Geburtshilfe Frauenheilkd 2023; 83(08): 919-962
DOI: 10.1055/a-2066-2051
GebFra Science
Guideline/Leitlinie

Endometrial Cancer. Guideline of the DGGG, DKG and DKH (S3-Level, AWMF Registry Number 032/034-OL, September 2022). Part 1 with Recommendations on the Epidemiology, Screening, Diagnosis and Hereditary Factors of Endometrial Cancer, Geriatric Assessment and Supply Structures

Article in several languages: English | deutsch
Günter Emons
1   Universitätsmedizin Göttingen, Klinik für Gynäkologie und Geburtshilfe, Göttingen, Germany
,
Eric Steiner
2   Frauenklinik GPR Klinikum Rüsselsheim am Main, Rüsselsheim, Germany
,
Dirk Vordermark
3   Universität Halle (Saale), Radiotherapie, Halle (Saale), Germany
,
Christoph Uleer
4   Facharzt für Frauenheilkunde und Geburtshilfe, Hildesheim, Germany
,
Kerstin Paradies
5   Konferenz onkologischer Kranken- und Kinderkrankenpfleger (KOK), Hamburg, Germany
,
Clemens Tempfer
6   Frauenklinik der Ruhr-Universität Bochum, Bochum/Herne, Germany
,
Stefan Aretz
7   Institut für Humangenetik, Universität Bonn, Zentrum für erbliche Tumorerkrankungen, Bonn, Germany
,
Wolfgang Cremer
8   Praxis für Frauenheilkunde Hamburg, Hamburg, Germany
,
Volker Hanf
9   Frauenklinik Nathanstift – Klinikum Fürth, Fürth, Germany
,
Peter Mallmann
10   Uniklinik Köln, Frauenheilkunde, Köln, Germany
,
Olaf Ortmann
11   Universität Regensburg, Fakultät für Medizin, Klinik für Frauenheilkunde und Geburtshilfe, Regensburg, Germany
,
Thomas Römer
12   Evangelisches Klinikum Köln Weyertal, Gynäkologie Köln, Köln, Germany
,
Rita K. Schmutzler
13   Universitätsklinikum Köln, Zentrum Familiärer Brust- und Eierstockkrebs, Köln, Germany
,
Lars-Christian Horn
14   Universitätsklinikum Leipzig, Institut für Pathologie, Leipzig, Germany
,
Stefan Kommoss
15   Universitätsklinikum Tübingen, Universitätsfrauenklinik Tübingen, Tübingen, Germany
,
Sigurd Lax
16   Institut für Pathologie, LKH Graz Süd-West, Graz, Austria
,
Elisa Schmoeckel
17   Pathologisches Institut der LMU München, München, Germany
,
Theresa Mokry
18   Universitätsklinikum Heidelberg, Diagnostische und Interventionelle Radiologie, Heidelberg, Germany
,
Dieter Grab
19   Universitätsklinikum Ulm, Frauenheilkunde und Geburtshilfe, Ulm, Germany
,
Michael Reinhardt
20   Klinik für Nuklearmedizin, Pius Hospital Oldenburg, Oldenburg, Germany
,
Verena Steinke-Lange
21   MGZ – Medizinisch Genetisches Zentrum München, München, Germany
22   Medizinische Klinik und Poliklinik IV, LMU München, München, Germany
,
Sara Y. Brucker
15   Universitätsklinikum Tübingen, Universitätsfrauenklinik Tübingen, Tübingen, Germany
,
Ludwig Kiesel
23   Universitätsklinikum Münster, Frauenklinik A Schweitzer Campus 1, Münster, Germany
,
Ralf Witteler
23   Universitätsklinikum Münster, Frauenklinik A Schweitzer Campus 1, Münster, Germany
,
Markus C. Fleisch
24   Helios, Universitätsklinikum Wuppertal, Landesfrauenklinik, Wuppertal, Germany
,
Heinrich Prömpeler †,
Michael Friedrich
26   Helios Klinikum Krefeld, Klinik für Frauenheilkunde und Geburtshilfe, Krefeld, Germany
,
Stefan Höcht
27   XCare, Praxis für Strahlentherapie Saarlouis, Saarlouis, Germany
,
Werner Lichtenegger
28   Universitätsmedizin Berlin, Frauenklinik Charité, Campus Virchow-Klinikum, Berlin, Germany
,
Michael Mueller
29   Universitätsklinik für Frauenheilkunde, Inselspital Bern, Bern, Switzerland
,
Ingo Runnebaum
30   Universitätsklinikum Jena, Frauenklinik, Jena, Germany
,
Petra Feyer
31   Vivantes Klinikum Neukölln, Klinik für Strahlentherapie und Radioonkologie, Berlin, Germany
,
Volker Hagen
32   Klinik für Innere Medizin II, St.-Johannes-Hospital Dortmund, Dortmund, Germany
,
Ingolf Juhasz-Böss
33   Universitätsklinikum Freiburg, Gynäkologie Freiburg, Freiburg, Germany
,
Anne Letsch
34   Universitätsklinikum Schleswig Holstein, Campus Kiel, Innere Medizin, Kiel, Germany
,
Peter Niehoff
35   Strahlenklinik, Sana Klinikum Offenbach, Offenbach, Germany
,
Alain Gustave Zeimet
36   Medizinische Universität Innsbruck, Universitätsklinik für Gynäkologie und Geburtshilfe, Innsbruck, Austria
,
Marco Johannes Battista
37   Universitätsmedizin Mainz, Poliklinik für Geburtshilfe und Frauengesundheit, Mainz, Germany
,
Edgar Petru
38   Med. Univ. Graz, Frauenheilkunde, Graz, Austria
,
Simone Widhalm
39   Semi-Colon, Mönchengladbach, Germany
,
Birgitt van Oorschot
40   Universitätsklinikum Würzburg, Interdisziplinäres Zentrum Palliativmedizin, Würzburg, Germany
,
Joan Elisabeth Panke
41   Medizinischer Dienst des Spitzenverbandes Bund der Krankenkassen e. V. Essen, Essen, Germany
,
Joachim Weis
42   Albert-Ludwigs-Universität Freiburg, Medizinische Fakultät, Tumorzentrum Freiburg – CCCF, Freiburg, Germany
,
Timm Dauelsberg
43   Universitätsklinikum Freiburg, Klinik für Onkologische Rehabilitation, Freiburg, Germany
,
Heidemarie Haase
44   Frauenselbsthilfe, Bonn, Germany
,
Matthias W. Beckmann
45   Universitätsklinikum Erlangen, Frauenklinik, Erlangen, Germany
,
Sebastian Jud
46   Mutterhaus der Borromäerinnen, Trier, Germany
,
Edward Wight
47   Frauenklinik des Universitätsspitals Basel, Basel, Switzerland
,
Franz-Josef Prott
48   Facharzt für Radiologie und Strahlentherapie, Wiesbaden, Wiesbaden, Germany
,
Oliver Micke
49   Franziskus Hospital Bielefeld, Klinik für Strahlentherapie und Radioonkologie, Bielefeld, Germany
,
Werner Bader
50   Klinikum Bielefeld Mitte, Zentrum für Frauenheilkunde, Bielefeld, Germany
,
Nicola Reents
39   Semi-Colon, Mönchengladbach, Germany
,
Ulla Henscher
51   Physio-Akademie, Hannover, Germany
,
Reina Tholen †,
Miriam Schallenberg
44   Frauenselbsthilfe, Bonn, Germany
,
Nils Rahner
53   Amedes Group Bonn, Bonn, Germany
,
Doris Mayr
54   LMU München, Pathologisches Institut, München, Germany
,
Michael Kreißl
55   Universität Magdeburg, Medizinische Fakultät, Universitätsklinik für Radiologie und Nuklearmedizin, Germany
,
Katja Lindel
56   Städtisches Klinikum Karlsruhe, Karlsruhe, Germany
,
Alexander Mustea
57   Universitätsklinikum Bonn, Zentrum Gynäkologie und gynäkologische Onkologie, Bonn, Germany
,
Vratislav Strnad
58   Universitätsklinikum Erlangen, Brustzentrum Franken, Erlangen, Germany
,
Ute Goerling
59   Universitätsmedizin Berlin, Campus Charité Mitte, Charité Comprehensive Cancer Center, Berlin, Germany
,
Gerd J. Bauerschmitz
1   Universitätsmedizin Göttingen, Klinik für Gynäkologie und Geburtshilfe, Göttingen, Germany
,
Jan Langrehr
60   Martin-Luther-Krankenhaus, Klinik für Allgemein-, Gefäß- und Viszeralchirurgie, Berlin, Germany
,
Joseph Neulen
61   Uniklinik RWTH Aachen, Klinik für Gynäkologische Endokrinologie und Reproduktionsmedizin, Aachen, Germany
,
Uwe Andreas Ulrich
62   Martin-Luther-Krankenhaus, Johannesstift Diakonie, Gynäkologie, Berlin, Germany
,
Monika J. Nothacker
63   AWMF, AWMF-IMWi, Berlin, Germany
,
Susanne Blödt
63   AWMF, AWMF-IMWi, Berlin, Germany
,
Markus Follmann
64   Deutsche Krebsgesellschaft, Office des Leitlinienprogramms Onkologie, Berlin, Germany
,
Thomas Langer
64   Deutsche Krebsgesellschaft, Office des Leitlinienprogramms Onkologie, Berlin, Germany
,
Gregor Wenzel
64   Deutsche Krebsgesellschaft, Office des Leitlinienprogramms Onkologie, Berlin, Germany
,
Sylvia Weber
1   Universitätsmedizin Göttingen, Klinik für Gynäkologie und Geburtshilfe, Göttingen, Germany
,
Saskia Erdogan
1   Universitätsmedizin Göttingen, Klinik für Gynäkologie und Geburtshilfe, Göttingen, Germany
› Author Affiliations
 

