Search Results (111)

Background/Objectives: Advanced endometrial cancer (FIGO III–IV) is characterised by poor prognosis and a heterogeneous biological profile, and molecular classification enables treatment personalisation by identifying subtypes with distinct therapeutic targets. We aimed to characterise the molecular and histopathological features of FIGO III–IV cases in a Polish multicentre cohort and to discuss the resulting treatment implications. Methods: This retrospective multicentre study included 915 consecutive patients with endometrial cancer operated on between April 2022 and May 2025 at three oncology centres in south-eastern Poland. Molecular subtyping (POLEmut, p53abn, dMMR/MSI-H, NSMP) was performed using immunohistochemistry (IHC) and next-generation sequencing (NGS). FIGO stage was assigned according to the FIGO 2009 classification. Results: Among 888 patients with a known molecular subtype, FIGO III–IV cases accounted for 15.9% (n = 141). The p53abn subtype predominated (35.5%), followed by dMMR/MSI-H (26.2%), NSMP (24.1%), and POLEmut (5.7%). The proportion of p53abn increased with stage (I–II vs. III–IV, p < 0.001), whereas dMMR/MSI-H remained stable regardless of stage (p = 0.83). POLEmut was absent in FIGO IV (0/16; 95% CI 0.0–19.4%), which should be regarded as an exploratory observation requiring prospective validation. Conclusions: The molecular profile of advanced endometrial cancer may inform treatment strategy; the therapeutic implications presented here are descriptive and hypothesis-generating, as the study did not include survival data. The dMMR/MSI-H subtype identifies patients who may benefit from immunotherapy in accordance with current clinical indications, supporting routine MMR testing regardless of disease stage. Conversely, p53abn tumours point to the need for a more intensive treatment strategy, in line with current guidelines. The absence of POLEmut in FIGO IV is an exploratory observation requiring prospective validation. Treatment de-escalation in POLEmut FIGO IIIC remains subject to further clinical validation and requires individualised assessment after complete staging. Full article

Background/Objectives: Molecular classification has reshaped risk assessment in endometrial cancer (EC), but the strength and clinical applicability of the evidence vary across molecular subgroups, assay platforms, patient populations, and treatment settings. This systematic review critically evaluated the prognostic and predictive value of TCGA-derived classifiers, additional biomarkers, multiple-classifier tumors, and molecularly informed therapeutic strategies. Methods: A protocol was developed a priori but was not prospectively registered. PubMed/MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Library were searched for primary studies published from January 2013 through June 2026. Clinical guidelines were used only to provide clinical context and were not included in the formal evidence set. Because of substantial methodological heterogeneity, findings were synthesized narratively by study design and clinical question. Risk of bias was assessed using QUADAS-2, the Newcastle–Ottawa Scale, and RoB 2. Results: Seventy-four studies involving approximately 42,000 patients were included. POLE-mutated tumors showed the most favorable outcomes in most cohorts, whereas p53-abnormal tumors, defined by abnormal immunohistochemical patterns, generally had the poorest prognosis. Mismatch repair deficiency identified by immunohistochemistry and microsatellite instability-high status identified by PCR- or NGS-based testing were highly related but analytically distinct biomarkers and were not treated as exact synonyms. The NSMP group remained heterogeneous; integrated assessment of estrogen/progesterone receptor expression, CTNNB1, L1CAM, ARID1A, and chromosome 1q alterations may improve risk discrimination, although most of these markers remain investigational. In multiple-classifier tumors, available data support a practical hierarchy in which a pathogenic POLE mutation generally takes precedence, followed by MMR deficiency and then p53 abnormality. Across studies, molecular classification usually added prognostic information to clinicopathologic assessment, but the magnitude of benefit varied, and no overall certainty rating was assigned. Conclusions: Molecular classification is incorporated into contemporary guidelines and can support prognostic assessment and treatment selection when interpreted together with stage, histology, and other clinicopathologic factors. The strongest current clinical utility relates to POLE, MMR/MSI, p53 immunohistochemistry, and HER2 in selected settings; additional NSMP and multi-omics biomarkers require prospective validation, assay standardization, and demonstration of clinical utility before routine adoption. Full article

