Induction of Vitiligo-like Hypopigmentation with Use of Topical Imiquimod for Superficial and Nodular Basal Cell Carcinomas Roxanne Rajaii, DO,* Elizabeth Young, DO,** Sean Stephenson, DO,*** Michelle Legacy, DO,**** Lynn Sikorski, DO****

*Dermatology Resident, PGY3, Beaumont Hospital – Farmington Hills, Farmington Hills, MI **Traditional Rotating Intern, Capital Region Medical Center – Jefferson City, MO ***Dermatopathologist, Dermatopathology Laboratory of Central States – Troy, MI ****Dermatologist, Beaumont Hospital – Farmington Hills, Farmington Hills, MI

Disclosures: None Correspondence: Roxanne Rajaii, DO; [email protected]

Abstract This case report presents a 60-year-old Caucasian male who had been treated with imiquimod 5% cream for numerous superficial and nodular basal cell carcinomas, with treatments five times per week for six weeks, resulting in vitiligo-like hypopigmentation that eventually extended beyond the borders of the treatment area. Imiquimod is an immune-response modulator currently FDA-approved for the treatment of external anogenital warts, actinic keratoses, and superficial basal cell carcinomas. Hypopigmentation is a rare side effect of topical imiquimod use, but it has been noted in previous literature of imiquimod treatment for both condylomata acuminata and superficial and nodular basal cell carcinomas. Previous studies report this phenomenon being attributed to the drug’s Th1-stimulating activity. With this striking patient presentation, we aim to demonstrate the importance of discussing this rare side effect with any patient who is to be treated with imiquimod, particularly in cases involving younger patients or lesions in cosmetically sensitive areas.

Introduction that after a full course of therapy, the macules began to depigmentation. On histopathological examination, Topical imiquimod 5% is an immune-response- coalesce and enlarge to form patches several times the both areas showed evidence of mild post-inflammatory modifying cream that induces cellular immune responses size of the initial lesion and beyond the area of cream hypopigmentation (Figures 4a-d) with some retained like local release of pro-inflammatory cytokines and application. The most striking areas of involvement stimulation of antigen-presenting cells. These effects included the arms and chest (Figures 1-3). 2x make it a treatment modality for condyloma acuminata, The patient denied any other significant irritation and actinic keratosis, and basal cell carcinoma, particularly side effects with topical application of imiquimod but the superficial subtype. The side-effect profile of topical did recall having feelings “similar to having the flu” imiquimod is well known, and the more common during each treatment course. He denied use of any potential adverse reactions of erythema, xeroderma, other topical treatments, including over-the-counter crusting, and irritation are regularly discussed. One therapies, to the areas being treated with imiquimod. of the least common side effects, dyspigmentation, In this patient, despite discontinuation of imiquimod particularly hypopigmentation, is dramatic when and over several years of follow-up, repigmentation in it occurs but seldom encountered, so it is often not these areas was not observed. Furthermore, the patient discussed with patients prior to treatment. Our case experienced the same side effect with each application 4x discusses a patient who experienced hypopigmentation of imiquimod. Although topical therapies to help with not only at the treatment site but also beyond the well- repigmentation of these lesions were offered to the circumscribed treatment area. patient, he refused treatment for the hypopigmented Case Report areas and denied being bothered by their appearance. This case presents a 60-year-old Caucasian male at our The patient’s medical history included osteoarthritis clinic with a significant history of numerous, biopsy- and hyperlipidemia. He denied any personal or family proven, superficial and nodular basal cell carcinomas history of autoimmune disorders and depigmenting dated from August 2010 to present. They were located diseases such as vitiligo, thyroid disease, Addison’s on his arms, chest, and back and were treated with disease, and alopecia areata. The patient also denied any 10x topical imiquimod 5% cream five times per week for personal or family history of diabetes with the exception a total treatment course of six weeks to each lesion. On of his father, who suffered from diabetes mellitus type examination, the patient had multiple hypopigmented II. The patient’s surgical history was significant for macules coalescing into large hypopigmented patches bilateral knee surgery. The patient denied any tobacco involving and extending locally far beyond the use. His medications included simvastatin. treatment site. The patient reported that approximately two weeks following every six-week treatment course, Two punch biopsies were taken from affected he observed hypopigmented macules developing at the areas on the left anterior shoulder and left anterior site of application. He stated that these hypopigmented proximal upper arm, respectively, in order to macules were initially the size of the initial lesion but distinguish between hypopigmentation and true Figure 1 Figure 2 Figure 3 20x

Figures 4a-d. (H&E, 2x-20x) Biopsy of a Figures 1-3. Patient with multiple hypopigmented macules coalescing into large hypopigmented hypopigmented patch showing retained patches at the site of topical imiquimod therapy. melanocytes at the dermoepidermal junction.

