 |
|
Treatment of an Ulcerated Hemangioma With Recombinant Platelet-Derived Growth Factor
Jeffrey L. Sugarman, MD, PhD;
Theodora M. Mauro, MD;
Ilona J. Frieden, MD
From the Department of Dermatology, University of California, San Francisco.
Arch Dermatol. 2002;138:314-316.
REPORT OF A CASE
We report a case of a 7-month-old girl with a large facial hemangioma
whose ulceration was successfully treated with 0.01% becaplermin (Regranex
[Ortho-McNeil Pharmaceutical, Raritan, NJ], recombinant human platelet-derived
growth factor-BB) gel. She was noted to have a hemangioma precursor on her
face and a heart murmur at the time of birth. After further evaluation, she
was found to have a type 1 interrupted aortic arch, ventricular septic defect,
and patent ductus arteriosis, and she subsequently underwent surgery to correct
her cardiac anomalies. These associated abnormalities are part of PHACE syndrome:
the association of posterior fossa brain malformations, hemangiomas, arterial
anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities.1
Her hemangioma continued to grow rapidly, progressively obstructing
the vision in her right eye, and at age 3 months she was started on oral corticosteroid
therapy (prednisolone, 4 mg/kg daily, tapered to 4 mg/kg every other day,
and then to 2 mg/kg every other day over 2 months). Her hemangioma initially
appeared to improve, but ulceration developed at age 5 months (Figure 1), worsening despite an increase in the prednisolone dosage
to 3.5 mg/kg daily. The hemangioma bled focally and oozed serosanguineous
fluid, and the patient experienced increasing pain. Initially, wound cultures
were negative for bacterial growth and home wound care consisted of bacitracin
zinc-polymyxin B sulfate (Polysporin; Glaxo Wellcome Inc, Research Triangle
Park, NC) and nonstick dressings that were changed every 3 days for approximately
6 weeks. Subsequently, dressings were changed to topical metronidazole gel
and Mepilex Saftec (Mölnlycke Health Care, Götenborg, Sweden) dressings
that were changed every other day.
|
|
|
|
Figure 1. Ulcerated hemangioma at age 5
months.
|
|
|
Because of worsening ulceration, she was admitted to the University
of California, San Francisco Hospital to receive intravenous antibiotics,
adequate pain control (with conscious sedation with midazolam and morphine
for dressing changes), and more aggressive wound care. A second culture of
her ulcerated hemangioma yielded coryneform gram-positive rods. On admission,
her physical examination revealed a vigorous young infant with a large hemangioma
measuring approximately 9 x 8 cm, encompassing nearly the entire upper
forehead and medial aspects of her right nose, including extensive involvement
of the upper eyelid, causing partial closure of the right eye. The 4.5 x
6-cm ulceration, which extended into the subcutaneous tissue overlying the
right eyebrow, had a friable oozing surface (Figure 2).
|
|
|
|
Figure 2. Ulcerated hemangioma at age 7
months, immediately prior to treatment with becaplermin. Condition is worse
despite topical treatments.
|
|
|
THERAPEUTIC CHALLENGE
The challenge was to heal the ulcerated portion of the hemangioma to
control pain and prevent further extension and scarring.
SOLUTION
The decision was made to start applying becaplermin to the ulcerated
portion of the hemangioma. The ulcer was gently debrided with half-strength
hydrogen peroxide and saline 2 times daily. A thin coat of becaplermin was
applied to the ulcer in the morning, and metronidazole gel was applied in
the evening. These were covered with a hydrogel (Inerpan [Sherwood Medical,
St Louis, Mo] or Vigilon [Bard Urological, Covington, Ga) and Telfa (Kendall
Healthcare, Mansfield, Mass) dressing. Therapy with prednisolone was also
tapered to 2.5 mg/kg every other day and eventually discontinued. Within 5
days, the ulcerated portion shrank to 4.2 x 4.0 cm and began to improve
rapidly. At a 6-week follow-up at age 8.5 months, it was completely reepithelialized
(Figure 3).
|
|
|
|
Figure 3. Hemangioma 6 weeks
after treatment with becaplermin.
|
|
|
COMMENT
Becaplermin, a commercially available form of platelet-derived growth
factor (PDGF), is approved by the Food and Drug Administration for the treatment
of cutaneous diabetic ulcers and also has been reported to facilitate the
healing of pressure ulcers and mixed arteriovenous diabetic ulcers.2-3 Playing a critical role in tissue repair
and wound healing, PDGF acts as a potent mitogen for fibroblasts and smooth
muscle and endothelial cells, as well as a chemotactic factor for inflammatory
cells.4-5 In addition, PDGF has
also been shown to induce vessel formation and to promote tumor growth by
stimulation of angiogenesis.6-7
Although fibroblasts and smooth muscle cells of resting tissues contain low
levels of PDGF receptors, the  PDGF receptor is markedly up-regulated
in inflammatory tissue, leading to increased responsiveness to PDGF.8
Ulceration is the most common complication of hemangiomas, occurring
in up to 10% of cases.9 In many cases, ulcerations
are relatively minor, but when severe, as in our case, they can become a major
management problem, causing soft tissue destruction, functional impairment,
and pain, as well as being complicated by bleeding and infection. In our patient,
corticosteroids and topical treatments were ineffective in healing the ulceration,
and the wound was believed to be too fibrinous and exudative to be effectively
penetrated by pulsed dye laser (another treatment for ulcerated hemangiomas),
which therefore was not an option.
Because becaplermin works at least in part by promoting angiogenesis,
we were concerned about the possibility that it might cause further proliferation
of the hemangioma, but given the severity of the ulceration, its proximity
to the eyelid margin, and the observation that the ulcerated portion no longer
appeared to be in a proliferative phase (there was no hemangioma visible at
the base of the ulcer), we decided to proceed. Fortunately, it promoted healing
of the ulcer and had no appreciable effect on proliferation of the hemangioma.
