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Citation: Pappa, C.; Le Thanh, V.;
Smyth, S.L.; Zouridis, A.; Kashif, A.;
Sadeghi, N.; Sattar, A.; Damato, S.;
Abdalla, M.; Laganà, A.S.; et al.
Mixed Endometrial Epithelial
Carcinoma: Epidemiology, Treatment
and Survival Rates—A 10-Year
Retrospective Cohort Study from a
Single Institution. J. Clin. Med. 2023,
12, 6373. https://doi.org/
10.3390/jcm12196373
Academic Editor: Andrew M.
Fribley
Received: 22 August 2023
Revised: 20 September 2023
Accepted: 29 September 2023
Published: 5 October 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Journal of
Clinical Medicine
Article
Mixed Endometrial Epithelial Carcinoma: Epidemiology,
Treatment and Survival Rates—A 10-Year Retrospective Cohort
Study from a Single Institution
Christina Pappa 1, Valentina Le Thanh 1, Sarah Louise Smyth 1, Andreas Zouridis 1, Ammara Kashif 1,
Negin Sadeghi 1, Alisha Sattar 1, Stephen Damato 1, Mostafa Abdalla 2, Antonio Simone Laganà3,
Federico Ferrari 4, Sean Kehoe 1, Susan Addley 5and Hooman Soleymani majd 1, *
1Department of Gynaecological Oncology, Oxford University Hospitals NHS Foundation Trust,
Oxford OX3 7LE, UK; christina.pappa@ouh.nhs.uk (C.P.); valentina.lethanh@ouh.nhs.uk (V.L.T.);
andreas.zouridis@ouh.nhs.uk (A.Z.); ammara.kashif@ouh.nhs.uk (A.K.); sean.kehoe@ouh.nhs.uk (S.K.)
2
Gynaecology—Guy’s and St Thomas’ NHS Foundation Trust, London SE1 9RT, UK; mostafa.abdalla@nhs.net
3
Unit of Obstetrics and Gynecology, “Paolo Giaccone” Hospital, Department of Health Promotion, Mother and
Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo,
90127 Palermo, Italy; antoniosimone.lagana@unipa.it
4Department of Clinical and Experimental Sciences, University of Brescia, 25136 Brescia, Italy;
federico.ferrari@unibs.it
5Department of Gynaecological Oncology, University Hospitals of Derby and Burton NHS Foundation Trust,
Derby DE22 3NE, UK; susan.addley@nhs.net
*Correspondence: hooman.soleymanimajd@msd.ox.ac.uk
Abstract:
Mixed endometrial carcinoma (MEEC) refers to rare endometrial tumours that are com-
posed of two or more distinct histotypes, at least one of which is serous or clear cell. The aim of
this study was to evaluate the epidemiology, treatment outcomes and survival rates of patients with
mixed endometrial carcinoma. The medical records of 34 patients diagnosed with MEEC between
March 2010 and January 2020 were reviewed retrospectively. Clinicopathological variables and treat-
ment strategies were assessed, and overall survival and disease-free survival rates were evaluated.
The histology of endometrioid and serous component was found in 26 (76.5%) patients, followed
by serous and clear-cell components (5/34, 14.5%) and mixed endometrioid serous and clear-cell
components (3/34, 8.8%). The median age at diagnosis was 70 years (range 52–84), and the median
follow-up time was 55 months. The 5-year disease-free survival and the 5-year overall survival
were 50.4% and 52.4%, respectively. Advanced disease stage was identified as an independent
predictor of inferior disease-free (<0.003) and overall survival (p< 0.001). Except for stage, none
of the traditional prognostic factors was associated with disease recurrence or death from disease.
MEECs represent rare high-risk endometrial carcinomas with significant diagnostic and treatment
challenges. Undoubtedly, the implementation of a molecular analysis can offer further diagnostic
and management insights.
Keywords: mixed endometrial carcinoma; high grade; recurrence; clear cell; serous; survival
1. Introduction
Endometrial cancer represents the most common gynaecological malignancy in the
developed world, with a globally increased incidence due to the extended life expectancy
and possibly the high prevalence of associated risk factors [
1
]. It is the sixth most diagnosed
cancer in women, with 417,000 new cases and 97,000 deaths in 2020 [2].
