Warts

Genital warts are the visible manifestation of infection by one or more of the nearly 100 recognized human papillomaviruses (HPVs). Visible genital warts typically are caused by HPV types 6 and 11, which rarely are associated with invasive squamous cell carcinoma of the external genitalia. (1) HPV types 16, 18, 31, 33, and 35 have been found in genital warts and are associated with squamous intraepithelial neoplasia (1); types 16 and 18 are associated most strongly with malignant potential. (2) These virus types also are associated with vaginal, anal, and cervical intraepithelial dysplasia, and squamous cell carcinoma.

Drug treatment of genital warts (3) and management of anorectal warts (4) have been addressed previously. This article provides an updated overview of the management of genital warts.

Diagnosis

Diagnosis of genital and anal warts is primarily clinical. The differential diagnosis includes benign or malignant neoplasm (e.g., squamous cell carcinoma in situ, Bowen's disease); molluscum contagiosum (especially in patients with human immunodeficiency virus [HIV]); condyloma lata; fibroepitheliomas; and pearly penile papules. Genital warts typically present as flesh-colored, exophytic lesions on the external genitalia, including the penis, vulva, scrotum, perineum, and perianal skin. External warts can appear as small bumps, or they may be flat, verrucous, or pedunculated. Less commonly, warts can appear as reddish or brown smooth, raised papules (Figure 1) or as dome-shaped lesions of 1 to 4 mm on keratinized skin (5,6) (Figure 2).

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Internal warts can affect the mucous membranes of the vagina, urethra, anus, and mouth. Intra-anal warts are present primarily in patients who have had receptive anal intercourse, although perianal warts can occur in men or women who have no history of anal intercourse. Patients with internal warts may have discomfort, pain, bleeding, or difficulty with intercourse; these symptoms are more common in patients with larger, cauliflower-like lesions. Urethral lesions may impair the passage of bodily fluids.

Diagnosis by biopsy and viral typing is not recommended for patients with routine or typical lesions. (1) Biopsy is indicated if the diagnosis is uncertain or if the patient is immunocompromised; has a poor response to appropriate therapy; has warts that are pigmented, indurated, fixed, or ulcerated; or is at high risk for HPV-related malignancy (e.g., chronic genital warts, tobacco use, history of abnormal Papanicolaou [Pap] smears). The role of HPV testing in women with abnormal Pap smears has been reviewed previously. (7)

Treatment Options and Methods

Untreated visible genital warts may resolve spontaneously, remain the same, or increase in size. The primary treatment goal is removal of symptomatic warts. Some evidence suggests that treatment also may reduce the persistence of HPV DNA in genital tissue, and therefore may reduce infectivity. (1) However, there is currently no evidence that treatment of genital warts has a favorable impact on the incidence of cervical and genital cancer, (1) and there have been no controlled studies on the effects of treatment of external genital warts and HPV transmission rates. (8)

The choice of therapy is based on the number, size, site, and morphology of lesions, as well as patient preference, treatment cost, convenience, adverse effects, and physician experience. Assuming that the diagnosis is certain, switching to a new treatment modality is appropriate if there is no response after three treatment cycles. Routine follow-up at two to three months is advised to monitor response to therapy and evaluate for recurrence. (1)

Treatment methods can be chemical or ablative. The mechanism of action for each treatment method is summarized in Table 1, (9) and treatment courses and cycles are summarized in Table 2. Typical response rates, adverse effect rates, and recurrence risks are summarized in Table 3 (8-13); the response rate for all treatments is approximately 60 to 90 percent, and the response rate for placebo is zero to 50 percent. (8,11)

CHEMICAL TREATMENTS (PATIENT-APPLIED)

Podofilox (Condylox). Podofilox is a 0.5 percent gel or solution containing purified extract of the most active compound of podophyllin. To prevent local irritation, patients should allow the solution to dry before moving around. The solution should be applied with a cotton swab; gel should be applied with a finger. Some physicians prefer to perform the initial application. Podofilox is not recommended for treatment of perianal, rectal, urethral, or vaginal lesions. Five randomized trials comparing podofilox with podophyllin found no difference in wart clearance rates. (8)

Imiquimod (Aldara). Imiquimod 5 percent cream is a topical cell-mediated immune response modifier that comes in single-use packets. Patients should apply a thin layer to external, visible warts, then rub in the cream until it vanishes. The area is washed with soap and water six to 10 hours after treatment. Imiquimod may weaken condoms and diaphragms, and sexual contact is not recommended while the cream is on the skin.