RAJAII, YOUNG, STEPHENSON, LEGACY, SIKORSKI melanocytes at the dermoepidermal junction. 10x References MITF-1 showed positively staining melanocytes at the 1. Mashiah J, Brenner S. Possible mechanisms in dermoepidermal junction (Figures 5a-b). A periodic the induction of vitiligo‐like hypopigmentation acid-Schiff stain showed no fungi. by topical imiquimod. Clin Exp Dermatol. Discussion 2008;33(1):74-6. Vitiligo-like hypopigmentation is a rare side effect 2. Dahl M. Imiquimod: A cytokine inducer. J Am of topical imiquimod application. Of the few cases Acad Dermatol. 2002;47(4):205-8. that have been reported, the majority occurred following treatment of condyloma acuminate, 3. Kim C, Ahn J, Kang S, Hwang H, Lee M, and a small subset followed treatment of basal 5-7,11 20x Pyun J, Kang H. Imiquimod induces apoptosis cell carcinomas. The exact mechanism of the of human melanocytes. Arch Dermatol Res. hypopigmentation, often with concurrent poliosis, 2009;302(4):301-6. has been debated, and several theories are currently in favor. 4. Serra M, Menicanti C, Pennacchioli E, Tosti G. Vulvar vitiligo-like depigmentation and multiple Imiquimod’s stimulation of toll-like receptor 7 halos of hypomelanosis at the trunk following with up-regulation of nuclear factor-kappaB and treatment with imiquimod 5% cream for vulvar subsequent induction of multiple pro-inflammatory condylomata: casual or related events? An Bras cytokines, along with stimulation of antigen- Dermatol. 2014;89(5):806-7. presenting cells and other cellular immune-response Figures 5a-b. (10x-20x) Positive mediators, is responsible for the treatment’s efficacy. MITF-1 staining of melanocytes at the 5. Jacob S, Blyumin M. Vitiligo-like The T-helper-1 subset population of lymphocytes dermoepidermal junction. Hypopigmentation with Poliosis following induces further proliferation of T-helper cells and undergoing treatment with imiquimod. Treatment of Superficial Basal Cell cytotoxic T-cells. Pro-inflammatory cytokines Carcinoma with Imiquimod. Dermatol Surg. such as tumor necrosis factor (TNF)-α, interferon 2008;34(6):844-5. (IFN)-α, interleukin (IL)-6, IL-8, IL-10, Conclusion In conclusion, vitiligo-like hypopigmentation and IL-12 are produced. IL-12 stimulates the following topical imiquimod use is a rare side 6. Sriprakash K, Godbolt A. Vitiligo-like existing T-helper-cell subset to produce more effect and one uncommonly discussed with patients depigmentation induced by imiquimod treatment IFN-α and IL-2, further ensuring a cascade before treatment. Even less likely is extension of of superficial basal cell carcinoma. Australas J of pro-inflammatory cytokines and activated Dermatol. 2009;50(3):211-3. 1,2 the hypopigmentation beyond the confines of T-lymphocytes. IFN-α, IL-6, IL-8, and IL-10 the treatment area. Considering the striking and are known mediators in the pathogenesis of vitiligo, 7. Grahovac M, Ehmann LM, Flaig M, often persistent course of the hypopigmentation, and it is logical to believe imiquimod could induce Reibke R, Wollenberg A. Giant Basal Cell 1,2,5 we recommend more practitioners have detailed similar pigmentary changes. Carcinoma. Improvement and Vitiligo-Like discussions of imiquimod’s extensive side-effect Hypopigmentation after Intermittent Treatment profile with patients before recommending its use, With this robust increase of the T-lymphocyte with 5% Imiquimod. Acta Dermatovenerol Croat. particularly in patients concerned with cosmesis. population, a small subset of autoreactive cytotoxic 2012;20(4):272-83. T-cells against melanocytes can be