Objective: This study aimed to assess the concordance between pre-operative imaging results and intra-operative findings in patients with endometrial carcinoma, based on pre-operative risk stratification and the clinical indication for obtaining imaging. Methods: We identified all patients who had surgery for newly diagnosed endometrial carcinoma at our institution from January 2017 to January 2021 and categorized them as low or high risk. We reviewed pre-operative images or radiologic evidence of extrauterine disease and correlated with intra-operative findings, and we categorized the findings as true positive or false negative. Results: We identified a total of 1970 patients for this analysis. Within the study cohort, 1247 tumors (63.3%) were low-risk histology, 719 (36.5%) were high-risk histology, and 4 patients (0.2%) had no pre-operative biopsy. Pre-operative imaging was performed for 676 low-risk (54.2%) and 700 high-risk patients (97.4%) (p <.001) and detected the presence of extra-uterine disease in 50 of 676 low-risk (7.4%) and 140 of 700 high-risk patients (20%). In the low-risk cohort, there was radiologic evidence of extra-uterine disease present for 12 of 60 patients (20%) with an abnormal exam or ultrasound, 16 of 126 patients (12.7%) with symptoms or a delayed diagnosis, and 16 of 490 asymptomatic patients (3.3%). In the high-risk cohort, there was radiologic evidence of extra-uterine disease present for 32 of 66 patients (48.5%) with symptoms or a delayed diagnosis, 21 of 46 patients (45.7%) with an abnormal exam or ultrasound, and 84 of 583 asymptomatic patients (14.4%). A total of 122 of 1376 patients (8.9%) had a change in clinical management based on pre-operative imaging findings: 32 of 676 (4.7%) low-risk and 90 of 700 high-risk patients (12.9%). Conclusions: Over 90% of patients with low-risk tumors had no findings suspicious for metastatic disease on pre-operative imaging, indicating limited utility in that cohort. However, pre-operative imaging yielded clinically meaningful information in patients with high-risk histology, particularly, those with symptoms, delayed diagnosis, or concerning exam findings.

OBJECTIVE:The International Federation of Gynecology and Obstetrics 2023 endometrial cancer staging system includes 21 sub-stages and proposes a shift from pure anatomical staging to an approach incorporating histology, grade, lymphovascular invasion, and molecular classification. We sought to evaluate the overall survival prognostic ability of the International Federation of Gynecology and Obstetrics 2023 endometrial cancer staging system compared with the International Federation of Gynecology and Obstetrics 2009 system. METHODS:We collected clinicopathologic characteristics, molecular profiling results, and survival outcomes for all patients with a new diagnosis of endometrial cancer treated at our institution between 2016 and 2020. All cases underwent pathology review by a gynecologic pathologist at our institution. An International Federation of Gynecology and Obstetrics 2009 and 2023 stage was assigned. We applied R2ϵ statistics based on an isotonic proportional hazards model to compare prognostic ability between the 2 staging systems. RESULTS:Of 2067 patients with endometrial cancer, 952 (46%) underwent tumor molecular profiling. When comparing International Federation of Gynecology and Obstetrics 2009 and 2023 staging, 538 (26.0%) patients were upstaged and 100 (4.8%) were downstaged in the 2023 system. Five-year overall survival estimates were similar across most stages between the 2 staging systems, with some exceptions: the International Federation of Gynecology and Obstetrics 2023 IA3 sub-stage demonstrated improved outcomes (100% vs 70.3% for International Federation of Gynecology and Obstetrics 2009 IIIA) and the IICmp53abn group had poorer prognosis (73% vs 86.8% for International Federation of Gynecology and Obstetrics 2009 II). Using isotonic proportional hazards regression models, the 2023 model slightly numerically outperformed the 2009 model for overall survival (R2ϵ 0.546 vs 0.415); however, adjusted 95% confidence intervals were under-developed. CONCLUSIONS:Using a real-world, large, well-annotated cohort of patients with endometrial cancer with expert pathology review, we were able to calculate 5-year progression-free and overall survival rates for each sub-stage. The International Federation of Gynecology and Obstetrics 2023 model demonstrated slightly improved prognostic discrimination compared with the International Federation of Gynecology and Obstetrics 2009 model; however, small patient numbers in each sub-stage and concerns regarding over-fitting limit this analysis.