Mixed epithelial endometrial carcinoma (MEEC) is a rare entity, accounting for less
than 3% of the epithelial endometrial malignancies. The 2020 World Health Organization
(WHO) classification defines mixed endometrial carcinoma as a tumour composed of two
or more spatially distinct histological types, at least one of which is serous or clear-cell
J. Clin. Med. 2023,12, 6373. https://doi.org/10.3390/jcm12196373 https://www.mdpi.com/journal/jcm
J. Clin. Med. 2023,12, 6373 2 of 14
carcinoma [
3
]. The two components should be unambiguously morphologically and im-
munohistochemically distinct histotypes of endometrial carcinoma [
4
]. Mixed endometrial
carcinomas are regarded as high-grade neoplasms by definition, and they exhibit aggressive
behaviour, resulting in a poor prognosis [5,6].
The proportion of each cell type can vary widely between tumours, and this can impact
the prognosis and treatment of the cancer. The diagnosis and management of MEEC can be
challenging, as it is difficult to distinguish between the different types of epithelial cells and
determine the best treatment approach. The histological classification following the mor-
phological characterization of the tumour, allied with confirmatory immunohistochemistry,
particularly among the high-grade histotypes, is frequently hampered by overlap between
histologic subtypes and significant interobserver variability and poor reproducibility even
among the most experienced pathologists [6–8].
Treatment for MEEC typically involves surgical removal of the tumour, along with
adjuvant chemotherapy or radiotherapy, depending on the stage and characteristics of the
cancer [
5
,
9
,
10
]. Prognosis can be difficult to predict in MEEC due to the varied cell types
and molecular features, but certain factors, such as the presence of clear-cell carcinoma or
lymph node involvement, have been associated with poorer prognosis [11,12].
The rationale for accurately diagnosing mixed endometrial carcinoma is that even a mi-
nor component of serous or clear-cell carcinoma within an otherwise typical endometrioid
carcinoma may confer an adverse outcome similar to a pure serous or clear-cell carci-
noma [13–15].
There are limited data available specifically on the recurrence rates for mixed epithelial
endometrial carcinoma (MEEC), as it is a rare and relatively understudied subtype of
endometrial cancer [16,17].
The aim of the study was to assess and present the 10-year experience of the epi-
demiology, treatment outcomes and survival patterns of patients with mixed epithelial
endometrial carcinoma managed in a single tertiary cancer referral centre in the United
Kingdom.
2. Materials and Methods
This study represents a retrospective analysis of women with mixed epithelial en-
dometrial carcinoma treated in Oxford University Hospitals, NHS Foundation Trust, a
tertiary cancer referral centre, between March 2010 and January 2020.
The study was registered as a service evaluation project (registration number 6604)
with no patient identifiable data. Informed written consent for potential future research
purposes was obtained from all the participants at the time of the operation. The service
evaluation protocol was registered in accordance with the Oxford University Hospitals
Trust requirements. The design, analysis, interpretation of data, drafting and revisions
conform to the Helsinki Declaration, the Committee on Publication Ethics’ guidelines
(http://publicationethics.org/, accessed on 10 March 2023) and the Reporting of Studies
Conducted Using Observational Routinely Collected Health Data (RECORD) Statement
validated by the Enhancing the Quality and Transparency of Health Research Network
(www.equator-network.org, accessed on 10 March 2023) [18].
Women with a histological diagnosis of mixed epithelial endometrial carcinoma and
no previous surgery concerning endometrial malignancy (primary surgery) were recruited.
Patients with histology other than mixed epithelial endometrial carcinoma and patients
with inadequate follow-up data were excluded.
We retrospectively reviewed and analysed the medical records of the patients diag-
nosed with mixed endometrial carcinoma. The initial diagnosis was made through targeted
hysteroscopic biopsy, pipelle endometrial biopsy or endometrial curettage, obtaining as
much material as possible, according to our previously published experience [
19
]. Sub-
sequently, all patients had imaging with magnetic resonance imaging (MRI) and/or a
computerized tomography (CT) scan to assess locoregional or systemic spread of the dis-
J. Clin. Med. 2023,12, 6373 3 of 14
ease. The treatment plan was implemented following the review of the multidisciplinary
team (MDT).
All eligible patients had surgical management with total hysterectomy and bilat-
eral salpingo-oophorectomy. Full surgical staging, including pelvic and para-aortic lym-
phadenectomy and omentectomy plus/minus peritoneal washing, was performed based
on clinical judgement, depending on the patient’s performance status.
