NCCN临床实践指南：子宫肿瘤（2025.V2）

指南妇产科· 妇科疾病 · 2025

Authors

NCCN Guidelines Version 2.2025 Endometrial Carcinoma

# NCCN Guidelines Index Table of Contents Discussion

NCCN Guidelines Index Table of Contents Discussion

# PRINCIPLES OF MOLECULAR ANALYSIS

PRINCIPLES OF MOLECULAR ANALYSIS

Abstract

Version 2.2025, 01/31/25 © 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.

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

POLE sequencing No POLE pathogenic mutation POLE pathogenic mutation MMR IHC or MSI testing Aberrant dMMR or MSI-H NSMP p53 aberrant POLE Normal p53 immunohistochemistry Normal/Wild-type pattern Aberrant/Mutant pattern 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. g Diagnostic algorithm for integrated genomic-pathologic classification of endometrial carcinomas. 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 imaging (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.

Note

ENDO-7A

a (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). t Consider omitting imaging for stage IA, grade 1-2 endometrium-limited carcinoma.

FOOTNOTES FOR ENDO-7

ENDO-8

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). i Principles of Imaging (ENDO-B). u See Healthy Lifestyles (HL-1) and Nutrition and Weight Management (SNWM-1) in the NCCN Guidelines for Survivorship.

CRITERIA FOR CONSIDERING FERTILITY-SPARING OPTIONS

ENDO-9

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

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

i Principles of Imaging (ENDO-B).

v 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. w Consider ablative RT for 1-5 metastatic lesions if the primary cancer has been controlled (category 2B) (

ENDO-10

x May include patients with isolated common iliac or para-aortic lymph node recurrence. y Consider preoperative EBRT in select patients. z Recommended for small-volume vaginal and/or paravaginal disease. aa Consider brachytherapy for locoregional disease with a vaginal component. bb Post-resection consolidation EBRT can be considered in patients who were not previously irradiated or who are deemed to have additional tolerance for radiation. 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).

CLINICAL PRESENTATION THERAPY FOR RELAPSE ADDITIONAL THERAPY

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). cc HER2 testing is recommended for advanced or metastatic disease. -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). cc HER2 testing is recommended for advanced or metastatic disease. 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) (

ADDITIONAL

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 thologic 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 ≥4 (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). 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. • Molecular analysis of endometrial carcinoma has identified four clinically significant molecular subgroups associated with differing clinical prognoses: POLE mutations, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), no specific molecular profile (NSMP), and p53 aberrant.

PRINCIPLES OF PATHOLOGY

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

NCCN Guidelines Index

Peritoneal & serosal evaluation & washings

Retroperitoneal evaluation

If there is no mapping on a hemi-pelvis, a side-specific LND is performed Para-aortic LNDdone at attending discretion

ENDO-C

5 OF 6

PRINCIPLES OF EVALUATION AND SURGICAL STAGING WHEN SLN MAPPING IS USED

Any suspicious nodes must be removed regardless of mapping d Checkpoint inhibitors and/or monoclonal antibodies included in this regimen may be continued as maintenance therapy. Refer to the original study protocol for maintenance therapy dosing schedules. e 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. f For stage III with measurable disease post surgery and stage IV with or without measurable disease. g For patients who have not received prior trastuzumab therapy.

Excision of SLN with ultrastaging

Primary or Adjuvant Therapy (Stage I-IV) Chemoradiation Therapy

Systemic Therapy Preferred Regimen • Cisplatin plus RT followed by carboplatin/paclitaxel p The cisplatin/doxorubicin/paclitaxel regimen is not widely used because of concerns about toxicity. q 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. r Bevacizumab may be considered for use in patients whose disease has progressed on prior cytotoxic chemotherapy. s 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.

Note: All recommendations are category 2A unless otherwise indicated. 20 Homesley HD, Filiaci V, Gibbons SK, et al. A randomized phase III trial in advanced endometrial carcinoma of surgery and volume directed radiation followed by cisplatin and doxorubicin with or without paclitaxel: A Gynecologic Oncology Group study. Gynecol Oncol 2009;112:543-552. 21

PRINCIPLES OF PATHOLOGY AND MOLECULAR ANALYSIS

Undifferentiated

Uterine Sarcoma (UUS) [13] [14] [15] [16] Infiltrative sheets of pleomorphic epithelioid and/or spindle cells.

NCCN Guidelines Version 2.2025 Uterine Sarcoma

UTSARC-A 5 OF 8

Continued

References

PRINCIPLES OF PATHOLOGY AND MOLECULAR ANALYSIS NCCN Guidelines Version 2.2025 Uterine Sarcoma

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

PRINCIPLES OF IMAGING

UTSARC-B 1 OF 2

PRINCIPLES OF IMAGING REFERENCES

UTSARC-B 2 OF 2 f These hormonal therapies may be considered for patients with uterine sarcomas that are ER/PR-positive, preferably with small tumor volume or an indolent growth pace. g Ovarian 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.

Anti-Estrogen Hormone

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

NCCN Guidelines Index

ST-2

CAT-1

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 intervention

Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.

Other recommended intervention

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. 5] [6] [7] 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 algorithms, which have been incorporated into this revised Discussion text (see the NCCN Guidelines for Uterine Neoplasms). The NCCN Clinical Practice Guidelines in Oncology (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 members of the panel during the process of developing 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 data from key PubMed articles as well as articles from additional sources deemed as 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, antimisogynist, anti-ageist, anti-ableist, and anti-fat-biased; and inclusive 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

NCCN Guidelines Version 2.2025 Uterine Neoplasms

MS-3

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

(

Endometrial Cancer

Data show that almost 67% of patients with adenocarcinoma of the endometrium are diagnosed with disease confined to the uterus at diagnosis. 9 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 metrorrhagia 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. 10 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 an age ≥ 65 years. Analysis of SEER data suggests that survival is increased in patients who are younger, have early-stage disease, and have lower-grade disease. 11 In addition to grade and depth of myometrial invasion, other risk factors associated with poor prognosis include age, lymph node involvement, tumor size, lymphovascular space invasion (LVSI), and lower uterine segment invasion. 12, 13 Depth of myometrial invasion is considered one of the critical criteria for evaluation of surgical-pathologic staging. 14, 15 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 gynecologic oncologists be involved in the primary management of all patients with endometrial cancer.

MS-4 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. 16 ince 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, highgrade 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. 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. 17, 18 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 predisposition, 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. 19 e 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 genomic 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. 8] [29] [30] 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. 20, 31, 32, 5, 27, 33 n 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. 29, 34 This strategy also enables select patients to defer surgery (and surgical menopause) and to preserve fertility. Prophylactic hysterectomy/bilateral salpingo-oophorectomy (BSO) is recommended after childbearing is complete. 35, 36 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. 37, 38 About 90% of patients with endometrial carcinoma have metrorrhagia, 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%. 39, 40 Thus, a negative endometrial biopsy in a symptomatic patient must be followed by a fractional D & C under anesthesia. 39, 41 ysteroscopy may be helpful in evaluating the endometrium for lesions, such as a polyp, if the patient has persistent or recurrent bleeding. 42 ndometrial 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. 4] [45] [46] [47] [48] [49] In patients with extrauterine disease, a serum CA-125 assay may be helpful in monitoring clinical response. 50, 51 [54]

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).

