The Journal Of Pathology[JOURNAL]
Sun
200 papers
SOX10 distinguishes oligodendrogliomas from low-grade glioneuronal tumors/low-grade gliomas with oligodendrocyte-like features.
Zhou D, Hu X, Wang Y … +3 more , Tang F, Du Z, Xiong J
J Pathol Clin Res · 2026 Jul · PMID 42381604 · Full text
Oligodendrogliomas exhibit significant morphological overlap with low-grade glioneuronal tumors/low-grade gliomas with oligodendrocyte-like features, posing challenges in histopathological diagnosis. SOX10, a transcripti...
Oligodendrogliomas exhibit significant morphological overlap with low-grade glioneuronal tumors/low-grade gliomas with oligodendrocyte-like features, posing challenges in histopathological diagnosis. SOX10, a transcription factor critical for oligodendrocyte maturation and central nervous system myelination, may serve as a diagnostic marker. We evaluated the diagnostic utility of SOX10 immunohistochemical expression in 300 oligodendrogliomas versus 52 low-grade glioneuronal tumors/low-grade gliomas with oligodendrocyte-like features. Notably, SOX10 was negative in 251/300 (83.7%) oligodendrogliomas but diffusely positive in 47/52 (90.4%) low-grade glioneuronal tumors/low-grade gliomas with oligodendrocyte-like features (except polymorphous low-grade neuroepithelial tumors of the young, PLNTY). SOX10 expression was significantly higher in the latter group (p < 0.001) and showed a WHO grade dependent up-regulation in oligodendrogliomas (p < 0.001). The diagnostic utility of SOX10 was evident in IDH1-immunonegative cases, yielding 72% sensitivity, 90.4% specificity, and a 78.3% positive predictive value for oligodendroglioma. Combining H3K27me3 loss with SOX10 negativity markedly improved diagnostic sensitivity for oligodendroglioma to 88.5%, substantially surpassing the 35% sensitivity achieved with H3K27me3 loss alone. Additionally, an immunohistochemical panel comprising SOX10, Olig2, and IDH1 aided in discriminating non-neoplastic oligodendrocyte hyperplasia from oligodendroglioma and evaluating the presence of peritumoral tumor residue, particularly in IDH1-immunonegative oligodendroglioma. In conclusion, SOX10 negativity effectively excludes low-grade glioneuronal tumors/low-grade gliomas with oligodendrocyte-like features (except PLNTY) and non-neoplastic oligodendrocyte hyperplasia from oligodendrogliomas. SOX10 serves as a specific diagnostic marker, enhancing pathological diagnostic accuracy.
Pan-TRK expression and NTRK gene aberrations in meningiomas: association with tumor grade and proliferative activity.
Zhu Y, Sun M, Lu W … +5 more , Wang Z, Xi H, Song Y, Xu H, Lin X
J Pathol Clin Res · 2026 Jul · PMID 42381583 · Full text
Tropomyosin receptor kinase (TRK) fusions are actionable oncogenic drivers, and pan-TRK immunohistochemistry (IHC) serves as a reliable screening tool for NTRK gene aberrations. However, the expression profile and clinic...
Tropomyosin receptor kinase (TRK) fusions are actionable oncogenic drivers, and pan-TRK immunohistochemistry (IHC) serves as a reliable screening tool for NTRK gene aberrations. However, the expression profile and clinical significance of pan-TRK in meningiomas remain unclear. This study aimed to characterize pan-TRK expression, its correlation with clinicopathological features, and underlying NTRK rearrangement status in meningiomas. We retrospectively analyzed 70 primary intracranial tumor specimens, including 50 meningiomas (21 WHO grade 1, 26 grade 2, and 3 grade 3) and 20 non-meningioma CNS tumors (9 solitary fibrous tumors, 6 hemangioblastomas, and 5 schwannomas) from the First Affiliated Hospital of China Medical University (2020-2022). Pan-TRK IHC was performed using the Ventana EPR17341 antibody, with fluorescence in situ hybridization (FISH) validating NTRK gene aberrations in positive cases. Clinicopathological correlations were analyzed using chi-square/Fisher's exact tests and Spearman's rank correlation. Pan-TRK immunoreactivity was detected in 12/50 (24.0%) meningiomas, predominantly with cytoplasmic staining (75.0%). Positivity was significantly higher in high-grade (WHO 2/3) meningiomas (7/29, 46.7% versus 3/21, 14.3% in grade 1; p = 0.031) and tumors with Ki-67 index ≥5% (7/15, 46.7% versus 5/35, 14.3% in Ki-67 <5%; p = 0.027). No pan-TRK expression was observed in non-meningioma tumors (0/20). FISH confirmed NTRK gene aberrations in 2/12 (16.7%) pan-TRK-positive cases (both WHO 3 anaplastic meningiomas), with strong/moderate IHC staining correlating with aberrations. Pan-TRK is frequently expressed in meningiomas, particularly in high-grade and proliferative tumors, and may have preliminary utility in differentiating meningiomas from other CNS tumors. However, NTRK gene aberrations are rare, necessitating FISH or next-generation sequencing confirmation for pan-TRK-positive cases to identify candidates for TRK-targeted therapy. Further studies are needed to clarify the biological role of non-fusion-mediated pan-TRK overexpression in meningioma progression.
Ectonucleotidases CD39 and CD73 expression levels are independent and inverse predictors of survival in muscle-invasive bladder cancer.
