CME/CE

DECEMBER 2007

External Genital Warts: An Update

E.J. Mayeaux, Jr, MD

The bad news is that there is no one treatment that can reliably cure external genital warts in all women—but the good news is that with a wide range of topical and surgical options, most patients can find a therapy that is both tolerable and effective.

Continuing Medical Education

GOAL To review the prevalence and treatment of external warts due to human papillomavirus (HPV) in women, with an emphasis on choosing the best therapeutic option for each case. OBJECTIVES To explore the high incidence of genital HPV infection and its risk factors in women. To differentiate between low-risk HPV types leading to external genital warts and high-risk types associated with cervical cancer. To review patient-applied and provider-applied treatment options. ACCREDITATION This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Albert Einstein College of Medicine and Quadrant HealthCom Inc. Albert Einstein College of Medicine is accredited by the ACCME to provide continuing medical education for physicians. This activity has been peer reviewed and approved by Brian Cohen, MD, professor of clinical OB/GYN, Albert Einstein College of Medicine. Review date: October 2007. It is designed for OB/GYNs, primary care physicians, and nurse practitioners. Albert Einstein College of Medicine designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity. Participants who answer 70% or more of the questions correctly will obtain credit. To earn credit, see the instructions on page 45 and mail your answers according to the instructions on page 46. CONFLICT OF INTEREST STATEMENT The “Conflict of Interest Disclosure Policy” of Albert Einstein College of Medicine requires that authors participating in any CME activity disclose to the audience any relationship(s) with a pharmaceutical or equipment company. Any author whose disclosed relationships prove to create a conflict of interest, with regard to their contribution to the activity, will not be permitted to present. The Albert Einstein College of Medicine also requires that faculty participating in any CME activity disclose to the audience when discussing any unlabeled or investigational use of any commercial product, or device, not yet approved for use in the United States. Dr. Mayeaux reports that he is a consultant to Kenwood Therapeutics. The disclosure reported by the author presents no conflict of interest to the article. The author reports no discussion of off-label use. Dr. Cohen reports no conflict of interest.

Human papillomavirus (HPV) epithelial infections cause a spectrum of disease that includes nonmalignant condylomata, epithelial dysplasias, and cancers. As HPV is not reportable, comprehensive prevalence data are not available. However, it is thought to be one of the most common sexually transmitted infections (STIs) in women of reproductive age.

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EPIDEMIOLOGY

The Centers for Disease Control and Prevention (CDC) estimates that 5.5 million Americans on average acquire genital HPV annually.1 It is thought that 6.2 million new HPV infections occurred in 2000 among those aged 15 to 44 years, of which 4.6 million (74%) occurred among those aged 15 to 24 years.2

Genital warts in women may develop anywhere in the squamous epithelium of the lower genital tract, and multiple sites are found in about 50% of patients.3 Although such warts are often asymptomatic, some patients may experience anogenital pruritus, burning, vaginal discharge, and/or bleeding. Rarely, dyspareunia or obstruction of the urethra, vagina, or rectum may occur.

Human papillomavirus primarily infects the basal layer of epithelial cells. It usually exists in a latent state for about 3 months. The virus replicates in dividing epithelial cells, eventually producing genital warts. The majority of anogenital HPV infections are subclinical, and are identified only by whitening on application of 5% acetic acid (acetowhite effect), or a finding of HPV DNA without associated epithelial abnormalities. There are no readily available, specific clinical diagnostic methods for identifying subclinical infections.

Key Points

Human papillomavirus (HPV) infection can cause a spectrum of diseases ranging from nonmalignant skin growths to epithelial dysplasias and cancers. HPV infects the nuclei basal layer of epithelial cells, where it usually exists for about 3 months in a latent state. The majority of anogenital HPV infections are subclinical. There are no readily available clinical diagnostic methods to identify subclinical infections. Imiquimod, podophyllin, and podofilox are contraindicated in pregnancy. Interferon therapy is not recommended as a primary modality because it is inconvenient, ineffective, and associated with a high frequency of systemic adverse effects. Cesarean delivery should not be performed solely to prevent HPV transmission to the newborn. The use of a cryoprobe in the vagina is not recommended because of the risk of vaginal perforation and fistula formation. Patients with warts on the anal mucosa should undergo digital rectal examination or anoscopy to detect rectal warts.

