Endometrial cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up

Abstract

•This ESMO Clinical Practice Guideline provides key recommendations for managing endometrial cancer.•The guideline covers clinical and pathological diagnosis, staging and risk assessment, treatment and follow-up.•Treatment and management algorithms according to risk groups and for advanced/metastatic or recurrent disease are provided.•Authorship includes a multidisciplinary group of experts from different institutions in Europe, the USA and South America.•Recommendations are based on available scientific data and the authors’ collective expert opinion. Incidence and epidemiologyWorldwide, endometrial cancer (EC) ranks seventh among all female cancers with the majority of cases occurring between 65 and 75 years of age.1Morice P. Leary A. Creutzberg C. et al.Endometrial cancer.Lancet. 2016; 387: 1094-1108Abstract Full Text Full Text PDF PubMed Scopus (895) Google Scholar In Europe, uterine cancer ranks fourth among female neoplasms, with an incidence of 12.9-20.2:100 000 and a low mortality rate: 2.0-2.7:100 000.2Ferlay J. Colombet M. Soerjomataram I. et al.Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods.Int J Cancer. 2019; 144: 1941-1953Crossref PubMed Scopus (3586) Google Scholar,3Bray F. Ferlay J. Soerjomataram I. et al.Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2018; 68: 394-424Crossref PubMed Scopus (45734) Google Scholar This discrepancy is due to the fact that 80% of ECs are confined to the uterus at diagnosis and present with postmenopausal bleeding, which leads to prompt detection.1Morice P. Leary A. Creutzberg C. et al.Endometrial cancer.Lancet. 2016; 387: 1094-1108Abstract Full Text Full Text PDF PubMed Scopus (895) Google ScholarEC is more prevalent in high/intermediate developed countries. Risk factors for EC include body mass index (BMI) (with an increased incidence of +21% for BMI 22-27.2, +43% for BMI 27.5-29-5 and +273% for BMI >30), hypertension, hyperinsulinaemia and prolonged exposure to unopposed estrogen (often related to nulliparity and infertility associated with polycystic ovarian syndrome or tamoxifen use).4Arthur R.S. Kabat G.C. Kim M.Y. et al.Metabolic syndrome and risk of endometrial cancer in postmenopausal women: a prospective study.Cancer Causes Control. 2019; 30: 355-363Crossref PubMed Scopus (12) Google Scholar,5Friberg E. Orsini N. Mantzoros C.S. et al.Diabetes mellitus and risk of endometrial cancer: a meta-analysis.Diabetologia. 2007; 50: 1365-1374Crossref PubMed Scopus (378) Google ScholarMortality rates have been increasing by 1.9% per year on average, mainly attributed to the increasing incidence of obesity, a known risk factor for the most frequent type of EC.6Lauby-Secretan B. Scoccianti C. Loomis D. et al.Body Fatness and Cancer--Viewpoint of the IARC Working Group.N Engl J Med. 2016; 375: 794-798Crossref PubMed Scopus (1440) Google Scholar,7Rahib L. Smith B.D. Aizenberg R. et al.Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States.Cancer Res. 2014; 74: 2913-2921Crossref PubMed Scopus (3915) Google ScholarECs have traditionally been classified into two subtypes according to their histopathological characteristics (type 1 and 2).8Bokhman J.V. Two pathogenetic types of endometrial carcinoma.Gynecol Oncol. 1983; 15: 10-17Abstract Full Text PDF PubMed Scopus (1735) Google Scholar This classification system, however, is in a transition period and is being replaced by a clearly-defined system based on molecular phenotypes.9Cancer Genome Atlas Research N. Kandoth C. Schultz N. et al.Integrated genomic characterization of endometrial carcinoma.Nature. 2013; 497: 67-73Crossref PubMed Scopus (2782) Google ScholarAlthough >90% of ECs are sporadic, 5%-10% are hereditary, usually as a part of the hereditary non-polyposis colorectal cancer syndrome (HNPCC) or Lynch syndrome. Women with HNPCC have a 10-fold risk of developing EC, as well as an increased risk of colon and ovarian cancer. These are usually microsatellite-unstable tumours and tend to occur at a younger age.10Domchek S.M. Robson M.E. Update on genetic testing in gynecologic cancer.J Clin Oncol. 