6] [57] This reported understaging 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. 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). 58 0] [61] [62] Separate staging systems for malignant epithelial tumors and uterine sarcomas are now available (see Staging section of the algorithm).

MS-6

In 2017, the AJCC Cancer Staging Manual was further updated (which took effect in January 2018). 63 e 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. 61 Currently stage IA describes tumors with less than 50% myometrial invasion, and stage IB describes those with 50% or more myometrial invasion. Stage II describes patients with tumors that invade the cervical stroma. Patients with uterineconfined disease and endocervical glandular involvement (mucosal involvement) without cervical stromal invasion are no longer considered stage II. 61 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. 61 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. 62 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). 64

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 or more LVSI-involved vessels in at least one hematoxylin and eosin (H & E) slide (for clinically relevant LVSI in endometrial cancer). 65 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. (https://cap.objects.frb.io/protocols/cp-femalereproductive-endometrium-18protocol-4100.pdf). This CAP protocol was revised to reflect the updated pTNM requirements from the AJCC Cancer Staging Manual (8 th edition) and 2015 FIGO Cancer Report. 63, 66 trogen receptor (ER) testing is recommended in the setting of stage III, IV, or recurrent endometrioid carcinoma. Evaluation of human epidermal growth factor receptor 2 (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. 67 9] [70] [71] [72] The panel recommends HER2 IHC testing (with reflex to HER2 fluorescence in situ hybridization [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 TP53aberrant 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). 73 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. 74 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. 75

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. 76 9] [80] 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. 81, 82 4] [85] 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. 86 One of the trials did not standardize adjuvant treatment after staging surgery with lymphadenectomy and 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. 80 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) less than 50% myometrial invasion; 2) tumor less than 2 cm; and 3) well or moderately differentiated histology. 87, 88 However, this may be difficult to accurately determine before final pathology results are available. If 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. 89 dal 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

MS-8

information regarding the risk of para-aortic nodal metastases in patients without disease in the pelvic nodes. 57, 87, 90, 91 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. 76 summary, lymph node dissection identifies patients requiring adjuvant treatment with radiation therapy (RT) and/or systemic therapy. 92 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 Endometrial Carcinoma). 6 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 Endometrial Carcinoma) includes recommendations about SLN mapping. 4] [95] [96] [97] 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). 98 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. 99 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. 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 2 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 ( 99m Tc); colored dyes are available in a variety of forms (Isosulfan Blue 1%, Methylene Blue 1%, and Patent Blue 2.5% sodium). Indocyanine green (ICG) recently emerged as a useful imaging dye that requires a near-infrared camera for localization, provides a very high SLN detection rate, and is commonly used in many practices at the present time. 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). 93, 106 8] [109] [110] [111] [112] 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 LNs. 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

MS-9

to avoid the morbidity of a standard lymphadenectomy with SLN mapping. 111, 113 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. 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. 93, 112 literature review and consensus recommendations for SLN mapping in endometrial cancer were released by the Society of Gynecologic Oncology (SGO). 97 Close adherence to the NCCN SLN surgical algorithm was found to result in accurate prediction of pelvic lymph node metastasis with a less than 5% false-negative rate. 93 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). 99 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. 114 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% paraaortic detection rate. 89 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. 115 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, recurrence-free survival (RFS) at 50 months was 84.7%, and no difference was detected between patients with and without a positive SLN (P = .5). 5). 116 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. 43, 49 storically, SLN mapping was controversial in patients with high-risk histology (eg, serous carcinoma, clear cell carcinoma, carcinosarcoma). 76, 117 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. 112, 118, 119 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. 120 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. 121 ore studies have suggested the value of using SLN mapping for surgical staging in high-grade endometrial cancer. 122

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

MS-10 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. 96, 108, 110, 113, 114 trastaging typically includes two components: serial sectioning with review of multiple H & E-stained slides with or without cytokeratin IHC staining. 123 Recent data highlight the potential significance and impact of SLN ultrastaging to improve the accuracy of detecting micrometastases. 124 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. 125 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. 126 8] [129] [130] [131] Studies have recently begun to investigate the significance of ITCs discovered during SLN mapping in early-stage endometrial cancer. The AJCC 8 th edition cancer staging manual indicates that the lymph nodes with ITCs should be clearly reported even though they do not affect the overall staging. 132 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. 133 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. 134 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. 135 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 (TH)/BSO and lymph node assessment in patients with early-stage endometrial cancer. 136 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. 7] [138] [139] [140] [141] [142] 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. 138, 142 CCN Guidelines Version 2.2025 Uterine Neoplasms

MS-11

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. 141, 143 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. 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). 144, 145 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. 143 Laparoscopic staging was associated with improved postoperative quality of life across several parameters. 140 e LACE trial compared outcomes of patients with stage I endometrial carcinoma (n = 760) who were randomized to undergo TH or total laparoscopic hysterectomy (TLH), where half of the patients received concomitant lymphadenectomy. 137 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. 146 A recent follow-up study of a multicenter randomized trial evaluated outcomes for TLH versus TH 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. 147 Laparotomy may still be required for certain clinical situations (eg, patients who are older, those with a very large uterus) or certain metastatic presentations. 141, 148, 149 1] [162] 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. 154, 155, 163 sts for robotic equipment and maintenance remain high. 164 150,151,160- 162,165 7] [168] For reviews on the robotic-assisted surgery for gynecologic malignancies and associated cost issues, see Sinno and Fader and Gala et al. 169, 170 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. ] [173] [174] NCCN Guidelines Version 2.2025 Uterine Neoplasms

MS-12

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 Endometrial Carcinoma and in this Discussion and Lymphadenectomy and Sentinel Lymph Node Mapping in this Discussion). 83 6] [177] 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-cancerdatabase/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. 178, 179 Surgical restaging, including lymph node dissection, can also be done. 87 Based on the imaging and/or surgical restaging results, recommended adjuvant treatment options are provided in the algorithm (see Adjuvant Treatment for Incompletely Surgically Staged in the NCCN Guidelines for Endometrial Carcinoma).

Fertility-Sparing Therapy

1] [182] [183] [184] Likewise, it may also be selectively used for 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 high-risk patients (eg, those with high-grade endometrioid

MS-13

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. 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. 184, 186 8] [189] In patients with persistent endometrial carcinoma after 6 months of failed hormonal therapy, the panel recommends pelvic MRI to exclude myoinvasion and nodal/ovarian metastasis before continuing fertility-sparing therapy.

In a study of patients who are premenopausal and have 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. 175 Other studies also suggest that ovarian preservation may be safe in select patients. 176, 177

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). 178, 179, 190, 191 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 II endometrial carcinoma. Thus, for patients suitable for primary surgery, TH or radical hysterectomy is recommended along with BSO, cytology (peritoneal lavage), and evaluation of lymph nodes if indicated (see Principles of Evaluation and Surgical Staging in the NCCN Guidelines for Endometrial Carcinoma). 83 n these patients, radical or modified radical hysterectomy may improve local control and survival when compared with TH. 192, 193 Alternatively, the patient may undergo EBRT and brachytherapy (category 2B) followed by TH/BSO and surgical staging.

