Mario M Leitao

Oncologic outcomes based on lymphovascular space invasion in node-negative FIGO 2009 stage I endometrioid endometrial adenocarcinoma: a multicenter retrospective cohort study

The 2023 International Federation of Gynecology and Obstetrics (FIGO) staging system includes lymphovascular invasion quantification as a staging criterion for endometrioid endometrial carcinomas; no lymphovascular invasion and focal invasion (≤4 vessels involved) are grouped as one category, and substantial invasion as another. To assess the association between lymphovascular invasion and oncologic outcomes. We retrospectively identified patients with FIGO 2009 stage I endometrioid endometrial cancer treated surgically with total hysterectomy and lymph node assessment at two tertiary care centers between January 1, 2012, and December 31, 2019. Lymphovascular space invasion was categorized as focal (<5 vessels involved), substantial (≥5 vessels involved), and no lymphovascular invasion using WHO criteria. Of 1555 patients included, 65 (4.2%) had substantial, 119 (7.7%) had focal, and 1371 (88.2%) had no lymphovascular invasion. Median age was 64 years (range 24-92). Thirty-five patients (53.8%) with substantial, 44 (37%) with focal, and 115 (8.4%) with no lymphovascular invasion had stage IB disease (p<0.001); 21 (32.3%) with substantial, 24 (20.2%) with focal, and 91 (6.6%) with no lymphovascular invasion had grade 3 disease (p<0.001). Thirty-six patients (55.4%) with substantial, 80 (67.2%) with focal, and 207 (15.1%) with no lymphovascular invasion received adjuvant treatment (p<0.001). Median follow-up was 61.5 months (range 0.8-133.9). Five-year progression-free survival rates were 68.7% (substantial), 70.5% (focal), and 90.7% (no invasion) (p<0.001). On multivariate analysis, any lymphovascular invasion was associated with increased risk of progression/death (adjusted HR (aHR)=1.84 (95% CI 1.73 to 1.96) for focal; 2.17 (95% CI 1.96 to 2.39) for substantial). Compared with focal, substantial lymphovascular invasion was associated with an aHR for disease progression of 1.18 (95% CI 1.00 to 1.39). Focal and substantial lymphovascular invasion were associated with increased risk of disease progression and do not appear to be prognostically distinct. Focal versus no lymphovascular invasion have different prognostic outcomes and should not be combined into one category.

2009 International Federation of Gynecology and Obstetrics (FIGO) stage IIIA endometrial cancer: oncologic outcomes based on involvement of adnexa, serosa, or both

To assess clinicopathologic features and survival outcomes of patients with endometrial carcinoma involving adnexal, full-thickness serosal, or combined involvement. This international, multi-institutional, retrospective study examined patients with 2009 International Federation of Gynecology and Obstetrics (FIGO) stage IIIA endometrial cancer and tumors involving the uterine serosa and/or adnexa, who were surgically staged between 2000 and 2019. Patients with sarcoma histology, concurrent endometrial/ovarian malignancy, neoadjuvant treatment, positive lymph nodes, or peritoneal disease were excluded. Of 185 patients identified, 139 had tumors with adnexal-only, 40 with serosal-only, and six with combined adnexal/serosal involvement. Median age at diagnosis was 60 years (range 23-89). Among tumors of endometrioid histology, 12 (48%) with serosal-only and 17 (19%) with adnexal-only involvement were FIGO grade 3 (p=0.007). Twenty-three tumors with serosal-only (64%) and 50 with adnexal-only (37%) involvement had lymphovascular invasion (p=0.004). Non-endometrioid histology was present in five tumors (83%) with combined adnexal/serosal, 15 (38%) with serosal-only, and 50 (36%) with adnexal-only involvement.Median follow-up was 77 months (range 0.6-254). Five-year progression-free survival and overall survival rates for all patients with stage IIIA disease were 73.8% (SE 3.5%) and 81.0% (SE 3.1%), respectively. For patients with adnexal-only, serosal-only, and combined adnexal/serosal involvement, 5-year progression-free survival rates were 80% (SE 3.8%), 61% (SE 8.3%), and 33% (SE 19.2%), respectively (p<0.01); 5-year overall survival rates were 85% (SE 3.3%), 70% (SE 7.8%), and 60% (SE 21.9%), respectively (p=0.09). On univariate analysis, tumors having serosal involvement with/without adnexal involvement, non-endometrioid histology, and lymphovascular invasion were significantly associated with progression. On multivariate analysis, tumors having serosal involvement with/without adnexal involvement remained significantly associated with recurrence (adjusted HR=2.2, 95% CI 1.2 to 4.3; p=0.01). Patients with 2009 FIGO stage IIIA endometrial cancer have distinct survival outcomes depending upon adnexal and/or serosal involvement. Progression-free survival was worse for patients with serosal involvement after adjusting for histology, adjuvant treatment, and lymphovascular space invasion.

