J. Pathol. [JOURNAL]
Sun
200 papers
Topological analysis of the human lymph node reticular network predicts outcome in breast cancer.
Llewellyn AM, D'Costa SL, Lam CY … +5 more , Gore JA, Lachina V, Shewring DJ, Acton SE, Naidoo K
J Pathol · 2026 Jul · PMID 42003567 · Full text
Axillary LNs (ALNs) initiate immune responses in breast cancer (BC) but how and when ALNs become dysfunctional, facilitating metastasis, is unclear. The fibroblastic reticular cell (FRC) network within ALNs provides stru...
Axillary LNs (ALNs) initiate immune responses in breast cancer (BC) but how and when ALNs become dysfunctional, facilitating metastasis, is unclear. The fibroblastic reticular cell (FRC) network within ALNs provides structural support and mediates immune homeostasis, but we have yet to elucidate whether this network changes during BC progression. An unbiased computational approach was used to quantify features of the immunolabelled FRC network in ALNs derived from patients with BC. Platelet-derived growth factor receptor β (PDGFRβ) was identified as a robust immunomarker for human FRC and used to quantify how FRC network topology changes during BC progression and after treatment. Formalin-fixed paraffin-embedded ALNs (n = 331) from 179 patients with BC and 23 benign reactive controls were assessed for FRC network metrics, including lacunarity and branchpoints, alongside de-identified clinico-pathological data. These data were then integrated using multivariate, principal component and survival analyses. In node-negative, post-neoadjuvant chemotherapy triple-negative BC, denser FRC networks in uninvolved nodes significantly improved survival (p = 0.0365). [Correction added on 09 May 2026, after first online publication: The word 'treatment-naïve' has been corrected to 'post-neoadjuvant chemotherapy' in the preceding sentence.] Conversely, similar changes seen in node-positive BC significantly worsened survival (p = 0.0407), regardless of BC subtype or treatment. In metastatic ALNs, FRC network disruption grew proportionately to axillary tumour burden, and this significantly correlated with poorer outcomes (p = 0.043). Interestingly, increased FRC alignment within these metastases significantly improved survival (p = 0.0205). This study showed that changes in human ALN FRC network topology predicts BC prognosis. This could improve how we risk stratify patients in future, and provide a new avenue for mechanistic, translational research. © 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.
Human induced pluripotent stem cell-derived chimeric antigen receptor-macrophages eradicate IL-13Rα2-positive solid tumors.
Yang Y, Wang L, Zhang Y … +27 more , Lyu S, Ruan Q, Wang C, Dou F, Liang G, Yan G, Wang M, Fan H, Qi H, Kong W, Guo H, Liu Q, Wang W, Mao M, Huang Y, Zhou X, Duan J, Song W, Huang B, Cheng Y, Zhou L, Xu S, Shen J, Ping YF, Bian XW, He Z, Shi Y
J Pathol · 2026 Jul · PMID 41983511 · Publisher ↗
Macrophages exhibit extensive tumor infiltration capacity across diverse solid malignancies, establishing macrophage-targeted immunotherapies as an emerging frontier in oncology. Genetic engineering of macrophages using...
Macrophages exhibit extensive tumor infiltration capacity across diverse solid malignancies, establishing macrophage-targeted immunotherapies as an emerging frontier in oncology. Genetic engineering of macrophages using chimeric antigen receptor (CAR) technology - enabling recognition and phagocytosis of neoplastic cells - is emerging as a potential therapeutic strategy against solid tumors. Human induced pluripotent stem cells (iPSCs) provide a renewable platform for the efficient differentiation of functionally competent macrophages. In this study, we engineered human iPSC-derived CAR macrophages (iCAR-M) targeting interleukin-13 receptor subunit alpha 2 (IL-13Rα2). Pan-tumor transcriptomic and immunohistochemical analyses revealed that IL-13Rα2, a tumor-associated antigen, was overexpressed in human glioblastoma (GBM), uterine carcinosarcoma (UCS), and melanoma specimens. In vitro phagocytosis assays revealed target-specific clearance of IL-13Rα2-positive tumor cells by iCAR-M. Intracranial administration of iCAR-M potently suppressed tumor growth, enhanced intratumoral cytotoxic T-cell infiltration, and prolonged the survival of humanized, immunocompetent mice bearing GBM xenografts. The administered iCAR-M maintained phagocytic capacity in vivo and acquired an M1-like pro-inflammatory phenotype. Comprehensive safety assessment revealed no detectable evidence of systemic toxicity or treatment-related neurotoxicity. Collectively, these results demonstrate the potent efficacy and favorable safety profile of iPSC-derived, IL-13Rα2-targeted CAR macrophages, supporting their therapeutic potential against solid tumors. © 2026 The Pathological Society of Great Britain and Ireland.
Cellular origins and etiological factors for squamous cell carcinoma and related cancer types of the bladder.
Su X, Duan X, Bai S … +19 more , Su P, Xiao J, Shi Y, Wu D, Liu Q, Tao K, Han B, Wu JX, Cheng S, Ding S, Liu N, Chen Y, Ren J, Yuan S, Shen Q, Yin Z, Tian F, Liu M, Yang G
J Pathol · 2026 Jul · PMID 41978986 · Publisher ↗
Squamous cell carcinoma (SCC) of the bladder is a rare disease with poor prognosis and limited molecular profiling. Here we present a multi-layer, comparative investigation on bladder SCC and related cancers, namely pure...