Ledderose S, Schwenke J, Eismann L … +3 more , Rodler S, Rudelius M, Ledderose C
J Pathol Clin Res · 2026 Jul · PMID 42334004 · Full text
Bladder cancer is one of the leading causes of cancer-related mortality worldwide. Long-term survival is particularly poor in patients with muscle-invasive bladder cancer (MIBC). Modulation of purinergic signaling throug...
Bladder cancer is one of the leading causes of cancer-related mortality worldwide. Long-term survival is particularly poor in patients with muscle-invasive bladder cancer (MIBC). Modulation of purinergic signaling through the ectonucleotidases CD39 and CD73 has emerged as a promising therapeutic strategy in cancer medicine. Altered expression patterns of these molecules have been linked to prognosis in various malignancies. In this study, we assessed the value of CD39 and CD73 expression as prognostic markers and potential therapeutic targets in MIBC. CD39 and CD73 expression was determined by immunohistochemistry using tissue microarrays from 180 patients with MIBC. Associations between tumoral and stromal expression and clinicopathological variables, including overall survival (OS), tumor-specific survival (TSS) and disease-free survival (DFS), were analyzed. Tumor cells did not express CD39. High stromal CD39 expression was significantly associated with a lower T category and UICC stage as well as prolonged median OS, TSS, and DFS. High CD73 expression by tumor cells was significantly associated with poorer OS and TSS. Stromal CD73 expression was not significantly correlated with survival outcomes. Our findings indicate distinct and compartment-specific roles for CD39 and CD73 in MIBC. They suggest that high CD73 expression in tumor cells and low CD39 expression in stromal cells are negative prognostic indicators and potential therapeutic targets in MIBC.
Oestrogen receptor phosphorylation profiles and in silico PAM50 subtyping reflect sexual dimorphism in breast cancer.
Chatterji S, Diack A, Szostok M … +9 more , Morgan MD, Silvestri V, Ottini L, Moelans CB, van Diest PJ, Selli C, Sims AH, Abu-Eid R, Speirs V
J Pathol Clin Res · 2026 Jul · PMID 42333999 · Full text
Breast cancer (BC) is most prevalent in females but also accounts for <1% of male cancer cases and 0.2% of male cancer-related deaths. Distribution of histological subtypes, receptor status, and age of diagnosis varies b...
Breast cancer (BC) is most prevalent in females but also accounts for <1% of male cancer cases and 0.2% of male cancer-related deaths. Distribution of histological subtypes, receptor status, and age of diagnosis varies based on sex, and a growing body of evidence supports sex-specific molecular differences in BC. However, this is limited by the smaller number of male cases available for study compared to the thousands of cases of female BC. We combined publicly available male BC gene expression datasets for 195 patients from 4 studies and split randomly into discovery and validation sets. Clustering and gene expression analysis were performed. Two stable clusters were identified initially, confirmed in the validation set. Cluster C1 was enriched for genes associated with MAPK signalling and arylesterase activity. Cluster C2 showed enrichment of genes associated with proliferation, invasion, and metastasis, along with enrichment of gene ontology and pathway terms related to ECM regulation, particularly collagen-containing ECM. Of note, when stratified by ERα and PR status, no enrichment was observed with the predicted PAM50 classification. ERα and MAPK signalling were enriched in both clusters, albeit through different gene sets. Since these pathways were enriched, we investigated the signalling regulation of ERα based on immunohistochemical expression of phosphorylated ERα (S104, S118, S167, S294) and their prognostic roles. This analysis also revealed distinctions from female BC, showing a lack of prognostic outcome for any of these biomarkers. We show that male BC does not align with female BC in the same way that intrinsic subtypes of female BC are not identical. As BC heterogeneity is well recognised, we propose that male BC should be considered as a potentially unique clinical subtype of BC.
Tumor Invasive Border Index (TIBI) in colorectal cancer: linking infiltrative morphology to molecular insights.
Kehusmaa A, Härkönen J, Li H … +27 more , Sirniö P, Äijälä VK, Karjalainen H, Kastinen M, Tapiainen VV, Mantere T, Pohjanen VM, Elomaa H, Sirkiä O, Pasquier N, Ahtiainen M, Helminen O, Wirta EV, Mattila TT, Lindgren O, Savela J, Rintala J, Meriläinen S, Saarnio J, Rautio T, Seppälä TT, Böhm J, Mecklin JP, Mäkinen MJ, Tuomisto A, Ivaska J, Väyrynen JP
J Pathol · 2026 Jun · PMID 42312545 · Publisher ↗
Tumor border configuration influences colorectal cancer (CRC) prognosis, yet its molecular determinants remain unclear and existing assessment criteria have faced challenges with reproducibility. We introduce the Tumor I...
