Induction of vitiligo after imiquimod treatment of condylomata acuminata
© Li et al.; licensee BioMed Central Ltd. 2014
Received: 12 March 2014
Accepted: 6 June 2014
Published: 13 June 2014
Condylomata acuminata (genital warts) is the most common sexually transmitted disease, and imiquimod is the sole FDA-approved medication for combating this condition. Vitiligo associated with imiquimod treatment of condylomata acuminata is rare.
A 28-year-old male with condylomata acuminata of the penis presented to our clinic. After removing his condylomata acuminata, we advised him to use imiquimod 5% cream to prevent relapse. When he presented to our clinic again about 12 weeks later, he complained of vitiligo patches on his penis and scrotum. Physical examination showed vitiligo patches involving the glans penis, shaft of the penis, and scrotum, and remaining pigmented areas within the plaques of vitiligo.
A skin biopsy of the dorsal surface of the penis showed a complete absence of melanocytes and melanin granules in the basal layer; the dermis was normal.
This is the first report of a case of imiquimod-induced vitiligo diagnosed by histopathological examination. This adverse effect should be considered when dermatologists prescribe this medication.
KeywordsCondylomata acuminata Imiquimod Vitiligo
Comparison of published cases of imquimod-induced vitiligo or vitiligo-like depigmentation in English literature
Age (year)/ gender
Family genetic history
Brown et al. 2005 
Multiple depigmented patches on the scrotum ranging from 3 mm to 2 cm
Stefanaki et al. 2006 
Dorsal surface of penis, scrotum, and pubic area
Vitiligo, slight repigmentation
Senel et al. 2007 
Glans penis, shaft of penis, and scrotum
Al-Dujaili et al. 2007 
Penile shaft and scrotum
Serrão et al. 2008 
Shaft of penis
Zhang et al. 2011 
Coronoid sulcus and corpus penis
Ivory-white patch nearly 4 × 2 cm
Zhang et al. 2011 
Depigmented patches with irregular pigmented edges
Wang et al. 2013 
Perineum and perianal
Depigmentation patches with clear demarcation lines
Here, we present an unusual case of imiquimod-induced vitiligo in a 28-year-old male, whose diagnosis was made using clinical and histopathological methods.
Imiquimod is an immune response modifier with the chemical structure 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amin. Since imiquimod was authorized on the US market in 1997 and on the Chinese market in 2003, it has been approved as a patient-applied topical treatment for condylomata acuminata in adults. We find it is a well-tolerated drug but with the frequent side effects of erythema, burning, blistering, and excoriation. We also noted its other adverse effect of inducing localized vitiligo, which occurred in the treated areas.
Vitiligo is a condition characterized by depigmentation of the skin and mucous membranes, with well-demarcated, depigmented macules and patches. The etiology of vitiligo is unknown, but research suggests that it may involve autoimmune, genetic, and other factors. Autoimmune disorders are often associated with thyroid abnormalities, pernicious anemia, systemic lupus erythematosus, and other diseases. Our patient denied any family history of vitiligo or autoimmune disorder, the possibility of which was excluded by laboratory analysis. He denied use of any other topical treatments in the areas treated with imiquimod 5% cream. The features of his depigmented patches and histopathology support the diagnosis of vitiligo. Therefore, we believe that the vitiligo patches of our patient were induced by the imiquimod. We were able to obtain a small amount of superficial skin from the dorsal surface of the genital lesions in the perineal region. All eight of the patients reported in the English literature refused biopsies of the depigmented areas, and one even refused to have the lesions photographed. Therefore, our patient is the first to undergo histopathological examination and whose diagnosis was based on clinical and histopathological findings.
The possible mechanism for the destruction of the human papilloma virus (HPV) by imiquimod is that it stimulates peripheral blood monocytes, macrophages, and dendritic cells to produce such cytokines as interferon alfa (IFN-α), interleukin-12 (IL-12), and tumor necrosis factor alfa (TNF-α), so imiquimod can enhance the host’s innate and cellular immune response and combat anogenital HPV infection [12, 13]. To study the safety and effectiveness of imiquimod 5% cream in the treatment of external anogenital warts, Edwards et al. applied it on 109 patients; 50% of the patients experienced eradication of all treated baseline warts . Other studies also indicated that imiquimod 5% cream was effective in treating condylomata acuminata. However, imiquimod not only kills the HPV but also destroys melanocytes. Similarly, the mechanism of imiquimod-induced vitiligo may be that the medication activates the Langerhans cells in the lesions via antigen presentation, leading to the destruction and apoptosis of the melanocytes. Imiquimod-induced apoptosis of melanocytes was confirmed by TUNEL assay, Hoechst 33258 staining, and measuring mitochondrial membrane potential in melanocytes . Moreover, imiquimod can induce cytokines such as IFN-α, TNF-α, IL-6, IL-8, and nitric oxide to cause vitiligo . Additionally, imiquimod binds to Toll-like receptor-7 and −8, increasing production of proinflammatory cytokines such as IFN-α, TNF-α, and LI-12 [17, 18], which play a role in the pathogenesis of vitiligo.
Accompanying the use of imiquimod on increasing numbers of patients with condylomata acuminata, dermatologists should keep this potential side effect in mind.
Imiquimod 5% cream, as an immune response modifier and a safe drug, is used to treat condylomata acuminata, basal cell carcinoma, Bowen’s disease, common and plantar warts, molluscum contagiosum, and other disorders. However, mild-to-moderate, local and systemic, adverse effects of imiquimod may occasionally occur. Among its adverse effects, imiquimod-induced vitiligo should be anticipated when dermatologists prescribe this drug.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal. This study was proved by Institutional Review Board of Qianfoshan Hospital, Shandong University.
