Roberto Berretta

Sentinel node mapping in high-intermediate and high-risk endometrial cancer: Analysis of 5-year oncologic outcomes

To assess 5-year oncologic outcomes of apparent early-stage high-intermediate and high-risk endometrial cancer undergoing sentinel node mapping versus systematic lymphadenectomy. This is a multi-institutional retrospective, propensity-matched study evaluating data of high-intermediate and high-risk endometrial cancer (according to ESGO/ESTRO/ESP guidelines) undergoing sentinel node mapping versus systematic pelvic lymphadenectomy (with and without para-aortic lymphadenectomy). Survival outcomes were assessed using Kaplan-Meier and Cox proportional hazard methods. Overall, the charts of 242 patients with high-intermediate and high-risk endometrial cancer were retrieved. Data on 73 (30.1%) patients undergoing hysterectomy plus sentinel node mapping were analyzed. Forty-two (57.5%) and 31 (42.5%) patients were classified in the high-intermediate and high-risk groups, respectively. Unilateral sentinel node mapping was achieved in all patients. Bilateral mapping was achieved in 67 (91.7%) patients. Three (4.1%) patients had site-specific lymphadenectomy (two pelvic areas only and one pelvic plus para-aortic area), while adjunctive nodal dissection was omitted in the hemipelvis of the other three (4.1%) patients. Sentinel nodes were detected in the para-aortic area in eight (10.9%) patients. Twenty-four (32.8%) patients were diagnosed with nodal disease. A propensity-score matching was used to compare the aforementioned group of patients undergoing sentinel node mapping with a group of patients undergoing lymphadenectomy. Seventy patient pairs were selected (70 having sentinel node mapping vs. 70 having lymphadenectomy). Patients undergoing sentinel node mapping experienced similar 5-year disease-free survival (HR: 1.233; 95%CI: 0.6217 to 2.444; p = 0.547, log-rank test) and 5-year overall survival (HR: 1.505; 95%CI: 0.6752 to 3.355; p = 0.256, log-rank test) than patients undergoing lymphadenectomy. Sentinel node mapping does not negatively impact 5-year outcomes of high-intermediate and high-risk endometrial cancer. Further prospective studies are warranted.

Pattern of recurrence in endometrial cancer. The murderer always returns to the scene of the crime

Endometrial cancer recurrence occurs in about 18 % of patients. This study aims to analyze the pattern recurrence of endometrial cancer and the relationship between the initial site of primary disease and the relapse site in patients undergoing surgical treatment. We retrospectively reviewed all surgically treated patients with endometrial cancer selecting those with recurrence. We defined primary site disease as uterus, lymph nodes, or peritoneum according to pathology analysis of the surgical specimen. The site of recurrence was defined as vaginal cuff, lymph nodes, peritoneum, and parenchymatous organs. Our primary endpoint was to correlate the site of initial disease with the site of recurrence. The study enrolled 1416 patients. The overall recurrence rate was 17,5 % with 248 relapses included in the study. An increase of 9.9, 5.7, and 5.7 times in the odds of relapse on the lymph node, peritoneum, and abdominal parenchymatous sites respectively was observed in case of nodal initial disease (p < 0.001). A not significant difference in odds was observed in terms of vaginal cuff relapse (OR 0.9) between lymph node ad uterine primary disease (p = 0.78). An increasing OR of 8.7 times for nodal recurrences, 46.6 times for peritoneum, and 23.3 times for parenchymatous abdominal recurrences were found in the case of primary peritoneal disease (p < 0.001). Endometrial cancer tends to recur at the initial site of the disease. Intraoperative inspection of the adjacent sites of primary disease and targeted instrumental examination of the initial sites of disease during follow-up are strongly recommended.

Characteristics and outcomes of surgically staged multiple classifier endometrial cancer