Tumor border configuration influences colorectal cancer (CRC) prognosis, yet its molecular determinants remain unclear and existing assessment criteria have faced challenges with reproducibility. We introduce the Tumor Invasive Border Index (TIBI), a novel and reproducible method that quantifies the proportion of tumor stroma and adipose tissue within a hotspot at the deepest point of invasion. TIBI was evaluated in two CRC cohorts (n = 1,100 and n = 776) and analyzed in relation to tumor and patient features. Molecular correlates of an infiltrative growth pattern were explored in The Cancer Genome Atlas (TCGA) CRC cohorts (n = 350), with key features validated independently. High TIBI, indicating an infiltrative border, was associated with advanced disease, tumor budding, lymphovascular invasion, and an immune microenvironment characterized by lower M1-like macrophage and granulocyte densities. High TIBI independently predicted higher CRC-specific mortality, with multivariable hazard ratios of 1.52 (95% CI 1.07-2.17) in cohort 1 and 2.45 (95% CI 1.37-4.37) in cohort 2. Molecular analysis revealed associations with mismatch repair proficiency, TP53 and KRAS mutations, MYC signaling downregulation, and epithelial-mesenchymal transition upregulation. L1CAM and DSG3 were among the genes showing high expression in infiltrative tumors. As experimental validation, we identified a CRC cell line with high expression of L1CAM and DSG3 and demonstrated that silencing them reduced invasion in vitro. A TIBI-associated gene signature also predicted infiltrative growth and adverse outcome in the TCGA gastric cancer cohort. These findings highlight molecular characteristics of tumor border configuration and establish TIBI as a clinically relevant tumor biomarker. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Lipodystrophy and adipose tissue recovery are mediated by the Wnt/lipogenesis axis during skin fibrosis.
Madhavan SR, Moore P, Varshney R … +8 more , Montegut M, Ma Q, Klatt K, Parameswaran R, Ertugral EG, Kothapalli CR, Rudolph MC, Atit RP
J Pathol · 2026 Jun · PMID 42299858 · Publisher ↗
Acquired lipodystrophy in the dermal white adipose tissue (DWAT) is an early phenotype of skin fibrosis, followed by the accumulation of extracellular matrix (ECM). Lipodystrophy syndromes are estimated to affect 1 in 20...
Acquired lipodystrophy in the dermal white adipose tissue (DWAT) is an early phenotype of skin fibrosis, followed by the accumulation of extracellular matrix (ECM). Lipodystrophy syndromes are estimated to affect 1 in 20,000 people and are associated with metabolic comorbidities. Recently, we showed that fibrosis-associated lipodystrophy depended on sustained Wnt signaling, although the mechanism remains unclear. Transcriptomic profiling of mature dermal adipocytes in vivo revealed that Wnt activation downregulated the de novo lipogenesis (DNL) axis enzymes within 48 h. We further found that expression of fatty acid synthase (FASN), a key DNL enzyme, depends on sustained Wnt activation in vitro and in vivo. In a bleomycin model, and in human systemic sclerosis (< 1 year disease duration) and keloids, FASN was significantly downregulated. Notably, inhibition of FASN in mice during reversal of Wnt-induced fibrosis impaired the recovery of DWAT lipid content and ECM architecture. Collectively, these findings demonstrate that acquired lipodystrophy in skin fibrosis is mediated by a previously unrecognized role of the Wnt-DNL axis. These findings underscore the importance of this pathway in lipodystrophy and fibrosis and highlight its potential as a therapeutic target in skin fibrosis. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Clinicopathological and molecular characterization of HPV-associated cervical poorly cohesive carcinoma: a rare aggressive entity.
Liu W, Wang XJ, Cui YM … +12 more , Liu JC, Zhang J, Zhang LB, Lei X, Weng X, Shen W, Miao WX, Ye JC, He TM, Xu Q, Shi Y, Hu D
J Pathol Clin Res · 2026 Jul · PMID 42289532 · Full text
Primary signet-ring cell carcinoma and poorly differentiated adenocarcinoma with poorly cohesive morphology in the cervix are rare conditions, and their clinicopathological features remain poorly described. This study de...
Primary signet-ring cell carcinoma and poorly differentiated adenocarcinoma with poorly cohesive morphology in the cervix are rare conditions, and their clinicopathological features remain poorly described. This study defines primary cervical poorly differentiated adenocarcinomas meeting the diagnostic criteria for poorly cohesive carcinoma as outlined in the 2019 WHO Classification of Digestive System Tumors as 'HPV-associated cervical poorly cohesive carcinomas' (HPV-associated CPCC) and describe their clinicopathological and molecular features. Sixteen HPV-associated CPCC cases were analyzed and classified into three histological subtypes: signet-ring cell carcinoma (n = 4), not otherwise specified (n = 6), and mixed types (n = 6). All patients were Chinese (median age: 46 years; range: 30-66). Vaginal bleeding was the primary presenting symptom (100.0%). High-risk human papillomavirus (HPV) was identified in all tumors, with HPV-18 as the predominant genotype (n = 13), HPV-16 in two cases, and a single case exhibiting concurrent infection with HPV-16, -18, and -58. Overall, 56.3% presented with advanced-stage disease (International Federation of Gynecology and Obstetrics [FIGO] IIIB-IVB), frequently involving regional lymph nodes (56.3%) and distant sites (18.8%). Histopathological examination revealed diffuse stromal infiltration (100%), lymphovascular invasion (75.0%), necrosis (75.0%), and desmoplasia. Immunohistochemically, all cases showed p16 block positivity. Variable expression of antibody-drug conjugate targets was observed, with HER2-low expression (33.3%), and positive staining for Trop-2 (85.7%), nectin-4 (42.9%), and tissue factor (92.3%). During follow-up, disease-specific mortality was 50.0%. The 3-year overall survival rate was 56.3%, which was significantly lower in advanced-stage disease (45.0%) than in early-stage disease (75.0%). Whole-exome sequencing revealed low tumor mutational burden (median 1.28 Muts/Mb), recurrent mutations in AK1, ARHGAP39, KRT24, MICAL3, SLC6A9 (27.3%), KRAS, and KMT2C (18.2%), alongside MUC2 copy gain (63.6%) and bidirectional Y_RNA alterations (gain 54.5%/loss 45.5%). Collectively, HPV-associated CPCC represents a distinct and aggressive subtype characterized by distinctive histopathological features, a predominant association with HPV18, frequent presentation at advanced stages, and marked molecular and biomarker heterogeneity.
