Papillomaviruses are a large group of DNA viruses widely distributed in animals and humans, most commonly inducing benign papillomas or warts. Recurrent skin and anogenital warts may be disfiguring, impose a considerable psychological burden, and are a frequent cause of medical office visits.
A subset of human papillomaviruses (HPVs) designated as high-risk types, most often HPV-16 and -18, is now recognized as the primary etiologic agent for cervical cancer and its precursor lesions; a subset of the malignancies at other anogenital sites and in the upper aerodigestive tract; and, rarely, squamous cell cancer of the digits.
In immunocompromised patients, HPV infections persist and increase the risk of developing anogenital neoplasias. In contrast, infection with the common cutaneous HPV types 1, 2, 4, 27, etc., is not thought to have any oncogenic potential. The high prevalence of genital HPV infection in sexually active young adults is a significant concern, as effective antiviral treatments do not exist. A decade ago, prophylactic vaccines based on virus-like particles (VLPs) that prevented transmission in animal models of papillomavirus infection were developed. Human vaccine studies subsequently demonstrated safety and nearly complete (>90%) efficacy for preventing type-specific genital HPV infection and the development of associated dysplasias.
What are the Symptoms and Signs of Genital Warts?
Genital warts appear in many sizes and shapes. Some people get a few warts. Others get many warts. The most common signs (what you see) of these warts are:
- Small, scattered bumps that are skin-colored or a bit darker.
- A cluster of bumps that look like cauliflower.
- Growths in the genital area can rise, flat and smooth, or rough.
Genital warts often have no symptoms (what someone feels). Sometimes the warts itch, burn, hurt, or bleed. Genital warts can appear on the following areas of the body: Females Vulva (external female genitals), vagina, cervix, and groin. It seems on males’ penis, scrotum, thigh, and groin. Inbox sexes can appear on the mouth or throat after having oral sex with an infected person. In or around the anus after anal sex with someone who has HPV.
Who Gets Genital Warts?
Genital infection with HPV occurs most commonly by intimate contact. In contrast, infection of non-genital skin may occur via direct skin-to-skin contact or indirectly through contaminated surfaces and objects (e.g., swimming pools, gymnasium).
Genital warts in prepubertal children are uncommon and produce particular concern in healthcare providers. Although viral transmission may occur during delivery, from close family contacts, or by autoinoculation from skin warts, these lesions may have been caused by sexual abuse and should always be carefully considered.
Infection of the lower anogenital tract with HPV is one of the most common sexually transmitted infections. The prevalence of cervical HPV infection varies significantly in different countries, and by age, it is exceptionally high in young women, ranging from 20% to 45%. In the US, an estimated twenty million people have genital HPV infections at any one time.
Behavioral risk factors include sexual intercourse at an early age and the number of lifetime sexual partners. In men who have sex with men (MSM), anal HPV infection is very prevalent (up to 75%). Circumcised men are less likely to carry and transmit HPV infection.
In the US, prevention and early detection programs have reduced the incidence rate of cervical cancer by approximately 75%, to 8 per 100 000 women per year. In 2010, 12 200 new cases of cervical cancer were diagnosed in the US, resulting in 4200 deaths. High-risk oncogenic HPV types account for most of the observed risk for developing cervical cancer, although smoking, cervical inflammation, parity, and oral contraceptive use have been proposed as cofactors.
How do Dermatologists Diagnose Genital Warts?
The diagnosis of cutaneous and genital warts is straightforward if typical clinical features are present. Occasionally, various other diagnoses must be considered, and a biopsy may be required to confirm and identify dysplastic lesions. Giant condyloma acuminatum, or Buschke–Löwenstein tumor, is clinically suspected by its size and fistulas or abscesses.
Condylomata acuminata are rarely confused with condylomata lata of secondary syphilis. Still, serologic testing for syphilis (and, as indicated, other sexually transmitted diseases) is recommended in patients with genital warts, and dark-field examination for spirochetes may be required.
Mollusca contagiosa preferentially involves the mons pubis and can be distinguished by their umbilication with dermoscopy.
In men, pearly penile papules are typical anatomic structures consisting of several rows of discrete, monomorphic, dome-shaped, 1 to 2 mm bumps around the corona and sulcus of the glans penis. A similar picture exists in women, called vestibular papillomatosis, with tiny, uniformly shaped, finger-like projections at the introitus and on the labia minora.
