（2026.V1）NCCN临床实践指南：子宫肿瘤

指南妇产科· 妇科疾病 · 2026

NCCN Guidelines Version 1.2026 Uterine Neoplasms

Table of Contents Discussion

*Nadeem R. Abu-Rustum, MD MD Q/Chair Memorial Sloan Kettering Cancer Center

*Susana M. Campos, MD, MPH, MS t/Vice Chair Dana-Farber/Brigham and Women's Cancer Center

Sudha Amarnath, MD §Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taissuc Cancer Institute

Rebecca Arend, MD 0'Oreal Comprehensive Cancer Center at UAB

Emma Barber, MD Q Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Kristin Bradley, MD §University of Wisconsin Carbone Cancer Center

Rebecca Brooks,MD ΩUC Davis Comprehensive Cancer Center

Junzo Chino, MD §Duke Cancer Institute

Hye Sook Chon, MD Ω Moffitt Cancer Center

Marta Ann Crispens, MD θ Vanderbilt-Ingram Cancer Center

Shari Damast, MD §Yale Cancer Center/Smilow Cancer Hospital

Christine M.Fisher,MD,MPH§University of Colorado Cancer Center

Peter Frederick,MD Q Roswell Park Comprehensive Cancer Center

David K. Gaffney, MD, PhD 8untsman Cancer Institute at the University of Utah

Stephanie Gaillard,MD,PhD t$\_$ Johns Hopkins Kimmel Cancer Center

Robert Giontli II, MD 16 Abramson Cancer Center at the University of Pennsylvania

Scott Glaser, MD §

City of Hope National Medical Center

Brooke E. Howitt, MD $ \neq$ Stanford Cancer Institute

Kari Kendra, MD, PhD †Liaison The Ohio State University Comprehensive Cancer Center-James Cancer Hospital and Solove Research Institute

Lisa Landrum, MD, PhD √ Indiana University Melvin and Bren Simon Comprehensive Cancer Center

Jayanthi Lea, MD $\Omega$ Comprehensive Cancer Center

Nita Lee,MD,MPHΩ The UChicago Medicine Comprehensive Cancer Center

Gina Mantia-Smaldone, MD Ω Fox Chase Cancer Center

Andrea Mariani, MD ΩMayo Clinic Comprehensive Cancer Center

David Mutch, MD Q

Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Christa Nagel, MD Ω

The Ohio State University Comprehensive Cancer Center-James Cancer Hospital and Solove Research Institute

Larissa Nekhlyudov,MD,MPH B Dana-Farber/Brigham and Women's Cancer Center

Chika Nwachukwu,MD,PhD\S

UC San Diego Moores Cancer Center

Mirna Podoll, MD ÷ ¥ Vanderbilt-Ingram Cancer Center

Kerry Rodabaugh,MD

Fred & Pamela Buffett Cancer Center

Ritu Salani, MD, MBA Q UCLA Jonsson Comprehensive Cancer Center

John Schorge, MD Ω

St. Jude Children's Research Hospital/The University of Tennessee Health Science Center

Scott Schuetze, MD, PhD

University of Michigan Rogel Cancer Center

Jean Siedel,DO,MSΩ

University of Michigan Rogel Cancer Center

Pamela Soliman, MD, MPH $\Omega$

The University of Texas MD Anderson Cancer Center

Stefanie Ueda,MD $\Omega$

UCSF Helen Diller Family Comprehensive Cancer Center

Renata Urban,MDΩ

Fred Hutchinson Cancer Center.

Emily Wyse ¥

Patient Advocate

NCCN

Nicole McMillian, MS

Vaishnavi Sambandam, PhD

Q Gynecologic oncology

D Internal medicine

+Medical oncology

≠ Pathology

§ Radiotherapy/Radiation oncology

*Discussion Section Writing Committee

NCCN Guidelines Index Table of Contents Discussion

National Comprehensive Cancer Cancer Network®

Find an NCCN Member Institution:https://www.nccn.org/home/member-institutions.

NCCN Uterine Neoplasms Panel Members Summary of the Guidelines Updates

Uterine Sarcoma

Diagnosed After Total Hysterectomy or Supracervical Hystereectomy± Bilateral Salapingo-Oophorectomy.

Uterine Neoplasms

(UTSARC-1)

NCCN Categories of Evidence and Consensus: All recommendations are category 2A unless otherwise indicated.

Uterine Neoplasms(UN-1)

Endometrial Carcinoma

Diagnosed by Biopsy or Myectomy(UTSARC-1)Low-Grade Endometrial Stromal Sarcoma(ESS) or

Adenosarcoma Without Sarcomatous Overgrowth

Disease Limited to the Uterus(ENDO-1)

(UTSARC-2)

See NCCN Categories of Evidence and Consensus.

Suspected or Gross Cervical Involvement(ENDO-2)

Adenosarcoma With Sarcomatous Overgrowth

Suspected Extrauter Disease (ENDO-3)

(UTSARC-2)

NCCN Categories of Preference:

Adjuvant Treatment for Surgically Staged Disease

(ENDO-4),(ENDO-5),(ENDO-6)

myosarcoma, and Other Sarcomas Such as Perivascular

All recommendations are considered appropriate.

Management After Simple/ Total Hysterectomy and BSO

Without Surgical Staging(ENDO-7)

Recurrence(UTSARC-5)

See NCCN Categories of Preference.

Criteria for Considering Fertility-Tparing Options (ENDO-8)

Surveillance (ENDO-9)

Principles of Pathology and Molecular Analysis

See NCCN Categories of Preference.

Locoregional Recurrence (ENDO-10)

(UTSARC-A)

See NCCN Categories of Preference.

Serous Carcinoma(ENDO-11)

Principles of Imaging(UTSARC-B)

Clear Cell Carcinoma(ENDO-12)

Systemic Therapy for Uterine Sarcoma(UTSARC-C)

Uterine Neoplasms

Principles of Radiation Therapy For Uterine Neoplasms

(UN-A)

Principles of Gynecologic Survivorship(UN-B)

Principles of Pathology and Molecular Analysis (ENDO-A)Principles of Imaging (ENDO-B)

Staging(ST-1)

Abbreviations(ABBR-1)

The NCCN Guidelines are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network®(NCCN®) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.C2025.

NCCN Guidelines Version 1.2026 Uterine Neoplasms

Version 1.2026, 11/04/25 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index Table of Contents Discussion

UPDATES Continued

Updates in Version 1.2026 of the NCCN Guidelines for Uterine Neoplasms from Version 3.2025 include:

Uterine Neoplasms

UN-1

• Initial Evaluation; New bullet added: Assess for distress

• Footnote e is new: Refer to the NCCN Distress Thermometer and Problem List, which includes social determinants of health. See NCCN Guidelines for Distress Management (DIS-A).

Endometrial Carcinoma

General

• The NCCN Guidelines for Management of Immunotherapy-Related Toxicities title changed to NCCN Guidelines for the Management of Immune

Checkpoint Inhibitor-Related Toxicities

ENDO-1

• Footnote f revised: Ovarian preservation may be safe in select patients who are premenopausal with early-stage stage IA G1, endometrioid cancer,

normal-appearing ovaries, and no family history of breast/ovarian cancer or Lynch syndrome. Absence of p53 abnormality, mismatch repair (MMR)

deficiency, lymphovascular space invasion (LVSI), and positive cytology are preferred. Salpingectomy is recommended.

ENDO-3

• Additional Workup; 1st bullet revised: Imaging as clinically indicated

• Suitable for primary surgery; Abdominal; pelvic-confined disease; Primary Treatment: Revised, TH/BSOc + surgical staging/debulking (consider

preoperative chemotherapy ) or Preoperative systemic therapy

• Footnote k revised: Consider ablative RT ablation for 1–5 metastatic lesions if hysterectomy is performed (category 2B) (Palma DA, et al. Lancet

2019;393:2051-2058).

ENDO-6

• Footnote removed: Combination therapy depends on assessment of both locoregional and distant metastatic risk. Consider combination therapy for

stage IIIB and IIIC disease.

ENDO-7

• This page was extensively revised and reorganized including:

New page title added: Management After Simple Total Hysterectomy And BSO Without Surgical Staging

Clinical Intrauterine Findings: Changed to, Post TH + BSO, but incompletely surgically staged

The pathway for "Stage IA, G1–2 with myometrial invasion and no LVSI" was moved before Imaging.

Column header revised: Adjuvant or Additional Treatment

ENDO-7A

• Footnote removed: Consider omitting imaging for stage IA, grade 1–2 endometrium-limited carcinoma.

NCCN Guidelines Version 1.2026 Uterine Neoplasms

NCCN Guidelines Index Table of Contents Discussion

UPDATES Continued

Endometrial Carcinoma–continued

ENDO-8

• Criteria for considering fertility-sparing options for management of endometrioid endometrial carcinoma (All criteria must be met)

1st column revised: Well-differentiated (Grade 1) endometrioid adenocarcinoma (preferred) on hysteroscopy, dilation and curettage (D&C) confirmed

by expert pathology review

• 2nd Column; 1st Bullet revised: Consultation with a fertility expert prior to therapy

• Primary Treatment

Revised: Levonorgestrel IUD (preferred for fertility preservation)

New bullet added: Consider hysteroscopic tumor evaluation and resection

• Column header revised: Surveillance changed to Monitoring

Revised: Endometrial evaluation every 3–6 mo (either hysteroscopy, D&C, or endometrial biopsy)

• Revised bifurcated pathways

Complete response by 6 mo

◊ Recommendation revised to be to become two separate bullets: "Encourage conception (with continued surveillance/endometrial sampling every 6–12 mo" and "Consider maintenance progestin-based therapy..."

◊ Last column; Top pathway revised: Ovarian preservation may be considered in select patients who are premenopausal

Endometrial cancer present at 6–12 6 mo

◊ After Endometrial cancer present at 6 mo, new pathway added for "Consider dual-progestin therapy [(Megestrol or Medroxyprogesterone) +

Levonorgestrel IUD] if not previously added"

• Footnote f added: Ovarian preservation may be safe in select patients who are premenopausal with stage IA G1, endometrioid cancer, normalappearing ovaries, and no family history of ovarian cancer or Lynch syndrome. Absence of p53 abnormality, MMR deficiency, LVSI, and positive

cytology are preferred. Salpingectomy is recommended.

ENDO-9

• Isolated metastases; Therapy for Relapse; Bullets revised

"Consider resection and/or EBRT/SBRT..."

Consider systemic therapy (category 2B)

• Footnote u revised: Consider ablative RT ablation for 1–5 metastatic lesions if the primary cancer has been controlled (category 2B) (Palma DA, et al.

Lancet 2019;393:2051-2058).

ENDO-10

• Column header revised: Therapy For Locoregional Relapse

"No prior RT to site..." pathway revised:

◊ EBRT± brachytherapy ± systemic therapy (category 2B for systemic therapy)

– Surveillance (ENDO-9) was added

◊ Surgical exploration + resection ± intraoperative RT (IORT) (category 3 for IORT)

– Revised: Locoregional disease Disease not confined to vagina or paravaginal soft tissue

Prior EBRT to site..." pathway revised:" Surgical exploration + resection ± IORT (category 3 for IORT)

• Additional Therapy; Top pathway revised: EBRT ± brachytherapy ± systemic therapy (category 2B for systemic therapy)

Updates in Version 1.2026 of the NCCN Guidelines for Uterine Neoplasms from Version 3.2025 include:

NCCN Guidelines Version 1.2026 Uterine Neoplasms

NCCN Guidelines Index Table of Contents Discussion

UPDATES Continued

Endometrial Carcinoma–continued

ENDO-11

• Serous carcinoma

Additional Workup: Consider CA-125 moved to be the last bullet. (Also for ENDO-12, ENDO-13, ENDO-14)

Additional Treatment for Noninvasive stage IA: Recommendations significantly revised, by removing qualifiers related to negative or positive

washings. New recommendations give the options: Observe or Systemic therapy ± vaginal brachytherapy or Vaginal brachytherapy. (Also for ENDO12)

• Footnote bb is new: Washings can help determine treatment planning. (Also for ENDO-12)

ENDO-12

• Clear Cell Carcinoma

Footnote cc was added: Principles of Molecular Analysis (ENDO-A 2 of 4). (Also for ENDO-13)

ENDO-13

Footnote b was added: Disease is not amenable to resection or patient is not suitable for surgery based on comorbidities. (Also for ENDO-14)ENDO-14

• Carcinosarcoma

Primary Treatment; Stages revised:

◊ Stage IA Stage I

◊ Stage IB, II, III, IV

Additional Treatment for Stage I: Systemic therapy + vaginal brachytherapy ± EBRT

Footnote cc revised: HER2 testing is recommended for advanced or metastatic disease. See Principles of Molecular Analysis (ENDO-A 2 of 4).

Footnote removed: Consider EBRT if both high-grade epithelial components and sarcoma are dominant (>50% of sarcoma component in uterine

tumor) (Matsuo K, et al. Surg Oncol 2018;27:433-440).

ENDO-A 1 of 4

• Footnote c revised:"...The current definition of substantial LVSI is ≥4 ≥5 (LVSI-involved vessels in at least one hematoxylin and eosin [H&E] slide) for

defining clinically relevant LVSI in endometrial cancer (Peters EEM, et al. Int J Gynecol Path 2022;41:220-226 WHO 5th Edition)."

ENDO-A 2 of 4

• 1st Bullet revised: "...associated with differing clinical prognoses: POLE mutations POLE-mutated, microsatellite instability-high (MSI-H) or..."

• 8th Bullet revised: "HER2 IHC testing (with or without reflex to HER2 fluorescence in situ hybridization [FISH] for equivocal IHC) is recommended for all p53 aberrant carcinomas regardless of histology and all metastatic/recurrent disease."

• 10th Bullet revised: Consider NTRK and RET gene fusion testing for metastatic or recurrent endometrial carcinoma.ENDO-B

• Initial Workup; Non-Fertility-Sparing Treatment; 2nd Bullet; 2nd arrow sub-bullet revised: "Consider chest imaging (chest x-ray)..."

• Footnote b revised: High-grade endometrial carcinoma includes: poorly differentiated endometrioid, serous, clear cell, undifferentiated carcinoma, and carcinosarcoma, and mesonephric-like adenocarcinoma.

ENDO-C

• Principles of Surgical Staging for Endometrial Cancer; New bullet added: Ovarian preservation may be safe in select patients who are premenopausal with stage IA G1 endometrioid cancer, normal-appearing ovaries, and no family history of ovarian cancer or Lynch syndrome. Absence of p53

abnormality, MMR deficiency, LVSI, and positive cytology are preferred. Salpingectomy is recommended.

Updates in Version 1.2026 of the NCCN Guidelines for Uterine Neoplasms from Version 3.2025 include:

NCCN Guidelines Version 1.2026 Uterine Neoplasms

NCCN Guidelines Index Table of Contents Discussion

UPDATES

Endometrial Carcinoma–continued

ENDO-D 1 of 6

• Primary or Adjuvant Therapy (Stage I-IV)

Chemoradiation Therapy; Other Recommended (if cisplatin and carboplatin are unavailable); The following agents were removed:

◊ Capecitabine/Mitomycin (category 2B)

◊ Gemcitabine (category 2B)

◊ Paclitaxel (category 2B)

Systemic Therapy

◊ Preferred; 5th Bullet revised: Carboplatin/Paclitaxel + Bevacizumab (for stage III–IV tumors with measurable disease)

◊ Other Recommended; New regimen added: Carboplatin/Paclitaxel/Durvalumab + Durvalumab/Olaparib (for stage III–IV pMMR tumors) (category 2B)

• Footnote b revised: For stage III or IVA with measurable disease post surgery or stage IVB with or without measurable disease. For patients not

meeting the eligibility criteria for NRG-GY018, carboplatin/paclitaxel + pembrolizumab should be considered for stage III–IV dMMR tumors (Van Gorp T,et al. Ann Oncol 2024;35:968-980 Published online August 23, 2024).

• Footnote c revised: NCCN Guidelines for Management of Immunotherapy-Related Toxicities For immunotherapy regimens, also refer to NCCN

Guidelines for the Management of Immune Checkpoint Inhibitor-Related Toxicities. (Also for ENDO-D 3A of 6)

• Footnote d revised: Checkpoint inhibitors and/or monoclonal antibodies and/or PARP inhibitors included in this regimen may be continued as

maintenance therapy. Refer to the original study protocol for maintenance therapy dosing schedules. (Also for ENDO-D 3A of 6)

• Footnote e is new: Pembrolizumab and berahyaluronidase alfa-pmph subcutaneous injection may be substituted for IV pembrolizumab. Pembrolizumab and berahyaluronidase alfa-pmph has different dosing and administration instructions compared to IV pembrolizumab. (Also for ENDO-D 3A of 6)

ENDO-D 2 of 6

• Recurrent Disease; First-Line Therapy

Revised header: Useful in Certain Circumstances (Biomarker-directed therapy: after prior platinum-based therapy including neoadjuvant and adjuvant)◊ Added: "MMR-proficient (pMMR) tumors: Carboplatin/Paclitaxel/Durvalumab + Durvalumab/Olaparib (category 2B)"

◊ New bullet added clarifying the noted regimens: "Biomarker-directed therapy: after prior platinum-based therapy including neoadjuvant and

adjuvant"

ENDO-D 3 of 6

• Recurrent Disease; Second-Line or Subsequent Therapy;

Useful in Certain Circumstances (Biomarker-directed therapy); The following regimens were added:

◊ pMMR tumors: Axitinib + Avelumab

◊ TMB-H tumors: Ipilimumab + Nivolumab

◊ MSI-H/dMMR tumors

– Tislelizumab-jsgr

– Retifanlimab-dlwr (category 2B)

◊ HER2-positive tumors (IHC 1+, 2+ or 3+): Fam-trastuzumab deruxtecan-nxki (for carcinosarcoma)

◊ RET gene fusion-positive tumors: Selpercatinib

ENDO-D 3A of 6

• Footnote o revised: "NCCN recommends TMB-H testing if not previously done. Pembrolizumab is The included checkpoint inhibitors are indicated for

patients with unresectable or metastatic tumors with TMB-H [≥10 mutations/megabase (mut/Mb)]..."

• Footnote p revised: For recurrent endometrial cancer, NCCN recommends MSI-H or dMMR testing if not previously done.

Continued

Updates in Version 1.2025 of the NCCN Guidelines for Uterine Neoplasms from Version 3.2024 include:

NCCN Guidelines Version 1.2026 Uterine Neoplasms

NCCN Guidelines Index Table of Contents Discussion

UPDATES Continued

Endometrial Carcinoma–continued

ENDO-D 4 of 6

• Hormonal Therapy for Recurrent or Metastatic Endometrial Carcinoma

Useful in Certain Circumstances; ER-positive tumors; The following regimens were added:

◊ Letrozole/Palbociclib

◊ Abemaciclib/Fulvestrant

• Hormonal Therapy for Uterine-Limited Disease Not Suitable for Primary Surgery or for Those Desiring Uterine Preservation for Fertility; Other

Recommended; First bullet revised: Progestational agents Continuous progestin-based therapy

ENDO-D 5 of 6 and ENDO-D 6 of 6

• References updated to reflect changes in the algorithm

Uterine Sarcoma

UTSARC-2

• Column Header Revised: Pathologic Findings/Histologic Grade Following TH ± BSO (Also for UTSARC-3)

• Additional Therapy

Low-grade ESS or Adenosarcoma without SO

◊ Stage I revised: BSO (preferred) or Observe, if menopausal or prior BSO

◊ Stage II, III, IVA, IVB revised: "BSO ± anti-estrogen hormone therapy Systemic endocrine therapy ± EBRT..."

Adenosarcoma with SO

◊ Stage I revised: BSO or Observe, if menopausal or prior BSO

• Footnote removed: See Discussion. Nasioudis D, et al. Int J Gynecol Cancer 2019;29:126-132.

UTSARC-4

• Isolated metastases; Therapy for Relapse revised:

Resectable: Consider preoperative or postoperative EBRT/SBRT

Unresectable:

◊ "... Local therapy (EBRT/SBRT or local ablative therapy)

◊ If response, consider surgery ± EBRT/SBRT

• Footnote l is new: Metastasectomy is the historical standard for patients with oligometastatic disease; the ultimate choice of local control modality may depend on factors such as performance status, patient preference, lesion location/accessibility, ability to preserve normal tissue function, and anticipated morbidity of a treatment modality.

• Footnote n is new: See Principles of Interventional Oncology (SARC-F pages 1–3) in the NCCN Guidelines for Soft Tissue Sarcoma.

UTSARC-5

• Therapy for Relapse:

No Prior RT: "Surgical exploration + resection ± IORT (category 3 for IORT)..."

Prior RT: "Surgical exploration + resection ± IORT ± systemic therapy (category 3 for IORT)..."

Updates in Version 1.2025 of the NCCN Guidelines for Uterine Neoplasms from Version 3.2024 include:

NCCN Guidelines Version 1.2026 Uterine Neoplasms

NCCN Guidelines Index Table of Contents Discussion

Updates in Version 1.2025 of the NCCN Guidelines for Uterine Neoplasms from Version 3.2024 include:

Uterine Sarcoma

UTSARC-A 1 of 8

• Molecular Analysis for Sarcoma; 2nd Bullet revised: "...is informative for predicting rare pan-tumor targeted therapy opportunities and should include at least MSI, BRCA 1/2, NTRK 1/2/3, MSI, RET fusion, ALK, and TMB..."

UTSARC-C 1 of 3

• Advanced, Recurrent/Metastatic or Inoperable Disease; Second-Line or Subsequent Therapy

Useful in Certain Circumstances (Biomarker-directed therapy); New regimens added:

◊ TMB-H tumors: Ipilimumab + Nivolumab

◊ CDK4 amplification: Palbociclib

UTSARC-C 1A of 3

• Footnote d is new: PEComa or tuberous sclerosis complex (TSC) pathogenic variant muscle tumor..

• Footnote f is new: Pembrolizumab and berahyaluronidase alfa-pmph subcutaneous injection may be substituted for IV pembrolizumab. Pembrolizumab and berahyaluronidase alfa-pmph has different dosing and administration instructions compared to IV pembrolizumab.

UTSARC-C 2 of 3

• Table title revised: Anti-Estrogen Hormone Therapy for Low-Grade ESS or Adenosarcoma Without SO or Hormone Receptor-Positive (ER/PR-Positive Uterine Sarcomas)

Preferred; 1st Bullet revised: Aromatase inhibitors for low-grade ESS or adenosarcoma without SO

Other Recommended; Bullets revised:

◊ Megestrol acetate (category 2B for ER/PR-positive uterine sarcomas)

◊ Medroxyprogesterone acetate (category 2B for ER/PR-positive uterine sarcomas)

◊ Bullet removed, "Aromatase inhibitors (for ER/PR-positive uterine sarcomas)" as well as corresponding agents:

– Anastrozole

– Letrozole

– Exemestane

UTSARC-C 3 of 3

• References updated to correspond with algorithm.

UPDATES

Continued

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Uterine Neoplasms

NCCN Guidelines Index Table of Contents Discussion

All staging in guideline is based on 2009 FIGO staging.(ST-1, ST-2, ST-3, and ST-4)INITIAL CLINICAL FINDINGSC

![### 8 8 9 0 P11 11 19:47\nNCCN NCCN Guidelines Version 1.2026\nNCCN Guidelines\n8 9 10 11 11 10 11 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10\n](2/aj0YEe4oUhYkBdfpda0fYP/figure64c5ecfc2ed7403996f765507151f1bf_0_5.png) a Initial preoperative evaluation for known or suspected malignancy.

bPreoperative imaging and biopsy may help to identify uterine sarcomas, although biopsy sensitivity is less than for endometrial cancer. If there is suspicion of malignancy, fragmentation/morcellation should be avoided.

cSee Principles of Pathology for Endometrial Carcinoma(ENDO-A) and Principles of Pathology and Molecular Analysis for Uterine Sarcoma(UTSARC-A).

d See Principles of Imaging for Endometrial Carcinoma(ENDO-B) and Principles of Imaging for Uterine Sarcoma(UTSARC-B).

e Refer to the NCCN Distress Thermometer and Problem List, which includes social determinants of health. See NCCN Guidelines for Distress Management(DIS-A).

f Consider referral to a center of expertise that specializes in the treatment of malignant mesenchymal tumors (sarcoma).

g Should be treated as a high-grade endometrial cancer.

h Also known as malignant mixed mesodermal tumor or malignant mixed Müller tumor, and including those with either homologous or heterologous stromal elements.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Endometrial Carcinoma

NCCN Guidelines Index Table of Contents Discussion

![INITIAL CLINICAL FINDINGS\nPrimary surgery\nSuitable for primary surgery\nTotal hysterectomy and bilateral salpingo-oophorectomy (TH/BSO)C and surgical staging d,e,f\n|Adjuvant treatment for surgically staged,e:\n● Stage I (ENDO-4)\n● Stage II (ENDO-5)\n● Stage III-IV (ENDO-6)\nDisease limited to the uterus\nNot suitable for primary surgery\nExternal beam radiation therapy (EBRT)g and/or brachytherapy9 (preferred)\nSurveillance (ENDO-9)\nary surgeryb\nLevonorgestrel intraturalerine device [IUD]\nin select patientsh\n](2/aj0YEe4oUhYkBdfpda0fYP/figurebcd58730e2bd46569deca1ea21a4209f_0_4.png) a See(UN-1) for classification of uterine neoplasms.

b Disease is not amenable to resection or patient is not suitable for surgery based on comorbidities.

c Principles of Pathology and Molecular Analysis(ENDO-A).

d Minimally invasive surgery(MIS) is the preferred approach when technically feasible. See Principles of Evaluation and Surgical Staging(ENDO-C).

e The degree of surgical staging to assess disease status depends on preoperative and intraoperative findings. Multidisciplinary expertise is recommended.See Principles of Evaluation and Surgical Staging(ENDO-C).

f Ovarian preservation may be safe in select patients who are premenopausal with stage IA G1, endometrioid cancer, normal-appearing ovaries, and no family history of ovarian cancer or Lynch syndrome. Absence of p53 abnormality, mismatch repair (MMR) deficiency, lymphovascular space invasion (LVSI), and positive cytology are preferred. Salpingectomy is recommended.

g Principles of Radiation Therapy for Uterine Neoplasms(UN-A).

h Systemic Therapy for Endometrial Carcinoma(ENDO-D).

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Endometrial Carcinoma

NCCN Guidelines Index Table of Contents Discussion

INITIAL CLINICAL FINDINGS (Endometrioid Histology)a

![Suspected or gross cervical involvement\nCervical biopsy or pelvis MRI (if not previously done)\nNegative result\nresult\nNegative result\nSuzpected or surgerical\nfor primary vsible MRI (if not previously done)\nSuitable for primary surgery\nTH/BSOC and surgical staging®\nEBRT$^{9}\pm brachytherapy9:\nTH/BSO^{c}\nfor primary\nor or surgerstical\nEBRT^{9}\pm brachytherapy4:\n\nSurveillance resection, if rendered operable and definitive RT9 if inoperable\nNot suitable for primary surgery\nSystemic therapy (category 2B)\nSurgical resection if rendered operable or EBRT9 and brachytherapy9\nand Surgical Staging(ENDO-C).\nSurveillance resection, if rendered operable and if inoperable\nSurveyillance (ENDO-9)\n](2/aj0YEe4oUhYkBdfpda0fYP/figureb630271ae77d4815abf4223751f68db5_0_5.png) a See (UN-1) for classification of uterine neoplasms.

b Disease is not amenable to resection or patient is not suitable for surgery based on comorbidities.

cPrinciples of Pathology and Molecular Analysis (ENDO-A).

eThe degree of surgical staging to assess disease status depends on preoperative and intraoperative findings. Multidisciplinary expertise is recommended. See Principles of Evaluation and Surgical Staging(ENDO-C).

g Principles of Radiation Therapy for Uterine Neoplasms(UN-A).

h Systemic Therapy for Endometrial Carcinoma (ENDO-D).

i Principles of Imaging(ENDO-B).

j Clear demonstration of cervical stromal involvement.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Endometrial Carcinoma

NCCN Guidelines Index Table of Contents Discussion

![INITIAL CLINICAL (Endometrioid Histology)a\nASUS-suspected intrauterine consider CA-125\nADDITIONAL WORKUP\nNo evidence of extrauterine disease\nABdominal/ pelvic-confined disease\nPreoperative systemic therapy\n±EDRT9\nSystemic therapy\n± EBRT9\n± stereotactic body\nRT (SBRT)^k\n± TH/BSOC\n± brachytherapyg\n± systemic therapyh $\pm$ systemic therapyh $4-12$ weeks post RT\nor\nRe-evaluate for surgical resection\nSurgical therapy\nSystemic therapyh $\pm$ ERDEPPG\n→ Reserveanetic and/or response response\nDistant metastases\nπ systematic therapyh $95^{\circ}$ RT (SBRT)^k\n√ESPERINGE7\nRe-evaluate for surgical resection\nSurgical resection and/or and response response\nInsiderature 80-155\nADSTant metastases\nT/BSO^c\nRe-evaluate for surgical resection\nENDO-9)\nSurveillance (ENDO-9)\n](2/aj0YEe4oUhYkBdfpda0fYP/figure7b738c9744b944c19b9a0ee09357e90e_0_4.png) a See (UN-1) for classification of uterine neoplasms.

b Disease is not amenable to resection or patient is not suitable for surgery based on comorbidities.

cPrinciples of Pathology and Molecular Analysis (ENDO-A).

g Principles of Radiation Therapy for Uterine Neoplasms(UN-A).

h Systemic Therapy for Endometrial Carcinoma(ENDO-D).

${}^{i}$ Principles of Imaging (ENDO-B).

k Consider ablation for 1-5 metastatic lesions if hysterectomy is performed.

l The surgical goal is to have no measurable residual disease.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN

NCCN Guidelines Version 1.2026 Endometrial Carcinoma

NCCN Guidelines Index Table of Contents Discussion

All staging in guideline is based on 2009 FIGO staging.(ST-1)

CLINICAL FINDINGS(Endometrioid Histology)a

HISTOLOGIC GRADE/ADJUVANT TREATMENT9,h,m

|FIGO Stage|Histologic Grade|Adjuvant Treatment| |---|---|---| |IA|G1, G2|Observation preferred or Consider vaginal brachytherapy if lymphovascular space invasion (LVSI) and/or age ≥ 60 yn| |IA|G3|Vaginal brachytherapy preferred or Consider observation if no myoinvasion or Consider EBRT if either age ≥ 70 y or LVSI(category 2B) IB| |IA|IB|G1| |G2|IB|Vaginal brachytherapy preferred or Consider EBRT if ≥60 y and/or LVSI or Consider observation if age <60 y and/or LVSI| |G3|IB|RT (EBRT and/or vaginal brachytherapy) ± systemic therapy (category 2B for systemic 2B)|

a See(UN-1) for classification of uterine neoplasms.

eThe degree of surgical staging to assess disease status depends on preoperative and intraoperative findings. Multidisciplinary expertise is recommended.See Principles of Evaluation and Surgical Staging(ENDO-C).

9 Principles of Radiation Therapy for Uterine Neoplasms(UN-A).

h Systemic Therapy for Endometrial Carcinoma(ENDO-D).

m Initiate EBRT as soon as the vaginal cuff is healed, preferably no later than 12 weeks after surgery.

nVaginal brachytherapy is strongly suggested if two risk factors are present.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Endometrial Carcinoma

NCCN Guidelines Index Table of Contents Discussion

All staging in guideline is based on 2009 FIGO staging.(ST-1)

HISTOLOGIC GRADE/ADJUVANT TREATMENT9,h,m

CLINICAL FINDINGS(Endometrioid Histology)a

||FIGO Stage|Histologic Grade|Adjuvant Treatment| |---|---|---|---| |Surgically staged:e: Stage I0,p|II|G1-G3|EBRT (preferred) and/or vaginal brachytherapyq ± systemic therapy (category 2B for systemic therapy)|

Surveillance (ENDO-9)

a See(UN-1) for classification of uterine neoplasms.

eThe degree of surgical staging to assess disease status depends on preoperative and intraoperative findings. Multidisciplinary expertise is recommended.See Principles of Evaluation and Surgical Staging(ENDO-C).

g Principles of Radiation Therapy for Uterine Neoplasms(UN-A).

h Systemic Therapy for Endometrial Carcinoma(ENDO-D).

m Initiate EBRT as soon as the vaginal cuff is healed, preferably no later than 12 weeks after surgery.

○Consider additional imaging if not previously done. See Principles of Imaging(ENDO-B).

$^{p}$ Adverse cervical risk factors including depth of stromal invasion, grade, LVSI, and adverse fundal risk factors influencing therapy decisions for stage l disease(ENDO-4),such as depth of myometrial invasion and LVSI, may also impact the choice of adjuvant therapy for stage II disease.

9Vaginal brachytherapy is also an option for grade 1 or 2,≤50% myometrial invasion, no LVSI, and microscopic cervical invasion (Harkenrider MM, et al. Int J Radiat Oncol Biol Phys 2018;101:1069-1077).

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Endometrial Carcinoma

NCCN Guidelines Index Table of Contents Discussion

All staging in guideline is based on 2009 FIGO staging.(ST-1)

CLINICAL FINDINGS $(E$ endometrioid Histology)a

ADJUVANT TREATMENT9,h

Surgically staged°:Systemic therapy Stage III, IVr^±BERT

a See (UN-1) for classification of uterine neoplasms.

eThe degree of surgical staging to assess disease status depends on preoperative and intraoperative findings. Multidisciplinary expertise is recommended.See Principles of Evaluation and Surgical Staging(ENDO-C).

g Principles of Radiation Therapy for Uterine Neoplasms(UN-A).

h Systemic Therapy for Endometrial Carcinoma(ENDO-D).

Additional imaging if not previously done. See Principles of Imaging (ENDO-B).

NCCN

NCCN Guidelines Version 1.2026 Endometrial Carcinoma

NCCN Guidelines Index Table of Contents Discussion

MANAGEMENT AFTER SIMPLE TOTAL HYSTERECTOMY AND BSO WITHOUT SURGICAL STAGING

CLINICAL INTRAUTERINE FINDINGS(Endometrioid Histology)a

![Stage IA, G1-2 with myometrial invasion and no LVSI\nStage IA, G3 no LVSI\nEndometrial Carcinoma\nStage IB, any grade or Any myometrial invasive carcinoma\nStage III\nSurgically restaged\nSurgically not restaged\nAdjuvant treatment for surgically.\nStage I (ENDO-4)\n●Stage I (ENDO-5)\n●Stage III (ENDO-6)\nRT9 (EBRT [preferred] and/or vaginal not restaged\nSurgically therapy (category 2B for systemic therapyh)\nAdjuvant treatment for surgically.\nStage II (ENDO-4)\nSurgically restaged\nAdjuvant treatment for surgically.\nAdjuvant treatment:●Stage I (ENDO-4)\nAdjuvant treatment for surgically\nSurgically restaged\nAdjuvant treatment for surgically\nAdjuvant treatment for surgically\nAdjuvant treatment for surgically\nAdjuvant treatment for surgically\nAdjuvant treatment for surgically\nAdjuvant treatment for,Gsaticy lages and surgesically restaged\nStage II (ENDO-5)\nAdjuvant treatment forjugically neuroline carcinoma\nStage II (ENDO-6)\nAdjualvant treatment:●Stage I (ENDO-4)\nAdjuvant treatment for$d^3$ \nStage II (ENDO-5)\nAdujant treatment:●Stage II (ENDO-6)\n](2/aj0YEe4oUhYkBdfpda0fYP/figure5d37b33f0c854e07b9d2b7929ce42dbf_0_6.png) All staging in guideline is based on 2009 FIGO staging.(ST-1)

Note: All recommendations are category 2A unless otherwise indicated.

Footnotes on ENDO-7A

Surveillance (ENDO-9)

NCCN Guidelines Version 1.2026 Endometrial Carcinoma

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

ENDO-7A

a See (UN-1) for classification of uterine neoplasms.e The degree of surgical staging to assess disease status depends on preoperative and intraoperative findings. Multidisciplinary expertise is recommended. See Principles of Evaluation and Surgical Staging (ENDO-C).

g Principles of Radiation Therapy for Uterine Neoplasms (UN-A).h Systemic Therapy for Endometrial Carcinoma (ENDO-D).i Principles of Imaging (ENDO-B).

FOOTNOTES FOR ENDO-7

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Endometrial Carcinoma

NCCN Guidelines Index Table of Contents Discussion

CRITERIA FOR CONSIDERING FERTILITY-SPARING OPTIONS FOR MANAGEMENT OF ENDOMETRIID ENDOMETRIID CARCINOMA(All criteria must be met)

● Grade 1 endometrioid adenocarcinoma (preferred) on hysteroscopy, dilation and curettage (D&C)confirmed by expert pathology review

●Disease limited to the endometrium on MRI(transvaginal ultrasoundil

● Absence of suspicious or metastatic disease on imaging

●No contraindications to medical therapy or pregnancy

●Patients should undergo counseling that fertility-sparing option is NOT standard of care for the treatment of endometrial carcinoma

● Consultation with a fertility expert

•Recommendation molecular evaluation of tumor and evaluation for inherited cancer risk(UN-1)

●Ensure negative pregnancy test

●Weight management/Lifestyle modification or the supporting case for the

PRIMARY TREATMENT

MONITORING

● Megestrol Medroxyprogesterone evaluation and

● Consider hysteroscopic tumor evaluation and resection

•Consider dual-progestin therapy of endometrial biopsy)

+ Levonorgestrel IUD]

●Weight management/lifestyle modification

Complete response

Endometrial evaluation every 3-6 mo(either hysteroscopy,D&C, or endometrial biopsy)

Consider dual-progestin therapy [(Megestrol or Medroxyprogesterone) + Levonorgestrel lUD] if not previously added

d MIS is the preferred approach when technically feasible. See Principles of Evaluation and Surgical Staging (ENDO-C).

e The degree of surgical staging to assess disease status depends on intraoperative findings.Multidisciplinary expertise is recommended. See Principles of Evaluation and Surgical Staging(ENDO-C).

f Ovarian preservation may be safe in select patients who are premenopausal with stage IA G1,endometrioid cancer, normal-appearing ovaries, and no family history of ovarian cancer or Lynch syndrome.Absence of p53 abnormality, MMR deficiency, LVSI, and positive cytology are preferred.Salpingectomy is recommended.

iPrinciples of Imaging(ENDO-B).

s See Healthy Lifestyles (HL-1) and Nutrition and Weight Management (SNWM-1) in the NCCN Guidelines for Survivorship.

TH/BSO with stagingd,e after childbearing complete or progression every 6-12 mo to ose 2 endometrial mo

ENDO-8

![NCCN\nNational Comprehensive Cancer Network®\n](2/aj0YEe4oUhYkBdfpda0fYP/figurefbb35d718caa49988c98cfe85d593c69_0_1.png)

NCCN Guidelines Version 1.2026 Endometrial Carcinoma

NCCN Guidelines Index Table of Contents Discussion

![SURVEILLANCE\nCLINICAL PRESENTATION\nTherapy for Locoregional Relapse(ENDO-10)\n\n•Physical exam (including pelvis) every 3-6 mo for 2-3 y,then every 6-12 mo for up to year 5,then annually\n●CA-125 if initially elevated or serous histology\n●lmaging as indicated based on symptoms or examination findings suspicious for recurrence\n●Clinical evaluation and management of potential long-term and late effects of treatment${}^{t}$ (Also see Principles of Gynecologic Survivorship (UN-B), NCCN Guidelines for Survivorship, and NCCN Guidelines for Smoking)\nDisseminated metastases\nSystemic therapy${}^{t}$ \n±palliative EBRT${}^{9}$ \nIn isolated Ablative therapy${}^{u}$ \nConsider resection and/or EBRT/SBRT${}^{9}$ \nConsider the treatment therapy\nNot amenable tolocal treatment\n\nFurther recurrence\n\n(See below)\nThreat as nematically\nAssiderated and/or EBRT/SBRT${}^{9}$ \nOblative therapy\n●Consider systemic counseling.\n●Consider ablation for 1-5 metastatic lesions if the primary cancer has been controlled.\nSystemic therapy${}^{t}$ \n±palliative EBRT${}^{9}$ \nIf progression, the process and the process and the process and the process and the process and the process and the process and the process and the process and the process and the process and the process and the process and the process and the process and the process and the process and the process and the process and the p\n](2/aj0YEe4oUhYkBdfpda0fYP/figure475eb03b214740db8fa04a9120884973_0_4.png) g Principles of Radiation Therapy for Uterine Neoplasms(UN-A).

h Systemic Therapy for Endometrial Carcinoma(ENDO-D).

iPrinciples of Imaging(ENDO-B).

t Patient education should include symptoms of potential recurrence, lifestyle, obesity, exercise, sexual health (including vaginal dilator use, lubricants/moisturizers, and local estrogen and hormone therapy for menopause), smoking cessation, and nutrition counseling.

uConsider ablation for 1-5 metastatic lesions if the primary cancer has been controlled.

