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ORIGINAL ARTICLE
Normal endometrial cells in cervical cytology: systematic review of prevalence and relation to significant endometrial pathology Karen Canfell, Yoon Jung Kang, Mark Clements, Aye Myat Moa and Valerie Beral ................................................................................................... J Med Screen 2008;15:188–198 DOI: 10.1258/jms.2008.008069
See end of article for authors’ affiliations
................... Correspondence to: Dr Karen Canfell, Sydney Rotary Research Fellow, Cancer Epidemiology Research Unit, Cancer Council NSW, 153 Dowling Street, Woolloomooloo, New South Wales, Australia;
[email protected] Accepted for publication 6 October 2008
...................
Objectives To estimate the prevalence of normal endometrial cells (NECs) and the proportion of NECs associated with significant endometrial pathology in conventional and liquid-based cytology (LBC) cervical smears; and to assess the association between NECs and clinical symptoms in women with endometrial hyperplasia or carcinoma. Methods Systematic review of the literature and meta-analysis of prevalence and proportion data. The review was confined to studies reporting on NECs in smears from postmenopausal women or women aged 40þ. Results A total of 22 relevant primary studies were identified from 1970 to 2007. The overall summary estimate for the prevalence of NECs in smears from postmenopausal women or women aged 40þ in all screening smears was 0.4% (95% CI 0.2– 0.7%); this was 0.3% (95% CI 0.1 – 0.5%) and 0.9% (95% CI 0.5–1.4%) for conventional and LBC smears, respectively; P ¼ 0.003 for difference. The overall estimate for the proportion of NECs associated with significant endometrial pathology was 7% (95% CI 4–10%); this was 11% (95% CI 8 –14%) and 2% (95% CI 1 –2%) for conventional and LBC smears, respectively; P , 0.001 for difference. In women with significant endometrial pathology, the presence of NECs in followed-up women was associated with abnormal uterine bleeding in 79% (95% CI 68 –87%) of cases. Conclusion Compared with conventional cytology, LBC may be associated with a higher prevalence of NECs but these are less likely to be associated with endometrial pathology. This finding might be explained by more consistent use of sampling instruments for LBC with better access to the endocervical canal or alternatively by changes over time, broadly coincident with the introduction of LBC, in the population in which NECs are reported. In followed-up women with NECs, most endometrial pathology is accompanied by symptoms, implying that a relatively smaller number of additional cases are identified through follow-up of asymptomatic women.
INTRODUCTION
E
ndometrial carcinoma is one of the most common gynaecological malignancies, occurring predominantly in postmenopausal women.1 The established risk factors include obesity2 and use of oestrogen-only hormone replacement therapy (HRT) and tibolone.3 The established protective factors include use of oral contraceptives, high parity and late age at last birth.1 No widely accepted screening test for endometrial carcinoma exists, but cervical cytology has been found to be of some use in detecting endometrial disease. However, the sensitivity of cervical cytology for detection of endometrial pathology is relatively low, ranging from 25% to 55%.4,5 In one review, it was estimated that 48% of endometrial carcinomas are preceded by abnormal cervical cytology.6 It has been suggested that the likelihood of endometrial cell shedding is increased in higher tumour stage and endocervical involvement. Therefore, if atypical or malignant endometrial cells are identified in the cervical smear, reporting of the presence of such cells is warranted and further investigation is appropriate.4,7 – 10
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The management of normal endometrial cells (NECs) in cervical cytological smears is less clearly established. An association between the presence of normal exfoliated endometrial cells and significant pathological outcomes was proposed in the 1960s and 1970s after analysis of samples obtained by endocervical aspiration.11 – 13 Endometrial cells are a normal component of the smear in the first half of the menstrual cycle when endometrial breakdown and shedding occurs. Over 60% of smears obtained from women in the first few days of the cycle may have endometrial cells present14 and clusters of endometrial cells of stromal, glandular or mixed origin are observed.15 However, if NECs are observed in smears taken when physiological exfoliation is not expected – the second half of the menstrual cycle – the pathological significance may be greater, although cell shedding at this time can be associated with use of oral contraceptives, intrauterine contraceptive devices or use of HRT.7 Because the rates of endometrial carcinoma are highest in postmenopausal women, NECs observed in smears from women aged 40þ may be of greater clinical significance.
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Systematic review of normal endometrial cells in cervical cytology
Irrespective of whether or not NECs are observed in cervical cytology, a proportion of patients with significant endometrial disease are symptomatic, presenting with abnormal uterine bleeding and therefore warranting further investigation. Options for management include transvaginal ultrasound, hysteroscopy, endometrial biopsy, and dilatation and curettage. In the UK, transvaginal ultrasound is used as the first-line procedure, followed by further investigation if the endometrial thickness is greater than 4 mm.16,17 Most patients prefer to undergo endometrial assessment with hysteroscopy to rule out the risk of cancer.18 However, the procedure has some associated complications, including uterine perforation.19 – 21 In one study of operative hysteroscopy, the overall complication rate was 3%, with a 1% rate of uterine perforation22 although the complication rate is lower for diagnostic hysteroscopy.19 In a proportion of women, the presence of NECs without symptoms could potentially signal the presence of significant endometrial pathology. The reporting of NECs and the associated management strategies must therefore take into consideration the number of additional cases of endometrial disease detected by active follow-up of asymptomatic women, beyond those that are detected symptomatically. In the UK, initial observations suggest an increase in the prevalence of NECs since the transition from conventional to liquid-based cytology (LBC) was initiated in 2003 (Prof. Julietta Patnick, personal communication). It is possible that the reported increase relates to the difference in sampling instrument associated with the transition to LBC. Conventional cytology in the UK prior to the 2003 technology change was often-performed using the Ayer or (after 1987) the Aylesbury wooden spatulas, whereas LBC samples are generally obtained using a cervical broom. Therefore, more consistent sampling of cells in the endocervix – and potentially of the lower uterine segment – may have been a consequence of the transition to LBC, and this could have increased the prevalence of endometrial cells in the cervical smear. The objectives of the current study were, first, to perform a systematic review of the literature in order to estimate the prevalence of NECs in conventional and LBC smears. The second objective was to assess the proportion of NECs associated with significant endometrial pathology and quantify any differences in the underlying rate of significant pathological outcomes between conventional and LBC smears. The third objective was to assess the association between NECs and uterine bleeding in women with significant endometrial pathology, in order to quantify the proportion of women who are diagnosed only through active follow-up of NECs, and not via investigation of symptoms. We also summarized the available information on factors that can modify the likelihood of observing NECs on the smear, including the effects of use of oral contraceptives, intrauterine contraceptive devices, HRT and tamoxifen.