There are several possible reasons why becaplermin was effective without
causing hemangioma growth. The depth of ulceration appeared to extend to subcutaneous
tissue, without any visible evidence of hemangioma at the ulcer base, and
it is possible that the proliferative potential of the lesion had been destroyed
by the ulceration itself. In addition, the patient was receiving therapy with
systemic steroids at the time the medication was used. This may have blunted
any potential stimulatory effect of becaplermin on the hemangioma by contributing
to the down-regulation of PDGF, an effect that has been demonstrated in at
least 1 case of a hemangioma treated with intralesional corticosteroid.10 In addition, other factors, such as antibiotics and
more aggressive wound care while in the hospital, may have contributed to
more rapid healing of the ulceration.
Finally, an intriguing (though unproven) possibility is that the granulation
tissue promoted by becaplermin arises through a different angiogenic pathway
than the hemangioma itself. There is evidence for biological differences among
granulation tissue, hemangioma tissue, and chronic wounds at the molecular
level. For example, the erythrocyte-type glucose transporter protein (GLUT-1)
is highly expressed in endothelial cells of hemangiomas of infancy but is
absent from other benign vascular proliferations including granulation tissue.11 In addition, PDGF expression is down-regulated in
chronic compared with acute wounds.12 Thus,
becaplermin might act specifically to promote the healing of the ulcerated
portion of the hemangioma without stimulating proliferation of the tumor vasculature.
Our case illustrates that becaplermin may be useful in the treatment
of ulcerated hemangiomas that have not responded to conservative therapy.
Although we remain concerned about the possibility that becaplermin could
stimulate hemangioma growth, its use may be considered in cases of ulcerated
hemangioma that have the potential for significant morbidity and have failed
conventional treatment.
AUTHOR INFORMATION
Accepted for publication July 6, 2001.
Corresponding author: Ilona J. Frieden, MD, University of California,
San Francisco, Department of Dermatology, Box 0316, San Francisco, CA 94143-0316
(e-mail: ijfrieden{at}orca.ucsf.edu).
REFERENCES
| |
1. Frieden IJ, Reese V, Cohen D. The association of posterior fossa brain malformations, hemangiomas,
arterial anomalies, coarctation of the aorta and cardiac defects, and eye
abnormalities. Arch Dermatol. 1996;132:307-311.
ABSTRACT
2. Miller MS. Use of topical recombinant human platelet-derived growth factor-BB
(becaplermin) in healing of chronic mixed arteriovenous lower extremity diabetic
ulcers. J Foot Ankle Surg. 1999;38:227-231.
PUBMED
3. Rees RS, Robson MC, Smiell JM, Perry BH. Becaplermin gel in the treatment of pressure ulcers. Wound Repair Regen. 1999;7:141-147.
FULL TEXT
|
ISI
| PUBMED
4. Heldin CH, Westermark B. The role of platelet-derived growth factor in vivo. In: Clark RAF, ed. The Molecular and Cellular Biology
of Wound Repair. 2nd ed. New York, NY: Plenum Press; 1996:249-273.
5. Rosenkranz S, Kazauskas A. Evidence for distinct signaling properties and biological responses
induced by the PDGF receptor a and b subtypes. Growth Factors. 1999;16:201-216.
ISI
| PUBMED
6. Risau W, Drexler H, Mironov V, et al. Platelet-derived growth factor is angiogenic in vivo. Growth Factors. 1992;7:261-266.
PUBMED
7. Forsberg K, Valyi-Nagy I, Heldin CH, Hertly M, Westermark B. Platelet derived growth factor (PDGF) in oncogenesis: development of
a vascular connective tissue stroma in xenotransplanted human melanoma producing
PDGF-BB. Proc Natl Acad Sci U S A. 1993;90:393-397.
FREE FULL TEXT
8. Rubin K, Terracio L, Ronnstrand L, Heldin CH, Klareskog L. Expression of PDGF receptors is induced on connective tissue cells
during chronic synovial inflammation. Scand J Immunol. 1988;27:285-294.
FULL TEXT
|
ISI
| PUBMED
9. Bowers RE, Graham EA, Tomlinson KM. The natural history of the strawberry nevus. Arch Dermatol. 1960;82:667-680.
ISI
10. Hasan Q, Tan ST, Gush J, Peters SG, Davis PF. Steroid therapy of a proliferating hemangioma: histochemical and molecular
changes. Pediatrics. 2000;105:117-121.
FREE FULL TEXT
11. North PE, Waner M, Mizeracki A, Mihm MC. GLUT-1: a newly discovered immunohistochemical marker for juvenile
hemangiomas. Hum Pathol. 2000;31:11-22.
FULL TEXT
|
ISI
| PUBMED
12. Shukla A, Dubey MP, Srivastava R, Srivastava BS. Differential expression of proteins during healing of cutaneous wounds
in experimental normal and chronic models. Biochem Biophys Res Commun. 1998;244:434-439.
FULL TEXT
|
ISI
| PUBMED
SECTION EDITOR: GEORGE J. HRUZA, MD; ASSISTANT SECTION EDITORS: DEE
ANNA GLASER, MD; ELAINE SIEGFRIED, MD
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
Hemangiomas of Infancy: Treatment of Ulceration in the Head and Neck
Thomas et al.
Arch Facial Plast Surg 2005;7:312-315.
ABSTRACT
| FULL TEXT
Response of Ulcerated Perineal Hemangiomas of Infancy to Becaplermin Gel, a Recombinant Human Platelet-Derived Growth Factor
Metz et al.
Arch Dermatol 2004;140:867-870.
ABSTRACT
| FULL TEXT
|
