AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Vascular anomalies are among the most common congenital abnormalities observed in infants and children. Unfortunately, these lesions are also among the most confusing and misunderstood conditions, largely because of a history of inconsistent terminology used for classification. Commonly accepted names have been based on external appearance, such as strawberry nevus, cherry hemangioma, and port-wine stain, or based on histology, such as capillary hemangioma, cavernous hemangioma, and arteriovenous fistula. However, lesions with a similar appearance may have markedly different growth patterns; conversely, lesions that are biologically identical may differ greatly in external appearance because of the location and depth of the lesion. Thus, the most clinically applicable and simplest classification scheme is based on the biological activity of the blood vessels contained in these lesions.

This classification system, proposed by Mulliken and Glowacki, divides vascular anomalies into lesions that are biologically active (hemangiomas) and those that are not (vascular malformations). The goal of this article is to clarify the differences between hemangiomas and vascular malformations by reviewing the clinical characteristics, diagnosis, and treatment options of both types of conditions. Once the distinctions are understood, clinicians will be able to accurately describe the expected course of these particular lesions to parents.

Pathophysiology

The varied origins of vascular tumors include true neoplastic growth, structural malformations, and hamartomatous transformations. The specific underlying biologic process forms the principal foundation of Mulliken and Glowacki's classification of this broad class of lesions.

The rapidly progressive nature of hemangiomas intimates a neoplastic process; however, the precise point in fetal, embryonic, or postnatal development that gives rise to hemangiomas remains elusive. Whether hemangiomas represent embryonic mesodermal rests or arise de novo secondary to the activation of some angiogenic signaling is uncertain. The similarity between the proliferative phase of wound healing and the growth of hemangiomas suggests a prominent etiogenic role of disordered angiogenesis as the precipitating cause of hemangiomas. Furthermore, the increased numbers of mast cells in hemangiomas, through their production of heparin, influences the migration of capillary endothelial cells. Finally, the in vitro identification of selective steroid inhibition of angiogenesis through heparin binding supports the clinical experience of hastened regression with steroid therapy.

By comparison, vascular malformations represent abnormal embryonic and fetal morphogenesis during the retiform stage of development of endothelial channels (approximately day 48 of human embryogenesis). As such, these lesions are neither neoplastic nor proliferative; rather, they grow commensurate with the child. Vascular malformations are best characterized by their principal cell type, the degree of blood or lymph flow (which may influence clinical symptoms), and the structures involved. Coincident with their underlying dysmorphogenic nature, these lesions may involve elements of different vascular channels.

Frequency

United States

Hemangiomas are the most common benign tumor observed in infancy, occurring in approximately 10% of white infants. These lesions are observed more commonly in premature infants weighing less than 1000 grams (prevalence as high as 30%). Capillary vascular malformations occur in 3 per 1000 infants.

Mortality/Morbidity

• Hemangiomas: Complete involution occurs in 70-90% of patients; however, minor atrophic scars or residual ectatic vessels may remain. In the remaining 10-30% of patients, residual, baggy, atrophic skin; excess fibrofatty tissue; and even severe disfigurement may develop. Hemangiomas may also occur in areas where vital structures are compressed (see Complications).
• Vascular malformations: These lesions do not improve or resolve with time (see Complications).

Race

• Hemangiomas are less common in African American and Asian infants.

Sex

• The female-to-male ratio for hemangiomas is 3:1. The female-to-male ratio for vascular malformations is 1:1.

Age

• Hemangiomas: The infant is healthy but develops a red lesion during the first few weeks of life. The lesion continues to grow for 6-18 months and then reaches a plateau. Spontaneous involution occurs, which may last for a number of years.
• Vascular malformations: All are present at birth. The lesion grows proportionately with the child and is permanent.

