Are you confident of the diagnosis?
Characteristic findings on physical examination
Condyloma acuminatum, commonly called anogenital warts, are typically diagnosed clinically, using visual examination, sometimes aided by a magnifying glass. Patients or clinicians may notice lesions, which may be on anogenital skin or mucous membranes. Lesions typically are papules, 2 to 5 mm in diameter, although smaller or larger lesions can be present. Lesions can be either papilliform, having an exophytic component, or sessile (Figure 1), having a broad base.
The surface of lesions can be verrucous or flat, with the former more common for mucosal lesions. The color of lesions can range, even in the same atient, from flesh-colored to darker or lighter (Figure 2, Figure 3). Often more than one lesion is present, and lesions can be grouped in a particular part of the anogenital area. Lesions can develop following autoinoculation from shaving or trimming.
Lesions in men typically occur on and around the penis or anus. Intraurethral lesions can occur, sometimes associated with hematuria, altered urinary stream, or frank bleeding. Scrotal lesions in immunocompetent men are very uncommon. Lesions in women typically occur on the vulva, cervix, perineum, or anus. A pelvic or anoscopic examination, with use of a colposcope, might be necessary to examine lesions in the vagina or cervix, or anus. Condyloma acuminatum can also appear in the oral or nasopharyngeal cavity.
In both sexes, lesions on keratinized skin are usually asymptomatic; a small minority of patients, however, can experience pruritus, bleeding, irritation, pain, or vaginal discharge. Some patients complain of a foul smell emanating from lesions arising in intertriginous areas. Large lesions can lead to difficulty with intercourse, vaginal delivery, or defecation.
Clinicians considering a diagnosis of genital warts should take a complete sexual history from the patient, including history of sexually transmitted diseases (STDs), including HIV; gender of sex partners; and anatomic areas that have been exposed during sexual contact. Clinicians should inquire about the patient’s HIV status, including (if positive) viral load and CD4 count, and (if negative) history of HIV testing to determine need for an HIV test. A general medical history should assess whether immunosuppression might be present for other reasons, and a social history should assess history of cigarette smoking, which is associated with human papillomavirus (HPV) infection.
Expected results of diagnostic studies
Histopathologic examination of biopsied tissue can confirm a diagnosis of condyloma acuminatum and/or rule out more concerning diagnoses, such as squamous cell carcinoma or its variants (including verrucous carcinoma) or Bowenoid papulosis. Biopsy is not necessary in the vast majority of cases but should be considered in the following cases:
Lesion(s) fail to respond or worsen during therapy
Atypical lesion(s), including the presence of pigmentation, induration, bleeding, or ulceration
Expected results of diagnostic studies
Histopathologic findings of condyloma acuminatum include epithelial hyperplasia and koilocytes, without other features of cellular atypia (Figure 4, Figure 5, Figure 6). HPV testing does not have a role in the clinical evaluation of persons who have, or are concerned about, condyloma acuminatum, since results of such testing would not alter clinical management.
The differential diagnosis of condyloma acuminatum includes the following entities:
Molluscum contagiosum. Also typically asymptomatic papules, but which can usually be distinguished from condyloma acuminatum by the smooth, dome-shaped morphology, usually accompanied by a central umbilcation (highlighted by the application of a small amount of liquid nitrogen) of molluscum contagiosum.
Condyloma lata. A manifestation of secondary syphilis that typically appear as plaques in the anogenital area that have a moist, sometimes weepy surface. Patients should be assessed for other signs and symptoms of syphilis clinically. Darkfield microscopy, if available, can be used to visualize spirochetes to differentiate condyloma lata (from which Treponema pallidum var pallidum, the causative agent of syphilis, can be recovered) from condyloma acuminatum. Serologic tests for syphilis can also be performed, although they will not be able to rule out condyloma acuminatum, as patients with syphilis might also have condyloma acuminatum.
Vulvar papillomatosis. A normal variant in women characterized by smooth papillary projections, each arising from an individual base, near the proximal to the vaginal introitus. In condyloma acuminatum, by contrast, multiple papillary projections can arise from an individual base.
Pearly penile papules. These occur along the penile corona or coronal sulcus in uncircumcised men and can be differentiated clinically from condyloma acuminatum by their monomorphic shape and typical distribution.
