Condyloma Acuminatum

INTRODUCTION ˇ@

Background: The viral nature of genital warts was first recognized in 1907 when Ciuffo induced warts after autoinoculation of cell-free wart extracts (Ciuffo, 1907). With the development of molecular biology techniques, the human papillomavirus (HPV) was identified as the virus responsible for condyloma acuminatum. In the mid-1970s, zur Hansen proposed that HPV was likely important in the etiology of genital tract neoplasias (zur Hansen, 1976). The DNA of the first genital wart was characterized in 1980. Today, over 80 distinct HPV subtypes have been identified. This group of viruses is strongly linked to the development of cervical dysplasia, cervical cancer, and vulvar dysplasia.

Genital warts are spread 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 months (Becker, 1987).

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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 20 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 (Gissmann, 1980).

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, and 45, incorporate a portion of their genetic material into the host DNA. The E6 and E7 genes can produce oncoproteins that alter cell growth regulation. Specifically, E6 oncoprotein inactivates the tumor suppressor gene p53, and the oncoprotein produced by E7 inactivates pRB (retinoblastoma) (Koutsky, 1997).

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Frequency:
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Mortality/Morbidity: Condyloma acuminatum often is asymptomatic.

Race: No racial predilection exists.

Sex: The prevalence of condyloma acuminata seems to be similar in men and women. One study from a sexually transmitted disease clinic in the state of Washington found 13% of men and 9% of women had condyloma acuminata (US Department of Health and Human Services 1996, Koutsky, 1988).

Age: The highest rates of genital HPV infection are found in sexually active women younger than 25 years, even after correcting for the number of lifetime sexual partners. Most of these infections seem to be transient (Ho, 1998; Burk, 1996; Figueroa, 1995).

CLINICAL ˇ@

History:

Physical:

Causes: Approximately 20 different types of HPV can infect the anogenital tract.

WORKUP ˇ@

Lab Studies:
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Imaging Studies:
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Procedures:
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Histologic Findings: Biopsy of the vulvar skin associated with condyloma shows evidence of hyperkeratosis, acanthosis, and parakeratosis. A chronic inflammatory infiltrate often is observed within the dermis. Koilocytosis, which is perinuclear cytoplasmic halos, commonly is observed in the superficial epithelial cells. Other microscopic findings include basilar hyperplasia with binucleated and multinucleated cells and enlarged parabasal cells with a foamy nuclear chromatin.

Staging: No staging system exists for condyloma acuminata.

TREATMENT ˇ@

Medical Care: A variety of medical treatments exists for condyloma acuminata, and no single treatment regimen is superior.

Surgical Care: Surgical treatment of condyloma acuminata usually is reserved for patients in whom local therapy has failed. Several options are available, including local excision, laser therapy, cryotherapy, and electrosurgical excision.

Activity:

MEDICATION ˇ@

No one superior treatment exists for condyloma acuminata (Auborn, 2000). Simple topical therapies are the initial treatments of choice for most patients. They are cost-effective and result in minimal toxicities. Most result in a 30-90% success rate in eliminating visible condyloma; however, many clinical studies using topical therapies are not well designed, making comparisons between therapies difficult.
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Drug Category: Antimitotics -- Arrests dividing cells in mitosis, resulting in death of proliferating cells.

Drug Name
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Podophyllin (Podocon-25, Podofin) -- Treatment results in necrosis of visible wart tissue. Exact mechanism of action is unknown. Great variability exists in the potency of podophyllin between batches. American podophyllum contains one-fourth the amount of the Indian source. Warts visible after 6 treatments usually do not respond to further therapy (Hellberg, 1995).
Adult Dose Apply concentration of 25% sparingly onto lesions; wash treatment area 4 h after application; repeat q1-2wk until eliminated
Pediatric Dose Apply as in adults
Contraindications Documented hypersensitivity; diabetes; impaired peripheral circulation; avoid use on mucous membranes, eyes, bleeding warts, moles, birthmarks, or unusual warts with hair
Interactions None reported
Pregnancy X - Contraindicated in pregnancy
Precautions Powerful caustic and severe irritant; do not use if surrounding tissue is swollen or irritated; do not use large amounts; avoid contact with cornea; should be applied by a physician or trained nurse; redness or burning of the skin can occur 6-24 h after treatment
Drug Name
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Podofilox (Condylox) -- Topical antimitotic that can be synthesized chemically or purified from plant families Coniferae and Berberidaceae (eg, species of Juniperus and Podophyllum).
Active agent of podophyllin resin and is available as a 0.5% solution. Can apply solution to warts at home.
Adult Dose Apply 0.5% solution to warts bid for 3 d; repeat qwk for up to 4 wk
Pediatric Dose Apply as in adults
Contraindications Documented hypersensitivity
Interactions None reported
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Avoid contact with eyes; if eye contact occurs, immediately flush eye with copious quantities of water and seek medical advice; not for use on mucous membranes of genital area, including urethra, rectum, and vagina; do not exceed frequency of application or duration of usage