Abstract

Summary The S3-guideline on endometrial cancer, first published in April 2018, was reviewed in its entirety between April 2020 and January 2022 and updated. The review was carried out at the request of German Cancer Aid as part of the Oncology Guidelines Program and the lead coordinators were the German Society for Gynecology and Obstetrics (DGGG), the Gynecology Oncology Working Group (AGO) of the German Cancer Society (DKG) and the German Cancer Aid (DKH). The guideline update was based on a systematic search and assessment of the literature published between 2016 and 2020. All statements, recommendations and background texts were reviewed and either confirmed or amended. New statements and recommendations were included where necessary.

Aim The use of evidence-based risk-adapted therapies to treat women with endometrial cancer of low risk prevents unnecessarily radical surgery and avoids non-beneficial adjuvant radiation therapy and/or chemotherapy. For women with endometrial cancer and a high risk of recurrence, the guideline defines the optimum level of radical surgery and indicates whether chemotherapy and/or adjuvant radiation therapy is necessary. This should improve the survival rates and quality of life of these patients. The S3-guideline on endometrial cancer and the quality indicators based on the guideline aim to provide the basis for the work of certified gynecological cancer centers.

Methods The guideline was first compiled in 2018 in accordance with the requirements for S3-level guidelines and was updated in 2022. The update included an adaptation of the source guidelines identified using the German Instrument for Methodological Guideline Appraisal (DELBI). The update also used evidence reviews which were created based on selected literature obtained from systematic searches in selected literature databases using the PICO process. The Clinical Guidelines Service Group was tasked with carrying out a systematic search and assessment of the literature. Their results were used by interdisciplinary working groups as a basis for developing suggestions for recommendations and statements which were then modified during structured online consensus conferences and/or additionally amended online using the DELPHI process to achieve a consensus.

Recommendations Part 1 of this short version of the guideline provides recommendations on epidemiology, screening, diagnosis, and hereditary factors. The epidemiology of endometrial cancer and the risk factors for developing endometrial cancer are presented. The options for screening and the methods used to diagnose endometrial cancer are outlined. Recommendations are given for the prevention, diagnosis, and therapy of hereditary forms of endometrial cancer. The use of geriatric assessment is considered and existing structures of care are presented.


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I  Guideline Information

Guidelines program of the DGGG, OEGGG and SGGG

For information on the guidelines program, please refer to the end of the guideline.


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Citation format

Endometrial Cancer. Guideline of the DGGG, DKG and DKH (S3-Level, AWMF Registry Number 032/034-OL, September 2022). Part 1 with Recommendations on the Epidemiology, Screening, Diagnosis and Hereditary Factors of Endometrial Cancer, Geriatric Assessment and Supply Structures. Geburtsh Frauenheilk 2023; 83: 919–962


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Guideline documents

The complete German-language long version of this guideline together with a list of the conflicts of interest of all the authors are available on the homepage of the AWMF: https://register.awmf.org/de/leitlinien/detail/032-034OL


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Guideline authors

See [Tables 1] and [2].

Tab. 1 Lead and/or coordinating guideline authors.

Coordinator:

Prof. Dr. Günter Emons; Göttingen

Co-coordinator:

Prof. Dr. Eric Steiner; Rüsselsheim

Editorial team:

Saskia Erdogan, M. A.; Göttingen

Sylvia Weber; Göttingen

Tab. 2 Contributing guideline authors.

Contributing professional societies and organizations (in alphabetical order)

Persons

* These persons contributed significantly to the compilation of the guideline. They did not participate in voting on recommendations and statements.

1 † 04.02.2021; 2 † 04.06.2022

Gynecological Endoscopy Working Group of the DGGG [AG Endoskopische Gynäkologie der DGGG]

Prof. Dr. Ingo Runnebaum

Prof. Dr. Uwe Ulrich

AGO Study Group

Prof. Dr. Stefan Kommoss

Association of German Tumor Centers [Arbeitsgemeinschaft Deutscher Tumorzentren e. V.] (ADT)

Prof. Dr. Olaf Ortmann

Gynecological Oncology Working Group of the DGGG and DKG [Arbeitsgemeinschaft Gynäkologische Onkologie der DGGG und DKG] (AGO)

Prof. Dr. Peter Mallmann

Prof. Dr. Ingolf Juhasz-Böss

Working Group of the DKG: Conference of Oncological Nursing and Pediatric Nursing [Arbeitsgemeinschaft Konferenz Onkologische Kranken- und Kinderkrankenpflege in der DKG] (KOK)

Kerstin Paradies

Palliative Medicine Working Group of the German Cancer Society [Arbeitsgemeinschaft Palliativmedizin der Deutschen Krebsgesellschaft e. V.] (APM)

Prof. Dr. Birgitt van Oorschot

Dr. Joan E. Panke

Prevention and Integrative Oncology Working Group of the DKG [Arbeitsgemeinschaft Prävention und integrative Medizin in der Onkologie der Deutschen Krebsgesellschaft] (PRiO)

Prof. Dr. Volker Hanf

Prof. Dr. Oliver Micke

Radiological Oncology Working Group [Arbeitsgemeinschaft Radiologische Onkologie] (ARO)

Prof. Dr. Stefan Höcht

Prof. Dr. Vratislav Strnad

Working Group for Supportive Measures in Oncology [Arbeitsgemeinschaft Supportive Maßnahmen in der Onkologie] (AGSMO)

Prof. Dr. Petra Feyer

DKG Working Group for Hereditary Tumor Disease [Arbeitsgemeinschaft erbliche Tumorerkrankungen in der DKG] (AET)

Prof. Dr. Stefan Aretz

Prof. Dr. Rita Schmutzler

German Psycho-oncology Working Group [Arbeitsgemeinschaft für Psychoonkologie in der DKG] (PSO)

Prof. Dr. Joachim Weis

PD Dr. Ute Goerling

Working Group for Oncological Rehabilitation and Social Medicine [Arbeitsgemeinschaft für onkologische Rehabilitation und Sozialmedizin] (AGORS)

Dr. Timm Dauelsberg

Medical Oncology Working Group of the DKG [Arbeitsgemeinschaft internistische Onkologie der Deutschen Krebsgesellschaft e. V.] (AIO)

Dr. Volker Hagen

Prof. Dr. Anne Letsch

Federal Association of German Radiotherapists [Berufsverband der Deutschen Strahlentherapeuten e. V.] (BVDST)

Prof. Dr. Peter Niehoff

Prof. Dr. Franz-Josef Prott

Professional Association of Gynecologists [Berufsverband der Frauenärzte] (BVF)

Dr. Wolfgang Cremer

Professional Association of Gynecological Oncologists in Private Practice in Germany [Berufsverband niedergelassener Gynäkologischer Onkologen in Deutschland] (BNGO)

Dr. Christoph Uleer

Contributing experts (without a vote)

PD Dr. Marco J. Battista

PD Dr. Dr. Gerd J. Bauerschmitz

Prof. Dr. Markus Fleisch

Prof. Dr. Sigurd Lax

Prof. Dr. Clemens Tempfer

Contributing experts (without a vote)

