Warts are benign proliferations of skin and mucosa caused by the human papillomavirus (HPV). Currently, more than 100 types of HPV have been identified. Certain HPV types tend to infect skin at particular anatomic sites; however, warts of any HPV type may occur at any site. The primary clinical manifestations of HPV infection include common warts, genital warts, flat warts, and deep palmoplantar warts (myrmecia). Less common manifestations of HPV infection include focal epithelial hyperplasia (Heck disease),[1] epidermodysplasia verruciformis, and plantar cysts. Warts are transmitted by direct or indirect contact, and predisposing factors include disruption to the normal epithelial barrier.
Treatment is difficult, with frequent failures and recurrences. Many warts, however, resolve spontaneously within a few years even without treatment.
A small number of high-risk HPV subtypes are associated with the development of malignancies, including types 6, 11, 16, 18, 31, and 35. Malignant transformation most commonly is seen in patients with genital warts and in immunocompromised patients. HPV types 5, 8, 20, and 47 have oncogenic potential in patients with epidermodysplasia verruciformis.
Warts can affect any area on the skin and mucous membranes. The HPV virus infects the epithelium, and systemic dissemination of the virus does not occur. Viral replication occurs in differentiated epithelial cells in the upper level of the epidermis; however, viral particles can be found in the basal layer.
Warts are caused by HPV, which is a double-stranded, circular, supercoiled DNA virus enclosed in an icosahedral capsid and comprising 72 capsomers. More than 100 types of HPV have been identified. Note the following wart types and HPV types:
Warts are widespread in the worldwide population. Although the frequency is unknown, warts are estimated to affect approximately 7-12% of the population. In school-aged children, the prevalence is 10-20%. An increased frequency also is seen among immunosuppressed patients and meat handlers.
Although warts may affect any race, common warts appear approximately twice as frequently in whites as in blacks or Asians.[2] Focal epithelial hyperplasia (Heck disease) is more prevalent among American Indians and Inuit.[1]
Male-to-female ratio approaches 1:1.
Warts can occur at any age. They are unusual in infancy and early childhood, increase in incidence among school-aged children, and peak at 12-16 years.[3]
Approximately 65% of warts disappear spontaneously within 2 years. When warts resolve on their own, no scarring is seen. However, scarring can occur as a result of different treatment methods. Growth of periungual or subungual warts may result in permanent nail dystrophy.
Treatment failures and wart recurrences are common, more so among immunocompromised patients. Normal appearing perilesional skin may harbor HPV, which helps explain recurrences.
Common warts are usually asymptomatic, but they may cause cosmetic disfigurement or tenderness. Plantar warts can be painful, and extensive involvement on the sole of the foot may impair ambulation. Malignant change in nongenital warts is rare but has been reported and is termed verrucous carcinoma.[4, 5, 6] Verrucous carcinoma is considered to be a slow-growing, locally invasive, well-differentiated squamous cell carcinoma that may be easily mistaken for a common wart. It can occur anywhere on the skin but is most common on the plantar surfaces. Although this type of cancer rarely metastasizes, it can be locally destructive.
Alert patients to the risk factors for transmission of warts. These include trauma or maceration of the skin, frequent wet work involving hands, hyperhidrosis of feet, swimming pools, and nail biting. Butchers and slaughterhouse workers also are at increased risk for developing warts.
Alert patients that some warts may require multiple treatments and may be resistant to several treatment modalities. In addition, some warts may regress spontaneously without treatment.
For patient education resources, visit the Skin Conditions and Beauty Center. Also see the patient education articles Warts and Plantar Warts.
HPV is spread by direct or indirect contact. It can resist desiccation, freezing, and prolonged storage outside of host cells. Autoinoculation also may occur, causing local spread of lesions. The incubation period for HPV ranges from 1-6 months; however, latency periods of up to 3 years or more are suspected.
Common warts also are termed verruca vulgaris. They appear as hyperkeratotic papules with a rough, irregular surface. They range from smaller than 1 mm to larger than 1 cm. They can occur on any part of the body but are seen most commonly on the hands and knees (see image below).
View Image | Common wart on the hand. |
Filiform warts are long slender growths, usually seen on the face around the lips, eyelids, or nares.
Deep palmoplantar warts also are termed myrmecia.[7] They begin as small shiny papules and progress to deep endophytic, sharply defined, round lesions with a rough keratotic surface, surrounded by a smooth collar of calloused skin (see the image below). Because they grow deep, they tend to be more painful than common warts. Myrmecia warts that occur on the plantar surface usually are found on weight-bearing areas, such as the metatarsal head and heel. When they occur on the hand, they tend to be subungual or periungual.
