Verrucae (common warts, verruca vulgaris, flat warts, verruca plana, plantar warts, verruca plantaris, myrmecia, filiform/digitate warts, subungal/periungal warts, anogenital warts, condyloma acuminatum, venereal warts, epidermodysplasia verruciformis, Lewandowsky-Lutz dysplasia)

Table I.

Cutaneous warts are transmitted by direct skin-to-skin contact and are often seen at sites of trauma or microtrauma, such as the hands and feet. Anogenital warts are sexually transmitted infections that pass from person to person via direct contact of genital skin or mucous membranes.

HPV infection probably begins with entry of the virus through microabrasions into keratinocytes along the stratum basale. The viral DNA then replicates as the basal cells differentiate toward the epithelial surface with eventual production of complete virions that are then released as the dead superficial keratinocyte is shed.

In cutaneous and anogenital warts, viral replication induces hyperplasia of all epidermal layers except the basal layer causing acanthosis, parakeratosis, and hyperkeratosis. Rete ridges protrude deeper into the dermis resulting in the characteristic papillomatous finding on histology. Koilocytosis and cytoplasmic keratohyalin inclusion bodies are also seen.

HPV infections can induce cellular dysplasia resulting in low and high-grade neoplasias. Increased risk of dysplasia has been associated with viral DNA integration into host cell chromosomes, and with certain HPV types (e.g. 16, 18). In these cases, histopathology may depict basaloid proliferation, a high nuclear/cytoplasmic ratio, and increased mitoses with occasional dyskaryosis.

HPV infections may regress after local and systemic immune responses, primarily involving cell-mediated immunity with interferon induction. Individual variations in cell-mediated immunity likely account for differences in severity and duration of disease. Immunodeficient/immunocompromised patients with defective or absent cell-mediated immunity as in WHIM (warts, hypogammaglobulinemia, infections, myelokathexis), common variable immunodeficiency (CVID), severe combined immunodeficiency (SCID), HIV/AIDS, lymphomas, and immunosuppressive drugs may develop widespread, severe, and/or recalcitrant infections.

The clinical course is highly variable ranging from spontaneous resolution after a few weeks/months to infections lasting many years in an active or latent state. In children, for example, common cutaneous warts have been found to spontaneously resolve in 50% and 90% of children within 1 and 5 years, respectively. Persistent and latent infections may result from viral production of various immune system suppressing proteins.

Epidermodysplasia verruciformis is an autosomal recessive genodermatosis (chromosome 17) that results in defective cutaneous immunity and therefore an increased susceptibility to cutaneous HPV infections and subsequent cutaneous malignancies, particularly at a young age. An acquired form has been described in patients with impaired cell-mediated immunity (e.g. HIV/AIDS).

Systemic Implications and Complications

Immunocompromised state

In patients with new-onset, rapid, and/or diffuse cutaneous HPV infections, one must consider the possibility of a new immunocompromised state (e.g. HIV/AIDS, lymphoma, etc) and adequately investigate.

Malignancy

Cutaneous and anogenital warts are predominantly benign lesions, but a clear oncogenic potential exists from papillomavirus infection, particularly when infected with certain high-risk types (e.g. 16, 18) or in patients with congenital or acquired epidermodysplasia verruciformis (EV).

Except in patients with EV, it is extremely rare for non-anogenital cutaneous warts (e.g. common warts, plantar warts, etc) to incite neoplasia as the HPV strains responsible for these infections are much less oncogenic. With respect to the more oncogenic HPV strains (often involving anogenital lesions), current preventive medicine guidelines should be followed, such as regular screening exams (e.g. pap smear, HPV DNA testing) and consideration of high-risk HPV vaccination, to best avoid malignant lesions or transformation.

Recurrent respiratory papillomatosis

Although not typically diagnosed by skin exam, recurrent respiratory papillomatosis (RRP) is a systemic, non-cutaneous complication of HPV infection and may present concomitantly with cutaneous or anogenital warts in infants with peripartum HPV exposure. RRP lesions often cause hoarseness but can also cause respiratory distress/stridor, obstruction, and infection. Malignant transformation may also rarely occur. Appropriate expert consultation (e.g. ENT, pediatrics) should be obtained.

