ×).Right: Higher power photomicrograph depicts a non-proliferative inactive endothelial layer (H&E, 20 ×).
FIGURE 21.7. Tufted angioma. Left: An 8-month-old boy presents with a tufted angioma involving the right side of the face. Middle: Small cannon ball–like clusters of curvilinear capillaries are seen at multiple levels in the superficial and deeper dermis (H&E, 4 ×). Right: Higher power photomicrograph shows clustering glomeruloid architecture within the clusters with focal spindle cell regions at the periphery corresponding to focal lymphatic endothelial differentiation (H&E, 20 ×).
Overview. CMs are among the most common vascular anomalies, with a frequency of approximately 3 in 1,000 live births, and an equal gender distribution. They usually present at birth as pink or red intradermal discolorations that may involve small areas or involve an entire limb or face (Figure 21.6). True CMs tend to be progressive, and thicken, darken, and become nodular with age. Conversely, a subset of CMs (macular stains) often located on the central aspect of the face and nape of the neck, variously termed “salmon patch,” “nevus simplex,” or vascular stain,” lighten or disappear within the first few years of life.
Associated Conditions. Significantly, some CMs may be associated with underlying abnormalities or syndromes. Facial or extremity CMs may result in soft-tissue hypertrophy with underlying skeletal changes. Facial CMs tend to darken in color and develop fibrovascular changes. Thickened purple nodules may appear in adulthood and pyogenic granuloma may manifest at any age. Overgrowth of CMs in the face may manifest as lip or gingival enlargement, or maxillary or mandibular overgrowth with subsequent skeletal asymmetry and malocclusion. Overgrowth of extremity CMs is almost always seen in the form of combined capillary–lymphatic malformations or capillary–lymphatic–venous malformations (CLVM), manifesting as Klippel-Trenaunay syndrome (slow-flow C-L-VM, axial elongation, and limb hemihypertrophy) or Parkes Weber syndrome (AVM, cutaneous CM, and skeletal or soft-tissue hypertrophy of the limb).
CMs in the midline in the lumbar or even cervical area may be associated with underlying spinal dysraphism. In the occiput, one should be concerned for an underlying encephalocele, while a CM in the upper back may indicate an AVM of the spinal cord (Cobb’s syndrome).
Sturge-Weber syndrome consists of facial CM in the trigeminal nerve distribution, ipsilateral leptomeningeal, and ocular vascular anomalies and seizures. The capillary stain involves the ophthalmic (V1) trigeminal dermatome, while patients with either maxillary (V2) or mandibular (V3) involvement are at low risk for having the disorder. The leptomeningeal vascular abnormalities can lead to seizures, contralateral hemiplegia, and variable developmental delay of motor and cognitive skills. MRI with contrast (gadolinium) is more sensitive than CT in revealing pial vascular abnormalities (CM, VM, AVF, and AVM), cerebral atrophy, and prominent cortical sulci. Children who have ipsilateral increased choroidal vascularity are at risk for retinal detachment, glaucoma, and blindness, particularly if the CM involves both V1 and V2 areas.
Treatment. The flashlamp-pumped PDL is the treatment of choice for CMs. The PDL uses a wavelength (577, 585, or 595 nm) that selectively targets oxyhemoglobin and results in intravascular thrombosis. Lightening of the lesion is usual, occurring in 50% to 90% of patients. However, complete resolution of the lesion is unusual. Better results are obtained for younger patients treated in early childhood. For patients who do not respond to PDL, or those who no longer demonstrate lightening of the lesion, typically after 6 to 10 treatments, alternative treatment options include newer laser devices such as a long-pulsed tunable dye laser at 595 nm, alexandrite (755 nm), or Nd:YAG (1,064 nm) lasers and intense pulsed light (IPL).
Soft-tissue and skeletal hypertrophy may require surgical intervention, such as contour resection for macrocheilia and orthognathic procedures for asymmetric vertical maxillary excess or for mandibular prognathism. Excision of localized fibrovascular nodules is easily accomplished. In rare instances, it may be necessary to excise a thickened CM in an entire facial aesthetic unit and resurface with a skin graft.
Overview. VMs present clinically as soft, compressible, blue subcutaneous masses (Figure 21.8), which enlarge with physical activity or in a dependent position. Dilated anomalous intradermal venous channels account for the blue coloration. Lesions are typically painful in the morning, as a result of stasis and microthrombi. Like other vascular malformations, VMs grow proportionately with the child and often enlarge during puberty.
Associated Conditions. Head and neck VMs tend to be the most common and are often more extensive than apparent from the outside, extending to the underlying muscle or bone, as well as into oral mucosa or salivary glands. As a result, these lesions may be complicated by epistaxis or hemoptysis, airway compromise, and abnormal speech and dentition. More often, patients may present with facial asymmetry or concerns about cosmesis. Extremity VMs may present with limb hypertrophy or asymmetry and may even have pathologic fractures with osseous extension.
