|A small hemangioma of infancy|
A hemangioma, also known as infantile hemangioma (IH), is one of the most common benign tumors of infancy and occurs in approximately 5–10% of infants, though it occurs past infancy on rare occasions. Infantile hemangiomas are benign vascular tumors composed of an increased number of unique endothelial cells that line blood vessels. This is not to be confused with hemagioblastoma, a vascular tumor found in the CNS that is associated with von Hippel Lindau syndrome. They occur more frequently in female, premature and low birth weight infants. Infantile hemangiomas usually appear within the first weeks of life and grow most rapidly during the first three to six months of life. For most hemangiomas, 80% of infantile hemangioma size is generally reached by 3 months of age. Usually, growth and proliferation is complete and involution commences by twelve months of age. However, involution occurs slowly over many years with a majority of infantile hemangioma regression occurring by five years of age. Although infantile hemangiomas spontaneously regress over time, some may leave residual redundant fibrofatty tissue, scar, residual telangiectasia, or pigmentary changes. The word "hemangioma" comes from the Greek haema- (αίμα), "blood"; angeio (αγγείο), "vessel"; -oma (-ωμα), "tumor".
Signs and symptoms
Infantile hemangiomas typically develop in the first few weeks or months of life. They are more common in Caucasians, in premature children whose birth weight is less than 3 pounds (1.4 kg), in females, and in twin births. Early lesions may resemble a red scratch or patch, a white patch, or a bruise. The majority of hemangiomas occur on the head and neck, but they can occur almost anywhere. The appearance and color of the hemangioma depends on its location and depth within the level of the skin.
Superficial hemangiomas are situated higher in the skin and have a bright red, erythematous to reddish-purple appearance. Superficial lesions can be flat and telangiectatic, composed of a macule or patch of small, varied branching capillary blood vessels. They can also be raised and elevated from the skin, forming papules and confluent bright red plaques like raised islands. Infantile hemangiomas have historically been referred to “strawberry hemangiomas” in the past, as raised superficial hemangiomas can look like the side of a strawberry without seeds. Superficial hemangiomas in certain locations, such as the posterior scalp, neck folds and groin/perianal areas are at potential risk of ulceration. Ulcerated hemangiomas can present as black crusted papules or plaques, or painful erosions or ulcers. Ulcerations are prone to secondary bacterial infections which can present with yellow crusting, drainage, pain or odor. Ulcerations are also at risk for bleeding, particularly deep lesions or in areas of friction. Multiple superficial hemangiomas, more than 5 can be associated with extracutaneous hemangiomas, the most common being a liver (hepatic) hemangioma and these infants warrant ultrasound examination.
Deep hemangiomas present as poorly defined, bluish macules that can proliferate into papules, nodules or larger tumors. Proliferating lesions are often compressible, but fairly firm. Many deep hemangiomas may have a few superficial capillaries visible evident over the primary deep component or surrounding venous prominence. Deep hemangiomas have a tendency to develop a little later than superficial hemangiomas and may have longer and later proliferative phases as well. Deep hemangiomas rarely ulcerate, but can cause issues depending on their location, size and growth. Deep hemangiomas near sensitive structures can cause compression of softer surrounding structures during the proliferative phase, such as the external ear canal and the eyelid. Mixed hemangiomas are simply a combination of superficial and deep hemangiomas, and may not be evident for several months. Patients may have any combination of superficial, deep or mixed infantile hemangiomas.
Infantile hemangiomas are often classified as focal/localized, segmental or indeterminate. Focal infantile hemangiomas appear localized to a specific location and appear to arise from a solitary spot. Segmental hemangiomas are larger, appear to encompass a region of the body. Larger or segmental hemangiomas that span over a large area can sometimes have underlying anomalies that may require investigation especially when located on the face, sacrum or pelvis.
Hemangioma on the scalp of a two-year-old child, in the "rest stage"
The vast majority of hemangiomas are not associated with complications. Hemangiomas may break down on the surface, called ulceration. Ulceration can be painful and problematic. If the ulceration is deep, significant bleeding and infection may occur in rare occasions. If a hemangioma develops in the larynx, breathing can be compromised. If located near the eye, a growing hemangioma may cause an occlusion or deviation of the eye that can lead to amblyopia. Very rarely, extremely large hemangiomas can cause high-output heart failure due to the amount of blood that must be pumped to excess blood vessels. Lesions adjacent to bone may cause erosion of the bone.
The most frequent complaints about hemangiomas stem from psychosocial complications. The condition can affect a person's appearance and provoke attention and malicious reactions from others. Particular problems occur if the lip or nose is involved, as distortions can be difficult to treat surgically. The potential for psychological injury develops from school age onward. It is therefore important to consider treatment before school begins if adequate spontaneous improvement has not occurred. Large hemangiomas can leave visible skin changes secondary to severe stretching that results in altered surface texture.