Dr. Barbara Zimmer*

Ilkas Luckas*

Federal Association of Senior Physicians in Gynecology and Obstetrics [Bundesarbeitsgemeinschaft Leitender Ärztinnen und Ärzte in der Frauenheilkunde und Geburtshilfe] (BLFG)

Prof. Dr. Michael Friedrich

Professional Association of German Pathologists [Bundesverband Deutscher Pathologen e. V.] (BDP)

Prof. Dr. Lars-Christian Horn

Prof. Dr. Doris Mayr

German Society for General and Visceral Surgery [Deutsche Gesellschaft für Allgemein- u. Viszeralchirurgie] (DGAV)

Prof. Dr. Jan Langrehr

German Society of Endocrinology [Deutsche Gesellschaft für Endokrinologie e. V.] (DGE)

Prof. Dr. Matthias W. Beckmann

PD Dr. Sebastian Jud

German Society of Gynecology and Obstetrics [Deutsche Gesellschaft für Gynäkologie und Geburtshilfe e. V.] (DGGG)

Prof. Dr. Sara Y. Brucker

German Society for Gynecological Endocrinology and Fertility [Deutsche Gesellschaft für Gynäkologische Endokrinologie und Fertilität]

Prof. Dr. Ludwig Kiesel

Dr. Ralf Witteler

German Society of Human Genetics [Deutsche Gesellschaft für Humangenetik] (GfH)

Dr. Verena Steinke-Lange

Dr. Nils Rahner

German Society of Hematology and Medical Oncology [Deutsche Gesellschaft für Hämatologie und Medizinische Onkologie e. V.] (DGHO)

Prof. Dr. Anne Letsch

Dr. Volker Hagen

German Society of Nuclear Medicine [Deutsche Gesellschaft für Nuklearmedizin e. V.] (DGN)

Prof. Dr. Michael J. Reinhardt

Prof. Dr. Michael Kreißl

German Society for Palliative Medicine [Deutsche Gesellschaft für Palliativmedizin e. V.] (DGP)

Prof. Dr. Anne Letsch

German Society of Pathology [Deutsche Gesellschaft für Pathologie e. V.] (DGP)

Prof. Dr. Lars-Christian Horn

Prof. Dr. Doris Mayr

German Society for Radiation Oncology [Deutsche Gesellschaft für Radioonkologie e. V.] (DEGRO)

Prof. Dr. Dirk Vordermark

Prof. Dr. Katja Lindel

German Society for Ultrasound in Medicine [Deutsche Gesellschaft für Ultraschall in der Medizin e. V.] (DEGUM)

Prof. Dr. Dieter Grab

Prof. Dr. Werner Bader

German Society for Ultrasound in Medicine [Deutsche Gesellschaft für Ultraschall in der Medizin e. V.] (DEGUM)

Prof. Dr. Heinrich Prömpeler1

German Menopause Society [Deutsche Menopause Gesellschaft] (DMG)

Prof. Dr. Thomas Römer

Prof. Dr. Joseph Neulen

German Roentgen Society [Deutsche Röntgengesellschaft e. V.]

Dr. Theresa Mokry

Self-help Group for Women after Cancer [Frauenselbsthilfe Krebs e. V.] (FSH)

Heidemarie Haase

Miriam Schallenberg

Northeast German Society of Gynecological Oncology [Nord-Ostdeutsche Gesellschaft für Gynäkologische Onkologie] (NOGGO)

Prof. Dr. Werner Lichtenegger

Prof. Dr. Alexander Mustea

Swiss Society of Gynecology and Obstetrics [Schweizerische Gesellschaft für Gynäkologie und Geburtshilfe] (SGGG)

Prof. Dr. Michael D. Mueller

PD Dr. Edward Wight

Semi-Colon, Family Support for Persons with Bowel Cancer [Semi-Colon, Familienhilfe Darmkrebs e. V.]

Simone Widhalm

Nicola Reents

Central Association of Physiotherapists [Zentralverband der Physiotherapeuten/Krankengymnasten] (ZVK)

Ulla Henscher

Reina Tholen2

Austrian Society of Gynecology and Obstetrics [Österreichische Gesellschaft für Gynäkologie und Geburtshilfe] (OEGGG)

Prof. Dr. Alain-Gustave Zeimet

Prof. Dr. Edgar Petru

The guideline was moderated by Dr. Susanne Blödt, Dr. Monika Nothacker, Dr. Markus Follmann and Thomas Langer, (AWMF-certified guidelines advisors/moderators).


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Abbreviations

EC: expert consensus
ST: statement


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#

II  Guideline Application

Purpose and objectives

The most important reason to compile this interdisciplinary guideline is the unchangingly high epidemiological importance of endometrial cancer and the associated burden of disease.

New data on pathological/molecular classifications and adjuvant and palliative treatments have been published in recent years, which made it necessary to update the guideline. The use of evidence-based risk-adapted therapies to treat women with low-risk endometrial cancer prevents unnecessarily radical surgery and avoids non-beneficial adjuvant radiation therapy and/or chemotherapy. This reduces treatment-induced morbidity, improves patientsʼ quality of life and avoids unnecessary costs. For women with endometrial cancer and a high risk of recurrence, the guideline defines the optimum level of radical surgery and indicates whether chemotherapy and/or adjuvant radiation therapy is necessary. An evidence-based optimum use of different treatment modalities should improve the survival rates and quality of life of these patients.


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Targeted areas of patient care

This guideline covers both outpatient and inpatient care.


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Target user groups/Target audience

The recommendations in this guideline are aimed at all physicians and members of professions involved in the care of patients with endometrial cancer. They primarily include gynecologists, general practitioners, radiologists, pathologists, radio-oncologists, hematologists and medical oncologists, psycho-oncologists, specialists for palliative medicine nursing staff.

Other groups targeted by the guideline are:

  • scientific medical societies and professional organizations;

  • advocacy groups for women (womenʼs health organizations, patient and self-help organizations);

  • quality assurance institutions and projects at federal and Länder levels (e.g., the Association of German Tumor Centers, etc.);

  • health policy institutions and decision-makers at federal and Länder levels;

  • funding agencies.


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Adoption and period of validity

The validity of this guideline was confirmed by the executive boards/heads of the participating professional societies/working groups/organizations/associations as well as by the boards of the DGGG, SGGG, OEGGG and the DGGG/OEGGG/SGGG guidelines commission in September 2022 and was thus approved in its entirety. This guideline is valid for 5 years – from September 2022 through to September 2027. Because of the contents of this guideline, this period of validity is only an estimate. The guideline can be reviewed and updated at an earlier point in time if urgently required. Likewise, the guidelineʼs period of validity can be extended if the guideline still reflects the current state of knowledge.


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#

III  Methodology

Basic principles

The method used to prepare this guideline was determined by the class to which this guideline was assigned. The AWMF Guidance Manual (version 1.0) has set out the respective rules and requirements for different classes of guidelines. Guidelines are differentiated into lowest (S1), intermediate (S2), and highest (S3) class. The lowest class is defined as consisting of a set of recommendations for action compiled by a non-representative group of experts. In 2004, the S2 class was divided into two subclasses: a systematic evidence-based subclass (S2e) and a structural consensus-based subclass (S2k). The highest S3 class combines both approaches.

This guideline was classified as: S3.


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Assessment of evidence using the Oxford CEBM system

To evaluate evidence (levels 1 – 5), this guideline used the most recent 2011 version of the Oxford Centre for Evidence-based Medicine levels of evidence ([Table 3]).

Tab. 3 Levels of Evidence according to Oxford Centre for Evidence-Based Medicine 2011.

Question

Level 1*

Level 2*

Level 3*

Level 4*

Level 5

*  Level may be downgraded because of study quality, extended confidence intervals (imprecise effect estimates), inconsistencies between studies, or because the absolute effect value is very small, as well as lack of transferability (study question does not correspond to the clinically relevant question). An upgrade of the evidence level is possible in case of large or very large effects.

**  As a general rule, a systematic review is always better than a single study.

***  Consecutive inclusion = patients are continuously recruited.

1  The STROBE statement, among others, can be used for quality assessment: http://www.strobe-statement.org/index.php?id=strobe-aims.

2  Single-patient studies in which patients receive alternating intervention and control intervention.

3  Follow-up study of a population from a completed RCT.

4  Study in which cases and controls are drawn from an ongoing cohort study.

How widespread is the problem?