CLINICAL

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History

• Hemangioma
• • Parents often describe a small red dot appearing during the first few weeks of life. Initially, parents may mistake this lesion for a scratch that does not heal. The lesion then grows disproportionately fast compared with the child.
  • Hemangiomas exhibit spontaneous involution, but this process may continue for years. By the time the patients are aged 5 years, 50% of all hemangiomas resolve; by age 7 years, 70% resolve.
  • A residual skin deformity, such as excess fibrofatty tissue or cutaneous telangiectasia, may persist.
  • Those hemangiomas that show signs of involution by age 3 years have better cosmetic results, whereas lesions that are ulcerated always leave residual scars.
  • The head and neck area is involved in 60% of cases, followed by the trunk and then the extremities.
  • Multiple hemangiomas occur in as many as 20% of patients.
• Vascular malformations
• • These lesions always are present at birth. They may be subtle at first, but the color does not fade and often darkens.
  • The growth of vascular malformations is proportionate to the growth of the child and never extends beyond its initial boundaries.
  • Capillary vascular malformations (port-wine stain) roughly follow sensory nerve distribution.
  • Venous malformations may not be clinically evident at birth but become more evident as the child ages.
  • Aching pain has been associated with extremity lesions.
  • Patients typically have a strong family history of varicose veins.

Physical

• Hemangioma
• • Serial physical examinations reliably distinguish between hemangiomas and vascular malformations.
  • The key feature for hemangioma is disproportionate growth compared to the child.
  • Superficial hemangiomas are characterized by a bright strawberry-red pigmentation.
  • Deeper hemangiomas appear as purple- or blue-pigmented lesions.
  • Rapid growth occurs over the next 3-6 months.
  • Plateau and cessation of growth usually occur when patients are aged 6-18 months.
  • Involution occurs over years. Involution is often preceded by a graying appearance and softer tissue turgor of the lesion.
• Vascular malformations
• • Capillary vascular malformations are initially pale with normal overlying skin texture but may darken as the patient ages.
  • Nodularity and a darker purple pigmentation also may occur in adulthood because of increasing dilation of the dermal vessels.
  • Venous malformations become more evident as the child grows.
  • These malformations gradually dilate and may cause distortion of facial features.
• Arteriovenous malformations may appear similar to venous malformations. In addition, they may demonstrate increased warmth, an audible bruit, a palpable thrill, or visible pulsations. Hypertrophy of the involved limb or structure is more common with arteriovenous malformations than with simple venous malformations.

Causes

• Hemangioma
• • Hormonal influence is suggested by the 3:1 female-to-male ratio.
  • The mechanism by which angiogenesis is stimulated and then turned off is not known.
• Vascular malformations
• • Capillary vascular malformations possibly occur because of a lack of proper sympathetic vasomotor control.
  • Venous malformations are due to errors in development of the venous system and may result in hypoplasia, hyperplasia, and aplasia of the deep and superficial systems.

DIFFERENTIALS

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Other Problems to be Considered

Hemangioendothelioma
Hemangiopericytoma
Klippel-Trenaunay-Weber syndrome
Lymphangioma
Skeletal muscle hemangioma
Sturge-Weber syndrome

WORKUP

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Lab Studies

• No lab test reliably distinguishes hemangiomas from vascular malformations; however, identification of elevated angiogenic growth factors, such as basic fibroblastic growth factor, secreted in the urine of patients with hemangiomas may be useful in distinguishing proliferative vascular tumors from nonproliferating lesions.
• Perform a CBC count to rule out platelet trapping if the patient has spontaneous bleeding.
• Perform clotting studies if the patient has evidence of hemorrhage or hematoma formation.

Imaging Studies

• Plain films
• • Hemangiomas demonstrate soft tissue fullness and are not usually associated with bone involvement; however, bony distortion due to mass effect may be observed.
  • Vascular malformations may be associated with skeletal overgrowth or bony destruction due to high-flow lesions. Phleboliths also may be observed.
• Ultrasound
• • Both early hemangiomas and vascular malformations are high-flow lesions and are difficult to differentiate.
  • Venous malformations demonstrate slow flow.
• Angiography
• • Angiography is not often necessary unless embolization is used prior to surgical excision.
  • Hemangiomas demonstrate peripheral feeding arteries and draining veins.
  • Whereas hemangiomas demonstrate intense parenchymal staining, vascular malformations typically demonstrate ectatic vessels without parenchyma.
  • Arteriovenous malformations are characterized by rapid venous shunting.
• Magnetic resonance imaging and magnetic resonance angiography
• • MRI and magnetic resonance angiography accurately distinguish hemangiomas from vascular malformations, including arteriovenous malformations.
  • These studies are the most useful of all imaging studies.
• Nuclear medicine is useful for screening the entire body for vascular anomalies.