Optical mapping reveals a higher level of large-scale structural variants in a family with paternally transmitted myotonic dystrophy and independent Parkinson's disease.
Hasan MM, Craddock J, Gong T … +7 more , Lyons RJ, Stevanovski I, Chintalaphani SR, Deveson IW, Jaratlerdsiri W, Kumar KR, Hayes VM
J Pathol · 2026 Jun · PMID 42261605 · Publisher ↗
Myotonic dystrophy type 1 (DM1) is a clinically challenging multisystem neuromuscular hereditary disorder, with generational increase in severity and earlier age at onset. It is caused by an unstable cytosine-thymine-gua...
Myotonic dystrophy type 1 (DM1) is a clinically challenging multisystem neuromuscular hereditary disorder, with generational increase in severity and earlier age at onset. It is caused by an unstable cytosine-thymine-guanine repeat expansion at the DMPK locus, accompanied by associated genetic and epigenetic modifications. While somatic mosaicism and meiotic instability are well established, to the best of our knowledge, no study has performed a genome-wide interrogation for global inherited instability. Performing whole-genome optical mapping, with sequence base-resolved structural variant verification, we examine global inherited genomic instability in an atypical paternally transmitted DM1 family presenting with a range of neurological manifestations, including early-onset Parkinson's disease (PD). While the juvenile-onset DM1 proband presented with a 10-fold repeat expansion with associated hypermethylation, her partially hypermethylated asymptomatic protomutation father transmitted a 1.8-fold contracted allele in the younger premutation sibling. Adult-onset symptomatic DM1 and PD phenotypic paternal aunts showed significant genome-wide copy number alteration, including PD-associated chr19 aneuploidy loss, with additional losses on chr16, 17, and 22. In the absence of potentially pathogenic de novo or maternally inherited structural variants, the proband presented with large paternally inherited aberrations impacting gene candidates CASC15, CBFA2T3, GPHN, H3F3A, SDK1, and SPAG16, with advanced global hypomethylation. Here we suggest that inherited genomic instability may contribute to phenotypic variability, including multi-neurological presentations and single-generation repeat expansion or contraction. By providing a landscape of inherited large structural variants, this single-family study expands knowledge of this broad and growing class of diseases. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
FTO-mediated m6A modification of protein disulfide-isomerase activates VEGFA-VEGFR2 to suppress programmed cell death in osteosarcoma.
Wang J, Hao Y, He M … +1 more , Zhou W
J Pathol · 2026 Jun · PMID 42246398 · Publisher ↗
Osteosarcoma (OS) is a primary bone malignancy, and its progression can be hindered by inducing programmed cell death (PCD). Protein disulfide-isomerase (PDI) regulates cancer cell death; however, its functional role in...
Osteosarcoma (OS) is a primary bone malignancy, and its progression can be hindered by inducing programmed cell death (PCD). Protein disulfide-isomerase (PDI) regulates cancer cell death; however, its functional role in OS remains unclear. P4HB expression was assessed in tumor tissues and cells from patients with OS using RT-qPCR. The effects of P4HB on OS cell lines were evaluated. Western blotting was used to assess the impact of P4HB on various forms of PCD (apoptosis, ferroptosis, and pyroptosis). Bioinformatics analysis identified the upstream and downstream mechanisms of P4HB in OS progression. A xenograft tumorigenesis study was performed to elucidate the role and mechanism of P4HB in OS progression. Elevated P4HB expression was observed in OS tissue samples and cell lines. Downregulation of P4HB suppressed OS cell growth, migration, and invasiveness and induced PCD. Functional enrichment analysis and experimental validation revealed that PDI upregulated vascular endothelial growth factor A (VEGFA) vascular endothelial growth factor receptor 2 (VEGFR2) signaling. Methylation analysis showed that the m6A demethylase fat mass and obesity-associated protein (FTO) decreased P4HB m6A levels and enhanced VEGFA-VEGFR2 signaling in OS cells. Moreover, FTO overexpression enhanced the proliferative, migratory, and invasive capabilities of OS cells and decreased PCD. Finally, FTO knockdown inhibited tumor growth and lung metastasis of OS by decreasing the activity of the PDI/VEGFA-VEGFR2 signaling axis. Mechanistically, FTO-mediated m6A modification of P4HB regulates PCD in OS through activation of this axis. © 2026 The Pathological Society of Great Britain and Ireland.
YAP-activated lymph node fibroblasts contribute to extracellular matrix remodeling associated with extranodal extension of oral squamous cell carcinoma.
Zhang Q, Jiang S, Abliz A … +4 more , Chen S, Hu Q, Ding L, Wang Y
J Pathol Clin Res · 2026 Jul · PMID 42237748 · Publisher ↗
Desmoplasia, characterized by excessive expansion of cancer-associated fibroblasts (CAFs) and aberrant extracellular matrix (ECM) deposition, is widely present especially in invasive cancers. The extranodal extension (EN...