View Image | Plantar warts. |
Flat warts also are termed plane warts or verruca plana. They are characterized as flat or slightly elevated flesh-colored papules that may be smooth or slightly hyperkeratotic. They range from 1-5 mm or more, and numbers range from a few to hundreds of lesions that may become grouped or confluent. These warts may occur anywhere; however, the face, hands, and shins tend to be the most common areas. They may appear in a linear distribution as a result of scratching or trauma (Koebner phenomenon). Regression of these lesions may occur, which usually is heralded by inflammation.
Butcher's warts are seen in people who frequently handle raw meat. Their morphology is similar to common warts, with a higher prevalence of hyperproliferative cauliflowerlike lesions. They are seen most commonly on the hands.
A mosaic wart is a plaque of closely grouped warts. When the surface is pared, the angular outlines of tightly compressed individual warts can be seen. These usually are seen on the palms and soles.
Focal epithelial hyperplasia, also termed Heck disease,[1] is an HPV infection occurring in the oral cavity, usually on the lower labial mucosa. It also can be seen on the buccal or gingival mucosa and rarely, on the tongue. The lesions appear as multiple flat-topped or dome-shaped pink-white papules. They usually are 1-5 mm, with some lesions coalescing into plaques. They are seen most frequently in children of American Indian or Inuit descent.
A cystic wart appears as a nodule on the weight-bearing surface of the sole. The nodule usually is smooth with visible rete ridges but may become hyperkeratotic. If the lesion is incised, cheesy material may be expressed. The etiology of these lesions is uncertain. One theory is that a cyst forms, originating from the eccrine duct, and secondary HPV infection occurs. Another theory is that the epidermis infected with HPV becomes implanted into the dermis, forming an epidermal inclusion cyst.
The diagnosis of warts is made primarily on the basis of clinical findings. Immunohistochemical detection of HPV structural proteins may confirm the presence of virus in a lesion, but this has a low sensitivity. Viral DNA identification using Southern blot hybridization is a more sensitive and specific technique used to identify the specific HPV type present in tissue. Polymerase chain reaction may be used to amplify viral DNA for testing. Although HPV may be detected in younger lesions, it may not be present in older lesions.
Paring of warts may reveal minute black dots, which represent thrombosed capillaries. Obtain a biopsy if doubt exists regarding the diagnosis.
Histopathologic features of common warts include digitated epidermal hyperplasia, acanthosis, papillomatosis, compact orthokeratosis, hypergranulosis, dilated tortuous capillaries within the dermal papillae, and vertical tiers of parakeratotic cells with entrapped red blood cells above the tips of the digitations. Elongated rete ridges may point radially toward the center of the lesion. In the granular layer, HPV-infected cells may have coarse keratohyaline granules and vacuoles surrounding wrinkled-appearing nuclei. Koilocytic (vacuolated) cells are pathognomonic for warts.
Deep palmoplantar warts appear similar to common warts except that most of the lesion lies deep to the plane of the skin surface. This endophytic epidermal growth often has the distinctive feature of polygonal, refractile-appearing, eosinophilic, cytoplasmic inclusions composed of keratin filaments, forming ringlike structures. Basophilic nuclear inclusions and basophilic parakeratotic cells loaded with virions may be in the upper layers of the epidermis.
Flat warts resemble common warts on light microscopy; however, the features tend to be muted. Cells with prominent perinuclear vacuolization around pyknotic, strongly basophilic, centrally located nuclei may be in the granular layer. These may be referred to as "owl's eye cells."
Butcher's warts have prominent acanthosis, hyperkeratosis, and papillomatosis. Small vacuolized cells with centrally located shrunken nuclei may be seen in clusters within the granular layer rete ridges.
Filiform warts may appear similar to common warts but tend to have prominent papillomatosis.
Focal epithelial hyperplasia is characterized by a hyperplastic mucosa with thin parakeratotic stratum corneum, acanthosis, blunting and anastomosis of rete ridges, and pallor of epidermal cells as a result of intracellular edema. Some areas may have prominent keratohyaline granules, and some vacuolated cells may be present.
A cyst filled with horny material characterizes cystic warts. The wall is composed of basal, squamous, and granular cells. Many of the epithelial cells may have large nuclei and clear cytoplasm with eosinophilic inclusion bodies. The cyst may rupture, resulting in a foreign body granuloma.
