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Anogenital warts 

Anogenital warts
Chapter:
Anogenital warts
Author(s):

Pauline Handy MBE

DOI:
10.1093/med/9780199571666.003.22
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Introduction

References to anogenital warts date back to Roman and Hellenic periods, with Celsus observing, in the 1st century ad, that anal warts resulted from sexual intercourse.

Aetiology

Human papilloma virus (HPV) is a genus in the family of papilloma viruses with a double-stranded DNA structure. The virion is 55nm in diameter. The capsid (envelope) comprising 72 capsomeres has an icosahedral symmetry. Hybrid capture II and polymerase chain reaction (PCR) are highly sensitive in detecting HPV.

HPV is classified by the nucleotide sequence of the major capsid gene L1 into >100 types which are identified by a number and are usually site specific (Table 22.1). Types frequently detected in anogenital squamous cell carcinoma are described as oncogenic (‘high risk’) and the remainder as non-oncogenic (‘low risk’). The ‘low-risk’ types HPV6 and HPV11 account for ~90% of anogenital warts; ‘high-risk’ HPV is found in >95% of cervical squamous cell carcinoma (HPV16 in 50%, HPV18 in 20%).

Table 22.1 HPV types in lesions

Lesion

HPV types (more common types in bold)

Skin warts

1, 2, 3, 10, 7, 4, 7, 26, 28, 29, 41, 49, 57, 60, 63, 65

Anogenital warts

6, 11, 16, 30, 40, 41, 42, 43, 44, 54, 55

Squamous intra-epithelial lesions*

6, 11, 16, 18, 31, 30, 33, 34, 35, 56, 57, 58, 59, 61, 62, 64, 67, 68, 69, 70

Anogenital squamous cell carcinoma

16, 18, 31, 45, 33, 35, 39, 51, 52, 54, 56, 66, 68

Oral warts

2, 6, 11, 16 (7, 13, 18, 32 in HIV +ve)

Laryngeal papilloma

6, 11

Head and neck carcinoma

16, 18, 33, 57

* Cervical, vaginal, vulval, anal, or penile intra-epithelial neoplasia.

Infection begins in the basal stem cells of the epithelium. Active viral replication occurs in the well-differentiated layers near the surface with sudden amplification of virus to 100,000 genomes per cell. Virions are then released from desquamating cells.

Epidemiology and natural history

Genital tract HPV DNA is found in 10–20% of those aged 15–49 years. However, <10% have clinically apparent lesions, i.e. ~1% overall. The peak age of prevalence is 20–24 years in ♀ and 25–34 years in ♂. The infection rate is ↑ in smokers (>5-fold).

The median incubation period of exophytic warts is 3 months (range 2 weeks–9 months, but can be much longer). In the immunocompetent, warts eventually regress with immune response which usually begins after a period of 3–6 months of active growth. Response to E6 antigen leads to clearance but E7 results in persistent or relapsing infection. In ~95% HPV can no longer be detected 2 years after infection.

Transmission

Transmission is through contact with apparent or subclinical epithelial lesions and/or genital fluids containing infective virus, usually during sexual intercourse (including non-penetrative contact). Resultant micro-abrasions enable viral inoculation into the basal layers of the epithelium. Occasional reports of anogenital types at other sites (e.g. fingers) and non-anogenital types on anogenital skin suggest digital–genital trans-mission (including auto-inoculation). This may explain the absence of a history of genital–genital/anal or orogenital–anal sexual contact reported in ~1% of ♀ with anogenital warts (no data available for ♂). The finding of oral, laryngeal, conjunctival, and nasal lesions in those with anogenital warts (~5%), with the same HPV type, suggests orogenital transmission.

Mother-to-child transmission may occur during vaginal delivery, with a 10–70% rate of neonatal infection, and has also been reported following Caesarean section. In pre-pubertal children digital warts may be transmitted to anogenital regions, up to 20% of which may be due to skin types.

Clinical features

Symptoms

Usually little physical discomfort but disfiguring lesions may lead to psychological distress. Peri-anal or large growths may cause irritation and soreness. Urethral, anal, and cervical warts may cause bleeding and urethral warts may distort the urinary stream.