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 the guidelines for disease limited to the uterus. ] [196] Consider preoperative chemotherapy. 197 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)

MS-14 stereotactic body RT (SBRT). Ablative radiation can be considered for 1 to 5 metastatic lesions if disease is otherwise controlled (category 2B). 198 tients Not Suited for Primary Surgery For uterine-confined disease 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 IUD can also be considered for select patients (eg, estrogen and progesterone receptor-positive [ER/PRpositive]). Patients receiving hormonal therapy alone should be closely monitored by endometrial biopsy (eg, consider endometrial biopsies every 3-6 months). 37, 199 1] [202] [203] EBRT and brachytherapy may be administered with or without platinum-based chemosensitization, depending on the clinical situation and medical fitness of the patient. If rendered operable, local treatment consisting of surgery should follow. Systemic therapy alone is also a primary treatment option (category 2B), but should be followed by EBRT + brachytherapy if the patient remains inoperable.

] [206] [207] 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 (ie, age, positive LVSI, tumor size, and lower uterine segment or surface glandular involvement). 208, 209 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. 61 However, by necessity, much of the discussion in this manuscript has been based on data from patients staged using the older FIGO/AJCC staging system. The implications of stage migration should be considered when evaluating historical data.

1] [212] 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.

Significant 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

MS-15

4] [215] The NCCN Panel prefers 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 brachytherapy alone. 216 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 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. 217 juvant 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.

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). 218, 219 In the third trial (ASTEC/EN.5), only 50% of the patients were thoroughly staged as part of a companion surgical protocol. 81, 220 However, formal surgical staging was mandated for all patients in the GOG 99 trial. 221 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. 218, 222 Radiation was not shown to increase OS. 223 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. 219 pooled randomized trial (ASTEC/EN.5) suggested that adjuvant pelvic RT alone did not improve either relapse-free survival (ie, PFS) or OS in patients with intermediate-risk or high-risk early-stage endometrial cancer,

MS-16

but there was an improvement in pelvic control. 220 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 low-risk patients. 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. 85, 224 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. 221, 225, 226 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. 218, 221 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 greater than 50%, and LVSI. 221 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). 218, 225 VSI 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. 6] [227] [228] [229] [230] [231] [232] [233] The use of vaginal brachytherapy and/or whole pelvic RT should be carefully tailored to a patient's pathologic findings.

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); 61 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. 234 e GOG 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

MS-17

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 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. 235 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 locoregional relapse (LRR), distant relapse (DR), OS, and DFS, and treatment given (EBRT vs. vaginal brachytherapy) was predictive for LRR and DFS. 208 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. 236, 237 [240] [241] [242] 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. 228 Evaluation of secondary malignancies in the context of increased genetic susceptibility (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. 221, 222 herefore, some clinicians suggested that adding systemic therapy to adjuvant RT may provide added therapeutic benefit (ie, decrease in distant metastases). 210, 243 Studies have evaluated the role of systemic therapy in highest risk uterine-confined disease. 243, 244 PFS is improved with adjuvant sequential chemotherapy. 243 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. 243 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 superiority of any of these treatments were not demonstrated. Acute toxicity was greater in the combination therapy. 245

Advanced Stage/Extrauterine Disease

] [248] 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). 249 However,

MS-18

systemic therapy is regarded as the foundation of adjuvant therapy for patients with extrauterine disease. 1] [252] 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. 253, 254 The pembrolizumab/carboplatin/paclitaxel regimen is recommended for stage III or IVA with measurable disease or for stage IVB with or without measurable disease. Since the NRG-GY018 trial did not include patients with carcinosarcoma histology, the NCCN Panel do not recommend the pembrolizumab/carboplatin/paclitaxel treatment option for patients with carcinosarcoma disease. The dostarlimab carboplatin/paclitaxel option is recommended for patients with stage IIIA, IIIB, or IIIC1 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.

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. 255,256 A randomized phase III GOG (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 abdominopelvic RT versus 7 cycles of combined doxorubicin (60 mg/m 2 ) and cisplatin (50 mg/m 2 ) 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. 205 e GOG 122 study established the role of adjuvant multiagent systemic chemotherapy for curative intent in patients with extrauterine disease. Thus, in the NCCN Guidelines, systemic therapy forms the established framework of adjuvant therapy for patients with stage III or IV disease. 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. 205 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. 207, 257, 258 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 tumordirected radiation (involved-field radiation either to the pelvis or to the pelvis plus para-aortic nodes). Results indicate that the 3-drug regimen did not improve survival when compared with the 2-drug regimen after 3 years

MS-19

of follow-up and that the more intensive chemotherapy resulted in greater toxicity (eg, hematologic toxicity, sensory neuropathy, myalgia). 206 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. 259 In a multicenter retrospective review of 73 patients with stage IIIA endometrial carcinoma, surgery followed by both chemotherapy and RT provided the highest 5-year OS. 260 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%. 261 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. 248 ltimodality 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. 262 e 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; 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 radiotherapy 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). 263, 264 Patients with serous cancers and with 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. 265 e 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. 266 This trial supported the benefit of using chemotherapy alone by concluding that the combined therapy was not associated with longer relapse-free survival 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, MMR-deficient (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 that were p53 abnormal. 267 Results are awaited for an ongoing PORTEC-4a trial investigating molecular profile-based directed adjuvant treatment in high-risk endometrial cancer. 268

MS-20

High-Risk Endometrial Carcinoma Histologies

Overview

0] [271] [272] [273] [274] [275] [276] Carcinosarcomas are aggressive tumors that are staged as high-grade endometrial cancer. 277, 278 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. 273, 276, 279, 280 ven 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. 63 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/abdominal/pelvic CT may be useful before surgery to assess if extrauterine disease is present; PET may also be useful. 269 Patterns of failure often mimic those of ovarian cancer.

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 Principles of Evaluation and Surgical Staging in the NCCN Guidelines for Endometrial Carcinoma). 281 8] [289] [290] [291] [292] [293] [294] For patients with clear cell or serous carcinomas with no residual disease 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. 295, 296 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) vaginal 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 brachytherapy is recommended. 271, 288, 292, 297 r 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). 298 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. 205,297,299 288 Multimodality therapy including systemic therapy, EBRT, and vaginal brachytherapy appears to be more effective.

MS-21

1] [302] [303] [304] 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 distance 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, the panel recommends EBRT with (or without) brachytherapy and systemic therapy, or surgery with (or without) intraoperative RT (IORT) and systemic therapy. For patients previously treated with brachytherapy only at the recurrence site, surgery with (or without) IORT is recommended (category 3 for IORT).

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. Reirradiation is used only in the context of limited disease for palliation and lack of other options. 0] [311] Prognosis is worse if there is extravaginal extension or pelvic lymph node involvement. 310 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 or common iliac lymph node invasion, and upper abdominal or peritoneal 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

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. 3] [314] [315] [316] [317] 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.