Multiple modalities are available for the treatment of warts, but none is uniformly effective.[8, 9] Start with the least painful, least expensive, and least time-consuming methods. Reserve the more expensive and invasive procedures for refractory extensive warts. Immunosuppressed individuals often are refractory to wart treatments. Various treatment methods are available. The British Association of Dermatologists has treatment guidelines for cutaneous warts. See British Association of Dermatologists' Guidelines for the Management of Cutaneous Warts 2014 for more information.[10]
Providing no treatment at all is certainly safe and cost effective. Consider this as an option, since 65% of warts may regress spontaneously within 2 years. Without treatment, however, patients risk warts that may enlarge or spread to other areas. Treatment is recommended for patients with extensive, spreading, or symptomatic warts or warts that have been present for more than 2 years.
Salicylic acid is a first-line therapy used to treat warts.[11] It is available without a prescription and can be applied by the patient at home. Cure rates from 70-80% are reported.
A nonblinded, randomized controlled trial compared treatment of plantar warts with 50% salicylic acid topical (Verrugon) applied daily with cryotherapy with liquid nitrogen (up to 4 treatments 2-3 wk apart). The study found no significant difference between the treatments in clearance of the plantar warts at 12 weeks and again at 6 months.[12] The lesser cost of the salicylic acid topical treatment made it more cost-effective than the liquid nitrogen treatment.
Several topical agents are available that can be applied by trained personnel in a physician's office. Cantharidin is an extract of the blister beetle that causes epidermal necrosis and blistering. Dibutyl squaric acid, also known as squaric acid dibutyl ester (SADBE), and diphencyclopropenone (DCP) are contact sensitizers. Trichloroacetic acid is a caustic compound that causes tissue necrosis. Podophyllin is a cytotoxic compound used more commonly in the treatment of genital warts. Aminolevulinic acid (ALA) is a photosensitizer that has been successfully used topically in combination with blue light to treat flat warts.[13]
Several prescription medications have proven beneficial in treating warts. These can be applied at home by the patient. Imiquimod is an immune response modifier approved for the treatment of genital warts. Reports indicate successful treatment of common warts.[14]
Cidofovir is an antiviral agent used for the treatment of cytomegalovirus infection in HIV patients. Several reports describe successful treatment of recalcitrant warts using various concentrations of topical cidofovir.[15, 16, 17, 18, 19]
Podophyllotoxin is a purified ingredient of podophyllin. Since it tends to work better on mucosal surfaces, it is used primarily to treat genital warts. Little information is available regarding treatment of nongenital warts with this medication.
5-Fluorouracil is a topical chemotherapeutic agent primarily used to treat actinic keratoses. It has been reported to be effective in treating warts when used under occlusion daily for up to 1 month. It has been used in children.[20]
Tretinoin is a topical retinoic acid that primarily is used to treat acne. It has been successful in treating flat warts.
When warts are persistent and refractory to topical agents, consider intralesional injections as an alternative.
Intralesional immunotherapy using injections of Candida, mumps, or Trichophyton skin test antigens has been shown to be effective in the treatment of warts, with reports of success in up to 74% of patients.[21]
Bleomycin is a chemotherapeutic agent that inhibits DNA synthesis in cells and viruses. Cure rates have ranged from 33-92%.[22, 23]
Interferon-alfa is a naturally occurring cytokine with antiviral, antibacterial, anticancer, and immunomodulatory effects. Cure rates of 36-63% have been reported.
In one study, photodynamic therapy with topical 5-aminolevulinic acid applied to the warts, followed by photoactivation with red 633-nm light-emitting diodes at 2- to 3-week intervals resulted in 68% improvement.[24]
Systemic agents that have been used to treat warts include cimetidine, retinoids, and intravenous cidofovir.
Cimetidine is a type-2 histamine receptor antagonist commonly used to treat peptic ulcer disease. Because of its immunomodulatory effects at higher doses, cimetidine was considered a possible treatment for warts; however, results have varied. Double-blind placebo-controlled studies have shown no benefit.[25]
Retinoids are synthetic vitamin A analogs that may help with extensive disabling hyperkeratotic warts in immunocompromised patients. They may help alleviate pain and facilitate the use of other treatments. Retinoids also have helped reduce the number of lesions in immunosuppressed renal transplant patients. The limiting side effects include liver function abnormalities, increased serum lipid levels, and teratogenicity.
