eMedicine Specialties > Dermatology > Diseases of the Vessels
Infantile Hemangioma
Updated: Aug 18, 2009
Introduction
Background
Infantile hemangiomas are benign vascular neoplasms that have a characteristic clinical course marked by early proliferation and followed by spontaneous involution. During the proliferative phase in the neonatal period or early infancy, a rapidly dividing endothelial cell proliferation is responsible for the enlargement of infantile hemangiomas. Finally, an involutional phase occurs, whereby most infantile hemangiomas are clinically resolved by age 9 years.
Hemangiomas are the most common tumors of infancy, and most infantile hemangiomas are medically insignificant. Occasionally, infantile hemangiomas may impinge on vital structures, ulcerate, bleed, or cause high-output cardiac failure or significant structural abnormalities. Rarely, a cutaneous infantile hemangioma may be associated with one or more underlying congenital anomalies.
Pathophysiology
Infantile hemangiomas are composed of proliferating, plump endothelial cells. Early in proliferation, the cells are in disarray, but, with time, they form vascular spaces and channels replete with blood cells (see Media File 1).
Histopathology of a proliferating infantile hemangioma with plump endothelial cells in the dermis.
These benign-appearing endothelial cells produce limited basement membrane structures. Hemangiomas assume a lobular architecture as proliferation slows and ends. Mast cells appear to affect this process and are implicated in the promotion of feeding arterioles and veins that supply each lobule. They also have been found in high concentrations during involution.
Takahashi hypothesized that during the third trimester of fetal development, immature endothelial cells coexist with immature pericytes, which maintain their proliferative capacity for a limited period during postnatal life.1 Angiogenic peptides, such as beta-fibroblast growth factor, vascular endothelial growth factor (VEGF), and proliferating cell nuclear antigen, induce proliferation of these immature cells, resulting in the development of the hemangioma. As the endothelial cells differentiate, an influx of mast cells, various myeloid cells, and tissue inhibitors of metalloproteinases (TIMPs) occurs.2 TIMPs, along with interferon and transforming growth factor produced by the mast cells, terminate the endothelial cell proliferation and passively induce involution by senescence of endothelial cells.
Frequency
United States
Infantile hemangiomas occur in 10-12% of white non-Hispanic infants, 1.4% of black infants, and 0.8% of Asian infants. The incidence of infantile hemangiomas is approximately 22-30% of preterm infants with birthweight less than 1 kg; for preterm infants with birthweight greater than 1.5 kg,3 the incidence is the same as for term infants. An increased incidence is recognized in infants from multiple gestations. The incidence is increased with older maternal age, maternal placenta previa, and preeclampsia.4 Some, but not all, surveys have demonstrated increased incidence in infants born to mothers who have undergone prenatal chorionic villus sampling.
Mortality/Morbidity
Most infantile hemangiomas are benign and do not cause any morbidity or mortality. Occasionally, they may impinge on vital structures and interfere with breathing, vision, eating, or hearing. Ulceration of certain areas (eg, diaper area, neck, mucosal surfaces) is not uncommon. Excessive bleeding is infrequent and rarely, if ever, life threatening. In the past, infantile hemangiomas were confused with other vascular neoplasms, particularly kaposiform hemangioendothelioma and tufted angiomas, which can incite a consumptive coagulopathy that may be life threatening. This is referred to as Kasabach-Merritt phenomenon (KMP). It is now generally accepted that infantile hemangiomas are rarely, if ever, responsible for KMP.5,6
Large cutaneous or visceral hemangiomas (particularly liver) can result in high-output cardiac failure resulting from increased vascular flow. Permanent significant structural abnormalities may result, particularly when facial structures are involved. The highest risk appears to be with involvement of the nasal tip, lips, and ears.7 Segmental hemangiomas, which cover a particular section or area of skin, may be markers for underlying malformations or developmental anomalies of the heart, blood vessels, or nervous system (PHACES and PELVIS syndromes and lumbosacral hemangiomas) and, depending on the severity of the associated anomaly, can result in increased morbidity or mortality.8,9
*PHACES syndrome - Posterior fossa abnormalities (Arnold-Chiari and Dandy-Walker malformations), hemangiomas (cervicofacial and/or laryngeal), arterial anomalies (carotid, cerebral, and vertebral), cardiac anomalies (especially coarctation of the aorta), eye abnormalities, and sternal or abdominal clefting)
*PELVIS syndrome - Perineal hemangioma with any of the following: external genital malformations, lipomyelomeningocele, vesicorenal abnormalities, imperforate anus, or skin tag)
Race
Hemangiomas occur most commonly in white infants, with an incidence rate 10-12 times that of black and Asian infants.
Sex
Females are affected more often than males by a ratio of 3:1. This disparity is higher (9:1) in those infants with large cervicofacial segmental hemangiomas associated with PHACES syndrome.
Age
Thirty percent of infantile hemangiomas are present at birth, and 70% of them initially appear in the first several weeks of life.