Desmoplasia, characterized by excessive expansion of cancer-associated fibroblasts (CAFs) and aberrant extracellular matrix (ECM) deposition, is widely present especially in invasive cancers. The extranodal extension (ENE) of nodal metastasis involves the extension of invasive tumor cells through the lymph node capsule into the perinodal adipose tissue, leading to systemic metastasis. Thus, the specific roles of desmoplasia in ENE formation need to be identified. This study aimed to investigate the association between desmoplasia and its role in ENE formation of oral squamous cell carcinoma, with a focus on Yes-associated protein (YAP)-mediated fibroblast activation and ECM remodeling. Transcriptome profiling and histopathology study based on tissue microarrays were performed to explore the association of metastasis-associated CAFs (MAFs) in ECM remodeling with ENE formation. Primary MAFs were isolated from ENE-positive (ENE) and ENE-negative (ENE) lymph nodes for functional characterization. The regulatory role of YAP in MAF-mediated ECM remodeling was investigated through immunohistochemistry, gene knockdown, and co-culture assays with HSC-3 tumor cells. A high degree of desmoplasia and rich collagen remodeling in lymph nodes was associated with higher ENE risk. ENE MAFs exhibited superior proliferative capacity, enhanced migration, and increased ECM remodeling activity compared to ENE MAFs. Co-culture experiments demonstrated that ENE MAFs significantly promoted HSC-3 cell invasion through Matrigel. Exploratory RNA sequencing revealed enrichment of ECM receptor interaction and Hippo-YAP pathway in ENE lymph nodes. Nuclear YAP localization in MAFs correlated with elevated expression of ECM components (collagen type I alpha 1 [COL1A1], fibronectin 1 [FN1], Tenascin C) and matrix metalloproteinase-2. YAP knockdown in ENE MAFs significantly attenuated both ECM remodeling capacity and pro-invasion ability in vitro. These findings suggest that YAP-activated MAFs contribute to ECM remodeling that may create a stromal environment permissive for ENE formation, though direct in vivo validation is needed to establish causality.
Dopamine inhibits retinal pathological neovascularization in the oxygen-induced retinopathy mouse model.
Wang Q, Shi J, Ouyang S … +17 more , Zhang T, Yang H, Zhu J, Wang L, Lv Y, Dong S, Chen R, Ling X, Jiao S, Dong M, Yan W, Yang J, Yan B, Chen J, Qu J, Zhao F, Zhou X
J Pathol · 2026 Jun · PMID 42237060 · Publisher ↗
Pathological neovascularization is the leading cause of childhood blindness in retinopathy of prematurity (ROP). Anti-vascular endothelial growth factor agents are commonly used to treat this condition, yet their variabl...
Pathological neovascularization is the leading cause of childhood blindness in retinopathy of prematurity (ROP). Anti-vascular endothelial growth factor agents are commonly used to treat this condition, yet their variable efficacy and off-target effects demand alternative strategies. Here, we investigated the relationship between retinal dopamine (DA) dynamics and pathological angiogenesis in the oxygen-induced retinopathy (OIR) mouse model mimicking ROP pathogenesis. We determined the individual effects of apomorphine (APO), a non-selective DA receptor agonist, and selective agonists or antagonists of dopamine D1 receptor (Drd1) and dopamine D2 receptor (Drd2), on pathological neovascularization. Integrating single-cell RNA sequencing with Müller cell-specific Drd2 knockout OIR mice, we identified that Drd2-mediated signaling in Müller cells orchestrates hypoxia-inducible factor alpha and vascular endothelial growth factor A biosynthesis in Müller cells during the hypoxic-ischemic phase of OIR. Collectively, OIR-induced dopaminergic deficiency and impaired Drd2 activity in Müller cells synergistically exacerbate pathological angiogenesis. © 2026 The Pathological Society of Great Britain and Ireland.
Aberrant alternative splicing of purinergic receptor P2RX4 prevents sensitivity towards combinatorial treatment in colorectal and pancreatic cancer.
Steup C, Dosch J, Dietz-Fricke C … +10 more , Khosraviseftejani S, Engel E, Valk AF, Menger D, Welker P, Wild PJ, Kennel KB, Kantlehner M, Ziegler PK, Greten FR
J Pathol · 2026 Jun · PMID 42231750 · Publisher ↗
Recently, we suggested the combination of chemotherapy and P2RX4 inhibition as a promising novel therapeutic approach for P2RX4-expressing epithelial tumors to prevent paracrine resistance. Here, we aimed to assess wheth...
Recently, we suggested the combination of chemotherapy and P2RX4 inhibition as a promising novel therapeutic approach for P2RX4-expressing epithelial tumors to prevent paracrine resistance. Here, we aimed to assess whether determining P2RX4 expression status in colorectal and pancreatic cancer patients would allow stratification of potentially responsive patients. Therefore, P2RX4 expression levels were determined by RNA sequencing and immunohistochemistry. Subcellular localization of P2RX4 isoforms was analyzed in HeLa cells and patient-derived tumor organoids. In contrast to its RNA expression profile, P2RX4 protein levels exhibited differential regulation in human colorectal and pancreatic cancer epithelia due to alternative splicing. Interpatient heterogeneity was greater in colorectal cancer than in pancreatic cancer. Notably, these variations in expression did not correlate with overall patient survival. Alternative P2RX4 transcripts gave rise to functionally distinct protein isoforms that differed in subcellular localization and total protein abundance. Only the correctly spliced, canonical P2RX4 isoform was localized to the plasma membrane and was capable of mediating downstream signaling. Accordingly, P2RX4 inhibition in combination with chemotherapy was effective exclusively in patient-derived tumor organoids expressing the canonical P2RX4 transcript. In summary, immunohistochemical, but not transcriptomic, assessment of P2RX4 expression enabled the prediction of sensitivity to combinatorial treatment and facilitated the identification of patients who may benefit from P2RX4 inhibition during chemotherapy. Given the lower degree of heterogeneity observed in pancreatic cancer, this tumor entity may represent a promising candidate for early-phase clinical evaluation of chemotherapy combined with P2RX4 inhibition. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
CLEC14A correlates with neutrophil infiltration in hepatocellular carcinoma and mediates neutrophil recruitment across liver endothelial cells.
