Human Reproduction Open, Vol. 2023, No.

1, hoac057, 2023
https://doi.org/10.1093/hropen/hoac057

ESHRE PAGES

ESGO/ESHRE/ESGE Guidelines for

the fertility-sparing treatment of
patients with endometrial
carcinoma†,‡
Alexandros Rodolakis 1*, Giovanni Scambia 2,
François Planchamp 3, Maribel Acien 4, Attilio Di Spiezio Sardo5,
Martin Farrugia6, Michael Grynberg7,8,9, Maja Pakiz 10,
Kitty Pavlakis11,12, Nathalie Vermeulen 13, Gianfranco Zannoni 14,
Ignacio Zapardiel 15, and Kirsten Louise Tryde Macklon16
1
Unit of Gynaecologic Oncology, Alexandra Hospital, National and Kapodistrian University of Athens School of Health Sciences, Athens,
Greece 2Fondazione Policlinico Universitario A. Gemelli IRCCS—Università Cattolica del Sacro Cuore, Roma, Italy 3Clinical Research
Unit, Institut Bergonie, Bordeaux, France 4Obstetrics and Gynecology Department, San Juan University Hospital, Miguel Hernández
University, Alicante, Spain 5Gynecology and Obstetrics Unit, Department of Public Health, School of Medicine, University of Naples
Federico II, Napoli, Campania, Italy 6Spencer Private Hospitals, East Kent, UK 7AP-HP, Department of Reproductive Medicine & Fertility
Preservation, Hôpital Antoine-Béclère, Clamart, France 8AP-HP, Department of Reproductive Medicine & Fertility Preservation, Hôpital
Jean Verdier, Bondy, France 9University Paris-Saclay, Saint-Aubin, France 10Department for Gynecologic and Breast Oncology, University
Medical Centre, Maribor, Slovenia 111st Pathology Department, Alexandra Hospital, National and Kapodistrian University of Athens
School of Health Sciences, Athens, Greece 12Pathology Department, “IASO” Women’s Hospital, Athens, Greece 13European Society of
Human Reproduction and Embryology, Strombeek-Bever, Belgium 14Department of Pathology, Dipartimento Scienze della Salute della Donna
e del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy 15Department of Gynecologic
Oncology, La Paz University Hospital, Madrid, Spain 16Fertility Department, Copenhagen University Hospital, Copenhagen, Denmark

*Correspondence address. Unit of Gynaecologic Oncology, Alexandra Hospital, National and Kapodistrian University of Athens School of
Health Sciences, Athens 115 28, Greece. E-mail: [email protected] https://orcid.org/0000-0001-9283-4480

Submitted on November 18, 2022; ; editorial decision on November 24, 2022

STUDY QUESTION: How should fertility-sparing treatment of patients with endometrial carcinoma be performed?
SUMMARY ANSWER: Forty-eight recommendations were formulated on fertility-sparing treatment of patients with endometrial carcinoma.
WHAT IS KNOWN ALREADY: The standard surgical treatment of endometrial carcinoma consisting of total hysterectomy with bilat-
eral salpingo-oophorectomy drastically affects the quality of life of patients and creates a challenge for clinicians. Recent evidence-based
guidelines of the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy & Oncology (ESTRO) and
the European Society of Pathology (ESP) provide comprehensive guidelines on all relevant issues of diagnosis and treatment in endometrial
carcinoma in a multidisciplinary setting. While addressing also work-up for fertility preservation treatments and the management and
follow-up for fertility preservation, it was considered relevant to further extend the guidance on fertility-sparing treatment.
STUDY DESIGN, SIZE, DURATION: A collaboration was set up between the ESGO, the European Society of Human Reproduction
and Embryology (ESHRE) and the European Society for Gynaecological Endoscopy (ESGE), aiming to develop clinically relevant and
evidence-based guidelines focusing on key aspects of fertility-sparing treatment in order to improve the quality of care for women with en-
dometrial carcinoma across Europe and worldwide.
PARTICIPANTS/MATERIALS, SETTING, METHODS: ESGO/ESHRE/ESGE nominated an international multidisciplinary develop-
ment group consisting of practising clinicians and researchers who have demonstrated leadership and expertise in the care and research of
endometrial carcinoma (11 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2016,
identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgement was
based on the professional experience and consensus of the development group. The guidelines are thus based on the best available

†
ESHRE pages content is not externally peer reviewed. The manuscript has been approved by the Executive Committees/Boards of ESGO, ESHRE and ESGE.
‡
These guidelines were developed by ESGO, ESHRE and ESGE and are published in the International Journal of Gynecological Cancer, Human Reproduction Open and Facts, Views, & Vision in ObGyn.
Initiated through ESGO, the decision to develop multidisciplinary guidelines has been made jointly by the ESGO, ESHRE and ESGE. The ESGO has provided administrative support. The ESGO,
ESHRE and ESGE are non-profit knowledgeable societies.
C The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.
V
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse,
distribution, and reproduction in any medium, provided the original work is properly cited.
2 Rodolakis et al.

evidence and expert agreement. Prior to publication, the guidelines were reviewed by 95 independent international practitioners in cancer
care delivery and patient representatives.
MAIN RESULTS AND THE ROLE OF CHANCE: The multidisciplinary development group formulated 48 recommendations in four
sections; patient selection, tumour clinicopathological characteristics, treatment and special issues.
LIMITATIONS, REASONS FOR CAUTION: Of the 48 recommendations, none could be based on level I evidence and only 16 could
be based on level II evidence, implicating that 66% of the recommendations are supported only by observational data, professional experi-
ence and consensus of the development group.
WIDER IMPLICATIONS OF THE FINDINGS: These recommendations provide guidance to professionals caring for women with endome-
trial carcinoma, including but not limited to professionals in the field of gynaecological oncology, onco-fertility, reproductive surgery, endoscopy,
conservative surgery and histopathology, and will help towards a holistic and multidisciplinary approach for this challenging clinical scenario.
STUDY FUNDING/COMPETING INTEREST(S): All costs relating to the development process were covered from ESGO, ESHRE
and ESGE funds. There was no external funding of the development process or manuscript production. G.S. has reported grants from
MSD Italia S.r.l., advisory boards for Storz, Bayer, Astrazeneca, Metronic, TESARO Bio Italy S.r.l and Johnson & Johnson, and honoraria for
lectures from Clovis Oncology Italy S.r.l. M.G. has reported advisory boards for Gedeon Richter and Merck. The other authors have
reported no conflicts of interest.
DISCLAIMER: This document represents the views of ESHRE, ESGO and ESGE which are the result of consensus between the relevant stakehold-
ers and where relevant based on the scientific evidence available at the time of preparation.
The recommendations should be used for informational and educational purposes. They should not be interpreted as setting a standard of care, or
be deemed inclusive of all proper methods of care nor exclusive of other methods of care reasonably directed to obtaining the same results. They do
not replace the need for application of clinical judgement to each individual presentation, nor variations based on locality and facility type.

Key words: uterine cancer / guideline / fertility preservation / endometrial carcinoma / oncofertility

WHAT DOES THIS MEAN FOR PATIENTS?

Even if not very common, endometrial carcinoma is diagnosed in pre-menopausal women. The standard treatment for endometrial carci-
noma is removal of the uterus and ovaries (total hysterectomy with bilateral salpingo-oophorectomy). While effectively increasing the chan-
ces of surviving the disease, this treatment is devastating for young women, who would no longer be able to carry a pregnancy. This article
provides clinical guidance to oncologists and fertility specialists on fertility-sparing treatments in endometrial carcinoma, being medical treat-
ments that can pause further progression of the cancer and allow patients to achieve a pregnancy before the removal of the uterus and
ovaries. The guidance includes recommendations for the most effective treatments, and also on how to select patients that could benefit
from this approach. Upfront, the guidance recommends that patients with endometrial carcinoma undergoing fertility-sparing treatments
are supported by a multidisciplinary team, including at least an oncologist and fertility specialist.

