Journal of Pathology Clinical Research最新文献

{"title":"PRAME predicting outcome in uveal melanoma","authors":"Sally Owens,&nbsp;Naomi Walsh,&nbsp;Noel Horgan,&nbsp;Patrick Murtagh,&nbsp;Katie Hanratty,&nbsp;Grainne Finegan,&nbsp;Laura Ivers,&nbsp;John Crown,&nbsp;Susan Kennedy","doi":"10.1002/2056-4538.70116","DOIUrl":"10.1002/2056-4538.70116","url":null,"abstract":"<p>Uveal melanoma (UM) is the most common primary intra-ocular malignancy in adults and carries a high risk of metastatic disease, affecting approximately 50% of patients despite advances in local tumour control. PRAME (PReferentially expressed Antigen in MElanoma) has emerged as a marker for metastatic risk; however, evidence is largely derived from mRNA expression studies rather than routine immunohistochemistry (IHC). This study evaluates PRAME protein expression by IHC in a large UM cohort and examines its association with clinicopathological features and survival outcomes. A total of 403 UM cases were included. PRAME IHC was performed on tissue microarrays (TMAs) and/or whole tumour sections and scored as positive based on nuclear staining in &gt;10% of tumour cells. Associations were assessed using chi-square and Mann–Whitney <i>U</i> tests. Survival outcomes were analysed using Kaplan–Meier curves and Cox proportional hazards models. PRAME positivity was identified in 5% of TMA cases and 40% of whole-section cases. On TMAs, PRAME expression was associated with worse overall survival (median 26 versus 50 months; <i>p</i> = 0.03) but not metastasis-free survival (MFS). In contrast, whole-section PRAME expression was strongly associated with shorter MFS (median 5 versus 20 months; <i>p</i> &lt; 0.001) and worse overall survival (median 13 versus 52 months; <i>p</i> = 0.04). In multivariate analysis including age, American Joint Committee on Cancer stage and BAP1 status, whole-section PRAME positivity remained an independent adverse predictor of MFS (hazard ratio = 10.5, <i>p</i> = 0.002). PRAME IHC is a clinically meaningful prognostic biomarker in UM, particularly when assessed on whole tumour sections, where it provides strong independent prognostic information.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"12 6","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13662831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149185335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An X-ray micro-CT protocol enables non-destructive 3D visualization of glandular architecture in archived paraffin-embedded prostate cancer tissue","authors":"Santiago Laguna-Castro,&nbsp;Erna Mäkinen,&nbsp;Teemu Tolonen,&nbsp;Antti Kaipia,&nbsp;Jari Hyttinen","doi":"10.1002/2056-4538.70119","DOIUrl":"10.1002/2056-4538.70119","url":null,"abstract":"<p>The prostate is organized as a complex glandular network, and prostate cancer is accompanied by architectural changes that cannot always be inferred from two-dimensional (2D) histology. The study of these features in three dimensions (3D) in cancerous tissue is important because glandular features have shown potential value for disease characterization and risk stratification beyond that obtained from individual 2D sections. Large collections of clinically annotated material preserved in paraffin remain an important research source. However, many 3D imaging methods require destructive or labor-intensive preparation, limiting access to valuable material that needs to be re-archived. In this proof-of-concept study, we developed an X-ray micro-computed tomography (micro-CT) workflow for direct 3D imaging of archived paraffin-embedded prostate specimens with near-zero sample manipulation. Imaging and denoising parameters were optimized to balance image quality with acquisition time. Paraffin-embedded prostate core punches (<i>n =</i> 5) from five radical prostatectomy specimens were imaged by micro-CT and subsequently processed for histology. Digitized histological sections were aligned with corresponding micro-CT planes for qualitative comparison, while pre-sectioning micro-CT data provided an intact geometric reference for exploratory assessment of histology-associated dimensional changes at the whole-core and glandular-lumen levels. The optimized workflow yielded micro-CT images with discernible glandular morphology and qualitative structural correspondence with matched histological sections. Exploratory measurements suggested modest dimensional change at the whole-core level and greater variability at the lumen level; none of the tested deformation metrics reached conventional statistical significance. Illustrative 3D segmentation presented the glandular epithelium and lumina as spatially continuous structures within a cancer-containing region. These findings support the feasibility of X-ray micro-CT as a non-destructive approach for 3D characterization of prostate glandular architecture directly from paraffin-embedded tissue, providing volumetric context for structures identified on histology while preserving the specimen for subsequent histological assessment.