Matteo Loverro

Focal lymphovascular space invasion: Friend or foe? A large retrospective analysis on stage I endometrioid endometrial carcinomas

Literature is inconsistent with respect to clinical value of lymphovascular space invasion (LVSI) semiquantitative assessment. We aim to investigate the prognostic role of LVSI extent in stage I endometrioid endometrial carcinomas (ECs) classified by immunohistochemistry (IHC) analysis. Patients with stage I endometrioid EC undergone primary surgery were retrospectively included. Following World Health Organization definition for LVSI pathologic evaluation, subjects were divided into: LVSI-negative; LVSI-focal; LVSI-substantial. An IHC-based model was utilized to classify patients into: p53-aberrant (p53abn); mismatch repair deficient (MMRd); mismatch repair proficient with positive estrogen receptors (MMRp-ERpos); and mismatch repair proficient with negative estrogen receptors (MMRp-ERneg). 2091 subjects were included and divided into: 78.0 % (n:1631) LVSI-negative, 10.6 % (n:221) LVSI-focal, and 11.4 % (n:239) LVSI-substantial. Presence of LVSI (any extent) was associated with older age, larger tumor size and deeper myometrial infiltration. Patients with LVSI-substantial presented with higher incidence of grade 3 tumors, p53abn and MMRd status. Conversely, most LVSI-negative and LVSI-focal cases were MMRp-ERpos. At multivariable regression, LVSI-substantial was independently associated with reduced 5-year disease-free survival (DFS) and overall-survival (OS). LVSI-negative and LVSI-focal groups had similar DFS (p = 0.42) and OS (p = 0.09), whereas comparison with LVSI-substantial demonstrated significantly poorer outcomes for patients with substantial invasion. These findings were confirmed in sub-analyses of cases with grade 1-2 endometrioid and myometrial infiltration, and in the MMRp-ERpos cohort. In stage I endometrioid ECs, LVSI-focal was not associated with reduced oncologic outcomes compared to LVSI-negative. In contrast, LVSI-substantial was associated with aggressive clinicopathologic and molecular features and behaved as an independent prognostic factor for reduced survival. Our results were further confirmed in two low-risk EC settings: grade 1-2 with myometrial infiltration, and the MMRp-ERpos group.

Trends and current aspects of reconstructive surgery for gynecological cancers

Gynecologic cancers can lead to gynecologic tract destruction with extension into both the gastrointestinal and urinary tracts. Recurrent disease can also affect the surrounding bony pelvis and pelvic musculature. As opposed to advanced ovarian cancer, where cytoreduction is the goal, in these scenarios, an oncologic approach to achieve negative margins is critical for benefit. Surgeries aimed at achieving a R0 resection in gynecologic oncology can have a significant impact on pelvic anatomy, and require reconstruction. Overall, it appears that these types of radical surgery are less frequently performed; however, when required, multidisciplinary teams at high-volume centers can potentially improve short-term morbidity. There are few data to examine the long-term, quality-of-life outcomes after reconstruction following oncologic resection in advanced and recurrent gynecologic cancers. In this review we outline considerations and approaches for reconstruction after surgery for gynecologic cancers. We also discuss areas of innovation, including minimally invasive surgery and the use of 3D surgical anatomy models for improved surgical planning.In the era of 'less is more', pelvic exenteration in gynecologic oncology is still indicated when there are no other curative-intent alternatives in persistent or recurrent gynecological malignancies confined to the pelvis or with otherwise unmanageable symptoms from fistula or radiation necrosis. Pelvic exenteration is one of the most destructive procedures performed on an elective basis, which inevitably carries a significant psychologic, sexual, physical, and emotional burden for the patient and caregivers. Such complex ultraradical surgery, which requires removal of the vagina, vulva, urinary tract, and/or gastrointestinal tract, subsequently needs creative and complex reconstructive procedures. The additional removal of sidewall or perineal structures, like pelvic floor muscles/vulva, or portions of the musculoskeletal pelvis, and the inclusion of intra-operative radiation further complicates reconstruction. This review paper will focus on the reconstruction aspects following pelvic exenteration, including options for urinary tract restoration, reconstruction of the vulva and vagina, as well as how to fill large empty spaces in the pelvis. While the predominant gastrointestinal outcome after exenteration in gynecologic oncology is an end colostomy, we also present some novel new options for gastrointestinal tract reconstruction at the end.

