Classification of Benign Endometrial Glandular Cells in Cervical Smears from Postmenopausal Women

60 CANCER CYTOPATHOLOGY Classification of Benign Endometrial Glandular Cells in Cervical Smears from Postmenopausal Women Edi Brogi, M.D., Ph.D. Rosemary Tambouret, M.D. Debra A. Bell, M.D. Department of Pathology, Cytology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. BACKGROUND. The Bethesda System recommends reporting benign endometrial cells in cervical smears from postmenopausal (PMP) women as aglandular cell abnormality. However, PMP women on hormone replacement therapy (HRT) sometimes may experience endometrial shedding. The significance of such a finding has not been investigated in detail. METHODS. The authors evaluated 85 PMP women with cervical smears that contained benign endometrial glandular cells. Clinical information, including vaginal bleeding and the use of HRT or tamoxifen, was recorded, and follow-up was obtained. RESULTS. Thirty-three PMP women were not on HRT, and 11 women were symptomatic. Twenty women underwent endometrial biopsy: Two symptomatic patients had endometrial adenocarcinoma, and 3 symptomatic patients and 1 asymptomatic patient had endometrial polyps. The frequency of abnormal findings was 18%. Forty-seven PMP women received HRT; 15 were symptomatic. Twenty-two patients underwent endometrial biopsy: 1symptomatic patient had cystic hyperplasia, and 2symptomatic patients and 1asymptomatic patient had an endometrial polyp. The frequency of abnormal findings was 8.5%. No one type of HRT was correlated with specific findings. Five PMP women were on tamoxifen, and two of them were symptomatic. Four patients underwent endometrial sampling: Two of them had an endometrial polyp, which was symptomatic in one patient. CONCLUSIONS. These data confirm that benign endometrial glandular cells in cervical smears from PMP women may indicate endometrial pathology, especially if vaginal bleeding is present. Although atypical endometrial hyperplasia or carcinoma was not identified in the group of PMP women on HRT, endometrial abnormalities of alesser degree were present in 8.5% of patients. Thus, the authors favor continued classification of benign endometrial glandular cells in cervical smears of PMP women, whether or not they are on HRT, as a glandular cell abnormality. Cancer (Cancer Cytopathol) 2002;96:60 6. 2002 American Cancer Society. Presented in part in abstract form at the annual meeting of the United States and Canadian AcademyofPathology,Atlanta,Georgia,March6,2001. Address for reprints: Edi Brogi, M.D., Ph.D., Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; Fax: (212) 717-3203; E-mail: brogie@ mskcc.org Received April 19, 2001; revision received September 18, 2001; accepted September 19, 2001. KEYWORDS: benign endometrial glandular cells, hormone replacement therapy, post-menopausal women, cytology, cervical smears. Benign appearing endometrial glandular cells are anormal component in exfoliative gynecologic preparations obtained from premenopausal women during the first half of the menstrual cycle (from Day 1to Days 10 14); the presence of benign endometrial glandular cells in cervical smears is considered abnormal under any other circumstance. 1 Inparticular, the presence of benign endometrial cells in exfoliative specimens from postmenopausal (PMP) women may disclose serious uterine pathology and warrants further evaluation. 2 5 Accordingly, the Bethesda System guidelines recommend reporting 2002 American Cancer Society Published online 26 March 2002 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/cncr.10478

Benign Endometrial Cells in Postmenopause/Brogi et al. 61 benign endometrial cells in smears from PMP women as glandular cell abnormalities. 