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"12 6","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13659285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149167350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The molecular landscape of nodular fasciitis: novel USP6 fusions, genomic stability, and an exploratory clinicopathological model – a 20-year retrospective study","authors":"Kristijan Skok,&nbsp;Maximilian T Buchwald,&nbsp;Maria Anna Smolle,&nbsp;Theresa Godschachner,&nbsp;Andreas Leithner,&nbsp;Christian Viertler,&nbsp;Bernadette Liegl-Atzwanger","doi":"10.1002/2056-4538.70117","DOIUrl":"10.1002/2056-4538.70117","url":null,"abstract":"<p>Nodular fasciitis (NF) is a benign myofibroblastic neoplasm characterized by rapid growth and recurrent <i>USP6</i> rearrangements. Despite its benign nature, NF may exhibit worrisome histologic or clinical features that mimic sarcoma, posing diagnostic challenges. The relationship between molecular diversity and morphologic heterogeneity remains incompletely understood. We retrospectively analyzed 283 NF cases diagnosed between 2000 and 2024 at a tertiary referral center. Molecular testing for <i>USP6</i> rearrangements was performed in 44 cases using targeted RNA sequencing. Histologic features, clinical parameters, and fusion partner distribution were evaluated, with emphasis on lesions showing infiltrative or worrisome morphology. Selected cases underwent additional genomic profiling, including hybrid-capture DNA sequencing and copy-number analysis. Among 44 molecularly confirmed cases, 18 distinct <i>USP6</i> fusion partners were identified. The most frequent fusion was <i>MYH9</i>::<i>USP6</i> (40.9%), followed by <i>COL1A1</i>::<i>USP6</i>, <i>MIR22HG</i>::<i>USP6</i>, and <i>RRBP1</i>::<i>USP6</i>. Rare and previously unreported fusions, including <i>CLK1</i>::<i>USP6</i> and <i>FOSL2</i>::<i>USP6</i>, further expanded the molecular spectrum. Two cases with infiltrative, aggressive-appearing morphology showed no additional pathogenic alterations and a genomically stable profile. Based on these findings, we propose an exploratory, hypothesis-generating framework to summarize the observed clinicopathological spectrum of NF. NF demonstrates substantial molecular heterogeneity but retains a genetically simple and largely benign biological behavior. Even lesions with alarming morphology appear genomically stable and clinically indolent. The proposed framework may facilitate diagnostic interpretation and provide a conceptual framework for future studies but requires validation before any biological or clinical implications can be inferred.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"12 6","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.70117","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149138256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment methods of pathological complete response in neoadjuvant head and neck cancer clinical trials: a scoping review","authors":"Peter Robinson,&nbsp;Charlotte Catrina Currie,&nbsp;Hisham Mehanna,&nbsp;Muhammad Shahid Iqbal,&nbsp;James O'Hara,&nbsp;Elsa Campôa,&nbsp;Myrto Moutafi,&nbsp;Max Robinson","doi":"10.1002/2056-4538.70114","DOIUrl":"https://doi.org/10.1002/2056-4538.70114","url":null,"abstract":"<p>Head and neck cancer (HNC) trials have demonstrated pathological complete response (pCR) in patients receiving neoadjuvant treatment prior to surgery; however, systematic reviews have reported marked variation in pCR rates. This scoping review was designed to determine the definition, criteria, and assessment methodologies for pCR in interventional neoadjuvant HNC clinical trials. The review was conducted in accordance with the <i>JBI Manual for Evidence Synthesis</i> and the protocol prospectively registered. Medical databases, trial registries, and grey literature were systematically searched, and eligibility criteria applied. Study characteristics and pCR assessment methodologies were extracted and described. A total of 4,931 sources were identified, and screening identified 114 trials. Only 22 studies had publicly accessible protocols for assessment. Trials were initiated between 1989 and 2025, and the majority were phase II investigating chemotherapy + immunotherapy regimens (51%). pCR was most frequently classified as a secondary endpoint (55%), and reported pCR rates