Continuing Education Activity

Genital warts (condyloma acuminatum) are a sexually transmitted infection caused by the human papillomavirus (HPV) types 6 and 11. These are spread by skin-to-skin contact, usually during sex. These present in clusters or separately and can be found in the genital or anal area. This activity describes the evaluation and management of genital warts and explains the role of the interprofessional team in improving care for patients with this condition.

Objectives:

• Outline the etiology of genital warts.
• Review the importance of biopsy in the evaluation of genital warts.
• Explain the use of physically destructive therapies and topical agents in the management of genital warts.
• Summarize the importance of collaboration and communication among the interprofessional team members to educate patients on the importance of the HPV vaccine, which will enhance the delivery of care for patients with genital warts.

Introduction

Genital warts (condyloma acuminatum) are the clinical manifestations of a sexually transmitted infection caused by some types of human papillomavirus (HPV).[1]

Warts are a recognized symptom of genital HPV infections. About 90% of those exposed who contract HPV will not develop genital warts. Only about 10% who are infected will transmit the virus. HPV types 6 and 11 cause genital warts. There are over 100 different known types of HPV viruses. HPV is spread through direct skin-to-skin contact with an infected individual, usually during sex. While some types of HPV cause cervical and anal cancer, these are not the same viral types that cause genital warts. It is possible to be infected with different types of HPV at the same time.[1]

Etiology

HPV is transmitted primarily through penetrative sex. While HPV also can be transmitted via non-penetrative sexual activity, it is less common.[1][2]

• There is conflicting evidence about the effect of condoms on prevention.
• About 30% of genital warts will disappear within four months of their initial appearance.
• Most genital warts will recur within three months of completion of initial therapy, even if therapy was followed correctly. 
• Recurrence rates depend on the patient's general health and immune status, previous HPV vaccinations, specific HPV strain, number of inoculations (sexual frequency with an infected partner), use of condoms, and the viral load.
• Smoking increases the risk of getting genital warts.
• Approximately three out of four unaffected partners of patients with warts develop them within eight months of contact.
• Although 90% of HPV infections are cleared within two years of infection, it is possible for a latency period to occur, with the first occurrence or a recurrence happening months or even years later.
• Latent HPV is transmissible, and if an individual has unprotected sex with an infected partner, there is a 70% chance they will become infected.
• In individuals with a prior HPV infection, the appearance of new warts may be either from a new exposure or a recurrence.
• Anal or genital warts may be transmitted during birth and may be an indicator of sexual abuse.
• Genital warts may sometimes result from autoinoculation by warts elsewhere on the body, such as from the hands.

Epidemiology

Genital HPV infections have an estimated prevalence of 10% to 20%, with clinical manifestations in 1%. The incidence of HPV infection has been increasing. About 80% of those infected are between the ages of 17 and 33 years, with the peak age group being 20 to 24.  It has been estimated that 2.9% of the US male population will have genital HPV DNA. 

Although treatments can remove warts, they do not remove HPV. Warts may sometimes spontaneously regress. Traditional theories postulate that the virus remains in the body for a lifetime. However, it is now believed that the virus may be either cleared or suppressed to levels below what polymerase chain reaction (PCR) tests can measure.

HPV infection appears to be the cause of most cases of anal cancer (about 90%) and virtually all cases of cervical cancer in women, with HPV type 16 accounting for about 50% of these.  (Cervical cancer is the fourth most common cancer in women.) Some vulvar cancers have been linked to HPV infections (29% to 43%), while vaginal cancer is associated with HPV infections about 70% of the time (HPV Types 16 and 18).[3]

In men, Bowen disease of the penis and about 35% to 40% of all penile cancers are associated with HPV infections.[4]

Risk factors for HPV persistence include age, smoking, immunosuppression, and simultaneous infection with multiple HPV types.[5]

HPV Vaccinations

An HPV vaccination is available. 

For previously unvaccinated adults, the CDC suggests vaccinations for those 27 to 45 years of age. 

For adolescents, the CDC suggests the vaccine be given at ages 11 or 12 years, but may be started as early as 9. 