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TRANSMISSION

Prior or coexisting HPV infection does not affect the risk of acquiring new HPV infections. Risk is most strongly associated with sex with a new partner—ie, exposure to new strains.4 Although vaginal intercourse is the predominant mode of transmission, HPV may also be transmitted through nonpenetrative sexual contact (eg, in virgins).4

Contrary to traditional thinking, male condom use can reduce the risk of male-to-female transmission by 70%.5 Other risk factors include current smoking and oral contraceptive (OC) use, which may be surrogate markers for other sexual behaviors.4 Use of the quadrivalent HPV vaccine may decrease the risk of external HPV lesions when administered prior to exposure.

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VIRAL TYPES

More than 30 HPV types can infect the human genital area.6 Anogenital HPV types are subdivided based on oncogenic risk. High-risk types (eg, 16, 18, 31, 33, 35) are strongly associated with cervical neoplasia. They usually cause flat lesions that are only identified on Papanicolaou smear or application of acetic acid. Persistent infection with high-risk HPV types is the most important risk factor for cervical neoplasia.

More than 90% of anogenital warts result from low-risk HPV types 6 or 11. Some 66% of affected individuals have a transient infection that is subsequently cleared without treatment.7 Among adolescent women, the average HPV infection lasts a median of 5.6 months, although high-risk HPV types tend to be more persistent.8

Clinical warts may present as cauliflower-like, flesh- to pink-colored lesions (condylomata acuminate); dome-shaped, flesh-colored, smooth papules; flat papules; or keratotic warts that may be confused with cancer.9,10 Typical exophytic condylomata are more likely to occur on keratinized skin. Multiple lesions may coalesce, producing large condylomata.

Genital HPV infections can be associated with warts in the urethra, meatus, cervix, vagina, anus, and/or oral cavity. Cervical warts are especially worrisome, as they may lead to high-grade dysplasia or cancers.9 Anal infection is also troubling, as intromissive anal intercourse confers an increased risk of anal dysplasias and cancer.

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DIAGNOSIS

There are no specific screening tests for external HPV lesions, which are usually identified visually. Although usually unnecessary, detection of flat HPV lesions can be enhanced with the use of a colposcope or hand lens and 5 minutes’ application of 5% acetic acid. A biopsy should be obtained from any lesion that has an atypical appearance, is pigmented, or is resistant to therapy. Histologic examination of HPV lesions usually demonstrates koilocytic atypia, including enlarged cells with perinuclear halos and hyperchromatic nuclei. Tests for HPV DNA typing are not indicated for external lesions.11

The differential diagnosis for HPV lesions includes condyloma latum (syphilis), which presents as smooth, broad-based papules. Benign skin lesions such as seborrheic keratoses, nevi, microglandular hyperplasia, and hymenal remnants may occasionally be confused with condylomata. Molluscum contagiosum and herpetic lesions must be excluded as well.

More serious HPV mimics include bowenoid papulosis, malignant melanoma, and Buschke-Lowenstein tumor.11 As squamous cell carcinomas may arise in or resemble genital warts, biopsy is recommended. It is very important to distinguish vulvar papillomatosis (a normal variant) from condylomata acuminata, because inappropriate treatment may produce chronic pelvic pain. Warts, dysplasia, and cancer all may be similar in appearance. A higher index of suspicion for malignancy should be maintained for immunocompromised patients, atypical-appearing lesions, lesions refractory to treatment, and pigmented lesions. A biopsy should be obtained in these cases, but again, HPV typing is generally not useful.12

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THERAPY

The CDC recommends that treatment be guided by patient preference (Table).6 None of the available treatments is superior to the others, and no single treatment is ideal for all patients or all warts. Practitioners should be familiar with at least one patient-applied treatment and one provider-applied therapy.6 No data suggest specific treatment modalities in the setting of concomitant human immunodeficiency virus (HIV) infection.