METHODS Two investigators (YJK and AMM) searched Medline and EMBASE for articles published between 1970 and 2007 relating to NECs in cervical cytology, with the final search performed on 19 February 2008. The search terms used as specified for Medline were (Pap smear OR vaginal smear [MESH] OR cervical cytology OR LBC OR uterine cervical dysplasia [MESH] OR uterine cervical neoplasms [MESH] OR cervical intraepithelial neoplasia [MESH] OR CIN) AND (endometrial cells OR endometrial neoplasm OR endometrial hyperplasia). We also searched the reference www.jmedscreen.com
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lists of identified papers for further relevant source articles. The titles and abstracts were reviewed for inclusion according to the following criteria: reporting original data on NECs in smears from postmenopausal women or from women aged 40 or older; and presenting data on one or more of the following subjects: the prevalence of NECs in cervical cytology when the majority of smears were taken in the screening context and the total number of smears in the population were precisely reported; the proportion of NECs with associated endometrial pathology; or the association between the presence of NECs and clinical symptoms in women with endometrial disease. We excluded conference abstracts and early publications from multiple reports of the same study. The two investigators independently conducted the search, reviewed titles and abstracts, and extracted data from included studies, with disagreements and queries resolved at each stage via consultation with a third investigator (KC). The smear technology for each study was classified as conventional or LBC. Studies reporting that 85% or more of smears were prepared using a particular technology were classified on that basis. Studies not specifying a technology, or in which both conventional and LBC specimens were included without specifying the relative proportions, were further reviewed and classified according to study period and country. For European and Canadian studies we assumed that studies conducted before 2003 involved conventional cytology. In the USA, ThinPrep LBC (Cytyc Corp, Marlborough, MA, USA) received Food and Drug Administration approval in 1996; by the end of 2001, the market share for ThinPrep in the USA was over 50%, growing to 70% by 2005.23 Therefore, we assumed that studies conducted in USA before 1997 involved conventional cytology and studies conducted after 2001 predominantly involved LBC; for studies conducted in the period 1997– 2001, the smear technology, if unspecified, was classified as predominantly conventional cytology. Sensitivity analysis was performed to assess the impact of these assumptions. Most studies involving LBC did not specify the manufacturer, and we were therefore unable to classify our results on the basis of specific liquid-based technologies. We classified the population in which NECs were reported for each eligible study as one of the two types – Type 1 populations involved women who were postmenopausal and/or 50 years or older, whereas Type 2 populations involved women aged 40 or older. For studies providing data on NEC prevalence, we classified the study according to whether the prevalence was reported as a percentage of all smears (including those from younger women), or as a percentage of smears taken from the population in which NECs were reported; and separate analysis was performed for the two prevalence estimates. For studies that included premenopausal women over 40 years of age and provided information on whether NECs were observed in the first or second half of the menstrual cycle, we extracted results only for NECs in the second half of the cycle. A number of studies conducted in the USA reported on NEC prevalence in different smear series before and after the implementation of The Bethesda System (TBS) 2001 for cytological reporting. Prior to the implementation of TBS 2001, NECs in postmenopausal women were reported, whereas TBS 2001 recommended reporting of NECs in all women over 40 years of age.8 For some studies, relevant data could be extracted from both smear series. Because the year in which LBC became the dominant technology in the USA (2001) broadly coincided with the change in the cytology reporting to TBS 2001 (and hence a chance in the group of women in which NECs were reported), we also performed stratified analysis according to the study population in which Journal of Medical Screening
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NECs were reported. Additionally, to account for potential confounding by study population in the assessment of differences due to smear technology, we performed multivariate logistic regression to adjust for the study population. For the purposes of the review ‘significant endometrial pathology’ was defined as endometrial hyperplasia (generally including simple endometrial hyperplasia with atypia and complex endometrial hyperplasia) or endometrial carcinoma. Because the various studies did not consistently report on the association between NECs and benign endometrial polyps, we did not include this outcome in our review. Data were analysed using Stata 9 software (StataCorp, TX, USA) and R version 2.7.1 (R Foundation for Statistical Computing, Vienna, Austria). Because the data were highly heterogeneous, we used random effects meta-analysis to calculate pooled estimates of prevalence and proportions with 95% CI. In order to test for the significance of differences in prevalence and proportions by smear technology while adjusting for study population, we used generalized linear mixed regression models with binomially distributed outcomes, a logit link and a global random effect to calculate P values for univariate and multivariate analyses.