..
Introduction .. 2021a,b,c). While addressing also work-up for fertility preservation
.. treatments and the management and follow-up for fertility preserva-
Endometrial carcinoma is the sixth most commonly diagnosed cancer .. tion, it was considered relevant to further extend the guidance on
..
in women worldwide, with increasing incidence in post-menopausal .. fertility-sparing treatment for endometrial carcinoma.
women (Sung et al., 2021). The estimated number of new cases of .. A collaboration was set up between the ESGO, the European
..
endometrial carcinoma in Europe in 2020 was 130 051 with .. Society of Human Reproduction and Embryology (ESHRE) and the
29 963 deaths, and the incidence has been rising with ageing and in- ..
.. European Society for Gynecological Endoscopy (ESGE), aiming to de-
creased obesity of the population (World Health Organization, 2020). .. velop clinically relevant and evidence-based guidelines focusing on key
Although not that common in pre-menopausal women, endometrial
..
.. aspects of fertility-sparing treatment (patient selection, tumour clinico-
carcinoma and its standard treatment of total hysterectomy with bilat- .. pathological characteristics, medical treatment and special issues).
..
eral salpingo-oophorectomy drastically affects the quality of life of .. These guidelines are intended for use by all health professionals who
patients and creates a challenge for clinicians. Recent evidence-based .. are involved in the fertility-sparing treatment of patients with endome-
..
guidelines of the European Society of Gynecological Oncology .. trial carcinoma, across all allied disciplines. Even though our aim is to
(ESGO), the European SocieTy for Radiotherapy and Oncology .. present the highest standard of evidence in an optimal fertility-sparing
..
(ESTRO) and the European Society of Pathology (ESP) provide com- .. treatment, ESGO, ESHRE and ESGE acknowledge that there will be
prehensive guidelines on all relevant issues of diagnosis and treatment .. broad variability in practices between the various centres worldwide
..
in endometrial carcinoma in a multidisciplinary setting (Concin et al., . and also significant differences in infrastructure, access to medical and
Fertility-sparing treatment in endometrial carcinoma 3

..
surgical technology, and training, medicolegal, financial and cultural .. and critically appraised. A systematic, unbiased literature review of rel-
aspects that will affect the implementation of any treatment guidelines. .. evant studies published between September 2016 and September
..
.. 2021 was carried out using the Medline database (see Supplementary
Responsibilities ... Data 1). The bibliography was also supplemented by additional older
.. relevant references (if any). The literature search was limited to publi-
These guidelines are a statement of evidence and consensus of the mul- ..
tidisciplinary development group based on their views and perspectives
.. cations in English. Priority was given to high-quality systematic reviews,
.. meta-analyses, and randomized controlled trials, but studies of lower
of currently accepted approaches for the fertility-sparing treatment of ..
patients with endometrial carcinoma. Any clinician applying or consult-
.. levels of evidence were also evaluated. The search strategy excluded
..
ing these guidelines is expected to use independent medical judgement .. editorials, letters and in vitro studies. The reference list of each identi-
.. fied article was reviewed for other potentially relevant articles. Based
in the context of individual clinical circumstances to determine any ..
patient’s care or treatment. These guidelines make no warranties of .. on the collected evidence and clinical expertise, the development
.. group drafted guidelines for all the topics. These guidelines were dis-
any kind regarding their content, use or application and the authors dis- ..
claim any responsibility for their application or use in any way. .. cussed and retained if they were supported by sufficiently high-level
.. scientific evidence and/or when a large consensus among experts was
..
.. obtained. An adapted version of the Infectious Diseases Society of
..
Materials and methods .. America-United States Public Health Service Grading System was used
.. to define the level of evidence and grade of recommendation for each
..
The guidelines were developed using a five-step process as defined by .. of the recommendations (Dykewicz, 2001) (Fig. 2). In the absence of
the ESGO Guideline Committee standard operative procedures man- .. any clear scientific evidence, judgement was based on the professional
..
ual (Fig. 1). The strengths of the process include creation of a multidis- .. experience and consensus of the development group.
ciplinary international development group, use of scientific evidence .. ESGO/ESHRE/ESGE established a large multidisciplinary panel of
..
and international expert consensus to support the guidelines, and an .. practising clinicians who provide care to patients with endometrial car-
international external review process (physicians and patients). This ..
.. cinoma to act as independent expert reviewers for the guidelines de-
development process involved three meetings of the international de- .. veloped. These reviewers were selected according to their expertise
velopment group, chaired by Professor Alexandros Rodolakis
..
.. and active involvement in clinical practice or research, while geographi-
(National and Kapodistrian University of Athens, Greece, for ESGO), .. cal balance ensured a global perspective. Patients with endometrial
Dr Kirsten Louise Tryde Macklon (University Hospital of Copenhagen,
..
.. carcinoma were also included. The independent reviewers were asked
Denmark, for ESHRE) and Professor Giovanni Scambia (Fondazione .. to evaluate each recommendation according to its relevance and feasi-
..
Policlinico Universitario A Gemelli IRCCS, Rome, Italy, for ESGE). .. bility in clinical practice (only physicians), so that comprehensive quan-
ESGO/ESHRE/ESGE nominated practising clinicians involved in the .. titative and qualitative evaluations of the guidelines were completed.
..
management of patients with endometrial carcinoma and who have .. Patients were asked to evaluate qualitatively each recommendation
demonstrated leadership through their expertise in clinical care and re- ..
.. (according to their experience, personal perceptions, etc). Evaluations
search, national and international engagement, and profile as well as .. of the external reviewers (n ¼ 95) were pooled and discussed by the
dedication to the topics addressed to serve on the expert panel. The ..
.. international development group before finalizing the guidelines. The
objective was to assemble a multidisciplinary development group. It .. list of the 95 external reviewers is available in Supplementary Data 2.
was therefore essential for the validity and acceptability of the guide- ..
..
lines to include professionals from all relevant disciplines—that is, ..
gynaecological oncology, onco-fertility, reproductive surgery, endos- ..
..
copy, conservative surgery and histopathology. To ensure that the .. Results and discussion
statements were evidence-based, the current literature was reviewed
..
.. Patient selection
..
.. Fertility-sparing treatment in endometrial carcinoma is an option for a
..
.. subgroup of women who are selected based on thorough evaluation of
..
.. reproductive potential. Fertility-sparing treatments should be exclusively
.. applied in women with early-stage, non-metastatic disease. Implicit pa-
..
.. tient evaluation should take into consideration the reproductive poten-
.. tial and also risk factors that affect the potential for the patient to carry
..
.. a pregnancy successfully, including the status of the uterus.
.. To date, no literature exists on the reproductive potential specifi-
..
.. cally for women with endometrial carcinoma, although it must be as-
..
.. sumed that the same markers of fertility apply to this group of patients
.. as to any woman of fertile age. Markers of ovarian reserve, such as
..
.. anti-Müllerian hormone, antral follicle count and Day 2–5 FSH levels as
.. well as age and BMI of the patients can possibly all be used to estimate
..
Figure 1. Development process. .. the ovarian function and the capacity of ovaries to produce mature
.. oocytes after controlled ovarian stimulation. Patients with a diminished
4 Rodolakis et al.

LEVELS OF EVIDENCE

I Evidence from at least one large randomised, controlled trial of good methodological quality (low potential for bias) or meta-
analyses of well-conducted, randomised trials without heterogeneity
II Small, randomised trials or large randomised trials with a suspicion of bias (lower methodological quality) or meta-analyses
of such trials or of trials with demonstrated heterogeneity
III Prospective cohort studies
IV Retrospective cohort studies or case-control studies
V Studies without control group, case reports, experts’ opinions

GRADES OF RECOMMENDATIONS

A Strong evidence for eficacy with a substantial clinical beneit, strongly recommended
B Strong or moderate evidence for eficacy but with a limited clinical beneit, generally recommended
C Insuficient evidence for eficacy or beneit does not outweigh the risk or the disadvantages (adverse events, costs, …),
optional
D Moderate evidence against eficacy or for adverse outcome, generally not recommended
E Strong evidence against eficacy or for adverse outcome, never recommended

Figure 2. Levels of evidence and grades of recommendations.

