9.  Screening for Cervical Cancer

RECOMMENDATION

Routine screening for cervical cancer with Papanicolaou (Pap) testing is

recommended for all women who are or have been sexually active and who

have a cervix. Pap smears should begin with the onset of sexual activity

and should be repeated at least every 3 years (see Clinical Intervention).

There is insufficient evidence to recommend for or against an upper age

limit for Pap testing, but recommendations can be made on other grounds

to discontinue regular testing after age 65 in women who have had regular

previous screenings in which the smears have been consistently normal.

There is insufficient evidence to recommend for or against routine

screening with cervicography or colposcopy, or for screening for human

papilloma virus infection, although recommendations against such

screening can be made on other grounds (see Clinical Intervention).

Burden of Suffering

Approximately 16,000 new cases of cervical cancer are diagnosed each

year, and about 4,800 women die from this disease annually.1 The lifetime

risk of dying from cervical cancer in the U.S. is 0.3%.1a Although the 5-

year survival rate is about 90% for persons with localized cervical cancer,

it is considerably lower (about 14%) for persons with advanced (Stage IV)

disease. The incidence of invasive cervical cancer has decreased

significantly over the last 40 years, due in large part to organized early

detection programs. Although all sexually active women are at risk for

cervical cancer, the disease is more common among women of low

socioeconomic status, those with a history of multiple sex partners or

early onset of sexual intercourse, and smokers. The incidence of invasive

cervical cancer among young white women has increased recently in the

United States. Infection with human immunodeficiency virus (HIV) and

certain types of human papilloma virus (HPV) also increases the risk of

cervical cancer.2

Accuracy of Screening Tests

The principal screening test for cervical cancer is the Pap smear.

Although the Pap smear can sometimes detect endometrial, vaginal, and

other cancers,3,4 its use as a screening test is intended for the early

detection of cervical dysplasia and cancer. Other proposed cervical

screening tests include cervicography, colposcopy, and testing for HPV

infection. The role of pelvic examination, which usually accompanies the

collection of the cervical specimen, is discussed in Chapter 14 in relation

to ovarian cancer screening.

Precise data on the sensitivity and specificity of the Pap smear in

detecting cancer and dysplasia are lacking due to methodologic problems.

Depending on study design, false-negative rates of 1-80% have been

reported; a range of 20-45% has been quoted most frequently, primarily in

studies comparing normal test results with subsequent smears.5-11

Studies using cone biopsy results as the reference standard have reported

false-negative rates as low as 10%.12 Although reliable data are lacking,

specificity is probably greater than 90%13 and may be as high as 99%.6,11

The detection of precursor cervical intraepithelial neoplasia (CIN) by Pap

smears may have poor specificity for cervical carcinoma, however,

because a substantial proportion of CIN-1 lesions do not progress to

invasive disease or may regress spontaneously. The test-retest reliability

of Pap smears is influenced to some extent by variations in the expertise

and procedures of different cytopathology laboratories.

A large proportion of diagnostic errors may be attributable to laboratory

error. In one study of over 300 laboratories given slides with known

cytologic diagnoses, false-negative diagnoses were made in 7.5% of

smears with moderate dysplasia or frank malignancy, and false-positive

diagnoses were made in 8.9% of smears with no more than benign

atypia.14 A survey of 73 laboratories in one state revealed a false-

negative rate of 4.4% and a false-positive rate of 2.7%.15 These data were

reported in 1990, before the introduction of federal legislation designed

to improve the accuracy of cytopathologic laboratory interpretation.16

With the adoption of the Bethesda system for classification of cervical

diagnoses,17 a large proportion of benign smears are interpreted as

"atypical," a finding that poses little premalignant potential but that

often generates intensive follow-up testing.

Another cause of false-negative Pap smears is poor specimen collection

technique. A 1991 survey of 600 laboratories found that 1-5% of

specimens received were either unsatisfactory or suboptimal, generally

because endocervical cells were absent from the smear.18 Another study

found that poor sampling technique accounted for 64% of false-negative

results.19 The Pap smear has traditionally been obtained with a spatula,

to sample the ectocervix, and a cotton swab, to obtain endocervical cells.

A 1990 survey found that about half of physicians used a spatula and

cotton swab to collect Pap smears.20 In recent years, new devices have

been introduced to improve sampling of the squamocolumnar junction.

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 cotton swab.21-30 There is conflicting evidence,