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Endometrial Carcinoma

NCCN Guidelines Index Table of Contents Discussion

CLINICAL PRESENTATION

THERAPY FOR LOCOREIONAL RELAPSE

ADDITIONAL THERAPY

![###\nLocoregional recurrence\n±3raotherytherapy&g(category 2B for systemic therapy)\nNo prior RT to site of recurrence or previous vaginal brachytherapy only\n\nSurgical exploration\n±3raotherytherapy±intraoperative RT(IORT)\nSurveillance (ENDO-9)\nEBRTg\n± systemic therapy)\nDisease confined to vaginal or soft tissue\n±erential therapy\nEBRTg,z\n± systemic therapy)\nDisease not confined to lymph node(s)\nVagina or soft tissue\nMicroscopic residual disease\n±EBRT9,z\n±erential therapy\nGross upper and abdominal\n+seminated residual disease\nTherapy for Thedyamp [ENDO-9)]\nUper abdominal abdominal residual disease\nThedno-9)]\nGross upper and abdominal metastases (ENDO-9)]\nThedno-9)\n](2/aj0YEe4oUhYkBdfpda0fYP/figureac42891fe11048ef91d698aa375d685f_0_7.png) g Principles of Radiation Therapy for Uterine Neoplasms(UN-A).

h Systemic Therapy for Endometrial Carcinoma(ENDO-D).

iPrinciples of Imaging(ENDO-B).

vMay include patients with isolated common iliac or para-aortic lymph node recurrence.

wConsidered preoperative EBRT in select patients.

x Recommended for small-volume vaginal and/or paravaginal disease.

y Consider brachytherapy for locregional disease with a vaginal component.

z Post-resection consolidation EBRT can be considered in patients who were not previously irradiated or who are deemed to have additional tolerance for radiation.

Surveillance (ENDO-9)ENDO-10

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Endometrial Carcinoma: Serous Carcinoma

NCCN Guidelines Index Table of Contents Discussion

![ADDITIONAL WORKUP\n PRIMARY TREATMENT\n TREATMENT\n Noninvasive stage IA\n No residual uterine disease and negative surgical staging\n Noninvasive stage IA\n Observe\6 bb\n or\n Noninvasive der stage IA\n Systemic therapy h % vaginal brachytherapy g or \\ vaginal brachytherapy g\n or\nStaging\n Noninvasive Systemed ondetometrial Carcinoma: Serous Carcinoma\n ADDITIONAL WORKUP\n TREATMENT\n PRIMARY TREATMENT\n Observe\68aninvasive surging th stage IA\n Observe\68aninvasive surging th stage IA\n Systemic therapy h % vaginal brachytherapy g or vaginal brachytherapy g\n Noninvasive Systemed therapy h % vaginal brachytherapy g (ENDO-9) |\ngmission of Medical Treatment\n Biopsy findings: Serous carcinomaaa\n| Imagingi · Consider carcinoma aa\n| 4- Bachytherapy^g\n surging.d e Systematic therapy h % suitable for primary surgery\n STable program of survival during surgical surgery\n Not suitable for primary surgery\nEBRT^9 ± brachytherapy^g\n Systolic therapy'su6b\n ARPT9 based on and Surgical Staging (ENDO-C). 9 Principles of Imaging (ENDO-B).h Systemic Therapy for Endometrial Carcinoma (ENDO-D). 16 Principles of Imaging (ENDO-B). aa HER2 testing is recommended for advanced or metastatic disease. See Principles of Molecular Analysis (ENDO-A 2 of 4).\n Survey difference (ENDO-9)\n [Normal Study in the end of the end is the following the following 16深圳市\n BeRT5 ± vaginal brachytherapy g or vaginal brachytherapy g\n Systemic therapy^h,aa ± vaginal brachytherapy g or vaginal brachytherapy g\n Surgical therapy'su6b\n Re-evaluate for surgerical resection and/or RT9 based on response\n](2/aj0YEe4oUhYkBdfpda0fYP/figure4a15a5afd1764715aa085d03dfcec6c6_0_4.png) b Disease is not amenable to resection or patient is not suitable for surgery based on comorbidities.

d MIS is the preferred approach when technically feasible. See Principles of Evaluation and Surgical Staging (ENDO-C).

e The degree of surgical staging to assess disease status depends on intraoperative findings. Multidisciplinary expertise is recommended. See Principles of Evaluation and Surgical Staging(ENDO-C).

g Principles of Radiation Therapy for Uterine Neoplasms(UN-A).

h Systemic Therapy for Endometrial Carcinoma(ENDO-D).

${}^{i}$ Principles of Imaging (ENDO-B).

aa HER2 testing is recommended for advanced or metastatic disease. See Principles of Molecular Analysis (ENDO-A 2 of 4).

bb Washings can help determine treatment planning.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Endometrial Carcinoma:Clear Cell Carcinoma

NCCN Guidelines Index Table of Contents Discussion

![# 2.3.4\n 3.6\n 3.7\n 3.8\n 3.9\n 3.7\n 3.8\n 3.4\n 3.6\n1.2000 1.2006\nNCCN\n General Results Version 1.2026\n NCCN Guidelines 1.026.5\n 3.6\n 3.4\n 3.5\n 3.6\n1.2004\nADDITIONAL WORKUP\n PRIMARY TREATMENT\n No residual uterine disease and negative surgical staging\nNoninvasive system stage IA\n |TH/BSO and surgical stage IA\n+ vaginal brachytherapyg\nor\nNot suitable for primary surgery\n|ST-1\n| Systemic therapy h $2.5$\+ vaginal brachytherapyg\nor\nADquinal brachytherapyg\n\n\n|SeBT9 ± BUbrachytherapyg\n± brachytherapyg\n\n||PRIVE stage IA\n|Invasive stage IA\n± vaginal brachytherapyg\nor\nSystemic therapy h $2.5$\+ vaginal brachytherapyg\nodged during the subsequent therapy\n+ average transgedy 3.5\n2.6.6\+ AU 7.1\n3.6.7\n1.2004\n1.5.6\n1.3\nSurgery\nNot suitable for primary surgery\n|ST-1|Re-evaluate for surgical surgery resection and/or RT9 based on response\nAll staging in guideline is based on 2009 FIGO staging.(ST-1)\n8.6.5.6\n9.6.6\n1.2.4\n1.3.5\n1.4.6\n1.5.6\n1.6.7\n1.5.6\n1.4.6\n1.5.5\n1.6.8\n1.5.6\n1.5.7\n1.6.9\n1.5.6\n1.5.5\n1.6.9\n1.5.6\n1.5.7\n1.6.8\n1.5.5\n1.6.9\n1.5.6\n1.5.5\n1.6.9\n1.5.7\n1.6.8\n1.5.5\n1.6.9\n1.5.5\n1.6.9\n1.5.7\n1.6.8\n1.5.5\n1.6.9\n1.5.5\n1.6.9\n1.5.5\n1.6.8\n1.5.4\n1.5.6\n1.5.7\n1.5.6\n1.5.5\n1.6.9\n1.5.5\n1.6.8\n1.5.4\n1.5.6\n1.5.7\n1.5.6\n1.5.5\n1.6.9\n1.5.5\n1.6.9\n1.5.5\n1.6.9\n1.5.4\n1.5.6\n1.5.5\n1.6.9\n1.5.5\n1.6.9\n1.5.4\n1.5.6\n1.5.5\n1.6.8\n1.5.4\n1.5.6\n1.5.7\n1.5.6\n1.5.5\n1.6.9\n1.5.5\n1.6.9\n1.5.4\n1.5.6\n1.5.5\n1.6.9\n1.5.4\n1.5.5\n1.6.9\n1.5.4\n1.5.6\n1.5.5\n1.6.9\n1.5.4\n1.5.6\n1.5.4\n1.5.5\n1.6.9\n1.5.5\n1.6.9\n1.5.4\n1.5.6\n1.5.4\n1.5.5\n1.6.9\n1.5.5\n1.6.9\n1.5.4\n1.5.6\n1.5.4\n1.5.5\n1.6.9\n1.5.4\n1.5.6\n1.5.4\n1.5.5\n1.6.9\n1.5.4\n1.5.6\n1.5.4\n1.5.6\n1.5.4\n1.5.6\n1.5.4\n1.5.6\n1.5.4\n1.5.6\n1.5.4\n1.5.6\n1.5.4\n1.5.6\n1.5.4\n1.5.6\n1.5.4\n1.5.6\n1.5.4\n1.5.6\n1.5.4\n1.5.6\n1.5.4\n1.5.6\n1.5.4\n1.5.6\n1.5.4\n1.5.6\n1.5.4\n1.5.6\n1.5.4\n1.5.6\n1.5.4\n1.5.6\n1.5.4\n1.5.6\n1.5.4\n1.5.6\n1.5.4\n1.5.6\n1.5.4\\n](2/aj0YEe4oUhYkBdfpda0fYP/figure15458d38921240c4a151962868ea54e3_0_4.png) All staging in guideline is based on 2009 FIGO staging.(ST-1)

e The degree of surgical staging to assess disease status depends on intraoperative findings. Multidisciplinary expertise is recommended.

See Principles of Evaluation and Surgical Staging (ENDO-C).

b Disease is not amenable to resection or patient is not suitable for surgery based on comorbidities.

9 Principles of Radiation Therapy for Uterine Neoplasms(UN-A).

h Systemic Therapy for Endometrial Carcinoma (ENDO-D).

d MIS is the preferred approach when technically feasible. See Principles of Evaluation and Surgical Staging(ENDO-C).

${}^{i}$ Principles of Imaging (ENDO-B).

bb Washings can help determine treatment planning.

cc Principles of Molecular Analysis (ENDO-A 2 of 4).

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Endometrial Carcinoma:

NCCN Guidelines Index Table of Contents Discussion

All staging in guideline is based on 2009 FIGO staging.(ST-1)

ADDITIONAL WORKUP

![# Biopsy findings: Undifferentiated/ dedifferentiated/ cadence CA-125\n | Imagingi $\cdot$ Consider primary surgery\n Not suitable\n for primary surgery\n Suitable for\n Shysteo program\n ± EBRT9\n staging d,e\n ± EBRT9\n ± vaginal brachytherapy9\n Re-evaluate for surgical resection and/or RT9 based on response\n Systemic therapyh $\pm EBRT^{�9}$\n $\pm EBRT^{⑨}$ based on response\n](2/aj0YEe4oUhYkBdfpda0fYP/figurefe561615cf3a43cd8278db9fc00cd446_0_6.png) b Disease is not amenable to resection or patient is not suitable for surgery based on comorbidities.

d MIS is the preferred approach when technically feasible. See Principles of Evaluation and Surgical Staging(ENDO-C).

eThe degree of surgical staging to assess disease status depends on intraoperative findings. Multidisciplinary expertise is recommended. See Principles of Evaluation and Surgical Staging(ENDO-C).

g Principles of Radiation Therapy for Uterine Neoplasms(UN-A).

h Systemic Therapy for Endometrial Carcinoma(ENDO-D).

iPrinciples of Imaging(ENDO-B).

CC See Principles of Molecular Analysis (ENDO-A 2 of 4).

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Endometrial Carcinoma: Carcinosarcoma

NCCN Guidelines Index Table of Contents Discussion

![# 2.3.4\n 3.6\n 3.7\n 3.8\n 3.9\n 3.7\n 3.8\n 3.4\nADDITIONAL WORKUP\nAdditional WORKUP\nPRIMARY for primary surgery\nTH/BSO and surgical staging d,e consider surgical tumor debulking for gross disease\nStage I\nStandarditional TREATMENT\nAdditional Treatment TREATMENT\nSystemic therapy$h+3$vaginal brachytherapy$g,ee\n* $\pm$ SBRT$g,ff$\pm$EBRT$g,ff$\pm$Vaginal brachytherapy$g,ee\n|ENDR99|Re-evaluate for surviable resection of systemic therapy$h+2$-envolutional therapyplastic therapy\n\nor\n#####################(ENDO-9)\n](2/aj0YEe4oUhYkBdfpda0fYP/figurebea5fd20f36d48b39c4b5abf79e57fca_0_4.png) b Disease is not amenable to resection or patient is not suitable for surgery based on comorbidities.

d MIS is the preferred approach when technically feasible. See Principles of Evaluation and Surgical Staging (ENDO-C).

eThe degree of surgical staging to assess disease status depends on intraoperative findings. Multidisciplinary expertise is recommended.

See Principles of Evaluation and Surgical Staging (ENDO-C).

g Principles of Radiation Therapy for Uterine Neoplasms(UN-A).

h Systemic Therapy for Endometrial Carcinoma(ENDO-D).

iPrinciples of Imaging(ENDO-B).

aa HER2 testing is recommended for advanced or metastatic disease. See Principles of Molecular Analysis (ENDO-A 2 of 4).

dd Also known as malignant mixed mesodermal tumor or malignant mixed Müllerian tumor.

ee Initiation of chemotherapy within 3-6 weeks postoperatively should be considered. Vaginal brachytherapy can be interdigitated with chemotherapy starting 6 weeks postoperatively.

ff Consider EBRT if both high-grade epithelial components and sarcoma are dominant(>50% of sarcoma component in uterine tumor)(Matsuo K,et al. Surg Oncol 2018;27:433-440).

NCCN Guidelines Version 1.2026 Endometrial Carcinoma

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

ENDO-A 1 OF 4 References

• Uterus

Hysterectomy type

Specimen integrity (intact, opened, morcellated, other)

Tumor site (endometrium, lower uterine segment, polyp)

Tumor size

Histologic type

Histologic grade (if applicable)

Myometrial invasion (depth of invasion in mm/myometrial thickness in mm)

Cervical stromal involvementb

LVSIc

• Other tissue/organ involvement (fallopian tubes, ovaries, vagina, parametrium, peritoneum, omentum, other)

• Peritoneal/ascitic fluid cytologyd

• Lymph nodes (when resected)

Sentinel lymph nodes (SLNs) should undergo ultrastaging for detection of low-volume metastasis.e

Isolated tumor cells are staged N0(i+) and should not upstage patients, but should be considered in the discussion of adjuvant therapy.

Level of nodal involvement (ie, pelvic, common iliac, para-aortic)

Number of lymph nodes with isolated tumor cells, micrometastasis, and macrometastasis

Thorough gross evaluation of the SLN tissue specimen is recommended to ensure that lymph node tissue is included. This could be performed

either by the surgeon (depending on experience/comfort level with gross evaluation) or by seeking an intraoperative pathology consultation.

• Morphologic evaluation of endometrial carcinoma to determine histologic type—especially in high-grade cancers—is challenging and issues exist regarding diagnostic reproducibility.4,5

Pathologic Assessment for Carcinoma (including carcinoma, carcinosarcoma, and neuroendocrine carcinoma):

Procedure:

• TH/BSO: Total hysterectomy + bilateral salpingo-oophorectomy

• RH: Radical hysterectomy

a Principles of Evaluation and Surgical Staging (ENDO-C).b Additional information including depth of invasion in mm/cervical wall thickness in mm may be requested by radiation oncologists to aid in the decision for EBRT.c Pathologists may be asked to quantify LVSI. The current definition of substantial LVSI is ≥5 (LVSI-involved vessels in at least one hematoxylin and eosin [H&E] slide) WHO 5th Edition).

d Although cytology by itself does not affect FIGO staging, cytology results should still be obtained because positive cytology is an adverse risk factor.e Ultrastaging commonly entails thin serial sectioning of the gross SLN and review of multiple H&E-stained sections with or without cytokeratin immunohistochemistry (IHC) for all blocks of SLN. There is no standard protocol for lymph node ultrastaging.

PRINCIPLES OF PATHOLOGYa,1,2,3

Continued

NCCN Guidelines Version 1.2026 Endometrial Carcinoma

NCCN Guidelines Index Table of Contents Discussion

• Molecular analysis of endometrial carcinoma has identified four clinically significant molecular subgroups associated with differing clinical prognoses: POLE-mutated, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), no specific molecular profile (NSMP),and p53 aberrant.6,7

• Retrospective analyses indicate that these four molecular subgroups may respond to therapy differently and therefore may require

escalation or de-escalation of therapy compared to previous guidelines. Prospective randomized trials are ongoing to determine the role of a molecular profile–guided treatment strategy in the management of high-intermediate-risk and high-risk endometrial carcinomas.

• Ancillary studies for POLE mutations (pathogenic mutations in the exonuclease domain), immunohistochemical (IHC) staining for mismatch repair (MMR) or MSI testing, and p53 IHC are recommended to complement morphologic assessment regardless of histologic tumor type.8

See Figure 1: Pathology and Genomics in Endometrial Carcinoma (ENDO-A 3 of 4).

• Comprehensive molecular profiling is strongly encouraged via an FDA-approved assay, or a validated test performed in a Clinical Laboratory Improvement Amendment (CLIA)-certified laboratory, in the initial evaluation of uterine neoplasms.

• For tumors that are POLE-mutated, MSI-H, p53 aberrant, or NSMP, clinical trial enrollment is strongly encouraged.

• Molecular testing may be performed on the initial biopsy or D&C material or the final hysterectomy specimen.

• Evaluation for MMR status is commonly done using IHC. Molecular profiling via next-generation sequencing (NGS) panels or MSI polymerase chain reaction (PCR) assay are acceptable alternatives.

MSI testing is recommended if IHC results are equivocal.

MLH1 loss should be further evaluated for promoter methylation to assess for an epigenetic mechanism.

Genetic counseling for any suspected germline mutation is strongly recommended.

For those who have a strong family history of endometrial and/or colorectal cancer, genetic counseling and testing are recommended

regardless of MMR or MLH1 promoter methylation results [see Lynch Syndrome (LS-1) in the NCCN Guidelines for Genetic/Familial HighRisk Assessment: Colorectal, Endometrial, and Gastric].

• HER2 IHC testing (with or without reflex to HER2 fluorescence in situ hybridization [FISH] for equivocal IHC) is recommended for all p53

aberrant carcinomas regardless of histology and all metastatic/recurrent disease.9-12

• Estrogen receptor (ER) and progesterone receptor (PR) testing is recommended in the settings of stage III, stage IV, and recurrent disease.

• Consider NTRK and RET gene fusion testing for metastatic or recurrent endometrial carcinoma.

• Consider tumor mutational burden (TMB) testing through an FDA-approved assay, or a validated test performed in a CLIA-certified

laboratory.13

PRINCIPLES OF MOLECULAR ANALYSIS

Note: All recommendations are category 2A unless otherwise indicated.

ENDO-A 2 OF 4 References

Continued

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PRINCIPLES OF MOLECULAR ANALYSIS

FIGURE 1: PATHOLOGY AND GENOMICS IN ENDOMETRIAL CARCINOMA

(The decision to use molecular testing/classification depends on the availability of resources and the multidisciplinary team of each center.) ${}^{f,g}$

![No POLE pathogenic mutation\nPOLE sequencing\nMOLE\nNormal\nPOLE pathogenic mutation\nAberrant\ndMMR or MSI-H\nNormal/Wild-type pattern\nNormal/Wild-type pattern\nAberrant/Mutant pattern\np53 immunohistochemistry\nAberrant/Mutant pattern\ndMMR or MSI-H\nNSMP\np53 aberrant\n](2/aj0YEe4oUhYkBdfpda0fYP/figurebad4a42d87d547e89c89295a8963bc95_0_7.png) f Adapted with permission from Murali R, Delair DF, Bean SM, et al. Evolving roles of histologic evaluation and molecular/genomic profiling in the management of endometrial cancer.J Nat Compr Canc Netw 2018;16:201-209.

9Diagnostic algorithm for integrated genomic-pathologic classification of endometrial carcinomas.

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References

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PRINCIPLES OF IMAGINGa,1-9

a MRI is performed with and without contrast and CT is performed with contrast unless contraindicated. Contrast is not required for screening chest CT.b High-grade endometrial carcinoma includes: poorly differentiated endometrioid, serous, clear cell, undifferentiated carcinoma, carcinosarcoma, and

mesonephric-like adenocarcinoma.

c Uterine risk factors identified post TH include: high-grade carcinomas (above criteria), myoinvasion >50%, cervical stromal involvement, LVSI, and tumor >2 cm.d Indications may include abnormal physical exam findings; bulky uterine tumor; vaginal or extrauterine involvement; delay in presentation or treatment; and abdominal or pulmonary symptoms.

e Indications may include abnormal physical exam findings such as vaginal tumor; palpable mass or adenopathy; and new pelvic, abdominal, or pulmonary

symptoms.

References

Initial Workup

• Non-Fertility-Sparing Treatment

Consider chest imaging (chest x-ray). If an abnormality is seen, then chest CT without contrast may be performed.

Consider pelvis MRI to establish the origin of the tumor (endocervical vs. endometrial) and assess local disease extent.

Consider preoperative pelvis ultrasound if uterine size is not clear on exam.

For high-grade carcinoma,b consider chest/abdomen/pelvis CT (preferred) to evaluate for metastatic disease.

For patients who underwent TH with incidental finding of endometrial cancer or whose cancer was incompletely staged (ENDO-7) with

uterine risk factors,c consider chest/abdomen/pelvis CT to evaluate for metastatic disease.

Consider neck/chest/abdomen/pelvis/groin fluorodeoxyglucose (FDG)-PET/CT if metastasis is suspected in select patients.

Other initial imaging should be based on symptomatology and clinical concern for metastatic disease.d

• Fertility-Sparing Treatment

Pelvis MRI (preferred) to exclude myoinvasion and assess local disease extent; pelvic transvaginal ultrasound if MRI is contraindicated or

unavailable.

Consider chest x-ray. If an abnormality is seen, then chest CT without contrast may be performed.

Consider neck/chest/abdomen/pelvis/groin FDG-PET/CT if metastasis is suspected in select patients.

Other imaging should be based on symptomatology and clinical concern for metastatic disease.e

Follow-up/Surveillance

• Non-Fertility-Sparing Treatment

Imaging should be guided by patient symptoms, risk assessment, and clinical concern for recurrent or metastatic disease.e

• Fertility-Sparing Treatment

Repeat pelvis MRI (preferred) for patients with persistent endometrial carcinoma after 6–9 months of ineffective treatment, especially if

considering further fertility-sparing approaches.

Other imaging should be based on symptomatology and clinical concern for metastatic disease.e

Consider pelvis ultrasound surveillance for patients with ovarian preservation.

Suspected Recurrence or Metastasis

• Abdomen/pelvis CT and/or chest CT is recommended based on symptoms or physical exam findings.e

• Consider whole body FDG-PET/CT and/or abdomen/pelvis MRI in select patients as clinically indicated.

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1 Salani R, Khanna N, Frimer M, et al. An update on post-treatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of

Gynecologic Oncology (SGO) recommendations. Gynecol Oncol 2017;146:3-10.

2 Haldorsen IS, Salvesen HB. What is the best preoperative imaging for endometrial cancer? Curr Oncol Rep 2016;18:25.3 Elit L, Reade CJ. Recommendations for follow-up care for gynecologic cancer survivors. Obstet Gynecol 2015;126:1207-1214.4 Vargas HA, Akin O, Zheng J, et al. The value of MR imaging when the site of uterine cancer origin is uncertain. Radiology 2011;258:785-792.5 Sohaib SA, Houghton SL, Meroni R, et al. Recurrent endometrial cancer: patterns of recurrent disease and assessment of prognosis. Clin Radiol 2007;62:28-34;

discussion 35-36.

6 Hensley ML, Barrette BA, Baumann K, et al. Gynecologic Cancer InterGroup (GCIG) consensus review: uterine and ovarian leiomyosarcomas. Int J Gynecol Cancer 2014;24(9 Suppl 3):S61-S66.

7 Lakhman Y, Katz SS, Goldman DA, et al. Diagnostic performance of computed tomography for preoperative staging of patients with non-endometrioid carcinomas of the uterine corpus. Ann Surg Oncol 2016;23:1271-1278.

8 Colombo N, Creutzberg C, Amant F, et al; ESMO-ESGO-ESTRO Endometrial Consensus Conference Working Group. ESMO-ESGO-ESTRO Consensus Conference on Endometrial Cancer: diagnosis, treatment and follow-up. Ann Oncol 2016;27:16-41.

9 Sala E, Rockall AG, Freeman SJ, et al. The added role of MR imaging in treatment stratification of patients with gynecologic malignancies: what the radiologist needs to know. Radiology 2013;266:717-740.

PRINCIPLES OF IMAGING REFERENCES

Note: All recommendations are category 2A unless otherwise indicated.

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Principles of Surgical Staging for Endometrial Cancer1-15

• TH/BSO and lymph node assessment is the primary treatment for apparent uterine-confined endometrial carcinoma, unless patients desire

(and are candidates for) fertility-sparing options (ENDO-8).1-3 Select patients with metastatic endometrial carcinoma are also candidates for hysterectomy (Principles of Pathology and Molecular Analysis [ENDO-A]).

• Endometrial carcinoma should be removed en bloc to optimize outcomes; intraperitoneal morcellation or tumor fragmentation should be

avoided.

• TH/BSO and lymph node assessment may be performed by any surgical route (eg, laparoscopic, robotic, vaginal, abdominal), although the

standard in those with apparent uterine-confined disease is to perform the procedure via a minimally invasive approach. Randomized trials,a Cochrane Database Systematic Review, and population-based surgical studies support that minimally invasive techniques are preferred in this setting due to a lower rate of surgical site infection, transfusion, venous thromboembolism, decreased hospital stay, and lower cost of

care, without compromise in oncologic outcome.4-9

• The lymph node assessment includes evaluation of the nodal basins that drain the uterus, and often comprises either SLN mapping and

resection of sentinel nodes or a pelvic nodal dissection with or without para-aortic nodal dissection. This continues to be an important

aspect of surgical staging in patients with uterine-confined endometrial carcinoma, as the procedure provides important prognostic

information that may alter treatment decisions.

• SLN mapping is preferred (see pages 2–6 of ENDO-C).15

• Pelvic lymph nodes from the external iliac, internal iliac, obturator, and common iliac nodes are frequently removed for staging purposes.

• Para-aortic nodal evaluation from the inframesenteric and infrarenal regions may also be utilized for staging in patients with high-risk tumors such as deeply invasive lesions, high-grade histology, and tumors of serous carcinoma, clear cell carcinoma, or carcinosarcoma.

• Excision of suspicious or enlarged lymph nodes in the pelvic or aortic regions is important to exclude nodal metastasis.

• Some patients may not be candidates for lymph node dissection.

• Visual evaluation of the peritoneal, diaphragmatic, and serosal surfaces with biopsy of any suspicious lesions is important to exclude

extrauterine disease.

• While peritoneal cytology does not impact staging, FIGO and AJCC nonetheless recommend that surgeons continue to obtain this during the TH/BSO.

• Cytology results should not be taken in isolation to guide adjuvant therapy.

• Omental biopsy is commonly performed in those with serous carcinoma, clear cell carcinoma, or carcinosarcoma histologies.

• For stage II disease, TH/BSO is the standard procedure. RH should only be performed if needed to obtain negative margins.

• Ovarian preservation may be safe in select patients who are premenopausal with stage IA G1 endometrioid cancer, normal-appearing

ovaries, and no family history of ovarian cancer or Lynch syndrome. Absence of p53 abnormality, MMR deficiency, LVSI, and positive

cytology are preferred. Salpingectomy is recommended.

PRINCIPLES OF EVALUATION AND SURGICAL STAGING

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF EVALUATION AND SURGICAL STAGING WHEN SLN MAPPING IS USED

Principles of Sentinel Lymph Node(s) Mapping for Endometrial Cancer Staging10-26

• Prospective and retrospective studies demonstrate that compared to systemic lymphadenectomy (LND), SLN mapping with ultrastaging

may increase the detection of lymph node metastasis with low false-negative rates in patients with apparent uterine-confined disease.10-23,26 If SLN mapping is considered, the expertise of the surgeon and attention to technical detail is critical. Recent evidence indicates that SLN

mapping may also be used in high-risk histologies (ie, serous carcinoma, clear cell carcinoma, carcinosarcoma).24,25

• SLN mapping can be considered for the surgical staging of apparent uterine-confined malignancy when there is no metastasis demonstrated by imaging studies or no obvious extrauterine disease at exploration.

• A cervical injection with dye has emerged as a useful and validated technique for identification of lymph nodes that are at high risk for

metastases (ie, SLN in patients with early-stage endometrial cancer10-12).

• Superficial (1–3 mm) and optional deep (1–2 cm) cervical injection leads to dye delivery to the main layers of lymphatic channel origins in the cervix and corpus, namely the superficial subserosal, intermediate stromal, and deep submucosal lymphatic sites of origin (see Figure 1 on ENDO-C 4 of 6).26

• Injection into the uterine cervix provides excellent dye penetration to the uterine vessels and main uterine lymphatic trunks that condense in the parametria and appear in the broad ligament leading to pelvic and occasionally paraaortic sentinel nodes.

• The uterine body lymphatic trunks commonly cross over the obliterated umbilical artery with the most common location of pelvic SLN being medial to the external iliac, ventral to the hypogastric, or in the superior part of the obturator region (see Figure 2 on ENDO-C 4 of 6).

• A less common location is usually seen when the lymphatic trunks do not cross over the obliterated umbilical and move cephalad following the mesoureter; in these cases, the SLN is usually seen in the common iliac presacral region (see Figure 3 on ENDO-C 4 of 6).

• Indocyanine green (ICG) is the preferred imaging dye for SLN mapping.20,26,27

• The radiolabeled colloid most commonly injected into the cervix is technetium-99m (99mTc); colored dyes are available in a variety of forms(Isosulfan Blue 1%, Methylene Blue 1%, and Patent Blue 2.5% sodium).

• Low-volume nodal metastasis to SLN detected only by enhanced pathologic ultrastaging is another potential value to staging with

SLN.10, 21-23

• The key point to successful SLN mapping is adherence to the SLN algorithm, which requires the performance of a side-specific nodal

dissection in cases of failed mapping and removal of any suspicious or grossly enlarged nodes regardless of mapping (see Figure 4 on

ENDO-C 5 of 6).10-12,23,25

• For cases of failed SLN mapping, reinjection of the cervix may be considered. An additional 1 mL in the non-detected side can be infiltrated in the superficial cervical area.

• If there is no mapping on a hemi-pelvis, then a side-specific LND is recommended. However, if expert gynecologic pathology is available, a

frozen section to assess myoinvasion can be obtained and LND can be avoided if no myoinvasion or cervical invasion is identified.

• SLN identification should always be done prior to hysterectomy, except in cases where a bulky uterus must be removed to allow access to

iliac vessels and lymph nodes.

Continued

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Principles of Sentinel Lymph Node(s) Mapping for Endometrial Cancer Staging (continued)10-26

• SLNs are processed using ultrastaging, which typically includes two components: serial sectioning with review of multiple hematoxylin and eosin (H&E)-stained slides with or without cytokeratin IHC staining.

Protocols of serial sectioning and ultrastaging vary among gynecologic pathologists.28 Comparison of two different ultrastaging protocols

in endometrial cancer SLN did not reveal significant advantages when serial H&E sectioning and IHC staining were used.29

• Recent data highlight the potential importance of ultrastaging for detection of low-volume metastasis. In general, SLN mapping allows for

increased intraoperative surgical precision to identify nodes more likely to harbor metastasis combined with enhanced pathology protocols,which has been shown to increase the detection of nodal metastasis, which may alter stage and adjuvant therapy recommendations.

• Lymph nodes with isolated tumor cells should be clearly reported. In endometrial cancer, when isolated tumor cells are detected in the

absence of macrometastasis and micrometastasis, the lymph node stage is designated pN0(i+).30

PRINCIPLES OF EVALUATION AND SURGICAL STAGING WHEN SLN MAPPING IS USED

Note: All recommendations are category 2A unless otherwise indicated.

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Figure 1: Common cervical injection sites for mapping uterine cancer

![](2/aj0YEe4oUhYkBdfpda0fYP/figure23a435b06a0749a4896a4f030456bed6_0_7.png) Figure 2: Most common location of SLNs (blue, arrow) following a cervical injectiona

![](2/aj0YEe4oUhYkBdfpda0fYP/figure55f61ac2c3ad4431a54c0e6982f7ae0f_0_9.png) Figure 3: Less common location of SLNs(green, arrow) usually seen when lymphatic trunks are not crossing over the umbilical ligament but following the mesoureter cephalad to common iliac and presacral regiona

![](2/aj0YEe4oUhYkBdfpda0fYP/figureb6d3a3205ae245ee9aef250c051d1c16_0_11.png) aFigures 1,2, and 3 are reproduced with permission from Memorial Sloan Kettering Cancer Center.© 2013, Memorial Sloan Kettering Cancer Center.

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Figure 4: The SLN algorithm for surgical staging of endometrial cancerb

Peritoneal & serosal evaluation & washings

![Retroperitoneal evaluation\nExcision of SLN with ultrastaging\nAny suspicious nodes must be removed regardless of mapping\nRetroperitoneal evaluation\nExcision of SLN with ultrastaging\nIf there is no mapping on a hemi-pelvis, a side-specific LND is performed\nPara-aortic LND-done at attending discretion\n](2/aj0YEe4oUhYkBdfpda0fYP/figurea5b815122c8d4f2ea063c58bcfafe4d8_0_7.png) bReproduced with permission from Barlin JN, Khoury-Collado F, Kim CH, et al. The importance of applying a sentinel lymph node mapping algorithm in endometrial cancer staging: Beyond removal of blue nodes. Gynecol Oncol 2012;125:531-535.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF EVALUATION AND SURGICAL STAGING REFERENCES

1American College of Obstetricians and Gynecologists.ACOG practice bulletin, clinical management guidelines for obstetrician-gynecologists, number 65, August 2005:management of endometrial cancer. Obstet Gynecol 2005;106:413-425.

2Bakkum-Gamez JN, Gonzalez-Bosquet J, Laack NN,et al. Current issues in the management of endometrial cancer. Mayo Clin Proc 2008;83:97-112.

3Edge SB, Byrd DR, Compton CC. AJCC Cancer Staging Manual, 7th edition. New York: Springer; 2010.

4Walker JL, Piedmeont MR, Spirtos NM, et al. Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer. Gynecologic Oncology Group Study LAP2. J Clin Oncol 2009;27:5331-536.

5Kornbith AB, Huang HQ, Walker JL, et al. Quality of life of patients with endometrial cancer undergoing laparoscopic international federation of gynecology and obstetrics staging compared with laparotomy: a Gynecologic Oncology Group Oncology Group study. J Clin Oncol 2009;27:5337-5342.

Galaaal K, Bryant A, Fisher AD, et al. Laparoscopy versus laparotomy for the management of early stage endometrial cancer. Cochrane Database Syst Rev 2012;9:CD006655.

Scalici J, Laughlin BB, Finan MA, et al. The trend towards minimally invasive surgery(MIS) for endometrial cancer:an ACS NPQRIP evaluation of surgical outcomes. Gynecol Oncol 2015;136:512-515.

8Fader AN, Weise RM, Sinno AK, et al. Utilization of minimally invasive surgery in endometrial cancer care: a quality and cost disparity. Obstet Gynecol 2016;127:91-100.

9Mannschreck D, Matsuno RK, Moriarty JP,et al.Disparities in surgical care among women with endometrial cancer. Obstet Gynecol 2016;128:526-534.

10Abu-Rustum NR,Khoury-Collado F,Pandit-Taskar N,et al. Sentinel lymph node mapping for grade 1 endometrial cancer: is it the answer to the surgical staging dilemma?Gynecol Oncol 2009;113:163-169.

11Khoury-Collado F, Glaser GE, Zivanovic O, et al.Improving sentinel lymph node detection rates in endometrial cancer: how many cases are needed?Gynecol Oncol 2009;115:453-455.

12Khour-Collado F, Murray MP, Hensley ML, et al.Sentinel lymph node mapping for endometrial cancer improves the detection of metastatic disease to regional lymph nodes. Gynecol Oncol 2011;122:251-254.

13Frimer M, Khoury-Collado F, Murray MP, et al.Micrometastasis of endometrial cancer to sentinel lymph nodes: is it an artifact of uteramine manipulation? Gynecol Oncol 2010;119:496-499.

14 Leitao MM Jr, Khoury-Collado F, Gardner G, et al. Impact of incorporating an algorithm that utilizes sentinel lymph node mapping during minimally invasive procedures on the detection of stage IIIC endometrial cancer. Gynecol Oncol 2013;129:38-41.

15 Holloway RW, Abu-Rustum NR, Backes FJ,et al.Sentinel lymph node mapping and staging in endometrial cancer: A society of gynecologic oncology literature review with consensus recommendations. Gynecol Oncol 2017;146:405-415.

16 Kim CH, Soslow RA, Park KJ, et al. Pathologic ultrastaging improves micrometastasis detection in sentinel lymph nodes during endometrial cancer staging.Int J Gynecol Cancer 2013;23:964-970.

17 Barlin JN, Khoury-Collado F, Kim CH, et al.The importance of applying a sentinel lymph node mapping algorithm in endometrial cancer staging: Beyond removal of blue nodes. Gynecol Oncol 2012;125:531-535.

18Vidal F, Legueque Potton M, S et al. Evaluation of the sentinel lymph node algorithm with blue dye labeling for early-stage endometrial cancer in a multicentric setting.Int J Gynecol Cancer 2013;23:1327-1243.

19 Abu-Rustum NR.The Increasing credibility of sentinel lymph node mapping in endometrial cancer. Ann Surg Oncol 2013;20:353-354.

20 Sinno AK,Fader AN,Roche KL,et al.A comparison of colorimetric versus theometric sentinel lymph node mapping during robotic surgery for endometrial cancer.Gynecol Oncol 2014;134:281-286.

21 Holloway RW, Gupta S, Stavitski NM, et al. Sentinel lymph node mapping with staging lymphadenectomy for patients with endometrial cancer increases the detection of metastasis. Gynecol Oncol 2016;141:206-210.

22 Paley P, Veljovich DS, Press JZ, et al. A prospective investigation of fluorescence imaging to detect sentinel lymph nodes at robotic-assisted endometrial cancer staging. Am J Obstet Gynecol 2016;215:117.e1-7.

23 Sinno AK, Peijnenberg E, Fader AN, et al. Reducing overtreatment: a comparison of lymph node assessment strategies for endometrial cancer. Gynecol Oncol 2016;143:281-286.

24Schiovone MB, Zivanovic O, Zhou Q, et al. Survival of patients with uterine carcinosarcoma undergoing sentinel lymph node mapping. Ann Surg Oncol 2016;23:196-202.

25 Soliman PT, Westin SN, Dioun S, et al. A prospective validation study of sentinel lymph node mapping for high-risk endometrial cancer. Gynecol Oncol 2017;146:234-239.

26 Rossi EC, Kowalski LD, 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;18:384-392.

27 Frumovitz M, Plante M, Lee PS, et al. Near-infrared fluorescence for detection of sentinel lymph nodes in women with cervical and uterine cancers(FILM): a randomised, phase 3, multicentre, non-Inferiority trial.Lancet Oncol 2018;19:1394-403.

28 Cormier B, Rozenholc AT, Gotlieb W, et al. Sentinel lymph node procedure in endometrial cancer: A systematic review and proposal for standardization of future research. Gynecol Oncol 2015;138:478-485.

29 Euscher E, Sui D, Soliman P, et al. Ultrastaging of sentinel lymph nodes in endometrial carcinoma according to use of 2 different methods. Int J Gynecol Pathol 2018;37:242-251.

