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Current And Emerging Concepts In Wart Treatment

A challenge at times for clinicians to diagnose and manage, plantar verrucae may cause pain and cosmetic issues for patients. Accordingly, this author surveys the literature and discusses a wide range of treatment options ranging from salicylic acid and cimetidine to bleomycin, duct tape and laser therapy.

Viral warts or verruca pedis (plantar warts) are common skin conditions that arise in both children and adults. Human papilloma virus (HPV), a DNA virus, is responsible for plantar verrucae. On the feet and hands, the HPV subtypes typically include 1, 2, 4, 27 and 57. Both an epidermal abrasion and a transiently impaired immune system are necessary to inoculate a keratinocyte.1   

As HPV can exist on fomites, showers and swimming pools with abrasive non-slip surfaces can be high-risk areas for simultaneously harboring the virus and causing an epidermal abrasion. Thirty percent of warts may clear spontaneously but those that do not often are cosmetically unappealing, painful and irritating to the patient.2 The virus seems to encourage basal cell replication. Hyperplasia of the granular and prickle cell layer occurs in addition to the dermal papillae arching its vasculature up into the wart. Keratinocytes, with an eccentric nucleus surrounded by a halo (koilocytes), show viral damage of the cells.

Plantar warts are clinically defined as well-circumscribed lesions with overlying hyperkeratosis. Upon debridement of the hyperkeratosis, pinpoint bleeding may be visible along with interruption of skin lines. One may elicit pain through lateral compression of the plantar lesion but warts may also be painful upon ambulation with direct pressure. If the wart involves the nail unit, the nail may become dystrophic from the pressure and presence of the lesion.

There are several treatments from non-surgical to surgical methods for plantar verrucae. However, none of them are specific to eradicating an HPV strain.

How To Evaluate The Patient
With Plantar Warts

Patients seek treatment for their plantar verruca due to embarrassment or pain.3 As a patient’s immune status plays a role in wart development, it is important to assess his or her past and current immune state. For a thorough history and physical, one should consider the answers to key questions of the patient (see “Questions To Ask A Patient With Plantar Warts”) and incorporate a visual inspection to determine the type of wart present.

Here are key questions one can ask when evaluating a patient with plantar warts.

Plantar warts can be painful depending on anatomic location and patient sensitivity. The diagnosis and management of plantar warts can be challenging as the various presentations on the lower extremity range from the flesh-colored endophytic plantar wart and periungual lesions to mosaic warts and a filiform cutaneous horn-like lesion. Differential diagnoses include pitted keratolysis, punctate keratosis, corn, callus, molluscum contagiosum and squamous cell carcinoma (particularly the subtype verrucous carcinoma).3

Commonly, a plantar wart will be a flesh-colored, discrete lesion that may occur singly or in multiples. A confluence of these lesions will appear as a mosaic pattern. Lesions may occur on non-weightbearing areas or weightbearing areas. As I previously stated, pain on lateral compression may assist in diagnosis but patients may report pain on direct compression due to ambulation. One of the most common signs a plantar verruca is present is the interruption of the dermal glyphics of the foot. One can see this interruption of the skin lines with the naked eye but it is enhanced when viewing with a dermatoscope. Following the reappearance of the skin lines throughout the lesion aids the clinician in determining its resolution.

Asking about hyperhidrosis, picking of lesions and worsening of the lesion after previous treatments allows the clinician to determine if the Koebner phenomenon is present. The Koebner phenomenon, or isomorphic response, is the development of pathologic lesions in traumatized uninvolved skin (i.e., what can occur during treatment of a verruca).3 Many recognize this response in psoriatic lesions but it also occurs in Kaposi’s sarcoma, lichen planus and warts caused by HPV.3

After trauma to the skin, new lesions that arise are histopathologically identical to the original lesion. Many patients report having a small lesion at the first physician visit and consent to a procedure that they thought would be curative only to subsequently have multiple and sometimes larger lesions return a few weeks to months after the procedure. This causes frustration for both the clinician and patient. It is important to keep this phenomenon in mind when choosing the treatment plan, especially for a patient who has a failed excision of the lesion. Ultimately, clearance of the lesion is based upon the patient’s immune status, the HPV type present and its reaction to the therapy one applies, and the extent and longevity of the warts.3