Prognosis of isolated tumor cells and use of molecular classification in early stage endometrioid endometrial cancer

We assessed the prognosis and molecular subtypes of early stage endometrioid endometrial cancer with isolated tumor cells within sentinel lymph nodes (SLNs) compared with node negative disease. Patients diagnosed with stage IA, IB, or II endometrioid endometrial cancer and primary surgical management were identified from January 1, 2007 to December 31, 2019. All SLNs underwent ultrastaging according to the institutional protocol. Patients with cytokeratin positive cells, micrometastases, and macrometastases were excluded. Clinical, pathology, and molecular subtype data were reviewed. Overall, 1214 patients with early stage endometrioid endometrial cancer met the inclusion criteria, of whom 1089 (90%) had node negative disease and 125 (10%) had isolated tumor cells. Compared with node negative disease, the presence of isolated tumor cells had a greater association with deep myometrial invasion, lymphovascular space invasion, receipt of adjuvant therapy, and adjuvant chemotherapy with or without radiation (p<0.01). There was no significant difference in survival rates between patients with isolated tumor cells and node negative disease (3 year progression free survival rate 94% vs 91%, respectively, p=0.21; 3 year overall survival rate 98% vs 96%, respectively, p=0.45). Progression free survival did not significantly differ among patients with isolated tumor cells who received no adjuvant therapy or chemotherapy with or without radiation (p=0.31). There was no difference in the distribution of molecular subtypes between patients with isolated tumor cells (n=28) and node negative disease (n=194; p=0.26). Three year overall survival rates differed significantly when stratifying the entire cohort by molecular subtype (p=0.04). Patients with isolated tumor cells demonstrated less favorable uterine pathologic features and received more adjuvant treatment with similar survival compared with patients with nodenegative disease. Among the available data, molecular classification did not have a significant association with the presence of isolated tumor cells, although copy number-high status was a poor prognostic indicator in early stage endometrioid endometrial cancer.

Establishing guidelines for sentinel lymph node ultrastaging in endometrial cancer

Many sentinel lymph node (SLN) ultrastaging protocols for endometrial cancer exist, but there is no consensus method. This study aims to develop guidelines for size criteria in SLN evaluation for endometrial cancer, to determine whether a single cytokeratin AE1:AE3 immunohistochemical slide provides sufficient data for diagnosis, and to compare cost efficiency between current and limited ultrastaging protocols at a large tertiary care institution. Our current SLN ultrastaging protocol consists of cutting two adjacent paraffin block sections at two levels (L1 and L2), 50 μm apart, with two slides at each level stained with hematoxylin and eosin and cytokeratin AE1:AE3 immunohistochemistry. We retrospectively reviewed digitized L1 and L2 slides of all positive ultrastaged SLNs from patients treated for endometrial cancer between January 2013 and January 2020. SLN diagnosis was defined by measuring the largest cluster of contiguous tumor cells in a single cross section: macrometastasis (>2.0 mm), micrometastasis (>0.2 to ≤2.0 mm or >200 cells), or isolated tumor cells (≤0.2 mm or ≤200 cells). Concordance between L1 and L2 results was evaluated. Cost efficiency between current (two immunohistochemical slides per block) and proposed limited (one immunohistochemical slide per block) protocols was compared. Digitized slides of 147 positive SLNs from 109 patients were reviewed; 4.1% of SLNs were reclassified based on refined size criteria. Complete concordance between L1 and L2 interpretations was seen in 91.8% of SLNs. A false-negative rate of 0%-0.9% in detecting micrometastasis and macrometastasis using a limited protocol was observed. Estimated charge-level savings of a limited protocol were 50% per patient. High diagnostic accuracy in SLN interpretation may be achieved using a limited ultrastaging protocol of one immunohistochemical slide per block and linear measurement of the largest cluster of contiguous tumor cells. Implementation of the proposed limited ultrastaging protocol may result in laboratory cost savings with minimal impact on health outcomes.

ARIA II: a randomized controlled trial of near-infrared Angiography during RectosIgmoid resection and Anastomosis in women with ovarian cancer

Ovarian cancer with extensive metastatic disease involving pelvic structures often requires rectosigmoid resection for complete gross resection; however, it is associated with increased surgical morbidity. There are limited data, and none in ovarian cancer, on near-infrared assessment of perfusion in rectosigmoid resections with anastomosis. To compare the rate of pelvic complications (pelvic abscesses, anastomotic leaks, and infections) within 30 days of surgery with and without near-infrared assessment of perfusion at time of rectosigmoid resection and re-anastomosis in patients undergoing cytoreductive surgery for ovarian cancer. We hypothesize the use of near-infrared technology (intravenous indocyanine green and endoscopic near-infrared fluorescence imaging), compared with standard intra-operative assessment, to evaluate anastomotic perfusion at time of rectosigmoid resection and re-anastomosis will result in lower rates of post-operative pelvic complications. This is a planned multicenter randomized controlled trial. Patients who undergo rectosigmoid resection as part of their ovarian cytoreductive surgery will be randomized 1:1 to standard assessment of anastomosis with the surgeon's usual technique (control arm) or assessment with near-infrared angiography using indocyanine green and endoscopic fluorescence imaging (experimental arm). Randomization will occur after rectosigmoid resection has been completed and the surgeon declares their plan to create a diverting ostomy. Randomization will be stratified by plan for diverting ostomy. Main inclusion criteria include patients with primary or recurrent ovarian, fallopian tube, or primary peritoneal cancer who are scheduled for cytoreductive surgery with suspected need for low-anterior rectosigmoid resection. Rate of 30-day post-operative pelvic complications. 310 (155 per arm) ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Q2 2027 and Q4 2027, respectively. NCT04878094.