Treatment Options

Numerous treatment options exist and some work best for certain subtypes (e.g. flat vs plantar warts), many are off-label, and some must be avoided in pregnancy (check pregnancy category prior to consideration if patient is pregnant).

Medical (topical)

• Salicylic acid 17% liquid +/- lactic acid [Keratolytic therapy]. Applied daily at bedtime after soaking the lesion with warm water for 10-20 min then paring down superficial dead skin. Continue for 7-10 days past the appearance of resolution to better avoid recurrence.

• Cantharidin 0.7% solution [Blistering agent]. Applied every other week during office visits only and optionally covered with a bandage. Leave on for 2-6 hours, then remove the bandage and wash the area. After the blister has healed, the efficacy is greatly increased if keratolytic therapy is utilized between office visits. There is a risk of dyspigmentation in darker skin types. This treatment option is particularly useful in young children due to painless application, although the blistering response can be painful.

• Intralesional immunotherapy. Intradermal superficial injection (0.1-0.4 mL) of skin test antigen (e.g. Candida, Bacillus Calmette-Guerin) into the largest lesion(s), repeated monthly if needed and preferably combined with other modalities. This treatment option is often very effective and may result in concomitant regression/resolution of non-injected warts.

• Compounded formulas (often requires special pharmacy).

Example A: Salicylic acid (20%) + 5-fluorouracil (2%) in DMSO. Applied nightly for 4-6 weeks or resolution, covering with a bandage overnight. Side effects include erythema/inflammation and may cause hyperpigmentation.

Example B: 5-fluorouracil (2%) + pyruvic acid (2%) + occlusion. Apply to the wart then cover with duct tape for 3-5 days, then remove/soak/pare-down wart, repeat as needed. Side effects include erythema/inflammation and may cause hyperpigmentation.

Example C: Cantharidin + podophyllin (5%) + salicylic acid 30% mixture. A compound mixture applied once weekly during office visits for 4 weeks, and typically washed off 4-8 hours after application. Side effects may be severe and include chemical burns, sensitization, or other more serious reactions to podophyllin.

• IImiquimod 5% cream [Immunomodulator]. Applied daily for 3-5 days per week at bedtime for up to 16 weeks. Occlusion after application can improve the efficacy of this modality. It is usually a painless application with minimal side effects such as erythema, mild burning, and itching. Particularly useful in pediatric patients with lesions not responsive to first line therapy (e.g. keratolytic therapy, cryotherapy) or for lesions on the face. Expensive and less effective on very hyperkeratotic lesions.

• 5-fluorouracil 5% cream/solution [Pyrimidine analog inhibits DNA synthesis]. Applied twice daily for 3-5 weeks, preferably under occlusion or in combination with salicylic acid. Side effects include erythema/inflammation and may cause hyperpigmentation. Good topical choice for adults, but avoid in pregnancy. Sun protection should be used if applied in areas of sun exposure.

• Tretinoin cream or gel [Retinoid]. Applied daily until mild irritation/inflammatory response develops then decrease to every other day or every few days to maintain irritation until warts resolve. May take several weeks/months and causes exfoliation and skin irritation, but overall side-effects are mild and thus is a good first-line topical choice for children, particularly for facial flat warts when more aggressive destructive methods should be avoided. Sun protection should be used if applied in areas of sun exposure. To protect the surrounding skin, a layer of Aquaphor/Vaseline can be applied around the wart prior to the tretinoin application.

• Dinitrochlorobenzene (DNCB) [Type IV immune response]. Allergic sensitivity to DNCB must first be induced, typically by applying 1% to 2% DCNB to the volar aspect of the forearm. Once sensitivity has been induced, apply 0.5% to 2% DNCB every 1-2 weeks to the wart during office visits, cover with a bandage and wash off the next morning. Titrate concentration and frequency of application to produce the goal of a constant, mild, itchy, erythematous lesion. Effective, particularly for recalcitrant warts in children. There are relatively mild side effects that include the intended symptoms, but there is a risk of blistering or worse contact dermatitis. DNCB is mutagenic and office application needs to be considered depending on the patient.

