Human Papillomavirus Infections in Incarcerated Women
The factors associated with the development of lower genital tract neoplasia (cancers) are directly related to lifestyle, poverty, sexual risk taking behaviors, and access to health care. Historically it has been observed that women who have multiple sexual partners or have a partner who has had multiple sexual partners are at highest risk for the development of cervical cancer. Human papillomavirus (HPV) is the most important etiological agent in neoplastic change. In the past two decades, HIV and HPV co-infection has been associated with more rapid development of cervical cancer. Most incarcerated women are at very high risk for cervical cancer due to their lifestyles and to the high rate of HIV co-infection in this population. This paper reviews the present knowledge of this viral infection and the management of HPV infection in incarcerated populations.
Human papillomavirus (HPV) is a sexually transmitted disease. The role of HPV in malignant transformation has become fairly well-established. HPV DNA has been found in over 95% of cervical condyloma accuminata, all premalignant cervical lesions, and invasive cancers. Due to poor access to preventive health care in developing countries of the world and in selected populations in the developed world, cervical cancer remains the leading cause of cancer death worldwide.
An accurate evaluation of the prevalence of human papillomavirus infections is difficult because the infection is not reportable, most infections are subclinical, sensitivity of detection varies with the method used, and regression of infection occurs. However, HPV is thought to be the most common viral sexually transmitted disease. It is estimated that 20 to 40 million persons in the United States are infected with HPV. HPV is very common, as can be demonstrated by studies of mass screening using hybridization techniques on cells collected from cervical smears. Ten to 30 percent of specimens had evidence of HPV infection. The Centers for Disease Control and Prevention (CDC) have observed an increase in the prevalence of HPV infection obtained through surveys of office visits for HPV from 1966 to 1988: a five-fold increase occurred during that period. In some populations, cross sectional studies of cytologically normal women suggest that 20 to 40 percent of sexually active women have detectable HPV infection. That prevalence decreases with age.
HPV is classified by subtype. Some subtypes are more or less likely to be associated with cervical cancer. Genital subtypes can vary by geography and ethnicity. In the United States, HPV 16 has been found to be the most prevalent sub-type. HPV 16 is also the predominant subtype in countries around the world except for Indonesia, where HPV 18 is more common. There is significant geographic variation in the prevalence of some of the less common viral subtypes. A clustering of HPV 45 has been apparent in Western Africa, while HPV 39 and HPV 59 have been almost entirely confined to Central and South America.
Most HPV infections occur in young adults with a peak in the late teens and early twenties. Currently HPV infections have reached epidemic proportions in young, sexually active populations. Of note, the mean age for women who develop cervical dysplasia is 25 years old, while carcinoma-in-situ and invasive cervical cancer has an older mean age of 30 and 50 years respectively. The decreasing prevalence of human papillomaviral infections with age is thought to be related to increasing development of both cell mediated immunity and mucosal IgA immunity.
Human papillomavirus infection is predominantly transmitted by micro trauma to the genital mucosa that occurs as part of normal sexual behavior. Viral particles are introduced in this way in the basement membrane of the skin. Over two-thirds of partners of persons infected with HPV developed condylomata on average two to three months after exposure. Transmission occurs from male to female, female to male, male to male, and female to female. PCR studies suggest all coital contacts are infected with one exposure. The incubation period is long, and can be difficult to accurately assess because of subclinical infections and the effect of host immunity. It is estimated to be anywhere from three weeks to 20 months. While condoms are thought to be slightly protective for cervical infections by HPV, they are not protective against transmission from contact between external genital skin. Human papilloma virus can also be transmitted vertically during childbirth. Juvenile laryngeal papillomatosis is a rare sequellum of vaginal delivery. Other potential modes of transmission have not been well-documented. These include fomites and close, non-sexual contact such as with children. Co-factors for transmission, persistence, and neo-plastic change in HPV infections include tobacco use, oral contraceptives, and possibly concurrent sexually transmitted diseases such as herpes simplex, chlamydia trachomatis, cytomegalovirus, and Epstein-Barr virus.