What To Look For In A Wart Treatment

Therapeutic options aim at eliminating the signs and symptoms of the wart as there is no cure for HPV. Not all therapies work on all patients and often one must combine two or more treatments on the patient’s foot to have a clinical change. An ideal wart therapy is painless, resolves most or all lesions, offers no scarring post-treatment, involves one to three office visits and offers lifetime HPV immunity.3 Also, since randomized controlled clinical trial evidence is lacking, a preponderance of the literature on lower extremity warts are either anecdotal in nature or small case series that show several therapies seem to have an effect.3

Since no single treatment technique and no specific antiviral therapy has been developed, plantar warts are a therapeutic challenge for both clinicians and patients. Different modalities described in the literature range from tissue keratolysis (salicylic acid) to immunotherapy (bleomycin) to tissue destructive (cryotherapy, surgical excision).3 Eradication of verruca pedis/plantar warts ultimately is based on the activation of the body’s immune system to fight the virus. Many treatment options are available with differing success rates. The clinician may choose therapy based upon cost, pain induction and other side effects that are tolerable with the patient’s occupation and/or lifestyle.

Unique to plantar verrucae, sharp debridement of the lesion is necessary to remove the hyperkeratotic covering in order to improve topical therapy penetration and provide symptomatic pain relief. One would debride the lesion prior to considering most in-office therapies. Many times, pinpoint bleeding will occur upon debridement. Avoid prior debridement if using a non-ablative laser (i.e., pulsed dye or YAG) for the lesion. The target chromophore for these devices is oxyhemoglobin and if blood is present on the surface, the laser’s target may be too superficial to have a therapeutic effect.

A Quick Word About Folk Remedies

Folk remedies. Patients have described numerous folk remedies that utilize fruit (rubbing a banana on the wart), a vegetable plus the right environment (performing a ritual with a potato during the full moon and then burying it), and animals (rubbing a toad on the wart). However outlandish these might seem, it is important to realize that since most warts have a finite presence, these remedies may coincide with the wart’s spontaneous resolution.

Key Considerations With Salicylic Acid And Cryotherapy

Salicylic acid. Salicylic acid, a keratolytic that lyses the epidermis, is the first-line therapy (compounded up to 60 percent strength) that many clinicians choose to use in the office but it is also what the patient may unwillingly choose when faced with the over-the-counter (OTC) options (17 percent or 40 percent preparations).3 After debridement, the clinician will apply salicylic acid to an aperture pad with subsequent application of occlusive tape. The patient must keep the area dry for five to seven days. In contrast, the OTC preparations require daily or every other day application of the salicylic acid preparation. Both home and in-office therapy may require multiple treatments but from a retrospective review of evidence-based data, salicylic acid in general has an effectiveness of about 75 percent.4 As it is cost-effective and not often painful, salicylic acid is an effective initial therapy for many patients.

Cryotherapy. Another in-office, first-line therapy performed by clinicians is cryotherapy, the application of liquid nitrogen directly to the verruca. This is a generally painful therapy that causes a cell-mediated response via local inflammation but does not kill the virus directly. The newly available over-the-counter cryotherapies are not as cold as liquid nitrogen. Like liquid nitrogen, the over-the-counter version may cause hypopigmentation, blistering, a “ring wart” or circular resurgence of the wart around where the skin was frozen (a Koebner response), and pain. Generally, one would apply the cryogen to the wart until a white halo appears (i.e., freezing of the skin) once every two weeks. As differences in technique can vary in the literature, cure rates range from 39 to 92 percent.3 A more aggressive technique may yield better results but may also lead to more adverse events for the patient. One can also use this therapy in combination with other modalities like salicylic acid.

Can Topical Retinoids Have An Impact?

Topical retinoids. Dermatologists commonly use topical retinoids for acne as they alter keratinization in the epidermis, act as an anti-inflammatory and inhibit cell proliferation. While adapalene 0.1% gel (Differin, Nestle Skin Health) is a treatment of mild to moderate acne, Gupta and Gupta assessed the use of the medication for plantar verrucae.5 In the randomized study, 50 patients (424 plantar warts) received either adapalene 0.1% gel under occlusion or cryotherapy. Group A applied adapalene 0.1% twice daily under occlusion and Group B received cryotherapy once every two weeks. The study authors followed patients weekly until the warts cleared and assessed patients at monthly visits for six months post-clearance to dtermine if there was any recurrence.