Squamous cell carcinoma (SCC) of the bladder is a rare disease with poor prognosis and limited molecular profiling. Here we present a multi-layer, comparative investigation on bladder SCC and related cancers, namely pure urothelial carcinoma (UC), UC with squamous differentiation, and bladder adenocarcinoma. The mutational signatures of SCC, UC with squamous differentiation, and pure UC imply similar etiologies, with APOBEC-derived signatures found in around a third of samples. SCC and UC with squamous differentiation both highly express basal/squamous markers, different from the luminal profile in UC. We have also dissected the tumor microenvironment and cell type-specific expression in primary tumor and lymph node metastases of SCC at single-cell resolution, and SCC tumor cells also exhibit high expression of basal/squamous markers compared with the luminal feature in UC and adenocarcinoma. Similar mutational signatures present at different contributing fractions, combined with distinct transcriptomic features in various types of bladder cancer, provide an interesting perspective on etiological factors and suggest tumor initiation from potentially different urothelial cell types. The molecular landscape of SCC and related bladder cancers presented in this study improves our understanding of their etiologies and possible cellular origins, and may facilitate future prevention strategies and therapy development. © 2026 The Pathological Society of Great Britain and Ireland.
Endoplasmic reticulum stress and the unfolded protein response in lung diseases: molecular pathways and therapeutic interventions.
Song L, Liu Y, Xu C … +4 more , Zhang Y, Xu K, Yao D, Huang X
J Pathol · 2026 Jul · PMID 41978971 · Full text
Endoplasmic reticulum stress (ERS) occurs when the protein-folding capacity of the endoplasmic reticulum (ER) is overwhelmed, triggering the unfolded protein response (UPR) to restore homeostasis. However, severe or pers...
Endoplasmic reticulum stress (ERS) occurs when the protein-folding capacity of the endoplasmic reticulum (ER) is overwhelmed, triggering the unfolded protein response (UPR) to restore homeostasis. However, severe or persistent ERS can shift the UPR toward pro-inflammatory, apoptotic, and fibrotic signaling, thereby exacerbating tissue injury. The pathogenesis and progression of lung diseases, which involve highly heterogeneous cell populations, are significantly influenced by these mechanisms. Indeed, ERS and UPR activation are now recognized as central players in the pathophysiology of numerous lung diseases. This review examines the impact of dysregulated ERS/UPR signaling across different lung diseases, with a particular focus on its cell-type-specific effects and disease-specific implications. Furthermore, we discuss emerging therapeutic strategies designed to modulate these pathways. A comprehensive understanding of the cell-type-specific outcomes of ERS/UPR is therefore crucial for developing targeted interventions to mitigate or reverse lung disease progression. © 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.
The NRF2 readout beyond genotyping.
Suzuki Y, Ge M
J Pathol · 2026 Jul · PMID 41944556 · Publisher ↗
Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality, and many patients derive limited benefit from current systemic therapies. Until now, clinical and translational efforts have largely focused...
Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality, and many patients derive limited benefit from current systemic therapies. Until now, clinical and translational efforts have largely focused on recurrent genomic alterations in the Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 (NRF2) axis, yet mutation status alone often fails to capture the biological heterogeneity and context dependence of NRF2 pathway dysregulation. In recent years, growing evidence has highlighted the NRF2 activation state as a clinically relevant feature that better reflects resistance phenotypes and therapeutic liabilities than genotyping alone. The recent work by Härkönen et al, published in The Journal of Pathology, suggests that anchoring genotype to phenotype using functional readouts is essential for defining NRF2 hyperactivity. Mechanistic studies further suggest that NRF2 hyperactivity can impose context-dependent metabolic liabilities. We discuss the next steps towards clinical translation, including prospective NRF2 activation-state stratification, integration of immune context for immunotherapy, and biomarker evaluation of redox and metabolic combinations based on NRF2-associated vulnerabilities. © 2026 The Pathological Society of Great Britain and Ireland.
Tissue-level heterogeneity in FECD: Descemet's membrane phenotypes and association with TCF4 CTG18.1 expansion.
Maeno S, Oie Y, Kai C … +1 more , Nishida K
J Pathol · 2026 Jul · PMID 41944554 · Full text
Late-onset Fuchs endothelial corneal dystrophy (FECD) is commonly framed as a corneal endothelial disease characterised by guttae accumulation and progressive thickening of Descemet's membrane (DM). However, clinical for...
Late-onset Fuchs endothelial corneal dystrophy (FECD) is commonly framed as a corneal endothelial disease characterised by guttae accumulation and progressive thickening of Descemet's membrane (DM). However, clinical forms and evolutionary profiles vary widely. Vaitinadapoulé et al systematically analysed as many as 500 keratoplasty-derived DMs from 25 European centres using flat mounts and transmitted light microscopy with structured scoring of extracellular matrix (ECM) lesions. The study revealed five FECD phenotypes and spatially organised lesion patterns and supports multiple pathological phenotypes. Radial organisation emerged as a dominant architectural theme, often accompanied by peripheral striae, with changes evident in both central and peripheral DM. Principal component analysis and unsupervised clustering showed modest separability, while manual classification identified dominant phenotypes with appreciable overlap, suggesting pathological phenotypes arise from a combination of lesion features and organisational patterns. In a genotyped subset, DM architectures differed by TCF4 CTG18.1 expansion status, linking tissue architecture to repeat biology. This ECM atlas provides a pathology-anchored framework for FECD heterogeneity and motivates prospective clinical correlation and quantitative image analysis. © 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.