..
ovarian reserve might still benefit from fertility-sparing surgery, .. causes of endometrial carcinoma, owing to prolonged exposure to
attempting a pregnancy with heterologous oocytes. .. oestrogen as well as persistent progesterone deficiency (Hardiman
..
As with any woman seeking to become pregnant, age is a prognos- .. et al., 2003; Shao et al., 2014). Polycystic ovary syndrome is frequently
tic factor for success also in women with endometrial carcinoma. In a
.. found among patients with endometrial carcinoma who are under
..
recent meta-analysis, it was found that the highest chance of achieving .. 35 years of age. These patients are more often obese, insulin-resistant
..
a live birth for women with endometrial carcinoma was in those youn- .. or diagnosed with more advanced disease (Okamura et al., 2017).
ger than 35 years (live birth rate 30.7%). In studies including women .. Insulin resistance, a condition with hyperinsulinaemia and hyperglycae-
..
up to age 40 years, a live birth rate of 23.0% was reported (Herrera .. mia due to the inability of muscle, liver and fat cells to take up and
Cappelletti et al., 2022). .. store glucose sufficiently, is often seen in obese patients and can in the
..
Several lines of evidence indicate a strong relationship between .. worst cases lead to type 2 diabetes. Women with polycystic ovary
weight and endometrial carcinoma. Indeed, maintaining a healthy weight .. syndrome and endometrial carcinoma have been found to more often
..
or BMI, as well as weight loss through bariatric surgery or lifestyle .. fail to respond to medroxyprogesterone acetate therapy (Okamura
changes in obese women, reduced the risk of endometrial carcinoma
.. et al., 2017). Associated abnormalities, such as obesity, nulliparity, in-
..
(Sundar et al., 2017). Being overweight or obese is considered to have .. fertility and diabetes, can all independently act as risk factors for endo-
a negative effect on fertility, conception, time to pregnancy and preg-
..
.. metrial carcinoma. Obesity and polycystic ovary syndrome additively
nancy outcomes (Ribeiro et al., 2022). In overweight and obese women .. contribute to the evolution of metabolic syndrome. Polycystic ovarian
..
who have received endometrial carcinoma fertility-sparing therapy, .. morphology (not necessarily polycystic ovary syndrome) may be a
weight loss could positively affect pregnancy rate and improve live birth .. prognostic factor in patients with endometrial carcinoma who achieved
..
rate (Gonthier et al., 2014; Chen et al., 2016; Obermair et al., 2020). .. complete remission after fertility-sparing therapy with progestin, inde-
A recent study showed that 5% weight loss increased pregnancy and .. pendently of BMI (Fukui et al., 2017). Because of the risks associated
..
live birth rates significantly in overweight and obese women (Zhang .. with metabolic syndrome, it is important that women with polycystic
et al., 2021). Studies have demonstrated the positive effects of bariatric
.. ovary syndrome are aware of the positive effects of lifestyle changes
..
surgery for positive response rates to intra-uterine progestin, a reduc- .. and medical treatment to reduce their risk of cardiovascular disease
tion in systemic inflammation and recruitment of immune cell types
.. and type 2 diabetes.
..
protective to the endometrium and a reduction in circulating bio- .. Lynch syndrome is associated with the development of endometrial
..
markers of insulin resistance (HbA1c and HOMA-IR (homeostasis .. carcinoma, often with an earlier age at onset, together with a detect-
model assessment of insulin resistance)) and inflammation (hsCRP .. able and treatable pre-malignant or early malignant stage (Dominguez-
..
(high-sensitivity C-reactive protein) and IL-6 (interleukin 6)) .. Valentin et al., 2020). With regards to fertility-sparing treatment, there
(MacKintosh et al., 2019; Barr et al., 2021; Naqvi et al., 2022). .. is no consensus as to whether patients with endometrial carcinoma
..
Polycystic ovary syndrome is an endocrine system disorder among .. and Lynch syndrome could be considered as appropriate candidates,
women of reproductive age represented by polycystic ovarian mor-
.. since there is no evidence on the safety of the conservative approach
..
phology with abnormal uterine bleeding. It is known as one of the . in this population (La Russa et al., 2018). Recently, a systematic review
Fertility-sparing treatment in endometrial carcinoma 5

..
evaluating the potential prognostic factors of patients with early-stage .. Health status, obesity
endometrial carcinoma and complex atypical endometrial hyperplasia ..
.. • Following fertility-sparing therapy for endometrial carcinoma,
who received fertility-sparing treatment was published, but among the .. weight loss in overweight and obese women or maintaining a
1099 patients only 9 (0.8%) had a family history of Lynch syndrome (Li ... healthy BMI is important for improving the chances of
et al., 2019). Outcomes of women treated with this conservative ap- ..
.. pregnancy (natural or after ARTs) and live birth. Therefore,
proach are good, even if fatalities following this treatment have been .. weight loss in overweight and obese women or maintaining a
described (Ferrandina et al., 2005; Kothari et al., 2008). ..
.. healthy BMI after fertility-sparing treatment is strongly
Considering the specificities of Lynch syndrome and its association .. suggested as soon as possible (Level of evidence II, Grade A).
with other malignancies, some points should be taken into account on ..
.. Lynch syndrome
decision-making, in particular: ..
..
(1) Younger age of endometrial carcinoma diagnosis and probably higher .. • The presence of any concurrent/metachronous cancer should
..
risk of disease progression. .. • be determined (Level of evidence II, Grade A).
(2) Risk of synchronous ovarian cancer, which represents the third .. Patients should be informed about the higher risk of
.. persistence/recurrence as compared with other patients
most common cancer in women with this syndrome (Nakamura .. (Level of evidence II, Grade A).
et al., 2014).
..
.. • Fertility-sparing treatment in women with Lynch syndrome
(3) Different molecular mechanisms cause the disease, and it is not clear .. should be discussed on a case-by-case basis (Level of
if hormonal therapy can be effective. Indeed, in this syndrome, lesions
..
.. evidence II, Grade A).
are caused by genetic mutations, and the molecular mechanisms in- ..
volved in the disease appear different from those of sporadic cancers
..
..
(Corrado et al., 2021). However, patients with Lynch syndrome may ..
.. Tumour clinicopathological characteristics
at the same time also have a hyper-oestrogenic state, which could be ..
the cause of the endometrial carcinoma and that could potentially be .. Pathological diagnosis of endometrial hyperplasia and endometrial car-
..
treated with progestins. .. cinoma is of critical importance for optimal risk stratification and treat-
(4) Resistances to conservative treatment and recurrences are more ..
.. ment decisions; therefore, diagnostic errors may strongly influence
common in mismatch repair-deficient patients (Zakhour et al., 2017; .. patient outcome. It was shown that using a World Health
Chung et al., 2021; Raffone et al., 2021). In this case, hysteroscopic ..
.. Organization (WHO) two-tier classification with two diagnostic cate-
resection has been described as an option for improving outcome .. gories, hyperplasia without atypia and endometrial hyperplasia/endo-
(Chung et al., 2021). ..
.. metrioid intra-epithelial neoplasia, improved reproducibility (Kendall
.. et al., 1998; Bergeron et al., 1999; Trimble et al., 2006; Ordi et al.,
No data about the difference in management of endometrial carci- ..
noma and complex endometrial hyperplasia are available—in particu- .. 2014). The distinction between atypical endometrial hyperplasia and
..
lar, in the Lynch syndrome population. .. well-differentiated endometrial carcinoma showed poor intra-observer
.. and inter-observer agreement (Grevenkamp et al., 2017). Moreover,
..
.. poor inter-observer agreement exists when evaluating the grade of en-
Recommendations .. dometrial carcinomas specifically in curettage material (Lax et al.,
General recommendations
..
.. 2000; Scholten et al., 2004). Three additional retrospective single-
.. institutional studies demonstrated a poor correlation between pre-
• Patients with a pregnancy wish should be referred to ..
specialized care, especially those with genetic syndrome
.. operative endometrial sampling and final diagnosis (Garcia et al., 2017;
..
(Level of evidence V, Grade A). .. Lago et al., 2018; Piotto et al., 2020). Although the International
• Joint care and counselling with a multidisciplinary team of at .. Society of Gynaecological Pathologists recommends the use of a binary
..
least gynaecologic oncologists, fertility specialists, pathologists .. grading system by combining Grades 1 and 2 into a single low-grade
.. category which reduces the degree of disagreement, for patients desir-
and radiologists should be proposed to all patients with a ..
pregnancy wish (Level of evidence V, Grade A). .. ing a fertility-sparing treatment approach, it will continue to be neces-
..
Reproductive potential
.. sary to distinguish Grades 1 and 2 (Soslow et al., 2019).
.. Endometrial sampling has suboptimal accuracy in predicting the tu-
..
• No recommendations can be given based on the literature. .. mour grade compared with the final surgical specimen, especially in
However, evaluation of the reproductive potential and
.. early-stage endometrial carcinoma in low/intermediate grade tumours
..
consultation with fertility specialists should be performed .. (G1–G2). Therefore, as suggested in a multicentre prospective study
.. on fertility-preserving surgery in endometrial carcinoma, a second
prior to fertility-sparing treatment (Level of evidence V, ..
Grade B). .. opinion from an expert pathologist is important to minimize risk asso-
..
Age-specific age limits
.. ciated with preserving the uterus (Ushijima et al., 2007).
.. Recent publications advocate the use of the immunohistochemical
..
• Women should be counselled about their reduced chances of .. evaluation of several biomarkers such as PTEN, PAX2, ARID1A or b-
achieving a live birth with their own gametes with increased .. catenin in order to detect endometrial hyperplasia/endometrioid
..
age (Level of evidence II, Grade A). .. intra-epithelial neoplasia, increasing thereafter inter-observer agree-
.. ment. Yet, the use of the above markers for diagnostic purposes is still
6 Rodolakis et al.

