OBJECTIVE: Efforts have been made to better risk stratify patients given the rise in incidence of endometrial cancer (EC). The 2023 FIGO staging now incorporates histologic subtype and molecular classification into determination of EC stage. We sought to elucidate if the new staging system demonstrated prognostic differences compared to the 2009 staging system.
METHODS: A retrospective chart review was performed on women treated for EC at our institution from September 2013 to May 2023 and combined with the publicly available TCGA Nature 2013 dataset. Detailed clinical information was captured. Patients were restaged according to the 2023 guidelines. Survival estimates were obtained using Kaplan-Meier method, and the log-rank test was used to compare survival curves for progression-free survival (PFS).
RESULTS: 919 patients were included in our analysis. The datasets were comparable regarding histologic grade, stage, and age at diagnosis. 175 (31.5%) of patients in the institution dataset and 115 (31.6%) patients in the TCGA dataset experienced a stage change. Most patients whose stage changed were upstaged (275/290; 94.8%). 3-year PFS estimates for stage IA patients with no stage change versus those upstaged were 92.3% (95% CI: 87.2, 95.4) v. 72.0% (95% CI: 68.4, 84.9), p = 0.002. No significant differences in survival difference were seen in other stage subsets.
CONCLUSIONS: Modest survival differences exist in patients with EC originally staged as IA who underwent upstaging. No significant survival difference is observed in patients who are restaged to stage II or III subsets. Improved risk stratification is needed in assessing prognosis and adjuvant therapy for patients with endometrial cancer.

OBJECTIVE: The Cancer Genome Atlas study revealed an association between copy-number high (p53 abnormal) genetic mutation and poor prognosis in endometrial cancer in 2013. This retrospective study investigated outcomes in patients with abnormal p53 expression and stage I, low-grade endometrial endometrioid carcinoma (EEC).
METHODS: We enrolled women with stage I, grade 1 or 2 EEC who received comprehensive staging and adjuvant therapy between January 2019 and December 2022 at MacKay Memorial Hospital, Taipei, Taiwan. Pathologists interpreted immunohistochemistry stains of cancerous tissues to detect p53 mutation. We compared recurrence, survival, progression-free survival, and overall survival between p53 abnormal and p53 normal groups.
RESULTS: Of the 115 patients included, 26 had pathologically confirmed abnormal p53 expression. Of these 26 patients, five (19.2%) experienced recurrence, and two died due to disease progression. By contrast, no patients in the normal p53 group experienced disease recurrence or died due to disease progression. Significant intergroup differences were discovered in recurrent disease status (19.4% vs. 0%, p<0.001), mortality (7.7% vs. 0%, p<0.001), and progression-free survival (p<0.001). The overall survival (p=0.055) also showed powerful worse trend.
CONCLUSIONS: For patients with stage I, low-grade EEC, abnormal p53 expression may be used as an indicator of poor prognosis. Therefore, we suggest considering aggressive adjuvant therapies for these patients.

No prospective study has validated molecular classification to guide adjuvant treatment in endometrial cancer (EC), and not even retrospective data are present for patients with morphological low-risk EC. We conducted a retrospective, multicenter, observational study including 370 patients with low-risk endometrioid EC to evaluate the incidence and prognostic role of p53 abnormal expression (p53abn) in this specific subgroup. Among 370 patients, 18 had abnormal expressions of p53 (4.9%). In 13 out of 370 patients (3.6%), recurrences were observed and two were p53abn. When adjusting for median follow-up time, the odds ratio (OR) for recurrence among those with p53abn versus p53 wild type (p53wt) was 5.23-CI 95% 0.98-27.95, p = 0.053. The most common site of recurrence was the vaginal cuff (46.2%). One recurrence occurred within the first year of follow-up, and the patient exhibited p53abn. Both 1-year and 2-year DFS rates were 94.4% and 100% in the p53abn and p53wt groups, respectively. One patient died from the disease and comprised p53wt. No difference in OS was registered between the two groups; the median OS was 21.9 months (16.4-30.1). Larger multicenter studies are needed to tailor the treatment of low-risk EC patients with p53abn. Performing molecular classification on all EC patients might be cost-effective, and despite the limits of our relatively small sample, p53abn patients seem to be at greater risk of recurrence, especially locally and after two years since diagnosis.

