Giulio Sozzi

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.

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.

Long-term survival outcomes in high-risk endometrial cancer patients undergoing sentinel lymph node biopsy alone versus lymphadenectomy

Endometrial cancer is the most common gynecologic neoplasm. To date, international guidelines recommend sentinel lymph node biopsy for low-risk neoplasms, while systematic lymphadenectomy is still considered for high-risk cases. This study aimed to compare the long-term survival of high-risk patients who were submitted to sentinel lymph node biopsy alone versus systematic pelvic lymphadenectomy. Patients with high-risk endometrial cancer according to the 2021 European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology risk classification were retrospectively analyzed. The primary aim of the study was to compare the long-term overall survival and disease-free survival of high-risk endometrial cancer patients undergoing sentinel lymph node biopsy versus systematic lymphadenectomy. A supplementary post-hoc survival analysis of cases with nodal metastasis was performed to compare sentinel lymph node and lymphadenectomy survival outcomes in this subset of patients. The study enrolled 237 patients with histologically proven high-risk endometrial cancer. Patients were followed up for a median of 31 months (IQR 18-40). During the follow-up, 38 (16.0%) patients had a recurrence, and 19 (8.0%) patients died. Disease-free survival (85.2% vs 82.8%; p=0.74) and overall survival (91.3% vs 92.6%; p=0.62) were not different between the sentinel lymph node alone and lymphadenectomy groups. Furthermore, neither overall survival (96.1% vs 91.4%; p=0.43) nor disease-free survival (83.7% vs 76.4%; p=0.46) were different among sentinel lymph node alone and lymphadenectomy groups in patients with nodal metastasis. Sentinel lymph node mapping alone in high-risk endometrial cancer appears to be an oncologically safe technique over a long observational time. Systematic lymphadenectomy in this population does not offer a survival advantage.

A randomized controlled trial on the oncologic outcomes of use of the intrauterine manipulator in the treatment of apparent uterine-confined endometrial carcinoma: the MANEC Trial

The intrauterine manipulator used during a hysterectomy for endometrial cancer has been suggested as a reason for worsening oncologic outcomes. However, only a few non-randomized retrospective studies have investigated this association. To compare 4-year recurrence-free survival in the group of patients who undergo hysterectomy using an intrauterine manipulator with that of those who undergo hysterectomy without it. Patients with endometrial cancer who undergo laparoscopic hysterectomy performed with an intrauterine manipulator would have a lower recurrence-free survival than patients who undergo laparoscopic hysterectomy without a manipulator. Multicenter, parallel arm, open-label, randomized controlled trial. Adult women diagnosed with apparently uterine-confined endometrial cancer of any histology are eligible. We exclude women who had synchronous or previous (2, and had inadequate baseline organ function. 4-Year recurrence-free survival defined as any relapse or death related to endometrial cancer or treatment calculated from randomization to the date of the first recurrence-free survival event. With an accrual time of 4 years, a minimum follow-up length of 4 years, and a two-sided type I error of 0.05, we need to enroll 515 women per arm to have a statistical power of 80% to reject the null hypothesis (HR for recurrence=1), assuming that patients who undergo hysterectomy with the use of the intrauterine manipulator have a 3-year recurrence rate of 12.5% and without the use of the intrauterine manipulator of 8.5% (HR for recurrence=1.50), and that 5% of patients are lost at follow-up in each arm, with a median time of 24 months. Accrual completion is expected in 2028, and result presentation in 2032. ClinicalTrial.gov ID NCT05687084.

Semiquantitative evaluation of lymph-vascular space invasion in patients affected by endometrial cancer: Prognostic and clinical implications

The interpretation of lymph-vascular space invasion (LVSI) is usually qualitative, as presence or absence. The aim of this study is to investigate the prognostic role of LVSI in patients affected by endometrial cancer, when evaluated with a semiquantitative analysis. This retrospective multicentre study enrolled patients who received a histologically confirmed diagnosis of endometrial cancer. The assessment of LVSI was semiquantitative in accordance with the three-tiered scoring system (absent, focal and diffuse). Among 1258 patients with surgical-stage endometrial cancer, LVSI has been found in 32.8% of cases (n = 412), whose 12.7% (n = 160) were focal, and 20% (n = 252) diffuse. The rate of lymph node metastasis increased from the 5% in patients with no LVSI to 15% in patients with focal LVSI and 33% in those with diffuse LVSI (p < 0.001). Distant recurrences were more frequent in patients with diffuse LVSI than in focal or no LVSI (24.9% versus 14.7% and 6.6%, respectively, p < 0.001). Diffuse LVSI was found to significantly increase the risk of distant metastasis (adjusted odds ratio (A OR) 2.57, p < 0.001). Adjuvant radiation were associated with improved overall survival (OS) and disease-free survival (DFS) in patients with diffuse LVSI. The presence of diffuse LVSI is an independent risk factor for both lymph node metastasis and distant recurrence in endometrial cancer patients, and it is associated with a significantly decreased OS and DFS. Adjuvant radiation improved survival regardless of grading, histotype and lymph nodal metastasis in women with diffuse LVSI.