RESULTS The initial search identified 411 studies, 37 of which were potentially eligible according to the title/abstract and 22 of which met the inclusion criteria after full review14,24 – 44 (Table 1). Of these, 12 reported on the prevalence of NECs in cervical cytology, 19 reported on the proportion of women with NECs who had significant endometrial pathology and 10 reported on the association between the presence of NECs and clinical symptoms in women with significant endometrial pathology. Because the identified studies involved retrospective review of information from clinical smear series, they were all considered to be only of ‘low’ or ‘fair’ quality according to the QUADAS criteria for diagnostic accuracy studies (which specify that ‘high quality’ studies involve prospective recruitment and blind interpretation of the reference standard with respect to the test).45
Prevalence of NECs in cervical cytology Figure 1A and B detail the results for the prevalence of NECs in cervical smears taken in the screening context. Figure 1A provides results for the majority of the studies in which prevalence was reported as a percentage of all smears, including those from younger women; whereas Figure 1B provides results for the smaller number of studies reporting on prevalence as a percentage of the population in which NECs were reported; either postmenopausal women (type 1) or women aged 40þ (type 2). The reported prevalence of NECs in all smears varied between 0.1% and 1.4% (Figure 1A) and the overall summary estimate was 0.4% (95% CI 0.2 –0.7%). For conventional smears, the corresponding prevalence was 0.3% (95% CI 0.1 –0.5%), whereas for LBC the prevalence was 0.9% (95% CI 0.5 –1.4%); this difference was significant in a univariate regression analysis (P ¼ 0.003). For studies reporting on NEC prevalence only within type 1 or type 2 populations, the range reported was between 0.2% and 3.0% (Figure 1B) and the overall summary estimate was 0.7% (95% CI 0.4 –1.4%); for conventional smears prevalence was 0.6% (95% CI 0.3 –1.1%), whereas for LBC the prevalence was 1.2% (95% CI 0.3 –4.2%); this difference was not significant (P ¼ 0.23). Journal of Medical Screening
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In the analysis of NEC prevalence, we were unable to perform multivariate analysis to adjust for the type of study population because studies reporting results for all combinations of smear technology and population were not available. However, if studies were classified by study population rather than smear technology, univariate analysis indicated a significant difference in prevalence (P , 0.001). Therefore, the study population appears to have an impact on NEC prevalence that may be independent of the smear technology.
Histological outcomes following NECs Table 2 and Figure 2 summarize the results for the studies reporting on histological outcomes following smear reports of NECs. The majority of studies were retrospective audits of cytology and pathology records for which referral practices varied, and the rate of follow-up of NECs varied between 18% and 79% (in studies in which this was specified). The proportion of followed-up women who were found to have any significant endometrial pathology ranged from 1% to 24% in the various studies. The overall estimate for the proportion was 7% (95% CI 4–10%) (Figure 2A); for conventional smears it was 11% (95% CI 8–14%) and for LBC it was 2% (95% CI 1–2%). The difference in proportions associated with smear technology was significant both in the univariate analysis and after adjusting for study population (P , 0.001). If only endometrial carcinoma outcomes were considered, the overall estimate of the proportion of NECs with underlying carcinoma was 3% (95% CI 2–5%) (Figure 2B). In the case of conventional smears, the summary estimate was 4% (95% CI 3–7%), whereas for liquid-based smears, it was 1% (95% CI 1–2%); the difference associated with the smear technology was significant in the univariate analysis (P ¼ 0.001), but in this case was not significant after adjusting for population (P ¼ 0.08).
Sensitivity analysis for smear technology We performed sensitivity analysis to assess the impact on our estimates of including post-1996 studies in which the test technology had been classified on the basis of study period and country (and not explicitly specified in the primary study). For both estimates of NEC prevalence and of rates of significant endometrial pathology, the results did not change substantially when these studies were excluded. The sensitivity analysis was remarkably robust compared to all of the main study findings. The only qualitative change was weaker support for a difference in the prevalence of NECs in all smears between conventional smears and LBC, with a p value of 0.05 compared to a p value of 0.003 in the main analysis.
