There are more than 1 million new cases of noncervical human papillomavirus (HPV) genital infections per year in the United States, and the incidence is increasing. Manifestations range from multiple, exophytic external genital warts to subclinical infections detectable only with colposcopic examination with acetic acid or DNA probes. Although all age groups are affected, sexually active young adults account for most visits to physicians' offices. HPV serotypes 6 and 11 are the most commonly found in external genital warts.
HPV infects the active basal layers of the skin through microabrasions that frequently occur during intercourse. Heterosexual and homosexual activity can spread HPV. A latency period of many years may occur before the disease becomes apparent, making epidemiology and control of spread of the virus difficult. Condylomata acuminata are most frequently found on the prepuce in men and on the vulva in women.
HPV lesions can usually be diagnosed by their gross appearance. Detection of flat HPV lesions can be enhanced with the use of a colposcope and 5% acetic acid, which produces characteristic acetowhite changes. Any lesion that has an atypical appearance, is pigmented, or is resistant to therapy should be biopsied to rule out malignancy. Laboratory tests for the detection of HPV DNA are not useful for external genital warts. There is no widely accepted screening test for the diagnosis of external HPV lesions except physical examination (Table 41-1).
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TABLE 41-1. DIFFERENTIAL DIAGNOSIS FOR CONDYLOMATA ACUMINATA |
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External genital warts typically worsen during pregnancy. Cesarean section is indicated only if the condylomata physically obstruct the pelvic outlet, not to prevent HPV infection of the newborn. Although infant exposure to maternal HPV is common, studies indicate that HPV rarely colonizes the baby. Condylomata acuminata during pregnancy may be treated to reduce the risk of postpartum hemorrhage and poor healing in condylomatous tissue after delivery, but there are no published prospective studies of the efficacy of treating lesions to control these problems. The use of 5-fluorouracil and podophyllin is contraindicated in pregnancy. Cryotherapy has been shown to be safe and effective, and it remains the treatment of choice during pregnancy.
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HPV 6 and 11 can cause laryngeal papillomatosis, but the route of transmission is not understood. Perinatal transmission rates are believed to be low, considering the high prevalence of maternal HPV infections and the low rates of perinatal infection. One study suggested a transmission rate as high as 30% for babies born to mothers with latent HPV infection but also observed that all of the babies cleared the HPV DNA by 5 weeks of age.
The presence of genital HPV infection in children should arouse the suspicion of child abuse. HPV lesions may be seen in girls and boys, and sexual and nonsexual routes of transmission have been identified. Types of nonsexual transmission that have been documented include gestational, during birth, and from familial nonsexual contacts. When HPV lesions are found, a thorough history should be obtained, and testing for other sexually transmitted diseases should be considered. The child should be checked carefully for signs of abuse. All U.S. states require that any suspected child abuse be reported to the appropriate authorities.
External genital warts are more prevalent and difficult to treat in patients with concomitant human immunodeficiency virus (HIV) infection, and the severity of HPV lesions worsens as HIV infection progresses. HPV infection occurs in 40% to 52% of homosexual men and up to 95% of heterosexual women with HIV. Most treatments for HPV are effective, but they may require more treatment episodes over a longer duration to overcome the higher recurrence rates. An increased risk of cervical and anal carcinoma has been found in women with HIV infection, and cervical dysplasia is part of the Centers for Disease Control and Prevention (CDC) criteria for acquired immunodeficiency syndrome (AIDS). There is a need for careful, repetitive examination of the cervix and perineum of HIV-infected women.
The goal of treating noncervical HPV infections is the elimination of obvious, symptomatic, or troublesome lesions—not eradication of the virus. Because many warts regress over time, treatments that do not have a significant risk of scarring should be considered primarily. Modern approaches have a much better safety profile than older methods, but they are still plagued with high recurrence rates and variable success rates. Treating male sexual partners with HPV infection has not appeared to change the posttreatment failure rate in women with cervical
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dysplasia. These findings should not deter the clinician from appropriately counseling, examining, and treating HPV-infected men.
The epidemiology and transmissibility of HPV should be explained to the patient so that steps can be taken to decrease further spread. Inform patients that they are contagious to sexual partners. Sexual abstinence, monogamous relationships, and condoms may help decrease the spread of the virus. However, condoms do not cover all of the areas where the virus infects, and they represent imperfect barriers.
THERAPY
5-Fluorouracil was once commonly used for many types of lesions. Cases of clear cell carcinoma arising in vaginal adenosis after 5-fluorouracil treatment for condylomas has been reported. These problems and the possibility of severe side effects have eliminated this drug as a preferred treatment modality.
In 1998, the Morbidity and Mortality Weekly Report published a list of recommended therapies, with several new therapies since that report. Treatment should be guided by patient preference. Practitioners should be familiar with at least one patient-applied treatment (i.e., imiquimod and podofilox) and one provider-applied therapy. Large exophytic lesions generally should be pared down before therapy.