OBJECTIVE:To examine if preoperative serum albumin (SA) level is associated with worse survival following primary debulking surgery (PDS) for epithelial ovarian cancer (EOC). METHODS:In this retrospective study, we identified patients with stage III-IV EOC who underwent PDS at our institution from 1/1/2015-8/31/2022. Patients were assigned to the low albumin (LA; SA < 3.5 g/dL) or normal albumin (NA; SA ≥ 3.5 g/dL) group. Exclusion criteria included age ≥ 80 years, age 75-79 years with poor physical status or high likelihood of complex surgery, secondary malignancy, and missing preoperative SA level. Median and 5-year progression-free (PFS) and overall survival (OS) rates were calculated using Kaplan-Meier method. Log-rank test was used for categorical variables and Wald test for continuous variables. RESULTS:Overall, 636 patients were identified, 65 (10%) in the LA and 571 (90%) in the NA group. Median follow-up was 73 months (95% CI: 68-76). Comparing the LA versus NA group, 5-year PFS rate was 18.3% (95% CI: 9.2%-29.9%) vs 26.5% (95% CI: 22.6%-30.5%), respectively (P = 0.107); 5-year OS rate was 56.1% (95% CI: 41.5%-68.4%) vs 66.1% (95% CI: 61.6%-70.3%), respectively (P = 0.053). Complete gross resection (CGR) was achieved in 66% of patients with LA compared to 78% with NA (P = 0.029). On multivariate analysis of OS, age, histology, BRCA status, and CGR were statistically significant prognostic factors, but preoperative SA was not. CONCLUSIONS:Five-year survival rates were similar between patients with and without hypoalbuminemia. Relying on preoperative SA level alone, patients may be selected for neoadjuvant chemotherapy who would have equivalent survival outcomes with PDS.

OBJECTIVE:To assess clinical utility of pre-operative imaging in cervical cancer beyond pelvic magnetic resonance imaging (MRI) in patients with pre-operative International Federation of Gynecology and Obstetrics (FIGO) stage IB2 or less. METHODS:We retrospectively identified patients who underwent evaluation or received consultation for newly diagnosed cervical squamous cell carcinoma, adenocarcinoma, or adeno-squamous carcinoma at our institution from January 2006 until February 2024. Patients with stage ≤IB2 disease on examination and a pre-operative pelvic MRI demonstrating a tumor ≤4 cm were included. Cases with evidence of gross pelvic nodal involvement or unequivocal parametrial/vaginal extension on MRI were excluded. All patients then underwent surgical treatment. Patients were included if they also underwent chest, abdominal, and pelvic computed tomography with/without positron emission tomography. Additional imaging was performed prior to consultation at our institution or at the treating physician's discretion. We sought to assess the findings of additional imaging in identifying extra-pelvic gross nodal or extra-nodal abdominal and/or chest disease. We did not seek to identify the role of imaging in identifying microscopic disease in normal-sized lymph nodes and such cases were included. RESULTS:Among 183 patients, the median age at diagnosis was 36 years (range; 18-81); 100 (54.6%) had adenocarcinoma, 78 (42.6%) squamous cell carcinoma, and 5 (2.7%) adeno-squamous carcinoma. The final pathologic FIGO 2018 stages included IA1 (n = 34, 18.6%), IA2 (n = 18, 9.8%), IB1 (n = 96, 52.5%), IB2 (n = 14, 7.7%), IB3 (n = 1, 0.5%), and IIIC1 (n = 20, 10.9%). The median tumor size was 0 mm (range; 0-38) on imaging and 8 mm (range; 0-41) on final pathology. Twenty-eight patients (15.3%) had non-specific/borderline enlarged pelvic lymph nodes on MRI, 6 (21.4%) of whom had final pathologic lymph node involvement. Thirty-four patients (18.6%) had "extra-pelvic" findings on computed tomography with/without positron emission tomography; 21 (61.8%) had non-specific findings, and 13 (38.2%) underwent further diagnostic intervention but none had cervical cancer metastases. There were no cervical cancer-related findings on additional imaging beyond MRI of the pelvis. Additionally, no extra-pelvic disease was encountered intra-operatively. The false-positive rate for imaging to detect extra-pelvic intra-abdominal metastasis of cervical carcinoma was 100% (13 of 13, 95% confidence interval [CI] 75.3% to 100%), with no false negatives (0%, 95% CI 0% to 1.7%). CONCLUSIONS:For patients with cervical carcinoma ≤4 cm and confined to the cervix on pre-operative MRI, additional imaging appears to be of limited utility, leading to unnecessary interventions.

