AIM: Hereditary spherocytosis (HS) refers to a heterogeneous disorder varying in genotypic and phenotypic features manifested by the production of spherocytes. The diseased cells can be eliminated from the circulatory sy...AIM: Hereditary spherocytosis (HS) refers to a heterogeneous disorder varying in genotypic and phenotypic features manifested by the production of spherocytes. The diseased cells can be eliminated from the circulatory system either by macrophages in the spleen in the extravascular pathway or the intravascular pathway via the complement cascade. This study aimed to investigate the status of red blood cell (RBC) surface molecules CD55 (decay accelerating factor), CD35 (complement receptor type 1-CR1), CD59 (MACIF), CD47 (marker of self) and CD71 (transferrin receptor) from individuals diagnosed with HS. METHODS: This study aims to quantitatively assess RBC surface molecules (CD35, CD55, CD59, CD47 and CD71) on peripheral RBCs from 42 HS patients and 30 healthy controls, carried out by flow cytometry using monoclonal antibodies. RESULTS: Our findings show that HS patients had a significant 58% decrease in anti-CD35 binding compared with healthy controls. This is the first study to demonstrate the presence of erythrocytes with reduced CD35 levels in HS patients. Compared with the control group, HS patients had comparable levels of CD59 and CD47, but their CD55 levels were significantly reduced, with a 30% decrease in anti-CD55 binding. The expression level of CD71 was higher in HS patients (3.33%) compared with healthy controls in our study. CONCLUSION: The diminished levels of CD35 and CD55 in HS patients may influence RBC clearance, possibly through mechanisms that remain fully understood and require further investigation, including their potential role in haemolytic crises. Further research employing molecular techniques is required to clarify their exact role in HS.
Pye H, Brettle DS, Lyons C
… +5 more, Versaevel F, Barale-Thomas E, Zatloukal K, Treanor D, Bigpicture consortium
J Clin Pathol
· 2025 Sep · PMID 40645763
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AIMS: In the end-to-end digital pathology workflow, variability can be introduced at each step, resulting in differences in the final image dataset. The effectiveness of quality control processes at each step of the work...AIMS: In the end-to-end digital pathology workflow, variability can be introduced at each step, resulting in differences in the final image dataset. The effectiveness of quality control processes at each step of the workflow will impact the extent and relevance of this variability. METHODS: To assess the maturity of whole slide imaging (WSI) quality processes for the whole digital pathology workflow, we conducted an online questionnaire across 19 digitally active members of the Bigpicture consortium. RESULTS: A key finding was that a lower proportion of centres are implementing rigorous quality processes and checks processes at the post-scanning steps of the WSI workflow, such as 'digital reporting and display' (44%) and computational analysis (34%), when compared with pre-scanning steps such as 'pre-staining' (72%) and 'staining' (77%). CONCLUSIONS: This information allows us to identify priorities for quality improvement of the overall WSI workflow.
AIM: To analyse the expression of early, intermediate and late neuronal immunomarkers in multinodular and vacuolating neuronal tumour (MVNT) and understand the histogenesis of this rare tumour. MATERIALS AND METHODS: Thi...AIM: To analyse the expression of early, intermediate and late neuronal immunomarkers in multinodular and vacuolating neuronal tumour (MVNT) and understand the histogenesis of this rare tumour. MATERIALS AND METHODS: This is a retrospective study over a period of 5 years and included seven cases. Demographic, radiological and histopathological features were assessed. Immunohistochemistry was done for early (OLIG2, MAP2, Doublecortin), intermediate (alpha-internexin, neurofilament) and late neuronal immunomarkers (NeuN, synaptophysin). RESULTS: All tumours were located in the cerebral hemisphere, mostly confined to temporal lobes with long-standing seizure as the most common symptom. On Magnetic resonance imaging (MRI), these tumours appeared mostly solid and were hypointense on T1 weighted image, hypointense to hyperintense on T2 weighted image. Six out of the seven cases showed nodular as well as diffuse growth pattern, located within deep cortical and superficial subcortical white matter. The nodules were composed of intermediate to large neuronal cells with prominent nucleoli and cytoplasmic vacuolation. The vacuolated neuronal cells showed immunolabelling for early neuronal immunomarkers and an autophagic immunomarker p62. The expression of late and intermediate neuronal immunomarkers was variable to absent. CD34 positive ramified neural elements were observed in the adjoining cortex of six cases. Follow-up data for four cases showed indolent behaviour. CONCLUSION: MVNT tumour cells consistently express early neuronal immunomarkers with variable expression of intermediate and late, suggesting maturation arrest early in the development. A combination of neuronal immunomarkers may be useful to diagnose these tumours when the classical histopathological pattern is not present.
