Condyloma Acuminatum

Author: Robert V Higgins, MD; Chief Editor: David Chelmow, MD Background The viral nature of genital warts was first recognized in 1907 when Ciuffo induced warts after autoinoculation of cell-free wart extracts.[1] The human papillomavirus (HPV) was identified with the development of molecular biology techniques as the virus responsible for condyloma acuminatum. Zur Hansen proposed that HPV was likely important in the etiology of genital tract neoplasias in the mid 1970s.[2] The DNA of the first genital wart was characterized in 1980. Today, more than 120 distinct HPV subtypes have been identified. This group of viruses is strongly linked to the development of cervical cancer. HPV contributes to 90% of anal cancers and 40% of vulva, vaginal, and penile cancers. Squamous cell carcinoma of the oropharynx is associated with HPV in 50% of cases.[3,
4]

Specifically, E6 oncoprotein inactivates the tumor suppressor gene p53, and the oncoprotein produced by E7 inactivates pRB (retinoblastoma).[11] Epidemiology Frequency United States Accurate data concerning the frequency of HPV infection in the US population are difficult to ascertain. Studies reporting the diagnosis of HPV by visual inspection of genital condyloma report the lowest prevalence rates. The highest prevalence rates are reported by studies typing HPV from exfoliated genital tract cells. Most researchers believe HPV is the most common sexually transmitted disease (STD) in the United States. An estimated 500,000 to 1 million new cases of genital warts are diagnosed each year. Data indicate that up to 75% of individuals who have sexual contact with an HPV-infected partner will develop external genital warts.[12] In the United States, 20 million individuals are infected with HPV each year.[13, 14, 15, 16, 17] In the United States, young adults aged 15-24 years account for approximately one half of new HPV infections each year.[18] Condyloma acuminata are clinically apparent in 1% of the sexually active population. Molecular studies indicate 1020% of men and women aged 15-49 years have been exposed to HPV. The prevalence of HPV is higher in certain populations. A prevalence rate of 4-13% has been reported by STD clinics. Young adults in the United States, ages 15 to 24 years, account for approximately one-half of new HPV infections each year. The incidence of HPV infection has clearly increased in the last 35 years based on clinical observations. Data from the National Disease and Therapeutic Index, which is a random survey of private physicians indicate in 1966, 169,000 people consulted a physician about genital warts. By 1984, this number had risen to 1,150,000 consultations. Today, researchers believe at least 1 million new cases of genital warts are diagnosed each year.[19, 18] Several investigators report an increased prevalence of anogenital HPV infections during pregnancy. During pregnancy, the prevalence of condyloma increases from the first to third trimester and decreases significantly in the postpartum period. The risk of condyloma acuminata in pregnancy is 2-fold. Vulvar condyloma can rarely become large enough to obstruct labor. Cesarean delivery decreases, but does not completely prevent, HPV transmission with development of laryngeal papillomas in the infant.[20, 21, 22, 23] International Globally, HPV is the most common sexually transmitted infection.[24, 25] A study in Finland in the mid-1980s demonstrated an annual incidence of cytologic cervical HPV infection of 7%.[26] A study of Finnish males found 6.5% had evidence of HPV in exfoliative cells obtained from the urethra and genital epithelium.[27] Mortality/Morbidity Condyloma acuminatum is often asymptomatic.

