Genital warts: causes, symptoms, diagnosis, treatment

More than 20 types of human papillomavirus (HPV) can infect the genital tract. Most HPV infections are asymptomatic, subclinical, or unrecognized. Visible genital warts are usually caused by HPV types 6 or 11. Other HPV types that can be isolated from the anogenital area (eg, types 16, 18, 31, 33, and 35) are strongly associated with cervical dysplasia. The diagnosis of genital warts can be confirmed by biopsy, although biopsy is rarely necessary (eg, in complicated cases, failure of standard therapy, worsening of clinical picture during treatment, immunosuppression, pigmented/hardened/ulcerated warts). There are no data to support the use of type-specific HPV DNA testing in the routine diagnosis or management of patients with visible genital warts.

HPV types B and 11 can also cause warts in the vagina, on the cervix, inside the urethra, and inside the anus. Intraanal warts occur predominantly in patients who engage in receptive anal intercourse and are distinct from perianal warts, which may occur in men and women who do not engage in anal intercourse. In addition to genital lesions, these HPV types can cause warts of the conjunctiva, nasopharynx, and oral cavity. HPV types 6 and 11 are rarely associated with invasive squamous cell carcinoma of the external genitalia. Depending on their size and anatomical location, genital warts may be painful, easily bruised, and/or itchy.

HPV types 16, 18, 31, 33, 35 are rarely found in visible genital warts and are associated with squamous cell intraepithelial neoplasia (squamous cell carcinoma in situ, papular bowenoid, erythroplasia of Queyrat, Bowie's disease). These HPV types are associated with vaginal, anal and cervical intraepithelial dysplasia and squamous cell carcinoma. Patients with visible genital warts may be simultaneously infected with multiple HPV types.

Treatment of genital warts

The primary goal of treatment for visible genital warts is to remove warts that cause symptoms. Treatment may result in a "wart-free" period. Genital warts often cause no symptoms. None of the currently available treatments alter the natural history of HPV infection or eradicate the infection. Removing warts may or may not reduce their infectivity. If left untreated, visible genital warts may resolve on their own, remain unchanged, or increase in size. There is no evidence that treatment of visible warts will affect the development of cervical cancer.

Treatment regimens for genital warts

The choice of treatment for genital warts should be based on patient preference, available resources, and the experience of the health care provider. No single drug currently available is more effective than all others or is the ideal drug for all patients.

Treatment options currently available for visible genital warts include topical therapies applied by the patient (podofilox and imiquamod) and therapies administered by a health care provider (cryotherapy, podophyllin resin, trichloroacetic acid, bichloroacetic acid, interferon) and surgery. Most patients have one to ten genital warts, measuring 0.5 to 1.0 cm2 in area, which are responsive to most treatment options. Factors that may influence the choice of treatment include wart size, number, location, morphology, patient preference, cost, ease of administration, side effects, and health care provider experience. A treatment plan or protocol is important because many patients require a course of therapy rather than a single treatment. In general, warts located on moist surfaces and/or in skin folds respond better to topical treatment with drugs such as trichloroacetoacetic acid (TCA), podophyllin, podofilox, and imiquamod than warts located on dry skin surfaces.

If the physician's treatment methods do not result in significant improvement after three treatment courses, or complete resolution of warts after six treatment courses, the treatment method should be changed. The risk/benefit ratio of the treatment course should be fully assessed to avoid over-healing the patient. The physician should always weigh and, if necessary, modify the patient's local treatment methods and the physician's methods.

Complications are rare when treatment is performed correctly. Patients should be advised that hypo- and hyper-pigmented scars are common after excisional wart removal. Sunken or hypertrophic scars are rare but may occur if the patient has not had sufficient time between treatments. Treatment rarely results in disabling chronic pain syndromes such as vulvodynia or hyperesthesia at the treatment site.