Signs (Plate 13

Warts (usually multiple) appear most commonly at sites likely to be traumatized during sexual intercourse with HPV detectable in apparently normal surrounding skin. Peri-anal and anal warts (almost always below the pectinate line) may occur in both ♂ and ♀, more commonly but not only with receptive anal sex. May be found on the cervix and in the vagina, anal canal, urethral meatus, with rare involvement of urethra and bladder (Table 22.2)

Table 22.2 Relative frequency (reported range) of location of genital warts

% of cases (range)

% of cases (range)

Prepuce

65 (49–80)

Posterior aspect of introitus

73 (77–94)

Frenum, corona and glans

46 (22–70)

Labia minora/majora, clitoris

32

Urethral meatus

34 (24–45)

Cervix

34 (6–64)

Penile shaft

27 (16–55)

Vagina

42 (32–52)

Scrotum

23 (2–25)

Urethra

8

Perianal area

8 (3–15)

Perianal area

18 (13–85)

Perineum

23

Lesions are either pedunculated or sessile and sometimes pigmented. They may be:

  • condylomata acuminata—soft/non-keratinized, ‘cauliflower-like’ in appearance, found on mucosae/warm moist non-hairy skin

  • keratinized—resembling skin warts, usually on dry anogenital skin

  • smooth papules on dry skin (e.g. penile shaft).

Subclinical infection may be detected as aceto-white patches with 5% acetic acid, better visualized through a colposcope (Anogenital warts low specificity). Atypical balanoposthitis/vulvitis may be associated with HPV Anogenital warts.

Giant condyloma of Buschke and Lowenstein

Usually associated with HPV6 and HPV11. Resembles a very large wart but invades the dermis and underlying tissue (e.g. corpus cavernosum). Starts as a keratotic papule and grows into a large cauliflower-like lesion. Most commonly located on the glans penis, but may occur anywhere on the penis, scrotum, vulva, vagina, rectum, and bladder. Does not metastasize but malignant transformation (verrucous carcinoma) develops in up to 50%. Diagnosed histologically. Liable to recur if not completely excised.

Diagnosis

  • Usually on clinical appearance.

  • Internal examination:

    • speculum for vaginal/cervical warts

    • proctoscopy for anal warts if peri-anal lesions present

    • urethral meatoscopy (with an otoscope) if meatal warts.

  • Biopsy under local anaesthetic if in doubt, or lesion atypical or pigmented. This may be aided by the use of a colposcope.

  • Routine DNA detection is unnecessary and is not cost effective.

Differential diagnosis

See Table 22.3

Table 22.3 Differential diagnosis of external anogenital warts

Achrocordon (skin tag)

Molluscum contagiosum

Epidermal/melanocytic naevi

Condylomata lata (secondary syphilis)

Sebaceous glands

Seborrhoeic keratosis

Penile pearly papules

Dermatofibroma

Vulval papillae

Angiokeratoma

Ectopic sebaceous glands (Fordyce spots)

Epidermal cyst

Prominent hair follicles

Lichen planus

Nabothian follicles (cervix)

Psoriasis

Penile/anal intra-epithelial neoplasia

Giant condyloma of Buschke and Lowenstein

Squamous cell carcinoma

Basal cell carcinoma

Pregnancy and infection in the neonate and children

Warts may rapidly enlarge with pronounced vascularity during pregnancy (probably as a result of altered immunocompetence or ↑ oestrogen/progesterone) and regress in the puerperium, often with complete resolution. Warts do not usually obstruct vaginal delivery.

Neonatal infection commonly clears within 6 weeks. Persistence is usually subclinical but may lead to recurrent respiratory papillomatosis or ano-genital or extra-genital warts. Recurrent respiratory papillomatosis incidence is 0.25% in children (3 months–5 years of age) born to mothers with warts. Mostly caused by HPV6 and HPV11. Usually located on the vocal cords and epiglottis (laryngeal papillomas), rarely on the entire larynx, tracheobronchial tree, or even the lungs.

Perinatal infection is the usual cause of anogenital warts in children up to 3 years of age. However, sexual abuse and non-sexual transmission should be considered in older children.

Management

General principles

The aim of treatment is essentially cosmetic or for symptomatic relief. Treatments have no direct effect against HPV and only limited impact on viral clearance and infectivity. Diagnosis of subclinical infection is of no practical benefit.

