Cervical Cancer Screening and Prevention
DEFINITION
Cervical carcinoma originates from the endocervical squamocolumnar epithelial junction. Squamous cell carcinoma represents 90% of cervical carcinomas and develops from precancerous lesions and cervical dysplasia.1
PREVALENCE
Cervical cancer is the second leading cause of death from cancer in women worldwide. It is the third most common gynecologic malignancy in the United States and ranks 13th in cancer deaths for American women.2 In the United States, an estimated 13,000 new cases of invasive cervical cancer were diagnosed each year, with 4100 deaths.3,4 Cervical cancer mortality in the United States has decreased over the last five decades by 70%, largely as a result of the introduction of the Papanicolaou (Pap) test.
PATHOPHYSIOLOGY
Invasive cervical cancer develops from a preinvasive state termed cervical intraepithelial neoplasia (CIN). CIN 1 represents mild dysplasia and is now classified as low-grade squamous intraepithelial lesions (LSILs), CINs 2 and 3 encompass moderate-to-severe dysplasia and are classified as high-grade squamous intraepithelial lesions (HSILs) based on the Bethesda cervical cytology reporting system.5 Most LSILs spontaneously resolve, whereas high-grade squamous intraepithelial lesions (HSILs) are more likely to progress to invasive cervical cancer. HSILs are typically detected at an average of 10 to 15 years younger than for invasive cervical cancer. For example, the typical age range for diagnosis of carcinoma in situ is 25 to 35 years, whereas that for invasive cancer is older than 40 years.6
Infection of the cervical epithelium with oncogenic types of human papillomavirus (HPV) is essential to the development of cervical cancer and its precursor lesions (Fig. 1).7,8 Early epidemiologic studies found that at least 76% of cases of CIN could be attributed to HPV infection.9 Women with CIN lesions in the study exhibited the typical epidemiologic profile of sexually transmitted infection: more sexual partners, earlier age at first sexual intercourse, and lower socioeconomic status.
Figure 1 Role of human papillomavirus infection in the development of cervical cancer.
(Adapted with permission from Wright TC Jr, Schiffman M: Adding a test for human papillomavirus DNA to cervical-cancer screening. N Engl J Med 2003;348:489-490.)
Evidence supporting the association between infection by carcinogenic HPVs and the subsequent development of virtually all cervical cancer is conclusive. Cervical squamous intraepithelial lesions demonstrate the classic morphologic changes of HPV infection, such as epithelial hyperplasia (acanthosis) and degenerative cytoplasmic vacuolization (koilocytosis) in terminally differentiated keratinocytes with atypical nuclei.10 HPV has been observed in these lesions using electron microscopy.11 In addition, HPV structural proteins have been detected in surgical specimens using immunohistochemical staining with antibodies that specifically detect HPV viral antigens.12 Large serial studies from 22 countries have shown that more than 90% of cervical squamous cell carcinomas contain DNA from high-risk HPV types, presumably transmitted during sexual activity.7 A more recent study13 indicated the worldwide HPV prevalence in cervical cancer is as high as 99.7%. Furthermore, HPV DNA has been extracted from metastatic cervical cancer tissues and cervical cancer tumor cell lines in culture.14,15
Eighty types of HPV have been sequenced, and approximately 30 of these infect the female and male genital tracts.16 Eighteen genital HPV subtypes (16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, and 82) are classified as high risk because of their close causative association with cervical cancer.17
Research in the last decade has provided a better understanding of the molecular carcinogenesis of HPV. In vitro infection of human epithelial cells by carcinogenic HPV subtypes induces indefinite cell growth, or cell immortalization.18,19 Two HPV viral proteins, E6 and E7 proteins, are required for cell immortalization.20–22
Further studies23–25 revealed that E6 proteins from high-risk HPV interact with the cellular tumor suppressor protein p53. The p53 suppresses cell proliferation by arresting growth in the G1 phase of the cell cycle. E6 proteins from high-risk HPV complexes with p53 and results in the rapid proteolytic degradation of p53 proteins.23,24 The decreased level of p53 protein abolishes the cell’s ability to suppress uncontrolled cell proliferation.25 On the other hand, E7 proteins from high-risk HPV bind to another cellular tumor suppressor, the retinoblastoma protein (pRB), and disrupt the complex between the cellular transcription factors E2F-1 and pRB. The free E2F-1 stimulates cellular DNA synthesis and uncontrolled cell proliferation.26 E6 and E7 proteins from HPV-16 can also cooperate to induce centrosome-related mitotic defects and genomic instability.27 It is clear that persistent infection by oncogenic HPVs is a prerequisite for the development of cervical cancer and its precursor lesions, although only a few women infected with HPV eventually develop cervical cancer.
