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Are Benign Cellular Changes on a Papanicolaou Smear Really Benign?
A Prospective Cohort Study
Karen L. Margolis, MD, MPH;
Linda F. Carson, MD;
Peter A. Setness, MD;
Michael W. Stanley, MD;
Michelle J. Henry-Stanley, MS, CT(CMIAC);
Janet Beneke, MD;
Bradley Linzie, MD;
Ronald C. McGlennen, MD
Arch Fam Med. 1999;8:433-439.
ABSTRACT
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Objectives To determine the underlying prevalence of cervical intraepithelial neoplasia (CIN) in women with benign cellular changes on a Papanicolaou smear, and to evaluate follow-up strategies to identify women at high risk for serious underlying pathology.
Methods Nonpregnant women aged 18 to 75 years with benign cellular changes on a Papanicolaou smear were recruited from primary care clinics of an urban teaching hospital. The subjects (N=132) were tested at baseline for the presence of human papillomavirus using the polymerase chain reaction technique, and underwent repeated cervicovaginal smears at 3, 6, and 9 months. At 12 months colposcopy was performed. The main study outcome was the proportion of subjects with CIN as determined by colposcopic biopsy specimens. We determined the sensitivity, specificity, and predictive values of historical risk factor information, human papillomavirus testing, and repeated cervicovaginal smears for the detection of CIN.
Results Cervical intraepithelial neoplasia was found in 30 of 132 women, of whom 27 (20%) had low-grade CIN (CIN I) and 3 (2%) had high-grade CIN (CIN II). Underlying CIN was significantly more common in women younger than 35 years or who had a history of Trichomonas infection or venereal warts, a positive human papillomavirus test result, or abnormal follow-up smears. However, no follow-up strategy combined high sensitivity with a low referral rate for colposcopy.
Conclusions The prevalence of underlying high-grade CIN in women with benign cellular changes is low. However, further prospective studies in other settings are needed before routine follow-up can unequivocally be recommended.
INTRODUCTION
THE BETHESDA System was introduced in the late 1980s to address shortcomings in the systems of categorizing and reporting cervical cytology, among which was the breadth and lack of uniform diagnostic criteria of the "atypical category."1-2 Under the Bethesda System, the term atypical squamous cells is reserved for cases in which the abnormal cytological findings are of uncertain significance. Inflammatory, infectious, and reactive changes are placed in a new category called benign cellular changes. The National Cancer Institute's interim guidelines for management of abnormal cervical cytology do not specify any follow-up for women with benign cellular changes, implying that routine screening should continue.3 However, no prospective study has shown that women with benign cellular changes truly have a low risk for cervical neoplasia.
For several decades after the introduction of the Papanicolaou cervicovaginal smear, the atypical or class II smear was regarded as a benign variant of normal and routine annual follow-up was recommended.4-5 This view was called into question by 3 early studies that found underlying dysplasia or carcinoma in 70% to 80% of women with persistently atypical smears.6-8 As colposcopy became widely available in the 1980s, the emphasis in cervical screening expanded from detection of carcinoma of the cervix before the onset of symptoms to include primary prevention of cervical cancer by detection of preneoplastic lesions. This spurred numerous subsequent studies of women with atypical cells, which reported a wide range in the rate of underlying cervical intraepithelial neoplasia (CIN), from 13% to 80% and higher.9-29 Many of the studies were retrospective, drawn from referral populations, or used imprecise or poorly defined cytologic and histologic terminology. However, the studies with the most rigorous methods12, 17-18,22, 27-29 found rates of underlying CIN spanning the same range.
Four carefully designed prospective studies of women with cervical cytologic atypia found underlying CIN in 11% to 16% of cases, even when a subsequent smear was normal.12, 17-18,29 These findings prompted many authors to call for colposcopy to evaluate even 1 atypical cervical smear.12, 15, 19, 21-22,27 Others have urged a more conservative approach, citing the potential for enormous expenditures and iatrogenic complications from aggressive management.17-18,20, 25 Most of the studies of atypia cited here did not use Bethesda System nomenclature, but many included smears that would now be classified as benign cellular changes. Because there is not a one-to-one correspondence between the old and new diagnostic categories, it is difficult to apply the results of these studies to determine whether women with benign cellular changes on a Papanicolaou smear truly represent a low-risk group. Only 1 study, to our knowledge, has attempted to determine the underlying rate of neoplasia in women with benign cellular changes.30 This study retrospectively examined 1000 women with benign cellular changes and 1000 women with normal smears, of whom 613 and 640 had follow-up smears, and found squamous intraepithelial lesions (SIL) in 3.9% and 1.6% of these, respectively.
