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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 “butcher’s 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 specific subset of periungual warts known as “butcher’s 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 host’s 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 with HPV (1). Ungual warts begin in skin that con- tains 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 ony- cholysis 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, immunosuppres- sion, and long-standing warts confer resistance (6). Several potential complications can occur without therapy. For example, larger warts can be disfigur- ing and may lead to destruction eventually involv- ing 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 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: [email protected]. 545 Dermatologic Therapy, Vol. 25, 2012, 545–550 Printed in the United States · All rights reserved © 2012 Wiley Periodicals, Inc. DERMATOLOGIC THERAPY ISSN 1396-0296

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INVITED ARTICLE

Management of ungual wartsJordana Herschthal*, Michael P. McLeod* & Martin Zaiac*†*Department of Dermatology and Cutaneous Surgery, University of MiamiMiller School of Medicine and †Greater Miami Skin and Laser Center, MiamiBeach, 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 cellcarcinoma, while HPV 2 and 7 are associated with “butcher’s warts.” Current treatments range fromtopical and intralesional therapies to systemic agents and surgical procedures. Despite the numerousavailable possibilities for treatment, intralesional bleomycin appears to be the most effective treatmentfor 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 asperiungual, whereas those occurring beneath thenail are referred to as subungual. Human PapillomaViruses (HPV) 1, 2, 4, 27, and 57 are generally thecause of benign ungual warts, commonly affectingchildren and young adults (2). HPV 16 and 18 arerare causes and are associated with malignanttransformation to squamous cell carcinoma (SCC)(3,4). There is a specific subset of periungual wartsknown as “butcher’s warts,” which occur in peoplehandling animal products and are caused by HPV 2and 7 (3,4). A break in the skin barrier due to traumaor maceration allows entry of the virus, and factorssuch as the host’s humoral and cellular immunitystatus determine if the HPV will be pathogenic. Thishelps to explain the increased incidence of ungualwarts in nail biters, occupations involving wet work,and those with compromised immunity (1,5).

Warts can develop clinically anywhere from afew weeks to greater than a year after inoculation

with HPV (1). Ungual warts begin in skin that con-tains a granular layer, such as the proximal andlateral nail folds and the hyponychium. Appearingas skin-colored, rough papules, warts can progressto larger, verrucous papules coalescing intoplaques. Black dots can often be seen on thesurface clinically or with a dermatoscope, whichcorrelate with blood vessels and help distinguishthe wart from other growths. Diffuse or linear ony-cholysis and splinter hemorrhages can be seenwith subungual warts. A hyperkeratotic nail bed isassociated with warts of the hyponychium,whereas a hyperkeratotic cuticle is due to warts ofthe proximal nail fold. Ridges and grooves of thenail plate are due to pressure of the wart on thenail matrix.

Treatment should be initiated and chosen basedon factors such as lesion size, number, histology,host age and immunity, and resistance to priortherapy. Though warts have a tendency to resolvespontaneously, older age of host, immunosuppres-sion, and long-standing warts confer resistance (6).Several potential complications can occur withouttherapy. For example, larger warts can be disfigur-ing and may lead to destruction eventually involv-ing bone. Ungual warts can spread to other areasof the body and other individuals. SCC in situand SCC are risks in the carcinogenic HPV strains.Multiple treatments from topical to surgical are

Address correspondence and reprint requests to: Martin Zaiac,MD, Chairman, Department of Dermatology, HerbertWertheim College of Medicine, Florida InternationalUniversity, Director, Greater Miami Skin and Laser Center,Mount Sinai Medical Center, 4308 Alton Road, Suite 750,Miami Beach, FL 33140, or email: [email protected].

545

Dermatologic Therapy, Vol. 25, 2012, 545–550Printed in the United States · All rights reserved

© 2012 Wiley Periodicals, Inc.

DERMATOLOGIC THERAPYISSN 1396-0296

Page 2: 3 Management of Ungual Warts

available, but aggression does not necessarily cor-relate with improvement.

