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Obstetrics & Gynecology 2002;100:445-450
© 2002 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Significant Increase of Benign Endometrial Cells on Papanicolaou Smears in Women Using Hormone Replacement Therapy

Sharon L. Mount, MD, Elisabeth K. Wegner, MD, Gamal H. Eltabbakh, MD, Jennifer I. Olmstead, MD and Anne E. Drejet, MBBS

From the Departments of Pathology and Obstetrics and Gynecology, University of Vermont College of Medicine, Burlington, Vermont.

Address reprint requests to: Sharon L. Mount, MD, Fletcher Allen Health Care, Department of Pathology, 111 Colchester Avenue, Burlington, VT 05401; E-mail: sharon.mount{at}vtmednet.org.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: To determine the prevalence of benign endometrial cells on Papanicolaou smears from postmenopausal women and to compare the prevalence and histologic diagnosis in women who use hormone replacement therapy (HRT) with those who do not.

METHODS: Papanicolaou smear diagnoses from postmenopausal women and women over age 50 between April 1995 and December 1998 were retrieved and linked with follow-up smears and biopsies. Hormone status of women with benign endometrial cells smears was obtained from requisition forms or phone conversation with primary care providers. All surgical pathology material as well as Papanicolaou smears from women subsequently diagnosed with endometrial adenocarcinoma were reviewed. Relative prevalence with 95% confidence intervals was determined.

RESULTS: A total of 589 of 52,662 Papanicolaou smears from postmenopausal women were diagnosed with benign endometrial cells, a prevalence of 1.1%. Also, HRT was reported in 16,073 (31%), no HRT was reported in 33,170 (63%), and hormone status was unknown in 3379 (6%). Smears from 245 HRT users, 324 nonusers, and 20 with unknown hormone status were diagnosed with benign endometrial cells. There was a significant increased prevalence of benign endometrial cells in women on HRT compared with nonusers (relative prevalence 1.56, 95% confidence interval 1.32, 1.84, P < .001). Among 436 women with known hormonal status and follow-up, 12 (2.7%) had endometrial carcinoma, three (1.5%) in HRT users and nine (3.7%) in nonusers (P = .175). In addition, HRT users had significantly less abnormal endometrial histology than non-HRT users (2.6% versus 7.4%, P = .025).

CONCLUSION: We found that HRT is significantly associated with an increased prevalence of benign endometrial cells on Papanicolaou smears. Women on HRT who have benign endometrial cells on their Papanicolaou smears, however, have less abnormal endometrial histology compared with women not using HRT who have benign endometrial cells on their Papanicolaou smears.

Although endometrial cells are detected on Papanicolaou smears, the significance of such a finding depends on the cytologic features of these cells, the patient age and menopausal status, and the menstrual phase during which these cells are detected. Benign endometrial cells may be detected on Papanicolaou smears obtained during the first 14 days of the menstrual cycle, in women with abnormal uterine bleeding, submucous uterine leiomyomata, endometriosis or endometritis, after abortion or delivery, women using intrauterine contraceptive devices, and women using estrogen replacement therapy.1,2 The Bethesda 2001 System3 recommends that benign endometrial cells be reported in women 40 years or older under the category of "other." In addition, the endometrial forum group workshop consensus decision was to discontinue the documentation of hormonal status on Papanicolaou smear reports.3 Although most investigators agree on the significance of finding atypical or malignant endometrial cells on Papanicolaou smears, the significance of benign endometrial cells on Papanicolaou smears especially from asymptomatic women is controversial.

It has been estimated that more than 36 million women in the United States will become menopausal during the next decade.4 As it is expected that many of these women will receive hormone replacement therapy (HRT), the prevalence and clinical significance of benign endometrial cells on Papanicolaou smears in these women needs to be critically assessed. The purpose of the current study was to determine the prevalence of benign endometrial cells on Papanicolaou smears from postmenopausal women and to compare the prevalence and histologic diagnosis among women with benign endometrial cells who use HRT and those who do not.