Molecular and pathologic data to guide selection of patients with endometrioid endometrial cancer for ovarian preservation

To investigate the association of molecular and pathologic factors with concurrent or recurrent ovarian disease to guide ovarian preservation in endometrioid endometrial cancer. Patients with endometrial cancer ≤50 years of age at diagnosis were grouped by elective oophorectomy versus ovarian preservation at staging (January 2010 to June 2021). Tumors were stratified by molecular sub-type and Among 317 patients with endometrial cancer who underwent bilateral oophorectomy, 27 (9%) had malignant ovarian tumors, of whom 11 (41%) had no gross ovarian involvement on intra-operative survey. For patients with sequencing, concurrent malignant ovarian tumors were diagnosed in 0/14 (0%) The integration of molecular and pathologic data may improve risk stratification of pre-menopausal patients with endometrial cancer and enhance candidate selection for ovarian preservation.

Prognostic value of “aggressive” histology in surgically staged clinically uterine-confined endometrial carcinoma

We compared oncologic outcomes across "aggressive" histopathological subtypes of apparent early-stage, high-grade endometrial carcinoma. 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 χ 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. 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.

Endometrial carcinosarcoma without myoinvasion

Uterine carcinosarcoma without myoinvasion, limited to the endometrial lining/polyp or with no residual uterine disease at the time of hysterectomy, is extremely uncommon, with unknown oncologic outcomes. Thus, this study aimed to evaluate the long-term outcomes of patients with carcinosarcoma without myoinvasion. Patients with International Federation of Gynecology and Obstetrics 2009 stage IA carcinosarcoma without myoinvasion who underwent surgery from December 1998 to January 2023 were identified from 11 centers worldwide. Patients were classified by tumor status (limited to the endometrium, limited to polyp, no residual disease in the hysterectomy specimen) and by type of adjuvant therapy (chemotherapy vs no chemotherapy). Survival analysis follow-up was limited to the first 5 years after surgery. Of 97 patients included, 28 (28.9%) had disease confined to a polyp, 55 (56.7%) to the endometrium, and 14 (14.4%) had no residual disease in the hysterectomy specimen. Patients received observation only (n=16, 16.5%), vaginal brachytherapy alone (n=14, 14.4%), external beam radiation therapy ± vaginal brachytherapy (n=5, 5.2%), chemotherapy ± vaginal brachytherapy (n=51, 52.6%), and chemotherapy and external beam radiation therapy ± vaginal brachytherapy (n=7, 7.2%), whereas adjuvant therapy was unknown in 4 patients (4.1%). A total of 29 patients (29.9%) recurred, mostly with a distant pattern of relapse. The 5-year recurrence-free survival was 63.5% (95% CI 53.4% to 75.4%) and the overall survival was 72.0% (95% CI 62.6% to 82.9%). The median follow-up for patients without recurrence was 56.9 months (interquartile range; 21.8-72.9). No significant differences were observed in recurrence-free survival and overall survival based on status of the tumor (p=.99 and p=.43, respectively). The difference in recurrence-free survival and overall survival was not statistically significant based on the receipt of chemotherapy (p=.08 and p=.07, respectively). Patients with carcinosarcoma without myoinvasion have a poor prognosis, with a high recurrence rate with distant pattern. The use of chemotherapy did not achieve statistical significance but may be limited by our small series.

Correspondence on “ESGO/ESTRO/ESP guidelines for the management of patients with cervical cancer: update 2023” by Cibula et al

Correspondence on 'ESGO/ESTRO/ESP Guidelines for the management of patients with cervical cancer – Update 2023*'

Mapping the landscape of sentinel lymph nodes in endometrial cancer: let us continue in the right direction

Risk Stratification of Stage I Grade 3 Endometrioid Endometrial Carcinoma in the Era of Molecular Classification

