Human papillomavirus infection-Condyloma

Human papillomavirus DNA is present in practically every squamous malignancy of the female genital tract. This article reviews the pathophysiology of HPV, clinical findings, diagnostic techniques, treatment options, and management during pregnancy

Genital warts have been recognized for centuries, but their

Condyloma in Perineum
Condyloma in Perineum

infectious nature was not described until 1894. A virus was implicated as an etiologic agent in 1907, but the human papillomavirus (HPV) particle was not seen with electron microscopy until 1949. To this day, there has been no convincing demonstration of a method for culturing HPV in tissue.

The spectrum of disease includes clinical (genital warts) and subclinical HPV infection of the cervix, vagina, vulva, perineal body, and anus; an association of HPV with intraepithelial neoplasia of the vulva, vagina, cervix, and penis; and juvenile laryngeal papillomatosis. More recently, it has been demonstrated that HPV DNA is present in practically every squamous malignancy of the female and male genital tracts. Because of this association with malignant disease, the diagnosis and therapy of HPV infection has taken on greater significance.
Over the past decade, a case load increase of more than 1,000% has been noted in sexually transmitted disease clinics and private office consultations. HPV infection is associated with other STDs and its prevalence correlates with sexual activity. Peak occurrence is between ages 15 and 35. Between 50% and 70% of sexual partners of women with HPV have or will develop genital warts.
HPV produces an overt infection in 30% of cases and subclinical infection in 70%. The virus can also exist in a latent state. During this period it can be identified only by recombinant DNA technology.
In studies using cervical cytology to estimate the prevalence of genital HPV infection, 2% to 3% of unselected Pap smears were positive. When HPV DNA sequencing was applied to these Pap smears, an additional 20% were found to be positive for HPV infection.
This virus can occupy multiple sites in the female genital tract. If the cervix is infected, 77% of women infected will have vaginal lesions. Similarly, 36% of women who have vulvar infection will also have an infected cervix. These facts suggest that HPV satisfies the criteria for an infectious etiology as a multicentric source of carcinoma of the vulva and vagina. Although most investigators do not believe HPV is the primary etiologic agent of genital squamous tract malignancies, most believe it is a strong co-carcinogen. Finding HPV in any area of the genital tract suggests the virus will be present in the remainder of the genital tract.
Pathophysiology
It has been suggested that microtrauma allows the virus to enter the skin or mucosa of the genital tract. The virus enters the cells at the basal layer and matures as it passes through the parabasal, spinous, and granular layers of the epithelium. At the granular cell level, viral DNA replication, late protein synthesis, and viral particle assembly are carried out. Integration of the viral DNA into the host genome does not occur until the cervical intraepithelial neoplasia III/carcinoma in situ stage of development.
HPV DNA has been found in as many as 90% of cervical cancers examined; the remaining 10% may represent HPV DNA types not yet characterized. HPV DNA type 16 (in 50% of cancers), HPV 18 (in 14%), HPV 45 (in 8%), and HPV 31 (in 5%) are the most prevalent types worldwide. Thus far, 16 genital HPV types have been detected in cervical cancer, including HPV 6, 11, 26, 33, 35, 51, 52, 55, 56, 58, 64, and 68, in addition to the four just named. These types belong to a group of viruses prevailing in high-grade squamous intraepithelial lesions of the cervix. HPV 18 appears to be the predominant type in adenocarcinomas and adenosquamous tumors, which account for approximately 5% of cervical tumors.
There is still no general agreement on the prognostic meaning of HPV type in carcinomas of the cervix. HPV types 16 and 18 have been implicated as risk factors influencing the frequency of nodal metastases and relapse, but other reports have failed to show any correlation between HPV type and prognosis.
Clinical findings
Overt condyloma acuminatum may be seen in the perianal area, perineal body, vulva, vagina, or cervix; subclinical HPV infection may also be seen in each of these areas.
Vulvar condyloma appear as pinkish, whitish, or pigmented sessile tumors with lobulated or pointed finger-like projections on their surfaces. These are found most commonly in the vulvar area and less commonly in the vagina and the cervix. HPV infection may be missed during routine examination when it manifests as a flat lesion with minimal elevation or as a pink papular plaque with a smooth surface.
Subclinical HPV infection is more common than overt infection. The most common lesion is the elongated vaginal papilla with clustered epithelial projections in a central capillary. Aceto-white epithelium is another common manifestation. It may be detected by a colposcopic examination of the vulva after application of 5% acetic acid, which causes the individual cells to swell, giving a white color to wart or neoplastic epithelium. The lesions are usually multifocal and are more common in the upper third of the vagina.
