Bruna Tirapelli Goncalves

Empty node packet in endometrial cancer: predictors and clinical significance in the sentinel lymph node era

This study aimed to evaluate clinical and pathological factors associated with the occurrence of empty node packets during sentinel lymph node mapping in patients with endometrial cancer. We performed a retrospective cohort study including patients with histologically confirmed endometrial carcinoma who underwent sentinel lymph node mapping between November 2012 and December 2023. An empty node packet was defined as the intra-operative removal of a presumed sentinel node with no lymphoid tissue identified on final pathological examination. Logistic regression models were used to identify independent predictors. Of 489 patients who had sentinel lymph node mapped, 23 (4.7%) had an empty node packet. In the univariate analysis, body mass index and myometrial invasion were significantly associated (p < .05). In the multi-variable analysis, only body mass index remained independently associated (odds ratio 1.075, 95% confidence interval 1.01 to 1.14, p = .022) with an empty node packet. Tumor histology, grade, type of tracer, and surgical approach were not associated. No nodal recurrences occurred in patients with an empty node packet. Empty node packets are uncommon but clinically relevant during sentinel lymph node mapping for endometrial cancer. Higher body mass index was the only independent predictor, underscoring the influence of patient-related factors on mapping accuracy.

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.

Does sentinel node mapping impact morbidity and quality of life in endometrial cancer?

To evaluate the prevalence of post-operative complications and quality of life (QoL) related to sentinel lymph node (SLN) biopsy vs systematic lymphadenectomy in endometrial cancer. A prospective cohort included women with early-stage endometrial carcinoma who underwent lymph node staging, grouped as follows: SLN group (sentinel lymph node only) and SLN+LND group (sentinel lymph node biopsy with addition of systematic lymphadenectomy). The patients had at least 12 months of follow-up, and QoL was assessed by European Organization for Research and Treatment of Cervical Cancer Quality of Life Questionnaire 30 (EORTC-QLQ-C30) and EORTC-QLQ-Cx24. Lymphedema was also assessed by clinical evaluation and perimetry. 152 patients were included: 113 (74.3%) in the SLN group and 39 (25.7%) in the SLN+LND group. Intra-operative surgical complications occurred in 2 (1.3%) cases, and all belonged to SLN+LND group. Patients undergoing SLN+LND had higher overall complication rates than those undergoing SLN alone (33.3% vs 14.2%; p=0.011), even after adjusting for confound factors (OR=3.45, 95% CI 1.40 to 8.47; p=0.007). The SLN+LND group had longer surgical time (p=0.001) and need for admission to the intensive care unit (p=0.001). Moreover, the incidence of lymphocele was found in eight cases in the SLN+LND group (0 vs 20.5%; p<0.001). There were no differences in lymphedema rate after clinical evaluation and perimetry. However, the lymphedema score was highest when lymphedema was reported by clinical examination at 6 months (30.1 vs 7.8; p<0.001) and at 12 months (36.3 vs 6.0; p<0.001). Regarding the overall assessment of QoL, there was no difference between groups at 12 months of follow-up. There was a higher overall rate of complications for the group undergoing systematic lymphadenectomy, as well as higher rates of lymphocele and lymphedema according to the symptom score. No difference was found in overall QoL between SLN and SLN+LND groups.

Subclonal loss of DNA mismatch repair proteins in endometrial carcinomas: an unusual pattern with distinct molecular characteristics

Subclonal loss of mismatch repair (MMR) proteins in endometrial carcinoma has recently been identified through immunohistochemistry (IHC) evaluations, characterized by discrete areas of tumors with complete loss of nuclear expression adjacent to tumor cells with retaining expression. Controversies persist regarding reporting findings and managing such cases. Therefore, we conducted a detailed clinicopathological and molecular analysis on a large cohort of endometrial carcinoma cases with subclonal loss of MMR proteins to explore potential reclassification into different molecular categories that could influence diagnostic and treatment strategies. Eligible endometrial carcinoma cases underwent IHC evaluation for PMS2/MLH1/MSH2/MSH6. Cases showing subclonal loss of MMR proteins underwent macrodissection of both proficient and deficient MMR expression areas, followed by testing for microsatellite instability (Idylla), MLH1 promoter methylation (next-generation sequencing), POLE mutations (next-generation sequencing), and p53 expression (IHC). The proposed molecular evaluation was performed in both proficient and deficient areas. Clinical and pathological data for patients with subclonal loss were also analyzed. We evaluated 356 cases of endometrial carcinoma, identifying subclonal loss in 16 patients (4.4%), predominantly endometrioid (15 cases, 93.75%) and International Federation of Gynecology and Obstetrics stage I (13 cases, 81.25%). Subclonal loss of MSH6 occurred independently in 6 cases (37.5%), and concurrently with subclonal loss of MLH1 in 2 cases (12.5%). Complete loss of MLH1/PMS2 was observed in 2 cases (12.5%). MLH1 promoter methylation was detected in 6 cases (37.5%), with 4 cases showing methylation in both areas analyzed. POLE mutations were found in 3 cases (18.75%), occurring in both deficient and proficient areas. The correlation between IHC findings and molecular results varied, providing valuable predictive and prognostic insights that could guide treatment decisions in some patients. Molecular evaluation should be standard practice in all endometrial carcinoma cases exhibiting subclonal loss of MMR proteins to accurately delineate tumor characteristics. Subclonal loss should be reported distinctly, warranting a more comprehensive diagnostic approach to enhance tumor classification.