Sebaceous glands of the prepuce and labia majora appear as white-gray to yellow, small bumps with a regular array. Epidermoid cysts, steatocystomas, or angiokeratomas of the scrotum seldom pose diagnostic problems.
Detection of subclinical genital HPV infection requires soaking with 5% acetic acid for 3 to 5 minutes; this leads to whitening (“aceto-whitening”) of lesions, and using a colposcope for magnification will further increase diagnostic accuracy. However, aceto-whitening is not specific to HPV-induced lesions and is also observed in infectious or inflammatory conditions such as Candida vulvitis or balanoposthitis, psoriasis, lichen planus, or eczematous dermatitis.
Bowenoid papulosis consists of red-brown papules or confluent, sometimes leukoplakia-like plaques that may be difficult to distinguish from condylomata.
Erythroplasia of Queyrat is a well-defined, velvety erythematous plaque of the glans or vulva that must be differentiated from erosive lichen planus and Zoo’s balanitis.
Bowen’s disease can present as a solitary patch or plaque, sometimes scaly, of the vulva or penis, most often in older individuals.
Extramammary Paget’s disease appears as a well-defined red plaque in the groin or pubic region or on the vulva, penile root, or perianal skin, with distinctive histopathologic features.
Vulvar carcinomas are etiologically heterogeneous. Basaloid and warty vulvar carcinomas typically arise in younger women, are found adjacent to vulvar intraepithelial neoplasia (VIN), and are associated with risk factors related to sexual practices. Carcinomas with basaloid or warty histology are related to HPV infection, whereas keratinizing squamous carcinomas are not.
In contrast, the more common keratinizing vulvar carcinoma in older women, which typically arises adjacent to lichen sclerosus and epidermal hyperplasia, infrequently contains HPV DNA and thus is regarded as a distinct entity.
Heterogeneity in etiology has also been described for anal SCC. In all genders, most anal cancers are attributable to HPV infection. Cancers of the anal canal that are positive for high-risk HPV (16, 18, 31, 33) tend to occur in younger men and women with high-risk sexual behaviors (especially MSM), have basaloid histology, and arise adjacent to AIN.
In contrast, HPV-negative anal cancers usually affect older men, are well keratinized, and arise from perianal skin without AIN.
Heterogeneous etiology has also been described for penile cancer, analogous to that observed for vulvar and anal squamous cell cancers. Immunosuppression and the history of HPV-associated malignancy are notable risk factors for developing a (second) anogenital cancer attributable to HPV.
Anogenital warts in children may give rise to suspicion of sexual abuse. In most cases, however, several criteria will argue for a non-abusive transmission of HPV. These include the age of fewer than three years, wart location distant from the anus or vulva, detection of HPV-2 or other skin-specific HPV types, genital condylomata in the mother, and an absence of signs of physical abuse or other sexually transmitted diseases.
Oral warts or condylomata may resemble the papules of focal epithelial hyperplasia (Heck’s disease. A distinct oral condition with the name “verrucous proliferative leukoplakia” is clinically like oral florid papillomatosis but does not contain HPV DNA and has a substantial risk of progression to metastatic squamous cell cancer.
Additional diagnostic considerations may include leukoedema (grayish-white translucent plaques, sometimes with a “moth-eaten” appearance that favors the buccal mucosa and may become less evident upon stretching), a white sponge nevus and hereditary benign epithelial dyskeratosis.
How do Dermatologists Treat Genital Warts?
HPV infection is typically widespread and multifocal throughout the anogenital tract, and subclinical lesions are often present. Genital warts may be disfiguring and pose a significant psychological burden. Thus, regardless of the applied therapeutic modality, reported recurrence rates are high (25–65%), and it is unproven whether treatment reduces transmission rates to new sexual partners.
Limiting the number of partners remains the mainstay of decreasing transmission. Condom use may also be helpful, and it has promoted regression of flat penile lesions and CIN and clearance of HPV in couples infected with the same HPV type55.
Treatment is time-consuming, uncomfortable, and limited to visible warts and intraepithelial neoplasia with a considerable risk of progression. Current therapies for genital warts include destructive, antiproliferative, and immunomodulatory modalities.
Condom use may also be helpful, and it has promoted regression of flat penile lesions and CIN and clearance of HPV in couples infected with the same HPV type55. Treatment is time-consuming, uncomfortable, and limited to visible warts and intraepithelial neoplasia with a considerable risk of progression.