Histopathology

Genital warts are typically diagnosed visually, with confirmatory biopsy generally unnecessary. These exophytic lesions form due to enlargement of the dermal papillae and are lined by hyperplastic squamous epithelium that shows koilocytes, which are squamous epithelial cells characterized by an acentric, hyperchromatic nucleus displaced by a large perinuclear vacuole.[6]

History and Physical

Genital warts may occur separately or in clusters. They may be found in the anal or genital area, including the penile shaft, scrotum, vagina, or labia majora. They can also be found on internal surfaces of the vagina and the anus. They can be small (5 mm or less in diameter) or spread into large masses in the genital or anal area. Their color is variable but tends to be skin-colored or darker, and they may occasionally bleed spontaneously.

Sometimes warts may cause itching, redness, or discomfort. An outbreak of genital warts may also cause psychological distress. In most cases, the only identifiable symptoms of an HPV infection are warts.

Evaluation

The diagnosis of genital warts is usually made visually, although a biopsy may be necessary for confirmation. Small warts may sometimes be confused with molluscum contagiosum. Genital warts typically rise above the skin surface, have parakeratosis, and demonstrate nuclear changes typical of HPV infections (nuclear enlargement with perinuclear clearing). Because genital warts are caused by low-risk HPV types, DNA tests should not be used for diagnosis or in low-risk HPV infections.

Some practitioners use an acetic acid solution to help identify small warts and affected skin areas, but this practice is controversial.  

A biopsy is recommended if there is uncertainty about the diagnosis or if the patient is immunocompromised. Pigmented and ulcerated lesions should also be considered for biopsy.

Cystoscopy should be considered in patients where the glans is involved, the patient has lower urinary tract symptoms, or there are significant urethral symptoms. In patients who have no symptoms, some experts have suggested waiting until any glans lesions have healed to avoid possible transfer of the HPV virus into the urethra.[7][8]

Treatment / Management

There is no cure for HPV. Removing visible warts does not necessarily reduce the transmission of the underlying HPV infection.[9][10][11] About 80% of individuals with HPV will clear the infection spontaneously within 18 to 24 months.

Treatment varies depending on the number, size, and location of warts. Treatment can cause permanent depigmentation, itching, pain, and scarring.

Urethral meatus warts are best treated with surgery to minimize long-term complications.

The American Urological Association does not recommend treating sub-clinical (invisible) lesions.

Treatments are either ablative (vaporization, resection, coagulation, or excision) or involve the use of topical agents. Physically ablative treatments are more effective at wart removal; but in many cases, topical agents are preferred by patients as initial therapy, especially for smaller lesions.

Topical Agents

Topical agents may be very effective, are self-applied by patients, and are less traumatic than surgical intervention. However, patient compliance is spotty and recurrences are common.

Podophyllotoxin solution 0.15% to 0.5% in a gel or cream can be applied to the affected area and is not washed off. Podofilox (an anti-mitotic drug) appears to be safer than podophyllin.[12] It works by binding microtubular subunits.[13] The gel form is easier for patients to apply than the liquid with equal efficacy.[14] The recommended application schedule (apply BID for three days followed by four days off, then repeat) can be confusing for some patients. Side effects include localized burning, itching, pain, and inflammation. Should not be used in pregnancy. The original precursor topical therapy, podophyllin, is no longer recommended by the CDC due to its high level of mutagens.[15]

Imiquimod is a topical immune response cream applied to the affected area but may cause fungal infections and flu-like symptoms. Imiquimod is an immune enhancer and increases cytokines (such as tumor necrosis factor-alpha (TNF-a) and interferon alfa). This causes an enhanced cytotoxic immune reaction based on T cell-mediated response factors.[13] Wart recurrence rates are better than podophyllin-based therapies and it tends to cause non-scarring healing.[16] The recommended application schedule for imiquimod 5% cream is three times per week.[17] Usage of imiquimod 3.75% cream has been recommended as being equally effective while minimizing local side effects such as pain, burning, inflammation, itching, and erythema.[18][19][20] Usage may also be limited by cost as the medication is relatively expensive if not covered by insurance.

