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Infantile Hemangioma
Clinical Resolution With 5% Imiquimod Cream
Maria I. Martinez, MD;
Ignacio Sanchez-Carpintero, MD, PhD;
Paula E. North, MD, PhD;
Martin C. Mihm, Jr, MD
From the Clínica las Americas, San Juan de Puerto Rico (Dr Martinez);
University Clinic of Navarre, Spain (Dr Sanchez-Carpintero); Massachusetts
General Hospital and Harvard University, Boston (Drs Sanchez-Carpintero and
Mihm); Arkansas Children's Hospital and University of Arkansas for Medical
Sciences, Little Rock (Dr North).
Arch Dermatol. 2002;138:881-884.
REPORT OF CASES
CASE 1
A 7-month old boy in otherwise excellent health presented for consultation
at the Clínica las Americas in San Juan, Puerto Rico, with an infantile
(juvenile) hemangioma on the frontal scalp (3.0 x 2.5 cm; Figure 1). The hemangioma, protuberant and dusky red with a cutaneous
and a subcutaneous component, was noticed by his mother at age 2 months and
enlarged rapidly. Magnetic resonance imaging showed a soft tissue mass extending
to the outer table of the skull, suggestive of infantile hemangioma.
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Figure 1. Infantile hemangioma on the frontal
scalp of a 7-month-old boy (patient 1) immediately prior to initiation of
topical imiquimod therapy.
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CASE 2
A 4-month-old otherwise healthy girl presented to the same clinic with
a red-gray bulbous hemangioma, 4.5 cm in diameter, on the frontal scalp that
appeared at 1 month of age and grew rapidly. Findings of magnetic resonance
imaging supported the clinical diagnosis of infantile hemangioma.
THERAPEUTIC CHALLENGE
The parents of both patients expressed interest in some form of active
treatment but found conventional therapies, including laser surgery and intralesional
corticosteroid injections, overly aggressive.
SOLUTION
The option of topical 5% imiquimod cream 3 times per week was offered.
This was found acceptable by both parents, who fully understood that this
was an off-label use of the medication.
In patient 1, aged 7 months, the lesion appeared less protuberant after
4 weeks of 3-times-weekly application of imiquimod, consistent with partial
regression. Because of inflammation of the area with erythema and crusting
(Figure 2), a resting period of
2 weeks was given. A similar inflammatory effect has been reported in other
imiquimod-treated skin conditions. At the end of this 2-week period, there
was no inflammation, and a marked reduction in the size of the hemangioma
was observed.
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Figure 2. Crusting and erythema after 4
weeks of 3-times-weekly topical imiquimod therapy (patient 1; age, 8 months).
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Treatment was then restarted, increasing the frequency to every other
day and continuing for 2 weeks. Inflammation with crusting reappeared. Treatment
was again suspended, and follow-up examination 4 weeks later showed virtually
complete clinical regression of the hemangioma with return to normal skin
color. The patient at this time was 10 months old. Healing occurred without
scarring and without affecting the growth of hair at the site where the hemangioma
had been present. Other than local inflammation and crusting during therapy,
no other adverse effect was noted. Findings from a neurologic examination
were normal at the time of therapy cessation. At the most recent follow-up
visit, 4 months after stopping therapy, the patient, now 14 months old, was
in excellent health with no neurologic abnormalities and no recurrence of
the lesion (Figure 3).
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Figure 3. Persistent, virtually complete
resolution of the hemangioma (patient 1; age, 14 months) 4 months after cessation
of imiquimod therapy.
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In patient 2, aged 4 months, topical application of imiquimod was started
3 times weekly. However, after 3 weeks of therapy the mother became concerned
about the development of crusting and discontinued the medication. During
the next 2 months, the lesion grew rapidly, and the patient returned to the
clinic for reevaluation. Imiquimod therapy was then restarted at increased
frequency of application (every other day), to be continued for a full 6 weeks.
This course of therapy was completed despite recurrence of erythema and crusting.
At follow-up examination 4 weeks after termination of therapy, at which time
the patient was 9 months old, there was nearly complete regression of the
lesion with normal hairs covering the area and no evidence of scarring. At
last follow-up at age 16 months, findings of the patient's neurologic examination
remained normal, and there was no evidence of recurrence of the hemangioma.
COMMENT
We report here for the first time to our knowledge the apparent efficacy
of topical application of the immune response modifier imiquimod in the treatment
of infantile hemangioma. Infantile hemangioma is a distinct category of benign
vascular tumor characterized by presentation within the first few weeks of
life and rapid growth during the first year followed by a variable degree
of spontaneous involution over a period of several years.1
The true infantile hemangioma often first appears as a pale, blanched area
of the skin, which then reddens and progressively enlarges.2
Recent studies have shown that infantile hemangiomas possess a distinct vascular
phenotype shared by placental vessels but not by other types of vascular tumors.3 Lesions of this unique type are clearly different
than "congenital hemangiomas," which are fully formed at birth and have been
reported in some cases to show more rapid involution.4
The lesions described in this report are clinically typical infantile hemangiomas,
appearing after birth and showing the dramatic postnatal growth characteristic
of this entity. Their regression during imiquimod treatment, therefore, does
not reflect the rapid spontaneous involution associated with congenital hemangiomas.