The extracted data included the age; body mass index (BMI); underlying comorbidities
of the patient; length of hospitalization; and information about the surgical procedure,
such as the type of surgery, surgical time and estimated blood loss. With regard to the
tumour, we recorded the initial diagnosis; histological type; tumour dimensions; presence
of lymphovascular space invasion (LVSI); presence of cervical, adnexal or parametrial
invasion; status and number of lymph nodes; status of omentum and cytology; and the
final staging. Intraoperative, acute and late postoperative complications were also recorded.
For the patients who received adjuvant therapy, we recorded the type of therapy, the
regiment and the associated complications, whenever available.
Follow-up was recorded in months from the date of surgery up to the study period
when the patients were last tracked. Follow-up was initially every 3 months for the
first 2 years; every 6 months from year 3 to year 5; and then annually, if required. Each
clinical visit included history taking, investigation for signs and symptoms suspicious of
disease relapse and clinical examination for the detection of treatment complications and
assessment of evidence of recurrence.
Disease-free survival (DFS) was measured from the date of surgery until the date of
first recurrence or death from any cause, and overall survival (OS) was measured from the
diagnosis date until death.
We performed a statistical analysis using the IBM SPSS Statistics 29.0.1.0 version soft-
ware. Continuous variables are presented as mean
±
standard deviation or median (range),
and categorical variables are presented using frequency (n) and percentage (%). Descriptive
statistics were used to summarize the demographic and clinical characteristics of patients.
An independent t-test was used to compare the continuous variable. Furthermore, clas-
sified variables were analysed using the chi-square (
χ
2) test. The Kaplan–Meier method
was used to perform disease-free survival (DFS) and overall survival (OS) analyses, and
log-rank tests were used to compare survival rates. Potential risk factors for recurrence and
mortality were analysed and assessed using univariate and multivariate Cox regression
analyses. A p-value < 0.05 was considered to be statistically significant.
3. Results
A total of 863 patients were surgically managed for endometrial carcinoma in our
centre between March 2010 and January 2020. There were 35 women who were diagnosed
with mixed epithelial endometrial carcinoma, representing less than 4% of the uterine
malignancies treated in our unit, during the study period. Among them, one was excluded
due to missing data.
Therefore, a total of 34 patients were included in the study. The basic characteristics
of the patients and the histopathological and treatment characteristics are presented in
Table 1.
The mean age at diagnosis was 70 years (range 58–84), and 44.1% of the patients had
a BMI over 30 kg/m
2
. All of the women were postmenopausal, 61% of them had known
hypertension (HTN) and 14% also had a diagnosis of breast cancer with unknown BRCA
status. Underlying diabetes was recorded in 2 patients and 4 patients were recorded as
smokers. Average time interval from the first MDT meeting to the day of the surgery was
55 days.
J. Clin. Med. 2023,12, 6373 4 of 14
Table 1. Demographic data, treatment details and clinicopathological characteristics.
N (%)
Recurrence (N
of each
Subgroup)
p-Value
Overall
Mortality (N of
each
Subgroup)
p-Value
Demographic
data
Age
0.301 0.288
<65 6 (17.6) 5 3
≥65 28 (82.4) 7 15
BMI
0.222 0.203
<30 19 (55.9) 6 10
≥30 15 (44.1) 6 8
Associated comorbidities
HTN 4 (11.8) 1 0.854 2 0.801
DM 2 (5.9) 0 0.908 0 0.902
COPD 4 (11.8) 2 0.885 2 0.813
Breast cancer 5 (14.7) 3 0.113 2 0.071
Smoke 4 (11.8) 2 0.801 3 0.768
Treatment
details
Surgical approach
0.325 0.346
Laparoscopy 27 (79.4) 9 13
Laparotomy 7 (20.6) 3 5
Pelvic lymph node dissection
0.203 0.192
No 7 (20.6) 3 5
Yes 27 (79.4) 9 13
Adjuvant treatment
0.209 0.103
No 6 (17.6) 1 4
Yes 28 (82.4) 11 14
Histological
features
Histological type
E + S 26 (76.5) 8
0.789
12
0.586
S + CC 5 (14.7) 3 4
E + S + CC 3 (8.8) 1 2
FIGO stage
<0.003 <0.001
IA 18 (53) 2 7
IB 6 (17.6) 1 2
IIIA 1(2.9) 1 1
IIIB 2 (5.9) 2 2
IIIC1 7 (20.6) 6 6
FIGO stage
category
<0.021 <0.011
Early (I) 24 (70.6) 3 9
Advanced
(II–IV) 10 (29.4) 9 9
J. Clin. Med. 2023,12, 6373 5 of 14
Table 1. Cont.