Local and current random sample or census (complete survey)

Systematic review of surveys that can be applied to local circumstances**

Local survey that is not based on a random sample**

Case series**

Not applicable

Is this diagnostic or controlling test accurate? (Diagnostic)

Systematic review of cross-sectional studies with reference standard applied throughout and blinding

Single cross-sectional study with reference standard applied throughout and blinding

Non-consecutive*** study or study without applied reference standard**

Case-control study or study with inappropriate or non-independent reference standard**

Expert opinion based on pathophysiological considerations

What would happen if we did not apply therapy? (prognosis)

Expert opinion based on pathophysiological considerations

Single cohort study of patients in the early stages of the disease (inception cohort study)

Cohort study or control arm of a randomized trial*

Case series or case-control study or a prognostic cohort study with low methodological quality1**

Not applicable

Does this approach help? (use of the intervention)

Systematic review of randomized trials or N-of-1 studies2

Randomized trial or observational study with dramatic effects

Controlled cohort study/follow-up study3**

Case series or case-control studies or studies with historical controls**

Expert opinion based on pathophysiological considerations

What are common side effects? (harm of intervention)

Systematic review of either randomized trials or embedded case-control studies4. Or N-of-1 study with patients matching the research question or observational study with dramatic effects

Randomized trial or (exceptionally) observational study with dramatic effects

Controlled cohort study/follow-up (post-marketing surveillance) study, with sufficient number of cases to identify a common side effect. If long-term side effects are to be recorded, the follow-up must be sufficient**.

What are rare side effects? (harm of the intervention)

Systematic review of randomized trials or N-of-1 studies

Randomized trial or (exceptionally) observational study with dramatic effects

Is this screening test useful? (screening)

Systematic review of randomized studies

Randomized trial


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Grading of recommendations

The grading of evidence in an S3-guideline using a level-of-evidence system allows the strength of the recommendations made in the guideline to be graded. The degree of recommendation is differentiated into three levels and the different strengths of recommendation are indicated by the respective choice of words. This commonly used grading of recommendations is not just used by the AWMF but also by the German Medical Association in its National Guidelines on Care (Nationale Versorgungsleitlinien, NVL). The wording chosen to indicate the strength of the recommendations should be explained in the background text.

In this context, the terms “grade,” “level” or “strength” indicate the degree of certainty about issuing the recommendation after weighing up the benefits and the harms; they are not an indication of whether the recommendation itself is binding. Guidelines are recommendatory in nature, i.e., they cannot be binding. Individual statements and recommendations are differentiated by symbols and syntax ([Table 4]).

Tab. 4 Grading of recommendations.

Recommendation grade

Description

Expression

A

Strong recommendation

shall

B

Recommendation

should

0

Recommendation open

can

The above-described classification of “recommendations” reflects both the assessment of the evidence and the clinical relevance of the studies on which the evidence is based as well as factors which were not included in the grading of evidence, such as the choice of patient cohort, intention-to-treat and outcome analyses, medical actions and ethical behavior towards the patient, country-specific applicability, etc. In contrast, high, moderate, or low levels of evidence may result in a strong, simple, or open recommendation. A recommendation can only be upgraded or downgraded to a grade A or a grade 0 recommendation if the level of evidence is moderate. In exceptional cases, the highest level of evidence is only accorded a limited/open recommendation or vice versa, and this must be explained in the background text. The downgrading of a high level of evidence to a weaker/open recommendation in exceptional cases or the reverse must be justified in the background text.

  • Strong level of evidence → grade A or grade B recommendation

  • Moderate level of evidence → grade A or grade B or grade 0 recommendation

  • Weak level of evidence → grade B or grade 0 recommendation


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Statements

Expositions or explanations of facts, circumstances, or problems with no direct recommendations for action in this guideline are referred to as “statements.” It is not possible to provide any information about the grading of evidence for these statements.


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Achieving consensus and strength of consensus

At structured NIH-type consensus-based conferences (S2k/S3 level), authorized participants attending the session vote on draft statements and recommendations. The process is as follows. A recommendation is presented, its contents are discussed, proposed changes are put forward, and all proposed changes are voted on. If a consensus (> 75% of votes) is not achieved, there is another round of discussions, followed by a repeat vote. Finally, the extent of consensus is determined, based on the number of participants ([Table 5]).

Tab. 5 Level of consensus based on extent of agreement.

Level of consensus

Extent of agreement in percent

Strong consensus

> 95% of voters agree

Consensus

> 75 – 95% of voters agree

Majority consensus

> 50 – 75% of voters agree

Dissent

< 50% of voters agree


#

Expert consensus

As the term already implies, this refers to consensus decisions taken specifically with regards to recommendations/statements issued without a prior systematic search of the literature (S2k) or where evidence is lacking (S2e/S3). The term “expert consensus” (EC) used here is synonymous with terms used in other guidelines such as “good clinical practice” (GCP) or “clinical consensus point” (CCP). The strength of the recommendation is graded as previously described in the chapter Grading of recommendations but without the use of symbols; it is only expressed semantically (shall/should/can).


#
#

IV  Guideline

1  Epidemiology and risk factors, prevention of endometrial cancer

1.1  Epidemiology and risk factors

No.

Recommendations/Statements

GoR

LoE

Sources

3.1

The risk of endometrial cancer increases with age.

ST

1

[1]

3.2

Hormone replacement therapy with estrogens alone without progestin protection is a risk factor for the occurrence of endometrial cancer in non-hysterectomized women. The effect depends on the duration of use.

ST

2

[2], [3], [4], [5], [6], [7], [8], [9]

3.3

Continuous combined hormone replacement therapy with estrogens and synthetic progestogens has no or a protective effect on endometrial cancer risk.

ST

2

[10]

3.4

Using progesterone or dydrogesterone as part of combined hormone replacement therapy, an increase in the risk of developing endometrial cancer has been observed when used for more than 5 years.

ST

4

[11], [12]

3.5

Sequential combined hormone replacement therapy may increase the risk of developing endometrial cancer. The effect depends on the duration, type, and dose of progestin use.

ST

3

[3], [4], [6], [7], [9], [13], [14]

3.6

No increase in endometrial cancer risk has been observed with the use of sequential combined hormone replacement therapy with a duration of use < 5 years and use of a synthetic progestin for at least 10 days per month.

ST

3

[4], [6], [7], [14]

3.7

Tamoxifen therapy is a risk factor for the occurrence of endometrial carcinoma. The effect depends on the duration of use.

ST

1

[15], [16], [17], [18], [19]

3.8

Oral contraceptives reduce the risk of developing endometrial cancer. The strength of the effect depends on the duration of use.

ST

3

[20], [21], [22]

3.9

Ovarian stimulation therapy increases endometrial cancer risk compared with population-based controls but not compared with infertile women.

ST

3

[23], [24], [25]

3.10

An increased risk of developing endometrial cancer has been observed with tibolone.

ST

3

[4], [6], [14], [26]

3.11

Late menarche age and late age at birth of last child are associated with reduced risk, and late menopausal age is associated with increased risk of endometrial cancer.

ST

3

[27], [28], [29]

3.12

Diabetes mellitus, impaired glucose tolerance, metabolic syndrome, and polycystic ovary syndrome (PCOS) increase the risk of endometrial cancer.

ST

3

[30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44]

3.13

An elevated body mass index (BMI) increases the risk of developing endometrial cancer.

ST

3

[45], [46], [47], [48], [49], [50]

3.14

Hereditary predisposition in the context of Lynch syndrome or Cowden syndrome increases the risk of endometrial cancer.

ST

3

[51], [52]


#

1.2  Risk-reducing factors

No.

Recommendations/Statements

GoR

LoE

Sources

3.15

Physical activity is associated with a reduced risk of endometrial cancer.

ST

3

[54], [55], [56], [57], [58], [59], [60]

3.16

The use of intrauterine devices (copper IUD or levonorgestrel IUD used therapeutically) is associated with a reduced risk of endometrial cancer.

ST

3

[61], [62]


#

1.3  Summary of risk-increasing and risk-reducing factors

See [Table 6].

Tab. 6 Risk of occurrence of endometrial carcinoma …

is increased …

is decreased …

  • with increasing age.

  • by therapy with tamoxifen depending on the duration of therapy.

  • by hormone therapy with estrogens alone without progestin protection in non-hysterectomized women depending on the duration of use.

  • by long-term use (> 6 or > 10 years) of continuous-combined hormone therapy.

