CERVICAL CANCER AND OTHER HPV-RELATED STUDIES

Portland Kaiser Cohort Study of HPV and Cervical Neoplasia

The Portland Kaiser Permanente cohort study of human papillomavirus (HPV) infection and cervical neoplasia was established in 1989-1990 by enrolling almost 24,000 women obtaining routine Pap smear screening at any one of seven Portland Kaiser-Permanente screening clinics. The enrollment phase yielded a prevalent case-control comparison which demonstrated that HPV was the primary risk factor for cervical intraepithelial neoplasia explaining other traditional risk factors, an "atypia" study which showed HPV testing could be used to clarify borderline smears, and a study of determinants of HPV DNA in controls and several ancillary studies on the women with atypia. In the prospective years of the project, we have focused on 3 sub-cohorts: the incidence , recurrence, and progression cohorts. An incident case-control study based on the first five years of follow-up has been published. The full cohort based on up to 10 years of follow-up is underway.

The Guanacaste Study of HPV Natural History

Guanacaste Province is an area in Costa Rica with a very high incidence rate of cervical cancer. This prospective cohort study of HPV infection and cervical neoplasia is based on the recruitment and ongoing 7-year follow-up of a random sample of approximately 10,000 women 18+ years of age, residing in Guanacaste. The study is the companion to the prospective study of HPV and cervical neoplasia in Portland, which is a very low-risk, well-screened, mainly white middle-class U.S. population. Enrollment in 1993-1994 included a personal interview, cervical cytologic smears, Cervicography, cervical swabs for HPV, and a blood specimen. Participation was about 93% and all women with any screening abnormality were referred for colposcopy and biopsy. The prevalent phase of the study permitted several studies of HPV infection, cytology, Cervicography, and the whole spectrum of cervical neoplasia. The epidemiologic risk factors for each stage of neoplasia were identified, controlling for the central role of type-specific HPV infection. Follow-up of the cohort at six month to yearly intervals depending on disease status is now underway, to examine the origins of high-grade cervical intraepithelial neoplasia.

Vaccine Trial

A large randomized trial is planned in Costa Rica to evaluate the efficacy of two virus-like particle (VLP)-based prophylactic human papillomavirus (HPV) vaccines developed at NCI. Volunteers in the trial will be screened for cervical disease at entry and will receive three VLP or three placebo vaccinations over the course of six months. Participants will be actively followed for a period of four years and information will be collected on side effects of the vaccine (safety), immune induction by the vaccine (immunogenicity), and the occurrence of cervical disease (efficacy).

ASCUS/LSIL Triage Study (ALTS)

This project is a study of the clinical management of low-grade cervical cytologic abnormalities. The major hypothesis to be tested is whether HPV testing can reliably triage the common cytologic diagnoses of ASCUS (Atypical squamous cells of undetermined significance) and LSIL (Low-grade squamous intra-epithelial lesions), which represent the bulk of cervical abnormalities seen on Pap smears. Currently, the most aggressive standard of care is immediate colposcopy and biopsy of all suspected lesions. This type of aggressive management is expensive with some associated morbidity, and probably represents over-treatment, since evidence indicates that most cases of ASCUS and LSIL eventually regress. This clinical trial of management alternatives consists of three arms: immediate colposcopic referral of all patients; triage using HPV testing as an adjunct to cytology; and conservative management with repeat Pap smears. All participants are being followed every 6 months for two years. Over 5,000 women were randomized during enrollment that ended in December, 1998.

ALTS Immunology

The ALTS Immunology Study is a prospective study designed to identify biomarkers associated with a permissive versus protective immune response to low-grade cervical lesions. Approximately 900 women with low-grade cervical disease have been enrolled in this study and are being followed at 6 month intervals for two years. Cellular and humoral immunological responses at entry will be correlated with progression, persistence or regression of low-grade lesions during follow-up. Immunological parameters are also being measured over time in a subgroup of approximately 300 women in our study. Both systemic and local responses are being examined.

