Dermatologic Therapy, Vol.

25, 2012, 545550 Printed in the United States All rights reserved

2012 Wiley Periodicals, Inc.

DERMATOLOGIC THERAPY
ISSN 1396-0296

INVITED ARTICLE

Management of ungual warts

Jordana Herschthal*, Michael P. McLeod* & Martin Zaiac*
*Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine and Greater Miami Skin and Laser Center, Miami Beach, Miami, Florida

ABSTRACT: Warts are the most common nail tumor generally caused by human papilloma virus (HPV) 1, 2, 4, 27, and 57. HPV 16 and 18 are associated with malignant transformation to squamous cell carcinoma, while HPV 2 and 7 are associated with butchers warts. Current treatments range from topical and intralesional therapies to systemic agents and surgical procedures. Despite the numerous available possibilities for treatment, intralesional bleomycin appears to be the most effective treatment for periungual warts. KEYWORDS: bleomycin, cryotherapy, human papilloma virus

Introduction
Warts are the most common tumor of the nail (1). Those occurring around the nail are referred to as periungual, whereas those occurring beneath the nail are referred to as subungual. Human Papilloma Viruses (HPV) 1, 2, 4, 27, and 57 are generally the cause of benign ungual warts, commonly affecting children and young adults (2). HPV 16 and 18 are rare causes and are associated with malignant transformation to squamous cell carcinoma (SCC) (3,4). There is a specic subset of periungual warts known as butchers warts, which occur in people handling animal products and are caused by HPV 2 and 7 (3,4). A break in the skin barrier due to trauma or maceration allows entry of the virus, and factors such as the hosts humoral and cellular immunity status determine if the HPV will be pathogenic. This helps to explain the increased incidence of ungual warts in nail biters, occupations involving wet work, and those with compromised immunity (1,5). Warts can develop clinically anywhere from a few weeks to greater than a year after inoculation
Address correspondence and reprint requests to: Martin Zaiac, MD, Chairman, Department of Dermatology, Herbert Wertheim College of Medicine, Florida International University, Director, Greater Miami Skin and Laser Center, Mount Sinai Medical Center, 4308 Alton Road, Suite 750, Miami Beach, FL 33140, or email: drmartyz@aol.com.

with HPV (1). Ungual warts begin in skin that contains a granular layer, such as the proximal and lateral nail folds and the hyponychium. Appearing as skin-colored, rough papules, warts can progress to larger, verrucous papules coalescing into plaques. Black dots can often be seen on the surface clinically or with a dermatoscope, which correlate with blood vessels and help distinguish the wart from other growths. Diffuse or linear onycholysis and splinter hemorrhages can be seen with subungual warts. A hyperkeratotic nail bed is associated with warts of the hyponychium, whereas a hyperkeratotic cuticle is due to warts of the proximal nail fold. Ridges and grooves of the nail plate are due to pressure of the wart on the nail matrix. Treatment should be initiated and chosen based on factors such as lesion size, number, histology, host age and immunity, and resistance to prior therapy. Though warts have a tendency to resolve spontaneously, older age of host, immunosuppression, and long-standing warts confer resistance (6). Several potential complications can occur without therapy. For example, larger warts can be disguring and may lead to destruction eventually involving bone. Ungual warts can spread to other areas of the body and other individuals. SCC in situ and SCC are risks in the carcinogenic HPV strains. Multiple treatments from topical to surgical are

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available, but aggression does not necessarily correlate with improvement.

