8th Postgraduate Course for Training in Reproductive Medicine and Reproductive Biology

Cytology as a Cervical screening Test: How effective is it?

S. Bomfim Hyppolito
Federal University of Ceara
Fortaleza-Ceara-Brazil

Objective : To assess the effectiveness of cytology Pap smear as a screening test to early detection of Low and High Grade Squamous Intraepithelial Lesions (LHSIL and HGSIL) and cervical cancer, as well.

Search strategy : A computerized Medline search and a manual literature search of a relevant unpublished paper.
All was conducted to identify registered randomized trials and other quasi-randomized studies discussing the effectiveness of Pap smear as a screening test for cancer and pre-cancerous lesions within the last ten years . Few studies developed before that were also included because they were found relevant by the investigator.

Selection criteria : Studies : randomized or quasi-randomized trials
  • Participants : Women attending for primary screening, colposcopy/biopsy following an abnormal smear.
  • Interventions : Different Designs of Cervical Smear Collection Devices, and other tests or lab techniques developed to enhance Pap smear tests and cervical detection screening programs but that also tested Pap smear sensitivity and specificity.
  • Outcome measures : Sensitivity and specificity rates and other measured outcomes which addressed to efficacy of Pap smear test per se or when compared with other screening tests.

Data collection and analysis : Data were extracted by the reviewer and any discrepancy was discussed with the senior advisor and modified.

Main results : Eight randomized or quasi randomized trials published during the last ten years investigating different Kind of cervical collection devices and slide preparation techniques, and comparing also HPV-DNA and cervicography tests with Pap smear test demonstrated that: Pap smear sensitivity medium rate is around 60% (29 to 80%).

Conclusions : Pap smear is just a screening test and is subjected to limitations. It reduces the incidence of cervical cancer but it is not expected to detect all the precursor lesions and it is not appropriate to detect large invasive neoplasias.
In spite of the apparent simplicity in detection of cervical intraepithelial neoplasias and of cancer of the cervix, numerous biochemical, cytological and socio-economic problems are involved on the efficiency of cytology as a screen test. The challenge is to enhance it with high cost-effective approaches.

 

Background

Although efforts to reduce the health impact of cervical cancer have been initiated in countries all over the world, most attempts in developing countries have not been successful due to such factors as limited access to necessary health interventions, and inability to provide accurate Pap smear services to all those who need them.

Since 1943 when Papanicolaou and Traut proposed a new technique - Pap smear test - to detect precursors of cervical cancer in women, cytological screening has been one, and probably the most successful of several public health measures introduced for the prevention of cancer. On the other hand, the effectiveness of this screening technology is taken for granted, and this may have been a mistake. The quality of Pap smear can be influenced by many factors, including the technique of collecting the cells from the cervix and the method of preserving and handling the smear plus the accuracy of data interpreters. The perception that the Pap smear is infallible has led many to believe that a negative test means the absence of cervical cancer.

Recent data (Melamed MR et al, 1998) from International Academy of Cytology Task Force shows that the undetected abnormalities rate is around 10-35% of abnormal Pap smear slides. This means that one out of every five or one out of every four abnormalities are not detected. Other more comprehensive studies (Hussein Y et al, 1997) shows results between 20 and 30%. This corresponds to sensitivity rates of 70% to 80%.

Cervical screening has been proven to be effective in decreasing the incidence of invasive disease where comprehensive programs exist (Parkin 1985, Duguid 1985). In spite of this, cervical cancer is still an important reproductive health problem in women, especially in developing countries where at least 200.000 women die from the disease each year.

It has become a consensus nowadays that the adequacy of a cervical smear is considered when there is the presence of endocervical cells, since their presence means the transformation zone, from which premalignant change arises, has been catched. It seams to be a reliable assumption, as the updated Cochrane review study (Martin-Hirsch P, et al 1997) on cervical smear collection devices concluded, that the widely used Ayre spatula is the least effective device for cervical sampling and that it should be replaced by the Aylesbury spatula because it allows better endocervical collection sample. So, they have agreed , detection rates of endocervical cells appear to be a valid and convenient surrogate for the ability to detect dyskaryosis. Ayre spatula is the more commonly used device on several countries, including Brazil, and cytopathology labs are not considering the inclusion of endocervical cells in the smear as a quality standard issue. Other authors (Kristensen GB et al,1989) advocate that a large-scale application of the spatula-cytobrush method should result in fewer repeat smears required and fewer false-negative tests.

Additionally the location of the transformation zone varies; it moves towards ectocervix during reproductive life and is indrawn in the endocervix with menopause. So the appropriateness of the sampling instrument is bests determined by the characteristics of the women’s cervix and the location of the transformation zone.

Even if one collects adequate Pap smear, poor transfer of the cells to the slide may result in a sample either too thick or uneven for accurate exam. Many investigators ( Hutchinson ML et al, 1992) are now testing and proposing different smears preparation techniques such as the monolayers system and comparing it to conventional preparations. According to Noorani H Z, 1997, these techniques may increase the effectiveness of the Pap test. The collection of cervical cells remain the same, but the cells are rinsed from the collection device into a vial of preservative solution. Automated process gently disperse the sample, then separate cervical epithelial cells from debris by filtration (ThinPrep) or density gradient centrifugation (CytoRich). The results seem to reduce inadequate smears, but increases cost, becoming not feasible to include on Cervical Cancer detection screening programs in developing countries.

Each smear might contains approximately 300.000 epithelial cells and at least 5 minutes careful look is required for each slide reading. It is impossible for a cytotechnologist to screen with accuracy a large number of smears a day. As developing countries have few lab resources, they are also usually overloaded and there are also very few persons who are well trained to read the slides. To improve screening profile requires a selective screening program and a continuing training program for cytotechnologists. Several authors (Schneider A, 1996) ,though ,are proposing screening for cervical intraepithelial neoplasia grade 2/3 can significantly be improved by Human Papillomavirus (HPV) testing. Some authors (Dunggan et al, 1998) understand that other risk factors such as the age of the women and a history of cigarette smoking were significant predictors of triaged co-incidental CIN II/III and would limit the adoption of HPV testing as an universal, adjunctive test for the identification of those cervical neoplasias. Sideri M et al, 1998 also found that the classification model based in the demographic and lifestyle variables showed comparable results with molecular hybridization for HPV, so that it appears to be a simple and economic possibility for triaging patients with mild dyskaryotic smears in a screening program. So, other alternative strategies can be conducted to enhance Pap smear screening profile.