2019; 37: 2501-2509Crossref PubMed Scopus (11) Google ScholarDiagnosis, pathology and molecular biologyThe traditional dualistic histopathological classification coined by Bokhman split EC into two groups: type I and type II. The endometrioid subtype was categorised as type I, while all other histological subtypes were classified as type II cancers. Type II cancers were associated with a higher risk of relapse compared with type I.8Bokhman J.V. Two pathogenetic types of endometrial carcinoma.Gynecol Oncol. 1983; 15: 10-17Abstract Full Text PDF PubMed Scopus (1735) Google Scholar Tumours are graded according to the International Federation of Gynecology and Obstetrics (FIGO) defined criteria and are moving towards a two-tier grading combining grade 1 (G1) and grade 2 (G2) endometrioid carcinomas as low grade and grade 3 (G3) as high grade.11Soslow R.A. Tornos C. Park K.J. et al.Endometrial carcinoma diagnosis: Use of FIGO grading and genomic subcategories in clinical practice: Recommendations of the International Society of Gynecological Pathologists.Int J Gynecol Pathol. 2019; 38: S64-S74Crossref PubMed Scopus (120) Google Scholar In addition, multiple factors have been traditionally identified as high risk for recurrent disease: histological subtype, G3 histology, myometrial invasion ≥50%, lymphovascular space invasion (LVSI), lymph node metastases and tumour diameter >2 cm. Substantial LVSI is a major poor prognostic factor. Substantial LVSI is defined as widespread invasion of tumour emboli into vascular spaces at and beyond the invasive front of the tumour. Substantial LVSI can be diagnosed on haematoxylin and eosin (H&E) slides without the need for additional immunostains. Although the extent of LVSI may vary per H&E slide, LVSI foci are often found in multiple slides. If the extent of LVSI is limited to fewer than four vessels, it is regarded as focal LVSI. Substantial LVSI is defined as four or more LVSI-positive vessels in at least one H&E slide. In contrast to substantial LVSI, minimal or focal LVSI has limited impact on prognosis.12Bosse T. Peters E.E. Creutzberg C.L. et al.Substantial lymph-vascular space invasion (LVSI) is a significant risk factor for recurrence in endometrial cancer--A pooled analysis of PORTEC 1 and 2 trials.Eur J Cancer. 2015; 51: 1742-1750Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, 13Peters E.E.M. Leon-Castillo A. Smit V. et al.Defining substantial lymphovascular space invasion in endometrial cancer.Int J Gynecol Pathol. 2022; 41: 220-226Crossref PubMed Scopus (2) Google Scholar, 14Peters E.E.M. Leon-Castillo A. Hogdall E. et al.Substantial lymphovascular space invasion is an adverse prognostic factor in high-risk endometrial cancer.Int J Gynecol Pathol. 2022; 41: 227-234Crossref PubMed Scopus (1) Google Scholar Alongside these characteristics, L1 cell adhesion molecule (L1CAM) is another significant indicator of high-risk disease.15Zeimet A.G. Reimer D. Huszar M. et al.L1CAM in early-stage type I endometrial cancer: results of a large multicenter evaluation.J Natl Cancer Inst. 2013; 105: 1142-1150Crossref PubMed Scopus (157) Google Scholar,16Bosse T. Nout R.A. Stelloo E. et al.L1 cell adhesion molecule is a strong predictor for distant recurrence and overall survival in early stage endometrial cancer: pooled PORTEC trial results.Eur J Cancer. 2014; 50: 2602-2610Abstract Full Text Full Text PDF PubMed Google Scholar Expression of L1CAM is most frequent in p53-abnormal (p53-abn) tumours but is also predictive of worse outcome among tumours with no specific molecular profile (NSMP).17Van Gool I.C. Stelloo E. Nout R.A. et al.Prognostic significance of L1CAM expression and its association with mutant p53 expression in high-risk endometrial cancer.Mod Pathol. 2016; 29: 174-181Crossref PubMed Scopus (47) Google Scholar,18Stelloo E. Nout R.A. Osse E.M. et al.Improved risk assessment by integrating molecular and clinicopathological factors in early-stage endometrial cancer-combined analysis of the PORTEC cohorts.Clin Cancer Res. 2016; 22: 4215-4224Crossref PubMed Scopus (350) Google ScholarIn recent years, it has become increasingly clear that the traditional classification lacks reproducibility and yields heterogenous molecular groups that hamper advances and implementation of precision medicine.19Gilks C.B. Oliva E. Soslow R.A. Poor interobserver reproducibility in the diagnosis of high-grade endometrial carcinoma.Am J Surg Pathol. 