External Genital Warts, Recommended Treatment

Self-administered treatment

Podofilox, 0.5% solution or gel. Patients may apply podofilox solution with a cotton swab, or podofilox gel with a finger, twice daily for 3 days, followed by a 4-day rest period. This cycle may be repeated if necessary, for a total of 4 cycles. The total area of warts treated should not exceed 10 cm2 ^, and the total volume of podofilox should not exceed 0.5 ml per day. If possible, a health care professional should perform the first treatment to demonstrate how to apply the product correctly and which warts to treat. The safety of podofilox during pregnancy has not been established.

Or Imiquamod 5% cream. Patients should apply imiquamod cream with their finger, at night, three times a week, for up to 16 weeks. It is recommended to wash the area with mild soap and water 6-10 hours after application. With this treatment, many patients experience wart clearance in 8-10 weeks or sooner. The safety of podofilox during pregnancy has not been established.

Treatment carried out by a doctor

Cryotherapy with liquid nitrogen or cryoprobe. Repeat applications every 1-2 weeks.

Podophyllin resin, 10-25% in tincture of benzoin. A small amount should be applied to each wart and allowed to air dry. To avoid problems with systemic absorption and toxicity, some experts recommend limiting the amount of preparation (< 0.5 ml podophyllin) or wart area (10 cm2 ⁾ per application. Some experts suggest washing off the preparation 1-4 hours after application to avoid tissue irritation. Repeat weekly if necessary. The safety of podofilox during pregnancy has not been established.

Or trichloroacetic acid (TCA) or dichloroacetic acid (DCA) 80-90%. Apply a small amount only to the warts and leave until dry, until a white "frost" appears. To remove unreacted acid, use powder with talc or sodium bicarbonate (baking soda). If necessary, repeat the procedure weekly.

Or Surgical excision - tangential excision with scissors, tangential razor excision, curettage or electrosurgery.

External Genital Warts, Alternative Treatments

Intralesional administration of interferon

Or Laser surgery

The patient can carry out the treatment independently if the location of the warts allows their treatment. Podofilox in the form of a 0.5% solution or gel is relatively inexpensive, easy to use, safe and can be used by patients at home. Podofilox is an antimitotic drug that causes destruction of warts. Most patients noted mild to moderate pain or local irritation after treatment. Imiquimod is a locally acting immunostimulant that promotes the production of interferon and other cytokines. Before the wart disappears, there are usually local inflammatory reactions, most often mild or moderate.

Cryotherapy destroys warts by cytolysis caused by heat and requires special equipment. Its main disadvantage is that proper use requires considerable preparation, without which warts often cannot be completely cured, and as a result the effectiveness of the method may be low or the risk of complications increases. Pain during application of liquid nitrogen occurs due to necrosis, and quite often blisters form at the site of application. Although local anesthesia (whether by topical agents or injections) is not routinely used, its use facilitates treatment when there are a large number of warts or when the area to be frozen is large.

Podophyllin resin contains many components, including the lignan podophyllin, which is an antimitotic agent. The resin is most often prepared in 10-25% tincture of benzoin. However, this preparation varies widely in concentration and in the content of active and inactive components. The length of time that podophyllin preparations remain active is unknown. It is important to apply podophyllin resin thinly to the wart and allow it to air dry before touching the area with clothing. Heavy application or insufficient air drying may result in local irritation due to the drug spreading to unaffected skin.

TCCA and BCA are caustic substances that destroy warts by chemically coagulating proteins. They are widely used, but have not been studied enough. TCCA solutions have very low viscosity (compared to water) and, if applied too generously, can quickly spread, damaging a significant area of normal adjacent tissue. TCCA and BCA preparations should be applied very carefully and allowed to dry before the patient sits or stands up. If intense pain occurs, the acid can be neutralized with soap or soda.