Clinical
History
Infantile hemangiomas exhibit a characteristic evolution, with early rapid growth (proliferation) followed by slow involution.10 The earliest sign of an infantile hemangioma is blanching of the involved skin. This may be followed by fine telangiectasias and then a red or crimson macule. Rarely, a shallow ulceration may be the first sign of an incipient infantile hemangioma.
Rapid growth during the neonatal period (birth to 4 wk) is the historical hallmark of infantile hemangiomas. This rate is characteristically beyond the growth rate of the infant, thereby differentiating this neoplasm from vascular malformations that grow commensurate with the infant. As proliferation ensues, the infantile hemangioma becomes elevated and may be dome shaped, lobulated, plaquelike, tumoral, or any combination of these morphologies.11,12 The proliferation phase occurs during the first year, with the most growth occurring during the first 4-6 months of life. Proliferation slows considerably between the middle and end of the first year of life. During this time, the hemangioma may remain quiescent or may begin to involute.13
The involutional phase of an infantile hemangioma may be rapid or prolonged. No specific characteristics appear to influence the rate or completeness of involution of infantile hemangiomas. The exception is a separate type of hemangioma referred to as a rapidly involuting congenital hemangioma (RICH), which proliferates in utero and is fully developed at birth.14 RICHs tend to completely involute during the second year of life. Congenital hemangiomas are not considered to be a variant of the infantile hemangioma.
Fifty percent of infantile hemangiomas complete involution by age 5 years and 70% by age 7 years; the remainder may take an additional 3-5 years to complete the process.15 Of lesions that have involuted by age 6 years, 38% have residual evidence with scar formation, telangiectasia, or redundant or anetodermic skin. Infantile hemangiomas that take longer to involute have a higher incidence of permanent cutaneous residua. Eighty percent of infantile hemangiomas that complete involution after age 6 years may exhibit cutaneous residua.16
Physical
Eighty percent of infantile hemangiomas are focal and solitary. Sixty percent of cutaneous hemangiomas occur on the head and neck, 25% on the trunk, and 15% on the extremities (see Media File 2). Hemangiomas also can occur in extracutaneous sites, including the liver, gastrointestinal tract, larynx, CNS, pancreas, gall bladder, thymus, spleen, lymph nodes, lung, urinary bladder, and adrenal glands.
This proliferating superficial infantile hemangioma on the trunk required no therapy.
Features of early proliferating infantile hemangiomas (birth to age 6 wk) include blanching of the involved skin, followed by fine telangiectasias, and then a red or crimson macule or papule that often is surrounded by a faint halo of vascular blanching. Occasionally, an infantile hemangioma is heralded by a shallow ulceration, especially lip and buttock lesions (see Media File 3).17
Exquisitely painful ulcerated mixed hemangioma (superficial and deep) of the left deltoid in a 6-month-old female infant. This lesion was treated successfully with pulsed dye laser.
As infantile hemangiomas proliferate (birth to age 12 mo), depending on their size and depth, their morphology and texture may be dome shaped, bosselated, plaquelike, tumoral, or any combination of these morphologies.
If the infantile hemangioma is located in the subcutaneous tissue, the overlying skin may be completely normal. Color varies with the depth from the surface and can be bright red or crimson (superficial dermis), purple, blue, or flesh colored with predominant involvement of the deeper tissues. Telangiectases and large superficial veins radiating from the infantile hemangioma often are associated. The consistency is firm, rubbery, and tense and expands with increased intravascular pressure (eg, with crying when on the head and neck). Tenderness to palpation is a variable generally uncommon feature of infantile hemangiomas.
Most infantile hemangiomas reach a maximum size of 0.5-5 cm, but they can range from the size of a pinhead to greater than 20 cm in diameter. Most infantile hemangiomas remain well circumscribed and focal. A minority may be segmental in nature, covering a larger portion of the cutaneous surface. This variant has more superficial than deep involvement, as is seen with extensive facial lesions (see Media File 4).
This superficial and deep infantile hemangioma resulted in astigmatism of the left eye, requiring spectacles to correct the refractive error and to prevent amblyopia. Further growth of this hemangioma necessitated a course of oral prednisolone. The hemangioma shrunk rapidly, and the patient's astigmatism decreased such that the spectacles were unnecessary 1 month after beginning steroids.
Another variant is an abortive or reticular infantile hemangioma, previously referred to as a telangiectatic hemangioma. This variant of infantile hemangioma is almost completely flat and may simply present with an erythematous blush of the affected skin. As its prior name suggests, an abortive or reticular infantile hemangioma often has telangiectasia coursing through it. This variant may be confused with a capillary malformation; however, the rapid growth characteristics and presence of visible telangiectases assist in differentiation. This variant has been seen in association with underlying vascular and other congenital anomalies (PHACES and PELVIS syndromes and with underlying vascular anomalies on an extremity).18
During involution, which may begin as early as a few months from birth or as late as 2-3 years, the infantile hemangioma shrinks centrifugally from the center of the lesion. This is less notable with deeper lesions. The superficial lesions become less red, taking on a duskier maroon-to-purple color, and finally regaining normal flesh tones (often referred to as "graying"). With involution, the infantile hemangiomas become softer and more compressible with decreased tenderness, and they exhibit less expansion during increased intravascular pressure (eg, crying).