Twenty-four out of 25 patients in Group A had complete clearance of 286 warts in about 36 days.5 Group B’s cryotherapy treatments had 24 out of 25 patients develop complete clearance of 124 warts in 52 days. Group A patients experienced no adverse events while Group B had scarring, pain and redness (all the side effects that are expected with the use of cryotherapy). There was no recurrence in any patient. In this study, adapalene 0.1% gel seemed to clear warts faster and with fewer side effects than cryotherapy alone. One should keep in mind that plantar verrucae is an off-label indication for adapalene 0.1% gel and this is one study showing efficacy.

What The Literature Reveals About Topical  5-FU, CimetidineAnd Duct Tape

Topical 5-fluorouracil (5-FU). While topical 5-FU is primarily indicated for actinic keratosis, physicians have used it off-label for warts as it is believed 5-FU inhibits cellular proliferation.6 In a prospective, randomized, controlled study, Salk and colleagues compared topical 5-FU application under tape occlusion versus tape occlusion alone for plantar warts.6 Nineteen out of 20 patients in the 5-FU/tape arm had complete resolution after 12 weeks of treatment. A minor number of patients had recurrence six months later but overall, a majority of patients remained verruca-free.

Cimetidine. Research has shown that cimetidine, an H2-receptor antagonist, inhibits suppressor T-cell function at its histamine 2 receptor site.7 While Mullen and colleagues originally demonstrated that cimetidine can help treat recalcitrant warts in children, they expanded the treatment regimen for use in adults with daily doses of 20 to 40 mg/kg.7 In an eight-year retrospective study, authors reviewed patients (ages 3 to 25-plus) who had received cimetidine as monotherapy or after failing other treatments.7 Across all age groups, treatment success was 84.3 percent with 86 percent in the pediatric group and 75.8 percent in the adult group. Adults had four times the recurrence rate of the children in the study. Open-label studies involving cimetidine have shown promise but small randomized controlled trials did not show a difference between the drug and placebo.3 While cimetidine appears to be a safe option, its efficacy rate across the literature is quite variable, making its success difficult to distinguish from a placebo-like effect.

Duct tape. Noting the increasingly common practice of using duct tape to treat plantar warts in clinical practice and among laypeople as well, Focht and coworkers compared duct tape to cryotherapy in a 2002 study.8 Having warts on all parts of the body, 61 patients aged 3 to 22 years old received either cryotherapy treatment every two to three weeks (up to six sessions) or duct tape application once every six days for up to two months. Eighty-five percent of the warts resolved in the duct tape arm versus 60 percent in the cryotherapy arm.

The mechanism of action remains unclear but may be related to local irritation caused by the adhesive or the act of occlusion that duct tape causes. However, in the aforementioned study, it was difficult for the patients with plantar warts to keep the tape on consistently due to hyperhidrosis and shoe gear.8 Although duct tape may be a cost-effective therapy for those who are unwilling or unable to see a physician, more research is necessary to determine the true efficacy for plantar verrucae.

A Closer Look At Cantharidin And Bleomycin

Cantharidin. Cantharidin (Cantharone, Dormer Labs), a blistering agent, is derived from the beetle Cantharis vesicatoria.3 It is not FDA-approved in the United States so physicians must order cantharidin from distributors in other countries. After debridement of the wart, one would apply a thin layer of cantharidin (also available in a compounded formula with podophyllin and salicylic acid) and cover the wart with occlusive tape. Wash the area with soap and water in anywhere from six to 24 hours, and a possible blister may form. Repeat this once every two weeks. It is not painful to apply cantharidin but it may be quite disabling when the blister forms. While the literature reports cure rates as high as 80 percent with cantharidin, there are no randomized, controlled studies utilizing cantharidin on plantar warts.3

Bleomycin. Bleomycin, a potent DNA and protein synthesis inhibitor, is a chemotherapeutic agent that has antiviral, antibacterial and antitumor properties.9 One would reserve this treatment as therapy for recalcitrant warts.3 Bleomycin causes tissue necrosis that elicits an immune response. One should not use the medication in pregnant or breastfeeding women, children, immunosuppressed or vascularly compromised patients. If the clinician injects bleomycin without a lidocaine mixture or block, it is extremely painful upon injection. Within a day, a black ecchymotic eschar may form.

