Anogenital warts (AGWs) are a very common disease. They are caused mostly by low-risk human papillomaviruses (HPV) 6 and 11, particularly the former. Clinical presentation is mostly of growths in the areas of friction of the anogenital region. The treatment is classified as patient/home applied or administered by a professional. In cases with atypical presentations or resistance to recommended therapies, great care should be taken to establish a differential diagnosis taking into account normal anatomical variations, infectious etiologies, precancers and cancers, as well as benign dermatological growths. The prevention of AGWs can be achieved by the use of the quadrivalent prophylactic HPV vaccine administered prior to sexual debut, as well as the meticulous use of condoms. Where coverage of the quadrivalent vaccine has been high, marked reductions in AGWs are being seen in young women of vaccine-eligible age, as well as in young males (as herd immunity effect).
Introduction
Anogenital warts (AGWs) are caused by human papillomavirus (HPV), particularly genotypes 6 and 11. Condylomata acuminata and condyloma are synonymous terms. They are clinically evident skin or mucosal growths in the anogenital area. They are an important reason for consultation in primary care, dermatology, gynecology, and urology care settings and an important burden on the health-care system because patients often need to visit health-care providers repeatedly for management, as well as major sources of negative psychosexual reactions. The advent of the quadrivalent vaccine, effective against HPV-6/11/16/18, has the potential to drastically change the epidemiology of this condition.
Epidemiology
Many reports, prior to the introduction of the quadrivalent vaccine as a public health program against HPV infection and disease, showed that AGWs were a common worldwide public health problem affecting young men and young women, although more commonly noted in males. The incidence of AGWs in an HPV vaccine trial’s placebo group, which included women from 16 countries, was 0.87 cases per 100 person-years-at-risk (PY) . In a further study of physician and hospital billing as well as the sexually transmitted infection (STI) databases of British Columbia, Canada, the incidence ranged from 131 to 154 per 100,000 population in males, and from 120 to 121 per 100,000 population in Canadian females . American data derived from the Medstat Marketscan database for 2000 as well as data from the Integrated Health Care Information Services (IHCIS) National Benchmark Database of U.S. health claims for 1998–2001 reported higher incidence rates from 170 to 205 per 100,000 PY . In a study performed in sexual health clinics in Australia, prior to the introduction of the school-based government-funded HPV vaccine in young women and girls, the incidence of AGWs was estimated at an annual incidence of 2.19 cases of genital warts per 1000 Australians (95% confidence interval (CI): 1.88–2.49), with peak incidence in women aged 20–24 years at 8.61 cases per 1000 and in men aged 25–29 years at 7.40 cases per 1000 . It is noteworthy that 5.6% of sexually active American adults aged 18–59 reported having ever been diagnosed with AGWs . For Nordic women aged 18–45, the proportion was 10.6% .
In the study of the placebo arm of the quadrivalent HPV vaccine, the risk factors for HPV-6 and HPV-11 related to AGWs included infection at baseline, acquisition of new sex partners, a higher number of sex partners, and DNA positivity at baseline for a high-risk HPV type . A United Kingdom (UK) study of risk factors for AGWs revealed that many were common to both males and females. Univariate analysis noted younger age, more lifetime sexual partners, failure to use condoms, and greater cigarette smoking and alcohol consumption to be associated with AGWs, while there was a negative association for previous infection with Chlamydia trachomatis , Neisseria gonorrhoeae , hepatitis B, and genital herpes .
It is to be realized that a proportion of low-grade cervical abnormalities, as well as low-grade and occasional high-grade disease of the vulva and vagina are associated with HPV-6 and HPV-11 infections .
Epidemiology
Many reports, prior to the introduction of the quadrivalent vaccine as a public health program against HPV infection and disease, showed that AGWs were a common worldwide public health problem affecting young men and young women, although more commonly noted in males. The incidence of AGWs in an HPV vaccine trial’s placebo group, which included women from 16 countries, was 0.87 cases per 100 person-years-at-risk (PY) . In a further study of physician and hospital billing as well as the sexually transmitted infection (STI) databases of British Columbia, Canada, the incidence ranged from 131 to 154 per 100,000 population in males, and from 120 to 121 per 100,000 population in Canadian females . American data derived from the Medstat Marketscan database for 2000 as well as data from the Integrated Health Care Information Services (IHCIS) National Benchmark Database of U.S. health claims for 1998–2001 reported higher incidence rates from 170 to 205 per 100,000 PY . In a study performed in sexual health clinics in Australia, prior to the introduction of the school-based government-funded HPV vaccine in young women and girls, the incidence of AGWs was estimated at an annual incidence of 2.19 cases of genital warts per 1000 Australians (95% confidence interval (CI): 1.88–2.49), with peak incidence in women aged 20–24 years at 8.61 cases per 1000 and in men aged 25–29 years at 7.40 cases per 1000 . It is noteworthy that 5.6% of sexually active American adults aged 18–59 reported having ever been diagnosed with AGWs . For Nordic women aged 18–45, the proportion was 10.6% .