HPV may be detected more frequently if attention is given to the vagina. Vaginal condylomas can be found in as many as one third of patients who have vulvar condylomas. In general, condylomas in the upper third of the vagina are considered high risk, as the HPV DNA types found here tend to be those associated with malignant potential (types 16, 18, and 31). Condylomas in the lower third of the vagina tend to be low risk and of HPV DNA type 6 or 11. Usually condyloma in the vagina are multiple and appear as white elevations. Frequently, a vaginal discharge accompanies the infection. Presence of HPV should be investigated in patients with recurrent episodes of bacterial vaginosis or Candida albicans infection, since mild immunosuppression allows both HPV and C albicans to flourish.
condyloma acuminatum of the cervix was a rare lesion in the past but is now being seen with increased frequency. Subclinical papillomavirus infection is generally accepted as the most common manifestation of HPV disease in the cervix.
Diagnosis
The main techniques for detecting HPV infection are listed below:
·         Physical examination
·         Cytology
·         Colposcopy
·         Histologic studis
·         HPV antigen detection studies
·         HPV DNA molecular hybridization
Physical examination of the genital tract is simple and noninvasive, but used alone this method detects only 10% of HPV infections. Other diagnoses that may be confused with genital warts are fibroepithelial polyps, introital papillosis, molluscum contagiosum, melanocytic nevi, condyloma latum, and vulvar intraepithelial neoplasia (VIN). On occasion, even normal anatomy may be mistaken for condyloma.
Cytologic studies are a relatively inexpensive approach to diagnosing HPV infection. Findings include koilocytosis, dyskaryosis, atypical parabasal cells, and multinucleation. However, HPV is underdiagnosed in routine cytologic examinations. Colposcopic examination after soaking with 5% acetic acid allows detection of 70% of subclinical papillomavirus infections. The colposcope is also helpful in selecting areas to be biopsied.
The histologic findings of genital warts are basal cell hyperplasia, papillomatosis, koilocytosis, and parakeratosis. Koilocytosis is the most commonly used marker for HPV infection. However, the specific koilocytotic atypia seen in lesions is caused by high-grade HPV DNA types such as 16 and 18, especially in advanced grades of CIN.
Antigens to HPV can be detected in cytologic and histologic specimens by using immunostaining techniques with antiserum from rabbits immunized to bovine papillomavirus. The cells carrying the virus are well differentiated. As dysplasia progresses, it is increasingly difficult to detect HPV antigen; at the CIN III/CIS stage, it is not detectable.
Cloning techniques have now given us the ability to obtain typing of HPV DNA. HPV DNA types 6 and 11 are thought to be of low malignant potential and generally are found in the vulva and lower third of the vagina. HPV DNA types 16, 18, 31, and other high-number types are found in the upper third of the vagina and the cervix and are more frequently associated with malignant conditions.
However, in questionable situations, HPV DNA typing can be useful.
These include lesions that might be confused with those of HPV, as well as cases involving koilocytosis with atypia in patients who desire to know their HPV type.
Treatment
HPV must be regarded as having the potential for infecting the entire genital tract, since only very early disease tends to be localized. The object of therapy is to remove all overt and subclinical HPV infections detected during the diagnostic evaluation.
Treatment options are listed below:
Treatments for HPV
·         Keratolytic agents
o       Podophyllin resin
o       Trichloroacetic acid [TCA]
·         5 fluorouracil [5-FU]
·         Cryotherapy
·         Laser Therapy
·         Electrocautery
·         Surgical Ablation
·         Immunotherapy
o       Injectable Interferons
o       Imiquimod cream
·         Dinitrochlorobenzene [DNCB]
When a patient presents with a small amount of localized disease, a simple approach is best. When disease is more extensive, more intensive therapy may be needed.
Podophyllin resin is one keratolytic agent that has been widely used. It acts by poisoning the mitotic spindle of the virus. The resin is applied directly to the surface of the wart and washed off after 6 hours; it is then reapplied on a weekly basis.
Podophyllin resin varies from lot to lot, and its side effects are unpredictable. It is contraindicated during pregnancy because of the possibility of teratogenesis and even carcinogenesis. Its use should be severely limited when applied to mucosal surfaces. This treatment may be for appropriate for patients with minimal vulvar or perianal lesions.
Trichloroacetic acid (TCA), another keratolytic agent, acts by precipitating surface proteins. It should be used at a strength of 85% and applied directly to the vulvar, anal, or vaginal lesions with a small cotton-tipped applicator. It produces a white slough that peels in several days, leaving a small ulcer. Application of 85% TCA can be repeated every 2 to 3 weeks. Again, recurrences are frequent.
5-fluorouracil (5-FU) is a pyrimidine antimetabolite that causes sloughing of growing tissue. At 5% concentration, 5-FU is useful in the treatment of multiple, small, nonkeratinized vaginal lesions; it may also be used for lesions of the vulva. It is more effective for small HPV lesions involving the vestibule and inside labia minora. It is usually applied once a week into the vagina and/or the vestibule of the vulva, for 12 weeks. It is important to instruct the patient in use of 5-FU and to obtain informed consent.
Cryotherapy for HPV disease may be applied either as a single cycle or as repetitive 2-minute freeze-and-thaw cycles to destroy infected wart tissue. It may be performed either by probe or by application of liquid nitrogen. Patients frequently require more than one application to clear the overt or subclinical papillomavirus infection. In comparative studies, cryotherapy has been more effective than podophyllin and as effective as electrical cautery or laser therapy. Treatment of the vulvar area should be preceded by application of a local anesthetic agent.
