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Giorgio Bogani ‍ ‍,1 Luca Lalli,2 Jvan Casarin,3 Fabio Ghezzi,3 Valentina Chiappa,1
Francesco Fanfani,4 Giovanni Scambia ‍ ‍,4 Francesco Raspagliesi1

► Additional supplemental ABSTRACT

material is published online WHAT IS ALREADY KNOWN ON THIS TOPIC
only. To view, please visit the
Objective To assess the role of histopathological
⇒ Molecular classification overcomes the limitation of
journal online (https://​doi.​org/​ and molecular features in predicting the risk of nodal
current histological risk assessment, being an ac-
10.​1136/​ijgc-2​ 024-​005416). metastases in apparent early-­stage endometrial cancer
curate tool for prognostic assessment. Only limited
patients undergoing sentinel node mapping.
data, evaluating the association between molecular
For numbered affiliations see Methods This is a prospective trial. Consecutive
end of article. classes of risk and nodal disease, are available. The
patients with apparent early-­stage endometrial cancer,
present prospective study aims to test the role of
undergoing laparoscopic hysterectomy, bilateral salpingo-­
histological and molecular features in predicting
Correspondence to oophorectomy, and sentinel node mapping, were enrolled. positive nodes in endometrial cancer patients un-
Dr Giorgio Bogani, Fondazione Histological and molecular features were used to predict
IRCCS Istituto Nazionale dei
dergoing sentinel node mapping.
the node positivity.
Tumori, 20133 Milan, Italy; ​ WHAT THIS STUDY ADDS
Results Charts of 223 apparent early-­stage endometrial
giorgiobogani@y​ ahoo.​it
cancer patients were included in this study. Four (1.8%) ⇒ This study highlighted that conventional histolog-
patients were excluded from this study due to the lack ical features represent the most accurate tool for
Received 27 February 2024 of data about molecular features. Additionally, nine (4%) predicting disease harboring in non-­bulky sentinel
Accepted 16 April 2024 patients did not meet the inclusion criteria (due to the lymph nodes. However, p53 abnormality correlates
Published Online First presence of peritoneal carcinomatosis or bulky nodes with a high risk of having an advanced disease at
23 April 2024 (the presence of p53 abnormality correlated with the presentation.
presence of advanced stage disease (p<0.001)). The study
population included 178 (84.8%) and 32 (15.2%) patients HOW THIS STUDY MIGHT AFFECT RESEARCH,
with endometrioid and non-­endometrioid endometrial PRACTICE OR POLICY
cancer, respectively. According to pathological uterine ⇒ In apparent early stage endometrial cancer, the inte-
risk factors, 93 (44.3%), 45 (21.4%), 40 (19.1%), and 32 gration between histological and molecular features
(15.2%) were classified as low, intermediate, intermediate-­ seems the most appropriate approach for assessing
high, and high-­risk, respectively. Using the surrogate patient risk.
molecular classification, 10 (4.8%), 42 (20%), 57 (27.1%),
and 101 (48.1%) were included in the POLE mutated, p53
abnormal, MMRd/MSI-­H, and NSMP, respectively. Overall, INTRODUCTION
41 (19.5%) patients were detected with positive nodes.
Molecular features were not associated with the risk of Endometrial cancer is one of the most common gyne-
having nodal metastases (OR 1.03, 95% CI 0.21 to 5.05, cological malignancies. Over the last decade, the
p=0.969 for POLE mutated; OR 0.788, 95% CI 0.32 to incidence of endometrial cancer (49 560 in 2013 vs
1.98, p=0.602 for p53 abnormal; OR 1.14, 95% CI 0.53 to 66 200 in 2023) and endometrial cancer-­associated
2.42, p=0.733 for MMRd/MSI-­H). At multivariable analysis, deaths (8190 in 2013 vs 13 030 in 2023) has
only deep myometrial invasion (OR 3.318, 95% CI 1.357 to increased by more than one-­third in the USA.1 Similar
8.150, p=0.009) and lymphovascular space invasion (OR trends have been observed in European countries.2
6.584, 95% CI 2.663 to 16.279, p<0.001) correlated with The increase in life expectancy and the prevalence
the increased risk of positive nodes. of risk factors, including obesity, are the main causes
Conclusion Our data suggest that molecular explaining this trend.2
© IGCS and ESGO 2024. No
commercial re-­use. See rights
classification does not seem useful to tailor the need of Surgery, including hysterectomy (with or without
and permissions. Published by nodal dissection in apparent early-­stage endometrial salpingo-­oophorectomy), represents the mainstay of
BMJ. cancer. p53 abnormality predicts the risk of having treatment of apparent early-­stage disease.3 4 However,
advanced disease at presentation. Further external
To cite: Bogani G, Lalli L, the role of retroperitoneal staging is still controver-
validation is needed.
Casarin J, et al. Int J Gynecol sial.3 4 Cumulative results of two large randomized
Cancer 2024;34:1366–1372. Clinical trial registration NCT05793333.
trials showed that lymphadenectomy increases

