Genital warts and genital papillomavirus disease

VIRAL INFECTIONS

Genital warts and genital papillomavirus disease Charles J N Lacey

Genital warts (condylomata acuminata) are usually caused by human papillomavirus (HPV) types 6 and 11. However, a much wider spectrum of HPV types can infect the genital mucosa, causing clinical disease (e.g. bowenoid papulosis, cervical cancer) or subclinical disease (e.g. cervical intraepithelial neoplasia (CIN) detectable by cytology or colposcopy), or can exist in a latent form in essentially normal epithelium.

Epidemiology Genital HPV infection is sexually transmitted and occurs in a considerable proportion of the population. The prevalence of HPV DNA in the genital tract peaks at 15–40% at 20–25 years of age; after 40 years of age, the prevalence stabilizes at less than 10%. Anogenital warts are the most common clinically diagnosed viral STI in the UK; in 2003, there were 70,665 new cases. The incidence of new cases is highest in men aged 20–24 years and in women aged 16–19 years. Between 1972 and 2003, the number of all genital wart diagnoses per year increased by eightfold in men and 11-fold in women.1

Aetiology HPV virions are small (60 nm), non-enveloped, icosahedral capsids enclosing an 8 kb, circular dsDNA genome. HPV is exclusively epitheliotropic and infects cutaneous or mucosal epithelium. Many new cutaneous HPV types have been detected in recent years and about 300 different genotypes of HPV have been described. A substantial proportion (Figure 1) are detected almost exclusively in genital or mucosal lesions, and can be subdivided into those less likely (low risk, e.g. those causing warts) or more

What’s new ? • Prophylactic HPV vaccines are being developed and may be licensed by 2006 • It is now standard practice to offer self-treatment for genital warts to patients who are able to undertake it • It is no longer recommended that women with genital warts undergo routine interval cytology

Charles J N Lacey is Reader in Sexual Health and HIV Medicine at Hull York Medical School in the University of York, UK. Conflicts of interest: none declared.

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likely (high risk, e.g. those causing intraepithelial neoplasia or cancer) to be associated with neoplasia. HPV DNA analysis of biopsies of genital warts from immunocompetent adults shows that almost all lesions contain HPV-6 or HPV-11; 20% contain coinfections with other genital types.

occur on the vaginal introitus, fourchette, labia minora, clitoris, vagina, cervix, perineum and perianal area (Figure 4). In both sexes, proctoscopy may reveal lesions in the anal canal as far as the dentate line (the squamocolumnar cell junction between the anal canal and the rectum). Bowenoid papulosis is an HPV-16-induced disease of male and female external genitalia. It comprises itchy, pigmented papules with high degrees of intraepithelial neoplasia (Figure 5). In women, these may be associated with multifocal genital tract pre-cancer involving the cervix, vagina, vulva or anus. Buschke–Löwenstein tumours (giant condylomata) are uncommon, locally aggressive, non-metastasizing verrucous carcinomas. They contain HPV-6 or HPV-11. Cervix – although macroscopic inspection of the cervix only occasionally shows white patches or papillomas, colposcopy reveals a spectrum of change, from condylomata (Figure 6) to CIN grade III (Figure 7). Condyloma acuminata are occasionally seen in the oral cavity and are usually associated with orogenital contact. Respiratory papillomatosis caused by HPV-6 or HPV-11 presents in children and young adults. In children, the infection is acquired from the mother during childbirth. The latency period and mode of transmission in adults is less clear.

Pathology Warts – biopsies of genital warts show elongation of the dermal papillae (papillomatosis) and hyperplasia of the stratum spinosum (acanthosis). In the stratum granulosum, large, vacuolated cells (koilocytes) are seen. The nuclei of these cells are deeply basophilic and are surrounded by an apparently structureless halo. Hyperkeratosis can be seen in lesions arising from, for example, the penile shaft, labia majora and buttocks. Many genital warts arise from non-keratinized epithelia of the prepuce, glans, labia minora and introitus; at these sites, hyperkeratosis is not seen. HPV infection of the cervix can cause exophytic papillomas, but flat, non-condylomatous lesions are more common. In these lesions, papillomatosis is absent and acanthosis is minimal. Intraepithelial neoplasia – varying degrees of intraepithelial neoplasia are seen in cervical HPV infection. The cells exhibit failure of maturation, excessive and abnormal mitotic activity, increased nuclear:cytoplasmic ratio and loss of orderly intraepithelial differentiation. Similar changes are seen less commonly in lesions of the external genitalia (Figure 2). The changes of intraepithelial neoplasia are classified as: • grade I (de-differentiation confined to the deepest third of the epithelium) • grade II (de-differentiation in the deepest two-thirds) • grade III (de-differentiation through the full thickness).

