Cervical Cancer 

Cervical cancer is the second most common malignancy in women worldwide, and it remains a leading cause of cancer-related death for women in developing countries. In the United States, cervical cancer is relatively uncommon. (See Epidemiology.)

The incidence of invasive cervical cancer has declined steadily in the United States over the past few decades; however, it continues to rise in many developing countries. The change in the epidemiological trend in the United States has been attributed to mass screening with Papanicolaou tests. Furthermore, cervical cancer is a preventable disease, primarily with newly approved human papillomavirus (HPV) vaccines and secondarily through treatment of preinvasive disease.

Papanicolaou test screening is recommended in women who meet screening criteria, regardless of symptoms. However, symptoms, abnormal Papanicolaou test results, or women with a gross lesion of the cervix are best evaluated with colposcopy and biopsy. For further recommendations concerning cervical cancer screening, evaluation and management of abnormal Papanicolaou test results, and treatment of cervicalintraepithelial neoplasia (CIN) grade 1, see the American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines.^[1] Also see Clinical and Workup.

The treatment of cervical cancer varies with the stage of the disease. For early invasive cancer, surgery is the treatment of choice. In more advanced cases, radiation combined with chemotherapy is the current standard of care. In patients with disseminated disease, chemotherapy or radiation provides symptom palliation. (See Treatment.)

Early epidemiological data demonstrated a clear association between cervical cancer and sexual activity. Major risk factors observed were sex at a young age, multiple sexual partners, promiscuous male partners, and history of sexually transmitted diseases. However, the search for a potential sexually transmitted carcinogen was unsuccessful until breakthroughs in molecular biology enabled scientists to detect viral genome in cervical cells.

Strong evidence now implicates human papillomaviruses (HPVs) as prime suspects.^{[2, 3, 4]} HPV viral DNA has been detected in more than 90% of premalignant and malignant cervical lesions compared with a consistently lower percentage in controls. Both animal data and molecular biologic evidence confirm the malignant transformation potential of papilloma virus–induced lesions. Squamous intraepithelial lesions (SILs) are found predominantly in younger women, while invasive cancers are detected more often in women 10-15 years older, suggesting slow progression of cancer.

HPV infection occurs in a high percentage of sexually active women. Most of these infections clear spontaneously within months to a few years, and only a small proportion progress to cancer. This means that other crucial factors must be involved in the process of carcinogenesis.

Three main factors have been postulated to influence the progression of low-grade SILs to high-grade SILs. These include the type and duration of viral infection, with high-risk HPV type and persistent infection predicting a higher risk for progression; host conditions that compromise immunity, such as multiparity or poor nutritional status; and environmental factors such as smoking, oral contraceptive use, or vitamin deficiencies.

In addition, various gynecologic factors significantly increase the risk for cervical cancer. These include early age of first intercourse and higher number of sexual partners.

Human papillomavirus

HPV is a heterogeneous group of viruses that contain closed circular double-stranded DNA. The viral genome encodes 6 early open reading frame proteins (ie, E1, E2, E3, E4, E6, E7), which function as regulatory proteins, and 2 late open reading frame proteins (ie, L1, L2), which make up the viral capsid.

To date, 77 different genotypes of HPV have been identified and cloned, among which types 6, 11, 16, 18, 26, 31, 33, 35, 39, 42, 43, 44, 45, 51, 52, 53, 54, 55, 56, 58, 59, 66, and 68 have the propensity to infect anogenital tissues.

The HPVs that infect the human cervix fall into 2 broad risk categories. The low-risk types, HPV 6b and 11, are associated with low-grade SILs but are never found in invasive cancer. The high-risk types, mostly HPV 16 and 18, are found in 50-80% of SILs and in up to 90% of invasive cancers. Although less common, types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82 should also be considered carcinogenic.

The major difference between the 2 types is that after infection, the low-risk HPVs are maintained as extrachromosomal DNA episomes, while the high-risk HPV genome is found integrated into the host cellular DNA. The recombination event often leaves E6 and E7 directly coupled to the viral promoter and enhancer sequences, allowing their continued expression after integration.