Complete understanding of the natural history of HPV disease has significantly improved over the last 20 years, but key issues remain unanswered. Topics requiring further research include HPV age-specific outcomes, risk of progression and regression of disease, and factors important in the acquisition of immunity following infection.[5] Genital warts are transmitted by sexual contact. Approximately two thirds of individuals who have sexual contact with an infected partner develop genital warts. The exact incubation time is unknown, but most investigators believe the incubation period is 3 weeks to 8 months.[6, 7] Pathophysiology HPV is a group of double-stranded DNA viruses. The genome encodes 6 early open reading frames (E1, E2, E4, E5, E6, E7) and 2 late open reading frames (L1, L2). The E genes encode proteins important in regulatory function, and the L genes encode for viral capsid proteins. This group of viruses can infect many different sites, including the larynx, skin, mouth, esophagus, and the anogenital tract. Approximately 40 different types of HPV can infect the anogenital tract. Infection caused by the HPV virus results in local infections and appears as warty papillary condylomatous lesions. HPV infections in the genital area are sexually transmitted.[8, 9, 10] HPVs associated with genital tract lesions have been divided into low risk and high risk based on each genotype's association with benign or malignant lesions. Most genital condylomata are due to infection by HPV-6 or HPV-11. These HPV types replicate as an episome and rarely incorporate their genetic material into the host DNA. In contrast, HPV-16 and HPV-18 can be recovered in approximately 70% of squamous cell carcinomas of the cervix. These high-risk HPV types, along with types 31, 33, 45, 51, 52, 56, 58, and 59 incorporate a portion of their genetic material into the host DNA. The E6 and E7 genes can produce oncoproteins that alter cell growth regulation.

Pruritus or occasional bleeding may lead the patient to seek medical care. Patients who do not develop immunity to HPV can develop potentially serious sequelae. HPV infection of the vulva can result in the development of vulvar intraepithelial neoplasia (dysplasia) or squamous cell carcinoma of the vulva. Most research indicates that HPV infection is strongly associated with the development of cervical dysplasia and cervical carcinoma. HPV confers more than 99% of the attributable risk for the development of cervical dysplasia.[28] Vaginal dysplasia and vaginal cancer are also associated with HPV exposure.

Race Most studies indicate that no racial predilection exists for the acquisition of genital warts. Dinh and associates analyzed data from the 1999-2004 National Health and Nutrition Examination Surveys which collect data from a random sample of the United States civilian population. These investigators reported that non-Hispanic whites had a higher prevalence of genital warts when compared with other racial/ethnic groups.[29] One US survey reported that among women, the prevalence of HPV infection due to any HPV type was 39% for non-Hispanic blacks, and 24% for non-Hispanic whites and Mexican Americans.[30] Sex The prevalence of condyloma acuminata seems to be similar in men and women. One study from an STD clinic in Washington State found that 13% of men and 9% of women had condyloma acuminata (US Department of Health and Human Services, 1996).[13] HPV infections have been reported in approximately one third of US college females.[31] This incidence is higher than in the male population. This presumed higher incidence of HPV infection in females may be the result of detection of HPV infection in cytologic smears performed for cervical cancer screening. Females seek medical care for genital warts more frequently than men.[16] Age The highest rates of genital HPV infection are in sexually active females aged 18-25 years. This incidence is independent of the number of lifetime sexual partners. Most of these infections (90%) are transient.[32, 33, 34] An estimated 5.6% of sexually active adults in the United States aged 18-59 years have been diagnosed with genital warts by a medical provider.[29] The prevalence of genital warts in children younger than 18 years is unknown.[35]

less exposure to the HPV. An alternative theory is that by age 30 years, women have acquired immunity to HPV.[38] The presence of genital condyloma in the pediatric population presents a diagnostic and therapeutic challenge. Vertical transmission of HPV can occur via in utero exposure to amniotic fluid or transmission of HPV from the maternal genital tract. An incubation period of several months is usually required between virus infection at delivery and clinical manifestations in the infant. The average latency period is 3 months, but periods as long as 20 months have been reported.[39] Cases of childhood condylomata outside a reasonable incubation period after vertical transmission should arouse the suspicion of child abuse. Treatment of condyloma in the infant includes excision under general anesthesia or the use of podophyllin.[40]