however, that the endocervical brush increases the detection rate for

abnormal smears or affects clinical outcomes.31-33 There is also

conflicting evidence regarding the importance of collecting endocervical

cells. Although some large series have reported that CIN is detected over

2 times more frequently when endocervical cells are present,34,35 other

series36,37 have shown no association between the presence of

endocervical cells and the detection rate for dysplasia. The brush is more

expensive than the cotton swab, but studies suggest that this cost is

easily recovered by the reduced need for repeat testing.38 Other methods

for improving the sensitivity of cervical cancer screening, such as acetic

acid washes to improve the visibility of lesions, remain

investigational.39,40

There are important potential adverse effects associated with inaccurate

interpretation of Pap smears. False-negative results are significant

because CIN or more invasive lesions may escape detection and progress

to more advanced disease during the period between tests. The potential

adverse effects of false-positive results include patient anxiety

regarding the risk of cervical cancer,41,42 as well as the unnecessary

inconvenience, discomfort, and expense of follow-up diagnostic

procedures. Studies have shown that the distribution of patient education

materials that explain the meaning of abnormal results is associated with

a reduction in patient anxiety and stress and a better patient

understanding of test results.43-45

Other tests, such as cervicography and colposcopy, have been proposed to

help improve the sensitivity of screening,46 but their accuracy and

technical requirements are suboptimal. Cervicography, in which a

photograph of the cervix is examined for atypical lesions, has a

sensitivity that is comparable to the Pap smear (approximately 60%) but a

much lower specificity (approximately 50%); the reported positive

predictive value in most studies is only 1-26%, and about 10-15% of

cervigrams are unsatisfactory.47-51 Colposcopy, in which the cervix is

examined under magnification with acetic acid washing and suspicious

lesions are biopsied, is widely performed on women with abnormal Pap

smears but has poor sensitivity (34-43%), specificity (68%), and positive

predictive value (4-13%) when used as a screening test for cervical

neoplasia in asymptomatic women.52-54 Other disadvantages of

colposcopy screening include its cost, the limited availability of the

equipment, the time and skills required to perform the procedure, and

patient discomfort. Using a 10-point score for assessing pain, one study

reported that women who underwent colposcopy gave the procedure a

range of scores from 3 to 4.6.55

Another proposed screening strategy is testing for HPV infection, a known

risk factor for cervical cancer. Of the more than 70 types of HPV that have

been identified, several oncogenic forms (e.g., types 16 and 18) have a

strong epidemiologic association with cervical cancer. However, the

natural history of how HPV infection progresses to cancer is poorly

understood.56 One study of women infected with either HPV type 16 or 18

found that 67% of the lesions remained unchanged or regressed after a

mean of 5 years, 29% progressed to a more advanced stage of dysplasia,

and 3% recurred.57 The high prevalence of HPV infection in young women

also limits its predictive value. In one study, nearly half of female college

students had evidence of HPV when tested by polymerase chain reaction

technology.58 The reported positive predictive value of this HPV test for

CIN-2 or CIN-3 lesions and carcinoma is less than 10%.59 HPV typing to

identify women with oncogenic strains may improve the future accuracy

of the test and its role in directing follow-up, but its current suitability

for routine screening in asymptomatic women is limited by its poor

predictive value, uncertain natural history, and, due to the absence of an

effective treatment, the lack of evidence that screening affects clinical

outcomes.60

Effectiveness of Early Detection

Early detection of cervical neoplasia provides an opportunity to prevent or

delay progression to invasive cancer by performing clinical interventions

such as colposcopy, conization, cryocautery, laser vaporization, loop

electrosurgical excision, and, when necessary, hysterectomy.61 There is

evidence that early detection through routine Pap testing and treatment of

precursor CIN can lower mortality from cervical cancer. Correlational

studies in the United States, Canada, and several European countries

comparing cervical cancer data over time have shown dramatic reductions

in the incidence of invasive disease and a 20-60% reduction in cervical

cancer mortality rates following the implementation of cervical screening

programs.62-70 Case-control studies have shown a strong negative

association between screening and invasive disease, also suggesting that

screening is protective.71-75 These observational studies do not

constitute direct evidence that screening was responsible for the

findings,76 and randomized controlled trials to provide such evidence have

not been performed. Nonetheless, the large body of supportive evidence

accumulated to date has prompted the adoption of routine cervical cancer

screening in many countries and makes performance of a controlled trial

of Pap smears unlikely for ethical reasons.

Observational data suggest that the effectiveness of cervical cancer

screening increases when Pap testing is performed more frequently.72

Aggressive dysplastic and premalignant lesions are less likely to escape

detection when the interval between smears is short. There are, however,

diminishing returns as frequency is increased.71,77 Although studies have

shown that reducing the interval between Pap smears from 10 years to 5

years is likely to achieve a significant reduction in the risk of invasive

cervical cancer, case-control studies and mathematical modeling have

demonstrated that increasing to a 2-3-year interval offers only slight

added benefit.71,78-80 There is little evidence that women who receive

annual screening are at significantly lower risk for invasive cervical

cancer than are women who are tested every 3-5 years. These findings

were confirmed in a major study of eight cervical cancer screening

programs in Europe and Canada involving over 1.8 million women.81

According to this report, the cumulative incidence of invasive cervical

cancer was reduced 64.1% when the interval between Pap tests was 10

years, 83.6% at 5 years, 90.8% at 3 years, 92.5% at 2 years, and 93.5% at 1

year. These estimates were for women aged 35-64 who had at least one

screening before age 35, and they are based on the assumption of 100%

compliance.