The importance of laboratory quality is recognized. However there are not yet consistent and systematic guidelines for cervical cytopathology laboratories in many countries. Matsuura et al, 1996, suggest that a composite diagnosis with cytology, colposcopy and punch biopsy is necessary for a correct evaluation of cases and thus increasing the accuracy rates of cytology. Others ,such as Hathorne et al, 1997, advocate the evaluation of cytotechnology trainees through a Compucyte Pathfinder database technique which can reasonably evaluate the performance of human resources of labs who interpret Pap test. In one or other way the quality assurance must be met, and it should be on continuous base.

Women usually do not have regular contact with the health care system or do not have regular Pap smear for various reason. The great majority of positive cases are women who have never had a Pap smear test because of lack of information about the need for preventive care or because they have not had access to cervical cancer detection screening test. There must be more comprehensive cervical cancer screening program services and the identification of simple low-cost screening strategies using local people for performing collecting samples or performing other low technology but appropriate tests. That might help to recruit ever screened women and, at the same time would give assess to better follow-up of negative pap test, thus enhancing its sensitivity.

This systematic bibliographic review intends to study to the issues that are specifically addressed to the efficacy of Pap smear as a Cervical Cancer screening test: sensitivity and specificity.

Search strategy for identification of studies

A computerized Medline search was conducted to identify all randomized or quasi-randomized trials which were related to cytology as a cervical cancer screening test with a major preference on the ones published within the last ten years.

The methods (matches) for identifying trials in the Medline were as follows:
  1. cervical cancer screening
  2. cervical cancer screening test
  3. cytology Pap smear
  4. Pap smear sensitivity
  5. Pap smear specificity
  6. search through name of authors
  7. search by name of publications
  8. search by year of publication

Methods of the Review

At first the studies were selected taking into account the following issues : Title of the study (objective), Type of study, Number of subjects, Methodology, Institution (setting of the study), Outcomes, Investigators and Publication.

The studies selected were:

Title of study Institution Investigators Publication
Predictors of co-incidental CIN II/III amongst a cohort of women with CIN I detected by a screening Pap test Department of Pathology, Foothills Hospital and the University of Calgary, Alberta Canada Duggan MA, McGregor SE, Stuart GC, Morris S, Chang-Poon V, Schepansky A, Honore L Eur J Gynaecol Oncol 1998;19(3):209-214
Comparison of the CytoRich System with conventional cervical cytology Department of Pathology, Creighton University School of Medicine, Omaha Nebraska, USA Bishop, JW Acta Cytol 1997 Jan;41(1):15-23
Early cervical neoplasia confirmed by conization: diagnostic accuracy of cytology, colposcopy and punch biopsy Department of Obstetrics and Gynecology, University of Occupational and Environmental Health, Iseigaoka, Japan Matsuura Y, Kawagoe T, Toki N, Sufihara K, Kashimura M Acta Cytol 1996 Mar;40(2):241-246
Comparison of the reliability of Repeat cervical smears and colposcopy in Patients with abnormal cervical cytology Louisiana State University Medical Center Mayeaux J, Harper MB, Abreo F, Pope JB, Phillips GS J Fam Pract 1995 Jan;40(1):57-61
Should cervical cytological testing be augmented by cervicography or human papillomavirus deoxyribonucleic acid detection? Department of Obstetrics and Gynecology and Pathology Sinai Hospital, Detroit Reid R, Greenberg MD, Lorincz A, Jenson BA, Loverty CR, Husain M, Daound Y, Yado B, White T., Cantor D, Goldrath M Am J Obstet Gynecol 1991 Jun;164:1461-1469
Screening for cervical intraepithelial neoplasia grade 2/3:validity of cytological study, cervicography and human papillomavirus detection Department of Gynecology Friedrich Schiller University Jena, Germany Schneider A, Yahm DM, Kirchmayr R, Schneider VL Am J Obstet Gynecol 1996 May;174(5):1534-1541
The Validation of Cervical Cytology, Sensitivity, Specificity and Predictive Values Institute for Clinical Cytology and the Institute for Medical Statistics and Epidemiology, Technical University of Munich Soost HJ, Lange HJ, Lehmacher W, Ruffing -Kullmann B Acta Cytol 1991 Jan;35(1):8-13
The Bethesda classification for squamous intraepithelial lesions: histologic, cytological, and viral correlates Department of Pathology, University of Virginia Health Sciences Center, Charlottesville Tabbara S, Saleh AD, Andersen WA, Barber SR, Taylor PT, Crum CP Obstet Gynecol 1992 Mar;79(3):338-346

 Description of the studies

1. Duggan et al, 1998

Objective: To determine the target group through the high-risk prediction approach, to select the CIN I, CIN II cases diagnosed by Pap test for HPV testing.

Study Design: 622 women referred to three hospital-based colposcopic clinics for investigation of a Pap test abnormality interpreted as CIN I were approached and consented to participate in a 33 month prospective study of the natural outcome of CIN I lesions. At the colposcopic examination a cervical scrape/endocervical sampling for routine cytology was performed using Ayre spatula and/or Cytobrush. A second scrape for HPV typing was next taken with a prewashed Ayre spatula. Consensus regarding pathological and colposcopic criteria was reached amongst the clinics. All investigators were masked to the results of the HPV testing. The women were divided into two groups based on the colposcopic impressions and the repeat Pap test. Group A comprised those whose lesions by both investigative modalities was considered to be CIN I or lesser (</=CIN I) and to group B those with CIN II or greater (>/=CIN II).

Findings: Out of 537 women (there were excluded subjects) recruited for the study, group A was comprised of 342 (63.7%) triaged as </= CIN I by combined colposcopic and Pap test, and group B was comprised of 195 (36.3%) women triaged as >/=CIN II. 36,3% of cervical abnormalities classified as CIN I by Pap test were found to be CIN II/III when correlated with subsequent colposcopic directed biopsy. Triaged co-incidental CIN II/III lesions, however tended to have more HPV positive samples and a higher prevalence of HPV 16/18.

2. Bishop JW, 1997

Objective: To compare the CytoRich system with conventional cervical cytology in a university medical center hospital.