1366 Bogani G, et al. Int J Gynecol Cancer 2024;34:1366–1372. doi:10.1136/ijgc-2024-005416

 Original research

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morbidity but does not improve oncologic outcomes compared outcomes), and CT scan. All patients included had total laparoscopic
with the execution of hysterectomy alone.5 Nevertheless, several hysterectomy with or without bilateral salpingo-­oophorectomy and
retrospective studies highlighted the potential role of lymphadenec- sentinel node mapping. Details about the execution of sentinel node
tomy in tailoring appropriate adjuvant treatments.6 The growing mapping and ultrastaging have been reported in a previous inves-
adoption of sentinel node mapping overcomes surgery-­ related tigation by our study group.16 17 Side-­specific lymphadenectomy
issues, providing reliable data on nodal status.7 8 The adoption of was performed in cases of failure of mapping into the hemipelvis.
ultrastaging sentinel node mapping allows the identification of low-­ Looking at the pathological evaluation, all lymph nodes were placed
volume diseases, including isolated tumor cells and micrometas- in formalin and subsequently embedded in paraffin. The sentinel
tases, which are not detectable with conventional histopathological nodes were sectioned parallel to their major axis, forming slices
evaluation.9 2–3 mm thick, which were then stained (hematoxylin and eosin).
One of the most impacting innovations in the field of endometrial Finally, in case of negative results, two sections were subjected
cancer is the adoption of molecular and genomic profiling. Starting to immunohistochemical examination with cytokeratins (AE1 and
from the data published by The Cancer Genomic Atlas (TCGA) in AE3) to identify low-­volume disease (ie, micrometastasis or isolated
2013, the European Society for Medical Oncology (ESMO) and tumor cells) with ultrastaging. When nodal metastasis was iden-
European Society of Gynaecological Oncology/European SocieTy for tified, the lymph node was fixed in formaldehyde and included in
Radiotherapy and Oncology/European Society of Pathology (ESGO/ paraffin for further control sections. The non-­sentinel lymph nodes
ESTRO/ESP) guidelines, as well as the updated 2023 International were dissected along the major axis, stained (hematoxylin and
Federation of Gynecology and Obstetrics (FIGO) staging system, eosin), and subsequently examined traditionally. According to the
promoted the use of surrogate classification to capture the hetero- American Joint Committee on Cancer classification, macrome-
geneity of this complex disease.3 4 10–12 Endometrial cancer patients tastasis, micrometastasis, and isolated tumor cells were defined
are classified into four subgroups: (1) POLE mutated (POLEmut), by the presence of clusters of neoplastic cells >2 mm, 0.2 to 2
(2) mismatch repair deficiency/microsatellite-­instable (dMMR/MSI-­ mm, and <0.2 mm, respectively.9 Frozen section was not routinely
H), (3) TP53-­mutant or p53 abnormal (p53abn), and (4) no specific performed on nodes removed.
mutational profile (NSMP). Accumulating data support the prog- In case of the presence of either macrometastasis or microme-
nostic value of this classification.10–14 However, to date, no prospec- tastasis in the evaluated nodes, patients were classified with posi-
tive data support the adoption of this surrogate classification to tive nodes (FIGO stage IIIC). The findings of isolated tumor cells did
tailor surgical and adjuvant treatments. The aim of this prospective
not change the FIGO staging, but where considered having positive
study was to define the value of conventional histopathological and
node in the present study. Positive nodes were considered in a hier-
molecular features in predicting the risk of positive nodal disease
archical fashion (macrometastasis > micrometastasis > isolated
in endometrial cancer.
tumor cells). Stratification by molecular classification followed
the surrogates of the TCGA classification,11 and the patients were
grouped as follows: POLE-m ­ ut (polymerase-­epsilon mutated),
METHODS dMMR/MSI-­H (mismatch repair deficient/microsatellite instability
high), p53-­abn (p53 abnormal), and NSMP (non-­specific mutational
Patients were prospectively enrolled in this trial between January
2022 and June 2023. The protocol was approved by the Institutional profile). In case of multiple molecular classifications, the so called
Review Board (IRB) of the Fondazione IRCCS Istituto Nazionale dei ‘multiple classifier’, the current guidelines were followed.12 13
Tumori di Milano (IRB#140.20). The trial was registered in c​ linical- Evaluating peri-­operative outcomes, we used the Clavien-­Dindo
trials.​gov under the identification number NCT05793333. This a severity system to classify the severe complications and the Martin
prospective study designed to test the role of molecular features criteria to improve the quality of reporting of complications.16 17
(not only limited to four molecular classes) in predicting node posi- Criteria for adjuvant therapy administration and detailed descrip-
tivity and long-­term survival outcomes. All patients included signed tions of follow-­up protocols are reported elsewhere.16 17 Adjuvant
informed consent for research purpose. therapy was chosen by radiation oncologists and medical oncol-
Inclusion criteria were: (1) histologically confirmed endome- ogists. The choice of delivering adjuvant therapy depended on the
trial cancer; (2) clinical stage I disease; (3) having retroperitoneal ESGO/ESTRO/ESP class of risk evaluated using conventional histo-
staging via sentinel node mapping. Exclusion criteria were: (1) pathological data and molecular features.3 In low-­risk disease,
age <18 years; (2) consent withdrawal; (3) having sentinel node adjuvant therapy was not performed. In the case of intermediate-­
mapping plus backup lymphadenectomy; (4) clinical stage II–IV risk disease, vaginal brachytherapy or external beam radiotherapy
disease; (5) presence of bulky nodes detected at pre-­operative was considered the standard of care.16 17 The high-­risk patients
workup or at the time of surgery. In the present analysis, we aimed underwent radiotherapy with or without chemotherapy, or chemo-
to identify factors predicting positive nodes. Patients were staged therapy alone, as adjuvant treatment. External beam radiotherapy
according to the 2009 FIGO staging system, since the trial started was administered using three-­dimensional conformal or intensity-­
before 2023.15 Histological classification and degree of glandular modulated radiotherapy to deliver standard pelvic doses of 45–50.4
differentiation were classified according to the WHO and FIGO clas- Gy and para-­aortic doses of 45 Gy. Immune checkpoint inhibitors
sification systems, respectively.13–15 were not administered during the study period. Systematic therapy
Patients included had pre-­ operative workup including trans- included the use of a platinum-­based combination plus paclitaxel.
vaginal ultrasound, radiomics analysis (data will be reported in a When chemotherapy was the only adjuvant modality, four to six
dedicated paper when mature for being correlated with survival cycles (more commonly, six cycles) were delivered in standard