..
debated (Mutter et al., 2014; Ayhan et al., 2015; Sanderson et al., .. the presence of an endometrioid-type tumour (Auclair et al., 2019)
2017; Yen et al., 2018). .. (Fig. 3). Once the area to biopsy has been identified, the
..
The differentiation of endometrial carcinoma is the most important .. alligator forceps is positioned with the jaws opened at the level of
predictor of stage and response to treatment with progestins. Women ... the endometrium to be sampled (Fig. 3A). Next, the jaws are
with Grade 1 Stage IA endometrioid endometrial carcinoma (without .. dragged across the tissue for about 0.5–1 cm (Fig. 3B). At this
..
myometrial invasion) seem to have a greater chance of responding to .. point, the jaws are closed, grasping the piece of tissue to be exam-
treatment with progestins, whereas the likelihood of presenting with .. ined (Fig. 3C and D), which is then retrieved—together with the
..
advanced disease in the future is really low. In the available literature, .. hysteroscope—from the uterine cavity, without retracting the tip of
there are few reported cases of conservative treatment of Grade 2 .. the forceps into the operating channel of the hysteroscope (Fig. 3E
..
Stage IA endometrial carcinoma. In a multicentre worldwide project .. and F).
endorsed by the Gynaecologic Cancer Intergroup, among 23 patients .. Where the area to be biopsied is noted to be hypotrophic/atro-
..
with Grade 2 Stage IA endometrioid endometrial carcinoma treated .. phic, a different technique is more appropriate. Using a bipolar elec-
by hysteroscopic resection plus progestin, 17 patients showed com-
.. trode or 5-Fr scissors, precise cuts can be made to collect adequate
..
plete response. The recurrence rate was 41.1% (Falcone et al., 2020). .. tissue samples, which are then removed with the grasping forceps.
Five young women with Grade 2 Stage IA endometrial adenocarci-
.. Another option can be the use of an intra-uterine tissue removal
..
noma who wished to preserve fertility treated with combined oral .. device, which allows collection of a larger amount of tissue, or of a
medroxyprogesterone acetate/levonorgestrel-intra-uterine device
.. 15-Fr bipolar office resectoscope, with a cutting loop, which allows
..
showed a complete response in three of the five cases, with partial re- .. tissue to be collected also from the subendometrial layer, when
sponse in the other two patients (Hwang et al., 2017). Among four
.. needed.
..
patients with Grade 2 Stage IA endometrial carcinoma treated with .. A meta-analysis of 65 studies on the accuracy of hysteroscopy in
..
oral megestrol acetate (160 mg per day), with metformin (500 mg, .. the diagnosis of endometrial carcinoma including 26 346 women
three times a day) in cases of metabolic syndrome, 75% (3/4) of the .. (29% post-menopausal), assessed the diagnostic accuracy of hyster-
..
patients had a complete response; one of whom relapsed and .. oscopy for the detection of endometrial carcinoma and hyperplasia
achieved again complete response and a fourth patient who had myo- .. (Clark et al., 2002). The overall sensitivity of hysteroscopy was
..
metrial invasion during fertility-sparing treatment (Shan et al., 2021). .. 86.4% with a specificity of 99.2% for the detection of endometrial
Of eight patients with Grade 2 presumed Stage IA endometrioid ade- .. carcinoma (Clark et al., 2002). A meta-analysis evaluated the diag-
..
nocarcinoma who underwent fertility-sparing treatment, complete re- .. nostic accuracy of endometrial biopsy performed under direct hys-
sponse was found in seven of the eight cases, with three developing a .. teroscopic visualization versus blind or hysteroscopic oriented for
..
recurrence and were treated with second-line fertility-sparing therapy .. diagnosis of endometrial pathology (Di Spiezio Sardo et al., 2022).
(Yu et al., 2020). .. Studies included a total of 1470 women and showed that hystero-
..
The cornerstone investigation for the diagnosis of endometrial carci- .. scopic guided endometrial biopsy is more accurate for the diagnosis
noma is an endometrial biopsy. Several methods to obtain endometrial .. of endometrial pathology than blind or hysteroscopic oriented bi-
..
tissue samples are in use, such as curettage techniques using a Pipelle, .. opsy (Di Spiezio Sardo et al., 2022).
Novak, Vabra or dilation and curettage using metal sharp curettes as
.. Whether hysteroscopy might increase the dissemination of tumour
..
well as hysteroscopic guided endometrial biopsy (Narice et al., 2018; .. cells into the peritoneal cavity is an old debate; actually, the possible
Di Spiezio Sardo et al., 2020). Dilation and curettage has long been
.. spread of malignant endometrial cells into the peritoneal cavity follow-
..
considered the standard method to obtain a histological diagnosis and .. ing diagnostic hysteroscopy has been shown not to alter tumour stag-
despite its many deficiencies is still preferred by many authors
.. ing and has not been shown to adversely affect the patient’s prognosis
..
(Rodolakis et al., 2015). Falcone et al showed that, compared with .. (Chang et al., 2011). Tissue removal devices also do not result in in-
Pipelle biopsy, dilation and curettage is associated with the lowest rate
.. creased dissemination of malignant cells into the peritoneal cavity
..
(<10%) of histological under-grading and correlates better with the .. when used as an initial biopsy method in the diagnosis of endometrial
..
histological result of the final specimen (Auclair et al., 2019; Falcone .. carcinoma and are not associated with surgical upstaging of patients
et al., 2017). Several other studies dispute this and argue that a blind .. compared with conventional endometrial biopsy methods (Kelly et al.,
..
approach will sample <50% of the endometrial cavity. Consequently, .. 2021). The International Federation of Gynecology and Obstetrics
nearly 10% of endometrial lesions could be missed—in particular, focal .. (FIGO) staging system states that the confirmed diagnosis of a positive
..
abnormalities, with a high percentage of false-negative results .. peritoneal washing does not alter the tumour stage and is recorded
(Bettocchi et al., 2001; Goldstein, 2010). It is suggested that blind tech- .. separately from the report issued on the staging itself (Amant et al.,
..
niques should no longer be offered to obtain endometrial histology .. 2018).
and a visually oriented hysteroscopic approach to diagnose endome- .. The absence of myometrial invasion should be determined
..
trial carcinomas should be favoured (Ramshaw and Narayansingh, .. before making the decision to proceed with the fertility-sparing ap-
2019). .. proach. The great majority of published trials are focused on evaluating
..
Over the past 25 years, hysteroscopy and directed endometrial bi- .. performance of different imaging modalities on assessment of deep
opsy has been recognized as the gold standard in diagnosing endome- .. myometrial invasion. The methodology and statistical analysis are
..
trial malignancy. The endometrial biopsy with ‘grasp’ technique has .. therefore set to estimate sensitivity and specificity to discriminate 50%
replaced the traditional hysteroscopic ‘punch’ biopsy, as it allows re-
.. of myometrial invasion. There are no specific data for discriminating
..
moval of larger portion of endometrial tissue. This technique achieves .. between no myometrial invasion and shallow myometrial invasion. So,
a high concordance of histologic type and tumour grade, especially in
.. the performance of transvaginal ultrasound (US) or MRI for
Fertility-sparing treatment in endometrial carcinoma 7

Figure 3. Hysteroscopic endometrial biopsy with ‘grasp technique’ (sequentially ordered from A to F).

determining absence of myometrial invasion or shallow myometrial in-

.. et al., 2004; Alcazar et al., 2015; Christensen et al., 2016; Fruhauf
..
vasion is being extrapolated from the data about diagnosing deep myo- .. et al., 2017; Bi et al., 2020; Costas et al., 2022). Transvaginal US and
metrial invasion.
.. pelvic MRI show comparable diagnostic performances in assessing
..
Myometrial invasion can be evaluated using different techniques, in- .. myometrial invasion and cervical stromal invasion in early endometrial
cluding transvaginal US and pelvic MRI (Kim et al., 1995; Manfredi
.. carcinoma. A systematic review and meta-analysis showed the
..
8 Rodolakis et al.