We performed a prospective follow-up study in a cohort of women with benign cellular changes, using colposcopy with directed biopsy to determine the underlying prevalence of CIN. We also studied several other initial follow-up strategies that might be useful for identifying women with serious underlying pathology: (1) 1 or more repeated smears at 3-month intervals, (2) human papillomavirus (HPV) testing, (3) selective colposcopy based on known cervical cancer risk factors or the absence of vaginal infection, and (4) combinations of all of these.
SUBJECTS AND METHODS
SETTING AND SUBJECTS
The setting was Hennepin County Medical Center, Minneapolis, Minn, an urban county teaching hospital. The study was approved by the human subjects committee at the hospital. Approximately 10,000 cervicovaginal smears are interpreted annually in the cytopathology laboratory, which is certified by the College of American Pathologists. The subjects were aged 18 to 75 years and had a smear showing benign cellular changes between March 1, 1990, and November 21, 1991, at the gynecology, family medicine, or internal medicine clinic. This smear will hereafter be referred to as the index smear to distinguish it from the follow-up study smears.
The study recruitment period occurred before Bethesda System diagnostic terminology was officially in use at Hennepin County Medical Center. All index smears with diagnoses of interest (benign epithelial atypia, reactive atypical endocervical cells, and reparative changes) were reviewed by the study cytopathologist (M.W.S.) to confirm the diagnosis of benign cellular changes. The major morphologic criteria included minimal nuclear enlargement (1.5-2 times normal intermediate cell nucleus [35 µm2]), finely granular chromatin, minimal nuclear hyperchromasia, and smooth, rounded, uniform nuclear outlines.31 Occasional cells with binucleation, multinucleation or degenerated nuclei, one or more nucleoli (for immature squamous metaplastic cells), cytoplasmic polychromasia or vacuolization, and small perinuclear halos without peripheral cytoplasmic thickening were also believed to be consistent with benign cellular changes.31 Features of typical repair and infection were included, but changes due to atrophy or irradiation were excluded.
We excluded women who had had a hysterectomy or were pregnant. At the inception of the study, the standard of practice in our institution required colposcopy for persistently abnormal smears. Thus, we only included women whose most recent cervicovaginal smear prior to the index smear was negative by medical record review or self-report. We also excluded women with a previous history of CIN on cytology or histology, women who had undergone colposcopy with biopsy after the index smear, and women who were unwilling or unable to consent.
STUDY OVERVIEW
The study cohort was evaluated prospectively. We collected the following data at study entry using an interviewer-administered questionnaire: demographic information, smoking history, sexual and reproductive history, and history of infections and sexually transmitted diseases. Specimens were obtained for HPV DNA analysis, Chlamydia testing, and vaginal fluid examination. Cervicovaginal smears were scheduled to be performed at 3, 6, and 9 months after the index smear. Colposcopy with directed biopsy was scheduled to be performed 12 months after the index smear, unless any of the interim smears showed either low-grade or high-grade SIL (LSIL or HSIL), in which case colposcopy was performed as soon as possible. Women with normal smears, benign cellular changes, or abnormal cytological findings of uncertain significance continued the standard protocol. The minimum criteria for completing the study were attendance at the initial enrollment visit and completion of colposcopy.