Association between NECs and symptoms All eligible studies in the review of the association between NECs and clinical symptoms in women with significant endometrial pathology involved only postmenopausal women, and Table 3 and Figure 3 summarize the results. In women with NECs who also had significant pathology, the proportion with symptoms (abnormal uterine bleeding) varied from 43% to 100% and the summary estimate was 79% (95% CI 68–87%) (Figure 3A). For endometrial carcinoma, the summary estimate for the proportion with symptoms was 77% (95% CI 62– 87%) (Figure 3B). It should be noted that several studies reported symptoms in all women with significant pathology or carcinoma, and these had to be excluded from the random effects meta-analysis, for technical reasons. Therefore, in this sense the summary estimates for www.jmedscreen.com
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USA USA USA USA
USA USA
USA USA USA
Chang et al. 28 Ashfaq et al. 29 Montz et al. 30 Sarode et al. 31
Wu et al. 32 Mount et al. 33
Brogi et al. 34 Cai et al. 35 Browne et al. 36
USA
GomezFernandez et al. 26
Canada
1992– 1995
USA
Yancey et al. 25
Gray et al. 27
1972– 1987
USA
Cherkis et al. 24
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1999 1992– 1999 2000– 2003
Unspecified (5 years) 1995– 1998
1994– 1999 1997– 2000 1994– 1998 1995– 1998
1989– 1992
1972– 1985
Unspecified (8 years)
The Netherlands
Vooijs et al. 14
Period
Country
Study
Table 1 List of included studies
Predominantly conventional Predominantly conventional Predominantly conventional for early series (Population 1)
Predominantly conventional Predominantly conventional
Predominantly conventional Predominantly conventional Predominantly conventional Conventional
Conventional
Conventional
Conventional
Conventional
Conventional
Smear technology Women aged 35 –55. For premenopausal women, the study provides information on NEC prevalence throughout the cycle. Data analysed for women aged 50þ and in the postmenopausal period Women aged 40þ who were either in the second half of their menstrual cycle or in the postmenopausal period Women who were either in the second half of their menstrual cycle or in the postmenopausal period Women aged 35þ who were either in the second half of their menstrual cycle or in the postmenopausal period Postmenopausal women (designated as group 2 in the study) Postmenopausal women Postmenopausal women Women aged 45þ Postmenopausal women aged 55þ Postmenopausal women Women who were either aged 50þ or in the postmenopausal period Women aged 50þ Postmenopausal women The study involved two populations – postmenopausal women ( pre-TBS 2001 from 2000 to 2001) and a later series in women aged 40þ ( post-TBS 2001 from 2002 to 2003)
Population
2008
X p
p
X p
X X p
p
X
X
X
X
p
Reporting on prevalence of NECs in a screening population (refer Figure 1)
p p p
p p
p p p p
p
p
p
p
X
Reporting proportion of NECs associated with significant endometrial pathology (refer Table 2 and Figure 2)
X p
p
X X p p
p p
X
X
X
X
X
Reporting association between presence of NECs and symptoms (refer Table 3 and Figure 3)
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USA
USA
USA
Simsir et al. 37
Thrall et al. 38
39
USA
USA
Kapali et al. 43
Moroney et al. 44
2001– 2005
2003– 2004
2002– 2005
1997– 2002 2002– 2006
1999– 2003
2002– 2003
1998– 2002
Period
Predominantly LBC (87% of samples) Predominantly LBC (.90% of samples) LBC
Conventional Predominantly LBC
Predominantly LBC (96% of samples) Predominantly conventional (85% of samples – Populations 1 and 2)
Predominantly LBC for later series (Population 2) Predominantly conventional
Smear technology
Assumed predominant smear technology based on country and period in which study was conducted (see text)
USA
Beal et al. 42
The Netherlands USA
Siebers et al. 40 Aslan et al. 41
Bean et al.
Country
Study
Table 1 (Continued)
Women aged 40þ
Women aged 40þ
The study involved two series in women aged 40þ (Population 1: 1999–2001; Population 2: 2002–2003) Postmenopausal women Women who were either in the second half of their menstrual cycle or in the postmenopausal period, or of unknown menopausal status (Population 2) Women aged 40þ
Women aged 40þ who were either in the second half of their menstrual cycle or in the postmenopausal period Women aged 40þ
Population
X p
p
p p
p
p
X
Reporting on prevalence of NECs in a screening population (refer Figure 1)
p p p
p p
X X
X
X
p
Reporting association between presence of NECs and symptoms (refer Table 3 and Figure 3)
p
X
p
X
p
p
Reporting proportion of NECs associated with significant endometrial pathology (refer Table 2 and Figure 2)
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Figure 1 (A) Summary estimate for prevalence of normal endometrial cells (NECs) in older women as a percentage of all smears (from women of all ages). (B) Summary estimate for prevalence of NECs in older women in the postmenopausal period or women aged 40þ years
the proportion of women with symptoms may be conservative. However, it is likely that the presence of symptoms influenced the probability of follow-up in women with NECs, and it remains possible that undetected endometrial pathology was present in some asymptomatic women with NECs who were not followed-up. Therefore, these findings can be considered only in relation to the existing management practices with NECs.
Effect of other factors Use of oral contraceptives decreases the prevalence of endometrial cells observed in the first half of the cycle14 and may result in NECs or breakthrough bleeding in the latter half of the cycle.7 In women using an intrauterine contraceptive device, the prevalence of endometrial cells increases throughout the menstrual cycle, with an average prevalence of 26% in the first half of the cycle and 6% in the second half of the cycle.14 Use of tamoxifen may be associated with endometrial hyperplasia46 and it may also be associated with clusters of parabasal cells that can be mistaken for endometrial cells.4 Use of HRT may be associated with endometrial thickening, abnormal uterine bleeding and increased prevalence of NECs. However, in women using HRT, abnormal uterine bleeding does not appear to have a strong association with histological outcomes.47 Among women with NECs, rates of significant endometrial pathology in HRT users and non-users are not well-defined.4,29,33,34,37 Mount et al. 33 reviewed results from 52,662 smears from women who were postmenopausal or over the age of 50, and found that HRT users had a significantly higher prevalence of NECs (the study did not report on whether HRT-users were current or ever-users at the time of cytological sampling, or on the type of HRT). The overall NEC prevalence was 1.1% in this population, with a prevalence of 1.52% in HRT-users and 0.097% in non-users. Therefore, all four factors considered above may increase the likelihood of observing NECs in the smear. Use of oral contraceptives or HRT may increase the prevalence of www.jmedscreen.com
NECs, but the impact on the positive predictive value for endometrial disease is not clear, as these factors can modify the risk of developing endometrial cancer.
