Management of anogenital warts (condylomata acuminata)

ARTICLE

Epidemiology and pathogenesis

* Acquisition rates correlate with the number of lifetime sexual partners, being > 50% in people with > 5 partners, and being inversely correlated with condom use.

* Incubation time is highly variable, from an average of 2-3 months to 6-18 months or more.

* Condylomas represent the "tip of the iceberg", afflicting 0.5-1% of the general population. Warts tend to develop in areas submitted to friction during intercourse.

* Co-infection with high-risk HPV types is detectable in a third of condyloma patients. Oncogenic HPV types may sometimes cause symptomatic maculopapular lesions but tend merely to cause subclinical epithelial lesions only. On the cervix uteri high risk HPV infection is associated with 30-40% risk of developing transient CIN (cervical intraepithelial neoplasia) and is associated with a 16-fold excess risk of developing subsequent cervical cancer [1-3]. However, the vast majority regress spontaneously within 2 years in women < 25-30 years of age. About 15% of CIN lesions persist and may potentially progress to cervical cancer within an average of 12-13 years. Continued oncogenic HPV transforming protein expression seems necessary for malignant transformation.

Transmission

* Sexual transmission dominates [1-3].

* Naso-oro-pharyngeal-genital HPV DNA is detectable by PCR in 30-80% of babies born to HPV DNA positive women. The biological implication of this is unclear; some believe that this represents transient contamination, which commonly clears within a few months. However, low HPV DNA levels on buccal mucosa have been traced with highly sensitive PCR technique in half of children aged 3-11 [4].

* Auto- or allo- inoculation from digital warts or genital lesions is possible in some cases [5].

Clinical presentation

Symptoms [6-10]

Condylomas may cause bleeding, itching, burning, fissuring, dyspareunia, balanoposthitis or vulvitis and are psychologically distressing, causing anxiety, guilt, anger, and loss of self-esteem and concerns about future fertility and cancer risk.

Multicentric distribution [7-10]

* The preputial sac (glans, coronal sulcus, frenulum and inner aspect of fore skin) is most commonly afflicted in uncircumcised men, while penile shaft warts often occur in circumcised men.

* The labium, clitoris, and vestibule are often afflicted in women, and about one third also have occult cervical and/or vaginal warts.

* Urethral meatus warts are seen in 20-25% of males and 4-8% of females.

* Perianal warts occur in about 20% of females, occasionally in heterosexual men and commonly in homosexual men. Intra-anal warts often occur when receptive anal intercourse is practised. Warts are rarely found beyond the dentate line of the anal canal.

* Condylomas of the nailbed, the lips, the oral cavity, the larynx, conjunctiva or the nipples are exceptional.

Multiform morphology [7-10]

* Single, multiple or plaque lesions may develop; generally 5-15 broad-based or pedunculated warts of 1-10 mm diameter are present.

* Several lesion types exist: on moist epithelium often acuminate ("pointed") and/or macular ("flat") lesions, and on dry skin papular ("rounded") and keratinised warts. Punctuated and/or loop-like vascular patterns are seen at magnification unless warts are very keratinised.

* Colour tones vary from pinkish-red in acuminate warts with highly vascularised dermal cores, to greyish-white in keratinised lesions, or brown on dry skin and reddish-brown or grayish-black in bowenoid papulosis.

HPV associated premalignant lesions of the external genitals

Bowenoid papulosis, Bowen's disease [9, 10]

Greyish-white or brownish-red-grayish-black maculopapular lesions associated with oncogenic HPV and full thickness IN.

Giant condyloma (Buschke-Löwenstein) [9, 10]

A rare semi-malignant variant of HPV 6/11 disease, characterised by aggressive down-growth into underlying dermal structures. A complex histological pattern may exist with areas of benign condyloma intermixed with foci of atypical epithelial cells.

Laboratory procedures

* Routine STD examination. Chlamydia trachomatis may possibly contribute to increased cervical cancer risk [11].