Topical and intralesional therapy

Keratolytic agents

Keratolytic agents are those that destruct theviral-infected epidermis. Salicylic acid is the mostcommonly used agent. Other keratolytics includelactic acid, bichloroacetic acid, and trichloroace-tic acid. The advantages to keratolytics are thevarious mediums available, painless application,and cheaper cost. For increased effectiveness,patients should use occlusion and must have strictdaily compliance over a period of weeks to months.Contact dermatitis to colophony found in the col-lodion base can occur and systemic toxicity in chil-dren has been reported (7). A recent randomized,controlled study comparing cryotherapy to sali-cylic acid 50% for the treatment of plantar wartsshowed no differences in clearance rates at 12weeks and 6 months, with the latter being morecost-effective (8). Combination therapies may alsoenhance efficacy (9).

Cantharidin

Cantharidin is extracted from Cantharis vesicatoria,the blister beetle. Once the painless medicationis applied and occluded for 24 hours, a blister willform within 2 weeks. Reapplication may be neces-sary. Acantholysis induced by the blister leads toepidermal cell death. The process is nonscarring,though an eczematous reaction can occur. The curerate has been reported to be around 80% (10).

Podophyllotoxin

Podophyllin is derived from Podophyllum pelta-tum, the mayapple plant, as a resin (11). Podophyl-lum hexandrum contains a higher concentrationof podophyllotoxin, the active ingredient in podo-phyllin resin. Podophyllotoxin leads to mitoticarrest by binding microtubules in metaphase (12).In a randomized study of genital warts comparingself-administered 0.5% podophyllotoxin appliedtwo times a day for 3 days a week in weekly inter-vals to podophyllin applied weekly, clearance rateswere 94% in the podophyllotoxin group and 74%in the podophyllin group (13). This has not beenstudied in ungual warts.

Virucidal

Virucidal agents are those that directly destructthe virus. Formaldehyde and glutaraldehyde treat-

ments achieve comparable results to salicylic acidand cryotherapy (1). Glutaraldehyde is availableas an alcohol solution or 10% water miscible gel. Asmall study with glutaraldehyde showed an 80%cure rate for periungual warts (14). The treatmentis painless and nonscarring. A reversible dyspig-mentation and eczematous reaction can occur.Formaldehyde, on the other hand, is availablein a 3% solution or 0.7% gel. A study comparing10% formaldehyde with monochloracetic acidcompared with 10% formaldehyde alone showeda 61.4% clearance rate with no statistically signifi-cant difference between the two groups (15). Form-aldehyde can also produce an eczematous reactionthrough sensitization.

Immunotherapy

Immunotherapy induces a host’s immunity todestroy the virus. For example, imiquimod actsthrough toll-like receptor 7 to produce variouscytokines including interferon-a, tumor necrosisfactor- a, interleukins 1 and 6 (16). Effective ingenital and facial warts, imiquimod may be usefulfor periungual warts as well. In an open-label studyassessing imiquimod 5% cream for periungual andsubungual warts, 12/15 (80%) of participants hadcomplete clearance at 16 weeks (17). Squaric aciddibutylether (SADBE) and diphenylcycloprope-none are contact sensitizers. Weekly applicationsin varying concentrations from 0.001% to 1% are apainless treatment option (1). An eczematous reac-tion is used to gauge appropriate concentrations.One study with twice-weekly SADBE applicationsover 10 weeks showed an 84% clearance rate (18).

Candida or mumps antigen

Candida antigen upregulates the Th1 immune reac-tion in the hopes of targeting the wart cells (19).Injection of Candida or mumps antigen has beendirectly compared with cryotherapy. A completeclearance was noted in 74% of the Candida group(after the anergic group was excluded) comparedwith 55% in the cryotherapy group in 115 patientswho received treatment every 3 weeks withCandida or mumps antigen, or a double-thaw cyclewith cryotherapy (20).

It has successfully been used for warts inchildren that did not respond to liquid nitrogen(21). Notably, 47% of the treated warts completelycleared with 3.78 treatments (21). The responserate was likely not as high in this study because thewarts treated in this study were specifically recalci-trant 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 atthe injection site (21). Additionally, delayed typehypersensitivity reactions have also been reported(21,23).