Topical and intralesional therapy

Keratolytic agents Keratolytic agents are those that destruct the viral-infected epidermis. Salicylic acid is the most commonly used agent. Other keratolytics include lactic acid, bichloroacetic acid, and trichloroacetic acid. The advantages to keratolytics are the various mediums available, painless application, and cheaper cost. For increased effectiveness, patients should use occlusion and must have strict daily compliance over a period of weeks to months. Contact dermatitis to colophony found in the collodion base can occur and systemic toxicity in children has been reported (7). A recent randomized, controlled study comparing cryotherapy to salicylic acid 50% for the treatment of plantar warts showed no differences in clearance rates at 12 weeks and 6 months, with the latter being more cost-effective (8). Combination therapies may also enhance efcacy (9). Cantharidin Cantharidin is extracted from Cantharis vesicatoria, the blister beetle. Once the painless medication is applied and occluded for 24 hours, a blister will form within 2 weeks. Reapplication may be necessary. Acantholysis induced by the blister leads to epidermal cell death. The process is nonscarring, though an eczematous reaction can occur. The cure rate has been reported to be around 80% (10). Podophyllotoxin Podophyllin is derived from Podophyllum peltatum, the mayapple plant, as a resin (11). Podophyllum hexandrum contains a higher concentration of podophyllotoxin, the active ingredient in podophyllin resin. Podophyllotoxin leads to mitotic arrest by binding microtubules in metaphase (12). In a randomized study of genital warts comparing self-administered 0.5% podophyllotoxin applied two times a day for 3 days a week in weekly intervals to podophyllin applied weekly, clearance rates were 94% in the podophyllotoxin group and 74% in the podophyllin group (13). This has not been studied in ungual warts. Virucidal Virucidal agents are those that directly destruct the virus. Formaldehyde and glutaraldehyde treat-

ments achieve comparable results to salicylic acid and cryotherapy (1). Glutaraldehyde is available as an alcohol solution or 10% water miscible gel. A small study with glutaraldehyde showed an 80% cure rate for periungual warts (14). The treatment is painless and nonscarring. A reversible dyspigmentation and eczematous reaction can occur. Formaldehyde, on the other hand, is available in a 3% solution or 0.7% gel. A study comparing 10% formaldehyde with monochloracetic acid compared with 10% formaldehyde alone showed a 61.4% clearance rate with no statistically signicant difference between the two groups (15). Formaldehyde can also produce an eczematous reaction through sensitization. Immunotherapy Immunotherapy induces a hosts immunity to destroy the virus. For example, imiquimod acts through toll-like receptor 7 to produce various cytokines including interferon-a, tumor necrosis factor- a, interleukins 1 and 6 (16). Effective in genital and facial warts, imiquimod may be useful for periungual warts as well. In an open-label study assessing imiquimod 5% cream for periungual and subungual warts, 12/15 (80%) of participants had complete clearance at 16 weeks (17). Squaric acid dibutylether (SADBE) and diphenylcyclopropenone are contact sensitizers. Weekly applications in varying concentrations from 0.001% to 1% are a painless treatment option (1). An eczematous reaction is used to gauge appropriate concentrations. One study with twice-weekly SADBE applications over 10 weeks showed an 84% clearance rate (18). Candida or mumps antigen Candida antigen upregulates the Th1 immune reaction in the hopes of targeting the wart cells (19). Injection of Candida or mumps antigen has been directly compared with cryotherapy. A complete clearance was noted in 74% of the Candida group (after the anergic group was excluded) compared with 55% in the cryotherapy group in 115 patients who received treatment every 3 weeks with Candida or mumps antigen, or a double-thaw cycle with cryotherapy (20). It has successfully been used for warts in children that did not respond to liquid nitrogen (21). Notably, 47% of the treated warts completely cleared with 3.78 treatments (21). The response rate was likely not as high in this study because the warts treated in this study were specically recalcitrant and the immune responses in children are