Histologic Findings

• Hemangioma: Proliferating hemangiomas are plump and have actively dividing endothelial cells. The basement membrane is multilaminated (due to a high proliferation rate), and mast cells are abundant (up to 40 times normal). Involuting hemangiomas have flat endothelial cells, vascular thrombosis, and collagen and fat deposition.
• Vascular malformations (ectatic capillaries, veins, or lymphatics): These anomalies show no evidence of rapid endothelial proliferation. Capillary vascular malformation has dilated capillaries and venules of variable density in the dermis.

TREATMENT

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Medical Care

• Hemangioma
• • Of hemangiomas, 70-90% resolve completely.
  • The key is to determine which lesions require early intervention to minimize long-term complications or disfigurement.
  • Steroids, both systemic and intralesional, have been used to treat rapidly growing hemangiomas. The mechanism by which steroids induce regression is not entirely clear. Both local and systemic administration of steroids may lead to adverse cushingoid effects.
  • Another antiangiogenic agent being investigated is interferon alfa-2a. This agent has shown promise in the treatment of pulmonary hemangiomatosis, life-threatening hemangiomas, and diffuse neonatal hemangiomatosis. Adverse effects include hemodynamic changes, viral symptoms, neutropenia, alopecia, anemia, and depression.
  • Chemotherapy is reserved for life-threatening hemangiomas.
  • Cyclophosphamide may reverse the platelet-trapping coagulopathy associated with Kasabach-Merritt syndrome.
  • Because of its long-term risks, radiation therapy plays a role only in the treatment of drug-resistant congestive heart failure.
• Vascular malformations
• • Capillary vascular malformations are treated surgically. See Surgical Care.
  • Treatment for venous malformations is compression garment therapy. Early use may prevent long-term morbidity and the need for surgery.
  • Sclerotherapy may be used for spider veins and true varicose veins.

Surgical Care

• Hemangioma
• • Surgical care is most commonly used when involution is incomplete or leaves excess fibrofatty tissue or redundant skin. Complex reconstruction may be required for significant distortion of facial features. Excision prior to full involution should be considered for lesions that are pedunculated, bulky, occurring on the nasal tip, or ulcerated. Debulking is required if these lesions are obstructing vital structures (eg, visual-field obstruction).
  • Techniques using cryotherapy (ablation with liquid nitrogen) and sclerotherapy have essentially been abandoned because of unfavorable scarring and inconsistent results. Embolization is used only for selective cases such as lesions associated with life-threatening platelet trapping.
  • Laser photocoagulation (eg, yellow dye, argon) remains a controversial treatment modality for hemangiomas. This technique appears to be more effective for early and superficial lesions than for thick, mature hemangiomas.
• Vascular malformations
• • Excisional treatment is warranted for venous malformations because spontaneous involution is not anticipated. Occasionally, the specific nature of the lesion is uncertain and excision is indicated for diagnosis.
  • Laser photocoagulation is the treatment of choice for superficial capillary vascular malformations. Multiple treatments are required, and 100% clearance is not always possible. Laser therapy can also be used to coagulate superficial venous malformations of the face.
  • Venous stripping may be required to treat varicose veins associated with certain vascular malformations. One notable exception to the use of this procedure is in persons with Klippel-Trenaunay syndrome in whom the varicose veins may serve as the principal venous return from the lower extremity.
• Arteriovenous malformations
• • Complete excision of the malformation is required because subtotal resections result in recurrence. Preoperative embolization may be used, followed shortly with operative resection, preferably within 24 hours.
  • Simple ligation or embolization is contraindicated for arteriovascular anomalies because rapid collateral arterial flow develops.

Consultations

Consultations are required frequently, depending on the location of the lesions, rapidity of growth, associated symptoms or deformities, or simply to assure spontaneous regression or benignity.