9] [320] [321] Tamoxifen has a 20% response rate in disease that does not respond to standard progesterone therapy. 322, 323 Tamoxifen has also been combined with progestational agents; however, a few patients had grade 4 thromboembolic events with this combination regimen. 314, 315, 324 In some patients, aromatase inhibitors (eg, anastrozole, letrozole) may be substituted for progestational agents or tamoxifen. 320, 321, 325, 326 erolimus combined with letrozole is recommended for recurrent disease of endometrioid histology. In the phase 2 trial, in patients with progressive 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. 327 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 responded to the everolimus/letrozole therapy, while 25% showed a response with the medroxyprogesterone acetate/tamoxifen regimen. 328 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. 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. 254 The patients who had received adjuvant therapy at least 12 months before were included. The patients were stratified based on the dMMR or MMRproficient (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 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. 253 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 patient 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.

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 as Category 1, preferred, first-line therapy options for recurrent endometrial carcinoma.

Chemotherapy for endometrial cancer has been extensively studied. 330, 331 ther multiagent regimens such as carboplatin/paclitaxel, carboplatin/docetaxel, and carboplatin/paclitaxel/bevacizumab are included as first-line therapy options for the recurrent disease setting.

3] [334] [335] A phase III trial (GOG 209) compared carboplatin and paclitaxel versus cisplatin, doxorubicin, paclitaxel, and filgrastim (granulocyte colony-stimulating factor). 332 Trial data show that oncologic outcomes are similar, but the toxicity and tolerability profile favor carboplatin/paclitaxel. 336 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. 337, 338 phase II trial initially examined the addition of bevacizumab to carboplatin and paclitaxel among 15 patients with advanced or recurrent endometrial carcinoma. 339 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. 340 ollective 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. 340 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. 341 Another metaanalysis of three studies also concluded similar results where the triplet combination increased the OS and PFS at > 12 months with an ORR of 76%. 342

Other combination therapies such as cisplatin/doxorubicin, cisplatin/doxorubicin/paclitaxel, ifosfamide/paclitaxel (for carcinosarcoma),

MS-24

and cisplatin/ifosfamide (for carcinosarcoma) are added as subsequenttherapy 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) 4] [345] 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 have ranged from 31% to 81%, but with relatively short durations. The median survival for patients in such trials remains approximately 1 year. 330, 331 multiagent chemotherapy regimens are contraindicated, then single-agent therapy options for recurrent disease include cisplatin, carboplatin, doxorubicin, liposomal doxorubicin, paclitaxel, albumin-bound paclitaxel, topotecan, temsirolimus, cabozantinib, and docetaxel (category 2B for docetaxel). 320, 349 When singl agents are used as second-line treatment, responses range from 4% to 27%; paclitaxel is the most active in this setting. 349 Some oncologists have used liposomal doxorubicin, because it is less toxic than doxorubicin; the response rate of liposomal doxorubicin is 9.5%. 350 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. 351, 352 Bevacizumab was shown to have a 13.5% response rate and OS rate of 10.5 months in a phase II trial for persistent or recurrent endometrial cancer. 353 [355] [356] Useful in Certain Circumstances, Biomarker-Directed Therapies In the advanced endometrial cancer cohort (n = 24) of the phase Ib KEYNOTE-028 trial, durable antitumor responses were noted in a small subset of patients with programmed death ligand 1 (PD-L1)-positive tumors (3 partial response, 3 stable disease). 357 9] [360] 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 complete response, 5 partial response, and 3 stable disease). 358 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. 361 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. 362 rther 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. 357, 363, 364 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. 365 The Keynote-775 phase 3 trial randomly assigned NCCN Guidelines Version 2.2025 Uterine Neoplasms

MS-25

827 patients with pMMR (MSI-stable), previously treated advanced endometrial cancer to receive pembrolizumab/lenvatinib combination or chemotherapy (doxorubicin or paclitaxel). 366 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). 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.

Other anti-PD-1 inhibitors, such as dostarlimab and nivolumab, have also shown antitumor activity against MSI-H tumors. Dostarlimab is being evaluated in the ongoing GARNET phase 1 trial for patients with advanced endometrial cancer with dMMR/MSI-H disease. The ORR after 16.3 months was 43.5% with a manageable safety profile. 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. 367 The PD-L1 inhibitor, avelumab, has shown an ORR of 26.7% in advanced endometrial cancer with dMMR tumor as monotherapy. Nivolumab and avelumab 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 2B subsequent therapy option.

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 a 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. 368 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. 369 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. The NCCN Panel has designated the regimen a category 2B option for HER2-positive carcinosarcoma in both disease settings. 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 carcinosarcoma treatment only. For treating carcinosarcoma, ifosfamide was historically considered the most active single agent. 370-372 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/ifosfamide regimen. 370,373 OS was 13.5 months with ifosfamide/paclitaxel versus 8.4 months with ifosfamide alone. 299, 370 CCN Guidelines Version 2.2025 Uterine Neoplasms

MS-26 Radiotherapy Principles

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. 211 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 definitely; 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. 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, 374 studies have focused on subtle effects on quality of life (eg, diarrhea, bowel symptoms) that deserve further investigation. 229, 231, 375 In the PORTEC-2 trial, vaginal brachytherapy was associated with better quality of life when compared with EBRT without a significant detriment to outcome.

Post-Treatment Surveillance

The recommended post-treatment surveillance protocol for endometrial cancer is shown in the algorithm (see Surveillance in the NCCN Guidelines for Endometrial Carcinoma). 43, 49 These recommendations recognize that the value of intensive surveillance has not been demonstrated in this disease; therefore, ancillary testing is not recommended. 376, 377 tients with clinical stage I and stage II endometrial cancer have a recurrence rate of approximately 15%; [377] [378] [379] [380] 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. 377 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.

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 abdomen/pelvis MRI can be considered in select patients as clinically indicated.

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 (available at https://www.nccn.org/professionals/physician_gls/pdf/survivorship.pdf), the NCCN Guidelines for Smoking Cessation (available at https://www.nccn.org/professionals/physician_gls/pdf/smoking.pdf), and http://www.cancer.org/treatment/survivorshipduringandaftertreatment/inde 2] [383] 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. 376, 377, 380, 384 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. 376, 385 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%). 386

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. 387, 388 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. 0] [391] In females with stage I to II 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. 392 owever, estrogen trials in postmenopausal females without a history of malignancy have demonstrated a significantly increased risk for breast cancer. 393 itially, 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. 394 owever, 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. 395

MS-28

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. 396, 397 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. 398, 399 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). 400, 401 erine 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). 402 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. 403 Even rarer subtypes of malignant mesenchymal tumors that can occur in the uterus include adenosarcoma, rhabdomyosarcoma (RMS), and PEComa. 404 Carcinosarcomas were previously categorized and included in the sarcoma treatment algorithms until the mid-2000s, but are now considered and treated as high-grade epithelial tumors (carcinomas). 273 Screening for Lynch syndrome is not usually done for patients with malignant mesenchymal tumors.

Pathology and Molecular Analysis

Expert gynecologic pathology review is recommended for the assessment and histologic differentiation of uterine sarcomas including uLMS, UUS, ESS, and adenosarcoma. 83 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 (fallopian 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.