..
sensitivity and specificity of transvaginal US for diagnosing deep .. extremely low and therefore sentinel lymph node biopsy is not rec-
myometrial invasion are 75% and 82%, respectively. The sensitivity .. ommended in a fertility-sparing approach.
..
and specificity for MRI according to the same review is 83% and ..
82%, respectively, without any statistical differences observed ...
(Alcazar et al., 2017). The vast majority of trials report similar .. Recommendations
.. Review of initial pathology by an experienced histopathologist
results, with sensitivity and specificity ranging between 75% and ..
..
84% for transvaginal US and between 82% and 90% for MRI (for di- .. • A request for a second opinion by an experienced
agnosing deep myometrial invasion). The sensitivity and specificity .. histopathologist is recommended if fertility-sparing treatment
for cervical stromal invasion ranges between 69% and 82% and be-
..
.. is considered (Level of evidence III, Grade A).
tween 93% and 96%, both for transvaginal US and MRI .. • The G1, G2, G3 grading system is recommended. The binary
..
(Christensen et al., 2016; Pineda et al., 2016; Rodriguez-Trujillo .. grading system for endometrial carcinoma should not be used
et al., 2016; Guo et al., 2017; Lin et al., 2017; Masroor et al., 2018; .. for these patients (Level of evidence III, Grade A).
..
Yildirim et al., 2018; Alcazar et al., 2019; Gil et al., 2019; Goel .. • The use of immunohistochemistry (PTEN, ARID1A, etc) for
et al., 2019; Sanchez et al., 2019; Bi et al., 2020; Capozzi et al., .. the evaluation of several biomarkers is not recommended for
..
2021; Chen et al., 2021; Cubo-Abert et al., 2021; Gaston et al., .. diagnostic purposes (Level of evidence IV, Grade D).
2021; Jónsdóttir et al., 2021; Nagar et al., 2021; Sobocan et al.,
..
.. Differentiation of the tumour
2021; Tong et al., 2021; Wang et al., 2021; Yang et al., 2021; Bi ..
et al., 2021a,b; Costas et al., 2022).
.. • Fertility-sparing treatment is considered for endometrioid
..
Subjective assessment of myometrial invasion yields the highest diag- .. patients with endometrial carcinoma with Grade 1, Stage IA
.. without myometrial invasion and without risk factors (Level of
nostic accuracy (overall accuracy of 75.7%) compared with objective ..
methods, such as deepest invasion/normal myometrium ratio (overall .. evidence V, Grade A).
.. • Evidence for Grade 2 endometrioid endometrial carcinoma is
accuracy of 67.3%) or tumour/uterine anteroposterior diameter ratio ..
(overall accuracy of 68.1%) (Fruhauf et al., 2017). The diagnostic accu- .. limited. Therefore, fertility-sparing treatment should be discussed
.. on a case-by-case basis (Level of evidence IV, Grade C).
racies of transvaginal US and MRI are the highest when performed by ..
expert practitioners. The advantage of MRI over transvaginal US is .. Establishing a reliable histopathology
..
mainly the contribution of MRI for assessing extra-uterine disease (i.e. ..
lymph node assessment).
.. • Hysteroscopic-guided endometrial biopsy is preferred over
.. blind biopsy for confirming diagnosis of endometrial
The probability of extra-uterine disease or lymph node involve- ..
ment for early-stage, low-risk endometrial carcinoma is extremely
.. carcinoma (Level of evidence III, Grade A).
..
low. However, the basic clinical-radiologic staging should be per- .. Myometrial invasion
..
formed (as surgical staging is not possible in a fertility-sparing ap- .. •
.. Pre-operative assessment of myometrial invasion in patients
proach). Chest radiology, either a computed tomography (CT)
.. with endometrial carcinoma should be performed using MRI
scan or a plain X-ray examination, should be performed in all .. or transvaginal US by a specialized radiologist/sonographer.
women with endometrial carcinoma to exclude pulmonary spread ..
.. Standardized high-quality protocols for MRI should be used to
(Sundar et al., 2017). Abdominal US or CT can be used for evaluat- .. reach the highest possible accuracy (Level of evidence III,
ing the spread to abdominal organs. Lymph nodes can be assessed
..
.. Grade A).
using CT, MRI or positron emission tomography (PET)-CT. MRI is .. • CT should not be used for pre-operative assessment of
a good diagnostic tool for detecting pelvic or para-aortic lymph
..
.. myometrial invasion in patients with endometrial carcinoma
nodes with a low to moderate sensitivity but a high specificity. .. (Level of evidence III, Grade A).
..
PET-CT shows the highest specificity but a moderate sensitivity for ..
detecting lymph node metastasis. The choice of the diagnostic tool .. Exclude extra-uterine disease/synchronous or metastatic
..
(US, CT, PET-CT, MRI) should be made individually according to .. • MRI or CT scan is recommended for detecting pelvic or para-
the patient’s characteristics and imaging accessibility (Xu et al., ..
.. aortic lymph nodes and distant metastases (Level of evidence
2019; Yang et al., 2019; Bi et al., 2020; Bus et al., 2021). .. II, Grade B).
Synchronous or metastatic ovarian cancer occurs in 5–29% of .. •
.. Adnexal involvement should be ruled out by pelvic MRI or
patients with endometrial carcinoma, and younger women .. transvaginal US (Level of evidence II, B).
<45 years of age are five times more likely to have synchronous
..
..
ovarian cancer than women aged >45 years (Obermair et al., ..
..
2020). However, in women with low-risk disease (no myometrial ..
invasion, Grade 1 endometrioid histology, normal looking ovaries) .. Treatment
..
no cases of ovarian cancer were detected (Knez et al., 2021). .. The cornerstone of the fertility-sparing treatment for endometrial car-
Adnexal involvement can be identified using pelvic MRI or transva- .. cinoma and its precursor endometrial hyperplasia has traditionally
..
ginal US (Guillon et al., 2019; Obermair et al., 2020). There are no .. been continuous progestin-based therapy. To date, there are no ran-
data about systematic use of sentinel lymph node biopsy in a .. domized controlled trials comparing the different types of medical
..
fertility-sparing setting. The probability of lymph node involvement .. treatment in women with endometrial hyperplasia or Grade 1 endo-
in low-risk endometrial carcinoma without myometrial invasion is
.. metrial endometrioid carcinoma.
Fertility-sparing treatment in endometrial carcinoma 9

A meta-analysis assessed the safety and efficacy of the available ..

..
medical treatment (Piatek et al., 2021). Medroxyprogesterone acetate ..
and megestrol acetate are the most used progestins. Both have been ..
..
administered orally every day, but dosage varied among studies, while ..
medroxyprogesterone acetate has also been given intra-muscularly ..
..
twice a week. Megestrol acetate has been shown to result in higher ..
remission rates than medroxyprogesterone acetate and other hor- ..
..
monal treatments, possibly due to its relatively higher bioavailability ..
following oral administration (Lucchini et al., 2021). Patients who re-
..
..
ceived an oral progestin as monotherapy are more likely to experience ..
disease recurrence and more systemic adverse effects. An alternative
..
..
way of progestin administration is the use of levonorgestrel-intra- ..
uterine device, but its efficacy has not been compared with oral proges-
..
..
tins (Floyd et al., 2021). This device in combination with oral progestins ..
or GnRH analogues has been shown to have a satisfactory remission
..
..
rate and low recurrence rate, with higher cumulative effectiveness com- ..
..
pared with the levonorgestrel-intra-uterine device alone (Fang et al., ..
2021; Gallo et al., 2021). Gonadotropin-releasing hormone analogues ..
..
show a satisfactory response rate when used alone, and in combination ..
with intra-uterine progestin therapy or oral aromatase inhibitors. In ..
..
obese patients, GnRH analogues in combination with levonorgestrel- ..
intra-uterine device or oral aromatase inhibitors seem to be preferable ..
..
(Emons and Grundker, 2021). ..
Tamoxifen has been evaluated in the treatment of advanced stage ..
..
and recurrent endometrial carcinoma, giving inconsistent results, so .. Figure 4. Schematic representation of hysteroscopic
this form of treatment has not been used in early-stage endometrial ..
.. resection of focal endometrial endometrioid carci-
carcinoma (Kim et al., 2018; van Weelden et al., 2019). Different med- .. noma following the ‘three steps’ technique.
ical treatment regimens have been described in the literature, including ..
..
the use of hydroxyprogesterone caproate, norethisterone acetate, nat- ..
ural progesterone, aromatase inhibitors (letrozole, anastrozole) and
..
..
combined oral contraceptives. There are no comparative studies to .. inserted when the histologic report confirmed early endometrial carci-
determine their efficacy (Peiretti et al., 2019; Zhou et al., 2021). Few .. noma G1 on the lesion, with the surrounding endometrium and the
..
studies have evaluated them and no studies assessing efficacy sepa- .. underlying myometrium free of disease. When endometrial hyperplasia
rately are available (Peiretti et al., 2019; Zhou et al., 2021).
.. is diagnosed, the surgical treatment consisted of superficial endometrial
..
Combined treatment with hysteroscopic resection followed by ei- .. resection, preserving the basal layer of the endometrium, followed by
ther oral/intra-uterine-released progestins or GnRH analogues appears
.. insertion of the levonorgestrel-intra-uterine device right after the pro-
..
to be an effective alternative to traditional fertility-sparing treatment in .. cedure (Giampaolino et al., 2019).
young women with endometrial endometrioid carcinoma and endome-
.. A systematic review suggests a higher effectiveness of a high-dose
..
trial hyperplasia (Falcone et al., 2017; Casadio et al., 2019; .. progestins protocol (Piatek et al., 2021). As monotherapy, the dose
Giampaolino et al., 2019; Gallo et al., 2021). It has been shown to
.. recommendations for megestrol acetate are 160–320 mg/day and for
..
provide certainty on tumour staging as well as myometrial involvement .. medroxyprogesterone acetate 400–600 mg/day (Concin et al.,
.. 2021a,b,c). Levonorgestrel at a dose of 52 mg is the only intra-uterine-
and to allow optimal cytoreduction, facilitating the subsequent thera- ..
peutic effect of progestins (Casadio et al., 2019). .. released progestin ever evaluated.
.. The exact duration of treatment has not been clearly defined.
Mazzon et al. (2005) first described the three-step hysteroscopic re- ..
section of focal endometrial endometrioid carcinoma, consisting of re- .. However, most studies have found a median time to regression of 4–
..
section of the tumour lesion (Step 1), the endometrium adjacent to .. 6 months. The presence of risk factors, such as obesity and insulin re-
the lesion (4–5 mm outside) (Step 2) and the myometrium underlying .. sistance, may require a longer treatment time (Floyd et al., 2021).
..
the lesion (3–4 mm) (Step 3); once the pathology report confirmed .. Therefore, 6–12 months is the recommended duration of therapy
Grade 1 (G1) endometrial carcinoma without myometrial invasion, .. within which a complete response should be achieved. If there is no
..
then medical therapy with megestrol acetate (160 mg daily) for .. response after 6–12 months, radical surgery is suggested (Gallo et al.,
6 months was administered (see Fig. 4). .. 2021). The cut-off point for the duration of treatment for obtaining a
..
Giampaolino et al. (2019) described a combined fertility-sparing .. complete response has been proposed to be 15 months, and after
treatment, but they made a distinction between early endometrial car- .. that time no response has been observed and/or oncological safety
..
cinoma and endometrial hyperplasia. Patients diagnosed with early en- .. cannot be assessed (Shim et al., 2021).
dometrial carcinoma underwent hysteroscopic resection following the
.. The aim of conservative treatment is to obtain a complete response,
..
three-steps technique by Mazzon et al. (2005), adding multiple random .. defined as a negative biopsy. The global response rates after conserva-
endometrial biopsies; a levonorgestrel-intra-uterine device was
.. tive medical treatment, with or without previous surgical hysteroscopic
10 Rodolakis et al.