Epidemiology Frequency United States Accurate data concerning the frequency of HPV infection in the US population are difficult to ascertain. Studies reporting the diagnosis of HPV by visual inspection of genital condyloma report the lowest prevalence rates. The highest prevalence rates are reported by studies typing HPV from exfoliated genital tract cells. Most researchers believe HPV is the most common sexually transmitted disease (STD) in the United States. An estimated 500,000 to 1 million new cases of genital warts are diagnosed each year. Data indicate that up to 75% of individuals who have sexual contact with an HPV-infected partner will develop external genital warts.[12] In the United States, 20 million individuals are infected with HPV each year.[13, 14, 15, 16, 17] In the United States, young adults aged 15-24 years account for approximately one half of new HPV infections each year.[18] Condyloma acuminata are clinically apparent in 1% of the sexually active population. Molecular studies indicate 1020% of men and women aged 15-49 years have been exposed to HPV. The prevalence of HPV is higher in certain populations. A prevalence rate of 4-13% has been reported by STD clinics. Young adults in the United States, ages 15 to 24 years, account for approximately one-half of new HPV infections each year. The incidence of HPV infection has clearly increased in the last 35 years based on clinical observations. Data from the National Disease and Therapeutic Index, which is a random survey of private physicians indicate in 1966, 169,000 people consulted a physician about genital warts. By 1984, this number had risen to 1,150,000 consultations. Today, researchers believe at least 1 million new cases of genital warts are diagnosed each year. [19, 18] Several investigators report an increased prevalence of anogenital HPV infections during pregnancy. During pregnancy, the prevalence of condyloma increases from the first to third trimester and decreases significantly in the postpartum period. The risk of condyloma acuminata in pregnancy is 2-fold. Vulvar condyloma can rarely become large enough to obstruct labor. Cesarean delivery decreases, but does not completely prevent, HPV transmission with development of laryngeal papillomas in the infant.[20, 21, 22, 23]

A cytologic screening of the cervix in more than 400,000 women supports a higher incidence of HPV in young women. This study found that the rate of HPV infection is twice as frequent in women younger than 30 years than it is in women older than 30 years.[36] The prevalence of HPV in a representative sample of US females aged 14-59 years was 26.8%. Women aged 20-24 years had a prevalence rate of 44.8%.[37] The reason for the higher prevalence in younger women is not completely understood. Some investigators hypothesize that older women have fewer sexual partners and, consequently,

International Globally, HPV is the most common sexually transmitted infection.[24, 25] A study in Finland in the mid-1980s demonstrated an annual incidence of cytologic cervical HPV infection of 7%.[26] A study of Finnish males found 6.5% had evidence of HPV in exfoliative cells obtained from the urethra and genital epithelium.[27] Mortality/Morbidity Condyloma acuminatum is often asymptomatic.

Pruritus or occasional bleeding may lead the patient to seek medical care. Patients who do not develop immunity to HPV can develop potentially serious sequelae. HPV infection of the vulva can result in the development of vulvar intraepithelial neoplasia (dysplasia) or squamous cell carcinoma of the vulva. Most research indicates that HPV infection is strongly associated with the development of cervical dysplasia and cervical carcinoma. HPV confers more than 99% of the attributable risk for the development of cervical dysplasia.[28] Vaginal dysplasia and vaginal cancer are also associated with HPV exposure.

Race Most studies indicate that no racial predilection exists for the acquisition of genital warts. Dinh and associates analyzed data from the 1999-2004 National Health and Nutrition Examination Surveys which collect data from a random sample of the United States civilian population. These investigators reported that non-Hispanic whites had a higher prevalence of genital warts when compared with other racial/ethnic groups.[29] One US survey reported that among women, the prevalence of HPV infection due to any HPV type was 39% for non-Hispanic blacks, and 24% for non-Hispanic whites and Mexican Americans.[30] Sex The prevalence of condyloma acuminata seems to be similar in men and women. One study from an STD clinic in Washington State found that 13% of men and 9% of women had condyloma acuminata (US Department of Health and Human Services, 1996).[13] HPV infections have been reported in approximately one third of US college females.[31] This incidence is higher than in the male population. This presumed higher incidence of HPV infection in females may be the result of detection of HPV infection in cytologic smears performed for cervical cancer screening. Females seek medical care for genital warts more frequently than men.[16] Age The highest rates of genital HPV infection are in sexually active females aged 18-25 years. This incidence is independent of the number of lifetime sexual partners. Most of these infections (90%) are transient.[32, 33, 34] An estimated 5.6% of sexually active adults in the United States aged 18-59 years have been diagnosed with genital warts by a medical provider.[29] The prevalence of genital warts in children younger than 18 years is unknown.[35]