O'Rourke JM, Kavanagh D, O'Keeffe A … +22 more , Savoye K, Yang K, Patten DA, Willoughby CE, Llovet JM, Neag G, Reeves HL, Hewett PW, Kalia N, Shah T, Ma YT, Hunter K, Flint J, McMurray JL, Cain O, Spill F, Mann DA, Naylor AJ, Heath V, Weston CJ, Bicknell R, Shetty S
J Pathol · 2026 Jun · PMID 42223241 · Publisher ↗
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths globally, and cases are predicted to rise dramatically over the next few years. Overcoming the immune microenvironment in HCC remains a challenge...
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths globally, and cases are predicted to rise dramatically over the next few years. Overcoming the immune microenvironment in HCC remains a challenge, and innate immune populations such as tumour-associated neutrophils can potentially impair the success of immunotherapy. Elucidating the mechanisms of neutrophil recruitment across liver endothelium could lead to new approaches to boost the efficacy of immunotherapy. CLEC14A is an endothelium-specific receptor regulating sprouting angiogenesis, upregulated in low shear environments. We found CLEC14A to be highly expressed in both HCC vessels and on vasculature during acute liver injury, leading us to hypothesise that CLEC14A may regulate neutrophil recruitment to the liver and HCC. We found that CLEC14A positively correlated with a neutrophil signature and infiltration in public datasets and surgically resected tissue from HCC. Spatial transcriptomics (ST) of CLEC14A- and CLEC14A-expressing tumours confirmed upregulation of myeloperoxidase in CLEC14A tumours and correlation with other shear-dependent markers but a negative correlation with vascular endothelial growth factor A. To build on our correlation studies, we explored the role of CLEC14A in neutrophil recruitment across liver endothelium. We undertook in vitro recruitment studies with flow-based human liver endothelial assays and in vivo models of neutrophil recruitment. Using siRNA knockdown of CLEC14A and specific blocking antibodies to CLEC14A, we found that CLEC14A knockdown blocked the firm adhesion of neutrophils to liver endothelium, but this was independent of its interaction with its known ligand MMRN2. Finally, we confirmed that Clec14a deficiency led to a significant reduction in neutrophil recruitment across the sinusoids in an ischaemia-reperfusion liver injury model. We unveil a link between the angiogenic receptor CLEC14A and neutrophil recruitment. Targeting of CLEC14A on tumour endothelium is potentially a new approach to regulating neutrophil infiltration in HCC. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Targeting fibrosis in the treatment of lower urinary tract dysfunction.
Limkar AR, Vrba SM, Ricke EA … +4 more , Fabry Z, Lee MS, McVary KT, Ricke WA
J Pathol · 2026 May · PMID 42200686 · Publisher ↗
Benign prostatic hyperplasia (BPH) is a widely prevalent age-associated disease that is the main contributor to lower urinary tract dysfunction (LUTD) in aging men. Although prostate fibrosis has been recognized as a con...
Benign prostatic hyperplasia (BPH) is a widely prevalent age-associated disease that is the main contributor to lower urinary tract dysfunction (LUTD) in aging men. Although prostate fibrosis has been recognized as a contributor to BPH pathophysiology, there are not any clinically available therapeutics that target this aspect of disease progression. In this study, we evaluated the antifibrotic potential of thalidomide using both in vitro and in vivo models of BPH/LUTD. Using benign human prostate stromal cells stimulated with transforming growth factor β-1 (TGFβ1) followed by targeted transcriptomic profiling and assessment of canonical TGFβ signaling, we demonstrate that thalidomide attenuates expression of profibrotic genes, including extracellular matrix components. In aged male mice with LUTD, thalidomide administration led to a reduction in prostate collagen deposition and decreased organization of collagen fiber alignment. Functionally, thalidomide treatment improved LUTD in aged male mice, while prostate mass, androgen receptor expression and downstream signaling targets, and proliferative index remained unchanged, suggesting that the observed therapeutic effects are primarily mediated by antifibrotic mechanisms. Our findings highlight thalidomide's potential to modulate prostatic fibrosis and improve voiding function and support further investigation into the role of antifibrotic therapies as novel treatments for BPH/LUTD. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Histiocytosis development and clinical variation through the lens of genomics.
Kemps PG, van Halteren AG, van Wezel T … +1 more , Hogendoorn PC
J Pathol · 2026 May · PMID 42200684 · Publisher ↗
Histiocytic neoplasms are rare haematologic diseases characterised by clonal expansions of cells with a monocyte, macrophage or dendritic cell phenotype. Their clinical manifestations are diverse, ranging from indolent l...
