Significance of Endometrial Cells in Cervicovaginal Smears

ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 7,No. 6 Copyright 1977, Institute for Clinical Science Cervicovaginal Smears BERNARD GONDOS, M.D. and EILEEN B. KING, M.D. Department of Pathology, University of California, San Francisco, CA 94143 ABSTRACT A study was undertaken to determine the significance of finding normal endometrial cells in routine cervicovaginal smears. The results indicate that the presence of normal endometrial cells in cervicovaginal smears in patients under 40 is generally not of significance, but similar findings in older patients correlate significantly with pathologic changes in the endometrium. In the older age group, therefore, such findings clearly indicate a need for further evaluation, including tissue sampling of the endometrium. Introduction Normal endometrial cells are frequently observed in cytologic specimens obtained during the early part of the menstrual cycle. It has also been noted that the presence of normal appearing endometrial cells during the second half of the cycle or in the postmenopausal period may be associated with endometrial carcinoma or its precursors, when cellular samples are obtained by endocervical aspiration.10 Whether or not a similar association exists for cervicovaginal smears has not been determined. The present study was undertaken to evaluate the significance of such findings and to develop a rational approach for handling cases in which normal endometrial cells are found in routine smears. The files of the University of California at San Francisco Medical Center Cytology Laboratory were reviewed for the period 1969-1975. In this period, there were 1,634 cases in which cervicovaginal smears contained normal endometrial cells. Of these, there were 238 with histologic follow-up within six months after the smears were taken, including 147 in the over 40 age group and 91 in the 40 and under age group. In all of these cases, cytologic and histologic specimens as well as the patients charts were thoroughly reviewed. In addition, all cases in the Surgical Pathology files, during the same period, which had a diagnosis of hyperplasia, polyp or carcinoma of the endometrium were checked. Those with cervicovaginal specimens obtained in the preceding six months were subjected to similar review. Materials and Methods 4 8 6 Results The principal findings are summarized in tables I and II. In the 40 and under age

ENDOMETRIAL CELLS IN CYTOLOGIC SMEARS 4 8 7 group, there were only two of 91 cases (2.2 percent) associated with abnormal histologic findings. One of these was a benign polyp in a 34 year old woman who was having irregular bleeding and the other was a case of mild adenomatous hyperplasia in a 38 year old woman who had been bleeding daily for more than four months. There were no cases of carcinoma in this group. Follow-up data on all 91 cases, including the two with abnormal findings, revealed no further evidence of histologic abnormalities. In the over 40 age group, there were 32 of 147 cases (22.8 percent) with abnormal histologic findings, including seven with polyps, 23 with hyperplasia and two with adenocarcinoma of the endometrium. Of the cases with hyperplasia, there were four with cystic hyperplasia 11 with adenomatous hyperplasia, six with cystic and adenomatous hyperplasia and two with atypical adenomatous hyperplasia. One of these cases initially diagnosed as adenomatous hyperplasia in 1970 subsequently developed endometrial carcinoma five years later. The cases without evidence of histologic abnormality were further analyzed to determine the cause for the shedding of endometrial cells (table III). In the younger age group, the majority, approximately two-thirds, involved specimens taken during the first 10 days of the menstrual cycle. The presence of endometrial cells during the so-called exodus period is an expected finding. The remainder of cases were associated with intermenstrual and excessive menstrual bleeding, uterine leiomyomata, presence of an intrauterine device or bleeding owing to an impending or recent abortion. In four cases, no explanation could be found for the presence of endometrial cells. In the over 40 age group, leiomyomata were frequently implicated as the causative factor. They were generally multiple TABLE I Cervicovaginal Smears of Women 40 and Under Tissue Diagnosis Number Percem Normal endometrium 89 97.8 Polyp 1 1.1 Hyperplasia 1 1.1 Carcinoma 0 Total Cases 91 and included submucous lesions associated with bleeding. Two other large categories consisted of patients with perimenopausal bleeding and those with unexplained postmenopausal bleeding. Many of the latter were receiving estrogens for menopausal symptoms. Most of the cases in the older age group were associated with abnormal bleeding. There were 13 cases in which there were no clinical findings to account for the shedding of endometrial cells. The association of bleeding with the presence of endometrial cells was analyzed to determine the relative numbers of symptomatic and asymptomatic patients. The cases were again divided according to age group (table IV). Of the patients 40 and under, relatively few (18 percent) had abnormal bleeding. As indicated previously, most were associated with normal menses or early postmenstrual shedding. In the older age group, the majority did have evidence of abnormal bleeding, including the two with carcinoma. However, of those with TABLE II Cervicovaginal Smears of Women Over 40 Tissue Diagnosis Number Percent Normal endometrium 115 18.2 Polyp 7 4.8 Hyperplasia 23 15.6 Carcinoma 2 1.4 Total Cases 147