Bogani G, et al. Int J Gynecol Cancer 2024;34:1366–1372. doi:10.1136/ijgc-2024-005416 1367

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Figure 1 Study design.

doses. Owing to the short-­term follow-­up data, we did not perform shows details about the prevalence of different molecular features
survival analysis. in various classes of risk.
Overall, 41 (19.5%) patients were detected with positive nodes.
Macrometastases and low volume disease (micrometastases and
RESULTS isolated tumor cells) were observed in 21 (10%) and 20 (9.5%)
Overall, 223 apparent early-­stage endometrial cancer patients were patients, respectively. Online Supplemental Material 2 shows
included in this study. Nine (4%) patients did not meet the inclu- details regarding patients with positive nodes. Molecular features
sion criteria and were excluded. Additionally, four (1.8%) patients were not associated with the risk of having nodal metastases (OR
were excluded by this study due to the lack of data about molecular 1.03, 95% CI 0.21 to 5.05, p=0.97 for POLE mutated; OR 0.788,
features (inadequate results). The study population included 210 95% CI 0.32 to 1.98, p=0.602 for p53 abnormal; OR 1.14, 95% CI
(94.2%) patients: 178 (84.8%) and 32 (15.2%) with endometrioid 0.53 to 2.42, p=0.73 for MMRd/MSI-­H); even patients with NSMP
and non-­endometrioid endometrial cancer, respectively. Figure 1 did not have an increased risk having positive nodes (OR 1.03,
shows the study design. 95% CI 0.52 to 2.04, p=0.99). At univariate analysis, only conven-
Table 1 reports baseline characteristics of patients included. tional pathological factors influenced the risk of nodal metastases
According to pathological uterine risk factors (using conventional (histology, FIGO grade, myometrial invasion, and lymphovascular
pathological characteristics according to the ESGO/ESTRO/ESP space invasion (LVSI)).
guidelines), 93 (44.3%), 45 (21.4%), 40 (19.1%), and 32 (15.2%) At multivariable analysis, only deep myometrial invasion (OR
were classified as low, intermediate, intermediate-­high, and high-­ 3.318, 95% CI 1.357 to 8.150, p=0.009) and the presence of LVSI
risk, respectively. Using the surrogate molecular classification, 10 (OR 6.584, 95% CI 2.663 to 16.279, p<0.001) correlated with the
(4.8%), 42 (20%), 57 (27.1%), and 101 (48.1%) were included risk of having positive nodes. Table 3 reports data regarding factors
in the POLE mutated, p53 abnormal, MMRd/MSI-­H, and NSMP, predicting the presence of positive nodes. Online Supplemental
respectively. Table 2 shows the correlation between histological Material 3 shows the distribution of patients with positive nodes,
uterine risk factors (assessed per the ESGO/ESTRO/ESP guidelines) according to histological and molecular features. Restricting the
and molecular classes of risk. Online Supplemental Material 1 analysis on macrometastases only, we observed that molecular

