Introduction: This research describes an eight-year case-series of ovarian carcinoma by surgical (pTNM) staging and surgical procedure, explores the characteristics of ovarian surface epithelial cell (OSEC) tumours by histopathological type in a single centre of reference. Material and Methods: survival analysis with overall survivor probabilities for n=263 patients for 12 months and 60-month tumour free survival status (TFS). Results by staging (pTNM stage classification), histotype and for poor surgical candidate (PSC) status are shown. Histotype high grade serous carcinoma (HGSC) was the most frequently diagnosed type (63%). Results: 12-month survivor probabilities according to histotype, rank as follows: clear cell carcinoma (CCC) - 14%; rare carcinoma (RC) - 15%; carcinosarcoma (CS) - 29%; HGSC - 46%; low grade serous carcinoma (LGSC) - 74%; endometrioid carcinoma (EC) - 79%; mucinous carcinoma (MC) - 80% and borderline tumours (BLT) - 94%. At 60 months results are: RC and MC - 0%; CCC - 14%; HGSC - 16%; CS - 29%; LGSC - 62%; EC - 66%; and BLT - 94%. Overall median survival time is 26 months (CI95% 15 to 37); and 20 months when BLT excluded (CI95% CI 15 to 25). Conclusions: These results may guide further research for the OSEC pathology and its histotypes.

Most bone tumors are metastatic. Breasts, lungs, kidneys, and thyroid are the primary sites most commonly involved in bone metastasis-type outcomes. This case study describes the involvement of a patient with a bone tumor located in the axial skeleton, initially in the sacral region. However, the primary site was undefined. Therefore, it was necessary to expand the investigation with immunohistochemistry, which demonstrated a metastatic tumor compatible with endometrioid adenocarcinoma. But even after examination, no active lesion was found in the endometrial region. The study was observational, descriptive, and aimed to discuss the importance of more specific investigative methods. In this context, immunohistochemistry stands out as an exquisite method capable of optimizing diagnosis, therapy, and consequently, prognosis.

BACKGROUND: High-grade endometrial cancers (EAC) are aggressive tumors with a high risk of progression after treatment. As EAC may harbor mutations in the RAS/MAPK pathways, we evaluated the preclinical in vitro and in vivo efficacy of avutometinib, a RAF/MEK clamp, in combination with the focal adhesion kinase (FAK) inhibitors defactinib or VS-4718, against multiple primary EAC cell lines and xenografts.
METHODS: Whole-exome sequencing (WES) was used to evaluate the genetic landscape of five primary EAC cell lines. The in vitro activity of avutometinib and defactinib as single agents and in combination was evaluated using cell viability, cell cycle, and cytotoxicity assays. Mechanistic studies were performed using Western blot assays while in vivo experiments were completed in UTE10 engrafted mice treated with either vehicle, avutometinib, VS-4718, or their combination through oral gavage.
RESULTS: WES results demonstrated multiple EAC cell lines to harbor genetic derangements in the RAS/MAPK pathway including KRAS/PTEN/PIK3CA/BRAF/ARID1A, potentially sensitizing to FAK and RAF/MEK inhibition. Five out of five of the EAC cell lines demonstrated in vitro sensitivity to FAK and/or RAF/MEK inhibition. By Western blot assays, exposure of EAC cell lines to defactinib, avutometinib, and their combination demonstrated decreased phosphorylated FAK (p-FAK) as well as decreased p-MEK and p-ERK. In vivo the combination of avutometinib/VS-4718 demonstrated superior tumor growth inhibition compared to single-agent treatment and controls starting at Day 9 (p < 0.02 and p < 0.04) in UTE10 xenografts.
CONCLUSIONS: Avutometinib, defactinib, and to a larger extent their combinations, demonstrated promising in vitro and in vivo activity against EAC cell lines and xenografts. These preclinical data support the potential clinical evaluation of this combination in high-grade EAC patients.