The heterogeneity of Fuchs endothelial corneal dystrophy.
Patel SP
J Pathol · 2026 Apr · PMID 41944537 · Publisher ↗
Late-onset Fuchs endothelial corneal dystrophy (FECD) is characterized by distinct extracellular matrix deposits (guttae) within the basement membrane (Descemet's membrane) of the corneal endothelium. In a recent study p...
Late-onset Fuchs endothelial corneal dystrophy (FECD) is characterized by distinct extracellular matrix deposits (guttae) within the basement membrane (Descemet's membrane) of the corneal endothelium. In a recent study published in The Journal of Pathology, Vaitinadapoulé et al (2026) describe the diversity of guttae patterns in FECD through analysis of 500 Descemet's membrane specimens removed during surgery, with genotyping performed in one-fifth of patients for the commonly associated TCF4 trinucleotide repeat expansion. The diversity and clustering of guttae phenotypes in the total cohort and in those with and without TCF4 association have implications for commonly used diagnostic grading criteria for FECD, the development of therapeutics, and our understanding of disease development. Investigating and embracing this diversity holds promise for advancing our understanding of FECD. © 2026 The Pathological Society of Great Britain and Ireland.
Distantly metastatic differentiated thyroid carcinoma is kinase-driven and enriched for DNA repair and DNA methylation gene alterations.
Kong W, Bao L, Hu J … +17 more , Li G, Liu Y, Ran W, Zhang T, Gu H, Zhang X, Wang M, Ji H, Zong X, Zhang Y, Dang S, Li D, Fa L, Yu X, Pan X, Li X, Wang J
J Pathol · 2026 Jul · PMID 41881819 · Publisher ↗
Although distant metastasis is uncommon in differentiated thyroid carcinoma (DTC), it remains the leading cause of thyroid cancer-related mortality. The genetic landscape of distantly metastatic DTC (DMDTC) has not been...
Although distant metastasis is uncommon in differentiated thyroid carcinoma (DTC), it remains the leading cause of thyroid cancer-related mortality. The genetic landscape of distantly metastatic DTC (DMDTC) has not been well characterized in large cohorts. This study aimed to identify functional genetic alterations in DMDTC and validate their biological significance. We included 78 patients with DMDTC and performed DNA-based next-generation sequencing (NGS) in all cases, followed by RNA-based NGS for fusion gene detection, along with a review of previously reported isolated cases. Plasmids harbouring novel variants, including SPON1::ALK and RFTN1::BRAF fusions, and mutations in PTEN (c.322_345del, c.740del, c.968dup), STK11 (c.842C>T, c.1225C>T), and DNMT3A (c.891G>A, c.2312G>A, c.2595A>T, c.2606G>A) were constructed and transfected into TPC-1 and HEK293T cells to investigate downstream signalling. The methylation status of differentially methylated genes (DMGs) associated with DNMT3A mutations was analysed using the Infinium MethylationEPIC v2.0 BeadChip, with several DMGs validated by real-time quantitative PCR. The cohort consisted of 25 males and 53 females, with a mean age of 60.3 years at the diagnosis of metastasis. Histological types included papillary carcinoma (31 cases), follicular carcinoma (44 cases), and oncocytic carcinoma (3 cases). The lung and bone were the most common metastatic sites. Multiple metastases and older age were associated with metastasis-free and overall survival. Genetic alterations involving phosphorylation signalling pathways were identified in 61 cases, among which pathological alterations of DNA damage repair (DDR)-related genes were detected in ten cases. Novel RFTN1::BRAF and SPON1::ALK fusions, along with PTEN (c.740del, c.968dup) and STK11 (c.842C>T) mutations, could enhance downstream phosphorylation levels. DNMT3A mutations (c.891G>A, c.2312G>A, c.2595A>T, c.2606G>A) induced genome-wide methylation dysregulation, with altered expression of SLC12A7, FLNC, HMGB2, BNC2, and DAPK1. This study shows that DMDTCs are characterized by dysregulated phosphorylation signalling, accompanied by chromosomal instability and aberrant methylation, thus underscoring DDR gene-targeted therapy as a promising strategy. © 2026 The Pathological Society of Great Britain and Ireland.
Multinodular and vacuolating neuronal tumor: molecular genetics and DNA methylation analysis of 12 cases.
Lian F, Wang DD, Gong J … +6 more , Luo T, Guo LA, Wang WM, Chen N, Yao XH, Piao YS
J Pathol · 2026 Jul · PMID 41879092 · Publisher ↗
Multinodular and vacuolating neuronal tumor (MVNT) was recognized as a distinct neuronal tumor entity in the revision of the 2021 World Health Organization (WHO) Classification of Tumors of the CNS. In this study, we ret...