2013; 37: 874-881Crossref PubMed Scopus (224) Google Scholar,20de Boer S.M. Wortman B.G. Bosse T. et al.Clinical consequences of upfront pathology review in the randomised PORTEC-3 trial for high-risk endometrial cancer.Ann Oncol. 2018; 29: 424-430Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar This is particularly problematic for future clinical trials with targeted approaches that will demand inclusion of cancers with molecular similarities. The EC classification originally proposed by The Cancer Genome Atlas (TCGA) project serves this purpose well, as it is based upon the combination of somatic mutational burden and somatic copy number alterations.9Cancer Genome Atlas Research N. Kandoth C. Schultz N. et al.Integrated genomic characterization of endometrial carcinoma.Nature. 2013; 497: 67-73Crossref PubMed Scopus (2782) Google Scholar This TCGA approach results in the molecular stratification of ECs into four distinct molecular groups; (i) ultramutated [>100 mutations/megabase (mut/Mb)] with pathogenic variations in the exonuclease domain of DNA polymerase epsilon (POLE)-ultramutated (POLEmut), (ii) hypermutated (10-100 mut/Mb), microsatellite-unstable, (iii) somatic copy number-high with frequent pathogenic variants in TP53 and (iv) somatic copy number-low with frequently phosphoinositide 3-kinase (PI3K) and WNT signalling abnormalities. Importantly, a range of publications on large and clinically well-annotated (trial) cohorts have shown that surrogate markers can be utilised for a TCGA-inspired molecular classification in routine surgical pathology, without the need for extensive sequencing.18Stelloo E. Nout R.A. Osse E.M. et al.Improved risk assessment by integrating molecular and clinicopathological factors in early-stage endometrial cancer-combined analysis of the PORTEC cohorts.Clin Cancer Res. 2016; 22: 4215-4224Crossref PubMed Scopus (350) Google Scholar,21Kommoss S. McConechy M.K. Kommoss F. et al.Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series.Ann Oncol. 2018; 29: 1180-1188Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar, 22Talhouk A. McConechy M.K. Leung S. et al.A clinically applicable molecular-based classification for endometrial cancers.Br J Cancer. 2015; 113: 299-310Crossref PubMed Scopus (387) Google Scholar, 23Leon-Castillo A. de Boer S.M. Powell M.E. et al.Molecular classification of the PORTEC-3 trial for high-risk endometrial cancer: impact on prognosis and benefit from adjuvant therapy.J Clin Oncol. 2020; 38: 3388-3397Crossref PubMed Scopus (153) Google Scholar This pragmatic alternative relies on a small number of well-established immunohistochemical (IHC) markers (MSH6, PMS2 and p53) in combination with targeted tumour sequencing (POLE hotspot analysis) and also automatically serves to pre-screen for Lynch syndrome as it incorporates reflex testing of the mismatch repair (MMR) proteins (Table 1).Table 1Molecular and clinicopathological features of endometrial cancer molecular subgroupsPOLEmut (i.e. POLE EDM)dMMR (i.e. MSI)NSMP (i.e. p53-wt)p53aberrant (i.e. p53-abn, p53-mut)Prevalence in TCGA cohort, %5-1525-3030-405-15Associated molecular features>100 mut/Mb, SCNA-very low, MSS10-100 mut/Mb, SCNA-low, MSI<10 mut/Mb, SCNA-low, MSS<10 mut/Mb, SCNA-high, MSSMost frequently associated histological featuresEndometrioidEndometrioidMostly low gradeAll histological subtypesOften high gradeOften high gradeNotable absence of TILsMostly high gradeAmbiguous morphologyLVSI substantialSquamous differentiationHigh cytonuclear atypiaProminent TILs and TLSsProminent TILsMELF-type invasionER/PgR diffuseLow level of TILSAssociated clinical featuresLower BMIHigher BMIHigher BMILower BMIEarly stage (IA-IB)Lynch syndromeAdvanced stageEarly onsetLate onsetDiagnostic testNGS/Sanger/Hotspot:P286R, V411L, S297F, A456P, S459FMMR-IHC: MLH1, MSH2, MSH6, PMS2MSI assayp53-IHCMutant-like/abnormal stainingPrognosisExcellentIntermediateIntermediateStage-dependentPoorAdapted from McAlpine et al.,119McAlpine J. Leon-Castillo A. Bosse T. The rise of a novel classification system for endometrial carcinoma; integration of molecular subclasses.J Pathol. 