• Squaric acid dibutylester (SADBE) [Type IV immune response]. Similar to DNCB, allergic sensitivity must first be induced, typically by applying 1% to 2% SADBE in acetone under occlusion. Once sensitivity has been induced, apply 0.5% to 5% every 1-2 weeks to the wart during office visits, cover with a bandage and wash off the next morning. Titrate the concentration and frequency of application to produce the goal of constant, mild, itchy, erythematous lesion. Effective, particularly for recalcitrant warts.

• A third sensitizer, diphenylcyclopropenone (DPCP), has also been used with similar technique and results. There are relatively mild side effects that include the intended symptoms, but there is a risk of blistering or worse contact dermatitis. SADBE and DPCP are typically not as effective as DNCB, but they have not been found to be mutagenic.

• Tri- or Bichloroacetic acid 10%-90% solution [Caustic/peeling agent]. Applied once weekly during office visits for at least 4 weeks. Remove residual/excess acid with a neutralizing agent. Side effects with higher concentrations include severe pain, burning, and sometimes ulcerations.

• Cidofovir 1% cream/ointment [Antiviral]. Applied nightly, covered with a bandage, then washed off in the morning. This is a relatively new topical therapy for recalcitrant warts that has shown promise in immunocompetent or immunocompromised children and adults, and has also been rarely used intravenously for severe, diffuse warts (albeit with systemic side effects). There are very mild side effects when used topically, but it is very expensive.

• Podophyllotoxin [Anti-mitotic agent]. Podofilox solution (0.5%, 0.15%) applied every other day for 3 weeks or twice daily for 3 consecutive days. Side effects include mild burning and erythema. Contraindicated during pregnancy.

• Podophyllin (10%, 25%) applied once weekly during office visit for at least 4 weeks, washed off 8-12 hours after application. Side effects may be worse than podofilox and include chemical burns, sensitization, and other more serious complications. Contraindicated in pregnancy.

• Sinecatechins 15% ointment. Polyphenol E compound extracted from green tea with unknown mechanism of action, approved for anogenital warts but have been used for cutaneous warts. Apply three times a day until resolution for up to 16 weeks; may cause mild/moderate/severe local irritation. Occlusion after the application may aid in effectiveness.

• Bleomycin 1 mg/mL [Cytotoxic chemotherapeutic agent]. Intralesional injection every 2-4 weeks until resolution with a maximum dose of typically 1-2 mg per wart. The solution can be mixed with lidocaine for anesthetic and additional cytotoxic effects. This treatment option is expensive and side effects include pain, inflammation, vasospasm, Raynaud’s, and possible eschar formation with tissue necrosis. Various sized needles and methods may be used for injection. Special ventilation hoods may be required when mixing. Best for subungal, plantar, or recalcitrant warts. Serious systemic side effects may occur (e.g. pulmonary fibrosis); however, bleomycin is considered a relatively safe option when used cutaneously in limited amounts. Recent reports of a translesional multipuncture technique used with very low concentration bleomycin (0.1 U/mL) may be effective with fewer side effects.

• Formalin (4%) or formaldehyde (10%) solutions. Applied daily after showering with weekly paring of the wart. This treatment option is mutagenic and may take many months of monotherapy, and may induce formalin sensitivity.

Medical (systemic)

• Cimetidine 30-50 mg/kg oral daily [H2 receptor antagonist]. Cimetidine is taken daily in four divided doses for up to 3 months and is thought to work by providing a slight improvement in cell-mediated immunity. It is rarely utilized because it requires a supra-pharmacological dose that may produce anti-androgen effects and has minimal efficacy with lack of good data.

• Isotretinoin 20-40 mg/day [Retinoid]. Some reports of oral isotretinoin proving effective for the treatment of recalcitrant facial flat warts. Care must be taken to follow all typical precautions and iPledge^TM monitoring (e.g. appropriate counseling, two forms or contraception in females, monitoring CBC, liver function, and triglycerides, etc).