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 FDAapproved assay is informative for predicting rare pan-tumor-targeted therapy opportunities. The panel recommends testing of at least NTRK, MSI, and TMB proteins. Since the molecular profiling is informative in many mesenchymal malignancies for accurate classification, 405 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 becomes 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. 404, 406 LGESSs 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.

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 fail to 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 example, high-grade ESS is often misdiagnosed as UUS due to a shared lack of smooth muscle differentiation. 416 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, phyllodiform 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. 417 The panel 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. 419, 420 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). 421 Therefore, the panel notes that diffuse expression of myogenic 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. FOXO1 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. 422 The panel notes that extensive sampling should be performed to exclude epithelial components and diagnoses of carcinosarcoma 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.

MS-31

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. 423 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. 63, 424 nfirmation 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, myomectomy, 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). 425 e panel recommends ER/PR testing for LMS, ESS, and adenosarcoma to guide decisions regarding management of the 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. 426 A systemic review 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. 427 In another multicenter retrospective study, the PFS for patients who underwent BSO versus ovarian preservation as 38 versus 11 months (P = .071). 428 erine sarcoma should be removed en bloc to optimize outcomes; intraperitoneal morcellation is contraindicated. 171, 174 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. 429 Additional surgical resection should be individualized based on clinical scenarios and intraoperative findings. 0] [431] [432] 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) antiestrogen 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. 404, 433, 434 nti-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). 435 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 sarcomatous overgrowth (SO) in advanced stages, the panel recommends BSO with a consideration of systemic therapy and EBRT. EBRT is palliative for stage IVB disease.

MS-32

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. 436 Adjuvant radiotherapy in ESS has been demonstrated to reduce local recurrence rates but again with limited effect on survival. 437, 438 ecause 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. 439 though 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 inhibitors 440 (preferred for low-grade ESS or adenosarcoma without SO), fulvestrant, 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 are also included as a category 2B option. 404, 429, 435 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.

High-Grade Endometrial Stromal 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. 441 3] [444] [445] 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. 441 Therefore, routine postoperative RT is not recommended for stage I patients with uLMS and UUS. 433 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. 446 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). 447 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.

The recurrence rate is high in uLMS (50%-70%). 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. 448 stemic therapy with (or without) palliative EBRT or best supportive care is recommended for metastatic disease. 449 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. 450 Pre-or postoperative 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. 2] [453] [454] For recurrent lowgrade 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, [455] [456] [457] [458] [459] [460] doxorubicin/ifosfamide, and doxorubicin/dacarbazine (see Systemic Therapy in the NCCN Guidelines for Uterine Sarcoma). 404, 406, 449 Doxorubicin is an active single agent for uLMS and is less toxic than combination regimens. 404, 449 e 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.

For second-line or subsequent therapy, trabectedin is included as a preferred option for unresectable or metastatic uLMS that has been treated with a prior anthracycline-containing regimen. 2] [463] [464] The phase III data revealed a 2.7-month PFS benefit versus dacarbazine in metastatic liposarcoma or leiomyosarcoma that progressed after anthracycline-based therapy. 465 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-

MS-34 0.81; P = .0012). 466 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). [469] [470] [471] [472] [473] [474] [475] [476] [477] [478] [479] [480] [481] [482] [483] 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. 484 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.

] [487] [488] The panel also recommends larotrectinib or entrectinib for NTRK gene fusion-positive tumors. For PEComa, albumin-bound sirolimus is recommended as a first-line therapy option and sirolimus, everolimus, temsirolimus 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, rucaparib, and niraparib are included as second-line/subsequent therapy options for BRCA2-altered uLMS. 489

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 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 http://www.cancer.org/treatment/survivorshipduringandaftertreatment/inde 2] [383] 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. 490 In gynecologic oncology treatment, drugs that more commonly cause adverse reactions include carboplatin, cisplatin, docetaxel, liposomal doxorubicin, and paclitaxel.

MS-35

2] [493] In addition, patients can have mild allergic reactions or severe infusion reactions. Infusion reactions are more common with paclitaxel. 494 Allergic reactions (ie, true drug allergies) are more common with platinum agents (ie, carboplatin, cisplatin). 494, 495 nagement of drug reactions is discussed in the NCCN Guidelines for Ovarian Cancer. 494 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. 7] [498] Patients must be desensitized with each infusion if they previously had a reaction. Almost all patients can be desensitized (about 90%). 490 To maximize safety, it is prudent to desensitize patients in the intensive care unit. 490

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. Longterm 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 NCCN Guidelines Version 2.2025 Uterine Neoplasms

MS-36

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.

ts received, possible side effects, and recommended follow-up.

|• Well-differentiated (grade 1) endometrioid adenocarcinoma on dilation and curettage (D & C)|counseling u lifestyle modification • Weight management/ + levonorgestrel IUD] medroxyprogesterone) [(megestrol or progestin therapy • Consider dual-preservation) (preferred for fertility Levonorgestrel IUD Medroxyprogesterone Megestrol • Continuous progestin-based therapy:|Encourage conception (with continued surveillance/ endometrial sampling every 6-12 mo and consider maintenance progestin-based therapy if patient is not actively trying to conceive)|TH/BSO with staging d,e after childbearing complete or progression of disease on endometrial sampling (ENDO-1) considered in select patients who are premenopausal TH/BSO with staging d,e (preferred by 12 months) (ENDO-1) select patients considered in may be preservation • Ovarian may be preservation • Ovarian| |---|---|---|---|

|NCCN Guidelines Version 2.2025 Endometrial Carcinoma|NCCN Guidelines Index Table of Contents Discussion| |---|---|

|• Consultation with a fertility expert prior to therapy • Recommend molecular evaluation of tumor and evaluation for inherited cancer risk (UN-1) pregnancy test • Ensure negative|Endometrial evaluation every 3-6 mo (either D & C or endometrial biopsy)|

||NCCN Guidelines Version 2.2025 Endometrial Carcinoma|NCCN Guidelines Index Table of Contents Discussion|

|SURVEILLANCE|CLINICAL PRESENTATION|THERAPY FOR RELAPSE|

|• 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-care Palliative Care) Guidelines for (NCCN • Consider resection and/or EBRT g or Ablative therapy w • Consider systemic therapy h (category 2B) Not amenable to local treatment or Further recurrence|• 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-care Palliative Care) Guidelines for (NCCN • Consider resection and/or EBRT g or Ablative therapy w • Consider systemic therapy h (category 2B) Not amenable to local treatment or Further recurrence||

||NCCN Guidelines Version 2.2025 Endometrial Carcinoma|NCCN Guidelines Version 2.2025 Endometrial Carcinoma|NCCN Guidelines Version 2.2025 Endometrial Carcinoma|NCCN Guidelines Version 2.2025 Endometrial Carcinoma|NCCN Guidelines Version 2.2025 Endometrial Carcinoma| |---|---|---|---|---|---|

||WORKUP ADDITIONAL WORKUP||PRIMARY TREATMENT PRIMARY TREATMENT|No residual uterine disease and negative staging surgical|ADDITIONAL TREATMENT ADDITIONAL TREATMENT Observe|

