Epidemiology of cervical cancer

Cervical cancer is the third most common cancer and the fourth leading cause of cancer-related deaths among women worldwide, with an estimated 530,232 cases diagnosed and 275,008 fatalities worldwide in 2008. Cancer rates, however, vary dramatically by whether or not a country has an adequate screening program. In the United States, the disease accounted for only 1.6% of cancer cases and 1.4% of cancer mortality among women in 2008. The incidence rate of cervical cancer in developed nations has decreased steadily over the last half-century. This decline in incidence of cervical cancer is largely the result of improved cervical cytology services and coverage over the period.

In the United States, cervical cancer disproportionately affects racial minorities and women of lower socioeconomic standing. Invasive cervical cancer is more common among black and Hispanic women than among white women. Moreover, survival of the disease is less probable for black women than for white women. Cervical cancer incidence and mortality increase with decreased socioeconomic status among all racial groups.

Internationally, the burden of cervical cancer falls most heavily on developing nations. About 85% of the cases and 88% of the deaths due to cervical cancer occur in developing nations. Women in developing nations are at a 35% greater lifetime risk of cervical cancer than women in high-income countries. Although cervical cancer is most common in women older than 50 years, in developing nations, cervical cancer is becoming increasingly prevalent among women during their reproductive years (ages, 15–49 years). Because cervical cancer has a greater cure rate when discovered at an asymptomatic early stage, in countries without screening programs, patients are disproportionately diagnosed with advanced stage and thus incurable disease.

HPV: epidemiology and molecular biology

Infection of the cervix with HPV is necessary, although not sufficient, to cause cervical neoplasia and cervical cancer. HPV is among the most prevalent sexually transmitted viruses in the human population. It is estimated that 50% to 80% of sexually active women contract genital HPV during their lifetime. Around 80% of HPV infections clear within 2 years and do not cause cervical neoplasia and invasive cervical cancers. Persistent infection with HPV is required for the development of cervical dysplasia and invasive cervical cancer.

In the United States, an approximate 6.2 million persons are infected with the virus each year. HPV infection is present in 13.3% of US women with normal cervical cytology, comparable with the global prevalence of 11.4%. HPV is more common in lesser-developed regions. In Eastern Africa, where age-standardized incidence and mortality are greatest, HPV is prevalent in 33.6% of women with normal cervical cytology. HPV is most commonly identified on cervical testing among adolescent women (ages, 14–24 years) and is associated with sexual debut.

Certain HPV subtypes increase the likelihood that an infection of the cervix with HPV will develop into cervical dysplasia and invasive cervical cancer. Fifteen HPV subtypes are classified as high risk for cervical cancer (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82). HPV-16 and HPV-18, the 2 highest-risk subtypes, are present in 71% of cervical carcinoma. The prevalence of HPV-16 and HPV-18 is variable worldwide, ranging from 2.0% among women with normal cervical cytology in Western Europe to 9.7% among women with normal cervical cytologic in Eastern Europe.

Infection with a high-risk HPV subtype is the single greatest risk factor for invasive cervical cancer. Other risk factors include tobacco smoking, high parity, long-term hormonal contraceptive use, and infection with human immunodeficiency virus (HIV). The risk of HPV infection is greater in women with multiple sexual partners, and HPV is a common coinfection with other sexually transmitted infections, including HIV.

HPV: epidemiology and molecular biology

Infection of the cervix with HPV is necessary, although not sufficient, to cause cervical neoplasia and cervical cancer. HPV is among the most prevalent sexually transmitted viruses in the human population. It is estimated that 50% to 80% of sexually active women contract genital HPV during their lifetime. Around 80% of HPV infections clear within 2 years and do not cause cervical neoplasia and invasive cervical cancers. Persistent infection with HPV is required for the development of cervical dysplasia and invasive cervical cancer.

In the United States, an approximate 6.2 million persons are infected with the virus each year. HPV infection is present in 13.3% of US women with normal cervical cytology, comparable with the global prevalence of 11.4%. HPV is more common in lesser-developed regions. In Eastern Africa, where age-standardized incidence and mortality are greatest, HPV is prevalent in 33.6% of women with normal cervical cytology. HPV is most commonly identified on cervical testing among adolescent women (ages, 14–24 years) and is associated with sexual debut.

Certain HPV subtypes increase the likelihood that an infection of the cervix with HPV will develop into cervical dysplasia and invasive cervical cancer. Fifteen HPV subtypes are classified as high risk for cervical cancer (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82). HPV-16 and HPV-18, the 2 highest-risk subtypes, are present in 71% of cervical carcinoma. The prevalence of HPV-16 and HPV-18 is variable worldwide, ranging from 2.0% among women with normal cervical cytology in Western Europe to 9.7% among women with normal cervical cytologic in Eastern Europe.