Pandiri M, Stengel A, Zhang J
… +28 more, Wang P, Shao H, Velmurugan S, Jacob A, Symes E, Kaur A, Rojek A, Sojitra P, Wiredja D, Zhou Q, Chang H, Patil E, Patel JL, Patel AB, Menon M, Ghosh S, Wool GD, Arber DA, Pan Z, Findley A, Badar T, Tariq H, Sallman D, Bell RC, Perry A, Haferlach C, Fitzpatrick C, Venkataraman G
We investigated the prognostic impact of blast counts, allelic state determinants (number of hits, del(17p), variant allele frequency, complex karyotype),and a novel karyotypic clonal cell fraction (≤50% clonal cells vs...We investigated the prognostic impact of blast counts, allelic state determinants (number of hits, del(17p), variant allele frequency, complex karyotype),and a novel karyotypic clonal cell fraction (≤50% clonal cells vs >50% clonal cells (termed 'CK50')) in 495 individuals with mutated ( ) myeloid neoplasms. Outcome examined was 24-month survival (OS24). The cohort (median age 71) included 29% (144/495) myelodysplastic syndromes (MDS)/MDS-acute myeloid leukaemia (AML) (1%-19% blasts) and 71% (351/495) AML (≥20% blasts), with 18% (81/460) having low CK50. Overall, 83% received front-line hypomethylating agents. Higher blast counts (<20% vs ≥20%) were marginally associated with CK50 (p=0.08). In the OS24 analysis, blast count showed a marginal association with OS24 (HR 1.3 (95% CI 1.0 to 1.6); p=0.07), while CK50 predicted significantly inferior outcomes (HR=1.7 (95% CI 1.2 to 2.3); p=0.002). In a multivariable model including all allelic state determinants, only CK50 and complex karyotype remained relevant for predicting adverse outcomes.
AIM: To investigate the histomorphological, immunophenotypic and molecular pathological features of Epstein-Barr virus (EBV)-positive polymorphic B-cell lymphoproliferative disorders (LPD) of the central nervous system (...AIM: To investigate the histomorphological, immunophenotypic and molecular pathological features of Epstein-Barr virus (EBV)-positive polymorphic B-cell lymphoproliferative disorders (LPD) of the central nervous system (CNS) in people living with HIV. METHODS: Seven HIV-positive patients with primary CNS lesions were retrospectively analysed. According to the 5th edition of the WHO Classification of Haematolymphoid Tumours and 2022 International Consensus Classification of mature B-cell lymphomas, these patients were pathologically diagnosed based on their H&E staining, immunohistochemistry, immunoglobulin heavy chain (IGH) clonality analysis, EBV-encoded RNA (EBER) fluorescence in situ hybridisation (FISH) and clinical data. RESULTS: MRI revealed lesions in the frontal lobe, cerebellar vermis, occipital lobe, temporal lobe, basal ganglia and thalamus, with four patients exhibiting lesions in multiple locations. Histopathological examination revealed polymorphic lymphocytic infiltrates in brain tissue, including lymphocytes, histiocytes, immunoblasts, plasma cells, atypical large B-cell and Hodgkin-Reed-Sternberg-like cells, with B-cell predominantly. Lymphocytic infiltration was mainly perivascular, with focal coagulative necrosis observed in four cases. Immunohistochemistry identified B-cell (CD20+, CD79a+), large B-cell and immunoblasts (CD30+), T-cell (CD3+), histiocytes (CD68+) and plasma cells (CD138+). All cases were positive for BCL-2 and Ki67 (20%-60%+), with three cases positive for EBNA2. All cases were negative for LMP1, HHV8, Bcl-6 and CD15. EBER in situ hybridisation was positive in all cases, and five cases showed IGH clonal rearrangement. FISH testing for IGH breakage recombination was negative in all seven cases. CONCLUSION: Accurate diagnosis of EBV-positive polymorphic B-cell LPD in the CNS of HIV patients requires a comprehensive approach including histology, immunophenotyping, molecular testing, and clinical information.