  • by sequential combined hormone therapy depending on the duration, type and dose of progestogen use.

  • when progesterone or dydrogesterone is used as part of continuous combined and sequential hormone therapy.

  • with use of tibolone.

  • with late menopause.

  • in diabetes mellitus, impaired glucose tolerance, metabolic syndrome and polycystic ovarian syndrome.

  • with increased body mass index.

  • with increased waist-hip ratio.

  • in the presence of a hereditary disposition (especially Lynch – or Cowden syndrome).

  • in the case of a positive family history of endometrial and/or colon carcinoma.

  • by continuous combined hormone therapy with conjugated equine estrogens and medroxyprogesterone acetate as progestogen.

  • when taking oral contraceptives depending on the duration of intake.

  • with late menarche age.

  • with late age at birth of the last child.

  • with physical activity.

  • with IUD use, especially levonorgestrel-IUD.

  • in smokers.

  • with increasing parity.


#
#

2  Screening and diagnosis of endometrial cancer

2.1  Screening/diagnosis in asymptomatic women

No.

Recommendations/Statements

GoR

LoE

Sources

4.1

The available data do not show that screening of asymptomatic women at no increased risk for endometrial cancer with transvaginal ultrasound reduces endometrial cancer-specific mortality.

EC

4.2

Transvaginal ultrasonography in asymptomatic women without increased risk of endometrial cancer for the purpose of early detection of endometrial cancer shall not be performed.

EC

4.3

Available data do not show that screening of asymptomatic women at increased risk for endometrial cancer (such as Lynch syndrome, obesity, diabetes mellitus, hormone replacement therapy, metabolic syndrome, PCO syndrome) with transvaginal ultrasound reduces endometrial cancer-specific mortality.

EC

4.4

Available data do not show that screening with endometrial biopsy, Pipelle, Tao Brush, tumor marker, fractional curretage or hysteroscopy of asymptomatic women at increased risk for endometrial cancer (such as Lynch syndrome, obesity, diabetes mellitus, hormone replacement therapy, metabolic syndrome, PCO syndrome) reduces endometrial cancer-specific mortality.

ST

4

[63], [64], [65]

4.5

Transvaginal ultrasonography in asymptomatic women at increased risk for endometrial cancer (such as Lynch syndrome, obesity, diabetes mellitus, hormone replacement therapy, metabolic syndrome, PCO syndrome) for the purpose of early detection of endometrial cancer shall not be performed.

EC

4.6

In asymptomatic patients on tamoxifen therapy, transvaginal ultrasound examination for early detection of endometrial carcinoma shall not be performed. This also applies to prolonged therapy over 10 years.

A

3

[15], [66], [67], [68], [69], [70], [71]


#

2.2  Work-up for abnormal premenopausal uterine bleeding ([Fig. 1])

Zoom Image
Fig. 1 Investigations for abnormal premenopausal bleeding. [rerif]

No.

Recommendations/Statements

GoR

LoE

Sources

4.7

The risk of endometrial cancer or atypical endometrial hyperplasia in premenopausal women with abnormal uterine bleeding is less than 1.5%.

ST

2

[72]

4.8

In women with premenopausal abnormal uterine bleeding, pathologic findings that do not pertain to this Guideline (e.g., disturbed early pregnancy, cervical pathology, fibroids) should first be excluded clinically and sonographically. In women with endometrial findings without sonographic malignancy criteria and without risk factors (suspicious cytology, obesity, Lynch syndrome, diabetes, polyps), conservative therapy should be attempted initially unless the bleeding is hemodynamically relevant. If conservative therapy fails, hysteroscopy/curettage should be performed.

EC

4.9

For the reliable diagnosis of endometrial carcinoma, hysteroscopy in combination with fractionated curettage is the gold standard.

ST

3

[73], [74], [75]

4.10

Diagnostic procedures such as Pipelle and Tao Brush in the symptomatic patient have shown comparable positive and negative predictive values in the diagnosis of endometrial cancer as curettage plus hysteroscopy in smaller series. However, larger comparative studies are lacking.

ST

3

[76]

4.11

There is currently no nationwide, quality-assured availability of procedures such as Pipelle and Tao Brush in Germany.

EC


#

2.3  Work-up for postmenopausal bleeding (PMB) ([Fig. 2])

Zoom Image
Fig. 2 Algorithm “Diagnostic approach for bleeding in peri- or postmenopausal women”. [rerif]

No.

Recommendations/Statements

GoR

LoE

Sources

4.12

A woman with first-time postmenopausal bleeding and endometrial thickness ≤ 3 mm (double) should initially have a sonographic and clinical follow-up in three months.

B

1

[77]

4.13

Persistence or recurrence of clinical symptoms or increase in endometrial thickness shall lead to histologic evaluation.

EC


#

2.4  Diagnostic imaging

No.

Recommendations/Statements

GoR

LoE

Sources

4.14

In endometrial cancer, surgical staging with histopathological examination is the reference method for local spread diagnosis.

For distant metastases outside the usual surgical area, imaging is the primary diagnostic method.

EC

4.15

In histologically-confirmed primary endometrial carcinoma, transvaginal sonography should be performed to assess myometrial infiltration and cervical infiltration.

B

3

[78]

4.16

Preoperative imaging by transvaginal sonography is used for documentation and surgical planning, even though the final locoregional staging is surgical-histologic.

EC

4.17

In primary endometrial carcinoma, MRI should be performed for preoperative evaluation of myometrial infiltration and cervical involvement if transvaginal sonography is not informative.

B

3

[78]

4.18

If needed for non-invasive assessment of locoregional lymph nodes, e.g., imaging diagnostics to determine spread prior to primary radiotherapy or planning surgical approach for advanced carcinoma disease (cT3), this should be done by cross-sectional imaging (CT/MRI).

B

3

[79], [80], [81], [82], [83], [84]

4.19

In the case of primary radiotherapy, locoregional diagnostics to determine spread should be performed by MRI if possible. If MRI is not possible, CT should be performed as an alternative.

EC

4.20

If there is a reasonable suspicion of distant metastasis, possible distant metastases should be evaluated by cross-sectional imaging (and skeletal scintigraphy, if necessary) and histologic confirmation, if necessary, for treatment planning.

B

3

[79], [80], [83]


#

2.5  Pathology ([Fig. 3], [Tables 7] to [12])

Zoom Image
Fig. 3 Recommended algorithm for the molecular classification of endometrial cancer. [rerif]

Tab. 7 Binary/dualistic model of endometrial cancer.

Type 1 carcinoma

Type 2 carcinoma

Sources: [98], [99], [100], [101]

Age

55 – 65 years

> 65 years

Clinical constellation

obesity, hypertension, diabetes mellitus (metabolic syndrome)

no special features

Hyperestrogenism

usually present

usually absent

Stage

usually FIGO I

usually ≥ FIGO II

Prognosis

favorable

unfavorable

Hereditary predisposition

Lynch syndrome, Cowden syndrome

poss. BRCA?

Endometrial hyperplasia

usually present

absent

Histological subtype

endometrioid

serous, clear-cell

Molecular changes

PTEN, ARID-1A, MSI

TP53, HER2, PIK3CA

Molecular type

NSMP, MMR deficiency, POLE mutation

TP53 mutation (serous-like)

Tab. 8 WHO classification of endometrial hyperplasia (nomenclature).

Description

glandular cystic hyperplasia

low/moderate grade adenomatous hyperplasia

high-grade adenomatous hyperplasia

WHO 1994/2003

simple hyperplasia without atypia

complex hyperplasia without atypia

atypical hyperplasia

WHO 2014 and WHO 2020

non-atypical hyperplasia

atypical hyperplasia, syn. endometrial intraepithelial neoplasia (EIN)

Tab. 9 The new (revised 2020) FIGO/TNM classification of endometrial cancer.

TNM category

FIGO stages

Definition

1  Assessment of endocervical glands alone should be classified as stage I.

2  Positive cytology should be diagnosed separately and documented without change in stage.

3  The presence of bullous edema is not sufficient to classify a tumor as T4. Infiltration of the mucosa of the bladder or rectum requires evidence by biopsy.