   MATERIALS AND METHODS
TOP
ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Papanicolaou smear diagnoses showing benign endometrial cells in postmenopausal women or women older than 50 years were retrieved from the computer files of Fletcher Allen Health Care, Burlington, Vermont, for the period April 1995–December 1998. These Papanicolaou smears were diagnosed by five board-certified pathologists and included both conventional and monolayer specimens. Histiocytes (stromal cells) of presumed endometrial origin were not included in the diagnosis of benign endometrial cells. The smears were collected from patients residing in northern New England, including Vermont, New Hampshire, and northern Maine. The smears were collected from private physician offices as well as family planning clinics and hospital collection. The category of "50 years or older or postmenopausal" was chosen because of the frequent lack of precise information regarding dates of last menstrual period on the requisition slip and the variation in definitions between post- and perimenopausal status. Diagnoses were split into categories based on whether or not the patient reported taking HRT on the Papanicolaou smear requisition slip.

Follow-up information was gathered using the Sun-Quest system (SunQuest Information Systems, Tucson, AZ), which links cytologic specimens with surgical pathology biopsy specimens as well as with subsequent Papanicolaou smear results. For the purpose of this study, follow-up information was defined as either gynecologic surgical pathology material obtained within the first year after the benign endometrial cells on Papanicolaou smear or subsequent Papanicolaou smears. Among patients with both surgical pathology and Papanicolaou smear follow-up data, only the surgical pathology material was counted. Among patients followed-up with Papanicolaou smears, the follow-up time ranged from 6 months to 4.25 years. Clinical information, including the use of HRT not reported on the requisition forms from women with benign endometrial cells, was gathered from the physicians obtaining the Papanicolaou smears by phone. Two board-certified pathologists (AED, SLM) reviewed all surgical pathology material including endometrial biopsy, curettage, and hysterectomy specimens. In addition, Papanicolaou smears from patients subsequently diagnosed with endometrial malignancies were reviewed to confirm that the endometrial cells present on the Papanicolaou smear were benign.

Surgical pathology gynecologic diagnoses were those defined in Kurman’s Blaustein’s Pathology of the Female Genital Tract, 4th ed.,5 and cytologic diagnoses as per Kurman’s and Solomon’s The Bethesda System for Reporting Cervical/Vaginal Cytologic Diagnoses.6 We excluded patients with significant epithelial cell abnormality (atypical squamous cells of undetermined significance favor dysplasia, atypical glandular cells of undetermined significance, atypical endometrial cells, or more malignant diagnoses) on the benign endometrial cells on Papanicolaou smear.

Institutional Review Board approval for this study was obtained from the University of Vermont Committee on Human Research.

Statistical analysis was performed using the relative prevalence with 95% confidence intervals, {chi}2, and analysis of variance test. The statistical program used was Epi Info 2000 1.1 (Epidemiology Program Office, Center for Disease Control, Atlanta, GA). P < .05 was considered statistically significant.


   RESULTS
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
A total 52,662 Papanicolaou smear diagnoses from women 50 years or older or who were considered by their clinicians as postmenopausal were identified during the study period. Of these smears, the requisition slip listed HRT use in 16,073 (31%) women and no HRT in 33,170 (63%). Also, 3379 requisition slips (6%) were left blank and thus considered to be of unknown HRT status. Five hundred eighty-nine of the total number of Papanicolaou smears examined during this period, or 1.1%, were diagnosed with benign endometrial cells. Of these, 245 Papanicolaou smears were in the HRT user group and 324 were in the nonuser group. Twenty smears with benign endometrial cells had unknown hormone status and thus were included in the calculation of the prevalence of benign endometrial cells, but excluded from the more specific analysis of the HRT user and nonuser group benign endometrial cells prevalence. The prevalence of benign endometrial cells in HRT users was 1.52%, and the prevalence in non-HRT users was 0.097%. There was a significant increased prevalence of benign endometrial cells in women on HRT compared with nonusers with the relative prevalence of benign endometrial cells in women taking HRT compared with nonusers 1.56 (95% confidence interval 1.32, 1.84, P < .001).