DISCUSSION The significance of NECs in cervical cytology depends on several factors, including the age and menopausal status of the woman and, if premenopausal, the phase of the menstrual cycle during which sampling was performed. Based on data from multiple studies, we estimated the overall prevalence of NECs as a percentage of the entire screening population to be 0.4% of which 7% of followed-up women are found to have significant pathology. If only conventional smears are considered, the estimated prevalence of NECs is 0.3%, of which 11% are associated with significant pathology. In contrast, for LBC smears, the estimated prevalence of NECs is 0.9%, of which only 2% are associated with significant pathology. These results imply that, irrespective of the smear technology, the rate of underlying endometrial pathology detectable by NECs in screening smears is approximately 20–30 per 100,000 on a population basis. The results also imply that the positive predictive value of NECs for significant pathology is reduced when LBC is used as the smear technology. Our analysis has several limitations, the most important of which is that the primary studies reporting on NEC prevalence involved a retrospective review of smear records, and were conducted in different countries at different times. Data for conventional cytology and in LBC were obtained from different studies, so in the comparison of smear technologies we were not able to control for differences in histological follow-up rates or other differences in management practice in various settings. Therefore, we cannot exclude the possibility that factors other than smear technology had an impact on NEC reporting rates. Potentially, the most important of these is the population in which NECs were reported. Although our finding that the rate of underlying significant endometrial pathology in NECs from LBC smears is significantly lower Journal of Medical Screening
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Predominantly LBC Conventional Predominantly LBC Predominantly LBC LBC
Predominantly conventional‡
866 56 1784 1049 2494
1200
Women aged 40þ ( post-TBS 2001)
Women aged 40þ who were either in the second half of the cycle or in the postmenopausal period Women aged 40þ Postmenopausal women Postmenopausal women Women aged 40þ Women aged 40þ
836
Post-menopausal women ( pre-TBS 2001)
80
436
220 227
93
136
Not specified 367
Not specified 206
440
Not specified† 154
Postmenopausal women
Women who were either aged 50þ or in the postmenopausal period Women aged 50þ
Postmenopausal women aged 55þ Postmenopausal women
Women aged 45þ
Postmenopausal women
Postmenopausal women
Women aged 40þ who were either in the second half of the cycle or in the postmenopausal period Women who were either in the second half of the cycle or in the postmenopausal period Women aged 35þ who were either in the second half of the cycle or in the postmenopausal period Postmenopausal women
Group in which NECs are reported
‡
†
For some studies the proportion of smears with NECs in which histological follow-up was available was not reported In this study, only symptomatic women had histological follow-up Assumed predominant smear technology based on country and period in which study was conducted (see text) § This study included all women aged 40þ in the analysis of NEC prevalence (refer Figure 1) but for histological outcomes only data from postmenopausal women are used
Thrall et al. 39 Siebers et al. 40 Beal et al. 42§ Kapali et al. 43 Moroney et al. 44
Browne et al. 36 – Population 1 Browne et al. 36 – Population 2 Simsir et al. 38
Cai et al. 35
Brogi et al. 34
Mount et al. 33
Sarode et al. 31 Wu et al. 32
Montz et al.
30
Ashfaq et al. 29
Predominantly conventional‡ Predominantly conventional‡ Predominantly conventional‡ Conventional Predominantly conventional‡ Predominantly conventional‡ Predominantly conventional‡ Predominantly conventional‡ Predominantly conventional‡ Predominantly LBC‡
Conventional
Gray et al. 27
Chang et al.
Conventional
Gomez-Fernandez et al. 26†
28
Conventional
Conventional
Cherkis et al. 24
Yancey et al. 25
Smear technology
Study
Total no. of women with NECs
159 8 440 499 370
(18.4%) (14.3%) (24.7%) (47.6%) (14.8%)
226 (18.8%)
211 (25.2%)
69 (44.8%)
28 (N/A)
41 (51%)
160 (37%)
81 (37%) 61 (27%)
93 (N/A)
96 (74%)
132 (34%)
43 (N/A)
162 (79%)
131 (N/A)
179 (41%)
n (%) with follow-up histology
Table 2 Summary of studies reporting endometrial histology outcomes after the identification of NECs in cytological smears
2 0 2 2 3
(3.1%) (0%) (1.3%) (0.5%) (3.0%)
4 (1.8%)
1 (0.5%)
2 (2.9%)
4 (14.3%)
0 (0%)
1 (0.6%)
4 (4.9%) 5 (8.2%)
4 (4.3%)
2 (2.1%)
7 (5.3%)
9 (20.9%)
10 (6.2%)
12 (9.2%)
23 (12.8%)
n (%) with premalignant histology
0 (0%) 2 (25.0%) 3 (2.0%) 4(1.1%) 5 (5.0%)
7 (3.1%)
6 (2.8%)
3 (4.3%)
1 (3.6%)
2 (5.0%)
12 (7.5%)
4 (4.9%) 9 (14.8%)
1 (1.1%)
9 (9.4%)
1 (0.8%)
0 (0%)
7 (4.3%)
1 (0.8%)
20 (11.2%)
n (%) with endometrial carcinoma
2 2 5 6 8
(3.1%) (25.0%) (3.3%) (1.6%) (7.9%)
11 (4.9%)
7 (3.3%)
5 (7.3%)
5 (17.9%)
2 (4.9%)
13 (8.1%)
8 (9.9%) 14 (23.0%)
5 (5.4%)
11 (11.5%)
8 (6.1%)
9 (20.9%)
17 (10.5%)
13 (9.9%)
43 (24.0%)
Total – n (%) with any significant pathology
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Figure 2 (A) Summary estimate for overall proportion of followed-up women with normal endometrial cells (NECs) found to have significant endometrial pathology. (B) Summary estimate for overall proportion of followed-up women with NECs found to have endometrial carcinoma
than for conventional smears was made in the context of adjusting for study population, it remains possible that the lower positive predictive value of NECs in LBC smears is related to a change in the population in which NECs are reported (i.e. in women aged 40þ rather than in postmenopausal women), which was broadly coincident in time with the introduction of LBC technology. In addition, not all primary studies reported on the type of smear technology used, and in those cases we based the classification of smear technology on the study period and country. However, sensitivity analysis showed that our main results were not sensitive to this factor. Despite these limitations, the included primary studies do represent the best available information on outcomes following a finding of NECs in cervical cytology, and our review represents a synthesis of that information. www.jmedscreen.com