LABORATORY AND DIAGNOSTIC METHODS
The specimen for HPV DNA testing was obtained by rotating a dacron swab in the cervical os. The swab was then immersed and agitated in ViraPap transport medium (Digene Diagnostics Inc, Silver Springs, Md), which was then frozen at -30°C. A second specimen was then collected for chlamydia testing using a DNA probe assay (Gen-Probe Inc, San Diego, Calif). Vaginal fluid was examined microscopically for motile Trichomonas organisms on a saline-mounted slide and for yeast and fungus on a potassium hydroxide–mounted slide. Bacterial vaginosis was diagnosed by the presence of clue cells on a saline-mounted slide, fishy amine odor on addition of 10% potassium hydroxide, and vaginal fluid pH greater than 4.5. Gonococcal cultures were performed if clinically indicated. Fungal, trichomonal, chlamydial, and gonococcal infections and bacterial vaginosis were treated according to standard regimens.32 Some women may have been treated prior to the baseline study visit for vaginal infections that were present at the time of the index smear. Thus, a baseline infection was also considered to be present if the index smear showed fungal elements or Trichomonas organisms.
Analysis for HPV DNA was performed using the following technique. DNA extraction was based on a previously described modification of the concentrated salt precipitation protocol packaged as a commercial kit (Puregene; Gentra Systems Inc, Research Triangle Park, NC).33 Using the Amplitaq kit (Perkin-Elmer Cetus, Norwalk, Conn), polymerase chain reaction was used to amplify HPV DNA as previously described.34 This technique was capable of amplifying HPV types 6, 11, 16, 18, 31, 33, and 45. A detailed description of the methods is available from the authors on request.
We used a wooden Ayre spatula and a cotton-tipped endocervical swab to collect the cervicovaginal smears. All study smears were interpreted by one cytotechnologist and one cytopathologist (M.J.H.-S. and M.W.S.) who were masked to noncytologic data.
Two experienced colposcopists (L.F.C. and P.A.S.) performed all of the study colposcopy examinations. This included examination of the cervix and vagina under low and high magnification both before and after the application of 5% acetic acid to the cervix. The appearance and margins of the transformation zone were documented on a standard colposcopy form. The presence of white epithelium, acetowhite epithelium, atypical vessels, mosaicism, and punctation were also noted on the form. An endocervical speculum was used if necessary to visualize the margins of the transformation zone. The examination was considered to be satisfactory if the entire squamocolumnar junction was seen. Endocervical curretage was performed if a lesion extended into the endocervical canal, if the entire squamocolumnar junction could not be visualized, or if CIN had been noted on any of the study smears without a corresponding colposcopic lesion. Up to 3 punch biopsy specimens were obtained from abnormal areas.
All biopsy specimens were interpreted independently by 2 pathologists (J.B. and B.L.) who were masked to clinical, cytologic, and colposcopic data. Any discrepancies were resolved by simultaneous review over a double-headed microscope. The histologic criteria for the diagnosis and grading of CIN were as described by Wright et al.35 Lesions with a marked HPV cytopathic effect and an orderly basal cell layer ("flat condylomata") were included in the low-grade CIN (CIN I) category.
ANALYSIS
The outcome of interest was the presence of any grade of CIN. These were further categorized as low-grade CIN and high-grade CIN (CIN II and III). The primary outcome was the proportion of subjects with any grade of CIN, and the secondary outcome was the proportion of subjects with high-grade CIN. We calculated the sensitivity, specificity, and predictive value of historical risk factors, HPV testing, and repeated cervicovaginal smears for the primary outcome. We tested univariate associations with the key outcomes using the  2 and Fisher exact tests for categorical variables. For continuous variables, we used the 2-tailed t test for normally distributed variables and the Wilcoxon rank sum test for nonnormally distributed variables.
RESULTS
COHORT RECRUITMENT AND CHARACTERISTICS
During the recruitment period, 17,540 cervicovaginal smears were interpreted at Hennepin County Medical Center. Of these, 1752 (10%) showed benign epithelial atypia (n=1455), reactive atypical endocervical cells (n=219), or reparative changes (n=78). Four hundred seventy-three of these smears were performed at nonstudy clinics, leaving 1279 potentially eligible smears. Of these, 218 women did not respond to recruitment telephone calls or letters. Of the remaining 1061 women, 899 were excluded for the reasons listed in Table 1. We enrolled 162 women into the study, and 132 subjects (81%) completed the study. We were only able to collect limited data on women who did not enroll in the trial; however, women who refused enrollment were similar in age to women who enrolled (mean age, 34.6 years vs 35.2 years). Women who did not respond to recruitment calls or letters were younger (mean age, 27.6 years).