A cytologic screening of the cervix in more than 400,000 women supports a higher incidence of HPV in young women. This study found that the rate of HPV infection is twice as frequent in women younger than 30 years than it is in women older than 30 years.[36] The prevalence of HPV in a representative sample of US females aged 14-59 years was 26.8%. Women aged 20-24 years had a prevalence rate of 44.8%.[37] The reason for the higher prevalence in younger women is not completely understood. Some investigators hypothesize that older women have fewer sexual partners and, consequently, less exposure to the HPV. An alternative theory is that by age 30 years, women have acquired immunity to HPV.[38] The presence of genital condyloma in the pediatric population presents a diagnostic and therapeutic challenge. Vertical transmission of HPV can occur via in utero exposure to amniotic fluid or transmission of HPV from the maternal genital tract. An incubation period of several months is usually required between virus infection at delivery and clinical manifestations in the infant. The average latency period is 3 months, but periods as long as 20 months have been reported.[39] Cases of childhood condylomata outside a reasonable incubation period after vertical transmission should arouse the suspicion of child abuse. Treatment of condyloma in the infant includes excision under general anesthesia or the use of podophyllin.[40]

Physical

Single or multiple papular eruptions may be observed. Eruptions may appear pearly, filiform, fungating, cauliflower, or plaquelike. They can be quite smooth (particularly on penile shaft), verrucous, or lobulated. Eruptions may seem harmless or may have a disturbing appearance. Carefully search for simultaneously involved multiple sites. Eruptions' color may be the same as the skin, or they may exhibit erythema or hyperpigmentation. Check for irregularity in shape, form, or color suggestive of melanoma or malignancy. Propensity has been established for penile glans and shaft in men and for vulvovaginal and cervical areas in women. In contrast to early reports, presence of external condyloma acuminata in both men and women warrants a thorough search for cervical or urethral lesions. Such internal lesions have been found in more than one half of females with external lesions. One report indicates that infected males have a 20% chance of having subclinical urethral lesions. More than 50% of female patients with external lesions have been found to have negative Papanicolaou (Pap) tests but tested positive for HPV infection using in situ hybridization. Urethral meatus and mucosal lesions can occur. Some are subclinical. Hair or the inner aspect of uncircumcised foreskin hides some lesions. Search for evidence of other STDs (eg, ulcerations, adenopathy, vesicles, discharge).

Look for perianal lesions, particularly in patients with history or risk of immunosuppression or anal intercourse.

Antroscopy

Prehospital Care Generally, prehospital care is unwarranted and inappropriate; however, reassure the patient and search for the possibility of another underlying reason prehospital care was requested. Emergency Department Care Type of workup, treatment regimens, and necessary follow-up care for condyloma acuminata generally are far beyond the scope of ED practice. However, the following procedures may be implemented if indicated:

Causes

Several of the epidermotropic human papillomaviruses (HPVs) cause condyloma acuminata. HPV types 6 and 11 most commonly are isolated, but many of the more than 60 types of HPV potentially cause condyloma. Male sexual partners of women with cervical intraepithelial neoplasia often have infections with the same viral type.

Differentials

Molluscum Contagiosum Rhabdomyolysis

Laboratory Studies As indicated by history and examination, test for other STDs, such as HIV, gonorrhea, chlamydia, and syphilis. Although not ED tests, the following are listed strictly for educational purposes and to assist readers in understanding and managing potential complications:

Use pressure to stop any bleeding. Relieve urethral obstruction in rare cases. Reassure the patient. Search for evidence of other coexistent STDs and treat if found. Do not begin treatment of condyloma in the ED.

Although not ED treatments, the following are listed strictly for educational purposes and to assist readers in understanding and managing potential presenting complications of condyloma acuminata. Further details on management are included in the Centers for Disease Control and Prevention sexually transmitted diseases treatment guidelines.[3] Cryotherapy Cryotherapy may be performed using an open spray or cotton-tipped applicator for 10-15 seconds and repeated as needed. Lift away mobile skin from underlying normal tissue before freezing. Cryotherapy is an excellent first-line treatment, particularly for perianal lesions. Response rates are high with few adverse sequelae.