Early diagnosis of Buschke–Löwenstein tumor and other verrucous carcinomas is essential to allow wide excision with clear resection margins. Surgery is the only established treatment that may cure the disease, although recurrence rates are high, and the tumor can result in death. Cytotoxic chemotherapy and injections of interferon-α have led to remissions or cures in individual patients.
Skin and genital warts tend to resist standard treatment modalities in transplant recipients and HIV-infected patients. A surgical approach followed by non-invasive treatment of recurrent warts may be appropriate.
During pregnancy, genital warts can increase in size and destructive procedures, including surgery, cryotherapy, TCA application, and laser treatments, are appropriate to remove lesions, which may reduce the risk the newborn will acquire. However, this assumption is not proven, and the presence of condylomata is not an indication of delivery by cesarean section. Podophyllin and podophyllotoxin are teratogenic and thus must not be used in pregnant women.
Intraepithelial neoplasia treatment (bowenoid papulosis, erythroplasia of Queyrat, Bowen’s disease) is more aggressive than benign condylomata. Before therapy, an aiming biopsy (e.g., colposcopically directed) is always required to exclude (micro) invasion histologically.
For patients with Bowenoid papulosis and erythroplasia younger than 45 years, superficial destruction (e.g., with cryotherapy or laser vaporization) of lesions may be appropriate to avoid mutilation. In immunocompetent patients less than 35 years of age, bowenoid papulosis is a benign and self-limited disease. Nevertheless, prolonged observation appears mandatory to detect recurrences.
Local Destructive Therapy for Anogenital Warts
Destructive or ablative therapies for genital warts include cryotherapy, trichloroacetic acid (TCA), electrosurgery, curettage, scalpel or scissors excision, laser vaporization, and photodynamic therapy with topical aminolevulinic acid. When anesthesia is required, topical application or injection of a local agent is usually sufficient. However, general anesthesia may be indicated for surgical debulking of large lesions and occasionally in children.
Ablative laser therapy is also helpful for vaginal, vulvar, or anal intraepithelial neoplasias. It should take precautions to avoid the inhalation of virus particles in the aerosol plume when laser or electrosurgical procedures are performed.
Application of TCA 70–90% solution is a commonly utilized office-applied therapy that results in local tissue destruction. Although scarring may occur following dermal injury, TCA has the advantage of a complete lack of systemic toxicity, and It can use during pregnancy.
Cryotherapy is inexpensive, effective, and does not require anesthesia; as a result, it is often used as a first-line therapy followed by patient-applied podophyllotoxin. Liquid nitrogen is applied with a cotton swab, spray gun, or closed system cryoprobe. Two freeze-thaw cycles, the extent of which is visually controlled, lead to wart necrosis, and multiple treatments result in remission rates of 78% to 88%, with recurrences in 20–40% of patients.
At-home application of potassium hydroxide (KOH) 5% solution has induced regression of genital warts in men.
Cutaneous warts may be treated by daily application of salicylic acid/lactic acid/collodion (1:1:4) or other salicylic acid preparations for up to 12 weeks, which results in regression in two-thirds of patients.
Application of petrolatum to the surrounding normal skin protects against the corrosive effect of the concentrated acid. Weight pressure causes profound inward growth of plantar warts (Myrmecia). The resulting pain can be reduced by repeated shaving the hyperkeratotic surface to a level at which capillary bleeding occurs.
Cryotherapy with liquid nitrogen may be utilized for persistent or recurrent verrucae, including periungual lesions, with cure rates similar to or better than salicylic.
Cryotherapy that does not include a rim of surrounding skin or topical application of the blistering agent cantharidin may produce a “doughnut wart” due to clearance in the center but not at the lesion’s periphery.
Additional destructive modalities include curettage or scissor excision (especially for filiform warts and other exophytic lesions), electrosurgery, laser treatment (e.g., with CO2 or pulsed dye lasers), and photodynamic therapy. Combination therapy with topical agents following destruction may reduce the rate of recurrence.
Topical and Intralesional Cytotoxic Therapy
Podophyllin is a crude resin extract from the roots of the Mayapple Podophyllum peltatum (North America), or Podophyllum emodi (Far East), used since 1942for the treatment of genital warts. Systemic toxicity can occur when applied in large volumes. Even death, intrauterine demise, and teratogenicity have been reported. Because of low efficacy and potential toxicity, podophyllin use is no longer recommended.