Source: [102]

TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

T1

I1

Tumor limited to corpus uteri

T1a

IA1

Tumor confined to endometrium or infiltrates less than half of myometrium

T1b

IB

Tumor infiltrates half or more of the myometrium

T2

II

Tumor infiltrates the cervical stroma but does not spread beyond the uterus

T3 and/or N1 or N2

III

Local and/or regional spread as described below:

T3a

IIIA

Tumor invades serosa and/or adnexa (direct spread or metastases)

T3b

IIIB

Vaginal or parametrial involvement (direct spread or metastases)

N1

IIIC1

Metastases in pelvic lymph nodes2

N2

IIIIC2

Metastases in para-aortic lymph nodes with or without metastases in pelvic lymph nodes

T4

IVA

Tumor infiltrates bladder and/or rectal mucosa3

M1

IVB

Distant metastases, including intra-abdominal metastases (excluding metastases to vagina, pelvic serosa, or adnexa, including metastases to inguinal and intra-abdominal lymph nodes other than para-aortic and/or pelvic lymph nodes).

Tab. 10 Clinicopathologic characteristics of each molecular type of endometrial carcinoma.

POLE mutant

MMR deficient

No special molecular profile

P53 abnormal

* In multiple classifiers, additional p53 may be abnormal or MMR deficient.

Abbreviations: TIL = tumor infiltrating lymphocytes, PER = peritumoral inflammation.

Sources: [86], [92], [103], [104], [105], [106], [107], [108], [109], [110]

Frequency

9%

28%

50%

12%

Age

Younger women

All age groups

All ages

Association with obesity

No

No

Yes

No

Relation to hyperestrogenism

No

No

Yes

No

Hereditary component

Rare

10% (Lynch)

Rare

BRCA possible

Precursor lesion

Atypical hyperplasia/EIN

Atypical hyperplasia/EIN

Atypical hyperplasia/EIN

None

Molecular alterations

POLE mutations

Microsatellite instability

Heterogeneous

P53 mutations

Number of mutations

Very high (ultramutated)

High (hypermutated)

Moderate

Low

Histology

Often endometrioid G3, TIL/PER

Endometrioid low/high grade, un-/dedifferentiated, TIL/PER

Endometrioid low grade

Serous, carcinosarcoma, endometrioid high grade

Diagnostics

POLE Mutation analysis

MMR Immunohistochemistry

Diagnosis of exclusion

P53 immunohistochemistry

Immunohistochemistry

P53 wild type*, MMR normal*

P53 wild type*, MMR deficient

P53 wild type, MMR normal

P53 abnormal, MMR normal

Tumor stage

Often low

Wide range

Often low

Usually high, metastases frequent (lymph nodes, organ)

LVSI

Frequent

Frequent

Variable

Frequent

Prognosis

Very good

Good

Good

Poor

Tab. 11 ESGO/ESTRO/ESP risk stratification of endometrial cancer based on molecular classification.

Risk group

Molecular classification unknown

Molecular classification known1,2

1  The data on POLE-mutated endometrial cancers stage III–IVA and MMR-deficient or NSMP clear-cell endometrial cancers with myometrial infiltration are not sufficient to allow these patients to be classified into a prognostic risk group based on a molecular classification. Prospective recording of these tumors is recommended.

2  See text for “multiple classifier” (example: patients with POLE mutation and p53 aberration must be classified as POLE-mutated).

3  The WHO uses two-stage grading for endometrioid carcinomas; G1 and G2 carcinomas are considered low-grade, G3 carcinomas are considered high-grade (WHO 2020, Casey & Singh 2021).

LVI = lymphovascular invasion, MMR-d = MMR deficient (corresponds to microsatellite instability), NSMP = no special molecular profile (complete investigation of the molecular pathology of EC shows no POLE mutation and MMR deficiency with wild-type p53), POLE-mut = polymerase-E mutation

Source: [111]

Low

Stage IA endometrioid + low-grade3 + LVI negative or focal

Stage I – II

POLE-mut endometrioid carcinoma, without residual tumor

Stage IA

MMR-d/NSMP endometrioid carcinoma, low-grade, LVI negative or focal

Intermediate

Stage IB endometrioid + low-grade* + LVI negative or focal

Stage IA endometrioid + high-grade* + LVI negative or focal

Stage IA non-endometrioid (serous, clear-cell, undifferentiated carcinoma, carcinosarcoma, mixed) without myometrial infiltration

Stage IB

MMR-d/NSMP endometrioid carcinoma, low-grade, LVI negative or focal

Stage IA

MMR-d/NSMP endometrioid carcinoma, high-grade, LVI negative or focal

Stage IA

p53-abn and/or non-endometrioid (serous, clear-cell, undifferentiated carcinoma, carcinosarcoma, mixed), without myometrial infiltration

High-intermediate

Stage I endometrioid + significant LVI irrespective of grade and depth of invasion

Stage IB endometrioid high-grade* irrespective of LVI status

Stage II

Stage I

MMR-d/NSMP endometrioid carcinoma, significant LVI, irrespective of grade and depth of invasion

Stage IB

MMR-d/NSMP endometrioid carcinoma, high-grade* irrespective of LVI

Stage II

MMR-d/NSMP endometrioid carcinoma

High

Stage III–IVA without residual tumor

Stage I–IVA non-endometrioid (serous, clear-cell, undifferentiated carcinoma, carcinosarcoma, mixed) with myometrial infiltration, without residual tumor

Stage III–IVA

MMR-d/NSMP endometrioid carcinoma without residual tumor

Stage I–IVA

p53-abn endometrioid carcinoma with myometrial infiltration, without residual tumor

Stage I–IVA

MMR-d/NSMP serous or undifferentiated carcinoma or carcinosarcoma with myometrial infiltration, without residual tumor

Advanced metastatic disease

Stage III–IVA with residual tumor

Stage IVB

Stage III–IVA with residual tumor, irrespective of the molecular type

Stage IVB, irrespective of the molecular type

Tab. 12 Summary of standard*, risk, and prognostic factors and their therapeutic relevance for endometrial cancer and malignant mixed Müllerian tumors (MMMT; carcinosarcoma).

Name

Standard factor

Risk/prognostic factor

Therapy-relevant

*  Standard factors refer to parameters which are essential for the histopathological report or investigations which must be routinely performed.

1  Tumor located in the uterine isthmus may point to an association with Lynch syndrome. Because of the anatomical proximity, there may be an increased risk of cervical invasion which must be assessed by ultrasound/radiologically.

2  Tumor size probably has prognostic significance in endometrioid endometrial cancer. The molecular data are not included.

3,4  The MELF pattern is associated with a higher rate of (occult) lymphovascular invasion and consequently a higher number of lymph node metastases.

Tumor stage

yes

yes

yes

Depth of myometrial invasion

yes

yes

yes

Lymph node status

yes

yes

yes

Histological tumor type (WHO classification)

yes

yes

yes

Size of lymph node metastases

yes

unclear

no

Number of lymph nodes with metastatic involvement

yes

unclear

no

Extracapsular extent of lymph node metastases

yes

unclear

no

Status of peritoneal cytology

yes

unclear

no

Perineural invasion (PN status)

yes

unclear

no

Lymphovascular invasion (L status)

yes

yes

yes

Extent of lymphovascular invasion

yes

yes

unclear

Venous invasion (V status)

yes

unclear

no

Resection margins (residual tumor status; R-classification)

yes

yes

yes

Grading

yes

yes

yes

Tumor location in the uterus

yes

unclear1

no

Three-dimensional tumor size in cm

yes

unclear2

no

Associated endometrial hyperplasia

no

no

no

Pattern of invasion

Yes

unclear3

no4

Hormone receptor status

no

unclear

no

L1CAM

no

yes/unclear

unclear

Molecular classification

complete molecular classification desirable

yes

yes

Molecular markers (except POLE, MMR, p53)

no

no

no

Nomogram

no

no

no

No.

Recommendations/Statements

GoR

LoE

Sources

4.21

Histopathological diagnosis of endometrial carcinoma results from the combination of histomorphological and immunohistochemical parameters and, if necessary, supplementary molecular pathological findings.

EC

4.22

The terminology and morphologic diagnosis of endometrial hyperplasia shall be based on the current edition of the WHO classification.

EC

4.23

Mixed carcinomas of the endometrium have two or more histologic subtypes according to the WHO classification (2020), with one of these components being either serous or clear cell.

EC

4.24

Molecular pathologically, carcinosarcomas (malignant Müllerian mixed tumors, MMMT) are assigned to carcinomas. Histological evaluation of carcinosarcomas shall be performed according to the current WHO classification. FIGO and TNM classification shall be analogous to that for endometrial carcinoma.