30 Olawaiye AB, Mutch DG. Lymphnode staging update in the American Joint Committee on Cancer 8th Edition cancer staging manual. Gynecol Oncol 2018;150:7-8.

![NCCN\n](2/aj0YEe4oUhYkBdfpda0fYP/figured4e2393ef3e3444db0a3d23ce62ac824_0_1.png) National Comprehensive Cancer Network®

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NCCN Guidelines Index Table of Contents Discussion

SYSTEMIC THERAPY FOR ENDOMETRIAL CARCINOMA

|Primary or Adjuvant Therapy (Stage I-IV)|| |---|---| |Chemoradiation Therapy|Systemic Therapy| |Preferred|Preferred| |●Cisplatin plus RT followed by Carboplatin/Paclitaxel1,2|$\text{Carboplatin/Paclitaxel}+\text{Pembrolizumab}(\text{for stage III-IV tumors, except for}$ $carcinosarcoma) (category 1)b,d,e,3,4 $<$ \text{carcinosarcoma} (category 1)d,f,5 $<$ \text{carboplatin/Paclitaxel}+Dostarlimab-gxly (for stage III-IV tumors) (category 1)d,f,5 $<$ \text{carbology} 1)d,f,6 $<$ \text{carbology} 1)d,g,6 $<$ \text{carboplatin/Paclitaxel}+Durvalumab(for stage III-IV dMMR tumors only) $$(category 1)d,g,6 $$ $<$ \text{carboplatin/Paclitaxel}+D_{\text{prattumab}}($$AVorplatin/Paclitaxel $+D_{\text{trastuzumab} }($for stage III-IV HER2-positive uterine $-$ \text{serous carcinoma} $or\,carcinosarcoma $)$ $d,h,7 $ $.$ $\cdot$ Carboplatin/Paclitaxel $+$ Bevacizumab $(for$ stage III-IV tumors $d,8,9$ $)$ $,$ Carboplatin/Paclitaxel $+$ Carboplatin/Paclitaxel10 $*$ \text{Other Recommended} $ $)$ $.$ $C) $\text{Carboplatin/Paclitaxel/Durvalumab}+$ Durvalumab/Olaparib $(for$ stage III-IV pMMR tumors) $(category 2B)^{d,11}$ $*$|

a An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.

b For stage III or IVA with measurable disease or stage IVB with or without measurable disease. For patients not meeting the eligibility criteria for NRG-GY018,carboplatin/paclitaxel + pembrolizumab should be considered for stage III-IV dMMR tumors (Van Gorp T,et al. Ann Oncol 2024;35:968-980).

cFor immunotherapy regimens, also refer to NCCN Guidelines for the Management of Immune Checkpoint Inhibitor-Related Toxicities.

d Checkpoint inhibitors and/or monoclonal antibodies and/or PARP inhibitors included in this regimen may be continued as maintenance therapy. Refer to the original study protocol for maintenance therapy dosing schedules.

e Pembrolizumab and berahyaluronidase alfa-pmph subcutaneous injection may be substituted for IV pembrolizumab. Pembrolizumab and berahyaluronidase alfa-pmph has different dosing and administration instructions compared to IV pembrolizumab.

f For adult patients with primary advanced endometrial carcinoma: stage IIIA, IIIB, or IIIC1 with measurable disease post surgery; stage IIIC1 with carcinosarcoma, clear-cell, serous, or mixed histology regardless of the presence of measurable disease; and stage IIIC2 or stage IV regardless of the presence of measurable disease.

g For stage III with measurable disease post surgery and stage IV with or without measurable disease.

h For patients who have not received prior trastuzumab therapy.

References

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SYSTEMIC THERAPY FOR ENDOMETRIAL CARCINOMAa

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References

RECURRENT DISEASEi,j First-Line Therapy for Recurrent Diseasec,k

Preferred

• Carboplatin/Paclitaxel + Pembrolizumab (except for carcinosarcoma) (category 1)d,e,l,3

• Carboplatin/Paclitaxel + Dostarlimab-gxly (category 1)d,l,5

• Carboplatin/Paclitaxel + Durvalumab (for dMMR only) (category 1)d,l,6

• Carboplatin/Paclitaxel + Trastuzumab

(for HER2-positive uterine serous carcinoma or carcinosarcoma)d,h,7

• Carboplatin/Paclitaxel (category 1 for carcinosarcoma)m,10

Other Recommended

• Carboplatin/Docetaxeln

• Carboplatin/Paclitaxel + Bevacizumabd,8,9

Useful in Certain Circumstances

• MMR-proficient (pMMR) tumors

Carboplatin/Paclitaxel/Durvalumab + Durvalumab/Olaparib (category 2B)d,11

• Biomarker-directed therapy: after prior platinum-based therapy

including neoadjuvant and adjuvant

pMMR tumors

◊ Lenvatinib + Pembrolizumab (category 1)12,13

TMB-high (TMB-H) tumorso

◊ Pembrolizumabe,14

MSI-H/dMMR tumorsp

◊ Pembrolizumabe,15

◊ Dostarlimab-gxly16

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Table of Contents Discussion

SYSTEMIC THERAPY FOR ENDOMETRIAL CARCINOMAa

|RECURRENT DISEASE|RECURRENT DISEASE| |---|---| |Second-Line or Subsequent Therapyc,k|| |Other Recommended|Useful in Certain Circumstances (Biomarker-directed therapy)| |•Cisplatin/Doxorubicin ${}^{17}$|·pMMR tumors| |•Cisplatin/Doxorubicin/Paclitaxelq,17|Lenvatinib + Pembrolizumab (category 1)12,13| |•Cisplatin/Gemcitabine ${}^{18}$|Axitinib + Avelumab25| |•Cisplatin|●TMB-H tumorsos| |•Carboplatin|Pembrolizumabe,14| |•Doxorubicin|Ipilimumab + Nivolumab26| |•Liposomal Doxorubicin|·MSI-H/dMMR tumorsp| |·Paclitaxel19|Pembrolizumabe,15| |·Albumin-bound Paclitaxelr|Dostarlimab-gxly16| |·Topotecan|Avelumab| |·Bevacizumabs,20|Nivolumabt,27| |·Temsirolimus21|Tislelizumab-jsgr28| |·Cabozantinib|Retifanlimab-dlwr(category 2B)29| |·Lenvatinib22|·HER2-positive tumors(IHC 3+ or 2+)| |·Gemcitabine23|Fam-trastuzumab deruxetcan-nxki30| |·Docetaxel(category 2B)|·HER2-positive tumors (IHC 1+, 2+ or 3+)| |·Ifosfamide(for carcinosarcoma)|Fam-trastuzumab deruxetcan-xki (for carcinosarcoma)31| |·Ifosfamide/Paclitaxel(for carcinosarcoma)24|·NTRK gene fusion-positive tumors| |·Cisplatin/lfosfamide(for carcinosarcoma)|Larotrectinib Entrectinib| ||Repotrectinib,32| |·RET gene fusion-positive tumors|| |·Selpercatinib|Selpercatinib|

Footnotes on ENDO-D 3A of 6

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Continued References

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a An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.c For immunotherapy regimens, also refer to NCCN Guidelines for the Management of Immune Checkpoint Inhibitor-Related Toxicities.d Checkpoint inhibitors and/or monoclonal antibodies and/or PARP inhibitors included in this regimen may be continued as maintenance therapy. Refer to the original

study protocol for maintenance therapy dosing schedules.

h For patients who have not received prior trastuzumab therapy.i Cisplatin, carboplatin, liposomal doxorubicin, paclitaxel, and docetaxel may cause drug reactions (see NCCN Guidelines for Ovarian Cancer–Management of Drug

Reactions [OV-D]).

j Chemotherapy regimens can be used for all carcinoma histologies. Carcinosarcomas are now considered and treated as high-grade carcinomas.k If not used previously, these agents can be used as second-line or subsequent therapy as clinically appropriate.l For adult patients with recurrent endometrial carcinoma with or without measurable disease.m Carboplatin/paclitaxel is preferred only for patients who have not received any prior systemic therapy. Can be considered as an option under the "Other

Recommended" list if or when re-use is appropriate in the first-line setting for recurrent disease.

n Docetaxel may be considered for patients in whom paclitaxel is contraindicated.o NCCN recommends TMB-H testing if not previously done. The included checkpoint inhibitors are indicated for patients with unresectable or metastatic tumors with

TMB-H [≥10 mutations/megabase (mut/Mb)], whose disease has progressed following prior treatment and who have no satisfactory alternative treatment options.

p For recurrent endometrial cancer, NCCN recommends MSI or MMR testing if not previously done.q The cisplatin/doxorubicin/paclitaxel regimen is not widely used because of concerns about toxicity.r Albumin-bound paclitaxel is a reasonable substitute for patients with a hypersensitivity to paclitaxel. If a skin test is done, and is positive, then the patient requires

desensitization to paclitaxel. Albumin-bound paclitaxel is not a reasonable substitute for paclitaxel if the patient’s skin test is positive.

s Bevacizumab may be considered for use in patients whose disease has progressed on prior cytotoxic chemotherapy.t Nivolumab and hyaluronidase-nvhy subcutaneous injection may be substituted for IV nivolumab. Nivolumab and hyaluronidase-nvhy has different dosing and

administration instructions compared to IV nivolumab.

u NTRK-positive tumors that are naïve to prior NTRK-targeted therapy or have progressed on prior NTRK therapy.

SYSTEMIC THERAPY FOR ENDOMETRIAL CARCINOMA FOOTNOTES FOR ENDO-D (2 OF 6) AND ENDO-D (3 OF 6)

Note: All recommendations are category 2A unless otherwise indicated.

ENDO-D

3A OF 6 References Continued

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SYSTEMIC THERAPY FOR ENDOMETRIAL CARcinoma

|Hormonal Therapy for Recurrent or Metastatic Endometrial Carcinoma|| |---|---| |Preferred|Other Recommendedum| |●Megstrol acetate/Tamoxifen (alternating)|●Medroxyprogesterone acetate/Tamoxifen| |●Everolimus/Letrozole|(alternating) ●Progestational agents ●Medroxyprogesterone acetate| ||Abemaciclib/Letrozole| ||Medroxyprogesterone acetate| ||Abemaciclib/Fulvestant|

|Hormonal Therapy for Uterine-Limited Disease Not Suitable for Primary Surgery or for Those Desiring Uterine Preservation for Fertility (ENDO-1)V|| |---|---| |Preferred|Other Recommended| |●Levonorgestrel IUD|●Continuous progestin-based therapy ● Megestrol acetate ● Medroxyprogesterone acetate ●Dual progestin agents| ||Levonorgestrel IUD/Megestrol acetate| ||Levonorgestrel IUD/Medroxyprogesterone acetate|

V Hormonal therapy is typically used for lower-grade endometrioid histologies, preferably in patients with small tumor volume or an indolent growth pace.

Note: All recommendations are category 2A unless otherwise indicated.

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SYSTEMIC THERAP FOR ENDOMETRIAL CARCINOMA-REFERENCES

1de Boer SM, Powell ME, Mileshkin L, et al. Toxicity and quality of life after adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer(PORTEC-3): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol 2016;17:1114-1126.

2Greven K, Winter K, Underhill K, et al. Final analysis of RTOG 9708: adjuvant postoperative irradiation combined with cisplatin/paclitaxel chemotherapy following surgery for patients with high-risk endometrial cancer. Gynecol Oncol 2006;103:155-159.

3 Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer, N Engl J Med 2023;388:2159-2170.

4 Van Gorp T, Cibula D, Lv W, et al. ENGOT-11EN/G035/KEYNOTE-B21:A randomised, double-blind, phase III study of pembrolizumab or placebo plus adjuvant chemotherapy with or without radiotherapy in patients with newly diagnosed, high-risk endometrial cancer. Ann Oncol 2024;35:968-980.

5 Powell MA, Bjorge L, Willmott L, et al. Overall survival in patients with endometrial cancer treated with dostarlimab plus carboplatin-placitaxel in the randomized ENGOT-EN6/GOG-3031/RUBY trial. Ann Oncol 2024;35:728-738.

6Westin SN, Moore K, Chon HS, et al. Durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olapabir as first-line treatment for advanced endometrial cancer: The phase III DUO-E trial. J Clin Oncol 2024;42:283-299.

Fader AN, Roque DM, Siegel E,et al. Randomized phase II trial of carboplatin-paclitaxel compared with carboplatin-paclitaxel-trastuzumab in advanced(stage-III) or recurrent uterine serous carcinomas that overexpress Her2/Neu(NCT01367002): Updated overall survival analysis. Clin Cancer Res 2020;26:3928-3935.

8 Rose PG,Ali S, Moslemi-Kebria M, Simpkins F. Paclitaxel, carboplatin, and bevacizumab in advanced and recurrent endometrial carcinoma. Int J Gynecol Cancer 2017;27:452-458.

9Aghajanian C,Filiaci V, Dizon DS, et al. A phase II study of frontline over�linaxel/carboplatin/bevacizumab, paclitaxel/carboplatin/temsirolimus, or ibxepilone/carboplatin/bevacizumab in advanced/recurrent endometrial cancer. Gynecol Oncol 2018;150:274-281.

10 Miller DS,Filiaci VL, Mannel RS,et al. Carboplatin and paclitaxel for advanced endometrial cancer: Final overall survival and adverse event analysis of a phase III trial(NRG Oncology/GOG0209). J Clin Oncol 2020;38:3841-3850.

11 Westin SN,Moore K,Chon HS,et al.Durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first-line treatment for advanced endometrial cancer: The phase III DUO-E trial. J Clin Oncol 2024;42:283-299.

12 Makker V, Colombo N, Casado Herráez A, et al. Lenvatinib plus pembrolizumab in previously treated advanced endometrial cancer: updated efficacy and safety from the randomized phase III Study 309/KEYNOTE-775. J Clin Oncol 2023;41:2904-2910.

13 Marth C, Moore RG, Bidzinski M, et al. First-line envatinib plus pembrolizumab versus chemotherapy for advanced endometrial cancer: A randomized, open-label, phase III III. J Clin Oncol 2025;43:1083-1100.

14 Marabelle A, Fakhim L, Lopez J,et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label,phase 2 KEYNOTE-158 study. Lancet Oncol 2020;20:1353-1365.

15 O'Malley DM,Bariani GM, Cassier PA,et al. Pembrolizumab in patients with microsatellite instability-high advanced endometrial cancer: Results from the KEYNOTE-158 study.J Clin Oncol 2022;40:752-761.

16 Oaknin A, Tinker AV, Gilbert L,et al. Clinical activity and safety of the anti-programmed death 1 monoclonal antibody dostarlimab for patients with recurrent or advanced mismatch repair-deficient endometrial cancer a nonrandomized phase 1 clinical trial. JAMA Oncol 2020;6:1766-1772.

ENDO-D 6 OF 6 SYSTEMIC THERAPY FOR ENDOMETRIAL CARCINOMA -REFERENCES

NCCN Guidelines Index Table of Contents Discussion

Abstract

Note: All recommendations are category 2A unless otherwise indicated.

References

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Uterine Sarcoma

NCCN Guidelines Index Table of Contents Discussion

![INITIAL CLINICAL FINDINGS\nADDITIONAL EVALUATION\n * Expert pathologic review and consider molecular testing^{\bullet}\n+Discrete residual cervix\n+Imaging^c,d\n·\nTumor initially fragmented.0 Rievol.0\nor Residual cervix\n+Consider re-exploration/resection\nConsider completion salpingo-ophorectomy in low-grade ESS or adenosarcoma(ER-positive tumor)\n30\nTH with en bloc resection $\pm BSO^{d,f,g}$ \nDisease limited to uterus\n+Additional surgical resection for intraoperative discovery of extrauterine disease is individualized\nLow-grade ESS or Adenosarcoma\nADenosarcoma\n(UTSARC-2)\nor\nHigh-grade ESS or UUS\nor LMS\nor Other sarcomas\nResection±BSO+g\nSurgical resection and resection on:estanding on:estanding to/BSO+g\n+Resectability\nNo surgical resection resection\nNo surgical resection and/or Palliative EBRT $\pm$ borachytherapy\n\n\n@\nHigh-grade ESS or UUS or LMS or Other sarcomas (EG,PECoina) \nToplyfield and/or Palliative EBRT $\pm$ and or Brachytherapy\n\n\n@\nHigh-grade ESS or UUS or LMS or LMS or LMS\nor LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or \n](2/aj0YEe4oUhYkBdfpda0fYP/figure26fc824d89a046999b0ee4a91f1e9b66_0_4.png) a Preoperative imaging and biopsy may help to identify uterine sarcomas, although biopsy sensitivity is less than for endometrial cancer. If there is suspicion of malignant mesenchymal sarcoma, fragmentation/morcellation should be avoided.

e Disease is not amenable to resection, or patient is not suitable for surgery based on comorbidities.

b Principles of Pathology and Molecular Analysis(UTSARC-A).

f Oophorectomy is individualized for patients of reproductive age. Favor BSO if ER/PR positive.

cPrinciples of Imaging(UTSARC-B).

9 Morcellation should be avoided.

dFor incidental finding of uterine sarcoma after TH/BSO or fragmented specimen: recommend imaging and consider additional surgical resection on an individual basis.

h Systemic Therapy (UTSARC-C).

i Principles of Radiation Therapy for Uterine Neoplasms(UN-A).

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Uterine Sarcoma

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![PATHOLOGIC FINDINGS/ HISTOLOGIC GRADE J；FOLLOWING TH ± BSO\n\nLow-grade ESS or Adenosarcoma without sarcomatous overgrowth (SO) Stage I\n\nStage I\n\nBSO (preferred) or Observe, if prior BSO\n\nStage II, III, IVA, IVB\n\nBSO\nor\nObserve, if prior BSO\n\nStage II, III, IVA, IVB\n\nBSO\nor\nObserve, if prior BSO\n\nSurveillance\n(UTSARC-4)\n\nAdITIONAL THERAPY\n\nADITIONAL THERAPY\n\nStage II, III, IVA, IVB\n\nBSO\nor\nObserve, if prior BSO\n\nSurveillance\n(UTSARC-4)\n](2/aj0YEe4oUhYkBdfpda0fYP/figureea4d12f5677543a7ac7303a2df68d075_0_4.png) h Systemic Therapy (UTSARC-C).

i Principles of Radiation Therapy for Uterine Neoplasms (UN-A).

i Principles of Pathology and Molecular Analysis (UTSARC-A 2 of 8).

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

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PATHOLOGIC FINDINGS/HISTOLOGIC GRADEJ FOLLOWING TH ±BSO

ADDITIONAL THERAPY

![●High-grade ESS\nHISTOLOGIC GRADEJ FOLLOWING TH ±BSO\nStage I\nStage III\nObserve\nConsider observation if completely resected with negative margins\nor\nConsider systemic therapy\nand/or\nConsider EBRT\n(UTSARC-4)\nStage IVD\nStage IVA\nSystemic therapy\nand/or\nEBRT\nStage IVB\nSystemic therapy h\n±palliative EBRT'\n](2/aj0YEe4oUhYkBdfpda0fYP/figure9525a4892ef148fbb38daf7bfa04d083_0_6.png) h Systemic Therapy (UTSARC-C).

iPrinciples of Radiation Therapy for Uterine Neoplasms(UN-A).

j Principles of Pathology and Molecular Analysis (UTSARC-A 2 of 8).

Note: All recommendations are category 2A unless otherwise indicated.

![NCCN\nNational Comprehensive Cancer Network®\n](2/aj0YEe4oUhYkBdfpda0fYP/figure5ca45bbc484f4426a5fe8c07e169691a_0_1.png)

NCCN Guidelines Version 1.2026 Uterine Sarcoma

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![SURVEILLANCE\nRECURRENCE\nTHERAPY FOR RELAPSE\nTherapy for Relapse (UTSARC-5)\n\nH&P exam every 3-4 mo (consider every 6 months for low-grade, early-stage sarcomas) for 2-3 y, then every 6-12 mo lmaging^c\nClinical evaluation and management of potential long-term and late effects of treatment^{k} [also see Principles of Gynecologic Survivorship (UN-B), NCCN Guidelines for Survivorship for Survivorship, and NCCN Guidelines for Smoking\nCassation]\nIsolated metastases\nUnresectable\nSystemic therapy\nIsactiveable\n|f response, consider surgery and/or\nLocal recurrence: \n●Vagina/pelvis\n●Imaging negative for distant metastatic disease\n●Therapy for Relapse (UTSARC-5)\n\nUnresectable\nSurgical regression\nor Consider preoperative or postoperative systemic therapy\nConsider preoperative or postoperative EBRT/SBRT\nDisseminated disease\nResectable\n|f response, consider surgery and/or\n±EBRT/SBRT| 2 for the local ablative therapy\nor\nDisseminated disease\nSystemic therapyh $\pm$ palliative EBRT\nor\nBest supportive care (see NCCN Guidelines for Palliative Care)\n](2/aj0YEe4oUhYkBdfpda0fYP/figure29b32b082400412d8210dcac108284c1_0_4.png) Principles of Imaging(UTSARC-B).

h Systemic Therapy (UTSARC-C).

iPrinciples of Radiation Therapy for Uterine Neoplasms(UN-A).

k Patient education should include symptoms of potential recurrence, lifestyle, obesity, exercise, sexual health (including vaginal dilator use, lubricants/moisturizers, and local estrogen and hormone therapy for menopause), smoking cessation, and nutrition counseling.

Metastasectomy is the historical standard for patients with oligometastatic disease; the ultimate choice of local control modality may depend on factors such as performance status, patient preference, lesion location/accessibility, ability to preserve normal tissue function, and anticipated morbidity of a treatment modality.

m Observation may be an option in select, completely resected cases with no evidence of disease on postoperative imaging.

n See Principles of Interventional Oncology (SARC-F pages 1-3) in the NCCN Guidelines for Soft Tissue Sarcoma.

Note: All recommendations are category 2A unless otherwise indicated.

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NCCN Guidelines Version 1.2026 Uterine Sarcoma

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RECURRENCE

THERAPY FOR RELAPSE

![NCCN\nNational Experiments\n9449\nPiral therapy\n87491\nFor residual disease:\+resection\n±IORT\nConsider preoperative EBRT,Io\n±systemic therapy\n±systemic therapy\nRadiologically\nisolated vaginal/pelvicrecune\nNo prior RT\nPrior RT\n\nSurgical exploration + resection $\pm IORT\pm$ systemic therapy\nor\nSelected reirradiation with EBRT' and/or brachytherapy'\n](2/aj0YEe4oUhYkBdfpda0fYP/figure10dae4e2fe1445f8ad02544553cc024c_0_6.png) ${}^{c}$ Principles of Imaging (UTSARC-B).

${}^{i}$ Principles of Radiation Therapy for Uterine Neoplasms(UN-A).

°The use of preoperative EBRT would preclude postoperative EBRT.

P For low-grade ESS or adenosarcoma without SO, the first choice of systemic therapy is anti-estrogen hormone therapy. See Systemic Therapy(UTSARC-C).

Note: All recommendations are category 2A unless otherwise indicated.

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UTSARC-A 1 OF 8

PRINCIPLES OF PATHOLOGY AND MOLECULAR ANALYSISa,1,2

Procedure:

• TH ± BSO: Total hysterectomy ± bilateral salpingo-oophorectomy and en bloc resection of tumor

Pathologic Assessment for Sarcoma (including LMS, adenosarcoma, ESS, and UUS):

• Expert gynecologic pathology review is highly recommended

• Uterus

Hysterectomy type

Specimen integrity (intact, opened, morcellated, other)

Tumor size

Myometrial invasion (for adenosarcoma only)

Histologic type

Histologic grade (for adenosarcoma only)

LVSI

• Other tissue/organ involvement (fallopian tubes, ovaries, vagina, parametrium, peritoneum, omentum, other)

• Peritoneal/ascitic fluid cytology (if collected)

• Lymph nodes (when resected)

Level of nodal involvementb (ie, pelvic, common iliac, para-aortic)

Number of lymph nodes with metastasis

Footnotesa Also see Principles of Evaluation and Surgical Staging (ENDO-C).b Routine node dissection is not required in the absence of clinical suspicion of nodal involvement.

References1 American College of Obstetricians and Gynecologists. ACOG practice bulletin, clinical management guidelines for obstetrician-gynecologists, number 65, August 2005: management of endometrial cancer. Obstet Gynecol 2005;106:413-425.

2 Krishnamurti U and Crothers BA. Protocol for the examination of specimens from patients with primary sarcoma of the uterus. College of American Pathologists 2021.

https://documents.cap.org/protocols/Uterus.Sarc_4.2.0.0.REL_CAPCP.pdf

3 Parra-Herran C, Howitt BE. Uterine mesenchymal tumors: Update on classification, staging, and molecular features. Surg Pathol Clin 2019;12:363-396.

Molecular Analysis for Sarcoma:

• Recommend molecular profiling in gynecologic mesenchymal malignancies for accurate classification3

(Table 1 [UTSARC-A 2 of 8]).

• Comprehensive genomic profiling in setting of metastatic disease as determined by an FDA-approved assay, or a validated test performed in a CLIA-certified laboratory, is informative for predicting rare pan-tumor targeted therapy opportunities and should include at least MSI,

BRCA 1/2, NTRK 1/2/3, RET, ALK, and TMB. Preferred on tissue; if tissue is not available, blood-based assays may be considered.

Continued

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Table 1

|Uterine Sarcoma|Uterine Sarcoma|Uterine Sarcoma|Uterine Sarcoma|Uterine Sarcoma|Uterine Sarcoma| |---|---|---|---|---|---| |Tumor|Hallmarks for Histologic Diagnosis|Relevant Molecular Finding|Tests Needed to Confirm Diagnosis|Relevant Prognostic Features|Other| |Conventional (spindle cell) Liomyosarcoma (LMS)|Cellular spindle cell proliferation with interlacing long fascicles with $\geq 2$ of the following: moderate to severe atypia, tumor cell necrosis, or mitotic index (MI) $\geq 10/10$ high-power fields (HPFs).|Complex karyotypes are the hallmark of the hallmark of LMS. The most commonly altered genes include TP53,ATRX,RB1, PTEN, DAXX, MDM2, CDKN2A, CDKN2C, PDGFRB, and BRCA2.|Immunoexpression of smooth muscle markers such as desmin, smooth muscle actin (SMA), and/or caldesmon; however, tumors may have variable expression and even lose expression of ≥1 markers. Approximately 1/3 of LMS express ER/ PR. Abnormal expression of ≥2 IHC markers TP53,ATRX,RB1,PTEN, DAXX, MDM2, and MTAP may favor LMS in smooth muscle tumors that do not fulfill traditional histologic criteria for LMS. Genomic risk stratification may predict clinical outcomes.|Prognosis is best predicted by stage. Morphology has not been shown to predict clinical behavior. Limited data suggest PR expression may be a positive prognostic marker in low-stage LMS.|| |Epithelioid LMS1|Epitheli histology comprising $\geq 50\%$ of the overall tumor supports classification as an epithelioid smooth muscle tumor. Diagnostic criteria for epithelioid LMS are controversial. By WHO 5th edition, epithelioid LMS is assigned when $\geq 1$ of the following features is present: moderate to severe atypia, tumor cell necrosis, MI of $\geq 4/10$ HPFs. Recent studies suggest assigning epithelioid LMS when $\geq 2$ features are present.2|PGR fusions by FISH and/ or targeted RNA sequencing in a small subset with uniform nuclear atypia and rhabdoid features.|Immunoexpression of desmin, SMA, and/ or caldesmon without MelanA expression is supportive. In some cases of epithelioid LMS, HMB -45 may be expressed.|Unknown|Epithelioid LMS may morphologically and immunohistochemically overlap with malignant PECooma for which there is no gold standard diagnostic test. Detection of pathogenic TSC1/2 mutations or TFE3 fusion may favor PECooma.|

Note: All recommendations are category 2A unless otherwise indicated.

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Table 1(continued)

$^{c}$ There are a number of sarcomas reported as low-grade ESS harboring novel fusions and a subset behave more aggressively than typical low-grade ESS; data are evolving in this area for optimal classification.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF PATHOLOGY AND MOLECULAR ANALYSIS

Table 1(continued)

|Uterine Sarcoma|Uterine Sarcoma|Uterine Sarcoma|Uterine Sarcoma|Uterine Sarcoma| |---|---|---|---|---| |Tumor|Hallmarks for Histologic Diagnosis|Relevant Molecular Finding|Additional Confirmatory Tests|Relevant Prognostic Features| |High-Grade Endometrial Stromal Sarcoma(ESS)5-13|YWHAE::NUTM2 fusion-positive tumors have a high-grade round cell component with delicate branching vasculature. Generally the MI is≥10/10 HPFs.YWHAE-altered high-grade ESS may be associated with a low-grade fibrous or fibromyoxid spindle cell component with low MI. ZC3H7B::BCOR fusion-positive tumors have high-grade spindle cells embedded in myxoid matrix. BCOR internal tandem duplication (ITD)- positive tumors share morphologic features of ZC3H7B::BCOR fusion-positive tumors. Tongue-like infiltration and LVSI are present in all subtypes.|YWHAE::NUTM2 fusion, ZC3H7B::BCOR fusion, or BCOR ITD.|IHC panel of CD10, ER, PR, cyclin D1, ±BCOR are recommended. Diffuse strong expression of cyclin D1 is present in all subtypes, and/or BCOR is strongly and diffusely expressed in the YWHAE-rearranged sarcomas but positive in only ~50% of the BCOR-altered sarcomas. CD10 is negative in the high-grade round cell component of altered subtype, but may be positive in BCOR-altered mutant subtypes. ER and PR are negative in the high-grade component of YWHAE-altered subtype, and variably positive in BCOR-altered tumors.|Slightly higher rate of lymph node involvement and trend towards worse outcomes when compared to low-grade ESS.| |Undifferentiated Uterine Sarcoma(UUS)13-16|Infiltrative sheets of pleomorphic epithelioid and/or spindle cells.||This is essentially a diagnosis of exclusion, and thus there are no confirmatory tests. An IHC panel of CD10, cyclin D1, desmin, SMA, caldesmon, pan-CK, EMA, BRG1, IN1I, pan-Trk, ALK, HMB45, MelanA, SOX10, S100, CD34, and STAT6 is recommended to consider other tumor types. Absence of ESS-associated fusions by FISH and/or targeted RNA sequencing is recommended.|ER and/or PR expression may correlate with improved survival. MI ≥ 11/mm2 is associated with decreased survival.|

Note: All recommendations are category 2A unless otherwise indicated.

Version 1.2026,11/04/25©2025 National Comprehensive Cancer Network® (NCCN®),All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

Continued References

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Table 1(continued)

|Uterine Sarcoma|Uterine Sarcoma|PRINCIPLES OF PATHOLOGY AND MOLECULAR ANALYSIS||| |---|---|---|---|---| |Uterine Sarcoma|Uterine Sarcoma|Relevant Molecular Finding|Additional Confirmatory Tests|| |Tumor|Hallmarks for Histologic Diagnosis|Relevant Molecular Finding|Additional Confirmatory Tests|Relevant Prognostic Features| |Perivascular Epithelioid Cell Tumor (PECoA)17-19|Mesenchymal neoplasm comprised of perivascular epithelioid and/or spinled cells that coexpress melanocytic and muscle markers. The tumor cells can demonstrate variable cytologic atpymit, activity, and melanin a pigment in a background of thin-walled vascular spaces and sclerotic stroma. Proposed algorithms stratify tumors into uncertain malignant potential and malignant as outlined below. Uncertain malignant potential (<3 of the following:≥5 cm size, high nuclear grade, >1 mitosis/50 mm2, necrosis, and vascular invasion). Malignant if ≥3 features (>5 cm, infiltrative growth, high nuclear grade, >1 mitosis/50 mm2, necrosis, and vascular invasion).|Inactivating mutations of TSC1/TSC2, and fusions of TFE3, RAD51B, or HTR4::ST3GAL1 can be seen. In situ hybridization to confirm rearrangement or fusion of TFE3 in TFE3-translocation-associated tumors.|Immunoexpression of cathepsin K, variable expression of melanocytic markers (HMB45 is most sensitive and MelanA is most specific), and ≥1 smooth muscle marker (SMA, desmin, and caldemon). Keratins and hormone receptors can be variably expressed. Translocation-associated tumors show diffuse TFE3 expression with weak to negative smooth muscle markers. TSC2 mutations may rarely occur in ESS; thus in tumors with ambiguous morphologic/immunophenotypic features, and TSC2 mutation identified, consideration for fusion testing is advised to exclude ESS.20|Tumor behavior is best predicted using tumor stratification into uncertain malignant potential and malignant subgroups. Treatment with mTOR inhibitors may be considered.17,21| |Inflammatory Myofibroblastic Tumor (IMT)|Spindle cell neoplasm comprised of spindled cells with admixed inflammatory infiltrate (usually lymphoplasmacytic) in a myxoid stroma. Histologic patterns include myxoid hypocellular areas (resembling fascilities), storiform or fascicular pattern with compact cellular areas with intersecting fascicles, and hyalinized dense collagenous matrix.|ALK rearrangements by FISH are seen in approximately 75% of patients. Common fusion partners include IGFBP5, THBS1, and TIMP3, RABNP2-ALK and RRBP1::ALK fusions are seen in aggressive IMT with epithelioid morphology. ALK- negative uterine IMTs are rare.|Immunoexpression of ALK(granular cytoplasmic) is sensitive and specific; seen in approximately 95% of patients and can be variable and focal. Immunoexpression of desmin, SMA, and/or caldesmon is common.|Typically benign and confined to the uterus; recurrence and extrauterine spread can occur. Tumors > 7 cm with necrosis, lymphovascular invasion, severe cytologic atypia, and high MI behave aggressively as do peritoneal IMTs. ALK-rearranged tumor may respond to ALK inhibitors rather than general tyrosine kinase inhibitors.|

Note: All recommendations are category 2A unless otherwise indicated.

Version 1.2026,11/04/25© 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

Continued References

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PRINCIPLES OF PATHOLOGY AND MOLECULAR ANALYSIS

Table 1(continued)

Note: All recommendations are category 2A unless otherwise indicated.

Version 1.2026,11/04/25©2025 National Comprehensive Cancer Network® (NCCN®),All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Continued References

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PRINCIPLES OF PATHOLOGY AND MOLECULAR ANALYSIS

Table 1(continued)

|Uterine Sarcoma|Uterine Sarcoma|Uterine Sarcoma|Uterine Sarcoma|Uterine Sarcoma| |---|---|---|---|---| |Tumor|Hallmarks for Histologic Diagnosis|Relevant Molecular Finding|Additional Confirmatory Tests|Relevant Prognostic Features| |Uterine Tumor Resembling Ovarian Sex Cord Tumor (UTROSCT)22-24|Bland spindle cell proliferation with extensive sex cord-like differentiation and no endometrial stromal component.|ESR1 or GREB1 fusions in the majority of tumors.|IHC expression of sex cord markers (inhibin, calretinin, SF1, FOXL2) and/or detection of GREB1 or ESR1 fusions by FISH (NCOA1, NCOA2, NCOA3) and/ or targeted RNA sequencing is confirmatory.|Tumors have uncertain malignant potential with ~25% being malignant. Necrosis and MI ≥2/10 HPFs and/ or presence of GREB1 fusion may increase likelihood of malignant behavior.| |Rhabdomyosarcoma (RMS)25-27|Embryonal subtype consists of small primitive cells that may form a cambium layer in botryoid tumors; strap cells and fetal cartilage can be seen. Marked atypia defines the pleomorphic subtype. Alveolar subtype consists of small primitive cells growing in nests or alveoli.|DICER1 mutations are present in ≥95% of embryonal RMS. PIK3CA and TP53 mutations in pleomorphic tumors. FOXO1 fusion in alveolar tumors.|IHC expression of myogenin and/ or MyoD1 is confirmatory of RMS differentiation. Extensive sampling must be performed to exclude carcinosarcoma or adenosarcoma with SO. FISH and/or targeted RNA sequencing for FOXO1 fusion is recommended to confirm alveolar subtype.|Embryonal subtype has better prognosis than pleomorphic and alveolar subtypes. Age and stage are prognostic factors.| |Müllerian Adenosarcoma (MAS)28-31|Biphasic tumor with benign often metaplastic epithelium associated with an atypical usually low-grade spindle cell proliferation exhibiting plenchio Fyllodges growth and periglandular stromal condensation. SO is defined by sarcoma comprising ≥25% of the tumor volume.|BAP1 loss is seen in a subset. ESR1 fusions are found in a minority of cases and BCORL1 fusions have been reported.d|Ancillary testing is usually not required.|High grade, myoinvasion, and SO are poor prognostic factors. High-grade cytologic features may also portend a worse prognosis.|

d 8q13 amplification and copy number gains of MYBL1 in a subset; NCOA2/3 fusions in a subset; rare FGFR2, KMT2C, DICER1, ATRX, and TP53 mutations; MDM2/CDK4 and TERT amplifications.

Note: All recommendations are category 2A unless otherwise indicated.

References

Version 1.2026,11/04/25 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

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PRINCIPLES OF PATHOLOGY AND MOLECULAR ANALYSIS REFERENCES

1Chiang S, Samore W, Zhang L,et al.PGR gene fusions identify a molecular subset of uterine epithelioid leiomyosarcoma with habidoid features. Am J Surg Pathol 2019;43:810-818.

2Chapel DB,Nucci MR, Quade BJ, Parra-Herran C. Epitheloid leiomyosarcoma of the uterus: Modern outcome-based appraisal of diagnostic criteria in a large institutional series. Am J Surg Pathol 2022:46:464-475.

3Arias-Stella JA 3rd, Benayed R, Oliva E, et al. Novel PLAG1 gene rearrangement distinguishes a subset of uterine myeloid omieosarcoma from other uterine myoxid mesenchymal tumors. Am J Surg Pathol 2019;43:382-388.

4Yoon JY,Marino-Enriquez A, Stickle N,et al.Myxoid smooth muscle neoplasia of the uterus: comprehensive analysis by next-generation sequencing and nucleic acid hybridization. Mod Pathol 2019;32:1688-1697.

5Lee CH, Ali RH, Rouzhabman M, et al. Cyclin D1 as a diagnostic immunomarker for endometrial stromal sarcoma with YWHAE-FAM22 rearrangement. Am J Surg Pathol 2012;36:1562-1570.

6Lee CH, Marino-Enriquez A, Ou W, et al. The clinicopathologic features of YWHAE-FAM22 endometrial stromal sarcomas: a histologically high-grade and clinically aggressive tumor. Am J Surg Pathol 2012;36:641-653.

7Lee CH, Ou WB, Mariño-Enriquez A, et al. 14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma.Proc Natl Acad Sci U S A 2012;109:929-934.

8Chiang S, Lee CH, Stewart CJR, et al. BCOR is a robust diagnostic immunohistochemical marker of genetically diverse high-grade endometrial stromal sarcoma, including tumors exhibiting variant morphology. Mod Pathol 2017;30:1251-1261.

9Hoang LN,Aneja A,Conlon N,et al.Novel high-grade endometrial stromal sarcoma: a morphologic mimicker of myloxoid leiomyosarcoma. Am J Surg Pathol 2017;41:12-24.

10Juckett LT, Lin DI, Madison R, et al. A pan-cancer landscape analysis reveals a subset of endometrial stromal and pediatric tumors defined by internal tandem stromal and pediatric tumors defined by internal tandem inhibition. Mod Pathol 2022;35:117-127.

11Lewis N, Lossl RA, Delair DF, et al. ZC3H7B-BCOR high-grade endometrial stromal sarcomas: a report of 17 cases of a newly defined entity. Mod Pathol 2018;31:674-684.

12 Marino-Enriquez A, Lauria A, Przybyl J, et al. BCOR internal tandem duplication in high-grade uterine sarcomas. Am J Surg Pathol 2018;42:335-341.

13 Cotzia P, Benayed R, Mullaney K, et al.Undifferentiated uterine sarcomas represent under-recognized high-grade endometrial stromal sarcomas.Am J Surg Pathol 2019;43:662-669.

14 Binzer-Panchal A, Hardell E, Viklund B, et al.Integrated molecular analysis of undifferentiated uterine sarcomas reveals clinically relevant molecular subtypes. Clin Cancer Res 2019;25:2155-2165.