In a placebo-controlled study of bleomycin versus saline solution for palmoplantar warts, researchers reconstituted a 15 mg bottle of bleomycin powder with 5 mL saline and kept it as stock solution.9 They then prepared a mixture of two parts 2% lidocaine and one part of a stock solution in a tuberculin syringe. After debridement, researchers injected the solution intralesionally in increments depending on the size of the lesion. They repeated this treatment in two weeks if necessary and followed patients for a year. After one or two injections, 96.1 percent of the palmoplantar warts responded.

For patients who would like to avoid injection, authors have described another technique of applying the bleomycin solution by dropping it on a debrided wart and noted a 92 percent clearance rate with this approach.10 Bleomycin has high rates of effectiveness but may not be the ideal therapy for every patient.

Does Candida Immunotherapy Have Potential For Plantar Warts?

Candida immunotherapy. Researchers have described the injection of Candida albicans skin test allergen as a therapeutic option for plantar warts.11 Previous articles have shown that injection of a site on the foot will often clear distant wart sites like the hands or knees.12

In a retrospective review of 80 patients who were injected with a C. albicans skin test allergen (Candin, Nielsen Biosciences) in the primary or largest plantar verruca, Vlahovic and colleagues found that 65 percent had successful treatment (skin lines returned to the lesion).13 Those who fell into the failure group either were lost to follow-up or did not meet the criteria of having skin lines return throughout the lesion. When examining the data further, researchers determined that four visits were necessary to clear the lesion (consistent with the literature), and that patients who had a previous tissue-destructive procedure (cantharidin, salicylic acid, various lasers) before initiating the Candida albicans skin test allergen regimen were almost three times more likely to clear once injection therapy started than those who had not had any previous therapy and began the Candida albicans skin test allergen injection process. These findings most likely demonstrate that warts need a multimodal approach to resolve.

Do HPV Vaccines Warrant A Closer Look For Plantar Verrucae?

HPV vaccine. Both Gardasil® (human papillomavirus quadrivalent (types 6, 11, 16, 18) recombinant vaccine, Merck) and Cervarix® (human papillomavirus bivalent (types 16 and 18) recombinant vaccine, GlaxoSmithKline) are HPV vaccines that are indicated to decrease the incidence of cervical cancer by preventing infection by certain HPV types.

Physicians give Gardasil to both males and females in a series of three injections: baseline, two months and six months. With the recent evidence that Gardasil protects males as well as females equally from developing genital warts, it seems that the 9 to 26 age range will be receiving the vaccination more so than ever before.14 This leads to the question: will this be helpful in eradicating current or preventing future plantar verruca in this population?

As there have been no clinical trials to address the use of the vaccines for verruca vulgaris and plantar verruca, there is only anecdotal evidence. In observations by investigators during the Gardasil clinical trials, they noted that patients who already had both verruca vulgaris and plantar verruca before their vaccination had some warts clear during the trial.15 Investigators also noted that Gardasil had a protective effect against neoplasia for patients who had HPV types 1, 2,and 3. Most plantar warts are caused by HPV types 1, 2, 4 or 63. The vaccine, however, does not cover the typical strains that affect the foot for transformation of an HPV infection into malignancy.

Since there is evidence of Gardasil’s cross protection with related HPV strains (45, 31, and 52) plus the aforementioned anecdotal evidence, it comes as little surprise that two articles in Archives of Dermatology reported a significant reduction of palmar and plantar verruca.16 In a 31-year-old man with a history of epilepsy and developmental delay, over 30 warts on his hands (and some on the feet) cleared after administration of the three Gardasil injections and there was no recurrence 18 months after the initial injection.15 The study did not identify the HPV type of this patient’s warts but he had no previous history of genital warts or other significant history. Other case series have shown anecdotal success with Gardasil for warts in multiple locations, including the feet.17 As this is a common vaccination in teenagers, it is important for the practicing clinician to note changes may or may not occur when the adolescent with plantar warts is subject to this injection.