1368 Bogani G, et al. Int J Gynecol Cancer 2024;34:1366–1372. doi:10.1136/ijgc-2024-005416

 Original research

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Table 1 Baseline characteristics of the study population
with POLE (10%) and MMRd/MSI-­H (12.3%) were more likely to
be detected with this occurrence than patients with p53 abnormal
N=210
(0%) and NSMP (3.9%) endometrial cancers (p=0.045).
Age, years 64 (56–73) The aim of this study was to focus on early-­stage endometrial
BMI, kg/m2 27 (23–30) cancer. Looking at the study design of the trial, nine patients were
Histology excluded due to peritoneal disease and bulky nodes. All the five
patients with peritoneal carcinomatosis were characterized by p53
 Endometrioid 178 (84.8%)
abnormalities, while two and two patients with bulky nodes were
 Non-­endometrioid 32 (15.2%) characterized by p53 abnormality and NSMP, respectively. Those
FIGO grade data highlighted that the presence of p53 abnormality might predict
 Grade 1 33 (15.7%) the presence of having an advanced stage of disease at presenta-
 Grade 2 113 (53.8%) tion (0% in POLE mutated and MMRd/MSI-­H, 1.9% in NSMP, and
14% in p53 abnormal; p<0.001).
 Grade 3 64 (30.5%)
Myometrial invasion
 <50% 132 (62.9%) DISCUSSION
 
>50% 78 (37.1%) Summary of Main Results
LVSI This is a prospective study evaluating predictors for nodal disease
 No 147 (70.0%)
in apparent early-­stage endometrial cancer undergoing sentinel
node mapping. The present study reported a number of noteworthy
 Focal 14 (6.7%)
findings. First, the surrogate molecular classification is not useful
 Substantial 49 (23.3%) to tailor the need of sentinel node mapping. Second, deep myome-
Positive nodes trial invasion and LVSI are the only variables predicting the risk of
 No 169 (80.5%) nodal involvement. Third, patients with NSMP are more likely to be
 Yes 41 (19.5%)
detected with low-­volume disease in comparison to patients with
p53 abnormal cancers.
Molecular classification
 dMMR/MSI-­H 57 (27.1%) Results in Context of Published Literature
 POLE mutated 10 (4.8%) The introduction of sentinel node mapping and molecular classifi-
cation represent two of the main advantages in endometrial cancer
 p53 abnormal 42 (20%)
management. Accumulating data supported the safety and effec-
 NSMP 101 (48.1%)
tiveness of adopting sentinel node mapping instead of lymphad-
Data are reported as median (range, 25% and 75% percentile); enectomy. Sentinel node mapping enables reduction in morbidity
number (%). related to lymphadenectomy, improving the diagnostic accuracy
BMI, body mass index; dMMR/MSI-­H, mismatch repair deficient/ (detecting patients harboring low volume nodal disease (through
microsatellite instability high; FIGO, International Federation of
Obstetrics and Gynecology; LVSI, lymphovascular space invasion;
ultrastaging)). The data reported by the TCGA and by the experi-
NSMP, non-­specific mutational profile; POLE, polymerase-­epsilon. ences of surrogate molecular classification highlighted the prog-
nostic role of this classification in identifying patients at risk of
recurrence.
classification was not able to predict the risk of having positive In comparison to conventional histopathological data, molec-
nodes (p=0.13). Similarly, no association was observed when we ular features provide more precise and reliable information for
tested the association between molecular features with macro- prognostication and for tailoring the most appropriate (adjuvant)
metastases+micrometastases (p=0.57). However, looking at the treatments.10–14 Since molecular data can be acquired at the
presence of isolated tumor cells only, we observed that patients time of pre-­ operative biopsy, several authors have speculated