Fusion Cell Markers in Circulating Tumor Cells from Patients with High-Grade Ovarian Serous Carcinoma

Cancer is primarily a disease in which late diagnosis is linked to poor prognosis, and unfortunately, detection and management are still challenging. Circulating tumor cells (CTCs) are a potential resource to address this disease. Cell fusion, an event discovered recently in CTCs expressing carcinoma and leukocyte markers, occurs when ≥2 cells become a single entity (hybrid cell) after the merging of their plasma membranes. Cell fusion is still poorly understood despite continuous evaluations in in vitro/in vivo studies. Blood samples from 14 patients with high-grade serous ovarian cancer (A.C. Camargo Cancer Center, São Paulo, Brazil) were collected with the aim to analyze the CTCs/hybrid cells and their correlation to clinical outcome. The EDTA collected blood (6 mL) from patients was used to isolate/identify CTCs/hybrid cells by ISET. We used markers with possible correlation with the phenomenon of cell fusion, such as MC1-R, EpCAM and CD45, as well as CEN8 expression by CISH analysis. Samples were collected at three timepoints: baseline, after one month (first follow-up) and after three months (second follow-up) of treatment with olaparib (total sample = 38). Fourteen patients were included and in baseline and first follow-up all patients showed at least one CTC. We found expression of MC1-R, EpCAM and CD45 in cells (hybrid) in at least one of the collection moments. Membrane staining with CD45 was found in CTCs from the other cohort, from the other center, evaluated by the CellSearch® system. The presence of circulating tumor microemboli (CTM) in the first follow-up was associated with a poor recurrence-free survival (RFS) (5.2 vs. 12.2 months; p = 0.005). The MC1-R expression in CTM in the first and second follow-ups was associated with a shorter RFS (p = 0.005). CEN8 expression in CTCs was also related to shorter RFS (p = 0.035). Our study identified a high prevalence of CTCs in ovarian cancer patients, as well as hybrid cells. Both cell subtypes demonstrate utility in prognosis and in the assessment of response to treatment. In addition, the expression of MC1-R and EpCAM in hybrid cells brings new perspectives as a possible marker for this phenomenon in ovarian cancer.

Reconsidering adjuvant radiotherapy in intermediate-risk cervical cancer: findings from the CIRCOL study group

To evaluate survival outcomes associated with intermediate-risk factors in patients who underwent radical hysterectomy for cervical cancer, with a focus on the role of adjuvant radiotherapy. A multicenter retrospective cohort database comprising 1280 patients who underwent radical hysterectomy for cervical cancer was analyzed. For inclusion, patients had tumors ≤4 cm (International Federation of Gynecology and Obstetrics 2018 stages Ia2-Ib2) and were treated surgically between January 2000 and December 2017. Patients with lymph node metastasis, positive surgical margins, or parametrial involvement were excluded. Intermediate-risk factors were defined as tumor size >2 cm to ≤4 cm, stromal invasion ≥10 mm, and presence of lymphovascular space invasion. A total of 759 patients met inclusion criteria, of whom 158 (20.8%) received external beam radiotherapy. Patients who received external beam radiotherapy were older, more often underwent open surgery, and exhibited a higher incidence of adverse pathological features, including larger tumors, deeper stromal invasion, and lymphovascular space invasion. In multivariate analysis, tumor size >2 cm (HR 5.25, 95% CI 1.86 to 14.8) and stromal invasion ≥10 mm (HR 2.68, 95% CI 1.14 to 6.30) were independently associated with increased recurrence risk. No variables were independently associated with cancer-specific mortality. The presence of ≥2 intermediate-risk factors significantly increased the risk of recurrence (HR 3.48, 95% CI 2.05 to 5.91) and cancer-related death (HR 2.47, 95% CI 1.04 to 2.89), regardless of radiotherapy use. Tumor size and depth of stromal invasion were associated with increased recurrence risks. Adjuvant radiotherapy was not associated with improved survival outcomes in patients with intermediate-risk features.