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Author: F. Allan Hubbell, MD, MSPH, Professor of Medicine and Social Ecology, Chief, Division of General Internal Medicine and Primary Care, Director, Center for Health Policy and Research, University of California, Irvine, CA.
Peer Reviewers: Charles Levenback, MD, Associate Professor, Department of Gynecologic Oncology, M.D. Anderson Cancer Center, Houston, TX; Lawrence G. Ratcliff, MD, Assistant Professor of Family Medicine, Wright State University School of Medicine, Dayon, OH.
Editor’s NotePrimary care physicians are on the front lines of efforts to improve cervical cancer control in the United States. Despite advances in screening, diagnosis, and treatment, cervical cancer remains one of the most common cancers among women in this country. Nearly 5000 women died of the disease in 1996. This figure is particularly disturbing because cervical cancer is almost entirely preventable. Even more disturbing are data suggesting that the decline in cervical cancer rates that have occurred over the last 40 years are leveling off, and it appears that incidence rates are actually rising in some groups of women. Therefore, it is important for primary care physicians to be knowledgeable about current recommendations for the prevention of this disease and about the factors that limit the effectiveness of preventive efforts.
Some of the recent developments related to cervical cancer prevention include the growing consensus that the human papillomavirus (HPV) is causally related to this disease and that infection with specific types of HPV put women at high risk. Ongoing studies are evaluating vaccines for this virus and determining whether HPV testing should be a routine part of cervical cancer screening programs. In the meantime, regular screening with the Papanicolaou (Pap) smear is the best preventive measure. Widespread adoption of the Bethesda System for interpreting Pap smears has provided more uniformity to the reporting of results. Moreover, new guidelines regarding the frequency of performing Pap smears from the U.S. Preventive Services Task Force provide a valuable reference for primary care physicians who are developing or revising plans for cervical cancer prevention in their offices.
Barriers to cervical cancer screening and follow-up continue to exist particularly among women who are elderly, socioeconomically disadvantaged, or ethnic minority members. Unfortunately, these are the very women who are at increased risk for developing cervical cancer. A number of studies have suggested approaches for improving screening for these women, but much more work is necessary. Another problem concerns follow-up of women who have abnormal Pap smears. Some studies have shown that up to 60% of women with abnormal smears do not return for additional care. Recommendations for triaging women with abnormal smears who do follow-up are in a state of evolution, but some reasonable guidelines are available. Primary care physicians can play major roles in assuring that their own patients receive appropriate preventive care and in helping community-based screening programs increase the number of women who participate.
This article will review these issues in some detail including current information about cervical cancer epidemiology, risk factors, etiology, screening techniques, screening frequency, and follow-up recommendations.
Cervical cancer remains an important public health problem, ranking second only to breast cancer as the most common malignancy among women in the world.1 In the United States, there were approximately 15,700 new cases of cervical cancer and 4900 deaths from this disease in 1996.2 The disease ranked ninth in incidence and accounted for 6% of all cancers among women. Invasive cervical cancer occurs across a broad age range but is most frequent in the fifth and sixth decades of life. Incidence rates for carcinoma in situ (CIS) are highest among the 25-29 age group.3 In the last 40 years, the incidence and mortality rates for cervical cancer have declined in the United States and in most other developed countries, largely due to the introduction of screening with the Pap smear. Unfortunately, these declining trends have recently leveled off, and the rates of cervical cancer are actually increasing among young white women.4
Many of the risk factors for cervical cancer are related to sexual activity. They include having multiple sexual partners (four or more), early age at first sexual intercourse (before age 18), and history of sexually transmitted diseases.5 Characteristics of males whose partners develop cervical cancer include history of genital warts, poor hygiene, number of sexual partners, and practice of unsafe sexual behaviors.6 Other factors such as low socio-economic status, cigarette smoking, dietary factors, and immunosuppression have also been linked to cervical cancer.7-10