Study Design: 2.32 parallel conventional cervical cytology and CytoRich samples were examined as part of a multiple center trial. Same patients conventional and CytoRich slides were submitted to separate cytotechnologists blindly. The results were compared and all nonmatching sample pairs were reviewed again.

Findings: CytoRich slides had 86.7% sensitivity for SIL and 99.1% specificity while the conventional slides had 63.6% sensitivity and 99.7% specificity. The biopsy correlation results were similar for the two methods.

3. Matsuura Y et al, 1996

Objective: To investigate through a long-term follow-up (more than five years) low grade cervical intraepithelial neoplasia associated with HPV infection.

Study Design: During the 10 years from 1984 to 1993, cold knife conization was performed on 151 patients with early cervical neoplasia proven by punch biopsy. The accuracy rates of cytology, colposcopy and punch biopsy were investigated. The cytological samples were obtained by a swabbing technique. All patients with abnormal cervical cytology underwent colposcopic evaluation. Punch biopsy of cervical tissue was obtained from the most severely abnormal colposcopic finding. Conization was performed in cases of severe dysplasia and by microinvasive carcinoma proven by punch biopsy.

Findings: The accuracy rates for severe dysplasia and CIS, microinvasive carcinoma and frankly invasive carcinoma were 65% (69 of 106), 16% (6 of 38) and 43% (3 of 7), respectively. The overall accuracy rate was 52% (78 of 151), Cytological underestimation occurred in 43% of the cases (66 of 151) and overestimation occurred in 5% (7 of 151).

4. Mayeaux J et al 1995

Objective:To determine the reliability of repeat cervical smears (Papanicolaou smears) in patients who have an abnormal initial smear, prospective data were selected on patients being followed up for a previously normal cervical smear.

Study Design: All patients with a cervical smear showing evidence of SIL, any form of atypia, or a second inflammatory smear result after treatment were routinely referred for colposcopy. Patients found on referral to have colposcopic evidence of invasive cancer were referred to the Oncology without biopsy of further workup and were excluded from the study. All cervical smears were obtained with the Unimar Cervex Brush. All Pap smears performed at the time of colposcopy (repeat cytological resting) were interpreted by the staff of the department. Smears were first examined by cytotechnologists. All abnormal smears, all normal smears in patients with previously abnormal smear, and one in 10 of all smears previously examined were reinterpreted by a pathologist. Acetic acid 5% was applied and all acetowhite lesions were noted. Lugol`s solution was sometimes applied to further define abnormalities. After the entire transformation zone had been adequately examined, an endocervical curettage was performed and directed biopsies were taken from the most abnormal-appearing areas of all lesions. All patients referred for colposcopy to the university’s Family Practice Center between August 1989 and June 1993 were considered for this study. Only patients with single, first-time colposcopies who were referred because of abnormal cytological smears were included. Eleven patients with colposcopic findings of invasive carcinoma or inadequate colposcopies also were excluded leaving a study population of 453 patients. The results of the initial and the repeat cytological evaluations were compared. Findings on repeat cytological evaluation were compared with the colposcopically directed cervical biopsy results (colpopathological findings). Sensitivity, specificity, and predictive values were calculated using methods described by Campion and Reid and Soost et al. Correlation coefficients were calculated between the initial and repeat cytological findings and the colposcopic biopsy results.

Findings: The study included a total of 453 patients with a mean age of 26. The calculated sensitivity for this population was 45% when screening for all CIN. When differentiating high grade from low-grade and benign lesion, the sensitivity of the repeat cervical smear (as measured against the reference standard of histologic evaluation of directed biopsy) was only 25%. The specificity of the repeat cervical smear was found to be 80% when the test was used to screen for CIN and 94% when it was used to detect high-grade lesion. The positive predictive value of the repeat cervical smear in delineating high-grade lesions was only 60%; the negative predictive value was 78%. Of the 428 patients, high-grade lesions were found by colposcopically directed cervical biopsy in 110 patients. Of these 110 biopsy-proven high-grade lesions, 75 patients (68%) had low-grade initial cervical smears and 83 (75%) had low-grade or benign repeat cervical smears.

5. Reid R et al, 1991

Objective:To compare three potential screening tests, used alone or in combination. A total of 1012 women aged 18 to 35 years were screened by cytological testing, cervicography, and hybridization for HPV-DNA

Study Design: This prospective survey examined the prevalence of lower genital tract HPV infection in a structured population of 1012 urban and suburban women aged 18 to 35, recruitment being undertaken in both a sexually transmitted disease clinic and private gynecological offices. Patients were then screened for HPV infection and cervical intraepithelial neoplasia, by means of cytological testing, cervicography and DNA hybridization of exfoliated cells. The study population was drawn from two groups: a high risk and a low-risk subset. The high risk sample consisted of 672 volunteers attending a clinic for STD. The low risk portion comprised 340 volunteers, recruited from four different gynecological clinics. Cytological screening was done with a two-slide technique-collection of an endocervical sample with a Zelsmyr Cytobrush and an exocervical sample with a dagger spatula. Results were reported as high-grade positive (CIN II/III or higher), low-grade positive (definitely abnormal, suggestive of well-developed koilocytotic atypia or cervical intraepithelial neoplasia grade I). After the Papanicolaou smear was completed the cervix was swabbed twice with 4% acetic acid and then photographed. Images were interpreted By subsequent projection onto a 10-foot screen, with the observer standing at a distance of 3 feet. The third screening method involved placing the residual cellular material from the Cytobrush and spatula within a special transport solution, for subsequent DNA extraction and Sothern blot hybridization with radiolabeled probes for HPV types 6,11,16,18,31,33,35,42,43,44,45,51,52 and 56. Results were grouped as positive for an oncogenic type (HPV types 16,18,31,33,35,45,51,52 and 56), positive for a low-risk type (HPV types 6, 11, 42 43 and 44), positive for an unknown type, or negative.

Findings: 343 definitely abnormal cervical test results (88 cytological results, 135 cervigrams, and 120 hybridization were concentrated among 298 patients. 123 equivocal cervical screening test results that were not confirmed by Southern blot hybridization. Papanicolaou smears detected 12 of the 23 high-grade lesions. Apart from disappointing accuracy (sensitivity 52%, specificity 92%) cytological screening carried the significant disadvantage of recalling another 76 patients with either low-grade or borderline atypia (only 13 of which contained some oncogenic HPV type) .

6. Schneider A, 1996

Objective: To evaluate the potential value of HPV test in augmenting the sensitivity of Pap smear or cervicographic screening test.

