Condyloma Acuminatum (Genital Warts)

Condyloma acuminatum (also known as genital warts or anogenital warts) refers to an epidermal manifestation attributed to the epidermotropic human papillomavirus (HPV), as in the images below. More than 180 types of double-stranded HPV papovavirus have been isolated to date. Many of these have been related directly to an increased neoplastic risk in men and women.

Approximately 90% of condylomata acuminata are related to HPV types 6 and 11. These 2 types are the least likely to have a neoplastic potential. Risk for neoplastic conversion has been determined to be moderate (types 33, 35, 39, 40, 43, 45, 51-56, 58) or high (types 16, 18),[1] with many other isolated types. The picture is complicated by proven coexistence of many of these types in the same patient (10-15% of patients), the lack of adequate information on the oncogenic potential of many other types, and ongoing identification of additional HPV-related clinical pathology.

For example, bowenoid papulosis, seborrheic keratoses, and Buschke-Löwenstein tumors have been linked to HPV infections though they were previously a part of the differential diagnosis of condyloma acuminatum. Bowenoid papulosis consists of rough papular eruptions attributed to HPV and is considered to be a carcinoma in situ. The eruptions can be red, brown, or flesh colored. They may regress or become invasive. Seborrheic keratoses previously were considered a benign skin manifestation. HPV has been linked to rough plaques indicative of this disease. It has both an infectious and an oncogenic potential. Finally, Buschke-Löwenstein tumor (ie, giant condyloma) is a fungating, locally invasive, low-grade cancer attributed to HPV.

Cells of the basal layer of the epidermis are invaded by human papillomavirus (HPV). These penetrate through skin and cause mucosal microabrasions. A latent viral phase begins with no signs or symptoms and can last from a month to several years. Following latency, production of viral DNA, capsids, and particles begins. Host cells become infected and develop the morphologic atypical koilocytosis of condyloma acuminatum.

The most commonly affected areas are the penis, vulva, vagina, cervix, perineum, and perianal area. Uncommon mucosal lesions in the oropharynx, larynx, and trachea have been reported. HPV-6 even has been reported in other uncommon areas (eg, extremities).

Multiple simultaneous lesions are common and may involve subclinical states as well-differentiated anatomic sites. Subclinical infections have been established to carry both an infectious and oncogenic potential.

Consider sexual abuse as a possible underlying problem in pediatric patients;[2] however, keep in mind that infection by direct manual contact or indirectly by fomites rarely may occur. Finally, passage through an infected vaginal canal at birth may cause respiratory lesions in infants.[2]

Frequency

United States

Annual incidence of condyloma acuminatum is 1%. It is considered the most common sexually transmitted disease (STD). Prevalence has been reported to exceed 50%. Highest prevalence and risk is among young adults in the third decade and in older teenagers. A 4-fold or more increase in prevalence has been reported in the last 2 decades.

International

International prevalence has been reported variably. Available data from England, Panama, Italy, the Netherlands, and other developed and underdeveloped countries report HPV infections to be at least as common as in the US.

Mortality/Morbidity

Mortality is secondary to malignant transformation to carcinoma in both males and females. This oncogenic potential has been reported to triple the risk of genitourinary cancer among infected males. Fortunately, this is rare with HPV types 6 and 11, which are the most commonly isolated viruses.

HPV infection appears to be more common and worse in patients with various types of immunologic deficiencies. Recurrence rates, size, discomfort, and risk of oncologic progression are highest among those patients. Secondary infection is uncommon.

Latent illness often becomes active during pregnancy. Vulvar condyloma acuminatum may interfere with parturition. Trauma then may occur, producing crusting or erythema. Bleeding has been reported in large lesions that can occur during pregnancy.

In males, bleeding has been reported due to flat warts of the penile urethral meatus, usually associated with HPV-16. Lesions may lead to disfigurement of area(s) involved. Finally, acute urethral obstruction in women also may occur.

Sex

Both sexes are susceptible to infection.

Overt disease may be more common in men (reported in 75% of patients); however, infection may be more prevalent in women.

Age

Prevalence is greatest in persons aged 17-33 years, with incidence peaking in persons aged 20-24 years.

Smoking, oral contraceptives, multiple sexual partners, and early coital age are risk factors for acquiring condyloma acuminatum.

Generally, two thirds of individuals who have sexual contact with a partner with condyloma acuminatum develop lesions within 3 months.

The chief complaint usually is one of painless bumps, pruritus, or discharge. Involvement of more than 1 area is common. History of multiple lesions, rather than 1 isolated wart, is common.

Oral, laryngeal, or tracheal mucosal lesions (rare) presumably are transferred by oral-genital contact.

History of anal intercourse in both males and females warrants a thorough search for perianal lesions.