Histiocytic neoplasms are rare haematologic diseases characterised by clonal expansions of cells with a monocyte, macrophage or dendritic cell phenotype. Their clinical manifestations are diverse, ranging from indolent lesions to aggressive systemic disease. Over recent decades, advances in genomic profiling have transformed the biological understanding of these conditions. The discovery of recurrent oncogenic mutations has reframed histiocytoses from primary inflammatory disorders to myeloid neoplasms, with a notable dependence on aberrant mitogen-activated protein kinase (MAPK) signalling. Novel genetic drivers continue to be uncovered, with many alterations correlating with distinct clinical and pathological phenotypes. Parallel studies have refined the understanding of disease ontogeny, demonstrating that diverse histiocytoses originate from haematopoietic stem/progenitor cells. In Langerhans cell histiocytosis, the differentiation stage of the mutated precursor cell is considered an important - but not the sole - determinant of disease extent and severity. Additional evidence suggests that specific clinical manifestations, such as neurodegenerative disease, may result from somatic mosaicism affecting tissue-resident macrophages derived from yolk sac progenitors. Collectively, these findings refine histiocytosis diagnosis, risk stratification, disease monitoring and treatment, with robust activity of kinase inhibitors in patients with severe or refractory disease. In this review, we synthesise recent genomic insights into histiocytosis development and variation, while addressing remaining questions and future directions. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Lymph node stromal topology as a hidden regulator of breast cancer outcome: commentary on reticular network analysis.
Vethencourt A, Salgado R, Gonzalez-Suarez E
J Pathol · 2026 May · PMID 42200492 · Publisher ↗
The axillary lymph node remains a cornerstone of breast cancer staging and therapeutic decision-making, yet it is still largely interpreted through a static anatomical framework. Emerging evidence challenges this paradig...
The axillary lymph node remains a cornerstone of breast cancer staging and therapeutic decision-making, yet it is still largely interpreted through a static anatomical framework. Emerging evidence challenges this paradigm, positioning tumor-draining lymph nodes as dynamic immunological ecosystems that actively regulate tumor progression and host response. In this context, Llewellyn et al introduce a quantitative framework to characterize fibroblastic reticular cell network topology and link nodal architecture to clinical outcomes. By quantifying features such as lacunarity, branching, and alignment in a breast cancer cohort, the authors show that fibroblastic reticular cell network organization is associated with prognosis in a context-dependent manner. While this approach represents a significant conceptual and methodological advance, its biological interpretation remains limited by the absence of functional validation and integrated immune profiling. Accumulating evidence indicates that lymph node microenvironments undergo profound immune reprogramming, highlighting the close interdependence between stromal topology and immune composition. These findings suggest that structural features alone may reflect distinct underlying biological states. Integrating spatial metrics with immune characterization may refine current staging systems, improve risk stratification, and ultimately inform future evolution of staging classifications by incorporating functional and spatial dimensions of nodal involvement. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
A subset of high-grade sarcomas with myogenic differentiation are associated with recurrent FGFR fusions.
Yeung MC, Saoud C, Chiang S … +2 more , Hameed M, Antonescu CR
J Pathol Clin Res · 2026 Jul · PMID 42185943 · Full text
Recurrent fusions involving FGFR1-4 genes have been previously described in rare subsets of mostly benign chondroid and mesenchymal neoplasms involving bone and soft tissue. However, a more comprehensive analysis of sarc...
Recurrent fusions involving FGFR1-4 genes have been previously described in rare subsets of mostly benign chondroid and mesenchymal neoplasms involving bone and soft tissue. However, a more comprehensive analysis of sarcomas associated with FGFR fusions, including their incidence and histotypes, has not been performed. Triggered by an FGFR1-rearranged unclassified high-grade sarcoma with myogenic differentiation, we investigated our molecular database for sarcomas with FGFR gene fusions to assess their recurrent potential and morphologic spectrum. A total of six unclassified sarcomas were identified, occurring in five females and one male, with a median age of 66.5 years. Tumors were located in the uterus and retroperitoneal/trunk soft tissue. Histologically, all tumors were high grade, composed predominantly of spindle cell morphology with variable cytologic atypia, high mitotic activity, and areas of necrosis. By immunohistochemistry, all tumors demonstrated evidence of myogenic differentiation, with focal or diffuse positivity for one or more markers (desmin, h-caldesmon, smooth muscle actin). However, none of the cases displayed diagnostic features of leiomyosarcoma or other known pathologic entities. Molecular studies revealed recurrent fusions involving FGFR1 (n = 3), FGFR2 (n = 1), and FGFR4 (n = 2), retaining the kinase domain. Additional recurrent genomic alterations included TP53 mutations, CDKN2A homozygous deletions, and RB1 alterations. Most patients followed an aggressive clinical course, including metastases and disease-related mortality. These findings expand the spectrum of sarcomas driven by FGFR gene fusions, underscoring the importance of molecular testing for accurate diagnosis and potential targeted therapy in high-grade sarcomas with myogenic features.
Do all colorectal mucinous adenocarcinomas arise via the serrated neoplasia pathway?
Vos AM, van Zwam PH, Rutgers N … +5 more , van Vliet S, Vink-Börger E, van der Post RS, Simmer F, Nagtegaal ID
J Pathol Clin Res · 2026 May · PMID 42166218 · Full text
Colorectal mucinous adenocarcinomas (MACs) and serrated adenocarcinomas (SACs) demonstrate considerable overlap in morphological and molecular features, suggesting a spectrum rather than two distinct tumour types. This s...