Multinodular and vacuolating neuronal tumor (MVNT) was recognized as a distinct neuronal tumor entity in the revision of the 2021 World Health Organization (WHO) Classification of Tumors of the CNS. In this study, we retrospectively analyzed 12 surgical cases, two of which exhibited ganglioglioma (GG)-like components. The cohort consisted of eight male and four female patients, with a median age of 31 years (age range: 18-53 years). Seizures were the most common clinical presentation, followed by headache and dizziness. Three patients were incidentally identified during physical examination. Ten tumors were located in the cerebral hemisphere, and the remaining two were found in the cerebellum and thalamus, respectively. Histopathological examination revealed clusters of neuroepithelial cells with large amphophilic vacuolated cytoplasm and eccentrically placed round nuclei containing prominent nucleoli. Immunohistochemically, these vacuolated cells were positive for OLIG2, MAP2, SYN and SOX10, and negative for GFAP and NEUN. DNA sequencing analysis identified no mutations in IDH1, IDH2, BRAF V600E, TERT promoter, or EGFR genes. Among the cohort, three cases harbored FGFR2 mutations, and FGFR2::INA gene fusion was detected in both MVNT and GG-like components. Two cases carried BRAF mutation, and one case exhibited MAP2K1 mutation. A novel BCAN::NTRK1 (exon 12-exon 9) gene fusion was identified in one case. DNA methylation profiling of eight cases revealed that none matched with a known CNS tumor type. Six cases formed a separate methylation cluster, suggesting a potential novel molecular subtype, while the remaining two cases exhibited transcriptional similarities to supratentorial pilocytic astrocytoma and rosette-forming glioneuronal tumor (RGNT), respectively. Postoperatively, all patients remained seizure free with no evidence of tumor progression. Only one patient died 16 months after surgery due to an unrelated traffic accident. © 2026 The Pathological Society of Great Britain and Ireland.
Acid ceramidase overactivity drives ceramide loss, leading to atopic dry skin and Th2-skewed immune polarization.
Takada M, Sashikawa-Kimura M, Ohno Y … +6 more , Hossain MR, Xie X, Iwabuchi K, Komine M, Ohtsuki M, Imokawa G
J Pathol · 2026 Jun · PMID 41873507 · Full text
Ceramide deficiency in the stratum corneum (SC) is a key etiological factor in atopic dermatitis (AD). To clarify the direct role of SC ceramide depletion in impairing SC barrier and water-holding functions and in initia...
Ceramide deficiency in the stratum corneum (SC) is a key etiological factor in atopic dermatitis (AD). To clarify the direct role of SC ceramide depletion in impairing SC barrier and water-holding functions and in initiating AD-like skin symptoms and disease-specific molecular alterations, we generated Tg mice overexpressing a mutant form of acid ceramidase (aCDase) under the control of the involucrin promoter, resulting in targeted expression in the upper epidermis. By 3 weeks of age, Tg mice developed noninflammatory, scaly skin characterized by severely compromised barrier integrity and water-holding capacity, along with significantly elevated epidermal aCDase activity and markedly reduced ceramide levels in the SC. Compared to WT controls, Tg mice also exhibited increased epidermal innervation and reduced intraepidermal semaphorin 3a protein levels. Additionally, Tg skin showed substantial changes in the expression of AD-associated biomarkers involved in barrier impairment, pruritus, and Th2 polarization. These included increased levels of Il10, Il17a, S100a7, S100a8, and S100a9 and decreased levels of Cxcl10, Ifng, Il2, Il13, Il33, Sema3a, and Tlr9. Repeated topical application of mite antigens induced allergic responses in Tg mice, but not in WT mice. These responses were characterized by prominent eosinophil infiltration in the dermis and significantly elevated serum IgE levels. Allergen-challenged ear skin from Tg mice also demonstrated significantly increased expression of inflammatory mediators related to AD, including Ccl17, Ccl22, Ccl26, Ccl27, Il3, Il13, Il22, and Il33. These findings establish Tg mice as a pathophysiologically relevant model of AD, presenting key features such as xerotic, pruritic skin, impaired barrier and water-retention functions, and Th2-dominant allergic inflammation. This model provides important insights into ceramide-dependent mechanisms in AD pathogenesis and offers a useful platform for therapeutic development. © 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.
Novel genomic risk stratification model for primary high-grade malignant peripheral nerve sheath tumor (MPNST).
Chang HY, Dermawan JK, Tap W … +3 more , Singer S, Chi P, Antonescu CR
J Pathol · 2026 Jun · PMID 41863012 · Publisher ↗
Risk stratification across the three main clinical subsets of malignant peripheral nerve sheath tumor (MPNST), neurofibromatosis type I (NF1-related), sporadic, and prior radiation therapy (RT), is based mainly on clinic...