Optimal management is enabled by a treatment protocol with clear guidelines on the choice of treatment and arrangements for review (Algorithms 22.1 and 22.2). Treatment choice depends on the morphology, number, and distribution of warts and should be made after considering the available options and discussing side-effects, e.g. scarring, with the patient. Serial documentation of the number, size, appearance, and distribution of warts in genital maps gives a visual record of treatment response. If the wart area is >4cm2 treatment under direct supervision of clinical staff is recommended. No treatment is an option particularly for vaginal/anal warts.

Condom use does not impact on anogenital HPV prevalence but may reduce the incidence of genital warts in ♂ and cervical neoplasia in ♀. Psychological distress may require referral for counselling. The possibility of a long incubation period should be discussed, especially if there are concerns about infidelity.

All treatments have significant failure rates. Soft non-keratinized warts respond well to podophyllotoxin (and podophyllin). Keratinized lesions are better treated with ablative methods e.g. cryotherapy, trichloroacetic acid (TCA), excision, or electrocautery. Imiquimod may be suitable for both types. Preferred initial treatment for small number/low volume warts of either type is ablation.

►Risk of scarring and pigment changes should be discussed before treatment.

Frequently asked questions

How have I caught them?

Genital warts are usually sexually transmitted by direct skin-to-skin contact. It is thought that ~90% of people who are infected with HPV have no visible warts. After infection it takes a mean of 3 months for warts to develop, but may extend to months or years.

Will they go on their own?

Warts left untreated may disappear on their own (usually within 18 months) but they can also grow and spread, becoming unsightly and more difficult to treat.

Will I ever get rid of them?

When warts are treated they should clear, but HPV may persist, depending on the host’s immunological response. Therefore the patient should be warned that they may recur. Recurrences are more likely within 3 months of treatment. HPV usually clears within 24 months although this may be longer, especially if the patient is immunocompromised.

Am I infectious?

Someone infected with HPV is infectious until it clears. The level of infection is probably greater when warts are present as viral shedding is likely to be greater.

Can I have sex?

It is often recommended that if visible warts are present condoms should be used during sex, although there is no clear evidence of benefit. Friction associated with coitus may spread warts. However, it is likely that the regular partner of someone who has warts will also be infected with the wart virus whether they have visible warts or not.

Do warts cause cervical cancer?

There are many strains of HPV, but those causing genital warts are different from the types associated with cervical cancer. It is recommended that a ♀ attends for routine smear tests which will detect abnormalities associated with the HPV strains that may be related to cervical cancer. ♀ with warts do not need extra smears.

My partner does not have warts. Does he/she need to be seen?

Only if there are concerns about possible warts or other STIs.

Specific treatments

  • Podophyllotoxin (self-applied) The active lignan ingredient of podophyllin resin and an antimitotic agent causing local tissue necrosis. Available as 0.5% solution or 0.15% cream. Should be applied twice daily for 3 consecutive days, repeated at weekly intervals for a total of up to 4–5 three-day treatments. Clearance rate 42–88%. Recurrence rate 10–91%. In ♀ 0.15% cream is more effective than 0.5% solution (81% vs 50%).

  • Cryotherapy. Liquid nitrogen spray (–180°C), swab (–20°C) or probe (–196°C), nitrous oxide probe (–75°C), or carbon dioxide snow (–79°C) may be used to freeze (for ~20 seconds) the wart(s) and a margin (‘halo’) of 1–3mm of surrounding epithelium. The depth of freezing achieved is variable and operator dependent. Local anaesthetic is usually not needed, but may be required depending on pain tolerance and extent of warts. Adequate cryotherapy causes immediate erythema followed in a few hours by blistering due to cytolysis of the epithelial cells. Healing takes 7–10 days with minimal scarring. If the treated area is large, severe ulceration may occur causing wound-care problems and scarring. Cryotherapy may be repeated at 1–2 week intervals. Clearance rate 63–88% after 1–10 (average 3) weekly treatments. Recurrence rate up to 39%.

  • Trichloroacetic acid (TCA) Caustic agent causes chemical coagulation leading to necrosis. Applied once a week as a 80–90% solution (unlicensed), ensuring protection of surrounding epithelium with petroleum jelly Treatment-induced pain, ulceration, irritation, and scarring limit its use. Clearance rate 50–81%. Recurrence rate 36%.