The growing adoption of molecular and genomic characterization is changing the current landscape of treatment of endometrial cancer patients. Using the surrogate molecular classification, endometrial cancer patients can be classified in four subgroups: POLE mutated (POLEmut), MMRd/MSI-H, p53 abnormal (p53abn), and no specific mutational profile (NSMP). However, some patients can harbor two or more molecular features (defined as multiple classifier). Since the rarity of this occurrence, evidence regarding multiple classifiers is still limited. Here, we described characteristics and outcomes of multiple classifiers. This is a multi-institutional retrospective study. Data of consecutive patients having 2 or more molecular features were collected. Survival was assessed using the Kaplan-Meier and Cox proportional hazard methods. Charts of 72 multiple classifiers were reviewed. Median (range) follow-up was 9.8 (1.2, 37.5) months. Overall, 31 (43%) patients had POLEmut. Patients with POLEmut-MMRd/MSI-H, POLEmut-p53abn, and POLEmut-MMRd/MSI-H-p53abn were 6 (8.3%), 20 (27.8%), and 5 (6.9%), respectively. Among those 31 patients, no recurrence occurred within a median follow-up of 10.5 months (only seven (22.6%) patients had at least 2-year follow-up). The remaining 41 (56.9%) patients were diagnosed with tumors harboring both p53 and MMRd/MSI-H. Among them, four (9.8%) recurrences occurred at a median follow-up time of 8.9 months. Adjuvant therapy (other than vaginal brachytherapy) was administered in 5/31 (16%) and 25/41 (61%) patients with and without POLEmut, respectively (p < 0.001). Multiple classifiers endometrial cancer with POLEmut are characterized by good prognosis even in case of presence of MMRd/MSI-H and/or p53abn. Additional studies with long-term follow-up are needed.

MIRaGE (Minimally Invasive suRGery in recurrent Endometrial cancer)

Endometrial cancer is one of the most common gynecologic malignancies. Recurrence occurs in 10% to 15% of early-stage and up to 70% of advanced-stage cases. Secondary cytoreductive surgery is critical when complete gross resection is achievable. Minimally invasive surgery may offer perioperative advantages, but data on patient selection and oncologic outcomes are limited. This retrospective study included patients with first abdominal recurrence of endometrial cancer who underwent secondary cytoreductive surgery at Fondazione Policlinico Universitario A. Gemelli IRCCS between 2010 and 2023. Patients were grouped by surgical approach (minimally invasive surgery [MIS]: laparoscopy/robotic-assisted vs open surgery). The primary endpoint was the identification of clinical and radiological preoperative predictors of successful MIS, defined as complete gross resection. Secondary endpoints included intraoperative and perioperative outcomes, and survival outcomes (overall survival and progression-free survival). Among 192 patients with abdominal recurrence, 74 (38.5%) underwent MIS. The 2 groups were not fully homogeneous, differing mainly in relapse site and recurrence pattern; nevertheless, complete gross resection was achieved in 97.3% of minimally invasive procedures and 94.9% of open surgeries (p = .42). Minimally invasive surgery was associated with lower blood loss (p < .001), fewer transfusions (p = .030), shorter operative times (p < .001), and reduced hospital stays (p < .001). Independent predictors of successful MIS were body mass index ≥30, early-stage disease, single-site relapse, and loco-regional or lymph-node recurrence. No significant differences were observed in survival outcomes, with comparable overall survival (p = .47) and progression-free survival (p = .43) between groups. Minimally invasive surgery may represent a feasible option for selected patients with recurrent endometrial cancer, providing perioperative advantages with comparable survival outcomes. Prospective multicenter studies are needed to confirm oncologic safety and to refine patient selection, also in the context of integration with novel therapies.

Fertility-sparing management of low-grade endometrial stromal sarcoma: A systematic review of oncologic and reproductive outcomes

Low-grade endometrial stromal sarcoma (LG-ESS) is a rare malignancy and the standard of care, precludes future childbearing. Although fertility-sparing treatment (FST) may be considered in carefully selected patients, high-quality evidence regarding its efficacy and safety is limited. This review aims to systematically evaluate the oncologic and reproductive outcomes associated with conservative treatment for LG-ESS. Pubmed Database, Scopus Database and Embase Database were screened in September 2024 from the first publication about women with LG-ESS treated with a surgical FST. We included the studies containing data about oncologic, and reproductive outcomes. This study adheres to PRISMA guidelines and is registered with PROSPERO (CRD42024605140). The quality of the studies was assessed using the Newcastle-Ottawa scale. 9 studies fulfilled inclusion criteria, and 89 patients were analyzed. Recurrence was observed in 51 out of 89 patients (57.3 %) with a mean recurrence-free interval ranging between 3 and 40.5 months. A mortality rate of 1.1 % was observed, with a mean follow-up duration ranging from 38.5 to 84.5 months. The overall pregnancy rate was 41.5 % and the live birth rate was 78.1 %. The preterm delivery rate was 8 % and 3.9 % of patients required assisted reproduction technology. Considering the limitations of the available evidence, FST in women with LG-ESS carries a relatively high risk of tumor relapse, though it does not increase the risk of death. Fertility outcomes seem to be encouraging. Resection of the malignant uterine lesion combined with adjuvant hormonal treatment may be considered for selected early-stage patients, with close follow-up.

