Diletta Fumagalli

Lymphadenectomy in early-stage ovarian cancer: is there still a role?

The role of systematic pelvic and para-aortic lymphadenectomy in presumed early-stage ovarian cancer remains controversial due to the lack of high-quality prospective evidence. No therapeutic benefit has been confirmed for systematic lymphadenectomy during surgical staging for apparent early-stage ovarian cancer. Lymphadenectomy may improve progression-free survival but has demonstrated no impact on overall survival, except for clear cell ovarian cancer, where a potential survival benefit has been suggested in retrospective studies. Systematic lymphadenectomy retains a diagnostic role in identifying occult nodal metastases (9% to 30% across series) undetected on pre-operative imaging or intra-operative assessment. The decision to perform lymphadenectomy should be individualized based on several factors, including histological sub-type, tumor grade, stage, and biomarker profile. Key considerations include the anticipated risk of lymph node metastasis, the opportunity to tailor adjuvant treatment by either omitting chemotherapy or offering maintenance targeted therapy, peri-operative morbidity, long-term sequelae impacting quality of life (eg, lower limb lymphedema), and cost-effectiveness. Systematic lymphadenectomy is guideline-recommended for high-grade tumors, including high-grade serous, high-grade endometrioid, and clear cell histologies, whereas it can be omitted in low-grade endometrioid and expansile mucinous sub-types. Its significance in low-grade serous and infiltrative mucinous ovarian cancers remains unclear, although guidelines frequently advocate for lymphadenectomy in these cases. To optimize patient selection, large-scale prospective studies with proper stratification by histotype and molecular profile are required. Emerging approaches to lymph node assessment, such as sentinel lymph node biopsy, artificial intelligence-assisted pre-operative imaging, and liquid biopsy, hold promise for improving staging accuracy.

Primary versus interval cytoreductive surgery in patients with rare epithelial or non-epithelial ovarian cancer

The standard treatment for advanced epithelial ovarian cancer is primary cytoreductive surgery, with the goal of achieving no residual disease. Neoadjuvant chemotherapy and interval cytoreductive surgery can be viable treatment options for patients with extensive disease that precludes complete tumor removal during initial surgery, or when significant comorbidities increase the surgical risk without adversely impacting overall survival rates. However, published studies mostly included patients with high-grade serous ovarian cancer, with an underrepresentation of non-high-grade serous epithelial and non-epithelial cancers. This review aimed to provide an overview of the available data on the outcomes of primary cytoreductive surgery versus interval cytoreduction in patients with rare ovarian cancer histotypes. Published literature on primary versus interval cytoreductive surgery in non-high-grade serous ovarian cancers from 2004 to 2024 was searched using PubMed, EMBASE, and Google Scholar and reported for each histological subtype. The outcomes of patients with low-grade serous, endometrioid, clear-cell, and mucinous carcinomas after neoadjuvant chemotherapy were reviewed. Furthermore, the results following neoadjuvant chemotherapy in non-epithelial ovarian cancers, such as ovarian germ cell tumors, sex cord-stromal tumors, and small-cell carcinoma of the ovary, have also been reported. Most data were derived from retrospective studies, with heterogeneity in design. Several ovarian cancer histotypes, including low-grade serous and mucinous carcinomas, may be less responsive than high-grade serous carcinomas to neoadjuvant chemotherapy. Consequently, primary cytoreduction with maximal surgical effort may confer a survival advantage. Other tumors responded well to neoadjuvant chemotherapy, allowing for interval fertility-sparing surgeries. Additional evidence is required because no prospective studies are currently available. Given the low incidence of these diseases, randomized controlled trials may not be feasible. However, national or international registries could play a pivotal role in determining the optimal approach for managing patients with these rare histotypes.

Rewinding the clock on positive peritoneal cytology in endometrial cancer: does it predict prognosis in low-risk disease?

