Anogenital warts (AGW) are epidermal growth lesions caused by the different genotypes of the human papillomavirus (HPV). HPV is usually sexually transmitted. AGW represent a failure of immune recognition, this is not linked to cervical cancer.
Prevalence and aetiology
HPV is so common that nearly all sexually active men and women get the virus at some point in their lives. In the US, 1 in 100 sexually active adults has genital warts. In SA, 66.7% of women have HPV. Low-risk HPV, types 6 & 11 are responsible for 90% of genital warts, which are rarely associated with pre-cancer and cancer.
The scale of the problem
Transmission does not require lesions to be present. They create a massive cosmetic problem and is a source of substantial psychological issues for the patient, including shame, embarrassment, anger, depression and guilt.
AGW and existing treatment modalities can also cause physical issues like pain, burning, irritation and itching.
They also cause a strain on the budget of healthcare systems. For instance, the direct cost of treatment of AGW in 2012 (UK) was R1183.44M.
Diagnosis
The challenge is to ensure that warts are correctly identified and other lesions are not missed. Initial diagnosis is often made or suspected by the patient. This must then be confirmed on clinical inspection.
They appear as papillomatous plaques or flat lesions that could be single or multiple. Lesions could be flesh coloured, white, pink or brown. They typically manifest in areas in close contact during sex - vulva, penis, groin, perineum and peri-anal skin. They sometimes also arise in the oral cavity.
Diagnosis of typical AGW does not require a histological diagnosis.
Types of lesions that can be confused with warts
There are a number of physiological and pathological lesions that could be confused with AGW. These include vestibular papillae, sebaceous cysts, syphilis on mucosal plates, molluscum contagiosum, lichen planus, psoriasis and Condylomata lata.
This also includes benign or malignant neoplastic lesions, papillomatosis, nevi, verrucous carcinoma, grade 2-3 vulval intraepithelial neoplasia, Bowen’s disease and lymphangioma.
When to biopsy
Experience in this regard is paramount. Refer to a vulval specialist if it doesn’t look like obvious warts.
A biopsy is usually indicated in flat warts, pigmented areas, older age group, immunosuppression and heavy smoking.
Treatment considerations
Treatment should be individualised. Patients often want immediate resolution but consideration should be given to size, number, morphology, location and keratinisation. It is important to note if these are new or recurrent lesions.
The wart area should be considered, as smaller surface areas often require treatment for a shorter period.
Treatment options
Ablative therapy
Ablative therapy is used daily by practitioners to remove warts. It’s often awkward and painful for the patients. There is a high rate of recurrence and a need for repeat therapy. There is also a high risk of bleeding, tissue destruction and scarring.
Cryotherapy, freezing with liquid nitrogen, may cause hypopigmentation.
Laser - carbon dioxide and Nd: YAG. Requires specialised and costly equipment and training.
In electrocautery, fumes may contain contagious particles.
In terms of surgery, scissors or scalpels are needed, especially in large obstructive lesions.
Trichloroacetic acid requires a skilled professional and may cause local burning/ ulceration.
Immunotherapies
This stimulates the body’s own immune system to clear the lesions. Imiquimod is used by the patient three nights a week for up to 16 weeks.
Sinecatechins is made from green tea polyphenols with anti-inflammatory, anti-proliferative, pro-apoptotic and anti-viral properties. Its mode of action is not fully known. It is applied three times a day for up to 16 weeks.
It has complete clearance rates of 40%-81%. It is similar to imiquimod but has higher recurrence rates.
Other topical agents
Podophyllotoxin 0.15% or 0.5% solution stops the division of infected cells leading to tissue necrosis. It is applied twice daily for three consecutive days separated by four-day intervals, repeated for up to four weeks. It needs to be applied carefully to the lesions avoiding normal skin. It has a clearance rate of 45%-94%.
The Nitric-zinc complex contains nitric acid, zinc, copper and organic acids. It is applied 1-4 x daily at two-weekly intervals. It has clearance rates in initial small studies of 90%-99%.
Imiquimod
This is a novel topically active positive immune response modifier. It enhances the body’s immune response against dysplastic cells and is a member of the imidazoquinolines family.
It has proven strong antiviral (HPV) and anti-tumour properties, enhancing non-specific and specific immune responses, especially in cell-mediated pathways.
Modes of action
It activates dendritic cells through Toll-like receptor 7. Activated dendritic cells migrate to local lymph nodes and initiate T-cell activity. It induces IFNa, IL6, IL12 and TNFa. T-cells travel via the bloodstream and selectively destroy tumour cells, other dysplastic cells and instigate resolution of actinic keratosis and superficial basal cell carcinomas.
It stimulates natural killer cells, macrophages and B lymphocytes, and induces immunologic memory.
Imiquimod induces cellular memory via the activation of effector T-cells, Langerhans cells, lymphocytes, and macrophages. These cells circulate lymphatically and activate the adaptive immune response. Imiquimod’s ability to induce immunologic memory results in a low incidence of recurrence and lowers the viral load. Patients wash the area with mild soap and then dry, and apply a small amount of cream onto the lesions for three nights per week for up to 16 weeks. Approximately 40% of patients may experience complete clearance at four weeks.
Advantages
It is highly selective with a specific effect on dysplastic cells and no effect on normal cells, but a treatment effect on subclinical actinic keratoses. Surface field treatment can be achieved.
It lowers HPV viral load and treats clinically visible and sub-clinical lesions, with excellent cosmetic outcomes. It is less invasive than some of the other treatments discussed and can be applied at home. It is available in pumps or sachets, is also on state formulary.
Disadvantages
Local skin reactions include redness, itching and burning. Flu-like symptoms are rare and only in a very severe reaction, including myalgia, headache, fatigue.
Treatment can take a few weeks.
Prevention of recurrence
Recurrence rates with conventional ablative therapies are relatively high, as these methods remove visible lesions without treating the underlying HPV infection.
Immunotherapies described above have a lower recurrence rate as they stimulate host immune response to clear warts.
Studies have shown that a combination of ablative techniques followed by immunotherapy may lead to even lower recurrence rates. The use of imiquimod prior to or after ablative therapy reduces the recurrence rate.
Summary
AGW warts are common and by the time the patients present they have probably had the lesions for a while. There are various treatments available and these should be offered to patients depending on factors such as size, number, type, recurrence and surface area.
A biopsy is indicated if the diagnosis is uncertain.
Ablative therapy may be associated with unwanted side effects.
Imiquimod is an effective treatment that is well tolerated and can be used on its own or in conjunction with other forms of treatment.
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