5-Flourouracil (5-FU)

5-FU is an antimetabolite that prevents prolifera-tion through DNA and RNA inhibition. It can beapplied as a cream or injected intralesionally. In aprospective, randomized, controlled trial compar-ing 5% 5-FU cream under tape occlusion to tapeocclusion alone for plantar warts over 12 weeks,an 85% clearance rate was observed in the formergroup at 6 months follow-up (24). A single-blind,randomized, controlled study using intralesional5-FU mixed with lidocaine and epinephrineachieved a 70% clearance rate (25).

Bleomycin

Bleomycin is derived from Streptomyces verticillusand is quite effective in recalcitrant ungual warts.Apoptosis of epidermal cells results from inhibitionof DNA and protein synthesis. Two different tech-niques exist (26). The first technique involves directinjection of approximately 0.2 cc of a 1 : 1 dilutionof bleomycin with sterile saline into the epidermisof the wart (27). The second technique requires a1 : 1 dilution of bleomycin with sterile saline aswell (1). The 1 mg/mL solution is applied as dropsto the wart surface and then punctured into thewart with a lancet approximately 40 times per5 mm2 area. Necrosis ensues in about 3–4 weeks.Treatments can be repeated. The author prefers touse 0.5 mg/mL and considers this to be the mosteffective treatment for recalcitrant periungualwarts. Systemic absorption can occur which limitsuse in children, pregnant women, and patientswith vascular disease or compromised immunesystems. Injection site pain and erythema occurwithin the first 72 hours, prior to eschar formation.Raynaud’s phenomenon and potential nail dystro-phy are also complications (26). Pre-treatmentwith intralesional lidocaine is recommended.Several randomized, controlled trials report curerates ranging from 16% to 94% (28).

Systemic therapies

Cimetidine

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

indirectly augments cell-mediated immunity(29,30). It has been shown to clear 82% of recalci-trant warts in an unblinded study (29). In betterdesigned studies, the clearance rate was muchlower at 26%, which did not differ from the placeboin a statistically significant manner (29). Thisfinding has been corroborated with other well-designed trials comparing cimetidine to placebo(31,32).

Interferon

Intravenous administration, treatment cost, andflu-like side effects reserve the use of interferon foronly extensive and recalcitrant peri and subungualwarts for which it has been used successfully (1,33).

Surgical

Cryotherapy

Cryotherapy is considered a second-line treatmentfor warts (7). Liquid nitrogen is the most com-monly used cryogen and is thought to directlycause necrosis of the HPV infected cells in the epi-dermis or induce an inflammatory reaction thatstimulates a cell-mediated reaction against theHPV infected cells (6). There are a number of treat-ment variables when using cryotherapy such asfreezing 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 thespray technique versus 47% with the cotton woolapplication (26). Interestingly, six warts present forat least 6 months or greater did not clear as well aswarts that had been present for less than 6 months(39% vs. 84%, respectively) (26). Longer freezetimes are associated with a better clearance rate,but also more blistering and pain (34). Doublefreeze-thaw cycles appear to confer no advantageover a single freeze-thaw cycle as there was nodifference observed between clearance rates at3 months in warts on the hands (35). Cryotherapywas also compared with salicylic acid clearance,with no significant difference in clearance between3 and 6 months (65% vs. 63%, respectively) (28). A10-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 experiencingblistering (36). Shorter time intervals betweentreatments are also associated with more blister-ing, but not a significant increase in clearancerate (36). It appears that surgical debulking plus

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soaking in water prior to cryotherapy may result inthe best clearance rate (83.5% complete clearance)with one treatment and 92.5% if two or more treat-ments were incorporated (37).

Excision

Simple surgical excision is not considered a stan-dard of therapy when treating warts because it isassociated with a 30% recurrence rate and signifi-cant scarring (1,6). In addition, a wart recurring inscar tissue is very difficult to treat.

CO2 laser

The 10,600 nm CO2 laser targets water as a chro-mophore and causes nonselective thermal tissuedestruction. At least two case series have demon-strated 64–71% clearance rates with 1–2 treatmentsof the CO2 laser and follow up at 1 year followinglaser treatment (6). Twenty-nine percent of thepatients reported temporary or permanent naildystrophy. Time for re-epithelization can be quiteprolonged, requiring up to 9 weeks (1). Total nailavulsions are required for warts that have spreadinto the nail bed or fold (1). Care should be taken toevacuate the laser plume generated during treat-ment because HPV DNA has been found in thevapor (38–42). This therapy is recommended assecond line for recalcitrant warts (1).