SCREENING
Remarkable new advances in the last decade have transformed our screening protocol. Cervical cytology specimen adequacy and more accurate interpretations of cervical cancer precursors have been achieved by using new liquid-based cervical cytologic smear technology (ThinPrep).28–30 Using the revised Bethesda cytology reporting system (2001), clinicians can better triage patients with abnormal cervical cytology based on less ambiguous terminology.31,32 Data from the National Cancer Institute-sponsored multicenter randomized clinical trial (ALTS trial, 2001) have demonstrated the clinical value of HPV testing in triaging women with atypical squamous cells of undetermined significance (ASC-US).31–33 After a diagnosis of ASC-US, clinicians can determine on the basis of HPV testing results whether a woman requires colposcopic examination or needs only to repeat Pap tests 1 year later. More recently, multiple large-scale, cross-sectional studies from several countries have compelled the U.S. Food and Drug Administration (FDA) to approve the hybrid capture 2 test for HPV as an adjunct to the Pap test in primary screening (March, 2003).34–38 It is now evident that virtually all squamous-cell cervical cancers are caused by one of the 18 types of oncogenic HPV.39 As a result, many groups, including the American Cancer Society, the American College of Obstetricians and Gynecologists, the American Society for Colposcopy and Cervical Pathology, and the U.S. Preventive Services Task Force have issued new screening guidelines since 2002.40–42 The following discussions will highlight the consensus recommendations from these organizations and provide clinicians with updates in screening protocols.
CURRENT PRACTICE GUIDELINES
Initiation of Screening
The basis of the above recommendation is that cervical cancer and its precursor lesions are almost always related to acquisition of oncogenic HPV infection through vaginal intercourse. It usually takes 3 to 5 years to develop these lesions after the first exposure to HPV infection, and cervical cancer in patients younger than 19 years is rare.43–46
The incidence of invasive cervical cancer was 0/100,000/year for ages 10 to 19 years and 1.7/100,000/year for ages 20 to 24 years, according to the data from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) program.47 In addition, studies on the natural history of LSILs and HPV infection in young women aged 13 to 22 years have shown that most HPV infections are transient, with a 70% regression rate within 3 years. Ninety percent of LSILs in this age group spontaneously regress.48–50 Furthermore, the average time of progression for HSILs to a carcinoma in situ or cancer for women younger than 25 years was approximately 5 years.51
Adding HPV DNA Testing to Screening
HPV DNA testing is now included in screening as an adjunct to the Pap test for women 30 years and older. This new screening protocol takes advantage of the high sensitivity and high negative predictive value of HPV DNA testing and the high specificity of cervical cytology. Multiple large-scale studies from several countries, evaluating the role of HPV testing in primary screening, have shown that the combination of a negative Pap test and a negative HPV DNA test indicates the absence of CIN 3 or cancer with almost 100% certainty.34–38 These studies demonstrate that 80% to 100% of cases of histologically confirmed CIN 2 or cancer were found to be positive for high-risk HPV. The sensitivity of HPV DNA testing to detect CIN 2 or a higher-grade lesion is higher than that of a single Pap test. The sensitivity is even higher than that of HPV DNA testing alone, when HPV DNA testing is combined with Pap testing.
The rationale for recommending HPV testing in women 30 years and older is based on the finding that the prevalence of high-risk HPV infection declines with age. Among women older than 29 years who have ASC-US, only 31.2% have a high risk for HPV positivity, whereas in women age 28 or younger, high-risk HPV positivity rises to 65%.52 Although HPV infections are extremely common in sexually active younger women, most of these infections will resolve spontaneously or cause only transient, minor lesions. It is very likely that HPV DNA positivity with increased age may reflect the persistence of HPV. This group of older women is at increased risk for development of cervical cancer. Therefore, the specificity and the positive predictive value of an HPV DNA test increases with the age of the woman.
Screening Interval
Women Younger Than 30 Years
The American Cancer Society recommends that cervical screening be performed annually with conventional Pap tests or every 2 years using liquid-based cytology after initiation of screening.40 The American College of Obstetricians and Gynecologists recommends that women in this age group should undergo annual screening.41 The recent guideline of the U.S. Preventive Services Task Force calls for screening every 3 years.42 The rationale for this screening interval was based on relative-risk data on invasive cervical cancer after a negative Pap test result.
The difference in risk for progression to invasive cancer in the intervals between screenings is very small when 1-, 2-, and 3-year screening intervals are compared by using conventional Pap tests. Most studies suggest that the relative risk with a 2-year screening interval is 1 to 2 above annual screening, and the relative risk with a 3-year screening interval is in the range of 2 to 3 above annual screening. Longer screening intervals of 4 to 10 years correlate with increased risk of invasive cervical cancer during the interval.53–59 A large, prospective cohort study of more than 120,000 women in the United States found no significant statistical difference in the age-adjusted incidence rate of HSILs, carcinoma in situ, or invasive carcinoma among women screened at 1, 2, or 3 years after a normal Pap test.60 In addition, the absolute risks of cervical cancer after one, two, and three or more consecutive negative Pap tests was estimated as 3.09, 2.56, and 1.43 per 100,000 women, respectively, based on long-term follow-up data from 2.4 million women belonging to a prepaid health plan.61
Women Older than 30 Years
If the Pap test and the HPV DNA test are both negative in a woman at or after age 30, screening should be performed every 3 years, according to the latest guideline from the American Cancer Society and the American College of Obstetricians and Gynecologists. This recommendation is based primarily on the following key evidence: high-risk HPV infection is required for the development of virtually all cervical cancer,39 and the time from initial HPV infection to development of cervical cancer usually exceeds 10 years.62 A similarly effective screening model exists in colon cancer screening. In a person age 50 years or older who has average risk and a negative colonoscopy, the next colonoscopy should be performed in 10 years. In contrast, because of the lack of definitive prospective data, the U.S. Preventive Services Task Force does not recommend for or against the routine use of HPV testing as a primary screening test.
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