2022, Volume 38, Number 3, Page(s) 235-239
Clinical Significance of Endometrial Cells in Pap Smear of Women Aged 40 Years and Older
Esra KELEŽ1, Ušur Kemal ÖZTÜRK1, Cihat Murat ALINCA1, Serkan AKIŽ1, Canan KABACA1, Handan ĒETINER2
1Department of Gynecologic Oncology, Zeynep Kamil Training and Research Hospital, ISTANBUL, TURKEY
2Department of Pathology, University of Health Sciences, Zeynep Kamil Training and Research Hospital, ISTANBUL, TURKEY
Keywords: Endometrial cells, Endometrial cancer, Papanicolaou (Pap) test, The Bethesda System
To investigate the histopathological follow-up results in women diagnosed with endometrial cells in the Papanicolaou (Pap) test.
Material and Method: Between January 2013 to December 2018, women with endometrial cells on the Pap test were searched from the hospital
electronic database. The patients with endometrial cells on the Pap test who underwent further histopathological evaluation and who were
followed-up for at least 1 year were enrolled in the study, while those who had a Pap test result other than endometrial cells, were lost during
follow-up, or had missing data were excluded.
Results: Out of 91,142 Pap smears, 121 (0.1%) cytologically had endometrial cells, and of those 65 cases were eligible for final analysis. The mean
age of patients with premalignant/malignant lesions (57.7 ± 2.9) was higher than those with benign lesions (50.1 ± 0.7), with 77% of them in
the postmenopausal period. Gynecologic premalignant/malignant lesions were detected in 9 (17.7%) patients including 2 (3.1%) endometrial
hyperplasias and 7 (10.8%) endometrial cancers. The menopausal status (p=0.010) and being 50 years and older (p=0.002) were significantly
associated with pre-neoplastic or neoplastic changes in patients with endometrial cells.
Conclusion: The presence of endometrial cells in Pap tests may be a harbinger of endometrial pathologies, especially at the age of 50 years and
over. The menopausal status is another possible determinant in detecting endometrial carcinoma. Further investigation may be suggested in
women aged ≥50 years and postmenopausal in the event of endometrial cell detection.
Endometrial cancer is the most common female genital
tract malignancy in developing countries 1
. Although the
Papanicolaou (Pap) test has been a valid test for screening
cervical carcinoma and its precursor lesions for many
years, there is currently no non-invasive methods to screen
for endometrial cancer.
Whether the presence of endometrial cells (ECs) in
cervicovaginal smear has any clinical value has been
investigated by researchers for years. The Bethesda System
(TBS) 1991 proposed notifying the asset of spontaneously
exfoliated, benign-appearing endometrial cells only in
postmenopausal women as an epithelial cell abnormality
2. The TBS 2001 suggested age-based reporting without
the need for clinical evaluation and determined the age limit
of reporting ECs as over 40 years 3. The TBS 2014 updated
its approach for the age limit of reporting ECs from 40 to 45
years 4. With the application of these guidelines on ECs
and the transition of conventional cytology to liquid-based
cytology in cervical screening testing techniques, ECs have
been more frequently noticed, assisting in the detection of
endometrial cancers 5,6.
Since several studies have addressed endometrial cells in
the early diagnosis of endometrial carcinomas, we aimed
to investigate the relationship of initial ECs cytology results
with histopathological results and patient demographic
We retrospectively searched our institutional electronic
database for the records of all women aged 40 years and
older who had ECs on the Pap test between January 1,
2013, and December 31, 2018. This study was approved
by the Research Ethics Committee and was conducted
in accordance with the ethical standards described in
an appropriate version of the 1975 Helsinki Declaration,
revised in 2000 (Approval number: 2019/18).
Demographic and histopathologic follow-up findings,
including pipelle aspiration biopsies, endocervical
curettages and/or hysterectomies within twelve months
after the index Pap smear were collected from the hospital
electronic medical records. The ThinPrep (Hologic Inc.,
Marlborough, Mass., USA) assay was used for liquid-based
Women aged 40 years and older, with cytological findings
compatible with endometrial cells, and who had at least
one-year of follow-up were included in the study. Women
who were lost during follow-up or had missing data,
and those who had a Papanicolaou test result other than
endometrial cells were excluded from the study.