* National Pap smear programmes for CIN screening should be followed [7]. Yearly screening is recommended in immunosuppressed women [9, 13].

* Biopsy is unnecessary for newly occurring acuminate warts but recommended for formal and differential diagnostic purposes in maculopapular lesions, in therapy resistant warty growths, and as a medicolegal procedure in children. Histology assessment is mandatory for cervical lesions [7], when the biopsy is taken under colposcopic guidance (gynaecology).

* HPV typing does not add significant information of practical value.

Clinical diagnostic routine procedures

The goals of investigation are to ensure appropriate diagnosis and treatment, to minimise psychosexual sequel, and to reduce infectivity [7].

Examination and mapping

* Inspection with good illumination and a hand lens (dermatoscope), or when available (specialist settings), colposcopy magnification.

* Females: vaginal speculum examination to identify vaginal and/or cervical warts.

* Both sexes: anoscopy if anal warts and a history of anal receptive sex.

* Both sexes: inspection of the urinary meatus by everting the meatal lips. Half of cases afflict the distal 10 mm of the urethra only. Use of a small speculum (spreader) or an otoscope recommended for deeper examination ("meatoscopy"). Only 5% of cases require urology investigation for adequate delineation of the proximal border. The posterior urethra is not involved without previous or simultaneous growth of meatal warts.

* Classification of warts as to morphology. Typical acuminate warts are pathognomonic and do not require biopsy. Papular and macular lesions are associated with differential diagnostic problems and require a biopsy for formal proof of the diagnosis and for evaluation of any IN.

The acetic acid test

* Application of 5% acetic acid may within 1-3 min turn lesions greyish-white for a few minutes ("acetowhitening"). Magnification and training is required for optimal evaluation and biopsy recommended for confirmation.

* The test is valuable for identifying and demarcating HPV lesions for targeted biopsy and during surgical therapy but not recommended for routine screening.

* False negative results occur, most commonly on dry genital skin.

* False positive results are common (lichen sclerosus, lichen ruber planus, psoriasis, balanoposthitis and vulvovaginitis, eczemas, genital herpes and traumatic microabrasions).

Differential diagnosis

Differential diagnosis includes a range of dermatological and infectious conditions, in particular when maculopapular lesions are pigmented or whitish.

In about 40% of males physiologic "penile pearly papules" develop during the late teens, when 1-3 rows of discrete non-coalescing 1-2 mm papules appear circumferentially on the proximal verge of the glans and/or symmetrically in the parafrenulum area. In some males only reminiscent papules are present. In females physiologically regularly shaped and non-coalescing, mostly symmetrical papillae often appear on the inner surface of the labia minora and in the vestibule ("micropapillomatosis labialis"). Sebaceous glands of the foreskin and of the vulva can be observed in a minority of normal individuals as multiple, discrete, greyish-yellow, non-indurated lesions on the inner aspect of the labia minora and prepuce.

Repetitive fissuring and/or inflammatory reactions in the genital area, such as in the posterior fourchette of the labia, should be differentiated from genital candidiasis and genital herpes.

Differentiation between BP and BD cannot be done histologically but relies on clinical criteria, the patient's age being of major importance: BP appears at 25-35 years of age and BD at 40-50 years or over. Differential diagnosis of giant condylomas versus well-differentiated squamous-cell carcinoma may require multiple surgical biopsies followed by excision with sound margins, as exact disease extent can only be assessed by histopathology evaluation.

Therapy

Counselling

Psychosexual counselling and a supportive attitude are important parts of proper therapy. The following issues should be discussed.

* Owing to latency periods after transmission, condylomas developing in only one partner in a steady relationship does not inevitably signify sexual contact outside the relationship.

* Use of condoms is recommended with new sexual contacts until successful treatment has been completed.