Nodal Assessment in Endometrial Atypical Hyperplasia

&lt;b&gt;&lt;i&gt;Objective:&lt;/i&gt;&lt;/b&gt; Atypical endometrial hyperplasia (AH) is the neoplastic precursor more often associated with endometrial cancer (EC). Nowadays, 25–50% of patients subjected to hysterectomy for preoperative AH are diagnosed with EC at the final pathological analysis. Furthermore, there is no consensus on which preoperative AH patients would benefit from sentinel lymph node mapping. This study aimed to evaluate nodal assessment and preoperative cancer risk factors in preoperative AH patients undergoing nodal surgical staging. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; Patients undergoing surgical treatment for AH were retrospectively included in the analysis. Patients were divided into two groups (AH and EC groups) based on the final surgical pathology. The ESGO/ESTRO/ESP risk classification was used for EC cases. &lt;b&gt;&lt;i&gt;Design:&lt;/i&gt;&lt;/b&gt; This was a retrospective study. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Of the 207 AH patients treated, 152 cases met the inclusion criteria. Among preoperative AH patients with final EC diagnosis, 39 patients were in the low-risk group (25.7%), 8 in the intermediate-risk group (5.3%), 4 in high-intermediate (2.6%), and 3 patients were allocated in the high-risk group (2.0%). Fifty-four total patients underwent nodal surgical staging. Only one nodal micrometastasis (0.7%) was found at ultrastaging. Multivariate analysis showed abnormal uterine bleeding (AUB) (&lt;i&gt;p&lt;/i&gt; = 0.01), hypertension (&lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.01), and endometrial thickness ≥20 mm (&lt;i&gt;p&lt;/i&gt; = 0.02) statistically more represented in patients with EC at final surgical analysis. EC risk was 2.9 (95% CI: 1.29–6.48) in AUB, 2.7 (95% CI: 1.06–6.92) in hypertension, and 3.1 (95% CI: 1.19–7.97) in endometrial thickness ≥20 mm cases. &lt;b&gt;&lt;i&gt;Limitations:&lt;/i&gt;&lt;/b&gt; The present study has limitations inherent in its retrospective nature. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; The overall risk of nodal metastases in preoperative AH patients was low. Conversely, 9.9% of the preoperative AH patients belonged to the intermediate or high-risk group for EC at the final histological examination. Preoperative cancer risk factors would identify AH patients for whom nodal staging could be suggested.

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.

Laparoscopic sentinel node mapping with intracervical indocyanine green injection for endometrial cancer: the SENTIFAIL study – a multicentric analysis of predictors of failed mapping

Laparoscopy is commonly used for endometrial cancer treatment, and sentinel lymph node (SLN) mapping has become the standard procedure for nodal assessment. Despite the standardization of the technique, there is no definitive data regarding its failure rate. The objective of this study is to identify factors associated with unsuccessful SLN mapping in endometrial cancer patients undergoing laparoscopic SLN mapping after intracervical indocyanine green (ICG) injection. We retrospectively evaluated a consecutive series of endometrial cancer patients who underwent laparoscopic SLN mapping with intracervical ICG injection, in four oncological referral centers from January 2016 to July 2019. Inclusion criteria were biopsy-proven endometrial cancer, total laparoscopic approach, and intracervical ICG injection. Exclusion criteria were evidence of lymph node involvement or extrauterine disease at pre-operative imaging, synchronous invasive cancer, the use of tracers different from ICG, and the use of neoadjuvant treatment. Bilateral and failed bilateral SLN mapping groups were compared for clinical and pathological features. In patients with an unsuccessful procedure, side-specific lymphadenectomy was performed. Logistic regression was used to identify predictors of failure. A total of 376 patients were included in the study. The overall bilateral and unilateral SLN detection rates were 96.3%, 76.3%, and 20.0% respectively. The failed bilateral mapping detection rate was 23.7%. The median number of sentinel nodes removed was 2.2 (range, 0-5). After multivariate analysis, lymph vascular space involvement [OR 2.4 (1.04-1.12), P=0.003], non-endometrioid histology [OR 3.0 (1.43-6.29), P=0.004], and intraoperative finding of enlarged lymph node [OR 2.3 (1.01-5.31), P=0.045] were identified as independent predictors of failure of SLN mapping. Lymph vascular space involvement, non-endometrioid histology, and intra-operative finding of enlarged lymph nodes were identified as independent risk factors for unsuccessful mapping in patients undergoing laparoscopic SLN mapping.