Background and Objectives: Gastric cancer (GC) is one of the most commonly diagnosed cancers and the fourth cause of cancer death worldwide. Personalised treatment improves GC outcomes. A molecular classification is needed to choose the appropriate therapy. A classification that uses on-slide biomarkers and formalin-fixed and paraffin-embedded (FFPE) tissue is preferable to comprehensive genomic analysis. In 2016, Setia and colleagues proposed an on-slide classification; however, this is not in widespread use. We propose a modification of this classification that has six subgroups: GC associated with Epstein-Barr virus (GC EBV+), GC with mismatch-repair deficiency (GC dMMR), GC with epithelial-mesenchymal transformation (GC EMT), GC with chromosomal instability (GC CIN), CG that is genomically stable (GC GS) and GC not otherwise specified (GC NOS). This classification also has a provision for biomarkers for current or emerging targeted therapies (Her2, PD-L1 and Claudin18.2). Here, we assess the implementation and feasibility of this inclusive working classification. Materials and Methods: We constructed a tissue microarray library from a cohort of 79 resection cases from FFPE tissue archives. We used a restricted panel of on-slide markers (EBER, MMR, E-cadherin, beta-catenin and p53), defined their interpretation algorithms and assigned each case to a specific molecular subtype. Results: GC EBV(+) cases were 6%, GC dMMR cases were 20%, GC EMT cases were 14%, GC CIN cases were 23%, GC GS cases were 29%, and GC NOS cases were 8%. Conclusions: This working classification uses markers that are widely available in histopathology and are easy to interpret. A diagnostic subgroup is obtained for 92% of the cases. The proportion of cases in each subgroup is in keeping with other published series. Widescale implementation appears feasible. A study using endoscopic biopsies is warranted.

UNASSIGNED: Iodine-125 brachytherapy is an effective eye-sparing treatment for uveal melanoma. Previous work has shown that uveal melanomas cluster into distinct molecular classes based on gene expression profiles - discriminating low-grade from high-grade tumors. Our objective was to identify clinical and molecular predictors of local recurrence (LR) and progression-free survival (PFS).
UNASSIGNED: We constructed a retrospective database of uveal melanoma patients from the University of Miami\'s electronic medical records that were treated between January 8, 2012, and January 5, 2019, with either COMS-style or Eye Physics plaque. Data on tumor characteristics, pretreatment retinal complications, post-plaque treatments, LR, and PFS were collected. Univariate and multivariate Cox models for cumulative incidence of LR and PFS were conducted using SAS version 9.4.
UNASSIGNED: We identified 262 patients, with a median follow-up time of 33.5 months. Nineteen patients (7.3%) had LR, and 56 patients (21.4%) were classified as PFS. We found that ocular melanocytosis (hazard ratio = 5.55, p < 0.001) had the greatest impact on PFS. Genetic expression profile did not predict LR outcomes (hazard ratio = 0.51, p = 0.297).
UNASSIGNED: These findings help physicians identify predictors for short-term brachytherapy outcomes, allowing better shared decision making with patients preoperatively when deciding between brachytherapy versus enucleation. Patients stratified to higher risk groups based on preoperative characteristics such as ocular melanocytosis should be monitored more closely. Future studies must validate these findings using a prospective cohort study.

Uterine clear cell carcinoma (CCC) consists of either pure clear cell histology but can also display other histological components (mixed uterine CCCs). In this study, the molecular and immunohistochemical background of pure and mixed uterine CCC was compared. Secondly, it was evaluated whether histological classification and molecular background affected clinical outcome.
A retrospective multicenter study was performed comparing pure uterine CCCs (n = 22) and mixed uterine CCCs (n = 21). Targeted next-generation sequencing using a 12-gene targeted panel classified cases as polymerase-ε (POLE) mutated, microsatellite instable (MSI), TP53 wildtype or TP53 mutated. Immunohistochemistry was performed for estrogen receptor, progesterone receptor, L1 cell adhesion molecule, MSH6, and PMS2.
The following molecular subgroups were identified for pure and mixed uterine CCCs, respectively: POLE mutated 0% (0/18) and 6% (1/18); MSI in 6% (1/18) and 50% (9/18); TP53 wildtype in 56% (10/18) and 22% (4/18); TP53 mutated in 39% (7/18) and 22% (4/18) (p = 0.013). Patients with mixed CCCs had improved outcome compared to patients with pure CCCs. Frequent TP53 mutations were found in pure CCCs and frequent MSI in mixed CCCs, associated with clinical outcome.
Pure and mixed uterine CCCs are two entities with different clinical outcomes, which could be explained by different molecular backgrounds. These results underline the relevance of both morphological and molecular evaluation, and may assist in tailoring treatment.