Surgical removal of warts has advantages over other methods in that warts can be removed quickly, usually in a single visit. However, it requires considerable clinical practice, some equipment, and longer treatment times. Once local anesthesia has been achieved, visible genital warts can be physically destroyed by electrosurgery, in which case additional hemostasis is usually not required. Alternatively, warts can be removed by tangential excision with sharp scissors or a scalpel, or by curettage. Because most warts are exophytic, this method may be complicated by wound formation within the epidermis. Hemostasis can be achieved by electrocautery or chemical hemostatic agents such as aluminum chloride solution. Sutures are not required or indicated in most cases if surgical removal is performed correctly. Surgical treatment is most appropriate for patients with a large number or large area of genital warts. CO2 laser and surgical treatment may be used in patients with multiple or intraurethral warts, especially if other treatments have failed.

Interferon, either natural or recombinant, has been used to treat genital warts systemically (subcutaneously, into a distant site, or intramuscularly) or intralesional (intralesional injection). Systemic use of interferon has not been shown to be effective. Interferon administered intralesionally has demonstrated comparable efficacy and recurrence rates to other methods. Interferon is thought to be effective because it has antiviral and/or immunostimulatory effects. However, interferon treatment is not recommended for routine use because of its inconvenience, the need for frequent visits, and its frequent systemic side effects, despite comparable efficacy to other methods.

Due to the lack of effective treatments available, some clinics use combination treatments (two or more simultaneous treatments for the same wart). Most experts believe that combination treatments do not increase effectiveness and may increase complications.

Cervical warts

In women with exophytic cervical warts, high-grade squamous intraepithelial lesion (SIL) should be excluded before treatment. Treatment should be carried out under specialist supervision.

Vaginal warts

Cryotherapy with liquid nitrogen. Due to the risk of perforation and fistula formation, the use of a cryoprobe in the vagina is not recommended.

Either THUK or BHUK, 80-90% are applied only to warts. The preparation should be applied in small quantities and only to warts, kept until dry, until a white "frost" appears. To remove unreacted acid, use powder with talc or sodium bicarbonate (baking soda). If necessary, repeat the procedure weekly.

Or Podophyllin, 10-25% in tincture of benzoin is applied to the affected area, which should be dry before removing the speculum. During one procedure, < 2 cm ² should be treated. If necessary, the procedure is repeated at intervals of 1 week. Due to the possibility of systemic absorption, some experts caution against using podophyllin in the vagina. The safety of podophyllin use during pregnancy has not been proven.

Warts in the urethral opening

Cryotherapy with liquid nitrogen.

Or

Podophyllin, 10-25% in tincture of benzoin. The area of application should be dried before contact with normal mucosa. If necessary, apply weekly. The safety of podophyllin use during pregnancy has not been proven.

Anal warts

Cryotherapy with liquid nitrogen.

Either THUK or BHUK, 80-90% is applied to warts. The preparation is applied in small quantities only to warts and kept until it dries, until a white "frost" appears. To remove unreacted acid, powder with talc or sodium bicarbonate (baking soda) is used. If necessary, repeat the procedure weekly.

Or surgical removal.

NOTE: Treatment of warts on the rectal mucosa should be performed under the supervision of an expert.

Oral warts

Cryotherapy with liquid nitrogen

Or surgical removal.

Follow-up observation

If visible warts respond well to treatment, follow-up is not necessary. Patients should be advised to monitor for recurrence, which is most common during the first three months. Because the sensitivity and specificity of self-diagnosis of genital warts is unknown, patients should be encouraged to return for follow-up at three months after treatment to monitor for recurrence. An earlier return visit will allow monitoring of wart resolution and potential complications of therapy and provides an opportunity for patient education and counseling. Women should be advised to undergo regular cytology screening. The presence of genital warts is not an indication for colposcopy.

Management of sexual partners

In the management of patients with genital warts, testing of sexual partners is not necessary because the role of reinfection appears to be minimal and, in the absence of curative therapies, treatments aimed at reducing the risk of transmission are of no value. However, because the diagnostic value of self-examination and mutual examination by partners is uncertain, partners of patients with genital warts may be tested to assess for genital warts and other STIs. Because treatment of genital warts probably does not eradicate HPV, patients and their partners should be advised that they may infect uninfected sexual partners. Condom use may reduce, but does not eliminate, the risk of transmission of HPV to an uninfected partner. Female partners of patients with genital warts should be reminded that cytology screening for cervical cancer is recommended for all sexually active women.