Podophyllotoxin has been identified as the most active constituent of podophyllin. A regimen of patient self-applied podophyllotoxin 0.5% solution twice a day for three days repeated in weekly cycles was effective without evidence of systemic absorption and toxicity.
Erythema and erosions are the most common side effects. Both podophyllin and podophyllotoxin are contraindicated during pregnancy. Warts of the urethral meatus and urethra are challenging to manage, and stenosis and stricture due to therapy are potentially severe complications. 5-Fluorouracil (5-FU) 5% the cream can be applied twice a week to treat intraurethral condylomata. It is used as an alternative to destructive treatments, intraepithelial neoplasias of the external genitalia.
Intralesional bleomycin is occasionally used to treat recalcitrant cutaneous warts, but injections are painful and may result in excessive cutaneous necrosis. However, its use in the genital area is limited by inflammatory side effects. In children and adults, successful treatment of cutaneous warts with 5-FU 5% cream applied daily under occlusion or with salicylic acid has also been described, and effective therapy with intralesional 5-FU has been reported.
Imiquimod is an imidazoquinoline compound with immunomodulatory activities that have been approved by the US Food and Drug Administration (FDA) for the topical treatment of condylomata acuminata. Treatment resulted in a reduction of viral load, presumably due to activation of cellular immune responses.
In clinical practice, destruction of genital warts by the physician followed by patient-applied imiquimod (often requiring several cycles) is favorable over either modality alone.
Imiquimod can be applied via suppositories (anal tampons) to prevent the recurrence of anal condylomata. It may use following surgical ablation to avoid the risk of scarring and stenosis of the anal canal. Occlusion and concurrent use of salicylic acid or cryotherapy may increase its efficacy.
Side effects of imiquimod include application site reactions (inflammation, erosion) that may require treatment-free periods. Imiquimod therapy is often more costly than other treatment options.
Sinecatechins 15% ointment, contains green tea leaf-derived catechins is FDA approved as a topical treatment for anogenital warts. It has to have immunostimulatory and antiproliferative properties.
Interferons have been used topically, intralesionally, and systemically for genital warts in controlled trials and have failed to demonstrate consistent efficacy. Systemic therapy, which is expensive and causes dose-related toxic side effects, is thus not recommended for routine clinical use. However, interferons may be helpful as an adjunct or salvage therapy in selected patients.
Increasing evidence that cellular immune responses play a critical role in wart clearance. Therefore it has inspired the development of topical and intralesional immunotherapy regimens. Topical and intralesional injection in anogenital warts was effective.
A decade ago, it used recombinant DNA technology to generate a prophylactic vaccine consisting of the L1 major capsid protein, which self-assembles into empty capsids designated virus-like particles (VLPs). VLPs resemble native virions morphologically and immunologically, carrying neutralization epitopes on their surface.
However, they do not contain the potentially oncogenic viral DNA as a safety advantage. Systemic immunizations with VLPs induce high-titer, long-lasting. Two HPV vaccines are now commercially available), with a primary goal of universally vaccinating children and adolescents before sexual activity (ideally before 12 years of age).
Gardasil™ is FDA-approved for use in individuals (female and male) 9 to 26 years of age to prevent anogenital warts, dysplasia, and cancer. Cervarix™ is FDA-approved for use in girls and women ages 9 to Twenty-five years to prevent cervical dysplasia and cancer-specific neutralizing antibodies.
Cidofovir is an acyclic nucleoside phosphonate with broad-spectrum activity against DNA viruses, including HSV and molluscum contagiosum. Although limited by the potential for renal toxicity, systemic treatment with cidofovir has shown efficacy in patients with HPV-associated lesions. The application of 1–3% cidofovir incorporated into an ointment, cream, or gel base has been successfully used in a limited number of immunocompetent or immunosuppressed patients with cutaneous warts, condylomata acuminata, and intraepithelial neoplasias.
The effects of retinoids on keratinocyte differentiation and proliferation may inhibit HPV replication and assembly. Eradication of extensive cutaneous or genital warts with oral retinoid therapy (isotretinoin) has been reported in immunocompetent and immunosuppressed patients.
The outcome of Genital Warts Treatment
Treatment can remove warts you see, but it may not get rid of the virus. If the infection remains, warts can return. If you still have the virus, you can spread it through sex. Wearing a condom during sex can reduce the risk of spreading the virus.