In the study of the placebo arm of the quadrivalent HPV vaccine, the risk factors for HPV-6 and HPV-11 related to AGWs included infection at baseline, acquisition of new sex partners, a higher number of sex partners, and DNA positivity at baseline for a high-risk HPV type . A United Kingdom (UK) study of risk factors for AGWs revealed that many were common to both males and females. Univariate analysis noted younger age, more lifetime sexual partners, failure to use condoms, and greater cigarette smoking and alcohol consumption to be associated with AGWs, while there was a negative association for previous infection with Chlamydia trachomatis , Neisseria gonorrhoeae , hepatitis B, and genital herpes .
It is to be realized that a proportion of low-grade cervical abnormalities, as well as low-grade and occasional high-grade disease of the vulva and vagina are associated with HPV-6 and HPV-11 infections .
Etiology
AGWs are mostly caused by HPV. HPVs constitute a large family of >200 genotypes, of which >100 have been sequenced to date. It cannot be cultivated in the traditional way, so diagnosis has relied on molecular techniques. A new HPV is recognized if the complete genome has been cloned and the DNA sequence of the L1 open reading frame differs by >10% from the closest known type. Differences between 2% and 10% homology define a subtype and <2% a variant. Some genotypes have a tropism for skin and around 30–40 have a tropism for the genital tract. Of these, some are at high risk of cancer (HRHPV) while others are at low risk (LRHPV). LRHPV can rarely cause anogenital cancers .
In the placebo arm of the quadrivalent HPV vaccine prospective study, HPV DNA was detected in 90.8% of genital wart biopsy samples; of these samples, 94.7% were positive for LRHPV-6 and/or HPV-11 . Of these women, 298 (84.9%) had a lesion that was related to HPV-6 or HPV-11 ( Fig. 1 ). Single genotype, 6.8% were due to one of the 14 HRHPV tested, with HPV-16 and HPV-18 accounting for 50.0%. Two HPV genotypes were detected in 20.1% of lesions, with the vast majority, 96.8%, containing HPV-6 and/or HPV-11. In 11.0% of AGWs, three to five genotypes were identified; it is noteworthy that in all of these lesions HPV-6 and/or HPV-11 DNA were detected. HRHPV types were also found in 31.0% of lesions . One limitation of this study is that only 14 types were looked for; assays for LR types other than 6 and 11 were not performed. As mixed infections were not uncommon, some of those with only high-risk HPV detection could have been caused by other low-risk HV than 6 and 11.
Natural history
The virus is readily transmitted through penetrative and non-penetrative sexual activity (vaginal, anal, and oral; same and opposite sex), and it can also be transmitted through nonsexual genital skin-to-genital skin contact and, occasionally, vertically from mother to child during delivery. On the other hand, in AGWs HPV-6 predominates; of note in recurrent respiratory papillomatosis (RRP), HPV-11 is chiefly responsible .
In a cohort of females in the placebo arms of the quadrivalent vaccine trials, with a mean age of 20 years and a median of two lifetime partners but no more than four lifetime partners, on day 1, 4.0% and 0.6% were positive for HPV-6 and HPV-11 DNA by polymerase chain reaction (PCR), respectively; 8.2% and 2.1% were positive for HPV-6 and HPV-11 by serologic testing, respectively. A total of 4.0% during the course of the studies had a biopsy confirming the diagnosis of AGWs. Of the women in the placebo arm who were seronegative for HPV-6 on day 1, 12.4% developed antibodies to HPV-6 during the follow-up period. Of those, 19.4% received a diagnosis of AGWs during the course of the study, with 90.2% positive for HPV-6; 3.8% of women who were seronegative for HPV-11 on day 1 developed antibodies to HPV-11 during the follow-up period. Similar to those women who seroconverted to HPV6, 19.6% of women that seroconverted for HPV11 were diagnosed with AGWs during the course of the study, with 90.0% of lesions positive for HPV-11. Of women who were positive by PCR for HPV-6 or HPV-11, but without a lesion at baseline, 12.6% and 5.4% developed HPV-6- or HPV-11-related AGWs, respectively.