Diagnosis Thorough genital examination is essential. In males, the prepuce must be retracted fully and the interior of the meatus must also be inspected. Proctoscopy is indicated in those with lesions at the anal verge. In females, careful inspection is required, particularly at the vaginal introitus; palpation is sometimes useful in the diagnosis and localization of lesions. Speculum examination of the cervix and vagina must be performed. Aceto-whitening – it has been shown that application of 5% acetic acid to the external genitalia in men and women or to the cervix can disclose previously unidentified subclinical HPV lesions. Widespread use of this technique is not recommended, however, because aceto-whitening can be a nonspecific finding, and the natural history and infectivity of the HPV lesions it discloses has not been defined. Cervical cytology and colposcopy – the UK NHS Cervical Screening Programme recommends that no changes are required to screening intervals in women with anogenital warts.2 If cytology is performed, it not uncommonly shows mild or borderline

Clinical features Genital warts occur in males on the frenulum, corona, glans, urinary meatus, prepuce, shaft of the penis, scrotum, groin, perineum and perianal area (Figure 3). In females, genital warts

Relative risk association of common anogenital human papillomavirus types • Low risk

6, 11, 40, 42, 43, 44, 53, 54, 57, 66

• High risk

16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 55, 56, 58, 59, 68

1

Glossary • CIN

Cervical intraepithelial neoplasia

• VAIN

Vaginal intraepithelial neoplasia

• VIN

Vulval intraepithelial neoplasia

• PIN

Penile intraepithelial neoplasia

• AIN

Anal intraepithelial neoplasia

3 Small, white, papular and flat, warty lesions around the frenulum and in the coronal sulcus.

2

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6 Pink, fleshy condylomata acuminata located circumferentially around the cervical os.

Management Many treatments for genital warts have been described, but all have practical limitations and they are not always successful. Genital warts often recur after apparent clearance. Treatments can be classified into self-treatments and clinic-based therapies. Patients should be involved in making such therapeutic choices. Clinic staff must check that those who choose self-treatment can recognize their warty lesions and undertake self-application. Self-treatments • Podophyllotoxin is the principal active therapeutic agent derived from podophyllin and is available as a purified, standardized preparation. It has significant safety and efficacy advantages over podophyllin. It is available in the UK as a cream or a solution and is licensed for self-treatment of external anogenital warts in men and women. Podophyllotoxin solution is used for penile warts, and cream in women and for anal warts. It is applied twice daily for 3 days, followed by a rest period of 4 days; these weekly cycles of self-treatment can be repeated for up to 6 weeks. • Imiquimod is an immunodulator and is available as a 5% cream for self-treatment of external anogenital warts. It is a ligand for toll-like receptor 7, and probably acts through stimulation of macrophages to release interferon-α and other cytokines; this seems to induce both innate and adaptive immune responses. Application at night for three nights per week for 4–16 weeks is recommended. It is more expensive than other current therapies. Clinic-based therapies • Trichloroacetic acid (TCA) 90–99% solution is useful for small, discrete lesions. It is applied directly and sparingly with an orange stick or fine swab. The treated areas are bathed twice daily and assessed at 7 days. TCA is a caustic agent and must therefore be stored and used carefully. Over-zealous use can cause scarring.

4 Large introital, vulval, perineal and perianal condylomata in a young, pregnant woman.

dyskaryosis, often reflecting subclinical cervical HPV-6/11 infection. In women presenting with genital warts who are below the recommended age for commencement of cervical screening (25 years), it is not necessary to perform cervical screening. Biopsy – excision or punch biopsy should be performed in all patients with external genital lesions in whom there is a clinical suspicion of intraepithelial neoplasia or cancer (Figure 8). STI screening – up to 20% of patients with genital warts have another STI; therefore, all patients should undergo appropriate screening tests. Differential diagnosis – normal variants of external genital appearances are often mistaken for warts; for example, multiple papillae that are regularly and symmetrically distributed and comprise fibro-epithelial elements occur on the corona and at the frenulum (pearly penile papules). Similar normal variants are commonly seen on the inner surface of the labia minora. The lesions of molluscum contagiosum should be distinguishable by their characteristic appearance.

5 Brown lesions of bowenoid papulosis on the vulva; histologically, vulval intraepithelial neoplasia grade III.

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7 Aceto-white lesion with mosaic on colposcopy; histologically, cervical intraepithelial neoplasia grade III.