CHEMICAL TREATMENTS (PHYSICIAN-APPLIED)

Podophyllin Resin. A 15 to 25 percent solution of podophyllin resin has been the standard treatment for genital warts. No more than 0.5 mL should be used, and the solution should not be applied to the cervix, vagina, or anal canal where the squamocolumnar junction is prone to dysplastic changes. Podophyllin is inexpensive but may require frequent office visits, which increase the overall cost of treatment. The solution should be allowed to dry completely after application to prevent irritation. Some specialists recommend that the area of application be washed thoroughly one to four hours after application to reduce local irritation, although there is no evidence that doing so improves patient outcomes. (1)

Trichloroacetic Acid. Treatment via chemical cautery with a solution of 60 to 90 percent trichloroacetic acid (TCA) is most effective when treating few small, moist lesions, although TCA also can be used for vaginal or anal lesions. A small amount should be applied and allowed to dry until a white frosting develops. If excess TCA is applied to nonaffected tissue, the patient should be instructed to wash the area with liquid soap or sodium bicarbonate.

Other Treatments. Treatment with 5 percent fluorouracil cream (Efudex) is no longer recommended because of severe local side effects and teratogenicity. (14) However, intralesional injection with fluorouracil/epinephrine/bovine collagen gel has been proven effective in Phase 3 clinical trials (15) and can be considered for use in patients with refractory disease. Another option in these patients is intralesional injection of interferon. It is not recommended for routine office use because of the high incidence of local and systemic side effects; it generally is recommended for use only by subspecialists. (1,14)

ABLATIVE TREATMENT

Cryotherapy. Cryotherapy is recommended for patients with small to moderate numbers of warts. It can be applied with a cryoprobe, liquid nitrogen spray, or a cotton-tipped applicator. The cold source is applied and held until a halo appears around the circumference of the lesion (about 10 to 20 seconds). Local anesthesia (topical or injected) may facilitate therapy if warts are present in many areas or if the area is large. No clinical trials have compared cryotherapy with placebo; randomized trials have found similar response rates for cryotherapy compared with podophyllin, TCA, and electrosurgery. (8)

Surgical Removal. Surgical treatment for warts involves removal to the dermal-epidermal junction. Options include tangential scissor excision, shave excision, curettage, and the loop electrosurgical excision procedure (LEEP). Treatment may cause scarring; operator experience is important, especially with LEEP, to avoid too deep a removal. The patient can be wart-free in one visit, but treatment requires local anesthesia and possibly specialist referral. This method is best for many warts or if a large area is involved.

Laser Treatment. Carbon dioxide laser treatment is best for extensive intraurethral warts and extensive vaginal warts. Laser treatment can create smoke plumes that contain HPV, so physicians performing this procedure should wear masks. Laser treatment may be useful in HIV-infected patients who have very large external genital warts or severe local symptoms.

Adverse Effects of Treatment

The side effects of each treatment method and the risk of recurrence are summarized in Table 13. (8-13) All of these treatment methods can cause considerable discomfort, erythema, epithelial erosion, ulceration at the treatment site, depigmentation, and scarring. Treatment should be confined to affected skin to minimize the risk of side effects. Little objective information has been published regarding the management of complications of therapy for genital warts; the use of non-prescription analgesics is a reasonable option to alleviate discomfort.

Patient counseling and education can help prepare patients for possible adverse effects and ensure that they have appropriate expectations. Patients must understand that HPV infections can be treated but not cured; that affected men and women, and sex partners of affected patients, are at risk for cervical or genital cancer; and that affected women and female sex partners of affected men should have regular Pap smears performed.

Selection of Treatment

The choice of initial treatment modality should be guided by a number of considerations, including wart morphology, size, number, and location. (1) Many treatment recommendations are based on expert opinion from consensus guidelines; few studies have directly compared different treatments. Patients should be told that no treatment ("watchful waiting") is an option for warts at any site, especially for warts in the vaginal and anal canal.