Recommendations of Other Groups

A consensus recommendation that all women who are or have been

sexually active, or who have reached age 18, should have annual Pap

smears has been adopted by the American Cancer Society, National Cancer

Institute, American College of Obstetricians and Gynecologists (ACOG),

American Medical Association, American Academy of Family Physicians

(AAFP), and others.82 The recommendation permits Pap testing less

frequently after three or more annual smears have been normal, at the

discretion of the physician. Guidelines for determining frequency based on

risk factors have been issued by ACOG.83 The consensus did not

recommend an age to discontinue Pap testing. The AAFP recommends that

screening can be discontinued at age 65 if there is documented evidence of

previously negative smears, but its recommendations are currently under

review.84 The American College of Physicians (ACP) recommends Pap

smears every 3 years for women aged 20-65, and every 2 years for women

at high risk.85 The ACP also recommends screening women aged 66-75

every 3 years if not screened in the 10 years before age 66. The Canadian

Task Force on the Periodic Health Examination recommends screening for

cervical cancer with annual Pap smears in women following initiation of

sexual activity or age 18, and after two normal smears, screening every 3

years to age 69.86 The Canadian Task Force recommends considering more

frequent screening for women at increased risk. In their guidelines for

adolescent preventive services (GAPS), the American Medical Association

recommends annual screening with a Pap test for female adolescents who

are sexually active or age 18 or older.87 Bright Futures also recommends

annual Pap testing for sexually active adolescent females.88 Similar

recommendations have been endorsed by the American Academy of

Pediatrics.89

Discussion

It has been estimated that screening women aged 20-64 every 3 years

with Pap testing reduces cumulative incidence of invasive cervical cancer

by 91%, requires about 15 tests per woman, and yields 96 cases for every

100,000 Pap smears. Annual screening reduces incidence by 93%, but

requires 45 tests and yields only 33 cases for every 100,000 tests.81

Empirical data also support the effectiveness of a 3-year interval. A study

of 25,000 Dutch women found that screening a stable population every 3

years reduced the incidence of squamous cell carcinoma of the cervix from

0.38 per 1000 to zero within 12 years.67 There are, in addition, important

economic considerations to performing Pap tests every 2-3 years, since

annual testing could double or triple the total number of smears taken on

over 92 million American women at risk,90 yet provide only limited added

benefit in lowering mortality.81

Annual testing, however, has been common. In the mid-1980s, a survey of

recently trained gynecologists found that 97% recommend a Pap test at

least once a year.91 The preference of many clinicians for performing

annual Pap smears is based on concerns that less frequent testing may

result in more harm than good, but reliable scientific data to support

these opinions are lacking. Specifically, advocates of annual testing have

expressed concerns that data demonstrating little added value to annual

testing are based on retrospective studies and mathematical models that

are subject to biases and invalid assumptions; that an interval longer than

1 year may permit aggressive, rapidly growing cancers to escape early

detection; that the public may obtain Pap smears at a lower frequency

than that publicized in recommendations; that a longer interval might

affect compliance among high-risk women, a group with poor coverage

even with an annual testing policy; that repeated testing may offset the

false-negative rate of the Pap smear; that the test is inexpensive and

safe; and that a large proportion of women believe it is important to have

an annual Pap test and, while visiting the clinician, may receive other

preventive interventions. Definitive evidence to support these concerns is

lacking.

Women who have never engaged in sexual intercourse are not at risk for

cervical cancer and therefore do not require screening.92-94 In addition,

screening of women who have only recently become sexually active (e.g.,

adolescents) is likely to have low yield. The incidence of invasive cancer

in women under age 25 is only about 1-3 per 100,000, a rate that is much

lower than that of older age groups.11 One study found that most women

with CIN who had become sexually active at age 18 were not diagnosed

with severe dysplasia or carcinoma in situ until age 30.93

Although invasive cervical cancer is uncommon at young ages, authorities

have recommended since the early 1980s that screening should begin with

the onset of sexual activity.82,92,94 This policy is based in part on the

concern that a proportion of young women with CIN may have an

aggressive cell type that can progress rapidly and go undetected if

screening is delayed to a later age. There is some evidence that

adenocarcinomas are accounting for a growing proportion of new cervical

cancer cases in young women,95,96 but the exact incidence and natural

history of aggressive disease in young women remain uncertain. The Pap

smear is also a poor screening test for adenocarcinoma, compared with

squamous cell carcinoma. Another reason given for early screening is the

concern that the incidence of cervical dysplasia occurring in young women

appears to be on the rise, coincident with the increasing sexual activity of

adolescents. On these grounds, testing should begin by age 18, since many

American teenagers are sexually active by this age. Screening in the

absence of a history of sexual intercourse may be justified if the

credibility of the sexual history is in question.

When screening is initiated, it is frequently recommended that the first

two to three smears be obtained 1 year apart as a means of detecting

aggressive tumors at a young age. There is little evidence to suggest,

however, that young women whose first two tests are separated by 2 or 3

years, rather than 1 year, have a greater mortality or person-years of life

lost.78 Recommendations to perform these first tests annually are based

primarily on expert opinion.

