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Observation
July 2004

Response of Ulcerated Perineal Hemangiomas of Infancy to Becaplermin Gel, a Recombinant Human Platelet-Derived Growth Factor

Arch Dermatol. 2004;140(7):867-870. doi:10.1001/archderm.140.7.867
Abstract

Background  Hemangiomas of infancy are the most common tumors of childhood , and ulceration is the most common complication. Many treatments have been usedfor hemangioma ulceration, although none are uniformly effective. A recent report described the successful use of 0.01% becaplermin gel, a recombinanthuman platelet-derived growth factor, for an ulcerated hemangioma refractory to standard care. We sought to further assess the responsiveness of hemangiomaulceration to 0.01% becaplermin gel and to compare its cost to that of conventional modalities.

Observations  We report a case series of 8 infants treated with becaplermin gel for ulcerated perineal hemangiomas of infancy. All infants were seen between Januaryand June 2003 in the pediatric dermatology clinic at Texas Children's Hospital.Six female and 2 male infants were included. All of the hemangiomas were large(≥6 cm2), and of superficial or mixed superficial and deep morphology. Rapid ulcer healing occurred in all patients within 3 to 21 days (average,10.25 days).

Conclusions  In this small series, 0.01% becaplermin gel was a safe and effective treatment for perineal hemangioma ulceration. The rapid healing achieved with0.01% becaplermin gel allows a reduction in the risk of secondary infection, pain, and need for hospitalization, as well as in the costs that often accumulatefrom multiple follow-up visits and long-term therapy.

A recombinant human platelet-derived growth factor-BB gel, 0.01% becaplermin gel (Regranex; Johnson & Johnson Wound Management Worldwide, a divisionof Ethicon, Somerville, NJ.), is approved in the United States for the treatment of lower extremity diabetic neuropathic ulcers and has also been reportedto facilitate the healing of pressure ulcers.1,2

Sugarman and colleagues3 reported the first case of 0.01% becaplermin gel used successfully for an ulcerated hemangiomaof infancy (HOI) refractory to standard care that included meticulous wound care, topical antibiotics, and systemic corticosteroids. Although these authorsdid not experience HOI proliferation in their study, they were concerned about the potential of platelet-derived growth factor, a known angiogenesis stimulator,to induce HOI proliferation.

We conducted a retrospective chart review of 8 patients with ulcerated perineal HOI who were treated with 0.01% becaplermin gel in the pediatricdermatology clinic at Texas Children's Hospital between January and June 2003.Although 1 of the HOI was located on the hip, this lesion was included inour study because its location under the diaper predisposed it to the same physical factors as the perineum. Data from all 8 cases are summarized in Table 1. Our experience from cases 1 and2 is described in detail below.

Table 1. 
Ulcerated Hemangiomas Treated With 0.01% Becaplermin Gel
Ulcerated Hemangiomas Treated With 0.01% Becaplermin Gel
REPORT OF CASES
CASE 1

A Hispanic female infant with a mixed superficial and deep segmental HOI over the labia majora, gluteal cleft, and buttock initially presentedto our service at the age of 6½ months with a small, superficial ulceration over her labia. Wound care was initiated with metronidazole gel and mupirocincream applied twice daily and covered with a barrier paste. She returned 2 months later with 2 additional superficial perineal ulcerations (1.5 cm2). These ulcerations were injected with 1 mL of a 1:1 mixture of 20mg/mL of triamcinolone and 6 mg/mL of betamethasone, and wound care was continued. One week later she was hospitalized for worsening ulceration. Wound culturesgrew Pseudomonas species. Despite treatment with intravenous antibiotics and continued wound care, the ulcers deepened to 3cm (Figure 1A). Metronidazole gel plus barrier paste was continued at night but replaced in the morning witha thin layer of 0.01% becaplermin gel covered with barrier paste. An outpatient follow-up visit 19 days later showed complete healing of the superior ulcerand dramatic improvement of the inferior ulcer (Figure 1B).

Figure 1.
A, Ulcerated hemangioma worsening in patient 1 despite wound care and treatment with intralesional steroids.B, Lesion appearance 19 days after starting treatment with 0.01% becaplermin gel.

A, Ulcerated hemangioma worsening in patient 1 despite wound care and treatment with intralesional steroids.B, Lesion appearance 19 days after starting treatment with 0.01% becaplermin gel.

CASE 2

A Hispanic female infant with a large, mixed superficial and deep segmentalHOI on the buttocks and gluteal cleft presented with a 3-month history ofmultiple mixed ulcerations that had been unresponsive to treatment with wound care and topical, intralesional, and systemic corticosteroids (Figure 2A). Treatment was initiated with a daily application ofbecaplermin gel followed by the application of a barrier paste. By her follow-up appointment 3 weeks later the ulcerations had completely healed (Figure 2B).