Without treatment, most infantile hemangiomas exhibit spontaneous involution
over the course of years. However, many leave unsightly fibrofatty residua
or scars or cause more serious complications such as airway obstruction, amblyopia,
and deformation of anatomic structures during their course of development.2 For these reasons, active therapeutic interventions
are often required. Current therapies such as laser treatment, surgical resection,
intralesional and systemic corticosteroids, and, for life-threatening hemangiomas,
systemic interferon alfa therapy are in many cases incompletely effective
or are associated with adverse effects and patient discomfort. Unquestionably,
there is need for a more definitive and highly effective medical therapy without
significant adverse effects.
Imiquimod—an imidazoquinoline amine—is an immune-response
modifier that acts by affecting the innate and acquired immune response to
challenges. It has been shown to be useful in the treatment of genital warts,5 superficial basal cell carcinoma,6
squamous cell carcinoma in situ,7 actinic keratoses,8 and other lesions. Successful treatment of lentigo
maligna has also been reported.9 These entities
have responded, as best understood, on the basis of enhanced immunologic reactions
in the skin. The effect on innate immunity is achieved through successful
production of a large number of cytokines, including interferon (IFN)  ,
interleukin (IL) 6, and tumor necrosis factor alpha (TNF-) among others.
Natural killer cell activity is increased, as is activation of macrophages
resulting in production of nitric oxide. There is likewise stimulation of
B-cell proliferation and maturation.10 Acquired
immunity is enhanced through production of interleukins such as IL-1, IL-5,
IL-8, IL-10, and IL-12 as well as granulocyte and macrophage stimulatory factor.
The production of IL-12 results in an increase in cytotoxic T lymphocytes
and the release of IFN- .10
Interferon alfa, administered through systemic means, has been shown
in the literature to be an effective treatment of hemangiomas.11
The exact mechanism of action is not fully understood. However, this route
of administration has been associated with the occurrence of significant neurologic
complications, especially spastic dysplegia.12
Locally produced by imiquimod, IFN- may clearly be 1 of the active
agents responsible for the regression of the hemangiomas cited in this report.
However, recent reports concerning the tumor-suppressive and antiangiogenic
effects of IL-1213-14 suggest
that this cytokine may also be important in the response of hemangiomas to
imiquimod.
In nude mice and rats, topical application of 1% and 5% cream has been
shown to result in a local increase in IFN- and TNF-.15 In a polyoma virus–induced hemangioendothelioma
model, topical imiquimod has been shown to result in an increased number of
intratumoral mast cells as well as elevated levels of tissue inhibitor of
metalloproteinase type 1 (TIMP-1) and TNF- with evidence of increased
apoptosis.16 Increased density of mast cells
and increased expression of TIMP-1 have also been reported in involutive-phase
hemangiomas compared with proliferative-phase lesions.17
Thus, imiquimod treatment may hypothetically be causing a recapitulation of
the natural involutive process of infantile hemangiomas.
A variety of studies in rodents, monkeys, and humans using in vivo and
in vitro techniques (including splenic cultures of human lymphocytes treated
with imiquimod) have shown the production of other cytokines, including IL-2
and IFN-, as a result of IL-12 production.18
Activation of natural killer cells by IFN- has the potential to cause
destruction of hemangioma cells. Interferon gamma–inducible IP-10 may
in turn have a direct antiangiogenic effect, as has been shown in experimental
tumor models.19 Clearly, a variety of mechanisms
may reasonably be involved in imiquimod-induced regression of infantile hemangiomas,
and further clinical and experimental studies are warranted.
In summary, we have successfully used topical imiquimod to treat 2 patients
with typical infantile hemangiomas of postnatal onset. These lesions in the
proliferative phase completely resolved within 3 to 5 months of therapy initiation.
There was no evidence of recurrence at a median of 6 months following the
last treatment. This remarkable response, albeit of a small number of patients,
with minimal adverse effects, warrants further clinical investigation. To
this end, we have launched a larger clinical study with pathologic correlation
and a mechanism-oriented investigation.
AUTHOR INFORMATION
Accepted for publication March 17, 2002.
A patent to protect the subject of this article has been applied for.
Corresponding author and reprints: Ignacio Sanchez-Carpintero, MD,
PhD, Division of Dermatopathology, Warren 827, Massachusetts General Hospital,
Boston, MA 02114.
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SECTION EDITOR: GEORGE J. HRUZA, MD; ASSISTANT SECTION EDITORS: DEE
ANNA GLASER, MD; ELAINE SIEGFRIED, MD
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