PURPOSE The role of adjuvant therapy in stage I grade 3 endometrioid endometrial carcinoma (EEC) is debatable. We sought to define the agreement between Post Operative Radiation Therapy in Endometrial Carcinoma 1 (PORTEC-1) high-intermediate risk (HIR) and Gynecologic Oncology Group (GOG)-99 HIR criteria, assess their concordance with The Cancer Genome Atlas molecular subtypes, and evaluate oncologic outcomes in this population. METHODS We identified patients with stage I grade 3 EECs who underwent surgical staging at our institution from January 2014 to January 2020. Patients were stratified into PORTEC-1 HIR, GOG-99 HIR, and The Cancer Genome Atlas molecular subtypes. Adjuvant treatment, and progression-free survival (PFS), and overall survival (OS) were analyzed. RESULTS Seventy-five patients were included. The agreement between PORTEC-1 and GOG-99 HIR classification was 68% (95% CI, 56.2 to 78.3), with a kappa of 0.36 ( P = .001). There was no agreement between PORTEC-1 or GOG-99 HIR classification and a dichotomized molecular classification (copy number-high [CN-H] v other subtypes), with a kappa of 0.03 ( P = .39) and −0.03 ( P = .601), respectively. There was no difference in PFS between PORTEC-1 HIR and non-HIR (HR, 10.9; 95% CI, 0.28 to 4.21) or between GOG-99 HIR and non-HIR (HR, 1.22; 95% CI, 0.32 to 4.6) stage I grade 3 EECs. Patients with CN-H compared with non-CN-H EEC had worse PFS (HR, 5.67; 95% CI, 1.73 to 18.63) and OS (HR, 5.05; 95% CI, 1.13 to 22.5). CONCLUSION In surgically staged patients with stage I grade 3 EEC, PORTEC-1 and GOG-99 HIR criteria were not prognostic and did not identify CN-H patients. Patients with CN-H EEC had worse PFS and OS compared with those with other molecular subtypes. The integration of the molecular classification with recognized clinicopathologic factors may identify patients with higher-risk stage I grade 3 EEC who benefit from additional therapy.

High-Sensitivity Mutation Analysis of Cell-Free DNA for Disease Monitoring in Endometrial Cancer

Abstract Purpose: We sought to determine whether sequencing analysis of circulating cell-free DNA (cfDNA) in patients with prospectively accrued endometrial cancer captures the mutational repertoire of the primary lesion and allows for disease monitoring. Experimental Design: Peripheral blood was prospectively collected from 44 newly diagnosed patients with endometrial cancer over a 24-month period (i.e., baseline, postsurgery, every 6 months after). DNA from the primary endometrial cancers was subjected to targeted next-generation sequencing (NGS) of 468 cancer-related genes, and cfDNA to a high-depth NGS assay of 129 genes with molecular barcoding. Sequencing data were analyzed using validated bioinformatics methods. Results: cfDNA levels correlated with surgical stage in endometrial cancers, with higher levels of cfDNA being present in advanced-stage disease. Mutations in cfDNA at baseline were detected preoperatively in 8 of 36 (22%) patients with sequencing data, all of whom were diagnosed with advanced-stage disease, high tumor volume, and/or aggressive histologic type. Of the 38 somatic mutations identified in the primary tumors also present in the cfDNA assay, 35 (92%) and 38 (100%) were detected at baseline and follow-up, respectively. In 6 patients with recurrent disease, changes in circulating tumor DNA (ctDNA) fraction/variant allele fractions in cfDNA during follow-up closely mirrored disease progression and therapy response, with a lead time over clinically detected recurrence in two cases. The presence of ctDNA at baseline (P &amp;lt; 0.001) or postsurgery (P = 0.014) was significantly associated with reduced progression-free survival. Conclusions: cfDNA sequencing analysis in patients with endometrial cancer at diagnosis has prognostic value, and serial postsurgery cfDNA analysis enables disease and treatment response monitoring. See related commentary by Grant et al., p. 305

Primary characteristics and outcomes of newly diagnosed low-grade endometrial stromal sarcoma

To assess potential predictive variables for nodal metastasis and survival outcomes in patients with newly diagnosed, low-grade endometrial stromal sarcoma. We performed a single-institution, retrospective analysis of consecutive patients with newly diagnosed, low-grade endometrial stromal sarcoma who presented between January 1, 1980 and December 31, 2019 and underwent hysterectomy at our institution or presented within 3 months of primary surgery elsewhere before recurrence. Patients who presented to our institution only at recurrence were excluded. Patients with <3 months of follow-up were excluded from survival analyses. We identified 127 consecutive patients for analysis. Median age at diagnosis was 48 years (range 19-88 years); 91 (74.6%) of 127 were pre-menopausal; and 74 (58.3%) of 127 had uterine-confined, stage I tumors. Of 56 patients (44.1%) who underwent lymph node sampling, 10 (17.9%) had nodal metastasis. Of the 10 with nodal metastasis, 1 (10%) did not have lymphadenopathy or extra-uterine disease, 4 (40%) had lymphadenopathy only, 1 (10%) had extra-uterine disease only, and 4 (40%) had both. Among the 29 patients without apparent extra-uterine disease or gross lymphadenopathy, there was one occult lymph node metastasis (3.4%). Gross lymphadenopathy at time of surgery was predictive for lymph node metastasis (p<0.001). Median follow-up was 69 months (range 4-336) for the 95 patients included in the survival analyses. The 5-year progression-free survival and disease-specific survival rates were 79.8% and 90.8%, respectively. Patients with stage I tumors had longer progression-free survival than those with stage II-IV disease (p<0.001); there was no difference in disease-specific survival (p=0.63). Post-operative observation versus adjuvant therapy with hormone blockade or radiation therapy did not result in progression-free survival differences for stage I or completely resected stage II-IV disease (p=0.50 and p=0.81, respectively). Similarly, there was no disease-specific survival difference for completely resected stage II-IV disease (p=0.3). Lymph node dissection in patients with low-grade endometrial stromal sarcoma should be reserved for those with clinically suspicious lymphadenopathy. Disease stage correlated with progression-free survival but not disease-specific survival. Post-operative therapy did not improve progression-free survival or disease-specific survival.