• Zinc sulfate 10 mg/kg oral daily [Mineral supplement]. Some reports of oral zinc supplementation aiding in wart resolution with minimal/no side effects.

• Vaccination. Vaccines have been shown to effectively prevent HPV infection, although vaccinations to date only focus on high-risk HPV types and some controversy exists regarding implementation in children/adolescents. Nevertheless, some theorize even vaccines only targeting high-risk HPV types (e.g. 16, 18) may still provide some collateral immunity against other types.

Surgical/Physical

• Cryosurgery (liquid nitrogen). Applied with a cotton tip applicator or spray device (preferred) every 3-4 weeks. Maintain freeze for 5-15 seconds depending on thickness of lesions, for one or two cycles. Side effects include pain, erythema, blisters, possible dyspigmentation (particularly in darker skin types), and scarring if too aggreessive. After a few days, once healing from cryosurgery has occurred, consider keratolytic therapy in between office visits.

• Duct tape occlusion. This involves the prolonged occlusive application of duct tape to the lesion for 7-14 days, removal for cleaning/soaking/paring, then reapplication of new duct tape. Repeat until the lesion is resolved. There is improved efficacy when combined with other modalities (e.g. 5-FU, imiquimod, keratolytic therapy).

• Curettage with electrosurgery (electrodesiccation). After local anesthesia, perform 1-3 cycles of lesion desiccation, then curettage, then desiccation of the lesion base. This is not typically first-line therapy and not recommended for plantar warts due to the risk of scarring. Recommend use of N-95 particulate mask to prevent incidental inhalation of viral particles.

• Laser phototherapy. Typically performed with CO2, fractionated CO2, or pulsed dye laser, and may be combined with topical or intralesional therapy (e.g. bleomycin). This treatment option is expensive, and is often best for recalcitrant lesions only. Variable laser settings may be used and side effects are dependent on laser choice. Recommend use of N-95 particulate mask to prevent incidental inhalation of viral particles.

• Photodynamic therapy. New reports of efficacy using 5-aminolevulinic acid photodynamic therapy in a stepwise fashion starting with low dose. Likely best for thin facial warts.

• Surgical excision. Good option for filiform/pedunculated warts via scissor snip excision and then treating the base with topical therapy; however, conventional excision of common or plantar warts best avoided or refer to Podiatry for evaluation.

Optimal Therapeutic Approach for this Disease

The clinical course of cutaneous warts is highly variable ranging from spontaneous resolution after a few weeks or months to infections lasting many years in an active or latent state. In children, for example, common cutaneous warts have been found to spontaneously resolve in 50% and 90% of children within 1 and 5 years, respectively. Therefore, observation is always a reasonable initial clinical choice, particularly in children where painful therapies may do more harm than good.

If one decides to administer treatment, therapeutic options consist of tissue destruction to destroy virus-containing epithelial cells, local chemotherapy, and medications that enhance normal innate immunity. For optimum patient benefit, the easiest, least painful, and least expensive modalities should typically be tried first, with more destructive and potentially scarring methods reserved for recalcitrant lesions or areas of less cosmetic concern.

Multiple treatment sessions and combination therapy are often required, and therapeutic success for common warts is often best achieved with cryosurgery or cantharidin application during regular office visits (every 2-4 weeks) combined with home therapy consisting of a keratolytic solution applied under duct tape occlusion. Intralesional immunotherapy is also a preferred treatment method of the authors.

Treatment strategy, however, differs greatly depending on age of patient, availability and cost of modalities, location and type of lesion, side effect profile, and response to initial treatment.

Patient Management

Observation may likely be the initial management decision, but regular patient visits should occur approximately every 2-4 weeks with follow-up of patient-applied therapy and/or repeat physician-applied therapy in clinic. Multiple treatment sessions and combination therapy will typically provide the optimal outcome. Consideration of patient age (child versus adult) and lesion location (cosmesis) should also direct therapeutic management.