Angiokeratomas of the scrotum or vulva. Papules that, in contrast to condyloma acuminatum, have a characteristic vascular (red or purple) color.
Skin tags. These can usually be distinguished from condyloma acuminatum by their smooth surface and pedunculated appearance.
Squamous cell carcinoma. This condition should be considered in evaluating lesions that ulcerate or fail to respond to typically effective treatments for condyloma acuminatum, or in persons who are immunocompromised, over 40 years old, or have atypical appearing lesions. In those cases, as discussed above, biopsy is indicated.
Bowenoid papulosis. Usually caused by HPV-16, Bowenoid papulosis exhibits histopathologic changes similar to Bowen’s disease, and carries a risk of progression to invasive squamous cell carcinoma. These lesions, however, often appear as flat, hyperpigmented papules.
Giant condyloma acuminatum (Bushke-Lowenstein tumor). An uncommon, aggressive verrucous carcinoma caused by HPV-6 that usually occurs on the penile glans or foreskin (and less commonly on perianal or vulvar tissue).
Who is at Risk for Developing this Disease?
Condyloma acuminatum are common among adults in the United States. According to a national study conducted by the Centers for Disease Control (CDC) during 1999-2004, 50.6% (95% confidence interval [CI], 4.9–6.4%) of sexually active adults aged 18-59 years reported having been diagnosed with genital warts. According to another study, incidence of first visits to physicians’ offices for condyloma acuminatum increased from the 1960s (under 100,000 visits per year) to 2009 (over 300,000 visits).
Surveillance for genital warts among men who have sex with men (MSM), men who have sex only with women (MSW) and women attending selected U.S. STD clinic during 2009 showed prevalences generally lower among women compared with men, with higher prevalences among MSM compared with MSW at some sites and higher prevalences among MSW compared with MSM at other sites. Prevalences among MSM, MSW, and women ranged from 1.5–8.0%, 2.3%–8.6%, and 1.0%–4.0%, respectively. Immunosuppressed persons are more likely to experience condyloma acuminatum. Prevalence of anogenital warts has decreased among females aged 15 to 24 years in the USA as a result of HPV vaccination.
Other studies have investigated the prevalence of HPV-6 and HPV-11, the types of HPV responsible for 90% of condyloma acuminatum, among adults in the United States. A national study of women conducted by CDC during 2003–4 using self-collected vaginal swabs found the overall prevalence of HPV-6 and HPV-11 infection to be 1.3% (95% CI, 0.8%-2.3%) and 0.1% (95% CI, 0.03%–0.3%), respectively. For HPV infection overall (not limited to HPV-6 or -11), increased prevalence of HPV infection was associated with age younger than 25 years, not being married, and increasing numbers of recent or lifetime sexual partners. Similar to the epidemiology of anogenital warts, prevalence of type-specific HPV infection among women aged 14–19 years has decreased since HPV vaccination became available, despite low vaccination uptake.
Risk factors associated with persistence of HPV infection (again, not limited to HPV-6 or -11) include older age, cigarette smoking or other tobacco use, immunocompromised state (including HIV), nutritional deficiencies, non-use of condoms, presence of other STDs, oral contraceptive use, uncircumcised status among men, and human leukocyte antigen (HLA) polymorphisms. Transmission occurs sexually in the vast majority of cases.
Most fomites (inanimate objects) are not responsible for substantial transmission, as HPV does not survive long on them. Shared sex toys, however, do appear to contribute to transmission.
Of particular concern is the presence of genital warts in children, which can be acquired sexually or nonsexually. Sexual assault or abuse should be considered as a potential route of exposure. All US states and territories have laws requiring that healthcare providers report suspected child abuse, including sexual assault or abuse, to local child-protective services authorities.
What is the Cause of the Disease?
HPV types 6 and 11 cause 90% of condyloma acuminatum, with other low-risk (noncarcinogenic) HPV types (including HP 40, 42, 43, 44, 54, 61, 70, 72, 81, and CP6108) accounting for the remaining 10% of cases. All types of HPV are DNA viruses that are small, nonenveloped, and double-stranded. Structurally, the HPV genome is housed in a capsid shell composed of major (L1) and minor (L2) structural proteins.
