Infantile hemangioma: How to treat this benign neoplasm of childhood

Certain risk factors identified in patients who develop IH have led to hypotheses about the pathogenesis of IH. The risk factors include female gender, prematurity, white race, non-Hispanic ethnicity,2-5 and infants born to mothers with placental abnormalities, such as preeclampsia and placenta previa, as well as those exposed to chorionic villous sampling (CVS).2-4,8

Although none of the hypotheses is universally accepted, abundant evidence implicates the placenta in IH pathogenesis. One theory contends that an underlying problem with the placenta causes an increased number of placental angioblasts or placental precursor cells to enter the fetal circulation. This theory accounts for the increased risk of IH in cases of preeclampsia, placenta previa, and CVS. In addition, studies that compare placental vasculature with IH endothelium show that both share numerous surface markers that were not found in other vascular anomalies or non-IH tumor vessels.4,5 Further support for a placental origin of IH is the clearly delineated life cycle of IH, which is similar to that of the placenta during gestation.4

In general, two schools of thought regarding the pathology of IH exist. The intrinsic theories suggest that a progenitor cell causes tumor formation via vasculogenesis, which is blood vessel formation occurring through a de novo production of endothelial cells. The extrinsic theories propose that abnormal environmental stimuli, such as hypoxia, estrogen, growth factors, or cytokines, lead to the development of IH. In this case, the lesion develops either by vasculogenesis; angiogenesis, which is blood vessel development arising from preexisting vessels; or a combination of both processes.4,5 Further research is needed in order to define the pathologic process more clearly, which can lead to new and better treatments for IH.

DIAGNOSIS AND CLINICAL FEATURES

Using guidelines created by Finn, Glowaki, and Mulliken, 90% of vascular anomalies are diagnosed during the history and physical examination.9 A few cases will require imaging studies. Doppler ultrasound is the least invasive and most cost-effective imaging option. If the diagnosis is still in question, a biopsy is needed in order to clarify the disease process. Histologically, IH appears as collections of endothelial cells that are plump and rapidly dividing, with or without an associated lumen.2

IH usually follows a predictable pattern of growth and recession. About half of all newborns who develop IH have a precursor lesion present at birth, whereas the lesions typically take form over the first few weeks of life in the remaining cases of IH.2,4,10 The classic presentation is a flat, red macule or patch that, in an initial proliferative phase, grows rapidly over the following 8 to 12 months.2,4,6-8

The ultimate appearance of the lesion can be one of several morphologies. The superficial type is described as a well-defined, raised, red mass. The appearance of this type of lesion is the reason it used to be known as a strawberry hemangioma. The deep type develops in the subcutaneous fat. The lesion is an ill-defined tumor with a bluish hue (see Figure 1). The combined type has qualities of both the superficial and deep types.2,4 The superficial type occurs the most often. In one study, 62% of IH lesions were superficial;2 15% and 22% of lesions were the deep and combined types, respectively.2 Most IH lesions are singular and localized; however, some lesions are larger, irregularly shaped, and plaquelike. This presentation is referred to as segmental IH.2

A short plateau phase occurs after the initial proliferative phase; neither growth nor regression occurs during this phase. Finally, the IH lesion involutes over a period of months to years at a rate of approximately 10% per year.2-5,8 Involution of a superficial lesion begins with a color change, from a cherry red to a dull or grayish red. As the process continues, the endothelial cells are substituted with fibrofatty tissue and the lesion becomes softer and easier to compress. Similarly, a color change to a more gray hue indicates the beginning of involution of a deep IH lesion.2 Involution, however, does not necessarily mean that the affected area will ultimately have a normal appearance. Approximately 38% of resolved lesions will have a residual defect—a fibrofatty mass of tissue or atrophied and wrinkled skin with telangiectasia, scarring, or yellowish discoloration.2,4,5,8,10

ADVERSE EFFECTS

Complications of IH that require treatment occur in 10% to 12% of patients.6 The most common complication is an ulceration developing within the lesion; this occurs in 5% to 13% of IH lesions.2,6

Ulceration tends to occur during the proliferative phase because the growth of the lesion surpasses epidermal elasticity and blood supply.2,6,10 Several factors predispose IH lesions to becoming ulcerated, including intertriginous, perineal, and perioral location; size larger than 6 cm3, and segmental type.2,4,6 Pain, infection, hemorrhage, and scarring are all associated with ulcerated IH.2,6 If a patient develops an ulceration, providing local wound care, treating the infection (if present), and managing pain are vitally important. Acetaminophen, acetaminophen with codeine, or topical lidocaine are safe options for managing the inevitable pain of an ulceration.2,6