2018; 244: 538-549Crossref PubMed Scopus (73) Google Scholar with permission from John Wiley and Sons.BMI, body mass index; dMMR, mismatch repair deficient; EDM, exonuclease domain mutation; ER, estrogen receptor; IHC, immunohistochemistry; LVSI, lymphovascular space invasion; MELF, microcystic elongated and fragmented type of invasion; MMR-IHC, mismatch repair immunohistochemistry; MSI, microsatellite instability; MSS, microsatellite stable; mut/Mb, mutations/megabase; NGS, next-generation sequencing; NSMP, no specific molecular profile; p53-abn, p53-abnormal; p53-mut, p53-mutant; p53-wt, p53-wild type; PgR, progesterone receptor; POLE, polymerase epsilon; POLEmut, polymerase epsilon-ultramutated; SCNA, somatic copy number alteration; TCGA, The Cancer Genome Atlas; TIL, tumour infiltrating lymphocyte; TLS, tertiary lymphoid structure. Open table in a new tab A simple and clearly defined diagnostic algorithm for the molecular EC classification has been proposed24Vermij L. Smit V. Nout R. et al.Incorporation of molecular characteristics into endometrial cancer management.Histopathology. 2020; 76: 52-63Crossref PubMed Scopus (80) Google Scholar (Figure 1). POLEmut EC can be diagnosed after the detection of a pathogenic mutation in the exonuclease domain of POLE. Guidance about the interpretation of pathogenic variants was recently described by Leon-Castillo et al.,25Leon-Castillo A. Britton H. McConechy M.K. et al.Interpretation of somatic POLE mutations in endometrial carcinoma.J Pathol. 2020; 250: 323-335Crossref PubMed Scopus (94) Google Scholar allowing for uniform classification of POLEmut EC. Subsequently, for cases that do not carry a pathogenic POLE variant, immunostaining of at least two (PMS2 and MSH6) or preferably four (PMS2, MLH1, MSH6 and MSH2) of the MMR proteins is carried out. Complete loss of expression of one or more of these MMR proteins is sufficient for the diagnosis of MMR-deficient (dMMR) EC.26Stelloo E. Jansen A.M.L. Osse E.M. et al.Practical guidance for mismatch repair-deficiency testing in endometrial cancer.Ann Oncol. 2017; 28: 96-102Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar Finally, p53 immunostaining serves as a near-perfect surrogate marker for an underlying TP53 mutation and is, therefore, used to classify EC as p53-abn (after excluding POLEmut and dMMR).27Singh N. Piskorz A.M. Bosse T. et al.p53 immunohistochemistry is an accurate surrogate for TP53 mutational analysis in endometrial carcinoma biopsies.J Pathol. 2020; 250: 336-345Crossref PubMed Scopus (75) Google Scholar Extensive study of these surrogate markers has shown a good relationship to clinical outcome, establishing their prognostic value. POLEmut EC has an excellent outcome and p53-abn EC has the poorest clinical outcome, independent of risk group, type of adjuvant treatment, tumour type or grade.21Kommoss S. McConechy M.K. Kommoss F. et al.Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series.Ann Oncol. 2018; 29: 1180-1188Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar, 22Talhouk A. McConechy M.K. Leung S. et al.A clinically applicable molecular-based classification for endometrial cancers.Br J Cancer. 2015; 113: 299-310Crossref PubMed Scopus (387) Google Scholar, 23Leon-Castillo A. de Boer S.M. Powell M.E. et al.Molecular classification of the PORTEC-3 trial for high-risk endometrial cancer: impact on prognosis and benefit from adjuvant therapy.J Clin Oncol. 2020; 38: 3388-3397Crossref PubMed Scopus (153) Google Scholar This implies that de-escalation of adjuvant treatment of POLEmut EC patients should be explored, as is currently being done in the clinical Postoperative Radiation Therapy in Endometrial Cancer (PORTEC)-4a trial.28van den Heerik A. Horeweg N. Nout R.A. et al.PORTEC-4a: international randomized trial of molecular profile-based adjuvant treatment for women with high-intermediate risk endometrial cancer.Int J Gynecol Cancer. 