The pathophysiology of infection with any HPV type begins with inoculation of virus into the epithelium through microabrasions. HPV infects basal keratinocytes; HPV then replicates in those cells and integrates into the host DNA. An episomal maintenance phase then occurs. As infected basal cells migrate toward the surface of the epidermis, and viral gene expression and amplification occurs.
Assembly of HPV virons occurs in the upper layer of the epithelium, from which virions can be released to infect other adjacent tissue and other hosts through sexual contact. The exophytic appearance of condyloma acuminatum is a result of those viral effects on the epithelium.
Most HPV infections are subclinical and self-limited, with clearance from the body through cell-mediated immunologic processes in 90% of cases within 2 years. The median duration of infection with low-risk HPV types is estimated at 8 months.
Systemic Implications and Complications
Condyloma acuminatum is typically not a serious medical condition. Cases in which lesions are large and obstructive of other functions, as discussed, are more serious. Additionally, some evidence exists that infection with more than one type of HPV is associated with HIV acquisition, although the relationship has not been conclusively demonstrated to be causal.
Managing a patient with condyloma acuminatum can have systemic implications, as follows:
The sexual history should trigger appropriate screening examinations for other STDs and HIV and counseling regarding ways to limit risk for acquiring or transmitting HPV infection or other STDs, including HIV.
The medical history and examination might lead to investigation of possible immunosuppression.
The social history should lead to counseling and/or referral to tobacco cessation programs for patients who use tobacco.
Treatment options are summarized in Table I.
|Podofilox 0.5% solution or gel, applied twice a day for 3 days, followed by 4 days of no therapy, for up to four cycles||Treatment of underlying immunosuppression, including HIV, if present||Surgical removal, using excision or curettage||Cryotherapy with liquid nitrogen or cyroprobe, repeated every 1-2 weeks|
|Imiquimod 5% cream, applied once daily at bedtime, three times per week for up to 16 weeks|
|Sinecatechins 15% ointment, applied three times daily for no longer than 16 weeks|
|Podophyllin resin 10%-25% in a compound tincture of benzoin, washed off 1-4 hours after application||Electrosurgery|
|Tricholoroacetic acid (TCA) or bichloroacetic acid (BCA) 80%-90%|
These treatments are all recommended by CDC for treatment of condyloma acuminatum. CDC also lists intralesional interferon, photodynamic therapy, and topical cidofovir as alternative treatments, with more side effects and/or less data on efficacy compared with recommended treatments.
Not treating condyloma acuminatum is also a reasonable option to consider.
Optimal Therapeutic Approach for this Disease
There is no single approach to management of condyloma acuminatum that is best for all patients. Management of condyloma acuminatum should rest on the following considerations.
To treat, or not to treat. As discussed, condyloma acuminatum are not a serious medical condition in most cases, meaning that there is no absolute medical indication to treat in all cases. That is especially so given that recurrences can occur in 30-70% of cases within 6 months of treatment, and that spontaneous regression has been reported in 20-30% of cases within 3 months.
Treatment effectiveness. There are few comparative effectiveness studies of condyloma acuminatum treatment, making it difficult to make evidence-based management decisions.
Cost. Patients might prefer certain modalities on the basis of cost considerations, including insurance coverage.
Convenience. Patients might prefer certain modalities on the basis of whether it’s patient-applied or provider-administered, and frequency of treatments.
Adverse effects. Patients might have preferences regarding adverse effects (eg, pain of a surgical or physical treatment, compared with irritation associated with medical therapies). Additionally, a theoretical concern with immune-modulating therapies such as imiquimod is that inflammation caused by the therapy might draw immune cells vulnerable to HIV infection or infected with HIV to the skin or mucous membrane, potentially increasing risk of HIV acquisition or transmission.
Clearance of HPV. Even with successful treatment of condyloma acuminatum, there is no guarantee that the patient will be cleared of infection with HPV-6 or -11, or other types of HPV, and therefore be non-infectious to sex partners, or non-vulnerable to re-infection from sex partners.
Those factors make it important to have a discussion with the patient to determine his or her preferences regarding treatment options, and to tailor treatment to those preferences.