In general, chemical treatments are more effective on moist, soft, non-keratinized warts in the genital area; keratinized lesions respond better to physical ablative treatments. (1) Keratinized and nonkeratinized lesions may respond to imiquimod. Patients with small or few warts may respond well to ablative therapy as first-line treatment, regardless of wart type. For ablative treatment procedures other than cryotherapy, local anesthesia with topical or injected lidocaine Xylocaine) should be used. Combination therapy with podophyllin or imiquimod plus cryotherapy is practiced in some centers, although there is no evidence for increased effectiveness with this approach. Figure 3 (5) summarizes a suggested approach to treatment selection.

[FIGURE 3 OMITTED]

ANATOMIC LOCATION

Cervical warts should be treated with the most convenient method, and patients should be evaluated by colposcopy to exclude high-grade squamous intraepithelial lesions and cervical cancer. Vaginal or anal warts may be treated most effectively with cryotherapy or TCA. Urethral meatus warts should be treated with cryotherapy or podophyllin. Podophyllin and fluorouracil no longer are recommended for treatment of internal lesions. (14)

COST CONSIDERATIONS

A recent cost-effectiveness analysis (10) found that treatment for simple genital warts costs approximately $200 to $300 for one course of podofilox, cryotherapy, electrodesiccation, surgical excision, LEEP, or laser treatment. Podophyllin resin, TCA, and imiquimod treatment were more expensive, and interferon treatment was much more expensive. For extensive condyloma that requires prolonged treatment, podofilox remains the least expensive patient-applied treatment. Surgical excision, LEEP, and electrodesiccation also were inexpensive, while cryo-therapy and podophyllin resin treatments were somewhat more expensive. Interferon treatment remained the most expensive alternative.

Special Management Issues

LARGE WARTS

Warts greater than 10 mm in diameter may be treated with surgical excision as primary therapy. Alternatively, imiquimod cream applied for three to four treatment cycles may reduce the size of warts and improve surgical outcomes. If patients have a more than 50 percent reduction in wart size after three to four treatment cycles, imiquimod should be continued until warts clear or until eight treatment cycles have been completed. If patients have a less than 50 percent reduction in wart size after the initial treatment cycles, surgical excision or other ablative therapy should be initiated.

MANAGEMENT OF SUBCLINICAL WARTS

Subclinical genital HPV infection (i.e., anogenital HPV infection without evident exophytic warts) may be identified via colposcopy, biopsy, acetic acid application, laboratory identification of HPV serology, or other methods. However, early treatment of subclinical lesions has not been shown to favorably affect the course of HPV infection in patients or their sex partners with regard to reduction in HPV transmission rates, symptoms, and recurrence. It is therefore not recommended that colposcopy, acetowhite staining, or other methods be used to screen for subclinical warts in a general patient population or in patients with a history of genital warts. (1,14) Patients who have a history of warts are presumed to have latent HPV infection and should be counseled about the importance of cervical cancer screening.

PREGNANCY

Podophyllin, podofilox, and fluorouracil should not be used in pregnant patients because of possible teratogenicity. Imiquimod is not approved for use in pregnant women, although treatment with this agent can be considered after informed consent has been obtained. (14) TCA has been used in pregnant patients without adverse effects. Surgical excision, cryotherapy, and electro-cautery are appropriate treatment options during pregnancy if treatment is necessary. Some guidelines indicate that cryotherapy is safe if only three to four treatments are given, based on an older case series of 34 pregnant women demonstrating the safety of some cryotherapy treatments. (16) The goal of treatment in pregnant women primarily is to minimize neonatal exposure to the virus by reducing the number of lesions present during delivery. Anogenital warts and laryngeal papillomatosis are potential complications in infected children.

IMMUNOCOMPROMISED PATIENTS

Patients with suppressed cell immunity associated with organ transplantation, HIV infection, or other conditions may have a poorer response to treatment for genital warts, increased relapse rates, and a higher risk of dysplasia.

Figure 1 used with permission from Jeffrey Callin, M.D.

Figure 2 used with permission from 3M Pharmaceuticals, Inc.