Positive peritoneal cytology in endometrial cancer is a known risk factor for worse oncologic outcomes but is not used for staging purposes or to guide adjuvant treatment. Additionally, its prognostic impact on low-risk patients remains unclear. Therefore, we investigated the role of positive peritoneal cytology in patients with endometrial cancer and focused on low-risk disease. This is a retrospective cohort study including all consecutive patients undergoing primary surgery for endometrial cancer at Mayo Clinic from 1999 to 2021. The role of positive peritoneal cytology was investigated in the entire cohort and in 2 subgroups: the National Comprehensive Cancer Network (NCCN) low-risk group, including low-risk patients according to NCCN guidelines (endometrioid, grade 1-2, stage IA) and the European Society of Gynecologic Oncology/European Society of Radiotherapy and Oncology/European Society of Pathology (ESGO/ESTRO/ESP) low-risk group, including low-risk patients according to ESGO/ESTRO/ESP guidelines (as NCCN, plus no lymphovascular space invasion). Univariate and multivariable analyses were used to evaluate the association of positive peritoneal cytology with recurrence within 5 years after surgery, and Kaplan-Meier survival analyses were performed in all groups. A total of 3517 patients were included, 1911 in the NCCN low-risk group and 1832 in the ESGO/ESTRO/ESP low-risk group. Positive peritoneal cytology was found in 15.9% of the entire cohort (559/3517), 8.1% of the NCCN low-risk group (154/1911), and 7.9% of the ESGO/ESTRO/ESP low-risk group (145/1832). In both low-risk groups, 5-year recurrence-free survival was worse in patients with positive peritoneal cytology (p < .01 and p = .03, respectively), but there was no difference in overall survival. On univariate analysis, age, tumor grade, and positive peritoneal cytology were significant predictors of recurrence in both subgroups. After multivariable analysis, positive peritoneal cytology remained independently associated with recurrence (p < .01 and p = .03, respectively). Positive peritoneal cytology was an independent predictor of recurrence and was associated with worse recurrence-free survival in patients with low-risk endometrial cancer. However, overall survival was not impacted.

Artificial intelligence model for enhancing the accuracy of transvaginal ultrasound in detecting endometrial cancer and endometrial atypical hyperplasia

Transvaginal ultrasound is typically the initial diagnostic approach in patients with postmenopausal bleeding for detecting endometrial atypical hyperplasia/cancer. Although transvaginal ultrasound demonstrates notable sensitivity, its specificity remains limited. The objective of this study was to enhance the diagnostic accuracy of transvaginal ultrasound through the integration of artificial intelligence. By using transvaginal ultrasound images, we aimed to develop an artificial intelligence based automated segmentation model and an artificial intelligence based classifier model. Patients with postmenopausal bleeding undergoing transvaginal ultrasound and endometrial sampling at Mayo Clinic between 2016 and 2021 were retrospectively included. Manual segmentation of images was performed by four physicians (readers). Patients were classified into cohort A (atypical hyperplasia/cancer) and cohort B (benign) based on the pathologic report of endometrial sampling. A fully automated segmentation model was developed, and the performance of the model in correctly identifying the endometrium was compared with physician made segmentation using similarity metrics. To develop the classifier model, radiomic features were calculated from the manually segmented regions-of-interest. These features were used to train a wide range of machine learning based classifiers. The top performing machine learning classifier was evaluated using a threefold approach, and diagnostic accuracy was assessed through the F1 score and area under the receiver operating characteristic curve (AUC-ROC). 302 patients were included. Automated segmentation-reader agreement was 0.79±0.21 using the Dice coefficient. For the classification task, 92 radiomic features related to pixel texture/shape/intensity were found to be significantly different between cohort A and B. The threefold evaluation of the top performing classifier model showed an AUC-ROC of 0.90 (range 0.88-0.92) on the validation set and 0.88 (range 0.86-0.91) on the hold-out test set. Sensitivity and specificity were 0.87 (range 0.77-0.94) and 0.86 (range 0.81-0.94), respectively. We trained an artificial intelligence based algorithm to differentiate endometrial atypical hyperplasia/cancer from benign conditions on transvaginal ultrasound images in a population of patients with postmenopausal bleeding.

Incidence of sentinel lymph node metastases in apparent early-stage endometrial cancer: a multicenter observational study