Since our institution is specifically focused on obstetrics
and gynecology, our pathologists are experienced in
gynecopathology. All pathological specimens were
performed by specialized gynecopathologists. The standard
was set based on ‘The Bethesda System For Reporting
Cervical Cytology’. According to the Bethesda System,
benign endometrial cells were evaluated in Pap smears
among women over 40 years of age. A diagnosis of benign
ECs was made based on the findings of three-dimensional
clusters with small and round nuclei, indistinct nucleoli,
and scant cytoplasm with indistinct cell borders which was
identified with the ‘The Bethesda System For Reporting
The patients were analyzed with respect to age (40-49,
≥50 years). The histopathological follow-up findings
were classified as benign, pre-malignant, and malignant.
Endometrial atrophy, endometrial breakdown, proliferative
endometrium, hormonal effect, endometritis, leiomyoma,
adenomyosis, and endometrial polyp were defined as
benign pathologies. Simple endometrial hyperplasia with
atypia, simple endometrial hyperplasia without atypia,
complex endometrial hyperplasia with atypia, and complex
endometrial hyperplasia without atypia were defined as
pre-malignant pathologies. Any malignant neoplasm was
defined as a malignant pathology.
All statistical analyses were performed using the Statistical
Package for the Social Science (IBM SPSS version 25) for
Windows software. Percentage and frequency values for
categorical variables, and mean (± standard deviation) for
quantitative variables were used in descriptive statistics of
the data. The relationship between categorical variables
was performed using Fisher’s exact test and Chi-Squared
test, where appropriate. The independent sample t-test was
used to compare quantitative data. In this study, the type I
error rate was set at 0.05. A p-value ≤ 0.05 was considered
A total of 91,142 Pap smears were screened in the study
period. Of these, 117 (0.1%) contained endometrial cells.
After excluding the patients who did not meet the eligibility
criteria, 65 patients with ECs remained for the final analysis.
The flow diagram of the study is shown in Figure 1
Fifty-six patients were assigned to the benign group and
nine patients were assigned to the premalignant/malignant
group. There was a significant difference between
histopathological findings and age groups (p=0.002). The
mean age of patients with premalignant/malignant lesions
(57.7±2.9) was significantly higher than those with benign
lesions (50.1±0.7) (p=0.033). Seven (77.8%) cases in the
premalignant/malignant group were in the postmenopausal
period, while 39 cases (69.6%) in the benign group were in
the reproductive age (p=0.010). The menopausal status was
significantly associated with pre-neoplastic or neoplastic
changes in postmenopausal endometrial tissue. The
patients’ detailed demographic and clinical characteristics
according to the pathology results are shown in Table I.
Histopathological findings were evaluated between the age
groups of 40-49 (n=32) and ≥50 (n=33) years. There was a
significant difference with respect to endometrial cancer in
women aged 50 and over (p=0.024) and endometrial polyps
in women aged 40-49 (p=0.047) years. Pre-malignant and
malignant lesions diagnosed in a total of 9 cases were as
follows: 2 patients were diagnosed with endometrial
hyperplasia, 2 patients were diagnosed with endometroid
endometrial carcinoma (Figure 2,3), and 5 patients were
diagnosed with non-endometroid endometrial carcinoma.
Histopathological results of women with endometrial cells
by age group are shown in Table II.
Click Here to Zoom
|Figure 2: Cluster of endometrial cells reported as benign in
ThinPrep smear preparation (Papanicolaou, x400).
Click Here to Zoom
|Figure 3: Histology of the patient’s ‘well differentiated endometrial
adenocarcinoma’ (Hematoxylin-Eosin, x400).
Click Here to Zoom
|Table II: Histopathological results of women with benign
endometrial cells by age groups.
In the present study, we examined the relationship between
the endometrial cells in Pap smears with the patient’s
histopathological findings and demographic characteristics.