Additional considerations are as follows:
Large lesions. For large lesions, surgical removal should be considered, as topical and physical modalities are usually of limited effectiveness.
Combining treatment modalities for condyloma acuminatum. This is commonly done, although limited data support the effectiveness of combination therapy. There is some evidence, for example, that cryotherapy and podophyllin together are more effective than podophyllin or trichloroacetic acid alone. Additionally, provider-administered therapy can be followed by patient-applied therapies to be used at home, in between office visits.
Treatment of condyloma acuminatum in pregnant women. Imiquimod, sinecatechins, podophyllin, and podofilox should not be used during pregnancy. Other modalities can be used with caution. HPV-6 and -11 are rare causes of respiratory papillomatosis in infants and children, although the mode of acquisition of that infection has not been definitively established. Reduction of risk of respiratory papillomatosis is not in and of itself an indication for Cesarian delivery, although obstruction of the vaginal canal from condyloma acuminatum or potential for bleeding during delivery because of friable lesions may be an indication.
Treatment of condyloma acuminatum in HIV-infected persons. HIV-infected persons are more likely to experience condyloma acuminatum than HIV-uninfected persons, and lesions might be more recalcitrant to treatment because of impaired cell-mediated immunity. However, the treatment approach should be similar regardless of HIV infection status.
Theoretically, modalities that are (or are thought to be) mediated by immune modulation (such as imiquimod or sinecatechins) might be less effective in HIV-infected persons. Some evidence indicates that in at least some patients with well-controlled HIV infection, however, those modalities might be effective.
Treatment of cervical condyloma acuminatum. Biopsy to exclude high-grade dysplasia should be performed before treatment is initiated. Consultation with a gynecologist is recommended in managing these lesions.
Treatment of vaginal condyloma acuminatum. CDC-recommended treatments include cryotherapy with liquid nitrogen or TCA or BCA 80%-90%, applied with caution. Use of a cryoprobe is not recommended, as it might result in vaginal perforation and fistula formation.
Treatment of condyloma acuminatum of the urethral meatus. CDC-recommended treatments include cryotherapy with liquid nitrogen or podophyllin 10%-25% in compound tincture of benzoin. Consultation with a urologist can be considered in some cases.
Treatment of anal condyloma acuminatum. CDC-recommended treatments include cryotherapy with liquid nitrogen or TCA or BCA 80%-90%, applied with caution.
Of note, evidence of current or prior HPV infection, including condyloma acuminatum, does not impact recommendations for HPV vaccination.
Patient follow up depends on the type of therapy chosen. A patient treated with cryotherapy, for example, should return in approximately 1-2 weeks, if possible, compared with a patient treated with a patient-applied medical therapy, who might be asked to return (assuming there are no serious adverse effects or concerns) after several months.
Patients often have many concerns regarding acquisition of HPV infection that causes warts, potential for transmission to sex partners, effectiveness of treatment, prevention of condyloma acuminatum in the future (including indications for vaccination against HPV infection), and relationship of condyloma acuminatum to other manifestations of HPV infection (including, and especially, cervical and/or anal dysplasia).
The following counseling messages have been developed by CDC to counsel patients regarding HPV infection in general and condyloma acuminatum in particular, and are reproduced from the 2015 CDC STD Treatment Guidelines:
Key counseling messages for all patients diagnosed with HPV infection:
Anogenital HPV infection is very common. It usually infects the anogenital area but can infect other areas including the mouth and throat. Most sexually active people get HPV at some time in their lives, although most never know it.
Partners who have been together tend to share HPV, and it is not possible to determine which partner transmitted the original infection. Having HPV does not mean that a person or his/her partner is having sex outside the relationship.
Most persons who acquire HPV clear the infection spontaneously and have no associated health problems. When the HPV infection does not clear, genital warts, precancers, and cancers of the cervix, anus, penis, vulva, vagina, head, and neck might develop.
The types of HPV that cause genital warts are different from the types that can cause cancer.
Many types of HPV are sexually transmitted through anogenital contact, mainly during vaginal and anal sex. HPV also might be transmitted during genital-to-genital contact without penetration and oral sex. In rare cases, a pregnant woman can transmit HPV to an infant during delivery.