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likely not as robust as their adult counterparts (22). Erythema, edema, and pruritus were reported at the injection site (21). Additionally, delayed type hypersensitivity reactions have also been reported (21,23). 5-Flourouracil (5-FU) 5-FU is an antimetabolite that prevents proliferation through DNA and RNA inhibition. It can be applied as a cream or injected intralesionally. In a prospective, randomized, controlled trial comparing 5% 5-FU cream under tape occlusion to tape occlusion alone for plantar warts over 12 weeks, an 85% clearance rate was observed in the former group at 6 months follow-up (24). A single-blind, randomized, controlled study using intralesional 5-FU mixed with lidocaine and epinephrine achieved a 70% clearance rate (25). Bleomycin Bleomycin is derived from Streptomyces verticillus and is quite effective in recalcitrant ungual warts. Apoptosis of epidermal cells results from inhibition of DNA and protein synthesis. Two different techniques exist (26). The rst technique involves direct injection of approximately 0.2 cc of a 1 : 1 dilution of bleomycin with sterile saline into the epidermis of the wart (27). The second technique requires a 1 : 1 dilution of bleomycin with sterile saline as well (1). The 1 mg/mL solution is applied as drops to the wart surface and then punctured into the wart with a lancet approximately 40 times per 5 mm2 area. Necrosis ensues in about 34 weeks. Treatments can be repeated. The author prefers to use 0.5 mg/mL and considers this to be the most effective treatment for recalcitrant periungual warts. Systemic absorption can occur which limits use in children, pregnant women, and patients with vascular disease or compromised immune systems. Injection site pain and erythema occur within the rst 72 hours, prior to eschar formation. Raynauds phenomenon and potential nail dystrophy are also complications (26). Pre-treatment with intralesional lidocaine is recommended. Several randomized, controlled trials report cure rates ranging from 16% to 94% (28).

indirectly augments cell-mediated immunity (29,30). It has been shown to clear 82% of recalcitrant warts in an unblinded study (29). In better designed studies, the clearance rate was much lower at 26%, which did not differ from the placebo in a statistically signicant manner (29). This nding has been corroborated with other welldesigned trials comparing cimetidine to placebo (31,32). Interferon Intravenous administration, treatment cost, and u-like side effects reserve the use of interferon for only extensive and recalcitrant peri and subungual warts for which it has been used successfully (1,33).

Surgical
Cryotherapy Cryotherapy is considered a second-line treatment for warts (7). Liquid nitrogen is the most commonly used cryogen and is thought to directly cause necrosis of the HPV infected cells in the epidermis or induce an inammatory reaction that stimulates a cell-mediated reaction against the HPV infected cells (6). There are a number of treatment variables when using cryotherapy such as freezing time, temperature, application technique (spray or cotton wool), and treatment intervals (22). After 3 months of treatments every 2 weeks, one study reported a 44% clearance rate using the spray technique versus 47% with the cotton wool application (26). Interestingly, six warts present for at least 6 months or greater did not clear as well as warts that had been present for less than 6 months (39% vs. 84%, respectively) (26). Longer freeze times are associated with a better clearance rate, but also more blistering and pain (34). Double freeze-thaw cycles appear to confer no advantage over a single freeze-thaw cycle as there was no difference observed between clearance rates at 3 months in warts on the hands (35). Cryotherapy was also compared with salicylic acid clearance, with no signicant difference in clearance between 3 and 6 months (65% vs. 63%, respectively) (28). A 10-second freeze was noted to be more effective (52% vs. 31%) than a brief freeze in clearing warts, but also resulted in 64% of patients experiencing blistering (36). Shorter time intervals between treatments are also associated with more blistering, but not a signicant increase in clearance rate (36). It appears that surgical debulking plus

Systemic therapies
Cimetidine Cimetidine, a well-known H2-receptor antagonist, inhibits suppressor T-cells at high doses, which

