Foot rings in a 10-year-old girl

Annular eruption on the patient's right great toe after 6 weeks of wart treatment.

THE CASE

You are asked to evaluate a 10-year-old girl for peculiar annular eruptions on her hands and feet following treatment for warts 6 weeks ago. What could be causing these eruptions?

DIAGNOSIS:

Ring warts secondary to treatment with cantharidin

CLINICAL FEATURES

Warts are common viral infections of the skin caused by human papillomavirus (HPV). There are over 100 types of HPV, and the type and anatomic site determine morphology.¹ Common warts (associated with HPV 1, 4, 27, 57)² typically present as rough hyperkeratotic papules with an irregular border.³ They most often occur on the dorsal part of the hand or palm, but can appear on any part of the body.⁴ Flat warts (associated with HPV 3 and 10)² are flat or slightly elevated flesh-colored lesions that are typically between 2 mm and 5 mm, and may be found in groups of anywhere from a few to dozens or more. They often present on the hands, knees, and shins. Plantar warts (associated with HPV 1)⁵ occur on the plantar aspect of the foot, and can present with multiple lesions that, if contiguous, can form a thick keratotic plaque.⁴ HPV is spread through skin-to-skin contact or through contaminated surfaces or objects.⁶ It infects the basal keratinocytes of cutaneous and mucosal epithelium to produce proliferative lesions at these sites that we recognize clinically as warts.

NATURAL HISTORY

HPV can have a long incubation period. One study on anogenital warts showed that the incubation period could vary from weeks to months, with an average of 3 months.⁷ Nongenital warts are generally harmless and resolve spontaneously within months to years, with a two-thirds remission at 2 years in immunocompetent individuals.⁸ Intact innate and cellular immunity are important in the regression of warts. Acquired antibodies play a role in the containment and reduction of HPV infectivity.⁹ Also, antibodies provide immune surveillance to prevent future infection from HPV.¹⁰

EPIDEMIOLOGY

Warts are among the most common presenting complaints in pediatric dermatology.⁶ According to 1 study, about one-third of schoolchildren have warts, with risk increased by the presence of affected family members or classmates.¹¹ Another study found that between 5% and 10% of pediatric patients had warts.¹² The peak incidence for warts in children is between the ages of 12 and 16 years. Although most wart-related cases are expected to be self-limited, patients frequently seek treatment in the meantime. One explanation could be that some patients with warts report considerable morbidities, particularly frustration and embarrassment.¹³

COMMON TREATMENTS AND OUTCOMES

Salicylic acid

Salicylic acid is a colorless organic acid that acts as a keratolytic agent. It destroys virally infected epidermis by reducing cohesion between corneocytes.¹⁴ It is also an irritant that activates an immune response to help eliminate HPV.¹⁵ Salicylic acid is available in many preparations and concentrations, but none has shown superiority over the others.¹⁶ A meta-analysis of 6 trials of salicylic acid (with or without additional lactic acid) in the treatment of cutaneous warts showed that salicylic acid was superior to placebo in eliminating warts with efficacy ranging from 0% to more than 80%.² Adverse events include 1 cellulitis case in a trial of 29 participants and minor skin irritations that were occasionally reported in some of these other trials.

Cryotherapy

Cryotherapy, usually with liquid nitrogen, is a freezing process that destructs the warts by damaging cells and their vascular supply, and by stimulating the immune system.² A meta-analysis of 3 trials showed no advantage of cryotherapy over placebo. However, meta-analysis of 4 studies of 707 subjects comparing salicylic acid and cryotherapy showed no significant difference in the cure rate of warts between the 2 treatments, and salicylic acid has been shown to be more effective than placebo. Cure rates varied from 9% to 50% in randomized trials. There are no differences in the long-term cure rates between different treatment intervals of 2, 3, or 4 weeks. The probability of being cured is inversely related to the diameter of the largest wart and the length of history.¹⁷ Adverse events from cryotherapy include pain, blistering, pigmentation of skin,¹⁸ tendon or nerve damage with aggressive therapy, and onychodystrophy in the treatment of periungual warts.¹⁹

Cantharidin

Cantharidin is a vesicant made from extracts of beetles belonging to the order of Coleoptera and the family of Meloidae.²⁰ Cantharidin is absorbed by the lipid membranes of epidermal cells, causing the activation or release of serine proteases. This leads to the disintegration of the desmosomal plaque, resulting in detachment of tonofilaments from desmosomes. The process gives rise to acantholysis and intraepidermal blistering.²¹ Topical treatment causes blistering after 24 hours to 48 hours of application.²⁰ The extent of blistering is limited by washing the treatment site with soap and water after a specified length of time.

Cantharidin was first suggested as a treatment for warts by Epstein and Kligman in 1958,²² and has since become one of the most widely used agents by pediatric dermatologists. Studies of cantharidin use for warts indicate that both researchers and clinicians consider the treatment to be effective and to have potential as a front-line therapy.^20,22-24 In addition to its well-documented use as a treatment for cutaneous warts, recent research has suggested that cantharidin might serve as an effective therapy for facial flat warts as well.²⁵ Among the reported adverse events associated with cantharidin use are pain or irritation, itching, or pruritus. While 1 study described these adverse events as “exceedingly rare,”²⁰ others have found them to be far more common.²²

With a few exceptions,^20,26 ring warts have received little attention as a potential adverse event in cantharidin treatment of warts. It is important for pediatric dermatologists to be aware of the potential for this adverse event in cantharidin treatment of warts because ring warts have the potential to be both embarrassing and frustrating to patients.