15Kolin DL, Dong F, Baltay M,et al.SMARCA4-deficient undifferentiated uterine sarcoma(malignant rhaboid tumor of the uterus); a clinicopathologic entity distinct from undifferentiated carcinoma. Mod Pathol 2018;31:1442-1456.

16Kolin DL, Quick CM, Dong F,et al. SMARCA4-deficient uterine sarcoma and undifferentiated endometrial carcinoma are distinct clinicopathologic entities. Am J Surg Pathol 2020;44:263-270.

17 Bennett JA, Braga AC, Pinto A, et al. Uterine PEPComas: A morphologic, immunohistochemical, and molecular analysis of 32 tumors. Am J Surg Pathol 2018;42:1370-1383.

18 Folpe AL,Mentzel T, Lehr A,et al. Perivascular endotheloid cell neoplasms of soft tissue and gynecologic origin: a clinicopathologic study of 26 cases and review of the literature. Am J Surg Pathol 2005;29:1558-1575.

19 Schoolmeester JK, Howitt BE, Hirsch MS, et al.Perivascular epithelioid cell neoplasm(PECoA)and the al. of the endoplatic tract: clinicopathologic and immunohistochemical characterization of 16 cases. Am J Surg Pathol 2014;38:176-188.

20 Chiang S, Vasudevaraja V, Serrano J,et al.TSC2-mutant uterine sarcomas with JAZF1-SUZ12 fusions demonstrate hybrid features of endometrial stromal sarcoma and PECooma and are responsive to mTOR inhibition. Mod Pathol 2023;35:117-127.

21WHO Classification of Tumours Editorial Board.Female Genital Tumours. Lyon(France): International Agency for Research on Cancer; 2020.WHO Classification of Tumours, 5th ed.; vol. 4.

22 Dickson BC,Childs TJ,Colgan TJ,et al.Uterine tumor resembling ovarian sex cord tumor. A distinct entity characterized by recurrent NCOA2/3 gene fusions.Am J Surg Pathol 2019;43:178-186.

23Goebel EA, Hernandez Bonilla S,Dong F,et al.Uterine tumor resembling ovarian sex cord tumor(UTROSCT): A morphologic and molecular study of 26 cases confirms recurrent NCOA1-3 rearrangement.Am J Surg Pathol 2020;44:30-42.

24Lee CH,Kao YC,Lee WR,et al. Clinicopathologic characterization of GREB1-rearranged uterine sarcomas with variable sex-cord differentiation. Am J Surg Pathol 2019;43:928-942.

25Leiner J,Le Loeraf.The current landscape of rhabdomyosarcomas: an update. Virchows Arch 2020;476:97-108.

26 Pinto A, Kahn RM, Rosenberg AE, et al. Uterine rhabdomyosarcoma in adults. Hum Pathol 2018;74:122-128.

27 de Kock L, Yoon JY, Apellaniz-Ruiz M, et al.Significantly greater prevalence of DICER1 alterations in urinerbalum phosamyarcoma compared to adenosarcoma. Mod Pathol 2020;33:1207-1219.

28 Hodgson A,Amemiya Y,Seth A,et al. High-grade Mullerian adenosarcoma: genomic and clinicopathologic characterization of a distinct neoplasm with prevalent TP53 pathway alterations and aggressive behavior.Am J Surg Pathol 2017;41:1513-1522.

29 Lee JC, Lu TP, Changou CA,et al. Genomewide copy number analysis of Müllerian adenosarcoma identified chromosomal instability in the aggressive subgroup.Mod Pathol 2016;29:1070-1082.

30 Howitt BE, Sholl LM, Dal Cin P,et al.Targeted genomic analysis of Müllerian adenosarcoma. J Pathol 2015;235:37-49.

31 Piscugioli S, Burke KA, Ng CKY, et al. Uterine adenosarcomas are mesenchymal neoplasms. J Pathol 2016;238:381-388.

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PRINCIPLES OF IMAGINGa,1-9

Initial Workup

• Chest/abdomen/pelvis CT

• For patients who underwent TH with incidental finding of uterine sarcoma or incompletely resected uterus/adnexa (ie, SCH, myomectomy,

possible tumor fragmentation, intraperitoneal morcellation) perform chest/abdomen/pelvis CT or abdomen/pelvis MRI and chest CT without contrast to evaluate for metastatic disease.

• Consider pelvis MRI to evaluate local tumor extension or residual abnormality in cases where the uterus or adnexa were not resected or

incompletely resected (ie, SCH, myomectomy, possible tumor fragmentation, intraperitoneal morcellation).

• Consider neck/chest/abdomen/pelvis/groin FDG-PET/CT to clarify ambiguous findings.

• Additional imaging should be based on symptomatology and clinical concern for metastatic disease.b

Follow-up/Surveillance

• Chest/abdomen/pelvis CT every 3–6 months for the first 3 years and then every 6–12 months for the next 2 years. Depending on histology

grade and initial stage, consider imaging annually or every other year thereafter up to an additional 5 years.c

• Optional abdomen/pelvis MRI and chest CT without contrast every 3–6 months for the first 3 years and then every 6–12 months for the next 2 years. Depending on histology, grade, and initial stage, consider imaging annually or every other year thereafter up to an additional 5 years.c

• Consider neck/chest/abdomen/pelvis/groin FDG-PET/CT if metastasis is suspected in select patients.

• Additional imaging should be based on symptomatology and clinical concern for metastatic disease.d

a MRI is performed with and without contrast and CT is performed with contrast unless contraindicated. Contrast is not required for screening chest CT.b Indications may include abnormal physical exam finding, bulky uterine tumor, vaginal or extrauterine involvement, delay in presentation or treatment, and abdominal or pulmonary symptoms.

c Follow-up imaging may be as frequent as every 3 months or change based on histology grade and/or stage of tumor.d Indications may include abnormal physical exam findings such as vaginal involvement; palpable mass or adenopathy; and new pelvic, abdominal, or pulmonary

symptoms.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF IMAGING REFERENCES

Note: All recommendations are category 2A unless otherwise indicated.

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1 Salani R, Khanna N, Frimer M, et al. An update on post-treatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of

Gynecologic Oncology (SGO) recommendations. Gynecol Oncol 2017;146:3-10.

discussion 35-36.

6 Hensley ML, Barrette BA, Baumann K, et al. Gynecologic Cancer InterGroup (GCIG) consensus review: uterine and ovarian leiomyosarcomas. Int J Gynecol Cancer 2014;24(9 Suppl 3):S61-S66.

![NCCN\n](2/aj0YEe4oUhYkBdfpda0fYP/figure3cfc471e34f440b689b6045db16638bf_0_1.png) National Comprehensive Cancer

NCCN Guidelines Version 1.2026

Uterine Sarcoma

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SYSTEMIC THERAPY FOR UTERINE SARCOMaA (Clinical trials strongly recommended)

|Advanced, Recurrent/Metastatic or Inoperable Disease|| |---|---| |First-Line Therapy|First-Line Therapy| |Preferred|Second-Line or Subsequent Therapyb| |● Doxorubicin|Trabectedin(for LMS)| |●Docetaxel/Gemcitabine|| |●Doxorubicin/Trabectedin(for LMS)1|Other Recommended| |●Doxorubicin/losfamide|●Dacarbazine/Gemcitabine| |●Dacarbazine/Doxorubicin (for LMS or lfosfamide ineligible)|Gemcitabine/Vinorelbine| |Useful in Certain Circumstances|●Dacarbazine| |●Biomarker-directed therapy|●Epirubicin| |NTRK gene fusion-positive tumors|●Ifosfamide| |◆Larrotectinib|●Liposomal Doxorubicin| |◆Entrectinib|Pazopanib| |◆Reprotectinibc,2|●Temozolomide| |IMT with ALK translocation|●Regorafenib8| |◆Crizotinib3|●Eribulin(category 2B)| |◆ Ceritinib4|| |◆ Brigatinib,6|Useful in Certain Circumstances (Biomarker-directed therapy)| |◆Lorlatinib|TMB-H tumorse| |◆ Alectinib|Pembrizumabf| |●RET fusion-positive tumors|●Ipilimumab + Nivolumab| |● Selpercatinib|●Consider PARP inhibitors for BRCA-altered LMS9,10-12| |●PEComa|Olaparib13| |●Albumin-bound Sirolimusd|Rucaparib| ||Niraparib| ||●PEComa| ||●PEComa| ||●Sirolimus| ||Everolimus| ||●CDK4 amplification| ||●Palbociclib14,15|

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a NCCN Guidelines for Ovarian Cancer–Management of Drug Reactions (OV-D).b If not used previously, first-line agents can be used as second-line or subsequent therapy as clinically appropriate.c NTRK-positive tumors that are naïve to prior NTRK-targeted therapy or have progressed on prior NTRK therapy.d PEComa or tuberous sclerosis complex (TSC) pathogenic variant muscle tumor.e For the treatment of patients with unresectable or metastatic TMB-H (≥10 mut/Mb) tumors that have progressed following prior treatment and have no satisfactory

alternative treatment options.

f Pembrolizumab and berahyaluronidase alfa-pmph subcutaneous injection may be substituted for IV pembrolizumab. Pembrolizumab and berahyaluronidase alfa-pmph has different dosing and administration instructions compared to IV pembrolizumab.

g For oncogenic or likely oncogenic mutations in BRCA2, may refer to definitions at oncokb.org.

Note: All recommendations are category 2A unless otherwise indicated.

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FOOTNOTES

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SYSTEMIC ENDOCRINE THERAPY FOR UTERINE SARCOMaA (Clinical trials strongly recommended)

|Anti-Estrogen Hormone Therapy for Low-Grade ESS or Adenosarcoma Without SO (ER/PR-Positive Uterine Sarcomas)h|| |---|---| |Preferred|Other Recommended| |● Aromatase inhibitorsi|● Fulvestant!| |Anastrozole|● Megestrol acetate (category 2B)| |Letrozole|● Medroxyprogesterone acetate (category 2B)| |Exemestane|| |●Consider gonadotropin-releasing hormone (GnRH) analogs with aromatase inhibitors|| |in patients who are premenopausal and not suitable for surgery(BSO)||

a NCCN Guidelines for Ovarian Cancer-Management of Drug Reactions(OV-D).

iOvarian ablation or suppression is needed in patients who are not postmenopausal. It is unknown if ovarian ablation or suppression is needed in order for fulvestrant to be effective in uterine sarcomas.

Note: All recommendations are category 2A unless otherwise indicated. UTSARC-C 3 OF 3

Authors

References

NCCN Guidelines Version 1.2026 Uterine Neoplasms

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PRINCIPLES OF RADIATION THERAPY FOR UTERINE NEOPLASMS

General Principles–Uterine Neoplasms

• RT is directed at sites of known or suspected tumor involvement and may include EBRT and/or brachytherapy. Imaging is required to assess locoregional extent and to rule out distant metastases before administration of RT. In general, EBRT is directed to the pelvis with or without

the para-aortic region. Brachytherapy can be delivered: 1) to an intact uterus, either preoperatively or definitively; or 2) more commonly, to

the vagina after hysterectomy. For the purposes of these guidelines, whole abdominal radiotherapy is not considered to be tumor-directed RT.

• Chemoradiation can be given concurrently or sequentially.

General Treatment Information

• Target Volumes

Pelvic radiotherapy should target the gross disease (if present), the lower common iliacs, external iliacs, internal iliacs, obturators,

parametria, upper vagina/para-vaginal tissue, and presacral lymph nodes (in patients with cervical involvement).

Extended-field radiotherapy should include the pelvic volume and also target the entire common iliac chain and para-aortic lymph node

region. The upper border of the extended field depends on the clinical situation but should at least be 1–2 cm above the level of the renal

vessels.

Pelvic tissues at risk, especially in the post-hysterectomy setting, can be highly variable depending on bowel and bladder filling. In this

situation, the internal target volume (ITV), which encompasses the range of organ movement and deformation, is considered the clinical

target volume (CTV), and should be fully covered in the treatment volume.

Note: All recommendations are category 2A unless otherwise indicated.

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General Treatment Information (continued)

• Dosing Prescription Regimen – External Beam

External-beam doses for microscopic disease should be 45–50 Gy. CT treatment planning should be utilized, and intensity-modulated

RT (IMRT) for normal tissue sparing should be considered, with appropriate attention to quality assurance (QA) and tissue interfraction

mobility.

Treating with IMRT technique is preferred to minimize toxicities in definitive treatment of the pelvis with or without para-aortic treatment.

Regular use of image-guided RT (IGRT) with orthogonal imaging and/or routine volumetric imaging (such as cone-beam CT) at the time of

treatment delivery is essential to ensure appropriate coverage of targets and sparing of normal tissues.

Postoperatively, if there is gross residual disease and the area(s) can be sufficiently localized, a boost can be added to a total dose of

60–70 Gy, respecting normal tissue sensitivity.

For gross nodal disease, consider boost to 60–65 Gy while respecting normal tissue constraints.

For neoadjuvant radiation, doses of 45–50 Gy are typically used. One could consider adding 1–2 high-dose-rate (HDR) insertions to a total

dose of 75–80 Gy low-dose-rate (LDR) equivalent, to minimize risk of positive or close margins at hysterectomy.

For pelvic-confined recurrent endometrial cancer without a prior history of radiation, fields would mirror adjuvant radiation. For

reirradiation, fields should be limited to gross disease and target dose prescribed to maximize control while minimizing risk to normal

tissues.

• Dosing Prescription Regimen – Brachytherapy

Initiate brachytherapy as soon as the vaginal cuff is healed, preferably 6–8 weeks after surgery but in general initiation of brachytherapy

should not exceed 12 weeks. For vaginal brachytherapy, the dose should be prescribed to the vaginal surface or at a depth of 0.5 cm from

the vaginal surface; the dose depends on the use of EBRT. The target for vaginal brachytherapy after hysterectomy should be no more than

the upper two-thirds of the vagina; in cases of extensive LVSI or positive margins, a longer segment of the vagina may be treated.

◊ For postoperative HDR vaginal brachytherapy alone, regimens include 6 Gy x 5 fractions prescribed to the vaginal surface, or

7 Gy x 3 fractions or 5.5 Gy x 4 fractions prescribed to 5 mm below the vaginal surface. While 7 Gy x 3 fractions prescribed at a depth

of 0.5 cm from the vaginal surface is a regimen used by many, the use of smaller fraction sizes may be considered to potentially further

limit toxicity in selected patients.

◊ When HDR brachytherapy is used as a boost to EBRT, doses of 4–6 Gy x 2 to 3 fractions prescribed to the vaginal mucosa are commonly used.

For medically inoperable uterine cancer, risk of extrauterine spread determines the combination of EBRT plus brachytherapy or

brachytherapy alone. Brachytherapy doses for definitive therapy are individualized based on the clinical situation. When available, imageguided therapy should be used. Based on the best available evidence, an equivalent dose at 2 Gy (EQD2) fractions D90 of ≥48 Gy should

be delivered to the uterus, cervix, and upper 1–2 cm of vagina if brachytherapy alone is used, and should be increased to 65 Gy for the

combination of EBRT and brachytherapy. If an MRI is used as part of planning, the target dose for the gross tumor volume (GTV) would be

an EQD2 of ≥80 Gy.

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Note: All recommendations are category 2A unless otherwise indicated.

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General Treatment Information (continued)

• Interstitial Brachytherapy

Interstitial brachytherapy is an advanced technique where multiple needles/catheters are inserted in the gross disease/target. Interstitial

brachytherapy may be preferred to maximize dose to the target and minimize dose to the organs at risk (OARs) for cases where

intracavitary brachytherapy is not possible, or anatomy favors interstitial brachytherapy. Three-dimensional treatment planning allows

volumetric delineation of targets and OARs on CT and/or MRI with dose-volume histograms. Dose and fractionation depend on prior RT

dose, target volume, and OAR doses.

Stereotactic Radiosurgery (SRS) and Stereotactic Body RT (SBRT) for Metastatic Disease

• SRS and SBRT are radiation treatment modalities that utilize advanced three-dimensional anatomic targeting accuracy to deliver precise,

ablative, high-dose ionizing radiation. The therapy maximizes the cell-killing effect of ionizing radiation while minimizing radiation-induced

injury in adjacent sensitive normal tissues. SRS and SBRT demand precise target localization, reproducibility of patient setup, and a sharp

radiation dose gradient. SRS is delivered exclusively to intracranial targets while SBRT describes stereotactic therapy to extracranial targets.

SRS and SBRT are delivered in 1 to 5 fractions of therapy with the expectation of durable control at the radiated site.

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Note: All recommendations are category 2A unless otherwise indicated.

UN-B

PRINCIPLES OF GYNECOLOGIC SURVIVORSHIP

Physical Effects

• Gynecologic cancer treatment typically involves surgery, chemotherapy, hormone therapy, RT, and/or immunotherapy. These treatments

cause acute, short-term, and long-term toxicities.

• Surgical approaches may be extensive and pose risks such as adhesion formation, which may cause pain and may contribute to small

bowel obstruction, urinary or gastrointestinal complications (eg, incontinence, diarrhea), pelvic floor dysfunction (manifested by a variety of urinary, bowel, and/or sexual effects), and lymphedema.

• Chemotherapy agents vary, though commonly used regimens may pose a significant risk of neurotoxicity, cardiac toxicity, development of hematologic cancers, and cognitive dysfunction.

• Long-term estrogen deprivation may cause symptoms such as hot flashes, vaginal dryness, and bone loss.

• RT may cause long-term complications (eg, fibrosis, vulvovaginal atrophy) and may predispose patients to secondary cancers of the

subcutaneous tissue, and/or underlying organs that are proximal to the radiation field.

• Prior pelvic RT may contribute to bone loss and increase the risk of pelvic fractures. Consider bone density testing and prophylactic use of bisphosphonates, particularly in patients with osteoporosis.

• Immunotherapy use is emerging, and to date, long-term effects of these treatments are unknown.

Additional Guidance

• NCCN Guidelines for Distress Management

• NCCN Guidelines for Smoking Cessation

• NCCN Guidelines for Survivorship

Psychosocial Effects

• Psychosocial effects after cancer may be psychological (eg, depression, anxiety, fear of recurrence, altered body image), financial (eg, return to work, insurance concerns), and/or interpersonal (eg, relationships, sexuality, intimacy) in nature.

Clinical Approach

• All gynecologic cancer survivors should receive regular general medical care that focuses on managing chronic disease, monitoring

cardiovascular risk factors, providing recommended vaccinations, and encouraging adoption of a healthy lifestyle.

• In order to assess the late and long-term effects of gynecologic cancers, clinicians should comprehensively document the patient’s history,conduct a thorough physical examination, and provide any necessary imaging and/or laboratory testing. All patients, whether sexually

active or not, should be asked about genitourinary symptoms, including vulvovaginal dryness. Referral to appropriate specialty providers

(eg, physical therapy, pelvic floor therapy, sexual therapy, psychotherapy) is recommended. As most treatments for gynecologic cancers

will cause sexual dysfunction, early menopause, and infertility, special attention to the resultant medical and psychosocial implications is

needed.

• Post-radiation use of vaginal dilators and moisturizers is recommended.

• For treatment-related menopause, hormone therapy should be considered.

• Communication and coordination with all clinicians involved in the care of survivors, including primary care clinicians, is critical. Providing cancer survivors with a summary of their treatment and recommendations for follow-up is recommended.

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Staging–Uterine Carcinomas and Carcinosarcoma

ST-1

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing.

Continued

Table 1AJCC Tumor-Node-Metastases (TNM) and International Federation of Gynecology and Obstetrics (FIGO) Surgical Staging Systems for Endometrial Cancer

Definitions for T, N, M

FIGO Stage

Primary Tumor

Primary tumor cannot be assessed

No evidence of primary tumor

Tumor confined to the corpus uteri, including endocervical glandular involvement

T1a IA

Tumor limited to the endometrium or invading less than half the myometrium

T1b IB

Tumor invading one half or more of the myometrium

Tumor invading the stromal connective tissue of the cervix but not extending beyond the uterus. Does NOT include endocervical glandular involvement

III

Tumor involving serosa, adnexa, vagina, or parametrium

T3a IIIA Tumor involving the serosa and/or adnexa (direct extension or metastasis)

T3b IIIB Vaginal involvement (direct extension or metastasis) or parametrial involvement

IVA Tumor invading the bladder mucosa and/or bowel mucosa (bullous edema is not sufficient to classify a tumor as T4)

National Comprehensive Cancer Cancer Network®

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Table 1 - Continued

N FIGO Regional Lymph Nodes Stage</td> <td>FIGO Regional Lymph Nodes</td> <td>9990009100</td> </tr> <tr> <td>NX</td> <td>$$\begin{array}{l}\text{Stage I/2}\\ \\ \\ \end{array}$$</td> <td>Regional lymph nodes cannot be assessed</td> </tr> <tr> <td>N0 (i+)</td> <td>No regional lymph node metastasis</td> <td>Isolated tumor cells in regional lymph node(s) no greater than 0.2 mm</td> </tr> <tr> <td>N1</td> <td>IIC1</td> <td>Regional lymph node metastasis to pelvic lymph nodes</td> </tr> <tr> <td>N1</td> <td>MI si</td> <td>Regional lymph node metastasis</td> </tr> <tr> <td>N1</td> <td>IIC1</td> <td>Regional lymph node metastasis</td> </tr> <tr> <td>N1</td> <td>IIC1</td> <td>Regional lymph node metastasis to pelvic lymph nodes</td> </tr> <tr> <td>N2</td> <td>IIIC2</td> <td>Regional lymph node metastasis (greater than 0.2 mm in diameter) to para- aortic lymph nodes, with or without positive pelvic lymph nodes</td> </tr> <tr> <td>N2a</td> <td>IIIC2</td> <td>Regional lymph node metastasis (greater than 2.0 mm in diameter) to para- aortic lymph nodes, with or without positive pelvic lymph nodes</td> </tr> <tr> <td>M</td> <td>FIGO Distant Metastasis</td> <td></td> </tr> <tr> <td>N0</td> <td>No distant metastasis</td> <td></td> </tr> <tr> <td>M1</td> <td>IVB Distant metastasis (includes metastasis to inguinal lymph nodes, intraperitoneal disease, lung, liver, or bone). (It excludes metastasis to pelvic or para-aortic lymph nodes, vagina, uterine serosa, or adnexa).</td> <td></td> </tr> <tr> <td>G</td> <td>Histologic Grade</td> <td></td> </tr> <tr> <td>G</td> <td>Grade cannot be assessed</td> <td></td> </tr> <tr> <td>G1</td> <td>Well differentiated</td> <td></td> </tr> <tr> <td>G2</td> <td>Moderately differentiated</td> <td></td> </tr> <tr> <td>G3</td> <td>Poorly differentiated or undifferentiated</td> <td>Continued</td> </tr> <tr> <td colspan="3">Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing.</td> </tr> <tr> <td colspan="3">Version 1.2026,11/04/25 © 2025 National Comprehensive Cancer Network® (NCCN®),All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.</td> </tr> </table>

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N0(i+) Isolated tumor cells in regional lymph node(s) no greater than 0.2 mm

N1 IIC1 Regional lymph node metastasis to pelvic lymph nodes

N1mi IIIC1 Regional lymph node metastasis (greater than 0.2 mm but not greater than 2.0 mm in diameter) to pelvic lymph nodes

N1a IIIC1 Regional lymph node metastasis(greater than 2.0 mm in diameter) to pelvic lymph nodes

N2I IIIC2 Regional lymph node metastasis to para-aortic lymph nodes, with or without positive pelvic lymph nodes

N2mi IIIC2 Regional lymph node metastasis (greater than 0.2 mm but not greater than 2.0 mm in diameter) to para-aortic lymph nodes, with or without positive pelvic lymph nodes

N2a IIIC2 Regional lymph node metastasis (greater than 2.0 mm in diameter) to para-aortic lymph nodes, with or without positive pelvic lymph nodes

Suffix (sn) is added to the N category when metastasis is identified only by sentinel lymph node biopsy.

M FIGO Distant Metastasis Stage

M0 No distant metastasis

M1 IVB Distant metastasis(includes metastasis to inguinal lymph nodes, intraperitoneal disease, lung, liver, or bone).(It excludes metastasis to pelvic or para-aortic lymph nodes, vagina, uterine serosa, or adnexa).

G Histologic Grade

GX Grade cannot be assessed

G1 Well differentiated

G2 Moderately differentiated

G3 Poorly differentiated or undifferentiated

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition(2017) published by Springer International Publishing.

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NCCN Guidelines Index Table of Contents Discussion

Staging-Uterine Sarcoma

Table 3

AJCC Tumor-Node-Metastases(TNM) and International Federation of Gynecology and Obstetrics (FIGO) Surgical Staging Systems for Uterine Sarcomas (includes Leiomyosarcoma and Endometrial Stromal Sarcoma)

Leiomyosarcoma and Endometrial Stromal Sarcoma

T FIGO Primary Tumor Stage

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

T1 I T1a IA T1a IB Tumor limited to the uterus

T1a IA Tumor 5 cm or less in greatest dimension

T1b IB Tumor more than 5 cm

T2 II Tumor extends beyond the uterus, within the pelvis

T2a ⅡIA Tumor involves adnexa

T2b IIB Tumor involves other pelvic tissues

T3 III Tumor infiltrates abdominal tissues

T3a IIIIA One site

T3b IIIB More than one site

T4 IVA T4 IVA T4 IVA T4 IVA T4 IVA

N FIGO Regional Lymph Nodes Stage

NX Regional lymph nodes cannot be assessed

NO No regional lymph node metastasis

NO(i+)|\| Isolated tumor cells in regional lymph node(s) no greater than 0.2 mm

N1 IIIC Regional lymph node metastasis

M FIGO Distant Metastasis Stage

MO No distant metastasis

M1 IVB Distant metastasis(excluding adnexa, pelvic, and abdominal tissues)

G Histologic Grade

GX Grade cannot be assessed

G1 Well differentiated

G2 Moderately differentiated

G3 Poorly differentiated or undifferentiated

Table 4. AJCC Prognostic Stage Groups

||T|N|M| |---|---|---|---| |Stage I|T1|T1|NO M| |Stage IA|T1a|NO|MO| |Stage IB|T1b|N0|MO| |Stage II|T2|NO|MO| |Stage IIIA|T3a|NO|MO| |Stage IIIB|T3b|NO|MO| |Stage IIIC|T1-3|N1|MO| |Stage IVA|T4|Any N|M0| |Stage IVB|Any T|Any N|M1|

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition(2017) published by Springer International Publishing.

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Table of Contents Discussion

Staging-Uterine Sarcoma

Table 4

AJCC Tumor-Node-Metastases(TNM) and International Federation of Gynecology and Obstetrics (FIGO) Surgical Staging Systems for Uterine Sarcomas (includes Müllerian adenosarcoma)

T FIGO Primary Tumor Stage

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

T1 I T1a IIA T1b IB*

T1a IA Tumor limited to the endometrium/endervix

T1b IB* Tumor invades less than or equal to half myometrial invasion

T1c IC* Tumor invades more than half myometrial invasion

T2 I II Tumor extends beyond the uterus, within the pelvis

T2a IIA Tumor involves adnexa

T2b IIB Tumor involves other pelvic tissues

T3T III Tumor infiltrates abdominal tissues

T3a III AIA One site

T3b IIIB More than one site

T4 IVA T4 IVA invades bladder or rectum

N FIGO Regional Lymph Nodes Stage

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N0(i+)Isolated tumor cells in regional lymph node(s) no greater than 0.2 mm

N1 IIIC Regional lymph node metastasis

M FIGO Distant Metastasis Stage

M0 No distant metastasis

M1 IVB Distant metastasis(excluding adnexa, pelvic, and abdominal tissues)

G Histologic Grade

GX Grade cannot be assessed

G1 Well differentiated

G2 Moderately differentiated

G3 Poorly differentiated or undifferentiated

Table 4. AJCC Prognostic Stage Groups

||T|N|M| |---|---|---|---| |Stage I|T1|NO|MO| |Stage IA|T1a|NO|MO| |Stage IB|T1b|NO|MO| |Stage IC|T1c|NO|MO| |Stage II|T2|NO|MO| |Stage IIIA|T3a|NO|MO| |Stage IIIB|T3b|NO|MO| |Stage IIC|T1-3|N1|MO| |Stage IVA|T4|Any|N0| |Stage IVB|Any T|Any|N1 M1|

*There is a discrepancy between the 2009 FIGO and 2017 AJCC staging documents in the tumor definitions for FIGO stages IB and IC. The NCCN Panel has chosen to use 2009 FIGO language as noted in Corrigendum to "FIGO staging for uterine sarcomas" [International Journal of Gynecology and Obstetrics (2009) 104:179].

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition

(2017) published by Springer International Publishing.

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NCCN Guidelines Version 1.2026 Uterine Neoplasms

NCCN Guidelines Index Table of Contents Discussion

|99mTc|technetium-99m|ICG|ABBREVIATIONS|OAR|organ at risk|| |---|---|---|---|---|---|---| |BSO|bilateral salpingo-ophorectomy|IGRT|image-guided radiation therapy|PCR|PCR polymerase chain reaction|| |||IHC|immunohistochemistry|PEComa|perivascular epithelioid cell|| |||IMRT|intensity-modulated radiation therapy|PEComa|tumor|| |CBC|complete blood count||therapy||tumor|| |||IMT|inflammatory myofibroblastic tumor|pMMR PR|mismatch repair proficient|| |CLIA|Clinical Laboratory Improvement Amendments|IORT|intraoperative radiation therapy|||| |CTV|clinical target volume|ITD|internal tandem duplication|QA|quality assurance|| |||ITV|internal target volume|||| |D&C|dilation and curettage|IUD|intrauterine device|RH|radical hysterectomy|| |dMMR|mismatch repair deficient|||RMS|rhabdomyosarcoma|| |||LDR|low dose rate|||| |EBRT|external beam radiation therapy|LFT|liver function test|SBRT|stereotactic body radiation|| |EQD2|equivalent dose at 2 Gy|LMS|leiomyosarcoma|||| |ER|estrogen receptor|LND|lymphadenectomy|SCH|supracervical hysterectomy|| |ESS|endometrial stromal sarcoma|LVSI|lymphovascular space invasion|SDUS|SMARCA4-deficient uterine sarcoma|| |FDG|fluorodeoxyglucose|MAS|Müllerian adenosarcoma||SLN|| |FIGO|International Federation of Gynecology and Obstetrics|MI|mitotic index|SMA|smooth muscle actin|| |FISH|fluorescence in situ hybridization|MIS|minimally invasive surgery|SO|sarcomatous overgrowth|| |FISH|fluorescence in situ hybridization|MMR|mismatch repair||SRS stereotactic radiosurgery|| ||GnRH|gonadotropin-releasing hormone GTV gross tumor volume|MSI -H mut/Mb|microsatellite instability-microsatellite instability-high mutations/megabase|TH TMB -H mutations/megabase|total hysterectomy TMB -H tumor mutational burden-high tubercous sclerosis complex| |H&E|hematoxylin and eosin||NGS|next-generation sequencing||| |H&P|history and physical|NSMP|no specific molecular profile|UTROSCT|uterine tumor resembling ovarian sex cord tumor|| |HDR|high dose rate|||UUS|undifferentiated uterine sarcoma|| |HPF|high-power field|||UUS|undifferentiated uterine sarcoma||

Version 1.2026,11/04/25©2025 National Comprehensive Cancer Network®(NCCN®),All rights reserved.NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

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NCCN Guidelines Index Table of Contents Discussion

|NCCN Categories of Evidence and Consensus|| |---|---| |Category 1|Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus(≥85% support of the Panel) that the intervention is appropriate.| |Category 2A|Based upon lower-level evidence, there is uniform NCCN consensus(≥85% support of the Panel) that the intervention is appropriate.| |Category 2B|Based upon lower-level evidence, there is NCCN consensus(≥50%, but <85% support of the Panel) that the intervention is appropriate.| |Category 3|Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.|

All recommendations are category 2A unless otherwise indicated.

|NCCN Categories of Preference|| |---|---| |Preferred|Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.| |Other recommended|Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.| |Useful in certain circumstances|Other interventions that may be used for selected patient populations (defined with recommendation).|

All recommendations are considered appropriate.

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Discussion Table of Contents

This discussion corresponds to the NCCN Guidelines for Uterine Neoplasms. Last updated: March 7,2025.

Overview $\ldots$ 2

Guidelines Update Methodology $\ldots$ 2

Literature Search Criteria.2.2

Sensitive/Inclusive Language Usage $\ldots$ 2

Initial Evaluation $\ldots$ 3

Endometrial Cancer.3

Molecular Analysis and Genetic Factors $\ldots$ 4

Diagnosis and Workup $\ldots$ 5

Imaging $\ldots$ 5

Disease Staging $\ldots$ 5

Principles of Evaluation and Surgical Staging for Endometrial Carcinoma $\ldots$ 6

Pathology $\ldots$ 6

Lymphadenectomy $\ldots$

SLN Ultrastaging $\ldots$ 10

Minimally Invasive Procedures 10

Primary Treatment. $\ldots$ 12

Disease Limited to the Uterus $\ldots$ 12

Suspected or Gross Cervical Involvement 13

Suspected Extrauterine Disease $\ldots$ 14

Adjustual Therapy 14

Uterine-Confined Disease 14

Advanced Stage/Extrauterine Disease $\ldots$ 18

High-Risk Endometrial Carcinoma Histologies..21

Overview $\ldots$ 21

Primary Treatment..21

Treatment of Recurrent or Metastatic Disease $\ldots$ 22

Locoregional Recurrence 22

Distant Metastases $\ldots$ .23

Hormonal Therapy $\ldots$ 23

Systemic Therapy for Recurrent Disease $\ldots$ (24)

Systemic Therapy Options for High-Risk Endometrial Histologies $\ldots$ 27

Radiotherapy Principles..28

Post-Treatment Surveillance $\ldots$ 28

Hormone Therapy for Hypoestrogenism $\ldots$ 29

Uterine Sarcomas $\ldots$ 30

Overview $\ldots$ 30

Pathology and Molecular Analysis $\ldots$ 30

Staging and Treatment $\ldots$ 33

Treatment of Recurrent or Metastatic Disease $\ldots$ 35

Systemic Therapy for Advanced, Metastatic/Recurrent or Inoperable Disease $\ldots$ $\ldots$ $\ldots$ $\ldots$ $\ldots$ $\ldots$ $\ldots$ $\ldots$ $\ldots$ $\ldots$ $\ldots$ $\ldots$

Post-Treatment Surveillance $\ldots$ 37

Drug Reactions $\ldots$ 37

Gynecologic Survivorship $\ldots$ .38

References..39

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Overview

Adenocarcinoma of the endometrium (also known as endometrial cancer,or more broadly as uterine cancer or carcinoma of the uterine corpus) is the fourth most common malignancy of the female genital tract in the United States with fastest increasing mortality. It is estimated that 69,120 new uterine cancer cases will occur in 2025, with 13,860 deaths resulting from the disease. ${ }^{1}$ The incidence of uterine corpus cancer has also continued to increase by about 1% per year since the mid-2000s. ${ }^{2}$ It is also the only cancer with reduced survival over the past four decades.Sstromal or mesenchymal sarcomas are uncommon subtypes accounting for approximately 3% of all uterine cancers.3,4 The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Uterine Neoplasms describe malignant epithelial tumors and uterine sarcomas; each of these major categories contains specific histologic groups that require different management (see Initial Clinical Findings in the NCCN Guidelines for Uterine Neoplasms).

Risk factors for uterine neoplasms include increased levels of estrogen(caused by obesity, diabetes, and high-fat diet), early age at menarche,nulliparity, late age at menopause, Lynch syndrome, ages between 55 and 64 years, and tamoxifen use.5-8 Thus, the incidence of endometrial cancer is increasing because of increased life expectancy and obesity.The Summary of the Guidelines Updates describes the most recent revisions to the algorithm, which have been incorporated into this revised Discussion text (see the NCCN Guidelines® for Uterine Neoplasms). The NCCN Guidelines cannot incorporate all possible clinical variations and are not intended to replace good clinical judgment or individualization of treatments."Many exceptions to the rule" were discussed among the Panel members during the update process for these Guidelines.Recommendations in the NCCN Guidelines are category 2A unless otherwise noted.

Guidelines Update Methodology

The complete details of the Development and Update of the NCCN Guidelines are available at www.NCCN.org.

Literature Search Criteria

Prior to the update of this version of the NCCN Guidelines for Uterine Neoplasms an electronic search of the PubMed database was performed to obtain key literature in uterine neoplasms published since the previous Guidelines update, using the following search terms: endometrial cancer or endometrial carcinoma or uterine sarcoma or endometrial stromal sarcoma or uterine leiomyosarcoma. The PubMed database was chosen as it remains the most widely used resource for medical literature and indexes peer-reviewed biomedical literature.

The search results were narrowed by selecting studies in humans published in English. Results were confined to the following article types:Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV;Guideline; Randomized Controlled Trial; Meta-Analysis; Systematic Reviews; and Validation Studies.

The data from key PubMed articles as well as articles from additional sources deemed relevant to these guidelines as discussed by the Panel during the Guidelines update process have been included in this version of the Discussion section. Recommendations for which high-level evidence is lacking are based on the Panel's review of lower-level evidence and expert opinion.

Sensitive/Inclusive Language Usage

NCCN Guidelines strive to use language that advances the goals of equity,inclusion,and representation.NCCN Guidelines endeavor to use language that is person-first; not stigmatizing; anti-racist, anti-classist, anti-misogynist, anti-ageist, anti-ableist, and anti-weight-biased; and inclusive

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of individuals of all sexual orientations and gender identities. NCCN Guidelines incorporate non-gendered language, instead focusing on organ-specific recommendations. This language is both more accurate and more inclusive and can help fully address the needs of individuals of all sexual orientations and gender identities. NCCN Guidelines will continue to use the terms men, women, female, and male when citing statistics, recommendations, or data from organizations or sources that do not use inclusive terms. Most studies do not report how sex and gender data are collected and use these terms interchangeably or inconsistently.If sources do not differentiate gender from sex assigned at birth or organs present, the information is presumed to predominantly represent cisgender individuals. NCCN encourages researchers to collect more specific data in future studies and organizations to use more inclusive and accurate language in their future analyses.

Initial Evaluation

For patients with known or suspected uterine neoplasms, the initial preoperative evaluation/workup for known or suspected malignancy includes a history and physical examination, complete blood count, expert pathology review with additional endometrial biopsy as indicated, imaging,recommendation of genetic evaluation of tumor and for inherited cancer risk, consideration of liver function tests(LFTs)/renal function tests or chemistry profile, and other studies(see Initial Evaluation and Principles of Imaging in the NCCN Guidelines for Uterine Neoplasms).9 Preoperative imaging and biopsy may help to identify uterine sarcomas, although biopsy sensitivity is less than that for endometrial cancer. An expert pathology review will determine whether a patient has a malignant epithelial tumor or a stromal/malignant mesenchymal tumor. Epithelial tumor types include pure endometrioid cancer and carcinomas with high-risk endometrial histology(including uterine serous carcinoma, clear cell carcinoma,carcinosarcoma [also known as malignant mixed Müllerian tumor(MMMT)],and undifferentiated/dedifferentiated carcinoma). Stromal or

mesenchymal tumor types(interchangeable terms) include uterine leiomyosarcoma(uLMS), endometrial stromal sarcoma(ESS),undifferentiated uterine sarcoma(UUS, previously called high-grade undifferentiated endometrial sarcoma), adenosarcoma, and perivascular epithelioid cell neoplasm(PEComa). Given the typical age group at risk for uterine neoplasms(ie,≥55 years) and the presence of comorbid illnesses,please also see the NCCN Guidelines for Older Adult Oncology.

Endometrial Cancer

Data shows that almost 67% of patients with adenocarcinoma of the endometrium are diagnosed with disease confined to the uterus at diagnosis.10 Regional and distant disease comprise approximately 21%and 8% of cases, respectively.