During the late involution phase (quiescent residual lesions), the skin may return to normal with no evidence of a previous pathologic process. Approximately 50-60% of all hemangiomas resolve incompletely, leaving permanent changes in the skin. These changes include telangiectases, superficial dilated veins, stippled scarring, anetoderma or epidermal atrophy (particularly with superficial lesions), hypopigmentation, and/or redundant skin with fibro-fatty residua (especially with subcutaneous lesions).16
Causes
Neither the cause nor the cell of origin of infantile hemangiomas has been elucidated. Theories abound and several lines of evidence support several divergent theories of the cell of origin, including placental tissue, endothelial progenitor cells, and mesenchymal stem cells.
A distinct group of tissue-specific markers, including Lewis Y, merosin, and FcγRII, but most notably glucose transporter 1 (GLUT-1), are uniquely coexpressed by hemangiomas and placental microvessels, suggesting a unique relationship between hemangiomas and placental microvessels. Two theories postulated to explain this observation include (1) colonization of receptive mesenchyme by potentially abnormal angioblasts switched toward a placental endothelial phenotype and (2) embolic placental endothelial cells that have reached fetal tissues from chorionic villi through right-to-left shunts.
The placenta and hemangioma share a similar life cycle of robust vascular growth. The placenta produces very high levels of the proangiogenic cytokine, vascular endothelial growth factor (VEGF). As a protective mechanism against uncontrolled angiogenesis in the fetus and mother, a soluble form of the VEGF receptor, sFlt-1, found in both amniotic fluid and maternal serum, is also produced by the placenta. sFlt-1 binds circulating VEGF, preventing excessive angiogenesis in nonplacental tissues. Postpartum, the connection to the placenta and sFlt-1 is removed, abrogating this negative feedback and allowing proliferation of cells, such as those in hemangiomas, responsive to VEGF.19,20
Hemangiomas fail to stain for numerous trophoblastic markers, somewhat discounting the placental embolism theory.21 Some reports suggest that infants born to mothers who have undergone chorionic villus sampling may be at an increased risk of developing hemangiomas, but this has not been uniformly observed.22 See Pathophysiology.
Several (VEGF receptors (VEGFRs) may play a role in the development of hemangiomas. VEGFR1 on endothelial cells acts as a decoy receptor such that the binding of VEGF to this receptor does not effect a change in the endothelial cell. However, the binding of VEGF to VEGFR2 elicits robust endothelial cell proliferation and migration. Hemangioma endothelial cells exhibit low levels of VEGFR1, with marked constitutive activation of VEGFR2. Gene transcription for VEGFR1 in hemangioma cells is dependent on nuclear factor of activated T cells (NFAT). This, in turn, is dependent on a pathway involving beta1 integrin, VEGFR2, and integrinlike receptor tumor endothelial marker-8 (TEM8).Missense mutations in genes encoding for VEGFR2 and TEM8 have been identified in a subset of infantile hemangiomas. These mutations are likely responsible for the constitutive activation of VEGFR2 and resultant hemangioma endothelial cell proliferation. Soluble VEGFR1 or anti-VEGF antibodies normalize the constitutive VEGFR2 signaling. Consequently, these or other similar molecules may be exploited in future hemangioma therapy.23
A CD133-positive, pluripotent cell has been isolated from an infantile hemangioma that demonstrates the ability to develop into a Glut-1–positive hemangioma in an immunodeficient mouse model.24 This hemangioma model exhibits growth characteristics typical of an infantile hemangioma, with both proliferating and involuting phases and the development of fibro-fatty residua during involution.
Mesenchymal stem cells may also play a role in the formation of infantile hemangiomas. These cells have been identified in hemangioma tissue.25 Mesenchymal stem cells retain the capacity to differentiate into numerous mesodermal cells, including adipocytes, suggesting that these cells may be the source of the resultant adipose tissue found in involuted hemangiomas.
Evidence to support a hereditary/genetic component in the development of most infantile hemangiomas is minimal; most appear to be sporadic. However, at least one report described a kindred in which infantile hemangiomas may be the result of an autosomal dominant trait.26 These infantile hemangiomas were seen in association with an increased incidence of vascular malformations (mostly capillary malformations) in various members of the same family.
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Further Reading
Clinical trials (recruiting)
Keywords
infantile hemangiomas, hemangioma of infancy, hemangioma, superficial hemangioma, deep hemangioma, compound hemangioma, strawberry mark, angioma, cavernous hemangioma, capillary hemangioma