Elderly women do not appear to benefit from Pap testing if repeated

cervical smears have consistently been normal.97,78 Modeling data

suggest that continued testing of previously screened women reduces the

risk of dying from cervical cancer by only 0.18% at age 65 and 0.06% at

age 74.80 Many older women have had incomplete screening, however. A

reported 17% of women over age 65 and 32% of poor women in this age

group have never received a Pap test.98 In a study of elderly minority

women with an average age of 75 years, the mean reported number of prior

Pap smears received since age 65 was 1.7.99 Further screening in this

group of older women is important78,100 and some studies suggest that it

is cost-effective.101 Women who have undergone a hysterectomy in which

the cervix was removed do not benefit from Pap testing, unless it was

performed because of cervical cancer. Post-hysterectomy screening has

the potential to detect vaginal cancer, but the yield and predictive value

are likely to be very low. Women who had hysterectomies performed in

which the cervix was left behind probably still require screening.

The effectiveness of cervical cancer screening is more likely to be

improved by extending testing to women who are not currently being

screened and by improving the accuracy of Pap smears than by efforts to

increase the frequency of testing. Studies suggest that those at greatest

risk for cervical cancer are the very women least likely to have access to

testing.102,103 Incomplete Pap testing is most common among blacks, the

poor, uninsured persons, the elderly, and persons living in rural

areas.98,104-106 In addition, many women who are tested receive

inaccurate results due to interpretative or reporting errors by

cytopathology laboratories or specimen collection errors by clinicians.

The failure of some physicians to provide adequate follow-up for abnormal

Pap smears is another source of delay in the management of cervical

dysplasia.107 Finally, a large proportion of patients with abnormal

smears (30% in studies of poor, elderly black women108) do not return for

further evaluation. Various techniques may enhance physician and patient

compliance with screening, follow-up of abnormal results, and patient

compliance with rescreening.109-112

CLINICAL INTERVENTION

Regular Pap tests are recommended for all women who are or have been

sexually active and who have a cervix ("A" recommendation). Testing

should begin at the age when the woman first engages in sexual

intercourse. Adolescents whose sexual history is thought to be unreliable

should be presumed to be sexually active at age 18. There is little

evidence that annual screening achieves better outcomes than screening

every 3 years. Pap tests should be performed at least every 3 years ("B"

recommendation). The interval for each patient should be recommended by

the physician based on risk factors (e.g., early onset of sexual intercourse,

a history of multiple sex partners, low socioeconomic status). (Women

infected with human immunodeficiency virus require more frequent

screening according to established guidelines.113) There is insufficient

evidence to recommend for or against an upper age limit for Pap testing,

but recommendations can be made on other grounds to discontinue regular

testing after age 65 in women who have had regular previous screening in

which the smears have been consistently normal ("C" recommendation).

Women who have undergone a hysterectomy in which the cervix was

removed do not require Pap testing, unless the hysterectomy was

performed because of cervical cancer or its precursors. Patients at

increased risk because of unprotected sexual activity or multiple sex

partners should receive appropriate counseling about sexual practices (see

Chapter 62).

	The use of an endocervical brush increases the likelihood of

obtaining endocervical cells, but there is conflicting evidence that

sampling these cells improves sensitivity in detecting cervical neoplasia.

Physicians should submit specimens to laboratories that have adequate

quality control measures to ensure optimal accuracy in the interpretation

and reporting of results. Thorough follow-up of test results should also be

ensured, including repeat testing and referral for colposcopy as indicated.

Physicians should consider providing patients with a pamphlet or other

written information about the meaning of abnormal smears to help ensure

follow-up and minimize anxiety over false-positive results.

	There is insufficient evidence to recommend for or against routine

cervicography or colposcopy screening for cervical cancer in

asymptomatic women, nor is there evidence to support routine screening

for HPV infection ("C" recommendation). Recommendations against such

screening can be made on other grounds, including poor specificity and

costs.

The draft update of this chapter was prepared for the U.S. Preventive

Services Task Force by Steven H. Woolf, MD, MPH.

REFERENCES

  1. Wingo PA, Tong T, Bolden S. Cancer statistics, 1995. CA Cancer J Clin

1995;45:8-30.

 1a. Ries LAG, Miller BA, Hankey BF, et al, eds. SEER cancer statistics

review, 1973-1991: tables and graphs. Bethesda: National Cancer

Institute, 1994. (NIH Publication no. 94-2789.)

  2. American Cancer Society. Cancer facts and figures-1993. Atlanta:

American Cancer Society, 1993.

  3. Mitchell H, Giles G, Medley G. Accuracy and survival benefit of

cytological prediction of endometrial carcinoma on routine cervical

smears. Int J Gynecol Pathol 1993;12:34-40.

  4. Sherman ME, Paull G. Vaginal intraepithelial neoplasia: reproducibility

of pathologic diagnosis and correlation of smears and biopsies. Acta Cytol

1993;37:699-704.

  5. Kim HS, Underwood D. Adenocarcinoma in the cervicovaginal

Papanicolaou smear: analysis of a 12-year experience. Diagn Cytopathol

1991;7:199-224.

  6. Soost HJ, Lange HJ, Lehmacher W, Ruffing-Kullmann B. The validation

of cervical cytology: sensitivity, specificity, and predictive values. Acta

Cytol 1991;35:8-14.