Novel preoperative predictive score to evaluate lymphovascular space involvement in endometrial cancer: an aid to the sentinel lymph node algorithm

Sentinel lymph node (SLN) dissection has been recognized as a valid tool for staging in patients with endometrial cancer. Several factors are predictors of recurrence and survival in endometrial cancer, including positive lymphovascular space invasion. The aim of this study is to formulate a pre-operative score that, in the event of no-SLN identification, may give an estimate of the true probability of lymphovascular space invasion and guide management. This was a multi-institutional retrospective study conducted from January 2007 to December 2017. We included all patients with any grade endometrial tumor with a complete pathological description of the surgical specimen and with a minimum follow-up of 12 months. All patients underwent a class A hysterectomy according to Querleu and Morrow and bilateral salpingo-oophorectomy. Lymphadenectomy was performed based on patient risk of node metastases. In order to verify the predictive capacity of the parameters associated with lymphovascular space invasion status, grading, abnormal CA125 (>35 units/ml), myometrial invasion, and tumor size, a synthetic score was calculated. The score was introduced in the receiver operating characteristic curve model in which the binary classifier was represented by the lymphovascular space invasion status. The ideal cut-off was calculated with the determination of the Youden index. Sensitivity and negative predictive value of lymphovascular space invasion score was calculated in patients with lymph node metastasis. Six hundred and fourteen patients were included in the study. The average age and BMI of patients were 64.8 (range 33-88) years and 30.1 (range 17-64) respectively. Of the 284 patients who underwent lymphadenectomy, 231 (81.3%) patients had no lymph node metastases, 33 (11.6%) patients had metastatic pelvic lymph nodes, 12 (4.2%) patients had metastatic aortic lymph nodes, and eight (2.8%) patients had both pelvic and aortic metastatic lymph nodes. Lymphovascular space invasion was associated with deep myometrial infiltration (P<0.001), G3 grading (P<0.001), tumor size ≥25 mm (P=0.012), abnormal CA125 (P<0.001), recurrence (P<0.001), overall survival (P<0.001), and disease-free survival (P<0.01). Of all patients with lymphovascular space invasion, 79% had an lymphovascular space invasion score ≥5. The score ranged from a minimum score of 1 to a maximum of 7. The score shows 78.9% sensitivity (95% CI 0.6971 to 0.8594), 65.3% specificity (95% CI 0.611 to 0.693), 29.4% positive predictive value (95% CI 0.241 to 0.353), and 94.4% negative predictive value (95% CI 0.916 to 0.964). We found that when lymphovascular space invasion score ≤4, there is a very low possibility of finding lymph nodal involvement. The preoperative lymphovascular space invasion score could complement the SLN algorithm to avoid unnecessary lymphadenectomies.

Laparoscopic laterally extended pelvic resection for gynecological malignancies

The role of surgery in platinum-resistant ovarian cancer: A call to the scientific community

In the last decade, a growing attention has been focused on identifying effective therapeutic strategies also in the orphan clinical setting of women with platinum-resistant disease. In this context, secondary cytoreductive surgery (SCS) remains a potential approach only in women with platinum sensitive relapse, but experimental data have been published supporting the role of SCS also in patients with platinum-resistant recurrence. In particular, surgery is emerging as a potential option in specific subgroups of women, such as those patients with low-grade serous histology, or low-volume relapse with disease located in the so-called pharmacological sanctuaries. Furthermore, contrasting evidences have suggested a potential role in this clinical setting of SCS combined with intraperitoneal hyperthermic chemotherapy. In this complex scenario we review here the available evidences regarding the role surgery in ovarian cancer patients with platinum resistant disease, trying also to understand which patients may benefit from this challenging, experimental approach.

Integrated pre-surgical diagnostic algorithm to define extent of disease in cervical cancer

Survival of patients with cervical cancer is strongly associated with the local extent of the primary disease. The aim of the study was to develop an integrated diagnostic algorithm, including ultrasonography (USG), magnetic resonance imaging (MRI), and examination under anesthesia, to define the local extent of disease in patients with newly diagnosed cervical cancer. Patients with biopsy proven cervical cancer who underwent primary surgery from January 2013 to December 2018 in four participating centers were recruited. Patients who underwent USG, MRI, and examination under anesthesia prior to surgery were included in the study. Those for whom complete data were not available were excluded. Data regarding tumor size, parametrial invasion, and vaginal involvement obtained by USG, MRI, and examination under anesthesia were retrieved and compared with final histology. Specificity and sensitivity of the three methods were calculated for each parameter and the methods were compared with each other. An integrated pre-surgical algorithm was constructed considering the accuracy of each diagnostic method for each parameter. A total of 79 consecutive patients were included in the study. Median age was 53 years (range 28-87) and median body mass index was 24.6 kg/m Our integrated diagnostic algorithm allows a higher accuracy in defining the local extent of disease and may be used as a tool to determine the therapeutic approach in women with cervical cancer.