Ultrastaging is accurate in detecting nodal metastases, but increases costs and may not be necessary in certain low-risk subgroups. In this study we examined the risk of nodal involvement detected by sentinel lymph node (SLN) biopsy in a large population of apparent early-stage endometrial cancer and stratified by histopathologic characteristics. Furthermore, we aimed to identify a subgroup in which ultrastaging may be omitted. We retrospectively included patients who underwent SLN (with bilateral mapping and no empty nodal packets on final pathology) ± systematic lymphadenectomy for apparent early-stage endometrial cancer at two referral cancer centers. Lymph node status was determined by SLN only, regardless of non-SLN findings. The incidence of macrometastasis, micrometastasis, and isolated tumor cells (ITC) was measured in the overall population and after stratification by histotype (endometrioid vs serous), myometrial invasion (none, <50%, ≥50%), and grade (G1, G2, G3). Bilateral SLN mapping was accomplished in 1570 patients: 1359 endometrioid and 211 non-endometrioid, of which 117 were serous. The incidence of macrometastasis, micrometastasis, and ITC was 3.8%, 3.4%, and 4.8%, respectively. In patients with endometrioid histology (n=1359) there were 2.9% macrometastases, 3.2% micrometastases, and 5.3% ITC. No macro/micrometastases and only one ITC were found in a subset of 274 patients with low-grade (G1-G2) endometrioid endometrial cancer without myometrial invasion (all <1%). The incidence of micro/macrometastasis was higher, 2.8%, in 708 patients with low-grade endometrioid endometrial cancer invading <50% of the myometrium. In patients with serous histology (n=117), the incidence of macrometastases, micrometastasis, and ITC was 11.1%, 6.0%, and 1.7%, respectively. For serous carcinoma without myometrial invasion (n=36), two patients had micrometastases for an incidence of 5.6%. Ultrastaging may be safely omitted in patients with low-grade endometrioid endometrial cancer without myometrial invasion. No other subgroups with a risk of nodal metastasis of less than 1% have been identified.

Waist-to-hip ratio measured with computed tomography as a predictor of surgical outcomes in minimally invasive procedures for early-stage endometrial cancer

This study aimed to determine if the waist-to-hip ratio, an emerging indicator of abdominal obesity, predicts poor outcomes, such as sentinel node mapping failure, post-operative complications, conversion to laparotomy, and increased operative time, in endometrial cancer surgery. This retrospective study included patients with apparent early-stage endometrial carcinoma who underwent minimally invasive surgery at the Mauriziano Umberto I Hospital in Turin, Italy from January 2021 to January 2025. The waist-to-hip ratio was calculated using pre-operative computed tomography scans with previously described methods. Two cohorts based on a waist-to-hip ratio cutoff of 0.85, as defined by the World Health Organization, were identified and compared with statistical tests as appropriate. Univariate and multi-variable linear regression models were fit to evaluate predictors of poor surgical outcomes. A total of 151 patients were included in the study. Abdominal obesity, as defined by an abnormal waist-to-hip ratio, was identified in 127 patients (84%), of whom 62 also had obesity according to the body mass index. Patients with abnormal waist-to-hip ratios were significantly older (median: 69 vs 61 years; p = .03), had higher body mass index (median: 29 vs 21 kg/m An abnormal waist-to-hip ratio was significantly associated with increased operative time during minimally invasive surgery for endometrial cancer, whereas body mass index was not. Further research is needed to determine the predictive potential of the waist-to-hip ratio for personalized surgical planning.

External validation of the annual recurrence risk model for tailored surveillance strategy in patients with cervical cancer

The annual recurrence risk model (ARRM), developed by the Surveillance in Cervical Cancer consortium and endorsed by the European Society of Gynecological Oncology, predicts the annual risk of cervical cancer recurrence. However, it lacks an external validation, which we aimed to address in the current retrospective study. We included patients with pathology confirmed T1a to T2b cervical cancers who underwent radical surgery at the European Institute of Oncology, Milan from January 2010 to December 2022. Using the ARRM risk calculator, patients were assigned a score from 0 to 100 points, which allowed classification into 5 risk groups (0, 1-25, 26-50, 51-75, and 76-100 points). Differences in 5-year disease-free survival were evaluated through log-rank tests with pairwise comparisons. Annual risk of recurrence was calculated using conditional survival analysis. Overall, 411 patients with cervical cancers were included: 0 (0.0%) scored 0 points, 149 (36.3%) scored 1 to 25 points, 224 (54.5%) scored 26 to 50 points, 37 (9.0%) scored 51 to 75 points, and 1 (0.2%) scored 76 to 100 points. The patient from 76 to 100 points was excluded from further analyses. The 5-year disease-free survival rates were 96.3% (95% CI 90.0 to 98.6), 85.7% (95% CI 80.1% to 89.9%), and 66.6% (95% CI 47.3% to 80.2%) in groups 1 to 25, 26 to 50, and 51 to 75 points, respectively (p < .01). Compared with 26 to 50 and 51 to 75 points, the annual risk of recurrence was lower in the 1 to 25 points group, at around 1% from year 1 to 5. The ARRM tool confirmed its validity in stratifying cervical cancer into groups with significantly different disease-free survival rates in an independent large population from a tertiary center. The annual risk of recurrence should be carefully considered when tailoring follow-up, always taking into account the patient's perspective.