Background/Objectives: Endometrial cancer is a heterogeneous malignancy that displays distinct molecular features and clinical behaviors. The molecular profile of endometrial cancer and its relationship with menopausal status, histological subtype, tumor grade, mismatch repair (MMR)/microsatellite instability (MSI) status, co-mutation patterns, and TCGA molecular classification were investigated in the current study. Methods: A total of 81 histopathologically confirmed endometrial cancer cases were retrospectively evaluated. Molecular profiling was performed using a targeted 71-gene NGS panel together with MSI-PCR and mismatch repair (MMR) immunohistochemistry. Because the targeted panel was not designed to detect genome-wide copy-number alterations or comprehensive mutational signatures, molecular subgroup assignment was performed using a surrogate TCGA-inspired molecular classification approach based on POLE mutation status, microsatellite instability (MSI)/Mismatch Repair (MMR) findings, and TP53 alterations. Histological subtypes, tumor grades, menopausal status, and molecular alterations were compared. Results: Of the cases evaluated, 57 (70.4%) were endometrioid and 24 (29.6%) were serous carcinoma. TP53 variations were significantly higher in serous carcinomas compared to endometrioid tumors (66.7% vs. 26.3%; p = 0.001). In endometrioid carcinomas, the mean number of variants increased with advancing tumor grade (Grade 1: 4.44; Grade 2: 9.68; Grade 3: 11.42; p = 0.006). Alterations in BLM, CDC27, MLH3, and MSH3 were more frequently observed in high-grade tumors. In exploratory analyses, no significant differences were detected between the premenopausal and postmenopausal groups regarding total variant load, number of altered genes, MSI status, or the distribution of TCGA-inspired molecular subgroups; however, these comparisons were limited by the small number of premenopausal patients. The most frequent co-mutation was observed between BLM and CDC27 (55.6%). In the TCGA-inspired molecular classification, the most prevalent subgroup was NSMP-proxy (33.3%). Conclusions: Serous and endometrioid endometrial cancers display distinct molecular characteristics. In endometrioid carcinomas, the genomic alteration load increases in parallel with advancing tumor grade. TCGA-inspired molecular classification and co-mutation analyses revealed the prominent molecular heterogeneity of endometrial cancer. In exploratory analyses, no significant differences were detected between the premenopausal and postmenopausal groups regarding total variant load, number of altered genes, MSI status, or the distribution of TCGA-inspired molecular subgroups. However, these findings should be interpreted with caution because of the limited number of premenopausal patients. Given the limited number of premenopausal patients, findings related to menopausal status should be considered exploratory and require validation in larger, independent cohorts. Full article

Endometrial carcinoma is a biologically and clinically heterogeneous neoplasm, for which molecular classification now plays a central role in determining prognosis and guiding treatment. The aim of this study was to develop and apply an in-house multi-gene NGS panel to expand the molecular characterization of endometrial tumors beyond the markers required for surrogate classification. Seventy primary endometrial carcinomas were selected and analyzed by immunohistochemistry for p53, mismatch repair proteins, ARID1A, and PTEN, and by NGS on DNA extracted from FFPE samples using a panel comprising 28 genes. Molecular classification was assigned according to the WHO algorithm into the subgroups POLE-mutated, MMR-deficient, p53-abnormal, and NSMP (No Specific Molecular Profile). Sixty-eight cases were evaluable by sequencing, and in 93% at least one pathogenic, likely pathogenic, or variant of uncertain significance was identified. The most frequent alterations involved PTEN, PIK3CA, ARID1A, and TP53. POLE-mutated tumors showed the highest mutational burden, while CTNNB1 alterations were predominantly associated with the NSMP subgroup. Overall, the proposed panel proved to be a useful tool for complementing conventional molecular classification and for highlighting additional genomic differences that may be biologically and clinically relevant. Full article