EC

4.25

Endometrioid carcinomas are graded according to FIGO. According to WHO, a two-stage grading “low grade” (G1 or G2) and “high grade” (G3) should be preferred. Serous, clear cell, de- or undifferentiated endometrial carcinomas as well as carcinosarcomas are by definition high-grade carcinomas.

EC

4.26

Quantification of lymphatic vessel infiltration should be included in the histopathologic report of findings.

Focal lymphatic vessel infiltration is defined as involvement of < 3 lymphatic vessels and extensive (“substantial”) lymphatic vessel infiltration as an involvement of ≥ 3 lymphatic vessels.

EC

4.27

Because of a potential therapeutic consequence, HER2 status should be determined in serous endometrial carcinoma.

EC

4.28

If pT1b and/or pT2 are clinically suspected, intraoperative histologic examination (frozen section) may be performed for verification.

EC

4.29

Myometrial infiltration depth or endocervical stromal infiltration shall be assessed macroscopically and microscopically.

EC

4.30

Frozen section examination shall not be performed primarily to assess histopathologic grading and to determine histologic tumor type.

EC

4.31

The tubes and ovaries shall be assessed macroscopically during the intraoperative frozen section examination, and findings suspicious for tumor shall be examined histologically.

EC

4.32

The tissue of a (fractionated) curettage or an endometrial biopsy shall be fully embedded.

EC

4.33

The report of findings from a (fractionated) curettage or an endometrial biopsy shall comment on the presence and type of endometrial hyperplasia.

If carcinoma is present, the histological tumor type shall be indicated according to the current WHO classification.

If tumor tissue is detected in the cervical fraction of a fractionated curettage, a specific statement shall be made on the presence or absence of endocervical stromal infiltration.

EC

4.34

The report of findings of a hysterectomy specimen in endometrial carcinoma shall include the following information:

  • Histological type according to WHO (in case of mixed tumors components in %)

  • Grading

  • Staging (pT)

  • Evidence/absence of lymphatic or blood vessel invasion (L and V status).

  • Detection/absence of perineural sheath infiltrates (Pn status)

  • Metric indication of depth of invasion in relation to myometrial thickness in cm/mm

  • Three-dimensional tumor size in cm/mm

  • Metric measurement of the minimum distance to the vaginal resection margin if vaginal infiltration is present

  • R classification (UICC)

EC

4.35

Processing of the tubes should be based on the SEE-FIM-like protocol.

EC

4.36

Routine immunohistochemical analysis of MMR proteins shall not be performed in the setting of endometrial hyperplasia.

EC

4.37

MSI analysis in endometrial carcinoma shall be primarily immunohistochemical.

The primary use of two antibodies (MSH-6 and PMS-2) is possible, with addition of the respective partner antibody (MSH2 or MLH1) in case of negative results.

Immunohistochemical analysis of MMR proteins shall be supplemented by molecular pathological methods (MLH-1 promoter methylation, MSI-PCR) according to the indication.

The exclusive use of molecular pathological methods shall not be performed.

Combined analysis by immunohistochemistry and molecular pathology shall not be performed routinely.

EC

4.38

Every newly diagnosed endometrial cancer shall be screened for MMR defect/MSI regardless of age and histological subtype.

MMR/MSI analysis thus also serves to identify patients who shall be offered human genetic counseling.

A

4

[85], [86], [87], [88], [89], [90]

4.39

In all histologically diagnosed primary EC, immunohistochemical determination of p53 as well as MMR proteins shall be performed.

A

4

[85], [86], [87], [88], [90], [91], [94]

4.40

In G3 or in intermediate, high intermediate, and high-risk EC, mutational analysis of the exonuclease domain of POLE shall be performed.

A

4

[86], [88], [90], [91], [92], [93], [94]

4.41

Molecular classification (P53 and MMR deficiency) shall be performed preoperatively, i.e., on the curettage material or endometrial biopsy.

EC

4.42

POLE mutation analysis can alternatively be performed postoperatively.

EC

4.43

In low risk EC, IHC determination of L1CAM can be performed.

0

4

[91], [92], [94], [95], [96], [97]

4.44

Molecular typing of endometrial carcinoma shall be performed on optimally fixed tissue, i.e. preferably on the curettage material. Due to a high concordance rate between curettage and hysterectomy specimens, a repeat determination on the surgical specimen shall not be performed if no additional tumor component is detectable on the hysterectomy specimen.

EC

4.45

At least one paraffin block shall be examined from omentectomy specimens with macroscopic tumor infiltration in endometrial carcinoma.

In the case of macroscopically absent tumor infiltration, four to six paraffin blocks (embedding of several specimens in one block is possible) shall be examined.

Any additional abnormal findings (e.g., intraomental lymph nodes) shall be described macroscopically and examined histologically.

EC

4.46

For lymphonodectomy specimens as part of surgical therapy for endometrial cancer, all removed lymph nodes shall be completely embedded and examined histologically.

EC

4.47

Lymph nodes up to approximately 0.2 cm maximum extent should be embedded in toto, and larger lymph nodes should be bisected or lamellated along their short axis and also embedded completely.

EC

4.48

The report of findings of lymphonodectomy specimens in endometrial carcinoma shall include the following information:

  • Indication of the number of affected lymph nodes in relation to the number of removed lymph nodes in assignment to the sampling location (pelvic, para-aortic),

  • Indication of the extent of the largest lymph node metastasis in mm/cm,

  • Indication of absence/evidence of capsular rupture of lymph node metastasis(s),

  • Indication of evidence of isolated tumor cells in the lymph node and evidence of lymphatic vessel invasion in the perinodal adipose tissue and/or lymph node capsule.

EC

4.49

Isolated tumor cells in the sentinel LC (< 0.2 mm) (pN0 [i+] are per se not an indication for adjuvant radiotherapy and/or chemotherapy. This is recommended only in case of corresponding additional risks (e.g. p53 mutation, type II EC, LVSI).

EC

4.50

For micrometastases (> 0.2 mm, < 2 mm) (pN1[mi]), adjuvant radiotherapy and/or chemotherapy should be given.

EC

4.51

Sentinel lymph nodes in endometrial carcinoma shall be lamellated parallel to their short axis and fully embedded and examined in sequential sections.

Sentinel lymph nodes that are negative in the hematoxylin-eosin stain shall additionally be examined by immunohistochemistry (so-called ultrastaging).

EC


#
#

3  Hereditary endometrial cancers

3.1  Introduction


#

3.2  Hereditary tumor syndromes with a higher risk of endometrial cancer ([Table 13])

Tab. 13 Tumor risks and mutation detection rates.

Lynch syndrome (LS)

Cowden syndrome (CS)

Mode of inheritance

autosomal-dominant

autosomal-dominant

Causative genes

MLH1, MSH2, MSH6, PMS2, EPCAM

PTEN

Frequency in the general population

1 : 279 – 370 [117], [121]

1 : 200 000? [124]

Frequency in unselected patient cohorts with endometrial cancer

approx. 3% [125]

< 0.5%

Frequency in patients with endometrial cancer aged < 50 years

approx. 10%

Endometrial cancer of the lower uterine segment

14 – 30% [120]

Spectrum of mutations in LS-associated endometrial cancer

approx. 15%, approx. 25%, approx. 50%, approx. 10% for MLH1, MSH2, MSH6, PMS2 [126]

Lifetime risk of endometrial cancer up to the 70th year of life (around 2.6% in the general population)

up to 75th year of life: MLH1 approx. 40%, MSH2 approx. 50%, MSH6 approx. 40%, PMS2 approx. 15% [127]

up to 70th year of life: 20 – 30% [128], [129]

Mean age at onset of

LS-/CS-associated endometrial cancer (years)

Overall: 50 years

MLH1: 44 (29 – 54), MSH2: 50 (36 – 66)

MSH6: 55 (26 – 69), PMS2: 57 (44 – 69)

[116], [117], [131], [132]

48 – 53 [133]

Metachronous carcinoma after a diagnosis of endometrial cancer

10 years: 25%, 15 years: 50%, 20 years: > 50% [114], [116], [134]

Endometrioid type

approx. 60 – 85%

approx. 85%

Other common tumors/tumor spectrum

colorectal cancer, duodenal cancer, gastric cancer, ovarian cancer, brain tumors, urothelial carcinoma

thyroid cancer, breast cancer, renal cancer, brain tumors, skin tumors

No.