UNASSIGNED: Since the seminal publication of the TCGA consortium in 2013, the molecular classification of endometrial cancer has been widely accepted as a new and powerful tool to better understand the natural history of this malignancy. Adoption of routine molecular classification around the world has been limited. We sought to demonstrate our initial experience in incorporating the four molecular subtypes for endometrioid carcinomas.
UNASSIGNED: This was a retrospective analysis at a single center in Portugal. Molecular classification was determined using immunohistochemical staining for MMR and p53 and Sanger Sequencing to determine POLE mutation status as per published PROMISE method. Descriptive statistics were reported.
UNASSIGNED: 20 patients with endometrioid histology were included. Median age of the cohort was 64 years (range 45-76). Median Body Mass Index (kg/m2) was 29.81 (range 21.3-43.1). In terms of tumor grading, 16 (80%) of the endometrial carcinomas of the cohort were low-grade (either grade 1 or grade 2). 16 (80%) of the cases were FIGO stage I. Regarding the molecular classification the tumors were classified as: MMRd [n = 6 (30%)]; p53 abn [n = 2 (10%)]; NSMP (n = 10 (50%)), POLE ultramut [n = 2 (10%)].
UNASSIGNED: Despite the small sample size, we were able to show that molecular classification is feasible. To our knowledge this is the first cohort of endometroid endometrial carcinomas fully characterized according to the TCGA classification in Portugal, from one single center.

Mesothelin (MSLN) is expressed in the mesothelium in normal tissues but is overexpressed in various malignant tumors. In this study, we searched for genes that were more frequently expressed in cases of endometrioid carcinoma (EC) with the MELF (microcystic, elongated, and fragmented) pattern using laser microdissection and RNA sequencing, and found that MSLN was predominantly expressed in cases with the MELF pattern. The role of MSLN in EC was analyzed by generating MSLN-knockout and -knockdown EC cell lines. MSLN promoted migration and epithelial-mesenchymal transition (EMT). Moreover, we found that cadherin-6 (CDH6) expression was regulated by MSLN. MSLN is known to bind to cancer antigen 125 (CA125), and we found that CA125 can regulate CDH6 expression via MSLN. Immunohistochemical investigations showed that MSLN, CA125, and CDH6 expression levels were considerably elevated in EC with the MELF pattern. The expression of CA125 was similar to that of MSLN not only in terms of immunohistochemical staining intensity but also the blood level of CA125. Our results showed that MSLN contributes to the migration and EMT of EC cells through upstream CA125 and downstream CDH6. Therefore, MSLN has potential as a therapeutic target for EC with the MELF pattern.

UNASSIGNED: Endometrial cancer (EC) is a heterogeneous disease with recurrence rates ranging from 15 to 20%. The discrimination of cases with a worse prognosis aims, in part, to reduce the length of surgical staging in cases with a better prognosis. This study aimed to evaluate the association between Insulin-like growth factor II mRNA-binding protein 3 (IMP3) expression and prognostic and morphological factors in EC.
UNASSIGNED: This retrospective, cross-sectional, analytical study included 79 EC patients - 70 endometrioid carcinoma (EEC) and 9 serous carcinoma (SC) - and 74 benign endometrium controls. IMP3 expression was evaluated by immunohistochemistry-based TMA (Tissue Microarray), and the results were associated with morphological and prognostic factors, including claudins 3 and 4, estrogen and progesterone receptors, TP53, and KI67.
UNASSIGNED: IMP3 expression was significantly higher in SC compared to EEC in both extent (p<0.001) and intensity (p=0.044). It was also significantly associated with worse prognostic factors, including degree of differentiation (p=0.024, p<0.001), staging (p<0.001; p<0.001) and metastasis (p=0.002; p<0.001). IMP3 expression was also significant in extent (p=0.002) in endometrial tumors compared with controls. In addition, protein TP53 and KI67 showed significant associations in extent and intensity, respectively.
UNASSIGNED: IMP3 expression was associated with worse prognostic factors studied. These findings suggest that IMP3 may be a potential biomarker for EC poorer prognosis.

There is growing evidence that the KDM5 family of histone demethylases plays a causal role in human cancer. However, few studies have been reported on the KDM5 family in endometrial carcinoma (EC). Moreover, it was found that there was some correlation between the KDM5 family and FOXO1 in EC. The current study was performed to explore the expressions of KDM5A, KDM5B, and FOXO1 in endometrioid adenocarcinoma detected by immunohistochemistry; paracancer endometrium, simple hyperplastic endometrium, and normal endometrium were used as control groups to explore the possible diagnostic value of KDM5A and KDM5B expression in endometrioid adenocarcinoma, with the aim of evaluating the potential of this marker in predicting the prognosis of endometrioid adenocarcinoma.