Clinical outcomes of patients with endometrioid epithelial ovarian cancer following surgical treatment

AbstractBackgroundEndometrioid epithelial ovarian cancer (EEOC) is rare, and its management poorly defined. We examined factors associated with 5‐year progression‐free survival (PFS) after surgery for EEOC.MethodsRetrospective study: treatment and outcomes of all EEOC patients undergoing initial surgery at, or presenting to, our institution within 3 months of initial surgery, 1/2002‐9/2017.ResultsIn total, 212 patients were identified. Median follow‐up, 63.9 months (range, 0.7–192); median age at diagnosis, 52 years (range, 20–88); disease stage: I, n = 145 (68%); II, n = 47 (22%); III/IV, n = 20 (9%); FIGO grade: 1, 127 (60%); 2, 66 (31%); 3, 17 (8%); unknown, 2 (1%). One hundred twenty‐eight (60%) had endometriosis; 75 (35%), synchronous endometrioid endometrial cancer (80%, IA); 101 (48%), complete surgical staging; 8 (5%), positive pelvic lymph nodes (LNs); 6 (4%), positive para‐aortic LNs; 176 (97%), complete gross resection; 123 (60%), postoperative chemotherapy; 56(28%), no additional treatment. Five‐year PFS, 83% (95% confidence interval [CI]: 76.6%–87.8%); 5‐year overall survival (OS), 92.7% (95% CI: 87.7%–95.8%). Age, stage, and surgical staging were associated with improved 5‐year PFS, and younger age at diagnosis with improved 5‐year OS (p &lt; 0.001). Chemotherapy did not improve 5‐year PFS in IA/IB versus observation, but improved survival in IC (hazard ratio [HR]: 1.01, 95% CI: 0.22–4.59, p = 0.99; HR: 0.17, 95% CI: 0.04–0.7, p = 0.006).ConclusionsAge, stage, and full surgical staging were associated with improved 5‐year PFS. Chemotherapy showed no benefit in IA/IB disease.

Multi-center, international endometrial cancer consortium highlights

The multi-center, international consortium on endometrial cancer held in January 2025 at Mayo Clinic in Rochester, Minnesota brought together leading experts in gynecologic oncology to explore the latest advancements in the understanding, diagnosis, and treatment of endometrial cancer. Discussions centered on key topics, including updates in molecular testing and disease staging, emerging treatment strategies for advanced and recurrent disease, fertility-sparing management, and critical pathology challenges, particularly, the assessment of lympho-vascular space invasion. Each topic was examined in dedicated working group sessions, fostering in-depth exchanges to identify research priorities and develop actionable strategies. This summary highlights the central themes and insights from the meeting, outlining a roadmap for future advancements in the field. By promoting inter-disciplinary collaboration, the meeting laid the foundation for future research, policy recommendations, and clinical innovations aimed at improving patient outcomes.

Uterine leiomyosarcoma

Uterine leiomyosarcoma is a rare and heterogeneous gynecological malignancy that poses a significant clinical challenge due to its aggressive nature and limited treatment options. Its multifactorial etiopathogenesis involves complex cytogenetic and molecular aberrations, including TP53, RB1, and chromothripsis-associated gene alterations. The non-specific clinical presentation, resembling other benign conditions, complicates early and accurate diagnosis, alongside intricate radiological and pathological patterns. Advanced imaging techniques, such as magnetic resonance imaging and computed tomography, are employed to differentiate uterine leiomyosarcoma from benign conditions, but no single test is definitive. For FIGO (International Federation of Gynecology and Obstetrics) stage I uterine leiomyosarcoma, treatment consists of en bloc total hysterectomy ± bilateral salpingo-oophorectomy. Patients with stage II to IV disease amenable to complete resection can undergo surgery followed by adjuvant systemic therapy and/or radiotherapy. Lymphadenectomy is unnecessary in patients lacking bulky nodes. Unresectable or unsuitable cases warrant primary systemic therapy and/or radiotherapy. Managing recurrent disease requires a multimodal approach tailored to factors such as the site and number of metastases, prior radiotherapy, and resectability. Multidisciplinary management and centralization in referral centers are crucial for individualized decision-making. Ongoing research explores the intricate cytogenetic and molecular aberrations of uterine leiomyosarcoma, paving the way for personalized treatment strategies. This review, developed following the European Society of Gynaecological Oncology/Gynecologic Cancer InterGroup/European Reference Network on Rare Adult Solid Cancers guidelines, explores the clinical presentation, diagnostic challenges, and evolving therapeutic strategies for uterine leiomyosarcoma, while also highlighting variations in clinical practice worldwide.

