Of the predominant gynecologic cancers, the incidence of cervical cancer in the United States has significantly declined over the years with the development of effective screening methods. Nevertheless, 12,710 women will be diagnosed with cervical cancer in the United States in 2011, and approximately 4,290 women will die of the disease.
Epidemiology
Age
The peak age of developing cervical cancer is 47 years. Approximately 47% of women with invasive cervical cancer are < 35 years old 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 due to their more advanced stage at diagnosis.
Socioeconomic class
Carcinoma of the uterine cervix primarily affects women from the lower socioeconomic class 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 female cancers. There are 500,000 estimated new cases and 240,000 deaths worldwide from cervical cancer every year. It remains a significant health burden in developing countries where > 80% of women diagnosed with cervical cancer are diagnosed at advanced stages. This is due, in part, to poor access to medical care and the unavailability of routine screening in many of these countries.
Etiology and risk factors
Sexual activity
Invasive cervical carcinoma can be viewed practically as a sexually transmitted disease.
Human papillomavirus
Molecular and epidemiologic evidence clearly indicates that certain types of human papillomavirus (HPV), which is 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, 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. The vaccine is composed of the major capsid protein of HPV which is the product of the L1 HPV gene. 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 virus-like particle vaccines against HPV-16 and HPV-18 has transformed the prospects for reducing the incidence of this disease on a global scale, achieving > 98% protection in randomized clinical trials against precursor lesions such as CIN grade 2/3 and adenocarcinoma in situ. However, screening for cervical cancer will have to continue, as only 2 of the 15 oncogenic HPV types are in the vaccines, and for two to three 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.
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 of developing invasive cervical carcinoma.
Other risk factors
include 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 byproducts or a local effect of tobacco-specific carcinogens. Nicotine(Drug information on 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 of AIDS-related malignancies, see chapter 24.)
Data suggest that patients who are immunocompromised due to 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 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.
