Cervical Cytology Practice Guideline
Approved by the ASC Executive Board November 10, 2000
II. Epidemiology and Public Health
II.A. Incidence and Mortality
Cervical cancer mortality has decreased 70% over five decades, largely attributable to the introduction of cervical cytology screening in the 1940’s. Cervical cancer, once a leading cause of cancer death in women in the US, now ranks 13th. An estimated 12,800 women are still diagnosed each year with invasive cervical cancer and approximately 4,600 will die of their disease.4 However, worldwide, cervical cancer is the second most common cancer in women (following breast cancer); it ranks first in many developing countries lacking screening programs.5
Cervical cytology screening targets squamous cell carcinoma, although epidemiological data includes statistics for all subtypes of cervical malignancy.4 Squamous cervical carcinoma is an ideal target for screening. The cervix is accessible, associated with low sampling morbidity, and therapeutic intervention is effective during the relatively slow development from precursor lesions to invasive cancer. Cervical neoplasia typically develops over 10 years prior to becoming invasive. Although “rapidly progressing” forms of invasive carcinoma of the cervix have been postulated, there is no firm evidence to suggest that the natural history of invasive carcinoma is changing. Upon detailed review, a number of cases of “rapidly progressive” cervical cancer can be ascribed, at least with the advantage of hindsight, to screening failure.6, 7, 8, 9
Scandinavian studies demonstrate most convincingly the value of screening Pap smears. Studies have shown those countries with formal screening programs and wide population coverage experienced substantial drops in incidence and mortality while neighboring countries with limited population screening did not.10, 11
The success of cervical cytology screening lies in its relative simplicity, low cost and noninvasive nature. Annual screening reduces the probability of developing invasive carcinoma by over 95%. Most cases of invasive cervical carcinoma occur because a patient is not screened, not screened at an appropriate interval, or there is inadequate follow up for an identified abnormality.12
II.B. Risk Factors for Cervical Cancer
II.B.1. Human Papillomavirus (HPV)
The pathogenesis of cervical neoplasia and cervical cancer is related to HPV, based on epidemiological, virological, and experimental evidence.13, 14 Most previously identified risk factors for cervical cancer such as early age of first intercourse and increased number of sexual partners, reflect risk of exposure to HPV.
There are more than 80 types of human papillomaviruses (HPVs) including some that cause the common warts that grow on hands and feet. Approximately 30 types have the ability to infect the anogenital tract and can be passed from one person to another through sexual intercourse. About 15 genital HPVs have been found in cervical cancer and are termed “cancer-associated” types. HPV 16 is the most important type associated with cancer in almost all geographic regions, along with HPVs 18, 31, and 45. Genital warts, known as condylomata acuminata, are generally associated with low-risk HPV types 6 and 11.
HPV infects reproducing cells; infection of the cervix occurs at the basal cell layer. HPV is a double stranded DNA virus that has three well studied regions: an upstream regulatory region (URR) gene that does not code proteins, early genes (E) which code for nonstructural proteins, and late (L) genes which code for structural proteins such as the viral capsid. When HPV infects a basal cell and is not integrated into the host genome, the viral DNA replicates within the host cell and remains within the cell as it grows toward the surface layers. The early genes are tightly regulated by E2, which suppresses the action of the oncogenes E6 and E7. When L genes are subsequently activated, entire encapsulated virions are produced which are expressed morphologically as “koilocytes.” When HPV is integrated into the host DNA, there is often disruption of the E2 regulatory gene. Loss of regulation leads to expression of E6 and E7, leading to cell proliferation. This proliferating cell population is at risk for transformation to high grade lesions or carcinoma.15, 16, 17
HPV infection is very common while cervical cancer is not. Host and environmental factors are postulated to influence the risk of progression from HPV infection to cancer precursors and invasive cancer.