Pathogenesis and Natural History
While 30 to 50% of sexually active people are infected with human papillomavirus, progression to cancer occurs in less than one percent of women. There are three possible scenarios for an HPV infection. There can be complete clearance of HPV after the acute infection. Alternatively, the infection can stay or become latent. And finally, there can be active progression of the infection. Observations supporting the transient nature of some infections include the increase of host immunity with age, and the anatomical changes in the normal maturation of the cervix. In the teenage and young adult group, the glandular endocervical lining is present on the exocervix (called cervical ectropion). As the cervix matures over a woman's reproductive life, the cervical ectropion is replaced through a process of squamous metaplasia to stratified squamous epithelium. The stratified squamous epithelium is thought to be more protective in general against sexually transmitted diseases. Hormonal environment may also play a role in the patient's susceptibility to HPV. Mucosal immunity occurs through the common mucosal immune system with production of IgA over time. This is a slow delayed response that does not immediately occur with initial exposure to HPV. Risk factors for persistent HPV infection and neo-plastic change include aneuploid dysplastic lesions, oncogenic HPV subtypes, immunosuppression, and certain HLA alleles.
Clinical Manifestations of HPV Infection
A vulvar condyloma can show a wide range of appearances. Small raised crusted lesions can appear on the vulvar or perianal region. Bigger condyloma can appear confluent, rising above the skin level. In immunocomprised patients, the condyloma can extend up onto the mons and back to the buttocks. Small papular changes on the skin can sometimes be attributed to HPV infection. These visual changes can either be completely asymptomatic or can be associated with vulvar pruritis and burning. Exophytic condyloma can also occur in a multifocal pattern in the vagina. Condyloma can also occur on the cervix. The majority of cervical condyloma are flat although raised leukoplakic lesions can be seen.
Intraepithelial neoplasia of the lower genital tract can be categorized by site. Vulvar intraepithelial neoplasm (VIN) appears as a discrete pigment change on the vulvar skin. This pigment change can be white, gray, black or red. Most commonly it is gray to black. The lesion may or may not be raised but always has a sharp border to it. VIN is commonly multifocal and frequently involves the perianal region as well. These lesions can be completely asymptomatic or can be associated with burning or itching.
Vaginal intraepithelial neoplasia (VAIN) is an asymptomatic mucosal change that can occur anywhere in the vagina. It is seen by colposcopic viewing as discrete, sharp bordered regions of white epithelium that may or may not be associated with atypical vascular changes. Cervical intraepithelial neoplasia (CIN) is also asymptomatic. This can appear as unifocal or multifocal white, discrete lesions seen by colposcopy. These lesions can be associated with atypical blood vessels such as a mosaic (cobblestone) or punctate vascular pattern. All intraepithelial neoplasia can be divided into low-grade or high-grade lesions. Low-grade lesions are usually histopathologically associated with cytopathic changes of HPV. High-grade lesions include moderate to severely dysplastic changes.
Invasive cancers of the lower genital tract, which include anal, vulvar, vaginal, and cervical cancers, have all been associated with human papillomavirus infections. Perianal cancers are highly associated with immunosuppression such as that observed in progressive HIV infection. Invasive vulvar cancers have a bimodal age distribution. In the younger age group, mean age 40 years, vulvar cancer is highly associated with HPV infection. These lesions are usually multifocal and can be associated with immunosuppression from HIV. The second age group (mean of 70 years), have unifocal vulvar cancers that are not HPV related. Vulvar and perianal cancers can appear as a raised or ulcerated lesion on the surface of the skin. Very small cancers may be asymptomatic. However with time, these cancers become painful and can bleed.
Vaginal cancers comprise one percent of all female genital malignancies. They are associated with HPV infection. The most common site of vaginal cancer is the posterior upper third of the vagina. Frequently these cancers are missed when they are small as they can be hidden by the speculum blades. Early cancers are asymptomatic. As the cancer grows, the major symptoms become bleeding and pain. On physical examination, these cancers will appear as discrete, raised, or ulcerated lesions that are hard on palpation.