Of the 589 Papanicolaou smears with benign endometrial cells, a total of 153 Papanicolaou smears (26%) did not have follow-up studies, were from women with duplicate benign endometrial cells on Papanicolaou smear diagnoses, or had unknown HRT status. For the purpose of analysis, only the first diagnosis of benign endometrial cells on Papanicolaou smear was counted. Thus, 436 women with benign endometrial cells, known HRT status, and follow-up clinical information were identified. Twelve (2.7%) of those women were diagnosed with endometrial carcinoma.

Table 1Go shows the number of postmenopausal women with benign endometrial cells on Papanicolaou smears classified according to HRT use, age, and follow-up histology, or Papanicolaou smear. There was no significant difference between the proportion of women using HRT and nonusers who had surgical pathology specimens (39.7% versus 34.3%, P = .246, respectively). Five women listed tamoxifen as the type of HRT. None of the patients using tamoxifen subsequently developed malignancy.


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  		Table 1. Postmenopausal Women With Benign Endometrial Cells on Papanicolaou Smears and Known Follow-Up and Hormone Replacement Therapy Status
 
Eighteen (7.4%) of 242 postmenopausal women who did not use HRT were found to have endometrial pathology (polyps, hyperplasia, or carcinoma) compared with five (2.6%) of 194 postmenopausal women who used HRT. The difference between the groups was statistically significant (P = .025).

Table 2Go shows the clinical history, tumor grade, and International Federation of Gynecology and Obstetrics stages of the patients with endometrial adenocarcinoma. Endometrial carcinoma was found in three HRT users and in nine HRT nonusers. There was no significant difference in the prevalence of endometrial carcinoma between postmenopausal women with benign endometrial cells on Papanicolaou smears who used HRT and those who did not (1.5% versus 3.7%, P = .175). Our study had a 90% power to detect a two-tailed difference of >=15% in the prevalence of endometrial carcinoma between both groups at {alpha} = 0.05. All three HRT users had abnormal vaginal bleeding. Two of the women not using HRT were still experiencing menstrual cycles at the time of benign endometrial cells, although the menstrual cycles were irregular. Six nonusers reported abnormal vaginal bleeding, and one nonuser was asymptomatic.


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  		Table 2. Endometrial Carcinoma Among Postmenopausal Women With Benign Endometrial Cells on Papanicolaou Smears According to Hormone Replacement Therapy
 

   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Although it seems intuitive that women using HRT would have a higher rate of benign endometrial cells on their Papanicolaou smears, according to a search of the literature using MEDLINE (years 1982–2002, English language, search terms: "endometrial cancer," "Papanicolaou smears," "hormone replacement therapy," "glandular cells"), this is the first study to report a statistically significant difference in the occurrence of benign endometrial cells on Papanicolaou smears of women using HRT versus nonusers. The findings of the current study regarding a higher incidence of endometrial pathology (polyps, hyperplasia, or carcinoma) among postmenopausal women not on HRT with benign endometrial cells on Papanicolaou smears compared with those on HRT are in agreement with those of Sarode et al.7 However, Yancey et al8 found no difference in the incidence of endometrial hyperplasia and carcinoma between postmenopausal women with endometrial cells on Papanicolaou smears who used HRT and those who did not. However, 42% of the Papanicolaou smears in their study had atypical endometrial cells or endometrial cells suspicious for carcinoma.

The significance of benign endometrial cells on cervical cytology has been controversial. Although some authors1,2,9,10 (Her-Juing H, Schuetz M, Cramer HM. Benign endometrial cells in postmenopausal women: A study of 61 cases with histologic follow-up [abstract]. Acta Cytol 1999; 43:912) have reported a relatively high incidence of endometrial carcinoma and hyperplasia among women with benign endometrial cells on Papanicolaou smears, others7,11–13 have reported low incidences of these histologic diagnoses. Table 3Go summarizes the major studies that investigated the endometrial histologic findings among women with benign endometrial cells on their Papanicolaou smears. The chance of finding endometrial carcinoma or hyperplasia among women with benign endometrial cells smears increases with increased patients’ age, postmenopausal status, presence of abnormal uterine bleeding, and if cervical cytology is obtained with endocervical aspiration.1,8–10,13,14