Risk stratification across the three main clinical subsets of malignant peripheral nerve sheath tumor (MPNST), neurofibromatosis type I (NF1-related), sporadic, and prior radiation therapy (RT), is based mainly on clinicopathologic parameters, such as size, grade, stage, and NF1 status. Moreover, no prior study investigated the additional impact of genomic alterations in the prognosis of high-grade MPNST using clinically validated DNA targeted next-generation sequencing (NGS) panels. Our goal was to integrate clinicopathologic and genomic parameters using an elastic-net penalized Cox proportional hazards machine learning model using OncoCast for risk prediction. Herein we perform comprehensive mutational and copy number profiling using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) on 81 primary localized high-grade MPNSTs (51% NF1-related, 38% sporadic, 11% RT-associated). The most common genomic alterations included NF1 (51% germline, 59% somatic), CDKN2A/B (62%), PRC2 components (SUZ12, EED) (53%), and TP53 (25%). Variables selected by OncoCast as significantly associated with survival were used to construct a three-tier risk stratification model for progression-free survival (PFS) and disease-specific survival (DSS). For PFS, patients with chr16 deletion were classified as high-risk, those with concurrent germline and somatic NF1 alterations as low-risk, and the remainder was assigned to the intermediate-risk group. For DSS, cases with fraction genome altered (FGA) > 50% were defined as high-risk, those with PRC2 abnormalities, CDKN2A deletion, TERT promoter mutation, or chr16 deletion as intermediate-risk, and cases lacking all the aforementioned alterations as low-risk. The high-risk group showed significantly inferior survival compared to the low-risk group (both PFS and DSS p < 0.001). Subgroup analysis showed that among NF1-related MPNST, co-occurring somatic NF1 mutation or WT TP53 was associated with superior PFS. Collectively, genomic alterations detected by clinical NGS panels provide potential new biomarkers for risk stratification that can be integrated with conventional parameters to provide improved prognostication and guide therapeutic strategies. © 2026 The Pathological Society of Great Britain and Ireland.
Functional reassessment of extended splice region variants in MYO7A with hearing loss and Usher syndrome.
Shi T, Huang Y, Su X … +3 more , Yu L, Zhao Y, Cheng J
J Pathol · 2026 Jun · PMID 41852313 · Full text
MYO7A is a causal gene, underlying Usher syndrome type 1B (USH1B) and both autosomal recessive (DFNB2) and dominant (DFNA11) non-syndromic hearing loss. Despite the large number of reported MYO7A variants (over 2,200), v...
MYO7A is a causal gene, underlying Usher syndrome type 1B (USH1B) and both autosomal recessive (DFNB2) and dominant (DFNA11) non-syndromic hearing loss. Despite the large number of reported MYO7A variants (over 2,200), variants located in an extended splice region remain difficult to interpret and are often classified as variants of uncertain significance (VUS). We investigated the clinical impact of MYO7A extended splice region variants, located within ±50 bp of exon-intron boundaries, by analyzing a nationwide Chinese cohort of 10,664 undiagnosed individuals with hearing loss. Twelve such variants (in 11 probands, two variants were in cis) were identified for functional analysis. Using minigene splicing assays coupled with in silico splicing predictions, we evaluated each variant's effect on pre-mRNA processing and applied ACMG/AMP guidelines for classification. Six of the tested variants completely disrupted normal splicing, and eight variants in total were reclassified from VUS to pathogenic or likely pathogenic based on aberrant transcript outcomes. Notably, several variants generated multiple distinct abnormal transcripts, and two-thirds of these variants fell within the myosin motor domain (others in the FERM2 domain). Splicing predictions from in silico algorithms were largely concordant with the experimental results, further supporting their utility in variant interpretation. This functional evidence enabled definitive molecular diagnoses in previously unresolved cases spanning DFNA11, DFNB2, and USH1B phenotypes. In summary, our study demonstrated that integrating experimental splicing assays with predictive tools can definitively determine the pathogenicity of extended splice region variants in MYO7A, thereby improving the diagnostic accuracy of genetic testing for both non-syndromic and syndromic hearing loss. This approach could be applied to other genes to enhance genetic diagnosis. © 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.
Could the naked mole-rat become the new standard for studying human gut health and probiotics?.
Pearson AC, Barreñada O, Brieño-Enríquez MA
J Pathol · 2026 Jun · PMID 41848207 · Full text
The naked mole-rat (NMR; Heterocephalus glaber) is a subterranean rodent native to the arid regions of the Horn of Africa. The NMR is the longest-lived rodent and is known for its distinctive physiological and social tra...
The naked mole-rat (NMR; Heterocephalus glaber) is a subterranean rodent native to the arid regions of the Horn of Africa. The NMR is the longest-lived rodent and is known for its distinctive physiological and social traits. This species has become a notable model organism for studying aging, cancer biology, behavioral ecology, and reproduction. Recently, NMRs have gained attention because their gastrointestinal tract features an exceptionally strong intestinal barrier, a large number of goblet cells, a thicker mucin layer, and reduced gut permeability. The NMR gut microbiome, similar to that observed in human centenarians, is highly diverse and characterized by a high microbial load. In fact, Hart et al (2026) demonstrated that spontaneous infection with Citrobacter braakii in the NMR causes clinical symptoms and histopathological changes that are very similar to those observed in human colitis. If left untreated, the disease can progress and become fatal. However, probiotic treatment can reverse the clinical and histopathological phenotypes. These findings indicate that, in addition to serving as a powerful model for aging, cancer, and reproduction, the NMR may also serve as a powerful tool for studying human diseases such as gut dysbiosis, gut barrier dysfunction, and colitis. © 2026 The Pathological Society of Great Britain and Ireland.
Genomic landscape and homologous recombination deficiency in malignant germ cell tumors reveals sex-specific therapeutic opportunities.
Xu B, Chen J, Peng H … +2 more , Su X, He C
J Pathol · 2026 Jun · PMID 41831125 · Publisher ↗
Malignant germ cell tumors (GCTs) are relatively rare tumors with limited therapeutic options. This study examined the homologous recombination deficiency (HRD) status and genomic characteristics in 14 patients with GCT...