  • Imiquimod 5% cream (self-applied) Stimulates innate and acquired immune responses. Applied once a day, 3 times a week, for up to 16 weeks. Clearance rate 50–62% with partial clearance (50% reduction) in 59–81% of the remainder. Recurrence rate 13–19%. More effective in ♀ than ♂ (64–72% versus 33–42%) and in uncircumcised than circumcised ♀ (62% versus 33%). Also used as an adjunct to ablative treatment. Erythema, burning, irritation, and tenderness are common side-effects, reflecting effective immune response, and do not warrant cessation of treatment unless severe.

  • Podophyllin 15–25%. A resin extracted from Podophyllum peltatum dissolved in alcohol or benzoin. In addition to the active ingredient podophyllotoxin, it contains quercetin and kaempherol which are mutagenic. (Teratogenic and oncogenic effects in animal experiments but no evidence in humans.) As there are safety concerns regarding the preparation of the solution and podophyllotoxin preparations are more effective with less toxicity, this preparation is no longer in general use.

  • Electrosurgery Tissue destruction by electrically produced heat. Common methods:

    • Electrocautery—application of heat to warts and surrounding tissue under local anaesthesia.

    • Hyfrecation—high-frequency (0.5–3MHz) low-power (1–30W) electricity heats the tissue causing necrosis. Patient return electrode (‘diathermy pad’) is not needed since low power is used. Two techniques are used: electrofulguration (current sparks across an air gap) and electrodessication (electrode in contact with or penetrating warts). Requires local anaesthesia.

    • Surgical diathermy—high-frequency (0.5–3MHz) high-power (up to 400W) electricity (requiring ‘diathermy pad’) to produce coagulation or cutting. More suitable for large warts. Requires general anaesthesia.

    Clearance rate ~94%. Recurrence ~24%.

  • Excision Excision using scalpel, curette, or scissors under local or general anaesthesia. Clearance rate 89–93%. Recurrence rate up to 29%.

  • Laser therapy Vaporization of warts under local or general anaesthesia. Clearance rate 27–89%. Recurrence rate 7–45%. Adverse effects include pain, itch, bleeding, and scar formation.

  • Cidofovir 1% cream (self-applied) Unlicensed for routine use. Applied daily for 5 days, repeated fortnightly (i.e. after 9 treatment-free days) for a total of up to 6 five-day treatments. Clearance rate 27–89%. Recurrence rate 7–45%.

  • 5-Fluorouracil 5% cream Pyrimidine analogue inhibiting RNA/DNA synthesis. Applied twice a week for up to 10 weeks. Not recommended for internal warts (especially urethral). Clearance rate 13–43%. Recurrence rate ~50%.

  • Interferon Various regimens have been described using interferon α‎, β‎, or γ‎ as intralesional or systemic injection (also as self-applied cream). However, its use is limited by a variable response rate, systemic side-effects, and expense. Clearance rates: intralesional 19–62%, systemic 7–51%, and topical 6–90%. Recurrence rates: intralesional up to 33%, systemic up to 23%, and topical ~6%. Cyclical low-dose injection used as an adjunct to laser therapy has been reported to reduce relapse rate.

  • Isotretinoin Conflicting results when used to treat genital warts. A recent study using oral isotretinoin 0.5mg/kg/day showed efficacy in the treatment of recalcitrant cervical warts. However, because of its teratogenicity, its use as first-line therapy for genital warts in ♀ is unacceptable.


Algorithm 22.1 Treatment algorithm for
genital warts in ♀

Algorithm 22.1
Treatment algorithm for genital warts in ♀


Algorithm 22.2 Treatment algorithm for
genital warts in ♂

Algorithm 22.2
Treatment algorithm for genital warts in ♂

Management: sexual partners

Current sexual partner(s) may benefit from assessment for undetected genital warts and other STIs, and there may be a need for explanation and advice about disease process.

Special situations

  • Pregnancy Treatment does not reduce perinatal transmission and is better deferred until the puerperium. Very rarely Caesarean section may be indicated because of obstruction. Cryotherapy, TCA, electrocautery, and laser vaporization are suitable if necessary. Excision may cause severe haemorrhage and diathermy of large lesions may cause intense postoperative pain. Imiquimod is not approved but has been used in exceptional circumstances (after discussion of risks and benefits with the patient and registration with 3M, the manufacturers).