Cervical cancer is highly associated with HPV infection. Asymptomatic cancers are picked up by Pap smear screening. On inspection, a cervical cancer can appear exophytic with a polypoid, raised growth on the exocervix, or endophytic, with expansion of the cancer in the endocervical canal. Early symptoms include post-coital spotting, abnormal vaginal bleeding, and an abnormal discharge. Late symptoms that herald metastatic spread include bladder outlet obstruction, constipation, back pain, and leg swelling.
Diagnosis of HPV infection and its clinical manifestations can be made by clinical examination, HPV DNA detection methods, cytology, and/or colposcopy with biopsy. Most basic and clinical investigations use one or more of three nucleic acid-based tests to detect and type HPV. These tests include hybrid capture system (HCS), in situ hybridization (ISH), and polymerase chain reaction (PCR). Presently hybrid capture II assay is used commercially for clinical HPV testing.
The Role of HPV Testing
The role of HPV testing has been intensively evaluated. It has been looked at as an adjunct to cervical cancer screening and as a triage tool for low-grade and atypical Pap smears for colposcopic referrals. Three recent studies have evaluated the utility of HPV testing. A longitudinal cohort of 2,011 women aged 15-19 was recruited by Woodman et al. Testing and cytology was performed every six months for three years. The cumulative risk of any HPV infection was 44% however most infections were of short duration. Twenty-eight of the 2,011 developed high-grade dysplasia. They concluded that the inevitability of acquiring an HPV infection and the transient nature of the infection made HPV testing for cervical cancer risk assessment inadequate.
A second study by Moscicki et al. prospectively screened 105 women who were HPV negative at baseline for a median of 50 months. Nineteen percent developed low-grade dysplasia and no women developed high-grade dysplasia. They concluded that the majority of young women with HPV infection never develop low-grade dysplasia.
Solomon et al. reported their preliminary finding from the ASCUS/LSIL Triage Study (ALTS) trial. They looked at 3,488 women with atypical squamous cells of uncertain significance (ASCUS) who were randomized to immediate colposcopy, HPV triage, or repeat Pap smear. They found that the prevalence of high-grade lesions was 5.1%. However, 56.1% of the women with ASCUS were positive for high risk HPV types. While they concluded that HPV testing has a greater sensitivity to detect a high-grade lesion compared with repeat Pap smear alone, there was a significantly increased number of women referred to colposcopy.
In conclusion, as most HPV infections are transient and are not associated with neo-plastic change, isolated HPV testing does not accurately identify those women destined to develop malignancy. At the present time, HPV DNA testing cannot be recommended for routine clinical use.
Treatment and Management
The goal of treatment is to destroy visible lesions for cosmetic reasons, reduction of symptoms, or treatment of preinvasive and invasive lesions. No treatment modality will eradicate the virus. For benign condyloma and preinvasive disease, local destruction with podophyllin, trichloroacetic acid, laser, or excision can be used. For invasive disease, either a radical surgical excision or radiation therapy is used.
Because HIV infected and immunocompromised patients have an increased incidence of persistence and progression to neoplastic change, they need to be monitored more closely over time. For routine screening, at least yearly Pap smears and visual inspection of the external genitalia should be performed. For a number of reasons, including poor follow-up care after release from prison, the current standard of practice for incarcerated HIV-infected women is to perform Pap smears every six months. Most institutions have colposcopy available on site. Some authors recommend a baseline colposcopy for all HIV infected women with the presence of HPV infection. There appears to be a reduction of accuracy of Pap smears in this group secondary to obscuring inflammation from cervicitis. Colposcopy should be done on all women with abnormal Pap smears including atypia and low-grade dysplasia. All dysplasias should be treated aggressively.
Human papillomavirus is a necessary but not sufficient factor for the development of lower genital tract neoplasia. Most HPV infections are with the high risk oncogenic subtype yet less than one percent of women with this infection will experience a malignant progression. Risk factors for progression to malignancy include immunosuppression and persistent HPV infection. Careful screening with good physical examination and Pap smear testing can detect most of preinvasive and invasive lower genital tract disease.
* Nothing to disclose.
This article was provided by Brown Medical School. It is a part of the publication HEPP News.