Condyloma Acuminatum

INTRODUCTION

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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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• In the US: Frequency of HPV infection in the population is difficult to estimate accurately. Studies reporting the diagnosis of HPV by visual inspection of genital condyloma report the lowest prevalence rates. Not surprising, the highest prevalence rates are reported by studies typing HPV from exfoliated genital tract cells. Regardless of the conflicting prevalence figures, HPV is a major sexually transmitted disease (Koutsky, 1988; Nuovo, 1994).

  Condyloma acuminata are clinically apparent in 1% of the sexually active population. Molecular studies indicate 10-20% of men and women aged 15-49 years have been exposed to HPV. Prevalence of HPV is higher in certain populations. Data from sexually transmitted disease clinics indicate a prevalence rate of 4-13%.

  Based on clinical observations, incidence of HPV infection clearly has increased in the last 35 years. Data from the National Disease and Therapeutic Index, which is a random survey of private physicians, indicate that, 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. Genital HPV infection now is the most common sexually transmitted disease (Bosch, 1995).

  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. First, the lesions can become large enough to obstruct labor. Secondly, with an abdominal delivery, the virus can be transmitted to the infant, resulting in laryngeal papillomas (Peng, 1990; Rando, 1989; Schneider, 1987; Shah, 1986).

• Internationally: Outside of the United States, HPV infections are common (Syrjanen, 1990). A study in Finland in the mid-1980s demonstrated an annual incidence of cytologic cervical HPV infection of 7% (Kjaer, 2000). A study of Finnish males found 6.5% had evidence of HPV in exfoliative cells obtained from the urethra and genital epithelium (Hippelainen, 1993).

Mortality/Morbidity: Condyloma acuminatum often is 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. Vaginal dysplasia also is associated with exposure to HPV.

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).

• A cytologic screening of the cervix in over 400,000 women supports the 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 as it is in women older than 30 years (Meisels, 1992).

• 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 (Evander, 1995).

• 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 usually is 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 (Davis, 1989). Unfortunately, most 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 would include excision under general anesthesia or the use of podophyllin (Shelton, 1986).

CLINICAL

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History:

• Most patients seek medical care when they notice “lumps?on the vulva, perianal area, or periclitoral area.

• These lesions generally are not painful, but they can be associated with pruritus.

• Bleeding can be observed if the lesions become confluent and are irritated by clothing.

Physical:

• Inspection of the female genital area requires good lighting.

• On gross inspection, typical condyloma usually is a discrete papillary growth that may arise from a single stalk.

• Condyloma acuminata can involve a large area in a sessile fashion.

• Subclinical infection is another common presentation of condyloma. Tiny, slightly raised areas can be felt or visualized on the vagina or cervix.

• These flat warts are best visualized using 3-5% acetic acid and a colposcope. Areas infected with HPV appear acetowhite.

• Often, a biopsy is needed to distinguish these lesions from cervical squamous intraepithelial lesions or vaginal intraepithelial lesions.

• The sexual partner(s) of a woman with condyloma should be examined by a physician and treated if indicated. Often the examination of the male fails to reveal any visible condyloma.

Causes: 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.

WORKUP

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Lab Studies:
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• Patients who present with condyloma acuminata do not necessarily need other laboratory studies; however, patients who are diagnosed with condyloma are at an increased risk for other sexually transmitted diseases.

• Consider testing for chlamydia, gonorrhea, syphilis, hepatitis B, hepatitis C, and HIV depending on the clinical situation.

• These patients need a Papanicolaou (Pap) test of the cervix if a Pap test has not been performed in the last 12 months.

• The need to determine the HPV type is controversial (Kaufman, 1999).

• HPV typing has been proposed to supplement Pap test screening (Cuzick, 2000).

• This typing can be used as a secondary triage of patients with atypical squamous cells of undetermined significance (ASCUS) on Pap tests (Cox, 1996).

• Other clinicians have proposed to use HPV typing in primary screening as an adjunct to Pap tests (Goodman 2000).

• In both of these scenarios, HPV typing can detect low-risk and high-risk HPV types found in the cervix.

• Histologic examination of the vulvar lesions to detect vulvar condyloma sometimes is difficult.

• Non-HPV conditions, such as vestibular papillomatosis and inflammatory squamous metaplasia, may be difficult to distinguish from condyloma with light microscopy.

• The pathologist may issue a pathology report suggesting the microscopic features of a vulvar biopsy are changes suggestive but not diagnostic of HPV.

• When the histologic diagnosis of condyloma is questionable, HPV testing may be useful.

• A wide variety of methods to detect HPV have been used since 1983.