Malignant germ cell tumors (GCTs) are relatively rare tumors with limited therapeutic options. This study examined the homologous recombination deficiency (HRD) status and genomic characteristics in 14 patients with GCT who underwent next-generation sequencing. HRD was evaluated using the genomic instability score (GIS), which incorporates three components: loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale transition (LST). Our findings showed that 57.1% (8/14) of participants were HRD positive. Female patients presented a significantly higher prevalence of HRD positivity (87.5%, 7/8) compared with male patients (16.7%, 1/6). HRD positivity in female cases had a mean GIS of 56 (range 48-76), including one patient harboring a germline BRCA2 p.S2670L (c.8009C>T) likely pathogenic mutation. LST demonstrated the strongest correlation with the integrated GIS (R = 0.945), followed by LOH (R = 0.872). Distinct mutation patterns were observed based on gender. GCTs in male cases predominantly exhibited mutations in TP53 (50% in yolk sac tumors; 50% in teratomas). GCTs in male cases also demonstrated TP53 mutations in one mediastinal yolk sac tumor and one mediastinal teratoma. Male cases showed recurrent alterations in KRAS, PRKDC, and CDKN1B, alongside frequent chromosome 12p amplifications in two cases. One particularly complex mediastinal teratoma in a male patient, featuring rhabdomyosarcomatous transformation, displayed bidirectional intergenic (TWSG1, MANEA-DT)-ROS1fusions, a HRAS-intergenic (RNH1) fusion, and MET focal amplification. These findings suggest a promising therapeutic opportunity with poly (ADP-ribose) polymerase (PARP) inhibitors for female patients with HRD-positive GCTs. Additionally, the complex composition of gene variants found in male patients with GCTs, including ROS1 fusions and MET focal amplification, points toward potential targeted therapeutic strategies. This study underscores the presence of sex-specific therapeutic vulnerabilities in GCTs, which warrant further exploration in larger cohorts. © 2026 The Pathological Society of Great Britain and Ireland.
Neutrophil extracellular traps aggravate lung injury by inducing pyroptosis of alveolar macrophages.
Lu J, Song R, Yang H … +1 more , Liu C
J Pathol · 2026 Jun · PMID 41823322 · Publisher ↗
Neutrophil extracellular traps (NETs) contribute to chronic obstructive pulmonary disease (COPD) pathogenesis by amplifying airway inflammation. Gasdermin D (GSDMD)-mediated pyroptosis is a critical driver of COPD progre...
Neutrophil extracellular traps (NETs) contribute to chronic obstructive pulmonary disease (COPD) pathogenesis by amplifying airway inflammation. Gasdermin D (GSDMD)-mediated pyroptosis is a critical driver of COPD progression. This study provides insights into COPD pathogenesis and provides a theoretical basis for potential therapeutic targets. Mice were exposed to cigarette smoke (CS) for 16 weeks to establish a COPD model. In vitro, alveolar macrophages (AMs) (MH-S) and alveolar epithelial cells (MLE-12) were treated with cigarette smoke extract (CSE). Subsequently, NETs were isolated from phorbol-12-myristate-13-acetate (PMA)-stimulated neutrophils. Lung histopathology, inflammatory markers, and pyroptosis-related proteins were analyzed. Co-immunoprecipitation analysis was used to verify the binding of GSDMD and ubiquitin molecules in cells. Interventions included DNase1 to degrade NET and GSDMD knockdown. In CS-exposed mice, NETs increased the levels of proinflammatory cells and mediators, and lung structure was further disrupted. Pyroptosis of AMs was increased, while phagocytosis of AMs was inhibited. However, treatment with DNAse1 partially reversed the results caused by CS exposure and NET induction. Consistently, NETs aggravated inflammatory response and pyroptosis in the CSE-induced MH-S cell model. Furthermore, NETs significantly caused an increase in ROS, which promoted the activation of GSDMD deubiquitination and subsequent pyroptosis pathway in AMs. DNase1 treatment or GSDMD silencing attenuated pyroptosis, reduced inflammatory mediators, and improved lung function. NETs aggravated CS-induced lung inflammation and injury by activating GSDMD to promote pyroptosis in AMs. Targeting GSDMD or NETs represents a novel therapeutic strategy for COPD. © 2026 The Pathological Society of Great Britain and Ireland.
Clinicopathological characteristics of patients with inoperable non-small cell lung cancer harboring circulating NRF2 pathway mutations.
Härkönen J, Tiainen S, Kujala J … +12 more , Muhonen L, Mohanasundaram P, Tikkanen T, Pöhner I, Patinen T, Adinolfi S, Väyrynen JP, Auvinen P, Mannermaa A, Pölönen P, Rauramaa T, Levonen AL
J Pathol · 2026 Jun · PMID 41771797 · Full text
Lung cancer is the leading cause of global cancer-related morbidity and mortality, with tobacco smoking as its strongest risk factor. Nuclear factor erythroid 2-related factor 2 (NRF2) is a redox-regulated transcription...