2020; 30: 2002-2007Crossref PubMed Scopus (48) Google Scholar Furthermore, recent data suggest that the greatest benefit for the addition of chemotherapy (ChT) in the adjuvant setting is for those ECs harbouring p53-abn which includes most serous cancers but also a significant portion of other histological subtypes such as carcinosarcomas.23Leon-Castillo A. de Boer S.M. Powell M.E. et al.Molecular classification of the PORTEC-3 trial for high-risk endometrial cancer: impact on prognosis and benefit from adjuvant therapy.J Clin Oncol. 2020; 38: 3388-3397Crossref PubMed Scopus (153) Google Scholar This shows how the molecular EC classification has the potential to improve patient management, reducing over- and undertreatment.In future trial designs, molecular classification should be encouraged as it would allow comparison between groups of patients sharing similar/analagous features.Molecular classification has been shown to be prognostically enlightening in low-, intermediate- and high-risk EC. Therefore, well-established IHC staining for p53 and MMR proteins (MLH1, PMS2, MSH2, MSH6) is now recommended as standard practice for all EC pathology specimens regardless of histological type and to complete the molecular classification following the diagnostic algorithm (Figure 1), by sequencing the exonuclease domain of POLE where available. As not all laboratories are currently able to carry out the molecular classification on all ECs, prioritisation of molecular classification should be done for cases where results are relevant to guiding adjuvant treatment recommendations. It applies particularly to those classified as being high grade or at high stage (≥FIGO stage II), as the clinical consequences for these patients will be most pronounced.In this transition phase, in which two EC classification systems exist, it is recommended that the classification system used is specified. As with other tumour sites undergoing a similar transition, ECs that have not (completely) been molecularly classified should be designated as EC not-otherwise-specified (EC-NOS) and continue the use of the histology-based classification system [e.g. endometrioid-type EC (EEC-NOS)].24Vermij L. Smit V. Nout R. et al.Incorporation of molecular characteristics into endometrial cancer management.Histopathology. 2020; 76: 52-63Crossref PubMed Scopus (80) Google Scholar This additional note will improve clarity for caretakers and patients. The histology-based classification remains unchanged and distinguishes endometrioid, serous, clear-cell and un/dedifferentiated EC. Uterine carcinosarcomas are metaplastic carcinomas with molecular features that overlap with serous and endometrioid adenocarcinomas and, therefore, should be included in this list of ‘epithelial endometrial malignancies’. Data on the prognostic and predictive value of the molecular classification for the rarer (non-endometrioid) histological EC variants are still limited to pilot studies; however, all molecular classes are identified in all histological subtypes.29Espinosa I. De Leo A. D’Angelo E. et al.Dedifferentiated endometrial carcinomas with neuroendocrine features: a clinicopathologic, immunohistochemical, and molecular genetic study.Hum Pathol. 2018; 72: 100-106Crossref PubMed Scopus (0) Google Scholar,30Kim S.R. Cloutier B.T. Leung S. et al.Molecular subtypes of clear cell carcinoma of the endometrium: Opportunities for prognostic and predictive stratification.Gynecol Oncol. 2020; 158: 3-11Abstract Full Text Full Text PDF PubMed Scopus (37) Google ScholarRecommendations•Histological type, FIGO grade, myometrial invasion and LVSI (focal/substantial) should be described for all EC pathology specimens [V, A].