FIGURE 21.8. Venous malformation. Top row: A 15-year-old boy with extensive venous malformation of the buttock and right thigh resulting in bleeding, pain, and severe distortion. Bottom row: Staged surgical reduction resulted in significant improvement as seen in postoperative images 1 year later (From Arneja J, Gosain AK. Vascular malformations. Plast Reconstr Surg. 2008;121:195e, with permission).
An associated condition is Blue-rubber bleb nevus syndrome, which occurs in a sporadic fashion. Patients present with multiple lesions on the trunk, palms, and soles of feet, as well as sessile or polypoid lesions in the gastrointestinal tract. Intestinal bleeding may be severe, requiring transfusion.
Treatment. MRI is extremely useful for confirming the diagnosis of VM and mapping the extent of involvement, with venography serving as an adjunct for surgical planning. VMs exhibit a brighter signal than fat on T2-weighted sequences. A coagulation profile should be ordered to exclude an underlying coagulopathy, as there is usually localized intravascular coagulopathy and patients are at risk for disseminated intravascular coagulopathy following trauma or intervention.
Percutaneous sclerotherapy is the first-line treatment. Agents that have been used include absolute ethanol, hypertonic saline, and 3% sodium tetradecyl sulfate. Local complications include full-thickness skin necrosis, blistering, and neural deficits, while systemic complications reported include renal toxicity and cardiac arrest. Adjuncts include the use of elastic compression garments for extremity VMs and daily prophylactic aspirin to reduce painful thrombotic events and formation of phleboliths.
Surgery is useful for head and neck lesions where cosmetic appearance is a concern, for severely symptomatic patients with bleeding, or for painful or well-localized lesions. Orthognathic surgery may also be used to correct malocclusion. Debulking of lesions may be useful for lesions in the hands and feet, and resection of intramuscular VMs in the thigh or calf may improve function.
Overview. AVMs are fast-flow lesions with a direct connection between the artery and vein, in the absence of an intervening capillary bed. The majority of patients (40% to 60%) present at birth, with an equal gender distribution. The epicenter of an AVM is called the nidus and consists of arterial feeders, micro- and macroarteriovenous fistulas, and ectatic veins. Intracranial AVM is more common than extracranial AVM, followed, in frequency of location, by limbs, trunk, and viscera. Schobinger’s staging system,20 accepted by the ISSVA, describes four stages.
Stage I lesions (quiescent phase), which usually last from birth till adolescence, are asymptomatic, with the AVM having the appearance of an involuting hemangioma or CM.
Stage II lesions (progressive phase) most often begin during adolescence, where the AVM enlarges and darkens, with increased warmth, palpable thrill or pulse, or murmur on auscultation. Trauma, pregnancy, or puberty may also cause progression to this stage.
Stage III lesions (destructive phase) are characterized by destructive lesions with pain, bleeding, ulceration, or bone erosions, and typically occur after years of progression.
Stage IV lesions (decompensation phase) are defined by cardiac decompensation with congestive heart failure.
Treatment. Color Doppler evaluation and ultrasonography are useful first-line tools to determine flow characteristics. MRI defines the anatomy and extent of the lesion, while angiography is useful in further characterizing the lesion and allows therapeutic embolization.
AVMs are usually treated when there are endangering signs and symptoms, such as ischemic pain, recalcitrant ulceration, bleeding, and increased cardiac output. Small localized AVMs may be primarily resected and reconstructed. Larger diffuse AVMs will require primary arterial embolization or superselective arterial embolization for temporary occlusion of the nidus (epicenter of the lesion), followed by resection 24 to 48 hours after embolization (Figure 21.9). This serves to reduce intraoperative bleeding, but it does not diminish the boundaries of resection. Agents used for embolization include particles (gelfoam and acrylic), absolute ethanol, and sodium tetradecyl sulfate. Better outcomes are seen with stage I or localized stage II AVMs. Ligation or proximal embolization of arterial feeding vessels should never be done, as this results in rapid recruitment of nearby arterial vessels to supply the nidus. Even after surgical resection, patients need to be followed up for years with clinical examination, ultrasonography, and/or MRI to monitor for recurrence.
FIGURE 21.9. Arteriovenous malformation. Progression of a high-flow arteriovenous malformation of the upper lip is seen over time. A. At 2 years of age. B. The AVM has enlarged markedly by 4 years of age. C, D. Preoperative superselective embolization was performed followed by surgical reduction of the AVM 48 hours later. E. Postoperative result. F. At age 10 years after further secondary surgery for revision of the vermillion–cutaneous junction, percutaneous sclerotherapy, and laser treatments (From Arneja J, Gosain AK. Vascular malformations. Plast Reconstr Surg. 2008;121:195e, with permission).