Longitudinal studies of genital HPV infection were performed at the University of Washington, and for those participants with incident HPV-6 or HPV-11 infection, the rate of AGWs was calculated. For 18–21-year-old male students the 24-month cumulative genital wart incidence was 57.9% (95% CI, 38.1–79.1%) among 46 men with incident detection of HPV-6 or HPV-11 infection, 2.0% (95% CI, 0.5–7.9%) among 161 men with incident detection of infection with other HPV types, and 0.7% (95% CI, 0.2–2.8%) . For female students 18–20 years of age recruited between July 1990 and September 1997, the 36-month cumulative incidence of clinically ascertained genital warts among women was 64.2% (95% CI, 50.7–77.4%) .
The incubation period for AGWs is short and considered to be between 3 weeks and 8 months . The observation of what happened to wives who developed AGWs within a period of 4–6 weeks after their husbands who were US soldiers returned from the Far East with AGWs or a history of recent AGWs contributed to define this incubation period . A mean incubation period of 3.1 months was observed in earlier studies of AGWs .
Clearance of genital warts is accompanied by a host cellular immune reaction characterized by infiltration of activated lymphocytes ( Fig. 2 ) explaining why some patients will clear their warts without therapeutic intervention. As most interventions target the AGWs and not the virus, whatever destruction is done, until the immune response is achieved, AGWs are likely to recur. Once cleared, some patients may have a recurrence weeks, months, or years after initial clearance. Once the immune response is achieved, it is very unlikely to detect the HPV that caused the warts.
Clinical manifestation
AGWs can present as multiple growths on the anogenital skin and/or mucous membranes. They present as polymorphic, asymmetric, exophytic fronds in the areas of trauma, friction, or shaving of the anogenital area. They may also present as papular to cauliflower-like growths or as flat papular lesions ( Fig. 3 ). Most patients notice the warts when they examine themselves, as generally AGWs cause little discomfort or pain. They may occasionally be pruritic or they may rarely cause local discharge and/or bleeding if they are secondarily infected.
Differential diagnoses
The diagnosis of AGWs is usually clinical. Those lesions that persist, or have atypical characteristics, should be biopsied. Normal variations can be erroneously diagnosed as AGWs. Sebaceous glands, also known as Fordyce spots, are symmetrical and can be seen on the inner portion of the labia minora. They are smooth and may look like papules; sometimes sebum can be expressed from larger ones. Vestibular papillae also known as micropapillomatosis labialis are symmetrical lesions that can be seen in the vestibular part of the vulva. They can be quite diffuse or limited to a few growths on Hart’s line. The normal outer ridge of the labia minora can be pronounced and this anatomical variation may be confused with AGWs; however, the labia are symmetrical.
High-grade squamous intraepithelial lesion of the vulva, otherwise known as VIN2/3, and of the anus can be warty-like. These lesions are precursor lesions to cancer. They are frequently multifocal and require careful monitoring and/or treatment. Verrucous cancer of the vulva is also a differential diagnosis ( Fig. 4 ). Secondary syphilis may present as condyloma lata, a condition that can be confused with AGWs as they resemble large flat warts ( Fig. 5 ). Buschke–Lowenstein tumors are slow-growing warty masses caused by the same genotypes as AGWs. They rarely invade, but require surgery to be removed.
Many benign conditions can be difficult to differentiate from AGWs. Some are infectious such as molluscum contagiosum, others are growths, for example, naevi, skin tags, and seborrheic dermatosis, while some others are dermatologic conditions such as papular lichen planus.
Warty lesions that are abnormally pigmented, bleeding, ulcerated, unresponsive to treatment, causing pain, or persistent should be biopsied to correctly assess the etiology of the lesion.
Treatment
External genital warts resolving time will be a median of 125 days . Recommended therapies are classified as patient applied or health professional administered ( Table 1 ).
| Treatment | Dosage | Comments |
|---|---|---|
| Treatment applied by the patient for external genital warts | ||
| Podofilox/podophyllotoxin 0.5% solution (Condyline™, Wartec™) |
|
|
| Imiquimod 5% cream 3 (Aldara™) |
|
|
| Imiquimod 3.75% cream 4 (Vyloma™/Zyclara™) |
| |
| Sinecatechins 10–15% ointment (Veregen) |
| May be more effective on keratinized AGWs than other topical treatments. |
| Treatment administered by a health-care professional for external genital warts | ||
| Cryotherapy (liquid nitrogen, carbon dioxide (dry ice or Histofreeze™) or nitrous oxide using cryoprobes) |
|
|
| Bi- or trichloroacetic acid |
|
|
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