Our findings are consistent with the hypothesis that smears using LBC technology are more likely to involve sampling instruments with better access to the endocervical canal (at least in the settings in which the primary studies were conducted), and are therefore more likely to sample NECs. However, such ‘directly sampled’ endometrial cells may show morphological distinction from exfoliated endometrial cells – directly sampled endometrial cells are likely to be wellpreserved and include endometrial stroma and epithelial cells with crush artefact, whereas exfoliated endometrial cells may be degenerate single cells or balls of cells (Dr Huw Llewellyn, personal communication). It is possible that the diagnostic implications of the two sampling scenarios are different. In postmenopausal women with significant endometrial pathology, we found that the presence of NECs in followed-up Journal of Medical Screening
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Unspecified 12 months
Women aged 40þ
36 months
12 months
Unspecified
18 months
Unspecified
12 months
12 months
24 months
Unspecified
Women aged 40þ
Women aged 40þ who were either in the second half of the cycle or the postmenopausal period Women aged 40þ
Predominantly conventional
Predominantly LBC Predominantly LBC LBC
Women aged 40þ
Postmenopausal women
Women who were either aged 50þ or in the postmenopausal period Women aged 50þ
Postmenopausal women
Postmenopausal women
Postmenopausal women
Predominantly LBC
Predominantly conventional Predominantly conventional Predominantly conventional Predominantly conventional Predominantly conventional Predominantly conventional
Group in which NECs are reported
Follow-up period
101
375
152
226
211
69
40
160
61
96
132
No. of NEC cases with histology follow-up
Assumed predominant smear technology based on country and period in which study was conducted (see text) In this study, the presence of symptoms in one case with hyperplasia and one case with adenocarcinoma were not specified (excluded from analysis)
†
Moroney et al. 44
Kapali et al.
Beal et al. 42
Browne et al. 36 – Population 1 Browne et al. 36 – Population 2 Simsir et al. 37
Brogi et al.
34
Mount et al. 33†
Wu et al.
32
Ashfaq et al. 29
Chang et al. 28
Reference
Smear technology
5 (5.0%)
4 (1.1%)
3 (2.0%)
7 (3.1%)
6 (2.8%)
3 (4.3%)
2 (5.0%)
12 (0.6%)
8 (13.1%)
Unspecified
1 (0.8%)
N (%) with endometrial carcinoma
5 (100%)
2 (50%)
2 (66.7%)
6 (85.7%)
3 (50.0%)
1 (33.3%)
2 (100%)
11 (91.7%)
6 (75%)
Unspecified
1 (100%)
N (%) of carcinoma with symptoms
Table 3 Summary of studies reporting the proportion of symptomatic women, in women with normal endometrial cells and significant pathology
8 (7.9%)
6 (1.6%)
7 (4.6%)
11 (4.9%)
7 (3.3%)
5 (7.2%)
2 (5.0%)
13 (8.1%)
17 (27.9%)
11 (11.5%)
8 (6.7%)
N (%) with any significant pathology
8 (100%)
3 (50%)
5 (71.4%)
9 (81.8%)
3 (42.9%)
3 (60.0%)
2 (100%)
11 (84.6%)
15 (88.2%)
10 (90.9%)
6 (75.0%)
N (%) of significant pathology with symptoms
196 Canfell et al.
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Systematic review of normal endometrial cells in cervical cytology
197
Figure 3 (A) Summary estimate for proportion of followed-up women with normal endometrial cells (NECs) found to have significant endometrial pathology who also present with symptoms. (B) Summary estimate for proportion of followed-up women with NECs found to have endometrial carcinoma who also present with symptoms
women is associated with abnormal uterine bleeding in the majority of cases. In the context of a management system that routinely refers women with postmenopausal bleeding for further evaluation, this finding implies that a relatively small number of additional cases are identified using the existing practices for follow-up of asymptomatic women with NECs. However, it should be borne in mind that the estimates for this proportion are based on relatively small numbers and that other considerations are also relevant in determining whether NECs are reported in cervical cytology. For example, shed endometrial cells are a differential diagnosis of squamous cell carcinoma in situ, and in LBC it may be more difficult to distinguish between endometrial cells and carcinoma in situ cells compared with conventional cytology (Dr Huw Llewellyn, personal communication). Currently, different approaches to the reporting and management of asymptomatic women with NECs are taken in various countries. Reporting of NECs in women over 40 years of age is currently recommended in England, the USA and New Zealand. In England, it is recommended that NECs observed outside the first 12 days of the cycle in women over 40 years of age be recorded, but the decision to refer is a clinical one, as all the relevant information may not have been available on the pathology request form.7 In the USA, the 1991 Bethesda System for cytological classification required the recording of the presence of endometrial cells only in postmenopausal women. However, this was modified in the 2001 Bethesda System, which required the reporting of the presence of endometrial cells in women 40 years of age or older, regardless of menopausal status or date of last menstrual period.8 The
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rationale for the change in reporting structure was the inability of the laboratory to reliably report on menopausal status or menstrual phase and other risk factors for NECs, such as use of exogenous hormones.8 Therefore, it was intended that the clinician used the information on the presence of NECs to interpret its significance and recommend further management in the context of other information. In New Zealand, a modified version of TBS 2001 is used for cytology classification and the recommendations specify that NECs are reported for all women 40 years of age or older, accompanied by a clinical note requesting that the clinician correlate the finding with any symptomatology of uterine pathology and refer accordingly.9 In the case of Australia, the 2005 National Health and Medical Research Council (NHMRC) guidelines for the management of asymptomatic women with abnormal cervical cytology specify that NECs in asymptomatic premenopausal and postmenopausal women should not be reported.10 In summary, this review has found that compared with conventional cytology, LBC may be associated with a higher prevalence of NECs, but these are less likely than in conventional smears to be associated with significant endometrial pathology. Most cases of significant endometrial pathology in followed-up women with NECs are accompanied by clinical symptoms, implying that under existing management practices, a relatively small number of additional cases are identified via the follow-up of asymptomatic women with NECs. These findings emphasize the importance of assessing symptomatic status at the time of smear taking, and of following-up symptomatic women, whether or not NECs are observed in cervical cytology.