•Molecular classification through well-established IHC staining for p53 and MMR proteins (MLH1, PMS2, MSH2, MSH6) in combination with targeted tumour sequencing (POLE hotspot analysis) should be carried out for all EC pathology specimens regardless of histological type [IV, A].Staging and risk assessmentAlthough EC is a surgically-staged disease according to the FIGO system (Supplementary Table S1, available at https://doi.org/10.1016/j.annonc.2022.05.009), preoperative staging may help to establish a recurrence risk group and to define resulting surgical management, mainly on the basis of assessment of myometrial/cervical invasion and lymph node metastases. The preoperative work-up includes clinical and gynaecological examination, transvaginal ultrasound, a full blood count and liver and renal function profiles. Of note, magnetic resonance imaging (MRI) is considered the most accurate imaging technique for preoperative assessment of EC due to its excellent soft tissue contrast resolution. Depth of myometrial invasion and cervical stromal invasion are both important aspects of EC staging. Dynamic contrast-enhanced MRI and T2-weighted images are useful tools in the assessment of these features, with an accuracy of 98% and 90% for assessing myometrial and cervical stromal invasion, respectively.31Peungjesada S. Bhosale P.R. Balachandran A. et al.Magnetic resonance imaging of endometrial carcinoma.J Comput Assist Tomogr. 2009; 33: 601-608Crossref PubMed Scopus (25) Google Scholar An abdominal and thoracic computed tomography (CT) scan should be considered for investigating the presence of extrapelvic disease. [18F]2-Fluoro-2-deoxy-d-glucose-positron emission tomography (FDG-PET)-CT demonstrates high specificity and positive predictive value for detecting distant metastases.32Gee M.S. Atri M. Bandos A.I. et al.Identification of distant metastatic disease in uterine cervical and endometrial cancers with FDG PET/CT: analysis from the ACRIN 6671/GOG 0233 multicenter trial.Radiology. 2018; 287: 176-184Crossref PubMed Scopus (48) Google Scholar FDG-PET-CT has an excellent diagnostic performance for detecting lymph node metastasis preoperatively and disease recurrence post-operatively in EC patients and can be considered as an additional diagnostic procedure.33Bollineni V.R. Ytre-Hauge S. Bollineni-Balabay O. et al.High diagnostic value of 18F-FDG PET/CT in endometrial cancer: systematic review and meta-analysis of the literature.J Nucl Med. 2016; 57: 879-885Crossref PubMed Scopus (72) Google Scholar EC is diagnosed after histopathological examination of samples from dilation and curettage (D&C), or Pipelle biopsy. Hysteroscopy may be helpful to have a representative biopsy or for removal of the target lesion.Recommendations•Obtaining endometrial sampling by biopsy or D&C are acceptable initial approaches to histological diagnosis of EC [IV, A].•The preoperative work-up should include clinical and gynaecological examination, transvaginal ultrasound, pelvic MRI, a full blood count and liver and renal function profiles [IV, B].•Additional imaging tests (e.g. thoracic and abdominal CT scan and/or FDG-PET-CT) may be considered in those patients at high risk of extrapelvic disease [IV, C].Management of local and locoregional diseaseSurgeryIn early-stage EC, the aim of surgery is to remove macroscopic tumour, examine for microscopic metastases and stage the tumour to assess the need for adjuvant therapy (see Figure 2). Laparotomy has been the traditional surgical approach for the treatment of EC. Large, randomised trials and a meta-analysis have demonstrated that minimally invasive techniques have operative outcomes similar to laparotomy with respect to prognosis.34Janda M. Gebski V. Davies L.C. et al.Effect of total laparoscopic hysterectomy vs total abdominal hysterectomy on disease-free survival among women with stage I endometrial cancer: a randomized clinical trial.JAMA. 2017; 317: 1224-1233Crossref PubMed Scopus (195) Google Scholar,35Walker J.L. Piedmonte M.R. Spirtos N.M. et al.Recurrence and survival after random assignment to laparoscopy versus laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group LAP2 Study.J Clin Oncol. 