|Biopsy findings: Serous carcinoma cc Biopsy findings: Clear cell carcinoma|• Consider CA-125 • Imaging i|Suitable for primary surgery|Noninvasive stage IA Invasive stage IA Stage IB, II ± vaginal • TH/BSO and Systemic therapy h ± EBRT g ± vaginal brachytherapy g or EBRT surgical staging d,e • Consider maximal tumor debulking for gross disease Noninvasive stage IA • TH/BSO and surgical staging d,e • Consider maximal tumor debulking for gross disease Invasive stage IA Stage IB, II Systemic therapy h ± EBRT g ± vaginal brachytherapy g or EBRT ± vaginal brachytherapy g Stage III, IV Systemic therapy h ± EBRT g ±|||

||:Clear Cell Carcinoma| |---|---|

||If Negative Washings Vaginal brachytherapy g ± systemic therapy h (category 2B for systemic therapy) or Observe If Positive Washings Systemic therapy h and vaginal brachytherapy g|

|All|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).|

|NCCN Guidelines Version 2.2025 Endometrial Carcinoma|NCCN Guidelines Index Table of Contents Discussion|

|No residual uterine disease and negative surgical staging||

||: Undifferentiated/Dedifferentiated Carcinoma NCCN Guidelines Version 2.2025 Endometrial Carcinoma|NCCN Guidelines Index Table of Contents Discussion||| |---|---|---|---|---|

||ADDITIONAL WORKUP||PRIMARY TREATMENT|ADDITIONAL TREATMENT|

|Undifferentiated/ dedifferentiated carcinoma Biopsy findings:|• Imaging i CA-125 • Consider|Suitable for primary surgery|• TH/BSO and surgical staging d,e • Consider maximal tumor debulking for gross disease|Systemic therapy h ± EBRT g ± vaginal brachytherapy g|

|||Not suitable for primary surgery|Systemic therapy h ± EBRT g ± vaginal brachytherapy g|Re-evaluate for surgical resection and/or RT g based on response|

|NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/03/27,22:35在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。|NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/03/27,22:35在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。|NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/03/27,22:35在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。|NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/03/27,22:35在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。|NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/03/27,22:35在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。| |---|---|---|---|---|

||: Carcinosarcoma NCCN Guidelines Version 2.2025 Endometrial Carcinoma|NCCN Guidelines Index Table of Contents Discussion|||

||ADDITIONAL WORKUP|PRIMARY TREATMENT||ADDITIONAL TREATMENT|

|Suitable for primary surgery Specimen integrity (intact, opened, morcellated, other) • Uterus Hysterectomy type Tumor site (endometrium, lower uterine segment, polyp) Tumor size Histologic type Histologic grade (if applicable) Myometrial invasion (|• TH/BSO and surgical staging d,e • Consider maximal tumor debulking for gross disease|Stage IA Stage IB, II, III, IV|Systemic therapy h ± EBRT g,ff ± vaginal brachytherapy g,ee Systemic therapy h + vaginal brachytherapy ee ± EBRT g,ff||

|Biopsy findings: Carcinosarcoma cc,dd|• Consider CA-125 • Imaging i surgery for primary Not suitable Uterine-confined disease ± pelvic nodal involvement on imaging|EBRT g ± brachytherapy g ± systemic therapy h or Systemic therapy h||Re-evaluate for surgical RT g based on response resection and/or Re-evaluate for surgical resection|

||Other metastatic disease|Systemic therapy h ± EBRT or Best supportive care|||

|||||References|

|||||ENDO-A 1 OF 4|

l Carcinoma|NCCN Guidelines Index Table of Contents Discussion|

|PRINCIPLES OF IMAGING REFERENCES||

||ENDO-B 2 OF 2|

||Continued|

||ENDO-C 1 OF 6|

|Continued|

|ENDO-C 3 OF 6|

|a An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. c NCCN Guidelines for Management of Immunotherapy-Related Toxicities. d Checkpoint inhibitors and/or monoclonal antibodies included in this regimen may be continued as maintenance therapy. Refer to the original study protocol for| |---|

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

|Reactions [OV-D]).|

|Letrozole/ribociclib| |---|

|Letrozole/abemaciclib|

|Brown J, Smith JA, Ramondetta L, et al. Combination of gemcitabine and cisplatin is highly active in women with endometrial carcinoma: Results of a prospective|

|phase 2 trial. Cancer 2010;116:4973-4979. 22 Picard M, Pur L, Caiado J, et al. Risk stratification and skin testing to guide re-exposure in taxane-induced hypersensitivity reactions. J Allergy Clin Immunol|

|2016;137:1154-1164. 23 Aghajanian C, Sill MW, Darcy KM, et al. Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. J Clin|

|Oncol 2011;29:2259-2265. 24 Oza AM, Elit L, Tsao MS, et al. Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group. J|

|Clin Oncol 2011;29:3278-3285. 25 Vergote I, Powell MA, Teneriello MG, et al. Second-line lenvatinib in patients with recurrent endometrial cancer. Gynecol Oncol 2020;156:575-582. 26 Grisham RN, Adaniel C, Hyman DM, et al. Gemcitabine for advanced endometrial cancer: a retrospective study of the Memorial Sloan-Kettering Cancer Center|

|experience. Int J Gynecol Cancer 2012;22:807-11. 27 Homesley HD, Filiaci V, Markman M, et al. Phase III trial of ifosfamide with or without paclitaxel in advanced uterine carcinosarcoma: a Gynecologic Oncology Group|

|Study. J Clin Oncol 2007;25:526-531. 28 Azad NS, Gray RJ, Overman MJ, et al. Nivolumab is effective in mismatch repair-deficient noncolorectal cancers: Results from Arm Z1D-A Subprotocol of the NCI-|

|MATCH (EAY131) study. J Clin Oncol 2020;38:214-222. 29 Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: DESTINYPanTumor02|

|phase II trial. J Clin Oncol 2024;42:47-58. 30 Solomon BJ, Drilon A, Lin JJ, et al. 1372P Repotrectinib in patients (pts) with NTRK fusion-positive (NTRK+) advanced solid tumors, including NSCLC: Update from|

|the phase I/II TRIDENT-1 trial [abstract]. Ann Oncol 2023;34:S787-S788.|

|Diagnosed|| |---|---|

|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|e Disease is not amenable to resection, or patient is not suitable for surgery based|

|malignant mesenchymal sarcoma, fragmentation/morcellation should be avoided. b Principles of Pathology and Molecular Analysis (UTSARC-A). c Principles of Imaging (UTSARC-B). d For incidental finding of uterine sarcoma after TH/BSO or fragmented specimen:|on comorbidities. f Oophorectomy is individualized for patients of reproductive age. Favor BSO if ER/PR positive.|

|recommend imaging and consider additional surgical resection on an individual||

|basis.||

|h Systemic Therapy (UTSARC-C).| |---|

|c Principles of Imaging (UTSARC-B). h Systemic Therapy (UTSARC-C). i Principles of Radiation Therapy for Uterine Neoplasms (UN-A).| |---|