N (%)
Recurrence (N
of each
Subgroup)
p-Value
Overall
Mortality (N of
each
Subgroup)
p-Value
Depth of
myometrial
invasion 0.834 0.775
<50% 23 (67.6) 5 10
≥50% 11 (32.4) 7 8
Cervical
stroma
involvement 0.141 0.987
No 30 (88.2) 9 15
Yes 4 (11.8) 3 3
Adnexal
involvement
0.178 0.137
No 33 (97.1) 11 17
Yes 1 (2.9) 1 1
Serosal breach
0.500 0.514
No 30 (88.2) 8 14
Yes 4 (11.8) 4 4
Parametrial
involvement
0.101 0.111
No 33 (97.1) 11 17
Yes 1 (2.9) 1 1
Pelvic lymph
node
involvement
0.482 0.503
No 20 (58.8) 5 11
Yes 7 (20.6) 6 6
Unknown 7 (20.6) 1 1
Paraaortic
lymph node
involvement
0.482 0.588
No 2 (5.9) 0 0
Yes 0 (0) 0 0
Unknown 32 (94.1) 12 18
LVSI
0.063 0.057
No 15 (44.1) 3 6
Yes 19 (55.9) 9 12
S, serous endometrial carcinoma; E, endometrioid endometrial carcinoma; CC, clear-cell endometrial carcinoma;
LVSI, lymphovascular space invasion; HTN, hypertension; DM, diabetes mellitus; COPD, chronic obstructive
pulmonary disease. Statistically significant results are highlighted in bold (p-value < 0.05).
Laparoscopy was performed in 27 patients. Seven patients (20.6%) underwent laparo-
tomy, three of whom after intraoperative conversion due to multiple previous abdominal
surgeries and extended adhesions. Twenty-seven patients had pelvic lymphadenectomy,
and two underwent para-aortic lymphadenectomy. Seven patients declined lymphadenec-
J. Clin. Med. 2023,12, 6373 6 of 14
tomy. On average, 13 pelvic lymph nodes were harvested (range 7–35). Lymph node
histology was positive for disease invasion in seven patients (20.6%), and 70% of patients
(24/34) also had omentectomy.
The mean length of hospitalization was 4 days (range 1–11 days), and the mean
estimated blood loss was 150 mL.
The most common histopathology was represented by endometrioid and serous
components (26/34, 76.5%), followed by serous and clear-cell components (5/354 14.5%)
and a mixture of endometrioid, serous and clear-cell components (3/34, 8.8%). All of
the endometrioid components were high-grade tumours. Twenty-eight patients (82.4%)
received adjuvant treatment following surgical management; eight had vault brachytherapy
(VBT), sixteen received a combination of platinum- and taxane-based chemotherapy (CT)
and radiotherapy (EBRT) and four received external beam radiotherapy (EBRT) only.
Adjuvant treatment was declined in six cases.
The median follow-up was 55 months (range 1–144). Twelve recurrences (35.2%) were
recorded, with mean time of recurrence being 11 (range 2–40) months after the comple-
tion of the initial treatment. Single vault recurrence was reported in one patient, three
women developed lung recurrence and eight women had nodal pelvic and/or extrapelvic
recurrence. Eighteen deaths were recorded (52.9%), with 82.4% of the patients having died
within 15 months after the initial treatment. The characteristics of the recurrent cases are
presented in Table 2.
Table 2. Characteristics of recurrent cases of mixed epithelial endometrial carcinoma.
No. Histology Stage
Myometrial
Invasion
Cervical
Involvement
Adnexal
Involvement
Lymph Node
Involvement
LVSI VBT EBRT CT Site of
Recurrence DFS OS
1 S + CC 1B Yes No No No No Yes Yes No
Pelvic LN
Peritoneal
deposits
12 13
2 E + S 1A No No No No Yes No No No Single Vault
Recurrence 40 44
3 E + S 3C1 Yes No No Yes Yes No Yes Yes
Extrapelvic LN
Peritoneal
deposits
6 8
4 E + S 1A No No No No Yes Yes No No Pelvic LN 10 11
5E+S+
CC 3A Yes No Yes No Yes No No No
Extrapelvic LN
Lung
Peritoneal
deposits
3 3
6 E + S 3C1 Yes Yes No Yes Yes No Yes Yes Extrapelvic LN 6 8
7 S + CC 3B Yes Yes No No Yes No No No Lung 1 3
8 S + CC 3B Yes Yes No UK Yes No No No Extrapelvic LN 3 3
9 E + S 3C1 No No No Yes No No Yes Yes Pelvic LN 15 15
10 E + S 3C1 No No No Yes No No No No Lung 1 2
11 E + S 3C1 Yes No No Yes Yes No Yes Yes Pelvic LN 36 38
12 E + S 3C1 No No No Yes Yes Yes Yes Yes Extrapelvic LN 11 13
S, serous endometrial carcinoma; E, endometrioid endometrial carcinoma; CC:, clear-cell endometrial carcinoma;
UK, unknown; LVSI, lymphovascular space invasion; VBT, vaginal vault brachytherapy; EBRT, external beam
radiotherapy; CT, chemotherapy; LN, lymph nodes; DFS, disease-free survival; OS, overall survival.