Many physicians believe that adenocarcinoma of the endometrium is a more treatable malignancy because the early symptoms of metrhoragria or post-menopausal vaginal bleeding often trigger patients to seek care when the disease is at an early and treatable stage. However, data show that the mortality rate for uterine cancer has increased more rapidly than the incidence rate.11 This increased mortality may be related to an increased rate of advanced-stage cancers, high-risk histologies(eg, serous carcinomas), and patients being diagnosed at≥65 years of age. Analysis of SEER data suggests that survival is increased in patients who are younger, have early-stage disease, and have lower-grade disease.12 In addition to grade and depth of myometrial invasion, other risk factors associated with poor prognosis include age, lymph node(LN) involvement,tumor size, lymphovascular space invasion(LVSI), and lower uterine segment invasion.13,14 Depth of myometrial invasion is considered one of the critical criteria for evaluation of surgical-pathologic staging.15,16 To further improve outcomes for patients with this disease, physicians need to identify patients who are at high risk and to tailor treatment appropriately to provide the best long-term survival. The Panel suggests that

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gynecologic oncologists be involved in the primary management of all patients with endometrial cancer.

Molecular Analysis and Genetic Factors

Most endometrial cancer(95%) is caused by sporadic(somatic)mutations. However, genetic mutations cause endometrial cancer in about 5% of patients, which occurs 10 to 20 years before sporadic cancer.17 Since there is increasing overlap in histopathologic features of these tumors, molecular analysis(eg, identification of characteristic translocations and/or mutations) and subtype classification are useful in selecting appropriate therapies. The Cancer Genome Atlas(TCGA) study performed an integrated genomic, transcriptomic, and proteomic analysis of 373 endometrial carcinomas including low-grade endometrioid,high-grade endometrioid, and serous carcinomas for their molecular classification. The study identified four major clinically significant molecular subtypes with differing clinical prognosis: POLE(DNA polymerase epsilon)mutations, microsatellite instability-high(MSI-H),copy number-low(wild-type p53), and copy number-high(abnormal p53). The POLE comprises tumors with POLE exonuclease domain mutations that includes P286R,V411L, S297F, A456P, and S459F and are collectively referred to as“hotspot POLE mutations”, with P286R and V411L being the most prevalent. Aside from these pathogenic mutations, numerous mutations exist whose significance remain unknown.18 The copy number-high group is characterized by an elevated incidence of TP53 alterations. These genomic classes are also associated with characteristic phenotypes. The endometrial cancers with POLE mutations are usually high-grade tumors with deep myometrial invasion and LVSI and usually have a good prognosis.19,20 The p53 mutant is the most aggressive subtype and requires a multimodality treatment, especially chemotherapy. The MSI-H tumors have an intermediate prognosis, but could be associated with other genetic cancer predispositions, and sensitivity to chemotherapy has been under investigation. Further studies have attempted to study the

association of TCGA subgroups with histologic features such as tumor grade and histologic type.21

The NCCN Guidelines for Uterine Neoplasms include a diagnostic algorithm for integrated genomic-pathologic classification of endometrial carcinomas based on the TCGA study and add that the decision to use molecular testing/classification depends on resource availability and each center's multidisciplinary team. The Panel encourages comprehensive molecular profiling via a validated and/or FDA-approved assay in the initial evaluation of uterine neoplasms to help facilitate cancer diagnoses. The Panel also encourages ancillary studies of POLE mutations, mismatch repair(MMR)/MSI, and aberrant p53 expression to complement the morphologic assessment of histologic tumor type. In addition, the Panel includes consideration for NTRK gene fusion testing for metastatic or recurrent endometrial carcinoma, and for tumor mutational burden(TMB)testing through a validated and/or FDA-approved assay. HER2 immunohistochemistry (IHC) testing (with or without reflex to HER2 fluorescence in situ hybridization [FISH] for equivocal IHC) is recommended for all p53 aberrant carcinomas regardless of histology.22-25 Estrogen receptor (ER) and progesterone receptor (PR) testing is recommended in the settings of stage III, stage IV, and recurrent disease.

Screening of the tumor for defective DNA MMR using IHC and/or MSI is used to identify which patients should undergo mutation testing for Lynch syndrome(see Lynch Syndrome in the NCCN Guidelines® for Colorectal Cancer Screening).17,26-32 Evaluation of MMR deficient(dMMR) status is commonly done using IHC and molecular profiling is an acceptable alternative. Testing may be performed on the initial biopsy, dilation and curettage(D&C) material, or the final hysterectomy specimen. MLH1 loss should be further evaluated for promoter methylation to assess for an epigenetic process rather than a germline mutation.29 Genetic counseling,molecular analysis, and testing are recommended for patients with all

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other MMR abnormalities. Patients with a significant family history of endometrial and/or colorectal cancer(even for those without MMR defects,who are MSI-stable, or those without screening) should be referred for genetic counseling and evaluation(See Lynch Syndrome in the NCCN Guidelines® for Genetic/Familial High-Risk Assessment: Colorectal,Endometrial, and Gastric). Screening for genetic mutations should be considered, especially for patients<50 years of age.8,17,26,33-36 If these patients have Lynch syndrome, they are at a higher lifetime risk(≤60%) for endometrial cancer; thus, close monitoring and discussion of risk-reducing strategies is recommended.26,37,38,6,33,39 In addition, their relatives may have Lynch syndrome. For patients and family members with Lynch syndrome but without endometrial cancer, a yearly endometrial biopsy is recommended to assess for cancer.35,40 This strategy also enables select patients to defer surgery(and surgical menopause) and to preserve fertility. Prophylactic hysterectomy/bilateral salpingo-ophorectomy(BSO)is recommended after childbearing is complete.41,42 In addition,interventions to decrease the risk from colorectal cancer are recommended(eg, annual colonoscopy).

Diagnosis and Workup

Currently, there is no validated screening test for endometrial carcinoma.43,44 About 90% of patients with endometrial carcinoma have metrorhagia, most commonly in the postmenopausal period. The workup was previously described above(see Initial Evaluation). Diagnosis can usually be made by an office endometrial biopsy, with a false-negative rate of about 10%.45,46 Thus, a negative endometrial biopsy in a symptomatic patient must be followed by a fractional D&C under anesthesia. 45,47 Hysteroscopy may be helpful in evaluating the endometrium for lesions,such as a polyp, if the patient has persistent or recurrent bleeding.48 Endometrial biopsy may not be accurate for diagnosing malignancies of the uterine wall such as mesenchymal tumors. The histologic information

from the endometrial biopsy (with or without endocervical curettage) is sufficient for planning definitive treatment.

Imaging

For detailed imaging recommendations by stage and planned treatment approach, see Principles of Imaging in the NCCN Guidelines for Uterine Neoplasms. Consideration of preoperative chest imaging (chest x-ray) is recommended. Based on the fertility-sparing or non-fertility-sparing treatment criteria, other imaging tests such as CT, MRI, ultrasound (US),and/or fluorodeoxyglucose (FDG)-PET/CT may be used to assess disease extent and to evaluate for metastatic disease as indicated based on clinical symptoms, physical findings, or abnormal laboratory findings.49-55 In patients with extrauterine disease, a serum CA-125 assay may be helpful in monitoring clinical response.56,57 However, serum CA-125 levels can be falsely increased in patients who have peritoneal inflammation/infection or radiation injury, may be normal in patients with isolated vaginal metastases, and may not predict recurrence in the absence of other clinical findings.58-60

Disease Staging

The FIGO(International Federation of Gynecology and Obstetrics) system is most commonly used for staging uterine cancer. The original 1970 criteria for staging endometrial cancer only used information gained from the presurgical evaluation(including physical examination and diagnostic fractional D&C). The 1970 staging system is rarely used today(eg, when the patient is not a surgical candidate).

Several studies demonstrated that clinical staging was inaccurate and did not reflect actual disease extent in 15% to 20% of patients.61-63 This reported under staging and, more importantly, the ability to identify multiple prognostic factors with a full pathologic review made possible with surgical staging motivated a change in the staging classification.

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Therefore, in 1988, FIGO modified its staging system to emphasize thorough surgical/pathologic assessment of data, such as histologic grade,myometrial invasion, and the extent and location of extrauterine spread(including retroperitoneal lymph node metastases).64 FIGO updated and refined the surgical/pathologic staging criteria for uterine neoplasms in 2009.65-68 Separate staging systems for malignant epithelial tumors and uterine sarcomas are now available(see Staging section of the algorithm).In 2017, the AJCC Cancer Staging Manual was further updated(which took effect in January 2018).69

The 2009 FIGO staging system streamlined stages I and II of endometrial carcinoma. These revisions were made because the survival rates for some of the previous sub-stages were similar.67 Currently stage IA describes tumors with<50% myometrial invasion, and stage IB describes those with≥50% myometrial invasion. Stage II describes patients with tumors that invade the cervical stroma. Patients with uterine-confined disease and endocervical glandular involvement (mucosal involvement)without cervical stromal invasion are no longer considered stage II.67 Stage IIIC is subdivided into IIIC1 (pelvic nodal involvement alone) and IIIC2 (para-aortic involvement +/- pelvic node involvement), reflecting the inferior survival in those patients with positive para-aortic nodes. 67 To maintain consistency, the NCCN Panel has reinterpreted historical studies using the 1988 FIGO staging system to reconcile those studies with the 2009 staging system.

In the 2009 FIGO staging the presence of positive peritoneal cytology no longer increases the disease stage, as its importance as an independent risk factor has been called into question.68 However, FIGO and AJCC continue to recommend that peritoneal washings be obtained and results be recorded(see Principles of Evaluation and Surgical Staging in the NCCN Guidelines for Endometrial Carcinoma).70

Principles of Evaluation and Surgical Staging for Endometrial Carcinoma

Staging should be done by a team with expertise in imaging, pathologic evaluation, and surgery. The amount of surgical staging that is necessary to determine disease status depends on preoperative and intraoperative assessment by experienced surgeons. Pathologic nodal assessment for apparent uterine-confined endometrial cancer informs both stage and adjuvant therapy. However, if final pathology shows a noninvasive endometrioid histology, nodal assessment can be eliminated. The NCCN sentinel lymph node(SLN) algorithm is recommended if sentinel node mapping is utilized.

Pathology

An expert pathologic review determines the specific epithelial histology of the tumor(endometrioid, serous, clear cell, carcinosarcoma, or undifferentiated). Morphologic evaluation of endometrial carcinoma to determine histologic type-especially in high-grade cancers-is challenging and issues exist regarding diagnostic reproducibility. The pathologic assessment of the uterus and the nodes is described in the algorithm. The assessment of the uterus includes the hysterectomy type,specimen integrity, tumor site and size, histologic type and grade if applicable, myometrial invasion(depth of invasion in mm/myometrial thickness in mm), cervical stromal involvement,and LVSI. Pathologists may be asked to quantify LVSI. The current definition of substantial LVSI is≥4 LVSI-involved vessels in at least one hematoxylin and eosin(H&E)slide(for clinically relevant LVSI in endometrial cancer).71 The pathologic assessment should also include assessment of involvement by other tissues such as the fallopian tubes, ovaries, vagina, parametrium,peritoneum, and omentum. The assessment of peritoneal/ascitic fluid cytology should also be obtained. If nodal resection was performed, the level of nodal involvement(ie, pelvic, common iliac, para-aortic) should be determined. SLNs should undergo ultrastaging for the detection of low-

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volume metastases(LVMs). Ultrastaging commonly entails thin serial sectioning of the gross SLN and review of multiple H&E-stained sections with or without cytokeratin IHC for all blocks of SLN. There is no standard protocol for lymph node ultrastaging. See Principles of Pathology in the NCCN Guidelines for Endometrial Carcinoma. The Protocol for the Examination of Specimens From Patients With Carcinoma and Carcinosarcoma of the Endometrium from the College of American Pathologists (CAP) is a useful guide. This CAP protocol was revised to reflect the updated pathologic TNM requirements from the AJCC Cancer Staging Manual (8th edition) and 2015 FIGO Cancer Report. 69,72

ER and PR testing is recommended in the setting of stage III, IV, or recurrent endometrioid carcinoma. Evaluation of HER2 overexpression should also be considered. Rottmann et al recently showed that 16% of 80 gynecologic carcinosarcomas (including uterine carcinosarcoma) showed HER2 overexpression and amplification when using the 2013 ASCO/CAP scoring system.22 Similar results were reported by Jenkins et al, Yoshida et al, and others.23,73-76 The Panel recommends HER2 IHC testing (with reflex to HER2 FISH for equivocal IHC) for possible treatment for advanced-stage or recurrent serous endometrial carcinoma or carcinosarcoma. HER2 IHC testing should also be considered in TP53-aberrant endometrial carcinoma regardless of histotyping.

As the grade of the tumor increases, the accuracy of intraoperative evaluation of myometrial invasion decreases(ie, assessment by gross examination of fresh tissue).77 In one study, the depth of invasion was accurately determined by gross examinations in 87.3% of grade 1 lesions,64.9% of grade 2 lesions, and 30.8% of grade 3 lesions.78 Studies show that in 15% to 20% of cases, the preoperative grade(as assessed by endometrial biopsy or curettage) is upgraded on final fixed pathologic evaluation of the hysterectomy specimen.79

Lymphadenectomy

Previously, a full standard lymphadenectomy(ie, dissection and assessment of both pelvic and para-aortic nodes) was recommended for all patients; however, to decrease side effects, a more selective and tailored nodal evaluation approach that includes the SLN algorithm is recommended by the NCCN Panel.80 No randomized trial data support routine full lymphadenectomy,81 although some retrospective studies have suggested that it is beneficial.82-84 Two randomized clinical trials from Europe reported that routine lymph node dissection did not improve the outcome of patients with endometrial cancer, but lymphadenectomy did identify those with nodal disease.85,86 However, these findings remain a point of contention.87-89 To avoid over-interpretation of these results, it is important to address the limitations of these randomized studies, including selection of patients, extent of lymph node dissection, and standardization of postoperative therapy.90 One of the trials did not standardize adjuvant treatment after staging surgery with lymphadenectomy; this has been identified as a weakness of the trial and may have contributed to the lack of difference in recurrence and survival in the two groups.84 The other concerns include the lack of central pathology review, subspecialty of surgeons, and adequacy of statistical power.

Decisions about whether to perform lymphadenectomy, and, if done, to what extent(eg, pelvic nodes only or both pelvic and para-aortic nodes),can be made based on preoperative and intraoperative findings. Criteria have been suggested as indicative of low risk for nodal metastases: 1)<50% myometrial invasion; 2) tumor<2 cm; and 3) well or moderately differentiated histology.91,92 However, this may be difficult to accurately determine before final pathology results are available. If an expert gynecologic pathology is available, a frozen section to assess myoinvasion can be obtained and lymphadenectomy avoided if no myoinvasion or cervical invasion is identified.93

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Nodal evaluation will identify those patients with nodal metastases.Identification of metastatic disease guides appropriate adjuvant treatment that has been shown to improve survival and decrease locoregional recurrence.

The question of whether to add para-aortic lymphadenectomy to pelvic node dissection has been debated. Prior studies have shown conflicting information regarding the risk of para-aortic nodal metastases in patients without disease in the pelvic nodes.63,91,94,95 Para-aortic lymphadenectomy up to the renal vessels may be considered for selective patients, including those with pelvic lymphadenectomy or high-risk histologic features. Many surgeons do not do a full lymphadenectomy in patients with grade 1 early-stage endometrial cancer.80

In summary, lymph node dissection identifies patients requiring adjuvant treatment with radiation therapy (RT) and/or systemic therapy.96 A subset of patients may not benefit from lymphadenectomy; however, it may be difficult to preoperatively identify these patients. The NCCN Panel recommends that nodal evaluation be performed in patients with endometrial carcinoma, including para-aortic lymphadenectomy in patients who are at higher risk (see Principles of Evaluation and Surgical Staging in the NCCN Guidelines® for Uterine Neoplasms).7 SLN mapping is the preferred alternative to full lymphadenectomy in the setting of apparent uterine-confined disease. The SLN surgical algorithm is described below.Lymphadenectomy is not recommended for patients with uterine sarcoma as metastasis to the nodes is unusual.

Sentinel Lymph Node Mapping

The section on surgical staging (see Principles of Evaluation and Surgical Staging in the NCCN Guidelines® for Uterine Neoplasms) includes recommendations about SLN mapping. SLN mapping may be considered for patients without suspicion of metastatic disease by preoperative imaging and no obvious extrauterine disease at exploration.97-101 In SLN

mapping, dye is injected into the cervix, which travels to the sentinel nodes. This has emerged as a useful and validated technique for identification of lymph nodes that are at high risk for metastases(ie, SLN in patients with early-stage endometrial cancer).102 Superficial (1-3 mm)and optional deep (1-2 cm) cervical injection leads to dye delivery to the main layers of lymphatic channel origins in the cervix and corpus, namely the superficial subserosal, intermediate stromal, and deep submucosal lymphatic sites of origin.103 Injection into the uterine cervix provides excellent dye penetration to the uterine vessels and main uterine lymphatic trunks that condense in the parametria and appear in the broad ligament leading to pelvic and occasionally paraortic sentinel nodes. The uterine body lymphatic trunks commonly cross over the obliterated umbilical artery with the most common location of pelvic SLN being medial to the external liac, ventral to the hypogastric, or in the superior part of the obturator region. A less common location is usually seen when the lymphatic trunks do not cross over the obliterated umbilical and move cephalad following the mesoureter; in these cases, the SLN is usually seen in the common iliac presacral region(see Figures 1-3 in Principles of Evaluation and Surgical Staging in the NCCN Guidelines for Endometrial Carcinoma). The radiolabeled colloid most commonly injected into the cervix is technetium-99m(99mTc); colored dyes are available in a variety of forms(Isosulfan Blue 1%, Methylene Blue 1%, and Patent Blue 2.5%sodium). Indocyanine green (ICG) is the preferred imaging dye for SLN mapping.93,103-109

A surgical SLN algorithm is proposed to decrease the false-negative rate in patients with apparent uterine-confined disease(see Figure 4 in Principles of Evaluation and Surgical Staging in the NCCN Guidelines for Endometrial Carcinoma).97,110 SLN mapping may be most appropriate for those at low to intermediate risk for metastases and/or for those who may not tolerate a standard lymphadenectomy.101,103,111-116 SLN identification should always be done prior to hysterectomy, except in cases where a

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bulky uterus must be removed to allow access to iliac vessels and lymph nodes.For example,suspicious or grossly enlarged nodes should be removed regardless of SLN mapping results.In SLN mapping, the surgeon's expertise and attention to technical detail are critical. Patients may be able to avoid the morbidity of a standard lymphadenectomy with SLN mapping.115,117 Because SLNs identify the primary lymphatic pathway,this increases the yield of finding metastatic disease during the mapping process. For cases of failed SLN mapping, reinjection of the cervix may be considered. An additional 1 mL in the non-detected side can be infiltrated in the superficial cervical area. However, if SLN mapping fails, a reflex side-specific nodal dissection should be performed and any suspicious or grossly enlarged nodes should be removed regardless of mapping.97,116

A literature review and consensus recommendations for SLN mapping in endometrial cancer were released by the Society of Gynecologic Oncology(SGO).101 Close adherence to the NCCN SLN surgical algorithm was found to result in accurate prediction of pelvic lymph node metastasis with a <5% false-negative rate.97 Additionally, results were published from the FIRES trial, which compared SLN mapping to lymphadenectomy for endometrial cancer in the largest multicenter prospective study to date(n = 385).103 Mapping of at least one SLN was successful in 86% of patients;sensitivity was 97.2%(95% CI, 85.0-100), and negative predictive value was 99.6% (95% CI, 97.9-100).

A systematic review of 17 studies with n > 30 patients revealed detection rates of 60% to 100%; detection rates for studies with larger cohorts(n >100) were at least 80%. Retrospective application of a surgical algorithm generated 95% sensitivity, 99% predictive value, and a 5% false-negative rate.118 Another systematic review and meta-analysis of 55 studies with n>10 patients (n = 4915) generated an overall detection rate of 81% with a 50% bilateral pelvic node detection rate and 17% paraaaic detection rate.93 In a retrospective analysis of patients with early-stage endometrial

cancer(n = 780) who underwent SLN mapping with lymphadenectomy versus lymphadenectomy alone, SLN mapping led to the detection of more metastasis(30.3% vs. 14.7%, P<.001) and was associated with greater use of adjuvant therapy.119 Long-term follow-up was reported from a prospective multicenter study in 125 patients with early-stage endometrial carcinoma who underwent SLN biopsy. Patients with a positive SLN underwent external beam RT(EBRT) and chemotherapy at a higher rate than those with a negative SLN. In patients with a detected SLN, relapse-free survival(RFS) at 50 months was 84.7%, and no difference was detected between patients with and without a positive SLN$({P=.5})^{120}$

SLN mapping should be done in institutions with expertise in this procedure. If patients have apparent distant metastatic disease(based on imaging and/or surgical exploration), removal of nodes for staging purposes is not necessary because it will not change management.49,55

Historically, SLN mapping was controversial in patients with high-risk histology(eg, serous carcinoma, clear cell carcinoma,carcinosarcoma).80,121 However, SLN mapping in patients with high-risk histologies(ie, grade 3, serous, clear cell, carcinosarcoma) has been reported with promising results as a potential alternative to complete lymphadenectomy.116,122,123 A recent multi-institutional retrospective study concluded that SLN mapping versus SLN mapping with lymphadenectomy in high-risk endometrial cancer did not impact survival outcomes.124 A recent prospective, multicenter cohort study(SENTOR trial) examined the diagnostic accuracy of SLN mapping versus lymphadenectomy for intermediate- and high-grade endometrial cancer in 156 patients. Of 27 patients with nodal metastasis, SLN mapping correctly identified 26 of them(96% sensitivity; 95% CI; 81%-100%), thus concluding the acceptable accuracy of SLN mapping in high-grade endometrial cancer.125

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More studies have suggested the value of using SLN mapping for surgical staging in high-grade endometrial cancer.126

SLN Ultrastaging

In general, SLN mapping allows for increased intraoperative surgical precision to identify nodes more likely to harbor metastasis combined with enhanced pathology protocols, which has been shown to increase the detection of nodal metastasis, which may alter stage and adjuvant therapy recommendations. Studies have suggested that SLN ultrastaging leads to upstaging in 5% to 15% of patients.100,112,114,117,118

Ultrastaging typically includes two components: serial sectioning with review of multiple H&E-stained slides with or without cytokeratin IHC staining.127 Recent data highlight the potential significance and impact of SLN ultrastaging to improve the accuracy of detecting micrometastases.128

In a cohort of 508 patients who underwent SLN mapping, ultrastaging detected 23 additional cases of micrometastasis that would have been missed by conventional H&E staining.129 A multicenter study of 304 patients with presumed low- or intermediate-risk disease showed that SLN biopsy and ultrastaging detected metastatic SLNs in a 3-fold greater number of patients than standard lymphadenectomy.130

The implications and appropriate management of micrometastases and isolated tumor cells (ITCs), jointly referred to as LVM, detected via SLN ultrastaging are not yet clear.101,114,117,131-135 Studies have recently begun to investigate the significance of ITCs discovered during SLN mapping in early-stage endometrial cancer. The AJCC 8th edition cancer staging manual indicates that the lymph nodes with ITCs should be clearly reported even though they do not affect the overall staging. ${ }^{136}$ When ITCs are detected in the absence of macrometastasis and micrometastasis, the lymph node stage is designated as pN0(i+).

A retrospective review examined 844 patients with endometrial cancer that underwent SLN mapping. ${ }^{137}$ The majority of patients with ITCs,micrometastasis, and macrometastasis received adjuvant chemotherapy(83%, 81%, and 89%, respectively). RFS at 3 years was $90\%$ for those with negative SLNs, $86\%$ for ITCs, and $86\%$ for micrometastasis. Only patients with SLN macrometastasis had significantly lower RFS $(71\%,$ P $<001)$ .

A prospective observational study of 519 patients compared outcomes for patients with SLN macrometastasis, micrometastasis, and ITCs, taking into account adjuvant treatment. ${ }^{138}$ Patients with SLN ITCs had a significantly better 3-year progression-free survival (PFS) compared with patients with SLN macrometastasis (95.5% vs. 58.5%), and outcomes were similar between patients with negative SLNs, ITCs, and micrometastasis. Recurrence was detected in only 1 of 31 patients with ITCs (stage IB carcinosarcoma) and adjuvant treatment did not appear to influence outcomes. Based on these early data, it is unclear if patients with SLN ITCs would derive significant benefit from adjuvant treatment. ${ }^{139}$ Future evaluation of prognosis/outcome may need to prospectively examine the threshold for and impact of adjuvant therapy for patients with scattered ITCs.

Minimally Invasive Procedures

Over the past decade, practice has trended towards minimally invasive approaches to total abdominal hysterectomy(TAH)/bilateral salpingo oophorectomy(BSO) and lymph node assessment in patients with early-stage endometrial cancer.140 Although these procedures may be performed by any surgical route(eg, laparoscopic, robotic, vaginal,abdominal), the standard in those with apparent uterine-confined disease is to perform the procedure via a minimally invasive approach.Randomized trials, a Cochrane Database Systematic Review, and population-based surgical studies support that minimally invasive

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techniques are preferred in the appropriate candidate due to a lower rate of surgical site infection,transfusion, venous thromboembolism,decreased hospital stay, and lower cost of care, without compromise in oncologic outcome.$^{140-146}$ Despite data showing that minimally invasive procedures result in lower perioperative complications and lower cost of care, racial and geographic disparities in access to minimally invasive surgical care have been observed.$^{142,146}$

A randomized phase III trial evaluated laparoscopy for comprehensive surgical staging; patients(n= 2616) with clinical stage I to IIA disease(GOG-LAP2) were assessed. $^{145,147}$ Patients were randomly allocated 2:1 to laparoscopy or laparotomy. Results from LAP2 indicate that 26% of patients needed conversion to laparotomy because of poor visibility,metastatic cancer, bleeding, increased age, or increased body mass index(BMI). Detection of advanced cancer was not significantly different between the groups. However, significant differences were noted in removal of pelvic and para-aortic nodes(8% not removed with laparoscopy vs. 4% with laparotomy, P<.0001). $^{148,149}$ Significantly fewer postoperative adverse events and shorter hospitalization occurred with laparoscopy compared with laparotomy. Recurrence rates were 11.4% for laparoscopy versus 10.2% for laparotomy. The 5-year overall survival(OS) rate was 84.8% for both arms of LAP2.147 Laparoscopic staging was associated with improved postoperative quality of life across several parameters. 144

The LACE trial compared outcomes of patients with stage I endometrial carcinoma(n=760) who were randomized to undergo total abdominal hysterectomy(TAH) or total laparoscopic hysterectomy(TLH), where half of the patients received concomitant lymphadenectomy.141 At a median follow-up of 4.5 years, disease-free survival (DFS) was 81.3% for laparotomy versus 81.6% for laparoscopy, with no significant differences observed between groups for recurrence and OS. Another randomized

trial(n= 283) comparing laparoscopy versus laparotomy reported shorter hospital stay, less pain, and faster resumption of daily activities with laparoscopy.150 A recent follow-up study of a multicenter randomized trial evaluated outcomes for TLH versus TAH in 279 patients with early-stage,low-risk endometrial cancer who did not undergo concomitant lymphadenectomy and reported comparable disease recurrence and 5-year survival rates. The results were also similar to studies with lymphadenectomy.151 Laparotomy may still be required for certain clinical situations(eg, patients who are older, those with a very large uterus) or certain metastatic presentations.145,152,153

Robotic surgery is a minimally invasive technology that has been increasingly used in the surgical staging of endometrial carcinoma due to its potential advantages over laparotomy, especially for patients who are affected by overweight. $^{154-158}$ Prospective cohort and retrospective studies suggest that robotic approaches perform similarly to laparoscopy and result in comparable or improved perioperative outcomes. $^{158-163}$ Oncologic outcomes appear to be comparable to other surgical approaches, although longer-term outcomes are still being investigated. $^{164-166}$ In certain patients,robotic surgery may result in less frequent conversion to laparotomy when compared with laparoscopic approaches and also appears to be safe and feasible in patients at higher anesthesiologic risk. $^{158,159,167}$

Costs for robotic equipment and maintenance remain high.168 154,155,164-166,169 The SGO, American Association of Gynecologic Laparoscopists(AAGL), and American Congress of Obstetricians and Gynecologists(ACOG) have published guidelines or position statements about robotic surgery.170-172 For reviews on the robotic-assisted surgery for gynecologic malignancies and associated cost issues, see Sinno and Fader and Gala et al.173,174

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Primary Treatment

These NCCN Guidelines divide pure endometrioid cancer into three categories for delineating treatment: 1) disease limited to the uterus; 2)suspected or gross cervical involvement; and 3) suspected extrauterine disease. Most patients with endometrial cancer have stage I disease at presentation, and surgery(with or without adjuvant therapy) is recommended for patients who are medically operable. As a general principle, endometrial carcinoma should be removed en bloc to optimize outcomes; intraperitoneal morcellation should be avoided.175-178

Disease Limited to the Uterus

To stage patients who are medically operable with endometrioid histologies clinically confined to the fundal portion of the uterus, the recommended surgical procedure includes removal of the uterus and bilateral tubes and ovaries with lymph node and abdominal assessment(see Principles of Evaluation and Surgical Staging in the NCCN Guidelines® for Uterine Neoplasms and in this Discussion and Lymphadenectomy and Sentinel Lymph Node Mapping in this Discussion).87 Ovarian preservation may be safe in select premenopausal patients with stage I endometrioid cancer.179-181 Minimally invasive surgery is the preferred approach when technically feasible and is considered a quality measure by the SGO and the American College of Surgeons(www.sgo.org/quality-outcomes-and-research/quality-indicators;https://www.facs.org/quality-programs/cancer-programs/national-cancer-database/quality-of-care-measures).

During surgery, the intraperitoneal structures should be carefully evaluated, and suspicious areas should be biopsied. While not specifically affecting staging, FIGO and AJCC recommend that peritoneal cytology should be collected, and results should be recorded. Cytology results should not be taken in isolation to guide adjuvant therapy. Enlarged or suspicious lymph nodes should be excised to confirm or rule out

metastatic disease. Retroperitoneal node dissection with pathologic evaluation-in the absence of clinically apparent lymphadenopathy-is useful when using the 2009 FIGO staging criteria, but its routine use has been questioned (see Lymphadenectomy in this Discussion). For stage II patients, TH/BSO is the standard procedure. Radical hysterectomy should only be performed if needed to obtain negative margins.

Patients with apparent uterine-confined endometrial carcinoma are candidates for sentinel node mapping, which assesses the pelvic nodes bilaterally and may be less morbid than complete lymphadenectomy(see Sentinel Lymph Node Mapping in this Discussion). Adherence to the NCCN SLN algorithm is critical.

Incomplete Surgical Staging

For patients with incomplete surgical staging and high-risk intrauterine features, imaging is recommended, especially in patients with higher grade histologies.182,183 Imaging can be omitted for stage 1A, grade 1-2 endometrium-limited carcinoma. Surgical restaging, including lymph node dissection, can also be done.91 Based on the imaging and/or surgical restaging results, recommended adjuvant treatment options are provided in the algorithm(see Adjuvant Treatment for Incompletely Surgally Staged in the NCCN Guidelines for Endometrial Carcinoma). For stage IB disease, any grade or any myometrial invasive carcinoma with LVSI and negative imaging that has not been surgically restaged, RT(EBRT and/or vaginal brachytherapy with or without systemic therapy) is recommended.The NCCN Panel notes systemic therapy as category 2B in this scenario.

Fertility-Sparing Therapy

Although the primary treatment of endometrial cancer is usually hysterectomy, continuous progestin-based therapy may be considered for highly selected patients with grade 1, stage IA (noninvasive) disease who wish to preserve fertility.184-188 Likewise, it may also be selectively used for

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young patients with endometrial hyperplasia who desire fertility preservation. The guidelines include an algorithm for fertility-sparing therapy in selected patients with biopsy-proven grade 1(preferably by D&C), stage IA noninvasive endometrioid adenocarcinoma(see Criteria for Considering Fertility-Sparing Options in the NCCN Guidelines for Endometrial Carcinoma). The Panel recommends consultation with a fertility expert and genetic evaluation of tumor and evaluation for inherited cancer risk. When considering fertility-sparing therapy, all of the criteria must be met as outlined in the algorithm(eg, no metastatic disease) and a negative pregnancy test must be ensured. Patients should also receive counseling that fertility-sparing therapy is not the standard of care for the treatment of endometrial carcinoma. TH/BSO with surgical staging is recommended after childbearing is complete, if therapy is not effective, or if progression occurs. Fertility-sparing therapy is not recommended for patients at high risk(eg, those with high-grade endometrioid adenocarcinomas, uterine serous carcinoma, clear cell carcinoma,carcinosarcoma, and uLMS).

Continuous progestin-based therapy may include megestrol acetate,medroxyprogesterone, or an intrauterine device (IUD) containing levonorgestrel.184,185,189 A complete response (CR) occurs in about 50% of patients. 184 The use of progestin-based therapy should be carefully considered in the context of other patient-specific factors, including contraindications such as breast cancer, stroke, myocardial infarction,pulmonary embolism, deep vein thrombosis, and smoking. The use of dual-progestin therapy can also be considered, which includes either megestrol acetate or medroxyprogesterone acetate and lUD containing levonorgestrel. The Panel also recommends counseling for weight management and lifestyle modification (see Healthy Lifestyles and Weight Management in the NCCN Guidelines for Survivorship).

In patients receiving progestin-based therapies, the NCCN Panel recommends close monitoring with endometrial sampling(biopsies or D&C) every 3 to 6 months. TH/BSO with staging is recommended: 1) after childbearing is complete; 2) if patients have documented progression on biopsy; or 3) if endometrial cancer is still present after 6 to 12 months of progestin-based therapy.188,190 Total hysterectomy with possible removal of ovaries with staging is the preferred option by 12 months of progestin-based therapy. Although some young patients who had subsequent negative endometrial biopsies after hormonal therapy were able to become pregnant(35%), the ultimate recurrence rate was high(35%).184,187,191-193 In patients with persistent endometrial carcinoma after 6 months of disease progression on hormonal therapy, the Panel recommends pelvic MRI to exclude myoinvasion and nodal/ovarian metastasis before continuing fertility-sparing therapy.

In a study of premenopausal patients with stage IA to B endometrial cancer, median 16-year follow-up data suggest that ovarian preservation is safe and not associated with an increased risk of cancer-related mortality. ${}^{179}$ Other studies also suggest that ovarian preservation may be safe in select patients. ${}^{180, 181}$

Suspected or Gross Cervical Involvement

For patients with suspected or gross cervical involvement(endometrioid histologies), cervical biopsy or pelvic MRI should be performed if not done previously(see Additional Workup in the NCCN Guidelines for Endometrial Carcinoma).182,183,194,195 If negative, patients are assumed to have disease that is limited to the uterus and are treated as previously described, although a radical hysterectomy may be performed when necessary to obtain negative margins. It may be difficult to distinguish primary cervical carcinoma from stage ll endometrial carcinoma.Thus,for patients suitable for primary surgery,TH or radical hysterectomy is recommended along with BSO, cytology(peritoneal lavage), and

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evaluation of lymph nodes if indicated (see Principles of Evaluation and Surgical Staging in the NCCN Guidelines for Endometrial Carcinoma).87 In these patients, radical or modified radical hysterectomy may improve local control and survival when compared with TH.196,197 Alternatively, the patient may undergo EBRT and brachytherapy (category 2B) followed by TH/BSO and surgical staging 4 to 12 weeks post RT.

For suspected gross cervical involvement in patients who are not suited for primary surgery, EBRT and brachytherapy is an effective treatment that can provide pelvic control and long-term PFS(see Principles of Radiation Therapy in the NCCN Guidelines for Uterine Neoplasms).204-207 If rendered operable, local treatment consisting of surgery should follow 4 to 12 weeks post RT or definitive RT if inoperable. Systemic therapy alone is also a primary treatment option(category 2B) but should be followed by EBRT+brachytherapy if the patient remains inoperable and surgical resection if rendered operable.

Suspected Extrauterine Disease

If extrauterine disease (endometrioid histologies) is suspected, imaging studies are recommended along with CA-125 testing (see Additional Workup in the NCCN Guidelines for Endometrial Carcinoma). ER testing is recommended in the setting of stage III or IV endometrioid tumors.Patients with no evidence of extrauterine disease are treated using guidelines for disease limited to the uterus. Patients with abdominal- or pelvic-confined disease require surgical intervention using TH/BSO with surgical staging and surgical debulking with the goal to have no measurable residual disease; several studies support debulking.87,198-200 Consider preoperative chemotherapy.201 For distant visceral metastasis (eg, liver involvement), recommended options include systemic therapy with (or without) EBRT with (or without) TH/BSO and with (or without)stereotactic body RT (SBRT). Ablative radiation can be considered for 105 metastatic lesions if disease is otherwise controlled(category 2B).202

Patients with unresectable extrauterine pelvic disease (ie, vaginal,bladder, bowel/rectal, nodal, or parametrial involvement) are typically treated with EBRT with(or without) brachytherapy with(or without)systemic therapy, followed by re-evaluation of tailored surgery 4 to 12 weeks post RT.208-211 Systemic therapy alone can also be considered.Based on treatment response, patients should be re-evaluated for surgical resection and/or RT.

Adjuvant Therapy

Uterine-Confined Disease

Thorough surgical staging provides important information to assist in selection of adjuvant therapy for endometrial tumors(see Principles of Evaluation and Surgical Staging in the NCCN Guidelines for Endometrial Carcinoma). Patients with stage I endometrial cancer who have thorough surgical staging are stratified by adverse risk factors(age, positive LVSI,tumor size, and lower uterine segment or surface glandular involvement).212,213 Recommended adjuvant treatment is outlined in the algorithm(see the NCCN Guidelines for Endometrial Carcinoma). Note that the treatment algorithm was revised in 2010 based on the updated FIGO staging.67 However, by necessity, much of the discussion in this manuscript has been based on data from patients staged using the older

Patients Not Suited for Primary Surgery

For uterine-confined diseases not suitable for primary surgery,EBRT and/or brachytherapy is the preferred treatment approach. Alternatively,progestational agents(such as medroxyprogesterone acetate and

megestrol acetate) and levonorgestrel lUD can also be considered for select patients(eg, ER- and PR-positive). Patients receiving hormonal therapy alone should be closely monitored by endometrial biopsy(eg,consider endometrial biopsies every 3-6 months).43,203

consider endometrial biopsies every 3-6 months).43,203

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FIGO/AJCC staging system. The implications of stage migration should be considered when evaluating historical data.

brachytherapy alone.220 EBRT can be considered in grade 2 tumors if additional risk factors are present such as age≥60 years and/or if LVSI is present. For stage IB, grade 3 disease with adverse risk factors, systemic therapy is added as a category 2B option(in addition to EBRT and/or vaginal brachytherapy).

The basic concept underlying the recommendations in the NCCN Guidelines is the trend toward selection of more aggressive adjuvant therapy for patients as tumor grade and myometrial and/or cervical invasion increase, as risk of systemic metastases increases.214-216 In surgical stage I and II endometrial cancer, other pathologic factors that may influence the decision regarding adjuvant therapy include LVSI,patient age,tumor volume, depth of invasion, and lower uterine segment or cervical glandular involvement. When administering adjuvant RT, it should be initiated as soon as the vaginal cuff has healed, but no later than 12 weeks after surgery.