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Genital warts in children Genital warts in children are discussed in MEDICINE 33:9, 18. 8 Large, atypical, suspicious warty lesion on the prepuce. Punch biopsy showed penile intraepithelial neoplasia grade III; circumcision specimen showed a fully excised early, invasive squamous carcinoma.

Human papillomavirus and genital cancer HPV-16 was first demonstrated in cervical cancer tissue in 1983. Accurate DNA detection systems have been gradually refined, and sensitive and specific techniques have been used to measure the prevalence of HPV DNA in properly controlled, large-scale epidemiological studies. This has led to the classification of genital HPV types into those associated with a ‘low risk’ of genital cancer and those associated with a ‘high risk’ (Figure 1). • HPV DNA is detectable in almost all cases of cervical cancer.3 • The association between HPV and cervical cancer is very strong and consistent in case-control studies. • The association is specific to high-risk oncogenic genotypes. • HPV viral load is linked to risk of malignancy. • Persistent infection with high-risk HPV is necessary for progression to CIN III.4 However, most high-risk cervical HPV infections are transitory, and often resolve within 12 months.5 Factors governing the natural history include endogenous (cellular, immunological, genetic, viral) and exogenous (e.g. sexual behaviour, environmental) influences.

• Cryotherapy is useful for keratinized, recurrent, large or meatal lesions. It can be administered by closed cryotherapy systems using nitrous oxide or liquid nitrogen, by direct-spray cryotherapy systems using liquid nitrogen, or by direct application of liquid nitrogen. When closed cryotherapy systems are used, application of water-soluble gel to the warts improves contact and release. Treatment can be given weekly. • Surgical treatment options for genital warts include curettage, electrosurgery and scissor excision under local or general anaesthesia. Discrete intrameatal or labia minora warts are removed easily with a sharp curette. Discrete keratinized lesions are effectively removed by electrosurgery under local anaesthesia. Patients with multiple or large genital warts at any site should be referred promptly for surgical treatment under general anaesthesia. Vaginal lesions are ideally assessed using a colposcope, with acetic acid and iodine staining, which enables proper definition of condylomata or intraepithelial neoplasia on the cervix and in the fornices and vagina. If vaginal intraepithelial neoplasia has been excluded, vaginal warts can treated using cryotherapy, electrosurgery, podophyllin or TCA. Oral warts – typical oral condylomata can be treated using cryotherapy, but referral to an oral medicine specialist is wise in many cases. Contact-tracing and barrier contraception – the usual incubation period for genital warts is 3 weeks to 8 months, though HPV can remain latent for longer than this. On initial evaluation, patients with genital warts should be advised that their current sexual partners should be examined. Studies have indicated that the infectivity of genital warts is about 60%. It is likely that subclinical lesions are infectious at some stage in their natural history, and that this may result in the development of clinical lesions in some sexual partners. Patients should be advised to use condoms for up to 12 weeks; this allows time for evaluation and treatment of partners and for short-term recurrence of disease in the patient. Use of barrier contraception may be unnecessary in couples in a stable sexual relationship who are discordant for the presence of genital warts, because in many of these couples the ‘normal’ partner may already have subclinical infection. Women who are the asymptomatic partner of men with genital warts should undergo a full genital tract examination.

Prophylactic human papillomavirus vaccines There has been progress in the last few years in the development of prophylactic HPV vaccines. These use virus-like particles (VLPs) that mimic the natural virus but are non-infectious. When injected intramuscularly, these vaccines cause production of high titres of neutralizing antibodies that can prevent infection. Two multivalent HPV VLP vaccines are in phase III trials. Initial results suggest that these vaccines are more than 90% effective,6,7 and initial licensing is expected in 2006. 

REFERENCES 1 www.hpa.org.uk/infections/topics_az/hiv_and_sti-warts/ epidemiology/epidemiology.htm 2 National guidelines for the management of anogenital warts. www.bashh.org.uk 3 Walboomers J M M, Jacobs M V, Manos M M et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999; 189: 12–19. 4 Nobbenhuis M A E, Walboomers J M M, Helmerhorst T J M et al. Relation of human papillomavirus status to cervical lesions and consequences for cervical-cancer screening: a prospective study. Lancet 1999; 354: 20–5. 5 Ho G Y, Bierman R, Beardsley L et al. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 1998; 338: 423–8. 6 Koutsky L A, Ault K A, Wheeler C M et al. A controlled trial of a human papillomavirus vaccine. N Engl J Med 2002; 347: 1645–51. 7 Harper D M, Franco E L, Wheeler C et al. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomized controlled trial. Lancet 2004; 364: 1757–65.

Prognosis There are no precise natural history studies, but recurrence of genital warts in the first year after initial presentation is common.

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