Lung cancer is the leading cause of global cancer-related morbidity and mortality, with tobacco smoking as its strongest risk factor. Nuclear factor erythroid 2-related factor 2 (NRF2) is a redox-regulated transcription factor frequently dysregulated in non-small cell lung cancer (NSCLC), leading to aggressive disease and resistance to therapy. In this study, we analyzed circulating cell-free tumor DNA from a real-world cohort to characterize clinicopathological features and identify risk factors associated with oncogenic NRF2 activation in inoperable NSCLC. Key findings were further validated using retrospective datasets. Our results demonstrate that NRF2 pathway-mutated NSCLC represents a smoking-associated, high-risk molecular subtype frequently accompanied by detrimental SMARCA4 mutations. Importantly, these co-occurring mutations cumulatively worsen clinical outcomes independently of other risk factors. We show that NRF2-mutated tumors generally exhibit lower leukocyte infiltration, while high tumor mutation burden independently correlates with increased cytotoxic T lymphocyte density, regardless of NRF2 status. Furthermore, our data indicate that NRF2 activation can be reliably identified through immunohistochemical detection of protein expression of markers AKR1B10 and AKR1C1, both of which correlate with inferior outcomes. As mutations in NRF2-regulating tumor suppressors KEAP1 and CUL3 are not confined to specific hotspot regions, our findings advocate for a multimodal profiling approach combining somatic mutation assessment with protein or transcriptomic evaluation of NRF2 targets. This comprehensive strategy effectively identifies oncogenic NRF2 hyperactivity, enhancing diagnostic accuracy and clinical decision-making in NSCLC management. © 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.
Pathological classification of Fuchs endothelial corneal dystrophy into several types and their relationships with CTG18.1 expansion repeats.
Vaitinadapoulé H, Onitiu D, Maurin C … +12 more , Travers G, Crouzet E, Dorado-Cortez O, Poinard S, He Z, Forest F, Ollier E, Touraine R, Gain P, Perone JM, Thuret G, French Fuchs Study Group (FFSG)
J Pathol · 2026 Jun · PMID 41736702 · Full text
Late-onset Fuchs endothelial corneal dystrophy (FECD) is the most common primary disease of the corneal endothelium and the leading indication for corneal transplantation in Western countries. It is characterized by prog...
Late-onset Fuchs endothelial corneal dystrophy (FECD) is the most common primary disease of the corneal endothelium and the leading indication for corneal transplantation in Western countries. It is characterized by progressive accumulation, over two to three decades, of extracellular matrix (ECM) components in Descemet's membrane (DM), leading to the formation of abnormal excrescences, known as guttae, and additional DM layers. Clinical forms and evolutionary profiles vary widely among patients. FECD is strongly associated with intronic CTG trinucleotide repeats (TNRs) in the transcription factor 4 (TCF4) gene. We analysed 500 DMs removed during keratoplasty for FECD across 25 European centres to identify different anatomopathological forms of the disease. Following flat mounting and dehydration, the samples were digitized using transmitted light microscopy and independently assessed by three independent readers. A total of ten parameters - six related to guttae and four on other forms of ECM - were scored. Principal component analysis and an unsupervised clustering method separated three clusters from these parameters. In addition, manual classification was performed by grouping samples with major common features. The number of TNRs in TCF4 was analysed by short tandem repeat (STR)- and triplet repeat primed-polymerase chain reaction (TP-PCR) for 109 patients. We found that (1) five FECD phenotypes exist; (2) guttae and other ECM structures were radially arranged in 95% of samples; (3) 33% of samples exhibited peripheral radial striae that corresponded to a hypertrophied form of similar structures present in healthy corneas; and (4) patients with fewer than 50 TNRs had only two out of five phenotypes and had a significantly higher number of peripheral radial striae (94% versus 49%, p < 0.001). Taken together, these new findings demonstrate the existence of different FECD phenotypes; reveal that lesions affect both the centre and the periphery of the endothelium; and suggest that radial deposits may be produced by pathological cells migrating from the periphery towards the centre. © 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.
What practicing pathologists and oncologists should know about the new computational pathology-based companion diagnostic tools.
Montezuma D, Oliveira SP, Zlobec I … +9 more , Khalili N, Temprana-Salvador J, Leh S, Ameisen D, Șerbănescu MS, Prelaj A, Kather JN, Zerbe N, L'Imperio V
J Pathol · 2026 Jun · PMID 41736658 · Full text
The integration of artificial intelligence into pathology is transforming the assessment of histological and immunohistochemical (IHC) slides, offering opportunities to reduce variability and streamline diagnostics. In p...