Impact of surgery and molecular classification in stage IV endometrial cancer

Evidence supporting the role of surgery after neoadjuvant chemotherapy in advanced endometrial cancer remains limited. Additionally, the prognostic relevance of molecular classification in this setting is poorly defined. We aimed to evaluate overall survival in patients with peritoneal and/or extra-abdominal spread, focusing on surgical approach and molecular sub-type. We retrospectively analyzed all patients with Fédération Internationale de Gynécologie et d'Obstétrique 2009 stage IVB (Fédération Internationale de Gynécologie et d'Obstétrique 2023 IIIB2, IVB, IVC) endometrial cancer treated between January 2012 and September 2023. Patients were stratified according to immunohistochemistry-based molecular classification, intra-abdominal disease extension, and treatment strategy. Kaplan-Meier and Cox regression analyses were used to assess overall survival. Differences across groups were evaluated using appropriate nonparametric and categorical statistical tests. Among 363 eligible patients, 229 (63.1%) underwent primary cytoreduction, 52 (14.3%) had interval debulking surgery, 55 (15.2%) received chemotherapy alone, and 27 (7.4%) were untreated. Patients receiving neoadjuvant or exclusive chemotherapy more frequently had extra-abdominal (p < .001) and upper abdominal disease (p < .001). In patients with extra-pelvic disease, overall survival was comparable between primary and interval surgery (p = .82). Among those treated with neoadjuvant treatment, surgical cytoreduction was strongly associated with improved overall survival (p < .001). Mismatch repair-deficient patients had better overall survival than those with p53 abnormal tumors (34 vs 21 months, p = .026). No specific molecular profile-estrogen receptor positive tumors showed longer overall survival than both p53 abnormal and no specific molecular profile-estrogen receptor negative sub-types (60 vs 34 and 21 months, p = .018 and p = .041, respectively). In multivariate analysis, extra-pelvic disease (p = .042) and exclusive chemotherapy (p < .0001) were independent negative prognostic factors. In advanced endometrial cancer, surgery remains a key component of management. Our findings suggest a potential survival advantage for patients who undergo surgery-either as primary treatment or following neoadjuvant chemotherapy-compared to those treated with chemotherapy alone. Molecular classification may offer prognostic insight even in stage IV disease, although further validation is required. These findings provide a benchmark for future studies in the evolving landscape of immunotherapy and personalized treatment.

Diagnostic performance of ultrasound-guided biopsy for detecting recurrent or persistent cervical cancer after chemoradiotherapy: a prospective, single-center study

This study aimed to compare the feasibility, diagnostic accuracy, and sample adequacy of trans-vaginal ultrasound-guided biopsy versus per-vagina biopsy for detecting persistent or recurrent pelvic disease after chemoradiotherapy for locally advanced cervical cancer. Procedure-related pain was also evaluated. This prospective, single-center diagnostic study conducted at Fondazione Policlinico Universitario Agostino Gemelli IRCCS (Rome, Italy) from November 2019 to September 2024 included consecutive patients with clinical or radiologic suspicion of persistent or recurrent cervical cancer after chemoradiotherapy. Patients undergoing trans-vaginal ultrasound-guided biopsy and per-vagina biopsy (index tests) were analyzed. Histology from pelvic exenteration or follow-up imaging when surgery was not performed served as the reference standard. Accuracy, sensitivity, and specificity were calculated for each index test and compared using the McNemar test. Feasibility was defined as the rate of successfully performed biopsies and adequacy as the proportion of samples yielding a conclusive histologic diagnosis. Fifty-three patients were included. A total of 44 of 53 patients (83.0%) underwent pelvic exenteration, whereas 9 of 53 (17.0%) underwent imaging follow-up. Ultrasound-guided biopsy was feasible in 52 of 53 cases (98.1%) compared with 40 of 53 cases (75.5%) for per-vagina biopsy. All samples obtained from both techniques were adequate. Ultrasound-guided biopsy showed a sensitivity of 0.84, specificity of 1.00, and accuracy of 0.87. Per-vagina biopsy showed a sensitivity of 0.55, specificity of 0.86, and accuracy of 0.60. Among 39 paired feasible cases, specificity did not differ significantly between the 2 techniques (p = .27); however, ultrasound-guided biopsy showed significantly higher sensitivity and accuracy (p = .022 and p = .021, respectively). Ultrasound-guided biopsy appeared to be a feasible method for histologic confirmation in suspected persistent or recurrent cervical cancer after chemoradiotherapy. It demonstrated superior diagnostic accuracy over per-vagina biopsy and holds potential for routine clinical application. Successful integration into clinical practice requires appropriate clinician training and access to specialized equipment.