The use of laser therapy is widespread and has the theoretic advantage of precise control of depth, margins, and hemostasis. However, laser ablation has the disadvantages of requiring operator control and expertise and of being able to treat only visible disease. The vulva and vestibule are the most convenient areas for laser therapy. Laser therapy of the vagina is complicated by difficulty in application and by scarring.
The use of 5-FU immediately following laser therapy in the vagina or vulva has been advocated, but success and morbidity rates need to be confirmed.
The use of electrocautery to destroy small volumes of condyloma acuminatum has been found to be partly effective. This method is particularly convenient for office use.
Surgical ablation has also been widely used to treat condyloma; however, it offers less precision than laser therapy and has the disadvantage of increasing scarring in the vulvar area.
Vaccine therapy has been attempted by a number of investigators and has been found to be no better than placebo in controlled trials.
Interferons, a family of proteins with antiviral, antiprolific, and immunomodulatory properties, are also being used to treat HPV infection. Three preparations are currently available: *-interferon II-A, *-interferon II-B, and *-interferon N-1. These may be given by intramuscular injection at a dosage of 2.5 to 3 million U three times a week for a minimum of 8 weeks, or 3 million U/m2 to a maximum of 4.5 million U three times a week for at least 8 weeks. The duration of this therapy can be extended 2 to 4 weeks if a partial response is noted.
A second route of interferon therapy is intralesional injection at a dosage of 250,000 to 1 million U for each wart, up to five warts at one time, three times a week for 3 weeks. However, since this mode of therapy is regional, duration may need to be extended beyond 3 weeks. Because the doses are somewhat lower for the *-interferon N-1 preparation, prescribing information should be reviewed.
Side effects are dose related and almost absent at the 3-million-U three-times-a-week level. The most frequent side effect of interferon is transient fever for 8 to 12 hours following injection. Other side effects are fatigue, myalgia, and headache; there may be a transient decrease in the white blood cell (WBC) count and elevation of liver function tests in fewer than 10% of individuals.
Interferons may be used for either small or large volumes of HPV disease. They are effective for intravaginal as well as vulvar warts. Recent unpublished data suggest that superior results are obtained by using interferon as initial therapy followed by cryotherapy, laser therapy, or 5-FU. It has also been suggested that this approach permits use of a lower dosage (1 million U) of interferon.
A newer product, imiquimod, is an interferon and cytokine inducer. It is available as a cream that is rubbed into external genital warts three times per week. The complete clearance rate in females is 72%, as reported in the initial marketing literature.
Still another chemotherapeutic option is dinitrochlorobenzene (DNCB) therapy.
Treatment during pregnancy
Overt condylomas typically enlarge during pregnancy. This growth is probably the result of high progesterone levels in the mother. The lesions may become large enough to cause hemorrhage. Podophyllin therapy is contraindicated because of its toxicity and risk of teratogenesis. Agents such as bleomycin and 5-FU are also contraindicated because of their antimitotic and cytotoxic actions. TCA solution may be useful, however. Cryotherapy and the CO2 laser have also been helpful in reducing the number and volume of warts. Imiquimod has a category B rating, but no clinical data on its use during pregnancy are available. In almost every case, HPV disease will diminish after delivery.
Extensive condylomas may develop during pregnancy. If multiple lesions are present in and on the genitalia, cesarean section may be necessary to prevent transmission of HPV infection to the infant. A strong association between clinical maternal genital condylomas and the subsequent development of laryngeal papillomatosis in infants delivered vaginally has been documented epidemiologically and corroborated by detection of HPV DNA sequences in both genital and laryngeal papilloma tissues. In one study, 78% of children with laryngeal papilloma had mothers with genital condylomas.
Possible modes of transmission include contact between the fetus and the mother's infected genital tract during delivery, transplacental transmission of maternal infection, and postnatal contact. However, despite the high prevalence of genital HPV infection, juvenile laryngeal papillomatosis is a rare disease, implying that transmission of maternal infection is uncommon. Because the method of transmission is not known and the risk is ill defined, there is currently no consensus on whether or not C/S delivery offers a protective benefit for the neonate.
Treatment of choice
For localized warts, TCA offers the best combination of effectiveness, low morbidity, and expense. When the labia and vulva are involved, the use of TCA or 5-FU is recommended. For extensive vulvar disease, laser therapy is best used for the labia, perineal body, or perianal areas. Alternatively, intralesional and/or intramuscular interferon, either alone or in combination with laser therapy or 5-FU, may offer the best hope of controlling the virus.

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