Vena cava resection and bypass for recurrent cervical cancer

Radical Hysterectomy for Early Stage Cervical Cancer

Radical hysterectomy and plus pelvic node dissection are the primary methods of treatment for patients with early stage cervical cancer. During the last decade, growing evidence has supported the adoption of a minimally invasive approach. Retrospective data suggested that minimally invasive surgery improves perioperative outcomes, without neglecting long-term oncologic outcomes. In 2018, the guidelines from the European Society of Gynaecological Oncology stated that a “minimally invasive approach is favored” in comparison with open surgery. However, the phase III, randomized Laparoscopic Approach to Cervical Cancer (LACC) trial questioned the safety of the minimally invasive approach. The LACC trial highlighted that the execution of minimally invasive radical hysterectomy correlates with an increased risk of recurrence and death. After its publication, other retrospective studies investigated this issue, with differing results. Recent evidence suggested that robotic-assisted surgery is not associated with an increased risk of worse oncologic outcomes. The phase III randomized Robotic-assisted Approach to Cervical Cancer (RACC) and the Robotic Versus Open Hysterectomy Surgery in Cervix Cancer (ROCC) trials will clarify the pros and cons of performing a robotic-assisted radical hysterectomy (with tumor containment before colpotomy) in early stage cervical cancer.

Surgical outcomes and morbidity in open and videoendoscopic inguinal lymphadenectomy in vulvar cancer: A systematic review and metanalysis”

Surgical evaluation of inguinal lymph nodes is essential to correctly guide the adjuvant treatment of vulvar cancer patients. Open inguinal lymphadenectomy (OIL) approach is the preferred route, while the videoendoscopic inguinal lymphadenectomy (VEIL) seems to be associated with better results. This meta-analysis aimed to compare the surgical outcomes of OIL vs VEIL in vulvar cancer. The meta-analysis was conducted according to the PRISMA guideline. The search string included the following keywords: "(vulvar cancer) AND ((inguinal) OR (femoral)) AND ((lymph node dissection) OR (lymphadenectomy))". Three double-blind researchers independently extracted data. Seventeen studies were considered eligible for the analysis. Seven studies were included in the OIL group and ten studies in the VEIL group. A total of 372 groins were included in OIL group and 197 groins in VEIL group. 153 groins (41.1 %) in the OIL group and 25 groins (12.6 %) in the VEIL group developed major complications. The analysis of all lymphatic and wound complications showed that VEIL had a lower rate of lymphatic and wound complications. Estimated blood loss (p = 0.4), hospital stay (p = 0.18), time of drainage (p = 0.74), number of lymph node excised (p = 0.74) did not show significant difference between the two approaches. VEIL route may be a valid alternative to OIL route with no differences in terms of surgical outcomes, except for operative time that is shorter for OIL. Future analysis of randomized controlled trials in this specific patient population are warranted to confirm these results.

Comparison of Two-Position and Four-Position Cervical Injection Techniques for Sentinel Lymph Node Mapping in Endometrial Cancer Using Methylene Blue

This clinical trial evaluates lymph node mapping in newly diagnosed endometrial cancer patients undergoing surgery. The standard technique uses a 2-point methylene blue cervical injection. The study aims to determine if increasing injection points improves mapping success.

Uterine Manipulator Versus No Uterine Manipulator in Endometrial Cancer Trial

Minimally invasive surgery is the recommended approach in endometrial cancer (EC) patients based on the results of two randomized controlled trials, given its advantages without compromised oncologic outcomes. The uterine manipulator is commonly used in benign and malignant pathologies to perform a laparoscopic or robotic hysterectomy. However, although regularly used, the uterine manipulator adoption in EC is a controversial technical aspect due to the raised concerns regarding the possible risk of disruption of the tumor mass, the spread of malignant cells, and seeding of the disease, particularly at the level of the vaginal cuff or spread of tumor cells, with increased risk of recurrence and death due to EC. On that basis, given that hysterectomy without a uterine manipulator is feasible, only a randomized controlled trial comparing oncologic outcomes in EC patients after use versus not use of the uterine manipulator will be able to provide high-quality evidence to answer this critical question and allow or exclude the use of a uterine manipulator during minimally invasive hysterectomy for EC.