Table 2 Correlation between histological and molecular risk factors

Class of risk* POLE mutated dMMR/MSI-­H p53 abnormal NSMP
Low risk (n=93) 2 (2.1%) 23 (24.7%) 6 (6.5%) 62 (66.6%)
Intermediate risk (n=45) 4 (8.9%) 15 (33.3%) 12 (26.7%) 14 (31.1%)
Intermediate-­high risk (n=40) 4 (10%) 14 (35%) 6 (15%) 16 (40%)
High risk (n=32) 0 5 (15.6%) 18 (56.3%) 9 (28.1%)
Data are reported as number (%).
*Classes of risk based on uterine risk factors according to the ESGO/ESTRO/ESP guidelines.
dMMR/MSI-­H, mismatch repair deficient/microsatellite instability high; ESGO/ESTRO/ESP, European Society of Gynaecological Oncology/
European SocieTy for Radiotherapy and Oncology/European Society of Pathology; NSMP, non-­specific mutational profile; p53 abn, p53
abnormal; POLE, polymerase-­epsilon.

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Table 3 Predictors of positive nodes
Univariate Multivariate
OR (95% CI) P value OR (95% CI) P value
Age, years* 0.978 (0.739 to 1.288) 0.862 – –
BMI, kg/m2† 0.95 (0.695 to 1.256) 0.653 – –
Histology 0.074 0.38
 Endometrioid Reference Reference
 Non-­endometrioid 2.155 (0.929 to 5.002) 0.571 (0.164 to 1.998)
FIGO grade 0.005 0.48
 Grade 1 and 2 Reference Reference
 Grade 3 2.706 (0.1.341 to 5.460) 1.461 (0.504 to 4.238)
Depth of myometrial invasion <0.001 0.009
 <50% Reference Reference
 >50% 6.875 (3.191 to 14.811) 3.318 (1.357 to 8.150)
Cervical stromal involvement 0.650 –
 No Reference –
 Yes 0.57 (0.240 to 2.412) –
Adnexal/serosal involvement 0.311 –
 No Reference –
 Yes 0.05 (0.001 to 65.560) –
LVSI <0.001 <0.001
 No Reference Reference
 Yes 11.24 (5.108 to 24.731) 6.584 (2.663 to 16.279)
Positive peritoneal washing 0.690 –
 No References –
 Yes 0.06 (0.001 to 50.801) –
POLE mutation 0.969 –
 No Reference –
 Yes 1.032 (0.211 to 5.053) –
dMMR/MSI-­H 0.733 –
 No Reference –
 Yes 1.140 (0.536 to 2.424) –
p53 abnormal 0.602 –
 No Reference –
 Yes 0.788 (0.322 to 1.928) –
NSMP 0.992 –
 No Reference –
 Yes 1.035 (0.523 to 2.048) –
*OR per 10-­year increase in age.
†OR per 5-­unit increase in BMI.
BMI, body mass index; dMMR/MSI-­H, mismatch repair deficient/microsatellite instability high; FIGO, International Federation of Obstetrics
and Gynecology; LVSI, lymphovascular space invasion; NSMP, non-­specific mutational profile; p53 abn, p53 abnormal; POLE, polymerase-­
epsilon.

about the potential role of molecular classification in tailoring the immense potential for refining surgical strategies, optimizing
surgical approach. Molecular classification has ushered in a new patient outcomes, and paving the way toward a more personalized
era in the management of endometrial cancer, offering unprece- approach to endometrial cancer care. Ideally, molecular classifi-
dented insights into tumor biology. The integration of molecular cation could be useful in identifying patients who should undergo
data into the decision-­making process for nodal dissection holds nodal dissection.