Overview. LMs consist of anomalous channels, vesicles, or pouches filled with lymphatic fluid. Approximately 65% to 75% are present at birth with the rest evident by 2 years of age. These are classified into microcystic, macrocystic, or combined (microcystic–macrocystic). LMs never regress but instead expand or contract depending on the ebb and flow of lymphatic fluid and the occurrence of inflammation and intralesional bleeding.
Macrocystic LMs are typically visible at birth and often detected by prenatal ultrasonography. Most of these lesions are located on the head and neck or axilla, where they were referred to as cystic hygromas. They tend to present as isolated poorly defined subcutaneous masses that expand over time, as anomalous channels become ecstatic. Cervicofacial LMs may inhibit normal vaginal delivery and subsequently lead to airway obstruction and problems with feeding and speech development. Head and neck LMs are characterized by skeletal hypertrophy (Figure 21.10). LM is the most common cause for macrocheilia, macroglossia, macrotia, and macromala. Lesions in the upper neck, floor of mouth, and tongue often lead to progressive distortion and overgrowth of the mandible. Overgrowth in the body of the mandible manifests as malocclusion, typically anterior open bite, and class III occlusion. Theories formulated to explain skeletal hypertrophy include intraosseous LM or local mass and pressure effects. Intra-abdominal LMs may present with abdominal pain, palpable mass, or symptoms of bowel obstruction. These can result in hypoalbuminemia secondary to protein-losing enteropathy.
Microcystic LMs are present at birth, but may not be obvious until complications such as infection or bleeding result. These are often located over proximal extremities, axillae, and chest regions and have been termed “lymphangioma circumscriptum” due to their common presentation as crops of thin-walled vesicles or hyperkeratotic papules arranged irregularly in groups, typically localized to one region (Figure 21.11). Further evaluation is indicated for these lesions to define the extent of involvement, and MRI studies are extremely helpful as the lesions may involve deeper dermal or subcutaneous structures and are rarely well circumscribed. Microcystic LMs can also present as verrucous lesions with black dots on the surface, with subsequent misdiagnosis as genital warts when found in the perineum. In this form, the most common symptom is recurrent oozing of clear liquid. Long-standing microcystic LMs may result in squamous cell carcinoma.
Combined LMs are frequently seen in the cheek, forehead, and orbit. They cause facial asymmetry, ocular proptosis, and distortion of features. Soft-tissue and bony hypertrophy are characteristics. A bulky tongue, covered with vesicles, impairs speech and is complicated by recurrent infection, swelling, bleeding, poor dental hygiene, and caries. In the cervicofacial region, micro-macrocystic LM can cause airway obstruction, sometimes necessitating tracheostomy. Cervicoaxillary LM commonly involves the thorax and mediastinum, causing recurrent pleural and pericardial effusion. Extensive LM in an extremity is associated with lymphedema. Pelvic LM manifests with perineal lymphangiectasias. Generalized LM denotes skeletal involvement, typically of the ribs, vertebrae, scapula, and long bones.
Treatment. Radiographic studies are useful in confirming and assessing the extent of disease. Ultrasonography can accurately distinguish macrocystic from microcystic LMs. Doppler flow studies can also distinguish LMs (no flow) from VMs or AVMs, based on flow velocity. MRI remains the gold standard for defining the extent of the lesion and is useful in determining involvement of deeper structures in microcystic LMs. Untreated LMs may be complicated by infection or intralesional bleeding. Antibiotics and observation, respectively, are the treatment for these episodes.
Surgical resection is the only way to potentially cure LMs. However, multiple procedures may be required and complete curative excision may not be possible due to the anatomical location of the LM, for example, in the head and neck region. Postoperative complications include local wound infection, hematoma, prolonged drainage, and nerve palsies. Localized and well-demarcated lesions generally have a better surgical outcome.
Percutaneous sclerotherapy has gained recent popularity as an alternative treatment due to high morbidity associated with surgical resection in some areas of the body. Agents used include absolute ethanol, doxycycline, bleomycin, acetic acid, sodium tetradecyl sulfate, or OK-432 (preparation of group A streptococcus treated with benzylpenicillin). Sclerotherapy has been shown to be more effective in treating macrocystic LMs compared with microcystic LMs.