Pap smear: This test is used to look for papillomatosis, acanthosis, koilocytic abnormality, and mild nuclear abnormality. Filter hybridization (Southern blot and slot blot hybridization), in situ hybridization, and polymerase chain reaction (PCR): These tests may be used for diagnosis and HPV typing. Hybrid capture

Other Tests

Acetowhitening: Subclinical lesions can be visualized by wrapping penis with gauze soaked with 5% acetic acid for 5 minutes. Using a 10-X hand lens or colposcope, warts appear as tiny white papules. A shiny white appearance of skin represents foci of epithelial hyperplasia (subclinical infection).

Adverse reactions include pain at time of treatment, erosion, ulceration, and postinflammatory hypopigmentation of skin. Cryotherapy is safe during pregnancy Electrodesiccation Smoke plume potentially may be infective. Curettage This may also be used.

Procedures Although not ED procedures, the following are listed strictly for educational purposes and to assist readers in understanding and managing potential presenting complications:

Colposcopy (stereoscopic microscopy): This is very useful to identify (mostly) cervical lesions, which are identified better using acetic acid. Biopsy: Biopsy is indicated for lesions that are atypical, recurrent after initial success, or resistant to treatment or in patients with a high risk for neoplasia or immunosuppression. Anoscopy

Surgical excision Excision has highest success rate and lowest recurrence rate. Initial cure rates are 63-91%.

Carbon dioxide laser treatment Use carbon dioxide laser treatment for extensive or recurrent condyloma acuminata. Potentially infectious HPV-6 DNA has been detected in the carbon dioxide laser plume. Local, regional, or general anesthesia is required. Eutectic mixture of local anesthetics (EMLA) cream may be used as an alternative anesthetic. Consultations

View full drug information 5-Fluorouracil (Adrucil, Efudex, Fluoroplex)

No longer recommended for routine use. Has antimetabolic and/or antineoplastic and immunostimulative activity. Useful in prevention of recurrence after condyloma ablation if started within 4 wk, especially in immunocompromised patients. View full drug information Bleomycin (Blenoxane)

No emergent ED consultation generally is indicated. Outpatient OB/GYN or urologic follow-up care is appropriate.

Medication Summary Although not ED medications, the following are listed strictly for educational purposes and to assist readers in understanding and managing potential presenting complications. Cytotoxic agents Class Summary Inhibit proliferation of cells at various stages of the cell cycle. View full drug information Podophyllum resin (Podocon-25, Pod-Ben-25)

Composed of cytotoxic glycopeptide antibiotics, which appear to inhibit DNA synthesis with some evidence of RNA and protein synthesis inhibition to a lesser degree; used in management of several neoplasms as a palliative measure; may cause a variety of adverse effects; observe patients frequently and carefully during and after treatment. View full drug information Imiquimod (Aldara)

Induces interferon production and is a cell-mediated immune response modifier. Has minimal systemic absorption but causes erythema, irritation, ulceration, and pain. Burning, erosion, flaking, edema, induration, and pigmentary changes may occur at application site. Imiquimod 5% cream comes in single-use packets. Interferons

Extract of various plants, which are cytotoxic. Effective in arresting mitosis in metaphase. Expect cure rate of 2050% if used as single agent. View full drug information Podofilox (Condylox)

Class Summary Interferons are not recommended as a primary treatment modality.[3] Naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. Alpha, beta, and gamma interferons exist and may be administered topically, systemically, and intralesionally. Topical, systemic, and intralesional interferons are not efficacious. View full drug information Interferon alfa-n3 (Alferon N)

Purified podophyllotoxin that is antimitotic, cytotoxic, and available for patient's home use. While exact mechanism of action on condyloma is unknown, podofilox results in necrosis of genital condyloma acuminata. Condylox is one agent containing podofilox. Slightly higher cure rates can be expected with podofilox than with podophyllin. Additionally, useful for prophylaxis. Trichloroacetic or bichloracetic acids

At various concentrations (up to 80%), these agents rapidly penetrate and cauterize skin, keratin, and other tissues. Bichloracetic acid is one such agent. Although caustic, this treatment causes less local irritation and systemic toxicity. Additionally, has low cost. Response is often incomplete, and recurrence is frequent.