The univariate Cox regression analysis indicated that the risk of recurrence and the risk
of death from disease are both correlated with an advanced stage of disease (HR = 5.05, 95%
CI 1.80–14.30, and p= 0.022; and HR = 3.29, 95% CI 1.42–9.79, and p= 0.032, respectively).
The univariate Cox proportional hazards analysis for the risk of recurrence and disease-
specific death is presented in Table 3.
J. Clin. Med. 2023,12, 6373 7 of 14
Table 3.
Univariate Cox proportional hazards analysis for the risk of recurrence and disease-specific
death for mixed epithelial endometrial cancer cases.
Recurrence Death from Disease
HR (95% CI) p-Value HR (95% CI) p-Value
AGE 1.02 (0.99–1.06) 0.204 1.02 (0.99–1.05) 0.310
BMI 1.05 (0.88–1.25) 0.614 1.11 (0.96–1.29) 0.170
Associated
comorbidities
HTN 1.04 (0.97–1.12) 0.291 1.02 (0.96–1.08) 0.605
DM 1.01 (0.98–1.02) 0.798 1.02 (1.01–1.03) 0.216
COPD 1.96 (0.44–8.42) 0.378 5.39 (2.28–11.96) 0.101
Breast cancer 2.20 (1.05–8.57) 0.106 2.08 (1.11–10.89) 0.223
Smoke 1.85 (0.34–3.01) 0.646 0.85 (0.78–2.11) 0.104
Surgical
approach
Laparoscopy
Laparotomy 1.04 (0.97–1.12) 0.291 1.02 (0.96–1.08) 0.605
Pelvic lymph
node dissection
No
Yes 0.85 (0.33–2.02) 0.667 0.57 (0.31–1.22) 0.094
Number of LN
removed 0.97 (0.93–1.01) 0.149 0.96 (0.93–0.99) 0.142
Adjuvant
treatment
No
Yes 1.39 (0.53–3.68) 0.483 0.89 (0.41–1.85) 0.739
Histological
type
E + S 2.93 (0.98–10.79) 0.059 3.78 (3.87–12.06) 0.107
S + CC 3.11 (1.02–12.13) 0.057 3.648
(1.22–10.89) 0.123
E + S + CC 3.62 (1.27–10.34) 0.066 2.33 (0.88–6.15) 0.088
FIGO stage
IA
IB 3.00 (0.95–9.50) 0.062 2.40 (0.87–6.65) 0.091
IIIA 4.93 (0.98–24.79) 0.053 10.78
(3.87–30.06) <0.001
IIIB 9.38 (1.08–81.33) 0.042 9.06 (1.91–42.98) 0.006
IIIC1 15.36
(3.00–78.92) 0.001 7.10 (1.48–34.00) 0.014
FIGO stage
category
Early (I)
Advanced (II-IV)
5.05 (1.80–14.30) 0.022 3.29 (1.42–9.79) 0.032
J. Clin. Med. 2023,12, 6373 8 of 14
Table 3. Cont.