Recommendations/Statements

GoR

LoE

Sources

10.1

The hereditary tumor syndromes (ETS) with a confirmed, significantly increased risk of endometrial cancer are Lynch syndrome (hereditary colorectal cancer without polyposis, HNPCC) and Cowden syndrome (CS) or PTEN hamartoma tumor syndrome (PHTS). Congenital carriers of these ETS are also at increased risk for other syndrome-specific intestinal and extraintestinal benign and malignant tumors.

ST

3

[112], [113], [114], [115], [116], [117], [118], [119], [120], [121], [122], [123], [130]


#

3.3  Determining the risk

No.

Recommendations/Statements

GoR

LoE

Sources

10.2

An important tool for detecting a genetically determined increased risk of endometrial carcinoma is the personal and family history taken by a physician, taking into account specific clinical criteria (in Lynch syndrome: Amsterdam I/II, revised Bethesda criteria).

EC


#

3.4  Procedure for suspected hereditary endometrial cancer

No.

Recommendations/Statements

GoR

LoE

Sources

10.3

If a hereditary form of endometrial cancer is suspected, the patient should present to a certified gynecologic cancer center or a center for hereditary tumor diseases.

EC


#

3.5  Psychosocial counseling and care options

No.

Recommendations/Statements

GoR

LoE

Sources

10.4

Already affected persons, carriers and not yet tested persons (risk persons) from families with a hereditary tumor syndrome should be informed about the possibility and benefit of psychosocial counseling and care.

EC


#

3.6  Investigating clinically suspicious findings ([Fig. 4])

Zoom Image
Fig. 4 Diagnostic MMR workup for abnormal findings obtained by immunohistochemical or molecular pathology examination. [rerif]

No.

Recommendations/Statements

GoR

LoE

Sources

10.5

If at least one revised Bethesda criterion is fulfilled, further (molecular) pathological examination shall be performed on the tumor tissue with regard to Lynch syndrome-typical changes.

This includes the examination of the immunohistochemical expression of the DNA mismatch repair proteins, microsatellite analysis and, if necessary, the examination of the methylation of the MLH1 promoter.

A

3

[113], [116], [117], [118], [131]

10.6

If a suspicious finding is raised during routine testing for MMR deficiency (immunohistochemical examination of MMR genes or microsatellite analysis), information and, if necessary, counseling under the Genetic Diagnostics Act shall be offered regarding diagnostic genetic testing for Lynch syndrome.

A

3

[113], [116], [117], [118], [131], [135]

10.7

In patients from families in which the Amsterdam criteria are fulfilled and whose tumor tissue does not show Lynch syndrome-typical abnormalities, Lynch syndrome is not excluded. Therefore, for assessment and, if necessary, further diagnostics, education and, if necessary, genetic counseling for diagnostic genetic testing should be offered in a center for familial tumor diseases with appropriate expertise.

EC

10.8

If there is evidence of MMR deficiency and suspicion of Lynch syndrome based on abnormal immunohistochemistry or molecular pathology (failure of MMR proteins) or high microsatellite instability (MSI-H), the affected individual shall be offered education and, if appropriate, genetic counseling for germline mutation analysis in the likely affected MMR gene(s).

A

3

[113], [116], [118], [131]


#

3.7  Approach for persons at risk of Lynch or Cowden syndrome

No.

Recommendations/Statements

GoR

LoE

Sources

10.9

Once the causative mutation is known in the family, the patient shall be advised to inform family members of the increased risk and the options for genetic counseling and (predictive) genetic testing.

EC

10.10

Once the familial mutation has been ruled out in an at-risk individual, the general cancer screening measures apply.

EC


#

3.8  Primary prevention in at-risk groups

No.

Recommendations/Statements

GoR

LoE

Sources

10.11

A separate recommendation for primary prevention by dietary measures or chemoprevention compared to the general population cannot be given due to lack of data for the mentioned risk groups.

EC


#

3.9  Screening for endometrial cancer in patients with Lynch and Cowden syndrome

No.

Recommendations/Statements

GoR

LoE

Sources

10.12

To date, no screening method for early detection of endometrial cancer has been shown to prolong life for Lynch syndrome and Cowden syndrome patients.

Therefore, from the limited data, no recommendations can be made for or against specific screening for early detection of endometrial carcinoma in Lynch syndrome or Cowden syndrome patients.

ST

4

[63], [64], [79], [136], [137]

10.13

Patients and persons at risk with Lynch syndrome or Cowden syndrome shall be recommended syndrome-specific screening examinations, especially colonoscopies, due to the broad tumor spectrum. Detailed guidance can be found in the relevant guidelines.

EC


#

3.10  Women with Lynch and Cowden syndrome

No.

Recommendations/Statements

GoR

LoE

Sources

10.14

Lynch syndrome and Cowden syndrome carriers shall be offered counseling on the advantages and disadvantages of prophylactic total hysterectomy after completion of family planning, and Lynch syndrome patients shall additionally be offered counseling on bilateral adnexal extirpation, if appropriate.

EC


#
#

4  Fragile patients/geriatric assessment

No.

Recommendations/Statements

GoR

LoE

Sources

12.1

Treatment decisions for older patients shall be based on current standard recommendations and modified by general status, life expectancy, patient preference and an individual benefit-risk assessment.

EC

12.2

Determination of general status in patients older than 75 years should be determined by geriatric assessment or by a screening/geriatric assessment algorithm, especially if surgery with general anesthesia or chemotherapy is planned to minimize complications as well as improve treatment adherence, chemotherapy tolerance and possibly survival.

B

3

[138], [139], [140], [141], [142], [143], [144]

12.3

The sole consideration of calendar age does not do justice to the complexity and multi-layered nature of the general status. Rather, geriatric assessment and management should include therapy-relevant geriatric domains (especially functionality-associated parameters such as activities of daily living, mobility, cognition, falls and morbidity-associated parameters such as multimedication, nutrition, fatigue and number of comorbidities) to adjust therapy selection accordingly and initiate supportive measures.

B

3

[138], [139], [144], [145]


#

5  Structures of care

5.1  Introductory remarks


#

5.2  Treatment in oncological centers ([Figs. 5] and [6])

Zoom Image
Fig. 5 Structures of care for the diagnosis and treatment of endometrial cancer. [rerif]
Zoom Image
Fig. 6 Treatment path in a certified gynecological cancer center. [rerif]

No.

Recommendations/Statements

GoR

LoE

Sources

13.1

Patients with endometrial cancer should be treated by an interdisciplinary team. This team should include all necessary disciplines in a cross-sector network. This is most likely to be feasible in a certified center.

EC

13.2

All patients with endometrial cancer shall be presented at an interdisciplinary tumor conference.

EC

13.3

Physician education and training in the treatment of the patient with endometrial cancer should be provided at a Gynecologic Cancer Center/Oncology Center.

EC


#
#
#
Zoom Image

#
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Correspondence/Korrespondenzadresse

Prof. Günter Emons
Universitätsmedizin Göttingen, Klinik für Gynäkologie und Geburtshilfe
Robert Koch Straße 40
37075 Göttingen
Germany   

Publication History

Received: 17 March 2023

Accepted after revision: 22 June 2023

Article published online:
15 August 2023

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

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Fig. 1 Investigations for abnormal premenopausal bleeding. [rerif]
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Fig. 2 Algorithm “Diagnostic approach for bleeding in peri- or postmenopausal women”. [rerif]
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Fig. 3 Recommended algorithm for the molecular classification of endometrial cancer. [rerif]
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Fig. 4 Diagnostic MMR workup for abnormal findings obtained by immunohistochemical or molecular pathology examination. [rerif]
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Fig. 5 Structures of care for the diagnosis and treatment of endometrial cancer. [rerif]
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Fig. 6 Treatment path in a certified gynecological cancer center. [rerif]
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Abb. 1 Abklärung bei abnormer prämenopausaler Blutung. [rerif]
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Abb. 2 Algorithmus „Diagnostisches Vorgehen bei Blutungen bei peri- bzw. postmenopausalen Frauen“. [rerif]
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Abb. 3 Empfohlener Algorithmus zur molekularen Klassifikation des Endometriumkarzinoms. [rerif]
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Abb. 4 Ablauf der MMR-Diagnostik bei auffälligem Befund in der immunhistochemischen oder molekular-pathologischen Untersuchung. [rerif]
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Abb. 5 Versorgungsstrukturen für die Diagnose und Therapie des Endometriumkarzinoms. [rerif]
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Abb. 6 Behandlungsnetzwerk im zertifizierten Gynäkologischen Krebszentrum. [rerif]
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