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soaking in water prior to cryotherapy may result in the best clearance rate (83.5% complete clearance) with one treatment and 92.5% if two or more treatments were incorporated (37). Excision Simple surgical excision is not considered a standard of therapy when treating warts because it is associated with a 30% recurrence rate and signicant scarring (1,6). In addition, a wart recurring in scar tissue is very difcult to treat. CO2 laser The 10,600 nm CO2 laser targets water as a chromophore and causes nonselective thermal tissue destruction. At least two case series have demonstrated 6471% clearance rates with 12 treatments of the CO2 laser and follow up at 1 year following laser treatment (6). Twenty-nine percent of the patients reported temporary or permanent nail dystrophy. Time for re-epithelization can be quite prolonged, requiring up to 9 weeks (1). Total nail avulsions are required for warts that have spread into the nail bed or fold (1). Care should be taken to evacuate the laser plume generated during treatment because HPV DNA has been found in the vapor (3842). This therapy is recommended as second line for recalcitrant warts (1). Pulsed dye laser (PDL) The PDL targets the microvasculature of warts by using the 577 nm absorption peak of oxyhemoglobin (1,22). By targeting the microvasculature, the blood supply to the wart is compromised and the wart begins to undergo necrosis. The necrosis leads to an upregulated cell-mediated response that likely targets the necrotic wart cells (1). There is typically not much pain associated with treatment of this laser and patients liken the treatment to a rubber band snapping against the surface of the skin (43). Additionally, there is very little downtime and scarring associated with treatment with the PDL because no wound is created (44,45). Unfortunately, the clearance rate is only approximately 33% with 24 sessions (44). Warts that are not on the hands or feet appear to respond better than acral areas (46,47). Erbium: Yag The Erbium:YAG (Er:YAG) laser emits light at the 2940 nm wavelength which is absorbed much

more strongly by water than the 10,600 nm CO2 laser, thereby creating a smaller zone of thermal damage beyond where the laser beam is directed (48). Warts have been reportedly cleared in 75% of patients following one treatment; however, one quarter of the patients have recurrences within 1 year of treatment, likely because the laser energy does not extend deep enough in the cutaneous tissue (49). Approximately 14% of patients are known to not respond to treatment (50). Up to 2 months following treatment may be required for erythema to subside (50). Additionally, the Er:YAG laser may be safer to operate than the CO2 laser because HPV DNA has not yet been detected in its laser plume (51). Thermo-fractional PDT This modality combines thermotherapy with a 1064 nm Nd:YAG laser prior to the use of a CO2 or Er:YAG ablative fractional laser, followed by the application of 5-ALA, and a light-emitting diode (52). It is thought that this method is benecial for warts because the microthermal zones created by the fractional lasers enhance penetration of the 5-ALA photosensitizer (52). In 20 patients with recalcitrant warts, 90% of the lesions were clear at 3 months following treatment, with no recurrences at 6 months. Unfortunately, all of the patients experienced signicant pain after the local anesthetic from the procedure wore off, and 75% required oral analgesics. Two patients in the CO2 and two in the Er:YAG fractional laser groups experienced postinammatory hyperpigmentation (52). Nd:YAG The 1064 nm Nd:YAG laser has successfully been used in ber-optic probes to treat respiratory papillomatosis induced by HPV 6 and 11, as well as genital lesions and cervical conization (53 55). Several case reports/series demonstrate 100% clearance rates (56,57). The Nd:YAG laser was directly compared with cryotherapy for the removal of HPV DNA and was shown to remove 100% of the HPV DNA, whereas cryotherapy only reduced the HPV DNA amount by 4% (58).

Other
Hypnosis/suggestive therapy Case reports and case series suggest that hypnosis and suggestive therapy may play a role in enhancing

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the immune system. This may hasten the resolution of warts (5965). As of this time, no trials exist to lend evidence to this therapeutic modality. Duct tape In 2002, Focht and colleagues demonstrated that using duct tape to treat a wart resulted in a higher clearance rate (85%) than 10 seconds of cryotherapy (60%) (66). Interestingly, warts that were distant from the lesions treated with duct tape also resolved, suggesting that perhaps a component of the duct tape elicited an immune response. This is an especially attractive treatment because no side effects were observed in the duct tape group. Clearly, more studies need to be conducted to determine the utility of this therapy for treating warts (22).

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Conclusion
Ungual warts are very common and frequently encountered in the clinical setting. A variety of treatment modalities have been discussed, encompassing topical, intralesional, systemic, and surgical approaches. In the authors opinion, intralesional bleomycin is the most effective treatment for periungual warts. Characteristics of both the patient and wart should be considered when choosing a therapy.
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19. 20.

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