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TABLE. Centers for Disease Control and Prevention Recommended Regimens for Condylomata Acuminata

Patient-applied Therapies

Imiquimod.—Imiquimod/imidazoquinolinamine, 5% cream, is an immune modifier that induces cytokines.13,14 It has almost no systemic side effects, and is classified as pregnancy category C. It may also help to induce “immune memory” and prevent future recurrences.15 It is indicated for use on external HPV infections, and contraindicated for occluded mucous membranes (eg, vagina, urethra, perianal area, cervix). Condoms and diaphragms should not be used during treatment, as imiquimod may damage latex. The patient should apply it three times a week, every other day, for up to 16 weeks. The affected area should be washed with mild soap and water 6 to 10 hours after application. Side effects include erythema, erosion, itching, skin flaking, and edema. Clearance occurs within 16 weeks in 37% to 54% of patients, with recurrences noted in 13% to 19%.9

Podofilox.—Podofilox/podophyllotoxin, 0.5% gel, solution, or cream, is the purified active component of podophyllin. It is contraindicated for use on occluded mucous membranes and during pregnancy. Podofilox is applied twice daily for 3 consecutive days followed by 4 consecutive days of no therapy (7 days total), repeated for a maximum of 4 weeks. Trials have shown that 45% to 77% of patients attained clearance within 4 to 6 weeks. Side effects include inflammation, irritation, erosion, burning, pain, and itching. Recurrences have been reported in 4% to 38% of patients. Effective contraception such as condoms/diaphragms for women of childbearing age is advised until the warts are cleared.9

Sinecatechins.—Sinecatechins, 15% ointment, is a new botanical treatment derived from green tea,16 and is FDA-approved for the treatment of external genital and perianal warts in patients aged 18 years or older. Catechins have shown chemopreventive properties against various cancers,16 as well as antiangiogenic and anti-HPV activity and inhibition of tumor invasion. The ointment is applied by the patient three times a day for 16 weeks. Partial or total clearance has been reported in more than 77% of patients. Local skin reactions are mild to moderate, with rare instances of pain and inflammation.17, 18 Sinecatechins is classified as pregnancy category C.

Provider-administered Therapies

Surgical Excision.—Surgical excision directly removes wart tissue. Studies demonstrate clearance in 35% to 72% of patients, with recurrence in 19% to 29% at 1 year.9

The loop electrosurgical excisional procedure (LEEP) is indicated for perineal condylomata; in skilled hands, it may be used for anal verge lesions. Late bleeding has been reported in 4% of patients, and can usually be controlled with Monsel’s solution or fulguration. In rare cases of infection, topical antibiotics can be applied. Hypopigmentation and hypertrophic scars are also rarely reported. Success rates range from 90% to 96%.11

Cryotherapy.—Cryotherapy with liquid nitrogen, nitrous oxide, or carbon dioxide cryoprobe is especially useful for discrete lesions. It is probably the safest therapy for use during pregnancy. The treated tissues slough after several days, followed by inflammation and then healing. Therapy is repeated every 1 to 2 weeks if necessary. Common complications include pain and local infection. The success rate is 71% to 79%, and recurrence rates are 38% to 73% by 6 months.9

Trichloroacetic/bichloroacetic (dichloroacetic) Acid.—Topical acid is also safe for use during pregnancy, but should not be applied to the cervix or urinary meatus. Trichloroacetic acid (TCA) must be compounded at a pharmacy, but bichloroacetic acid (BCA) can be obtained in a standard preparation. A 50% TCA solution is applied in a thin layer with a cotton-tipped applicator three times a week for a maximum of 4 weeks, or an 80% solution can be applied twice a day for 3 consecutive days per week for a maximum of 4 weeks. BCA may be applied to the wart weekly. Bicarbonate, talc, or soap and water may be used to neutralize any excess acid.11 Complications include ulceration, pain, and damage to adjacent skin. Response rates are 50% to 81%, and recurrence rates are high but undefined.9,11

Podophyllin.—A solution of 10% to 25% podophyllin in tincture of benzoin is best suited for small external lesions. Its use in pregnancy is contraindicated, and it is not recommended for use in occluded mucous membranes. Systemic reactions and death can occur when application is extensive/prolonged or involves the mucous membranes. Adverse reactions include nausea, vomiting, fever, confusion, coma, renal failure, ileus, and leucopenia. Podophyllin is applied by trained personnel once or twice weekly for a maximum of 4 weeks. The solution should be washed off 1 to 4 hours after the first application, and 4 to 6 hours after subsequent applications. Complications include local erosion, ulceration, and scarring, as well as irritation of adjacent skin. Success rates range from 20% to 77%, with recurrence rates of 23% to 65%.19,20

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CONCLUSION

External genital HPV infections are common in sexually active individuals. Although such infections are low-risk with regard to subsequent cancer, considerable psychological distress and social disruption can occur. Selection of treatment depends on the number, size, and location of lesions, as well as patient preference and the physician’s training. There is little evidence that one treatment option is more effective than any other.