ROCC/GOG-3043: a randomized controlled trial of robotic versus open surgery for early-stage cervical cancer

The Laparoscopic Approach to Cervical Cancer trial is the only randomized trial to date addressing the role of surgical approach in cervical cancer; however, this non-inferiority trial of minimally invasive surgery vs an open approach in patients undergoing radical hysterectomy for early-stage cervical cancer did not meet its primary end point of 4.5-year disease-free survival and was terminated early because of significantly worse disease-specific survival, overall survival, and locoregional recurrence in the minimally invasive surgery cohort. Our trial compares 3-year disease-free survival after robotic-assisted or abdominal radical or simple (in select cases) hysterectomy in early-stage cervical cancer. We hypothesize that disease-free survival is non-inferior after robotic-assisted vs abdominal radical or simple hysterectomy. This multi-center, randomized non-inferiority trial conducted through the Gynecologic Oncology Group has specified surgeon qualification criteria. It requires a pelvic magnetic resonance imaging scan in all patients before enrollment and will use 1:1 randomization to assign patients to robotic-assisted or abdominal hysterectomy. All surgeons must use specified tumor-containment techniques in both arms. It does not allow trans-cervical uterine manipulators. Patients with early-stage (2018 International Federation of Gynecology and Obstetrics stages IA2-IB2) cervical cancer. Histologic types are limited to squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma. Pelvic magnetic resonance imaging must confirm a tumor that is 4 cm or less without definitive extra-cervical spread. A simple hysterectomy is allowed in select cases after trial study principal investigator review. The primary end point is the 3-year disease-free survival between robotic-assisted or abdominal hysterectomy. The trial will randomly allocate 840 patients, with planned interim analysis for futility (oncologic safety) after we have randomly allocated 370 and 640 patients. 2030. ClinicalTrials.gov identifier: NCT04831580.

Oncologic and Perioperative Outcomes of Robot-Assisted Versus Conventional Laparoscopy for the Treatment of Clinically Uterine-Confined High-Grade Adenocarcinoma

The aim of this study was to compare oncologic and perioperative outcomes of robot-assisted laparoscopy (RA) and conventional laparoscopy (LSC) in apparent clinically uterine-confined, high-grade adenocarcinoma. A retrospective review was conducted to identify patients with newly diagnosed high-grade uterine adenocarcinoma treated at our institution between 1 January 2009 and 30 June 2021. Exclusion criteria included bulky extrauterine disease, no lymph node assessment, or synchronous tumors. Clinicopathologic details were obtained from medical records. Postoperative complications were classified using the Memorial Sloan Kettering Cancer Center Surgical Secondary Events system, and statistical analysis was performed using appropriate tests. Of 901 patients identified, 748 (83%) underwent RA and 153 (17%) underwent LSC. Median age was 65 years (range 25-92) and median body mass index was 30 kg/m RA demonstrated comparable oncologic outcomes to LSC in patients with high-grade endometrial carcinoma, with no significant difference in postoperative complications or long-term survival.

Management of patients with early-stage ovarian clear cell carcinoma: risk stratification and fertility conservation

We sought to describe clinicopathologic and treatment factors associated with oncologic outcomes in patients with early-stage ovarian clear cell carcinoma undergoing complete staging and in a sub-set of these patients undergoing fertility-conserving surgery. We retrospectively identified patients with ovarian clear cell carcinoma initially treated at our institution from January 1, 1996 to March 31, 2020. Survival was estimated using Kaplan-Meier curves and compared by log-rank test. Survival-associated variables were identified by Cox proportional hazards regression. Of 182 patients, mismatch repair and p53 protein expression were assessed by immunohistochemistry on 82 and 66 samples, respectively. There were no significant differences in progression-free survival or overall survival between mismatch repair-deficient (n=6, including 4 patients with Lynch syndrome; 7.3%) and mismatch repair-proficient patients, whereas aberrant p53 expression (n=3; 4.5%) was associated with worse progression-free (p<0.001) and overall survival (p=0.01). Patients with stage IA/IC1 disease had a 95% 5-year overall survival rate (95% CI 88% to 98%); patients with stage IC2/IC3 disease had a similar 5-year overall survival rate (76%; 95% CI 54% to 88%) to that of patients with stage IIA/IIB disease (82%; 95% CI 54% to 94%). There was no difference in 5-year overall survival in patients with stage IA/IC1 undergoing chemotherapy versus observation (94% vs 100%). Nine patients underwent fertility-sparing surgery and none experienced recurrence. Of five patients who pursued fertility, all had successful pregnancies. In patients with completely staged ovarian clear cell carcinoma, those with stage IA/IC1 disease have an excellent prognosis, regardless of chemotherapy. Aberrant p53 expression may portend worse outcomes. Additional investigation is warranted on the safety of fertility conservation in patients with stage IA/IC1 disease.