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Table 1. Reasons for Exclusion From Study
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The demographics and risk factors for cervical cancer reported by our cohort are summarized in Table 2. Although the study protocol required that the smear preceding the index smear was negative, we did not exclude women with a more remote history of an "atypical" smear. However, 111 (84%) of the women had never had any abnormal smears in the past. Twenty-five women (19%) were felt to have 1 or more baseline infections that could potentially explain the abnormality on the index smear: yeast infection was found in 14 women (11%), Chlamydia in 3 (2%), bacterial vaginosis in 6 (4%), and Trichomonas in 5 (4%).
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Table 2. Cohort Demographics and Cervical Cancer Risk Factors (N = 132)*
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RESULTS OF HPV TESTING, CYTOLOGIC FOLLOW-UP, AND COLPOSCOPY
The HPV specimens from 126 women were adequate for analysis. Overall, 24 (18%) of the specimens were positive for evidence of HPV DNA. The positive specimens were roughly equally divided betwen the low oncogenic risk types, 6 (n=4) and 11 (n=9), and the high oncogenic risk types, 16 (n=9) and 18 (n=2).
In part because of our study design, not all women had all 3 smears during the study. Some women underwent colposcopy before completing 1 year of follow-up because of a smear showing LSIL or HSIL, some women had 1 or more study smears read as unsatisfactory for diagnosis (most often because of obscuring blood or inflammation), and some women simply did not complete all of the study visits. Two women had no satisfactory follow-up smear during the study: 1 who had all 3 smears read as unsatisfactory, and 1 who did not attend any of the study visits after the baseline visit but did undergo colposcopy. The remaining 130 women are accounted for in Figure 1, which shows the results of the follow-up smears. The results are dichotomized as either within normal limits or abnormal (any other result, including benign cellular changes.) Twenty-four women had only 1 satisfactory follow-up smear after entry into the study. This group included 17 women whose first study smear showed LSIL or HSIL and underwent colposcopy without further cytologic testing. The remaining 7 women had only a single satisfactory study smear, which was normal in 4 women and abnormal in 3 women. Forty women had 2 satisfactory smears and, of these, both were normal in 20 women. In the remaining 20 women, 1 or both of the smears was abnormal. Of the 66 women who had 3 satisfactory study smears, all 3 were normal in 27 and the remaining 39 women had 1 or more abnormal smears. Thus, only 51 (39%) of our study cohort had all of their satisfactory smears diagnosed as normal in the year following the index smear.
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Results of follow-up study smears, categorized by number of satisfactory smears obtained during the study (N=130).
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At colposcopic biopsy, we found CIN I in 27 women and CIN II in 3 women. Thus, the overall rate of CIN was 22.7%, the rate of low-grade CIN was 20.4%, and the rate of high-grade CIN was 2.3%.
PREDICTORS OF CIN AT BIOPSY
Of the demographic and risk factor variables, only 3 were significant predictors of finding CIN at colposcopically directed biopsy. Cervical intraepithelial neoplasia was found in 31% of women younger than 35 years, but in only 14% of women 35 years and older (P=.02). Cervical intraepithelial neoplasia was found in 41% of women with a self-reported history of Trichomonas infection vs 18% of women with no history of Trichomonas infection (P=.01), and in 42% of women with a history of venereal warts vs 20% in women with no history of venereal warts (P=.03). Cervical intraepithelial neoplasia was found in 24% of women with a baseline infection vs 22% of women without a baseline infection (P=.90).
The HPV test result was also a significant predictor of the presence of underlying CIN, which was found in 38% of women with a positive HPV test result and 18% of women with a negative HPV test result (P=.03). Cervical intraepithelial neoplasia was found in 46% of women who were positive for HPV types 16 or 18, compared with 19% of women who tested negative for these types (P=.04).