  7. Foltz AM, Kelsey JL. The annual Pap test: a dubious policy success.

Milbank Mem Fund Q 1978;56: 426-462.

  8. Coppleson LW, Brown B. Estimation of the screening error rate from

the observed detection rates in repeated cervical cytology. Am J Obstet

Gynecol 1974;119:953-958.

  9. Benoit AG, Krepart GV, Lotocki RJ. Results of prior cytologic screening

in patients with a diagnosis of Stage I carcinoma of the cervix. Am J

Obstet Gynecol 1984;148:690-694.

 10. Jones DE, Creasman WT, Dombroski RA, et al. Evaluation of the

atypical Pap smear. Am J Obstet Gynecol 1987;157:544-549.

 11. Boyes DA, Morrison B, Knox EG, et al. A cohort study of cervical cancer

screening in British Columbia. Clin Invest Med 1982;5:1-29.

 12. Sfameni SF, Jobling TW, Trickey NRA, Havelock C. Evaluation of serial

cervical cytology in the assessment of preinvasive cervical neoplasia.

Aust NZ J Obstet Gynaecol 1989;29:40-43.

 13. Tawa K, Forsythe A, Cove JK, et al. A comparison of the Papanicolaou

smear and the cervigram: sensitivity, specificity, and cost analysis.

Obstet Gynecol 1988;71:229-235.

 14. Yobs AR, Swanson RA, Lamotte LC. Laboratory reliability of the

Papanicolaou smear. Obstet Gynecol 1985;65:235-243.

 15. DeBoy JM, Jarboe BR. Maryland's cytology labs: 1989-90 proficiency

testing results. Md Med J 1991;40: 107-111.

 16. Helfand M, O'Connor GT, Zimmer-Gembeck M, Beck JR. Effect of the

Clinical Laboratory Improvement Amendments of 1988 (CLIA `88) on the

incidence of invasive cervical cancer. Med Care 1992;30:1067-1082.

 17. The 1988 Bethesda System for reporting cervical/vaginal cytologic

diagnoses. Acta Cytol 1989;33: 567-574.

 18. Davey DD, Nielsen ML, Rosenstock W, Kline TS. Terminology and

specimen adequacy in cervico-vaginal cytology: the College of American

Pathologists Interlaboratory Comparison Program experience. Arch Pathol

Lab Med 1992;116:903-907.

 19. Dodd LG, Sneige N, Villarreal Y, et al. Quality-assurance study of

simultaneously sampled, non-correlating cervical cytology and biopsies.

Diagn Cytopathol 1993;9:138-144.

 20. Clement KD, Christenson PD. Papanicolaou smear cell recovery

techniques used by primary care physicians. J Am Board Fam Pract

1990;3:253-258.

 21. Helderman G, Graham L, Cannon D, Waters K, Feller D. Comparing two

sampling techniques for endocervical cell recovery on Papanicolaou

smears. Nurs Pract 1990;15:30-32.

 22. Hoffman MS, Hill DA, Gordy LW, Lane J, Cavanagh D. Comparing the

yield of the standard Papanicolaou and endocervical brush smears. J

Reprod Med 1991;36:267-269.

 23. Grossman MB, Clofine R. The efficacy of an endocervical brush in

obtaining adequate Papanicolaou smears. J Am Osteopath Assoc

1991;91:875-879.

 24. Lai-Goldman M, Nieberg RK, Mulcahy D, Wiesmeier E. The Cytobrush for

evaluating routine cervicovaginal-endocervical smears. J Reprod Med

1990;35:959-963.

 25. Koonings PP, Dickinson K, d'Ablaing G III, Schlaerth JB. A randomized

clinical trial comparing the Cytobrush and cotton swab for Papanicolaou

smears. Obstet Gynecol 1992;80:241-245.

 26. Ruffin MT IV, Van Noord GR. Improving the yield of endocervical

elements in a Pap smear with the use of the cytology brush. Fam Med

1991;23:365-369.

 27. Davey-Sullivan B, Gearhart J, Evers CG, Cason Z, Replogle WH. The

Cytobrush effect on Pap smear adequacy. Fam Pract Res J 1991;11:57-64.

 28. Buntinx F, Boon ME, Beck S, Knottnerus JA, Essed GGM. Comparison of

Cytobrush sampling, spatula sampling, and combined Cytobrush-spatula

sampling of the uterine cervix. Acta Cytol 1991;35:64-68.

 29. Fokke HE, Salvatore CM, Schipper MEI, Bleker OP. The quality of the

Pap smear. Eur J Gynaecol Oncol 1992;13:445-448.

 30. McCord ML, Stovall TG, Meric JL, Summitt RL Jr, Coleman SA. Cervical

cytology: a randomized comparison of four sampling methods. Am J Obstet

Gynecol 1992;166:1772-1779.

 31. Cauthen DB, Cullison M, Symm B, Peterson RF. Use effectiveness of the

Cytobrush in the primary care setting. J Am Board Fam Pract 1991;5:365-

368.