Endometrial cancer is one of the most rapidly increasing gynaecological malignancies worldwide. The clinically adapted molecular classification of endometrial carcinoma, derived from The Cancer Genome Atlas, comprises four major subtypes: POLE-mutated, mismatch repair-deficient, p53-abnormal expression, and no specific molecular profile. Its clinical implementation has improved prognostic stratification, risk assessment, and treatment decision-making in patients with endometrial carcinoma. However, current workflows rely on immunohistochemistry and targeted sequencing, which increase costs, turnaround times, and infrastructure requirements, thereby limiting their universal adoption in routine clinical practice. Recent advances in artificial intelligence (AI), particularly deep learning models capable of predicting molecular features directly from H&E-stained whole-slide images, have emerged as promising tools for precision oncology. In addition to reproducing established molecular classification, these approaches may reveal previously unrecognised biomarker-defined histologic patterns that are difficult to detect using conventional methods. This article synthesises the current evidence on AI-based molecular classification in endometrial carcinoma from a pathologist-centred perspective, emphasising the biological rationale, methodological limitations, and future directions for clinical translation. Full article

Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality worldwide despite substantial advances in screening, surgical techniques, systemic therapies, and multidisciplinary care. The increasing implementation of precision oncology has fundamentally transformed CRC management by enabling molecularly guided therapeutic strategies based on tumor-specific genetic alterations. In recent years, the molecular landscape of CRC has expanded considerably beyond traditional histopathological classification, incorporating a growing number of clinically actionable biomarkers with prognostic, predictive, and therapeutic significance. This review provides a comprehensive and up-to-date overview of the genetic landscape of CRC, focusing on established biomarkers currently integrated into clinical practice, including microsatellite instability/mismatch repair deficiency (MSI/dMMR), KRAS, NRAS, BRAF, HER2, and NTRK alterations. In addition, emerging biomarkers such as tumor mutational burden (TMB), POLE/POLD1 mutations, circulating tumor DNA (ctDNA), DNA damage repair (DDR) alterations, transcriptomic signatures, and artificial intelligence-based molecular prediction models are critically discussed. Particular emphasis is placed on their biological significance, diagnostic methodologies, prognostic and predictive value, and potential role in treatment selection. A structured, database-informed narrative review identified 140 relevant publications, primarily published between January 2020 and June 2026, supplemented by earlier seminal studies and major clinical guidelines. Based on the available evidence, we propose a Clinical Actionability Framework for CRC, categorizing biomarkers into three hierarchical tiers according to their level of clinical validation and therapeutic relevance: established standard-of-care biomarkers, emerging clinical biomarkers, and future precision oncology biomarkers. Collectively, current evidence supports a progressive transition from single-gene testing toward integrated multi-omics precision medicine. Advances in comprehensive genomic profiling, liquid biopsy technologies, transcriptomics, radiogenomics, and artificial intelligence are expected to further refine patient stratification, optimize therapeutic decision-making, and facilitate the development of adaptive precision oncology models. Understanding the evolving genetic landscape of CRC is therefore essential for maximizing treatment efficacy and improving patient outcomes in the era of personalized cancer care. Full article

