Guideline sources The following summarized guidelines for the evaluation and management of endometrial cancer are prepared by our editorial team based on guidelines from the European Society of Medical Oncology (ESMO 2022), the American Society for Radiation Oncology (ASTRO 2022), the European Society for Radiotherapy and Oncology (ESTRO/ESP/ESGO 2021), the Society of Obstetricians and Gynaecologists of Canada (SOGC 2018), the U.S. Preventive Services Task Force (USPSTF 2017), and the Society of Gynecologic Oncology (SGO/ACOG 2015). 1 2 3 4 5 6 7 Calculator Calculator Calculat Eastern Cooperative Oncology G FIGO staging of uterine corpus c Karnof https://web.pathway.md/diseases/recof2ZFRnHotHQ7q 1/11 6/29/23, 4:15 AM Endometrial cancer Pathway Guidelines 1. Screening and diagnosis Indications for screening: insufficient evidence to assess the balance of benefits and harms of performing screening pelvic examinations in asymptomatic, nonpregnant adult females. I Indications for testing: As per SOGC 2018 guidelines, assess for and exclude endometrial cancer in perimenopausal and postmenopausal patients with abnormal vaginal bleeding. B As per SOGC 2018 guidelines, perform endometrial tissue sampling in postmenopausal patients with bleeding and an endometrial thickness of 4-5. B Do not perform routine endometrial sampling in postmenopausal females without bleeding. B Show 3 more 2. Classification and risk stratification Surgical staging: perform comprehensive surgical staging with total hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy, and the collection of peritoneal cytology in patients with endometrial cancer. Make exceptions to this approach only after consultation with a practitioner specializing in the treatment of endometrial cancer, such as a gynecologic oncologist. A Show 2 more 3. Diagnostic investigations Initial evaluation: elicit a complete focused history and perform a physical examination in patients with suspected endometrial cancer. Pay attention to predisposing factors for excess estrogen stimulation of the endometrium, such as a long history of anovulation, obesity, menstrual irregularity, or long-term use of unopposed estrogen or tamoxifen. B Show 2 more 4. Diagnostic procedures Hysteroscopy: As per SOGC 2018 guidelines, consider performing a hysteroscopic examination in patients with persistent uterine bleeding with benign endometrial sampling or insufficient endometrial sampling after ultrasound. C As per ACOG 2015 guidelines, perform hysteroscopy with directed dilation and curettage to include any discrete lesions as well as the background endometrium, to confirm the diagnosis of a true premalignant endometrial lesion and exclude an associated endometrial carcinoma. A Biopsy and histopathology: https://web.pathway.md/diseases/recof2ZFRnHotHQ7q 2/11 6/29/23, 4:15 AM Endometrial cancer Pathway As per ESMO 2022 guidelines: Perform endometrial sampling by biopsy or dilation and curettage for histological evaluation of endometrial cancer. B Describe the histological type, the FIGO grade, myometrial invasion, and lymphovascular space invasion (focal/substantial) in all endometrial cancer pathology specimens. B As per ESGO 2021 guidelines, record the histopathologic type, grade, myometrial invasion, and lymphovascular space invasion (no/focal/substantial) in all patients with endometrial carcinoma. B As per SOGC 2018 guidelines: Obtain histologic evaluation of the endometrium in all patients with suspected endometrial cancer. B Consider obtaining a formal review of the histopathology in patients with high-grade tumors or rare histologic types, such as serous, clear cell, or mucinous types. C As per ACOG 2015 guidelines, perform endometrial sampling in an outpatient setting with disposable devices for histologic evaluation of the endometrium. A Show 3 more Molecular testing: As per ASTRO 2022 guidelines, obtain molecular testing in patients with endometrial cancer eligible for adjuvant therapy: obtain immunohistochemistry to assess for mutations in mismatch repair and TP53 genes consider obtaining POLE sequencing to identify hypermutated tumors. B As per ESMO 2022 guidelines, obtain molecular classification through well-established immunohistochemistry staining for p53 and mismatch repair proteins (MLH1, PMS2, MSH2, MSH6) in combination with targeted tumor sequencing (POLE hotspot analysis) in all endometrial cancer pathology specimens regardless of histological type. B As per ESGO 2022 guidelines, obtain molecular classification in all endometrial carcinomas, especially high-grade tumors. B Show 2 more 5. Medical management Setting of care: Plan staging and treatment