Figure 2.
A, Ulcerated hemangioma refractoryto treatment with topical, intralesional, and systemic steroids and woundcare in patient 2. B, Lesion appearance 3 weeks after starting treatment with0.01% becaplermin gel.

A, Ulcerated hemangioma refractoryto treatment with topical, intralesional, and systemic steroids and woundcare in patient 2. B, Lesion appearance 3 weeks after starting treatment with0.01% becaplermin gel.

CASE SERIES

Six female and 2 male infants with ulcerated perineal HOI were included in our series (Table 1). All ofthe HOI were large (≥6 cm2) and of superficial or mixed superficialand deep morphology. In all 8 cases, rapid healing of the ulceration occurredwithin 3 to 21 days (average, 10.25 days with 0.01% becaplermin gel). The ulcerations had been refractory to conventional therapy in 5 of the 8 patients,while in the remaining 3 patients 0.01% becaplermin gel was the only medication used. We did not note HOI proliferation in any of our patients. In fact, inpatient 1, in whom 0.01% becaplermin gel was inadvertently applied to ulcerated and nonulcerated HOI tissue, clinical findings consistent with involutionwere evident (Figure 1B).

COMMENT

Hemangiomas of infancy are the most common benign tumors of childhoodand ulceration, the most common complication of HOI, occurs in 5% to 15% ofcases.4,5 Ulceration generally develops during the proliferative phase of the HOI life cycle, and is morecommonly seen with lesions showing segmental morphology, ie, with a plaquelike, linear, and/or geographic pattern over a specific cutaneous territory.6 The perineum is the most frequent site of HOI ulceration,probably because of recurrent friction, maceration, and repeated exposure to urine and feces.7 Whereas wound care isimportant in the management of perineal HOI ulceration, adherent dressings are often inefficient in this location. Rapid ulcer healing is desirable toreduce pain, bleeding, and the risk of infection.

None of the current modalities of HOI ulceration management are uniformly effective. While meticulous wound care is essential, topical antibiotics (mostcommonly mupirocin or metronidazole), topical, intralesional and/or systemic corticosteroids, and pulsed-dye laser may be used as adjunct therapy. Surgicalexcision may be required in the most refractory cases.7

Platelet-derived growth factor, which promotes the recruitment and proliferation of cells involved in wound repair and enhances epithelialization,8 has been shown to promote angiogenesis. However, growthfactors are known to have either stimulatory or inhibitory effects, depending on the tissue affected, because individual transduction molecules may be presentin different amounts in different cell types.9 This may explain why 0.01% becaplermin induced ulcer healing, but not HOI proliferation,in our patients. Of interest is the significant involution observed at follow-up in patient 1, when it was discovered that 0.01% becaplermin had been inadvertentlyapplied to the entire HOI surface rather than on the ulcerated areas only. It remains to be seen whether 0.01% becaplermin has an effect, direct or indirect,on HOI involution; and if so, whether this effect varies by lesion morphology.

While the cost of 0.01% becaplermin gel may initially seem expensive, one must compare it with the cost of alternative therapies. In our experience,multiple follow-up visits and the long-term use of wound care agents, in addition to other conventional agents, are often required to achieve healing. We calculatedthe average cost of each topical medication when purchased from 4 separate pharmacies in Houston (Table 2),and added the standard costs of office visits, inpatient hospitalization, intralesional corticosteroid injections, and pulsed-dye laser therapy at ourinstitution. The rapid healing induced by 0.01% becaplermin gel not only reduced these costs, but also the risk of secondary infection, pain, and need forhospitalization, as 2 of our infants experienced prior to receiving this medication.

Table 2. 
Cost of Different Treatment Modalities for Hemangioma Ulcerations
Cost of Different Treatment Modalities for Hemangioma Ulcerations

In this small series, 0.01% becaplermin gel appears to be safe and effectivefor the management of HOI ulceration in the perineal location. A randomizedcontrolled trial of becaplermin gel for this indication, with outcome measures to include time to healing, presence or absence of HOI proliferation, cost,and quality of life, is currently in development.

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Article Information

Correspondence: Denise W. Metry, MD, 6621 Fannin St, CC 620.16, Houston, TX 77030 (dmetry@bcm.tmc.edu).

Accepted for publication October 8, 2003.

This study was presented in poster form at the annual meeting of the Society for Pediatric Dermatology; June, 2003; Seattle, Wash.

We thank Ilona Frieden, MD, for her continued support and guidance, John Luk, MD, for Figure 1, andDonna Ruddell for her administrative assistance.

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