observed. The autoreactive T-cells’ destruction of the local 8. Schöfer H, Van Ophoven A, Henke U, Lenz melanocyte population is believed to cause of some T, Eul A. Randomized, comparative trial on cases of vitiligo-like hypopigmentation following the sustained efficacy of topical imiquimod 5% imiquimod use. This mechanism would also explain cream versus conventional ablative methods the extension of pigmentary change beyond our in external anogenital warts. Eur J Dermatol. patient’s treatment area, as well as reports of halo 2006;16(6):642-8. phenomena occurring around pre-existing nevi with imiquimod treatment of distant sites.1,4,8 9. Stefanaki C, Nicolaidou E, Hadjivassiliou M, Melanocytes have also been shown to activate toll- Antoniou C, Katsambas A. Imiquimod-induced like receptor 7, the target of imiquimod, which vitiligo in a patient with genital warts. J Eur Acad could further explain the apoptosis and depletion of Dermatol Venereol. 2006;20(6):755-6. the local melanocyte population.11,13 10. Long F, Zhao L, Qian Y. Vitiligo or Vitiligo-like Permanent reduction in the local melanocyte Hypopigmentation Associated with Imiquimod population may explain the persistent nature of Treatment of Condyloma Acuminatum: Not a the pigmentary change.1,3,4,9 In a study of patients Casual Event. Chin Med J. 2017;130(4):503. with vitiligo-like hypopigmentation following imiquimod treatment, all but one case was found 11. Wang HW, Miao F, Shi L, Lü T, Huang Z, to be permanent. Stefanaki et al. observed a case Wang XL. Imiquimod-induced localized vitiligo of 2% repigmentation in a patient with vitiligo-like in wife and lichen planus in husband. Chin Med J. hypopigmentation following imiquimod treatment 2013;126(13):2593. for condyloma.9 One proposed non-immunological mechanism of depigmentation following 12. Li W, Xin H, Ge L, Song H, Cao W. imiquimod use is the benzyl alcohol found in the Induction of vitiligo after imiquimod treatment cream vehicle inducing a contact leukoderma.12 of condylomata acuminata. BMC Infect Dis. 2014;14(1):329. Hypopigmentation is an exceedingly uncommon side effect, and the extension beyond the circumscribed 13. Taylor JS, Maibach HI, Fisher AA, Bergfeld treatment area is even rarer; we believe this supports WF. Contact leukoderma associated with the use of an immunologic mechanism for pigmentary change hair colors. Cutis. 1993;52(5):273-80. following imiquimod use.4-7,9,12 There are no case reports of repigmentation in areas of basal cell 14. Kang H, Park T, Jin S. Imiquimod, a Toll-Like carcinomas treated with imiquimod complicated Receptor 7 Agonist, Inhibits Melanogenesis and by vitiligo-like hypopigmentation. This further Proliferation of Human Melanocytes. J Invest necessitates a thorough prescribing discussion so Dermatol. 2009;129(1):243-6. a patient can make an informed decision before

INDUCTION OF VITILIGO-LIKE HYPOPIGMENTATION WITH USE OF TOPICAL IMIQUIMOD FOR SUPERFICIAL AND NODULAR BASAL CELL CARCINOMAS Acknowledgment Author contributions: Drs. Rajaii and Young had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Drs. Rajaii, Young, Legacy, and Sikorski

Acquisition, analysis, and interpretation of data: Drs. Rajaii, Stephenson, Legacy, and Sikorksi

Drafting of the manuscript: Drs. Rajaii, Young, Stephenson, Legacy, and Sikorksi

Critical revision of the manuscript for important intellectual content: Drs. Rajaii, Young, Stephenson, Legacy, Sikorksi, and Lacasse

Abbreviations and acronyms IL: Interleukin INF: Interferon TNF: Tumor necrosis factor

RAJAII, YOUNG, STEPHENSON, LEGACY, SIKORSKI