* Use of condoms within an ongoing steady sexual relationship may not be needed as the partner will already have been exposed to the infection by the time of consultation. Use of condoms does not seem to influence the outcome of HPV associated morbidity once infection has become established in the individual.

* It is considered good clinical practice to encourage that current partners, and if advisable, other partners within the past 6 months, be assessed for the presence of lesions and for education and counselling.

* Periods of coital rest during therapy may minimise side effects such as burning and pain.

Goals and expectations of therapy

* No single treatment is ideal for all patients or all warts. Choice of therapy depends on the morphology and extent of warts and should be guided by the preference of the patient, available resources, and the experience of the health-care provider.

* All therapies are associated with local skin reactions such as burning, erosions and pain.

* Some regimens require multiple physician visits and thus are not convenient for the patients and are associated with high costs.

Recommended therapies

Current guidelines [7, 13, 14] focus on shared management between specialists and primary care physicians. Most condyloma patients can primarily be dealt with by the non-specialist, both in terms of investigation and treatment. Referral to various specialists is recommended [7] as outlined in table II.

Clinicians who treat patients should be available for at least one home therapy and one office therapy (table I). The average patient has a relatively small number of warts that can eventually be eliminated with most modalities. Patients with limited disease (1-5 warts) may benefit from simple office therapy.

Home therapy

Home-therapy adds the psychologically positive aspect of convenience and of retaining control of one's personal situation in the privacy of the home atmosphere.

1. Podophyllotoxin 0.5% solution or 0.15% cream

The crude plant extract Podophyllin is not recommended due to its low efficacy and high toxicity profile. Instead, pharmaceutical products based on purified podophyllotoxin - the most potent antiwart ingredient of the Podophyllum plant - appear to be safe, cost-effective and convenient for use as first-line routine therapy [15], in particular because of its rapid effect. Podophyllotoxin inhibits mitotic division and may induce necrotic involution of condylomas within 3-5 days after administration is initiated.

Two of the available products ensure optimal patient compliance: a 0.5% tinted ethanol solution (3.0 ml) and a 0.15% cream (5 g) formulation, which are sufficient for at least 4 treatment cycles.

* Each cycle consists of twice daily application for 3 days, followed by 4 drug free days. Before each treatment session the area is washed and dried. No washing off is required between applications.

* Half of patients are already cured after the first cycle. After 1-4 cycles, i.e. within about a month, cure is accomplished in 60-80% and significant improvement established in 70-90% of patients.

* The tinted 0.5% solution is convenient for penile warts; the foreskin is retracted and the solution containing patent blue as a colour indicator is applied to each wart area by a specially-designed plastic applicator or by cotton wool swabs.

* The 0.15% cream formulation is easy to apply for patients with vulva and anal warts. The uncoloured cream is rubbed into each wart area using the index finger, assisted by a hand-held mirror and a good light source.

* About half of patients experience mild-to-moderate transient burning or tenderness and about 5% some pain 2-3 days after starting therapy, predominantly associated with the first cycle of therapy. Erosions occurring as the warts necrotise are shallow and heal within a few days. Uncircumcised men with multiple warts of the preputial sac may experience transient problems in retracting the foreskin.

* Women of childbearing age must be informed that they must either use proper contraceptives, or abstain from penetrative sexual activity during therapy cycles.

2. Imiquimod 5% cream [16, 17]

Imiquimod (imidazoquinolinamine) is a nucleoside-like compound that, by topical application, acts as an immune response modifier by inducing epithelial cytokine production (interferon-alpha, interferon-gamma) and CD4⁺ T cell recruitment. This process may be followed by immune induced wart regression. The drug is very valuable in problem warts and patients motivated to accept the long duration for therapeutic response to develop (mean of 7-8, range 2-16 weeks). Recurrence rates from imiquimod are 13-19%, being lower than those reported from other modalities.