6 The categorization of benign endometrial cells in PMP women who are on hormonal replacement therapy (HRT), however, is more ambiguous, because one of the effects of HRT is stimulation of the endometrium, which may result in vaginal spotting or frank bleeding. Furthermore, the clinical significance of benign endometrial cells in cervical smears from PMP patients remains uncertain. In recent years, HRT is prescribed for prophylactic and therapeutic purposes to PMP women, and the finding of benign endometrial glandular cells in cervical smears from this group of patients is an increasingly frequent clinical problem. We sought to evaluate the frequency and significance of benign endometrial cells in cervical smears obtained from PMP women to determine the clinical impact of such a finding and how to report it. We identified and reviewed all cervical smears obtained in 1999 that contained benign endometrial cells from women age 50 years. Other pertinent clinical information, especially with regard to the use of HRT, also was noted. MATERIALS AND METHODS Cervical exfoliative preparations (conventional smears or ThinPrep slides) obtained from women age 50 years over the course of 1 year (January to December, 1999) that contained benign endometrial cells were retrieved from the files of the Cytology Laboratory at the Massachusetts General Hospital and reviewed by one pathologist (E.B.). Clinical information from the referring physician also was obtained with regard to confirmation of postmenopausal status, use and type of HRT, use of tamoxifen, and clinical symptoms. Any additional pertinent specimen from the same patient available in the files of our department also was reviewed. RESULTS During a 1-year period, 12,892 cervicovaginal smears were obtained from women age 50 years; of these, 103 smears from 102 patients contained benign endometrial cells. According to the available history, 88 of these patients were PMP women. Three patients were excluded because their cervicovaginal smears were not available for review. One patient who was receiving HRT had two consecutive cervical smears that contained benign endometrial cells. A total of 86 cervical cytologic preparations from 85 patients were reviewed, and the presence of benign endometrial cells was confirmed. For the purpose of this study, we defined benign endometrial cells only as benign-appearing clusters of endometrial cells of glandular type (see FIGURE 1. The appearance of endometrial glandular cells in a liquid-based preparation (A) and in a conventional Papanicolaou smear (B) is shown (original magnification, 600). Fig. 1). All samples were cervical. Patient age ranged from 50 years to 79 years (mean standard deviation: 58.6 6.8 years). Thirty-three PMP women with benign endometrial cells were not receiving any HRT at the time of cervical smear. Patient age ranged from 50 years to 74 years (mean standard deviation: 58.6 7.0 years). The presence of benign endometrial cells in the cervical smear was reported as a glandular cell abnormal-

62 CANCER (CANCER CYTOPATHOLOGY) April 25, 2002 / Volume 96 / Number 2 TABLE 1 Findings at Endometrial Biopsy in Postmenopausal Women Who Were Not on Hormone Replacement Therapy Vaginal bleeding Follow-up Endometrial biopsy Diagnosis Yes 11 patients (33%) 11 (100%) 10 concurrent 1 subsequent 2 endometrial carcinoma, 3 endometrial polyps, 3 atrophic endometrium, 2 proliferative endometrium, 1 inactive endometrium No 22 patients (67%) 9 (40%) 9 subsequent 1 endometrial polyp, 6 atrophic endometrium, 1 proliferative endometrium, 1 insufficient tissue ity in 23 women, benign cellular changes in 8 women, and within normal limits in 2 women. Eleven patients (33%) had reported vaginal bleeding, and all of them (100%) underwent endometrial sampling. An endometrial biopsy was obtained at the time of the cervical sample in 10 patients (90%) and after the cervical smear in 1 patient (10%). The pathologic findings in the 11 symptomatic patients were 2 low-grade endometrial adenocarcinomas (International Federation of Gynecology and Obstetrics [FIGO] Grade 1 and FIGO Grade 2), 3 endometrial polyps (1 associated with cystic hyperplasia), 3 patients with atrophic endometrium, 1 patient with inactive endometrium, and 2 patients with proliferative endometrium. Nine of 22 asymptomatic women (40%) underwent endometrial biopsy, all subsequent to the cervical smear report, yielding 1 endometrial polyp, 6 women with atrophic endometrium, and 1 woman with proliferative endometrium. Tissue was insufficient for diagnosis in one woman (see Table 1). Forty-seven patients were receiving HRT: Nineteen patients received cyclic oral estrogen/progesterone derivatives (Premarin/Provera), 2 patients received low doses of unopposed estrogen (Premarin), 4 patients used a topical estrogen