Because E7 binds and inactivates the Rb protein while E6 binds p53 and directs its degradation, the functional loss of both TP53 and the RB genes leads to resistance to apoptosis, causing uncensored cell growth after DNA damage. This ultimately results in progression to malignancy.

Human immunodeficiency virus

The role of human immunodeficiency virus (HIV) infection in the pathogenesis of cervical cancer is not fully understood. Studies have shown a higher prevalence of HPV infection in HIV-seropositive women than in seronegative women, and the HPV prevalence was directly proportional to the severity of immunosuppression as measured by CD4 counts.

Impaired lymphocyte function has been postulated to enhance latent or subclinical HPV activity, resulting in a higher rate of persistent infection. Whether HIV has a synergistic effect on HPV infection, either by direct molecular interaction or through an indirect immunologic effect, remains unclear.

Cervical cancer is the second most common malignancy in women worldwide, and it remains a leading cause of cancer-related death for women in developing countries. In the United States, cervical cancer is relatively uncommon. The incidence of invasive cervical cancer has declined steadily in the United States over the past few decades; however, it continues to rise in many developing countries. The change in the epidemiological trend in the United States has been attributed to mass screening with Papanicolaou tests.^[5]

The American Cancer Society estimated that in the United States in 2010, 12,200 new cases of cervical cancer would be diagnosed.^[6] In addition, more than 50,000 cases of carcinoma in situ are diagnosed each year. Internationally, 500,000 new cases are diagnosed each year. Unlike the United States, where the annual incidence is 6.8 cases or less per 100,000 women, rates in parts of South America and Africa range as high as 52.8 cases per 100,000 women.^[7]

Forouzanfar et al performed annual age-specific assessments of cervical cancer in 187 countries from 1980-2010. The global cervical cancer incidence increased from 378,000 cases per year in 1980 to 454,000 cases per year in 2010 (annual rate of increase, 0.6%). Cervical cancer death rates have been decreasing, but the disease still accounted for 200,000 deaths in 2010; 46,000 of these women were aged 15-49 years in developing countries.^[8]

Race- and age-related demographics

In the United States, cervical cancer is more common in Hispanic, African American, and Native American women than in white women. Additionally, women of these races also have higher mortality from cervical cancers compared with their white counterparts. The Center for Disease Control and Prevention’s Surveillance of Screening-Detected Cancers (Colon and Rectum, Breast, and Cervix)—United States, 2004–2006 reported that incidence rates of late-stage cervical cancer were highest among women aged 50-79 years and Hispanics.^[9] However, cervical cancer may be diagnosed in any woman of reproductive age.

Prognosis of cervical cancer depends on disease stage. In general, the 5-year survival rates are as follows:

• Stage I - Greater than 90%
• Stage II - 60-80%
• Stage III - Approximately 50%
• Stage IV - Less than 30%

The American Cancer Society estimated that 4,210 women would die of cervical cancer in the United States in 2010.^[6] This represents 1.3% of all cancer deaths and 6.5% of deaths from gynecologic cancers.

Cervical cancer is overrepresented among underserved and minority groups in the United States. It is imperative to increase awareness about the benefits of Papanicolaou test screening in these groups.

A Cochrane review found that the best approach to encourage women to undergo cervical screening involved invitations, such as fixed or open appointments, letters, telephone calls, verbal recommendations, prompts, and follow-up letters.^[10] However, these findings relate to screening in developed countries, and their relevance to developing countries is unclear. Further studies are required to determine the effectiveness of promising interventions, such as revealing in an invitation letter the gender of the smear taker, using a health promotion nurse, the use of lay outreach health workers, and intensive attempts at recruitment.

For patient education information, see the Cancer and Tumors Center, Women's Health Center, and Procedures Center, as well as Cervical Cancer, Pap Smear, and Colposcopy.