OBJECTIVE:To determine factors impacting successful bilateral sentinel lymph node mapping and empty nodal packet rate using indocyanine green for uterine cancer staging. METHODS:All women with clinical early-stage uterine cancer who underwent hysterectomy with sentinel lymph node mapping between January 1, 2014, and December 31, 2022, were included. The primary endpoint was the successful bilateral sentinel lymph node mapping rate. Secondarily, we assessed the empty nodal packet rate and identified factors impacting successful sentinel lymph node mapping and empty nodal packet rates. Appropriate statistical tests were used. RESULTS:A total of 2690 patients were included, with a median body mass index of 30.9 kg/m2 (range; 14.0-70.2). Of these, 1893 (70%) had low-grade endometrioid histology, 260 (10%) had high-grade endometrioid histology, and 537 (20%) had non-endometrioid histology. A total of 2499 (93%) cases were completed with minimally invasive surgery, and 191 (7%) via laparotomy. Bilateral sentinel lymph node mapping was successful in 2340 of 2690 patients (87%). The rate of bilateral mapping by body mass index group was 89% for body mass index <30 kg/m2, 86% for body mass index 30 to 39.9 kg/m2, 85% for body mass index 40 to 49.9 kg/m2, 83% for body mass index 50 to 59.9 kg/m2, 69% for body mass index ≥60 kg/m2 (p =.04). A total of 2196 (88%) minimally invasive surgery cases had bilateral mapping compared with 144 (75%) laparotomy cases (p <.001). On multi-variate analysis, age, body mass index, and surgical approach were independently associated with successful sentinel lymph node mapping. Empty nodal packets occurred in 98 of 2633 patients (3.7%). Increasing age and body mass index were associated with a higher empty nodal packet rate. Bilateral mapping increased from 82.5% in 2014 to 91.3% in 2022 (p =.03), whereas the empty nodal packet rate did not change (p =.2). CONCLUSIONS:High rates of successful sentinel lymph node mapping can be achieved across body mass index categories using indocyanine green. A decreased rate was noted in patients with body mass index ≥60 kg/m2 and in cases completed via laparotomy. Sentinel lymph node mapping success rates improved with continued experience.