vaginal cream, 3 patients took progesterone alone (Provera), and 1 patient was on sequential combination of estrogen and progesterone (Premphase). No additional information regarding the type of HRT was obtained from 18 women. One woman on HRT had two consecutive cervical smears, both containing benign endometrial cells, for a total of 48 cervical smears from this group of patients. Patient age ranged from 50 years to 79 years (mean standard deviation: 59.0 7.0 years). Ten patients on HRT (21%) reported a history of bleeding that was noted by the clinician as dysfunctional uterine bleeding in 1 woman, postmenopausal bleeding in 5 women, and last menstrual period in 4 women: One patient had bleeding prior to collection of the cervical smear, and three other patients reported bleeding 4 days, 10 days, and 26 days earlier. The presence of benign endometrial cells in cervical preparations from PMP women on HRT was reported as a glandular cell abnormality in 16 patients (including two smears from the same patient), as recommended by the Bethesda System guidelines; it was categorized as benign cellular change in 30 patients and, in 2 patients, was noted in the report under the heading squamous cell abnormality due to the presence of atypical squamous cells of uncertain significance. Twenty-two of 47 patients on HRT (47%) underwent endometrial sampling. The findings at endometrial biopsy in 12 of 15 symptomatic patients (80%) included 2 endometrial polyps, 1 cystic hyperplasia, 3 patients with inactive endometrium, 2 patients with proliferative endometrium, 2 patients with menstrual endometrium, and 2 patients with atrophic endometrium. The status of the endometrium was assessed in 10 asymptomatic women (31%). Endometrial sampling from 8 of 32 asymptomatic women on HRT showed 4 women with proliferative endometrium, 2 women with inactive endometrium, 1 woman with secretory endometrium, and 1 woman with an endometrial polyp. In one woman, the endometrial tissue was insufficient for diagnosis. One additional patient underwent a total hysterectomy that revealed atrophic endometrium (see Table 2). Five PMP women with benign endometrial cells in cervical smears had prior history of breast carcinoma and were receiving or had recently received tamoxifen. Patient age ranged from 54 years to 61 years (mean standard deviation: 55.4 2.4 years). The presence of benign endometrial cells in cervical exfoliative preparations from these patients was reported as glandular cell abnormality in three patients and benign cellular changes in two patients. Two of five patients (40%) on

Benign Endometrial Cells in Postmenopause/Brogi et al. 63 TABLE 2 Findings at Endometrial Biopsy in Postmenopausal Women on Hormone Replacement Therapy Vaginal bleeding Follow-up Endometrial biopsy Diagnosis Yes 15 patients (32%) 12 (80%) 6 concurrent 6 subsequent 1 cystic hyperplasia, 3 inactive endometrium, 1 proliferative endometrium, 1 menstrual endometrium (2 endometrial polyps, 1 proliferative endometrium, 2 atrophic endometrium, 1 menstrual endometrium) No 32 patients (68%) 10 (31%) 10 subsequent 1 endometrial polyp, 4 proliferative endometrium, 2 inactive endometrium, 1 atrophic endometrium, 1 secretory endometrium, 1 insufficient tissue tamoxifen had reported vaginal bleeding. Endometrial sampling was performed in four of five patients (80%) on tamoxifen and revealed atrophic endometrium in two patients and endometrial polyps in the other two patients. One of the patients with an endometrial polyp had been symptomatic: She underwent a subsequent hysterectomy that revealed inactive endometrium and adenomyosis. In addition to benign endometrial cells, cervical smears from seven patients contained clusters of spindly, deep endometrial stromal cells; this finding was slightly more frequent in PMP women who were on HRT (five of seven women) compared with women who were not receiving HRT (two of seven women). A preparation from a PMP woman on HRT contained large clusters comprised of both benign endometrial cells and spindly, deep stromal cells, likely representing sampling of the lower uterine segment, possibly secondary to vigorous brushing of the upper endocervical canal. DISCUSSION The Bethesda System guidelines recommend classification of benign endometrial cells in cervicovaginal preparations from PMP women as a glandular cell abnormality with cytologically benign endometrial cells. 