Journal of Medical Screening
2008
Volume 15
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Canfell et al. 18
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Authors’ affiliations Karen Canfell, DPhil, Sydney Rotary Research Fellow, Cancer Epidemiology Research Unit, Cancer Council New South Wales, 153 Dowling Street, Woolloomooloo, New South Wales, Sydney, Australia and School of Public Health, The University of Sydney, Australia Yoon Jung Kang, MPH (Hons), PhD Student, Cancer Epidemiology Research Unit, New South Wales, 153 Dowling Street, Woolloomooloo, New South Wales, Sydney, Australia and School of Public Health, The University of Sydney, Australia Mark Clements, PhD, Research Fellow, The National Centre for Epidemiology and Population Health, The Australian National University, Canberra, Australia Aye Myat Moa, MPH, Research Assistant, Cancer Epidemiology Research Unit, New South Wales, 153 Dowling Street, Woolloomooloo, New South Wales, Sydney, Australia Valerie Beral, FRS, Director, Cancer Epidemiology Unit, The University of Oxford, Oxford, UK
19 20 21
22 23 24 25 26 27
ACKNOWLEDGEMENTS
28
We thank Prof. Julietta Patnick and Dr Huw Llewellyn for constructive review of the manuscript. Funding source: This project was funded by the National Health Service Cervical Screening Programme in England.
29 30 31
REFERENCES 1 2 3 4 5 6 7
8 9
10
11 12 13 14 15 16 17
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Bray F, dos SSI, Moller H, et al. Endometrial cancer incidence trends in Europe: underlying determinants and prospects for prevention. Cancer Epidemiol Biomarkers Prev 2005;14:1132 –42 Reeves GK, Pirie K, Beral V, et al. Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study. Br Med J 2007;335:1134 Beral V, Bull D, Reeves G. Endometrial cancer and hormone-replacement therapy in the Million Women Study. Lancet 2005;365:1543 –51 Fadare O, Ghofrani M, Chacho MS, et al. The significance of benign endometrial cells in cervicovaginal smears. Adv Anat Pathol 2005;12:274 – 87 Mitchell H, Giles G, Medley G. Accuracy and survival benefit of cytological prediction of endometrial carcinoma on routine cervical smears. Int J Gynecol Pathol 1993;12:34 –40 Fukuda K, Mori M, Uchiyama M, et al. Preoperative cervical cytology in endometrial carcinoma and its clinicopathologic relevance. Gynecol Oncol 1999;72:273 – 7 Johnson EJ, Patnick J. Achievable standards, benchmarks for reporting, and criteria for evaluating cervical cytopathology. Second edition including revised performance indicators. Cytopathology 2000;11:212 – 41 Solomon D, Davey D, Kurman R, et al. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA 2002;287:2114 – 9 National Cervical Screening Programme (NZ). Bethesda 2001: New Zealand Modified. Codes, Descriptors and Assessment of Sample Adequacy for Cytology Laboratories. Wellington, New Zealand: Ministry of Health; 2005 National Health and Medical Research Council. Screening to Prevent Cervical Cancer: Guidelines for the Management of Asymptomatic Women with Screen Detected Abnormalities. See http://www.nhmrc.gov. au/publications/synopses/wh39syn.htm (last checked 15 February 2006) Liu W, Barrow MJ, Spitler MF, et al. Normal exfoliation of endometrial cells in premenopausal women. Acta Cytol 1963;7:211 –4 Ng AB. The cellular detection of endometrial carcinoma and its precursors. Gynecol Oncol 1974;2:162 –79 Ng AB, Reagan JW, Hawliczek S, et al. Significance of endometrial cells in the detection of endometrial carcinoma and its precursors. Acta Cytol 1974;18:356 –61 Vooijs GP, van der GY, Vooijs MA. The presence of endometrial cells in cervical smears in relation to the day of the menstrual cycle and the method of contraception. Acta Cytol 1987;31:427 –33 Chang BS, Pinkus GS, Cibas ES. Exfoliated endometrial cell clusters in cervical cytologic preparations are derived from endometrial stroma and glands. Am J Clin Pathol 2006;125:77 –81 Guruwadayarhalli B, Jones SE, Srinivasan V. Hysteroscopy in the diagnosis of postmenopausal bleeding. Menopause Int 2007;13:132 –4 Williams SC, Lopez C, Yoong A, et al. Developing a robust and efficient pathway for the referral and investigation of women with post-menopausal bleeding using a cut-off of , or ¼4 mm for normal thickness. Br J Radiol 2007;80:719 –23
Journal of Medical Screening
2008
Volume 15
Number 4
33 34 35 36 37 38 39
40
41
42
43 44 45 46 47