ranged from 0% to 100%. There was heterogeneity and incomplete documentation in both specimen preparation and pCR assessment. Where specified, most included assessment at both primary tumour and lymph nodes (50 of 69; 72%), and quantitative assessment calculating percentage residual viable tumour was common. While no formal guidelines for pCR assessment in HNC were identified, one trial outlined an immune-related pathological response criteria for oral squamous cell carcinoma, and another included a detailed ‘pathological response assessment’ proforma. Citation of methodologies used in other cancers, for example, lung and breast cancer, was a recurring theme. Based on these findings, we propose pragmatic definitions, assessment considerations, and a structured reporting proforma to support increased transparency and reproducibility in pCR reporting. While these proposed elements are not consensus based, they provide a foundation for harmonisation efforts and highlight priorities for development of international consensus guidelines to enable meaningful comparison of interventions and determine the validity of pCR as a surrogate endpoint in HNC.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"12 6","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.70114","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149072635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Profiling EGFR, c-MET, and B7H3 co-expression to guide next-generation dual-drug conjugate strategies in colorectal cancer","authors":"Yanan Yang,&nbsp;Huiyu Li,&nbsp;Shiwei Xiao,&nbsp;Mengxia Jiao,&nbsp;De Wu,&nbsp;Chunxia Ao,&nbsp;Yanggeling Zhang,&nbsp;Siyuan Yan,&nbsp;Shaomei Sun,&nbsp;Chen Yang,&nbsp;Renhong Tang,&nbsp;Xiyuan Wang,&nbsp;Junqiu Yue","doi":"10.1002/2056-4538.70118","DOIUrl":"https://doi.org/10.1002/2056-4538.70118","url":null,"abstract":"<p>Epidermal growth factor receptor (EGFR), cellular mesenchymal-epithelial transition factor (c-MET), and B7 homolog 3 (B7H3) are important targets for antibody-based drug development in colorectal cancer (CRC). To overcome the limitations of single-target antibody therapies – such as limited efficacy, widespread resistance, narrow patient populations, and treatment-related toxicities – various bispecific antibodies or antibody–drug conjugate (ADCs) targeting two targets are being extensively validated in clinical settings. A deeper understanding of their expression profiles and co-expression patterns of actionable therapeutic targets may guide more effective treatment strategies. We evaluated the immunohistochemical expression of B7H3, c-MET, and EGFR in a cohort of 193 CRC patients. Among which, B7H3 exhibited the highest positivity rate (80.83%) in CRC tissues, followed by c-MET (77.20%) and EGFR (47.15%). The positive rates of B7H3 showed no significant differences across patient gender, age, TNM stage, differentiation grade, or tumor site. In contrast, the c-MET positivity rate was elevated in patients with stage I–II disease, and the expression of EGFR was significantly higher in female patients than in male patients. Concurrent assessment of the three targets in metastatic lesions revealed that B7H3 expression levels were comparable between primary and metastatic tumors, whereas c-MET expression was significantly higher in primary lesions. Co-expression analysis indicated that the group with the highest patient coverage was the B7H3/c-MET dual-positive group, followed by the B7H3/EGFR, and c-MET/EGFR combinations, and the proportion of patients with at least one positive target exceeded 80%. Finally, mRNA profile from TIMER database reveals that <i>CD276</i> and <i>MET</i> expression in CRC tumor tissues were higher than those in the majority of normal tissues. Therefore, utilizing B7H3/c-MET combination therapies that integrate intracellular signaling inhibition with immune checkpoint modulation could potentially extend therapeutic benefits to a wider range of CRC patients.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"12 6","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.70118","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149072659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Artificial intelligence-assisted histopathological diagnosis of endocervical gastric-type adenocarcinoma: a multicenter model development and validation study","authors":"Jing Yang,&nbsp;Qiming He,&nbsp;Jing Peng,&nbsp;Yizhi Wang,&nbsp;Jiawen Li,&nbsp;Haoxiang Li,&nbsp;Yan Liu,&nbsp;Yuxiang Wang,&nbsp;Ajin Hu,&nbsp;Xitong Ling,&nbsp;Yingwen Zhang,&nbsp;Minxi Ouyang,&nbsp;Xinrui Chen,&nbsp;Lianghui Zhu,&nbsp;Yiqing Liu,&nbsp;Yexing Zhang,&nbsp;Siqi Zeng,&nbsp;Qiang Huang,&nbsp;Zihan Wang,&nbsp;Tian