The recommended postoperative (ie, adjuvant) treatment options for surgical stage II patients (using thorough surgical staging) are shown in the algorithm (see Adjuvant Treatment for stage II in the NCCN Guidelines for Endometrial Carcinoma). The NCCN Panel generally agrees on the role of adjuvant therapy for patients with an invasive cervical component if extrafascial hysterectomy is performed. However, for patients with stage II disease who have had a radical hysterectomy with negative surgical margins and no evidence of extrauterine disease, EBRT (preferred) and/or vaginal brachytherapy with (or without) systemic therapy (category 2B) are options. As with stage I disease, the presence of adverse risk factors(including depth of stromal invasion, grade, LVSI, and adverse fundal risk factors) should be considered when selecting adjuvant therapy for stage II disease.221

Noncident controversy centers on how much adjuvant therapy is necessary in patients with surgical stage I endometrial cancer. The practice of surgical staging has led to a decrease in the use of adjuvant therapy for stage I endometrial carcinoma, which is reflected in the option of observation in the NCCN Guidelines for selected patients with low-risk features(see section on Adjuvant Treatment in the NCCN Guidelines for Endometrial Carcinoma). ${ }^{96,213,214,217-219}$ The NCCN Panel prefers

Adjuvant RT

Several phase III trials have assessed adjuvant therapy in patients with uterine-confined disease. In summary, the use of adjuvant RT improves pelvic control in patients with selected risk factors(and may improve PFS)but has not been shown to improve OS. However, many of the earlier trials had limitations as the patients were primarily low risk (ie, they had low-risk intrauterine pathologic risk factors). It is recognized that in patients with uterine-confined disease, there is a spectrum of risk based on intrauterine pathologic findings. Adverse intrauterine pathologic risk factors include high-grade tumors, deep myometrial invasion(and consequently more advanced stage), LVSI(especially extensive), and serous or clear cell carcinoma histologies.

observation for patients with stage IA, grade 1/2 disease, but strongly suggests treatment with adjuvant vaginal brachytherapy for those≥60 years and/or those with LVSI. For patients with stage IA, grade 3 tumors,

especially in those who have been surgically staged, vaginal

brachytherapy is the preferred option, or observation can be considered if no myometrial invasion is present. If higher risk factors are present, ie, age≥70 years or LVSI, EBRT can be considered as a category 2B option. For

patients with stage IB, grade 1-2 disease, vaginal brachytherapy is preferred although observation can be considered if no adverse risk

factors are present. In these patients, the PORTEC-2 trial, without evaluation of pelvic nodes, found pelvic recurrence to be low with vaginal

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Four trials have evaluated the role of adjuvant external-beam pelvic RT in patients with endometrial carcinoma. In two of these trials, the patients were not formally staged(Postoperative Radiation Therapy in Endometrial Carcinoma [PORTEC-1], Aalders).222,223 In the third trial (ASTEC/EN.5),only 50% of the patients were thoroughly staged as part of a companion surgical protocol.85,224 However, formal surgical staging was mandated for all patients in the GOG 99 trial.225 Note that these trials used the older staging system (ie, before 2009).

The PORTEC-1 and GOG 99 trials suggest that external-beam pelvic RT provides a locoregional control benefit in selected patients with uterine-confined disease.222,226 Radiation was not shown to increase OS.227 It is important to note that the PORTEC-1 trial was powered to evaluate OS, although the GOG 99 trial was not. Similarly the Aalders'randomized trial found that RT reduced vaginal (ie, locoregional)recurrences but did not reduce distant metastases or improve survival.223 A pooled randomized trial (ASTEC/EN.5) suggested that adjuvant pelvic RT alone did not improve either RFS (ie, PFS) or OS in patients with intermediate-risk or high-risk early-stage endometrial cancer, but there was an improvement in pelvic control.224 However, the ASTEC/EN.5 study is very controversial; 51% of the patients in the ASTEC observation group received vaginal brachytherapy. Vaginal brachytherapy has been shown to decrease vaginal recurrence, and in PORTEC-2 vaginal brachytherapy was compared in a prospective randomized trial with EBRT in patients at low risk. Vaginal brachytherapy alone was shown to sufficiently control the pelvis and was less toxic than full pelvic RT. As most pelvic recurrences are vaginal, inclusion of vaginal brachytherapy in the "observation" arm of the ASTEC/EN.5 study weakens any conclusions regarding pelvic radiation.89,228 The Keys' trial (GOG 99) showed that adjuvant pelvic RT improved locoregional control and relapse-free interval (ie, PFS), without an OS benefit, although the study was not powered to evaluate OS.225,229,230 In both trials pelvic radiation was found to be of greater

benefit in patients>60 years with higher grade and more deeply invasive disease.

To help select the appropriate patient population that may benefit from adjuvant pelvic RT, the GOG 99 and PORTEC trials defined risk factors for patients at high-intermediate risk(HIR) for recurrence, although the definition differed between these trials.222,225 Risk factors for recurrence identified in both trials included higher age, deep myometrial invasion(>50%), higher grade (grade 2 or 3, serous or clear cell), and LVSI(especially extensive as defined in the PORTEC trials). Based on risk factors identified in GOG 99, HIR disease was defined as patients<50 years with grade 2 or 3 disease, myometrial invasion>50%, and LVSI.225 Patients 50 to 70 years of age were considered HIR if they had 2 of the 3 identified high-risk features. Patients ≥70 years were defined as HIR if they also had one risk feature present. Based on data from PORTEC-1,HIR patients were defined as having 2 of 3 risk factors (ie, age >60 years,deep myometrial invasion, grade 3 histology).222,229 LVSI was not considered in the original PORTEC trials, but a subsequent retrospective evaluation demonstrated increased recurrence with extensive LVSI, as defined by the protocol.

Due to concerns about potential toxicity of external-beam pelvic RT, the role of vaginal brachytherapy alone in uterine-confined disease has been evaluated. PORTEC-2 randomly assigned patients to external-beam pelvic RT versus vaginal brachytherapy alone in uterine-confined disease.PORTEC-2 showed excellent and equivalent vaginal and pelvic control rates with both adjuvant radiation approaches and no difference in OS.220 Given that vaginal brachytherapy is associated with significantly less toxicity than pelvic RT, vaginal brachytherapy alone is a reasonable choice for patients with uterine-confined endometrial cancer as defined in the PORTEC-2 trial.220,229-237 The use of vaginal brachytherapy and/or whole pelvic RT should be carefully tailored to a patient's pathologic findings.

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Both PORTEC-1 and PORTEC-2 specifically excluded patients with 1998 FIGO stage 1C and grade 3 endometrial carcinoma (2009 FIGO stage IB,grade 3);67 thus, the use of adjuvant brachytherapy alone in this higher risk subset remains more controversial. PORTEC studies did not evaluate lymph nodes and, therefore, in the context of complete surgical staging and the lack of a survival benefit, the need for pelvic irradiation remains controversial in uterine-confined disease.

A meta-analysis evaluated results from studies that compared adjuvant postoperative EBRT with or without vaginal brachytherapy and vaginal brachytherapy alone in stage II endometrial cancer. EBRT+ vaginal brachytherapy significantly reduced locoregional recurrence versus vaginal brachytherapy alone. OS was comparable in both arms.238

The G0G 249 trial examined vaginal cuff brachytherapy and 3 cycles of carboplatin/paclitaxel therapy (3 cycles) versus pelvic EBRT only in patients with high-risk, uterine-confined endometrial carcinoma (n = 601),including serous and clear cell carcinoma. GOG 249 reported significantly increased rates of nodal recurrence (primarily pelvic) in the brachytherapy plus chemotherapy arm compared with the pelvic EBRT arm. No significant between-group differences in vaginal or distant recurrence rates were observed. However, there were more extravaginal pelvic failures in the brachytherapy plus chemotherapy therapy arm. At a median follow-up of 53 months, 3-year RFS was 82% for both treatment arms; 3-year OS was 88% for the brachytherapy plus chemotherapy cohort and 91% for the pelvic EBRT cohort. Acute toxicity was more common and severe for patients receiving brachytherapy with chemotherapy. No differences in late-onset toxicities were observed.239 Questions were raised whether 3 cycles of chemotherapy were sufficient to control distant disease.

Analysis of pooled data from PORTEC-1 and PORTEC-2 ranked the predictive power of multiple variables on patient outcomes examined in these trials. Patient age, tumor grade, and LVSI were highly predictive for

locregional relapse(LRR), distant relapse(DR), OS, and DFS, and treatment given (EBRT vs. vaginal brachytherapy) was predictive for LRR and DFS.212 The benefit of adjuvant EBRT in the highest risk spectrum of uterine-confined disease remains controversial. Most NCCN Panel Members feel that patients with deeply invasive grade 3 tumors should receive adjuvant treatment. Two large retrospective SEER analyses of patients with endometrial cancer found that adjuvant RT improved OS in those with high-risk disease.240,241 In a meta-analysis of randomized trials,a subset analysis found that adjuvant pelvic RT for stage I disease was associated with a trend towards a survival advantage in the highest-risk spectrum (eg, those with 1988 FIGO stage IC grade 3) but not in patients at lower risk; however, other reviews have shown conflicting results.232,242-246

The long-term follow-up study (median 20.5 years) of 568 patients with early-stage endometrial carcinoma enrolled in the Aalders trial compared long-term outcomes in patients who received vaginal brachytherapy plus EBRT versus vaginal brachytherapy alone. The findings suggested no statistical difference in OS between the study groups, and in this cohort,patients <60 years of age who received EBRT had increased incidence of secondary cancers and subsequent higher mortality rates.~232~Evaluation of(eg, MSI-H) and radiation is ongoing.

Adjuvant Systemic Therapy

Patients with deeply invasive, grade 3,uterine-confined disease(2009 FIGO stage IB, grade 3[formerly 1988 FIGO stage IC, grade 3]) have a relatively poor prognosis. Despite adjuvant therapy with pelvic RT, a significant number of patients continue to have a significant risk of distant metastases, and an optimal adjuvant therapy is still sought.225,226 Therefore, some clinicians suggested that adding systemic therapy to adjuvant RT may provide added therapeutic benefit(ie, decrease in distant

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metastases).214,247 Studies have evaluated the role of systemic therapy in highest risk uterine-confined disease.247,248 PFS is improved with adjuvant sequential chemotherapy.247 However, the NCCN Panel feels that adjuvant systemic therapy is a category 2B recommendation in this setting because an OS advantage has not been shown.247 The GOG-249 phase 3 trial evaluated the benefit of adjuvant pelvic RT versus vaginal cuff brachytherapy plus 3 cycles of paclitaxel/carboplatin combination in 601 patients with high-intermediate and high-risk early-stage endometrial cancer. The 5-year RFS and OS were similar in both groups and the superiority of any of these treatments was not demonstrated. Acute toxicity was greater in the combination therapy.249

Advanced Stage/Extrauterine Disease

There is a consensus that patients with documented extrauterine disease are at increased risk for recurrence and need adjuvant therapy; however,the optimal form of adjuvant therapy has yet to be determined.250-252 Patients with extrauterine disease confined to the lymph nodes or the adnexa may be treated with pelvic or extended-field RT alone or with chemotherapy(radiation is targeted to sites of nodal disease).253 However,systemic therapy is regarded as the foundation of adjuvant therapy for patients with extrauterine disease. The NCCN Guidelines include carboplatin/paclitaxel as the preferred systemic therapy option in the primary/adjuvant setting for advanced-stage disease or high-risk histologies.254-256 The NCCN Guidelines recently added the pembrolizumab/carboplatin/paclitaxel and dostarlimab carboplatin/paclitaxel triplet regimens as category 1, preferred, primary therapy options for stage III or IV disease based on the data from phase III NRG-GY018 and RUBY trials, respectively, and the expanded FDA approvals.257-260 The pembrolizumab/carboplatin/paclitaxel regimen is recommended for stage III or IVA with measurable disease post-surgery or for stage IVB with or without measurable disease. Since the NRG-GY018 trial did not include patients with carcinosarcoma histology, the NCCN

Panel does not recommend the pembrolizumab/carboplatin/paclitaxel treatment option for patients with carcinosarcoma disease. The ENGOT-en11/GOG-3053/KEYNOTE-B21 trial261 evaluated the addition of pembrolizumab to adjuvant chemotherapy(with/without RT) among patients with newly diagnosed, high-risk endometrial cancer with dMMR and pMMR status. Although Kaplan-Meier estimates of 2-year DFS rates in a total of 1095 randomized patients(pembrolizumab, n = 545; placebo,n = 550) were 75% and 76% in the pembrolizumab and placebo groups,respectively, the hazard ratio(HR) for DFS was 0.31 (95% CI, 0.14-0.69)in the dMMR population (n = 281). For patients not meeting the eligibility criteria for NRG-GY018, carboplatin/paclitaxel + pembrolizumab should be considered for stage III-IV dMMR tumors.

The dostarlimab carboplatin/paclitaxel option is recommended for adult patients with primary advanced endometrial carcinoma: stage IIIA, IIIB, or IIIC1 post-surgery with measurable disease, stage IIIC1 with carcinosarcoma, clear-cell, serous, or mixed histology regardless of the presence of measurable disease; and stage IIIC2 or stage IV disease regardless of the presence of measurable disease. Another phase III trial(RUBY)262 evaluated dostarlimab plus carboplatin-paclitaxel compared with placebo plus carboplatin-paclitaxel in patients with primary advanced or recurrent endometrial cancer(EC). Dostarlimab in combination with carboplatin-paclitaxel demonstrated a statistically significant and clinically meaningful OS benefit with a statistically significant reduction in the risk of death[HR, 0.69; 95% CI, 0.54-0.89, P=.0020] in the overall population of patients with primary advanced or recurrent EC while demonstrating an acceptable safety profile.

For stages III and IV disease, carboplatin/paclitaxel/durvalumab regimen is recommended as a preferred regimen for dMMR tumors based on DUO-E trial and FDA approval.263,264 The DUO-E trial is a phase III, global, double-blind, placebo-controlled trial that randomly assigned advanced or

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recurrent endometrial cancer 1:1:1 to carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm);carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olarapib placebo(durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib(durvalumab + olaparib arm). In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (HR, 0.71; 95% CI, 0.57-0.89; P=.003) and durvalumab +olaparib arms (HR, 0.55; 95% CI, 0.43-0.69; P<.0001) versus control.Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab vs. control], 0.42;95% CI, 0.22-0.80; HR[durvalumab + olaparib vs. control], 0.41; 95% CI, 0.21-0.75). In the dMMR subgroup, median PFS was not reached (NR) versus 7.0 months for durvalumab versus control and median PFS was 31.8 versus 7.0 months for durvalumab + olaparib versus control. Based on these data and the FDA approval, the NCCN Panel (recommends carboplatin/paclitaxel/durvalumab as a category 1, preferred regimen for stage III-IV dMMR tumors only.

A randomized phase II study examined the addition of trastuzumab to carboplatin/paclitaxel for patients with advanced or recurrent HER2/neu-positive uterine serous carcinoma.265 Among patients with stage III/IV disease undergoing primary treatment(n = 41), median PFS was 17.7 months versus 9.3 months for the experimental and control arms,respectively(P=.013). PFS for patients with recurrent disease (n = 17)was 9.2 months versus 6.0 months (HR, 0.44; 90% CI, 0.23-0.83; P=.015). The addition of trastuzumab appeared to improve PFS without increasing overall toxicity. The safety and tolerability of the trastuzumab combination was further evaluated in 60 patients with advanced/recurrent uterine serous carcinoma with HER2/neu overexpression in a recent phase 2 trial with PFS as the primary endpoint. Trastuzumab appears to be safe and has a manageable toxicity profile when used in combination

with chemotherapy.266 The triplet therapy regimen carboplatin/paclitaxel/trastuzumab is recommended by the NCCN Panel as a preferred option for HER2-positive uterine serous carcinoma or HER2-positive carcinosarcoma as a primary therapy for stage III/IV disease.

The GOG performed a phase 2 trial of bevacizumab following 1 or 2 chemotherapy regimens.{}^{267} Among 52 eligible patients, 7 patients(13.5%)experienced clinical responses(1 CR and 6 partial responses[PRs];median response duration, 6.0 months), and 21 patients(40.4%) survived progression-free for at least 6 months. Adverse events were consistent with those expected of bevacizumab treatment. The efficacy of bevacizumab addition to paclitaxel and carboplatin and as a maintenance in advanced or recurrent endometrial cancer was further evaluated in another phase 2 trial with a larger cohort of post protocol patients.268 Collectively, the median PFS of 27 patients with endometrial cancer who received this triplet regimen was 20 months, and median OS was 56 months. Among 29 patients with measurable disease, the response rate was 82.8%(95% CI, 69.0%-96.5%; 15 CRs and 9 PRs). This triplet regimen of carboplatin/paclitaxel/bevacizumab is recommended as a preferred regimen for patients with stage III-IV disease with measurable disease.

For stages III and IV disease, systemic therapy forms the mainstay of treatment and can be combined with EBRT with(or without) vaginal brachytherapy. The combination of therapies depends on assessment of both locoregional and distant metastatic risk. Combination therapy can be considered for stages IIIB and IIIC disease.

Previously, whole abdominal RT was used for carefully selected patients deemed at risk for peritoneal failure, and RT appeared to have provided therapeutic benefit in retrospective studies. However, it is considered too toxic and has largely been abandoned. 269,270 A randomized phase III GOG

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(122) trial assessed optimal adjuvant therapy for patients with endometrial cancer who had extrauterine disease. In this trial, patients with stage III and intra-abdominal stage IV disease who had minimal residual disease were randomly assigned to whole abdominelpicv RT versus 7 cycles of combined doxorubicin (60 mg/m2) and cisplatin (50 mg/m2) treatment, with an additional cycle of cisplatin (AP). This GOG trial reported that AP chemotherapy improved PFS and OS when compared with whole abdominopelvic RT; however, acute toxicity (eg, peripheral neuropathy)was greater in the AP chemotherapy arm.209

The GOG 122 study established the role of adjuvant multiagent systemic chemotherapy for curative intent in patients with extraluterine disease.Thus, in the NCCN Guidelines, systemic therapy forms the established framework of adjuvant therapy for patients with stage III or IV disease. The whole abdominal RT as a single modality(as used in GOG 122) is considered inferior to chemotherapy and is too toxic; therefore, it is no longer recommended. For the purposes of these guidelines, whole abdominal RT is not considered to be tumor-directed RT (see Principles of Radiation Therapy in the NCCN Guidelines for Uterine Neoplasms).

Recurrences were frequent in both treatment arms of GOG 122, occurring in the pelvis and abdomen. Approximately 52% of patients with advanced endometrial carcinoma had recurrences, indicating the need for further therapeutic improvement in this high-risk patient population.209 A study found that combined modality adjuvant therapy(using chemotherapy and tumor-directed RT) may provide a therapeutic benefit when compared with single-modality adjuvant therapy.211,271,272

A follow-up study evaluated the role of chemotherapy “intensification” for this patient population. The GOG 184 trial compared two chemotherapy regimens (cisplatin and doxorubicin with [or without] paclitaxel) with tumor-directed radiation (involved-field radiation either to the pelvis or to the pelvis plus para-aortic nodes). Results indicate that the 3-drug regimen did

<EndOfPara>not improve survival when compared with the 2-drug regimen after 3 years of follow-up and that the more intensive chemotherapy resulted in greater toxicity(eg, hematologic toxicity, sensory neuropathy, myalgia).210

In a retrospective review of 116 patients with stage IIIC endometrial cancer, adjuvant RT significantly improved OS in patients with endometriod histology, high-grade tumors, and positive para-aortic lymph nodes. Conversely, patients with low-grade tumors and non-endometrioid histology who received RT had similar OS compared with those who did not.273 In a multicenter retrospective review of 73 patients with stage IIIIA endometrial carcinoma, surgery followed by both chemotherapy and RT provided the highest 5-year OS.274 A prospective study of 122 patients with fully resected locally advanced disease suggested a potential benefit of adjuvant chemoradiation followed by chemotherapy, with an estimated 5-year PFS and OS of 73% and 84%.275 Adjuvant therapy options were compared in a multicenter retrospective analysis of 265 patients with optimally resected stage IIIC endometrial carcinoma. Compared with patients receiving adjuvant RT or adjuvant RT plus chemotherapy,patients who received adjuvant chemotherapy alone had a 2.2-fold increased risk of recurrence and a 4.0-fold increased risk of death. 252

Multimodality therapy is now the basis of randomized trials evaluating therapy. The phase 2, RTOG 9708 trial assessed 46 patients for safety,toxicity,recurrence, and survival when chemotherapy (cisplatin/paclitaxel)was combined with adjuvant radiation in patients with high-risk endometrial cancer. The trial participants included patients with grade 2 or 3 endometrial adenocarcinoma with either >50% myometrial invasion,cervical stromal invasion, or pelvic-confined extrauterine disease. The OS and DFS favored the combined modality treatment.276

The phase 3, PORTEC-3 trial investigated the benefit of combined adjuvant chemotherapy and EBRT versus EBRT alone in 686 patients with endometrial cancer(stage I, grade 3 with deep invasion, LVSI, or both;

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stage II; stage III; or any patient with stage I to III serous or clear cell endometrial cancer). The 5-year OS was 81.4%(95% CI, 77.2-85.8) with chemoradiotherapy versus 76.1%(95% CI, 71.6-80.9) with RT alone(HR,0.70;95% CI, 0.51-0.97; P=.034) and 5-year failure-free survival was 76.5%(95% CI, 71.5-80.7) versus 69.1%(63.8-73.8; HR, 0.70; 95% CI,0.522-0.94; P=.016).277,278 Patients with serous cancers and stage III disease were shown to benefit the most from the addition of systemic therapy. The combination treatment was also shown to be associated with more severe adverse events.279

The GOG-258 phase 3 trial evaluated 707 patients with stage III or IVA,high-risk endometrial cancer who were randomly assigned 1:1 to receive chemoradiotherapy or chemotherapy only.280 This trial supported the benefit of using chemotherapy alone by concluding that the combined therapy was not associated with longer RFS when compared with chemotherapy alone(59% vs. 58%, respectively). OS results are pending.

A follow-up molecular analysis was performed of the PORTEC-3 trial to study the impact of chemoradiotherapy for each molecular subtype using tissue samples from the trial participants. The tumors were classified into p53 abnormal, POLE, dMMR, or no specific molecular profile. The 5-year RFS with chemoradiotherapy versus RT alone was p53 abnormal, 59%versus 36%; POLE, 100% versus 97%; dMMR, 68% versus 76%; and 80% versus 68% for no specific molecular profile, suggesting that systemic therapy was beneficial for those patients whose disease was p53 abnormal.281 Results are awaited for an ongoing PORTEC-4a trial investigating molecular profile-based directed adjuvant treatment in high-risk endometrial cancer.282

High-Risk Endometrial Carcinoma Histologies

Overview

Uterine serous carcinomas, clear cell carcinomas, carcinosarcomas, and undifferentiated/dedifferentiated carcinomas are considered more aggressive histologic variants of malignant epithelial tumors, with a higher incidence of extrauterine disease at presentation.283-290 Carcinosarcomas are aggressive tumors that are staged as high-grade endometrial cancer.291,292 Carcinosarcomas(also known as MMMTs) are metaplastic carcinomas and not uterine sarcomas; therefore, carcinosarcomas are included as part of the high-risk malignant epithelial tumors.287,290,293,294 Even patients with apparent early-stage disease may have distant metastases. Thus, fertility-sparing therapy is not recommended for these aggressive tumors. If done, SLN mapping should proceed with particular caution. Serous carcinomas, clear cell carcinomas, carcinosarcomas, and undifferentiated/dedifferentiated carcinomas are all considered high-risk histologies and high grade by default, although they are staged using the same FIGO/AJCC staging system as endometrial cancers. ${}^{69}$ Patients with uterine serous carcinoma, clear cell carcinoma, carcinosarcoma, or undifferentiated/dedifferentiated carcinomas may present with pelvic masses, abnormal cervical cytology, or ascites in addition to postmenopausal bleeding. Both the NCCN Panel and the SGO recommend that CA-125 and MRI or chest/abdomen/pelvis CT may be useful before surgery to assess if extrauterine disease is present; PET may also be useful. ${}^{283}$

Primary Treatment

Suitable for Primary Surgery

Multimodality therapy is typically recommended for these histologically aggressive tumors. Primary treatment includes TH/BSO with surgical staging, peritoneal lavage for cytology, omental and peritoneal biopsies,and consideration of maximal tumor debulking for gross disease(see

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Principles of Evaluation and Surgical Staging in the NCCN Guidelines for Endometrial Carcinoma).295 Minimally invasive surgery is the preferred approach when technically feasible.296-300

Additional treatment options are highly individualized and are based on the histology and stage of the tumor.301-308 For patients with clear cell or serous carcinomas with no residual uterine disease and negative surgical staging in the hysterectomy specimen, observation is the recommended option. For stage IA disease without myometrial invasion with negative peritoneal washings, options include vaginal brachytherapy with(or without) systemic therapy(category 2B for systemic therapy) or observation. If the washings are positive, both systemic therapy and vaginal brachytherapy are recommended. 309,310 For patients with invasive stage IA, IB, or II, options include systemic therapy with(or without) EBRT with(or without) vaginal brachytherapy; or EBRT with (or without) EBRT brachytherapy. For patients with clear cell or serous carcinoma at a more advanced stage (ie, stage III or IV), or with undifferentiated/dedifferentiated histology, systemic therapy with (or without) EBRT with (or without) vaginal without) EBRT with (or without) vaginal brachytherapy is recommended.285,302,306,311

For the patients with carcinosarcoma histology at stage IA, systemic therapy and vaginal brachytherapy are recommended with an option for EBRT, if it has high-grade epithelial components and is sarcoma dominant(>50% of sarcoma component in uterine tumor).312 The Panel notes that the initiation of chemotherapy within 3 to 6 weeks postoperatively should be considered and vaginal brachytherapy can be integrated with chemotherapy.

For patients with advanced histologies, whole abdominopelvic RT with (or without) vaginal brachytherapy is no longer recommended as a primary treatment option.209,311,313 302 Multimodality therapy including systemic therapy,EBRT, and vaginal brachytherapy appears to be more effective.

Data are conflicting regarding the rate of abdominal recurrence in these patients.311,314,318 Whole abdominal radiotherapy is not considered to be tumor-directed RT (see Principles of Radiation Therapy in the NCCN Guidelines for Uterine Neoplasms). As previously mentioned,tumor-directed RT refers to RT directed at sites of known or suspected tumor involvement and may include EBRT with (or without) vaginal brachytherapy. In general, tumor-directed EBRT is directed to the pelvis with (or without) the para-aortic region.

Not Suitable for Primary Surgery

For patients with disease that is not amenable to resection, or is not suitable for surgery due to comorbidities, the primary treatment option is EBRT with (or without) brachytherapy with (or without) systemic therapy and then re-evaluation for surgery. Alternatively, systemic therapy could be given first, and then patients can be re-evaluated for surgery before giving RT based on the tumor response. For patients with carcinosarcoma histology with unresectable tumor that has metastasized, the Panel recommends systemic therapy with (or without) EBRT or best supportive care.

Treatment of Recurrent or Metastatic Disease

Locoregional Recurrence

Patients with local or regional recurrences(negative for distant metastases on radiologic imaging) can be evaluated for further treatment (see Clinical Presentation in the NCCN Guidelines for Endometrial Carcinoma). For recurrences confined to the vagina or the pelvis alone, second-line treatment (typically with RT and/or surgery or systemic therapy) can be effective and selection depends on prior therapy. For patients with no prior RT exposure at the recurrence site or previous vaginal brachytherapy, the Panel recommends EBRT with (or without) brachytherapy and systemic therapy, or surgery with (or without) intraoperative RT (IORT) and systemic therapy (category 3 for IORT).

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For patients previously treated with EBRT at the recurrence site,recommended therapy for isolated relapse includes surgery with(or without) IORT(category 3 for IORT) plus or minus systemic therapy. Use of RT in the context of recurrence depends on the site of recurrence(inside or outside the prior radiation field), and dose of prior therapy. Re-irradiation is used only in the context of limited disease for palliation and lack of other options. In selected patients, radical surgery(ie, pelvic exenteration) has been performed with reported 5-year survival rates approximating 20%.319-322

Isolated vaginal recurrences treated with RT have good local control and 5-year survival rates of 50% to 70%.323-325 Prognosis is worse if there is extravaginal extension or pelvic lymph node involvement.324 After RT, it is unusual for patients to have recurrences confined to the pelvis. The management of such patients remains controversial.

Additional therapy options for disease confined to vagina or paravaginal soft tissues include EBRT with(or without) brachytherapy with(or without)systemic therapy. EBRT and systemic therapy are also included as options for the additional treatment of pelvic lymph node recurrence,para-aortic lymph node invasion, and upper abdominal or peritoneal microscopic residual recurrences as shown in the algorithm(see Additional Therapy in the NCCN Guidelines for Endometrial Carcinoma).

Distant Metastases

For gross upper abdominal residual disease, more aggressive treatment for relapse is recommended, as outlined for disseminated metastases in Therapy for Relapse in the NCCN Guidelines for Endometrial Carcinoma.

For resectable isolated metastases, consider surgical resection and/or EBRT, or ablative therapy. Ablative RT can be considered for 1 to 5 metastatic lesions if the primary cancer has been controlled(category 2B).2B).202 Providers can also consider systemic therapy(category 2B).Further recurrences or disease not amenable to local therapy are treated

as disseminated metastases. Treatment options for disseminated metastases are systemic therapy with(or without) palliative EBRT. For persistent progression of disseminated metastases, best supportive care is recommended(see the NCCN Guidelines for Palliative Care and http://emedicine.medscape.com/article/270646-overview).

Hormonal Therapy

The role of hormonal therapy in recurrent or metastatic cancer has been primarily evaluated in patients with endometrioid histologies only.Hormonal therapy is typically used for lower grade endometrioid histologies, preferably in patients with small tumor volume or an indolent growth pace. Hormonal agents for treating metastatic disease include megestrol acetate with alternating tamoxifen, everolimus/letrozole combination, progestational agents(such as medroxyprogesterone acetate and megestrol acetate), aromatase inhibitors, tamoxifen alone, or fulvestant.326-331 No particular drug, dose, or schedule has been found to be superior. The main predictors of response in the treatment of metastatic disease are well-differentiated tumors, expression of ER/PR receptors, a long disease-free interval, and the location and extent of extrapelvic(particularly pulmonary) metastases.

For asymptomatic or low-grade disseminated metastases, hormonal therapy with progestational agents has shown good responses,particularly in patients with ER/PR-positive disease.332-335 Tamoxifen has a 20% response rate in disease that does not respond to standard progesterone therapy.336,337 Tamoxifen has also been combined with progestational agents; however, a few patients had grade 4 thromboembolic events with this combination regimen.328,329,338 In some patients, aromatase inhibitors(eg, anastrozole, letrozole) may be substituted for progestational agents or tamoxifen.334,335,339,340

Everolimus combined with letrozole is recommended for recurrent disease of endometrioid histology. In the phase 2 trial, in patients with progressive

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or recurrent endometrial cancer who had received up to two prior therapies, the clinical benefit rate and objective response rate among 35 evaluable patients was 40% and 32%, respectively.341 In a following phase 2 study, patients(with or without prior chemotherapy) were treated either with the everolimus/letrozole combination or medroxyprogesterone acetate/tamoxifen regimen. Twenty-two percent of patients had disease respond to the everolimus/letrozole therapy, while 25% showed a response with the medroxyprogesterone acetate/tamoxifen regimen.342 Median PFS was 6 months for the everolimus/letrozole arm and 4 months for the hormonal therapy arm. Median OS was 31 months and 17 months for the everolimus/letrozole and medroxyprogesterone acetate/tamoxifen arms, respectively. Higher PFS was observed in both arms for patients who had not received any prior chemotherapy.

Other hormonal modalities have not been well-studied, and adjuvant therapy with hormonal agents has not been compared with cytotoxic agents.334,343 If disease progression is observed after hormonal therapy,cytotoxic chemotherapy can be considered. However, clinical trials or best supportive care (see the NCCN Guidelines for Palliative Care) are appropriate for patients with disseminated metastatic recurrence who have a poor response to hormonal therapy and chemotherapy.

Systemic Therapy for Recurrent Disease

Based on the current data, multiagent regimens are preferred for advanced disease, if tolerated. The NCCN Guidelines for Endometrial Carcinoma have updated the systemic therapy recommendation by including immunotherapy and chemotherapy-based combination regimens as preferred, first-line options for recurrent disease. The NRG-GY018,randomized, phase III trial evaluated the benefits of

pembrolizumab/carboplatin/paclitaxel regimen over the

carboplatin/paclitaxel regimen in 816 patients with stage III or IVA endometrial carcinoma with measurable disease, or stage IVB or recurrent

disease of any histologic subtype,except for carcinosarcoma.258 The patients who had received adjuvant therapy at least 12 months before were included. The patients were stratified based on the dMMR or MMR-proficient(pMMR) status of the tumors. The PFS was 74% versus 38% in the dMMR cohort for the triplet regimen versus the chemotherapy arm,respectively(HR, 0.30; 95% CI, 0.19-0.48; P<.001). In pMMR tumors,the median PFS was 13.1 months in the pembrolizumab arm versus 8.7 months in the chemotherapy arm(HR, 0.54; 95% CI, 0.41-0.71; P<.001).Another phase III, randomized trial(RUBY) showed benefits of adding dostarlimab to the carboplatin/paclitaxel regimen in 494 patients with stage III or IV or recurrent disease, including all histologies.257 At 24 months,PFS was 36.1% versus 18.1%(HR, 0.64; 95% CI, 0.51-0.80; P<.001)and OS was 71.3% versus 56%(HR, 0.64; 95% CI, 0.46-0.87) in the dostarlimab-based arm versus the chemotherapy arm, respectively.Significantly more benefits were observed in patients with dMMR/MSI-H tumors with PFS of 61.4% versus 15.7%(HR, 0.28; 95% CI, 0.16-0.50; P<.001) in the triplet versus the doublet therapy arms, respectively. From second interim analysis of the RUBY trial,262 dostarlimab in combination with carboplatin-paclitaxel also demonstrated a statistically significant and clinically meaningful OS benefit with a statistically significant reduction in the risk of death[HR, 0.69; 95% CI, 0.54-0.89, P=.0020] in the overall population of patients with primary advanced or recurrent EC while demonstrating an acceptable safety profile.

Based on the results from the NRG-GY018 and RUBY trials, the NCCN Panel has added pembrolizumab/carboplatin/paclitaxel(except for carcinosarcoma histology) and dostarlimab/carboplatin/paclitaxel category 1, preferred, first-line therapy options for recurrent endometrial carcinoma. Carboplatin/paclitaxel/durvalumab is also recommended as a category 1, preferred regimen for dMMR tumors only based on the DUO-E trial and recent FDA approval.263,264 The carboplatin/paclitaxel/trastuzumab regimen is also recommended for HER2-positive uterine serous carcinoma

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or carcinosarcoma as a preferred regimen for first-line therapy for recurrent disease.265 Chemotherapy for endometrial cancer has been extensively studied.344,345 Other multiagent regimens such as carboplatin/paclitaxel, carboplatin/docetaxel, and carboplatin/paclitaxel/bevacizumab are included as first-line therapy options for the recurrent disease setting.

Carboplatin and paclitaxel is an increasingly used regimen for advanced/metastatic or recurrent endometrial cancer; the response rate is about 40% to 62%, and OS is about 13 to 29 months.346-349 A phase III trial(GOG 209) compared carboplatin and paclitaxel versus cisplatin,doxorubicin, paclitaxel, and filgrastim (granulocyte colony-stimulating factor).346 Trial data show that oncologic outcomes are similar, but the toxicity and tolerability profile favor carboplatin/paclitaxel.350 Thus, the carboplatin/paclitaxel regimen is a preferred, first-line option in the NCCN Guidelines. For patients in whom paclitaxel is contraindicated, docetaxel can be considered in combination with carboplatin.351,352

A phase II trial initially examined the addition of bevacizumab to carboplatin and paclitaxel among 15 patients with advanced or recurrent endometrial carcinoma.353 Although this study was closed early due to the initiation of a national trial, a retrospective analysis was performed to include data from an additional 27 patients who had received carboplatin/paclitaxel/bevacizumab for advanced or recurrent disease.268 Collective median PFS was 20 months with a median OS of 56 months.An overall response rate(ORR) of 82.8% was noted, with an 87.5%response rate among the subset of 8 patients who received this triplet regimen as second-line therapy after carboplatin/paclitaxel.268 Another phase 2 randomized study showed that the carboplatin/paclitaxel/bevacizumab combination improved OS from 29.7 months to 40 months compared to the doublet regimen.354 Another meta-analysis of three studies also concluded similar results where the triplet

carboplatin/paclitaxel/bevacizumab combination improved OS from 29.7 months to 40 months compared to the doublet regimen.354 Another meta-analysis of three studies also concluded similar results where the triplet

combination increased the OS and PFS at>12 months with an ORR of 76%.355

Other combination therapies such as cisplatin/doxorubicin,cisplatin/doxorubicin/paclitaxel, ifosfamide/paclitaxel(for carcinosarcoma),and cisplatin/ifosfamide(for carcinosarcoma) have been added as subsequent-therapy options. A phase III randomized trial(GOG 177)compared 2 combination chemotherapy regimens in females with advanced/metastatic or recurrent endometrial carcinoma.The 273 participants were randomly assigned to 1) cisplatin/doxorubicin/paclitaxel;or 2) cisplatin/doxorubicin. The 3-drug regimen was associated with improved survival(15 vs.12 months, P<.04) but with significantly increased toxicity (ie, peripheral neuropathy); therefore, it is not widely used.356-358 These regimens are recommended as subsequent therapy options in the NCCN Guidelines, because most Panel members feel that carboplatin/paclitaxel is a less toxic and preferred first-line option. The response rates with other multiagent chemotherapies ranged from 31% to 81%, but with relatively short durations. The median survival for patients in such trials remains approximately 1 year.344,345

If multiagent chemotherapy regimens are contraindicated, then single-agent therapy options for recurrent disease include cisplatin,carboplatin, doxorubicin, liposomal doxorubicin, paclitaxel, albumin-bound paclitaxel, topotecan, bevacizumab, temsirolimus, cabozantinib, lenvatinib,gemcitabine, and docetaxel(category 2B for docetaxel).334,359-361335,362 When single agents are used as second-line treatment, responses range from 4% to 27%; paclitaxel is the most active in this setting. 362 Some oncologists have used liposomal doxorubicin, because it is less toxic than doxorubicin; the response rate of liposomal doxorubicin is 9.5%.363 Docetaxel is recommended for use as a single agent; however, it is a category 2B recommendation because it is less active(7.7% response rate) than other agents. 364,365 Bevacizumab was shown to have a 13.5%

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response rate and OS rate of 10.5 months in a phase II trial for persistent or recurrent endometrial cancer.267 Based on these studies, the NCCN Panel considers bevacizumab as an appropriate single-agent biologic therapy for patients who have progressed on previous cytotoxic chemotherapy.267,366-368

Useful in Certain Circumstances, Biomarker-Directed Therapies In the advanced endometrial cancer cohort (n = 24) of the phase lb KEYNOTE-028 trial, durable antitumor responses were noted in a small subset of patients with programmed death ligand 1 (PD-L1)-positive tumors (3 PR, 3 stable disease).369 Studies have also indicated that dMMR tumors are sensitive to programmed cell death protein 1 (PD-1) blockade.370-372 Results were published from a study of patients with dMMR tumors of various disease sites. Among patients with dMMR endometrial carcinoma who received pembrolizumab (n = 15), the objective response rate was 52% and the disease control rate was 73% (3 CR, 5 PR, and 3 stable disease).370 The phase 2 Keynote-158 trial further demonstrated robust antitumor activity of pembrolizumab with encouraging survival outcomes in patients with previously treated MSI-H/dMMR endometrial cancer and manageable adverse events.373 Pembrolizumab is included as a treatment option for patients with recurrent endometrial cancer with MSI-H/dMMR disease that has progressed on or following prior treatment with a platinum-containing regimen in any setting including neoadjuvant or adjuvant therapy. The Panel recommends that recurrent endometrial tumors be tested for MSI-H or dMMR if not done previously.The Panel also recommends TMB-H testing if not previously done and has included the pembrolizumab option for patients with TMB-H tumors (>10 mut/Mb), as determined by a validated and/or FDA-approved test, who have progressed following prior treatment and who have no satisfactory alternative treatment options.374

Further studies have indicated that pembrolizumab monotherapy is less active in patients with microsatellite-stable or pMMR disease versus MSI-H/dMMR disease. Only 16% to 31% of endometrial cancers are MSI-H/dMMR.369,375,376 The Keynote-146 phase 1/2 trial showed that the combination of pembrolizumab/lenvatinib had a promising antitumor response in patients with advanced endometrial cancer regardless of their tumor MSI status.377 The Keynote-775 phase 3 trial randomly assigned 827 patients with pMMR(MSI-stable), previously treated advanced endometrial cancer to receive pembrolizumab/lenvatinib combination or chemotherapy (doxorubicin or paclitaxel).378 The median PFS for the pembrolizumab/lenvatinib arm was 7.2 months versus 3.8 months for the chemotherapy arm(HR, 0.56; 95% CI, 0.47-0.66; P<.001). The median OS was also longer for the pembrolizumab/lenvatinib arm than for the chemotherapy arm(18.3 vs. 11.4 months; HR, 0.62; 95% CI, 0.51-0.75; P<.001). On the basis of Keynote-775 data, FDA approved pembrolizumab in combination with lenvatinib for patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. Based on these data, the NCCN Guidelines for Endometrial Carcinoma include lenvatinib/pembrolizumab as a category 1 option for pMMR tumors for patients who have received prior platinum-based therapy in any setting, including neoadjuvant and adjuvant therapy.