Large segmental hemangiomas of the head and neck can be associated with a disorder called PHACES syndrome. Large segmental hemangiomas over the lumbar spine can be associated with dysraphism, renal, and urogenital problems in association with a disorder called LUMBAR syndrome. Multiple cutaneous hemangiomas in infants may be an indicator for liver hemangiomas. Screening for liver involvement is often recommended in infants with 5 or more skin hemangiomas.
The cause of hemangioma is currently unknown; however, several studies have suggested the importance of estrogen signaling in hemangioma proliferation. In 2007, a paper from the Stanford Children's Surgical Laboratory revealed that localized soft tissue hypoxia coupled with increased circulating estrogen after birth may be the stimulus. There is also a hypothesis presented by researchers that maternal placenta embolizes to the fetal dermis during gestation resulting in hemangiomagenesis. However, another group of researchers conducted genetic analyses of single-nucleotide polymorphism in hemangioma tissue compared to the mother's DNA that contradicted this hypothesis. Other studies have revealed the role of increased angiogenesis and vasculogenesis in the etiology of hemangiomas. More research is required in order to fully understand the disproportionate nature of hemangioma growth, which will hopefully yield targeted therapeutics to treat its most complicated presentations.
The majority of infantile hemangiomas (IH) can be diagnosed by history and physical exam. In rare cases, imaging (ultrasound (US) with Doppler, magnetic resonance imaging (MRI)) and/or cytology or histopathology are needed to confirm the diagnosis. IH are usually absent at birth or there may be a small area of pallor, telangiectasias, or duskiness. A fully formed mass at birth usually indicates a diagnosis other than IH. Superficial hemangiomas in the upper dermis have a bright red strawberry color, whereas those in the deep dermis and subcutis, deep hemangiomas, may appear blue and be firm or rubbery on palpation. Mixed hemangiomas can have both features. A minimally proliferative IH is an uncommon type of IH that presents with fine macular telangiectasias with an occasional bright-red, papular, proliferative component. Minimally proliferative IH are more common in the lower body.
A precise history of the growth characteristics of the IH can be very helpful in making the diagnosis. In the first 4 to 8 weeks of life IH grow rapidly with primarily volumetric rather than radial growth. This is usually followed by a period of slower growth that can last up to 6–9 months, with 80% of the growth completed by 3 months. Finally, IH involute over a period of years. There are exceptions to these growth characteristics: minimally proliferative IH which do not substantially proliferate and large deep IH in which noticeable growth starts later and lasts longer.
If the diagnosis is not clear based on physical exam and growth history (most often in deep hemangiomas with little cutaneous involvement), then either imaging or histopathology can help confirm the diagnosis. On Doppler ultrasound an IH in the proliferative phase appears as a high flow soft-tissue mass usually without direct arteriovenous shunting. On MRI, IH show a well-circumscribed lesion with intermediate and increased signal intensity on T1 and T2-weighted sequences, respectively, and strong enhancement after gadolinium injections. There are fast flow vessels. Tissue for diagnosis can be obtained via fine needle aspiration, skin biopsy, or excisional biopsy. Under the microscope, hemangiomas are unencapsulated aggregates of closely packed, thin-walled capillaries, usually with endothelial lining. Blood-filled vessels are separated by scant connective tissue. Their lumens may be thrombosed and organized. Hemosiderin pigment deposition due to vessel rupture may be observed. The GLUT-1 histochemical marker can be helpful in distinguishing IH from other items on the differential diagnosis, such as vascular malformations.
Management of infantile hemangioma
Most hemangiomas disappear without treatment, leaving minimal to no visible marks. This may take many years, however, and a significant proportion of lesions may require some form of therapy. Indications for treatment of a hemangioma include functional impairment (ie visual or feeding compromise), bleeding, potentially life-threatening complications (ie airway, cardiac or hepatic disease), and risk of long-term or permanent disfigurement. Large hemangiomas can leave visible skin changes secondary to significant stretching of the skin or alteration of surface texture. When hemangiomas interfere with vision, breathing, or threaten significant disfigurement (most notably facial lesions and, in particular, nose and lips), they are usually treated. Medical therapies are most effective when utilized during the period of most significant hemangioma growth, which corresponds to the first five months of life. Ulcerated hemangiomas, a subset of lesions requiring therapy, are usually treated by addressing wound care, pain and hemangioma growth.
Treatment options for hemangiomas include medical therapies (systemic, intralesional and topical), surgery, and laser therapy. Prior to 2008, the mainstay of therapy for problematic hemangiomas was oral corticosteroids, which are effective and remain an option for patients in whom beta-blocker therapy is contraindicated or poorly tolerated. Following the serendipitous observation that propranolol, a non-selective beta blocker, is well tolerated and effective for treatment of hemangiomas, the agent was studied in a large, randomized controlled trial and was approved by the U.S. Food and Drug Administration for this indication in 2014. Propranolol has subsequently become the first-line systemic medical therapy for treatment of these lesions.