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  		Table 3. Review of Studies of Endometrial Histology Among Women With Benign Endometrial Cells on Papanicolaou Smears
 
A difficulty in a study of this nature is the definition of "follow-up." Not all women with the diagnosis of benign endometrial cells on their Papanicolaou smear underwent histologic evaluation. We chose to consider a subsequent Papanicolaou smear as indication that the woman involved still resided in our referral area and was not experiencing symptoms that would prompt a more thorough investigation. The relatively nontransient nature of our population and the fact that our institution receives the majority of surgical pathology specimens from the patients whose Papanicolaou smears are diagnosed at our institution lends some validity to this assumption. Interestingly, a recent publication concerning the presence of benign endometrial cells on Papanicolaou smears also included subsequent Papanicolaou smears as follow-up.11Another difficulty in our study is relying on data provided in the Papanicolaou smear requisition forms to identify women on HRT. It is possible that there was crossover between women identified as HRT-users and those identified as nonusers unknown to the health care provider filling these forms.

Because women without benign endometrial cells on Papanicoloau smear infrequently are evaluated with endometrial biopsy or curettage unless prompted by clinical suspicion other than the benign Papanicoloau smear, patients without benign endometrial cells were not used as a control group. In our study, this group of patients without benign endometrial cells would have included over 50,000 women.

Our findings of only a few cases of endometrial adenocarcinoma in women with benign endometrial cells on Papanicolaou smears are in agreement with those of Gomez-Fernandez et al.15 These authors found no difference in the prevalence of benign endometrial cells on Papanicolaou smears from women with endometrial hyperplasia or carcinoma and those from women with normal endometrial histology. The authors concluded that the presence of benign endometrial cells on Papanicolaou smears was not indicative of an increased likelihood of significant endometrial disease and that the reporting of benign endometrial cells on Papanicolaou smears may lead to unnecessary procedures and patient anxiety.

Our prevalence rate for benign endometrial cells of 1.1% is similar to that found by Chang et al11 who reported a prevalence of 1.4% in their study of 26,438 Papanicolaou smears from postmenopausal women. That study, however, included stromal cells of presumed endometrial origin, whereas our study only included endometrial epithelial cells as recommended by Bethesda 2001.3

A recent study by Montz12 found a single case (1.1%) of endometrial adenocarcinoma and two cases of atypical hyperplasia (3.2%) among 93 asymptomatic postmenopausal women with benign endometrial cells on Papanicolaou smears who used HRT. The study by Montz12 differs from our own in that women on cyclic HRT with benign endometrial cells during the expected withdrawal bleeding period were excluded. Therefore, only patients with "unanticipated" benign endometrial cells on Papanicolaou smears were included. Given that the Bethesda 2001 guidelines3 recommend that all benign endometrial cells in women age 40 or older be reported, with the rationale that menstrual dates are often reported inaccurately or not reported at all, the determination of "unanticipated" versus "anticipated" may be impractical.

To our knowledge, the current study is the largest to date with regard to the number of postmenopausal women with known HRT status, benign endometrial cells on their Papanicolaou smears, and follow-up information (n = 436). Most of the cases of endometrial carcinoma reported in the current study were low-risk early stage (11 of 12 or 91.7%). We were unable to compare this finding with other studies as most of the studies reporting benign endometrial cells on postmenopausal women did not list the grade and surgical stage of patients found to have endometrial carcinoma.

Van den Bosch et al16 evaluated the value of cervical cytology in the diagnosis of endometrial disease among 128 postmenopausal women presenting with uterine bleeding (90.6%) or with endometrial cells on the Papanicolaou smears (9.4%). These authors found cervical cytology to be of limited value in the diagnosis of postmenopausal endometrial disease. In the current study, abnormal uterine bleeding was present in 11 of the 12 women diagnosed with endometrial carcinoma. One can argue that most of these women would have been diagnosed on the basis of endometrial biopsies obtained in the workup of abnormal uterine bleeding and that the Papanicolaou smear did not contribute significantly to the detection of endometrial carcinoma among these women.

