Infantile Hemangioma Clinical Resolution with 5% Imiquimod Cream

THE CUTTING EDGE

SECTION EDITOR: GEORGE J. HRUZA, MD; ASSISTANT SECTION EDITORS: DEE ANNA GLASER, MD; ELAINE SIEGFRIED, MD 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; Clı´nica 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)

The Cutting Edge: Challenges in Medical and Surgical Therapeutics

REPORT OF CASES In patient 1, aged 7 months, the lesion appeared less protuberant after 4 weeks of 3-times-weekly appli- CASE 1 cation of imiquimod, consistent with partial regression. Because of inflammation of the area with erythema and A 7-month old boy in otherwise excellent health pre- crusting (Figure 2), a resting period of 2 weeks was sented for consultation at the Clı´nica las Americas in San given. A similar inflammatory effect has been reported Juan, Puerto Rico, with an infantile (juvenile) heman- in other imiquimod-treated skin conditions. At the end gioma on the frontal scalp (3.0ϫ2.5 cm; Figure 1). The of this 2-week period, there was no inflammation, and a hemangioma, protuberant and dusky red with a cutane- marked reduction in the size of the hemangioma was ous and a subcutaneous component, was noticed by his observed. mother at age 2 months and enlarged rapidly. Magnetic Treatment was then restarted, increasing the fre- resonance imaging showed a soft tissue mass extending quency to every other day and continuing for 2 weeks. to the outer table of the skull, suggestive of infantile he- Inflammation with crusting reappeared. Treatment was mangioma. again suspended, and follow-up examination 4 weeks later showed virtually complete clinical regression of CASE 2 the hemangioma with return to normal skin color. The patient at this time was 10 months old. Healing A 4-month-old otherwise healthy girl presented to the occurred without scarring and without affecting the same clinic with a red-gray bulbous hemangioma, 4.5 cm growth of hair at the site where the hemangioma had in diameter, on the frontal scalp that appeared at 1 month been present. Other than local inflammation and crust- of age and grew rapidly. Findings of magnetic reso- ing during therapy, no other adverse effect was noted. nance imaging supported the clinical diagnosis of infan- Findings from a neurologic examination were normal at tile hemangioma. the time of therapy cessation. At the most recent follow-up visit, 4 months after stopping therapy, the THERAPEUTIC CHALLENGE patient, now 14 months old, was in excellent health with no neurologic abnormalities and no recurrence of The parents of both patients expressed interest in some the lesion (Figure 3). form of active treatment but found conventional thera- In patient 2, aged 4 months, topical application of pies, including laser surgery and intralesional cortico- imiquimod was started 3 times weekly. However, after 3 steroid injections, overly aggressive. weeks of therapy the mother became concerned about the development of crusting and discontinued the medi- SOLUTION cation. During the next 2 months, the lesion grew rapidly, and the patient returned to the clinic for reeval- The option of topical 5% imiquimod cream 3 times per uation. Imiquimod therapy was then restarted at increased week was offered. This was found acceptable by both par- frequency of application (every other day), to be contin- ents, who fully understood that this was an off-label use ued for a full 6 weeks. This course of therapy was com- of the medication. pleted despite recurrence of erythema and crusting. At

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Figure 1. Infantile hemangioma on the frontal scalp of a 7-month-old boy Figure 3. Persistent, virtually complete resolution of the hemangioma (patient 1) immediately prior to initiation of topical imiquimod therapy. (patient 1; age, 14 months) 4 months after cessation of imiquimod therapy.

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 char- acteristic 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 ex- hibit spontaneous involution over the course of years. However, many leave unsightly fibrofatty residua or scars or cause more serious complications such as airway ob- struction, amblyopia, and deformation of anatomic struc- Figure 2. Crusting and erythema after 4 weeks of 3-times-weekly topical 2 imiquimod therapy (patient 1; age, 8 months). tures during their course of development. For these rea- sons, active therapeutic interventions are often required. Current therapies such as laser treatment, surgical re- follow-up examination 4 weeks after termination of section, intralesional and systemic corticosteroids, and, therapy, at which time the patient was 9 months old, for life-threatening hemangiomas, systemic interferon alfa there was nearly complete regression of the lesion with therapy are in many cases incompletely effective or are normal hairs covering the area and no evidence of scar- associated with adverse effects and patient discomfort. ring. At last follow-up at age 16 months, findings of the Unquestionably, there is need for a more definitive and patient’s neurologic examination remained normal, and highly effective medical therapy without significant ad- there was no evidence of recurrence of the heman- verse effects. gioma. Imiquimod—an imidazoquinoline amine—is an immune-response modifier that acts by affecting the COMMENT innate and acquired immune response to challenges. It has been shown to be useful in the treatment of genital We report here for the first time to our knowledge the warts,5 superficial basal cell carcinoma,6 squamous cell apparent efficacy of topical application of the immune- carcinoma in situ,7 actinic keratoses,8 and other response modifier imiquimod in the treatment of infan- lesions. Successful treatment of lentigo maligna has tile hemangioma. Infantile hemangioma is a distinct also been reported.9 These entities have responded, as category of benign vascular tumor characterized by pre- best understood, on the basis of enhanced immuno- sentation within the first few weeks of life and rapid logic reactions in the skin. The effect on innate immu- growth during the first year followed by a variable nity is achieved through successful production of a degree of spontaneous involution over a period of sev- large number of cytokines, including interferon (IFN) eral years.1 The true infantile hemangioma often first ␣, interleukin (IL) 6, and tumor necrosis factor alpha appears as a pale, blanched area of the skin, which (TNF-␣) among others. Natural killer cell activity is then reddens and progressively enlarges.2 Recent stud- increased, as is activation of macrophages resulting in ies have shown that infantile hemangiomas possess a production of nitric oxide. There is likewise stimula- distinct vascular phenotype shared by placental vessels tion of B-cell proliferation and maturation.10 Acquired

