Induction of Vitiligo-Like Hypopigmentation after Imiquimod Treatment of Extramammary Paget's Disease

Abstract

Dear Editor: Imiquimod 5% cream, an immune response modifier, is licensed for the treatment of extramammary Paget's disea se (EMPD). Although pigmentary changes associated with imiquimod treatment have been listed as possible side effects on the package insert, the reports are rare and sometimes inconsistent in the dermatology literature. Some studies described vitiligo-like hypopigmentation, while other studies reported hyperpigmentation after imiquimod use1. In our skin cancer clinic, we frequently applied imiquimod 5% cream every other night for 6~8 hours in EMPD patients who are poor surgical candidates or susceptible to local recurrence after surgery. After reviewing the clinical course of three male patients with EMPD, we found that whole skin lesions around scrotum applied with imiquimod were completely depigmented after 3 months in all cases (Fig. 1). The depigmentation did not extend beyond treatment area and affect other vitiligo-prone areas at all. Despite discontinuation of imiquimod, the hypopigmentation did not improve at all after at least 13 months follow-up in all cases. Imiquimod was the only product used and our patients did not have a history of vitiligo at all. Wood light examination shows an accentuation of the pigment loss, and H&E and Fontana Masson reveal decreased pigmentation in the basal layer of epidermis (Fig. 2). The average number of melanocytes in the basal layer counted by 3,4-dihydroxyphenylalanine staining and immunohistochemistry method using HMB-45 antibody was also significantly decreased (Fig. 3). Interestingly, two of our patients had experienced irritiation several times after cryotherapy and podophylline application before imiquimod treatment without inducing any depigmentation, respectively. This supports the likelihood that imiquimod may have caused the vitiligo-like hypopigmentation by a mechanism other than simple irritation. Several possible mechanisms could explain this hypopigmentation. Imiquimod binds to the Toll-like receptors (TLR) 7 and 8 which are cell-surface receptors recognizing ligands associated with pathogenic organisms. TLR-7 activates the T-helper (Th) 1 response and increases the production of pro-inflammatory cytokines mainly interferon-α, tumor necrosis factor-α and interleukin (IL)-12, all of which play a role in the pathogenesis of vitiligo2. The stimulation of the Th1 pathway also results in a predominantly perilesional CD4+ T cell infiltrate and many CD8+ T cells. The CD4+ cells are stimulated by IL-12 to produce IFN-α and IL-2. In addition, imiquimod promotes secretion of IL-6, IL-8, and IL-10, which are pro-inflammatory and pro-apoptosis cytokines that can also cause vitiligo3,4. A previous case report stated that a trial with macrolide immunomodulators could benefit patients, although lacking sufficient evidence5. Expanded use of imiquimod may increase localized depigmentation as observed in our case. Since patients could be emotionally sensitive to the depigmentation of pubic areas, we believe that dermatologists should be aware of this annoying side effect, particularly when using imiquimod on EMPD. Fig. 1 (A) Extramammary Paget's disease lesions around pubic area. (B) Relatively well defined whitish depigmented patches on the imiquimod application sites after 3 months. Fig. 2 The basal layer of epidermis shows no pigmentation (A) at a low magnification view (H&E stain, ×100), and (B) a high magnification view (×400). The basal layer of epidermis shows negative reaction for (C) Fontana-Masson staining ... Fig. 3 Melanocytes in the basal layer of epidermis stained by immunohistochemistry methods using (A) HMB-45 (×400) antibody, and (B) 3,4-dihydroxyphenylalanine staining (×400) were rarely observed in the depigmented lesions.