..
excision, in early-stage, low-grade endometrial carcinoma are high, from .. stimulation in these patients. As with stimulation protocols in patients
75% to 79.4% (Guillon et al., 2019; Li et al., 2019; Peiretti et al., 2019; .. with breast cancer, the use of letrozole with gonadotropins has shown
..
Lucchini et al., 2021). The significant highest complete response rates .. further protection in endometrial carcinoma (Zapardiel et al., 2016).
are obtained with the combination of hysteroscopic resection followed ... There seems to be higher pregnancy rates and live birth rates after
by progestin treatment, either by oral or by intra-uterine device adminis- .. fertility-sparing treatments with oral progestins compared with the
..
tration, which varies from 90% to 95.3%. High-dose oral progestins .. levonorgestrel-intra-uterine device only. A meta-analysis and system-
showed a complete response rate of between 76.3% and 77.7%, and .. atic review including 28 studies and 1038 patients found a pregnancy
..
levonorgestrel-intra-uterine device with oral progestins between 71.3% .. rate in the group that received oral progestin of 34% and live birth
and 72.9% (Chen et al., 2016; Qin et al., 2016; Falcone et al., 2017; Fan .. rate of 20% (Wei et al., 2017). In the groups that received the
..
et al., 2018; Garzon et al., 2021; Lucchini et al., 2021). Partial response .. levonorgestrel-intra-uterine device only, or both levonorgestrel-intra-
rates vary from 4.7% to 7% and the no response rates from 17.2% to .. uterine device and progestin, the pregnancy rates were 18% and 40%,
..
20.9% (Piatek et al., 2021; Roh et al., 2021). .. respectively, and live birth rates 14% and 35%, respectively (Wei et al.,
Factors affecting response rates are not completely defined, but
.. 2017). Combined treatment, with hysteroscopic resection followed by
..
they include the molecular profile of the disease, the weight of the pa- .. hormonal therapy, was found to achieve higher live birth rates than
tient (improved response rates in patients with a BMI <25 kg/m2),
.. with oral progestogen alone (Zhang et al., 2017; Herrera Cappelletti
..
low serum marker HE4 and low histological grade, and polycystic ovar- .. et al., 2022). A meta-analysis including 54 studies found a live birth
ian morphology on US scan, among others; although there is a lack of
.. rate of 53% in the hysteroscopy group compared with 33% in the pro-
..
evidence on their clinical utility for them to be used routinely (Fukui .. gestin only group (P ¼ 0.09) (Zhang et al., 2017). Certain factors have
et al., 2017; Li et al., 2019; Baxter et al., 2020; Behrouzi et al., 2020;
.. been associated with a superior pregnancy outcome. In a retrospective
..
Chung et al., 2021). .. study of 68 women with early-stage endometrioid cancer or endome-
..
No randomized controlled trial is available to set a clear and strict in- .. trial hyperplasia, a multivariate analysis revealed that a normal BMI,
terval or assessment method for the follow-up of patients after fertility .. shorter time to complete remission, a prolonged 3-month treatment,
..
preservation in endometrial carcinoma. However, since intensive follow- .. fewer hysteroscopic procedures, and a thicker endometrium were all
up to assess the endometrial response is needed, most authors recom- .. associated with successful pregnancy (Fan et al., 2021).
..
mend endometrial sampling every 3–6 months either by dilation and cu- .. There is a lack of studies directly comparing ART with expectant man-
rettage or by hysteroscopic biopsy (Zapardiel et al., 2016; Falcone et al., .. agement in women with endometrial carcinoma and no history of infertil-
..
2017; Casadio et al., 2020; Cho et al., 2021; Novikova et al., 2021). The .. ity. Younger patients with no known infertility history may attempt a
most established and reasonable option for surveillance seems to be a .. natural pregnancy, as long as close monitoring is provided and within a de-
..
hysteroscopic endometrial biopsy at 3 and 6 months. Two consecutive .. fined time, encouraging broader use of ART without significant delay (Park
complete response endometrial biopsies with a minimal interval of .. et al., 2013; Novikova et al., 2021; Vaugon et al., 2021). In a prospective
..
3 months are necessary to consider the success of the fertility-sparing .. study of 232 women with early endometrial carcinoma or endometrial hy-
treatment and to recommend pregnancy (Giampaolino et al., 2019). .. perplasia, who attempted conception, 38% used ART. In contrast to pre-
..
Then, if complete response is achieved, a 3- to 6- month follow-up bi- .. vious data, pregnancy rates as well live birth rates were superior in the
opsy is required until pregnancy or until definitive surgery is performed
.. natural conception group than in the ART group (54.7% vs 40.7% and
..
(Gallo et al., 2021). Due to this frequent follow-up, patient agreement is .. 49% vs 34%, respectively; P ¼ 0.04). In that study, women using ART
essential for early detection of complete response or relapse after
.. were significantly older (P ¼ 0.03) (Novikova et al., 2021). Therefore,
..
fertility-sparing management (Obermair et al., 2020). .. patients would benefit from being referred to a fertility specialist for an
The correct method of performing a hysteroscopic endometrial bi-
.. early consultation (Kohn et al., 2021). Using ART shortens the time to
..
opsy has been described above, but it is to be noted that the .. conception and avoids prolonged, unopposed oestrogen stimulation,
levonorgestrel-intra-uterine device should not be removed to perform
.. which results in oncological safety and reduction of the risk of relapse and
..
biopsy (Clark et al., 2002) (Fig. 5). In addition, pelvic examination and .. disease progression. No data are reported for obstetrical and neonatal
..
US scan might be recommended during the follow-up visits (Cho .. outcomes in babies born to mothers with endometrial carcinoma.
et al., 2021; Novikova et al., 2021). If recurrent disease is diagnosed .. Patients who decline definitive surgery after delivery and those
..
during the follow-up, a second attempt at fertility preservation could .. who do not plan their second pregnancy immediately after the
obtain a complete response, even if the complete response rate is .. first should be recommended to restart maintenance therapy with a
..
slightly lower than for first treatment (Wang et al., 2019). .. levonorgestrel-intra-uterine device (Novikova et al., 2021).
Different systematic reviews have suggested the importance of .. Gunderson et al. (2012) analysed 45 studies, including 280 patients
..
applying ART to achieve pregnancy in women who have had fertility- .. with G1 endometrial carcinoma treated with progestins. They found a
sparing treatment for endometrial carcinoma or endometrial hyperpla- .. complete response rate of 48% with a median time to response of
..
sia, to minimize time prior to definitive surgery and thereby minimize .. 6 months; in addition, recurrence rate after complete response was
the risk of relapse (Zapardiel et al., 2016; Zhang et al., 2017; Fan .. 35% and, finally, persistent or progressive disease was found in 25% of
..
et al., 2021; Floyd et al., 2021). Previous studies have shown a higher .. enrolled subjects. Another meta-analysis including young women with
probability of recurrence when the time to achieve complete response .. early-stage endometrial carcinoma has shown that a complete re-
..
is longer (Koskas et al., 2014). The type of ovarian stimulation and the .. sponse to treatment occurs in about 80% of patients, and the plateau
ART protocol should be tailored based on the characteristics of each
.. of response occurs after 12 months of progestin treatment.
..
patient, in consultation with a multidisciplinary team, as there is no .. Recurrence occurred in 17% after 12 months and in 29% after
clear optimal duration, protocol or number of attempts for ovarian
.. 24 months after treatment (Koskas et al., 2014). Qin et al. (2016)
Fertility-sparing treatment in endometrial carcinoma 11

Figure 5. Hysteroscopic endometrial biopsy with the grasp technique, with a levonorgestrel-intra-uterine device
in situ (the device should not be removed to perform endometrial biopsy during follow-up. Be careful not to catch the strings
of the device in the branches of the grasping forceps, so as not to accidentally remove it).

