Actas Dermo-Sifiliográficas (English Edition) Actas Dermo-Sifiliográficas (English Edition)
Actas Dermosifiliogr 2017;108:378-80 - Vol. 108 Num.4 DOI: 10.1016/j.adengl.2017.03.011
Case and Research Letter
Genital Vitiligo-like Hypopigmentation After Treatment With 5% Imiquimod
Hipopigmentación genital similar a vitíligo tras tratamiento con imiquimod 5%
P. García-Montero, , J.B. Repiso Jiménez, M.T. Fernández Morano, M. de Troya Martín
Departamento de Dermatología, Hospital Costa del Sol, Marbella, Málaga, Spain
To the Editor:

Imiquimod cream is a topical imidazoquinoline amine widely used in dermatology. It has antitumor, antiviral, and immunomodulatory properties that modify biologic response.1 It was first approved in 1997 for the treatment of genital warts and later received authorization for use in superficial basal cell carcinoma and actinic keratosis. Treatment regimens vary according to the disease. The summary of product characteristics for imiquimod mentions the possibility of “mild or moderate hypopigmentation” following its use2 but total loss of pigmentation, which is particularly relevant in the genital region, is not mentioned as a possible adverse effect.

Case Descriptions

A 45-year-old man with Fitzpatrick skin type iv and no relevant personal medical history presented with genital warts of 1 year duration. After screening for other sexually transmitted infections (STIs), the affected area was treated with cryotherapy. Two months later, the patient was administered another cycle of cryotherapy as the lesions had not cleared. He was also informed about the possibility of treatment with 5% imiquimod 3 times a week on alternate days if the warts did not improve. The lesions persisted and the patient was treated with 5% imiquimod for 16 weeks. At the next follow-up visit, the warts were found to have cleared completely, but there were several achromic macules on the shaft of the penis and foreskin that were more evident when viewed under Wood's light (Fig. 1). The rest of the physical examination was unremarkable. A blood workup including thyroid hormones, antithyroid antibodies, and antinuclear antibodies showed results within normal ranges. The lesions have remained stable without treatment over 4 years of follow-up and there has been no loss of pigmentation in any other areas.

Figure 1.

A, Achromic macules on the shaft of the penis and foreskin. B, More evident loss of pigmentation under Wood's light.

A 41-year-old woman with Fitzpatrick skin type iv and no relevant personal history presented with vulvar and perineal warts that had been present for 1 month. The patient was tested for other STIs and given a cervical smear and prescribed 5% imiquimod 3 times a week (on alternate days). At the next follow-up visit, after 16 weeks of treatment with imiquimod, the warts had disappeared completely. The genital examination revealed the presence of milky white symmetric stains, which were more pronounced under Wood's light, along the labia majora and perineum (Fig. 2). The rest of the physical examination was unremarkable. A blood workup including thyroid hormones, antithyroid antibodies, and antinuclear antibodies showed no alterations. The lesions have remained stable without treatment for 4 months and there has been no pigment loss in any other areas.

Figure 2.

A, Symmetric milky-white macules along the labia majora and perineum. B, The lesions appear more intense under Wood's light.

We have described 2 cases of vitiligo-like pigmentation secondary to the use of 5% imiquimod. When asked, both patients indicated that this loss of pigmentation would interfere with their sexual relations. We proposed performing a histologic examination but the patients refused.

Discussion

Fourteen cases of vitiligo-like hypopigmentation in the genital area have been described following the use of 5% imiquimod2–6 (Table 1). The cream was used to treat genital warts in 11 cases and extramammary Paget disease in three.3 Treatment duration ranged between 3 and 18 weeks. Histologic examination was performed in 4 cases and showed similar findings to those seen in vitiligo.3,4 One of the patients developed multiple concomitant halo nevi on the trunk.5 Tacrolimus 0.1% ointment resulted in a slight improvement in 2 patients,4,6 but repigmentation did not occur in the vast majority of cases over a maximum follow-up period of 18 months. Pronounced hypopigmentation in the genital area has not been described in association with other techniques, such as cryotherapy, curettage, or carbon dioxide laser therapy, but there have been reports of vitiligo-like extragenital lesions in basal cell carcinomas treated with 5% imiquimod.

Table 1.

Summary of Cases of Vitiligo-Like Hypopigmentation Secondary to 5% Imiquimod.