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Submissions gioma 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 Clinicians, local and regional societies, residents, and variety of mechanisms may reasonably be involved in fellows are invited to submit cases of challenges in imiquimod-induced regression of infantile hemangio- management and therapeutics to this section. Cases mas, and further clinical and experimental studies are should follow the established pattern. Submit 4 double- spaced copies of the manuscript with right margins warranted. nonjustified and 4 sets of the illustrations. Photomicro- In summary, we have successfully used topical graphs and illustrations must be clear and submitted as imiquimod to treat 2 patients with typical infantile positive color transparencies (35-mm slides) or black- hemangiomas of postnatal onset. These lesions in the and-white prints. Do not submit color prints unless proliferative phase completely resolved within 3 to 5 accompanied by original transparencies. Material months of therapy initiation. There was no evidence of should be accompanied by the required copyright recurrence at a median of 6 months following the last transfer statement, as noted in “Instructions for treatment. This remarkable response, albeit of a small Authors.” Material for this section should be submitted number of patients, with minimal adverse effects, to George J. Hruza, MD, Laser and Dermatologic Sur- warrants further clinical investigation. To this end, we gery Center Inc, 14377 Woodlake Dr, Suite 111, St Louis, MO 63017. Reprints are not available. have launched a larger clinical study with patholo- gic correlation and a mechanism-oriented investigation.