Airway obstruction is a rare but life-threatening complication of IH.2,4,6,10 Infants with IH lesions in a “beard” distribution along the jaw are at increased risk of airway involvement.2,4 These infants, therefore, need to be monitored frequently for signs of respiratory distress, including a barking cough and/or progressive stridor, especially during the first several months of life.2

Visual complications can result from periocular IH.2,4,6,10 In fact, 43% to 60% of patients with IH in this location will develop amblyopia. In this situation, the tumor becomes so large that it obstructs the visual axis and blocks stimuli from allowing normal visual development. This complication occurs more frequently when the lesion develops on the upper eyelid but can also occur when the lesion develops on the lower eyelid. Strabismus, myopia, tear duct obstruction, proptosis, and ptosis are other visual complications that are associated with periocular IH. The significance of these problems warrants referring any patient with periocular IH to an ophthalmologist.2

Multiple IH is another significant presentation. Although most cases manifest as a single lesion, a full 20% manifest as multiple lesions.1,2 Multiple IH is subcategorized as either benign or disseminated. Benign hemangiomatosis typically involves cutaneous tumors that grow for a short period of time and then completely resolve by age 2 years. Disseminated hemangiomatosis involves cutaneous and visceral tumors that can be life-threatening. Cutaneous lesions are the primary finding in 87% of infants with disseminated hemangiomatosis. Furthermore, the mortality rate for untreated disseminated hemangiomatosis is 77%; treatment decreases the mortality rate to 27%.2 Therefore, referral to a specialist is imperative for any child with multiple IH.

PHACES syndrome is a more serious, but extremely rare, complication seen in patients with segmental facial IH. The acronym represents the abnormalities that can be seen in patients with this syndrome: Posterior fossa defects, Hemangiomas, Arterial abnormalities, Coarctation of the aorta and cardiac malformations, Eye anomalies, and Sternal defects. An important note is that in 70% of cases, only one abnormality other than IH is involved. However, the severity of this syndrome warrants closely following any child with a segmental facial IH. Early referral to the appropriate specialist is prudent if any signs or symptoms of this syndrome should arise.2

Psychological effects can be devastating for both patients with IH and their parents. When the infant is a newborn and the tumor is rapidly growing, parental anxiety regarding disease progression can be quite significant. The burden of stares and questions from strangers and even accusations of child abuse further exacerbate parental concern.1 Prior to age 3 years, a child's body image is not well-developed, so longterm psychological repercussions are not likely if the lesion regresses completely by this age.1,10 Given that 60% of IH lesions develop on the head and neck and that 70% remain beyond age 3 years, however, the long-term psychological consequences are important considerations when deciding on when and how to treat these patients. Most clinicians advocate intervention before the child starts school in order to avoid the negative effect that comments and stares can have on the child.

MANAGEMENT AND TREATMENT

The wide range of clinical presentations requires an individual approach to each patient with IH. Educating the parents about the natural history of the disease is a critical first step. A discussion regarding the individual prognosis, potential complications, and the pros and cons of the various treatments is also important. Parents see the lesion daily and often cannot determine when and if the lesion has stopped growing or when involution has begun; therefore, taking measurements and photographs regularly is an optimal way to record lesion progression. This record will aid in making a decision on whether or not to actively treat a lesion.

In 1997, the American Academy of Dermatology outlined the key objectives of IH management: (1) prevent or reverse life- or function-threatening complications, (2) prevent permanent disfigurement, (3) minimize psychological stress for the patient and the family, (4) avoid aggressive and potentially scarring procedures, and (5) prevent or adequately treat ulceration to minimize scarring, infection, and pain.2 In accordance with these guidelines, many clinicians advocate active nonintervention for patients with small, singular lesions that are located in cosmetically insignificant areas. If active treatment of a lesion is warranted, several options are available.

Systemic corticosteroids are the first-line treatment of choice for large, aggressive, life- or function-threatening IH lesions.1-4,6,7,10 One daily oral dose of prednisone or prednisolone, 2 to 3 mg/kg, is given in the morning. Response to this treatment—a cessation of growth or the initiation of involution—usually occurs within 2 weeks; cessation of growth is the more common outcome.2,7 Treatment is more successful if initiated during the initial proliferative phase.10 Multiple courses of treatment may be necessary if growth resumes after termination of the medication.7 Parents should be counseled regarding the typical side effects of systemic corticosteroids, including cushingoid appearance, changes in personality, changes in appetite, hypertension, insomnia, and decreased growth velocity. These side effects are temporary and should resolve upon cessation of the medication.

Intralesional corticosteroid injections are an alternative to systemic corticosteroids.1-4,6,7,10 A total of 10 to 15 mg of triamcinolone acetonide (10 mg/mL) is injected into the lesion. The treatment can be repeated every 4 to 6 weeks.10 This treatment modality carries the risk of embolization with retinal artery occlusion and subsequent blindness; therefore, it should be limited to nonperiocular IH.2,7 Other adverse effects include subcutaneous fat atrophy, epidermal necrosis, and temporary dyspigmentation of the treated area; but these effects are all quite uncommon.