Guan,&nbsp;Yueping Liu,&nbsp;Ling Chen,&nbsp;Yan Ding,&nbsp;Yonghong He,&nbsp;Congrong Liu","doi":"10.1002/2056-4538.70113","DOIUrl":"10.1002/2056-4538.70113","url":null,"abstract":"<p>Endocervical gastric-type adenocarcinoma (GAS) is one of the most aggressive subtypes of cervical cancer and is frequently underdiagnosed due to morphological ambiguity, leading to delayed diagnosis. Despite the availability of molecular and genomic assays, their high cost, complexity, and limited reproducibility restrict clinical use. This study therefore proposes a highly sensitive artificial intelligence (AI)–assisted diagnostic system for GAS based exclusively on H&amp;E-stained histopathological images. We included 309 slides from 96 GAS cases collected at Peking University Third Hospital from January 2018 to January 2025, representing the largest GAS cohort reported to date for AI research. In addition, we incorporated other morphologically analogous diseases, encompassing a total of 1,320 slides sourced from four categories: normal cervical mucosa (NORM), benign endocervical lesion entities (BELE), HPV-associated adenocarcinoma (HPVA), and endometrioid carcinoma with mucinous differentiation (ECMD). We developed GASPath, based on a novel multiple instance learning framework that efficiently captures fine-grained morphological variations from H&amp;E-stained images. Beyond internal validation, GASPath was evaluated across 12 independent retrospective cohorts and further subjected to large-scale real-world validation on more than 7,000 samples from March 2024 to April 2025. Across three stages, GASPath demonstrated high performance. In internal validation (Stage I), it achieved an accuracy of 0.980 (95% CI 0.977–0.983) and an ROC-AUC of 0.995 (95% CI 0.994–0.997). In external validation (Stage II), the sensitivity reached 0.902 and improved to 0.968 with proposed strategies. For biopsy samples, GASPath achieved an ROC-AUC of 0.990 (95% CI 0.984–0.997). In large-scale real-world deployment (Stage III, <i>n</i> = 7,056), GASPath achieved a balanced accuracy of 0.953, with 100% sensitivity for GAS (45/45 cases correctly identified). The heatmaps highlight morphological features of GAS that are easily underestimated, such as irregular, angulated glands, subtle loss of nuclear polarity, and mild cytologic atypia, which show substantial morphological overlap with other diagnostic categories. GASPath enables high-sensitivity detection of GAS in routine H&amp;E-stained slides, obviating the need for extensive auxiliary testing while preventing underdiagnosis and misdiagnosis. This advancement addresses a critical gap by streamlining diagnostic workflows without compromising accuracy. Its implementation could enable cost-effective, scalable AI-assisted diagnostics, potentially transforming the early detection and management of this aggressive cancer subtype.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"12 5","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13531234/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148867526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased CCR5 expression in lymphoma cells and M2 macrophages is associated with poor prognosis in primary intestinal diffuse large B-cell lymphoma","authors":"Wei-Li Ma,&nbsp;Tsai-Yun Chen,&nbsp;Pei-An Fu,&nbsp;Jo-Pai Chen,&nbsp;Ming Yao,&nbsp;Hsiu-Po Wang,&nbsp;Been-Ren Lin,&nbsp;Chung-Wu Lin,&nbsp;Chia-Lang Hsu,&nbsp;Chung-Yu Huang,&nbsp;Ann-Lii Cheng,&nbsp;Sung-Hsin Kuo","doi":"10.1002/2056-4538.70112","DOIUrl":"10.1002/2056-4538.70112","url":null,"abstract":"<p>Few studies have evaluated the impact of organ-specific tumor microenvironments (TMEs) on clinical outcomes in diffuse large B-cell lymphoma (DLBCL). This study investigated potential molecular markers, the immune cell composition within the TME, and their associations with clinical outcomes in patients with primary intestinal DLBCL (PI-DLBCL). We initially analyzed RNA expression in tumor cells from 19 patients with PI-DLBCL in the experimental cohort. Candidate biomarkers were then assessed in lymphoma tissue from a total of 48 patients in the same cohort, including the 19 with RNA-expression data, and validated in an independent cohort of 29 patients with PI-DLBCL. Associations between these markers and clinicopathological features, event-free survival (EFS), and overall survival (OS) in the two cohorts were analyzed. In the RNA expression panel, CCL5 expression was higher in patients with advanced-stage PI-DLBCL and was associated with inferior EFS and OS. Its principal receptor, CCR5, expressed in approximately one-third of patients, was associated with lower complete response rates to first-line immunochemotherapy: 