reported more or less similar results with regression rate of 82.4%

.. unclear. There are no universally agreed guidelines for this manage-
..
(95% CI 75.3% to 88.7%) and a relapse rate of 25.0% (95% CI 15.8% .. ment. All reports are limited to small sample sizes. In the absence of
to 35.2%). Long-term oncological outcomes for hysteroscopic resec-
.. guidelines and unanimous consent, management is entrusted to rec-
..
tion have not been adequately studied, but relapse rates in studies of .. ommendations, retrospective studies and reviews.
..
women treated by combined therapy are reported to be lower than .. Definitive surgical treatment consists of total hysterectomy with or
those in most recent studies on progestin therapies alone (Falcone .. without bilateral salpingo-oophorectomy and surgical staging. It should
et al., 2017). Casadio et al. (2020) carried out the longest follow-up, ... be recommended after completion of childbearing due to a high recur-
..
with a median period of 36 months (range 24–60) and reported a re- .. rence rate, in cases of recurrence or no response at 6–12 months of
lapse rate of 8.7% in women with endometrial hyperplasia and of .. hormonal treatment, as well as in cases of disease progression either
..
11.11% in women with G1 endometrial carcinoma. .. in the uterus or elsewhere (Floyd et al., 2021; Gallo et al., 2021;
Complete response to progestins has been shown to be less fre- .. Concin et al., 2021a,b,c).
..
quent among obese than among non-obese patients (4/12 (33%) vs .. The aim of the definitive surgical treatment is to remove the uterus,
35/41 (85%); P ¼ 0.001), and in patients with a BMI 25 kg/m2
.. where the recurrence most commonly appears. Hence, the a priori re-
..
(P ¼ 0.0007, odds ratio (OR) ¼ 2.5; 95% CI 1.4 to 4.3) (Chen et al., .. moval of ovaries is not warranted (as staging of the disease after pri-
2016; Li et al., 2019). Furthermore, during the median follow-up of
.. mary conservative treatment is not indicated any more). Furthermore,
..
39 months, 22.3% of the women developed recurrence. One patient .. removal of ovaries has no therapeutic effect. A meta-analysis showed
..
(0.09%) died of the disease. Limited evidence indicates that metformin .. that there is no significant difference in overall survival if the ovaries
may improve the recurrence risk for patients with BMI 25 kg/m2 .. were or were not removed at the time of hysterectomy for early-
..
(Mitsuhashi et al., 2016, 2019). Although Novikova et al. (2021) .. stage endometrial carcinoma (Gu et al., 2017). Removal of the ovaries
reported that the levonorgestrel-intra-uterine device þ GnRH ana- .. should therefore be individualized according to the patient’s age, prob-
..
logues þ three dilation and curettage procedures was superior to .. ability of ovarian involvement, genetic/familiar high risk of primary
other treatments (complete response ¼ 96%, P ¼ 0.026) where two .. ovarian cancer or the presence of adnexal disease. In cases of ovarian
..
dilation and curettages were performed or oral medroxyprogesterone .. preservation, salpingectomy is recommended (Concin et al.,
acetate was prescribed, most other data failed to show a difference in
.. 2021a,b,c). The balance between the risks of ovarian cancer versus
..
efficacy and recurrence rate between oral progestins and the .. the consequences of surgical menopause should be considered, and
levonorgestrel-intra-uterine device (Lucchini et al., 2021; Novikova
.. oestrogen replacement after pre-menopausal bilateral salpingo-
..
et al., 2021). A meta-analysis showed that hysteroscopic resection fol- .. oophorectomy may be considered. In patients considered to be high
..
lowed by progestin therapy led to a complete response and a recur- .. risk for surgery or refuse definitive surgery, a second course of conser-
rence rate of 95.3% (95% CI 87.8% to 100%) and 14.1% (95% CI .. vative treatment (medical therapy or combined treatment) could be
..
7.1% to 26.1%), respectively (Fan et al., 2018). .. performed (Obermair et al., 2020).
Patients who partially respond to progestin treatment at 6 months .. As some women may still wish to maintain their reproductive poten-
..
may be advised to continue the treatment for an additional .. tial despite recurrence, repeating fertility-sparing treatment may be con-
3–6 months, and non-responders at the 6-month follow-up with per- .. sidered (Kalogera et al., 2014; Wang et al., 2019). There are limited
..
sistent disease confirmed by biopsy should be counselled about .. reports in the related literature on the efficacy of fertility-preserving
whether to undergo hysterectomy (Obermair et al., 2020). .. re-treatment in patients with relapse, and no consensus has been
..
The indications for post-pregnancy management, failure to conceive .. reached on the treatment of recurrence after fertility preservation. In a
and post-treatment conservative relapse in these patients are still
.. single-centre retrospective study, 51 patients were enrolled who had
12 Rodolakis et al.

.. • Weight control during fertility-sparing treatment is highly

persistent disease (residual carcinoma or endometrial hyperplasia on ..
endometrial biopsy) confirmed by dilation and curettage biopsy after .. recommended to increase the chance of response (Level of
..
9 months of progestin-based therapy (Cho et al., 2021). All patients .. evidence II, Grade A).
received the same dose and type of progestin as their initial therapy: ... Follow-up with maintenance treatment for patients willing or not
72.5% achieved complete response at a median time of 17.3 months; ..
.. willing to conceive immediately
among these patients, 32.4% experienced recurrence. If the disease is ..
progressive, a total hysterectomy with bilateral salpingo-oophorectomy .. • Two consecutive endometrial biopsies showing complete
..
and surgical staging is strongly recommended (Tock et al., 2018). .. response with a minimal interval of 3 months are necessary
.. to consider the success of the fertility-sparing treatment
..
.. (Level of evidence IV, Grade C).
Recommendations .. • The complete response is mandatory to consider follow-up
Selection of medication
..
.. with maintenance treatment until pregnancy is planned (Level
.. of evidence II, Grade A).
• A combined approach consisting of hysteroscopic tumour ..
.. • Clinical pelvic examination and US scan are recommended
resection, followed by oral progestins and/or levonorgestrel- .. at every 3-month follow-up visit (Level of evidence IV, Grade B).
intra-uterine device, is the most effective fertility-sparing ..
.. • Endometrial histological assessment should be performed
treatment both for complete response rate and live birth rate .. every 3–6 months by hysteroscopy according to the results of
compared with other treatment options (Level of evidence II, ..
Grade B).
.. imaging (Level of evidence IV, Grade B).
.. • MRI could be considered on a case-by-case basis (Level of
• Gonadotropin-releasing hormone analogues should not be ..
considered as a first-line treatment (Level of evidence II,
.. evidence IV, Grade C).
..
Grade B). .. Pregnancy
..
The role of hysteroscopic resection .. • Women undergoing fertility-sparing treatment for endometrial
..
.. hyperplasia or endometrial carcinoma should be encouraged
• If an early and focal myometrial invasion (1–2 mm) is ..
.. to actively aim to conceive as soon as the complete response
suspected from the resection material, a fertility-sparing .. is achieved (Level of evidence V, Grade B).
approach may be discussed on a case-by-case basis. In this .. • ART should be considered in order to improve success rate
circumstance, complete hysteroscopic lesion resection, ..
.. and reduce the interval to conception without a higher risk of
followed by oral progestins and/or levonorgestrel-intra- .. recurrence (Level of evidence III, Grade B). However, natural
uterine device, can be proposed as fertility-sparing treatment
..
.. conception may be considered in women with good
(Level of evidence IV, Grade C). .. reproductive potential within a defined time (6–9 months)
..
Dose of progestins .. (Level of evidence V, Grade C).
.. • Close surveillance by a multidisciplinary team should be continued
• Orally administered megestrol acetate at a dose of 160–320 mg/
..
.. and maintenance therapy with a levonorgestrel-intra-uterine
day or medroxyprogesterone acetate at a dose of 400–600 mg/ .. device should be recommended to women who decline surgery
..
day is recommended (Level of evidence III, Grade B). .. after delivery and who do not plan their second pregnancy
• A levonorgestrel-intra-uterine device at a dose of 52 mg, .. immediately after the first one (Level of evidence III, Grade B).
..
alone or in combination with oral progestins, is a safe and ..
.. Recurrence rate after fertility-sparing treatment
effective approach (Level of evidence III, Grade B). ..
.. • The risk of recurrence after fertility-sparing treatment for
Duration of treatment .. endometrial carcinoma may be equal for progestins or a
..
• The recommended duration of therapy is 6–12 months, .. levonorgestrel-intra-uterine device (Level of evidence II, Grade B).
..
within which a complete response should be achieved (Level ..
.. Definitive and completion surgeries
of evidence III, Grade B).
• The maximum time to achieve complete response should not .. • Definitive surgery is recommended in cases of non-
..
exceed 15 months (Level of evidence IV, Grade C). .. responders, inability to conceive, recurrence or disease
• In the absence of any kind of response at 6 months,
..
.. progression (Level of evidence II, Grade A).
multidisciplinary counselling is recommended for adapting the .. • For patients with a strong desire to preserve fertility, a
..
management on a case-by-case basis (Level of evidence IV, .. second conservative approach can be considered on a case-
Grade B). .. by-case basis (Level of evidence IV, Grade B).
.. • Completion surgery is recommended after completing
..
Response (partial vs complete vs no response) .. childbearing (Level of evidence II, Grade A).
.. • Removal of ovaries should be considered on a case-by-case
• Hysteroscopic resection followed by progestins either by oral ..
and/or intra-uterine device administration is recommended to
.. basis (Level of evidence III, Grade B).
..
achieve both the highest complete response rate and the ..
..
highest live birth rate (Level of evidence II, Grade B). ..
..
Fertility-sparing treatment in endometrial carcinoma 13