Colorectal mucinous adenocarcinomas (MACs) and serrated adenocarcinomas (SACs) demonstrate considerable overlap in morphological and molecular features, suggesting a spectrum rather than two distinct tumour types. This study investigates the presence of serrated morphological features, precursors, and molecular features in a large cohort of MAC. The study includes 698 MAC collected via the Dutch nationwide pathology databank. Histological review and mismatch repair evaluation were performed on all cases. Next generation sequencing was performed on 396 cases. Multiplex nested methylation-specific PCR (MSP) was performed on 260 microsatellite stable (MSS) cases. The majority of tumours were right-sided (62.6%). Precursor lesions were identified in 9.6% of cases, 88% of which were serrated. Serrated morphology was present in 71% of MAC. Of all cases, 33.8% were microsatellite unstable (MSI). Half of the evaluated cases were CpG island methylator phenotype high. Tumours were divided into six molecular subcategories BRAF/MSS (9.8%), BRAF/MSI (24.7%), KRAS/MSS (38.6%), KRAS/MSI (4.3%), double wild-type/MSS (16.7%), and double wild-type/MSI (5.8%). Based on the presence of a serrated precursor, and/or serrated morphology, and/or a serrated molecular profile, 83.1% of MAC in our cohort could be classified as serrated-MAC. Serrated-MAC developed in older patients, was more often right-sided, showed less perineural invasion, and fewer nodal metastases, when compared to MAC-NOS. Survival analysis showed no significant difference between serrated-MAC and MAC-NOS. We have confirmed that a large majority of colorectal MAC have similar characteristics to SAC.
Disrupted endocannabinoid signaling contributes to systemic inflammation in acute pancreatitis.
Goncalves-Romeu P, Cárdenas-Jaen K, de-Madaria E … +5 more , Hernández JM, Fluvià L, Torres-Ribas L, Closa D, Guillamat-Prats R
J Pathol · 2026 May · PMID 42153289 · Publisher ↗
Acute pancreatitis (AP) is an inflammatory disease that can lead to systemic complications in severe cases. The endocannabinoid system has emerged as a potential modulator of inflammation in AP. We investigated the role...
Acute pancreatitis (AP) is an inflammatory disease that can lead to systemic complications in severe cases. The endocannabinoid system has emerged as a potential modulator of inflammation in AP. We investigated the role of the endocannabinoid 2-arachidonoylglycerol (2-AG) and the cannabinoid receptors CB1 and CB2 during AP. A severity-dependent decrease in circulating 2-AG was found both in patients and a murine AP model. Restoring 2-AG - by avoiding its degradation via monoacylglycerol lipase inhibitor or direct 2-AG administration - reduced local and systemic inflammation, modulated peritoneal macrophage polarization, and mitigated lung injury. Notably, endocannabinoid system effects were consistent across sexes. Both cannabinoid receptors were involved in disease pathophysiology. Genetic Cnr1 knockout and pharmacological CB2 blockade showed distinct and complementary roles of both receptors in regulating inflammation, immune infiltration, and pulmonary damage. These findings highlight a protective role for 2-AG and highlight the endocannabinoid system - and cannabinoid receptors in particular - as a promising therapeutic target to modulate inflammation and reduce systemic complications in acute pancreatitis. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Testican-1-MMP axis in tumour extracellular matrix (ECM) remodelling: interaction dynamics analysis and an in silico perspective.
Youssefi S, Saleki K, Kadam P … +4 more , Mazloomi A, Mukherjee A, Dekker LV, Nateri AS
J Pathol · 2026 May · PMID 42141259 · Publisher ↗
The extracellular matrix (ECM) plays a pivotal role in facilitating tumour development, invasiveness, metastasis, and immunoevasive processes through dynamic ECM remodelling processes. Testican-1 (SPOCK1), an excretory m...
The extracellular matrix (ECM) plays a pivotal role in facilitating tumour development, invasiveness, metastasis, and immunoevasive processes through dynamic ECM remodelling processes. Testican-1 (SPOCK1), an excretory matricellular proteoglycan, is suggested to exert a role in the facilitation of ECM remodelling processes through interacting with matrix metalloproteases (MMPs) and even its less known forms. The structural mechanisms of interactions between testican-1 and MMPs were studied, and their roles in tumour-promotion pathway processes were also examined using a computational approach and immunofluorescence validated by colocalisation technique analysis. A computational analysis using docking, molecular dynamics (MD), and systems biology analysis was employed. HDock and GROMACS were chosen to analyse binding affinity and testican-1 stability with 28 different MMPs. H-bond, free energy, and root mean square fluctuation (RMSF) analyses were performed to confirm the interactions in the testican-1-MMP complexes. The systems biology toolkit implemented in this study consisted of STRING, BioGRID, and Cytoscape, which were employed for testican-1 interaction network and pathway analysis. Kaplan-Meier survival analysis using the GEPIA2 tool was utilised to correlate SPOCK1 gene expression and clinical survival measures for various malignancies. The docking analysis showed robust interactions between testican-1 and MMP23, MMP25, and MMP28. Additionally, testican-1-MMP complexes were confirmed to form stable interfaces based on comprehensive MD analysis, suggesting solid binding interfaces with the MMP-unique domain of testican-1. Our systems biology experiment indicated testican-1 as a central hub for interactions between immunoevasive and ECM remodelling processes. SPOCK expression was also shown to correlate with significant survival measures for different malignancies, revealing clinical implications in cancer. The testican-1-MMP computational analysis suggests testican-1 plays a pivotal role as a therapeutic target for a wide range of malignancies. SPOCK-MMP interactions could be targeted to interrupt tumour-promoting processes by arresting dynamic changes in the ECM, thereby improving patient survival. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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