Comprehensive management of vulvovaginal cancers

AbstractVulvar and vaginal cancers represent rare malignancies, with an incidence of 2.7 per 100,000 women for vulvar cancer, predominantly affecting women older than 60 years, although rising rates are observed in younger demographics. Approximately 90% of vulvar cancers are squamous cell carcinoma and frequently are associated with human papillomavirus (HPV) infection. Vaginal cancer, constituting less than 1% of all female cancers, similarly exhibit HPV‐related trends. This review delineates the etiology, histopathology, and treatment strategies for carcinomas and vulvovaginal melanomas and sarcomas. Surgical intervention remains the primary treatment modality for vulvar cancer, involving tumor resection and inguinofemoral lymph node staging. For locally advanced vulvar carcinoma, chemoradiation is advised when exenterative surgery would be indicated. Recurrence rates within 2 years after diagnosis range from 12% to 37%. Unfortunately, systemic treatments for recurrent or metastatic disease are limited, with 5‐year survival rates at approximately 20%. Current evidence primarily derives from retrospective studies or small phase 2 trials or otherwise is extrapolated from the treatment of cervical cancer. Enrollment in clinical trials is strongly advocated, along with prompt access to best supportive care to mitigate the effect of locoregional progression on quality of life. Moreover, the psychosocial implications of treatment on body image and sexuality necessitate careful consideration. Future HPV vaccination initiatives may reduce cancer incidence, although significant effects of such vaccination will manifest over decades, underscoring the urgent need to enhance treatment efficacy and minimize morbidity in vulvar and vaginal cancers.

Radical Hysterectomy for Cervical Cancer: the Right Surgical Approach

Radical hysterectomy with pelvic lymph node assessment is the standard initial therapy for early-stage cervical cancer. Radical hysterectomy via laparotomy (an "open" approach) was first described more than 100 years ago and has been the standard for decades. Minimally invasive surgery (MIS) has been increasingly adopted by many surgeons due to its reported perioperative benefits. MIS was deemed safe for radical hysterectomy for many years based on multiple retrospective publications. Recently, the Laparoscopic Approach to Cervical Cancer (LACC) trial reported that patients randomized to MIS had inferior oncologic outcomes. The results of the LACC trial and subsequent retrospective studies led multiple professional societies to state that open radical hysterectomy should remain the gold standard surgical approach. We acknowledge that the open approach for radical hysterectomy is an appropriate option for all cervical cancer patients eligible for surgical treatment. However, considering the limitations of the LACC trial and the available data from other retrospective studies, we feel the MIS approach should not be simply abandoned. There may still be a role for MIS in cervical cancer surgery for properly and carefully selected cases and with detailed counseling; surgeons should analyze their own outcomes closely in order to perform such counseling. Modification of surgical technique and maintaining proper oncologic surgical principles are key for MIS to remain a viable option. Tumor manipulation and contamination should be avoided. Transcervical uterine manipulators should not be used. Cervical and tumor containment prior to colpotomy, as is performed during an open approach, is required. This will all require validation in future trials. We await the results of ongoing randomized trials to further inform us. A one-size-fits-all approach may be short-sighted; we may need to decide treatment strategy based on the notion of the right surgical approach for the right patient by the right surgeon.

Assessing the Genomic Landscape of Cervical Cancers: Clinical Opportunities and Therapeutic Targets

Abstract Purpose: Tumor genomic profiling is increasingly used to guide treatment strategy in patients with cancer. We integrated tumor genomic, clinical demographic, and treatment response data to assess how prospective tumor-normal sequencing impacted treatment selection in patients with cervical cancer. Experimental Design: Cervical cancers were prospectively analyzed using the MSK-IMPACT (Memorial Sloan Kettering Cancer Center – Integrated Mutation Profiling of Actionable Cancer Targets) next-generation sequencing panel. Clinical data, including histology, stage at diagnosis, treatment history, clinical trial enrollment and outcomes, date of last follow-up, and survival status were obtained from medical records. Results: A total of 177 patients with cervical cancer (squamous, 69; endocervical adenocarcinoma, 50; gastric type, 22; adenosquamous, 21; and other, 15) underwent MSK-IMPACT testing. The most prevalent genomic alterations were somatic mutations or amplifications in PIK3CA (25%), ERBB2 (12%), KMT2C (10%), and KMT2D (9%). Furthermore, 13% of patients had high tumor mutational burden (TMB &amp;gt;10 mut/Mb), 3 of which were also microsatellite instability–high (MSI-H). Thirty-seven percent of cases had at least one potentially actionable alteration designated as a level 3B mutational event according to the FDA-recognized OncoKB tumor mutation database and treatment classification system. A total of 30 patients (17%) were enrolled on a therapeutic clinical trial, including 18 (10%) who were matched with a study based on their MSK-IMPACT results. Twenty patients (11%) participated in an immune checkpoint inhibition study for metastatic disease; 2 remain progression free at &amp;gt;5 years follow-up. Conclusions: Tumor genomic profiling can facilitate the selection of targeted/immunotherapies, as well as clinical trial enrollment, for patients with cervical cancer.