Special issues .. direct care (Stelloo et al., 2016; Kommoss et al., 2018; Britton et al.,
..
Despite the small number of studies available, with evidence not as .. 2019; Baxter et al., 2020; Dyer et al., 2021). It can be applied in endo-
.. metrial biopsy or curettage specimens, with high concordance with
robust, conservative treatment may be considered in women with ..
early-stage G2 endometrioid adenocarcinoma (stage IA G2 endome- .. hysterectomy material (Stelloo et al., 2016; Talhouk et al., 2017;
.. Kommoss et al., 2018; Britton et al., 2019; Dyer et al., 2021). ProMisE
trial carcinoma) or with well-differentiated G1 endometrioid adenocar- ..
cinoma with minimal myometrial invasion (1–2 mm) (Casadio et al., .. identifies the four Cancer Genome Atlas-based molecular subtypes for
.. endometrial carcinoma by using immunohistochemistry and sequencing
2020; Shan et al., 2021). Both these findings were exclusion criteria for ..
conservative treatment in the past. The combined treatment described
.. for the POLE exonuclease domain (Talhouk et al., 2015). The respec-
.. tive four subgroups are those with mismatch repair-deficient, POLE
above, consisting of endometrial hysteroscopic resection followed by ..
either oral/intra-uterine-released progestins or GnRH analogues,
.. mutations associated with highly favourable outcomes, and wild-type
..
appears feasible and safe in these women. .. or aberrant p53 expression (p53wt or p53abn, respectively), the latter
.. associated with aggressive disease. As for the small group of tumours
A positive oestrogen receptor and progesterone receptor status is ..
associated with a more favourable outcome in the majority of patients .. referred to as ‘multiple classifiers’, harbouring more than one molecu-
.. lar classifying feature, specifically those with a mismatch repair-deficient
with type I endometrial carcinoma (Kleine et al., 1990; Morice et al., ..
2016). However, their prognostic significance is not universally ac- .. p53abn or POLEmut-p53abn profile, there was supporting evidence to
.. categorise them as single classifier mismatch repair-deficient or
cepted and remains unclear (Jeon et al., 2006). Zhang et al. (2015) ..
conducted a systematic review and meta-analysis for the expression .. POLEmut, since outcomes correspond to those predicted by the
.. driver molecular subtype (Soslow et al., 2019; Baxter et al., 2020;
rate of oestrogen receptors and progesterone receptors in endome- ..
trial carcinoma which included 48 and 38 studies, respectively. They .. Leon-Castillo et al., 2020). Thereafter, all molecular tests should be
.. done in conjunction.
showed that oestrogen receptor and progesterone receptor positivity ..
was an independent favourable prognostic factor for survival. .. In the younger age group with low-grade, Stage IA endometrial car-
.. cinomas the greatest benefit of progesterone management is seen in
A meta-analysis of 13 studies, which included 635 patients, showed ..
that oestrogen receptor and progesterone receptor expressions are
.. women harbouring p53 wild-type tumours. Since the rare p53abn
.. tumours are more likely to progress, conservative therapy would
significantly predictive of response in endometrial hyperplasia and early ..
endometrial carcinoma to conservative treatment using the
.. probably be inappropriate, while for POLE-mutated carcinomas the
.. treatment choice in the conservative era is still unclear (Britton et al.,
levonorgestrel-intra-uterine device but not with oral progestins. ..
However, the authors concluded that their accuracy is insufficient to
.. 2019; Falcone et al., 2019; Beinse et al., 2020; Leon-Castillo et al.,
.. 2020). As for mismatch repair-deficient tumours, they seem to be usu-
be determined in clinical practice (Raffone et al., 2019). ..
.. ally of higher stage, less responsive to progesterone therapy and highly
Hormonal treatment with progestins can be the treatment of choice .. predictive of recurrence after initial regression (Zakhour et al., 2017;
for young women with endometrial hyperplasia or low-grade endome- ..
.. Chung et al., 2021; Puechl et al., 2021; Raffone et al., 2021).
trial carcinoma who wish to preserve fertility. Yet the complete re- .. Moreover, women with mismatch repair-deficient tumours should be
sponse and recurrence rates have been reported to range from 66.7% ..
.. tested for Lynch syndrome since they could be carriers of pathological
to 79.7% and 19% to 34%, respectively (Chung et al., 2021). .. mismatch repair-deficient gene variants (Ryan et al., 2017; 2020). If
Thereafter, incorporating tumour biology into management algorithms ..
.. Lynch syndrome is identified, appropriate counselling on the risk of de-
might help in developing more accurate risk stratification models to ..
guide treatment. There are insufficient data to support the routine use .. veloping additional cancers should be mandatory.
.. Unfortunately, the number of studies that have evaluated whether
of several immunohistochemical predictive markers in clinical practice. ..
The pre-treatment immunohistochemical evaluation of oestrogen re-
.. ProMisE classification could provide important information on treat-
.. ment choice for young women with low-grade, low-stage endometrial
ceptor and progesterone receptor was not found to be accurate in ..
predicting response to treatment, while their expression seems to be
.. carcinoma wishing to preserve fertility is limited. Available data
.. now do not show that in the context of low-risk disease the molecular
influenced by other parameters such as obesity (Busch et al., 2017; ..
Raffone et al., 2019; Travaglino et al., 2019). Research on other mole-
.. classification adds prognostic value. Large prospective studies are
.. needed to validate its clinical usefulness (Amant et al., 2021; Knez
cules reported to be involved in endometrial carcinogenesis, such as ..
.. et al., 2021).
PTEN, ARID1A, L1CAM and b-catenin may prove useful (Ayhan ..
et al., 2015; Karnezis et al., 2017; Hu et al., 2019). Specifically, muta- ..
..
tional analysis of CTNNB1 and TP53 might help to identify a subset of .. Recommendations
patients with low-grade, early-stage endometrial carcinoma who are at ..
.. Oestrogen and/or progesterone receptors status
higher risk of recurrence, while it was found that the immunohisto- ..
chemical expression of b-catenin was significantly increased in patients .. • Oestrogen and progesterone expressions seem to be
..
with endometrial carcinoma with progression compared with those .. predictive of response in conservative treatment and could be
without progression after fertility-preserving treatment (Kurnit et al., .. useful for patient counselling (Level of evidence III, Grade C).
..
2017; Hu et al., 2019). .. • Negative oestrogen and progesterone expressions are not a
The ProMisE molecular classifier has shown prognostic significance .. contraindication for fertility-sparing treatment (Level of
..
in endometrial carcinoma, thereby enabling early stratification of clinical .. evidence III, Grade C).
trials, referral for hereditary cancer testing, and risk assignment to
..
14 Rodolakis et al.

..
Molecular profiling of early-onset endometrial carcinoma and cor- ..
..
Funding
relation with response to treatment
.. All costs relating to the development process were covered from
• Performing the ProMisE molecular classifier in all young ..
patients with Grade 1, low-stage endometrial carcinoma who
... ESGO, ESHRE and ESGE funds. There was no external funding of the
.. development process or manuscript production.
wish to preserve fertility is encouraged, although available ..
data do not allow clinical applicability (Level of evidence IV, ..
.. Conflict of interest
Grade B). ..
• Immunohistochemistry for the identification of mismatch ..
.. G.S. has reported grants from MSD Italia S.r.l., advisory boards for
repair-deficient tumours is mandatory in order to identify .. Storz, Bayer, Astrazeneca, Metronic, TESARO Bio Italy S.r.l and
patients at high risk for Lynch syndrome (Level of evidence III, ..
.. Johnson & Johnson, and honoraria for lectures from Clovis Oncology
Grade A). .. Italy S.r.l. M.G. has reported advisory boards for Gedeon Richter and
• If a Lynch syndrome is identified, patients should have an ..
.. Merck. The other authors have reported no conflicts of interest.
appropriate counselling on the risk of developing additional ..
cancers (Level of evidence III, Grade A). ..
..
• In a tumour with p53abn phenotype, testing for MSH-H and .. References
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