Other reports have described intravenous cidofovir used for the treatment of extensive, disfiguring, and refractory warts.[26, 27, 28] This should be used with caution because of the risk of nephrotoxicity. Another report describes treatment failure.[29]
Several alternative treatments have been reported as successful in treating warts, including adhesiotherapy, hypnosis, hyperthermia, garlic, and vaccines.[30, 31]
Adhesiotherapy is performed by applying duct tape to the wart daily. This method is painless and inexpensive and has reports of good success.
Hypnosis has been used to treat refractory warts.[32] Several published studies have documented the success of hypnotherapy. Cure rates have been reported from 27-55%, with prepubertal children more likely to respond than adults. Patients in whom hypnotherapy fails may respond to hypnoanalysis for warts.
Hyperthermia involves immersing the involved surface in hot water (113ºF) for 30-45 minutes, 2-3 times per week.
Propolis is a resin that has been reported to be significantly more effective than Echinacea or placebo as an immunomodulating treatment for common and planar warts.[33]
Raw garlic cloves have been demonstrated to have antiviral activity. This can be rubbed onto the wart nightly, followed by occlusion.[34]
Tea tree oil possesses antimicrobial properties and when applied topically has also been reported as successful.[35]
Vaccines currently are in development.
Cryosurgery [36]
Liquid nitrogen (-196ºC) is the most effective method of cryosurgery. Apply liquid nitrogen using a cotton bud applicator or cryospray to the recommended 1-2 mm rim of normal skin tissue around the wart. Repeat every 1-4 weeks for approximately 3 months, as needed. Warn patients about pain and possible blistering after treatment.
Use with caution on the sides of fingers, since it can injure underlying structures and nerves. Other side effects may include scarring, ulceration, or pigment alteration. In addition, rarely cryosurgery can result in a central clearing with an annular recurrence of the wart surrounding the treated area, known as a "doughnut wart." Cure rates of 50-80% have been reported. Paring the wart, in addition to 2 freeze-thaw cycles, has been a valuable adjunct to cryosurgery for plantar warts.[37]
This is an expensive treatment, and is reserved only for large or refractory warts. Multiple treatments may be required. Local or general anesthesia may be necessary. A potential risk of nosocomial infection also exists in health care workers, since HPV can be isolated in the plume and can be inhaled.[38]
Carbon dioxide lasers have successfully treated resistant warts; however, the procedure can be painful and leave scarring. One retrospective study revealed a cure rate of 64% at 12 months with carbon dioxide lasers.[39]
The flashlamp-pumped pulse dye laser targets the blood vessels that feed warts and has shown mixed results in treating warts, with decreased risk of scarring and transmission of HPV in the smoke plume.[40]
Nd:YAG laser may be used for deeper, larger warts.
Although electrodesiccation and curettage may be more effective than cryosurgery, it is painful, more likely to scar, and HPV can be isolated from the plume. Avoid using surgical excision in most circumstances because of the risks of scarring and recurrence.
The goals of pharmacotherapy are to reduce morbidity and prevent complications. In addition to the medications listed below, propolis is a brownish resinous waxy material collected by honeybees from the buds of trees and used as a cement and used at 500 mg/day until warts resolve or until 3 mo, whichever occurs first.
Dibutyl squaric acid/diphencyclopropenone has also been used. Contact sensitizers induce allergic contact dermatitis, causing a localized inflammation and immune response. Apply solution in light-shielded accessible location (eg, arm) to achieve initial sensitization; repeat until reaction occurs; apply to warts q1-2weeks.
Immunomodulators have been used.[41]
The British Association of Dermatologists has treatment guidelines for cutaneous warts. See British Association of Dermatologists' Guidelines for the Management of Cutaneous Warts 2014 for more information.[10]
Clinical Context: Salicylic acid is available over the counter in 5-40% concentration and in a variety of vehicles, including creams, paints, gels, karaya gum, impregnated plasters, collodion, or sodium carboxycellulose tape. Lactic acid may be a second ingredient in some wart varnishes. By dissolving the intercellular cement substance, salicylic acid desquamates the horny layer of skin. Therapeutic effect may be enhanced by removal of surface keratin prior to application. Apply topically once or twice daily for several weeks.
Clinical Context: Podofilox is a purified ingredient of podophyllin and, therefore, is less irritating. It is available by prescription and can be applied by the patient at home. A 0.5% purified solution may be applied topically twice daily for 3 consecutive days, repeated weekly, not exceed 4 weeks.
Clinical Context: Podophyllum resin is an extract derived from the May Apple plant that contains several cytotoxic compounds. It has a powerful irritant effect and must be used with caution. It works better on mucosal surfaces than keratinized surfaces and is therefore more commonly used for genital warts. Trained personnel must apply it topically because of adverse effects; it may be left on the skin for 1-6 hours before washing.