Laser Therapy For Plantar Warts: What The Studies Show

Laser. One of the first lasers clinicians used on plantar verrucae, the carbon dioxide (CO2) laser is an ablative laser in the infrared spectrum with a beam that acts as a scalpel.18 The beam targets water and is non-selective in its tissue destruction. Even though the CO2 laser leaves a cauterized and clean surgical field, the area targeted must heal by secondary intention.

When performing this procedure on a patient, it is important the clinician discusses the possibility of scar, delayed healing and postoperative pain. Clinicians should wear a mask, have a smoke evacuator and take other precautions due to the plume that this laser creates.19 There have been no randomized controlled studies utilizing the CO2 laser as monotherapy for plantar verrucae but reports of its combined use with topical therapies like imiquimod 5% cream have shown moderate success.20

The neodymium yttrium aluminum garnet (Nd:YAG) laser has a wavelength of 1064 nm, which is also in the infrared range. However, this is a non-ablative laser, which targets the chromophore (the entity in the body that absorbs the laser wavelength) oxyhemoglobin, which allows for selective heating of the capillary rich active verrucae.21 The non-ablative pulsed dye laser also targets oxyhemoglobin around the 585 nm to 595 nm wavelength.21

In a study following 46 patients with plantar warts, the patients were treated with either the Nd:YAG laser or the pulsed dye laser. Due to the Nd:YAG wavelength being absorbed less well than the pulsed dye wavelength by oxyhemoglobin, the researchers applied the Nd:YAG at a fluence of 100 J/cm2 in comparison to the pulsed dye laser fluence of 8 J/cm2.

There was no significant difference in the use of the two lasers with a clearance rate of 73.9 percent for the pulsed dye laser group in comparison to 78.3 percent for the Nd:YAG laser group. However, the Nd:YAG laser treatment was more painful and the pulsed dye laser required more treatments. This observation is consistent with what I have seen in patients receiving laser therapy. Both lasers produce less downtime and possible scarring than the CO2 device.

What About Surgical Treatment Options?

Surgical treatment options. Excision of the verruca is common. It can involve sole excochleation of the lesion, curettage followed by cauterization or a true excisional procedure. No randomized, controlled studies have been published utilizing this technique for the foot.

As success rates are reportedly 65 percent to 85 percent, the most problematic sequelae of these procedures are scarring and recurrence.3 Both can occur in up to 30 percent of patients.23,24 Authors have attributed recurrence to activation of the Koebner phenomenon in which the latent virus next to the original wart becomes active.25 A recurring wart within a scar is a challenging entity to manage and will often result in frustration for the practitioner and patient. From an anatomic and pain perspective, scarring can be particularly problematic on the plantar foot. Authors do not recommend excision of plantar warts as a standard, first-line therapy due to pain, very possible recurrence and resulting plantar scar.26   

Looking At The Potential Of Microwave Therapy

Microwave therapy. In 2018, the FDA approved microwave therapy (Swift®, Emblation), a new technology that was developed and studied in the United Kingdom. In a pilot study, Bristow and colleagues evaluated the use of microwave therapy for 54 recalcitrant plantar warts.27 Of the 75.9 percent resolved warts, 94 percent cleared in over three treatments with the device. Patients reported moderate discomfort during the therapy but pain resolved immediately post-treatment. There were no plumes nor vapors produced by application of the device, and no special dressings or home care were necessary.

Microwaves produce dielectric heating and cause rapid temperature elevation in tissue. Via in vitro testing during the clinical study, the researchers showed that microwave activated keratinocytes, dendritic cells and immunomodulator moieties created anti-HPV immunity.27 This new modality (distributed in the United States by Saorsa) shows great potential and continues to be studied for warts and other skin conditions.

In Summary

Human papillomavirus infection of the skin is a fascinating and complex disease entity that creates a therapeutic conundrum for both patients and physicians. Wart treatment is more than just causing destruction to a skin lesion. Clinicians need to consider the host’s immune status, the type of HPV involved, the anatomical location and the tolerance for a certain procedure from a lifestyle perspective. The goal of therapy is to destroy the lesion in the fewest visits with the least pain.

At this time, there are a variety of well-studied as well as brand new therapies that one can use as monotherapy or in combination to create a positive therapeutic outcome for our patients dealing with plantar warts. 

Dr. Vlahovic is a Clinical Professor in the Department of Podiatric Medicine at the Temple University School of Podiatric Medicine.