The authors indicate that they do not have any conflicts of interest. Sources of funding: none reported.

Members of various family medicine departments develop articles for "Practical Therapeutics." This article is one in a series coordinated by the Department of Family and Geriatric Medicine at the University of Louisville School of Medicine, Louisville, Ky. Guest editor of the series is James G. O'Brien, M.D.

REFERENCES

(1.) Sexually transmitted diseases treatment guidelines 2002. Centers for Disease Control and Prevention. MMWR Recomm Rep 2002;51:1-78.

(2.) Munoz N, Bosch FX, de Sanjose S, Herrero R, Castellsague X, Shah KV, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348:518-27.

(3.) Woodward C, Fisher MA. Drug treatment of common STDs: Part II. Vaginal infections, pelvic inflammatory disease and genital warts. Am Fam Physician 1999;60:1716-22.

(4.) Pfenninger JL, Zainea GG. Common anorectal conditions: Part II. Lesions. Am Fam Physician 2001;64:77-88.

(5.) Batteiger BE. External genital warts. Best Pract Med 2000. Accessed online October 4, 2004, at: http://merck.micromedex.com/index.asp?page=bpm_brief&article_id=BPM01ID26.

(6.) Handsfield HH. Clinical presentation and natural course of anogenital warts. Am J Med 1997;102:16-20.

(7.) Apgar BS, Brotzman G. HPV testing in the evaluation of the minimally abnormal Papanicolaou smear. Am Fam Physician 1999;59:2794-800.

(8.) Wiley DJ. Genital warts. Clin Evid 2003;9:1741-53.

(9.) Beutner KR, Ferenczy A. Therapeutic approaches to genital warts. Am J Med 1997;102:28-37.

(10.) Alam M, Stiller M. Direct medical costs for surgical and medical treatment of condylomata acuminata. Arch Dermatol 2001;137:337-41.

(11.) French L, Nashelsky J, White D. What is the most effective treatment for external genital warts? J Fam Pract 2002;51:313.

(12.) Tyring S, Edwards L, Cherry LK, Ramsdell WM, Kotner S, Greenberg MD, et al. Safety and efficacy of 0.5% podofilox gel in the treatment of anogenital warts. Arch Dermatol 1998;134:33-8.

(13.) Edwards L, Ferenczy A, Eron L, Baker D, Owens ML, Fox TL, et al. Self-administered topical 5% imiquimod cream for external anogenital warts. HPV Study Group. Human Papillomavirus. Arch Dermatol 1998;134:25-30.

(14.) National guideline for the management of anogenital warts. Clinical Effectiveness Group (Association for Genitourinary Medicine and the Medical Society for the Study of Venereal Diseases). Sex Transm Infect 1999;75(suppl 1):S71-5.

(15.) Swinehart JM, Sperling M, Phillips S, Kraus S, Gordon S, McCarty JM, et al. Intralesional fluorouracil/epinephrine injectable gel for treatment of condylomata acuminata. A phase 3 clinical study. Arch Dermatol 1997;133:67-73.

(16.) Bergman A, Bhatia NN, Broen EM. Cryotherapy for treatment of genital condylomata during pregnancy. J Reprod Med 1984;29:432-5.

CHARLES M. KODNER, M.D., and SORAYA NASRATY, M.D. University of Louisville School of Medicine, Loiuseville, Kentucky

CHARLES M. KODNER, M.D., is associate professor in the Department of Family and Geriatric Medicine at the University of Louisville (Ky.) School of Medicine. Dr. Kodner received his medical degree from Washington University School of Medicine in St. Louis, and completed a family practice residency at St. John's Mercy Medical Center in St. Louis.

SORAYA NASRATY, M.D., is associate professor in the Department of Family and Geriatric Medicine at the University of Louisville School of Medicine. Dr. Nasraty received her medical degree from the University of Bonn (Germany) School of Medicine and completed a family medicine residency at the University of Louisville School of Medicine.

Address correspondence to Charles M. Kodner, M.D., Med Center One Building, Department of Family and Geriatric Medicine, University of Louisville, Louisville, KY 40202 (e-mail: charles.kodner@louisville.edu). Reprints are not available from the authors.

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