Recurrence Death from Disease
HR (95% CI) p-Value HR (95% CI) p-Value
Depth of
myometrial
invasion
<50%
≥50% 3.64 (1.08–8.90) 0.151 2.82 (1.48–11.40) 0.202
Cervical stroma
involvement
No
Yes 2.84 (0.75–12.71) 0.171 3.37 (0.98–11.11) 0.091
Adnexal
involvement
No
Yes 2.56 (1.11–8.92) 0.097 2.02 (0.97–4.20) 0.061
Serosal breach
No
Yes 2.15 (1.01–10.54) 0.264 1.89 (1.18–13.60) 0.305
Parametrial
involvement
No
Yes 2.88 (1.24–6.70) 0.064 3.20 (1.60–6.42) 0.081
Pelvic lymph
node
involvement
No
Yes 1.19 (1.02–1.71) 0.146 1.56 (0.77–3.16) 0.216
Unknown 2.20 (1.05–3.97) 0.106 1.08 (1.01–3.29) 0.103
Para-aortic
lymph node
involvement
No
Yes 3.52 (0.46–26.88) 0.221 3.82 (0.91–16.08) 0.067
Unknown 2.83 (0.89–8.97) 0.077 1.81 (0.66–5.00) 0.250
LVSI
No
Yes 1.94 (0.80–4.71) 0.142 1.83 (0.920–3.92) 0.118
HR, hazard ratio; S, serous endometrial carcinoma; E, endometrioid endometrial carcinoma; CC, clear-cell
endometrial carcinoma; LVSI, lymphovascular space invasion; HTN, hypertension; DM, diabetes mellitus; COPD,
chronic obstructive pulmonary disease. Statistically significant results are highlighted in bold (p-value < 0.05).
The multivariate Cox regression analysis after the adjustment of the covariates for
age, associated comorbidities, surgical approach, pelvic lymph node dissection, number
of retrieved lymph nodes, administration of adjuvant treatment, depth of myometrial
invasion, adnexal involvement, breaching of the uterine serosa, parametrial involvement,
pelvic lymph node involvement, para-aortic lymph node involvement and lymphovascular
space invasion (LVSI) confirmed that the stage of the disease is independently related to
J. Clin. Med. 2023,12, 6373 9 of 14
the risk of recurrence (HR = 12.86; 95% CI 2.76–217.67; p< 0.003) and the risk of death from
disease (HR = 15.57; 95% CI 3.16–246.50; p< 0.001).
The 5-year disease-free survival rate (DFS) in our study was 50.4% (95% CI 34.76–6.67),
and the 5-year overall survival (OS) rate was 52.4% (95% CI 36.92–78.43) (Figure 1).
Figure 1.
Kaplan–Meier curves for disease-free survival (DFS) (left) and overall survival (OS) (right)
for the population study (above) and for the five different stages (below).
We classified the complications as intraoperative, acute and late postoperative. There
were two cases with intraoperative diathermy injury to the obturator nerve. Acute postop-
erative complications recorded in three cases, including one case of grade IV complication
(ischemic stroke) and two cases of grade II complication (cellulitis and haematoma), as
classified by the Clavien–Dindo classification of surgical complications [
20
]. Regarding
late postoperative complications, three patients (8.8%) developed lymphatic-associated
complications in the form of lymphoedema.
4. Discussion
Mixed epithelial endometrial carcinoma (MEEC) is a rare and challenging subtype of
endometrial cancer that requires careful diagnosis and treatment planning to achieve the
best possible outcomes for patients.
To the best of our knowledge, there are limited data available that focus on the recur-
rence and survival rates of mixed epithelial endometrial carcinoma. However, studies have
reported on the overall recurrence rates for high-grade endometrial cancer cases, which
can include groups of MEEC. In our study, the overall 5-year survival rate was 52.4%,
which is consistent with the literature regarding non-endometrioid endometrial carcino-
mas [
16
,
21
,
22
]. Li et al. retrospectively studied 890 patients with stage IA endometrial
carcinoma, including 47 patients with mixed endometrial pathology. Compared with the
endometrioid subtype, mixed endometrioid and non-endometrioid subtypes had inferior
survival outcomes [13].
J. Clin. Med. 2023,12, 6373 10 of 14
One recent study analysed the recurrence patterns and risk factors for 834 patients
with endometrial cancer, including 48 patients with mixed histology tumours. The study
found that the 5-year recurrence rate for all patients with endometrial cancer was 14.1%.
For patients with mixed histology tumours, the 5-year recurrence rate was 33.3%. The
researchers also identified several risk factors for recurrence, including advanced stage,
lymph node involvement and high-grade tumours [6].
In our study, we found that the disease-free survival (DFS) and the overall survival (OS)
are independently related to the stage of the disease (p< 0.003 and < 0.001, respectively),
with the 5-year overall survival being 66.7% vs. 14.3% for stage I and stage III disease,
respectively. The 5-year disease-free survival (DFS) was found to be 69.9% in stage I disease
and 14.3%in stage III disease.