Identifying immunotherapy biomarkers for colorectal cancer (CRC) beyond MSI-high status is challenging. We evaluated CREBBP/EP300 and POLE/POLD1 mutations as candidate markers using public cohorts (MSK-CHORD, n = 5493; TCGA, n = 528; MetTropism, n = 24,496; ICI-treated, n = 1610). Regression with SHAP attribution, survival analyses, and pan-cancer transcriptomic profiling (n = 7628) were performed. CREBBP/EP300 mutations were independently associated with TMB-high MSS tumors (p < 0.00001). The co-mutation group (CREBBP/EP300 + POLE/POLD1; CoMut) was the strongest predictor of elevated TMB level (β = 3.63; p < 10⁻¹⁶; exp(β) = 37.7) with a median TMB of 155.9 vs. 7.4 and 5.4 Mut/Mb in single-mutation groups. CoMut also associated with improved survival (HR = 0.57, p = 0.035). In the ICI-treated cohort, both single-mutation groups (CREBBP/EP300-MUT-only; POLE/POLD1-MUT-only) and showed longer overall survival than wild type (34 and 28 vs. 17 months; p < 0.05), but only CREBBP/EP300 mutations independently reduced mortality risk (HR = 0.71, p = 0.0025). All groups shared immune-inflammatory transcriptomic enrichment. These findings support CREBBP/EP300 mutations as candidate immunotherapy biomarkers, and co-mutations with POLE/POLD1 define a TMB-high MSS subgroup that could refine TMB testing, pending prospective validation. Full article

Background/Objectives: The prognostic and predictive values of biomarkers in fertility-sparing management of atypical hyperplasia (AH) and endometrial cancer (EC) remain ill-defined. We aimed to identify the impact of tumour profiles on oncologic and reproductive outcomes to inform clinical decision-making. Methods: We conducted a systematic review and meta-analysis by searching MEDLINE, PubMed, Embase, Cochrane Library, Scopus, Google Scholar, and ClinicalTrials.gov, up to July 2026. We intended to include comparative studies or clinical trials, in English or French, assessing outcomes according to molecular or hormonal profiles in reproductive-aged women diagnosed with AH or EC. The primary outcome was the best overall complete remission (CR). Pooled odds ratios (ORs) were calculated using a random-effects model with logit transformation and restricted maximum likelihood estimation. Risk of bias was assessed using the Newcastle–Ottawa scale (NOS). The study protocol was registered in PROSPERO (CRD42025632885). Results: Eighteen retrospective studies comprising 965 patients were included. No specific molecular profile (NSMP) tumours demonstrated significantly higher odds of CR (OR 2.04, 95% CI 1.33–3.11). p53-abnormal (p53abn) and deficient mismatch repair (dMMR) tumours were significantly less likely to achieve CR compared to NSMP (OR 3.87, 95% CI 1.80–8.29 and OR 2.48, 95% CI 1.44–4.29, respectively). POLE-mutated (POLEmut) tumours showed CR comparable to NSMP (OR 1.39, 95% CI 0.60–3.24). Progesterone receptor (PR) positivity was strongly associated with CR (OR 7.73, 95% CI 2.77–21.63). Conclusions: NSMP and PR-positivity represented a favourable prognosis and potential prediction of CR. POLEmut tumours demonstrated CR rates comparable to NSMP, whereas p53abn and dMMR demonstrated unfavourable outcomes. These findings support a biologically tailored approach to patient selection for fertility-sparing management. Full article

Background/Objectives: Numerous innovations have changed diagnosis and treatment of endometrial cancer in recent years, with molecular classification being a major factor. Limited data exist on how molecular classification changes in recurrence or metastasis and what effect this may have on therapy. This retrospective study aimed to compare the molecular classification and other histopathological parameters of the primary tumor with those of recurrence or metastasis and to discuss their implications. Methods: A total of 43 patients with primary endometrial cancer and histologically confirmed recurrence treated at the Tuebingen University Women’s Hospital between January 2003 and January 2017 were identified within a cohort of 964 cases. Immunohistochemistry for mismatch-repair status, estrogen receptor, p53 and L1CAM, as well as next-generation sequencing of the POLE genes were performed. Further histopathological and clinical data were collected and statistical analyses were performed. Results: No POLE-mutated patients were found. A higher proportion of high-grade tumors was observed in the recurrence (30% vs. 46%). All p53-mutated patients remained p53-mutated, while a changed molecular profile of the NSMP and MMRd subtypes was observed in nine patients (21%). L1CAM remained stable in 70% of the patients. A change in molecular profile was not associated with altered prognosis. Conclusions: Our study underlines the importance of additional histopathological analysis in case of recurrence or metastasis for individualized therapy planning. Further studies with larger case numbers are necessary to validate our findings. Full article