  • Anogenital warts Podophyllin, podophyllotoxin, 5-fluorouracil, cidofovir, interferon, and isotretinoin are contraindicated because of possible teratogenic effects or lack of safety data.

  • Vagina Treatment may not be necessary especially if warts are small. Cryotherapy is the usual first-line therapy. Electrosurgery, TCA, podophyllin (total area treated <2cm2), or gynaecological referral are other options.

  • Cervix

    • Cervical warts—cryotherapy, electrosurgery, or TCA. If 25 years of age colposcopy ± biopsy best practice to exclude cervical intra-epithelial neoplasia (CIN) before treatment

    • Cytology—no changes to routine screening intervals necessary.

  • Urethral meatus If base of lesions seen, preferred treatment iscryotherapy or electrosurgery. Other options are podophyllotoxin or imiquimod, but use with caution. Deeper lesions require surgical ablation under direct vision.

  • Anal canal Surgical excision or laser preferred. If small and accessible—cryotherapy, TCA, electrosurgery.

  • Immunosuppressed patients Poor treatment response, ↑ relapse, and dysplasia more likely with ↓ cell-mediated immunity, e.g. following renal transplant or HIV infection. Careful follow-up required.

Vaccine

Virus-like particle (VLP), the capsid without DNA, is immunogenic but non-infectious. Two vaccines using VLP to induce immunity have been shown by trials to be effective. Gardasil® is a tetravalent (quadruple) vaccine containing recombinant VLP from HPV types 6, 11, 16, and 18, and a transformed Saccharomyces cerevisiae (yeast) cell line complexed with a conventional aluminum adjuvant. Cervarix® is a bivalent vaccine containing HPV types 16 and 18 VLPs derived from a recombinant baculovirus vector expression system using Trichoplusia ni (cabbage looper moth) cell line. Cervarix®, and to a lesser degree Gardasil®, provide some cross-protection against HPV types 31, 33, 45, and 58 (92%, 52%, 100%, and 65% with Cervarix®). Based on available evidence these vaccines are likely to prevent 70% of invasive cervical cancers and 60% of high-grade CIN if given to all girls before the onset of sexual activity. The quadrivalent vaccine is likely to be effective in preventing 90% of ano-genital warts if given to both sexes before the onset of sexual activity. While the HPV vaccination programme in the UK has chosen the bivalent vaccine for girls aged 12–13 (with an initial 2-year ‘catch-up’ of 13–18-year-old girls) programmes in some other countries have chosen the quadrivalent vaccine. An observational study in Australia has shown a reduction in the number of cases of anogenital warts in women and heterosexual men since the introduction of the quadrivalent HPV vaccine programme for girls. There is no evidence to support the use of HPV vaccines in those who have already acquired HPV vaccine, and studies to assess the effect of the vaccines in those already sexually active or HPV infected are being conducted. There is an anecdotal report of cessation of recurrence of recurrent respiratory papillomata in infants given the quadrivalent vaccine after initial surgical removal of the papillomata.

Frequently asked questions

Can I treat warts myself?

It is advisable not to treat warts at home with over-the-counter preparations. These preparations are designed for use on hands or feet and may damage genital skin.

There are special prescription-only preparations (podophyllotoxin and imiquimod) for home use, although the treatments recommended depend on the position, number, and appearance of the warts.

Can I pass them to my children?

The HPV types that usually cause genital infection almost exclusively favour this site and so are sexually transmitted. However, occasionally other types, such as those causing warts on the hands, can be spread to the genitals and have been found in children.

I am pregnant. Are the warts harmful to my baby?

Warts are common in pregnancy, often grow more quickly, and are more difficult to manage as certain treatments cannot be used. They often resolve spontaneously after the pregnancy is over. Although HPV can be transmitted to babies at delivery it is unusual. Treating the warts will not remove the underlying infection.

HPV and HIV

  • HPV infection has not been associated with ↑ risk of HIV acquisition.

  • Those with HIV infection appear to be at greater risk of acquiring or reactivating HPV.

  • Oral warts (due to HPV types 7, 13, 18, and 32) are more common in those with HIV infection.

  • Duration and natural history of concurrent HPV infection may be altered, leading to ↑ incidence of cervical and anal neoplasia.