Infection with a high-risk HPV subtype is the single greatest risk factor for invasive cervical cancer. Other risk factors include tobacco smoking, high parity, long-term hormonal contraceptive use, and infection with human immunodeficiency virus (HIV). The risk of HPV infection is greater in women with multiple sexual partners, and HPV is a common coinfection with other sexually transmitted infections, including HIV.

HPV infection, immune surveillance, and development of neoplasia

HPV are DNA viruses that infect the human anogenital tract and surface epithelium. HPV are small nonenveloped viruses, consisting of a capsid shell and a 7.9-kilobase genome. The HPV genome carries 8 protein-coding genes, 6 coding for early viral function (E1, E2, E3, E4, E6, and E7) and 2 coding for late viral function (L1 and L2). More than 100 HPV subtypes have been characterized to date. HPV subtypes are distinguished by genotypic diversity in the E6, E7, and L1 coding regions, sharing no greater than 90% genetic similarity in these regions. HPV-16 and HPV-18 are associated with 71% of cervical cancers; types 31, 33, 35, 45, 52, and 58 are found in association with an additional 21% of cervical cancers.

The virus is typically transmitted via sexual intercourse, during which the virus is deposited on the basement membrane of the cervical epithelium. Once present on the cervical epithelium, HPV infection may be transient or may persist and lead to the eventual development of cervical neoplasia and potentially cervical cancer. The course of infection depends on several stages in the natural history of cervical cancer. HPV DNA exists in cervical cells in either an episomal or an integrated state. Integration of viral DNA into the host genome may be necessary for persistent infection and development of cervical dysplasia.

Most HPV infections resolve within a few years and do not develop into precancerous lesions. A cell-mediated immune response is responsible for clearing viral particles and infected cells. Immunologic memory may protect against future infection, although it is limited to serologic HPV subtype, because women are susceptible to a subsequent infection with a different strain.

Cervical dysplasia typically begins in undifferentiated keratinocytes in the cervical transformation zone, where proliferating subcolumnar cuboidal reserve cells replace columnar cells with squamous epithelium. This site of epithelial metaplasia is at risk for dysplastic growth. Most invasive cervical cancers arise from the squamous epithelium in the transformation zone. However, between 10% and 25% of cervical cancer patients, are found to have adenocarcinoma of the glandular epithelia.

Growth at the precancerous stage is gradual and may progress to a higher level of dysplasia but may also regress and eventually clear. Levels of dysplasia diagnosed on cervical biopsy are roughly categorized into 3 levels of dysplasia: low-grade dysplasia (with minimal risk for progression to cancer) and moderate or severe levels of dysplasia (cocategorized as high-grade dysplasia). There is a fair amount of interobserver variation as to the diagnosis of the different levels of dysplasia and, to date, no reproducible way to predict which of these high-grade precancers will progress to invasive cancer.

An HPV infection in general progresses more rapidly from transmission to precancerous lesions than from precancerous lesions to cancer. Cervical lesions persist for years before progressing to cancer, which allows for time to intervene and prevent progression to cancer. Even in the absence of treatment, only a minority of cervical intraepithelial neoplasias (CINs), an estimated 1% of low-grade lesions and 5% to 12% of high-grade lesions, progress to invasive carcinoma. The progression of an infection to precancerous lesions and to invasive cancer is more probable and more rapid in women infected with high-risk subtypes HPV-16 and HPV-18. At the cellular level, HPV-16 and HPV-18 have greater transforming potential than lower-risk HPV subtypes. The oncogenicity of high-risk HPV-16 may further relate to its suppression of immune responses. However, 80% to 90% of women infected with HPV-16 and HPV-18 will not develop precancerous lesions.

HPV infection is more likely to persist in immunocompromised patients. Most notably, HIV coinfection is a risk for HPV infection and for the development of CIN and invasive cervical cancer. HIV broadly suppresses immune system function by killing macrophages and CD4 ⁺ T cells. The virus may also increase the risk of malignancy with HPV infection by altering interactions between cancer cells and lymphocytes.

Screening and diagnosis of cervical precancers

At the time that cervical cytologic examination was being introduced by Papanicolaou and Traut in 1943, cervical cancer was the leading cause of cancer mortality among US women. As of 2008, cervical cancer was the 15th most common cause of cancer mortality among US women. Organized cervical cancer prevention programs have precipitated a decline in cervical cancer rates in the developed world. When compared against historic cohorts, such programs have reduced the incidence of cervical cancer by as much as 75%.