Among the 4 molecular subgroups of endometrial carcinoma, the p53 abnormal (copy number high) subgroup has the worst prognosis; however, the histologic characteristics of this subgroup are not well established. Also, it is not well established whether low-grade tumors can belong to the p53 abnormal molecular subgroup and if so, what is the prognostic significance of the p53-mutated molecular subgroup in low-grade tumors. In the current study, we included 146 p53-mutated endometrial carcinomas and performed molecular subgrouping either based on a combination of immunohistochemical studies for p53 and MMR protein expression and POLE mutation testing (81 cases) or based on array-based and sequencing-based technologies (65 cases). We excluded cases that belonged to the POLE mutant or MSI molecular subgroups and only studied p53 abnormal (molecular subgroup) endometrial carcinomas (125 cases). In 71 cases, the molecular subgroup was determined by a combination of immunohistochemical studies and POLE mutation testing, and in 54 cases by array-based and sequencing-based methods. We reviewed 1 to 2 representative digital slides from each case and recorded the morphologic characteristics as well as clinical, treatment, and survival follow-up data. Overall, 47 cases were classified as endometrioid carcinoma, 55 serous carcinoma, and 23 other histotypes. Eight cases were FIGO 1, 21 were FIGO 2, and 91 were FIGO 3. A significant proportion of the cases (24.2%) were histologically classified as low-grade (FIGO 1 or 2) endometrioid carcinoma. There was no morphologic characteristic that showed prognostic implication. There was no significant difference in survival among different histotypes (P=0.60). There was no significant difference in survival among low-grade endometrioid (FIGO 1 or 2) versus high-grade (FIGO 3) tumors (P=0.98). Early-stage (stage I), low-grade tumors showed no significant survival advantage over early-stage, high-grade tumors (P=0.16) and this was more evident in FIGO 2 tumors. Although not statistically significant, the FIGO 2 tumors showed a trend toward worse survival than FIGO 3 tumors. Among the cases with available treatment data, more patients with early-stage high-grade tumors received adjuvant treatment, compared to patients with early-stage low-grade tumors, possibly explaining this trend (P=0.03). In conclusion, the findings of our study suggest that low-grade p53 abnormal endometrioid endometrial carcinomas (especially FIGO 2 tumors) have an aggressive course, with a prognosis similar to high-grade tumors. Furthermore, our study suggests that patients who had early-stage low-grade p53 abnormal disease might have been undertreated because of the \"low-grade\" histotype.

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OBJECTIVE: To assess the association of prevalence and size of pelvic sentinel node (SLN) metastases with risk factors in endometrial cancer (EC).
METHODS: Between June 2014 and January 2024 consecutive women with a uterine confined EC undergoing robotic surgery including detection of pelvic SLNs at a University Hospital were included. An anatomically based algorithm utilizing Indocyanine green (ICG) as tracer was adhered to. Ultrastaging and immunohistochemistry (IHC) was applied on all SLNs. The prevalence and size of SLN metastases was assessed with regards to pre- and postoperative histologic types and myometrial invasion estimates.
RESULTS: Of 1101 included women 72.6 % (759/1045) had low-grade, 7.6 % (79/1045) high-grade endometroid cancer and 19.8 % (207/1045) non-endometroid cancer. SLN-metastases were present in 174/1045 (16.6 %) women; 9.8 % of preoperatively presumed low-grade endometroid uterine stage 1A (6.4 % of low-grade stage 1A at final histology) and in 58.3 % and 47.8 % respectively in women with high-grade endometroid and non-endometroid uterine stage 1B cancer. In low-grade EC 45/95 (47.4 %) had only isolated tumor cells (ITC) in SLNs compared with 15/78 (19.2 %) in high-grade or non-endometroid cancer (p < .0001) CONCLUSION: This large population-based study, applying a consequent SLN-algorithm over time, provides important detailed information on the risk for, and size of, SLN metastases within risk groups of EC. The 9.8 % risk for metastases in women with presumed low grade uterine stage 1A endometrioid EC motivates detection of SLNs within this subgroup. The proportion of ITCs in SLNs was significantly lower in higher risk histologies.