Louise De Brot

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.

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.

Sentinel node mapping decreases the risk of failed detection of isolated positive para-aortic lymph node in endometrial cancer

Isolated positive para-aortic lymph node metastasis in endometrial cancer is an uncommon event, ranging from 1% to 3%. Our aim was to evaluate the impact of sentinel lymph node (SLN) mapping on the risk of isolated positive para-aortic lymph node metastasis. We retrospectively evaluated a series of 426 patients who underwent SLN mapping with at least one SLN detected from January 2013 to December 2021 (SLN group) compared with a historical series of 209 cases who underwent a systematic pelvic and para-aortic lymphadenectomy between June 2007 and April 2015 (LND group). Isolated para-aortic lymph node metastasis recurrences were included in the SLN group analysis. In the SLN group, 168 cases (39.4%) had backup systematic lymphadenectomy, and 56 (13.1%) had positive lymph nodes compared with 34 (16.3%) in LND group (p=0.18). The SLN group had higher rates of minimally invasive surgeries (p<0.001) and presence of lymphovascular space invasion (p<0.001). Moreover, SLN group had fewer other uterine risk factors, such as high-grade tumors (p<0.001), and deep myometrial invasion (p<0.001). We found that SLN mapped outside the pelvis at pre-sacral, common iliac areas, and para-aortic regions in 2.8% (n=12), 11.5% (n=49), and 1.6% (n=7) of cases, respectively. Overall, 52 (12.2%) patients had positive SLNs, and 3 (5.7%) positive SLNs were found outside the pelvis-one in the pre-sacral region, one in the common iliac area, and one in the para-aortic region. An isolated para-aortic lymph node was found in only 2 (0.5%) cases in the SLN group compared with 7 (3.3%) cases in the LND group (p=0.004). SLN protocol accurately predicts lymph node status and may decrease the risk of failed identification of isolated para-aortic lymph node metastasis compared with systematic lymphadenectomy.

Case Report of Small Cell Carcinoma of the Ovary, Hypercalcemic Type (Ovarian Rhabdoid Tumor) with SMARCB1 Mutation: A Literature Review of a Rare and Aggressive Condition

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and aggressive condition that is associated with the SMARCA4 mutation and has a dismal prognosis. It is generally diagnosed in young women. Here, we report a case of a young woman with SCCOHT harboring a rare molecular finding with a highly aggressive biological behavior. The patient had a somatic SMARCB1 mutation instead of an expected SMARCA4 alteration. Even though the patient was treated with high-dose chemotherapy followed by stem cell transplantation, she evolved with disease progression and died 11 months after her first symptoms appeared. We present a literature review of this rare disease and discuss the findings in the present patient in comparison to expected molecular alterations and options for SCCOHT treatment.

Presence and extent of lymphovascular invasion in surgical stage I squamous cell carcinoma of the cervix: a comprehensive, international, multicentre, retrospective clinicopathological study

The aim of this study was to determine whether the presence and extent of lymphovascular invasion (LVI) is prognostic in surgical stage I cervical squamous cell carcinoma (SCC). All available tumour slides and/or paraffin blocks from 426 patients with stage I cervical SCC treated surgically with curative intent were collected from 18 institutions and retrospectively analysed. Presence and extent of LVI (focal <5 spaces, extensive ≥5 spaces) were assessed on scanning magnification in large haematoxylin and eosin slide sets in 366 cases. Progression-free survival (PFS) was calculated as the time from surgery to first progression or death or last follow-up, whichever occurred first. Overall survival (OS) was defined as the time from surgery to death or last follow-up. Clinicopathological and statistical analyses were performed on 97 patients with the International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IA and 329 patients with stage IB SCC of the cervix. LVI, both focal and extensive, was more frequent in stage IB than in stage IA (p<0.001). Patients with stage IB carcinomas with extensive LVI had worse PFS [hazard ratio (HR) 2.86; 95% confidence interval (CI) 1.49, 5.49; p=0.005] and OS (HR 2.88; 95% CI 1.38, 6.02; p=0.012) than those with focal or no LVI. In stage IA, in contrast, the presence and extent of LVI did not associate with PFS (p=0.926) or OS. Extensive LVI was not statistically correlated with PFS and OS in substages IA1, IA2 or IB2. PFS (HR 3.7; 95% CI 1.61, 8.46; p<0.001) and OS (HR 4.18; 95% CI 1.58, 11.04; p=0.002) in stage IB1, and PFS (HR 7.78; 95% CI 0.87, 69.82; p=0.039) in stage IB3 were diminished in the presence of extensive LVI. In conclusion, in patients with FIGO stage I cervical SCC, the presence and extent of LVI has prognostic significance in stage IB carcinoma, and quantifying LVI is recommended.