Accepted for publication March 17, 2002. immunity is enhanced through production of inter- A patent to protect the subject of this article has been leukins such as IL-1, IL-5, IL-8, IL-10, and IL-12 applied for. as well as granulocyte and macrophage stimulatory Corresponding author and reprints: Ignacio Sanchez- factor. The production of IL-12 results in an in- Carpintero, MD, PhD, Division of Dermatopathology, War- crease in cytotoxic T lymphocytes and the release of ren 827, Massachusetts General Hospital, Boston, MA 02114. IFN-␥.10 Interferon alfa, administered through systemic REFERENCES 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 1. Jacobs AH. Strawberry hemangiomas: the natural history of the untreated lesion. Calif Med. 1957;86:8-10. administration has been associated with the occurrence 2. Waner M, Suen JY. The natural history of hemangiomas. In: Waner M, Suen JY, of significant neurologic complications, especially spas- eds. Hemangiomas and Vascular Malformation of the Head and Neck. New York, tic dysplegia.12 Locally produced by imiquimod, IFN-␣ NY: Wiley-Liss; 1999:13-45. may clearly be 1 of the active agents responsible for the 3. North PE, Waner M, Mizeracki A, et al. A unique microvascular phenotype shared regression of the hemangiomas cited in this report. How- by juvenile hemangiomas and human placenta. Arch Dermatol. 2001;137:559- 570. ever, recent reports concerning the tumor-suppressive 4. Boon LM, Enjolras O, Mulliken JB. Congenital hemangiomas: evidence for ac- 13,14 and antiangiogenic effects of IL-12 suggest that this celerated involution. J Pediatr. 1996;128:329-335. cytokine may also be important in the response of hem- 5. Beutner KR, Spruance SL, Hougham AJ, Fox TL, Owens ML, Douglas JM Jr. Treat- angiomas to imiquimod. ment of genital warts with an immune response modifier (imiquimod). J Am Acad Dermatol. 1998;38:230-239. In nude mice and rats, topical application of 1% 6. Marks R, Gebauer K, Shumack S, et al. Imiquimod 5% cream in the treatment of and 5% cream has been shown to result in a local superficial basal cell carcinoma: results of a multicenter 6-week dose-response increase in IFN-␣ and TNF-␣.15 In a polyoma virus– trial. J Am Acad Dermatol. 2001;44: 807-813. induced hemangioendothelioma model, topical imi- 7. Hengee UR, Stark R. Topical imiquimod to treat intraepidermal carcinoma. Arch quimod has been shown to result in an increased num- Dermatol. 2001;137:709-711. 8. Stockfleth E, Meyer T, Benninghoff B, Christofers E. Successful treatment of ac- ber of intratumoral mast cells as well as elevated lev- tinic keratosis with imiquimod cream 5%: a report of six cases. Br J Dermatol. els of tissue inhibitor of metalloproteinase type 1 2001;144:1050-1053. (TIMP-1) and TNF-␣ with evidence of increased 9. Ahmed I, Berth-Jones J. Imiquimod: a novel treatment for lentigo maligna. apoptosis.16 Increased density of mast cells and Br J Dermatol. 2000;143:843-845. increased expression of TIMP-1 have also been re- 10. Sauder DN. Immunomodulatory and pharmacologic properties of imiquimod. J Am Acad Dermatol. 2000;43:S6-S11. ported in involutive-phase hemangiomas compared 11. Ezekowitz RAB, Mulliken JB, Folkman J. Interferon alpha-2a therapy for life- 17 with proliferative-phase lesions. Thus, imiquimod threatening hemangiomas of infancy [published correction appears in N Engl treatment may hypothetically be causing a recapitu- J Med. 1995;333:395]. N Engl J Med. 1992;326:1456-1463. lation of the natural involutive process of infantile 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: hemangiomas. 527-530. A variety of studies in rodents, monkeys, and 13. Coughlin CM, Salhany KE, Gee MS, et al. Tumor cell responses to IFN gamma humans using in vivo and in vitro techniques (includ- affect tumorigenicity and response to IL-12 therapy and antiangiogenesis. Im- ing splenic cultures of human lymphocytes treated munity. 1998;9:25-34. with imiquimod) have shown the production of other 14. Sunamura M, Sun L, Lozonschi L, et al. The antiangiogenesis effect of interleu- ␥ kin 12 during early growth of human pancreatic cancer in SCID mice. Pancreas. cytokines, including IL-2 and IFN- , as a result of 2000;20:227-233. 18 IL-12 production. Activation of natural killer cells by 15. Dahl MV. Imiquimod: an immune response modifier. J Am Acad Dermatol. 2000; IFN-␥ has the potential to cause destruction of heman- 43:S1-S5.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 16. Sidbury R, Puscasiu E, Miller R, et al. Topical imiquimod immunotherapy inhib- 18. Duda DG, Sunamura M, Lozonschi L, et al. Direct in vitro evidence and in vivo its tumor growth in a mouse model of infantile vascular tumors [abstract]. JIn- analysis of the antiangiogenesis effects of interleukin 12. Cancer Res. 2000;60: vest Dermatol. 2000;114:770. 1111-1116. 17. Takahashi K, Mulliken JB, Kozakewich HP, Rogers RA, Folkman J, Ezekowitz RA. 19. Imbertson LM, Beaurline JM, Couture AM, et al. Cytokine induction in hairless Cellular markers that distinguish the phases of hemangioma during infancy and mouse and rat skin after topical application of the immune response modifier childhood. J Clin Invest. 1994;93:2357-2364. imiquimod and S-28463. J Invest Dermatol. 1998;110:734-739.

Editorial Comment

emangiomas are the most common tumor affecting infants. Common complications include disfigurement, ulceration, and significant pain. Despite the prevalence of this tumor, its epidemiology is not well documented, its patho- H genesis is unclear, and a uniform approach to therapy has not been defined.1 Topical or systemic corticosteroids are often prescribed during the rapid-growth phase in the first year of life with the expectation of controlling tumor growth. Sixty percent of infantile hemangiomas respond to treatment with corticoids.2 Minimal to moderate shrinkage can occur, but brisk involution does not. Insidious adverse effects include irritability, hypertension, and a recent concern about neurodevelopmen- tal impairment.3 Clearly, there is a need for a safe, effective alternative treatment.The use of imiquimod cream for the treatment of infantile hemangiomas is intriguing, and the response observed by these authors impressed them enough to apply for a use patent. However, clinicians must be very cautious about indiscriminately recommending imiquimod cream for this off-label application. Imiquimod has been used anecdotally to treat molluscum, common warts, and condyloma in children without reports of significant adverse effects, but it has not been used extensively in infants, a group at highest risk of percutaneous toxic effects. In addition, the occurrence of erythema and crusting reported in these cases suggests a risk of inducing prolonged ulceration, a complication that has been described in infantile hemangiomas treated with pulsed-dye laser. Until more data are available on the safety and efficacy of this treatment, the optimal candidate for a trial of imiquimod cream is an otherwise healthy infant with 1 or more small, superficial, focal hemangiomas that do not involve high-risk sites (face, hands, feet, or diaper area). Infants should be carefully monitored for quantity of medication, ulceration, pain, and central nervous system adverse effects. Elaine Siegfried, MD St Louis, Mo 1. Drolet BA, Esterly NB, Frieden IJ. Hemangiomas in children. N Engl J Med. 1999;341:173-181. 2. Enjolras O, Riche MC, Merland JJ, Escanda JP. Management of alarming hemangiomas in infancy: a review of 25 cases. Pediatrics. 1990;85:491-498. 3. AAP Committee on Fetus and Newborn. Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants. Pediatrics. 2002;109:330-338.

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