Table 3 shows how the follow-up smears performed in predicting CIN. Two of the cases of CIN occurred in the 2 women who had no adequate study smears. The remaining 28 cases of CIN are included in this analysis. The top half of the table shows an analysis of only the first adequate follow-up smear. The bottom half shows the results using all of the adequate follow-up smears. Cervical intraepithelial neoplasia was found at biopsy in 15% of women whose initial satisfactory study smear was normal, compared with 31% in women whose initial smear was abnormal (P=.03). Cervical intraepithelial neoplasia was found in 10% of women whose follow-up smears were all normal, compared with 29% of women who had 1 or more abnormal follow-up smear (P=.009). When the follow-up smear results were stratified by HPV test result, the highest rates of CIN were seen in women with abnormal smears and a positive HPV test result (40%-43%) and the lowest rates generally were seen in women with normal smears and a negative HPV test result (9%-11%).
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Table 3. Proportion of Women Found to Have CIN at Biopsy, Categorized by Follow-up Smear and HPV Results*
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Table 4 shows the sensitivity, specificity, and predictive values for detecting CIN, as well as the proportion of women referred for colposcopy for 5 different follow-up strategies to evaluate a smear showing benign cellular changes.
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Table 4. Performance Characteristics for Detecting CIN of 5 Different Follow-up Strategies to Evaluate Benign Cellular Changes*
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COMMENT
There is international consensus regarding the importance of detection and treatment of high-grade CIN, since these lesions have a substantial likelihood of progressing to invasive carcinoma.36-37 There is far less agreement about the necessity of prompt identification of CIN I, since most of these lesions will regress spontaneously.38 Nevertheless, most US studies have assumed the desirability of detecting both low-grade and high-grade CIN, and have raised concerns about the high rate of lesions with neoplastic potential that are found when women with variously defined "atypical cells" are subjected to colposcopy.9-29 Our study shows that women with benign cellular changes using Bethesda System criteria have a moderate rate of underlying CIN (23%) and a very low rate of high-grade CIN (2%). Our findings contrast with the study by Soofer and Sidawy30 of benign cellular changes, which found a 3.9% rate of SIL (nearly all low grade) on a subsequent smear in women with an initial smear showing benign cellular changes. However, this study was retrospective, had incomplete follow-up, did not use colposcopy with biopsy as the diagnostic standard, and provided no information regarding the demographic or clinical characteristics of the study population.
We cannot exclude the possibility that the rate of CIN would have been equally high had we performed colposcopy on a group of women with normal cervical smears. However, 2 reports suggest that this is unlikely. The study by Soofer and Sidawy30 found a signficantly higher rate of SIL in women with benign cellular changes compared with women with normal smears (3.9% vs 1.6%, P=.01), although the clinical importance of this difference is unclear. In the only population-based study of mildly abnormal cervical smears that has been published, Cecchini et al22 invited a sample of women in the municipality of Florence, Italy, with a cytologic report of "squamous atypia" during 1989 to undergo colposcopy. This abnormality represented 3.1% of more than 72,000 smears. More than 90% of invited women were examined: 2.4% were found to have CIN II-III and 11.1% were found to have CIN I. Although the study did not include a random sample of cytologically negative women, it reports on a group of cytologically negative women who self-referred for colposcopy. In these women the rates of CIN II-III and CIN I were 0.7% and 6.3%, respectively.22 Presumably this group was biased toward higher risk for CIN, so the true rate of CIN in cytologically normal women is probably even lower.
Although the importance of detecting underlying CIN I is open to debate, we report the performance characteristics of follow-up strategies that aim to identify this abnormality as well as high-grade CIN, of which we had too few cases to conduct a meaningful analysis.
None of the follow-up strategies we tested combined high sensitivity for detecting CIN with a low referral rate for colposcopy. Human papillomavirus testing alone had a very low sensitivity. The combination of a single follow-up smear with HPV testing was slightly more sensitive than a single smear alone, but nearly half of the women would be referred to colposcopy. Of interest is the fact that this strategy was nearly equivalent to using age younger than 35 years as a cutoff for referral to colposcopy. To our knowledge, this is the first study that has prospectively tested the multiple follow-up smear strategy that is often recommended as an alternative to colposcopic referral for all women with low-grade cytologic abnormalities.3 Even with a dedicated research staff, this strategy required enormous effort and did not achieve complete follow-up. We chose to present the results dichotomized to include follow-up smears showing benign cellular changes with the abnormal smears, which maximizes the sensitivity. Using a different cutoff for abnormal would lower the sensitivity and raise the specificity. As expected, this resulted in the highest sensitivity (82%) of the strategies we tested, but the sensitivity was not perfect and most patients would still be referred for colposcopy.