ENGOT-En9/LEAP-001 is another phase 3, randomized (1:1), open-label,active-controlled trial that evaluated the efficacy and safety of first-line pembrolizumab (PEM) plus lenvatinib (LEN) versus paclitaxel plus carboplatin (TC) in patients with newly diagnosed stage III/IV or recurrent endometrial cancer, with measurable or radiographically apparent disease.(N = 842).379 The prespecified statistical criteria were not met for PFS and OS. In the pMMR subgroup (n = 642), median PFS was 9.6 months (95% CI,8.2-11.9) in the LEN+PEM arm (n = 320) versus 10.2 months (95% CI,

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8.4-10.5) in the TC arm (n = 322) with an HR of 0.99 (95% CI, 0.82-1.21).The median OS was 30.9 months (95% CI, 25.4-37.7) versus 29.4 months (95% CI, 26.2-35.4), respectively, with an HR of 1.02 (95% CI,0.83-1.26; nominal P $=$2.46).

A subgroup analysis for PFS in the pMMR population of patients who had previously received neoadjuvant or adjuvant therapy showed a trend favoring LEN+PEM compared to TC (HR, 0.60; 95% CI, 0.37-0.97). Data from ENGOT-En9/LEAP-001, along with the results from Study 309/KEYNOTE-775, support the recommendation for LEN+PEM as a first-line therapy for recurrent endometrial cancer, and useful in certain circumstances as a biomarker-directed therapy for pMMR tumors after prior platinum-based therapy in any setting, including the neoadjuvant and adjuvant settings.

Other anti-PD-1 inhibitors, such as dostarlimab and nivolumab, have also shown antitumor activity against MSI-H tumors. Dostarlimab demonstrated durable antitumor activity in dMMR/MSI-H endometrial cancer (ORR 43.5%) with a manageable safety profile in the GARNET trial,380 an ongoing, single-arm, open-label, phase I trial of IV dostarlimab in advanced solid tumors. The NCCN Panel recommends dostarlimab for the treatment of patients with recurrent dMMR/MSI-H endometrial cancer that has progressed on or following prior treatment with a platinum-containing regimen in any setting including neoadjuvant or adjuvant therapy.

Nivolumab monotherapy has also demonstrated promising activity in endometrial carcinoma with dMMR tumors.381 Following FDA approval382 of nivolumab and hyaluronidase for subcutaneous injection across approved adult, solid tumor as monotherapy, monotherapy maintenance following completion of nivolumab, the NCCN Panel added that nivolumab and hyaluronidase-nvhy subcutaneous injection may be substituted for IV nivolumab. Nivolumab and hyaluronidase-nvhy has different dosing and administration instructions compared to IV nivolumab.

The PD-L1 inhibitor, avelumab, has shown an ORR of 26.7% in advanced endometrial cancer with dMMR tumor as monotherapy. Nivolumab and evelumab are included as biomarker-directed subsequent therapy options for recurrent dMMR/MSI-H endometrial tumors. The NCCN Panel also recommends larotrectinib or entrectinib for NTRK gene fusion-positive endometrial tumors as a category 2A subsequent therapy option.Repotrectinib is also recommended for NTRK gene fusion-positive tumors that are naïve to prior NTRK-targeted therapy or have progressed on prior NTRK therapy.383,384

Systemic Therapy Options for High-Risk Endometrial Histologies

The NCCN Panel notes that the systemic therapy options recommended in the NCCN Guidelines can be used for all carcinoma histologies. Among these, carboplatin/paclitaxel is included as category 1, preferred option for patients with carcinosarcoma histology. A randomized phase II study examined the addition of trastuzumab to carboplatin/paclitaxel for patients with advanced or recurrent HER2/neu-positive uterine serous carcinoma.25 Among patients with stage III/IV disease undergoing primary treatment(n = 41), median PFS was 17.9 months versus 9.3 months for the experimental and control arms, respectively (P=.013). PFS for patients with recurrent disease (n = 17) was 9.2 months versus 6.0 months (P=.003). The addition of trastuzumab appeared to improve PFS without increasing overall toxicity. The safety and tolerability of the trastuzumab combination was further evaluated in 61 patients in a recent phase 2 trial with PFS as the primary endpoint.266 The triplet therapy regimen carboplatin/paclitaxel/trastuzumab is recommended by the NCCN Panel as a preferred option for HER2-positive uterine serous carcinoma or HER2-positive carcinosarcoma as: 1) primary therapy for stage III/IV disease; or 2) a first-line option for recurrent disease. This triplet regimen is recommended for patients who have not received any prior trastuzumab therapy. In subsequent therapy, the NCCN Panel has included ifosfamide, ifosfamide/paclitaxel, and ifosfamide/cisplatin as options for

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carcinosarcoma treatment only. For treating carcinosarcoma, ifosfamide was historically considered the most active single agent.385-387 A phase III trial for advanced carcinosarcoma showed that the combination of ifosfamide and paclitaxel increased survival and was less toxic than the previously used cisplatin/ifsofamide regimen.385,388 OS was 13.5 months with ifosfamide/paclitaxel versus 8.4 months with ifosfamide alone.313,385

female at birth can use vaginal dilators to prevent or treat vaginal stenosis.Dilator use can start 2 to 4 weeks after RT is completed and can be used indefinitely(https://www.mskcc.org/cancer-care/patient-education/vaginal-health).

Post-Treatment Surveillance

Radiotherapy Principles

The recommended post-treatment surveillance protocol for endometrial cancer is shown in the algorithm(see Surveillance in the NCCN Guidelines for Endometrial Carcinoma). 49,55 These recommendations recognize that the value of intensive surveillance has not been demonstrated in this disease; therefore, ancillary testing is not recommended. 391,392

RT has been a widely used modality in the treatment of patients with endometrial cancer; it clearly improves locoregional control.

Tumor-directed RT refers to RT directed at sites of known or suspected tumor involvement and may include EBRT and/or vaginal brachytherapy.215 Imaging is required to assess locoregional extent and to rule out distant metastases before administration of RT. In general, EBRT

Patients with clinical stage I and stage II endometrial cancer have a recurrence rate of approximately 15%;392-395 50% to 70% of these patients are symptomatic. For most patients, disease recurs within 3 years of initial treatment. Because most recurrences are symptomatic, all patients should receive verbal and written information regarding the symptoms of potential recurrence.392 Patients with bleeding(vaginal, bladder, or rectal),decreased appetite, weight loss,pain(in the pelvis, abdomen, hip, or back),cough, shortness of breath, and swelling(in the abdomen or legs)should seek prompt evaluation and not delay until the next scheduled appointment.

Brachytherapy can be delivered: 1) to an intact uterus, either preoperatively or definitely; or 2) more commonly, to the vagina after

hystectomy. For the purposes of these guidelines, whole abdominal radiotherapy is not considered to be tumor-directed RT. The Panel notes that chemoradiation can be given concurrently or sequentially. RT is described in detail in the algorithm, including target areas and doses for pelvic RT and brachytherapy(see Principles of Radiation Therapy in the NCCN Guidelines for Uterine Neoplasms). Although adjuvant RT is typically not associated with high rates of severe morbidity,389 studies have focused on subtle effects on quality of life(eg, diarrhea, bowel symptoms)that deserve further investigation.233,235,390 In the PORTEC-2 trial, vaginal brachytherapy was associated with better quality of life when compared with EBRT without a significant detriment to outcome.233 Therefore, many patients who were previously treated with adjuvant EBRT are now appropriately treated with vaginal brachytherapy; this recommendation is reflected in the NCCN Guidelines. Patients treated with RT are prone to vaginal stenosis, which can impair sexual function. Individuals assigned

History and physical exam is recommended every 3 to 6 months for the first 2 to 3 years, and then every 6 to 12 months thereafter for up to the fifth year, then annually. For non-fertility-sparing treatment, imaging should be guided by patient symptoms, risk assessment, and clinical concern for recurrent or metastatic disease. The indications of metastatic disease may include abnormal physical exam finding, bulky uterine tumor,vaginal or extrauterine involvement, delay in presentation or treatment,and abdominal or pulmonary symptoms. For fertility-sparing treatment, the

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Panel recommends repeat pelvic MRI (preferred) for patients with persistent endometrial carcinoma after 6 to 9 months of disease progression on medical therapy, especially if considering further fertility-sparing approaches. Pelvic US surveillance can be considered for patients with ovarian preservation. Abdomen/pelvis MRI and/or chest CT is recommended based on symptoms or physical exam findings. Whole body FDG-PET/CT and/or abdomen/pelvis MRI can be considered in select patients as clinically indicated. Physical exam also includes CA-125 if initially elevated or serous histology is also recommended for surveillance.

In the absence of recurrence, post-treatment surveillance provides psychosocial reassurance and improves quality of life for patients and their families. Health maintenance has been incorporated into the follow-up schedule(eg, blood pressure determination, breast examination,mammography as clinically indicated, stool guaiac test, immunizations).Patients should receive counseling and education regarding lifestyle,obesity,exercise, smoking cessation, sexual health,nutrition,and potential late or long-term effects of treatment(see the NCCN Guidelines for Survivorship, NCCN Guidelines for Smoking Cessation, and https://www.cancer.org/cancer/survivorship.html).390,396-398 Other health problems that often coexist in patients with endometrial cancer can also be evaluated during follow-up.

Given the lack of prospective studies regarding the optimal frequency of post-treatment follow-up, the NCCN Panel believes that the algorithm represents a reasonable surveillance scheme. The use of vaginal cytology is no longer recommended for patients who are asymptomatic consistent with the SGO guidelines.391,392,395,399 Patients with stage I endometrial cancer have a low risk of asymptomatic vaginal recurrence(2.6%),especially after adjuvant brachytherapy, and vaginal cytology is not independently useful for detecting recurrences in this group of patients.391,400 A multi-institutional review examined the utility of various

surveillance methods in 254 patients with high-grade disease, revealing that symptoms led to the detection of the most recurrences(56%),followed by physical exam(18%), surveillance CT(15%), CA-125(10%),and vaginal cytology(1%).401

Hormone Therapy for Hypoestrogenism

After BSO, hypoestrogenism is associated with hot flashes, mood lability, vaginal dryness, pelvic soft tissue atrophy, osteoporosis, and an increased risk of cardiovascular disease. In patients who are postmenopausal,estrogen therapy was believed to reduce or reverse some of these signs and symptoms. However, patients who have had BSO for endometrial adenocarcinoma have usually been denied estrogen therapy for fear of inducing a higher relapse rate, because this cancer has historically been considered an estrogen-linked malignancy.402,403 As such, estrogen therapy for such patients remains controversial.

However, it has never been proven that relapse rates are higher in patients with endometrial cancer who receive estrogen therapy after hysterectomy. Several retrospective trials of estrogen therapy after treatment of early-stage endometrial cancer have shown no increase in tumor recurrence or cancer-related deaths. 404-406 In females with stage I to ll endometrial cancer who had hysterectomy, a randomized trial of estrogen therapy versus placebo did not find an increased rate of recurrence or new malignancy; the median follow-up was 35.7 months.407 However, estrogen trials in postmenopausal females without a history of malignancy have demonstrated a significantly increased risk for breast cancer.408

Initially, the Women's Health Initiative (WHI) Estrogen-Alone Trial in females who had hysterectomy (n = 10,739) reported that the risk of breast cancer and cardiovascular disease (eg, stroke) were increased and that estrogen therapy was of concern; thus, the trial was stopped.409

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However, recent long-term follow-up data from this trial suggest that the risk from estrogen-alone replacement therapy (without progesterone) may not be as high in younger patients (<60 years) who have had hysterectomy.410

epithelial tumors(carcinomas).287 Screening for Lynch syndrome is not usually done for patients with malignant mesenchymal tumors.

Pathology and Molecular Analysis

The NCCN Panel agrees that estrogen therapy is a reasonable option for patients who are at low risk for tumor recurrence, but initiating such therapy should be individualized and discussed in detail with the patient.411,412 If adjuvant treatment is carried out, there should be a 6- to 12-month waiting period before initiation of hormone therapy, and participation in clinical trials is strongly encouraged. Selective estrogen-receptor modulators(SERMs) may prove to be attractive options for hormone therapy.413,414 Long-term comparisons between conjugated estrogens and SERMs for hormone therapy are needed. Non-hormonal therapy may be considered in patients who are deemed poor candidates for hormone therapy(eg, people who smoke, those with a history of breast cancer, those with a history of multiple strokes).415,416

Expert gynecologic pathology review is recommended for the assessment and histologic differentiation of uterine sarcomas including uLMS, UUS,ESS, and adenosarcoma.87 The pathologic assessment of the uterus should include hysterectomy type, specimen integrity(intact, opened,morcellated, or other), tumor size, myometrial invasion(for adenosarcoma only), histologic type, grade(for adenosarcoma only), and LVSI.The assessment should also include other tissues/organ involvement(falloplant tubes, ovaries, vagina, parametrium, omentum, or other).Peritoneal/ascitic fluid cytology should also be done. If the lymph nodes are resected, the level of nodal involvement and the number of lymph nodes with metastasis should be determined. Routine node dissection is not required in the absence of clinical suspicion of nodal involvement.

Peritoneal/ascitic fluid cytology should also be done. If the lymph nodes are resected, the level of nodal involvement and the number of lymph nodes with metastasis should be determined. Routine node dissection is

Uterine Sarcomas

Overview

Uterine sarcomas are uncommon malignant mesenchymal tumors,accounting for approximately 3% of all uterine cancers, and include high or low-grade ESS, UUS, uLMS, and others such as PEComas(see Initial Clinical Findings in the NCCN Guidelines for Uterine Sarcoma).417 According to a 2012 systematic review of data from 1970 to 2011, uLMS was the most common subtype(63%), followed by ESS(21%) and less common subtypes such as UUS.418 Even rarer subtypes of malignant mesenchymal tumors that can occur in the uterus include adenosarcoma,rhabdomyosarcoma(RMS), and PEComa.419 Carcinosarcomas were previously categorized and included in the sarcoma treatment algorithms until the mid-2000s, but are now considered and treated as high-grade

Recent advances have expanded our understanding of the molecular features of these tumors, leading to the identification of genetic signatures that characterize some of the uterine sarcoma subtypes. Historically,mesenchymal tumors were primarily diagnosed using histopathologic criteria, and the results of molecular studies were not used in routine pathologic evaluation. However, given the overlap in histopathologic features of these tumors, molecular analysis(eg, identification of characteristic translocations) can help classify difficult cases and provide future therapeutic targets. The Panel notes that comprehensive genomic profiling in the setting of metastatic disease with a validated and/or FDA-approved assay is informative for predicting rare pan-tumor-targeted therapy opportunities. The Panel recommends testing of at least NTRK,MSI, and TMB proteins. The testing is preferred on tissue; if tissue is not available, then blood-based assays can be considered. Since the molecular profiling is informative in many mesenchymal malignancies for

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accurate classification,420 the NCCN Guidelines for Uterine Neoplasms include a table containing information on histologic and molecular findings,specific biomarkers, relevant confirmatory molecular tests, prognostic features, and other clinically useful information to help clinicians differentiate between and classify uterine sarcoma subtypes. This information is intended to complement histopathologic testing to improve differential diagnosis of relatively rare uterine sarcoma subtypes and provide safer, more effective care for patients with the disease. The Panel notes that this information is not exhaustive and intends to update these recommendations as more data become available.

Low-Grade and High-Grade Endometrial Stromal Sarcoma (ESS)ESSs are the second most common mesenchymal tumors of the uterus.ESSs are composed of cells resembling the endometrial stroma in the proliferative phase.419,421 Low-grade ESSs have distinct fingerlike patterns of myometrial invasion, and LVSI is usually present. ESS displays a heterogenous mix of morphologic and genetic features. A significant proportion of these tumors (ie, up to half) harbor JAZF1,PHF1, or EPC1 gene fusions and present as earlier-stage tumors. 422-425 The Panel notes that diagnosis of low-grade ESS can be confirmed by identifying any low-grade ESS-associated gene fusion by using FISH and/or targeted RNA sequencing, though the lack of rearrangement or fusion does not exclude the diagnosis. It is worth noting that in rare instances, low-grade ESS can transform into high-grade ESS (either at the time of primary diagnosis or recurrence), which will require histopathologic and molecular (eg, JAZF1 or PHF1 translocation)confirmation. There are a few sarcomas reported as low-grade ESS harboring novel fusions and a subset behave more aggressively than typical low-grade ESS.

A higher-grade and more aggressively behaving ESS variant with a unique genetic rearrangement YWHAE::FAM22A/B, also known as

YWHAE::NUTM2A/B, has been identified.426,427 This subtype is known as high-grade ESS. Another subtype of high-grade ESS harboring BCOR is either in the form of a ZC3H7B::BCOR fusion or an internal tandem duplication. Both ZC3H7B::BCOR fusion-positive and BCOR internal tandem duplication high-grade ESS have spindle and/or round cells embedded in myxoid matrix, and demonstrate strong and diffuse positivity for cyclin D1 and variable positivity for CD10, ER, and PR.428 IHC testing for CD10, cyclin D1, and BCOR and, in some cases,molecular analysis of BCOR alterations, may help differentiate between BCOR-altered high-grade ESS and myxoid ULMS due to overlapping morphologic features. It is currently unclear whether specific types of high-grade ESS (ie, YWHAE-altered or BCOR-altered) differ in prognosis and/or response to chemotherapy.

These findings provided support for subdividing ESS into distinct low- and high-grade entities based on histopathology, clinical behavior, and patient outcomes. The updated 2014 edition of the WHO Classification of Tumors of Female Reproductive Organs recognizes low-grade ESS and high-grade ESS as distinct histopathologic entities.429 The 5th edition on Female Genital Tumors in 2020 also recognizes BCOR-altered sarcomas as a distinct subtype of high-grade ESS.430

Undifferentiated Uterine Sarcoma (UUS)

UUSs are a group of high-grade/aggressive sarcomas characterized by infiltrative sheets of epithelioid and/or spindle cells that may be uniform or pleomorphic. As a class, it is a heterogenous group of high-grade mesenchymal neoplasms of the uterus that does not meet the diagnostic threshold for other characterized uterine mesenchymal neoplasms. As such,UUS is usually reserved as a diagnosis of exclusion, after other defined uterine mesenchymal neoplasms have been excluded using a multiprong approach that often requires a combination of extensive IHC panel and next-generation sequencing(NGS) molecular analysis.For

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example, high-grade ESS is often misdiagnosed as UUS due to a shared lack of smooth muscle differentiation.431 The Panel notes that molecular testing for BCOR alterations, which can occur in high-grade ESS as noted above, is useful to exclude a high-grade ESS diagnosis before rendering a diagnosis of UUS.

A subset of UUSs called SMARCA4-deficient uterine sarcomas (SDUSs)have distinctive morphology (eg, phylodiform architecture) along with biallelic inactivation of SMARCA4 that results in loss of SMARCA4::BRG1 expression. These tumors occur in younger patients and may be associated with very aggressive clinical behavior.432 The Panel recommends analysis of SMARCA4::BRG1 by IHC and/or SMARCA4 by DNA sequencing to confirm a diagnosis of SDUS with otherwise appropriate morphologic and immunophenotypic features. However, loss of SMARCA4::BRG1 alone does not constitute a diagnosis of SDUS, and other aggressive malignancies such as undifferentiated endometrial carcinoma may show loss of expression of this protein.

Uterine Leiomyosarcoma (uLMS)

uLMS are usually of the spindle cell (conventional) type, but less common variants with myxoid or epitheloid morphology also exist. Although morphology differs between subtypes, all express varying degrees of the smooth muscle markers, including desmin, smooth muscle actin (SMA),and caldeson. The Panel recommends an IHC panel including desmin and SMA to support a uLMS diagnosis, particularly if myxoid or epithelioid uLMS is suspected. Abnormal expression of at least two immunohistochemical markers TP53, ATRX, RB1, PTEN, DAXX, MDM2,and MTAP suggests LMS in smooth muscle tumor of uncertain malignant potential or atypical smooth muscle tumors that do not fulfill histologic criteria for LMS. Genomic risk stratification may predict clinical outcomes.

Myxoid uLMSs may appear histologically similar to BCOR-altered High Grade ESSs or inflammatory myofibroblastic tumor (IMT).The Panel

recommends cyclin D1 and/or BCOR IHC to help exclude an HGESS diagnosis, as the latter is often overexpressed in HGESS. A subset (25%)of myxoid ULMSs also harbor PLAG1 fusions. Therefore, a myxoid ULMS diagnosis may be supported by positive desmin and SMA IHC along with PLAG1 rearrangement by FISH assay or RNA sequencing. NR4A3 fusions are detected in a subset of myxoid LMS. One differential diagnosis that must be considered for epithelioid uLMS is PEComa, given the observed similarities in morphology and IHC for smooth muscle markers. IHC testing for HMB45 and melanA may be performed if a diagnosis of PEComa is being considered, with HMB45 being fairly sensitive and melanA being specific for PEComa compared with uLMS. However, it is recognized that uterine mesenchymal tumors with myomelanocytic differentiation can still be challenging to classify solely by IHC. A study examining this specific group of diagnostically challenging tumors supported the use of genomic profiling to aid in their classification.433

Uterine Tumor Resembling Ovarian Sex Cord Tumor (UTROSCT)UTROSCTs are very rare tumors with sex cord-like differentiation, but without a stromal component as observed in ESSs. Most of these tumors harbor either ESR1 or GREB1 fusions.434,435 The Panel recommends an IHC panel that includes sex cord markers (eg, inhibin, calretinin, SF1,FOXL2); UTROSCTs are often positive for a broad range of biomarkers. In some cases, FISH or RNA sequencing for ESR1 or GREB1 fusions may be helpful to confirm the diagnosis. Approximately 25% of these tumors are malignant; the Panel notes that the presence of necrosis, high mitotic index, and GREB1 fusions may be associated with malignant behavior.

Rhabdomyosarcoma

Uterine RMSs are an aggressive, heterogeneous group of tumors that are extremely rare in adult patients. Subtypes include alveolar, embryonal,and pleiomorphic; all express myogenic biomarkers(eg, myogenin and MyoD1).436 Therefore, the Panel notes that diffuse expression of myogenic

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biomarkers by IHC can help confirm a uterine RMS diagnosis. Prognosis differs between subtypes, with embryonal RMS having the best prognosis of the 3 subtypes. Molecular alterations also differ between subtypes.FOX01 fusions are found in alveolar RMS, whereas PIK3CA and TP53 mutations are found in pleomorphic RMS. DICER1 mutations are present in up to 95% of embryonal RMS. The embryonal subtype also is known to harbor FGFR4/RAS/AKT pathway mutations.437 The Panel notes that extensive sampling should be performed to exclude epithelial components and diagnoses of carcarcosarcoma and adenosarcoma with heterologous rhabdomyosarcomatous differentiation. The Panel recommends FISH and/or RNA sequencing for FOXO1 to help confirm cases of suspected uterine alveolar RMS.

Mullerian Adenosarcoma

Risk factors for worse outcome in Müllerian adenosarcoma generally include myometrial invasion or sarcomatous overgrowth.438 The presence of a high-grade stromal component has been proposed as an important pathologic predictor of outcome. Hallmarks for histologic diagnosis include biphasic tumor with benign often metaplastic epithelium associated with an atypical usually low-grade spindle cell proliferation exhibiting phyllodes growth and periglandular stromal condensation. Sarcomatous overgrowth(SO) is defined by sarcoma comprising ≥25% of the tumor volume. In a genome-wide copy number analysis of Mullerian adenosarcoma,439 16 tumors (8 with SO and 8 without SO) were subjected to a molecular inversion probe array analysis. Frequent gains of chromosomal 12q were noted (CDK4, MDM2, CPM, YEATS4, DDDIT3, GLI1, HMGA2, and STAT6)without association with SO status. The most frequent losses involved chromosomes 13q, 9p, 16q, and 17q and were almost limited to cases with SO. BAP1 loss is seen in a subset of patients. ESR1 fusions are found in a minority of cases and BCORL1 fusions have been reported.Other genomic alterations are also observed in different subsets: 8q13 amplification and copy number gains of MYBL1; NCOA2/3 fusions; rare

FGFR2,KMT2C,DICER1,ATRX,and TP53 mutations; and MDM2/CDK4 and TERT amplifications.439,440

Staging and Treatment

When evaluating suspected uterine sarcomas, biopsy may be helpful but is less sensitive than for endometrial cancers. The diagnosis of ESS and uLMS is often made after hysterectomy. The previous FIGO/AJCC staging systems for endometrial cancer were not appropriate for staging ESS and uLMS; patients were often upstaged when using the older AJCC staging system.441 A new staging system for ESS and uLMS from FIGO/AJCC took effect in 2009 accounting for the differences between uterine sarcomas and endometrial cancers.69,442

Confirmation of the type of mesenchymal malignancy by expert pathology review is critical. In addition, initial evaluation should include imaging of the chest/abdomen/pelvis by CT or combination MRI/CT. It is important to determine if the sarcoma is confined to the uterus or if extrauterine disease is present. Pelvic MRI can be used to evaluate local tumor extension or residual abnormality in cases where the uterus or adnexa were not resected or incompletely resected(ie, supracervical hysterectomy, myectomy, possible tumor fragmentation, intraperitoneal morcellation). Neck/chest/abdomen/pelvis/groin FDG-PET/CT may be used to clarify ambiguous findings. If medically operable, then hysterectomy with(or without) BSO and en bloc resection of tumor is the initial treatment of choice for uterine sarcomas(see Primary Treatment in the NCCN Guidelines for Uterine Sarcoma).443

The Panel recommends ER/PR testing for LMS, ESS, and adenosarcoma to guide decisions regarding management of ovaries, particularly in young patients who are premenopausal. In general, BSO is favored for low-grade ESS or tumors expressing ER/PR, although management of the ovaries may be individualized in patients of reproductive age.444 A systemic review

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and meta-analysis of 786 patients reported 46.8% of tumor recurrence rate in ovarian preservation group versus 24.2% recurrence in the BSO group.445 In another multicenter retrospective study, the PFS for patients who underwent BSO versus ovarian preservation as 38 versus 11 months(P=.071).446

Uterine sarcoma should be removed en bloc to optimize outcomes;intraperitoneal morcellation is contraindicated.175,178 For incidental diagnoses of uterine sarcoma after hysterectomy, or in the case of a fragmented specimen, imaging is recommended and re-exploration for surgical resection can be considered. The ovaries may be preserved in selected patients with early-stage uLMS who wish to retain hormonal function.447 Additional surgical resection should be individualized based on clinical scenarios and intraoperative findings. Lymphadenectomy is controversial.3,419,447-450 High-grade uterine sarcomas tend to show hematogenous metastases to the lungs; lymph node metastases are uncommon.

For medically inoperable sarcomas, options include systemic therapy and/or palliative EBRT with(or without) brachytherapy.

Low-Grade Endometrial Stromal Sarcoma

Recommended adjuvant therapy options for stage I ESS include BSO or observation(if menopausal or prior BSO). BSO with(or without) anti-estrogen hormone therapy is recommended for stages II to IV ESS.Adjuvant EBRT may be added for stage II, III, or IVA(category 2B).

Palliative EBRT may be added for patients with stage IVB disease.419,451,452

Anti-estrogen hormone therapy is also recommended for ESSs that have recurred or are unresectable(see Therapy for Relapse in the NCCN Guidelines for Uterine Sarcoma).453 Given the histologic similarities

between low-grade ESS and uterine adenosarcoma, the Panel recommends similar adjuvant therapy options for adenosarcoma as provided for low-grade ESS. For patients with uterine adenosarcoma with

SO in advanced stages, the Panel recommends BSO with a consideration of systemic therapy and EBRT. EBRT is palliative for stage IVB disease.

Case series of patients with ESS suggest long disease-free intervals in the absence of specific therapy and raise questions about the use of adjuvant RT.454 Adjuvant radiotherapy in ESS has been demonstrated to reduce local recurrence rates but again with limited effect on survival.455,456 Because of concerns about radiation exposure, frequent routine surveillance imaging is no longer recommended for patients who are young and asymptomatic after primary therapy for ESS.457

Although anti-estrogen hormone therapy is recommended for low-grade ESS, studies have not yet determined the optimal therapeutic approach for high-grade ESS. However, due to the more aggressive nature of these tumors(eg, those with YWHAE::FAM22 rearrangements), the NCCN Panel has recommended that high-grade ESS be treated according to the algorithms in place for uLMS and UUS.

Typical hormone therapy for low-grade ESS or adenosarcoma without SO or ER/PR-positive uterine sarcoma includes aromatase inhibitors1458(preferred for low-grade ESS or adenosarcoma without SO), fulvesturant,megestrol acetate(category 2B for ER/PR-positive uterine sarcoma), or medroxyprogesterone acetate(category 2B for ER/PR-positive uterine sarcoma). Gonadotropin-releasing hormone[GnRH] analogs with aromatase inhibitors are also considered as a preferred regimen in premenopausal patients who are not suitable for surgery(BSO).419,447,453 For ER/PR-positive uterine sarcomas, the anti-estrogen hormone therapy should preferably be considered for patients with small tumor volume or an indolent growth pace.

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High-Grade Endometrial Stromar Sarcoma, Leiomyosarcoma,Undifferentiated Uterine Sarcoma, and PEComa

The role of adjuvant radiotherapy in nonmetastatic disease is controversial. Most available data are retrospective except for a phase III randomized trial.459 Most retrospective studies of adjuvant RT suggest an improvement in local pelvic control but no appreciable or consistent improvement in OS, given the propensity of metastatic extrapelic disease as a site of first or eventual recurrence.460-463 In many series, the patients treated with adjuvant radiation presumably had higher-risk factors(eg,larger tumors, deeper myometrial invasion), thus biasing the data against radiotherapy. However, a phase III randomized trial in stage I and II uterine sarcomas reported that postoperative pelvic radiotherapy did not improve OS for uLMS when compared with observation.459 Therefore,routine postoperative RT is not recommended for stage I patients with uLMS and UUS.451 If used in more advanced stages, adjuvant RT needs to be individualized and based on careful analysis of surgical pathologic findings.

The role of adjuvant systemic therapy is also poorly defined; however,adjuvant systemic therapy has been used because of the high risk of systemic relapse. Given the uncertainties regarding any adjuvant treatment for stage I high-grade ESS, uLMS, USS, and other sarcomas(such as PEComa) after complete resection, observation is the only option. A systemic review and meta-analysis concluded that adjuvant chemotherapy in early-stage uLMS was not beneficial in reducing locoregional and distant recurrences over observation.464 Because of the increased risk profile in patients with completely resected stage II and III tumors, the Panel believes that it is appropriate to consider adjuvant systemic therapy and/or EBRT. Observation can be considered for patients with completely resected tumors with negative margins.(see Additional Therapy in the NCCN Guidelines for Uterine Sarcoma).465 In patients with stage IV incompletely resected or metastatic disease,

systemic therapy and/or EBRT is generally recommended. For stage IVB disease, systemic therapy with an option of palliative EBRT is recommended.

Treatment of Recurrent or Metastatic Disease

The recurrence rate is high in uLMS (50%-70%). ${ }^{3}$ The guidelines provide recommendations based on tumor resectability and patients' prior RT exposure (see Therapy for Relapse in the NCCN Guidelines for Uterine Sarcoma). Treatment recommendations are made according to the site and nature of the recurrence.

Local recurrences are classified as recurrence in the vagina/pelvis with imaging that is negative for distant metastatic disease. Surgical and RT treatment pathways are provided. The surgical pathway for treating local recurrence in patients without prior RT exposure includes the option of IORT(category 3 for IORT). Preoperative EBRT with(or without) systemic therapy are also options to consider. For residual disease following surgery in patients without preoperative RT,EBRT with(or without)brachytherapy with(or without) systemic therapy can be considered.Primary RT offers an alternative pathway for treating localized recurrence in patients without prior exposure. EBRT should be given along with the option of brachytherapy and systemic therapy. For both the surgical and RT treatment pathways, further adjuvant systemic therapy should be considered after initial treatment.

Patients with local recurrence who have had prior RT exposure can be treated with 1) surgery with the option of IORT with (or without) systemic therapy (category 3 for IORT);2) systemic therapy; or 3) selected reirradiation with EBRT and/or brachytherapy. A retrospective analysis of patients with ESS suggested that cytoreductive resection improved OS in patients with recurrent lesions.466

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Systemic therapy with (or without) palliative EBRT or best supportive care is recommended for metastatic disease.467 For patients with isolated metastases that is resectable, surgical resection or other ablative therapy(eg, radiofrequency ablation, SBRT) may be appropriate. Patients with uLMS who experience longer time to recurrence may have improved survival outcomes following metastasectomy.468 Pre-or post-operative EBRT and/or systemic therapy can be considered. Observation may be an option in select, completely resected cases with no evidence of disease on postoperative imaging. Systemic therapy and/or local therapy(tumor-directed EBRT or local ablative therapy) are reasonable options for patients with unresectable isolated metastases(see Therapy for Relapse in the NCCN Guidelines for Uterine Sarcoma).469-472 For recurrent low-grade ESS, the first choice of systemic therapy is anti-estrogen hormone therapy.

Systemic Therapy for Advanced, Metastatic/Recurrent or Inoperable Disease

If systemic therapy is used for treating high-grade uterine sarcoma,preferred first-line therapy options include single-agent doxorubicin,gemcitabine/docetaxel,473-478 doxorubicin/trabectedin for LMS,479 doxorubicin/ifosfamide, and doxorubicin/dacarbazine for LMS or ifosfamide-ineligible patients(see Systemic Therapy in the NCCN Guidelines for Uterine Sarcoma).419,421,467 Doxorubicin is an active single agent for uLMS and is less toxic than combination regimens.419,467

The LMS-04 phase 3 randomized trial with 150 patients (67 with uLMS and 83 with soft tissue LMS) tested the benefits of doxorubicin/trabectedin versus doxorubicin alone as first-line therapy. Median PFS for the combination arm was longer than for the doxorubicin arm (12.2 months vs.6.2 months, respectively; HR, 0.41; 95% CI, 0.29-0.58; P<.0001). Based on these findings, the Panel recommends doxorubicin/trabectedin for patients with LMS.

6.2 months, respectively; HR,0.41;95% CI,0.29-0.58; P<.0001).Based on these findings, the Panel recommends doxorubicin/trabectedin for patients with LMS.

For second-line or subsequent therapy, trabected in is included as a preferred option for unresectable or metastatic uLMS. Data indicate that trabecedin may be useful in patients who have exhausted standard chemotherapy.480-483 The phase III data revealed a 2.7-month PFS benefit versus dacarbazine in metastatic liposarcoma or leiomyosarcoma that progressed after anthracycline-based therapy.484 Follow-up subgroup analysis of patients with uLMS(n= 232) revealed PFS of 4.0 months for trabectedin versus 1.5 months for dacarbazine(HR, 0.57; 95% CI, 0.41-0.81;P=.0012).485 However, OS did not differ significantly between the treatment arms(13.4 months for trabectedin vs. 12.9 months for dacarbazine; HR,0.89;95% CI,0.65-1.24;P=.51). Other recommended regimens include gemcitabine/dacarbazine, gemcitabine/vinorelbine,dacarbazine, gemcitabine, epirubicin, ifosfamide, liposomal doxorubicin,pazopanib, temozolomide, regorafenib, and eribulin(category 2B).387,470,473,474,486-503

Eribulin is included based on results from a phase III trial comparing the survival benefit of eribulin and dacarbazine in 452 patients with advanced leiomyosarcoma or adipocytic sarcoma.504 Median OS was 13.5 and 11.5 months for eribulin and dacarbazine, respectively(HR, 0.77; 95% CI,0.62-0.95; P=.017).Eribulin was designated as category 2B upon Panel review of the mature trial data.

For first-line biomarker-directed therapies, the Panel recently added crizotinib, ceritinib, brigatinib, or llatinib, and alectinib for anaplastic lymphoma kinase(ALK) fusion-positive IMTs for uterine sarcomas based on the literature evidence derived from non-small cell lung cancer. 505-508 The Panel also recommends larotrectinib or entrectinib for NTRK gene fusion-positive tumors. Repotrectinib is also recommended for NTRK gene fusion-positive tumors that are naive to prior NTRK-targeted therapy or have progressed on prior NTRK therapy.383,384 Selpercatinib is recommended for RET-fusion positive tumors.509 Selpercatinib showed

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clinically meaningful activity in the RET fusion-positive tumour-agnostic population, with a safety profile consistent with that observed in other indications. For PECoA, albumin-bound sirolimus is recommended as a first-line therapy option and sirolimus, everolimus, and tiersrolimus are recommended as second-line or subsequent therapy options.

Pembrolizumab has been added for the treatment of patients with unresectable or metastatic TMB-H tumors that have progressed following prior treatment and have no satisfactory alternative treatment options.Olaparib, rucaporib, and niraparib are included as second-line/subsequent therapy options for BRCA2-altered uLMS.510

Post-Treatment Surveillance

The recommended post-treatment surveillance protocol for uterine sarcoma is depicted in the algorithm (see Surveillance in the NCCN Guidelines for Uterine Sarcoma). History and physical exam is recommended every 3 to 4 months (consider every 6 months for low-grade early-stage sarcomas) for the first 2 to 3 years, and then every 6 to 12 months thereafter. Imaging surveillance should include chest/abdomen/pelvis CT every 3 to 6 months for the first 3 years and then every 6 to 12 months for the next 2 years. Depending on histology,grade, and initial stage, annual to biannual imaging can be considered for an additional 5 years. Follow-up imaging may be as frequent as every 3 months or change based on histology grade and/or stage of tumor.Abdomen/pelvis MRI and chest CT without contrast is optional.

Abdomen/pelvis MRI and chest CT without contrast is optional.

Neck/chest/abdomen/pelvis/groin FDG-PET/CT can be considered if metastasis is suspected in select patients. Additional imaging should be based on symptomatology and clinical concern for metastatic disease.

Patients should receive education regarding the symptoms of recurrent disease. Patients with bleeding(vaginal, bladder, or rectal), decreased appetite, weight loss, pain(in the pelvis, abdomen, hip, or back), cough,shortness of breath, and swelling (in the abdomen or legs) should seek

prompt evaluation and not delay until the next scheduled appointment.Imaging may be helpful in the detection of recurrence. Patients should be educated regarding healthy lifestyle choices, obesity, exercise, smoking cessation, nutrition, and potential long-term and late effects of treatment.See Principles of Gynecologic Survivorship within the NCCN Guidelines for Uterine Neoplasms(also see the NCCN Guidelines for Survivorship,NCCN Guidelines for Smoking Cessation, and https://www.cancer.org/cancer/survivorship.html).396-398 The Panel also recommends patient education regarding sexual health, vaginal dilator use, and vaginal lubricants or moisturizers.