Immune checkpoint inhibitor (ICI) therapy serves as a standard treatment for advanced or recurrent malignant melanoma. Tumour neoantigenicity is an important factor for the effectiveness of the ICI therapy. However, the...Immune checkpoint inhibitor (ICI) therapy serves as a standard treatment for advanced or recurrent malignant melanoma. Tumour neoantigenicity is an important factor for the effectiveness of the ICI therapy. However, the absence of reliable biomarkers to predict ICI therapy efficacy remains an unresolved challenge. REV7 is a subunit of mutagenic DNA polymerase ζ and plays a role in generating genetic alterations following DNA damage. In this study, we examined REV7 as a potential predictive biomarker for ICI therapy in melanoma. Using RNA in situ hybridisation, we assessed REV7 expression in melanomas from 42 patients who received ICI therapy. Our analysis revealed that high REV7 expression correlated significantly with improved progression-free survival, durable clinical benefit and favourable clinical outcomes according to response evaluation criteria in solid tumours. These findings suggest that REV7 may be a potential predictive biomarker for ICI therapy response in melanoma.
AIMS: Breast cancer (BC) during pregnancy (PrBC) and the postpartum period (PPBC) often exhibits more aggressive tumour characteristics and is associated with a poorer prognosis compared with age-matched nonpregnant pati...AIMS: Breast cancer (BC) during pregnancy (PrBC) and the postpartum period (PPBC) often exhibits more aggressive tumour characteristics and is associated with a poorer prognosis compared with age-matched nonpregnant patients with BC. The underlying mechanisms for this increased aggressiveness remain unresolved. Intratumoral hypoxia, a known adverse prognostic marker in nonpregnant BC, has not yet been studied in PrBC/PPBC. This is particularly intriguing due to the potential exposure to angiogenesis-stimulating factors during pregnancy, which may influence tumour behaviour. METHODS: Tumour tissues from 148 patients with PrBC and 45 patients with PPBC were used to create a tissue microarray (TMA), and clinical and outcome data were obtained. The TMAs were stained for hypoxia-associated protein markers: glucose transporter-1, carbonic anhydrase IX and hypoxia-inducible factor-1α. RESULTS: Of all 193 tumours, 152 (79%) expressed at least one of these proteins indicative of intratumoral hypoxia. The presence of intratumoral hypoxia was associated with a higher histological grade (83% grade III vs 63%) and frequent hormone receptor negativity (68% vs 39%). In a multivariable analysis, the presence of intratumoral hypoxia indicated a significantly worse prognosis (HR 2.532, 95% CI 1.1 to 5.7) for patients with PrBC and PPBC. CONCLUSION: This unique study, the first in patients with PrBC and PPBC, showed that, despite their likely exposure to angiogenesis-stimulating factors, intratumoral hypoxia is frequent and affects 79% of patients. Importantly, patients with tumours overexpressing hypoxia markers have significantly worse survival. This suggests that hypoxia may be an important mechanism in carcinogenesis and clinical behaviour of PrBC and PPBC.