OBJECTIVE:Pre-operative endometrial assessment may be discordant with final pathology. We sought to determine the outcome of discordant cases. METHODS:We identified patients who had primary surgical treatment of stage I endometrioid endometrial carcinoma found on final hysterectomy specimen from January 1, 2000, to December 31, 2020. We collected relevant patient, clinical, and pathologic characteristics and defined low grade as cases with pre-operative grade 1 or 2 tumors and concordant final pathology, and high grade as cases with pre-operative grade 3 tumors and concordant final pathology. We defined discordant as cases with a high-grade histology on pre-operative biopsy, inclusive of non-endometrioid histology, and grade 1 or 2 on final pathology. We compared clinicopathologic characteristics and used Kaplan-Meier survival estimates to compare outcomes between groups. RESULTS:Overall, 2936 patients were included: 2606 (89%) low grade, 247 (8%) high grade, and 83 (3%) discordant. Five-year progression-free survival was 95.1% for low-grade, 86.9% for discordant, and 86.0% for high-grade tumors (p <.001). Five-year overall survival was 95.0% for low-grade, 93.4% for discordant, and 85.7% for high-grade tumors (p <.001). After adjusting for age, myometrial invasion, lymphovascular space invasion, washings (progression-free survival), performance of nodal dissection (overall survival), and adjuvant therapy, discordant cases were not independently associated with progression-free survival (hazard ratio 1.82, 95% confidence interval 0.71 to 4.65), and only high-grade tumors were independently associated with worse overall survival. CONCLUSIONS:The clinical behavior of stage I endometrioid endometrial carcinoma diagnosed as high grade on pre-operative biopsy and low grade on subsequent hysterectomy seems to differ from cases diagnosed as low grade on both pre-operative and final pathology. Further analyses and larger series will be needed to better clarify this question. Both pre-operative and final hysterectomy results should be considered along with age, myometrial invasion, and lymphovascular space invasion when counseling patients regarding prognosis and need for adjuvant therapy.

Objective Undifferentiated and dedifferentiated endometrial carcinomas are rare and clinically aggressive variants of the disease. We sought to define the molecular subtypes and genetic alterations affecting cancer-related genes of these rare histologic endometrial cancer types. Methods Patients with undifferentiated/dedifferentiated endometrial cancer subjected to clinical tumor-normal panel sequencing between January 1, 2014, to June 1, 2023, were retrospectively identified, and relevant demographic and clinicopathologic data were extracted from medical records. All cases underwent central pathology review. Endometrial carcinomas with mixed histology and synchronous tumors were excluded. Genomic data including somatic mutations, copy number alterations, and microsatellite instability (MSI), in addition to immunohistochemistry results, were extracted and utilized for molecular subtyping. Results A total of 35 patients met inclusion criteria, with a median age at diagnosis of 60 years (range, 36 to 85). Of these, 16 (46%) were undifferentiated and 19 (54%) dedifferentiated, with undifferentiated being more frequently of International Federation of Obstetrics and Gynecology (FIGO) 2009 stage IV at diagnosis than dedifferentiated (7/16, 40% vs 3/19, 17%, p = .05). All 4 molecular subtypes were present, with the majority being MSI-high/mismatch repair-deficient (n = 25, 71%); the remaining cases were of POLE molecular subtype (n = 2, 6%), copy number (CN)-high/TP53abnormal (n = 3, 9%), and CN-low/no specific molecular profile (n = 5, 14%). The most recurrent genetic alterations were found in PTEN (26/35, 74%), ARID1A (26/35, 74%), PIK3CA (21/35, 60%) ARID1B (14/35, 40%), and SMARCA4 (9/35, 26%). Pathogenic mutations in chromatin remodeling genes, including ARID1A and ARID1B, were absent in endometrial cancers of CN-high/TP53abnormal subtype. Conclusions Undifferentiated/dedifferentiated endometrial cancers are heterogeneous at the molecular level; however, the majority are MSI-high/mismatch repair-deficient, which may have therapeutic implications. Loss-of-function alterations in chromatin remodeling genes were present in all molecular subtypes except CN-high/TP53 abnormal undifferentiated/dedifferentiated endometrial cancers.