It is recommended that patients use and label a different set of ‘wart paring’ supplies (e.g. pumice stone, nail file, emery board), kept separate from their usual supplies to avoid spread of HPV to other skin locations or other individuals. Patients should be advised to avoid the shaving of legs, beard, etc if lesions are present in these areas, to prevent local spread. Lesions with clinical evidence or high-risk of malignancy should be biopsied.

Unusual Clinical Scenarios to Consider in Patient Management

Anogenital warts in children should elevate suspicion/concern of possible sexual abuse, whereas anogenital or cutaneous warts in the neonatal/infantile period is often indicative of perinatal HPV transmission.

New or rapid onset of diffuse, aggressive cutaneous or anogenital HPV infections could be the harbinger of systemic disease and/or immunosuppression, and would therefore indicate adequate workup and consultation.

What the Evidence?

Aldahan, AS, Mlacker, S, Shah, VV, Kamath, P, Alsaidan, M, Samarkandy, S, Nouri, K.. “Efficacy of intralesional immunotherapy for the treatment of warts: A review of the literature”. Dermatol Ther.. vol. 29. 2016 May. pp. 197-207. (A recent review of the literature discussing the various intralesional immunotherapies for treatment of warts.)

Alghamdi, KM, Khurram, H.. “Successful treatment of plantar warts with very diluted bleomycin using a translesional multipuncture technique: pilot prospective study”. J Cutan Med Surg. vol. 16. 2012. pp. 250-6. (Case report citing efficacy of diluted intralesional bleomycin using a different technique.)

Allen, AL, Siegfried, EC.. “What's new in human papillomavirus infection”. Curr Opin Pediatr. vol. 12. 2000. pp. 365-9. (Journal review article providing an overview of HPV infections and therapeutic options with primary focus on treatment in children.)

Amirnia, M, Khodaeiani, E, Fouladi, DF, Masoudnia, S.. “Intralesional immunotherapy with tuberculin purified protein derivative (PPD) in recalcitrant wart: A randomized, placebo-controlled, double-blind clinical trial including an extra group of candidates for cryotherapy”. J Dermatolog Treat. vol. 27. 2016. pp. 173-8. (This is a well-designed randomized double-blind placebo-controlled trial showing that intralesional injection with PPD antigen was effective at treating recalcitrant warts. Treatments were done every other week for 12 weeks (6 total treatments) and compared to injection with saline or treatment with cryotherapy at similar intervals. It is important to note is that the inclusion criteria for this study require at least 5mm induration 48-72hr after intradermal PPD placement on the volar surface of the forearm. This level of reactivity is often seen in patients from countries that receive routine BCG vaccination. This study did not test the efficacy of intralesional PPD antigen in patients who have a negative PPD test on the forearm.)

Bacelieri, R, Johnson, SM.. “Cutaneous warts: an evidence-based approach to therapy”. Am Fam Physician. vol. 72. 2005. pp. 647-52. (Concise, therapy-focused review specifically looking at salicylic acid, cryotherapy, imiquimod, bleomycin, retinoids, and intralesional immunotherapy.)

Bonnez, W, Reichman, RC., Mandell, GL, Bennett, JE, Dolin, R. “Papillomaviruses”. Principles and Practice of Infectious Diseases. vol. 2. 2009. (A widely used academic textbook on infectious disease, split into two volumes. Volume 2, Chapter 144 provides detailed information on papillomavirus infections to include virology, genetics, epidemiology, pathogenesis, clinical manifestations, diagnosis, and treatment options.)

Dobson, JS, Harland, CC.. “Pulsed dye laser and intralesional bleomycin for the treatment of recalcitrant cutaneous warts”. Lasers Surg Med. vol. 46. 2014. pp. 112-6. (Recent publication reporting the use of PDL and intralesional bleomycin for warts.)

Forcier, M, Musacchio, N.. “An overview of human papillomavirus infection for the dermatologist: disease, diagnosis, management, and prevention”. Dermatologic Therapy. vol. 23. 2010. pp. 458-76. (Journal review article that provides an extensive review of HPV infections to include photographs, although focuses primarily on current therapies for genital HPV infections.)

Habif, TP.. “Warts”. Clinical Dermatology. 2009. (An academic textbook of dermatology with an entire chapter devoted to warts and other viral infections. Provides succinct descriptions of clinical diagnostic features and provides therapeutic suggestions.)