2012; 30: 695-700Crossref PubMed Scopus (470) Google Scholar Even though the majority of patients included in these trials were low risk (e.g. G1 or G2), with only 17% of patients at higher risk (e.g. defined by G3), the laparoscopic approach can be extended to G3 tumours, since detrimental effects were not demonstrated. A robotic approach is a potential enhancement to standard laparoscopic surgery and may be especially beneficial in obese women. Standard surgery is hysterectomy with bilateral salpingo-oophorectomy. Preservation of ovaries can be considered in premenopausal patients with FIGO stage IA G1 EEC. Ovarian preservation is not recommended for patients at genetic risk for ovarian cancer (e.g. germline BRCA mutation, Lynch syndrome). Staging omentectomy should be considered in carcinosarcoma and serous type EC.Figure 2Stage I EC: surgery.Show full captionPurple: general categories or stratification; red: surgery; white: other aspects of management.EC, endometrial cancer; EEC, endometrioid-type endometrial cancer; LNE, lymphadenectomy.aExcept in those restricted to polyps.View Large Image Figure ViewerDownload Hi-res image Download (PPT)The risk of lymph node metastases ranges between <5% and 40% depending on grade, myometrial invasion and histology. Because the detection of lymph node metastases has an impact on adjuvant therapy, evaluation of lymph node status is recommended in patients with non-endometrioid histology, FIGO IB or G3 disease. Lymph node evaluation could be omitted in endometrioid FIGO IA G1-G2 disease since the risk of nodal metastasis is very low (<5%).36Katsoulakis E. Mattes M.D. Rineer J.M. et al.Contemporary analysis of pelvic and para-aortic metastasis in endometrial cancer using the SEER registry.Int J Gynaecol Obstet. 2014; 127: 293-296Crossref PubMed Google ScholarTwo prospective randomised trials have investigated the effect of systematic pelvic lymphadenectomy (LNE) in EC.37Benedetti Panici P. Basile S. Maneschi F. et al.Systematic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial.J Natl Cancer Inst. 2008; 100: 1707-1716Crossref PubMed Scopus (1156) Google Scholar,38Kitchener H. Swart A.M. Qian Q. et al.ASTEC study groupEfficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study.Lancet. 2009; 373: 125-136Abstract Full Text Full Text PDF PubMed Scopus (1388) Google Scholar These studies have not been able to demonstrate an improvement in prognosis, associated with LNE. Subsequently, multiple reasons were discussed to explain the results, such as the inclusion of patients with low-risk tumours, insufficient surgical quality and imbalance in adjuvant therapy. Therefore, it was concluded that both trials have shown that systematic LNE is not indicated in stage IA G1-G2 endometrioid tumours, but the trials could not provide firm guidance regarding optimal management of patients at a higher risk. The question of systematic LNE is being assessed in the ECLAT trial (NCT03438474).Sentinel node biopsy or sentinel LNE has emerged as alternative to lymph node dissection for lymph node staging. The sensitivity of sentinel LNE as a lymph node staging approach in early-stage EC patients has been endorsed by multiple studies favouring its implementation in surgical management.39Bogani G. Murgia F. Ditto A. et al.Sentinel node mapping vs. lymphadenectomy in endometrial cancer: A systematic review and meta-analysis.Gynecol Oncol. 2019; 153: 676-683Abstract Full Text Full Text PDF PubMed Google Scholar,40How J.A. O’Farrell P. Amajoud Z. et al.Sentinel lymph node mapping in endometrial cancer: a systematic review and meta-analysis.Minerva Ginecol. 2018; 70: 194-214PubMed Google Scholar The FIRES trial, the largest prospective cohort analysing the role of sentinel LNE in stage I EC, has shown that this approach can safely identify sentinel lymph nodes in EC. Currently the only data that support the sentinel LNE in terms of prognosis have been obtained from retrospective studies. Results from randomised clinical trials with a survival endpoint are still lacking. Sentinel LNE with indocyanine green is reported to be feasible and yields the best results from a technical perspective and is therefore the preferred method.41Rossi E.C. Kowalski L.D. Scalici J. et al.A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer staging (FIRES trial): a multicentre, prospective, cohort study.Lancet Oncol. 2017; 18: 384-392Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar Whether a positive pelvic sentinel lymph node evaluation indicates further retroperitoneal staging (pelvic and/or para-aortic LNE) is not yet defined. In conclusion, and based on data provided by prospective and retrospective studies,39Bog