Successful cervical cancer prevention programs integrate screening with management of cervical precancers. Three screening modalities, cervical cytologic testing (Papanicolaou test), cervical HPV testing, and visual inspection of the cervix, are commonly used for cervical screening. Women with positive test results may be referred for colposcopy, in which the transformation zone is visualized under magnification, and abnormal lesions may be biopsied. Histologically confirmed precancerous lesions may be treated by various excisional or ablational techniques. Specific recommendations for screening and management vary according to national and institutional guidelines. In developed nations, a 3-visit model for cervical precancer management is generally used in which screening, colposcopy with directed biopsy, and treatment proceed in 3 separate steps. Alternatively, either a 1-visit approach, in which a rapid screen is followed by immediate treatment, or a 2-visit approach, in which an abnormal Papanicolaou test result is triaged to evaluation and treatment in 1 visit (both known as see and treat), may also be used.

The Papanicolaou test, or Pap smear, has been the standard screening test for much of the past half-century. The test checks for morphologic abnormalities in fixed and stained cells from cervical epithelial sampling. Conventional cytologic testing has a specificity of 94% to 97% in distinguishing high-grade CIN. However, with a sensitivity of approximately 70% to 80%, false-negative results are frequent with Papanicolaou testing alone. Uneven sampling of cervical epithelia and sample loss and manipulation during preparation of cytology slides limit the sensitivity of the technique. Recently, liquid-based cytologic examination has emerged as an alternative to conventional cytologic examination. Improvements in sample preparation limit the number of unsatisfactory Papanicolaou tests, although they do not appreciably raise the sensitivity of cervical cytologic examination. The high frequency of false-negative results with cytologic testing necessitates repeated screening. Cervical cytologic examination has been effective with screening at regular intervals because of the long lead time of cervical precancers, although such screening requirements place a larger burden on patients and health systems.

Modern techniques in molecular biology allow detection of genital HPV infection with probes for HPV DNA and RNA, HPV proteins, and cellular markers. Hybrid Capture 2 (HC2; Qiagen), which is the most widely used of these tools, uses DNA hybridization probes for type-specific detection of HPV DNA and can detect 13 high-risk HPV subtypes, including HPV-16 and HPV-18. The sensitivity of detection with HPV testing for high-grade cervical lesions is approximately 95%. However, the technology does not discriminate between transient HPV infections and HPV-associated cervical lesions. As such, interpretation of test results is complicated by the moderate specificity of the technique, reported between 61% and 96% in various studies. The specificity of HPV testing is greatest among populations in which the prevalence of HPV is low and the incidence of cervical precancer is high. In a Finnish study of primary HPV testing (N = 33,100), the specificity of the test ranged from 93.4% to 95.6% in women aged 35 years and more, who have lower HPV prevalence yet higher CIN incidence than younger cohorts, as compared with 84.4% among women aged 25 to 34 years.

In clinical studies involving side-by-side comparison of cervical cytologic examination and HPV testing, sensitivity is consistently higher with HPV testing and specificity is consistently higher with cytologic examination. Because of the complementary strengths of each technique, HPV testing has been incorporated as an adjuvant test with cytologic examination. The Canadian Cervical Cancer Screening Trial, which examined conventional cytologic examination and the HC2 HPV test in a randomized controlled trial (N = 10,154), reported 100% sensitivity and 92.5% specificity for simultaneous Papanicolaou and HPV cotesting. However, a large number of additional colposcopies were required for diagnosis of each additional case of high-grade dysplasia when using combined testing than when using either test alone or when using either test only as a downstream test for abnormal screens, a process known as reflex testing. Colposcopy and biopsy adds significant additional cost as well as pain and anxiety to a screening program; thus, combined testing becomes viable only if offered at a less frequent interval than either test alone.

In much of the developed world, cervical cytologic examination remains the primary screening test. Several large-scale studies have evaluated HPV screening as a cotest along with primary cervical cytologic examination or for triage after cytologic examination, reporting greater predictive values than for cytologic examination alone. Nevertheless, as recently as 2010, the European Guidelines for Quality Assurance in Cervical Screening maintain cytologic examination as the standard, noting the risk of overdiagnosis and inconclusive evidence on adjuvant HPV testing. Specifics of screening programs vary amongst European Union nations. Recent guidelines issued from several major US organizations, including US Preventive Services Task Force, American Society of Colposcopy and Cervical Pathology, American Cancer Society, and American College of Obstetrics and Gynecology recommend Papanicolaou test alone starting at age 21 years, with reflex HPV testing for Papanicolaou tests showing atypical squamous cells of undetermined significance. These organizations have different opinions about the data suggesting that all women should undergo Papanicolaou and HPV cotesting starting at age 30 years, although they do all agree that if both tests are obtained and both show negative results, they should not be repeated before 3 years. They all agree that for regular-risk women, Papanicolaou testing alone every 3 years is acceptable for women aged 30 years and older.