Timmermans A, Opmeer BC, Veersema S, et al. Patients’ preferences in the evaluation of postmenopausal bleeding. BJOG 2007;114:1146 –9 Paschopoulos M, Polyzos NP, Lavasidis LG, et al. Safety issues of hysteroscopic surgery. Ann N Y Acad Sci 2006;1092:229 – 34 Nappi C, Di Spiezio SA, Greco E, et al. Prevention of adhesions in gynaecological endoscopy. Hum Reprod Update 2007;13:379 –94 Stamatellos I, Koutsougeras G, Karamanidis D, et al. Results after hysteroscopic management of premenopausal patients with dysfunctional uterine bleeding or intrauterine lesions. Clin Exp Obstet Gynecol 2007;34:35 –8 Shveiky D, Rojansky N, Revel A, et al. Complications of hysteroscopic surgery: “Beyond the learning curve”. J Minim Invasive Gynecol 2007;14:218 –22 Dobosz J. Testing Positive for Growth. MA, USA: Cytyc Corporation, 2008. See http://www.forbes.com/2005/03/30/ cz_jd_0330gurusow_inl.html (accessed May 2008) Cherkis RC, Patten Jr.SF, Andrews TJ, et al. Significance of normal endometrial cells detected by cervical cytology. Obstet Gynecol 1988;71:242 –4 Yancey M, Magelssen D, Demaurez A, et al. Classification of endometrial cells on cervical cytology. Obstet Gynecol 1990;76:1000 – 5 Gomez-Fernandez CR, Ganjei-Azar P, Capote-Dishaw J, et al. Reporting normal endometrial cells in Pap smears: an outcome appraisal. Gynecol Oncol 1999;74:381 –4 Gray JA, Nguyen GK. Cytologic detection of endometrial pathology by Pap smears. Diagn Cytopathol 1999;20:181 –2 Chang A, Sandweiss L, Bose S. Cytologically benign endometrial cells in the papanicolaou smears of postmenopausal women. Gynecol Oncol 2001;80:37 –43 Ashfaq R, Sharma S, Dulley T, et al. Clinical relevance of benign endometrial cells in postmenopausal women. Diagn Cytopathol 2001;25:235 –8 Montz FJ. Significance of ‘normal’ endometrial cells in cervical cytology from asymptomatic postmenopausal women receiving hormone replacement therapy. Gynecol Oncol 2001;81:33 –9 Sarode VR, Rader AE, Rose PG, et al. Significance of cytologically normal endometrial cells in cervical smears from postmenopausal women. Acta Cytol 2001;45:153 –6 Wu HH, Schuetz III MJ, Cramer H. Significance of benign endometrial cells in Pap smears from postmenopausal women. J Reprod Med 2001;46:795 –8 Mount SL, Wegner EK, Eltabbakh GH, et al. Significant increase of benign endometrial cells on Papanicolaou smears in women using hormone replacement therapy. Obstet Gynecol 2002;100:445 – 50 Brogi E, Tambouret R, Bell DA. Classification of benign endometrial glandular cells in cervical smears from postmenopausal women. Cancer 2002;96:60 –6 Cai N, Spitzer M, Wasserman PG. Endometrial cells in pap smears of postmenopausal women: cytohistologic correlation. J Low Genit Tract Dis 2003;7:250 –3 Browne TJ, Genest DR, Cibas ES. The clinical significance of benign-appearing endometrial cells on a Papanicolaou test in women 40 years or older. Am J Clin Pathol 2005;124:834 –7 Simsir A, Carter W, Elgert P, et al. Reporting endometrial cells in women 40 years and older: assessing the clinical usefulness of Bethesda 2001. Am J Clin Pathol 2005;123:571 – 5 Thrall MJ, Kjeldahl KS, Savik K, et al. Significance of benign endometrial cells in papanicolaou tests from women aged .or ¼ 40 years. Cancer 2005;105:207 –16 Bean SM, Connolly K, Roberson J, et al. Incidence and clinical significance of morphologically benign-appearing endometrial cells in patients age 40 years or older: the impact of the 2001 Bethesda System. Cancer 2006;108:39 –44 Siebers AG, Verbeek AL, Massuger LF, et al. Normal appearing endometrial cells in cervical smears of asymptomatic postmenopausal women have predictive value for significant endometrial pathology. Int J Gynecol Cancer 2006;16:1069 –74 Aslan DL, Crapanzano JP, Harshan M, et al. The Bethesda System 2001 recommendation for reporting of benign appearing endometrial cells in Pap tests of women age 40 years and older leads to unwarranted surveillance when followed without clinical qualifiers. Gynecol Oncol 2007;107:86 –93 Beal HN, Stone J, Beckmann MJ, et al. Endometrial cells identified in cervical cytology in women . or ¼ 40 years of age: criteria for appropriate endometrial evaluation. Am J Obstet Gynecol 2007;196:568 –5 Kapali M, Agaram NP, Dabbs D, et al. Routine endometrial sampling of asymptomatic premenopausal women shedding normal endometrial cells in Papanicolaou tests is not cost effective. Cancer 2007;111:26 –33 Moroney JW, Zahn CM, Heaton RB, et al. Normal endometrial cells in liquid-based cervical cytology specimens in women aged 40 or older. Gynecol Oncol 2007;105:672 –6 Whiting P, Rutjes AW, Reitsma JB, et al. The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews. BMC Med Res Methodol 2003;3:25 d’Arailh AS, Michy T, Pioud R, et al. [Uterine abnormalities in non-menopausal women received tamoxifen for breast cancer adjuvant therapy.]. Gynecol Obstet Fertil 2007;35:1215 –9 Hickey M. Bleeding with menopausal hormone therapy: physiological or pathological? Menopause Int 2007;13:188 –90
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