• Head and neck
• • Consultations may be warranted for vascular lesions that may impinge on the airways, visual sight, oral structures, or potentially involve the neural axis.
  • Consider consulting a plastic surgeon, pediatric surgeon, ophthalmologist, otolaryngologist, neurologist, and/or neurosurgeon, as indicated by the lesion.
• Intrathoracic/intra-abdominal lesions
• • For example, lesions involving the liver may result in platelet trapping or high-output heart failure, particularly in infants and children.
  • As such, early involvement of a pediatric surgeon, interventional radiologist, and/or thoracic or general surgeon may be indicated.
• Extremity lesions
• • In addition to visible lesions, deep-seated intramuscular vascular malformations may require surgical excision.
  • Laser therapy may dictate referral to a dermatologist or plastic surgeon.
  • An orthopedist, pediatric surgeon, interventional radiologist, and/or vascular surgeon may lend valuable expertise for more extensive or deep-seated lesions.

Diet

No special diet is required.

Activity

No activity limitation is required unless the patient is undergoing laser therapy or operative intervention.

MEDICATION

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Medical therapy is generally reserved only for proliferative lesions (eg, rapidly expanding hemangiomas), particularly in infants younger than 6 months. Hemangiomas in children older than 5 months or those lesions that are no longer rapidly proliferating respond less predictably to medical intervention. Venous malformations rarely respond to medical therapy.

Drug Category: Corticosteroids

Certain metabolites of cortisol exhibit antiangiogenic effects. In vitro, cortisol has also been shown to reduce estrogen-binding capacity in proliferating hemangiomas.

Drug Name	Methylprednisolone (Medrol, Solu-Medrol)
Description	Occasional use of high-dose steroid therapy required if no response to standard dose.
Pediatric Dose	30-100 mg/kg/d PO/IM/IV as single dose
Contraindications	Documented hypersensitivity; viral, fungal, or tubercular skin infections
Interactions	Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels; phenobarbital, phenytoin, and rifampin may decrease levels (adjust dose); monitor patients for hypokalemia when taking medication concurrently with diuretics
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications

Drug Name	Triamcinolone (Aristospan Intra-articular)
Description	Intralesional injection may reduce systemic effects of drug.
Pediatric Dose	0.2 mg/kg intralesional injection; 1-2 injections/wk; may require general anesthesia
Contraindications	Documented hypersensitivity; fungal, viral, and bacterial skin infections
Interactions	Coadministration with barbiturates, phenytoin, and rifampin decreases effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Multiple complications (eg, severe infections, hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression) may occur; abrupt discontinuation may cause adrenal crisis; major complications have been reported from periocular use

Drug Category: Biological response modifiers

Interferons may induce release of 2',5'-oligoadenylate synthetase, which inhibits proliferation of endothelial cells.

Drug Category: Sclerosing agents

Effect produced by irritation and inflammation of venous endothelium and thrombus formation. Injected vein is occluded and fibrous tissue develops, resulting in vein obliteration.

Drug Category: Antiplatelet therapies

Occasionally, lesions respond to no other therapy.

FOLLOW-UP

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Complications

• Hemangioma
• • Residual scars, excess fibrofatty tissue, or severe disfigurement in 10-30% of patients
  • Airway obstruction (subglottic hemangioma, nasal hemangioma)
  • Visual axis obstruction (preorbital or orbital hemangioma)
  • Oral/digestive tract obstruction
  • Bilateral auditory canal obstruction (bilateral parotid hemangiomas)
  • Kasabach-Merritt syndrome (platelet-trapping thrombocytopenia)
  • Congestive heart failure (especially with visceral hemangiomas)
• Vascular malformations
• • Severe disfigurement
  • Extremity overgrowth (Klippel-Trenaunay syndrome)
  • Seizures, hemiparesis/plegia cerebral atrophy from leptomeninges involvement (Sturge-Weber syndrome)
  • Congestive heart failure
  • Other steal phenomenon with distal ischemia
  • Platelet trapping
  • Massive bleeding

Prognosis

• Hemangioma
• • Complete involution in 70-90%
  • Risk of developing complications (listed above) in 10-30%
• Vascular malformations
• • Do not involute or fade
  • Satisfactory cosmetic results accomplished with surgical treatment modalities (see Surgical Care)

MISCELLANEOUS

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Medical/Legal Pitfalls

• Occasionally, Klippel-Trenaunay syndrome, an unusual venous malformation, is encountered.
• • In this condition, the major venous outflow tracts of the lower extremity have an anomalous deficiency.
  • Patients typically present with a triad of lower extremity varicosities, port-wine stains, and limb hypertrophy.
  • Patients may be referred for vein stripping of the obvious varicose veins; however, Klippel-Trenaunay syndrome is a contraindication for vein stripping because these varicosities may represent the predominant venous collaterals around the absent deep vein.