OUR patient

Our patient went home happy with treatment of salicylic acid.

REFERENCES

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2. Kwok CS, Gibbs S, Bennett C, Holland R, Abbott R. Topical treatments for cutaneous warts. Cochrane Database Syst Rev. 2012;9:CD001781.

3. Kuykendall-Ivy TD, Johnson SM. Evidence-based review of management of nongenital cutaneous warts. Cutis. 2003;71(3):213-222.

4. Bellew SG, Quartarolo N, Janniger CK. Childhood warts: an update. Cutis. 2004;73(6):379-384.

5. Corley E, Pueyo S, Goc B, Diaz A, Zorzopulos J. Papillomaviruses in human skin warts and their incidence in an Argentine population. Diagn Microbiol Infect Dis. 1988;10(2):93-101.

6. American Academy of Dermatology (AAD). Warts: medical student core curriculum in dermatology [PowerPoint]. AAD Web site. http://www.aad.org/education/medical-student-core-curriculum/warts. Updated July 29, 2011. Accessed July 22, 2013.

7. Oriel JD. Natural history of genital warts. Br J Vener Dis. 1971;47(1):1-13.

8. Massing AM, Epstein WL. Natural history of warts: a two-year study. Arch Dermatol. 1963;87(3):306-310.

9. Silverberg NB. Human papillomavirus infections in children. Curr Opin Pediatr. 2004;16(4):402-409.

10. Malejczyk J, Majewski S, Jablonska S. Cellular immunity in cutaneous and genital HPV infections. Clin Dermatol. 1997;15(2):261-274.

11. van Haalen, FM, Bruggink SC, Gussekloo J, Assendelft WJ, Eekhof JA. Warts in primary schoolchildren: prevalence and relation with environmental factors. Br J Dermatol. 2009;161(1):148-152.

12. Focht, Dean R 3rd, Spicer C, Fairchok MP. The efficacy of duct tape vs cryotherapy in the treatment of verruca vulgaris (the common wart). Arch Pediatr Adolesc Med. 2002;156(10):971-974.

13. Ciconte A, Campbell J, Tabrizi S, Garland S, Marks R. Warts are not merely blemishes on the skin: a study on the morbidity associated with having viral cutaneous warts. Australas J Dermatol. 2003;44(3):169-173.

14. Lin AN, Nakatsui T. Salicylic acid revisited. Int J Dermatol. 1998;37(5):335-342.

15. Sterling JC, Handfield-Jones S, Hudson PM; British Association of Dermatologists. Guidelines for the management of cutaneous warts. Br J Dermatol. 2001;144(1):4-11.

16. Gibbs S, Harvey I. Topical treatments for cutaneous warts. Cochrane Database Syst Rev. 2006;(3):CD001781. Update in: Cochrane Database Syst Rev. 2012;9:CD001781.

17. Berth-Jones J, Hutchinson PE. Modern treatment of warts: cure rates at 3 and 6 months. Br J Dermatol. 1992;127(3):262-265.

18. Bruggink SC, Gussekloo J, Berger MY, et al. Cryotherapy with liquid nitrogen versus topical salicylic acid application for cutaneous warts in primary care: randomized controlled trial. CMAJ. 2010;182(15):1624-1630.

19. McLaughlin JS, Shafritz AB. Cutaneous warts. J Hand Surg Am. 2011;36(2):343-344.

20. Moed L, Shwayder TA, Chang MW. Cantharidin revisited: a blistering defense of an ancient medicine. Arch Dermatol. 2001;137(10):1357-1360.

21. Bertaux B, Prost C, Heslan M, Dubertret L. Cantharide acantholysis: endogenous protease activation leading to desmosomal plaque dissolution. Br J Dermatol. 1988;118(2):157-165.

22. Epstein WL, Kligman AM. Treatment of warts with cantharidin. AMA Arch Derm. 1958;77(5):508-511.

23. Coloe J, Morrell DS. Cantharidin use among pediatric dermatologists in the treatment of molluscum contagiosum. Pediatr Dermatol. 2009;26(4):405-408.

24. Rodríguez-Martín M, Merino de Paz N, Contreras Ferrer R, et al. Cantharidin: a well-tolerated and effective therapy for Molluscum contagiosum in children. JPediatr Infect Dis. 2011;6(2):121-123.

25. Kartal Durmazlar SP, Atacan D, Eskioglu F. Cantharidin treatment for recalcitrant facial flat warts: a preliminary study. J Dermatolog Treat. 2009;20(2):114-119.

26. Rosenberg EW, Amonette RA, Gardner JH. Cantharidin treatment of warts at home. Arch Dermatol. 1977;113(8):1134. 

MS KUHN is a first-year medical student at Johns Hopkins University School of Medicine, Baltimore, Maryland. MS ZHAO is a first-year medical student at Johns Hopkins University School of Medicine, Baltimore. DR COHEN, the section editor for Dermatology: What’s Your Dx?, is director, Pediatric Dermatology and Cutaneous Laser Center, and associate professor of pediatrics and dermatology, Johns Hopkins University School of Medicine, Baltimore. The authors and section editor have nothing to disclose regarding affiliations with or financial interests in any organization that may have an interest in any part of this article. Vignettes are based on real cases that have been modified to allow the authors and editor to focus on key teaching points. Images also may be edited or substituted for teaching purposes.

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