6 In recent years, with the widespread use of HRT, cytopathologists frequently are challenged with the classification of benign endometrial cells in exfoliative cervicovaginal preparations from PMP women who are receiving HRT, and there is debate with regard to the significance and most appropriate designation of this finding. In addition to many beneficial effects, HRT stimulates the endometrium, and cyclic withdrawal of hormonal treatment may result in pseudomenstrual endometrial shedding, especially when sequential combinations of estrogen and progesterone derivatives are used. 7 12 Vaginal bleeding/spotting is one of the most common complaints among PMP women on HRT, and, not infrequently, it may lead to discontinuation of HRT. 7 12 This symptom is most common among PMP women who are starting HRT right after the onset of menopause, probably secondary to the additive effect of HRT and endogenous reproductive hormones that still are released at paraphysiologic levels right after the onset of menopause. 7 12 The Bethesda System guidelines do not provide specific recommendations on this issue, although it may be assumed that benign endometrial cells in PMP women on HRT also will be diagnosed as a glandular cell abnormality. 6 The lack of specific guidelines accounts for wide variability in the diagnostic interpretation of this finding, and we even found variability among cytopathologists in our own department. Objections to reporting the presence of benign endometrial cells in PMP women are the benign appearance of the cells; the concurrent use of HRT; and, in most women, the absence of clinical symptoms, specifically, vaginal bleeding. 13 In a recent study, Gomez Fernandez and coworkers concluded that reporting the presence of benign endometrial cells in cervical smears does not contribute to the clinical management of these patients, because clinicians will disregard this finding in asymptomatic women and, conversely, will evaluate patients with abnormal bleeding further, regardless of the findings in the cervical smear. 13 This conclusion was based on a follow-up study of women age 35 years with benign

64 CANCER (CANCER CYTOPATHOLOGY) April 25, 2002 / Volume 96 / Number 2 endometrial cells in their cervicovaginal samples. All symptomatic patients in the study (78%) underwent endometrial biopsy, resulting in the detection of 10 endometrial hyperplasias and 7 endometrial adenocarcinomas. The clinically asymptomatic patients (22%) were followed with routine office visits for a minimum of 3 years, and all had a negative clinical course. 13 To date, published reports have accepted as endometrial cells both endometrial glandular cells and the so-called superficial endometrial stromal cells. 1 In this study, we specifically limited the designation of benign endometrial cells only to endometrial cells of glandular type. In a recent study from our group, we reported that superficial endometrial stromal cells, also often referred to as sticky histiocytes, are not specific indicators of endometrial pathology. 14 Using an immunoperoxidase staining technique, Chang and coworkers recently established that superficial endometrial stromal cells consist of loose clusters of histiocytes and found that such cells are not predictive of endometrial disease. 15 Several published studies have indicated that benign endometrial cells may be shed by the endometrium in conjunction with a serious uterine pathology in PMP women who are not on HRT. Zucker et al. reported that advanced age, abnormal bleeding, and the presence of endometrial cells were predictive of endometrial adenocarcinoma in univariate and multivariate analyses. 3 The study population consisted of 102 women with Papanicolaou (Pap) smears that contained findings suggestive of an endometrial lesion, including histiocytes, high squamous maturation index, or endometrial cells, scored on a scale from 1 (benign) to 6 (malignant). It was found that 18 patients had endometrial adenocarcinoma, and all had endometrial cells on their Pap smears that were benign in 3 smears and abnormal in 15 smears. Two of the women with endometrial adenocarcinoma were asymptomatic, but the degree of atypia of their endometrial cells was not stated. None of the women in the study was on HRT. 3 Cherkis et al. studied 440 women with Pap smears that contained benign endometrial cells without regard to whether they were receiving HRT. 16 Twenty of 179 patients (11%) with 12 months of follow-up had endometrial adenocarcinoma, and 5 patients (25%) had been asymptomatic. Those authors also found that endometrial adenocarcinoma was clustered in women age 60 years. 