Alpha interferon has been approved by FDA for injectional use in refractory condyloma acuminata with some possible benefit. Alferon N is interferon alpha-n3, which has been used effectively for this purpose. Recurrence rate of 20-40% exists with intralesional interferon, but recurrence rate after successful treatment is lower than with other treatment modalities. Additionally, intralesional interferon is expensive and requires repeat office visits.

Furthermore, numerous adverse reactions may occur, including myalgias, fever, chills, GI symptoms, transient leukopenia, thrombocytopenia, LFT abnormalities, serum lipid abnormalities with intramuscular interferon, and theoretical risk of viral transmission with natural interferon products. Viral symptoms do abate with time, and all adverse effects resolve once therapy is stopped. Viral symptoms can be treated with acetaminophen or NSAIDs in the interim. Miscellaneous topical ointment Class Summary Another topical product that has gained FDA approval for genital warts includes kunecatechins. View full drug information Kunecatechins (Veregen)

Further Outpatient Care

Patient should have a follow-up visit with OB/GYN (female) or with urology (male) within 1 week. Treat patient using medications and, if ineffective, with cryotherapy, curettage, electrodesiccation, surgical excision, carbon dioxide laser treatment, or combination therapy. Evaluate and treat sexual partner(s). Perform workup for human papillomavirus (HPV) and other sexually transmitted diseases (STDs). Search for immunosuppression in patients with treatment failures and recurrences. Look for biopsy recurrences and treatment failures.

Inpatient & Outpatient Medications

Podofilox (purified podophyllotoxin) is available for home use by the patient.

Botanical drug product for topical use consisting of extract from green tea leaves. Mode of action unknown but does elicit antioxidant activity in vitro. Indicated for topical treatment of external genital and perianal warts (condylomata acuminatum) in immunocompetent patients. Vaccines Class Summary

Deterrence/Prevention No medications are 100% effective. A vaccine for HPV has been recently approved by the FDA. The Advisory Committee on Immunization Practices (ACIP) recommends routine HPV4 vaccination for females aged 11-12 years and catch-up vaccination for females aged 13-26 years.[5] Sexual abstinence and monogamy are protective.

A human papillomavirus vaccine is now available for prevention of HPV-associated dysplasias and neoplasia including cervical cancer, genital warts (condyloma acuminata), and precancerous genital lesions. The immunization series should be completed in boys, girls, and young men and women aged 9-26 years.[4] View full drug information Papillomavirus vaccine (Gardasil)

Condoms may discourage transmission. Complications

Local disfigurement Transformation to genitourinary malignancies in both males and females[6] Transmission to neonate or partners Recurrence of condyloma acuminata

Quadrivalent human papillomavirus (HPV) recombinant vaccine. First vaccine indicated to prevent cervical cancer, genital warts (condyloma acuminata), and precancerous genital lesions (eg, cervical adenocarcinoma in situ; cervical intraepithelial neoplasia grades 1, 2, and 3; vulvar intraepithelial neoplasia grades 2 and 3; vaginal intraepithelial neoplasia grades 2 and 3) due to HPV types 6, 11, 16, and 18. Vaccine efficacy mediated by humoral immune responses following immunization series. Indicated for prevention of condyloma acuminata caused by HPV types 6 and 11 in boys, men, girls, and women aged 9-26 years. Further Inpatient Care

Prognosis Many patients either fail to respond to treatment or condyloma acuminata recurs after adequate response. Recurrence rate of cervical dysplasia in women is not altered by treatment of sexual partners. Recurrence rates exceed 50% after 1 year and have been attributed to the following:

Generally, no further inpatient care is necessary unless the patient has malignant transformation of lesions to carcinoma.

Repeat infection from sexual contact Long incubation period of HPV Location of virus in superficial skin layers away from lymphatics Persistence of virus in surrounding skin, hair follicles, or sites not adequately reached by intervention used Missed or deep lesions Subclinical lesions An underlying immunosuppression

Patient Education

Identify and educate individuals at risk for condyloma acuminata. For excellent patient education resources, visit eMedicine's Sexually Transmitted Diseases Center. Also, see eMedicine's patient education article Genital Warts.