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.

Exploring isolated tumor cells entity in endometrial cancer

Endometrial cancer (EC) management includes nodal staging and molecular classification. Despite molecular advancements, the biological significance of isolated tumor cells (ITC) in EC remains unclear. This study aimed to characterize ITC in the context of pathological and molecular features MATERIALS AND METHODS: A multicenter, retrospective analysis included EC patients diagnosed between June 2018 and May 2024 who underwent surgical staging via sentinel lymph node (SLN) biopsy and molecular profiling. ITC cases detected through SLN ultrastaging or One Step Nucleic Acid Amplification (OSNA) were compared with N0 and N + (micro-/macrometastasis) groups. Among the 1821 patients included, nodal status was N0 in 84.5 %, ITC in 5.1 %, micrometastases in 5.3 %, and macrometastases in 4.5 %. ITC patients exhibited deep myometrial invasion in 67.7 % of cases vs. 28.7 % in N0 (p < 0.001). Diffuse lymphovascular space invasion (LVSI) was significantly higher in ITC (52.1 %) than N0 (12.2 %, p < 0.001). MMR deficiency was more frequent in ITC (33.3 %) vs. N0 (25.0 %, p = 0.07). POLE mutations were more common in N0 (4.2 %) and ITC (3.1 %) vs. N + (1.1 %), though not statistically significant. p53-abnormal tumors were significantly associated with N + status (19.4 %) compared to ITC (7.3 %, OR 0.33, p = 0.008). No relapses occurred among ITC patients with low-risk features. These findings suggest that ITC may represent an early form of nodal involvement, biologically distinct from micro- and macrometastases. The association with MMR deficiency and the absence of aggressive markers such as p53 abnormalities support a less aggressive profile. Integrating molecular and pathological features may refine risk stratification and inform management strategies for EC patients with ITC.

Hysteroscopic endometrial tumor localization and sentinel lymph node mapping. An upgrade of the hysteroscopic role in endometrial cancer patients

Given the growing interest in sentinel node mapping (SLN) biopsy in Endometrial Cancer (EC) patients, many efforts have been made to maximize the SLN bilateral detection rate. However, at present, no previous research assessed the potential correlation between primary EC location in the uterine cavity and SLN mapping. In this context, this study aims to investigate the possible role of intrauterine EC hysteroscopic localization in predicting SLN nodal placement. EC patients surgically treated from January 2017 to December 2021 were retrospectively analyzed. All patients underwent hysterectomy, bilateral salpingo-oophorectomy, and SLN mapping. During hysteroscopy, the location of the neoplastic lesion was described as follows: uterine fundus (comprising the most cranial portion of the uterine cavity up to the tubal ostium including the cornual areas), corpus uteri (from the tubal ostium to the inner uterine orifice), and diffuse (when the tumor invades more than 50% of the uterine cavity). Three hundred ninety patients met the inclusion criteria. The tumor pattern diffused to the whole uterine cavity was statistically associated with SLN uptake on common iliac lymph nodes (OR 2.4, 95%CI 1-5.8, p = 0.05). Patients'age is an independent factor associated with SLN failure (OR: 0.95, 95%CI 0.93-0.98, p < 0.001). The study showed a statistically significant association between EC hysteroscopically spread throughout the whole uterine cavity and SLN uptake at the common iliac lymph nodes. Furthermore, patient age negatively affected the SLN detection rate.

Urologic Complication after Laparoscopic Hysterectomy in Gynecology Oncology: A Single-Center Analysis and Narrative Review of the Literature

Background and Objectives: Minimally invasive surgery (MIS) has recently increased its application in the treatment of gynecological malignancies. Despite technological and surgical advances, urologic complications (UC) are still the main concern in gynecology surgery. Current literature reports a wide range of urinary tract injuries, and consistent scientific evidence is still lacking or dated. This study aims to report a large single-center experience of urinary complications during laparoscopic hysterectomy for gynecologic oncologic disease. Materials and Methods: All patients who underwent laparoscopic hysterectomy for gynecologic malignancy at the Department of Medicine and Surgery of the University Hospital of Parma from 2017 to 2021 were retrospectively included. Women with endometrial cancer, cervical cancer, ovarian cancer, uterine sarcoma, or borderline ovarian tumors were included. Patients undergoing robotic surgery with incomplete anatomopathological data or patients lost during follow-up were excluded from the analysis. Intraoperative and postoperative UC were analyzed and ranked according to the Clavien-Dindo classification. Results: Two hundred-sixty patients were included in the study: 180 endometrial cancer, 18 cervical cancer, nine ovarian cancer, two uterine sarcomas, and 60 borderline ovarian tumors. Nine (3.5%) UCs were reported (five intraoperative and four postoperative complications). No anamnestic variables showed a statistical correlation with the surgical complication in the univariable analyses. C1 radical hysterectomy, a higher FIGO stage, and postoperative adjuvant treatment (p-value = 0.001, p-value = 0.046, and p-value = 0.046, respectively) were independent risk factors associated with the occurrence of UC. Conclusions: The urological complication rates in patients with oncological disease are relatively rare events in the expert hands of dedicated surgeons. Radical hysterectomy, FIGO stage, and adjuvant treatment are independent factors associated with urinary complications.