Consensus on surgical technique for sentinel lymph node dissection in cervical cancer

The purpose of this study was to establish a consensus on the surgical technique for sentinel lymph node (SLN) dissection in cervical cancer. A 26 question survey was emailed to international expert gynecological oncology surgeons. A two-step modified Delphi method was used to establish consensus. After a first round of online survey, the questions were amended and a second round, along with semistructured interviews was performed. Consensus was defined using a 70% cut-off for agreement. Twenty-five of 38 (65.8%) experts responded to the first and second rounds of the online survey. Agreement ≥70% was reached for 13 (50.0%) questions in the first round and for 15 (57.7%) in the final round. Consensus agreement identified 15 recommended, three optional, and five not recommended steps. Experts agreed on the following recommended procedures: use of indocyanine green as a tracer; superficial (with or without deep) injection at 3 and 9 o'clock; injection at the margins of uninvolved mucosa avoiding vaginal fornices; grasping the cervix with forceps only in part of the cervix is free of tumor; use of a minimally invasive approach for SLN biopsy in the case of simple trachelectomy/conization; identification of the ureter, obliterated umbilical artery, and external iliac vessels before SLN excision; commencing the dissection at the level of the uterine artery and continuing laterally; and completing dissection in one hemi-pelvis before proceeding to the contralateral side. Consensus was also reached in recommending against injection at 6 and 12 o'clock, and injection directly into the tumor in cases of the tumor completely replacing the cervix; against removal of nodes through port without protective maneuvers; absence of an ultrastaging protocol; and against modifying tracer concentration at the time of re-injection after mapping failure. Recommended, optional, and not recommended steps of SLN dissection in cervical cancer have been identified based on consensus among international experts. These represent a surgical guide that may be used by surgeons in clinical trials and for quality assurance in routine practice.

Pre-operative imaging in clinical International Federation of Gynecology and Obstetrics stage IB2 or less cervical carcinoma

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. 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. 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%). 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.

Molecular Classification in Relation to Prevention of Endometrial Cancer Recurrence and Lifestyle Factors

Endometrial cancer (EC) is one of the most prevalent cancers in women worldwide with a significantly increasing incidence, especially in developed countries. One of the reasons for the increase in the incidence of this disease is the rising incidence of obesity as the biggest risk factor for the development of this disease. Other important risk factors are hypertension, diabetes mellitus and the general ageing of the population. These risk factors are not only associated with a higher risk of developing the disease, but also, for example, with post-operative complications affecting the quality of life of patients after surgery. The molecular classification of endometrial cancer, which has been introduced into clinical practice in recent years, is currently helping physicians to make treatment decisions for individual patients and predict prognosis. In this project, we would like to focus on the relationship of this molecular classification with genomic mutational signatures detected by whole-exome sequencing and their association with lifestyle risk factors for endometrial cancer (obesity - BMI, hypertension, diabetes mellitus), including the extent of staging lymphadenectomy. Identification and detailed analysis of dominant mutational profiles associated with a specific molecular subtype of EC and their influence on the presence of lifestyle risk factors may have a major impact on both disease development and prevention of disease recurrence. The possible relationship of the mutational profile with the extent of staging lymphadenectomy may help in deciding the extent of this surgical procedure, which subsequently affects the quality of life of patients, especially in patients with high BMI. Given the widespread prevalence of lifestyle risk factors in the developed world, a detailed understanding of the relationship between the genetic profile, its alterations and the prevalence of these risk factors, with potentially major implications for treatment success, is crutial.

A Trial of Robotic Versus Open Hysterectomy Surgery in Cervix Cancer

This is a randomized controlled trial to compare survival for patients who undergoe robotic assisted laparoscopy versus open hysterectomy and lymph node assessment for the treatment of early stage cervical cancer.

A Study of Intra-operative Imaging in Women With Ovarian Cancer

The purpose of this study is to find out whether using the PINPOINT imaging system intra-operatively can reduce the risk of anastomotic leaks and other complications after surgery for ovarian cancer, compared with standard intra-operative assessments alone. The PINPOINT endoscopic fluorescence imaging system uses a special camera and a fluorescent (glowing) dye that can evaluate the blood flow of the bowel in real-time. If there is an area that appears concerning, the surgeon can correct the problem during the procedure.