With the availability of effective screening, cervical cancer has become a disease of the economically disadvantaged. For example, higher risk for cervical cancer has been associated with Hispanic and black populations.11-14 Women in these ethnic groups may be more likely to experience factors contributing to development of the disease, such as having male partners who have multiple sex partners and using barrier methods of birth control less frequently.12,15 In addition, numerous studies have found that screening, treatment, and follow-up practices for Hispanics and black women are not as thorough as they are for other groups.16-18
A sexually transmitted agent has long been suspected in the etiology of cervical cancer. Such an agent would explain why most of the risk factors are associated with sexual activity. There is strong evidence that HPV is causally related to cervical cancer.19 Indeed, HPV DNA has been detected in over 90% of invasive cervical cancer tumors.20,21 However, infection with HPV is also very prevalent in the general population, and not all women with HPV develop cervical cancer. Therefore, recent attention has focused on viral types of HPV which have been consistently associated with cervical tumors. Several types, principally 16, 18, 31, 33, and 36, have been implicated with development of cervical cancer21,22-24 and its precursors.21,24-26
HPV infection in itself is not sufficient for development of cervical cancer. Many investigations have suggested the joint contribution of other factors such as Epstein-Barr virus,27 cytomegalovirus,28 polyamines and their oxidases,29 cigarette smoking,30,31 host genetic factors,32 and patient age.33 A proposed etiologic model suggests that HPV plays an initiating role, possibly in conjunction with some of these co-factors. According to the model, the development of dysplasia of cervix and progression to invasive cancer is affected by a complex interaction of host and environmental factors.34-36 In particular, the viral proteins E6 and E7 produced by high-risk types of HPV appear to be critical for malignant transformation because of their ability to inactivate certain tumor-suppressor proteins.37
Because cervical cancer is usually asymptomatic until late stages, prevention of the disease through regular Pap smear screening is of critical importance. The natural history of the disease is such that there is a well-defined progression from pre-malignant disease to cancer, and this process can occur over a long period of time.38,39 These characteristics make cervical cancer ideally suited for preventive efforts.40
Effectiveness of Screening. The effectiveness of the Pap smear as a screening test has never been tested in a randomized controlled trial but has been suggested by a number of other types of investigations. Case control studies have shown a strong negative association between screening and invasive disease.41,42 Moreover, most countries that have instituted mass Pap screening programs have noted a corresponding drop in invasive cervical cancer and mortality.43-45 While these observational studies do not constitute direct evidence that screening was responsible for the findings, the large body of supportive evidence has prompted the adoption of routine cervical cancer screening in many countries.
Unfortunately, not all women receive regular Pap smear screening. The unscreened populations include older women, the uninsured, ethnic minorities, especially Hispanics and elderly blacks, and poor women, particularly those in rural areas.7,8 The barriers to cervical cancer screening have been well described. They include poverty, lack of health insurance, limited transportation, language difficulties, lack of child care, lack of telephone access, and certain cultural-based attitudes and health behaviors.7,8,18
A number of studies have evaluated interventions aimed at improving the use of Pap smears. The interventions have included reminder systems46 and educational materials about cervical cancer.47,48 In addition, several projects have evaluated culturally specific programs to improve cervical cancer screening in different ethnic groups, including church-based education49 and consejeras50 for Hispanic women and talking circles for American Indian women.51 Most of the studies indicate that the methods improve the rates of Pap smear use, at least in the short term. To improve the effectiveness of cervical cancer screening, it is important for primary care physicians to assure that their own patients receive appropriate screening. They may also wish to participate in community-based programs that reach out to the medically indigent.
Frequency of Screening. The recommended frequency of cervical cancer screening is based largely on expert opinion. In 1988, the American Cancer Society, the National Cancer Institute, the American College of Obstetricians and Gynecologists, the American Medical Association, the American Academy of Family Physicians, and others recommended that all women who were sexually active or who had reached age 18 should have annual Pap smears.52 The recommendation allowed for less frequent testing after three or more annual smears had been negative. The groups differed somewhat in their recommendations regarding other issues such as the age that Pap smear testing should be discontinued.