Pulsed dye laser (PDL)

The PDL targets the microvasculature of warts byusing the 577 nm absorption peak of oxyhemoglo-bin (1,22). By targeting the microvasculature, theblood supply to the wart is compromised andthe wart begins to undergo necrosis. The necrosisleads to an upregulated cell-mediated responsethat likely targets the necrotic wart cells (1). Thereis typically not much pain associated with treat-ment of this laser and patients liken the treatmentto a rubber band snapping against the surface ofthe skin (43). Additionally, there is very little down-time and scarring associated with treatment withthe PDL because no wound is created (44,45).Unfortunately, the clearance rate is only approxi-mately 33% with 2–4 sessions (44). Warts that arenot on the hands or feet appear to respond betterthan acral areas (46,47).

Erbium: Yag

The Erbium:YAG (Er:YAG) laser emits light at the2940 nm wavelength which is absorbed much

more strongly by water than the 10,600 nm CO2

laser, thereby creating a smaller zone of thermaldamage beyond where the laser beam is directed(48). Warts have been reportedly cleared in 75% ofpatients following one treatment; however, onequarter of the patients have recurrences within1 year of treatment, likely because the laser energydoes not extend deep enough in the cutaneoustissue (49). Approximately 14% of patients areknown to not respond to treatment (50). Up to2 months following treatment may be required forerythema to subside (50). Additionally, the Er:YAGlaser may be safer to operate than the CO2 laserbecause HPV DNA has not yet been detected in itslaser plume (51).

Thermo-fractional PDT

This modality combines thermotherapy with a1064 nm Nd:YAG laser prior to the use of a CO2 orEr:YAG ablative fractional laser, followed by theapplication of 5-ALA, and a light-emitting diode(52). It is thought that this method is beneficial forwarts because the microthermal zones created bythe fractional lasers enhance penetration of the5-ALA photosensitizer (52). In 20 patients withrecalcitrant warts, 90% of the lesions were clear at 3months following treatment, with no recurrencesat 6 months. Unfortunately, all of the patients expe-rienced significant pain after the local anestheticfrom the procedure wore off, and 75% required oralanalgesics. Two patients in the CO2 and two in theEr:YAG fractional laser groups experienced postin-flammatory hyperpigmentation (52).

Nd:YAG

The 1064 nm Nd:YAG laser has successfully beenused in fiber-optic probes to treat respiratorypapillomatosis induced by HPV 6 and 11, as wellas genital lesions and cervical conization (53–55). Several case reports/series demonstrate 100%clearance rates (56,57). The Nd:YAG laser wasdirectly compared with cryotherapy for the removalof HPV DNA and was shown to remove 100% of theHPV DNA, whereas cryotherapy only reduced theHPV DNA amount by 4% (58).

Other

Hypnosis/suggestive therapy

Case reports and case series suggest that hypnosisand suggestive therapy may play a role in enhancing

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the immune system. This may hasten the resolutionof warts (59–65). As of this time, no trials exist tolend evidence to this therapeutic modality.

Duct tape

In 2002, Focht and colleagues demonstrated thatusing duct tape to treat a wart resulted in a higherclearance rate (85%) than 10 seconds of cryo-therapy (60%) (66). Interestingly, warts that weredistant from the lesions treated with duct tape alsoresolved, suggesting that perhaps a component ofthe duct tape elicited an immune response. Thisis an especially attractive treatment because noside effects were observed in the duct tape group.Clearly, more studies need to be conducted todetermine the utility of this therapy for treatingwarts (22).

Conclusion

Ungual warts are very common and frequentlyencountered in the clinical setting. A variety oftreatment modalities have been discussed, en-compassing topical, intralesional, systemic, andsurgical approaches. In the author’s opinion,intralesional bleomycin is the most effective treat-ment for periungual warts. Characteristics of boththe patient and wart should be considered whenchoosing a therapy.

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