AIMS: CD31 (platelet endothelial cell adhesion molecule 1) is a transmembrane glycoprotein involved in cell adhesion and signal transduction that is primarily expressed in vascular endothelial cells, platelets, neutrophi...AIMS: CD31 (platelet endothelial cell adhesion molecule 1) is a transmembrane glycoprotein involved in cell adhesion and signal transduction that is primarily expressed in vascular endothelial cells, platelets, neutrophils, and certain tumour cells. We investigated CD31 expression in cancer cells by conducting a pan-cancer gene expression analysis using data from cancer cell lines as well as an immunohistochemical analysis of surgically resected cancer specimens. The goal was to elucidate the frequency and distribution of CD31 expression across cancer types and its diagnostic significance. METHODS: Gene expression data from 1073 cancer cell lines were analysed to determine the frequency of CD31 expression across different cancer types. Immunohistochemical analysis was performed on 358 resected cancer specimens, focusing on adenocarcinomas and squamous cell carcinomas. The analysis compared the frequency of CD31 expression among specific cancer subtypes and between histological types. RESULTS: In gene expression analyses, adenocarcinomas showed a higher frequency of CD31 expression than did squamous cell carcinomas. Immunohistochemically, CD31 expression was observed in breast apocrine carcinomas (40.0%), hepatocellular carcinomas (18.8%), uterine endometrioid adenocarcinomas (31.6%), ovarian high-grade serous carcinomas (20.0%), ovarian clear cell carcinomas (40.0%) and urothelial carcinomas (25.0%). No CD31 expression was detected in oesophageal, renal, prostate or cervical cancers. CONCLUSIONS: CD31 expression is more frequent in adenocarcinomas than in squamous cell carcinomas, with variability among cancer subtypes. Recognising CD31-positive cancers is critical to avoid misdiagnosing them as endothelial-derived tumours. The mechanisms underlying CD31 expression in cancer remain unclear and warrant further investigation.
BACKGROUND: Deep learning (DL) models are effective pre-screening tools for detecting mismatch repair deficiency (dMMR) in colorectal carcinoma (CRC). These models have been trained and validated on large cohorts from th...BACKGROUND: Deep learning (DL) models are effective pre-screening tools for detecting mismatch repair deficiency (dMMR) in colorectal carcinoma (CRC). These models have been trained and validated on large cohorts from the Northern Hemisphere, without representation of African samples. We sought to determine the performance of a DL model in an ethnically heterogeneous cohort of patients from South Africa. METHODS: Our cohort comprised 197 CRC resection specimens, with scanned whole slide images tessellated and inputted into a transformer-based DL model trained on large international cohorts. Model performance was evaluated using area under the receiver operating characteristic curve (AUROC), sensitivity and specificity. The maximal Youden's J index was calculated to determine the optimal cut-off threshold for the model prediction score. RESULTS: Our model yielded an AUROC of 0.91 (±0.05). Using a prediction score threshold of 0.620 produced an overall sensitivity of 85.7% (95% CI 73.3% to 92.9%) and a specificity of 82.4% (95% CI 75.5% to 87.7%). The false negative cases were predominantly left-sided (71.4%) and did not show the typical dMMR/microsatellite instability-high histological phenotype. Sensitivity was lower (50%-75%) in cases showing isolated PMS2 or MSH6 loss of staining. Calibrating the classification threshold to 0.470, the sensitivity was optimised to 95.6% (95% CI 86.3% to 98.9%) with a specificity of 69.6% (95% CI 61.8% to 76.4%). This would have resulted in excluding 103 cases (52.3%) from downstream immunohistochemical (IHC) or molecular testing. CONCLUSIONS: Following appropriate region-specific calibration, we have shown that this model could be employed to accurately prescreen for dMMR in CRC, thereby reducing the burden of downstream IHC and molecular testing in a resource-limited setting.
AIMS: Research reporting checklists are itemised writing standards to improve transparency and facilitate reproducibility. Previous assessments of their recommendation or requirement have demonstrated improved checklist...AIMS: Research reporting checklists are itemised writing standards to improve transparency and facilitate reproducibility. Previous assessments of their recommendation or requirement have demonstrated improved checklist adherence across medical specialties and study designs. Here, we investigated the endorsement of reporting checklists within pathology, laboratory medicine and forensic science journals. METHODS: We queried Google Scholar Metrics and the Scopus CiteScore tool to identify top pathology and forensic medicine journals. Two authors independently assessed for the mention, recommendation or requirement or checklists-derived from the Enhancing the Quality and Transparency Of Health Research (EQUATOR) network-as well as study preregistration within each journal's aims and instructions for authors. Journal editors were contacted by one author every 3 weeks to confirm whether or not certain study designs would be considered for publication. RESULTS: Of the 88 journals evaluated, most did not mention or endorse the EQUATOR Network (73.9%) or International Committee of Medical Journal Editors reporting standards (51.1%). The most commonly reported checklists included Animal Research: Reporting of In Vivo Experiments (38.6%), Consolidated Standards of Reporting Trials (28.4%) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (25.0%). The CARE reporting checklist for case reports was required most often by five journals (5.7%). The final email response from journal editors and contacts was 9.1%. CONCLUSIONS: Reporting checklists were suboptimally mentioned and rarely required. Even with many basic and diagnostic science reporting checklists and initiatives, endorsement remains low. We recommend that authors, reviewers and editors become familiar with relevant reporting checklists for their fields and publishing spaces to improve checklist visibility and adherence for scientific transparency, reproducibility and rigour.