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E.J. Mayeaux, Jr, MD, is Professor, Department of Family Medicine, and Professor, Department of Obstetrics and Gynecology, Louisiana State University Health Sciences Center, Shreveport, LA.

References

1. Revzina NV, DiClemente RJ. Prevalence and incidence of human papillomavirus infection in women in the USA: a systematic review. Int J STD AIDS. 2005;16(8):528-537.
2. Weinstock H, Berman S, Cates W Jr. Sexually transmitted diseases among American youth: incidence and prevalence estimates, 2000. Perspect Sex Reprod Health. 2004;36(1):6-10.
3. Chuang TY, Perry HO, Kurland LT, Ilstrup DM. Condyloma acuminatum in Rochester, Minn., 1950-1978. I. Epidemiology and clinical features. Arch Dermatol. 1984;120(4):469-475.
4. Winer RL, Lee SK, Hughes JP, Adams DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students. Am J Epidemiol. 2003; 157(3):218-226.
5. Winer RL, Hughes JP, Feng Q, et al. Condom use and the risk of genital human papillomavirus infection in young women. N Engl J Med. 2006; 354(25):2645-2654.
6. Centers for Disease Control and Prevention, Workowski KA, Berman SM. Sexually transmitted diseases treatment guidelines, 2006. Genital warts. MMWR Recomm Rep. 2006;55(RR-11):62-67.
7. Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med. 1998;338(7):423-428.
8. Brown DR, Shew ML, Qadadri B, et al. A longitudinal study of genital human papillomavirus infection in a cohort of closely followed adolescent women. J Infect Dis. 2005;191(2):182-192.
9. Wiley DJ, Douglas JM, Beutner K, et al. External genital warts: diagnosis, treatment and prevention. Clin Infect Dis. 2002;35(Suppl 2):S210-S224.
10. Von Krogh G, Lacey CJ, Gross G, Barrasso R, Schneider A. European course on HPV associated pathology: guidelines for primary care physicians for the diagnosis and management of anogenital warts. Sex Transm Inf. 2000;76(3):162-168.
11. Mayeaux EJ, Harper MB, Barksdale W, Pope J. Noncervical human papillomavirus genital infections. Am Fam Physician. 1995;52(4):1137-1146.
12. Gunter J. Genital and perianal warts: new treatment opportunities for human papillomavirus infection. Am J Obstet Gynecol. 2003;189(3 Suppl):S3-S11.
13. Edwards L, Ferenczy A, Eron L, et al. Self-administered topical 5% imiquimod cream for external anogenital warts. HPV Study Group. Human papillomavirus. Arch Dermatol. 1998;134(1):25-30.
14. Megyeri K, Au WC, Rosztoczy I, et al. Stimulation of interferon and cytokine gene expression by imiquimod and stimulation of Sendai virus utilize similar signal induction pathways. Mol Cell Biol. 1995;15(4):2207-2218.
15. Ferenczy A. Treatment of external genital warts. J Lower Genital Tract Dis. 2000;4(3):128-134.
16. Beti H, Orasan R, Meyer KG, et al. Polyphenon-E ointment in the treatment of external genital warts-first phase III results. J European Acad Dermatol Vener 2004; 18(Suppl 2): P09.30, p.401.
17. Beutner K, Tatti S, Rodriguez Donando A, et al. Polyhenon E ointment in the treatment of anogenital warts- completing phase 3 study results. Abstracts of the 22nd International Papillomavirus Conference 2005 Vancouver, Canada, Abstract z-104, p.107.
18. Stockfleth E, Beutner K, Thielert C, et al. Polyphenon E ointment in the treatment of external genital warts. J European Acad Dermatol Vener 2005;19(Suppl 2): FC06.8, p.116.
19. Greene I. Therapy for genital warts. Dermatol Clin 1992; 10:253-67.
20. Brown DR, Fife KH. Human papillomavirus infections of the genital tract. Med Clin North Am 1990; 74:1455-85.

DISCLAIMER

The opinions expressed herein are those of the author and do not necessarily represent the views of the sponsor or the publisher. Please review complete prescribing information of specific drugs or combination of drugs, including indications, contraindications, warnings and adverse effects before administering pharmacologic therapy to patients.

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