OBJECTIVE:Compared to historical standards, intensity-modulated radiation therapy minimizes radiation dose to critical structures. Here, we characterize acute/chronic complications of intensity-modulated radiation therapy with concurrent chemotherapy following radical surgery for cervical cancer. METHODS:This single-institution, retrospective study included patients who underwent radical hysterectomy/trachelectomy followed by adjuvant intensity-modulated radiation therapy and radiosensitizing chemotherapy for clinical stage IA to IIA cervical cancer (01/2007-8/2021). Treatment-related adverse events were collected and graded at baseline, 3 weeks, and 5 weeks after intensity-modulated radiation therapy, and long-term (≥6 months). RESULTS:We identified 91 patients who received intensity-modulated radiation therapy with concurrent chemotherapy following radical hysterectomy (n = 84, 92%) or radical trachelectomy (n = 7, 8%). Post-operatively, 66 patients (73%) met Peters criteria, 21 (23%) met Sedlis criteria, and 4 (4%) had other high-risk features. Intensity-modulated radiation therapy doses were 5040 cGy in 66% (n = 60) of patients, 4500 cGy in 30% (n = 27), and 4500 to 5040 cGy in 4% (n = 4). The most common treatment-related adverse events were fatigue (n = 77, 85%) and gastrointestinal (n = 74, 81%), followed by hematologic (n = 26, 29%) and genitourinary (n = 35, 38%). From baseline to intensity-modulated radiation therapy completion, adverse event scores significantly worsened for hematologic (p < .002), fatigue (p < .0001), gastrointestinal (p < .0001), and genitourinary toxicities (p = .003). Acute grade 3 toxicities occurred in 2% (n = 2, gastrointestinal and fatigue). There was one chronic grade 3 toxicity: lymphedema requiring lymphovenous bypass in a patient who underwent full pelvic lymphadenectomy. We observed no long-term grade 3 bowel toxicity or radiation-associated secondary malignancy. CONCLUSIONS:Radical hysterectomy/trachelectomy followed by intensity-modulated radiation therapy with concurrent chemotherapy was associated with acceptable rates of acute/chronic toxicity. With modern post-operative intensity-modulated radiation therapy techniques, multimodal therapy for apparent stage I cervical cancer is reasonable with a very low rate of severe chronic genitourinary or gastrointestinal toxicities. Providers should continue to offer radical surgery for appropriate candidates.

BACKGROUND:It is unclear whether isolated tumor cells (ITCs) in sentinel lymph nodes (SLNs) adversely affect prognosis, especially in low-risk endometrial cancer. In a retrospective study, we showed a worse recurrence-free survival for low-risk endometrial cancer with ITCs than the node-negative group. PRIMARY OBJECTIVE:Our aim is to evaluate whether the likelihood of disease recurrence differs between a prospective cohort of patients with low-risk endometrial cancer with ITCs and an historical cohort with negative SLNs. STUDY HYPOTHESIS:We hypothesize that patients with low-risk endometrial cancer and ITCs will have a worse recurrence-free survival than patients who are node-negative. TRIAL DESIGN:This is a prospective, multi-center, single-arm observational study. Consecutive patients with low-risk endometrial cancer with ITCs in the SLNs will be accrued. Observation only will be suggested after surgery. MAJOR INCLUSION/EXCLUSION CRITERIA:We will include patients with endometrial cancer undergoing pelvic SLN biopsy and ultra-staging with the following characteristics: endometrioid histology, grades 1 to 2, <50% myometrial invasion, without substantial/extensive lympho-vascular space invasion. ITCs in SLNs are defined as tumor cell aggregates ≤0.2 mm or <200 cells. PRIMARY END POINT:The primary end point is recurrence-free survival, measured from the date of surgery to the date of recurrence, death, or last disease evaluation. SAMPLE SIZE:With a sample size of 132 women with low-risk endometrial cancer and ITCs, a 1-sided log-rank test achieves 85% power at a 0.05 significance level to detect an HR of 2.1. The expected number of events during the study is 17.3. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS:The study duration will be 60 months: 24 for enrollment and 36 for follow-up. The results are expected in 2029. TRIAL REGISTRATION:ClinicalTrials.gov: NCT06689956.