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To our knowledge, this is the only study correlating molecular an algorithm implementing both those variables would be useful to
features with the risk of having positive nodes in apparent early-­ identify patients at risk.
stage endometrial cancer undergoing sentinel node mapping.
Jamieson et al18 reported retrospective data of 172 patients under-
going sentinel node mapping plus lymphadenectomy. The authors
showed that molecular classification correlated with the probability CONCLUSIONS
of nodal involvement (p53 abnormal 44.8%; MMRd 14.9%; POLE This study showed that molecular features, per se, were not useful
mutated 14.2%; NSMP 10.8%). However, this research had different in predicting nodal disease, while conventional histopathological
inclusion criteria, in comparison to our study. Our study failed to features (deep myometrial invasion and LVSI) predicted the pres-
demonstrate an association between the surrogate molecular clas- ence of nodal disease in patients with apparent early-­stage endo-
sification and the risk of having positive nodes in apparent early-­ metrial cancer. Knowing the presence of p53 abnormality before
stage endometrial cancers undergoing sentinel node mapping. surgery might be useful to tailor the appropriate pre-­operative
The results of this study supported mature evidence correlating workup for identifying patients with advanced stage disease.
deep myometrial invasion and LVSI with the presence of lymphatic Further studies are warranted to confirm our results.
disease.15 19 20 The present study was designed to test the role
of molecular and histological features in predicting the presence Author affiliations
1
Department of Gynecologic Oncology, Fondazione IRCCS Istituto Nazionale dei
of positive nodes (including macrometastasis, micrometastasis,
Tumori di Milano, Milan, Italy
and isolated tumor cells). However, macrometastasis and low-­ 2
Unit of Clinical Epidemiology and Trial Organization, Fondazione IRCCS Istituto
volume disease (ie, micrometastasis and isolated tumor cells) Nazionale dei Tumori, Milan, Italy
3
have different prognostic roles and has an impact on the patient’s Department of Obstetrics and Gynecology, “Filippo Del Ponte” Hospital, University
journey.16 21 This study does not have enough power to test the of Insubria, Varese, Italy
4
Department of Women, Children and Public Health Sciences Gynecologic Oncology
ability of adopting molecular classification in predicting the pres-
Unit, Rome, Italy
ence of low-­volume disease.9 The study will continue to enroll
patients to test this association. X Giorgio Bogani @BoganiGiorgio
Contributors Author contribution: Conceptualization: GB, FR, GS. Methodology: all
Strengths and Weaknesses authors. Project administration: FR, GS. Supervision: FG, GS, FR. Writing – original
The main strengths of this study are its prospective nature and draft: all authors. Writing – review and editing: all authors. Guarantor: GB.
the innovative topic. The main weakness of the present research Funding The authors have not declared a specific grant for this research from any
is related to the small sample size. Additionally, some variables funding agency in the public, commercial or not-­for-­profit sectors.
(including tumor size and pattern of myometrial infiltration) are Competing interests None declared.
missing, thus limiting the generalization of our results. Six other Patient consent for publication Not applicable.
points deserve to be addressed. First, the molecular classification Ethics approval This study involves human participants and was approved
was evaluated on the uterine specimen after surgery, while it would by Fondazione IRCCS Istituto Nazionale dei Tumori di MIlano. Participants gave
be more interesting to test the role of molecular data achieved on informed consent to participate in the study before taking part.
pre-­operative endometrial samples. Evidence supporting the relia- Provenance and peer review Not commissioned; externally peer reviewed.
bility of pre-­operative and uterine samples is still lacking. Second, Data availability statement Data are available upon reasonable request.
certain molecular features (beyond TP53, MMRd/MSI-­H, and POLE) Supplemental material This content has been supplied by the author(s). It has
might play a role in predicting node positivity. A step forward in not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been
our protocol is to test molecular features (not limited to the four peer-­reviewed. Any opinions or recommendations discussed are solely those
classes) in relation to nodal disease and survival outcomes. Third, of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and
responsibility arising from any reliance placed on the content. Where the content
external validation is needed to confirm the reproducibility of these includes any translated material, BMJ does not warrant the accuracy and reliability
results. Hence, our results should be considered preliminary. Fourth, of the translations (including but not limited to local regulations, clinical guidelines,
patients with POLE and MMRd/MSI-­H were more likely to be diag- terminology, drug names and drug dosages), and is not responsible for any error
nosed with isolated tumor cells than patients with p53 abnormali- and/or omissions arising from translation and adaptation or otherwise.
ties and NSMP. However, due to the limited number of patients with ORCID iDs
isolated tumor cells, it was not possible to conduct any exploratory Giorgio Bogani http://orcid.org/0000-0001-8373-8569
analysis. Fifth, the prevalence of positive nodes reported in our Giovanni Scambia http://orcid.org/0000-0003-2758-1063
study might be considered low, especially considering that high-­
risk patients represent 15.2% of our series. Although in high-­risk
patients the prevalence of positive nodes is higher than 30%,22 the REFERENCES
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