The U.S. Preventive Services Task Force, the gold standard for evidence-based clinical prevention recommendations, recently issued an updated set of guidelines that differed slightly from those above.53 (See Table 1.) The group recommended that testing should begin at the age when a woman first engages in sexual intercourse, that Pap smears should be performed at least every three years, and that the interval between screening should be based upon risk factors (i.e., multiple sexual partners). In addition, the Task Force found insufficient evidence to recommend for or against an upper age limit for Pap smear testing, but stated that it would be reasonable to discontinue testing in women over the age of 65 years who had regular screening in which the smears were consistently negative. Finally, the group recommended that women who had undergone a hysterectomy in which the cervix was removed did not require Pap smear testing unless the hysterectomy was performed for treatment of cervical cancer.
Cost-Effectiveness of Screening. While there is little debate about the benefits of cervical cancer screening, there have been few formal analyses of its cost-effectiveness. The supportive evidence for Pap smears has been derived from many studies indicating reductions in the incidence of invasive disease. Cervical cancer screening may contribute to reductions in the incidence of disease, a shift in stage of diagnosis, improved survival rates, and, ultimately, reductions in avoidable mortality. Therefore, there is a general consensus that the use of the Pap smear as a screening technique is cost-effective if standardized protocols are followed.54
Performance and Interpretation of Pap Smears. Methods of specimen acquisition, preparation, and evaluation of the Pap smear have changed little since its introduction in the 1940s. Although it is highly effective in screening for preinvasive lesions of the cervix, a single test has a false-negative rate estimated to be 20% (usual estimates range from 10% to 45%) or a sensitivity of 80%.55 Approximately one-half of the false negatives are due to inadequate specimen sampling, and the other half are attributed to a failure to identify the abnormal cells or to interpret them accurately. Although reliable data are lacking, the specificity of the single Pap smear is probably at least 90%.56 To improve the adequacy of the cervical smear specimen, a variety of sampling devices is available (e.g., spatula, endocervical brush, broom, and cotton swab). Controlled studies have shown that using an endocervical brush in combination with a spatula is more likely to collect endocervical cells than using a spatula or a cotton swab.57 There is conflicting evidence, however, that the endocervical brush increases the detection rate for abnormal smears or affects clinical outcomes.58,59
Pap smears are not read as simply positive or negative but rather as a continuum of findings. Traditionally, Pap smear abnormalities were classified as mild dysplasia at one end of the spectrum and invasive carcinoma at the other end. In the 1960s, the term cervical intraepithelial neoplasia (CIN) was coined to describe histological findings.60 CIN refers to a spectrum of intraepithelial changes beginning with those traditionally classified as mild dysplasia and ending with CIS. A grading system for CIN classifies lesions from 1 to 3 based upon the percentage of cells from the basement membrane to the surface that are undifferentiated. When one-third or less of the distance from the basement membrane to the surface is involved, the lesions are called CIN 1; when more than one-third but less than two-thirds is involved, they are called CIN 2; and, when more than two-thirds is involved, they are called CIN 3. When malignant cells penetrate the underlying basement membrane of the epithelium and infiltrate the stroma, the lesion is called invasive cervical cancer. Invasive cervical cancer is also classified into three grades: grade 1, or well differentiated carcinoma; grade 2, or moderately differentiated carcinoma; and grade 3, or poorly differentiated carcinoma.61
In 1988, the National Cancer Institute convened a panel to address the issue of classification of Pap smears.62,63 The resulting Bethesda System (as modified in 1991) is now used by most laboratories in this country; therefore, primary care providers should be familiar it. The Bethesda System evaluates the specimen for adequacy, uses diagnostic terminology, and makes recommendations pertaining to the smear when necessary. (See Table 2.) Among the diagnostic terminologies are low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL). LSIL are consistent with HPV and mild dysplasia, whereas HSIL include moderate and severe dysplasia and CIS. Another category of abnormal squamous cells is atypical squamous cells of undetermined significance (ASCUS). The glandular cell abnormalities are divided into two categories: atypical glandular cells of undetermined significance (AGUS) and adenocarcinoma. Many laboratories now report lesions using both the histological and the cytological classifications (i.e., CIN I/LSIL or CIN III/HSIL).
Performing the screening Pap smear is only the first step in the process of cervical cancer control. It is important for patients with abnormal Pap smears to return for follow-up and to receive appropriate treatment for the abnormalities. Failure to return for follow-up results in fewer women diagnosed with CIN and higher rates of invasive disease.