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

|c Principles of Imaging (UTSARC-B).| |---|

|Footnotes a Also see Principles of Evaluation and Surgical Staging (ENDO-C).| |---|

|References 1 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.|

|Conventional (spindle|Cellular spindle cell proliferation with|Complex|Immunoexpression of smooth muscle|Prognosis is||

|cell) Leiomyosarcoma (LMS)|interlacing long fascicles with ≥2 of the following: moderate to severe atypia, tumor cell necrosis, or mitotic index (MI) ≥10/10|karyotypes are the hallmark of LMS. The most|markers such as desmin, smooth muscle actin (SMA), and/or caldesmon; however, tumors may have variable expression|best predicted by stage. Morphology has||

||high-power fields (HPFs).|commonly altered|and even lose expression of ≥1 markers.|not been shown||

|||genes include|Approximately 1/3 of LMS express ER/|to predict clinical||

|||TP53, ATRX, RB1,|PR.|behavior. Limited||

|||PTEN, DAXX,|Abnormal expression of ≥2|data suggest PR||

|||MDM2, CDKN2A,|immunohistochemical markers TP53,|expression may||

|||CDKN2C,|ATRX, RB1, PTEN, DAXX, MDM2, and|be a positive||

|||PDGFRB, and|MTAP may favor LMS in smooth muscle|prognostic marker||

|||BRCA2.|tumors that do not fulfill traditional|in low-stage LMS.||

||||histologic criteria for LMS. Genomic|||

||||risk stratification may predict clinical|||

||||outcomes.|||

|Epithelioid LMS 1|Epithelioid histology comprising ≥50% of the overall tumor supports classification as an|PGR fusions by FISH and/|Immunoexpression of desmin, SMA, and/ or caldesmon without MelanA expression|Unknown|Epithelioid LMS may morphologically and|

||epithelioid smooth muscle tumor. Diagnostic|or targeted RNA|is supportive. In some cases of epithelioid||immunohistochemically|

||criteria for epithelioid LMS are controversial.|sequencing in|LMS, HMB-45 may be expressed.||overlap with malignant|

||By WHO 5th edition, epithelioid LMS is|a small subset|||PEComa for which there|

||assigned when ≥1 of the following features is|with uniform|||is no gold standard|

||present: moderate to severe atypia, tumor cell|nuclear atypia and|||diagnostic test. Detection|

||necrosis, MI of ≥4/10 HPFs. Recent studies|rhabdoid features.|||of pathogenic TSC1/2|

||suggest assigning epithelioid LMS when ≥2 features are present. 2||||mutations or TFE3 fusion may favor PEComa.|

||||||References|

||||||Continued|

||||||UTSARC-A 2 OF 8|

||NCCN Guidelines Version 2.2025 Uterine Sarcoma|NCCN Guidelines Index Table of Contents Discussion||| |---|---|---|---|---|

|||||Relevant Prognostic Features|

||matrix and tumor necrosis or moderate to severe|targeted RNA sequencing in a|caldesmon, cyclinD1, and ALK is recommended||

||atypia or MI > 1/10 HPFs.|subset (~25%).|to exclude morphologic mimics.||

|||NR4A3 fusions are detected in a|||

|||subset of myxoid LMS.|||

|Low-Grade||||Stage is the most|

|Endometrial Stromal Sarcoma (ESS) 5-7||||important prognostic factor.|

|||||Continued|

|||||UTSARC-A 3 OF 8|

|Uterine Sarcoma||||| |---|---|---|---|---|

|High-Grade||||Slightly higher rate of|

|Endometrial Stromal Sarcoma (ESS) 5-13||||lymph node involvement and trend towards|

|||||worse outcomes when|

|||||compared to low-grade|

|||||ESS.|

|Cell Tumor (PEComa) 17-19|and muscle markers. The tumor cells can demonstrate variable cytologic atypia, mitotic activity, and melanin|of TFE3, RAD51B, or HTR4::ST3GAL1 can be|markers (HMB45 is most sensitive and MelanA is most specific), and|markers (HMB45 is most sensitive and MelanA is most specific), and|

||pigment in a background of thin-walled vascular spaces and sclerotic stroma. Proposed algorithms stratify tumors|seen. In situ hybridization to confirm rearrangement|≥1 smooth muscle marker (SMA, desmin, and caldesmon). Keratins|≥1 smooth muscle marker (SMA, desmin, and caldesmon). Keratins|

||into uncertain malignant potential and malignant as outlined|or fusion of TFE3 in TFE3-|and hormone receptors can be|and hormone receptors can be|

||below.|translocation-associated|variably expressed. Translocation-|variably expressed. Translocation-|

|||tumors.|associated tumors show diffuse|associated tumors show diffuse|

||||TFE3 expression with weak to|TFE3 expression with weak to|

||||negative smooth muscle markers.|negative smooth muscle markers.|

||||TSC2 mutations may rarely occur in||

||||ESS; thus in tumors with ambiguous||

||||morphologic/immunophenotypic|morphologic/immunophenotypic|

||||features, and TSC2 mutation|features, and TSC2 mutation|

||||identified, consideration for fusion|identified, consideration for fusion|

||||testing is advised to exclude ESS. 20||

|Inflammatory||||Typically benign and confined|

|Myofibroblastic||||to the uterus; recurrence and|

|Tumor (IMT)||||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.|

|Uterine Sarcoma||||||

|SMARCA4-Deficient|SDUS is characterized by sheets of epithelioid/|Biallelic SMARCA4|Absent CK expression and||Germline|

|Uterine Sarcoma (SDUS)|rhabdoid cells associated with hyalinized matrix.|inactivation|BRG1 loss (SMARCA4) and/or||SMARCA4|

||LVSI, high MI, and necrosis are common. A small||SMARCA4 mutation detectable||mutation testing|

||cell component or even spindled morphology may||by DNA sequencing is helpful to||should be|

||be focally present.||support a diagnosis of SDUS, in the||considered.|

||||appropriate morphologic context.|||

|||||Typically present|More commonly|

|||||with stage I|occurs in the|

|||||disease; ~1/3 recur|uterine cervix.|

|||||or metastasize.||

|||||Targeted therapy||

|||||against NTRK||

|||||inhibitors has shown||

|||||clinical benefit.||

|Ovarian Sex Cord Tumor (UTROSCT) 22-24|extensive sex cord-like differentiation and no endometrial stromal|the majority of tumors.|of sex cord markers (inhibin, calretinin, SF1, FOXL2) and/|potential with ~25% being malignant. Necrosis and MI ≥2/10 HPFs and/|

||component.||or detection of GREB1 or ESR1|or presence of GREB1 fusion may|

||||fusions by FISH (NCOA1, NCOA2,|increase likelihood of malignant|

||||NCOA3) and/or targeted RNA|behavior.|

||||sequencing is confirmatory.||

|Rhabdomyosarcoma (RMS) 25-27||DICER1 mutations are present in ≥95% of|IHC expression of myogenin and/ or MyoD1 is confirmatory of RMS||