Study Design: A cohort of 967 non pregnant women with a mean age of 37.1 was studied. Those women had no history of conization, hysterectomy, or cervical intraepithelial neoplasia or atypical cytological results in a cervical smear with 1 year before examination. These women underwent routine screening by two gynecologist between August 1992 and October 1993. On examination, first a Dacron-tipped swab was applied to the ectocervix and endocervix and to the posterior vaginal vault to collect cells for HPV analysis. Second, a cytological smear was taken separately from the ectocervix and endocervix with a cotton-tipped swab, with smears being put on separate glass slides. This smear was called the primary screening smear. In patients with a stenotic cervical canal a Cytobrush was used. Cytological smears were sent to five different routine laboratories; smears from each weekday were classified according to the Bethesda System for reporting cervical or vaginal cytological diagnosis. Third, two cervigrams were taken by use of a Cerviscope camera after application of 5% acetic acid to the cervix. All cervigrams were read on a 2x2 m screen, equivalent to a 16 times magnification by one interpreter who was blinded for cytological and hybrid capture results. Positive patients were recalled for colposcopy at an interval of between 21 and 259 days after entry examination. If colposcopy was negative and the entire squamocolumnar junction visible, only a repeat cytological smear and a swab for HPV detection were taken. If the squamocolumnar junction could not be seen, an endocervical curettage was performed. Histologic examination of the biopsy and curettage specimens was done in two pathology laboratories. In addition, all biopsy specimens were reevaluated by an independent pathologist. It was calculated a sample size of 1.000 patients (i.e. it was expected 20 patients with cervical intraepithelial neoplasia grade 2/3, of which 10 had to be detected by cytological study).

Findings: The presence of high-risk HPVs was age dependent with a peak at 20 to 25 years. Of the primary screening smears, 51 were classified as abnormal and were followed up by colposcopy and biopsy. In 34 cases no cervical intraepithelial neoplasia was detected; 22 of these 34 cases had a cytological diagnosis of atypical squamous cells of undetermined significance. No significant differences between the single methods with respect to sensitivity, specificity, and positive or negative predictive value were found. Augmentation of cytological examination by either HPV testing or cervicography showed a significantly increased sensitivity for detection of cervical intraepithelial neoplasia grade 2/3 (p=0.01=; however augmentation by HPV testing decreased specificity less and increased the positive predictive value compared with cervicography.

7. Soost HJ et al,1991

Objective: To exam cytological screening through a large computerized database to validate the sensitivity, specificity and predictive values of cervical cytology

Study Design: The result of 748.871 cytological examinations of 277.842 women from a ten-year period stored in a computer were used in this study. The evaluation of the validity of cytological screening, positive cytological findings (which included cytodiagnosis of dysplasia, carcinoma in situ, invasive carcinoma and questionable findings) were exclusively validated by subsequent histologic examination performed within one year. One or more positive follow-up smear were taken as evidence that the initial cytological screening was probably correct, but were not taken as absolute proof. Negative cytological findings (if no histologic examination was performed within one year) were validated by at least two subsequent cytological smears taken within three years. If both smears were negative, the first diagnosis was assumed to be correct. If a subsequent histologic finding was positive or if one of the two follow-up smear within three years was positive (severe dysplasia, carcinoma in situ, invasive carcinoma or questionable), the first smear was assumed to be FN. Negative findings that were reported with a recommendation for a repeat smear that had positive findings were not considered to be FN.

Findings: It was known the predictive value of a negative cytological examination was determined to be 99.8%; the predictive value of a positive cytological examination was 73.4% for an initial diagnosis of mild-to-moderate dysplasia, 90.6% for a diagnosis of severe dysplasia/carcinoma in situ, 94.5% for a diagnosis of carcinoma in situ or microinvasive carcinoma and 95.5% for an initial diagnosis of invasive carcinoma. Extrapolation from the validated cases to the entire screened population showed an overall sensitivity of 80% and a specificity of 99.4% for cytological screening for cervical cancer. The sensitivity was slightly lower for mild and moderate dysplasia (78.1%) and slightly higher for carcinoma in situ and severe dysplasia (81.4%) and invasive carcinoma (82.3%).

8. Tabbara S et al, 1992

Objective: To evaluate Pap smears, cervical biopsies and HPV-DNA status of patients applying the Bethesda System of classification to cervical squamous lesions.

Study Design: 75 consecutive biopsy specimens accessioned from the Colposcopy Clinic at the University of Virginia were selected for analysis. Cases were obtained principally from the practitioners or clinics supervised by three of the investigators. Biopsies were reviewed and classified as low-grade, high-grade, or nondiagnostic of an intraepithelial lesion . Distinction of low grade from high grade was based upon the distribution and quality of the nuclear atypia in the lesional epithelium. The criteria for low grade included the presence of either flat or exophytic condylomata, which were characterized by either macular or verrucous lesion in which cytological atypia was confined to the maturing or superficial cell population. All cases were analyzed cytologically by review of the Papanicolaou smear taken at the colposcopic examination and biopsy and without knowledge of the histologic diagnosis. Analysis was conducted with two investigators producing separate panels of diagnosis. All biopsy specimens were analyzed for HPV -DNA. Diagnostic agreement between reviewers was determined by the kappa statistic.

Findings: The reviewers agreed on cytology and histology in 79 and 88% of the cases, respectively. In 75% of cases, both reviewers agreed that a diagnostic cytological and histologic abnormality was present. Overall, reviewers 1 and 2 identified a cytological and histologic abnormality in 64 and 58 cases, respectively. The sensitivities (0.79 and 0.66=, specificities (0.82 and 0.80=, and positive predictive values (0.95 and 0.97) were good to excellent and were similar for reviewers 1 and 2, respectively. In contrast, the negative predictive values (i.e., of low-grade cytology for low-grade histology) were poor for both (0.45 and 0.49, respectively). A strong correlation was observed between histologic diagnosis and HPV type, reflecting primarily the strong association between HPV 16/18 and high grade. In contrast, the correlation between cytology and HPV type was not significant (p=.92=, reflecting the overall lack of correlation between a low-grade Papanicolaou smear and either a low-grade lesion or the absence of high-risk HPV types.

