College of American Pathologists
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  Significance of benign endometrial cells in
  cervicovaginal smears





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May 2006
PAP/NGC Programs Review

William D. Tench, MD

The significance of the presence of endometrial cells in Pap smears has been a controversy in gynecologic cytopathology since early reports by Liu, et al in 1963 and Ng, et al in 1974. The controversy has been complicated by the use of a variety of sampling devices and techniques, as well as the introduction of estrogenic and progestogenic hormones for use in birth control and postmenopausal hormone replacement therapy. In addition, the failure of the Pap smear in detecting endometrial cancer has proved it to be an unsatisfactory screening modality for this malignancy. Nevertheless, endometrial cells are commonly encountered in routine Pap smears, and guidelines for reporting their presence in Pap smears and their significance in patient management have been necessary. Though defining truly atypical features in exfoliated endometrial cells may prove to be a diagnostic challenge, once identified, there is a fairly good understanding of what the presence of these atypical cells may mean. Thus, the real challenge is understanding the significance of the presence of “normal appearing” endometrial cells. The 2001 Bethesda System for Reporting Cervical Cytology attempted to address this issue; however, it suffered from a dearth of studies that examined the issue in the era of variable, and frequently unknown, hormone use. Thus, the recommendations that were adopted were understood to be derived from conflicting studies that might not be truly relevant to modern conditions. Subsequent to the release of the Bethesda System 2001 guidelines, numerous, and occasionally conflicting, studies have attempted to address this issue. As is frequently the case, study designs and interpretations have varied widely, thus adding to the difficulty of gaining a clear understanding of the problem.

A recent report by Fadare, et al published in Advances in Anatomic Pathology (Fadare O, Ghofrani M, Chacho MS, Parkash V. September 2005;12[5]:274–287) has attempted to analyze this problem using a comprehensive meta-analysis of more than 80 publications on this topic, including the early reports from the ’60s and ’70s. The report begins with a thorough description of the features of normal endometrial cells, or NECs, including glandular and stromal cells, and includes features that may be more commonly encountered in liquid-based preparations. This is followed by an in-depth discussion of the normal physiology of the endometrium based on “currently more nuanced considerations.” In this discussion, it is reported that the endometrium engages in a dynamic remodeling process that occurs throughout the entire menstrual cycle. Based on several publications, exfoliation of NECs is reported to occur in about 24 percent of smears from days 0–12 and about two percent of smears from days 13–30. Defining the significance of NECs becomes even more problematic. Knowledge of the patients’ clinical status, especially in regard to menopausal status and use of hormones, as well as a definition of what constitutes significant pathology in the endometrium, creates significant obstacles to the reasonable interpretation of the reported data. Nevertheless, the authors attempt to analyze these issues with a thorough discussion of the impact of age, associated symptoms, hormonal use (including tamoxifen), and contraception.

After analyzing these parameters in detail, the authors examine the impact of the Bethesda System 2001 recommendations, namely reporting NEC in the smears of women greater than or equal to 40 years. They note that several studies have demonstrated increased frequency of the diagnosis of NECs and that this has been accompanied by an increase in endometrial biopsies related specifically to this finding. At the same time, however, they note that implementation of the Bethesda System 2001 guidelines has not, in general, increased the rate of the detection of significant endometrial pathology, however that is defined. They do identify one study in which a significant increase in the detection of endometrial cancer was identified in asymptomatic women as a result of the guidelines being implemented. The authors indicate that the issue of the age cut-off in the Bethesda System 2001 at greater than or equal to 40 years is a sensitivity versus specificity issue, and that given the current information, the current Bethesda System recommendation for reporting NECs is appropriate but worthy of continued examination.

Dr. Tench, a member of the CAP Cytopathology Committee, is with Palomar Medical Center, Escondido, Calif.