Challenges
in Medical and Surgical Therapeutics
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
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 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.
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.
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.
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.
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).
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.
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.
Imiquimodan
imidazoquinoline amineis 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/Article Information
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).
Corresponding author and reprints: Ignacio Sanchez-Carpintero, MD, PhD,
Division of Dermatopathology, Warren 827, Massachusetts General Hospital,
Boston, MA 02114.
Accepted for publication March 17, 2002.
A patent to protect the subject of this article
has been applied for.
SECTION EDITOR: GEORGE J. HRUZA, MD; ASSISTANT SECTION EDITORS: DEE ANNA
GLASER, MD; ELAINE SIEGFRIED, MD
1.
Jacobs AH.
Strawberry hemangiomas: the natural history of the untreated lesion.
Calif Med.
1957;86:8-10.
2.
Waner M, Suen JY.
The natural history of hemangiomas.
In: Waner M, Suen JY, eds. Hemangiomas and
Vascular Malformation of the Head and Neck. New York, NY:
Wiley-Liss; 1999:13-45.
3.
North PE, Waner M, Mizeracki A, et al.
A unique microvascular phenotype shared by juvenile hemangiomas and human
placenta.
Arch Dermatol.
2001;137:559-570.
ABSTRACT
| FULL TEXT
| PDF
| MEDLINE
4.
Boon LM, Enjolras O, Mulliken JB.
Congenital hemangiomas: evidence for accelerated involution.
J Pediatr.
1996;128:329-335.
MEDLINE
5.
Beutner KR, Spruance SL, Hougham AJ, Fox TL, Owens ML, Douglas JM Jr.
Treatment of genital warts with an immune response modifier (imiquimod).
J Am Acad Dermatol.
1998;38:230-239.
MEDLINE
6.
Marks R, Gebauer K, Shumack S, et al.
Imiquimod 5% cream in the treatment of superficial basal cell carcinoma:
results of a multicenter 6-week dose-response trial.
J Am Acad Dermatol.
2001;44: 807-813.
MEDLINE
7.
Hengee UR, Stark R.
Topical imiquimod to treat intraepidermal carcinoma.
Arch Dermatol.
2001;137:709-711.
FULL TEXT
| PDF
| MEDLINE
8.
Stockfleth E, Meyer T, Benninghoff B, Christofers E.
Successful treatment of actinic keratosis with imiquimod cream 5%: a report of
six cases.
Br J Dermatol.
2001;144:1050-1053.
MEDLINE
9.
Ahmed I, Berth-Jones J.
Imiquimod: a novel treatment for lentigo maligna.
Br J Dermatol.
2000;143:843-845.
MEDLINE
10.
Sauder DN.
Immunomodulatory and pharmacologic properties of imiquimod.
J Am Acad Dermatol.
2000;43:S6-S11.
MEDLINE
11.
Ezekowitz RAB, Mulliken JB, Folkman J.
Interferon alpha-2a therapy for life-threatening hemangiomas of infancy.
N Engl J Med.
1992;326:1456-1463. [published correction appears in N Engl J Med. 1995;333:395].
MEDLINE
12.
Barlow CF, Priebe CJ, Mulliken JB, et al.
Spastic diplegia as a complication of interferon alfa-2a treatment of
hemangiomas of infancy.
J Pediatr.
1998;132:527-530.
MEDLINE
13.
Coughlin CM, Salhany KE, Gee MS, et al.
Tumor cell responses to IFN gamma affect tumorigenicity and response to IL-12
therapy and antiangiogenesis.
Immunity.
1998;9:25-34.
MEDLINE
14.
Sunamura M, Sun L, Lozonschi L, et al.
The antiangiogenesis effect of interleukin 12 during early growth of human
pancreatic cancer in SCID mice.
Pancreas.
2000;20:227-233.
MEDLINE
15.
Dahl MV.
Imiquimod: an immune response modifier.
J Am Acad Dermatol.
2000;43:S1-S5.
MEDLINE
16.
Sidbury R, Puscasiu E, Miller R, et al.
Topical imiquimod immunotherapy inhibits tumor growth in a mouse model of
infantile vascular tumors [abstract].
J Invest Dermatol.
2000;114:770.
17.
Takahashi K, Mulliken JB, Kozakewich HP, Rogers RA, Folkman J, Ezekowitz RA.
Cellular markers that distinguish the phases of hemangioma during infancy and
childhood.
J Clin Invest.
1994;93:2357-2364.
MEDLINE
18.
Duda DG, Sunamura M, Lozonschi L, et al.
Direct in vitro evidence and in vivo analysis of the antiangiogenesis effects
of interleukin 12.
Cancer Res.
2000;60:1111-1116.
MEDLINE
19.
Imbertson LM, Beaurline JM, Couture AM, et al.
Cytokine induction in hairless mouse and rat skin after topical application of
the immune response modifier imiquimod and S-28463.
J Invest Dermatol.
1998;110:734-739.
MEDLINE
Edward E.
Rylander, M.D.
Diplomat American
Board of Family Practice.
Diplomat American
Board of Palliative Medicine.