The study revealed that menopausal status and being
aged ≥50 years were possible factors that may be useful in
detecting endometrial pathologies. The study also implied
the need for further comprehensive investigation in women
aged 50 years and over and who were postmenopausal in
the event of endometrial cell detection.
The Global Cancer Observatory 2020 data has revealed
417367 new corpus uteri cancer cases worldwide, leading
to 97370 deaths annually 7. The majority of endometrial
cancers can be diagnosed early due to abnormal uterine
bleeding symptoms; however, very few are asymptomatic.
Therefore, the presence of endometrial cells in Pap tests
can be helpful in discovering neoplastic endometrial tissue
changes in this group.
The reporting age of endometrial cells is still a controversial
issue. There was no significant difference in premalignant/
malignant lesions between women aged 45 years and
over and those aged 40-44, in which endometrial cells
were detected in the Pap test. Therefore the reporting
age of ECs was increased from 40 to 45 in the TBS 2014
guideline 4. Some studies have argued that the evaluation
of the endometrial cells in the Pap test according to the
menopausal state or the presence of symptoms is more
valuable in detecting pathologies 8,9. Thereupon, studies
have been proposed involving different age limits and
various variables 8,10-15. In our study, no pathological
lesions were found in women between the ages of 40-45
and 46-49, in contrast to women aged 50 and over, most
of whom were postmenopausal and had pre-neoplastic and
neoplastic lesions. In all, these results suggest that further
investigation may be beneficial in women aged 50 and
over and postmenopausal in the event of endometrial cell
Endometrial cells in the Pap test have received much
attention in the detection of endometrial pathologies. The
significance of demographic and clinical characteristics
in the prediction of malignancy in women with benign
endometrial cells has not yet been dealt with in depth.
Therefore, our paper calls into question whether there are
any other relevant factors besides ECs reported in cervical
cytology that could help in detecting significant pathologies.
In this context, we tried to examine the age and menopausal
status of the patients to increase the chance of discovering
pre-neoplastic and neoplastic lesions. In our view, our
results constitute a step towards enhancing the knowledge
on the importance of ECs’ association with malignancy.
Given that our findings are based on a limited number of
women with ECs, these results thus need to be interpreted
with care and validated with larger sample-sized studies.
While the reporting age of endometrial cells has been
updated over the years, potential risks such as patients’
anxiety, health care costs, excessive surgical procedures,
and complications that may occur in these interventions
have been carefully weighed besides the benefits of early
diagnosis 16. Increasing the reporting age limit for
ECs from 45 to 50 increases the likelihood of detecting
malignant tumors, but on the other hand, fails to discover
some early stages of malignant lesions 15. Our study
findings that ECs in Pap tests were significant in detecting endometrial pathologies in patients 50 years and older
are consistent with previous studies 9-11,14. Additional
large-scale multicenter studies are needed to support our
findings in the future.
We are aware that our research may have two limitations.
The first is that it is a single-center, small sample-sized
study. Unfortunately, we were unable to obtain relevant
data on the patients’ symptoms, the medications, the use
of intrauterine devices, and the day of the menstrual period
on which uterine sampling was performed due to the
retrospective nature of the study. The strengths of the study
were that it constituted the experience of one of the largest
tertiary institutions in the field of obstetrics and gynecology
in the country, and experienced gynecologic pathologists
evaluated the histopathological specimens. However, we
believe that our results will provide a comprehensive flow
of information into the growing body of literature on the
importance of reporting endometrial cells.
In conclusion, endometrial cells in Pap test could be a useful
aid for clinicians in the early diagnosis of endometrial
pathologies. Further evaluation with additional diagnostic
workup may therefore be beneficial in postmenopausal
women aged 50 years and older.
CONFLICT of INTEREST
The authors have no conflicts of interest to declare.
Concept: EK, CK, HĒ, Design: EK, CK, HĒ, Data
collection or processing: EK, HĒ, UKO, SA, Analysis or
Interpretation: CK, SA, EK, CMA, Literature search: EK,
HĒ, UKO, CMA, CK, Approval: EK, CK.
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