Infantile Hemangioma Clinical Presentation
- Author: Richard J Antaya, MD; Chief Editor: William D James, MD more...
History
Infantile hemangiomas exhibit a characteristic evolution, with early rapid growth (proliferation) followed by slow involution.[14] 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.[3, 4] 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; however, most hemangiomas have completed this phase by age 4 months. During this time, the hemangioma may remain quiescent or may begin to involute.[15]
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.[16] 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.[17] 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.[18]
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 image below). 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 image below).[5]
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 image below).
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 the infantile hemangioma with minimal or arrested growth (IH-MAG). These have been previously referred to as abortive, reticular, or telangiectatic infantile hemangiomas. By definition these IHs have a proliferative component equaling less than 25% of their total surface area. They are mostly 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 growth characteristics and presence of visible telangiectases assist in differentiation. This variant has been seen in association with underlying vascular and other extracutaneous congenital anomalies (PHACE and PELVIS syndromes and with underlying vascular anomalies on an extremity) as well as demonstrating a predilection for the lower body, in contradistinction to classic IHs.[19, 20]
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 fibrofatty residua (especially with subcutaneous lesions).[18]
Causes
Neither the cause nor the cell of origin of infantile hemangiomas has been definitively elucidated. Theories abound and several lines of evidence support several divergent theories of the cell of origin, including placental tissue, endothelial progenitor cells (EPCs), and mesenchymal stem cells.[21]
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.[22, 23]
Hemangiomas fail to stain for numerous trophoblastic markers, somewhat discounting the placental embolism theory.[24] 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.[25] See Pathophysiology.
An in utero local tissue environment of either hypoxia or acidity appears to influence the subsequent vasculature. Both of these microenvironmental conditions are potent inducers of angiogenesis, leading to increased production of hypoxia-inducible factor (HIF), which, in turn, causes VEGF gene transcription in association with cytokine-stromal cell-derived factor 1 (SDF-1). This appears to stimulate endothelial progenitor cells to proliferate and differentiate into endothelial cells.[26]
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.[27]
It is believed that infantile hemangiomas may be derived from endothelial progenitor cells (EPCs). EPCs are bone marrow-derived CD133 (or AC133) – positive, CD34-positive, and KDR (VEGFR-2)-positive pluripotent cells that demonstrate the ability to develop into Glut-1–positive endothelial cells.[28] A hemangioma model using these cells exhibits growth characteristics typical of an infantile hemangioma, with both proliferating and involuting phases and the development of fibrofatty residua during involution. The endothelial cells in an infantile hemangioma are thought to be primitive endothelial clonal cells that exhibit abnormal behavior.[29]
Two possibly interrelated theories exist regarding the pathogenesis of hemangiomas with regard to the EPCs, intrinsic and extrinsic. The intrinsic theory proposes that EPCs are monoclonal and behave differently from normal endothelial progenitor cells. The extrinsic theory postulates that the EPCs are polyclonal and behave normally and proliferate in response to the surrounding tissue angiogenic and angiostatic factors.[30]
Mesenchymal stem cells may also play a role in the formation of infantile hemangiomas. These cells have been identified in hemangioma tissue.[31] 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.[32] 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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