OBJECTIVE:Lymphovascular invasion can predict nodal spread and recurrence in endometrioid endometrial cancer; however, the impact of lymphovascular invasion quantification on local versus distant recurrence in surgically staged patients has not yet been established. METHODS:This multicenter, retrospective cohort study included surgically staged patients with International Federation of Obstetrics and Gynecology 2009 stage I node-negative endometrioid endometrial cancer. Patients were treated between January 2012 and December 2019 at 2 tertiary cancer centers. Staging included a total hysterectomy and lymph node assessment. The extent of lymphovascular invasion was defined using the World Health Organization criteria as focal (<5 vessels involved on at least 1 pathology slide) or substantial (≥5 vessels involved). Recurrence and death were considered as events. A competing risk analysis was performed and controlled for multicenter clustering. RESULTS:Overall, 1555 patients met the inclusion criteria: 65 (4.2%) had substantial invasion, 119 (7.7%) had focal, and 1371 (88.2%) had no invasion. The median follow-up was 61.5 months (range; 0.8-133.9). There were 173 evaluable events among the 1554 patients: 56 local recurrences, 43 distant recurrences, and 74 deaths without recurrence. Deep (>50%) myoinvasion and grade 3 histology were more frequently observed in patients with substantial myoinvasion. Overall, 323 patients (20.8%) received adjuvant therapy. The 5-year cumulative incidence failure rates for any recurrence were 6.0% for no, 19.5% for focal, and 19.0% for substantial invasion. Compared to no lymphovascular invasion, substantial invasion was associated with an increased risk of distant recurrence (adjusted HR 2.29, 95% CI 1.17 to 4.46). CONCLUSIONS:In patients with surgical stage I endometrioid endometrial cancer, the focal and substantial lymphovascular invasion was associated with a 3-fold increased risk of cumulative incidence failure versus no lymphovascular invasion. Patients with substantial invasion had more deeply invasive and grade 3 tumors and appeared to experience more distant than local recurrences. These findings challenge the International Federation of Obstetrics and Gynecology 2023 staging classification that combines no lymphovascular invasion and focal lymphovascular invasion into a single risk category.

BACKGROUND:We examined the prognostic value of positive peritoneal cytology (PPC) in International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IA grade 1 endometrioid endometrial cancer. METHODS:This single-institution retrospective cohort study included patients who underwent surgical staging with peritoneal cytology sampling and bilateral pathologic pelvic lymph node evaluation between 1/1/2008 and 8/1/2021. Exclusion criteria included suspicious/atypical cytology, lymphovascular space invasion, lymph node involvement (including isolated tumor cells), synchronous malignancies, no nodal evaluation, or receipt of adjuvant therapy. Patients were stratified by PPC or negative peritoneal cytology (NPC) status. Molecular classification and mutational profiling were available for some tumors. RESULTS:Of 1151 eligible patients, 50 (4 %) had PPC. Median age at surgery was 58 years and was similar between groups (P = 0.59). Depth of myometrial invasion, vaginal tears, age, prior secondary malignancies, and PPC were associated with progression-free survival (PFS) on univariable analysis. Five-year PFS rates were 95.2 % (NPC) and 88.8 % (PPC) (P = 0.02). PPC remained independently associated with worse PFS on multivariable analysis (adjusted HR: 2.63, 95 % CI: 1.19-5.80; P = 0.02), though recurrence was limited in number, with 31 events observed across the entire cohort. Molecular profiling of 216 tumors confirmed all four subtypes; subtype distribution did not correlate with outcomes. Tumors in the PPC group were enriched in ARID1A (82 % vs. 44 %, P = 0.001) mutations. CONCLUSION:PPC appears to be independently associated with worse PFS in low-grade, early-stage endometrial cancer despite excellent overall outcomes and absence of adjuvant therapy. ARID1A mutations may promote peritoneal dissemination in these otherwise low-risk tumors.