Patient Follow-Up. Rates of failure to return for follow-up and treatment after abnormal Pap test results vary, but typical estimates in mostly socioeconomically disadvantaged groups range from 30% to 40%.64 Many of the factors affecting Pap screening behavior, such as language, knowledge, culture and barriers to health care, also affect failure to return for follow-up.
A few studies have evaluated interventions aimed at improving rates of follow-up for abnormal Pap smears. The programs have included educational pamphlets, personalized follow-up letters, educational slide-tape programs, providing transportation, and structured telephone counseling.64-68 Like programs aimed at improving Pap smear screening, most of these programs improved follow-up rates somewhat. However, much more work is needed in this important area.
Management Options. Guidelines for the management of women with abnormal Pap smears are in a state of evolution as the value of HPV testing as a screening procedure is being evaluated. Because of the strong association of high-risk HPV types with cervical cancer, HPV testing may be included in future screening recommendations.37 In the meantime, reasonable guidelines are available that take into consideration the type of Pap smear abnormality and the likelihood that the abnormality will progress to invasive cervical cancer.37 Lesions consistent with ASCUS and LSIL are relatively unlikely to progress, whereas those consistent with HSIL are relatively likely to progress. In a multicenter study of LSIL, approximately two-thirds of the lesions regressed during long-term follow-up.69 On the other hand, HSIL lesions were clearly preinvasive and often progressed to invasive cervical cancer if untreated.70
Based on these considerations, patients with ASCUS or LSIL may be triaged according to whether their lesions are at low or high risk for becoming clinically significant.37 (See Table 3.) Women with ASCUS or LSIL who are at high risk include those over the age of 26, unreliable for follow-up, with a past history of abnormal cytology, unknown to the physician, with multiple sexual partners. In this scheme, patients with ASCUS or LSIL and a normal-appearing cervix should have a repeat Pap smear in six months. Those whose repeat smear suggests minor-grade cytologic atypia but are considered at low risk for developing higher grade lesions are followed at six-month intervals for up to two years and receive colposcopy only if the low-grade abnormality persists. Those women considered at high risk for progression would receive colposcopy as the next step. Generally, it is recommended that all patients with a lesion suspicious for cervical cancer on pelvic exam should receive a biopsy. Those patients with an unequivocally abnormal smear suggestive of HSIL should receive colposcopy. (See Table 3.)
Patients requiring colposcopy should be evaluated by a physician who is skilled with this procedure. The colposcopist uses a magnifying lens to view the cervix after an application of a dilute solution of acetic acid. Colposcopy enables the physician to evaluate the location and size of the lesion and to direct biopsies that will determine the definitive diagnosis made by histology. In a large review of articles by expert colposcopists, the sensitivity of colposcopy was 94% and the specificity was 51%. A colposcopic examination may also be either satisfactory or unsatisfactory. A satisfactory exam is one in which both the lesion and the squamocolumnar junction can be seen in entirety.
In general, management of abnormal Pap smears is a two-step process: biopsy and then treat. Classic teaching of colposcopy suggests obtaining biopsies of the colposcopically "worse" areas. Generally, acetowhite epithelium is considered abnormal, and as vascular atypias appear and become increasingly irregular, the suspicion for invasion increases. However, what seems to be the worst area may not necessarily be the area of occult invasion. Therefore, some experts recommend curettage in all non-pregnant patients with documented SIL (particularly during the learning curve of colposcopy) to establish a disease-free endocervical canal.37 They also recommend taking multiple biopsies including the squamocolumnar junction of the abnormal transformation zone.
Combined cytology, colposcopy, and histology will usually allow the physician to distinguish between patients with invasive cancer and those with SIL. Women with invasive disease should be treated according to the clinical stage of the lesion. Women with SIL should be treated on the basis of the histological biopsy diagnosis.10 Patients with CIN I require no further treatment because the majority of these lesions resolve spontaneously. On the other hand, patients with CIN II or CIN III require treatment to prevent development of invasive disease. There are two approaches to treating these lesions. The first approach uses conservative outpatient techniques including cryotherapy, laser vaporization, and the loop electric excision procedure (LEEP). These procedures may be used when the entire lesion and the entire transformation zone can be seen by colposcopy, there is no evidence of endocervical involvement, there is no discrepancy between the Pap smear results and the biopsy results, there is no evidence of an adenomatous lesion, and there is no evidence of invasive disease. The second approach is a surgical procedure called cervical conization or cone biopsy. This procedure involves resection of a conical area of cervical tissue that includes part of the endocervical canal. Patients who do not meet criteria for conservative management should undergo cone biopsy. (See Table 4.)