Background: Endometrial carcinoma (EC) is one of the most common gynaecological malignancies, with a steadily increasing incidence worldwide. In 2013, a novel molecular classification of ECs enabled patient stratification into four groups with important clinical management implications: (1) DNA Polymerase Epsilon (POLE)-mutated, (2) microsatellite instability-high (MSI-H/dMMR) hypermutated, (3) tumours with low somatic copy number alteration (low-SCNA), and (4) tumours with high SCNA and p53 deficiency. This molecular classification should also be used as a tool to identify hereditary cancer syndromes, as MSI-ECs can be associated with Lynch Syndrome (LS, ORPHA:144) while somatic POLE mutations may reflect polymerase proofreading-associated polyposis (PPAP syndrome, ORPHA:447877). Methods: From 2022 to 2024, molecular classification of ECs was routinely performed on 188 consecutive cases. The results were correlated with family history and constitutional genetic testing. Results: Somatic testing revealed that 45 ECs were dMMR and 23 carried POLE variants. Five POLE-mutated ECs also displayed concomitant MSI. For all 68 patients, cancer genetic counselling was proposed, but only 41 accepted, and of these, 26 patients were eligible for the genetic test. None of the POLE somatic variants were proven to be constitutive, whereas LS was diagnosed in seven patients with dMMR-EC; interestingly, two of these patients displayed a POLE-mutated EC. Conclusions: Our data strongly suggest that molecular classification of ECs is important to improve the identification of LS and highlight the relevance of investigating all molecular markers at once in order to identify overlaps between POLE mutations and MMR defects. Full article

Purpose: To describe the long-term, multimodal follow-up and multidisciplinary evaluation of two pediatric patients with CDH3-related retinopathy, discussing the genotypic and phenotypic spectrum of this rare cadherinopathy. Design: Retrospective observational case series. Methods: Two unrelated children with early-onset macular dystrophy and congenital hypotrichosis underwent a comprehensive ophthalmic examination, including spectral-domain optical coherence tomography (SD-OCT), blue-light fundus autofluorescence (BAF), microperimetry, and full-field electroretinography (ffERG), combined with dermatologic assessment and exome sequencing. Follow-up extended over 4 years in Patient 1 and 15 years in Patient 2. Results: Both patients showed sharply demarcated posterior pole chorioretinal atrophy with preservation of the peripheral retina and stable best-corrected visual acuity throughout follow-up. Microperimetry documented localized sensitivity loss with limited progression. SD-OCT revealed persistent ellipsoid zone disruption, retinal pigment epithelium atrophy, and outer retinal tubulations. Dermatologic evaluation confirmed congenital hypotrichosis without nail abnormalities; one patient exhibited mild fifth finger clinodactyly. Genetic testing identified the following two distinct homozygous CDH3 variants: a splice-site mutation (c.160+1G>A) and a frameshift insertion (c.1837dup, p.(Asp613Glyfs*4)). Conclusions:CDH3 retinopathy presents with a characteristic multimodal imaging pattern of localized macular atrophy and slow functional decline associated with congenital hypotrichosis. A comprehensive multidisciplinary approach was essential for the correct diagnosis and a better and more thorough definition of the clinical presentation. Detailed long-term follow-up supports the hypothesis of retinal pigment epithelium dysfunction or maldevelopment rather than widespread retinal degeneration. Recognition of this phenotype is critical for accurate diagnosis, genetic counseling, and future gene-therapy strategies targeting the preserved peripheral retina. Full article