Following the univariate and multivariate Cox regression analyses performed on our
sample, except for stage (p< 0.001), none of the traditional prognosticators was indepen-
dently associated with disease recurrence or death from disease. This could most possibly
be explained by the small sample of mixed endometrial cases in our cohort.
Most patients diagnosed with mixed endometrial carcinoma can be treated with a
laparoscopic approach, with less complication rates and a shorter hospital stay. In our
study, we found that both laparoscopic and open approaches have equivalent oncologic
outcomes, a result that is consistent with the current literature. Several studies comparing
laparoscopy and laparotomy for early-stage endometrial cancer have shown non-inferior
oncological outcomes with decreased estimated blood loss, less pain, shorter hospitalization
and enhanced recovery following minimal invasive surgery when compared with open
procedures [
23
,
24
]. The data that are available comparing minimally invasive and open
surgery specifically in high-risk and advanced-stage endometrial cancer cases have shown
no significant difference in the associated peri- and post-operative morbidity, as well as
in the oncologic outcomes, between the two routes of surgery [
25
,
26
]. However, based
on well-based evidence, uterine manipulator should be avoided in minimally invasive
techniques, as it has been proven to be associated with worse oncologic outcomes. [27,28]
In our cohort, we found no significance of systematic lymphadenectomy in the overall
and recurrence-free survival rates. Retrospective studies have shown a survival benefit
following systematic pelvic and para-aortic lymphadenectomy in patients with high-risk-
features endometrial carcinoma [
29
,
30
]. However, those results might bear a high risk of
bias as the therapeutic and prognostic value of systematic lymphadenectomy in high-risk
endometrial cancer has not been investigated in prospective randomized trials.
In the future, we hope that the completion of the open-label, randomized, controlled
trial Endometrial Cancer Lymphadenectomy Trial (ECLIAT) will help us to ascertain
whether systematic pelvic and para-aortic lymphadenectomy has a significant impact on
overall survival (OS) in patients with a high risk of recurrence of endometrial cancer FIGO
stages I and II [31].
Following the recent revision of the endometrial cancer staging system, we attempted
to reallocate the disease stage according to the new staging system, FIGO 2023, to assess the
potential stage migration and potential impact it might have on the recommended treatment
pathway [
32
]. Mixed epithelial endometrial carcinomas are considered, by definition, to be
aggressive histological types and therefore would have been staged as at least IC according
to the new staging system. In our study, all of the cases that were staged as stage IA (18/34)
and IB (6/34) involved at least some extent of myometrial invasion, which classifies them
as stage IIC FIGO stage 2023 (24/34), as they represent aggressive histological types with
any myometrial involvement. There was one case with proven adnexal involvement which
was staged as IIIA and would currently be staged as IIIA1 disease based on the FIGO 2023
staging system. Stage IIIB disease was found in two cases, and both would be classified
as stage IIIb1 according to the new 2023 staging system, due to vaginal and parametrial
involvement. Finally, all seven cases with macro-metastasis in the pelvic lymph nodes
(stage IIIC as per FIGO 2009) would currently represent stage IIIC1ii disease based on the
FIGO 2023 staging system. Stage upgrading to stage IIC according to the FIGO 2023 staging
J. Clin. Med. 2023,12, 6373 11 of 14
system occurred in all early-stage cases with IA and IB FIGO 2009 disease (24/34, 70.6%),
while stages IIIA (1/34, 2.9%), IIIB (2/34,5.9%) and IIIC (7/34, 20.6%) disease, according to
FIGO 2009 staging system, either remained unchanged or were classified under specific
newly added subcategories, according to the new staging system. Unfortunately, data
regarding molecular classification and characteristics were very limited in our study, and
they could not be safely integrated into the staging process to reflect their value in the
treatment recommendation.
During the last decade, the stratification of endometrial cancer has moved forward
and leaped from the histopathological classification based on tumour morphology and
tumour grade to a genomic-based classification, as described by The Cancer Genome Atlas
(TCGA) in 2013. Four distinct prognostic endometrial cancer groups were defined, namely
POLE ultra-mutated, MSI (microsatellite instability) hyper-mutated, copy-number low
and copy-number high, based on a combination of whole-genome or exome sequencing,
microsatellite instability (MSI) assays and copy number analysis. [33]
One step ahead, with the view to create a more cost-effective and easily applicable
method in more diagnostic settings, the ProMisE (Proactive Molecular Risk Classifier for
Endometrial Cancer) and the TransPORTEC initiative have developed and validated a
stratification system that can be applied to diagnostic specimens. Using a combination of
immunohistochemistry for mismatch repair (MMR), focused next-generation sequencing
(NGS) for detection of pathogenic POLE and immunohistochemistry for the p53 protein in
a common diagnostic specimen, patients are categorized according to one of four distinct
prognostic subtypes, which further direct adjuvant therapy and potential prognosis [
34
–
36
].