Kang, HS, Lee, MW, Paek, JO. “Comparison of cure rates and durations of treatment with diphenylcyclopropenone immunotherapy for warts in children/adolescents and adults”. Int J Dermatol.. 2014 Apr 2. (Recent publication highlighting the efficacy of DPCP immunotherapy and comparison between use in children versus adults.)

Keogh-Brown, MR, Fordham, RJ, Thomas, KS, Bachmann, MO, Holland, RC, Avery, AJ. “To freeze or not to freeze: a cost-effectiveness analysis of wart treatment”. Br J Dermatol. vol. 156. 2007. pp. 687-92. (Useful cost comparison of commonly used general practitioner wart therapies to include duct tape occlusion, salicylic acid, and cryotherapy.)

Kwok, CS, Gibbs, S, Bennett, C. “Topical treatments for cutaneous warts”. Cochrane Database Syst Rev. vol. 9. 2012 Sep 12. pp. CD001781(Updated meta-analysis of randomized controlled trials pertaining to cutaneous wart therapies confirming the effectiveness of salicylic acid, but finding lack of evidence to define any single therapy as best. Nevertheless, good compilation and analysis of clinical trials.)

Lipke, MM.. “An armamentarium of wart treatments”. Clin Med Res. vol. 4. 2006. pp. 273-93. (Extensive, well-written composition of the full gamut of cutaneous wart therapies to include folk remedies, hypnotic suggestive therapy, destructive therapies, virucidal therapies, antimitotic therapies, immunotherapy, and more.)

Mun, JH, Kim, SH, Jung, DS. “Oral zinc sulfate treatment for viral warts: an open-label study”. J Dermatol. vol. 38. 2011. pp. 541-5. (Publication reporting improvement in warts after oral zinc sulfate.)

Nofal, A, Yosef, A, Salah, E.. “Treatment of recalcitrant warts with Bacillus Calmette-Guerin: a promising new approach”. Dermatol Ther. vol. 26. 2013. pp. 481-5. (Recent publication citing efficacy of intralesional BCG for wart treatment.)

Olguin-Garcia, MG, Jurado-Santa Cruz, F, Peralta-Pedrero, ML. “A double-blind, randomized, placebo-controlled trial of oral isotretinoin in the treatment of recalcitrant facial flat warts”. J Dermatolog Treat. 2014 Feb 19. (Recent publication reporting improvement in facial warts after treatment with oral isotretinoin.)

Padilla Espana, L, Del Boz, J, Fernandez Morano, T. “Topical cidofovir for plantar warts”. Dermatol Ther. vol. 27. 2014. pp. 89-93. (Recent publication citing efficacy of topical cidofovir for plantar wart treatment.)

Qian, G, Wang, S, Deng, D. “Is the step-up therapy of topical 5-aminolevulinic acid photodynamic therapy effective and safe for the patients with recalcitrant facial flat wart?”. Dermatol Ther. vol. 27. 2014. pp. 83-8. (Recent publication discussing the use of step-up therapy of 5-ALA PDT for wart treatment.

Ramirez-Fort, MK, Sam, H, Manders, EK.. “Management of cutaneous human papillomavirus infection: surgery”. Curr Probl Dermatol. vol. 45. 2014. pp. 186-96. (Recent review of surgical options for wart treatment.)

Soni, P, Khandelwal, K, Aara, N. “Efficacy of intralesional bleomycin in palmo-plantar and periungal warts”. J Cutan Aesthet Surg. vol. 4. 2011. pp. 188-91. (Case report citing efficacy of intralesional bleomycin for wart treatment.

Stockfleth, E, Meyer, T.. “Sinecatechins (Polyphenon E) ointment for the treatment of external genital warts and possible future indications”. vol. 14. 2014. pp. 1033-43. (Recent publication discussing the use of Sinecatechins for wart treatment.)
**The original authors for this chapter were Drs. Justin Bandino and Christopher Sartori. The chapter was revised by Dr. Justin Bandino.