Characteristics of trials identified

Eight randomized or quasi randomized trials were identified. Four of those studies (Matsuura, Mayeux, Soost and Tabbara) were evaluating cytology test per se, having the histopathological exam as a gold standard, all taking the specimens through punch biopsies during colposcopic exam but one, (Matsuura that plus the punch biopsy also studied the cones which were done in all samples that had HGSIL detected in punch biopsies.

The others were comparing slide preparation techniques with the conventional one (Bishop) or comparing different screening tests (Duggan-HPV-DNA; Raid and Schneider - cervicography and HPV-DNA).

There has been used in these studies different collecting devices for conventional cytology Pap smear taking such as, Cervex Brush (Bioshop), Cervex Brush and Ayre spatula (Reid), Swabbing (Matsuura, Mayeux) and Swabbing plus Cervex Brush for stenotic Os (Schneider). Two trials have not pointed out which was the technique used for collecting the smears (Soost and Tabbara).

All trials but two (Soost and Tabbara have done a retrospective study) were conducted as a clinical prospective study.

The samples were taken from primary screening tests by Bishop, Matsuura, Reid Schneider and Soost, but Reid has taken half of the subjects from a high risk group (STD clinic), and Schneider`s subjects were pregnant women. Duggan, Mayeux and Tabbara have chosen already cytological SIL or abnormal (two consecutive inflammatory results after treatment) diagnosis from patients who were sent for colposcopy and punch biopsy.

Statistical analysis were conducted as follows: Duggan used x2 tests to compare subjects risk statues, Willcoxon to compare age and multiple logistic regression to analyze the influence of different variables. Bishop used K statistic technique to evaluate agreement between the screening test; Matsuura used the two-by-two table approach to determine sensitivity, specificity and predictive values; Mayeux mentioned having treated data through Microsoft Excel Version 4 and SAS Version 6.04; Reid used computerized data base and cross checked for accuracy and analyzed with BMDP-88 statistical package within and IBM 386 -2 microcomputer. Besides that standard statistical differences were analyzed by x2 test; Schneider used x2 testing or Fisher’s exact test; Soost studied the data on the two-by-two table to determine predictive value and than estimated sensitivity and specificity of the Cytological tests; finally, Tabbara used the K statistic method to compare diagnostic agreement between tests and cytological and histological results through the x2 statistical technique.

Results

According to the selected studies which were included in this bibliographic review, Pap smear efficacy can be quoted through the following sensitivity and specificity rates:

Author sensitivity specificity
Duggan 63.7% (*)
Bishop 63.6% 99.7%
Matsuura 51.0% 95.0%
Mayeux 45.0% 80.0%
Reid 52.0% 92.0%
Schneider 29.0% 96.0
Soost 80.0% (78.1)** 94.4%
Tabbara 79.0% (66.0%)** 82.0%

(*) not specified
(**) when cut-off point was for LGSIL

Those data are referred to the detection of Squamous Intraepithelial Lesions and invasive cancer of cervix as a whole, with the exception already being mentioned.

Discussion

The studies included in this bibliographic review show sensitivity rates for Pap smear which ranges from 29% to 80%. These large discrepancies lead to the assumption that Pap smear has not been properly tested. As a matter of fact due to the great impact that a cancer detection screening gives in discovering still symptomatic stages of the disease, no efforts has been done to evaluate the efficacy of Cytology as a cervical screening test as a preventive measure. The best result seen on the trials being reported here were in the detection of high grade squamous intraepithelial lesions - HGIL (moderate dysplasia/microcarcinoma), showing poor results in detecting low grade squamous intraepithelial lesions - LGSIL (mild dysplasias). Indeed it was not also good in detecting frankly invasive cervical neoplasias.

The studies which are being addressed in this paper do not evaluate cytology test per se but compare its result with other screening tests (HPV-DNA and cervicography) using different slide preparation techniques that may have brought confounding variables due to different hazardous conditions influencing their own sensitivity and specificity.

Different target groups with different prevalence of the disease also may have lead to the wide range of sensitivity rate of Pap smear test.

There was quite a consensus in the inclusion of endocervical cells in the smear as a major issue of improving sensitivity though one of the trials (Duggan et al, 1997) has not shown any difference comparing the results where those cells were not included with the ones where they were present in the sample to be studied.

Conclusions

In spite of the discrepancies that have already been discussed on can see the overall sensitivity rates can hardly reach a medium rate of 60.0% (29.0% to 80.0%) among the included studies in this bibliographic review.

The purpose of Pap smear test is to screen for intraepithelial lesions before they progress to invasive disease. Patients have come to expect the Pap test to have 100% sensitivity which means that a false-negative result is for sure somebody made a mistake. Many women and also many clinicians do not realize that Pap smear is just a screening test and is subjected to limitations. It reduces the incidence of cervical cancer but it is not expected to detect all the precursor lesions and it is no appropriated to detect large invasive neoplasias.

Nowadays the best methods for health promotion and recruitment for cervical cancer detection screening are still being investigated. Systematic follow-up, appropriate collect smear devices which allow the collection of endocervical cells and or metaplasic ones, and the targeted screening of women never tested has been considered as main strategies to reduce the number of invasive cases.

Finally, nevertheless the apparent simplicity in detection of cervical intraepithelial neoplasias and cancer of the cervix, numerous epidemiological, biochemical, cytological and socio-economic factors are involved on the efficiency of cytology as a screening test. The challenge is to enhance it with high cost-effective approaches.

Acknowledgments

Dr. Saloney Nazeer
Senior Advisor for this study
Department of Obstetrics and Gynecology
University of Geneva

Characteristics of excluded studies

Title of study Type of study No. of subjects Methodology Institution Outcomes Investigators Publication
Nylon brush improves collection of cervical cytological specimens A prospective randomized study ? Compare the efficacy of a combined endocervical and ectocervical nylon brush with the cotton-tipped swab and wooden spatula for obtaining specimens Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill The two methods were equally effective, however 96% of endocervical smears obtained with the nylon brush contained greater than 50 cells, compared with 58% of the swab. Dotters DJ. Carney CN, Droegemueller W Am J Obstet Gynecol 1988 Oct;159(4):814-819
Evaluation of the Endocervical Cytobrush and Cervex-Brush in Pregnant Women Randomized study 1.224 Using two CompuCyte Pathfinder units networked to a PC server and printer, eight cytotechnology students prescreened 1.224 gynecological cases Five staff cytotechnologists rescreened the cases Cytopathology Laboratory and Department of Laboratory Sciences, Thomas Jefferson University, Philadelphia, Pennsylvania Student diagnoses matched cytotechnologist target diagnoses in 1.107 to 1.224 total cases (90,4% Hawthorne C, Greening SE, Grassia R, Tiesi C, Weidmann J, Bibbo, M Acta Cytol 1997 Jan;41(1):160-165
Predicting nonattendance for colposcopy clinic follow up after referral for an abnormal Pap smear Retrospective cohort randomized study 493 women recommended for further assessment or treatment were studied by a Cox proportional hazards modeling National Center for Epidemiology and Population Health, Australian National University, Canberra The nonattendance rate was 2.2 women per 100 women-months and women who had had treatment were less likely t continue attending. Kavanagh AM,