on a multidisciplinary basis (generally at a tumor board meeting, composed according to local guidelines) and based on the comprehensive and precise knowledge of prognostic and predictive factors for outcomes, morbidity, and quality of life. B Treat patients in a specialized center by a dedicated team of specialists in the diagnosis and management of gynecological cancers, especially in high-risk and/or advanced-stage diseases. B Management of local/locoregional disease, total hysterectomy: As per ESMO 2022 guidelines, perform hysterectomy with bilateral salpingo-oophorectomy as the standard surgical procedure in patients with early-stage endometrial cancer. A Show 2 more https://web.pathway.md/diseases/recof2ZFRnHotHQ7q 3/11 6/29/23, 4:15 AM Endometrial cancer Pathway As per ESP/ESTRO/ESGO 2021 guidelines, perform total hysterectomy with bilateral salpingo-oophorectomy without vaginal cuff resection as the standard surgery in patients with stage I/II endometrial cancer. B Perform total hysterectomy with bilateral salpingo- oophorectomy and lymph node staging as the surgical standard of care in patients with stage II endometrial carcinoma. B Show 4 more As per SGO/ACOG 2015 guidelines: Consider performing vaginal hysterectomy in selected patients with early-stage endometrioid endometrial cancer deemed at high risk of surgical morbidity. C Assess the risk of extrauterine disease and potential for disease recurrence based on age, histologic cell type, and uterine tumor features in patients found to have endometrial cancer incidentally after hysterectomy. Consider individualizing treatment plans based on the findings. B Management of local/locoregional disease, lymph node excision and surgical restaging: As per ASTRO 2022 guidelines, perform bilateral sentinel lymph node mapping over standard pelvic lymphadenectomy to accurately detect subclinical nodal metastases, decrease morbidity, and guide the selection of adjuvant therapy in patients with endometrial cancer. B Show 3 more As per ESMO 2022 guidelines, consider performing sentinel lymphadenectomy for nodal assessment in patients with low-risk/intermediate-risk endometrial cancer, i.e. stage IA G1- G3 and stage IB G1-G2. B Consider omitting it in cases without myometrial invasion. Do not perform systematic lymphadenectomy in these patients. C Show 2 more As per ESP/ESTRO/ESGO 2021 guidelines, perform staging infracolic omentectomy in clinical stage I serous endometrial carcinoma, carcinosarcoma, and undifferentiated carcinoma. Consider omitting it in clear cell and endometrioid carcinoma in stage I disease. B Show 8 more As per SGO/ACOG 2015 guidelines: Consider performing lymphadenectomy to alter or eliminate the need for adjuvant therapy and its associated morbidity. C Avoid performing systematic lymphadenectomy in patients with low-grade disease (grade 1 or grade 2 endometrioid lesions with < 50% myometrial invasion and tumor size of 2 cm) as they are deemed to be at low risk of lymph node metastases. D Management of local/locoregional disease, ovarian preservation: As per ESMO 2022 guidelines, consider performing ovarian preservation in premenopausal patients with stage IA G1 endometrial endometrioid carcinoma. B As per ESP/ESTRO/ESGO 2021 guidelines, consider performing ovarian preservation in < 45 years old premenopausal patients with low-grade endometrioid endometrial carcinoma with myometrial invasion < 50% and no obvious ovarian or other extrauterine diseases. B Show 2 more https://web.pathway.md/diseases/recof2ZFRnHotHQ7q 4/11 6/29/23, 4:15 AM Endometrial cancer Pathway As per SGO/ACOG 2015 guidelines, consider performing ovarian conservation at the time of hysterectomy in premenopausal patients with endometrial cancer wishing to retain ovarian function, but individualizing the decision after evaluation of the risk of extrauterine disease and the potential for disease recurrence based on age, histologic cell type, and uterine tumor features. C Management of local/locoregional disease, adjuvant therapy: As per ASTRO 2022 guidelines, do not offer adjuvant radiotherapy in patients with FIGO stage IA grade 1 or 2 endometrioid carcinoma without intermediate- or high-risk factors. D Show 10 more As per ESMO 2022 guidelines, offer adjuvant vaginal brachytherapy to decrease vaginal recurrence in patients with stage IA G3 or IB G1-G2 endometrioid (mismatch repair deficient and no specific molecular profile) type and no or focal lymphovascular space invasion. A Show 4 more As per ESP/ESTRO/ESGO 2021 guidelines, do not offer adjuvant treatment in patients with low-risk endometrial carcinoma. D Show 6 more As per SGO/ACOG 2015 guidelines: Offer adjuvant radiotherapy in patients with certain stage I and stage II endometrial carcinomas to reduce the local recurrence rate. A Offer vaginal brachytherapy over whole pelvic irradiation as the adjuvant treatment of choice in certain patients with a high-intermediate risk of recurrent endometrial cancer. A Management of local/locoregional disease, systemic therapy: As per ASTRO 2022 guidelines, do not offer systemic therapy in patients with FIGO stage I-II endometroid adenocarcinoma. D Consider offering systemic therapy in patients with myoinvasive FIGO stage I-II endometrial cancer with high-risk histologies. D As per ESMO 2022 guidelines, do not offer adjuvant treatment in patients with stage IA (G1 and G2) with endometrioid (mismatch repair deficient and no specific molecular profile) type and no or focal lymphovascular invasion. D Show 4 more Management of local/locoregional disease (medically unfit patients): consider offering vaginal hysterectomy, with bilateral salpingo-oophorectomy if feasible, in patients unfit for standard surgical therapy. C Show 2 more Management of local/locoregional disease (fertility preservation): refer patients eligible for fertility-preserving treatment to specialized centers. Consider offering fertility-sparing treatment only in patients with atypical hyperplasia/endometrioid intra-epithelial neoplasia or grade 1 endometrioid endometrial carcinoma without myometrial invasion and without genetic risk factors. B Perform endometrial biopsy, preferably through hysteroscopy, in these patients. B Confirm the diagnosis of atypical hyperplasia/endometrioid intra-epithelial neoplasia or grade 1 endometrioid endometrial carcinoma by a pathologist experienced in gynecological pathology B Show 10 more https://web.pathway.md/diseases/recof2ZFRnHotHQ7q 5/11 6/29/23, 4:15 AM Endometrial cancer Pathway Management of local/locoregional disease (estrogen therapy): consider offering estrogen therapy, after thorough counseling about the risks and benefits, for the management of menopausal symptoms in the survivors of early-stage endometrial cancer. B Management of advanced/metastatic disease: As per ASTRO 2022 guidelines, offer adjuvant systemic therapy in patients with FIGO stage III-IVA endometrial cancer of any histology. A Consider offering EBRT with chemotherapy to decrease locoregional recurrence. Consider offering EBRT with concurrent chemotherapy followed by adjuvant chemotherapy in patients receiving radiotherapy. B Consider offering sequential chemotherapy followed by radiotherapy in patients receiving radiotherapy. E As per ESMO 2022 guidelines, consider offering hormone therapy with progestins, i.e. medroxyprogesterone acetate 200 mg or megestrol acetate 160 mg, B or with other options including aromatase inhibitors, tamoxifen, and fulvestrant, C as front-line systemic therapy in patients with low-grade carcinomas endometrioid histology. B Show 5 more As per ESGO 2021 guidelines, consider performing surgical tumor debulking including enlarged lymph nodes in patients with stage III-IV endometrial carcinoma (including carcinosarcoma), if complete macroscopic resection is feasible with acceptable morbidity and quality of life profile, following full preoperative staging and discussion by a multidisciplinary team. C Show 5 more As per ACOG 2015 guidelines, offer chemotherapy for the management of patients with advanced endometrial cancer. A Consider offering a combination of chemotherapy and radiotherapy. B Show 2 more 6. Therapeutic procedures Technical considerations for radiotherapy: deliver intensity-modulated radiotherapy to reduce acute and late toxicity in patients with endometrial carcinoma undergoing adjuvant EBRT. B Show 4 more 7. Perioperative care Preoperative staging: As per ESMO 2022 guidelines: Include the following in the preoperative work-up: clinical and gynecological examination transvaginal ultrasound, pelvic MRI CBC, liver and renal function profiles. B Consider obtaining additional imaging (such as thoracic and abdominal CT and/or FDG- positron emission tomography-CT) in patients at high risk of extrapelvic disease. C As per ESGO 2021 guidelines, include the following in the preoperative work-up: https://web.pathway.md/diseases/recof2ZFRnHotHQ7q 6/11 6/29/23, 4:15 AM Endometrial cancer Pathway family history general assessment and inventory of comorbidities geriatric assessment, if appropriate clinical examination, including pelvic examination expert transvaginal or transrectal ultrasound or pelvic MRI. B Show 2 more As per ACOG 2015 guidelines: Do obtain routine preoperative imaging for the evaluation of metastases. A Consider