• Currently, the 2 most accurate methods use 2 consensus primer polymerase chain reaction (PCR) systems. The commercially available system is the Hybrid Capture system with differential testing for 9 high-risk HPV types and 5 low-risk HPV types.

• Testing for HPV confirmation of equivocal vulvar histology results provides an objective method for confirming a diagnosis of condyloma.

Imaging Studies:
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• No imaging studies are indicated.

Procedures:
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• Patients who present with typical appearing condyloma acuminata do not need a vulvar biopsy.

• If clinical doubt about the diagnosis exists, perform a biopsy.

• The base of the lesion is injected with 1% lidocaine.

• A biopsy can be performed easily with an alligator mouth biopsy forceps.

• Silver nitrate applied to the base of the biopsy site controls any bleeding.

• Rarely, a suture is required to obtain hemostasis.

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.

TREATMENT

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

• The treatment strategy is to eliminate as many of the visible lesions as possible until the host immune system can control viral replication.

• Because most HPV infections spontaneously regress when the immune system controls viral replication, the need to treat subclinical or mild disease is controversial.

• Treatment usually is reserved for patients with visible vulvar condyloma.

• The type of treatment is influenced by previous therapies, sexual behavior, immune status, and the patient's willingness to comply with therapy.

• Patients who are HIV positive or immunosuppressed due to immunosuppressive drugs usually require more than one treatment method. Often, the condyloma in these patients is refractory to therapy.

• Regardless of the mode of therapy chosen, recurrence rates are high for any patient with condyloma acuminata. This can result in a high level of frustration for the patient and the physician.

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• For most patients, medical therapy should be the first option. These different medical treatment modalities can by performed in the physician's office or at home. Morbidity is low. Surgery should be reserved to treat condyloma resistant to medical therapy. Most patients should not need surgical therapy unless the condylomatous lesions are too large to treat medically or if the lesions would interfere with an abdominal delivery.

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.

• Simple excision

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  • Simple excision usually is performed in an outpatient surgical suite.

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  • After general or regional anesthesia is administered, the individual lesions are removed with a knife.

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  • This procedure is reserved for refractory cases or extensive disease.

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  • Reports in the literature indicate that within one year of surgery, complete wart clearance occurs in 35-72% of individuals treated with surgical excision. One report found surgical excision as effective as laser surgery (Duus, 1985).

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• Patients with a few small lesions can have vulvar condyloma removed in the office. The underlying skin should be anesthetized with 1% Xylocaine and the condyloma removed with a #15 knife blade. One or 2 sutures may be needed to reapproximate the healthy skin.

• Carbon-dioxide laser therapy (Duus, 1985; Reid, 1992)

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  • Laser treatment of vulvar condyloma acuminata effectively destroys the condyloma while sparing adjacent healthy tissue.

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  • This procedure is performed in outpatient surgery with general or regional anesthesia.

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  • The amount of energy needed to remove a condylomatous lesion with the laser will depend on parameters controlled by the surgeon. These parameters include the setting of the machine in watts, the length of time the beam is fired, and the spot size on the tissue. Some researchers calculate the power density, which equals the power (watts)/area (cm²). No exact power density is needed to remove vulvar or vaginal condyloma. The surgeon needs to be flexible in the application of the laser for each patient. If the laser is calibrated to 20 watts, continuous mode, the spot size can be adjusted easily to provide the proper power density (Lopow, 1986).

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  • Most patients experience significant discomfort beginning 24 hours after surgery and require narcotic analgesia.

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  • Laser therapy should be reserved for recalcitrant cases of condyloma or extensive disease.

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  • Complete wart clearance after laser surgery has been reported to occur in 23-52% of patients within 3 years of surgery.

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  • The recurrence rates are similar to surgical excision.

• Electrosurgery (Simmons, 1981)

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  • For isolated lesions unresponsive to topical therapy, electrosurgical techniques can be performed in the office with local anesthesia.

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  • The most popular method is to use a loop electrode that removes the lesion(s).

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  • Pain after surgery is common and can be treated with narcotic analgesics. Topical analgesics, such as lidocaine jelly, can be beneficial to some patients.

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  • A recurrence rate in one trial was 22% compared to 44% for podophyllin resin.

• Cryotherapy (Godley, 1987)

• Cryotherapy should be limited to small lesions that can be treated with small cryoprobes.

• Data from several clinical trials report a 63-88% clearance 3 months after therapy.

• The recurrence rate of 22% is similar to electrosurgery.

• This therapy is safe to use in pregnancy.

• The primary drawbacks are discomfort, ulceration, or scabbing at the treatment site.