Simpson JM

Aust NZ J Public Health 1996 Jun ;20(3) :266-271
Efficacy of the cytobrush versus the cotton swab in the collection of endocervical cells a randomized study 352/418 Compare the efficacy of the combined spatula-Cytobrush method to that of the spatula-cotton Department of Obstetrics and Gynecology, Odense University Hospital, Denmark The incidence of smears containing cylindrical and/or metaplastic cells was 89% by spatula-Cytobrush method as compared to 62% by the spatula-cotton swab (p<.001) Kristensen GB, Holund B, Grinsted P Acta Cytol 1989 Nov;33(6):849-851
Low grade cervical intraepithelial neoplasia associated with human papillomavirus infection. Long-term follow-up Cohort study 43 Cases of LGSIL were followed for more than five years with cytology, colposcopy and Vira Pap Department of Obstetrics and Gynecology, University of Occupational and Environmental Health , Kitakyushu, Japan Regressive disease was noted in 21 cases, and persistent and progressive disease was noted in 22. HPV DNA was negative in 81% of regressive disease and positive in 55% persistent and progressive disease. The clinical course of LGSIL correlates well with HPV infection Matsuura Y, Kawagoe T, Toke N, Sugihara K, Kashimura M Acta Cytol 1998 May;42(3):625-630
Early detection of cervical cancer by visual inspection: a population-based study in rural India Case control study 3784 women aged 35 and above undergo a pelvic exam and an unaided visual inspection by paramedicals. All subjects have had a cervical smear Tata Memorial Center Rural Cancer Project, Nargis Dutt Memorial Hospital, Barshi, Maharashtra, India The sensitivity of visual inspection by paramedical workers to detect cervical cancer was 90.0% using the low threshold and 60% with the high threshold to define a positive test. The values for specificity were 42.8% and 94.5%, respectively Nene BM, Deshpande S, Jayant K, Budukh AM, Dale PS, Deshpande DA, Chiwate AS, Malvi SG, Deokar S, Parkin DM, Sankaranarayanan Int J Cancer 1996 Dec;68(6):770-773
HPV-DNA hybridization allows differentiation of cervix lesions in Pap III cytological findings Case control study 30 A repeat Pap smear and a smear for HPV-DNA test were collected. All patients underwent colposcopy and histological assessment Abteilung für spezielle Onkologie, Frauenklinik der Medizinischen Hochschule Hannover The repeat Pap smear distinguished correctly in 15, colposcopy in 19 and the Hybrid Capture assay in 27 cases between neoplastic and inflammatory lesions. All invasive neoplasms were positive for HPV-DNA. So HPV test is a suitable non-invasive method for selection of lesions that need biopsy in women with Pap III Petry KU, Bohmer G, Linge G, Glaubity M, Maschek H Geburtshilfe Frauenheilkd 1996 Oct;56(10=:509-512
Atypical squamous cells. A case-series study of the association between Papanicolaou smear results and human papillomavirus DNA genotype case-series study 30 normal

29 CIN1

24 CIN2, (PAP smears)

30 women with atypical squamous cells but not cervical intraepithelial neoplasia on their Pap test where tested for HPV with Southern blot hybridization technique. Pas were reviewed according to Patterns criteria Department of Obstetrics and Gynecology, Michael Reese Hospital, Chicago, Illinois 33% women with atypical cells on Pap smears were positive for HPV DNA as compared to 17% with normal and 59% with CIN 1 or 2 Pap smears. HPV 16 was present in 70-80% of the HPV DNA - positive patients in each Pap smear group. so patients with atypical squamous cells on Pap smears had coexisting HPV infection and CIN in about 1/3 of cases Rader JS, Rosenzweig BA, Sjpirtas R, Padleckas R, Javaheri G, Gerardo L, Laimins LA J Reprod Med 1991 Apr;36(4=:291-297
Cervical cancer in Kenya :prospects for early detection at primary level A cohort retrospective study using Kaplan-Meier method and Cox`s proportional hazards regression analysis 452 The vital status of each patent was established by scrutiny of case records and by reply-paid postal inquiries International Agency for Research on Cancer, Lyon France 47,4% observed survival rate shows that detection was too late Sankaranarayanan R, Nair MK, Jayaprakash PG, Stanley G, Varghese C, Ramadas Vidé, Padmakurnary G, Padmanabh an TK Br J Cancer 1995 Oct ;72(4) :1039-1042
Screening for cervical intraepithelial neoplasia grade 2/3: validity of cytological study, cervicography, and human papillomavirus detection Cohort study 967 women mean aged 37.1 who underwent routine cytological screening cervicography and testing for high-risk human papillomavirus by hybrid capture were compared for their ability to detect CIN 2/3 Department of Gynecology, Friedrich Schiller University, Jena, Germany Cytological study identified 29%, cervicography 45% and testing for HPV 50% of CIN 2/3. When combined HPV test and Cervicograph augmented sensitivity of cytological study to 58% (p=0.01) Schneider A, Zahm DM, Kirchmayr R, Schneider VL Am J Obstet Gynecol 1996 May;174(5):1534-1541
How alarming is post-coital bleeding - a cytological, colposcopic and histopathologic evaluation Retrospective analysis study 110 retrospective analysis study of post-coital bleeding patients. All patients were evaluated by cytology and colposcopy. Positive cases underwent a directed biopsy Department of Obstetrics and Gynecology, Guru Teg Bahadur Hospital and University College of Medical Sciences, Delhi, India 85.5% of the patients had benign findings, 5.6% viral HPV and CIN1, 3,6% CIN2 and CIN3, AND 5.5% invasive cancer. Cytology had a sensitivity and specificity of 56% and 90%, respectively Shalini R, Amita S, Neera MA Gynecol Obstet Invest 1998;45(3):205-208
Risk factors for high-grade cervical intraepithelial neoplasia in patients with mild cytological dyskaryosis: human papillomavirus testing versus multivariate tree analysis of demographic data Prospective study using regression tree analysis 177 women were subjected to colposcopy because of a single routine Pap smear showing mild dyskaryosis. A structured interview sampling for HPV testing for the detection of viral DNA, colposcopic evaluation with cervical biopsies were performed for each subject I Clinica Ostetrico Ginecologica L. Mangiagalli, University of Milan, Italy The classification model based on the demographic and lifestyle variables showed comparable results with molecular hybridization for HPV (specificity, 0.75 versus 0,73; sensitivity, 0.61 versus 0.67, respectively).The use of demographic and lifestyle variables seems simple and economic possibility< for triaging patients with mild dyskaryotic smears in a screening program Sideri M, Sjpinaci L, Schettino F, Meyyetti M, Robertson C, Spolti N, Di Pace R, Crosignani P Cancer Epidemiol Biomarkers Prev 1998 Mar;7(3):237-241
Acetic acid visualization of the cervix to detect cervical dysphasia case control study   During 2 year period, patients attending FP clinics for regular examination had acetic acid applied. to the cervix and visualize. Suspicious acetoacid and normal Pap smear were referred for colposcopy and biopsy Department of Obstetrics and Gynecology, University of Wisconsin, Milwaukee. 15% patients had cervical intraepithelial neoplasia, (9=CINI, 4=CINII)