|||embryonal RMS.|differentiation.||

||||Extensive sampling must||

|||PIK3CA and TP53|be performed to exclude||

|||mutations in pleomorphic|carcinosarcoma or adenosarcoma||

|||tumors. FOXO1 fusion in|with SO.||

|||alveolar tumors.|FISH and/or targeted RNA||

||||sequencing for FOXO1 fusion is||

||||recommended to confirm alveolar||

||||subtype.||

|Müllerian Adenosarcoma (MAS) 28-31|Biphasic tumor with benign often metaplastic epithelium associated|BAP1 loss is seen in a subset. ESR1 fusions are|Ancillary testing is usually not required.||

||with an atypical usually low-grade|found in a minority of cases|||

||spindle cell proliferation exhibiting phyllodes growth and periglandular|and BCORL1 fusions have been reported. d|||

||stromal condensation.||||

||SO is defined by sarcoma comprising||||

||≥25% of the tumor volume.||||

||NCCN Guidelines Version 2.2025 Uterine Sarcoma|NCCN Guidelines Index Table of Contents Discussion| |---|---|---|

||Preferred Regimen||

||• Trabectedin (for LMS)||

|◊ Larotrectinib ◊ Entrectinib ◊ Repotrectinib c,2 IMT with ALK translocation ◊ Crizotinib 3 ◊ Brigatinib 5,6 ◊ Ceritinib 4|Other Recommended Regimens • Gemcitabine/dacarbazine • Gemcitabine/vinorelbine • Dacarbazine • Gemcitabine • Epirubicin • Ifosfamide • Liposomal doxorubicin • Pazopanib • Temozolomide • Regorafenib 8 • Eribulin (||

|◊ Lorlatinib|||

|◊ Alectinib|||

|• RET-fusion positive tumors Selpercatinib 7|||

|PEComa|||

|Albumin-bound sirolimus|||

|NCCN Guidelines Version 2.2025 Uterine Sarcoma|NCCN Guidelines Index Table of Contents Discussion| |---|---|

|◊ Rucaparib||

|◊ Niraparib||

|• PEComa||

|◊ Sirolimus||

|◊ Everolimus||

|◊ Temsirolimus||

||UTSARC-C 1 OF 3|

|Anastrozole| |---|

|Letrozole|

|Exemestane|

|• Consider|

|Exemestane • Fulvestrant g • Megestrol acetate (category 2B|

|NCCN Guidelines Index| |---|

|Table of Contents|

|Discussion|

|Table of Contents Discussion AJCC Tumor-Node-Metastases (TNM) and International Federation of Gynecology and Obstetrics (FIGO) Surgical Staging Systems for Endometrial PRINCIPLES OF GYNECOLOGIC SURVIVORSHIP Physical Effects Staging-Uterine Carcinomas and Carcinosarcoma Table 1 Cancer • Gynecologic NCCN Guidelines Index Table of Contents Discussion NCCN Guidelines Index NCCN Guidelines Version 2.2025 Table of Contents Uterine Neoplasms Discussion||| |---|---|---|

|Definitions for T, N, M|Definitions for T, N, M|Definitions for T, N, M|

|T|FIGO Stage|Primary Tumor|

|TX||Primary tumor cannot be assessed|

|T0||No evidence of primary tumor|

|T1|I|Tumor confined to the corpus uteri, including endocervical glandular involvement|

|T1a IA|T1a IA|Tumor limited to the endometrium or invading less than half the myometrium|

|T1b IB|T1b IB|Tumor invading one half or more of the myometrium|

|T2|II|Tumor invading the stromal connective tissue of the cervix but not extending beyond the uterus. Does NOT include endocervical glandular involvement|

|T3|III|Tumor involving serosa, adnexa, vagina, or parametrium|

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

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

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

|||Continued|

|||UN-B ST-1|

||-Continued|-Continued|-Continued| |---|---|---|---|

|N|FIGO Stage|Regional Lymph Nodes||

|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|IIIC1 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||||

|N2|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.||||

|M0||No distant metastasis|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).|||

|G3 Poorly differentiated or undifferentiated|G3 Poorly differentiated or undifferentiated|G3 Poorly differentiated or undifferentiated|G3 Poorly differentiated or undifferentiated|

||Prognostic Stage Groups|Prognostic Stage Groups|Prognostic Stage Groups| |---|---|---|---|

||T|N|M|

|Stage I|T1|N0|M0|

|Stage IA|T1a|N0|M0|

|Stage IB|T1b|N0|M0|

|Stage II|T2|N0|M0|

|Stage III|T3|N0|M0|

|Stage IIIA|T3a|N0|M0|

|Stage IIIB|T3b|N0|M0|

|Stage IIIC1 T1-T3 N1/N1mi/N1a M0||||

|Stage IIIC2 T1-T3 N2/N2mi/N2a M0||||

|Stage IVA|T4|Any N|M0|

|Stage IVB Any T|Any N|M1||

|M|FIGO Stage|Distant Metastasis||| |---|---|---|---|---|

|M0||No distant metastasis|No distant metastasis|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|||||

|||T|N|M|

|Stage I|T1|N0|M0||

|Stage IA|T1a|N0|M0||

|Stage IB|T1b|N0|M0||

|Stage II|T2|N0|M0||

|Stage IIIA|T3a|N0|M0||

|Stage IIIB|T3b|N0|M0||

|Stage IIIC|T1-3|N1|M0||

|Stage IVA|T4|Any N M0|||

|Stage IVB Any T Any N M1|||||

|Staging-Uterine Sarcoma|Staging-Uterine Sarcoma|Staging-Uterine Sarcoma| |---|---|---|

|Leiomyosarcoma and Endometrial Stromal Sarcoma|||

|T1|I|Tumor limited to the uterus|

|T1a IA|T1a IA|Tumor 5 cm or less in greatest dimension|

|T1b IB|T1b IB|Tumor more than 5 cm|

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

|T2a IIA|T2a IIA|Tumor involves adnexa|

|T2b IIB|T2b IIB|Tumor involves other pelvic tissues|

|T3|III|Tumor infiltrates abdominal tissues|

|T3a IIIA|T3a IIIA|One site|

|T3b IIIB|T3b IIIB|More than one site|

|T4|IVA|Tumor invades bladder or rectum|

|N|FIGO Stage|Regional Lymph Nodes|

|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|

|Stage IC|T1c|N0|M0||

|. 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|

|panel recommends repeat pelvic MRI (preferred) for patients with|

|persistent endometrial carcinoma after 6 to 9 months of failed medical|

|therapy, especially if considering further fertility-sparing approaches.|

|challenging tumors supported the use of genomic profiling to aid in their| |---|

|classification. 418|

|Uterine Leiomyosarcoma (uLMS)|

|uLMS are usually of the spindle cell (conventional) type, but less common|

|variants with myxoid or epithelioid morphology also exist. Although|

|morphology differs between subtypes, all express varying degrees of the|

|smooth muscle markers, including desmin, smooth muscle actin (SMA),|

|and caldesmon. The panel recommends an IHC panel including desmin|

|and SMA to support a uLMS diagnosis, particularly if myxoid or epithelioid|

|uLMS is suspected.|

|Myxoid uLMSs may appear histologically similar to BCOR-altered|

|HGESSs 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. 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|

References

引用 / 出处

NCCN临床实践指南：子宫肿瘤（2025.V2）. 2025.