 32. Szarewski A, Curran G, Edwards R, Cuzick J, Kocjan G, Bounds W,

Guillebaud J. Comparison of four cytologic sampling techniques in a large

family planning center. Acta Cytol 1993;37:457-460.

 33. Alons-van Kordelaar JJM, Boon ME. Diagnostic accuracy of squamous

cervical lesions studied in spatula-cytobrush smears. Acta Cytol

1988;32:801-804.

 34. Elias A, Linthorst G, Bekker B, Vooijs PG. The significance of

endocervical cells in the diagnosis of cervical epithelial changes. Acta

Cytol 1983;27:225-229.

 35. Mauney M, Eide D, Sotham J. Rates of condyloma and dysplasia in

Papanicolaou smears with and without endocervical cells. Diagn

Cytopathol 1990;6:18-21.

 36. Kivlahan C, Ingram E. Papanicolaou smears without endocervical cells:

are they inadequate? Acta Cytol 1986; 30:258-260.

 37. Mitchell H, Medley G. Longitudinal study of women with negative

cervical smears according to endocervical status. Lancet 1991;337:741-

742.

 38. Harrison DD, Hernandez E, Dunton CJ. Endocervical brush versus cotton

swab for obtaining cervical smears at a clinic: a cost comparison. J

Reprod Med 1993;38:285-288.

 39. Slawson DC, Bennett JH, Herman JM. Are Papanicolaou smears enough?

Acetic acid washes of the cervix as adjunctive therapy: a HARNET study. J

Fam Pract 1992;35:271-277.

 40. Van Le L, Broekhuizen FF, Janzer-Steele R, Behar M, Samter T. Acetic

acid visualization of the cervix to detect cervical dysplasia. Obstet

Gynecol 1993;81:293-295.

 41. Lerman C, Miller SM, Scarborough R, Hanjani P, Nolte S, Smith D.

Adverse psychologic consequences of positive cytologic cervical

screening. Am J Obstet Gynecol 1991;165:658-662.

 42. Lauver D, Rubin M. Women's concerns about abnormal Papanicolaou test

results. J Obstet Gynecol Neonatal Nurs 1991;20:154-159.

 43. Wolfe C, Doherty I, Raju KS, Holtom R, Richardson P. First steps in the

development of an information and counselling service for women with an

abnormal smear result. Eur J Obstet Gynecol Reprod Biol 1992;45:201-206.

 44. Wilkinson C, Jones JM, McBride J. Anxiety caused by abnormal result

of cervical smear test: a controlled trial. BMJ 1990;300:440.

 45. Stewart DA, Lickrish GM, Sierra S, Parkin H. The effect of educational

brochures on knowledge and emotional distress in women with abnormal

Papanicolaou smears. Obstet Gynecol 1993;81:280-282.

 46. Hocutt JE Jr, Clark RC, Pfenninger JL. Papanicolaou testing and

colposcopic screening. J Fam Pract 1992; 34:38-40.

 47. Cecchini S, Bonardi R, Mazzotta A, Grazzini G, Iossa A, Clatto S.

Testing cervicography and cervicoscopy as screening tests for cervical

cancer. Tumori 1993;79:22-25.

 48. Ferris DG, Payne P, Frisch LE, Milner FH, diPaola FM, Petry LJ.

Cervicography: adjunctive cervical cancer screening by primary care

clinicians. J Fam Pract 1993;37:158-164.

 49. Szarewski A, Cuzick J, Edwards R, Butler B, Singer A. The use of

cervicography in a primary screening service. Br J Obstet Gynaecol

1991;98:313-317.

 50. Blythe JG. Cervicography: a preliminary report. Am J Obstet Gynecol

1985;152:192-197.

 51. Tawa K, Forsythe A, Cove JK, et al. A comparison of the Papanicolaou

smear and the cervigram: sensitivity, specificity, and cost analysis.

Obstet Gynecol 1988;71:229-235.

 52. Hockstad RL. A comparison of simultaneous cervical cytology, HPV

testing, and colposcopy. Fam Pract Res J 1992;12:53-60.

 53. Nathan PM, Moss TR. Screening colposcopy in genitourinary medicine.

Int J STD AIDS 1991;2:342-345.

 54. Olatunbosun OA, Okonofua FE, Ayangade SO. Screening for cervical

neoplasia in an African population: simultaneous use of cytology and

colposcopy. Int J Gynecol Obstet 1991;36:39-42.

 55. Rodney WM, Huff M, Euans D, Hutchins C, Clement K, McCall JW III.

Colposcopy in family practice: pilot studies of pain prophylaxis and

patient volume. Fam Pract Res J 1992;12:91-98.

 56. Richart RM, Wright TC Jr. Controversies in the management of low-

grade cervical intraepithelial neoplasia. Cancer 1993;71:1413-1421.

 57. Kataja V, Syrjanen S, Jarvi RM, Yliskoski M, Saarikoski A, Syrjanen K.

Prognostic factors in cervical human papillomavirus infections. Sex Trans

Dis 1992;19:154-160.