Drug Category: Antineoplastic agents -- Topical preparation containing the fluorinated pyrimidine, 5-fluorouracil. Antineoplastic and antimetabolite agent.

Drug Name
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Fluorouracil (Efudex) -- Interferes with DNA synthesis by blocking methylation of deoxyuridylic acid, inhibiting thymidylate synthetase and, subsequently, cell proliferation. Limited data exist concerning the efficacy of this therapy for genital warts. Three case series indicate wart clearance in 10-50% of participants (Krebs, 1990). Experimental treatments injecting 5-FU with epinephrine and bovine collagen currently are in trials.
Adult Dose Apply 5% solution to warts 1-3 times per wk; wash off after 8 h
Pediatric Dose Not established
Contraindications Documented hypersensitivity; potentially serious infections
Interactions None reported
Pregnancy X - Contraindicated in pregnancy
Precautions Incidence of inflammatory reactions may occur with occlusive dressings; porous gauze dressing may be applied for cosmetic reasons without increase in reaction; adjacent healthy skin around warts should be coated with a protective gel before application; reproductive age group should use adequate contraception during therapy

Drug Category: Desiccants -- These are acids that are most effective when applied to moist warts. They are nontoxic and can be used in pregnancy.

Drug Name
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Trichloroacetic acid (Tri-Chlor) -- Cauterizes skin, keratin, and other tissues. Although caustic, causes less local irritation and systemic toxicity than others in the same class; however, response often is incomplete and recurrence occurs frequently (Abdullah, 1993).
Adult Dose Apply 50-85% solution to warts q1-2wk in physician's office; wash off after 4-6 h
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity; not for use on premalignant or malignant lesions
Interactions None reported
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions External use only; restrict use to treatment areas only; skin adjacent to warts needs to be protected; severe burning may occur

Drug Category: Immune response modifiers -- Stimulates production of cytokines and has demonstrated strong antiviral activity.

Drug Name
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Imiquimod (Aldara) -- Induces secretion of interferon alpha and other cytokines. Mechanism of action unknown (Edwards, 1998).
Adult Dose Apply 5% cream 3 times per wk hs; leave on skin for 6-10 h; treatment period not to exceed 16 wk
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity
Interactions None reported
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Not recommended for treatment of rectal, cervical, intravaginal, urethral, and intra-anal human papilloma infection; following surgery or drug treatment, do not use topical imiquimod until genital/perianal tissue is healed; local skin erythema, erosion, or abrasion can occur
Drug Name
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Interferon alfa 2b (Intron) -- Interferons have been used in the United States for the treatment of genital warts in various doses and preparations. Topical, intralesional, and systemic therapy have been used. Currently, no convincing evidence suggests that topical or systemic therapy is better than placebo (Eron, 1986; Monsonego, 1996; Welander, 1990; Bornstein, 1997).
Adult Dose 1 million U per lesion administered directly into the wart 3 times per wk for 3 wk; no more than 5 warts should be treated at once
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity
Interactions Theophylline may increase toxicity; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Depression and suicidal ideation may be adverse effects of treatment; flulike symptoms (eg, fever, dizziness, malaise, myalgia, headache) may occur
FOLLOW-UP ˇ@

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MISCELLANEOUS ˇ@

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BIBLIOGRAPHY ˇ@