Activity:

• The patient should refrain from sexual contact after any surgical procedure for condyloma acuminata.

• Soaking the genital area in warm water or sitz baths usually offers excellent pain relief.

• The genital area should be dried gently with a towel or a hair dryer.

• Loose fitting cotton underwear is helpful to avoid chafing.

• No other activity restrictions exist, although patients often have trouble sitting for long periods of time in the first week after surgery.

• Patients who have condyloma removed from the periurethral area may experience dysuria. Sitz baths and topical analgesics are beneficial.

MEDICATION

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

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

FOLLOW-UP

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Further Outpatient Care:
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• Patients who complete therapy for condyloma acuminata should have a clinical examination 3 months and 6 months after treatment.

• Most patients who develop recurrent or persistent disease are diagnosed within 6 months of therapy.

• If the patient appears disease free at the 6-month visit, yearly visits are recommended.

• The sexual partner(s) of a woman with condyloma should be examined by a physician and treated if indicated. Often the examination of the male fails to reveal any visible condyloma.

Deterrence/Prevention:
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• Because genital warts are sexually transmitted, the risk of acquiring HPV primarily is dependent on several factors related to sexual activity.

• These factors include the number of sexual partners, frequency of sexual intercourse, and the presence of genital warts on the sexual partners.

• Latex condoms offer some, but not complete, protection in the transmission of HPV.

• Women should avoid skin-to-skin contact with partners if genital warts are visible.

Complications:
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• The major complication from exposure of the vulva, vagina, or cervix to HPV is the development of dysplasia.

• Patients who develop condyloma acuminata usually have been exposed to low-risk HPV types such as HPV-6 and HPV-11. These HPV infections are associated with mild dysplasia that often is transient in nature.

• Many patients with mild dysplasia of the vulva, vagina, or cervix experience spontaneous regression of these lesions.

• Patients who are exposed to high-risk HPV types, such as HPV-16 or HPV-18, are at risk for developing high-grade dysplasias or carcinomas. The development of cancer occurs in a small percentage of these patients who do not have therapy for dysplasia.

Prognosis:
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• The prognosis of immunocompetent women diagnosed with condyloma acuminata is excellent.

• HPV infections are transient in the vast majority of these women.

• Unless the woman constantly is exposed to different HPV types, the infection eventually abates when the host immune system stops viral replication.

• Women who are immunocompromised due to immunosuppressive drugs or HIV infection are at higher risk of developing persistent disease. These women have a higher incidence of developing dysplasia of the vulva, vagina, or cervix.

Patient Education:
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• Inform patients that genital HPV is a sexually transmitted disease.

• The only way to prevent HPV infection is to avoid direct contact with the virus, which is transmitted by skin-to-skin contact.

• If the sexual partner has visible genital warts, sexual contact should be avoided until treatment is completed.

• Latex condoms offer some, but not complete, protection from transmission.

• Condoms should be used with vaginal, anal, or oral sex, because the virus may be found in the semen in the absence of visible warts.

MISCELLANEOUS

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Medical/Legal Pitfalls:
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• Patients who appear to have classic condyloma acuminata and do not respond to therapy should have a biopsy of one of the lesions. This will avoid continued treatment of lesions that are not HPV-related.

• Postmenopausal women who present with condyloma-appearing lesions should have a biopsy before initiation of therapy. These women have a greater chance of having vulvar dysplasia or vulvar cancer than younger women.

Special Concerns:
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• Many investigators report higher rates of HPV infections in pregnant women. If condyloma develops, rapid growth can be observed. Factors responsible include suppression of immunity during pregnancy and hormonal changes (Meisels, 1992).

• Small asymptomatic lesions do not need to be treated. Larger lesions can be treated with bitrichloroacetic acid or cryotherapy (Bergman, 1984). Occasionally, condyloma in pregnant women becomes large and macerated, requiring surgical excision after the first trimester. Interferon, podophyllin, and 5-fluorouracil should not be used in pregnancy.

• Pregnant women with genital warts can transmit the virus to the newborn.

• Infants can develop laryngeal papillomatosis in the first 5 years of life.

• The method of transmission is unknown.

• Approximately 60% of mothers with infants with laryngeal papillomatosis report having genital warts.

• Based on the frequency of HPV infection in this country, approximately 5% of all births are at risk for neonatal HPV exposure.

• The frequency of childhood laryngeal papillomatosis is extremely low, approximately 2000 cases per year in the United States. This would imply the transmission rate from mother to infant is low and does not warrant recommending a cesarean delivery for prevention of laryngeal papillomatosis. If the mother has huge condyloma that interferes with labor or delivery, a cesarean delivery may be needed.