UNASSIGNED: Soft tissue sarcomas (STS) are a heterogeneous group of tumors. For adequate therapeutic management, an accurate diagnosis is necessary. In Morocco, the diagnosis is essentially based on the morphological and immunohistochemical study. Compared to other techniques, fluorescence in situ hybridization (FISH) is easier to develop and less expensive. This study aims to assess the feasibility and utility of implementing FISH technique to improve diagnostic accuracy and establish a good classification.
UNASSIGNED: This is a retrospective cohort study. 211 cases of mesenchymal tumors were included. Hematoxylin Eosin Safran (HES) staining was performed in all cases followed by immunohistochemistry (IHC). FISH was performed in all cases with suspected STS. The probes used were EWSR1, MDM2 and SS18. The performance of FISH and histopathological test were evaluated by the ROC curve method (receiver operating characteristic). We evaluated the concordance between FISH and real time PCR by Cohen test.
UNASSIGNED: The real-time PCR technique showed good agreement with the FISH test by a Kappa coefficient of 60% (p = 0.035). FISH was able to confirm that it is more accurate (Youden\'s Index = 91%) than histological/immunohistochemical analysis (Youden\'s Index = 51%), as well as the positive predictive value was higher (100%) with an ROC curve finding a larger area under the curve of 0.953 (95% CI: 0.918-0.988), p = 0.000 which supports that FISH shows high performance to present an accurate final diagnosis.
UNASSIGNED: This is the first and the largest Moroccan series for the molecular diagnosis of STS by FISH. Our study shows that paraffin FISH is a sensitive and specific ancillary tool in the diagnosis of STS when used in the appropriate clinicopathological context.

BACKGROUND: Endometrial carcinoma (EC) is the most common gynecologic malignancy in developed countries and the fourth most frequent in women worldwide. The cornerstone of treatment for EC is surgery. Clinicopathological features are currently used to help determine the individual risk of recurrence and the need for adjuvant treatment after surgery. Nonetheless, there is significant interobserver variability in assigning histologic subtype when using a morphological classification, revealing the need for a more unified approach. The Cancer Genome Atlas (TCGA) project identified 4 distinct prognostic EC subtypes based on genomic abnormalities. Surrogate assays including 3 immunohistochemical markers (p53, MSH6, and PMS2) and 1 molecular test (mutation analysis of the exonuclease domain of DNA polymerase epsilon; POLE) allowed the development and validation of a simplified molecular classifier that correlates with the TCGA classification, has prognostic value, and can easily be used in clinical practice. This molecular classification categorizes EC in 4 subtypes: POLE mutated, mismatch repair-deficient, p53 abnormal, and no specific molecular profile. Applying this classification in clinical practice will help tailor adjuvant treatment decisions.
OBJECTIVE: The aim of this study is to retrospectively apply this novel molecular classification to a cohort of patients with EC treated in a comprehensive cancer center, to assess its applicability in clinical practice, to evaluate clinical outcomes by molecular subtypes, and to assess its prognostic value.
METHODS: In this retrospective cohort study, patients with primary EC diagnosed during and after 2013 and treated or followed at our institution, after definite surgery, will be included. Demographic and clinicopathological data will be obtained from electronic health records and from pathology reports. Laboratory methods will include immunohistochemical study of p53 and mismatch repair proteins, as well as POLE mutational analysis by genetic sequencing. The primary end point is recurrence-free survival and secondary end points are disease-specific survival and overall survival. A descriptive analysis of variables will be carried out. Survival analysis will be performed using the Kaplan-Meier method and the groups will be compared using the log-rank test.
RESULTS: This protocol was reviewed and approved by the Instituto Português de Oncologia do Porto, Portugal, ethics committee in October 2021; patient selection from our cancer registry began the same month. A total of 160 patients will be included. This work will present real-life results that will allow a better understanding of the Portuguese EC population and the distribution of the molecular subgroups throughout. We will use these results to understand the prognostic value of this classification in our population and its role in adjuvant therapy decisions. This study is anticipated to conclude in December 2022.
CONCLUSIONS: This study will provide important information regarding these women\'s outcomes according to this new molecular classification and will support its use when discussing a patient\'s need for adjuvant treatment.
UNASSIGNED: PRR1-10.2196/34461.