Special Notes

Pregnancy

Imiquimod, podophyllin, and podofilox should not be used during pregnancy. Because genital warts tend to proliferate and become friable during pregnancy, many experts recommend removing them during pregnancy. HPV types 6 and 11 can cause laryngeal papillomatosis in neonates and children. The route of transmission (transplacental, intrapartum, or postnatal) is unclear. The prophylactic value of cesarean section is unknown; thus, cesarean section should not be performed solely for the purpose of preventing transmission of HPV infection to the neonate. Rarely, cesarean section may be indicated in women with genital warts that interfere with the passage of the fetus through the birth canal or that, if localized in the vagina, would cause massive bleeding during vaginal delivery.

Patients with reduced immunity

Treatment of genital warts in individuals who are immunocompromised due to HIV infection or other causes may be less effective than in those with normal immune responses. Recurrence after treatment may be more frequent. The incidence of squamous cell carcinoma or similar genital warts may be higher in this population, and these patients are more likely to require biopsy to confirm the diagnosis.

Squamous cell carcinoma in situ

If a diagnosis of squamous cell carcinoma in situ is made, the patient should be referred to a specialist in this field. Excisive treatments are generally effective, but careful follow-up is necessary after their use. The risk that these lesions will progress to squamous cell carcinoma in situ exists, but is probably low. Female partners of such patients are at very high risk of developing cervical pathologies.

Subclinical genital HPV infection (without exophytic warts)

Subclinical HPV infection is much more common than exophytic warts in both men and women. Infection is often detected in the cervix by Pap smear, colposcopy, or biopsy, and in the penis, vulva, and other genital areas by the appearance of white spots after application of acetic acid. However, routine use of acetic acid and examination with a magnifying lens and light as screening tests for "subclinical" or "acetic white" genital warts is no longer recommended. The appearance of white spots after acetic acid application is not a specific test for HPV infection. Thus, many false-positive results may be detected in low-risk populations when used as a screening test. The specificity and sensitivity of this procedure remain to be determined. In special situations, experienced clinicians find this test useful for identifying flat genital warts.

Definitive diagnosis of HPV infection is based on detection of viral nucleic acid (DNA) or capsid proteins. Diagnosis of HPV infection by Pap smears does not usually correlate with detection of HPV DNA in cervical cells. Cellular changes in the cervix associated with HPV infection are similar to those seen in low-grade dysplasia and often spontaneously regress. Tests are available to detect DNA of some HPV types in cervical cells obtained by scraping, but their clinical value for patient management is unknown. Treatment decisions should not be made based on HPV DNA testing. Screening for subclinical genital HPV infection using DNA or RNA tests or acetic acid is not recommended.

Treatment

In the absence of concomitant dysplasia, treatment of subclinical HPV infection diagnosed by Pap smear, colposcopy, biopsy, acetic acid skin or mucosal preparation, or detection of HPV (DNA or RNA) is not recommended because the diagnosis often remains uncertain and treatment does not eliminate the infection. HPV has been detected in men and women in adjacent tissues after laser therapy for HPV-associated dysplasia and after attempts to eliminate subclinical HPV infection by extensive laser vaporization of the anogenital area. In the presence of concomitant dysplasia, the approach to treatment should be based on the degree of dysplasia.

Management of sexual partners

Screening of sexual partners is not necessary. Most partners are likely to already have subclinical HPV infection. There are no practical screening tests for subclinical HPV infection. Condom use may reduce the likelihood of infecting an uninfected or new partner; however, the period of infectivity is unknown. Whether patients with subclinical HPV infection are as contagious as patients with exophytic warts is unknown.

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