Since that time, topical timolol maleate in addition to oral propranalol has become a common therapy for infantile hemangiomas. According to a 2018 Cochrane review,  both of these therapies have demonstrated beneficial effects in terms of clearance of hemangiomas without an increase in harms. In addition, there was no difference detected between these two agents and their ability to reduce hemangioma size; however, it is not clear whether there is a difference in safety. All of these results were based on moderate to low quality evidence, thus further randomized controlled trials with large populations of children are needed to further evaluate these therapies. This review concluded that for now, there is no evidence to challenge oral propranalol as the standard systemic therapy for treatment of these lesions.
Other systemic therapies which may be effective for hemangioma treatment include vincristine, interferon- and other agents with antiangiogenic properties. Vincristine, which requires central venous access for administration, is traditionally used as a chemotherapy agent, but has been demonstrated to have efficacy against hemangiomas and other childhood vascular tumors, such as Kaposiform hemangioendothelioma and tufted angioma. Interferon-alpha 2a and 2b, given via subcutaneous injection, has shown efficacy against hemangiomas, but may result in spastic diplegia in up to 20% of treated children. These agents are rarely utilized now in the era of beta blocker therapy for hemangiomas.
Intralesional corticosteroid (usually triamcinolone) injection has been used for small, localized hemangiomas, where it has been demonstrated relatively safe and effective. Injection of upper eyelid hemangiomas is controversial, given the reported risk of retinal embolization, possibly related to high injection pressures. Topical timolol maleate, a non-selective beta blocker available in a gel-forming solution approved for the treatment of glaucoma, has been increasingly recognized as a safe and effective off-label alternative for treatment of small hemangiomas. It is generally applied two to three times daily.
Surgical excision of hemangiomas is rarely indicated, and limited to lesions which fail medical therapy (or when it is contraindicated), which are anatomically distributed in a location which is amenable to resection, and in which resection would likely be necessary and the scar will be similar regardless of timing of the surgery. Surgery may also be useful for removal of residual fibrofatty tissue (following hemangioma involution) and reconstruction of damaged structures.
Laser therapy, most often the pulsed dye laser (PDL), plays a limited role in hemangioma management. It is most often used for treatment of ulcerated hemangiomas, often in conjunction with topical therapies and wound care, and may speed healing and diminish pain. Laser therapy may also be useful for early superficial hemangiomas (although rapidly proliferating lesions may be more prone to ulceration following PDL treatment), and for the treatment of cutaneous telangiectasias which persist following hemangioma involution.
In the involution phase, a hemangioma finally begins to diminish in size. While it was previously thought that infantile hemangiomas improved by about 10% each year, newer evidence suggests that maximal improvement and involution is typically reached by 3.5 years of age. The majority of hemangiomas resolve by age 10, however, in some patients, the hemangioma doesn't completely resolve. Residual redness may be noted and can be improved with laser therapy, most commonly pulsed dye laser. Ablative fractional resurfacing may be considered for textural skin changes. Hemangiomas, especially those that have gotten very large during the growth phase, may leave behind stretched skin or fibrofatty tissue that may be disfiguring or require future surgical correction. Areas of prior ulceration may leave behind permanent scarring.
Additional long term sequelae stem from the identification of extracutaneous manifestations in association with the infantile hemangioma. For example, a patient with a large facial hemangioma who is found to meet criteria for PHACE syndrome, will require potentially ongoing neurologic, cardiac, and/or ophthalmologic monitoring. In cases of infantile hemangiomas that compromise of vital structures, symptoms may improve with involution of the hemangioma. For example, respiratory distress would improve with involution of a space occupying hemangioma involving the airway and high output heart failure may lessen with involution of a hepatic hemangioma and ultimately treatment may be tapered or discontinued. In other cases, such as an untreated eyelid hemangioma, resultant amblyopia does not improve with involution of the cutaneous lesion. For these reasons, it is important that infants with infantile hemangiomas be evaluated by an appropriate clinician during the early proliferative phase so that risk monitoring and treatment be individualized and outcomes can be optimized.
The terminology used to define, describe and categorize vascular tumors and malformations has changed over time. The term hemangioma was originally used to describe any vascular tumor-like structure, whether it was present at or around birth or appeared later in life. In 1982, Mulliken and Glowacki proposed a new classification system for vascular anomalies which has been widely accepted and adopted by the International Society for the Study of Vascular Anomalies (ISSVA). This classification system was recently updated in 2015. The classification of vascular anomalies is now based upon cellular features, natural history, and clinical behavior of the lesion. Vascular anomalies are divided into vascular tumors/neoplasms which include infantile hemangiomas, and vascular malformations which include entities with enlarged or abnormal vessels such as capillary malformations (port wine stains), venous malformations, and lymphatic malformations. In 2000, GLUT-1, a specific immunohistochemical marker, was found to be positive in infantile hemangiomas and negative in other vascular tumors or malformations. This marker has revolutionized the ability to distinguish between infantile hemangioma and other vascular anomalies.
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