The molecular classification of the PORTEC-3 trial population has confirmed the strong
prognostic value and the benefit from combined adjuvant therapy in p53abnormal tumours,
regardless of the histologic type. Furthermore, it has shown that POLE-ultramutated
(POLEmut) tumours had excellent outcomes, with almost no recurrence in both arms
regarding the 5-year recurrence-free survival, following combined adjuvant chemotherapy
and radiotherapy (CTRT) versus radiotherapy alone (RT), being 100% versus 97% [
37
]. The
identification of mismatch repair deficiencies (dMMR) or high microsatellite instability
(MSI-H) is found in a subset of endometrial cancers and is associated with a higher response
rate to immune checkpoint inhibitors, such as pembrolizumab [
38
,
39
]. Furthermore, in
absence of a specific molecular profile, the identification of L1CAM can be a useful predictor
of early relapse in high risk endometrial cancer type [
40
], and, similarly, the use of machine
learning algorithms, using multiple classical parameters, can help to build a prognostic
model [41].
Overall, the retrospective nature and the small sample size are the main limitations
of our study. The results should be interpreted with caution, as the absence of statistical
significance regarding the role of the different risk factors and variables in the recurrence
and survival rates might be attributed to the small sample size. To our knowledge, this is
the first study evaluating data exclusively for mixed epithelial endometrial carcinoma.
The management of mixed epithelial endometrial carcinoma (MEEC) presents several
challenges for clinicians and researchers that need to be addressed to improve oncologic
outcomes for patients. Accurate and early diagnosis plays a fundamental role in determin-
ing the appropriate treatment plan. Improved diagnostic techniques, such as molecular
profiling and imaging technologies, can help clinicians to effectively stratify the patients
and tailor subsequent treatment [
42
,
43
]. The heterogeneity of MEEC justifies individu-
alized treatment plans that consider the specific characteristics and biological behaviour
of the tumour. This may involve a combination of surgery, chemotherapy and radiation
therapy, as well as targeted therapies based on the molecular profile of the tumour. [
44
] The
identification of specific biomarkers associated with the distinct features of mixed endome-
trial carcinoma can guide treatment decisions and predict outcomes for patients [
45
,
46
].
Research is ongoing to identify potential biomarkers, such as mutations in certain genes
or expression of specific proteins, that may be useful in the diagnosis and treatment of
MEEC [
47
]. The need for more clinical trials that are specifically focused on MEEC to
J. Clin. Med. 2023,12, 6373 12 of 14
evaluate the effectiveness of different treatment approaches and identify new therapies
is undeniable, and collaboration between researchers and clinicians is essential to design
and implement clinical trials that address the unique challenges of MEEC. Finally, patient
education and support, including clinicians and patient advocacy groups, will be invalu-
able to help patients to navigate their treatment options and manage the emotional and
psychological impact of a rare and complex cancer diagnosis.
The global vision of the Gynaecological Oncology Committee and the allied specialties
should be to go beyond the tumour phenotype and decode and consolidate the tumour
biology to develop prognostic algorithms and individualized treatment approaches, with
the aim of improving the oncologic outcomes and the quality of life of the patients and
their families.
Author Contributions:
Conceptualization, H.S.m., A.S.L., F.F. and S.D.; methodology, C.P. and
H.S.m.; formal analysis, C.P.; data collection, V.L.T., A.K., N.S., A.S. and C.P.; writing—original draft
preparation, C.P.; writing—review and editing, C.P., A.Z., S.L.S., A.S.L., M.A., F.F., S.D., S.K., S.A.
and H.S.m.; visualization, C.P.; supervision, S.K. and H.S.m. All authors have read and agreed to the
published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement:
The study was conducted in accordance with the Declaration
of Helsinki and approved by the Institutional Review Board of Oxford University Hospitals NSH
Trust (ID: 6604, Ref:06/01/2020-SUWON-Soleymani-2).
Informed Consent Statement:
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement: Data are unavailable due to privacy restrictions.
Acknowledgments:
The authors would like to thank Jan Dodge, Lisa Clarke and Megan Ejikeme,
who helped with data collection.
Conflicts of Interest: The authors declare no conflict of interest.
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