Background: Endometrial carcinoma (EC) is now classified primarily by molecular subtype—POLE-ultramutated, mismatch repair–deficient (dMMR), TP53-mutant/copy-number-high (CNH), and “no specific molecular profile” (NSMP)—a framework that has reshaped prognostic counseling and adjuvant therapy decisions. Yet several practically important questions remain insufficiently addressed in real-world cohorts: whether all four mismatch repair genes confer an equivalent favorable prognosis, whether all POLE alterations carry the same survival benefit or only specific pathogenic variants, and whether molecular subtypes retain prognostic value after adjustment for histology and tumor burden. Methods: We addressed these questions in 2901 patients pooled from the MSK-IMPACT 50K Clinical Sequencing Cohort (n = 2372; discovery) and the TCGA UCEC PanCancer Atlas (n = 529; validation)—the largest dual-cohort genomic analysis of EC reported to date. We performed individual MMR gene and combined dMMR survival stratification, multivariable Cox regression adjusted for age, histology, and sample type, and a pathogenicity-aware sensitivity analysis for POLE variants, with tumor mutational burden (TMB) compared across subgroups. Results: Across both cohorts, all four MMR gene–mutant subgroups (MLH1, MSH2, MSH6, PMS2) conferred equivalently favorable overall survival (OS) (six-group log-rank p = 7.66 × 10⁻¹² in discovery; p = 6.78 × 10⁻³ in validation), confirming dMMR as a class-level prognostic designation independent of which MMR gene is altered. Multivariable Cox regression demonstrated that POLE-ultramutated status retained an independent favorable effect (HR = 0.62, p = 0.038 in MSK; HR = 0.35, p = 0.028 in TCGA) after adjustment for age, histology, and sample type, while the favorable dMMR effect was largely accounted for by histologic context. Critically, a pathogenicity-aware sensitivity analysis revealed that the exceptional survival of the POLE subgroup is confined to canonical exonuclease-domain hotspot mutations (event rate 0.9% in MSK), whereas POLE variants of uncertain significance behave indistinguishably from NSMP-like tumors. Consistent with this finding, TMB was markedly elevated in canonical pathogenic POLE cases (median 138.7 mut/Mb in MSK; 247.4 in TCGA) but not in POLE-VUS-only cases (median 29.0 and 15.0, respectively; p < 0.001 between groups in both cohorts), confirming that the ultramutator phenotype is confined to canonical pathogenic POLE variants. We additionally characterize Uterine Clear Cell Carcinoma as a distinct histologic entity (n = 73; 3.0%) and report the POLE + TP53 co-mutant group (n = 90; 3.8%). Conclusions: These findings refine the molecular classification of EC in clinically meaningful ways: they support class-level immunotherapy eligibility based on dMMR status regardless of the specific MMR gene altered, demonstrate that POLE-ultramutated classification requires variant-level pathogenicity assessment, and identify TP53-mutant/CNH patients as the population with the most urgent unmet therapeutic need. Full article

Background: Molecular classification has transformed risk stratification in endometrial cancer, providing prognostic information beyond traditional clinicopathologic features. However, the relationship between molecular subtype, nodal involvement, and recurrence risk remains incompletely defined. This study aimed to compare lymph node metastasis rates across molecular subgroups and evaluate survival outcomes and prognostic factors for recurrence. Methods: We conducted a retrospective study including 158 patients with a preoperative diagnosis of presumed early-stage endometrial carcinoma treated surgically between 2021 and 2024. Molecular classification was performed according to WHO criteria, including POLE-ultramutated, mismatch repair deficient (MMRd), p53-abnormal (p53-abn), and no specific molecular profile (NSMP). Sentinel lymph node biopsy (SLNB) was the primary method for nodal staging. Survival outcomes were assessed using a Kaplan–Meier analysis, and logistic regression was used to identify prognostic factors for recurrence. Results: NSMP was the most frequent molecular subtype (44.3%), followed by MMRd (29.1%), p53-abn (20.9%), and POLE-mutated tumors (5.7%). Overall, 11.4% of patients had nodal metastases, most commonly in the p53-abn subgroup, which showed significantly higher rates of positive sentinel lymph nodes (p = 0.010). Prognosis differed significantly across molecular subtypes. POLE-mutated and NSMP tumors demonstrated the most favorable outcomes, while p53-abn tumors showed the poorest overall survival and progression-free survival. In a univariate analysis, grade, lymphovascular space invasion (LVSI), myometrial invasion, FIGO stage, and molecular classification were associated with recurrence. Stratified analyses suggested LVSI as the most relevant prognostic factor within the MMRd subgroup. Conclusions: Molecular classification is strongly associated with nodal involvement and survival outcomes in early-stage endometrial cancer. Integrating molecular subtype with clinicopathologic factors may improve recurrence risk stratification and guide individualized surgical and adjuvant treatment strategies. Full article