4 8 8 GONDOS AND KING TABLE I I I F in d in g s A sso c ia te d w ith P resen ce o f E ndom etrial C e lls in Cases w ithout Polyp, H yp erplasia o r Carcinoma Number of Cases 40 and Under Over 40 First 10 days of cycle 60 15 Menometrorrhagia 6 - Perimenopausal bleeding - 34 Postmenopausal bleeding - 26 Leiomyoma 4 25 IUD 7 1 Threatened abortion 4 1 Post-abortion 4 - Unexplained 4 13 Total Cases 89 115 polyps and hyperplasia, six of 30 (20 percent) were asymptomatic. This compares with approximately 40 percent who were asymptomatic in the group without histologic endometrial abnormalities. During the time interval investigated, there were 17 cases of endometrial carcinoma in which cervicovaginal smears had been obtained. All were adenocarcinomas, and all were in patients over 40. The cytologic findings were diagnosed as malignant in 10, deferred but considered suspicious for malignancy in three, benign with normal endometrial cells present in two and negative in two (table V). Of note is the fact that abnormal bleeding was not present in four of the 17. Altogether, there were 48 cases of hyperplasia and polyp, two-thirds of which were associated with the presence of normal-appearing endometrial cells. There were no false positive diagnoses. T ABLE IV Association of Presence of Endometrial Cells with Abnormal Bleeding Number Tissue Diagnosis with Abnormal Bleeding (% Cases) 40 and Under Over 40 Normal endometrium 16/89 (18.0) 68/115 (59.1) Polyp 1/1 4/7 (57.1) Hyperplasia 1/1 20/23 (87.0) Carcinoma 2/2 Discussion The results of this study indicate that the presence of normal endometrial cells in cervicovaginal smears of women under 40 is unlikely to be associated with significant abnormality, particularly in asymptomatic individuals. On the other hand, a significant degree of correlation with abnormalities of the endometrium does exist in women over 40. Although abnormal bleeding is present in the majority of such cases, 20 percent of patients in the present series were asymptomatic. Endometrial cancer has shown a sharp rise in recent years,2,7,14 in contrast to the declining incidence of carcinoma of the cervix and the associated decrease in mortality from this type of cancer. Cytologic screening has had a clear impact on detection of carcinoma of the cervix, but not on carcinoma of the endometrium. The reasons for this difference can be related to the ease of obtaining specimens, accessibility to direct examination, preservation of cellular material and associated clinical symptoms. Abnormal bleeding patterns have been found to be much more useful than cytologic findings in indicating the need for endometrial biopsy or curettage. Recognition of malignant endometrial cells in a cervicovaginal specimen as a primary means of diagnosis is an infrequent occurrence. At the same time, there has been growing acceptance of the premise that endometrial hyperplasia is a precursor of adenocarcinoma of the endometrium,1 3,4,9,13 Consequently, detection of premalignant conditions takes on special importance. It is clear from the present study that precursors of endometrial carcinoma can be detected in the absence of clinical findings by virtue of the presence of exfoliated endometrial cells. Ng et al9 have suggested that the precursors of endometrial carcinoma, cystic, adenomatous and atypical hyperplasia,

