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Cervical Cancer

Cervical Cancer

Overview

The incidence of cervical cancer in the United States has significantly declined over the years as a result of the development of effective screening methods.

Nevertheless, in 2014 it is estimated that cervical cancer will be diagnosed in 12,360 women in the United States, and approximately 4,020 women will die of the disease. Currently, an estimated 249,496 women are living with cervical cancer in the United States.

Epidemiology

Age

The peak age of developing cervical cancer is 47 years. Approximately 47% of women with invasive cervical cancer are younger than 35 years at diagnosis. Older women (> 65 years) account for another 10% of patients with cervical cancer. Although these older patients represent only 10% of all cases, they are more likely to die of the disease because of their more advanced stage at diagnosis.

Socioeconomic Class

Carcinoma of the uterine cervix worldwide affects women from lower socioeconomic classes and those with poor access to routine medical care.

Geography

Although invasive cervical carcinoma is relatively uncommon in the United States compared with the more common cancers in women (breast, endometrial, and ovarian cancers), it is the second most common malignancy in women worldwide, accounting for 15% of all new cancers in females. Worldwide, there are an estimated 500,000 new cases of and 240,000 deaths from cervical cancer every year. It remains a significant health burden in developing countries, where more than 80% of women with cervical cancer receive the diagnosis at advanced stages. This is due, in part, to poor access to medical care and the lack of available routine screening in many of these countries.

Etiology and Risk Factors

Sexual Activity

Human papillomavirus

Molecular and epidemiologic evidence clearly indicates that certain types of human papillomavirus (HPV), which are sexually transmitted, are the principal causes of invasive cervical cancer and cervical intraepithelial neoplasia (CIN). More than 100 HPV types have been identified, and about 40 infect the genital tract. HPV-16 and HPV-18 are the types most commonly linked with cancer and are present in 70% of cervical cancers and high-grade CINs. Two vaccines to prevent cervical cancer were approved by the US Food and Drug Administration (FDA) and became available in 2006 and 2009, respectively.

Gardasil is a quadrivalent vaccine approved by the FDA in 2006 for prophylactic vaccination in girls and women aged 9 to 26 years. The vaccine is composed of the major capsid protein of HPV, which is the product of the L1 gene of HPV. The capsid protein assembles itself into virus-like particles, or VLPs. VLPs lack viral DNA and are therefore unable to induce cancer, but they are able to trigger an antibody response against the HPV types represented in the vaccine. Gardasil contains the recombinant VLPs assembled from the L1 proteins of HPV types 16 and 18, which cause approximately 70% of cervical cancers, as well as types 6 and 11, which cause more than 90% of genital wart cases. Cervarix is a bivalent vaccine also approved by the FDA to prevent cervical dysplasia and cervical cancer caused by HPV types 16 and 18. Prophylactic vaccination with these HPV VLP vaccines against HPV-16 and HPV-18 has transformed the prospects for reducing the incidence of this disease on a global scale, achieving more than 98% protection in randomized clinical trials against precursor lesions such as CIN grade 2/3 and adenocarcinoma in situ. Regrettably, according to a recent report of the National Health Interview Survey (2010 data), only 22.7% of eligible women received one or more doses and only 12.7% received the three required doses. Education, access, and cost were the main deterrents. Screening for cervical cancer will have to continue, because only 2 of the 15 oncogenic HPV types are in the vaccines, and for 2 to 3 decades at least, unvaccinated sexually active women will remain at risk for the disease. If both vaccination and screening are combined, the virtual elimination of cervical cancer and the other HPV-16– and HPV-18–associated cancers is possible. A novel vaccine that covers five additional subtypes of HPV (31, 33, 45, 52, and 58) in addition to the 6, 11, 16, and 18, has completed phase III testing.

Age of onset of sexual activity

Population studies of women with invasive cervical carcinoma have demonstrated that early age of onset of sexual activity also plays a role in the later development of the cancer. It is postulated that during the time of menarche in early reproductive life, the transformation zone of the cervix is more susceptible to oncogenic agents, such as HPV. Women who began sexual activity before 16 years of age or who are sexually active within 1 year of beginning menses are at particularly high risk for developing invasive cervical carcinoma.

Other risk factors

These risk factors include malnutrition (micronutrient deficiency), multiple sexual partners, a history of genital warts, and multiparity.

Cigarette Smoking

Cigarette smoking has been identified as a significant risk factor for cervical carcinoma. It is thought to increase the risk by twofold to fivefold. The mechanism may be related to diminished immune function secondary to a systemic effect of cigarette smoke and its by-products or a local effect of tobacco-specific carcinogens. Nicotine, when inhaled, becomes converted to cotinine, which becomes deposited in the cervix and adversely affects the function of cells of Langerhans, which are primarily involved in cell-mediated immunity.

Oral Contraceptives

Oral contraceptives may also play a role in the development of invasive cervical carcinoma. It can be postulated that most women who use oral contraceptives are more sexually active than women who do not, and this may represent a confounding factor rather than a true independent risk factor. However, estrogen and high parity maintains the transformation zone on the ectocervix, thus increasing exposure to the harsh acidic environment of the vagina and HPV. In addition, oral contraceptives also enhance HPV gene expression in the cervix, which can promote viral DNA integration into the host chromosome.

Immune System Alterations

In recent years, alterations in the immune system have been associated with an increased risk of invasive cervical carcinoma, as exemplified by the fact that patients who are infected with the human immunodeficiency virus (HIV) have increased rates of both preinvasive and invasive cervical carcinomas. These patients also are at risk for other types of carcinoma, including Kaposi sarcoma, lymphomas, and other squamous cell carcinomas of the head and neck and the anogenital region. (For further discussion see the "AIDS-Related Malignancies" chapter.)

Data suggest that patients who are immunocompromised as a result of immunosuppressive medications also are at risk for both preinvasive and invasive cervical carcinomas. This association is probably due to the suppression of the normal immune response to HPV, which makes patients more susceptible to malignant transformation. An exciting recent development in the prevention of carcinoma of the cervix is the increasing use of HPV vaccines; if used on a timely basis in young women (ideally before they are exposed to the HPV virus), they can decrease this infection and eventually the incidence of cervical cancer.

Signs and Symptoms

A symptom of advanced cervical carcinoma is intermenstrual bleeding in a premenopausal patient. Other commonly reported symptoms include heavier menstrual flow, menorrhagia, and/or postcoital bleeding. With effective screening, early cervical cancer is generally asymptomatic.

Less frequently, patients with advanced cancer will present with signs of advanced disease, such as back pain, bowel obstruction, and renal failure due to urinary tract obstruction. Only rarely are asymptomatic patients with a normal screening Pap smear found to have a lesion on the cervix as their only sign or symptom of cervical cancer. Foul-smelling vaginal discharge, pelvic pain, or both are occasionally observed.

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