An alternative to the biopsy first, treat afterward approach is one that uses LEEP as a diagnostic and treatment (see and treat) method.37 This approach is less expensive than a cone biopsy because it is an office procedure. However, LEEP is appropriate only when colposcopy confirms the presence of an unequivocally abnormal transformation zone. Otherwise, the two-step approach should be used.
There are a number of exciting new developments that may help to improve the prevention of cervical cancer. Some of them include educational efforts that encourage behavioral changes to prevent infection; development of a vaccine against HPV; and testing for HPV during screening efforts.
Based upon strong evidence that HPV infection is causative in cervical cancer, a recent NIH Consensus Conference on Cervical Cancer recommended several approaches to prevention.19 Among other things, the group recommended more educational efforts directed toward adolescents and health care providers regarding the strong causal link between acquisition of HPV as a sexually transmitted disease and development of cervical cancer and its precursors. They also recommended the delay of the onset of sexual intercourse and the use of barrier methods of contraception in the sexually active.
The group also looked forward to the development of an effective prophylactic vaccine against HPV. However, although experimental animal studies have demonstrated that vaccination against HPV is possible,71 many conceptual issues must be addressed before the vaccines are available for clinical trials. In addition to the construction of the vaccine, issues such as the immune response following vaccination and the selection of target populations will be complex to resolve. Some clinical trials have used vaccines as part of a therapeutic regimen,72 but none have used it as primary prevention.
Finally, the group noted the advantages of developing better predictive markers for progression of SIL to cervical cancer. While the Pap smear remains the best screening test for cervical cancer, much uncertainty still exists regarding which patients with LSIL will progress to HSIL or invasive cancer. Identifying HPV types could provide important information about which patients should undergo colposcopy and which patients could be followed safely with Pap smears. For example, patients with high-risk HPV types (i.e., 16 and 18) might benefit from more aggressive management. Several large clinical trials are currently under way to determine whether HPV testing can effectively triage patients, to develop clinical management guidelines and provide prognostic information, and to identify areas for cost reduction in screening and treatment.37
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Physician CME Questions
55. The association between the human papillomavirus (HPV) and cervical cancer can best be characterized as:
a. HPV has no proven relationship to cervical cancer.
b. HPV subtypes are causally related to cervical cancer
c. HPV causes cervical cancer in all infected women
d. HPV testing is recommended as part of cervical cancer screening
e. HPV is the sole cause of cervical cancer
56. One of the most common reasons for a false negative Pap smear is:
a. inadequate specimen sampling.
b. failure of women to follow-up after an abnormal smear.
c. failure of women to receive a screening Pap smear.
d. the use of the endocervical brush.
e. the combined use of the endocervical brush and the spatula.
57. The U.S. Preventive Services Task Force (USPSTF) made the following recommendation regarding Pap smear screening:
a. all women should receive Pap smears at least every three years.
b. women who have had a hysterectomy for cervical cancer do not require Pap smears.
c. women should begin to receive Pap smears at the age they become sexually active.
d. all women who are sexually active should receive regular Pap smears.
e. women over the age of 65 do not require Pap smears.
58. According the Bethesda System, women with which of the following lesions are most likely to develop cervical cancer:
d. CIN I.
59. In a woman with a Pap smear consistent with HSIL, a reasonable strategy for follow-up would be:
a. repeat the Pap smear in six months and if HSIL persists, perform colopscopy.
b. repeat the Pap smear in three years and if HSIL persists, perform colposcopy.
c. peform colposcopy right away.
d. ignore the findings because they are probably clinically insignificant.
e. repeat the Pap smear in six months and if HSIL persists perform a hysterctomy.