* Imiquimod cream, supplied in single use sachets, is applied in the evening three times per week and the area is washed the following morning. Treatment continues until there is total clearance of the warts, or for a maximum of 16 weeks.

* Total wart clearance occurs in about half of the cases, and about 70-90% of patients are significantly improved. In the original US studies clearance rates were higher for females (77%) than for circumcised males (40%). In European studies on uncircumcised males efficacy has been 62% after 13 weeks of therapy.

* Two thirds of patients develop mild to moderate erythema, erosions and tenderness. Erosions causing discontinuation of therapy during clinical studies are rare; a drug free rest period of a week or so is recommended, if required, which seems to be important in uncircumcised males.

* Safety of imiquimod during pregnancy has not been established.

Office therapy

1. Trichloracetic acid (TCA) 80-90% solution

TCA is a caustic agent that causes cellular necrosis. It is most suitable for small condylomas and is less efficacious on keratinised or large lesions. TCA is corrosive to the skin and other materials and a neutralising agent (e.g. sodium bicarbonate) should be available in case of excess application or spills.

* The physician applies TCA to the wart with a cotton tip, weekly, in the clinic. Great care must be taken in application as ulceration penetrating into the dermis may occur with overzealous use.

* Initial response rates are 70-80% after 1-4 visits to the out-patients clinic or doctor's surgery but the recurrence rate is up to 36%.

* An intense burning sensation may be experienced for up to 10 minutes after application. A shallow ulcer forms at the treatment site and heals within three weeks.

* TCA can be used safely during pregnancy.

2. Surgical treatment

* Method of choice is a matter of wart distribution, local tradition, and the clinical skills and experience of the physician.

* Routine use of local anaesthetic lidocaine/prilocaine cream is recommended; in the anogenital area the effect is accomplished within 10-15 minutes, which significantly reduces discomfort from the needle pricks associated with infiltration anaesthesia.

* The use of 5-10 mg/ml lidocaine for infiltration gives rapid epithelial anaesthesia. Adrenaline as adjuvant contributes to reducing any bleeding but is contra-indicated on the penis.

a) Scissors excision, electrosurgery and laser surgery

* Infiltration anaesthesia leads to separation of lesions, facilitates accurate removal and sparing of uninvolved skin bridges for optimal re-epithelisation to follow.

* Endpoint of tissue removal is the view of underlying tanned chamois-leather like papillary dermis; more excessive destruction leads to scarring. Some depigmentation often develops on sites of surgery, which is disadvantageous on very pigmented skin.

* Superficial scissors excision is feasible for exophytic warts, assisted by diathermy to control haemostasis and to destroy any conspicuous wart tissue remaining after the excision.

* Electrosurgery alone can be employed for both limited and extensive papular or flat lesions. Use of the considerably more expensive CO₂ laser surgical equipment usually gives identical results to those of diathermy

* Diathermy and laser therapy should be performed with the use of surgical masks by the treatment team, and a smoke evacuator is required.

b) Formal surgery

* Extensive wart proliferation on the foreskin is sometimes best managed by circumcision.

* Extensive intra-anal warts are best removed under general anaesthesia by a proctologist.

* In children and sensitive patients with extensive warts general anaesthesia is recommended for surgical procedures.

3. Cryotherapy

* Cryotherapy causes epidermal necrosis and dermal capillary injury. Clinic treatment is usually performed weekly. A "halo" is established a few millimetres around the lesion, when freezing is continued for 20 seconds. A freeze, thaw, freeze technique should be used.

* Open application is performed with liquid N₂ by a spray device or by direct swab application.

* Closed systems utilise CO₂, N₂O or N₂ led through a cryoprobe.

* Efficacy rates are 63-89% after an average of 3-4 visits to the clinic.

4. Interferons

* The role of IFN against HPV lesions is controversial but some [18] advocate their use as an adjunt to surgery in very recalcitrant cases. Several protocols exist.