OBJECTIVE:We compared oncologic outcomes across "aggressive" histopathological subtypes of apparent early-stage, high-grade endometrial carcinoma. METHODS:Patients who underwent surgical staging at our institution for newly diagnosed high-grade endometrial adenocarcinoma between January 1, 2009, and June 30, 2021, were retrospectively identified. We defined "aggressive" histology as International Federation of Obstetrics and Gynecology grade 3 endometrioid, serous, clear cell, carcinosarcoma, mixed, and undifferentiated/dedifferentiated subtypes. Clinicopathologic details were extracted from medical records. Continuous variables were analyzed using the Kruskal-Wallis test, categorical variables using Fisher's exact test or the χ2 test, and survival outcomes using the Kaplan-Meier method and Cox proportional hazards models. RESULTS:Of 1087 patients, 308 (28.3%) had grade 3 endometrioid adenocarcinoma, 357 (32.8%) serous adenocarcinoma, 64 (5.9%) clear cell carcinoma, 194 (17.8%) carcinosarcoma, 101 (9.3%) mixed adenocarcinoma, and 63 (5.8%) undifferentiated/dedifferentiated adenocarcinoma. Overall, 719 patients (66.1%) had International Federation of Obstetrics and Gynecology 2009 stage I, 51 (4.7%) stage II, 232 (21.3%) stage III, and 85 (7.8%) stage IV disease. Median age at surgery was 65.1 years (range; 24.8-92.1) and varied among histologies (p < .001). Overall, 462 patients (42.5%) had lymphovascular invasion, 333 (30.6%) had deep myometrial invasion (≥50%), and 160 (15.0%) had positive peritoneal cytology; all varied across histologies (p < .001). Rates of 5-year progression-free and overall survivals were 79% (standard error [SE] ± 3%) and 83% (SE ± 2%) for grade 3 endometrioid, 63% (SE ± 3%) and 66% (SE ± 3%) for serous, 73% (SE ± 6%) and 77% (SE ± 6%) for clear cell, 51% (SE ± 4%) and 54% (SE ± 4%) for carcinosarcoma, 59% (SE ± 5%) and 65% (SE ± 5%) for mixed, and 71% (SE ± 6%) and 76% (SE ± 6%) for undifferentiated/dedifferentiated (P<.001 for both). Peritoneal cytology, lymphovascular invasion, and age at surgery were independent predictors of worse progression-free and overall survivals on multivariable analysis. CONCLUSIONS:High-grade "aggressive" histologies in endometrial cancer are diverse tumors with distinct oncologic outcomes; therefore, they should not be treated as a single entity or used as a staging criterion.

OBJECTIVE:To examine the risk of sentinel lymph node (SLN) metastases in apparent uterine-confined endometrial cancer (EC) using molecular classification with clinicopathologic features and assess oncologic outcomes by molecular subtypes with micro- or macro-metastases in SLN. METHODS:Patients undergoing surgical staging for presumed uterine-confined EC of any histology, with successful bilateral SLN mapping were included. Primary tumors were assigned molecular subtypes using a published algorithm. SLN pathology was categorized as negative, isolated tumor cells (ITCs), or micro- or macro-metastases. RESULTS:Overall, 756 patients were included; 80 (10 %) had micro- or macro-metastases and 51 (7 %) had ITCs. On multivariate multinomial logistic regression, risk of micro- or macro-metastases versus negative SLN was higher for ECs with copy number-high (CN-H)/TP53abn (OR 3.1; 95 % CI 1.3-7), lymphovascular space invasion ([LVSI]; OR 8.0; 95 % CI 4-16), and deep myoinvasion (≥50 %; OR 3.33; 95 % CI 1.9-6.04). Three-year PFS rates by subtype for 68 patients with macro-metastases were 38 % (95 % CI 10-67 %) CN-low/no specific molecular subtype (CN-L/NSMP), 66 % (95 % CI 44-82 %) microsatellite instability-high (MSI-H), and 23 % (95 % CI 10-40 %) CN-H/TP53abn (p = 0.006). Three-year OS rates were 55 % (95 % CI 20-80 %) CN-L/NSMP, 83 % (95 % CI 61-93 %) MSI-H, and 55 % (95 % CI 34-71 %) CN-H/TP53abn (p = 0.048). CONCLUSIONS:Integrating molecular subtype with uterine risk factors (LVSI and myoinvasion) further stratifies risk of occult SLN metastases in patients undergoing surgical staging for early-stage EC. No molecular subgroup had exceedingly low SLN metastases detected, supporting continued universal SLN assessment. Patients with macro-metastases and CN-L/NSMP or CN-H/TP53abn EC had worse outcomes than those with MSI-H EC.