obtaining a preoperative assessment of metastatic disease with imaging (CT, MRI, or positron emission tomography/CT) or measurement of serum CA-125, or both, under special circumstances, such as when the patient is a poor surgical candidate because of medical comorbidities, when symptoms suggest possible metastasis to unusual sites (such as bones or the CNS), and when preoperative histology demonstrates a high- grade carcinoma (including grade 3 endometrioid, papillary serous, clear cell, and carcinosarcoma). C 8. Specific circumstances Patients with Lynch syndrome: obtain mismatch repair immunohistochemistry (plus analysis of MLH1 promotor methylation status in case of immunohistochemical loss of MLH1/PMS2 expression) or MSI tests in all endometrial carcinomas, irrespective of histologic subtype of the tumor, to identify patients with Lynch syndrome and triage for germline mutational analysis. B Show 3 more 9. Patient education General counseling: counsel patients about the suggested diagnostic and treatment plan and potential alternatives, including risks and benefits of all options. B Genetic counseling: As per ESGO 2021 guidelines, provide genetic counseling in patients with endometrial carcinoma as having an increased risk of Lynch syndrome. B As per SOGC 2018 guidelines, provide genetic counseling and testing to individualize risk- management interventions including screening strategies and treatment options in patients at increased risk of having inherited Lynch syndrome (such as a strong family history of endometrial, ovarian, and colorectal cancers) increasing the lifetime risk of developing endometrial cancer. B 10. Follow-up and surveillance Follow-up: As per ESMO 2022 guidelines, perform physical and gynecological examinations every 6 months for the first 2 years and then yearly until 5 years in patients with low-risk endometrial https://web.pathway.md/diseases/recof2ZFRnHotHQ7q 7/11 6/29/23, 4:15 AM Endometrial cancer Pathway cancer B Consider arranging phone follow-ups as an alternative to hospital-based follow- up consultations in low-risk patients. B Show 2 more As per ACOG 2015 guidelines: Follow up patients after treatment of endometrial cancer every 3-6 months for 2 years, then every 6 months for 3 years, and annually thereafter. Elicit a thorough patient history, assess for new symptoms associated with recurrence (such as vaginal bleeding, pelvic pain, weight loss, or lethargy), and perform a thorough speculum, pelvic, and rectovaginal examination during follow-ups. Do not obtain vaginal cytologic evaluation and annual CXRs because most vaginal recurrences are detected with clinical examination alone and CXR is of low utility in detecting asymptomatic recurrence. B Obtain radiologic evaluation, such as CT or positron emission tomography/CT of the chest, abdomen, and pelvis, only to investigate suspicion of recurrent disease and not for routine surveillance after treatment. B Management of recurrent disease: As per ESMO 2022 guidelines, offer radiotherapy with vaginal brachytherapy as the preferred primary therapy in patients with locoregional recurrence following primary surgery. B Consider adding systemic therapy to salvage radiotherapy. B Show 2 more As per ESGO 2021 guidelines, consider performing surgery in patients with recurrent disease (including peritoneal and lymph node relapse) only if complete removal of macroscopic disease can be achieved with acceptable morbidity. Consider offering systemic treatment and/or radiotherapy postoperatively depending on the extent and pattern of relapse and the amount of residual disease. C Show 16 more Clinical findings Symptoms Past medical history Abdominal pain Cervical cancer Abnormal vaginal bleeding Colorectal cancer Bloating Diabetes mellitus Change in bowel habits Lynch syndrome Early satiety Nulliparity Menstrual irregularity Obesity Pelvic pain PCOS Vaginal bleeding Past obstetric history Medication history Postmenopause Estrogens Abdominal exam Tamoxifen Abdominal distension Family history Imaging findings Lynch syndrome https://web.pathway.md/diseases/recof2ZFRnHotHQ7q 8/11 6/29/23, 4:15 AM Endometrial cancer Pathway Ovarian cancer Endometrial hyperplasia Lab findings HE4 serum cancer antigen 125 Likelihood Ratios Pertinent positives The following findings increase the probability of endometrial cancer in adults. 7 Finding LR+ Value Presence of age 70* 8.2 History of estrogens 3.9 Presence of diabetes mellitus 2.6 History of nulliparity 2.3 in patients with abnormal vaginal bleeding Show 1 more Pertinent negatives The following findings decrease the probability of endometrial cancer in adults. 