Clinical Context: Cantharidin is the dried extract of the blister beetle (also termed Spanish fly). It causes epidermal necrosis and blistering. Apply the 0.7% solution sparingly with the wooden end of cotton-tipped applicator in the physician's office, and allow it to completely dry; do not cover the area with a bandage after application; repeat the application at 3- to 4-week intervals may be required.
Clinical Context: Trichloroacetic acid is a caustic compound that causes immediate superficial tissue necrosis. It is available as 80% solution that is painted onto lesions in the physician's office; apply after excess keratotic debris is pared; repeat therapy weekly as necessary until the wart is cured.
Keratolytic agents cause cornified epithelium to swell, soften, macerate, and then desquamate.
Clinical Context: Imiquimod induces secretion of interferon alpha and other cytokines; it is FDA approved for the treatment of genital warts in adults; reports indicate success in the treatment of common warts in children. It is a 5% gel that is applied daily for 3 d/wk; it may be applied before bedtime and washed off after 6-10 hours; twice-daily administration for nongenital warts has been reported, but irritation may be increased.
Clinical Context: Interferon alfa 2b is a naturally occurring cytokine with antiviral, antitumor, and immunomodulatory actions; intralesional administration is more effective than systemic administration and is associated only with mild flulike symptoms. Treatments may be required for several weeks to months before beneficial results are seen. Consider this treatment as third line, and reserve it for warts resistant to standard treatments.
Clinical Context: PEG-IFN alfa-2a consists of IFN alfa-2a attached to a 40-kd branched PEG molecule. It is predominantly metabolized by the liver. It has immunomodulatory actions; intralesional administration is more effective than systemic administration and is associated only with mild flulike symptoms. Treatments may be required for several weeks to months before beneficial results are seen. Consider this treatment as third line, and reserve it for warts resistant to standard treatments.
Clinical Context: 5-Fluorouracil is a topical chemotherapeutic agent that is approved to treat actinic keratoses and superficial basal cell carcinoma; it has been found to be more successful in the treatment of flat warts than plantar and common warts. Apply a 5% solution or cream daily for up to 1 month; it may be used under occlusion, but the risk of irritation increases.
Immunomodulators stimulate the release of key factors that regulate the immune system.
Clinical Context: Bleomycin is a cytotoxic polypeptide that inhibits DNA synthesis in cells and viruses. It has affinity for HPV-infected tissue and induces vascular changes that result in epidermal necrosis. Bleomycin has been beneficial in treating resistant warts. Reserve this as a third-line treatment when standard therapies have failed. Inject 0.5-1 U/mL solution directly into the wart, not to exceed 1.5 U/treatment; less painful administration involves placing 1 mg/mL gtt onto wart and pricking it into the wart with a needle.
Clinical Context: Cimetidine is believed to have immunomodulatory effects at higher doses. It may be administered at 20-40 mg/kg PO qd divided q6h, not to exceed 2400 mg/day.
These type 2 histamine receptor antagonists are commonly used to treat peptic ulcer disease; owing to their immunomodulatory effects at higher doses, they have been used as treatment for warts. Results have been variable, and double-blinded, placebo-controlled studies have shown no benefit.
Clinical Context: Isotretinoin is a synthetic 13-cis isomer of the naturally occurring tretinoin (trans -retinoic acid); it is structurally related to vitamin A. It is approved for severe nodular acne but has also been helpful in certain keratinization disorders.
A US Food and Drug Administration–mandated registry is now in place for all individuals prescribing, dispensing, or taking isotretinoin. For more information on this registry, see iPLEDGE. This registry aims to further decrease the risk of pregnancy and other unwanted and potentially dangerous adverse effects during a course of isotretinoin therapy. It may be administered at 0.5-2 mg/kg/d PO divided bid with food.
Retinoidlike agents may be helpful in immunocompromised patients with extensive disabling hyperkeratotic warts. They may help alleviate pain and facilitate the use of other treatments. In addition, retinoids have helped reduce the number of lesions in immunosuppressed renal transplant patients. Topical retinoids may be useful in treating flat warts.
Clinical Context: 5-Aminolevulinic acid topical 20% solution is a topical porphyrin available as Levulan Kerastick. It is to be applied topically to warts and kept under occlusion for 5 hours and then exposed to red light-emitting diodes or another suitable red or blue light source.
Products that become cytotoxic following exposure to light may be beneficial.