Real-world outcomes of PARP inhibitor maintenance in advanced ovarian cancer: a focus on disease patterns and treatment modalities at recurrence

The utilization of poly-ADP-ribose polymerase (PARP) inhibitors (PARPi) as a first-line maintenance therapy for advanced ovarian cancer has increased significantly, with ∼80% of patients potentially eligible. This expansion has led to a rise in the population experiencing platinum-sensitive recurrence, yet data on first recurrence during PARPi are limited. This real-world study from a high-volume referral center aims to elucidate recurrence rates, disease distribution, and treatment modalities at the time of progression in PARPi-treated patients. We analyzed our prospectively maintained database to identify patients receiving first-line PARPi maintenance from January 2019 to December 2022 at our institution. A total of 373 cases were identified, 51.5% of which had a BRCA mutation. With a median follow-up of 38 months, 44.8% of patients experienced recurrence, with 90.3% having a platinum-free interval exceeding 6 months. Recurrences were oligometastatic in 44.9% of cases, with BRCA mutations strongly predicting this pattern (hazard ratio 3.014, confidence interval 1.486-6.113, P = 0.002). The median progression-free survival was 39 months, significantly longer for BRCA-mutated and homologous recombination deficiency-positive patients. Over one-third of platinum-sensitive recurrent patients were candidates for local treatments, and PARPi administration was prolonged in 53.7%. Despite the notable survival improvement, a significant proportion of the population will experience a platinum-sensitive recurrence on PARPi, for which local treatments are often a viable option. Our study highlights the need for further research to determine whether the ablation of oligometastatic sites has a significant impact on post-recurrence survival and to identify if there are patient categories that would benefit from personalized follow-up due to their susceptibility to oligometastatic recurrences and local treatments.

Role of minimally invasive secondary cytoreduction in patients with recurrent ovarian cancer

Retrospective series have shown minimally invasive secondary cytoreductive surgery is a feasible approach in selected cases of recurrent ovarian cancer. However, no predictors of minimally invasive secondary cytoreductive surgery feasibility are currently available. This study aims to identify predictive factors of minimally invasive secondary cytoreductive surgery feasibility and to compare perioperative and survival outcomes in a matched series of recurrent ovarian cancer patients who underwent secondary cytoreduction via an open or minimally invasive surgical approach. We retrospectively identified all platinum-sensitive recurrent epithelial ovarian cancer patients who underwent minimally invasive or laparotomic secondary cytoreductive surgery between January 2013 and July 2020. Each patient underwent a preoperative positron emission tomography (PET) computerized tomography (CT) scan and diagnostic laparoscopy before secondary cytoreductive surgery. A 1:2 propensity score-matched analysis was performed to balance predictive factors of minimally invasive secondary cytoreductive surgery. Overall, 276 patients were identified (62 minimally invasive and 214 open), and a complete gross resection was achieved in 262 (94.9%) patients. At multivariate analysis, predictive factors for minimally invasive secondary cytoreductive surgery were neoadjuvant chemotherapy at first diagnosis (p=0.007), site of recurrence (p=0.031), and number of lesions (p=0.001). In the 1:2 propensity-matched population (39 minimally invasive and 78 open), complete gross resection was similar for both groups (p=0.082). Early post-operative complications were significantly higher in the laparotomy (33.3%) than in the minimally invasive surgery (10.3%) group (p=0.004). Only one (2.6%) patient experienced a grade >3 early post-operative complication in the minimally invasive surgery group compared with 13 (16.7%) patients in the open cohort (p<0.001). The median follow-up period was 32 months (range: 1-92) in the propensity-matched population. The median post-recurrence survival was 81 months in the minimally invasive surgery group and was not reached in the open group (p=0.11). Patients with single or oligometastatic recurrences can be offered minimally invasive secondary cytoreductive surgery, mainly if localized in the lymph-nodes, and/or if they received neoadjuvant chemotherapy at primary diagnosis. Minimally invasive secondary cytoreductive surgery is associated with favorable perioperative outcomes with no differences in terms of post-recurrence survival with respect to open approach.