A large multicenter propensity match study of sentinel lymph node biopsy feasibility in endometrioid variants of endometrial cancer

Sentinel lymph node (SLN) biopsy algorithm has been routinely applied in all endometrial endometrioid tumors, however, no studies analyzed the feasibility of SLN mapping in endometrioid variants (EV), which included villoglandular, secretory, ciliated cell, mucinous, and squamous differentiation. This study aimed to demonstrate the feasibility of SLN biopsy in EV of EC. All patients undergoing minimally invasive surgical treatment for early-stage EC were included in the study. Patients were divided into 2 study groups: Group 1 which included patients with EV, and Group 2 which included patients with typical endometrioid histology. A propensity match analysis was performed according to age (≥65 years vs. no), BMI (≥30 kg/m After a 1:5 propensity-matched analysis, a total of 458 patients were identified (Group 1 n = 77, Group 2 n = 381). Overall detection rate was not statistically significant between the EV and the typical endometrioid group (94.8% vs. 92.4%, p = 0.319). Furthermore, neither bilateral nor unilateral detection rate was different between the two groups (70.1% vs. 74.8%, p = 0.267, and 23.4% vs. 17.8%, p = 0.120). BMI ≥30 kg/m SLN research/detection for EV of endometrial cancer is a feasible and highly sensitive technique. Obesity was confirmed to be a risk factor for SLN failure.

Obesity, an independent predictor of pre and postoperative tumor grading disagreement in endometrial cancer

Obesity is a known independent risk factor for endometrial cancer (EC), and obese patients have a 4.7-fold increased risk compared to the general population to develop the neoplasm. To date, a general pre and postoperative tumor grading agreement from 53 % to 82 % is reported for endometrial analysis, and a consensus on which factors might influence the tumor grading discordance is still absent. Furthermore, although obesity alters the endometrial microenvironment, no studies investigated the role of obesity in the grading agreement of EC patients. This study aims to analyze the role of obesity in the pre and postoperative tumor grading agreement. A retrospective analysis was conducted on EC cancer women subjected to surgical treatment. Upgrading discordance was defined as higher tumor grading on final pathological analysis compared to tumor grading on the preoperative examination. Downgrading discordance was defined as a lower tumor grading at the postoperative surgical specimen analysis compared to the preoperative biopsy. Of the 293 selected patients, 245 were included in the analysis. One hundred and forty nine (60.8 %) patients were tumor grade G1, 52 (21.2 %) G2, and 44 (18.0 %) G3. Grading agreement was 83.9 % for G1 patients, 51.9 % for G2 patients, and 83.3 % for G3 patients. The multivariate analysis showed obesity (BMI > 30 kg/m Our study for the first time showed obesity as the only factor in the multivariate analysis lowering the pre and postoperative tumor grading concordance. Grade 2 tumor was the factor that most frequently disagreed with the final surgical specimen analysis both in the general and in obese patients.

Proton Beam Therapy in Gynecological Cancers: A Systematic Review of Indications, Complications, and Limitations