 58. Bauer HM, Greer CE, Chambers JC, Tashiro CJ, Chimera J, Reingold A,

Manos MM. Genital human papillomavirus infection in female university

students as determined by a PCR-based method. JAMA 1991;265:472-477.

 59. Zazove P, Reed BD, Gregoire L, Gorenflo DW, Lancaster WD, Ruffin MT

IV, Hruszcyzk J. Presence of human papillomavirus infection of the uterine

cervix as determined by different detection methods in a low-risk

community-based population. Arch Fam Med 1993;2:1250-1257.

 60. Sedlacek TV, Sedlacek AE, Neff DK, Rando RF. The clinical role of

human papilloma virus typing. Gyn Oncol 1991;42:222-226.

 61. American College of Obstetricians and Gynecologists. Cervical

cytology: evaluation and management of abnormalities. Technical Bulletin

no. 183. Washington, DC: American College of Obstetricians and

Gynecologists, 1993.

 62. Cramer DW. The role of cervical cytology in the declining morbidity

and mortality of cervical cancer. Cancer 1974;34:2018-2027.

 63. Miller AB, Lindsay J, Hill GB. Mortality from cancer of the uterus in

Canada and its relationship to screening for cancer of the cervix. Int J

Cancer 1976;17:602-612.

 64. Anderson GH, Boyes DA, Benedet JL, et al. Organisation and results of

the cervical cytology screening programme in British Columbia, 1955-85.

BMJ 1988;296:975-978.

 65. Johanneson G, Geirsson G, Day N. The effect of mass screening in

Iceland, 1965-1974, on the incidence and mortality of cervical carcinoma.

Int J Cancer 1978;21:418-425.

 66. Laara E, Day NE, Hakama M. Trends in mortality from cervical cancer in

the Nordic countries: association with organized screening programmes.

Lancet 1987;1:1247-1249.

 67. Boon ME, de Graaf Guilloud JC, Rietveld WJ, Wijsman-Grootendorst A.

Effect of regular 3-yearly screening on the incidence of cervical smears:

the Leiden experience. Cytopathology 1990;1:201-210.

 68. Costa MJ, Grimes C, Tackett E, Naib ZM. Cervicovaginal cytology in an

indigent population: comparison of results for 1964, 1981 and 1989. Acta

Cytol 1991;35:51-56.

 69. Benedet JL, Anderson GH, Matisic JP. A comprehensive program for

cervical cancer detection and management. Am J Obstet Gynecol

1992;166:1254-1259.

 70. Sigurdsson K. Effect of organized screening on the risk of cervical

cancer: evaluation of screening activity in Iceland, 1964-1991. Int J

Cancer 1993;54:563-570.

 71. La Vecchia C, Decarli A, Gentile A, et al. Pap smear and the risk of

cervical neoplasia: quantitative estimates from a case-control study.

Lancet 1984;2:779-782.

 72. Clarke EA, Anderson TW. Does screening by Pap smears help prevent

cervical cancer? A case-control study. Lancet 1979;2:1-4.

 73. Aristizabal N, Cuello C, Correa P, et al. The impact of vaginal cytology

on cervical cancer risks in Cali, Colombia. Int J Cancer 1984;34:5-9.

 74. Berrino F, Gatta G, d'Alto M, et al. Efficacy of screening in preventing

invasive cervical cancer: a case-control study in Milan, Italy. IARC Sci

Publ 1986;76:111-123.

 75. Herrero R, Brinton LA, Reeves WC, Brenes MM, De Britton RC, Gaitan E,

Tenorio F. Screening for cervical cancer in Latin America: a case-control

study. Int J Epidemiol 1992;21:1050-1056.

 76. Skrabanek P. Cervical cancer screening. Lancet 1987;1:1432-1433.

 77. Miller AB, Visentin T, Howe GR. The effect of hysterectomies and

screening on mortality from cancer of the uterus in Canada. Int J Cancer

1981;27:651-657.

 78. Yu S, Miller AB, Sherman GJ. Optimising the age, number of tests, and

test interval for cervical screening in Canada. J Epidemiol Community

Health 1982;36:1-10.

 79. Brinton LA, Tashima KT, Lehman HF, et al. Epidemiology of cervical

cancer by cell type. Cancer Res 1987; 47:1706-1711.

 80. Eddy DM. Screening for cervical cancer. Ann Intern Med 1990;113:214-

226.

 81. International Agency for Research on Cancer 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 implication for screening policies. BMJ

1986;293:659-664.

 82. American Cancer Society. Guidelines for the cancer-related checkup:

an update. Atlanta: American Cancer Society, 1993. 

 83. American College of Obstetricians and Gynecologists.

Recommendations on frequency of Pap test screening. Committee Opinion

no. 152. Washington, DC: American College of Obstetricians and

Gynecologists, 1995.

 84. American Academy of Family Physicians. Age charts for periodic

health examination. Kansas City, MO: American Academy of Family

Physicians, 1994. (Reprint no. 510.)

 85. American College of Physicians. Screening for cervical cancer. In:

Eddy DM, ed. Common screening tests. Philadelphia: American College of

Physicians, 1991:413-414.