26% has koilocytosis and 19% had benign histologic findings

Van Le L, Broekhuizen FF, Janyer-Steele R, Behar M, Samter T Obstet Gynecol 1993 Feb;81(2):293-295
First steps in the development  of an information and counseling service for women with an abnormal smear result Randomized intervention study 144 comparing a newly constructed information leaflet with five others informing women and oriented when receiving an abnormal smear result Division of Public Health Medicine, United Medical School, Guy’s Hospital, London, UK 98% positive response rate which indicated women were satisfied with counselor and significant results with less anxiety Wolfe C, Doherty I, Raju KS, Holtom R, Richardson P Eur J Obstet Gynecol Reprod Biol 1992 Jul 24 ;45(3) :291-206
PCR-based high-risk HPV test in cervical cancer screening gives objective risk assessment of women with cytomorphologically normal cervical smears cohort study 1622 Women were included when they had no previous history of cervical dysplasia and their initial Pap smear was read as normal. Women were referred for colposcopically directed biopsies with 2 successive cervical smears read as Pap 3a (mild to moderate dyskaryosis) or one read as >or= Pap3b(severe dyskaryosis) All women were tested for 14 high-risk HPV genotypes Department of Pathology, Free University Hospital, Amsterdam, The Netherlands Women with normal Pap smears containing high-risk HPV genotypes were 116 times (95%CI, 13-990)more risk of developing CIN3 than women without high-risk HPV. So interval between screening should be shorten to the women at risk, when Pap test is properly assessed Rozendaal L, Walboomers JM, van der Linden JC, Voorhost FJ, Kenemans P, Helmerhorst TJ, van Ballegooijen M, Meijer CJ Int J Cancer 1996 Dec 11;68(6):766-769

The above studies were excluded for one of the following reasons: number of subjects or outcomes not clearly stated, and finally, some of those studies were not directly related to the evaluation of Pap smear effectiveness.

References

References to studies included in this review

  • Duggan MA, McGregor SE, Stuart GC, Morris S, Chan-Poon V, Schepansky A, Honors L, Predictors of co-incidental CIN II/III amongst a cohort of women with CIN I detected by a screening Pap test, Eur J Gynaecol Oncol 1998;19(3):209-214.

  • Bishop A, Sherris J, Tsu VD, Kilbourne Book M, Cervical dysplasia teatment: key issues for developing countries. Buss Pan Am Health Organ, 1996 Dec;30:4,378-86.

  • Matsuura Y, Kawagoe T, Toki N, Sufihara K, Kashimura M, Early cervical neoplasia confirmed by conization: diagnostic accuracy of cytology, colposcopy and punch biopsy.

  • Mayeaux J, Harper MB, Abreo F, Pope JB, Philips GS, Comparison of the reliability of repeat cervical smears and colposcopy in patients with abnormal cervical cytology, J Farm Pract 1995 Jan;40(1):57-61.

  • Reid R, Greenberg MD, Lorincz A, Jenson BA, Loverty CR, Husain M, Daound Y, Yado B, White T, Cantor D, Goldrath M, Should cervical cytological testing be augmented by cervicography or human papillomavirus deoxyribonucleic acid detection? Am J Obstet Gynecol 1991 Jun;164:1461-1469.

  • Schneider A, Yahm DM, Kirchmayr R, Schneider VL, Screening for cervical intraepithelial neoplasia grade 2/3: validity of cytological study, cervicography and human papillomavirus detection, Am J Obstet Gynecol 1996 May;174(5):1534-1541

  • Soost HJ, Lange HJ, Lehmarcher W, Ruffing-Kullmann B, The validation of cervical cytology, sensitivity, specificity and predictive values, Acta Cytol 1991 Jan;35(1):8-13.

  • Tabbara S, Saleh AD, Andersen WA Barber SR, Taylor PT, Crum CP, The Bethesda classification for squamous intraepithelial lesions: histologic, cytologic, and viral correlates, Obstet Gynecol 1992 Mar;79(3):338-346.