Background and Objectives: Gynecological cancers frequently require radiation therapy (RT) in primary, adjuvant, or salvage settings. However, photon-based RT is associated with non-negligible toxicity, and treatment of pelvic recurrences after prior irradiation remains challenging. Proton beam therapy (PBT), due to its favorable dose distribution and reduced exposure of organs at risk (OARs), has emerged as a potential alternative, particularly in re-irradiation scenarios. Despite its expanding use in other malignancies, evidence supporting PBT in gynecologic cancers remains limited. This systematic review aims to investigate the use of PBT in gynecological cancers and its associated complications. Materials and Methods: This systematic review was conducted according to PRISMA guidelines and registered in PROSPERO. A comprehensive search (2000–2025) identified studies investigating PBT in gynecologic cancers. Eligible designs included randomized trials and prospective and retrospective series. Reported adverse events were categorized as GI, GU, or other, and only grade ≥3 CT-CAE complications were considered. Results: Of 580 records screened, 9 studies comprising 232 patients met inclusion criteria. Most patients were treated for endometrial (n = 147) or cervical (n = 75) cancer; 90 received chemotherapy. Overall, severe toxicity occurred in 15.2% of patients. GI complications ranged from 0–14% and GU from 0–33%. Complication rates were lowest in adjuvant or de novo treatment series (0–10%), whereas re-irradiation cohorts showed higher rates (up to 33% GU). Comparative studies suggested a possible advantage of PBT over IMRT, particularly for GI toxicity, though data remain limited. Conclusions: Severe GI and GU toxicity after PBT in gynecologic cancers appears infrequent, particularly in primary and adjuvant settings, though re-irradiation remains challenging. Current evidence is restricted to small and heterogeneous studies. Ongoing phase II trials will provide prospective data to clarify feasibility, toxicity, and long-term outcomes. Until then, PBT in gynecologic oncology should be regarded as investigational.

Levonorgestrel-releasing intra-uterine device alone for managing early-stage endometrial cancer and endometrial hyperplasia with atypia in patients unfit for surgery: the ENDOIUD study

This study aimed to clarify the role of levonorgestrel-releasing intra-uterine device as a stand-alone therapy in managing patients with endometrial atypical hyperplasia/endometrial cancer who are not suitable for surgery, through the evaluation of cause-specific survival and the control of vaginal bleeding. This is a retrospective, multi-center study conducted in 9 referral gynecologic centers in Italy. Data regarding the clinical and oncological outcomes of patients with endometrial atypical hyperplasia/endometrial cancer (International Federation of Gynecology and Obstetrics Stage I) were analyzed. Patients were judged unsuitable for surgery due to an American Society of Anesthesiologists score ≥3 and the presence of multiple severe co-morbidities and, therefore, triaged to receive levonorgestrel-releasing intra-uterine device alone. A total of 78 women were enrolled. Fifteen patients (19.2%) had a diagnosis of endometrial atypical hyperplasia, whereas the other 63 (80.8%) had endometrial cancer. The baseline hemoglobin levels averaged 11.6 (range; 6-16), increasing to 12.1 (range; 7.8-14.9) during follow-up after levonorgestrel-releasing intra-uterine device insertion (p = .003). No patient experienced any side effects, and bleeding control was rated as excellent in most patients. Median disease-free survival was 43 months (range; 5-120) and median overall survival was 45 months (range; 5-120). Levonorgestrel-releasing intra-uterine device alone is a safe and effective approach, showing no side effects, and a promising oncological outcome in women with early-stage endometrial atypical hyperplasia/endometrial cancer unfit for surgery. Future prospective studies are required to clarify how to select patient candidates for this therapy and how to predict response to levonorgestrel-releasing intra-uterine device.

Exploring the cost-effectiveness of the OSNA method for patients facing endometrial cancer: Insights from a single-institution experience

The one-step nucleic acid amplification (OSNA) method has emerged as a potential alternative to ultrastaging for diagnosing lymph node metastasis. This study aims to assess the cost-effectiveness of the OSNA technique compared to ultrastaging for detecting SLN metastasis in patients with early-stage endometrial cancer (EC). This retrospective, observational, single-center study included 30 patients with EC who underwent surgical treatment. SLN mapping was performed using an intracervical injection of indocyanine green. SLNs were analyzed and classified as negative, as having isolated tumor cells, micrometastases, or macrometastases. The study evaluated and quantified the costs of the OSNA and ultrastaging procedures in euros. A total of 54 lymph nodes were analyzed using both the OSNA and ultrastaging methods. Concordant negativity was identified in 48 cases (89 %), while micrometastases were detected concordantly in 1 case (1.8 %). The cost for a single ultrastaging lymph node analysis, including immunohistochemistry, is approximately € 250, with a total processing time of 2 days. The cost for a single OSNA analysis is approximately € 236, boasting a significantly shorter processing time of 30-40 min. While materials and staff costs are comparable between both techniques, considering time-related expenses, the OSNA method proves to be more cost-effective than ultrastaging (p < 0.001). The OSNA method demonstrates diagnostic accuracy comparable to histopathological examination in detecting lymph node metastases, reinforcing its reliability for lymph node assessment in patients with EC. Our cost analysis reveals that the OSNA method is more cost-effective than ultrastaging when time-related expenses are considered.