In conclusion, our study demonstrates that the diagnosis of benign endometrial cells accounts for 1.1% of Papanicolaou smear diagnoses in postmenopausal women or women over the age of 50 and that HRT is significantly associated with increased prevalence of benign endometrial cells on Papanicolaou smears. In addition, in postmenopausal women with benign endometrial cells on their Papanicolaou smears, those who use HRT have significantly less abnormal endometrial histology than HRT nonusers.


   Footnotes
 
PII S0029-7844(02)02095-1

Received January 16, 2002. Received in revised form March 21, 2002. Accepted April 11, 2002.


   REFERENCES
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Gondos B, King EG. Significance of endometrial cells in cervicovaginal smears. Am Clin Lab Sci 1977;7:486–90.

2. Gray JA, Nguyen GK. Cytologic detection of endometrial pathology by Pap smears. Diagn Cytopathol 1999;20: 181–2.[Medline]

3. Bethesda 2001 Endometrial Forum Group Workshop Summary. Available at: http://bethesda2001.cancer.gov/postwrkshp_recs.html. Accessed 2002 Jul 22.

4. American College of Obstetricians and Gynecologists. Hormone replacement therapy. ACOG educational bulletin no. 247. Washington, DC: American College of Obstetricians and Gynecologists, 1998.

5. Kurman RJ. Blaustein’s pathology of the female genital tract. 4th ed. New York: Springer-Verlag, 1994.

6. Kurman RJ, Solomon D. The Bethesda system for reporting cervical/vaginal cytologic diagnoses: Definitions, criteria and explanatory notes for terminology and specimen adequacy. New York: Springer-Verlag, 1994.

7. Sarode VR, Rader AE, Rose PG, Rodriguez M, Abdul-Karim FW. Significance of cytologically normal endometrial cells in cervical smears from postmenopausal women. Acta Cytol 2001;45:153–6.[Medline]

8. Yancey M, Magelssen D, Demaurez A, Lee RB. Classification of endometrial cells on cervical cytology. Obstet Gynecol 1990;76:1000–5.[Abstract/Free Full Text]

9. Ng AB. The cellular detection of endometrial carcinoma and its precursors. Gynecol Oncol 1974;2:162–79.[Medline]

10. Cherkis RC, Patten SF, Andrews TJ, Dickinson JC, Patten FW. Significance of normal endometrial cells detected by cervical cytology. Obstet Gynecol 1988;71:242–4.[Abstract/Free Full Text]

11. Chang A, Sandweiss L, Bose S. Cytologically benign endometrial cells in the Papanicolaou smears of postmenopausal women. Gynecol Oncol 2001;80:37–43.[Medline]

12. Montz RJ. Significance of "normal" endometrial cells in cervical cytology from asymptomatic postmenopausal women receiving hormone replacement therapy. Gynecol Oncol 2001;81:33–9.[Medline]

13. Gomez-Fernandez CR, Ganjei-Azar P, Capote-Dishaw J, Averette HE, Nadji M. Reporting normal endometrial cells in Pap smears: An outcome appraisal. Gynecol Oncol 1999;74:381–4.[Medline]

14. Kerpsack JT, Finan MA, Kline RC. Correlation between endometrial cells on Papanicolaou smear and endometrial carcinoma. Southern Med J 1998;91:749–52.[Medline]

15. Gomez-Fernandez CR, Ganjei-Azar P, Behshid K, Averette HE, Nadji M. Normal endometrial cells in Papanicolaou smears: Prevalence in women with and without endometrial disease. Obstet Gynecol 2000;96:874–8.[Abstract/Free Full Text]

16. Van den Bosch T, Vandendael A, Wranz PA, Lombard CJ. Cervical cytology in menopausal women at high risk for endometrial disease. Eur J Cancer Prev 1998;7: 149–52.[Medline]




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