Combined Vascular Malformations
Slow-Flow Combined Malformations. Klippel-Trenaunay syndrome refers to a combined CLVM associated with soft-tissue/skeletal hypertrophy in one or more limbs. The CMs are multiple, often in a patchy geographic pattern, usually studded with hemolymphatic vesicles, and typically located on the anterolateral aspect of the thigh, buttock, or trunk. The anomalous veins are prominent laterally because of insufficient to absent valves; deep venous anomalies also occur. Lymphatic hypoplasia or localized lymphatic anomalies are primary defects. Limb hypertrophy can be minor to grotesque; some patients with classic CLVM have a short limb. Often there is lipomatous dorsal swelling and digital overgrowth on the opposite foot. If significant (>2 cm) limb length discrepancy exists, pediatric orthopedic evaluation should be obtained. Surgical options include percutaneous epiphysiodesis to induce growth arrest of the longer limb. Elastic support garments protect the limb from trauma and decrease swelling associated with venous insufficiency. Resection or sclerotherapy of veins is reserved for patients with symptomatic superficial varicose veins.
Proteus syndrome is a sporadic disorder characterized by connective tissue nevi, lipomas, several unusual tumors, and disproportionate skeletal growth, in addition to ocular, pulmonary, and renal abnormalities. Asymmetrical growth and soft-tissue changes are not present at birth; instead, they evolve later, which serves to differentiate Proteus syndrome from Klippel-Trenaunay syndrome. Vascular anomalies (CM, VM, LM, or combined forms) can occur, randomly distributed on the trunk and limbs. Proteus syndrome is thought to be caused by a dominant lethal gene that survives by somatic mosaicism. Management is largely supportive.
Maffucci syndrome denotes the coexistence of exophytic venous anomalies, with bony exostoses and enchondromatoses. These features usually do not manifest until early to mid-childhood. Enchondromas are discovered first, typically located in the metaphysis and epiphysis of the long bones. The venous lesions typically appear around 4 to 5 years of age as firm, dome-like, bluish spots, usually on a finger or toe. Venous anomalies also present in bones (particularly the limbs), leptomeninges, or gastrointestinal tract. Malignant degeneration, usually chondrosarcoma and other nonskeletal neoplasms, occurs in 20% to 40% of patients. Management is conservative unless venous malformations become symptomatic.
Fast-Flow Combined Malformations. Parkes-Weber syndrome is defined by overgrowth of an extremity together with the presence of an AVM with multiple AVFs. There is usually a cutaneous CM. It usually affects the lower limb and presents at birth with warmth, bruit, and thrill in a limb and proximal trunk. There is a geographic pink, macular stain and generalized enlargement. There may be lymphatic anomalies, either lymphedema or localized lesions.
FIGURE 21.10. Lymphatic malformation. Upper left: A 1-year-old male with lymphatic malformation of the head and neck; resection of submandibular soft-tissue involvement has been performed. Lower left: MRI demonstrates enlarged tongue and potential airway compromise. Upper right: Significant mandibular prognathism is noted by age 5 years. Lower right: MRI demonstrates persistent tongue enlargement at age 11 years despite previous surgical reduction and sclerotherapy (From Arneja J, Gosain AK. Vascular malformations.Plast Reconstr Surg. 2008;121:195e, with permission).
MRI in young children often reveals only diffuse hypervascularity of enlarged muscles and bones. MRA and MRV show generalized arterial and venous dilatation. Arteriography demonstrates microscopic AV fistulae throughout the affected limb, particularly near the joints. Significant limb length discrepancy may require percutaneous epiphysiodesis. Hypertrophied digits in the lower limb may result in severe deformity, papillomatosis, and recurrent infection, which in severe cases may require amputation.
Bannayan-Riley-Ruvalcaba syndrome is characterized by delayed motor and speech development, proximal myopathy, macrocephaly, pigmental penile macules, ileal and colonic hamartomatous polyps, subcutaneous lipomas, and Hashimoto thyroiditis. Vascular anomalies appear in wide spectrum from small nodular cutaneous lesions, intramuscular, intraosseous, and intracranial lesions to extensive AVM. Bannayan-Riley-Ruvalcaba syndrome is an autosomal dominant disorder, allelic with Cowden syndrome, and caused by mutations in PTEN, a tumor-suppressor gene. There is phenotypic overlapping, and patients with either syndrome are at risk for developing benign and malignant neoplasms.
FIGURE 21.11. Lymphatic malformation. Left: A 16-year-old boy with a recurrent lymphangioma circumscriptum of the left posterior trunk. Presenting symptoms consisted of daily episodes of pain and hemorrhage. Middle: CT scan revealed an extrafascial low-flow malformation. Right: A 6-month follow-up after treatment with wide-local excision to the deep fascia and placement of a split thickness skin graft (From Arneja J, Gosain AK. Vascular malformations. Plast Reconstr Surg. 2008;121:195e, with permission).
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