Interferon alfa inhibits the development of new blood vessels from preexisting vessels.2 Up to 80% of patients show a decrease in lesion size, making interferon alfa treatment possibly more effective than corticosteroids. However, potential adverse effects, such as spastic diplegia, may be severe; therefore, this medication is limited to use as an alternate treatment of life-threatening IH when corticosteroid therapy has failed.2,4,6,10

Imiquimod 5% cream, an immune response mediator, has recently been shown to be effective in superficial IH.3,4,7 This treatment has been used safely and successfully in children as young as 8 months. The typical reaction is edema, erythema, scaling, and crusting, which may be indicative of clinical response.3

Laser treatments, another viable option for patients with IH, have been used for almost 50 years.1,2,6,10 The newer pulsed dye lasers (PDLs) are effective for treating thin, superficial IH lesions and produce much less scarring than earlier lasers.1,2,6,7,11 In addition, PDLs are also used to treat ulcerations and residual skin defects.2,7 Intense pulsed light (IPL) has also been proven successful, particularly in treating ulcerated IH lesions. Several studies demonstrated the efficacy of IPL, while minimizing such side effects as purpura and scarring, which can still be seen with PDL.6,11

Surgery is an effective treatment option; however, the decision to resect or debulk a particular lesion should be individualized. Surgical intervention can be considered early on for IH lesions that are unlikely to resolve without residual defect. Resection may also be beneficial for patients with IH lesions that are small, pedunculated, or located around the eye when medical therapy has failed.2,7 Surgery should also be considered for a child with a residual lesion who is nearing school age in order to avoid ridicule and subsequent negative self-esteem.1,2,7,10

CONCLUSION

IH is the most common benign tumor of childhood. PAs who care for neonatal and pediatric patients must be familiar with the presentation and natural progression of IH. This allows them to provide appropriate and necessary parental education, which is a key factor in disease management. When provided with accurate information about typical disease progression, potential complications, and treatment options, parents will be better prepared to share in the decision-making process regarding their child's treatment. Furthermore, parents should be given a realistic prognosis based on the individual clinical presentation of their child, so they will have realistic expectations. JAAPA

Kerry Schlosser practices in dermatology in Encino, California. She has indicated no relationships to disclose relating to the content of this article.

Acetaminophen
Acetaminophen with codeine
Imiquimod (Aldara)
Interferon alfa (Intron A [alfa-2b], Roferon-A [alfa-2a])
Lidocaine
Triamcinolone acetonide (Kenalog-10)

REFERENCES

1. Williams EF 3rd, Hochman M, Rodgers BJ, et al. A psychological profile of children with hemangiomas and their families. Arch Facial Plast Surg. 2003;5(3):229-234.

2. Bruckner AL, Frieden IJ. Hemangiomas of infancy. J Am Acad Dermatol. 2003;48(4):477-493.

3. Ho NT, Lansang P, Pope E. Topical imiquimod in the treatment of infantile hemangiomas: a retrospective study. J Am Acad Dermatol. 2007;56(1):63-68.

4. Ritter MR, Butschek RA, Friedlander M, Friedlander SF. Pathogenesis of infantile haemangioma: new molecular and cellular insights. Expert Rev Mol Med. 2007;9(32):1-19.

5. Barnés CM, Christison-Lagay EA, Folkman J. The placenta theory and the origin of infantile hemangioma. Lymphat Res Biol. 2007;5(4):245-255.

6. Jorge BF, Del Pozo J, Castineiras I, et al. Treatment of ulcerated haemangiomas with a noncoherent pulsed light source: brief initial clinical report. J Cosmet Laser Ther. 2008;10(1):48-51.

7 Infantile hemangiomas (strawberry hemangiomas). In: James WD, Berger TG, Elston DM, eds. Andrews' Diseases of the Skin: Clinical Dermatology. 10th ed. Philadelphia, PA: Saunders; 2006:593-595.

8. Lopez Gutierrez JC, Avila LF, Sosa G, Patron M. Placental anomalies in children with infantile hemangioma. Pediatr Dermatol. 2007;24(4):353-355.

9. Finn MC, Glowacki J, Mulliken JB. Congenital vascular lesions: clinical application of a new classification. J Pediatr Surg. 1983;18(6):894-900.

10. Williams EF 3rd, Stanislaw P, Dupree M, et al. Hemangiomas in infants and children. An algorithm for intervention. Arch Facial Plast Surg. 2000;2(2):103-111.

11. Angermeier MC. Treatment of facial vascular lesions with intense pulsed light. J Cutan Laser Ther. 1999;1(2):95-100.