Background and Objectives: Molecular classification has emerged as a key determinant of prognosis in endometrial cancer and has recently been incorporated into the 2023 FIGO staging system. Tumors are categorized into four molecular subgroups—POLE-mutated (POLEmut), p53-abnormal (p53abn), mismatch repair-deficient (dMMR), and no specific molecular profile (NSMP)—each associated with distinct biological behavior and clinical outcomes. However, real-world data evaluating the relationship between molecular classification, FIGO stage distribution, and survival outcomes remain limited. Materials and Methods: This retrospective study included patients diagnosed with endometrial cancer between 2014 and 2022 at Dokuz Eylül University Hospital. Tumor samples were classified according to the ProMisE molecular algorithm using next-generation sequencing for POLE mutations and immunohistochemical evaluation of mismatch repair proteins and p53 expression. Clinicopathological characteristics, recurrence patterns, and survival outcomes were analyzed. Appropriate statistical analyses were performed. Results: A total of 156 patients were included (mean age 60.2 ± 10.0 years). The most common histology was endometrioid carcinoma (51.9%). Molecular subgroup distribution was NSMP (58.3%), dMMR (25%), p53abn (11.5%), and POLEmut (5.1%). Most patients presented with early-stage disease (83.4%). According to the 2023 FIGO molecular staging, 8.3% were classified as stage 2C m-p53abn and 5.8% as Stage 1Am-POLEmut. After a median follow-up of 39.5 months, the overall survival rate was 81.6%. Survival differed significantly across molecular subgroups, with the most favorable outcomes observed in the POLEmut (100%), followed by NSMP (85.2%), dMMR (78.4%), and p53abn (64.7%) (p = 0.011). Lymph node metastasis was significantly more frequent in the p53abn subgroup (p = 0.002), whereas distant metastasis rates did not differ between groups. Conclusions: Molecular classification was associated with differences in FIGO stage distribution and survival outcomes in this retrospective cohort and may provide additional prognostic information beyond traditional clinicopathological factors. The integration of molecular profiling into routine practice and staging systems may enable improved risk assessment and facilitate more personalized therapeutic strategies in endometrial cancer. Full article

Background: POLE-mutated endometrial carcinomas are associated with exceptionally favorable outcomes, forming the basis for treatment de-escalation in early-stage disease. Nevertheless, rare adverse clinical courses have been reported. This study describes an unusual case of late metastatic recurrence in a POLE-mutated tumor and provides a review of similar cases in the literature. Methods: We present a detailed clinical, radiological, pathological, and molecular description of a patient who developed metastatic recurrence 16 years after initial surgery. A systematic literature search was conducted to identify reports of recurrence, progression, or cancer-related death in POLE-mutated endometrial carcinoma, with extraction of recurrence patterns, genomic features, treatment, and outcomes. Results: The patient experienced sequential pulmonary, cerebral, and leptomeningeal metastases despite harboring a canonical POLE hotspot mutation, proficient mismatch repair status, wild-type TP53, no additional known driver mutation beyond PTEN alterations. The literature review identified a small number of similarly adverse cases. Reported recurrences were heterogeneous, though distant and occasionally central nervous system involvement were noted. Conclusions: While POLE-mutated tumors overall retain an excellent prognosis, rare cases may follow an atypical and aggressive course. Improved molecular annotation and integrated risk-stratification models are needed to better identify this minority of higher-risk patients. Full article