Having HPV does not make it harder for a woman to get pregnant or carry a pregnancy to term. However, some of the precancers or cancers that HPV can cause, and the treatments needed to treat them, might lower a woman’s ability to get pregnant or have an uncomplicated delivery. Treatments are available for the conditions caused by HPV, but not for the virus itself.
No HPV test can determine which HPV infection will clear and which will progress. However, in certain circumstances, HPV tests can determine whether a woman is at increased risk for cervical cancer. These tests are not for detecting other HPV-related problems, nor are they useful in women aged<25 years or men of any age.
Prevention of HPV
Two HPV vaccines can prevent diseases and cancers caused by HPV. The Cervarix and Gardasil vaccines protect against most cases of cervical cancer; Gardasil also protects against most genital warts. HPV vaccines are recommended routinely for boys and girls aged 11–12 years; either vaccine is recommended for girls/women, whereas only one vaccine (Gardasil) is recommended for boys/men (http://www.cdc.gov/vaccines/vpd-vac/hpv). These vaccines are safe and effective.
Condoms used consistently and correctly can lower the chances of acquiring and transmitting HPV and developing HPV-related diseases (e.g., genital warts and cervical cancer). However, because HPV can infect areas not covered by a condom, condoms might not fully protect against HPV.
Limiting number of sex partners can reduce the risk for HPV. However, even persons with only one lifetime sex partner can get HPV.
Abstaining from sexual activity is the most reliable method for preventing genital HPV infection.
Key counseling messages for persons diagnosed with condyloma acuminatum and their partners:
If left untreated, genital warts may go away, stay the same, or increase in size or number. The types of HPV that cause genital warts are different from the types that can cause cancer.
Women with genital warts do not need Pap tests more often than other women.
Time of HPV acquisition cannot be definitively determined. Genital warts can develop months or years after getting HPV. HPV types that cause genital warts can be passed on to another person even in the absence of visible signs of warts. Sex partners tend to share HPV, even though signs of HPV (e.g., warts) might occur in only one partner or in neither partner.
Although genital warts are common and benign, some persons might experience considerable psychosocial impact after receiving this diagnosis.
Although genital warts can be treated, such treatment does not cure the virus itself. For this reason, it is common for genital warts to recur after treatment, especially in the first 3 months.
Because genital warts can be sexually transmitted, patients with genital warts benefit from testing for other STDs. Sexual activity should be avoided with new partners until the warts are gone or removed. HPV might remain present and can still be transmitted to partners even after the warts are gone.
Condoms might lower the chances of transmitting genital warts if used consistently and correctly; however, HPV can infect areas that are not covered by a condom and might not fully protect against HPV.
A vaccine is available for males and females to prevent genital warts (Gardasil), but it will not treat existing HPV or genital warts. This vaccine can prevent most cases of genital warts in persons who have not yet been exposed to wart-causing types of HPV.
Persons should inform current partner(s) about having genital warts because the types of HPV that cause warts can be passed on to partners. Partners should receive counseling messages that partners might already have HPV despite no visible signs of warts, so HPV testing of sex partners of persons with genital warts is not recommended. Partner(s) might benefit from a physical examination to detect genital warts and tests for other STDs. No recommendations can be made regarding informing future sex partners about a diagnosis of genital warts because the duration of viral persistence after warts have resolved is unknown.
Unusual Clinical Scenarios to Consider in Patient Management
As discussed above, biopsy should be considered for unusual or recalcitrant lesions. Gynecologic, urologic, or surgical consultation should be considered if condyloma acuminatum are large or involve sensitive anatomic sites.
What is the Evidence?
Workowski, KA, Bolan, GA. “Sexually transmitted diseases treatment guidelines, 2015”. MMWR Recomm Rep.. vol. 64. 2015 Jun 5. pp. 1-137. (Specific section on anogenital warts available at: http://www.cdc.gov/std/tg2015/warts.htm . Summarizes mechanisms of action of treatments for condyloma acuminatum and recommendations for which modalities should and should not be used, depending on characteristics of the patient (eg, HIV infection, pregnancy) and anatomic location of the lesion. Includes counseling messages for patients with HPV infection and warts reproduced in this chapter. A separate section covers issues related to sexual assault and abuse of children [http://www.cdc.gov/std/tg2015/sexual-assault.htm.)