Special Concerns

• The majority of hemangiomas occur as isolated lesions, but a few syndromes are recognized.
• • Sternal clefting and midline abdominal effects: This is when the sternum and upper abdominal wall fail to fuse; it may be associated with extensive hemangiomas.
  • Neurological defects: Hemangiomas over the lumbosacral region may be associated with an underlying tethered cord.
  • Dandy-Walker syndrome: This is when posterior fossa abnormalities are associated with large plaquelike facial hemangiomas.
  • Cardiovascular defects: This is associated with infant hemangiomas and associated right-sided aortic arch coarctation.
• Associated vascular malformation syndromes are as follows:
• • Sturge-Weber syndrome: This is associated with facial capillary malformations. The ophthalmic distribution is associated with underlying leptomeninges involvement.
  • Klippel-Trenaunay syndrome: This is when capillary malformations are associated with underlying lymphatic and venous malformations with overgrowth of the effected extremity.
  • Parkes Weber syndrome: This is associated with capillary malformations overlying a high-flow vascular malformation.
  • Osler-Weber-Rendu syndrome (hereditary hemorrhagic telangiectasia): This autosomal dominant syndrome is characterized by small cutaneous vascular lesions on the lips and mucous membranes. It usually develops in adolescence. It may be associated with significant GI bleeding, hematuria, and CNS bleeding.
  • von Hippel-Lindau syndrome: This is associated with cerebellar cysts and vascular malformations of the retina and cerebellum.
• Other malformations are considered separately because they cannot be easily or accurately categorized into the hemangioma/vascular malformation classification system.
• • Macular stains (stork bites, angel's kiss, salmon patch): These usually develop on the forehead or nuchal area. Fading occurs during the first year; if the stain persists, then the patient has a true capillary vascular malformation.
  • Telangiectasias: These can be classified as capillary vascular malformations and are commonly observed as spider angiomas manifesting in childhood and adulthood. Laser photocoagulation is the treatment of choice.

MULTIMEDIA

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Media file 1:  Chest wall hemangioendothelioma in a newborn.
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Media file 2:  Hemangioma on the buttock of an infant prior to steroid therapy. Note the central ulceration.
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Media file 3:  Same hemangioma in Image 2 after one month of oral steroids. Note involution beginning.
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Media file 4:  Klippel-Trenaunay syndrome in a young person. Note the port-wine stain extending to the buttocks. These lesions can be associated with venous malformations involving the rectum and bladder.
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Media file 5:  An unusual variant of Klippel-Trenaunay syndrome involving the upper extremity.
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Media file 6:  An intramuscular arteriovenous malformation. This enlarging lesion resulted in compression and atrophy of noninvolved muscle within the compartment.
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REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
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• Abe S. Local steroid therapy of adnexal strawberry hemangiomas in infants-long term follow-up. Eur J Plast Surg. 1986;9:29.
• Coffin CM, Dehner LP, O'Shea PA. Vascular tumors. In: Pediatric Soft Tissue Tumors: A Clinical, Pathological, and Therapeutic Approach. Baltimore, Md: Lippincott, Williams & Wilkins; 1997:. 40-79.
• Kim EJ, Halim AX, Dowd CF. The relationship of coexisting extranidal aneurysms to intracranial hemorrhage in patients harboring brain arteriovenous malformations. Neurosurgery. Jun 2004;54(6):1349-57; discussion 1357-8.
• Low DW. Hemangiomas and vascular malformations. Semin Pediatr Surg. May 1994;3(2):40-61. [Medline].
• Mulliken JB, Glowacki J. Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg. Mar 1982;69(3):412-22. [Medline].
• Steinmetz OK, Palerme LP. Images in clinical medicine. Acquired arteriovenous fistula. N Engl J Med. May 20 2004;350(21):2180. [Medline].
• White CW, Wolf SJ, Korones DN, et al. Treatment of childhood angiomatous diseases with recombinant interferon alfa-2a. J Pediatr. Jan 1991;118(1):59-66. [Medline].

Article Last Updated: Sep 15, 2006