External Genital Warts

M. Bourcier, MD, FRCPC¹; D. R. Thomas, MD, FRCPC²

1. La Clinique de Dermatologie, Moncton, NB, Canada
2. Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada

Background

Human papillomavirus (HPV) is a very common sexually-transmitted disease that is associated with a number of benign, premalignant, and frankly malignant lesions of the anogenital tract. In Canada, its prevalence varies depending on a number of risk factors, but appears to be highest in people between 15-25 years of age. [Varela A, et al. Skin Therapy Lett – US FP Ed 1(2): 1-3 (2007 winter).] ThSkin The introduction of a relatively new immunomodulator, and the approval of a vaccine significantly improves treatment options in managing this condition.

Condyloma Acuminatum (anogenital warts) is a common form of HPV infection. The majority of these are due to infection with HPV 6 or 11, and are clinically benign. Genital warts are usually asymptomatic, but can cause pruritus, bleeding, or mild burning. The warts present as:

• small, verrucous papules
• discrete, sessile, smooth-topped papules or nodules
• large exophytic masses

Lesion color can range from flesh-colored to pink to reddish brown, and often they are multifocal. Lesion distribution generally corresponds with the areas of highest friction during sexual activity.

Risk Factors

• The number of sexual partners over a lifetime
• The sexual promiscuity of the sexual partners
• Correlations between oral contraceptives and smoking have been reported.[Trottier H, et al. Vaccine 24 Suppl 1:S1-15 (2006 Mar).] However, the literature has not consistently supported such findings.

Pathogenesis

The virus is inoculated directly into the epidermal layers of the skin through epithelial defects, especially with maceration. Genital infections are primarily contracted through sexual contact. These infections can then be transmitted to newborns via passage through the infected birth canal. [Kaye JN, et al. J Gen Virol 77(Pt 6):1139-43 (1996 Jun).]

Diagnosis

• Primarily made by visual inspection.
• For hard to detect lesions, particularly on the cervix, a 5% acetic acid solution can be applied to the suspected area. After a few minutes, the condylomata should appear as white patches on the mucosa. These changes are not diagnostic for HPV.
• A biopsy may be useful if:
  • diagnosis is uncertain.
  • lesions do not respond to standard therapy.
  • the disease worsens during therapy.
  • the patient is immunocompromised.
  • the warts are pigmented, indurated, fixed, bleeding, or ulcerated. [CDC. Genital Warts Treatment Guidelines 2006.

Differential Diagnosis

• Molluscum contagiosum
• Benign penile pearly papules
• Hymenal remnants
• Bowenoid papulosis
• Seborrheic keratosis
• Syphilitic condyloma lata
• Skin tags
• Squamous cell carcinoma
• Verrucous carcinoma (Giant condyloma of Buschke-Lowenstein)
• Vulvar dysplasia
• Linear epidermal nevus
• Lichen nitidus
• Angiokeratomas
• Milium
• Fordyce spots

In the majority of patients, treatment can induce wart-free periods; if left untreated, warts may resolve on their own, remain unchanged, or increase in size or number. Treatment can reduce, but does not eliminate, HPV infection. The choice of treatment should be guided by the preference of the patient, the available resources, and the health provider’s experience. No single treatment is ideal for all patients or all warts. The majority of patients require a course of therapy rather than a single treatment, and improvement will generally be seen within 3 months. [CDC. Genital Warts Treatment Guidelines 2006.] Before beginning any treatment, it is essential to screen patients for other sexually-transmitted diseases.

Most treatment modalities treat the symptom of the disease (warts) versus the disease itself. However, imiquimod, goes further by inciting an immunologic response, thereby providing a field effect in clinical and subclinical HPV.

There are three treatment modalities:

• Antiproliferative agents
• Destruction/excision therapies
• Immunomodulatory therapy
• Combination therapies

Antiproliferative Therapies

• Podophyllin resin 10%-25%
  • provider-administered
• Podophylox 0.5% solution or gel
  • can be applied by the patient
  • does not contain the mutagenic substances found in podophyllin resin.

Destruction/Excision Therapies

• Local cryotherapy is the most common destructive mode.
  • It is safe during pregnancy.
• Application of topical trichloracetic acid
• Electrocautery
• Ablative laser treatment
• Excision by scissor, curette, or scalpel
• All of these options have a risk of scarring.

Immunomodulatory Therapy

• Imiquimod
• Approved by Health Canada in 1999.
• Topical cream – administered by patient.
• Self-administration improves patient compliance.
• Enhances the cytotoxic immune response, which is usually seen as an inflammatory response.
• Applied directly to the affected skin 3 times per week for up to 16 weeks. Initially the frequency of applications can be reduced if the patient is over concerned by the degree of inflammation.
• Acts to reduce the viral load, thereby reducing recurrence rates to very low levels.
• A significant advantage is the ability to affect subclinical lesions.
• Is more effective in women than in men possibly because warts are more commonly found on mucosal skin.

Combination Therapy

• Often monotherapy can be inadequate for treating anogenital warts. Combination therapy can provide a better result.
• Treatment with imiquimod followed by excision of residual lesions may provide long-term clearance of anogenital warts in those patients for whom monotherapy was insufficient.[Carrasco D, et al. J Am Acad Dermatol 47(4 Suppl):S212-6 (2002 Oct).]

Figure 1: Algorithm for treatment of suspect lesions. [Adapted from Varela A, et al. Skin Therapy Lett – US FP Ed 1(2):1-3
(2007 Winter).] TCA= trichloroacetic acid

Prophylaxis

A quadrivalent HPV recombinant vaccine is now available in Canada, and is indicated in girls and women aged 9-26 years for the prevention of diseases caused by HPV types 6, 11, 16, and 18, which include genital warts, cervical cancer and other neoplasias of the cervix, vagina and vulva. It should be administered IM as three separate 0.5ml doses. Studies with this vaccine are now ongoing in males. Another bivalent HPV vaccine (for HPV types 16 and 18) is currently under review with Health Canada. There is no evidence for effectiveness in treating those who already have genital warts.

Conclusion

Most HPV infections are asymptomatic and can spontaneously clear on their own. However if treatment is required, there are a number of antiproliferative, destructive, immunomodulatory modalities available. Combination therapies have been shown to be advantageous. In general, the response time can be expected within 3 months of therapy. Patients should be evaluated throughout the course of therapy for treatment response and side-effects, and treatment should be changed if substantial improvement is not seen within that time frame. Cryotherapy combined with imiquimod appears to be very commonly used. A quadrivalent HPV recombinant vaccine is now available for girls and women 9-26 years of age, and a bivalent vaccine is under review with Health Canada. While not of benefit to those already infected, future generations may be spared considerable burden from external genital warts due to the development, approval, and release of HPV polyvalent vaccines. Not only does the vaccination largely prevent incident external genital warts, but it also protects against genital tract HPV-associated neoplasia.