Sinecatechins are an ointment of catechins extracted from green tea that appear to have a higher wart clearance rate than podophyllotoxin and imiquimod while causing less local irritation, but clearance takes longer than with imiquimod. The overall wart clearance rate is reported as high as 57.2%.[21] 

Sinecatechins are available as a 15% ointment. The exact mechanism of action is unknown, but they have immuno-stimulatory, anti-proliferative and anti-tumor properties and appear to work by reducing HPV gene products E6 and E7.[22] Side effects include local redness, inflammation, and pain.

Isotretinoin is a medication typically used for acne. It acts to reduce sebum, shrink sebaceous glands, provides an anti-inflammatory effect, and has anti-bacterial benefits. Isotretinoin has also shown significant efficacy when used as an adjunct to standard treatment of genital warts in immunocompromised patients, where the condyloma are extensive or if the lesions have proven resistant to initial therapy.[23][24][25][26] The dosage is 0.5 to 1 mg/kg/day.  Topical therapy is continued during treatment. There are many potential side effects to isotretinoin therapy so it must be used cautiously. In particular, it can cause very severe birth defects and so should absolutely not be used in pregnancy. For women of childbearing age, this means two pregnancy tests initially and monthly while on medication. They must also use two separate forms of birth control. Side effects include dry skin, chapped lips, frequent nosebleeds, dry eyes, dry mouth, and severe sun sensitivity while on the medication.  There may also be night blindness, hair thinning, muscle aches, arthralgias, rashes, stomach problems, and higher cholesterol levels. Liver damage, urethritis, and hydrocephalus have been reported but are quite rare.[27] Side effects are typically dose-dependent. There are a few reported cases of severe depression and suicide associated with the use of isotretinoin as well as possibly exacerbation of inflammatory bowel disease. For these reasons, isotretinoin is only dosed in 30-day intervals and it should be used cautiously.[23]

Trichloroacetic acid is not as effective as cryosurgery and should be avoided on the vagina, cervix, or urinary meatus.[6] It tends to have a high recurrence rate and should be applied only by a healthcare provider due to potential injury to surrounding tissues.[28]

Skin erosion and pain are most commonly reported with imiquimod and sinecatechins.

Physical (Surgical) Removal or Destruction

Direct surgical excision or physically destructive therapies are considered more effective on keratinized warts, especially if they are larger in size.[6]

Simple surgical excision under local anesthesia is simple and direct but will leave a scar and requires a small surgical procedure.[9]

Liquid nitrogen cryosurgery ablation is inexpensive, considered safe for use during pregnancy, and does not usually cause much scarring but requires cryosurgical equipment and training. It may require anesthesia due to pain and multiple treatments are often necessary. 

Electrocauterization is considered effective but causes scarring and requires some level of anesthesia.[6]

Laser vaporization has minimal bleeding but may be somewhat less effective than other ablative techniques. It is typically used for extensive areas of genital wart involvement, is relatively expensive, and may cause a plume of virus-containing smoke.[29][30]

Surgical removal under general anesthesia may be necessary for more extensive lesions, intra-anal warts, or in children. 

Photodynamic therapy with a photosensitizing agent (such as aminolevulinic acid) has demonstrated efficacy in eliminating external warts. The aminolevulinic acid is applied topically or directly intralesionally. The photosensitizing agent is absorbed quickly into the most rapidly growing cells. Light exposure activates the aminolevulinic acid releasing free oxygen singlet radicals resulting in the destruction of the wart by direct oxidative injury.[31][32][33][34] This technique is currently considered off-label.

Discontinued

• 5-fluorouracil (5-FU) 5% cream is no longer considered acceptable due to side effects.
• Interferon intralesional injections initially showed moderate efficacy with a complete response rate of 36% - 63% as monotherapy, but it has largely been supplanted by other treatments. Might still be considered for intractable cases as an adjunctive therapy.[18] 
• Podophyllin, podofilox, and especially isotretinoin should be avoided during pregnancy.