16 Kerpsack and coworkers also correlated the presence of endometrial cells on Pap smears and endometrial adenocarcinoma. 4 Their study group consisted of 52 patients, 44 of whom were PMP women, and 12 of these women were on HRT. Twenty-two of the PMP women were symptomatic. Thirty-one patients had benign endometrial cells on their smears, and the remaining smear findings varied from atypical to frankly malignant. Seven women were identified with endometrial adenocarcinoma on biopsy, all in PMP women, and two of these women were asymptomatic. None of the patients who developed carcinoma was on HRT. Two PMP women with benign endometrial cells on their smears had carcinoma: Both of these patients had reported vaginal bleeding. Ten smears contained atypical endometrial cells, but no significant endometrial pathology was associated with this finding: Endometrial sampling from four patients with smears that contained atypical glandular cells of undetermined significance yielded one finding of significant endometrial pathology. Those authors identified age, abnormal bleeding, and Pap smear results as independent predictors of significant endometrial pathology (atypical hyperplasia or carcinoma) and recommended an office endometrial biopsy upon finding any type of endometrial cell on cervical cytology in PMP patients, or, if this is not possible or is nondiagnostic, then they may recommend proceeding with dilatation and curettage. 4 Vaginal bleeding is an established clinical indicator of endometrial disease 3,13,15 and has been identified as an independent predictor of disease. 3 However, symptomatic vaginal bleeding, per se, does not identify all women with an underlying endometrial process. In 1974, Ng and coworkers detailed the results of endocervical canal aspiration cytology in which benign endometrial cells were found out of phase in premenopausal or PMP women. 2 Subsequent tissue sampling in 243 PMP women identified 14 patients (5.2%) with endometrial adenocarcinoma. Six of these 14 patients (42%) were asymptomatic. HRT was not mentioned in this study, and, most likely, none of the women in this study was receiving HRT. 2 In 1977, Gondos and King investigated a group of women age 40 years who shed benign endometrial cells on cervical smears. 5 Thirty-two of those patients had subsequent abnormal endometrial samples, including two patients with endometrial adenocarcinoma. Although the 2 women with carcinoma had disease associated with endometrial bleeding, 6 of the remaining 30 women (20%) with endometrial pathology (7 women with endometrial polyps and 23 women with endometrial hyperplasias) were asymptomatic. 5 The finding in our study of a 6% rate (2 of 33 patients) of endometrial carcinoma in the group of PMP women who were not receiving HRT is consistent with these prior studies. 2 5,16 Very few studies have investigated the significance of endometrial cells in PMP women on HRT. In 1990,

Benign Endometrial Cells in Postmenopause/Brogi et al. 65 Yancey and coworkers reported the results of a study evaluating the significance of benign and atypical endometrial cells in smears from PMP and premenopausal women after Day 12 of the cycle. 17 Forty-one of 127 PMP women had endometrial pathology. Thirty patients were on HRT, consisting of estrogen alone or combined with a progesterone derivative (medroxiprogesterone acetate) for 10 days at the end of each cycle. No difference was found in the incidence of endometrial adenocarcinoma or hyperplasia between the PMP women who were on HRT (13 of 30 patients) and the PMP women who were not on HRT (27 of 90 patients). Yancey and coworkers concluded that HRT should not exclude PMP women from further evaluation, because 5 of 11 PMP patients (45%) with typical appearing endometrial cells and endometrial disease were receiving estrogen therapy. 