Authors  Age, y/Sex  Fitzpatrick Skin Type  Indication  Distant Involvement  Personal History  Family History  Regimen  Clinical Outcome  Histology 
Brown et al., 20052  25, M  NR  GW  No  NR  NR  3 times/wk  NC  No 
Stefanaki et al., 2006  32, M  NR  GW  No  NCR  Father with vitiligo and diabetes mellitus  Alternate days, 3 mo  Minimum repigmentation without treatment  No 
Al Dujaili et al., 2007  21, M  NR  GW  No  NR  NR  3 times/wk, 4 mo  NR  No 
Senel et al., 2007  32, M  NR  GW  No  NCR  NCR  Alternate days, 2 mo  NC  No 
Serrao et al., 2008  26, M  NR  GW  No  NCR  NR  3 times/wk, 16 wk  NC  No 
Zhang et al., 2011  25, M  NR  GW  No  NCR  NCR  3 times/wk, 18 wk  NR  No 
Zhang et al., 2011  22, M  NR  GW  No  NCR  NCR  Alternate days, 12 mo  NR  No 
Kwon et al., 20123  NR, M  NR  EMPD  No  NCR  NR  Alternate days, 3 mo  NR  Yes 
Kwon et al., 20123  NR, M  NR  EMPD  No  NCR  NR  Alternate days, 3 mo  NR  Yes 
Kwon et al., 20123  NR, M  NR  EMPD  No  NCR  NR  Alternate days, 3 mo  NR  Yes 
Wang et al., 20136  36, F  NR  GW  No  NCR  NCR  Alternate days, 6 mo  Repigmentation with tacrolimus 0.1%  No 
Li et al., 20144  28, M  NR  GW  No  NCR  NCR  3 times/wk, 12 wk  Minimal improvement with tacrolimus 0.1%  Yes 
Serra et al., 20145  25, F  NR  GW  4 halo nevi on the trunk  NCR  NCR  3 times/wk, 12 wk  NC  No 
Maatouk et al., 2016  26, M  NR  GW  No  NCR  NCR  Once a wk, 3 wk  NC  No 
García-Montero et al.  45, M  IV Fitzpatrick  GW  No  NCR  NCR  3 times/wk, 16 wk  NC  No 
García-Montero et al.  41, F  IV Fitzpatrick  GW  No  NCR  NCR  3 times/wk, 16 wk  NC  No 

Abbreviations: EMPD, extramammary Paget disease; F, female; GW, genital warts; M, male; NC, no change; NCR, not clinically relevant; NR, not reported.

Several theories have been proposed to explain imiquimod-induced vitiligo-like hypopigmentation. First, imiquimod might directly induce apoptosis of melanocytes7; second, it might stimulate toll-like receptor 7, triggering the release of diverse cytokines, which would activate T cells, causing the destruction of melanocytes8; and finally pigment loss could be due to the Koebner phenomenon in predisposed patients.9 Regardless of the mechanism of this adverse effect, hypopigmentation in the genital area can have considerable emotional and sexual repercussions. Several studies have shown that vitiligo has an impact on a person's sex life, and genital involvement has been statistically associated with worsening of sexual relations.10

It is therefore essential to inform patients of the risk of hypopigmentation with 5% imiquimod and to stop treatment when pigment loss begins. Although vitiligo-like hypopigmentation is very rare in this setting, it would seem wise to identify at-risk patients (i.e., patients with dark skin, a personal or family history of vitiligo, halo nevi or postinflammatory hypopigmentation) in order to prevent its occurrence.

References
1
R.B. Skinner
Imiquimod
Dermatol Clin, 21 (2003), pp. 291-300
2
T. Brown,M. Zirvi,G. Cotsarelis,J.M. Gelfand
Vitiligo-like hypopigmentation associated with imiquimod treatment of genital warts
J Am Acad Dermatol, 52 (2005), pp. 715-716 http://dx.doi.org/10.1016/j.jaad.2004.10.861
3
H.H. Kwon,K.H. Cho
Induction of vitiligo-like hypopigmentation after imiquimod treatment of extramammary Paget's disease
Ann Dermatol, 24 (2012), pp. 482-484 http://dx.doi.org/10.5021/ad.2012.24.4.482
4
W. Li,H. Xin,L. Ge,H. Song,W. Cao
Induction of vitiligo after imiquimod treatment of condylomata acuminata
BMC Infect Dis, 14 (2014), pp. 329 http://dx.doi.org/10.1186/1471-2334-14-329
5
M.C. Serra,C. Menicanti,E. Pennacchioli,G. Tosti
Vulvar vitiligo-like depigmentation and multiple halos of hypomelanosis at the trunk following treatment with imiquimod 5% cream for vulvar condylomata: Casual or related events
An Bras Dermatol, 89 (2014), pp. 806-807
6
H.W. Wang,F. Miao,L. Shi,T. Lü,Z. Huang,X.L. Wang
Imiquimod-induced localized vitiligo in wife and lichen planus in husband
Chin Med J (Engl), 126 (2013), pp. 2593
7
C.H. Kim,J.H. Ahn,S.U. Kang,H.S. Hwang,M.H. Lee,J.H. Pyun
Imiquimod induces apoptosis of human melanocytes
Arch Dermatol Res, 302 (2010), pp. 301-306 http://dx.doi.org/10.1007/s00403-009-1012-0
8
J. Mashiah,S. Brenner
Possible mechanisms in the induction of vitiligo-like hypopigmentation by topical imiquimod
Clin Exp Dermatol, 33 (2008), pp. 74-76 http://dx.doi.org/10.1111/j.1365-2230.2007.02520.x
9
C.T. Burnett,D.J. Kouba
Imiquimod-induced depigmentation: Report of two cases and review of the literature
Dermatol Surg, 38 (2012), pp. 1872-1875 http://dx.doi.org/10.1111/j.1524-4725.2012.02512.x
10
J.I. Silverberg,N.B. Silverberg
Association between vitiligo extent and distribution and quality-of-life impairment
JAMA Dermatol, 149 (2013), pp. 159-164 http://dx.doi.org/10.1001/jamadermatol.2013.927

Please cite this article as: García-Montero P, Jiménez JBR, Morano MTF, Martín MdT. Hipopigmentación genital similar a vitíligo tras tratamiento con imiquimod 5%. Actas Dermosifiliogr. 2017;108:378–380.

Corresponding author.
Copyright © 2016. Elsevier España, S.L.U. and AEDV
Actas Dermosifiliogr 2017;108:378-80 - Vol. 108 Num.4 DOI: 10.1016/j.adengl.2017.03.011