Patient-Applied Treatments
Imiquimod Cream
Imiquimod cream (Aldara) is a immune-modifying agent that induces multiple subtypes of interferon-alpha, several cytokines, tumor necrosis factor, and interleukins. These factors activate natural killer cells, T cells, polymorphonuclear neutrophils, and macrophages that attack the tumor. The drug has almost no systemic side effects and is a pregnancy class B drug. It may help induce immune “memory” and prevent future recurrence. Side effects can include erythema, erosion, itching, skin flaking, and edema. Therapy can be temporarily halted if symptoms become problematic. Imiquimod demonstrates clearance rates of 72% for women and 33% for men, with more than 50% wart reduction rates of 85% for women and 70% for men. The drug appears to work best on moist tissues, which may account for its higher success rates in women.
Podofilox
Podofilox (Condylox) is a purified, active component of podophyllin. This purified form is better standardized, safer, and indicated for patient application. Podophyllin systemic reactions may occur with extensive application, after application to mucous membranes, or if left on the skin for long periods. Reported reactions include nausea, vomiting, fever, confusion, coma, renal failure, ileus, and leukopenia. Pain and ulceration may also occur. Because repeated application to the mouse cervix produced dysplastic changes, its use on the human uterine cervix is not recommended. It works by inhibition of nuclear division at metaphase. Success rates vary from 44% to 88%.
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Provider-Applied Treatments
Loop Electrosurgical Excisional Procedure
The loop electrosurgical excisional procedure (LEEP) can be used to treat perineal condylomata in male and female patients. It may also produce tissue for the pathologic study of lesions that are questionable or fail to respond to treatment as expected. HPV can be aerosolized, and HPV DNA has been found in laser and electrocoagulation smoke. Operators should wear a virus-filtering mask. LEEP has not been extensively studied in pregnancy.
Loops used for the removal of external lesions are typically smaller and shorter than standard cervical loops and are selected to allow easy removal of the lesion. The power setting must be high enough to allow easy passage with low tissue drag through the lesion and epidermis. The smoke evacuator should be activated before performing LEEP. Anesthesia can be obtained with 1% to 2% lidocaine with epinephrine (except on the penis, where epinephrine generally is avoided).
Follow-up protocols vary; typically, patients return in 2 weeks to 1 months for follow-up, unless unexpected pain or infection becomes a problem. Late bleeding has been reported in 4% of patients treated for vaginal lesions, and it can usually be controlled with Monsel's solution or fulguration. Infection is an uncommon complication that is usually controlled with topical (and rarely, systemic) antibiotics. Hypopigmentation and hypertrophic scars are rarely reported. Success rates for treating noncervical lesions with LEEP are in the range of 90% to 96%.
Cryotherapy
Cryotherapy works by freezing and killing abnormal tissue, which then sloughs off, and new tissue grows in its place. Local injection or topical anesthestic cream may be used but generally is unnecessary. Recalcitrant lesions can be treated with a freeze-thaw-refreeze technique to increase efficacy. Follow-up for retreatment is usually every 2 weeks until the lesion is resolved. The procedure does involve some pain during freezing and healing. Local infection and ulceration has been anecdotally reported. The success rate for cryotherapy is 71% to 79%.
Trichloroacetic Acid and Bichloracetic Acid
Trichloroacetic acid (TCA) and bichloracetic acid (BCA) work by physically destroying tissue. Because they are quickly inactivated after contact with tissue, toxicity is not a problem. TCA can be prepared in different strengths and must be compounded at a pharmacy. BCA can be obtained in a standard preparation. The follow-up schedule is every 1 to 3 weeks until the lesions resolve. The depth of penetration of the acid can be difficult to control, and penetration through the dermis can result in slow-healing ulcerations and scar formation. Pain also can be a problem with this therapy. The response rates are between 50% and 81%, and there is a high rate of recurrence.
Mechanical Excision
Shave biopsy removal of external genital warts by scissors or scalpel excision can be a simple, effective treatment. It may also produce tissue for the pathologic
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study. Scissors are especially effective for isolated pedunculated lesions. Cosmetic results are usually good, and the wound requires no sutures. Mechanical excisions should be performed at the middle level of the dermis. The goal is to not penetrate too deeply to avoid scarring. If penetration occurs to the level of fatty tissue, convert the area to a fusiform excision, and close with sutures.
INDICATIONS
CONTRAINDICATIONS AND PRECAUTIONS
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PROCEDURE
Apply the imiquimod cream to external genital warts three times each week every other day for up to 16 weeks. It should be rubbed into the lesion to increase absorption. The cream may be applied to the affected area, not exclusively to the lesion.
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(1) Application of imiquimod cream. |
Apply the podofilox solution with an applicator or toothpick twice daily for 3 consecutive days, with 4 consecutive days of no therapy each week, for a maximum 4 weeks.
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(2) Application of podofilox. |
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To remove a lesion with LEEP, first inject anesthetic under the site. With the operator's hand resting against the patient for stability, a medium-sized loop or “square” loop is introduced just above the base of the lesion and pulled completely through to debulk it.