Rarely, urethral bleeding or urinary obstruction may be the presenting complaint when the wart involves the meatus.

The patient's history may indicate presence of previous or other current STDs.

Coital bleeding may occur. Vaginal bleeding during pregnancy may be due to condyloma eruptions.

Latent illness may become active, particularly with pregnancy and immunosuppression.

Lesions may regress spontaneously, remain the same, or progress.

Pruritus may be present.

Discharge may be a complaint.

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 acuminatum 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.

Several of the epidermotropic human papillomaviruses (HPVs) cause condyloma acuminatum.

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.

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:

• 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

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).

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

• Antroscopy

Generally, prehospital care is unwarranted and inappropriate; however, reassure the patient and search for the possibility of another underlying reason prehospital care was requested.

Type of workup, treatment regimens, and necessary follow-up care for condyloma acuminatum generally are far beyond the scope of ED practice. However, the following procedures may be implemented if indicated:

• 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 acuminatum. 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.[4]

Cryotherapy is an excellent first-line treatment, particularly for perianal lesions.

Response rates are high with few adverse sequelae.

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.

Surgical excision

Excision has highest success rate and lowest recurrence rate.[5]

Initial cure rates are 63-91%.

Carbon dioxide laser treatment

Use carbon dioxide laser treatment for extensive or recurrent condyloma acuminatum.[6]

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.

No emergent ED consultation generally is indicated.

Outpatient OB/GYN or urologic follow-up care is appropriate.

Various topical and systemic treatments are available for the treatment of condyloma acuminatum, including options for home use by the patient (eg, purified podophyllotoxin, imiquimod, sinecatechins). Other treatments that are administered in the physician’s office or emergency department may include acetic acid applications or interferon injections.

An important preventive therapy for condyloma acuminatum and other dysplasias is the human papillomavirus vaccine (9vHPV, Gardasil 9). The FDA has expanded the age to receive the vaccine through age 45 years.[7]

Interleukin 10 (IL-10), which is not approved for use in the United States, is a cytokine with multiple biological activities. IL-10 suppresses the inflammatory response and regulates the differentiation and proliferation of T cells, B cells, natural killer cells, antigen-presenting cells, mast cells, and granulocytes. IL-10 acts on antigen-presenting cells (APCs) by down-regulating the expression of MHC class II and co-stimulatory molecules and the production of reactive oxygen and nitrogen intermediates. IL-10 also acts directly on IL-10 receptor-expressing T cells to reduce their cytokine production and pathological effects.

Class Summary

Inhibit proliferation of cells at various stages of the cell cycle.

Podophyllum resin (Podocon-25)

Extract of various plants, which are cytotoxic. Effective in arresting mitosis in metaphase. Expect cure rate of 20-50% if used as single agent.

Podofilox (Condylox)

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 acuminatum. Condylox is one agent containing podofilox. Slightly higher cure rates can be expected with podofilox than with podophyllin. Additionally, useful for prophylaxis.

Trichloroacetic acid topical (Tri-Chlor)

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.

5-Fluorouracil (Carac, Efudex, Fluoroplex, Tolak)

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.

Bleomycin

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.

Imiquimod (Aldara, Zyclara)

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.

Kunecatechins (Veregen)

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.

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.

Interferon alfa-n3 (Alferon N)

Alpha interferon has been approved by FDA for injectional use in refractory condyloma acuminatum 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.

Class Summary

One human papillomavirus (HPV) vaccine (9vHPV, Gardasil 9) is available in the United States for the prevention of HPV-associated neoplasias and dysplasias, including genital warts (condylomata acuminata).[7]

Human papillomavirus vaccine, nonavalent (Gardasil 9)

Recombinant vaccine that targets 9 HPV types (6, 11, 16, 18, 31, 33, 45, 52, 58). It is indicated for females and males aged 9-45 years to prevent genital warts and also dysplasias and neoplasia (eg, cervical, vulvar, vaginal, and anal cancers).

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.

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

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

No medications or vaccines are 100% effective. One human papillomavirus vaccine (9-valent, Gardasil 9) is available in the United States for the prevention of HPV-associated neoplasias and dysplasias, including genital warts (condylomata acuminata). The FDA has expanded the age to receive the vaccine through age 45 years.[7]

Sexual abstinence and monogamy are protective.

Condoms may discourage transmission.

See the list below:

• Local disfigurement

• Transformation to genitourinary malignancies in both males and females[8]

• Transmission to neonate or partners

• Recurrence of condyloma acuminatum

Many patients either fail to respond to treatment, or condyloma acuminatum 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:

• 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

Identify and educate individuals at risk for condyloma acuminatum.

For excellent patient education resources, visit eMedicineHealth's Sexual Health Center. Also, see eMedicineHealth's patient education article Genital Warts (HPV Infection).