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

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.

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.

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

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

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 Prömpeler 1
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 Tholen 2
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).

Abbreviations

EC

expert consensus

ST

statement

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.

Targeted areas of patient care

This guideline covers both outpatient and inpatient care.

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.

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.

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 .

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 quality 1 **	Not applicable
Does this approach help? (use of the intervention)	Systematic review of randomized trials or N-of-1 studies 2	Randomized trial or observational study with dramatic effects	Controlled cohort study/follow-up study 3 **	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 studies 4 . 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

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

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.

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 .

Fig. 6.

 Treatment path in a certified gynecological cancer center. [rerif]

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 )

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 )

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 )

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. 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	unclear 1	no
Three-dimensional tumor size in cm	yes	unclear 2	no
Associated endometrial hyperplasia	no	no	no
Pattern of invasion	Yes	unclear 3	no 4
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

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	I 1	Tumor limited to corpus uteri
T1a	IA 1	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 nodes 2
N2	IIIIC2	Metastases in para-aortic lymph nodes with or without metastases in pelvic lymph nodes
T4	IVA	Tumor infiltrates bladder and/or rectal mucosa 3
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 known 1,2
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-grade 3 + 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

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

3.2  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 )

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

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

Fig. 5.

 Structures of care for the diagnosis and treatment of endometrial cancer. [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