Differential Diagnosis

• Condyloma lata or secondary syphilis
• Familial benign pemphigus
• Herpes simplex infection
• Benign nevi
• Vulvar neurofibromatosis

Prognosis

A large number of cases of genital warts fail to respond to treatment and often recur, especially with repeated infections from sexual contact or the long-incubation period of HPV. Verifying patient compliance with therapy, changing the therapeutic agent, and adding isotretinoin can help. Morbidity associated with the disease is due to pruritus, bleeding, and the psychosocial burden of genital lesions, while mortality is due to its malignant transformation to squamous cell carcinoma. 

Immunocompromised patients are likely to have more resistant lesions than the general population with more frequent recurrences. They are also more likely for their lesions to develop a malignant transformation into squamous cell carcinoma.[35][36] In general, immunocompromised patients generally benefit from a combination of therapies, early addition of isotretinoin, a longer duration of treatment, and earlier implementation of surgery.[37]

Complications

Local complications with disfigurement are the most common complications of this disease. With untreated and advanced-stage disease, there is a risk of malignant transformation, which is the most feared complication. The current standard of care emphasizes treatment and primary prevention strategies, including vaccination, to prevent this devastating outcome. 

Deterrence and Patient Education

Gardasil is a vaccine used to protect against human papillomavirus types 6, 11, 16, and 18. Types 16 and 18 cause an estimated 70% of cervical cancers, and 6 and 11 cause an estimated 90% of genital warts. The vaccine prevents the disease but is not therapeutic. The vaccine must be given before exposure to the virus type to be effective. The vaccine was approved by the United States Food and Drug Administration (FDA) in 2006 for use in children as early as nine years of age, primarily for its prophylactic activity against cervical cancer. Gardasil 9 was FDA approved in 2014 to protect against the four HPV strains covered by the first generation of Gardasil as well as five other HPV strains responsible for 20% of cervical cancers (HPV-31, HPV-33, HPV-45, HPV-52, and HPV-58).[38]

Vaccines are preventative and should not be considered therapeutic. Quadrivalent or 9-valent vaccines are recommended and generally preferred over bivalent vaccines.

According to the Advisory Committee for Immunization Practices (ACIP), routine HPV vaccination is recommended for women 9 to 26 years of age, but it has shown high efficacy up to age 45. The CDC advises that unvaccinated adults above 26 years to age 45 may be given the vaccine after discussion with their provider. 

The ACIP recommends routine male HPV quadrivalent vaccinations at age 11-12.  If not previously given or incomplete (the vaccines are a three-dose series), the vaccine should be given up to age 21.  From ages 22 to 26, the vaccine is considered optional.  In other words, the optimal age for male HPV vaccination is 11 to 12 years, but it may be given up to age 45 years. 

It remains to be seen if the more extensive use of vaccines can reduce the prevalence and penetration of HPV exposure, infections, and complications.

Pearls and Other Issues

Experimentally, a nitric acid/zinc complex solution for topical application has been successfully used on difficult to treat warts. The solution includes dilute nitric acid, zinc, copper, and organic acids. The application of this solution causes destruction and desiccation of the wart through a combination of denaturation and active protein coagulation actions. So far, it appears to be well tolerated and effective.[39][40]

The use of antivirals such as topical cidofovir also appears promising, but more study is needed before it can be safely utilized clinically.[41][42][43][44]

Curcumin, a derivative of turmeric, has shown efficacy against genital warts anecdotally, but more study is needed to determine its true safety and effectiveness.[45]

Enhancing Healthcare Team Outcomes

Genital warts are very common in clinical practice. Because of the risk of cancer, there is now a vaccine available to prevent these warts. Healthcare workers, including nurse practitioners, physician assistants, and primary care physicians, need to work in an interprofessional effort to educate patients about the importance of the HPV vaccine as it can prevent a variety of genital cancers. The ACIP recommends routine male HPV quadrivalent vaccinations at age 11-12.  If not previously given or incomplete (the vaccines are a three-dose series), the vaccine should be given up to age 21. From ages 22 to 26, the vaccine is considered optional. In other words, the optimal age for male HPV vaccination is 11 to 12 years, but it may be given up to age 26 years.