Cervical Adenocarcinoma Case-Control Study

A multi-center case-control study of cervical adenocarcinomas and other rare histological forms of cervical cancer was conducted to examine the role of viral and non-viral exogenous and endogenous factors associated with cervical adenocarcinomas and adenosquamous carcinomas. Incident and histologically confirmed cases of in situ and invasive cervical tumors of glandular histology were ascertained. Two control groups were also selected for study. The first comprised a sample of women with squamous cell cervical cancer and the second comprised population controls selected by a modified random digit dialing method. A total of 595 women agreed to participate in the study. Participants responded to a detailed risk factor questionnaire and had blood and cervical specimens collected for HPV testing and other bioassays of interest.

Types of Cervical Cancer

The cervix is the narrow opening into the uterus from the vagina. The normal “ectocervix” (the portion of the uterus extending into the vagina) is a healthy pink color and is covered with flat, thin cells called squamous cells. The “endocervix” or cervical canal is made up of another kind of cell called columnar cells. The area where these cells meet is called the “transformation zone” (T-zone) and is the most likely location for abnormal or precancerous cells to develop.

Most cervical cancers (80 to 90 percent) are squamous cell cancers. Adenocarcinoma is the second most common type of cervical cancer, accounting for the remaining 10 to 20 percent of cases. Adenocarcinoma develops from the glands that produce mucus in the endocervix. While less common than squamous cell carcinoma, the incidence of adenocarcinoma is on the rise, particularly in younger women.

Causes of Cervical Cancer

Human Papillomavirus (HPV) is found in about 99% of cervical cancers. There are over 100 different types of HPV, the majority of which are considered Low Risk and do not cause cervical cancer. High Risk HPV types may cause cervical cell abnormalities or cancer. More than 70 percent of cervical cancer cases can be attributed to two types of the virus, HPV-16 and HPV-18, often referred to as High Risk HPV Types.

HPV is estimated to be the most common sexually transmitted infection in the United States. In fact, by age 50 approximately 80% of women have been infected with some type of HPV. The majority of women infected with the HPV virus do NOT develop cervical cancer. For most women the HPV infection is transient and 90% of infections resolve spontaneously within 2 years. A small proportion of women do not clear the HPV virus and are considered to have persistent infection. A woman with a persistent HPV infection is at greater risk of developing cervical cell abnormalities and cancer than a woman whose infection resolves on its own.

Signs and Symptoms of Cervical Cancer

Precancerous cervical cell changes and early cancers of the cervix generally do not cause symptoms. Abnormal or irregular vaginal bleeding, pain during sex, or vaginal discharge may be symptoms of more advanced disease.

Notify your healthcare provider if you experience:
• Abnormal bleeding, such as,
• Bleeding between regular menstrual periods
• Bleeding after sexual intercourse
• Bleeding after douching
• Bleeding after a pelvic exam
• Pelvic pain not related to your menstrual cycle
• Heavy or unusual discharge that may be watery, thick, and possibly have a foul odor
• Increased urinary frequency
• Pain during urination

Detecting Cervical Cancer

The best way to determine if precancerous or cancerous cells are present is with a Pap test. The Pap test can determine if cell changes have taken place that may indicate precancerous or cancerous development. (See Pap Testing for more information). In addition to a Pap test, your doctor may recommend an HPV test. The HPV test does not indicate the presence of precancerous or cancerous cells. It determines whether or not a woman has an HPV infection with any of the 13 high-risk HPV types. The test cannot tell you whether your infection is new or if it is persistent. This information will assist you and your doctor to determine appropriate follow-up and intervals for cervical cancer screening. (See HPV Testing for more information).

Protecting Myself from Cervical Cancer

Cervical cancer is one of the most preventable cancers today. If caught early, the 5-year survival rate is almost 100%. Regular Pap testing is the best method to protect against invasive cervical cancer. It is most important to remember that cervical cancer takes many years to develop. Regular Pap tests will help detect any precancerous or abnormal cells early enough so that cervical cancer can be prevented.

In addition to routine Pap testing, you may want to consider minimizing risk factors that could contribute to cervical cancer. Those factors include:

• Multiple sexual partners
• Multiple full-term pregnancies
• Sexual intercourse at an early age
• Chlamydia infection
• Cigarette smoking
• Use of oral contraceptives
• Weakened immune system or HIV infection