Foundation models are revolutionising pathology by leveraging large-scale, pretrained artificial intelligence (AI) systems to enhance diagnostics, automate workflows and expand applications. These models address computat...Foundation models are revolutionising pathology by leveraging large-scale, pretrained artificial intelligence (AI) systems to enhance diagnostics, automate workflows and expand applications. These models address computational challenges in gigapixel whole-slide images with architectures like GigaPath, enabling state-of-the-art performance in cancer subtyping and biomarker identification by capturing cellular variations and microenvironmental changes. Visual-language models such as CONCH integrate histopathological images with biomedical text, facilitating text-to-image retrieval and classification with minimal fine-tuning, mirroring how pathologists synthesise multimodal information. Open-source foundation models will drive accessibility and innovation, allowing researchers to refine AI systems collaboratively while reducing dependency on proprietary solutions. Combined with decentralised learning approaches like federated and swarm learning, these models enable secure, large-scale training without centralised data sharing, preserving patient confidentiality while improving generalisability across populations. Despite these advancements, challenges remain in ensuring scalability, mitigating bias and aligning AI insights with clinical decision-making. Explainable AI techniques, such as saliency maps and feature attribution, are critical for fostering trust and interpretability. As multimodal integration-combining pathology, radiology and genomics-advances personalised medicine, foundation models stand as a transformative force in computational pathology, bridging the gap between AI innovation and real-world clinical implementation.
Despite advances in cancer immunotherapies across various cancers, survival outcomes in colorectal cancer (CRC) with these agents remain largely unsatisfactory despite the high tumour burden. Colorectal stem cells (CSCs)...Despite advances in cancer immunotherapies across various cancers, survival outcomes in colorectal cancer (CRC) with these agents remain largely unsatisfactory despite the high tumour burden. Colorectal stem cells (CSCs), especially + CSCs, are the significant drivers in CRC initiation, progression and resistance to conventional therapies. Although native immune surveillance is sufficient to combat early tumour formation, CRC evades early immune detection with its well-documented adenoma-to-carcinoma sequence. The exact mechanism underlying this phenomenon still needs to be better understood. SRY-related HMG box gene 17 (), a transcription factor that specifies embryonic gut formation, is increasingly recognised as a significant factor in CRC tumourigenesis. However, its role as a tumour suppressor or oncogene is still debated. Evidence from a recent study highlighted the critical role of in reshaping the tumour immune ecosystem through the simultaneous inhibition of CD8+ T cells and selective suppression of expression in CSCs through transcriptional repression, thereby facilitating disease progression. Given its role in immune evasion, could be a promising marker in personalised therapy. Additionally, could play a role in the diagnostic arena, potentially identifying dysplasia in the gastrointestinal tract. Future clinical, basic and genetic studies focusing on are needed to ascertain its mechanistic role in tumour immunomodulation in CRC and diagnosing preneoplastic lesions in the gastrointestinal tract.