Drug Reactions

Virtually all drugs have the potential to cause adverse hypersensitivity reactions, either during or after the infusion.511 In gynecologic oncology treatment, drugs that more commonly cause adverse reactions include carboplatin, cisplatin, docetaxel, liposomal doxorubicin, and paclitaxel.Most of these drug reactions are mild infusion reactions (ie, skin reactions, cardiovascular reactions, respiratory or throat tightness), but more severe allergic reactions (ie, life-threatening anaphylaxis) can occur.512-514 In addition, patients can have mild allergic reactions or severe infusion reactions. Infusion reactions are more common with paclitaxel.515 Allergic reactions (ie, true drug allergies) are more common with platinum agents(ie, carboplatin, cisplatin).515,516

Management of drug reactions is discussed in the NCCN Guidelines for Ovarian Cancer.515 It is important to note that patients who have had severe life-threatening reactions should not receive the implicated agent again unless under the care of an allergist or expert in managing drug reactions. If a mild allergic reaction has previously occurred and it is appropriate to administer the drug again, a desensitization regimen should be used even if the symptoms have resolved; various desensitization regimens have been published and should be followed.517-519 Patients

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must be desensitized with each infusion if they previously had a reaction.Almost all patients can be desensitized(about 90%).511 To maximize safety, it is prudent to desensitize patients in the intensive care unit.

Gynecologic Survivorship

Treatment for gynecologic cancer typically involves surgery,chemotherapy, hormone therapy,RT, and/or immunotherapy, which may cause acute, short-term, and long-term toxicities. Surgical approaches may be extensive and cause adhesions to form, which in turn may cause pain and contribute to the development of small bowel obstruction, urinary or gastrointestinal complications (eg, incontinence, diarrhea), pelvic floor dysfunction(manifested by a variety of urinary, bowel, and/or sexual effects), and lymphedema. Chemotherapy agents vary, though commonly used regimens may pose a significant risk of neurotoxicity, cardiac toxicity,cognitive dysfunction, and the development of hematologic cancers. Long-term estrogen deprivation may cause symptoms such as hot flashes,vaginal dryness, and bone loss. RT may cause long-term complications(eg, fibrosis, stenosis, vulvovaginal atrophy) and may predispose patients to subsequent cancers of the skin, subcutaneous tissue, and/or underlying organs that are proximal to the radiation field. Use of immunotherapy agents in gynecologic cancers is emerging, and to date, long-term effects of these treatments are unknown.

Following completion of treatment, all gynecologic cancer survivors should receive regular general medical care that focuses on managing chronic diseases(eg, depression, diabetes, hypertension), monitoring cardiovascular risk factors, receiving recommended vaccinations, and encouraging adoption of a healthy lifestyle(eg, promoting exercise,smoking cessation). In order to assess the late and long-term effects of gynecologic cancers, clinicians should comprehensively document the patient's history, including prior treatment history, and conduct a thorough physical examination followed by necessary imaging and/or laboratory

testing. As most treatments for gynecologic cancers will cause sexual dysfunction, early menopause, and infertility, special attention to the resultant medical and psychosocial implications is needed. All patients,whether sexually active or not, should be asked about genitourinary symptoms, including vulvovaginal dryness. Post-radiation use of vaginal dilators and moisturizers is recommended. Psychosocial effects may include psychological(eg, depression, anxiety, fear of recurrence, altered body image),financial(eg,return to work,insurance concerns),and interpersonal(eg, relationships, sexuality, intimacy). Patients should be referred to appropriate specialty providers(eg, physical therapy, pelvic floor therapy, sexual therapy, psychotherapy) as needed, based on prior treatment history and assessed risk of developing late effects and/or existing concerns. Communication and coordination with all clinicians involved in the care of survivors, including primary care clinicians, is critical. Providing survivors with a summary of their treatment and recommendations for follow-up is also recommended. To this end, the SGO has developed templates for gynecologic cancer-specific Survivorship Care Plans to aid survivors and their clinicians in summarizing cancer history, treatments received, possible side effects,and recommended follow-up.

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potential impact on the increasing number of deaths. Am J Obstet Gynecol 2008;198:218 e211-216. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18226630.12. Chan JK, Sherman AE, Kapp DS, et al. Influence of gynecologic oncologists on the survival of patients with endometrial cancer. J Clin Oncol 2011;29:832-838. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21263082.

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表 1
FIGO Stage	Histologic Grade	Adjuvant Treatment
IA	G1, G2	Observation preferred or Consider vaginal brachytherapy if lymphovascular space invasion (LVSI) and/or age ≥ 60 yn
IA	G3	Vaginal brachytherapy preferred or Consider observation if no myoinvasion or Consider EBRT if either age ≥ 70 y or LVSI(category 2B) IB
IA	IB	G1
G2	IB	Vaginal brachytherapy preferred or Consider EBRT if ≥60 y and/or LVSI or Consider observation if age <60 y and/or LVSI
G3	IB	RT (EBRT and/or vaginal brachytherapy) ± systemic therapy (category 2B for systemic 2B)

表 2
	FIGO Stage	Histologic Grade	Adjuvant Treatment
Surgically staged:e: Stage I0,p	II	G1-G3	EBRT (preferred) and/or vaginal brachytherapyq ± systemic therapy (category 2B for systemic therapy)

表 3
Primary or Adjuvant Therapy (Stage I-IV)
Chemoradiation Therapy	Systemic Therapy
Preferred	Preferred
●Cisplatin plus RT followed by Carboplatin/Paclitaxel1,2	$\text{Carboplatin/Paclitaxel}+\text{Pembrolizumab}(\text{for stage III-IV tumors, except for}$ $carcinosarcoma) (category 1)b,d,e,3,4 $<$ \text{carcinosarcoma} (category 1)d,f,5 $<$ \text{carboplatin/Paclitaxel}+Dostarlimab-gxly (for stage III-IV tumors) (category 1)d,f,5 $<$ \text{carbology} 1)d,f,6 $<$ \text{carbology} 1)d,g,6 $<$ \text{carboplatin/Paclitaxel}+Durvalumab(for stage III-IV dMMR tumors only) $$(category 1)d,g,6 $$ $<$ \text{carboplatin/Paclitaxel}+D_{\text{prattumab}}($$AVorplatin/Paclitaxel $+D_{\text{trastuzumab} }($for stage III-IV HER2-positive uterine $-$ \text{serous carcinoma} $or\,carcinosarcoma $)$ $d,h,7 $ $.$ $\cdot$ Carboplatin/Paclitaxel $+$ Bevacizumab $(for$ stage III-IV tumors $d,8,9$ $)$ $,$ Carboplatin/Paclitaxel $+$ Carboplatin/Paclitaxel10 $$ \text{Other Recommended} $ $)$ $.$ $C) $\text{Carboplatin/Paclitaxel/Durvalumab}+$ Durvalumab/Olaparib $(for$ stage III-IV pMMR tumors) $(category 2B)^{d,11}$ $$

表 4
RECURRENT DISEASE	RECURRENT DISEASE
Second-Line or Subsequent Therapyc,k
Other Recommended	Useful in Certain Circumstances (Biomarker-directed therapy)
•Cisplatin/Doxorubicin ${}^{17}$	·pMMR tumors
•Cisplatin/Doxorubicin/Paclitaxelq,17	Lenvatinib + Pembrolizumab (category 1)12,13
•Cisplatin/Gemcitabine ${}^{18}$	Axitinib + Avelumab25
•Cisplatin	●TMB-H tumorsos
•Carboplatin	Pembrolizumabe,14
•Doxorubicin	Ipilimumab + Nivolumab26
•Liposomal Doxorubicin	·MSI-H/dMMR tumorsp
·Paclitaxel19	Pembrolizumabe,15
·Albumin-bound Paclitaxelr	Dostarlimab-gxly16
·Topotecan	Avelumab
·Bevacizumabs,20	Nivolumabt,27
·Temsirolimus21	Tislelizumab-jsgr28
·Cabozantinib	Retifanlimab-dlwr(category 2B)29
·Lenvatinib22	·HER2-positive tumors(IHC 3+ or 2+)
·Gemcitabine23	Fam-trastuzumab deruxetcan-nxki30
·Docetaxel(category 2B)	·HER2-positive tumors (IHC 1+, 2+ or 3+)
·Ifosfamide(for carcinosarcoma)	Fam-trastuzumab deruxetcan-xki (for carcinosarcoma)31
·Ifosfamide/Paclitaxel(for carcinosarcoma)24	·NTRK gene fusion-positive tumors
·Cisplatin/lfosfamide(for carcinosarcoma)	Larotrectinib Entrectinib
	Repotrectinib,32
·RET gene fusion-positive tumors
·Selpercatinib	Selpercatinib

表 5
Hormonal Therapy for Recurrent or Metastatic Endometrial Carcinoma
Preferred	Other Recommendedum
●Megstrol acetate/Tamoxifen (alternating)	●Medroxyprogesterone acetate/Tamoxifen
●Everolimus/Letrozole	(alternating) ●Progestational agents ●Medroxyprogesterone acetate
	Abemaciclib/Letrozole
	Medroxyprogesterone acetate
	Abemaciclib/Fulvestant

表 6
Hormonal Therapy for Uterine-Limited Disease Not Suitable for Primary Surgery or for Those Desiring Uterine Preservation for Fertility (ENDO-1)V
Preferred	Other Recommended
●Levonorgestrel IUD	●Continuous progestin-based therapy ● Megestrol acetate ● Medroxyprogesterone acetate ●Dual progestin agents
	Levonorgestrel IUD/Megestrol acetate
	Levonorgestrel IUD/Medroxyprogesterone acetate

表 7
Uterine Sarcoma	Uterine Sarcoma	Uterine Sarcoma	Uterine Sarcoma	Uterine Sarcoma	Uterine Sarcoma
Tumor	Hallmarks for Histologic Diagnosis	Relevant Molecular Finding	Tests Needed to Confirm Diagnosis	Relevant Prognostic Features	Other
Conventional (spindle cell) Liomyosarcoma (LMS)	Cellular spindle cell proliferation with interlacing long fascicles with $\geq 2$ of the following: moderate to severe atypia, tumor cell necrosis, or mitotic index (MI) $\geq 10/10$ high-power fields (HPFs).	Complex karyotypes are the hallmark of the hallmark of LMS. The most commonly altered genes include TP53,ATRX,RB1, PTEN, DAXX, MDM2, CDKN2A, CDKN2C, PDGFRB, and BRCA2.	Immunoexpression of smooth muscle markers such as desmin, smooth muscle actin (SMA), and/or caldesmon; however, tumors may have variable expression and even lose expression of ≥1 markers. Approximately 1/3 of LMS express ER/ PR. Abnormal expression of ≥2 IHC markers TP53,ATRX,RB1,PTEN, DAXX, MDM2, and MTAP may favor LMS in smooth muscle tumors that do not fulfill traditional histologic criteria for LMS. Genomic risk stratification may predict clinical outcomes.	Prognosis is best predicted by stage. Morphology has not been shown to predict clinical behavior. Limited data suggest PR expression may be a positive prognostic marker in low-stage LMS.
Epithelioid LMS1	Epitheli histology comprising $\geq 50\%$ of the overall tumor supports classification as an epithelioid smooth muscle tumor. Diagnostic criteria for epithelioid LMS are controversial. By WHO 5th edition, epithelioid LMS is assigned when $\geq 1$ of the following features is present: moderate to severe atypia, tumor cell necrosis, MI of $\geq 4/10$ HPFs. Recent studies suggest assigning epithelioid LMS when $\geq 2$ features are present.2	PGR fusions by FISH and/ or targeted RNA sequencing in a small subset with uniform nuclear atypia and rhabdoid features.	Immunoexpression of desmin, SMA, and/ or caldesmon without MelanA expression is supportive. In some cases of epithelioid LMS, HMB -45 may be expressed.	Unknown	Epithelioid LMS may morphologically and immunohistochemically overlap with malignant PECooma for which there is no gold standard diagnostic test. Detection of pathogenic TSC1/2 mutations or TFE3 fusion may favor PECooma.
Tumor	Hallmarks for Histologic Diagnosis	Relevant Molecular Finding	Tests Needed to Confirm Diagnosis	Relevant Prognostic Features
Myxoid LMS3.4	Infiltrative spindle cell proliferation with variable myxoid matrix and tumor necrosis or moderate to severe atypia or MI >1/10 HPFs.	PLAG1 fusion by FISH and/or targeted RNA sequencing in a subset (~25%). NR4A3 fusions are detected in a subset of myxoid LMS.	IHC panel of CD10,ER,PR, desmin, SMA, caldesmon, cyclinD1, and ALK is recommended to exclude morphologic mimics.	Unknown
Low-Grade Endometrial Stromal Sarcoma (ESS)5-7	Cytologically bland spindle cell neoplasm resembling proliferative endometrial stroma with distinctive finger-like myoinvasion and/or LVSI.	JAZF1::SUZ12 fusion most common (>50%) followed by JAZF1::PHF1, EPC1::PHF1, and MEAF6::PHF1 fusions; MBTD1-CXorf67, BRD8::PHF1, EPC2::PHF1, and EPC1::SUZ12;	CD10, ER positivity, PR positivity, and/ or demonstration of a low-grade ESS- associated fusion by FISH and/or targeted RNA sequencing is confirmatory.	Stage is the most important prognostic factor.

表 9
Uterine Sarcoma	Uterine Sarcoma	Uterine Sarcoma	Uterine Sarcoma	Uterine Sarcoma
Tumor	Hallmarks for Histologic Diagnosis	Relevant Molecular Finding	Additional Confirmatory Tests	Relevant Prognostic Features
High-Grade Endometrial Stromal Sarcoma(ESS)5-13	YWHAE::NUTM2 fusion-positive tumors have a high-grade round cell component with delicate branching vasculature. Generally the MI is≥10/10 HPFs.YWHAE-altered high-grade ESS may be associated with a low-grade fibrous or fibromyoxid spindle cell component with low MI. ZC3H7B::BCOR fusion-positive tumors have high-grade spindle cells embedded in myxoid matrix. BCOR internal tandem duplication (ITD)- positive tumors share morphologic features of ZC3H7B::BCOR fusion-positive tumors. Tongue-like infiltration and LVSI are present in all subtypes.	YWHAE::NUTM2 fusion, ZC3H7B::BCOR fusion, or BCOR ITD.	IHC panel of CD10, ER, PR, cyclin D1, ±BCOR are recommended. Diffuse strong expression of cyclin D1 is present in all subtypes, and/or BCOR is strongly and diffusely expressed in the YWHAE-rearranged sarcomas but positive in only ~50% of the BCOR-altered sarcomas. CD10 is negative in the high-grade round cell component of altered subtype, but may be positive in BCOR-altered mutant subtypes. ER and PR are negative in the high-grade component of YWHAE-altered subtype, and variably positive in BCOR-altered tumors.	Slightly higher rate of lymph node involvement and trend towards worse outcomes when compared to low-grade ESS.
Undifferentiated Uterine Sarcoma(UUS)13-16	Infiltrative sheets of pleomorphic epithelioid and/or spindle cells.		This is essentially a diagnosis of exclusion, and thus there are no confirmatory tests. An IHC panel of CD10, cyclin D1, desmin, SMA, caldesmon, pan-CK, EMA, BRG1, IN1I, pan-Trk, ALK, HMB45, MelanA, SOX10, S100, CD34, and STAT6 is recommended to consider other tumor types. Absence of ESS-associated fusions by FISH and/or targeted RNA sequencing is recommended.	ER and/or PR expression may correlate with improved survival. MI ≥ 11/mm2 is associated with decreased survival.

表 10
Uterine Sarcoma	Uterine Sarcoma	PRINCIPLES OF PATHOLOGY AND MOLECULAR ANALYSIS
Uterine Sarcoma	Uterine Sarcoma	Relevant Molecular Finding	Additional Confirmatory Tests
Tumor	Hallmarks for Histologic Diagnosis	Relevant Molecular Finding	Additional Confirmatory Tests	Relevant Prognostic Features
Perivascular Epithelioid Cell Tumor (PECoA)17-19	Mesenchymal neoplasm comprised of perivascular epithelioid and/or spinled cells that coexpress melanocytic and muscle markers. The tumor cells can demonstrate variable cytologic atpymit, activity, and melanin a pigment in a background of thin-walled vascular spaces and sclerotic stroma. Proposed algorithms stratify tumors into uncertain malignant potential and malignant as outlined below. Uncertain malignant potential (<3 of the following:≥5 cm size, high nuclear grade, >1 mitosis/50 mm2, necrosis, and vascular invasion). Malignant if ≥3 features (>5 cm, infiltrative growth, high nuclear grade, >1 mitosis/50 mm2, necrosis, and vascular invasion).	Inactivating mutations of TSC1/TSC2, and fusions of TFE3, RAD51B, or HTR4::ST3GAL1 can be seen. In situ hybridization to confirm rearrangement or fusion of TFE3 in TFE3-translocation-associated tumors.	Immunoexpression of cathepsin K, variable expression of melanocytic markers (HMB45 is most sensitive and MelanA is most specific), and ≥1 smooth muscle marker (SMA, desmin, and caldemon). Keratins and hormone receptors can be variably expressed. Translocation-associated tumors show diffuse TFE3 expression with weak to negative smooth muscle markers. TSC2 mutations may rarely occur in ESS; thus in tumors with ambiguous morphologic/immunophenotypic features, and TSC2 mutation identified, consideration for fusion testing is advised to exclude ESS.20	Tumor behavior is best predicted using tumor stratification into uncertain malignant potential and malignant subgroups. Treatment with mTOR inhibitors may be considered.17,21
Inflammatory Myofibroblastic Tumor (IMT)	Spindle cell neoplasm comprised of spindled cells with admixed inflammatory infiltrate (usually lymphoplasmacytic) in a myxoid stroma. Histologic patterns include myxoid hypocellular areas (resembling fascilities), storiform or fascicular pattern with compact cellular areas with intersecting fascicles, and hyalinized dense collagenous matrix.	ALK rearrangements by FISH are seen in approximately 75% of patients. Common fusion partners include IGFBP5, THBS1, and TIMP3, RABNP2-ALK and RRBP1::ALK fusions are seen in aggressive IMT with epithelioid morphology. ALK- negative uterine IMTs are rare.	Immunoexpression of ALK(granular cytoplasmic) is sensitive and specific; seen in approximately 95% of patients and can be variable and focal. Immunoexpression of desmin, SMA, and/or caldesmon is common.	Typically benign and confined to the uterus; recurrence and extrauterine spread can occur. Tumors > 7 cm with necrosis, lymphovascular invasion, severe cytologic atypia, and high MI behave aggressively as do peritoneal IMTs. ALK-rearranged tumor may respond to ALK inhibitors rather than general tyrosine kinase inhibitors.

表 11
Uterine Sarcoma	Uterine Sarcoma	Uterine Sarcoma	Uterine Sarcoma	Uterine Sarcoma	Uterine Sarcoma
Tumor	Hallmarks for Histologic Diagnosis	Relevant Molecular Findinging	Additional Confirmatory Tests	Relevant Prognostic Features	Other
SMARCA4-Deficient Uterine Sarcoma (SDUS)	SDUS is characterized by sheets of epithelioid/ rhabdoid cells associated with hyalinized matrix. LVSI, high M1,and necrosis are common. A small cell component or even spindled morphology may be focally present.	Biallelic SMARCA4 inactivation	Absent CK expression and BRG1 loss (SMARCA4) and/or SMARCA4 mutation detectable by DNA sequencing is helpful to support a diagnosis of SDUS, in the appropriate morphologic context.		Germline SMARCA4 mutation testing should be considered.
New and Emerging Entities
NTRK-Rearranged Sarcoma	Spindle cell neoplasm with fascicular, herringbone, or patternless growth. Entrapped glands may be present, sometimes with polypoid projections simulating adenosarcoma; however, there is typically no periglandular stromal condensation.	NTRK1/2/3 fusions	Frequent positivity for CD34 and/ or S100 (generally both but with variable extent). IHC for pan-TRK is typically positive, but this marker is not specific for the gene fusion.	Typically present with stage I vise 1 I disease; ~1/3 recur or metastasize. Targeted therapy against NTRK inhibitors has shown clinical benefit.	More commonly occurs in the uterine cervix.

表 12
Uterine Sarcoma	Uterine Sarcoma	Uterine Sarcoma	Uterine Sarcoma	Uterine Sarcoma
Tumor	Hallmarks for Histologic Diagnosis	Relevant Molecular Finding	Additional Confirmatory Tests	Relevant Prognostic Features
Uterine Tumor Resembling Ovarian Sex Cord Tumor (UTROSCT)22-24	Bland spindle cell proliferation with extensive sex cord-like differentiation and no endometrial stromal component.	ESR1 or GREB1 fusions in the majority of tumors.	IHC expression of sex cord markers (inhibin, calretinin, SF1, FOXL2) and/or detection of GREB1 or ESR1 fusions by FISH (NCOA1, NCOA2, NCOA3) and/ or targeted RNA sequencing is confirmatory.	Tumors have uncertain malignant potential with ~25% being malignant. Necrosis and MI ≥2/10 HPFs and/ or presence of GREB1 fusion may increase likelihood of malignant behavior.
Rhabdomyosarcoma (RMS)25-27	Embryonal subtype consists of small primitive cells that may form a cambium layer in botryoid tumors; strap cells and fetal cartilage can be seen. Marked atypia defines the pleomorphic subtype. Alveolar subtype consists of small primitive cells growing in nests or alveoli.	DICER1 mutations are present in ≥95% of embryonal RMS. PIK3CA and TP53 mutations in pleomorphic tumors. FOXO1 fusion in alveolar tumors.	IHC expression of myogenin and/ or MyoD1 is confirmatory of RMS differentiation. Extensive sampling must be performed to exclude carcinosarcoma or adenosarcoma with SO. FISH and/or targeted RNA sequencing for FOXO1 fusion is recommended to confirm alveolar subtype.	Embryonal subtype has better prognosis than pleomorphic and alveolar subtypes. Age and stage are prognostic factors.
Müllerian Adenosarcoma (MAS)28-31	Biphasic tumor with benign often metaplastic epithelium associated with an atypical usually low-grade spindle cell proliferation exhibiting plenchio Fyllodges growth and periglandular stromal condensation. SO is defined by sarcoma comprising ≥25% of the tumor volume.	BAP1 loss is seen in a subset. ESR1 fusions are found in a minority of cases and BCORL1 fusions have been reported.d	Ancillary testing is usually not required.	High grade, myoinvasion, and SO are poor prognostic factors. High-grade cytologic features may also portend a worse prognosis.

表 13
Advanced, Recurrent/Metastatic or Inoperable Disease
First-Line Therapy	First-Line Therapy
Preferred	Second-Line or Subsequent Therapyb
● Doxorubicin	Trabectedin(for LMS)
●Docetaxel/Gemcitabine
●Doxorubicin/Trabectedin(for LMS)1	Other Recommended
●Doxorubicin/losfamide	●Dacarbazine/Gemcitabine
●Dacarbazine/Doxorubicin (for LMS or lfosfamide ineligible)	Gemcitabine/Vinorelbine
Useful in Certain Circumstances	●Dacarbazine
●Biomarker-directed therapy	●Epirubicin
NTRK gene fusion-positive tumors	●Ifosfamide
◆Larrotectinib	●Liposomal Doxorubicin
◆Entrectinib	Pazopanib
◆Reprotectinibc,2	●Temozolomide
IMT with ALK translocation	●Regorafenib8
◆Crizotinib3	●Eribulin(category 2B)
◆ Ceritinib4
◆ Brigatinib,6	Useful in Certain Circumstances (Biomarker-directed therapy)
◆Lorlatinib	TMB-H tumorse
◆ Alectinib	Pembrizumabf
●RET fusion-positive tumors	●Ipilimumab + Nivolumab
● Selpercatinib	●Consider PARP inhibitors for BRCA-altered LMS9,10-12
●PEComa	Olaparib13
●Albumin-bound Sirolimusd	Rucaparib
	Niraparib
	●PEComa
	●PEComa
	●Sirolimus
	Everolimus
	●CDK4 amplification
	●Palbociclib14,15

表 14
Anti-Estrogen Hormone Therapy for Low-Grade ESS or Adenosarcoma Without SO (ER/PR-Positive Uterine Sarcomas)h
Preferred	Other Recommended
● Aromatase inhibitorsi	● Fulvestant!
Anastrozole	● Megestrol acetate (category 2B)
Letrozole	● Medroxyprogesterone acetate (category 2B)
Exemestane
●Consider gonadotropin-releasing hormone (GnRH) analogs with aromatase inhibitors
in patients who are premenopausal and not suitable for surgery(BSO)

表 15
	T	N	M
Stage I	T1	T1	NO M
Stage IA	T1a	NO	MO
Stage IB	T1b	N0	MO
Stage II	T2	NO	MO
Stage IIIA	T3a	NO	MO
Stage IIIB	T3b	NO	MO
Stage IIIC	T1-3	N1	MO
Stage IVA	T4	Any N	M0
Stage IVB	Any T	Any N	M1
Stage I	T1	NO	MO
Stage IA	T1a	NO	MO
Stage IB	T1b	NO	MO
Stage IC	T1c	NO	MO
Stage II	T2	NO	MO
Stage IIIA	T3a	NO	MO
Stage IIIB	T3b	NO	MO
Stage IIC	T1-3	N1	MO
Stage IVA	T4	Any	N0
Stage IVB	Any T	Any	N1 M1

表 17
99mTc	technetium-99m	ICG	ABBREVIATIONS	OAR	organ at risk
BSO	bilateral salpingo-ophorectomy	IGRT	image-guided radiation therapy	PCR	PCR polymerase chain reaction
		IHC	immunohistochemistry	PEComa	perivascular epithelioid cell
		IMRT	intensity-modulated radiation therapy	PEComa	tumor
CBC	complete blood count		therapy		tumor
		IMT	inflammatory myofibroblastic tumor	pMMR PR	mismatch repair proficient
CLIA	Clinical Laboratory Improvement Amendments	IORT	intraoperative radiation therapy
CTV	clinical target volume	ITD	internal tandem duplication	QA	quality assurance
		ITV	internal target volume
D&C	dilation and curettage	IUD	intrauterine device	RH	radical hysterectomy
dMMR	mismatch repair deficient			RMS	rhabdomyosarcoma
		LDR	low dose rate
EBRT	external beam radiation therapy	LFT	liver function test	SBRT	stereotactic body radiation
EQD2	equivalent dose at 2 Gy	LMS	leiomyosarcoma
ER	estrogen receptor	LND	lymphadenectomy	SCH	supracervical hysterectomy
ESS	endometrial stromal sarcoma	LVSI	lymphovascular space invasion	SDUS	SMARCA4-deficient uterine sarcoma
FDG	fluorodeoxyglucose	MAS	Müllerian adenosarcoma		SLN
FIGO	International Federation of Gynecology and Obstetrics	MI	mitotic index	SMA	smooth muscle actin
FISH	fluorescence in situ hybridization	MIS	minimally invasive surgery	SO	sarcomatous overgrowth
FISH	fluorescence in situ hybridization	MMR	mismatch repair		SRS stereotactic radiosurgery
	GnRH	gonadotropin-releasing hormone GTV gross tumor volume	MSI -H mut/Mb	microsatellite instability-microsatellite instability-high mutations/megabase	TH TMB -H mutations/megabase	total hysterectomy TMB -H tumor mutational burden-high tubercous sclerosis complex
H&E	hematoxylin and eosin		NGS	next-generation sequencing
H&P	history and physical	NSMP	no specific molecular profile	UTROSCT	uterine tumor resembling ovarian sex cord tumor
HDR	high dose rate			UUS	undifferentiated uterine sarcoma
HPF	high-power field			UUS	undifferentiated uterine sarcoma

表 18
NCCN Categories of Evidence and Consensus
Category 1	Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus(≥85% support of the Panel) that the intervention is appropriate.
Category 2A	Based upon lower-level evidence, there is uniform NCCN consensus(≥85% support of the Panel) that the intervention is appropriate.
Category 2B	Based upon lower-level evidence, there is NCCN consensus(≥50%, but <85% support of the Panel) that the intervention is appropriate.
Category 3	Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

表 19
NCCN Categories of Preference
Preferred	Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.
Other recommended	Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.
Useful in certain circumstances	Other interventions that may be used for selected patient populations (defined with recommendation).

图示：### 8 8 9 0 P11 11 19:47 NCCN NCCN Guidelines Version 1.2026 NCCN Guidelines 8 9 10 11 11 10 11 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10 11 10

图示：Suspected or gross cervical involvement Cervical biopsy or pelvis MRI (if not previously done) Negative result result Negative result Suzpected or surgerical for primary vsible MRI (if not previously done) Suitable for primary surgery TH/BSOC and surgical staging® EBRT$^{9}\pm brachytherapy9: TH/BSO^{c} for primary or or surgerstical EBRT^{9}\pm brachytherapy4: Surveillance resection, if rendered operable and definitive RT9 if inoperable Not suitable for primary surgery Systemic therapy (category 2B) Surgical resection if rendered operable or EBRT9 and brachytherapy9 and Surgical Staging(ENDO-C). Surveillance resection, if rendered operable and if inoperable Surveyillance (ENDO-9)

图示：INITIAL CLINICAL (Endometrioid Histology)a ASUS-suspected intrauterine consider CA-125 ADDITIONAL WORKUP No evidence of extrauterine disease ABdominal/ pelvic-confined disease Preoperative systemic therapy ±EDRT9 Systemic therapy ± EBRT9 ± stereotactic body RT (SBRT)^k ± TH/BSOC ± brachytherapyg ± systemic therapyh $\pm$ systemic therapyh $4-12$ weeks post RT or Re-evaluate for surgical resection Surgical therapy Systemic therapyh $\pm$ ERDEPPG → Reserveanetic and/or response response Distant metastases π systematic therapyh $95^{\circ}$ RT (SBRT)^k √ESPERINGE7 Re-evaluate for surgical resection Surgical resection and/or and response response Insiderature 80-155 ADSTant metastases T/BSO^c Re-evaluate for surgical resection ENDO-9) Surveillance (ENDO-9)

图示：NCCN National Comprehensive Cancer Network®

图示：SURVEILLANCE CLINICAL PRESENTATION Therapy for Locoregional Relapse(ENDO-10) •Physical exam (including pelvis) every 3-6 mo for 2-3 y,then every 6-12 mo for up to year 5,then annually ●CA-125 if initially elevated or serous histology ●lmaging as indicated based on symptoms or examination findings suspicious for recurrence ●Clinical evaluation and management of potential long-term and late effects of treatment${}^{t}$ (Also see Principles of Gynecologic Survivorship (UN-B), NCCN Guidelines for Survivorship, and NCCN Guidelines for Smoking) Disseminated metastases Systemic therapy${}^{t}$ ±palliative EBRT${}^{9}$ In isolated Ablative therapy${}^{u}$ Consider resection and/or EBRT/SBRT${}^{9}$ Consider the treatment therapy Not amenable tolocal treatment Further recurrence (See below) Threat as nematically Assiderated and/or EBRT/SBRT${}^{9}$ Oblative therapy ●Consider systemic counseling. ●Consider ablation for 1-5 metastatic lesions if the primary cancer has been controlled. Systemic therapy${}^{t}$ ±palliative EBRT${}^{9}$ If progression, the process and the process and the process and the process and the process and the process and the process and the process and the process and the process and the process and the process and the process and the process and the process and the process and the process and the process and the process and the p

图示：ADDITIONAL WORKUP PRIMARY TREATMENT TREATMENT Noninvasive stage IA No residual uterine disease and negative surgical staging Noninvasive stage IA Observe\6 bb or Noninvasive der stage IA Systemic therapy h % vaginal brachytherapy g or \\ vaginal brachytherapy g or Staging Noninvasive Systemed ondetometrial Carcinoma: Serous Carcinoma ADDITIONAL WORKUP TREATMENT PRIMARY TREATMENT Observe\68aninvasive surging th stage IA Observe\68aninvasive surging th stage IA Systemic therapy h % vaginal brachytherapy g or vaginal brachytherapy g Noninvasive Systemed therapy h % vaginal brachytherapy g (ENDO-9) | gmission of Medical Treatment Biopsy findings: Serous carcinomaaa | Imagingi · Consider carcinoma aa | 4- Bachytherapy^g surging.d e Systematic therapy h % suitable for primary surgery STable program of survival during surgical surgery Not suitable for primary surgery EBRT^9 ± brachytherapy^g Systolic therapy'su6b ARPT9 based on and Surgical Staging (ENDO-C). 9 Principles of Imaging (ENDO-B).h Systemic Therapy for Endometrial Carcinoma (ENDO-D). 16 Principles of Imaging (ENDO-B). aa HER2 testing is recommended for advanced or metastatic disease. See Principles of Molecular Analysis (ENDO-A 2 of 4). Survey difference (ENDO-9) [Normal Study in the end of the end is the following the following 16深圳市 BeRT5 ± vaginal brachytherapy g or vaginal brachytherapy g Systemic therapy^h,aa ± vaginal brachytherapy g or vaginal brachytherapy g Surgical therapy'su6b Re-evaluate for surgerical resection and/or RT9 based on response

图示：# 2.3.4 3.6 3.7 3.8 3.9 3.7 3.8 3.4 3.6 1.2000 1.2006 NCCN General Results Version 1.2026 NCCN Guidelines 1.026.5 3.6 3.4 3.5 3.6 1.2004 ADDITIONAL WORKUP PRIMARY TREATMENT No residual uterine disease and negative surgical staging Noninvasive system stage IA |TH/BSO and surgical stage IA + vaginal brachytherapyg or Not suitable for primary surgery |ST-1 | Systemic therapy h $2.5$\+ vaginal brachytherapyg or ADquinal brachytherapyg |SeBT9 ± BUbrachytherapyg ± brachytherapyg ||PRIVE stage IA |Invasive stage IA ± vaginal brachytherapyg or Systemic therapy h $2.5$\+ vaginal brachytherapyg odged during the subsequent therapy + average transgedy 3.5 2.6.6\+ AU 7.1 3.6.7 1.2004 1.5.6 1.3 Surgery Not suitable for primary surgery |ST-1|Re-evaluate for surgical surgery resection and/or RT9 based on response All staging in guideline is based on 2009 FIGO staging.(ST-1) 8.6.5.6 9.6.6 1.2.4 1.3.5 1.4.6 1.5.6 1.6.7 1.5.6 1.4.6 1.5.5 1.6.8 1.5.6 1.5.7 1.6.9 1.5.6 1.5.5 1.6.9 1.5.6 1.5.7 1.6.8 1.5.5 1.6.9 1.5.6 1.5.5 1.6.9 1.5.7 1.6.8 1.5.5 1.6.9 1.5.5 1.6.9 1.5.7 1.6.8 1.5.5 1.6.9 1.5.5 1.6.9 1.5.5 1.6.8 1.5.4 1.5.6 1.5.7 1.5.6 1.5.5 1.6.9 1.5.5 1.6.8 1.5.4 1.5.6 1.5.7 1.5.6 1.5.5 1.6.9 1.5.5 1.6.9 1.5.5 1.6.9 1.5.4 1.5.6 1.5.5 1.6.9 1.5.5 1.6.9 1.5.4 1.5.6 1.5.5 1.6.8 1.5.4 1.5.6 1.5.7 1.5.6 1.5.5 1.6.9 1.5.5 1.6.9 1.5.4 1.5.6 1.5.5 1.6.9 1.5.4 1.5.5 1.6.9 1.5.4 1.5.6 1.5.5 1.6.9 1.5.4 1.5.6 1.5.4 1.5.5 1.6.9 1.5.5 1.6.9 1.5.4 1.5.6 1.5.4 1.5.5 1.6.9 1.5.5 1.6.9 1.5.4 1.5.6 1.5.4 1.5.5 1.6.9 1.5.4 1.5.6 1.5.4 1.5.5 1.6.9 1.5.4 1.5.6 1.5.4 1.5.6 1.5.4 1.5.6 1.5.4 1.5.6 1.5.4 1.5.6 1.5.4 1.5.6 1.5.4 1.5.6 1.5.4 1.5.6 1.5.4 1.5.6 1.5.4 1.5.6 1.5.4 1.5.6 1.5.4 1.5.6 1.5.4 1.5.6 1.5.4 1.5.6 1.5.4 1.5.6 1.5.4 1.5.6 1.5.4 1.5.6 1.5.4 1.5.6 1.5.4 1.5.6 1.5.4 1.5.6 1.5.4\

图示：# Biopsy findings: Undifferentiated/ dedifferentiated/ cadence CA-125 | Imagingi $\cdot$ Consider primary surgery Not suitable for primary surgery Suitable for Shysteo program ± EBRT9 staging d,e ± EBRT9 ± vaginal brachytherapy9 Re-evaluate for surgical resection and/or RT9 based on response Systemic therapyh $\pm EBRT^{�9}$ $\pm EBRT^{⑨}$ based on response

图示：# 2.3.4 3.6 3.7 3.8 3.9 3.7 3.8 3.4 ADDITIONAL WORKUP Additional WORKUP PRIMARY for primary surgery TH/BSO and surgical staging d,e consider surgical tumor debulking for gross disease Stage I Standarditional TREATMENT Additional Treatment TREATMENT Systemic therapy$h+3$vaginal brachytherapy$g,ee * $\pm$ SBRT$g,ff$\pm$EBRT$g,ff$\pm$Vaginal brachytherapy$g,ee |ENDR99|Re-evaluate for surviable resection of systemic therapy$h+2$-envolutional therapyplastic therapy or #####################(ENDO-9)

图示：No POLE pathogenic mutation POLE sequencing MOLE Normal POLE pathogenic mutation Aberrant dMMR or MSI-H Normal/Wild-type pattern Normal/Wild-type pattern Aberrant/Mutant pattern p53 immunohistochemistry Aberrant/Mutant pattern dMMR or MSI-H NSMP p53 aberrant

图示：原图识别中

图示：Retroperitoneal evaluation Excision of SLN with ultrastaging Any suspicious nodes must be removed regardless of mapping Retroperitoneal evaluation Excision of SLN with ultrastaging If there is no mapping on a hemi-pelvis, a side-specific LND is performed Para-aortic LND-done at attending discretion

图示：NCCN

图示：INITIAL CLINICAL FINDINGS ADDITIONAL EVALUATION * Expert pathologic review and consider molecular testing^{\bullet} +Discrete residual cervix +Imaging^c,d · Tumor initially fragmented.0 Rievol.0 or Residual cervix +Consider re-exploration/resection Consider completion salpingo-ophorectomy in low-grade ESS or adenosarcoma(ER-positive tumor) 30 TH with en bloc resection $\pm BSO^{d,f,g}$ Disease limited to uterus +Additional surgical resection for intraoperative discovery of extrauterine disease is individualized Low-grade ESS or Adenosarcoma ADenosarcoma (UTSARC-2) or High-grade ESS or UUS or LMS or Other sarcomas Resection±BSO+g Surgical resection and resection on:estanding on:estanding to/BSO+g +Resectability No surgical resection resection No surgical resection and/or Palliative EBRT $\pm$ borachytherapy @ High-grade ESS or UUS or LMS or Other sarcomas (EG,PECoina) Toplyfield and/or Palliative EBRT $\pm$ and or Brachytherapy @ High-grade ESS or UUS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or LMS or

图示：PATHOLOGIC FINDINGS/ HISTOLOGIC GRADE J；FOLLOWING TH ± BSO Low-grade ESS or Adenosarcoma without sarcomatous overgrowth (SO) Stage I Stage I BSO (preferred) or Observe, if prior BSO Stage II, III, IVA, IVB BSO or Observe, if prior BSO Stage II, III, IVA, IVB BSO or Observe, if prior BSO Surveillance (UTSARC-4) AdITIONAL THERAPY ADITIONAL THERAPY Stage II, III, IVA, IVB BSO or Observe, if prior BSO Surveillance (UTSARC-4)

图示：●High-grade ESS HISTOLOGIC GRADEJ FOLLOWING TH ±BSO Stage I Stage III Observe Consider observation if completely resected with negative margins or Consider systemic therapy and/or Consider EBRT (UTSARC-4) Stage IVD Stage IVA Systemic therapy and/or EBRT Stage IVB Systemic therapy h ±palliative EBRT'

图示：NCCN National Comprehensive Cancer Network®

图示：NCCN National Experiments 9449 Piral therapy 87491 For residual disease:\+resection ±IORT Consider preoperative EBRT,Io ±systemic therapy ±systemic therapy Radiologically isolated vaginal/pelvicrecune No prior RT Prior RT Surgical exploration + resection $\pm IORT\pm$ systemic therapy or Selected reirradiation with EBRT' and/or brachytherapy'

图示：NCCN

引用 / 出处

（2026.V1）NCCN临床实践指南：子宫肿瘤. 2026.