Prognostic value of isolated tumor cells in sentinel lymph nodes in intermediate-risk endometrial cancer: results from an international, multi-institutional study

This study assessed oncologic outcomes of patients with intermediate-risk endometrioid endometrial cancer and isolated tumor cells (ITC) (≤0.2 mm or ≤200 cells) in sentinel lymph nodes (SLNs). Patients with SLN-ITC diagnosed between 2012 and 2019 were identified from 19 centers worldwide, while SLN-negative patients were identified at Mayo Clinic, Rochester between 2014 and 2018. Only patients with endometrioid endometrial cancer and intermediate-risk factors (low-grade endometrioid histology and myometrial invasion ≥50%; high-grade endometrioid histology and myometrial invasion <50%) were included. Oncologic outcomes were evaluated by grouping patients according to prognostic factors: SLN-ITC and lymphovascular space invasion (LVSI). SLN-ITC patients with post-operative observation or vaginal brachytherapy (VB) alone were compared with similar node-negative patients. Of the 166 patients included, those with simultaneous presence of SLN-ITC and LVSI were at higher risk of non-vaginal recurrence (HR 3.73 [95% CI 1.17 to 11.84], p = .01) compared with patients who were node-negative with no LVSI. Among the 122 patients (28 SLN-ITC, 94 node-negative) who underwent post-operative observation or VB alone, 1 isolated vaginal recurrence was documented in a node-negative patient, while non-vaginal recurrence occurred in 3 of 28 (10.7%) SLN-ITC and 7 of 94 (7.4%) node-negative patients. The median follow-up was 2.4 years (interquartile range; 1.8-3.0) among the remaining 25 ITC patients and 2.8 years (interquartile range; 0.8-4.2) among the remaining 87 node-negative patients. There was no difference in non-vaginal recurrence-free survival (SLN-ITC: 87.3% [95% CI 74.7% to 100.0%] vs node-negative: 82.2% [95% CI 69.1% to 97.9%], p = .46) or overall survival (SLN-ITC: 76.4% [95% CI 54.3 to 100.0] vs node-negative: 84.5% [95% CI 75.0 to 95.2], p = .28) between the 2 cohorts. In patients with endometrioid endometrial cancer and intermediate-risk factors (including patients who received chemotherapy/external beam radiotherapy), the combination of SLN-ITC and LVSI was associated with worse prognosis compared with patients with no risk factors or only 1 risk factor. In the sub-group of patients who received post-operative observation or VB alone, SLN-ITC did not worsen prognosis relative to node-negative patients.

Gastrin-releasing peptide receptor: a promising new biomarker to identify cervical precursor lesions and cancer

This study aimed to verify the relation between gastrin-releasing peptide receptor (GRPR), oncogenic Human Papillomavirus (HPV) and cervical lesions severity. GRPR mRNA levels were evaluated in cervical cancer-derived cell lines and in primary keratinocytes expressing HPV16 oncogenes by RT-PCR. GRPR protein expression was assessed by immunohistochemistry in organotypic cell cultures derived from keratinocytes transduced with HPV16 oncogenes and in 208 cervical samples, including 59 non-neoplastic tissue, 28 cervical intraepithelial neoplasia grade 3 (CIN3), 44 squamous cell carcinomas (SCC) and 77 adenocarcinomas (ADC). Generic primers (GP5+/GP6+) were used to identify HPV infection in tissue samples. Experiments involving cell lines were analyzed through non-parametric tests (Kruskal Wallis), and Fisher's Exact Test for human tissues samples. All statistical tests were considered significant at p <0.05. Immunohistochemical evaluation was conducted independently and blindly by two observers (AD- LO). Any discordant findings were resolved through discussion to reach a consensus score. GRPR mRNA levels were not increased in cells expressing HPV16 or HPV18 oncogenes. However, at the protein level, GRPR was upregulated in organotypic cell cultures containing HPV oncogenes. Besides, it was identified an association between GRPR expression and cervical lesion severity (p < 0.0001). The detection rate of high-risk HPV DNA was directly correlated with cervical disease. Nonetheless, HPV infection was not directly associated with GRPR in cervical samples. GRPR expression is highly predictive of cervical lesion severity, irrespective of HPV infection and might contribute to improving patient's therapeutic management as well as being used a marker of disease progression.

Outcomes of low-risk endometrial cancer with isolated tumor cells in the sentinel lymph nodes: a prospective, multi-center, single-arm, observational study (ENDO-ITC study)

It is unclear whether isolated tumor cells (ITCs) in sentinel lymph nodes (SLNs) adversely affect prognosis, especially in low-risk endometrial cancer. In a retrospective study, we showed a worse recurrence-free survival for low-risk endometrial cancer with ITCs than the node-negative group. Our aim is to evaluate whether the likelihood of disease recurrence differs between a prospective cohort of patients with low-risk endometrial cancer with ITCs and an historical cohort with negative SLNs. We hypothesize that patients with low-risk endometrial cancer and ITCs will have a worse recurrence-free survival than patients who are node-negative. This is a prospective, multi-center, single-arm observational study. Consecutive patients with low-risk endometrial cancer with ITCs in the SLNs will be accrued. Observation only will be suggested after surgery. We will include patients with endometrial cancer undergoing pelvic SLN biopsy and ultra-staging with the following characteristics: endometrioid histology, grades 1 to 2, <50% myometrial invasion, without substantial/extensive lympho-vascular space invasion. ITCs in SLNs are defined as tumor cell aggregates ≤0.2 mm or <200 cells. The primary end point is recurrence-free survival, measured from the date of surgery to the date of recurrence, death, or last disease evaluation. With a sample size of 132 women with low-risk endometrial cancer and ITCs, a 1-sided log-rank test achieves 85% power at a 0.05 significance level to detect an HR of 2.1. The expected number of events during the study is 17.3. The study duration will be 60 months: 24 for enrollment and 36 for follow-up. The results are expected in 2029. ClinicalTrials.gov: NCT06689956.