50% in the experimental cohort and 10% in the validation cohort and correlated with the 7-year worse OS rate in both the experimental (49.8% versus 71.4%, <i>p</i> = 0.082) and validation (0% versus 76.2%, <i>p</i> &lt; 0.001) cohorts. In both the experimental and validation cohorts, CCR5-positive tumors exhibited decreased CD86-positive (M1-like) and increased CD206-positive (M2-like) macrophage infiltration, consistent with an immunosuppressive TME. Multivariate analyses revealed that CCR5 expression was independently associated with worse EFS (<i>p</i> &lt; 0.001) and OS (<i>p</i> = 0.004) in patients with PI-DLBCL (combined experimental and validation cohorts). CCR5 expression indicates a biologically aggressive subtype of PI-DLBCL with poor clinical outcomes and M2 macrophage–dominant immunosuppression.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"12 5","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.70112","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148714304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic profiling of Mexican patients with B-cell precursor acute lymphoblastic leukemia reveals clinically significant somatic and potential germline variants","authors":"Daniel Martínez Anaya,&nbsp;María del Rocío Juárez-Velázquez,&nbsp;Ulises Juárez Figueroa,&nbsp;Michael Dean,&nbsp;Consuelo Salas Labadía,&nbsp;Marian Valladares Coyotecatl,&nbsp;Adriana Reyes León,&nbsp;Norma López Santiago,&nbsp;Luis Juárez Villegas,&nbsp;Marta Zapata Tarrés,&nbsp;Patricia Pérez-Vera","doi":"10.1002/2056-4538.70107","DOIUrl":"10.1002/2056-4538.70107","url":null,"abstract":"<p>B-cell precursor acute lymphoblastic leukemia (preB-ALL) is characterized by pathogenic variants currently used in precision oncology. However, the mutational landscape of Mexican children with preB-ALL has not yet been thoroughly explored and defined in terms of the clinical significance. We used a custom-designed next-generation sequencing exome panel, along with high-resolution chromosome microarrays and gene fusion-targeted assays, to characterize the mutational landscape of 73 Mexican children with preB-ALL, exploring the profile of clinically significant variants. We classified the variants following the AMP-ASCO-CAP 2017 and ACMG-CG 2019 guidelines recommendations. The mutational landscape includes a broad molecular spectrum of variants affecting cell cycle regulation, B-cell development, kinase signaling, and epigenetic regulation genes. Tier 1 diagnostic variants allowed the identification of pre-B ALL genetic subtypes, diminishing the preB-ALL NOS group from 63% to 37%. Furthermore, 37% of cases presented Tier 1 variants conferring intermediate to adverse prognoses (primarily involving <i>CRLF2</i> gene fusions, as well as <i>PAX5, IKZF1,</i> and <i>TP53</i> inactivating mutations). Notably, these patients exhibited high-risk clinical features and a lower event free survival rate than patients without these variants (60% versus 41.2%; <i>p</i> = 0.046; 95% CI). Between 19% and 42% of patients had Tier 2 variants targetable with JAK-STAT or RAS-MAPK signaling inhibitors. These patients showed a lower overall survival rate than patients without these variants (64% versus 90%; <i>p</i> = 0.048; 95% CI). Tier 1 potential germline variants in cancer predisposition genes (mainly <i>BRCA1/2</i> and <i>CHEK2)</i> were observed in 10% of patients, some of whom had a family history of cancer. This highlights the importance of genetic counseling for patients and their families. Finally, 33% of patients had Tier 3 variants that were predicted to be deleterious and potentially upgraded to pathogenic with plausible clinical relevance. In conclusion, the mutational landscape analysis revealed variants useful for oncologic management and genetic counseling of Mexican children with preB-ALL.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"12 5","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13439393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148674308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Not all NTRK fusions in mesenchymal neoplasia are driver events: implications on classification and targeted therapy","authors":"Mohamed A Yakoub,&nbsp;Purvil Sukhadia,&nbsp;Carla Saoud,&nbsp;Meera Hameed,&nbsp;Cristina R Antonescu","doi":"10.1002/2056-4538.70111","DOIUrl":"https://doi.org/10.1002/2056-4538.70111","url":null,"abstract":"<p><i>NTRK</i> fusions drive the pathogenesis of a distinctive group of mesenchymal neoplasms with significant impact on classification and targeted therapy. However, unexpected <i>NTRK</i> fusions have been reported in other sarcoma entities, raising uncertainty over their specificity and clinical