Predictive factors of surgical complications after pelvic exenteration for gynecological malignancies: a large single-institution experience

To evaluate pre-operative predictors of early (<30 days) severe complications (grade Dindo 3+) in patients with gynecological malignancy submitted to pelvic exenteration (PE). We retrospectively analyzed 129 patients submitted to surgery at Fondazione Policlinico Gemelli between 2010 and 2019. We included patients affected by primary or recurrent/persistent cervical, endometrial, or vulvar/vaginal cancers. Post-operative complications were graded according to the Dindo classification. Logistic regression was used to analyze potential predictors of complications. We performed 63 anterior PE, 10 posterior PE, and 56 total PE. The incidence of early severe post-operative complications was 27.9% (n=36), and the early mortality rate was 2.3% (n=3). More frequent complications were related to the urinary diversion and intestinal surgery. In univariable analysis, hemoglobin ≤10 g/dL (odds ratio [OR]=4.2; 95% confidence interval [CI]=1.65-10.7; p=0.003), low albumin levels (OR=3.9; 95% CI=1.27-12.11; p=0.025), diabetes (OR=4.15; 95% CI=1.22-14.1; p=0.022), 2+ comorbidities at presentation (OR=5.18; 95% CI=1.49-17.93; p=0.012) were predictors of early severe complications. In multivariable analysis, only low hemoglobin and comorbidities at presentation were independent predictors of complications. Pelvic exenteration is an aggressive surgery characterized by a high rate of post-operative complications. Pre-operative assessment of comorbidities and patient health status are crucial to better select the right candidate for this type of surgery.

Pelvic exenteration for vulvar cancer: contemporary outcomes from a multinational cohort study

Women with vulvar cancer are considerably older than those with other gynaecological malignancies, raising concerns about the tolerability of radical surgery. Yet, for locally advanced or recurrent disease, pelvic exenteration may be the only curative option. Robust evidence to guide decision-making in this population is lacking. This multicentre observational cohort study used data from the COREPEX registry including women who underwent anterior or total pelvic exenteration between 2005 and 2023 across 20 European tertiary referral centres. The primary outcome was overall survival (OS); secondary outcomes were progression-free survival (PFS) and major postoperative complications. Associations were assessed using multivariable Cox and binomial regression models adjusted for relevant covariates. Among 861 women, 79 (9.2%) had vulvar cancer. Median follow-up was 49 months for OS and 40 months for PFS. Women with vulvar cancer were older and more often overweight. Five-year OS was 32% (95% CI, 19-46) in vulvar cancer versus 29% (95% CI, 25-34) in other cancers, adjusted HR 1.05 (95% CI, 0.75-1.46). Five-year PFS was 34% versus 29%, adjusted HR 0.96 (95% CI, 0.69-1.34). Major complications occurred in 33% vs 29%, adjusted RR 1.12 (95% CI, 0.77-1.58). Lymph node metastases, positive margins, and recurrent or persistent disease independently predicted poorer survival. Despite their older age, women with vulvar cancer had survival and morbidity comparable to those with other gynaecological malignancies. These findings support pelvic exenteration as a curative option for selected women with vulvar cancer when complete resection is feasible.