ENDOMETRIAL CELLS IN CYTOLOGIC SMEARS 4 8 9 can be distinguished cytologically in endocervical aspirates. While this type of distinction is possible by careful examination of material obtained in endocervical aspirates, it is difficult and generally not feasible in cervicovaginal smears, in which endometrial cells are not as well preserved. The current findings indicate that, in cervicovaginal specimens, the presence of endometrial cells of normal appearance can be used as an indication of possible endometrial abnormality in the over 40 age group. In another study, significant correlation was observed between presence of normal endometrial cells in endocervical aspirates and histologic abnormalities in both postmenopausal patients and in premenopausal patients with specimens obtained during the second half of the cycle.10 While the latter correlation was not evident in our study, the difference most likely relates to the method of specimen collection. There is ample evidence that the aspiration technique is more reliable in the detection of endometrial abnormalities than the cervicovaginal specimen.11 Although our findings failed to demonstrate a correlation between shedding of normal endometrial cells and significant endometrial abnormality in the 40 and under age group, this may relate to the low incidence of endometrial abnormalities in younger women in our patient population. Others have noted that endometrial carcinoma is increasing in incidence in women under 40,6particularly in those who have taken sequential oral contraceptives.5,8,12 Thus, any case in which there is unexplained bleeding in a young woman requires further evaluation. In women over 40, our data clearly indicate that the presence of endometrial cells in cervicovaginal smears necessitates further evaluation and such a finding should be brought promptly to the attention of the submitting physician. TABLE V C y to lo g ic F indings in Cases o f E ndom etrial Polyp, H yperplasia and Carcinoma No. Cases Cytologic Diagnosis Malignant Deferred* Benigni Negative Carcinoma 17 10 3 2 2 Hyperplasia 35 24 11 Polyp 13 8 5 *Suspected malignancy Acknowledgments tendometrial cells present The authors wish to thank Judith C. Luce, C.T.(ASCP), and Virginia A. McGarry for their assistance in review of the slides and compiling of the data. References 1. B e u t l e r, H. K., D o c k e r t y, M.D., and R a n d a l l, L. M.: Precancerous lesions of the endom etrium. Amer. J. Obstet. Gynec. 86:433-443, 1963. 2. C h r is t o p h e r s o n, W. M., M e n d e z, W. M., P a r k e r, J. E., L u n d e n, F. E., and A h u j a, E. M.: Carcinoma of endometrium: a study of changing rates over a 15-year period. Cancer 27:1005-1008, 1971. 3. G o r e, H. and H e r t ig, A. T.: Premalignant lesions of the endometrium. Clin. Obstet. Gynec. 5:1148-1165, 1962. 4. G u s b e r g, S. B.: The individual at high risk for endom etrial carcinoma. Amer. J. Obstet. Gynec. 126:535-542, 1976. 5. Ke l l e y, H. W., M il e s, P. A., B u s t e r, J. E., and SCRAGG, W. H.: Adenocarcinoma of the endometrium in women taking sequential oral contraceptives. Obstet. Gynec. 47:200-202, 1976. 6. K e m p SON, R. L. and POKORN Y, G. E.: Adenocarcinoma of the endom etrium in women aged forty and younger. Cancer 21:650-662, 1968. 7. Kis t n e r, R. W., K r a n t z, K. E., L e b h e r z, T. B., L e w i s, G. L., R e a g e n, J. W., Sm it h, J., T o b i n, J. J., and W led, G. L.: Endometrial cancer: Rising incidence, detection and treatment. J. Reproduc. Med. 10:53-74, 1973. 8. L y o n, F. A. a n d F r is c h, M. J.: E n d o m e tria l abnorm alities occurring in young w o m e n on lo n g - te rm s e q u e n tia l o ra l c o n tr a c e p tio n. O bstet. G ynec. 47:639-643, 1976. 9. N g, A. B. P., R e a g e n, J. W., and C e c h n e r, R. L.: The precursors of endometrial cancer: a study of their cellular manifestations. Acta Cytol. 17:439^148, 1973.

4 9 0 GONDOS AND KING 10. N g, A. B. P., R e a g e n, J. W,, H a w l i c z e k, S., and W e n t z, B. W.: Significance of endometrial cells in the detection of endometrial carcinoma and its precursors. Acta Cytol 18:356-361, 1974. 11. R e a g e n, J. W. and N g, A. B. P.: The Cells of Uterine Adenocarcinoma. S. Karger, Basel, 2nd ed pp. 133-135, 1973. 12. Si l v e r b e r g, S. G. and M a k o s i, E. L.: Endometrial carcinoma in young women taking oral contraceptive agents. Obstet. Gynec. 46:503-506, 1975. 13. V e l l ios, F.: Endometrial hyperplasias, precursors of endometrial carcinoma. Pathology Annual, New York, Appleton-Century-Crofts, pp. 201-227, 1972. 14. W e is s, N. S., Sz e k e l y, D. R., and A u s t in, D. F.: Increasing incidence of endometrial cancer in the U nited States. New Eng. J. Med. 294:1259-1262, 1976. s t a t e m e n t o f o w n e r s h ip, m a n a g e m e n t a n d c ir c u l a t io n (Act of October 23, 1962; Section 4369, Title 39, United States Code) Date of Filing September 26, 1977 Title of Publication ANNALS OF CLINICAL AND LABORATORY SCIENCE Frequency of Issue Bimonthly Location of Known Office of Publication 230 N. Broad St., Philadelphia, PA 19102 Location of the Headquarters or General Business Offices of the Publisher Same as above Publisher Institute for Clinical Sciences, Inc. Editor F. William Sunderman, M.D., Ph.D. Managing Editor Same as above Owner Institute for Clinical Sciences, Inc. Known Bondholders, Mortgagees, and Other Security Holders Owing or Holding 1 Percent or More of Total Amount of Bonds, Mortgages or Other Securities None Average No. Copies Each Issue During Preceding 12 Months Actual Number of Copies of Single Issue Published Nearest to Filing Date A. Total No. Copies Printed (Net Press Run) 1850 1850 B. Paid Circulation 1. Sales Through Dealers and Carriers, Street Vendors and Counter Sales None None 2. Mail Subscriptions 1665 1739 C. Total Paid Circulation 1665 1739 D. Free Distribution by Mail, Carrier or Other Means, Samples, Complimentary, and Other Free Copies None None E. Total Distribution (Sum o f C and D) 1665 1739 F. Copies not Distributed 1. Office Use, Left-over, Unaccounted Spoiled After Printing 185 111 2. Returns from News Agents None None G. Total (Sum o f E and F should equal net press run shown in A ) 1850 1850 I certify that the statements made by me are correct and complete F. WILLIAM SUNDERMAN, M.D., Ph.D.