17 Those authors did not specify whether endometrial adenocarcinoma was detected only in women who were receiving estrogen alone or also in women who were receiving an estrogen/progesterone combination regimen. 17 Hormone doses in currently prescribed HRT regimens are much lower than they were 10 20 years ago, and they are designed to have only minimal impact on the endometrium. Nonetheless, HRT can have slightly different effects on the endometrium. A recent study evaluating the cytology and histology of endometrial changes secondary to different regimens of HRT documented slightly different endometrial responses in patients receiving the same HRT. 18 In addition to the range of responses secondary to different types of HRT regimens, patient compliance may introduce an additional element of variability and may have an impact on endometrial shedding. The modalities of HRT dosage and the manner of administration (continuous vs. cyclic vs. oral vs. transdermal) probably affect the endometrium differently, although that may be established only by a very large study. In our study, the number of patients on HRT was too small and the types of HRT were too varied to evaluate specific correlations with the shedding of benign endometrial cells. The total incidence of biopsy-proven endometrial disease in PMP women on HRT in our study was 8.5%, including three patients with endometrial polyps and one patient with cystic hyperplasia. None of the patients on HRT in our study had endometrial carcinoma; however, a benign endometrial process was identified in a substantial number of women, including one asymptomatic patient. For all of these reasons, we conclude that uniform reporting of the presence of benign endometrial cells in cervical exfoliative preparations from PMP women should be applied whether or not they are on HRT. We did not find established clinical guidelines on the management of patients with cervicovaginal smears that contain benign endometrial cells. Many of the asymptomatic women in our study group underwent endometrial biopsy, although at a lower rate than symptomatic women and independent of the use of HRT. We found that clinicians at our institution prefer to know about the presence of benign endometrial cells in cervicovaginal smears from PMP women and use this information, together with other clinical data, to decide on patient s management. Furthermore, the results from our study suggest that the presence of benign endometrial cells in cervicovaginal smears from PMP women, whether or not they are receiving HRT, is relevant information and may disclose underlying endometrial pathology. It is not surprising that the most serious pathology (endometrial adenocarcinoma) in our study occurred in PMP women who were not on HRT and who reported vaginal bleeding. However, even if none of the patients on HRT had endometrial adenocarcinoma, the incidence of benign uterine disease in this group of patients was not negligible. A recent study evaluated the significance of normal endometrial cells in cervicovaginal smears from 93 asymptomatic PMP women who were receiving HRT with follow-up endometrial biopsy. 19 Eighteen patients had abnormal findings, including 7 patients with endometrial polyps, 7 patients with simple hyperplasia (1 with atypia), 3 patients with of complex hyperplasia (1 with atypia), and 1 patient with endometrial adenocarcinoma. That author concluded that normal endometrial cells in cervicovaginal smears from asymptomatic PMP women may be an indication of endometrial disease. Although no review of the cervicovaginal smears was performed as part of that study, and the possibility that patients with abnormal follow-up endometrial biopsies may have contained atypical endometrial cells cannot be ruled out entirely, the overall findings of that study 19 support our results and interpretation. In our group of PMP women with benign endometrial cells in cervical smears, we also identified five patients (15%) who were on tamoxifen for the treatment of breast carcinoma. Although, in a recent study, Abadi et al. reported that endometrial cells (including benign endometrial cells) were significantly more frequent in smears from patients on tamoxifen who had endometrial adenocarcinoma, 20 we did not have enough patients in our study to draw any conclusions in this regard. The results of the current study indicate that the presence of benign endometrial cells in cervicovaginal preparations from PMP women should be mentioned in the cytology report, whether or not the patient is receiving HRT, because such a finding is associated