“Sexually Transmitted Disease Surveillance 2014”. 2015. (Specific section on genital warts available at: http://www.cdc.gov/std/stats14/other.htm. Summarizes recent epidemiologic data regarding condyloma acuminatum and HPV infection in the United States.)
Chin-Hong, PV, Husnik, M, Cranston, RD. “Anal human papillomavirus infection is associated with HIV acquisition in men who have sex with men”. AIDS. vol. 23. 2009. pp. 1135-42. (Reports an analysis of a cohort study that enrolled HIV-negative men who have sex with men that showed an association between HPV infection and HIV acquisition.)
Dunne, EF, Datta, SD, Markowitz, L. “A review of prophylactic human papillomavirus vaccines: recommendations and monitoring in the US”. Cancer. vol. 113. 2008. pp. 2995-3003. (Medical epidemiologists from CDC review the epidemiology of HPV infection, describe prophylactic HPV vaccines, and summarize postvaccine licensure monitoring.)
Flagg, EW, Schwartz, R, Weinstock, H. “Prevalence of anogenital warts among participants in private health plans in the United States, 2003-2010: potential impact of human papillomavirus vaccination”. Am J Public Health. vol. 103. 2013. pp. 1428-35. (Shows that prevalence of anogenital warts decreased among US females aged 15-24, likely resulting from HPV vaccination efforts.)
Forcier, M, Musacchio, N. “An overview of human papillomavirus infection for the dermatologist: disease, diagnosis, management, and prevention”. Dermatol Ther. vol. 23. 2010. pp. 458-76. (Very useful review of all aspects of HPV infection.)
Handler, MZ, Handler, NS, Majewski, S. “Human papillomavirus vaccine trials and tribulations: Clinical perspectives”. J Am Acad Dermatol. vol. 73. 2015. pp. 743-56.
Handler, NS, Handler, MZ, Majewski, S. “Human papillomavirus vaccine trials and tribulations: Vaccine efficacy”. J Am Acad Dermatol. vol. 73. 2015 Nov. pp. 759-67. (Two-part review focusing on (1) the debate over who should be vaccinated, at what age, and in which populations, and (2) cost-effectiveness of vaccination, the HPV vaccination rograms currently instituted around the globe, efficacy, and safety.)
Hansen, BT, Hagerup-Jenssen, M, Kjaer, SK. “Association between smoking and genital warts: longitudinal analysis”. Sex Transm Infect. vol. 86. 2010 Aug. pp. 258-62. (One of many articles that reported an association between tobacco use and condyloma acuminatum.
Markowitz, LE, Hariri, S, Lin, C. “Reduction in human papillomavirus (HPV) prevalence among young women following HPV vaccine introduction in the United States, National Health and Nutrition Examination Surveys, 2003-2010”. J Infect Dis. vol. 208. 2013. pp. 385-93. (Study shows that within 4 years of vaccine introduction, vaccine-type HPV prevalence decreased among females aged 14-19 years despite low vaccine uptake.)
Petrosky, E, Bocchini, JA, Hariri, S. “Use of 9-Valent Human Papillomavirus (HPV) Vaccine: Updated HPV Vaccination Recommendations of the Advisory Committee on Immunization Practices”. MMWR. vol. 64. 2015. pp. 300-304. (Includes public health recommendations regarding HPV vaccination.)
Schlecht, HP, Fugelso, DK, Murphy, RK. “Frequency of occult high-grade squamous intraepithelial neoplasia and invasive cancer within anal condylomata in men who have sex with men”. Clin Infect Dis. vol. 51. 2010. pp. 107-10. (Reports relatively high proportions of HIV-infected (and, to a lesser extent) HIV-uninfected men who have sex with men (47% and 26%, respectively) who underwent surgery for anal condyloma acuminatum who had lesions harboring at least some foci of dysplasia, including squamous cell carcinoma.)
Trottier, H, Franco, EL. “The epdidemiology of genital human papillomavirus infection”. Vaccine. vol. 24. 2006. pp. S1-15. (Excellent review of the epidemiology, including risk factors, of genital HPV infection. Also includes information on natural history and pathophysiology.)
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