* Low-dose recombinant alpha-IFN or beta-IFN injected s.c. 1.5 million units as 3 cycles consisting of 5-7 days therapy with a 4-week drug-free interval.

* High dose recombinant beta-IFN s.c. 4 million units 3 times a week for six weeks.

5. Treatment options for anatomical sites for special consideration

* Meatal warts: cryotherapy, electrosurgery and laser. Caution: adhesions/stenosis may occur. Podophyllotoxin 0.15% cream applied with a cotton wool swab for 3-4 days may give favourable results (von Krogh, personal observation)

* Intra-anal (anal canal) warts: TCA, electrosurgery and laser.

* Vaginal warts: TCA, electrosurgery and laser

* Cervical warts: excisional biopsy, cryotherapy, electrosurgery or laser.

Specialist referral

General recommendations [7] for specialist referral are outlined in table II.

Gynaecology

* In women > 25 years of age unless a negative Pap smear has otherwise been obtained within the past 3 years.

* In women with vulva intraepithelial neoplasia (VIN; bowenoid papulosis).

* In early pregnancy condylomas may become numerous and large but tend to regress spontaneously after delivery. Estimated 1:400 risk of infants developing laryngeal papillomatosis if maternal warts are present at delivery. No strict proof exists that treatment diminishes this risk, although active therapy aiming at reduction in viral burden seems wise. Treatment with TCA or surgery prior to the third trimester is recommended. Podophyllotoxin is contraindicated and imiquimod is not approved.

* Very rarely a Cesarean section is indicated because of blockage of the vaginal outlet with warts.

Immunosuppression

* HIV infected and transplant grafted patients are linked to significant increase in multicentric and refractory condyloma and of IN.

* Annual cytological screening is recommended.

Urology

* When the proximal border of meatus warts cannot be delineated.

* When recurrent meatal warts exist.

Children

* Condylomas in children are more common peri-anally than genitally and more frequent in girls than in boys.

* Potential sexual abuse must be kept in mind and has been documented in up to 20-40% of cases. Condylomas cannot be used as a medico-legal indicator of abuse because perinatal infection might have occurred with reactivation of viral expression after months or years. Auto- or hetero-inoculation from finger warts might have occurred.

* Document the extent of warts and biopsy-verify the diagnosis.

* Examine the entire skin for presence of cutaneous warts, bruises and scars.

* Children with AGW should be managed by a multidisciplinary team that includes a physical and psychosocial examination by a paediatrician.

* Examine for other STD when sexual abuse is likely.

* In children < 3 years of age vertical transmission is most likely.

* In children > 3 years of age there is a greater likelihood of sexual transmission.

* HPV typing such as in situ PCR does not inevitably provide forensic data; identical HPV DNA sequences in an abused child and the parents and/or the suspected aggressor can only provide circumstantial evidence, never final proof of sexual abuse.

Prognosis

* No therapy necessarily eradicates warts, maintains clearance and eliminates the virus. Reasonable expectation is cure, or at least induction of long-lasting remission of warts and/or symptoms. All lesions treated properly virtually disappear; however, up to 20-30% of patients develop new lesions at the borders of the treated tissue (recurrences) and/or at remote sites (re-occurrences). Frequency of recurrences is related to the follow-up time; for 70-80% of patients the life cycle of the disease is less than six months, and a patient is considered clinically cured half a year after the clearing of the last lesions [7].

* Patients should be seen 3-4 weeks after the end of treatment and then every three months for half a year if control examinations are negative.

* Women with condylomas have no increased risk of developing cervical carcinoma [20], the risk is generally low and ample time exists for removal of precursor lesions.

* As warts regress spontaneously in some patients, no treatment - at least periodically - is an option for warts at any site.

* Bowenoid papulosis is regarded a benign and self-limiting disease in immunocompetent individuals younger than 35 years. In older persons and in immunosuppressed patients lesions should be considered true premalig-
nant.

Article accepted on 20/8/01

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