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(3) Introduce a medium-sized loop just above the base of the lesion, and pull it completely through to debulk it. |
The remaining lesion should be carefully shaved down to the dermis using the side of the loop and fine “paint-brush” or feathering strokes. Fulguration can be used for hemostasis, but it is usually unnecessary. The bulk specimen may then be sent for histologic study if desired.
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(4) The remaining lesion should be carefully shaved down to the dermis. |
PITFALL: Care should be taken to not penetrate the dermis during the shave excision. A proper shave site has gently sloping sides, dermis at the base, and no subcutaneous fat showing through.
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In cryotherapy, the large, cotton-tipped applicators for liquid nitrogen are easy to use and require little skill. If using a standard long-handled, cotton-tipped applicator, increase the size of the cotton head by pulling wisps of cotton off of a cotton ball and loosely rolling them onto the applicator. Dip the applicator into liquid nitrogen for 5 to 10 seconds, and then place it on the lesion until a 2-mm ice ball forms beyond the edges of the lesion. Repeat the application once the iceball thaws. Therapy is repeated at 2-week intervals until the lesion resolves. Cryounits using NO2 may also be used (see Chapters 19 and 38).
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(5) Dip the applicator into liquid nitrogen for 5 to 10 seconds, and then place it on the lesion until a 2-mm ice ball forms beyond the edges of the lesion. |
A thin layer of TCA or BCA solution is applied only to the wart itself. If desired, the normal surrounding skin may be protected with petroleum jelly, but it is unnecessary if care is used in application of the acid. Bicarbonate, talc, or soap and water may be used to neutralize any excess acid. A 50% TCA solution is applied with a cotton-tipped applicator or toothpick to the affected area three times each week for a maximum of 4 weeks (most commonly used regimen), or an 80% solution can be applied twice daily for 3 consecutive days each week for a maximum of 4 weeks.
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(6) Protect the normal skin surrounding the lesion with petroleum jelly, and apply a thin layer of TCA or BCA to the wart. |
Before mechanical excision, wipe the area to be shaved with alcohol, and allow it to dry. Inject anesthetic just beneath the lesion to raise a wheal.
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(7) Inject anesthetic just beneath the lesion to raise a wheal. |
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Stabilize the area between the thumb and index finger. Using a no. 15 blade, shave the lesion flush with the level of the normal tissue. The blade should be held nearly parallel to the surrounding skin. Place the tissue in formalin, and send it for pathologic analysis. Apply Monsel's solution (i.e., ferric subsulfate), pressure, or cautery to stop bleeding.
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(8) Holding a no. 15 blade nearly parallel to the surrounding skin, shave the lesion flush with the level of the normal tissue. |
PITFALL: Care should be taken to not penetrate the dermis during the shave excision, because this can induce scarring.
Alternatively, scissors may be used to remove the lesions. With the jaws of the scissors partially closed, bring the smallest point of the opening up against the base of the lesion. As soon as the scissors start cutting the skin, gently lift the lesion upward with the blades of the scissors as you are cutting. This keeps the cut in a shallow plane that prevents formation of a deep crater.
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(9) Scissors may be used instead of a scalpel to excise the lesion. |
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CODING INFORMATION
In addition to the codes in the following chart, you may also consider using benign excision from the genitalia codes (11420–11426) or malignant excision from the genitalia codes (11620–11626), depending on the pathology findings.
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INSTRUMENT AND MATERIALS ORDERING
Suppliers for LEEP include Circon/Cryomedics, 2021 Cabot Boulevard West, Langhorne, PA 19047 (http://www.acmicorp.com/acmi/user); Ellman International, 1135 Railroad Avenue, Hewlett, NY 11557 (http://www.ellman.com); Utah Medical Products, 7043 South 300 West, Midvale, UT 84074 (http://www.utahmed.com); and Wallach Surgical Devices, 291 Pepe's Farm Road, Milford, CT 06460 (http://www.wallachsurgical.com). A suggested anesthesia tray that can be used for this procedure is listed in Appendix G.
Cryotherapy (NO2) units can be obtained from Circon/Cryomedics, 2021 Cabot Boulevard West, Langhorne, PA 19047 (http://www.acmicorp.com/acmi/user) and from Wallach Surgical Devices, 291 Pepe's Farm Road, Milford, CT 06460 (http://www.wallachsurgical). Liquid nitrogen Cryoguns can be obtained from national medical supply houses such as the Henry Schein Medical Catalog. Liquid Nitrogen can usually be obtained from local suppliers.
TCA must be compounded at a pharmacy. It can be obtained from pharmacies that are members of the Professional Compounding Pharmacies of America (Houston, TX). To locate a member pharmacy or obtain compounding information, call their toll-free number (800-331-2498).
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Imiquimod cream is available by prescription from pharmacies. The Aseptex submicron surgical mask (#1812) is available from 3M Surgical Division, St. Paul, MN 55144.
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