Additional references

  • Alleyne G, Early detection of cervical cancer. From the Director, Bulletin of the Pan Am Health Org 1996 Dec;30(4):283-.
  • Barrasso R, Yanardi C, Tranbaloc P, Outpatient excision of low grade cervical intraepithelial lesions using loop diathermy, Contracept Fertility Sex 1993 Jun;21(6):511-516
  • Barten G, Local treatment of cervical intraepithelial neoplasia with a 5 percent fluorouracil ointment. Yentrabls Gynakil 1987;109(24):1510-1516.
  • Blumenthal P, Gaffikin L, Maier N, Riseborough P, Workshop proceedings. Issues in cervical cancer:seeking alternatives to cytology, march 2-4, 1994, RH Training Materials JHPIEGO 1994;:
  • Calentano DD, deLissavoy G, Assessment of cervical cancer screening and follow-up programs. Public Health Rev 1989;17(2-3):173-240.
  • Deigan EA, Charmichael JA, Ohlke ID, Karchmar J, Treatment of cervical intraepithelial neoplasia with electrocautery: a report of 776 cases. Am J Obstet Gynecol 1986 Feb;154(2):255-259.
  • Duguid H, Duncan I, Currie J, Screening for intraepithelial neoplasia in Dundee and Angus 1962-8 and its relation to invasive cervical cancer, Lancet 1985;ii:1053-1056.
  • Gold M, Dunton CJ, Murray J, Macones G, Hanan C, Carlson JA Jr, Loop electrocautery excysional procedure:therapeutic effectiveness as an ablation and a conization equivalent. Gynecol Oncol 1996 May;61(2):241-244.
  • Gonzalez Salinas C, Madrigal de Leon HG, Palomeque Ramirey MP, Dickinson Bannack ME, Ponce Rosas ER, Fernandez Gonzaley Ortega MA, Knowledge and attitudes of female health workers regarding a program for the early detection of cervico-uterine cancer. Aten Primaria 1996 Sejp 30;18(5=:237-242.
  • Healey M, Warton B, Taylor N, Postoperative symptoms following LLETZ or radical cervical diathermy with fulguration: a randomized double-blind prospective study. Aust NZ Obstet Gynecol 1996 May,36(2):179-181.
  • Hutchinson ML, Agarwal P, Denault T, Berger B, Cibas ES, A new look at cervical cytology. ThinPrep multicenter trial, Acta Cytol 1992;Jul 36(4):499-504.
  • Hughes RG, Haddad NG, Smart GE Colguhoun M, McGoogan E, Macintryre CC, Prescott RJ, The cytological detection of persistent cervical intraepithelial neoplasia after local ablative treatment: a comparison of sampling devices. Br J Obstet Gynaecol 1992 Jun;99(6):498-502.
  • Kim YT, Kim JW, Kim DK, Song CH, Loop diathermy and cold-knife coniyzation in patients with cervical intraepithelial neoplasia: a comparative study. J Korean Med Sci 1995 Aug;10(4):281-.286.
  • Mahadevan N, Horwell DH, The value of cytology and colposcopy in the follow up of cervical intraepithelial neoplasia after treatment by laser excision. Br J Obstet Gynecol 1993 Jun;100(6):563-566.
  • Martin.-Hirsch P, Jarvis G, Kitchener H, Lilford R , Cervical smear collection devices: how effective are they at detecting endocervical cells and dyskariosis? (Chochrane Review). In: The Cochrane Library, Issue *, 1998. Oxford:Update Software.
  • Mateos Burguillo JF, Rodrigues Zarauz R Uguet de Resayre C, Bajo Arenas JM, Diagnosis, treatment and follow-up of H.P.V.-C-I.N. Eur J Gynecol Oncol 1995;16(1):48-53.
  • Melamed MR, Hutchinson ML, Kaufman EA, Schechter CB, Garner D, Kobler TP, Krieger PA, Reith A, Schenck U. Evaluation of costs and benefits of advances in cytologic technology . International Academy of Cytology Task Force summary. Diagnostic Cytology Towards the 21st Century: An International Expert Conference and Tutorial. Acta Cytol 1998 Jan;42(1):69.75.
  • Mitchell HS, Giles GG, Cancer diagnosis after a report of negative cervical cytology, Med J Aust 1996 Mar;4;164(5):270-273.
  • Mitchell H, Medley G, Evidence against diathermy as a beneficial treatment for human papilloma virus infection of the cervix. Aust NZ Obstet Gynecol 1989 Nove;29(4):439-442.
  • McCord ML, Stovall TG, Summitt RL Jr, Ling FW, Discrepancy of cervical cytology and colposcopic biopsy: is cervical connization necessary? Obstet Gynecol 1991 May;77(5):715-719.
  • Noorani Hussein Z, Assessment of techniques for cervical cancer screening project director, Ottawa Canadian Coordinating Office for Health Technology Assessment 1997, monograph, CCOHTA report 1997:2E, 33p.
  • Nene BM, Deshpande S, Jayant K, Budukh AM, Dale PS, Deshpande DA, Chiwate AS, Malvi SG, Deokar S, Parkin DM, Sankaranarayanan R, Early detection of cervical cancer by visual inspection: a population-based study in rural India. Int J Cancer 1996 Dec 11;68(6):770-773.
  • Parkin D, Nguyen-Dinh K, Joslin C, The impact of cervical screening on the incidence of cervical cancer in England and Wales, Br J Obstet Gynecol 1985;92:150-157
  • Powell B, The use of large loop excision of the transformation zone (LLETZ) in an outpatient setting, Aust NY J Obstet Gynecol 1996 Aug;36(3):338-346.
  • Rojas I, Rodrigues T, Pierotic M, Le Cerf P, Histological evaluation of cryosurgery in high grade intraepithelial neoplasia (CIN-III) of the uterine cervix. Rev Chill Obstet Ginecol 1993;58(3):200-204.
  • Sannito F, Luppari T, Treatment of HPV-positive CIN1 and CIN2 with intralesion administration of human interferon from fibroblasts associated with DTC (diathermal coagulation) of the cervical portio,. Minerva Ginecol 1993 Oct;45(10:489-491.
  • Solomon D, Frable WJ, Wooijs GP, Wilbur DC, Anma NS, Collins RJ, Davey DD, Knight BK, Luff RD, Meisels A, Navin J, Rosenthal DL, Sauer T, Stoler M. Suprun Hy Yamanchi K, ASCUS and AGUS criteria. International Academy of cytology- Towards the 21st Century: An international Expert Conference and Tutorial. Acta Cytol 1998 Jan;42(1):16-24.
  • Trejo Solorzano O, Lopey Velazquez JL, Hurtado Reyna H, de La Torre Rendon F, Tanariy E, Electrossurgery as treatment of high grade squamous intraepithelial lesions. Ginecol Obstet Mex 1997 Aug;65:332-338.
  • Wesley R, Sankaranarayanan R, Mathew B, Chandralekha B, Aysha Beegum A, Amma NS, Nair MK, Evaluation of visual inspection as a screening test for cervical cancer. BR J Cancer 1997;75(3):436-440.

print
Print this page

line

Edited by Aldo Campana,