We would like to thank Dr.Qing Sun, Dr.Ping Zhou, Dr.Wei Lu in qianfoshan hospital, Shandong university for helping in histological analysis. We also thank Dr. Xianmei Lu in Shandong provincial skin Hospital, Shandong University. This study was supported by the grant from Natural Science Foundation of Shandong (No. Y2008C160).
- Castle PE, Gage JC, Partridge EE, Rausa A, Gravitt PE, Scarinci IC: Human papillomavirus genotypes detected in clinician-collected and self-collected specimens from women living in the Mississippi Delta. BMC Infect Dis. 2013, 13: 5-10.1186/1471-2334-13-5.View ArticlePubMedPubMed CentralGoogle Scholar
- Shi H, Zhang X, Ma C, Yu N, Wang J, Xia L, Ge X, Liu M, Duan A: Clinical analysis of five methods used to treat condylomata acuminata. Dermatology. 2013, 227: 338-345. 10.1159/000355351.View ArticlePubMedGoogle Scholar
- Chen FP: Efficacy of imiquimod 5% cream for persistent human papillomavirus in genital intraepithelial neoplasm. Taiwan J Obstet Gynecol. 2013, 52: 475-478. 10.1016/j.tjog.2013.10.004.View ArticlePubMedGoogle Scholar
- Rosenblatt A, de Campos Guidi HG: Local and systemic adverse effects of imiquimod therapy for external ano condyloma acuminatum in men: report of three cases. Int J STD AIDS. 2012, 23: 909-910. 10.1258/ijsa.2012.012076.View ArticlePubMedGoogle Scholar
- Brown T, Zirvi M, Cotsarelis G, Gelfand JM: Vitiligo-like hypopigmentation associated with imiquimod treatment of condyloma acuminatum. J Am Acad Dermatol. 2005, 52: 715-716. 10.1016/j.jaad.2004.10.861.View ArticlePubMedGoogle Scholar
- Stefanaki C, Nicolaidou E, Hadjivassiliou M, Antoniou C, Katsambas A: Imiquimod-induced vitiligo in a patient with condyloma acuminatum. J Eur Acad Dermatol Venereol. 2006, 20: 755-756. 10.1111/j.1468-3083.2006.01533.x.View ArticlePubMedGoogle Scholar
- Al-Dujaili Z, Hsu S: Imiquimod-induced vitiligo. Dermatol Online J. 2007, 13: 10-PubMedGoogle Scholar
- Senel E, Seckin D: Imiquimod-induced vitiligo-like depigmentation. Indian J Dermatol Venereol Leprol. 2007, 73: 423-View ArticlePubMedGoogle Scholar
- Serrão VV, Páris FR, Feio AB: Genital vitiligo-like depigmentation following use of imiquimod 5% cream. Eur J Dermatol. 2008, 18: 342-343.PubMedGoogle Scholar
- Zhang R, Zhu W: Genital vitiligo following use of imiquimod 5% cream. Indian J Dermatol. 2011, 56: 335-336. 10.4103/0019-5154.82501.View ArticlePubMedPubMed CentralGoogle Scholar
- Wang HW, Miao F, Shi L, Lü T, Huang Z, Wang XL: Imiquimod-induced localized vitiligo in wife and lichen planus in husband. Chin Med J (Engl). 2013, 126: 2593-Google Scholar
- Schöfer H, Van Ophoven A, Henke U, Lenz T, Eul A: Randomized, comparative trial on the sustained efficacy of topical imiquimod 5% cream versus conventional ablative methods in external ano condyloma acuminatum. Eur J Dermatol. 2006, 16: 642-648.PubMedGoogle Scholar
- Skinner RB: Imiquimod. Dermatol Clin. 2003, 21: 291-300. 10.1016/S0733-8635(02)00094-3. ReviewView ArticlePubMedGoogle Scholar
- Edwards L, Ferenczy A, Eron L, Baker D, Owens ML, Fox TL, Hougham AJ, Schmitt KA: Self-administered topical 5% imiquimod cream for external anogenital warts: HPV Study Group. Human PapillomaVirus. Arch Dermatol. 1998, 134: 25-30. 10.1001/archderm.134.1.25.View ArticlePubMedGoogle Scholar
- Kim CH, Ahn JH, Kang SU, Hwang HS, Lee MH, Pyun JH, Kang HY: Imiquimod induces apoptosis of human melanocytes. Arch Dermatol Res. 2010, 302 (4): 301-306. 10.1007/s00403-009-1012-0. doi:10.1007/s00403-009-1012-0. Epub 2009 Dec 23View ArticlePubMedGoogle Scholar
- Ueyama A, Yamamoto M, Tsujii K, Furue Y, Imura C, Shichijo M, Yasui K: Mechanism of pathogenesis of imiquimod-induced skin inflammation in the mouse: a role for interferon-alpha in dendritic cell activation by imiquimod. J Dermatol. 2014, 41: 135-143. 10.1111/1346-8138.12367.View ArticlePubMedGoogle Scholar
- Schön MP, Schön M: Imiquimod: mode of action. Br J Dermatol. 2007, 157 (Suppl 2): 8-13.View ArticlePubMedGoogle Scholar
- Lacarrubba F, Nasca MR, Micali G: Advances in the use of topical imiquimod to treat dermatologic disorders. Ther Clin Risk Manag. 2008, 4: 87-97.PubMedPubMed CentralGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/14/329/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.