The fifth edition of the WHO classification of haematolymphoid tumours (WHO-HEM5) introduces significant updates to the classification of acute lymphoblastic leukaemia, ALAL (including mixed phenotype acute leukaemia (MP...The fifth edition of the WHO classification of haematolymphoid tumours (WHO-HEM5) introduces significant updates to the classification of acute lymphoblastic leukaemia, ALAL (including mixed phenotype acute leukaemia (MPAL)), myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK), and histiocytic and dendritic cell neoplasms, reflecting the advances in the understanding of the genetic basis of these diseases. This review provides an overview of these changes, highlighting a shift to a more refined molecular-genetic approach. The incorporation of newly recognised genetic subtypes into the classification scheme underscores the evolving landscape of these entities. Challenges in diagnosing ALAL/MPAL and MLN-TK are discussed, along with recent insights into histiocytic and dendritic cell neoplasms, including newly defined entities such as ALK-positive histiocytosis.The review also explores the practical implications of WHO-HEM5, particularly in resource-limited settings, where comprehensive molecular testing may be unavailable. While morphology and immunohistochemistry remain essential diagnostic tools, strategic use of flow cytometry and targeted fluorescence in situ hybridisation can facilitate risk-adapted classification and improve survival in regions with limited resources and therapeutic options. Future large-scale studies are necessary to establish the diagnostic and prognostic value of these newly genetically defined entities for diverse healthcare environments, and to standardise guidelines in refining disease classification and optimising patient outcomes.
AIMS: Glioma-associated oncogene homologue 1 () was recently shown to be coamplified with mouse double minute 2 (), cyclin-dependent kinase 4 () and some other adjacent genes in a significant subset of -altered mesenchym...AIMS: Glioma-associated oncogene homologue 1 () was recently shown to be coamplified with mouse double minute 2 (), cyclin-dependent kinase 4 () and some other adjacent genes in a significant subset of -altered mesenchymal tumours and well-differentiated/dedifferentiated liposarcomas, which are characterised by amplification. Given that is also amplified in low-grade osteosarcoma (LGOS), we investigated the prevalence of amplifications/fusions in a series of 15 cases of -amplified LGOS, an area that has not been previously explored. METHODS: This study conducted a retrospective analysis and examined amplifications/fusions in 15 cases of -amplified LGOS and 46 cases of other bone tumours and tumour-like lesions using fluorescence in situ hybridisation with a amplification probe and a break-apart probe. Six cases of LGOS were also tested by next-generation sequencing. RESULTS: Fluorescence in situ hybridisation analysis revealed that 13 of 15 (87%) LGOS cases exhibited amplification; no fusion gene was found. Next-generation sequencing revealed that all six tested cases showed amplification and one case had both amplification and gene fusion (). All 46 cases of other bone tumours and tumour-like lesions were negative for amplification and fusion. CONCLUSION: These results indicate that amplification is common in LGOS, and fusion could occur in LGOS.
INTRODUCTION: Overexpression of Preferentially Expressed Melanoma Antigen (PRAME) is associated with melanoma progression. In the case of uveal melanoma (UM), PRAME expression was identified as conferring a metastatic ri...INTRODUCTION: Overexpression of Preferentially Expressed Melanoma Antigen (PRAME) is associated with melanoma progression. In the case of uveal melanoma (UM), PRAME expression was identified as conferring a metastatic risk. AIM: This study aimed to review the available evidence regarding the prognostic value of PRAME expression in UM. METHODS: This study adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We included cohort studies and randomised clinical trials. The methodological quality of the studies was assessed by the Methodological Index for Non-Randomised Studies (MINORS). The meta-analysis was performed using Review Manager V.5.4. Heterogeneity was checked with the I2 test. If there was no heterogeneity, a fixed-effects model was adopted. RESULTS: Nine studies were included. The PRAME+ group showed significant differences in the development of metastases OR (M-H, Fixed, 95% CI): 3.46 (2.84, 4.22). The PRAME+ group had a significantly shorter time to metastasis MD (IV, Random, 95% CI): -28.31 (-55.41, -1.22) and a significantly lower percentage metastasis-free survival at 5-year follow-up MD (IV, Fixed, 95% CI): -21.67 (-25.74,-17.61). PRAME expression was an independent marker for the development of metastatic disease at any follow-up HR (IV, Fixed, 95% CI): 2.00 (1.60, 2.49). In addition, PRAME+tumours were significantly larger than PRAME-tumours MD (IV, Random, 95% CI): 0.22 (0.01, 0.42). CONCLUSIONS: PRAME is a good prognostic marker in UM. We believe that further studies are needed to determine the most cost-effective method for reporting PRAME overexpression.