7 Finding LR- Value No history of postmenopause 0.4 Absence of age 70* 0.8 No history of nulliparity 0.8 No history of estrogens 0.9 in patients with abnormal vaginal bleeding Show 1 more Studies 2019 PORTEC-3 (post-hoc) In women with high-risk endometrial cancer, chemoradiotherapy was superior to radiotherapy alone with respect to overall survival at 5 years. Stephanie M de Boer et al. Lancet Oncol. 2019 Sep. 2018 PORTEC-3 In women with high-risk endometrial cancer, chemoradiotherapy was not superior to radiotherapy with respect to overall survival at 5 years. Stephanie M de Boer et al. Lancet Oncol. 2018 Mar. Show 2 more https://web.pathway.md/diseases/recof2ZFRnHotHQ7q 9/11 6/29/23, 4:15 AM Endometrial cancer Pathway References 1. Nicole Concin, Xavier Matias-Guiu, Ignace Vergote et al. ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma. Int J Gynecol Cancer. 2021 Jan;31 1 12 39. Open 2. A Oaknin, T J Bosse, C L Creutzberg et al. Endometrial cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022 Sep;33 9 860 877. Open 3. Matthew M Harkenrider, Nadeem Abu-Rustum, Kevin Albuquerque et al. Radiation Therapy for Endometrial Cancer: An ASTRO Clinical Practice Guideline. Pract Radiat Oncol. 2022 Oct 21;S1879 8500 22 00273 9. Open 4. Marie-Claude Renaud, Tien Le. No. 291 Epidemiology and Investigations for Suspected Endometrial Cancer. J Obstet Gynaecol Can. 2018 Sep;40 9):e703-e711. Open 5. American College of Obstetricians and Gynecologists. Practice Bulletin No. 149 Endometrial cancer. Obstet Gynecol. 2015 Apr;125 4 1006 1026. Open 6. US Preventive Services Task Force, Kirsten Bibbins-Domingo, David C Grossman et al. Screening for Gynecologic Conditions With Pelvic Examination: US Preventive Services Task Force Recommendation Statement. JAMA. 2017 Mar 7;317 9 947 953. Open 7. Wendy Wolfman. No. 249 Asymptomatic Endometrial Thickening. J Obstet Gynaecol Can. 2018 May;40 5):e367-e377. Open 8. Feldman S, Cook EF, Harlow BL et al. Predicting endometrial cancer among older women who present with abnormal vaginal bleeding. Gynecol Oncol. 1995 Mar;56 3 376 81. Open 9. Lambert M. Cancer Screening Recommendations from the ACS A Summary of the 2017 Guidelines. Am Fam Physician. 2018 Feb 1;97 3 208 210. Open 10. American Society for Radiation Oncology. Choosing Wisely ASRO recommendations. Choosing Wisely. 2014. Open 11. Society of Gynecologic Oncology. Choosing Wisely SGO recommendations. Choosing Wisely. 2013. Open 12. Koh WJ, Abu-Rustum NR, Bean S et al. Uterine Neoplasms, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2018 Feb;16 2 170 199. Open 13. Carien L Creutzberg, Remi A Nout, Marnix L M Lybeert et al. Fifteen-year radiotherapy outcomes of the randomized PORTEC 1 trial for endometrial carcinoma. Int J Radiat Oncol Biol Phys. 2011 Nov 15;81 4):e631 8. Open 14. B G Wortman, C L Creutzberg, H Putter et al. Ten-year results of the PORTEC 2 trial for high- intermediate risk endometrial carcinoma: improving patient selection for adjuvant therapy. Br J Cancer. 2018 Oct;119 9 1067 1074. Open 15. Stephanie M de Boer, Melanie E Powell, Linda Mileshkin et al. Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer PORTEC 3 final results of an international, open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Mar;19 3 295 309. Open 16. Stephanie M de Boer, Melanie E Powell, Linda Mileshkin et al. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer PORTEC 3 patterns of recurrence https://web.pathway.md/diseases/recof2ZFRnHotHQ7q 10/11 6/29/23, 4:15 AM Endometrial cancer Pathway and post-hoc survival analysis of a randomised phase 3 trial. Lancet Oncol. 2019 Sep;20 9 1273 1285. Open 17. SGO Clinical Practice Endometrial Cancer Working Group, William M Burke, James Orr et al. Endometrial cancer: a review and current management strategies: part I. Gynecol Oncol. 2014 Aug;134 2 385 92. Open 18. SGO Clinical Practice Endometrial Cancer Working Group, William M Burke, James Orr et al. Endometrial cancer: a review and current management strategies: part II. Gynecol Oncol. 2014 Aug;134 2 393 402. Open 19. N Colombo, E Preti, F Landoni et al. Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013 Oct;24 Suppl 6:vi33 8. Open 20. Ann Klopp, Benjamin D Smith, Kaled Alektiar et al. The role of postoperative radiation therapy for endometrial cancer: Executive summary of an American Society for Radiation Oncology evidence- based guideline. Pract Radiat Oncol. 2014 May-Jun;4 3 137 144. Open 21. Martin Koskas, Fr d ric Amant, Mansoor Raza Mirza et al. Cancer of the corpus uteri: 2021 update. Int J Gynaecol Obstet. 2021 Oct;155 Suppl 1 Suppl 1 45 60. Open https://web.pathway.md/diseases/recof2ZFRnHotHQ7q 11/11