OBJECTIVE: Paediatric brain tumours are rare, and establishing a precise diagnosis can be challenging. Analysis of DNA methylation profiles has been shown to be a reliable method to classify central nervous system (CNS) tumours with high accuracy. We aimed to prospectively analyse CNS tumours diagnosed in Sweden, to assess the clinical impact of adding DNA methylation-based classification to standard paediatric brain tumour diagnostics in an unselected cohort.
METHODS: All CNS tumours diagnosed in children (0-18 years) during 2017-2020 were eligible for inclusion provided sufficient tumour material was available. Tumours were analysed using genome-wide DNA methylation profiling and classified by the MNP brain tumour classifier. The initial histopathological diagnosis was compared with the DNA methylation-based classification. For incongruent results, a blinded re-evaluation was performed by an experienced neuropathologist.
RESULTS: Two hundred forty tumours with a histopathology-based diagnosis were profiled. A high-confidence methylation score of 0.84 or more was reached in 78% of the cases. In 69%, the histopathological diagnosis was confirmed, and for some of these also refined, 6% were incongruent, and the re-evaluation favoured the methylation-based classification. In the remaining 3% of cases, the methylation class was non-contributory. The change in diagnosis would have had a direct impact on the clinical management in 5% of all patients.
CONCLUSIONS: Integrating DNA methylation-based tumour classification into routine clinical analysis improves diagnostics and provides molecular information that is important for treatment decisions. The results from methylation profiling should be interpreted in the context of clinical and histopathological information.

To evaluate the potential impact of the latest ESGO guidelines for endometrial cancer with molecular classification on the management strategy in a French cohort.
All patients treated between January 1st, 2014 and December 31, 2020 for an endometrial cancer at the Centre Hospitalier Intercommunal de Créteil (CHIC, FRANCE) were selected from our prospectively maintained database. All postoperative samples were reviewed to confirm histological subtype, myometrial infiltration, cytonuclear grade and presence of lymphovascular emboli. Analysis of p53, MLH1, MSH2, MSH6, PMS2 genes was performed by immunohistochemistry first then a systematic POLE sequencing was performed to identify gene mutation. The impact of the latest ESGO 2020 guidelines was assessed regarding adjuvant therapy, surgical strategy, and survival.
Eighty patients were analyzed, including 70% NSMP (n = 56), 13.75% MSI (n = 11), 10% p53 mutated (n = 8) and 6.25% POLEmut (n = 5). A total of 21 patients (26.3%) were reclassified using the latest ESGO classification. Patients classified at low risk or with advanced / metastatic disease were not reclassified using molecular analysis. Molecular analysis and the latest ESGO classification had the most important impact on patients initially classified at intermediate - high risk that were reclassified in intermediate (10/23) and in low (4/23) risk. Nine patients (11.3%) were overtreated according to the 2020 ESGO classification: six patients in the low - risk group (4 received vaginal brachytherapy and 2 external radiotherapy) and three in the intermediate risk group (3 received external irradiation and 1 received chemotherapy). None of the patients in our cohort would have been undertreated using the 2020 ESGO classification. Patients within the p53 mutated group were the most likely to experience recurrence (37.5%, 3/8) and none of the patients POLE mutated recurred.
Around one in 4 patients were reclassified in a more accurate prognostic group using molecular diagnosis and the latest ESGO guidelines which could decrease the use of adjuvant therapies to spare morbidity.