Two other findings from our study deserve emphasis. First, clinicians are often encouraged to take cervical cancer risk factors into consideration when deciding how aggressively to evaluate abnormal cervicovaginal cytology.3 With the exception of a history of Trichomonas infection or venereal warts, we did not find the patient histories to be useful in predicting the presence of underlying CIN. Even these variables had very low sensitivity (37% and 27%, respectively). Second, despite the fact that treatment of infection does not influence the natural history of atypia,13 treatment followed by a repeated smear is commonly recommended for evaluating an abnormal cervicovaginal smear. While treatment may be indicated for alleviation of symptoms or prevention of sequelae, the presence of an infection should probably not influence the selection of a follow-up strategy, since CIN was equally likely whether an infection was present or not.
Our study has several strengths. The study sample was limited to women with benign cellular changes according to the Bethesda System, a previously normal smear, and no history of CIN or cervical ablation. Second, 1 cytopathologist interpreted all of the cervicovaginal smears and the histologic diagnoses were the consensus of 2 pathologists who were masked to the cytologic results and colposcopic impression. Finally, unlike many studies based on patients referred to colposcopy clinics,11, 14-16,18-20,24, 26, 29, 39 our study sample was drawn from a primary care population.
We must mention some limitations of our study. First, our relatively small cohort was recruited from primary care clinics from 1 urban hospital and had stringent selection criteria; therefore, our findings may not be applicable to other settings. In addition, volunteers for research may differ substantially from the general population. However, neither our recruitment rate nor our dropout rate was unusual for a study of this length and complexity. Second, our polymerase chain reaction method may have had low sensitivity because it included only 8 HPV types. It is also possible that some subjects were initially HPV negative but became infected during the study. Different results might have been obtained if a broader range of pathogenic HPV types had been included, if HPV testing had been repeated at the time of colposcopy to detect incident HPV infections, or if we had used an endocervical brush rather than a cotton-tipped swab to collect the endocervical component of the smears. Although the endocervical brush is superior to other tools for retrieving endocervical cells, there is no evidence that its use results in greater sensitivity for detection of dysplasia.40
In summary, we found that women with benign cellular changes had a very low rate of high-grade CIN (2%), which is the direct precursor of invasive cervical carcinoma. The rate of CIN I was much higher (20%), but because the potential of these lesions to progress to invasive carcinoma is much lower, the importance of detecting them is less certain. More research is needed to determine if early detection and treatment of CIN I is beneficial. Furthermore, since no follow-up strategy for detecting CIN combined a high sensitivity with a low rate of referral for colposcopy, our results do not suggest a better alternative to routine follow-up for women with benign cellular changes on a Papanicolaou smear. Before we conclude that benign cellular changes are truly benign, it would be useful to replicate our study in other settings and include a comparison group of women with normal cytology.
AUTHOR INFORMATION
Accepted for publication December 5, 1998.
This research was supported by a Clinical Oncology Career Develpment Award for Primary Care Physicians from the American Cancer Society, Atlanta, Ga, and a grant from Hennepin Faculty Associates, Minneapolis, Minn (Dr Margolis).
Corresponding author: Karen Margolis, MD, MPH, Division of Clinical Epidemiology, Hennepin County Medical Center (865B), 701 Park Ave, Minneapolis, MN 55415 (e-mail: margo006{at}tc.umn.edu).
From the Departments of Medicine (Dr Margolis), Family Practice (Dr Setness), and Pathology (Drs Stanley, Beneke, and Linzie and Ms Henry-Stanley), Hennepin County Medical Center; and the Departments of Obstetrics/Gynecology (Dr Carson) and Pathology (Dr McGlennen), University of Minnesota, Minneapolis.
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