By Tracey C. Vlahovic, DPM, FFPM RCPS (Glasg)

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6. Salk RS, Grogan KA, Chang TJ. Topical 5% 5-fluorouracil cream in the treatment of plantar warts: a prospective, randomized, and controlled clinical study. J Drugs Dermatol. 2006;5(5):418-424.

7. Mullen BR, Guiliana JV, Nesheiwat F. Cimetidine as a first-line therapy for pedal verruca. J Am Podiatr Med Assoc. 2005; 95(3):229-234.

8. Focht DR 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.

9. Soni P, Khandelwal K, Aara N, Ghiya BC, Mehta RD, Bumb RA. Efficacy of intralesional bleomycin in palmo-plantar and periungual warts. J Cutan Aesthet Surg. 2011;4(3):188-191.

10. Munn SE, Higgins E, Marshall M, Clement M. A new method of intralesional bleomycin therapy in the treatment of recalcitrant warts. Br J Dermatol. 1996;135(6):969-971.

11. Signore RJ. Candida albicans intralesional injection immunotherapy of warts. Cutis. 2002; 70(3):185-192.

12. Clifton MM, Johnson SM, Roberson PK, Kincannon J, Horn TD. Immunotherapy for recalcitrant warts in children using intralesional mumps or Candida antigens. Pediatr Dermatol. 2003; 20(3):268-71.

13. Vlahovic T, Spadone S, Dunn SP, et al. Candida albicans immunotherapy for verrucae plantaris. J Am Podiatr Med Assoc. 2015; 105(5):395-400.

14. Melnick M. Gardasil protects boys and men from HPV too. Time. Available at . Published Feb. 3, 2011. Accessed June 16, 2019.

15. Venugopal SS, Murrell DF. Recalcitrant cutaneous warts treated with recombinant quadrivalent human papillomavirus vaccine (types 6, 11, 16, and 18) in a developmentally delayed, 31-year-old white man. Arch Dermatol. 2010;146(5):475-477.

16. Ault KA. Human papillomavirus vaccines and the potential for cross-protection between related HPV types. Gynecol Oncol. 2007;107(2 Suppl 1):S31-S33.

17. Daniel BS, Murrell DF. Complete resolution of chronic multiple verruca vulgaris treated with quadrivalent human papillomavirus vaccine. JAMA Dermatol. 2013;149(3):370-372.

18. Serour F, Somekh E. Successful treatment of recalcitrant warts in pediatric patients with carbon dioxide laser. Eur J Pediatr Surg. 2003;13(4):219-223.

19. Gloster HM, Roenigk R. Risk of acquiring human papillomavirus from the plume produced by the carbon dioxide laser in the treatment of warts. J Am Acad Dermatol. 1995; 32(3):436-441.

20. Zeng Y, Zheng Y, Wang L. Vagarious successful treatment of recalcitrant warts in combination with CO2 laser and imiquimod 5% cream. J Cosmet Laser Surg. 2014; 16(6):311-313.

21. Patil UA, Dhami LD. Overview of lasers. Ind J Plast Surg. 2008;41(Suppl):S101-S113.

22. El-Mohamady Ael-S, Mearag I, El-Khalawany M, Elshahed A, Shokeir H, Mahmoud A. Pulsed dye laser versus Nd:YAG laser in the treatment of plantar warts: a comparative study. Lasers Med Sci. 2014;29(3):1111-1116.

23. Pringle WM, Helms DC. Treatment of plantar warts by blunt dissection. Arch Dermatol. 1973;108(1):79-82.

24. Baruch K. Blunt dissection for the treatment of plantar verrucae. Cutis. 1990;46(2):145-147, 151-152.

25. Leman JA, Benton EC. Verrucas. Guidelines for management. Am J Clin Dermatol. 2000;1(3):143-149.

26. Arndt KA, Bowers KE, Alam M, Reynolds R, Tsao S (eds). Warts. In: Manual of Dermatologic Therapeutics, Sixth Edition. Lippincott, Williams & Wilkins, Philadelphia, 2002, pp. 241-251.

27. Bristow I, Lim WC, Lee A et al. Microwave therapy for cutaneous human papilloma virus infection. Eur J Dermatol. 2017; 27(5):511-518.

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