Immunodeficiency is associated with higher rates of HPV infection and progression. HIV infection, particularly in women with low CD4 counts, is associated with a high prevalence of HPV DNA and SIL detection.18, 19, 20 An increased incidence of HPV is also associated with other immunosuppressed states, such as organ transplant recipients, chronic renal failure, a history of Hodgkin21 lymphoma and immunosuppressive therapy.22
Currently, there is no consensus in the medical literature supporting routine HPV testing as part of cervical screening. There is a growing body of literature suggesting that HPV testing may be an option in the management of patients with equivocal abnormal results, however, this practice is not yet widely adopted. A large-scale clinical trial [the ASCUS/LSIL Triage Study (ALTS)] evaluating the cost-effectiveness of this approach, among other management strategies, is awaiting completion.23
II.B.2. Other Co-factors
Oral contraceptive use has also been associated with a 1.5 fold relative increased risk for developing cervical carcinoma. Although the increased risk has been ascribed to the lack of barrier type contraception (and therefore more exposure to HPV), controlled studies have found a relative increased risk suggesting a separate causal relationship.24, 25, 26
When controlled for confounding risk factors, cigarette smoking has been cited as an independent risk factor for the development of cervical carcinoma. Smokers were found to have a 50% higher risk for developing cervical carcinoma than nonsmokers. Risk increases with the increased number of cigarettes, duration of smoking history and use of unfiltered tobacco products.27, 28
Lack of cervical cytology screening is a significant risk factor for cervical cancer. Previous population studies suggested that African-Americans, Hispanics and Native Americans were considered at greater risk for cervical carcinoma in the United States. However, when corrected for screening coverage, race, as a risk factor is noncontributory.29
Historically, unscreened populations of women in the U.S. have included older women, uninsured and impoverished women, minority women – particularly Hispanic and older African-American women, and women residing in rural areas.30 Recent surveys indicate that many of these patterns remain unchanged despite increased screening efforts. In the 1994 National Health Interview Survey of the U.S. population, 77% of women reported having had a Pap test in the past three years. Age remains a factor; screening was higher among women 18-44 (82%) compared to women 65 and older (57%). However, there were no marked differences between African-Americans, Hispanic whites, and non-Hispanic whites, or metropolitan versus non-metropolitan residents in the 18-44 year old age group. Socioeconomic measures continue to show significant differences in screening coverage. Women who did not complete high school and whose family income was less than $20,000 reported lower rates of screening compared to women with education beyond high school or family income exceeding $20,000.31 Lack of access to health care, lack of routine examinations, lower education level and risk perception (“beliefs”) are barriers to cervical cytology screening that are reflected in socioeconomic status.32 When barriers to cervical cytology screening are removed, the incidence of invasive carcinoma declines in the population.33
Regular cytologic screening for cervical cancer reduces both the mortality and incidence of cervical carcinoma in the screened population. Annual cytological screening will reduce the incidence of invasive squamous carcinoma by more than 95%.12 Despite acknowledgement that routine screening Pap smears are effective, the interval of routine screening remains controversial. Various organizations have different recommendations for interval screening. The United States Preventive Services Task Force recommends cervical cytology screening every 3 years for sexually active women with an intact cervix.34 The American Cancer Society (ACS) suggests that annual screening cytology should be performed on all sexually active women until three adequate negative smears are obtained. The interval between subsequent screening is at the physician’s discretion.35 The American College of Obstetricians and Gynecologists’ recommendations are similar to the ACS, but more frequent continual screening of high-risk women is encouraged.36 The American College of Physicians recommends cervicovaginal cytology screening every three years between age 20 to 65.37 The College of American Pathologists advocates that, in general, all women who are, or have been sexually active, or who have reached 18 years of age, should have an annual cervical cytologic examination (Pap test) and pelvic examination.38 Despite the variety of interval recommendations, many physicians continue to perform annual screening in the US, which the American Society of Cytopathology endorses.
8 Kenter GG, Schoonderwald EM, Koelma IA, Arenta N, Hermans J, Fleuren GJ. The cytological screening history of 469 patients with squamous cell carcinoma of the cervix uteri; does interval carcinoma exist? Acta Obstet Gyn Scand 1996; 75:400-3.
9 IARC Working Group on Evaluation of Cervical Cancer Screening Programmes. Screening for squamous cervical cancer: duration of low risk after negative results of cervical cytology and its implications for screening policies. Br Med J Clin Res Ed 1986; 659-64
11 Hakama M, Magnus K, Petterssson F, Storm H, Tulinius H. Effect of organized screening on the risk of cervical cancer in the Nordic countries. In: Miller AB, Chamberlain J, Day NE, Hakama M, Prorock PC (Eds.) Cancer Screening. UICC Project on Evaluation of Screening for Cancer. Cambridge, UK: International Union Against Cancer; 1999; 153-62.
12 McCrory DC, Matcher DB, Bastian L, Datta S, Hasselblad V, Hickey J, Myers E, Nanda K. Evaluation of Cervical Cytology. Evidence Report/Technology Assessment No.5. (Prepared by Duke University under contract No. 290-97-0014.) AHCPR Publication No. 99-E010. Rockville, Maryland: Agency for Health Care Policy and Research, February 1999.
16 Richart RM, Masood S, Syrjanen KJ, Vassilakos P, Kaufman RH, Meisels A, Olszewski WT, Sakamoto A, Stoler MH, Vooijs GP, Wilbur DC. Human Papillomavirus; IAC Task Force Summary. Acta Cytol 1998; 42:50-58.
19 Palefsky JM, Minckoff H, Kalish LA, Levine A, Sacks HS, Garcia P, Young M, Melnick S, Miotti P, Burk R. Cervicovaginal human papillomavirus infection in immunodeficiency virus –1(HIV)-positive and high-risk HIV-negative women. J Natl Cancer Inst 1999; 91:226-236.
21 Harris NL, Jaffe ES, Diebold J, et. al. The world health organization classification of hematological malignancies report of the clinical advisory committee meeting, Airlie House, Virginia, November 1997. Mod Path 2000; 13:193-207.
24 Invasive squamous cell cervical carcinoma and combined oral contraceptives: results from a multinational study. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Int J Cancer1993: 55:228-36.
32 Martin LM, Calle EE, Wingo PA, Heath CW Jr. Comparison of mammography and Pap test use from the 1987 and 1982 National Health Interview Surveys: Are we closing the gaps? Am J Prev Med 1996; 12:82-90.