 86. Canadian Task Force on the Periodic Health Examination. Canadian

guide to clinical preventive health care. Ottawa: Canada Communication

Group, 1994:884-889.

 87. American Medical Association. AMA guidelines for adolescent

preventive services (GAPS): recommendations and rationale. Chicago:

American Medical Association, 1994.

 88. Green M, ed. Bright Futures: guidelines for health supervision of

infants, children and adolescents. Arlington, VA: National Center for

Education in Maternal and Child Health, 1994.

 89. American Academy of Pediatrics. Guidelines for health supervision II.

Elk Grove Village, IL: American Academy of Pediatrics, 1988.

 90. U.S. Bureau of the Census. Statistical abstract of the United States,

1993. 113th ed. Washington, DC: Bureau of the Census, 1993.

 91. Weisman CS, Celentano DD, Hill MN, et al. Pap testing: opinion and

practice among young obstetricians-gynecologists. Prev Med 1986;15:342-

351.

 92. Cervical cancer screening: summary of an NIH consensus statement.

BMJ 1980;281:1264-1266.

 93. Wright VC, Riopelle MA. Age at time of intercourse v. chronological

age as a basis for Pap smear screening. Can Med Assoc J 1982;127:127-

131.

 94. Canadian Task Force on Cervical Cancer Screening Programs. Cervical

cancer screening programs: summary of the 1982 Canadian task force

report. Can Med Assoc J 1982;127:581-589.

 95. Webb MJ, Sheehan TM. Invasive carcinoma of the cervix in young

women. Aust NZ Obstet Gynaecol 1989; 29:47-51.

 96. Miller BE, Flax SD, Arheart K, Photopulos G. The presentation of

adenocarcinoma of the uterine cervix. Cancer 1993;72:1281-1285.

 97. Van Wijngaarden WJ, Duncan ID. Rationale for stopping cervical

screening in women over 50. BMJ 1993; 306:967-971.

 98. Calle EE, Flanders WD, Thun MJ, Martin LM. Demographic predictors of

mammography and Pap smear screening in US women. Am J Public Health

1993;83:53-60.

 99. Mandelblatt J, Traxler M, Lakin P, Kanetsky P, Kao R. Mammography and

Papanicolaou smear use by elderly poor black women. Harlem Study Team.

J Am Geriatr Soc 1992;40:1001-1007.

100. Mandelblatt J, Gopaul I, Wistreich M. Gynecologic care of elderly

women: another look at Papanicolaou smear testing. JAMA 1986;256:367-

371.

101. Mandelblatt JS, Fahs MC. The cost-effectiveness of cervical cancer

screening for low-income elderly women. JAMA 1988;259:2409-2413.

102. Kleinman JC, Kopstein A. Who is being screened for cervical cancer?

Am J Public Health 1981;71:73-75.

103. Hayward RA, Shapiro MF, Freeman HE, et al. Who gets screened for

cervical and breast cancer? Results from a new national survey. Arch

Intern Med 1988;148:1177-1181.

104. Nasca PC, Ellish N, Caputo TA, Saboda K, Metzger B. An epidemiologic

study of Pap screening histories in women with invasive carcinomas of

the uterine cervix. NY State J Med 1991;91:152-156.

105. Mayer JA, Slymen DJ, Drew JA, Wright BL, Elder JP, Williams SJ.

Breast and cervical cancer screening in older women: the San Diego

Medicare Preventive Health Project. Prev Med 1992;21:395-404.

106. Harlan LC, Bernstein AB, Kessler LG. Cervical cancer screening: who

is not screened and why? Am J Public Health 1991;81:885-891.

107. Koss LG. The Papanicolaou test for cervical cancer detection: a

triumph and a tragedy. JAMA 1989;261:737-743.

108. Mandelblatt J, Traxler M, Lakin P, Kanetsky P, Thomas L, Chauhan P,

Matseoane S, Ramsey E, and the Harlem Study Group. Breast and cervical

cancer screening of poor, elderly, black women: clinical results and

implications. Am J Prev Med 1993;9:133-138.

109. Marcus AC, Crane LA, Kaplan CP, et al. Improving adherence to

screening follow-up among women with abnormal Pap smears: results

from a large clinic-based trial of three intervention strategies. Med Care

1992;30:216-230.

110. Curtis P, Skinner B, Varenholt JJ, Addison L, Resnick J, Kebede M.

Papanicolaou smear quality assurance: providing feedback to physicians. J

Fam Pract 1993;36:309-312.

111. Paskett ED, White E, Carter WB, Chu J. Improving follow-up after an

abnormal Pap smear: a randomized controlled trial. Prev Med 1990;19:630-

641.

112. Pachiarz JA, Abbott MI, Gorman B, Henneman CE, Kuhl M. Continuous

quality improvement of Pap smears in an ambulatory care facility. QRB

Qual Rev Bull 1992;18:229-235.

113. El-Sadr W, Oleske JM, Agins BD, et al. Evaluation and management of

early HIV infection. Clinical practice guideline no. 7. Rockville, MD: Agency

for Health Care Policy and Research, 1994:60-65. (AHCPR Publication No.

94-0572.)