66 CANCER (CANCER CYTOPATHOLOGY) April 25, 2002 / Volume 96 / Number 2 with an endometrial abnormality in a number of women. In our study, malignant endometrial pathology was identified only in the group of symptomatic PMP women who were not receiving HRT. Although no endometrial adenocarcinoma was detected in our study in the group of PMP women who were on HRT, that possibility cannot be excluded a priori. In our opinion, it is appropriate to report the presence of benign endometrial cells in cervicovaginal smears from PMP women and to classify them as glandular cell abnormality, as recommended by the 1991 Bethesda System guidelines. 6 This recommendation also applies to benign endometrial cells in cervicovaginal smears from PMP women who are on HRT. REFERENCES 1. DeMay RM. The Pap smear (cytology of glandular epithelium). In: DeMay RM, editor. The art and science of cytopathology: exfoliative cytology, vol 1. Chicago: ASCP Press, 1996:122 125. 2. Ng ABP, Reagan JW, Hawliczek S, Wenz B. Significance of endometrial cells in the detection of endometrial carcinoma and its precursors. Acta Cytol. 1974;18:356 361. 3. Zucker PK, Kadson EJ, Feldstein ML. The validity of Pap smears parameters as predictors of endometrial pathology in postmenopausal women. Cancer. 1985;56:2256 2263. 4. Kerpsack JT, Finan MA, Kline RC. Correlation between endometrial cells on Papanicolaou smear and endometrial adenocarcinoma. South Med J. 1998;91:749 752. 5. Gondos B, King EB. Significance of endometrial cells in cervicovaginal smears. Ann Clin Lab Sci. 1977;7:486 490. 6. Kurman RJ, Solomon D. The Bethesda System for reporting cervical and vaginal cytologic diagnosis. New York: Springer-Verlag, 1994:62 63. 7. Archer DF, Pickar JH, Bottiglioni F. Bleeding patterns in postmenopausal women taking continuous combined or sequential regimens of conjugated estrogens with medroxyprogesterone acetate. Obstet Gynecol. 1994;83:686 692. 8. Akkad AA, Habiba MA, Ismail N, Abrams K, Al-Azzawi F. Abnormal uterine bleeding on hormone replacement: the importance of intrauterine structural abnormalities. Obstet Gynecol. 1995;86:330 334. 9. Spencer CP, Cooper AJ, Whitehead MI. Management of abnormal bleeding in women receiving hormone replacement therapy. Br Med J. 1997;31:37 42. 10. Nand SL, Webster MA, Baber R, O Connor V. Bleeding pattern and endometrial changes during continuous combined hormone replacement therapy. Obstet Gynecol. 1998;91:687 684. 11. Archer DF, Pickar JH. Hormone replacement therapy: effect of progestin dose and time since menopause on endometrial bleeding. Obstet Gynecol. 2000;96:899 905. 12. Symons J, Kempfert N, Speroff L. Vaginal bleeding in postmenopausal women taking low-dose norethindrone acetate and ethynil estradiol combinations. Obstet Gynecol. 2000;96: 366 372. 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: 381 384. 14. Tambouret R, Bell DA, Centeno BA. Significance of histiocytes in cervical smears from peri/postmenopausal women. Diagn Cytopathol. 2001;24:271 275. 15. Chang A, Sabdweiss L, Bose S. Cytologically benign endometrial cells in the Papanicolaou smears of postmenopausal women. Gynecol Oncol. 2001;80:37 43. 16. Cherkis RC, Patten SF, Andrews TJ, Dickinson JC, Patten FW. Significance of normal endometrial cells detected by cervical cytology. Obstet Gynecol. 1988;71:242 244. 17. Yancey M, Magelssen D, Demaurez A, Lee RB. Classification of endometrial cells on cervical cytology. Obstet Gynecol. 1990;76:1000 1005. 18. Kaba S, Aoki T, Fukatsu T. Endometrial cytology in postmenopausal hormone replacement therapy. Diagn Cytopathol. 1997;19:161 167. 19. Montz FJ. Significance of normal endometrial cells in cervical cytology from asymptomatic postmenopausal women receiving hormone replacement therapy. Gynecol Oncol. 2001;81:33 39. 20. Abadi MA, Barakat RR, Saigo PE. Effects of tamoxifen on cervicovaginal smears from patients with breast cancer. Acta Cytol. 2000;44:141 146.