management. Herein, we investigate the incidence and structural variants of <i>NTRK</i> fusions among a large clinicopathologic and molecular sarcoma cohort. The goal was to distinguish primary driver <i>NTRK</i> fusions from potential passenger events and correlate with sarcoma histotypes. <i>NTRK1-3</i> fusions were queried across a large spectrum of sarcomas, profiled by targeted DNA and/or RNAseq. Fusions were classified as oncogenic when <i>NTRK</i> was the 3′ partner, in-frame, retained kinase domain (KD), and/or RNAseq confirmation; fusions of uncertain significance (FUS) when out-of-frame, lacking full KD, and/or RNAseq negative. We identified 48 cases with <i>NTRK</i> fusions, detected either by pathologist-initiated RNAseq for diagnosis (<i>n</i> = 27) or by clinician-initiated DNAseq for therapeutic target discovery (<i>n</i> = 21). For the latter subset, reflex RNAseq was activated for confirmation. Integrated review confirmed 33 (69%) oncogenic fusions. Remaining were FUS, apart from one indeterminate. In all except three cases, oncogenic fusions occurred in canonical <i>NTRK</i>-driven histotypes. In contrast, <i>NTRK</i> FUS were detected in various pathologic entities, including well-differentiated/dedifferentiated liposarcoma (<i>n</i> = 9, 60%), two osteosarcoma, and single cases of other subtypes. <i>NTRK1</i> fusions were the most common in both oncogenic and FUS groups (61%, 67%). <i>CDKN2A/B</i> deletions were observed mostly in oncogenic <i>NTRK1</i> fusions (71%), while <i>MDM2/CDK4</i> amplifications in the <i>NTRK1</i> FUS. The FUS group demonstrated lower <i>NTRK</i> mRNA expression, with a mean of −4.60, <i>p</i> &lt; 0.001. Pan-TRK immunohistochemistry was positive in cases with oncogenic <i>NTRK</i> fusions, and negative in FUS cases. Only two-thirds of <i>NTRK</i> fusions detected were functional drivers, mostly from pathologist-driven testing of suggestive histotypes. In contrast, genomic profiling in complex sarcomas often yields passenger FUS, lacking functional impact.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"12 5","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.70111","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148652456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor-type–specific expression of TTF-1 in primary central nervous system tumors classified by the 2021 WHO criteria","authors":"Lu Xu,&nbsp;Hong-Jiu Ren,&nbsp;Jian Gu,&nbsp;Bing-Wen Shan,&nbsp;Tong Ren,&nbsp;Chu-Hang Liu,&nbsp;Chun-Xian Cai,&nbsp;Xiao-Yu Zhang,&nbsp;Juan-Han Yu","doi":"10.1002/2056-4538.70109","DOIUrl":"10.1002/2056-4538.70109","url":null,"abstract":"<p>Thyroid transcription factor-1 (TTF-1) is a widely used immunohistochemical marker for tumors of thyroid and pulmonary origin; however, its expression profile and diagnostic relevance in primary central nervous system (CNS) tumors remain incompletely characterized, particularly following the revisions in the 2021 WHO Classification of CNS Tumors. We systematically evaluated TTF-1 expression in a cohort of 214 primary CNS tumors diagnosed between 2021 and 2024 at The First Affiliated Hospital of China Medical University and classified according to current WHO criteria. Immunohistochemistry for TTF-1 was performed, and expression patterns were correlated with histological tumor type, molecular classification, and WHO grade. Statistical analyses were conducted to compare expression frequencies across tumor subtypes. TTF-1 showed tumor-specific expression patterns. It was highly sensitive in central neurocytomas (89.47%) and fully specific for subependymal giant cell astrocytoma (SEGA) among circumscribed gliomas. Focal TTF-1 positivity was sporadically detected in high-grade diffuse gliomas, without significant links to molecular alterations, anatomical sites, or other common immunohistochemical indicators. TTF-1 was consistently negative in multiple newly classified and rare CNS tumors, whereas partial intracranial mesenchymal tumors with FET–CREB fusions presented TTF-1 positivity. In conclusion, TTF-1 serves as a reliable sensitive marker for central neurocytomas and a highly specific marker for SEGA. Given its occasional positivity in high-grade gliomas and certain intracranial mesenchymal tumors, pathologists should interpret TTF-1 results prudently to avoid misdiagnosing primary CNS lesions as metastatic tumors. TTF-1 is therefore a valuable auxiliary biomarker for difficult differential diagnosis of CNS tumors.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"12 4","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13382157/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148521551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}