The integration of artificial intelligence into pathology is transforming the assessment of histological and immunohistochemical (IHC) slides, offering opportunities to reduce variability and streamline diagnostics. In practical terms, most available tools and research models emulate the diagnostic capabilities of pathologists by detecting, grading, and classifying tumours and other diseases. More recent applications have moved beyond mimicry, aiming to predict established biomarkers, such as microsatellite instability or IHC-based markers, and to tackle even more ambitious tasks, such as directly predicting patient prognosis from H&E whole slide images. Remarkably, novel computational tools are now being designed as companion diagnostic assays, linking the automated evaluation of specific IHC biomarkers to the prediction of response to specific drugs, potentially marking a new chapter in the evolution of digital and computational pathology. The TROPION-PanTumor01 trial recently demonstrated the superiority of a supervised machine learning model (termed the quantitative continuous score [QCS] by the vendor) in assessing TROP2 IHC compared with human scoring, promising better stratification of patients with non-small cell lung cancer for treatment with datopotamab deruxtecan. The same approach has shown promise in refining HER2 (human epidermal growth factor receptor 2) and PD-L1 (programmed death-ligand 1) evaluations, revealing patient subgroups that may benefit from targeted therapies. Moreover, other similar approaches are progressively reaching the market, posing significant opportunities and challenges for clinicians involved in the care of patients with cancer. This Perspective is promoted by the European Society of Digital and Integrative Pathology (ESDIP, founded in 2016, and having long-standing experience in computational pathology, esdipath.org) and the European Interdisciplinary Society of Artificial Intelligence for Cancer Research (ESAC, a recently established initiative, founded in 2024, esac-network.eu), both bringing together clinicians, engineers and other professionals dedicated to the development and clinical translation of computational approaches aimed at improving patient care. It aims to provide an informed overview of novel computational pathology companion diagnostic tools, with a particular focus on the background that practicing pathologists and oncologists need to have with these tools, when transitioning from research to clinical practice, irrespective of their prior familiarity with computational approaches. © 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.
Deep learning-based H&E-derived risk scores in colorectal cancer: associations with tumour morphology, biology, and predicted drug response.
Reitsam NG, Jiang X, Liang J … +21 more , Grosser B, Grozdanov V, Loeffler CM, Gustav M, Lenz T, Muti HS, Carrero ZI, West NP, Quirke P, Foersch S, Jesinghaus M, Müller W, Yuan T, Hoffmeister M, Brenner H, Jonnagaddala J, Hawkins NJ, Ward RL, Grabsch HI, Märkl B, Kather JN
J Pathol · 2026 May · PMID 41716034 · Full text
Over recent years, several deep learning (DL) models have been presented to predict colorectal cancer (CRC) patient survival directly from haematoxylin and eosin (H&E)-stained routine whole-slide images (WSIs). Unlike tr...
Over recent years, several deep learning (DL) models have been presented to predict colorectal cancer (CRC) patient survival directly from haematoxylin and eosin (H&E)-stained routine whole-slide images (WSIs). Unlike traditional studies that rely on manually defined histopathological features, weakly supervised DL allows training directly on clinical endpoints without prior specification of the model's focus. This offers a unique opportunity to study the tissue morphology underlying these predictions, improving our understanding of disease biology. Here, we present a comprehensive analysis of the clinicopathological features, tumour morphology and biology, as well as gene expression-based predicted drug response of over 4,000 CRC patients derived from four different international cohorts with available H&E-inferred DL-based risk scores (low- versus high-risk as well as absolute risk scores). The results from our study suggest that conventional clinicopathological risk factors, such as grade of differentiation, presence of lymph node metastasis, tumour budding, and percentage of tumour necrosis, are positively associated with DL-based risk scores. Moreover, CRCs with direct tumour-adipocyte interactions are enriched in the DL-based high-risk group. Through detailed morphologic review, we provide comprehensive evidence that direct tumour-adipocyte interaction, a high degree of tumour budding, and poorly differentiated morphology are linked to high DL-based risk scores. Transcriptomic and genetic subgroups show only limited association with H&E-derived DL-based risk scores. Moreover, we present data suggesting that DL-based low- versus high-risk CRCs may be characterised by differential drug sensitivity. Our study highlights that DL-based risk scores derived from H&E WSIs not only align with established clinicopathological features but also highlight morphological features, such as tumour-adipocyte interaction, that are not routinely captured by established clinicopathological scoring systems. Moreover, DL-based risk groups may be associated with a differential treatment response, underlining their potential to guide patient stratification in routine clinical practice. © 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.
Extracellular matrix remodeling as a unique mechanism of expansion of periprostatic adipose tissue: implication for prostate cancer aggressiveness.
Estève D, Toulet A, Roumiguié M … +23 more , Bu D, Lacombe M, Péricart S, Belles C, Manceau C, Houël C, Ducoux-Petit M, Van Acker N, Dauvillier S, Jia Y, Hernandez M, Moutahir M, Franchet C, Doumerc N, Thoulouzan M, Le Gonidec S, Valet P, Malavaud B, Burlet-Schiltz O, Bouloumié A, Scherer PE, Milhas D, Muller C
J Pathol · 2026 May · PMID 41715916 · Publisher ↗
One of the most striking features of the adipose depot surrounding the prostate [periprostatic adipose tissue (PPAT)] is that its accumulation is independent of body mass index. Its volume varies considerably between ind...
One of the most striking features of the adipose depot surrounding the prostate [periprostatic adipose tissue (PPAT)] is that its accumulation is independent of body mass index. Its volume varies considerably between individuals, with some patients exhibiting abundant PPATs, which have been correlated to the occurrence of aggressive prostate cancer (PCa). However, abundant PPAT is not well defined at the biological level. We used a new statistical approach to define abundant PPAT by normalizing PPAT volume to prostate volume in a cohort of 351 patients using a linear regression model. Applying this definition, we confirmed the link between abundant PPAT and PCa aggressiveness, thereby validating our approach. At the biological level, we showed that abundant PPAT exhibited extensive extracellular matrix remodeling, notably of the collagen network, decreasing the mechanical constraints in hypertrophic adipocytes, leading to inflammation-free expansion. Degradation of the most abundant collagen in adipose tissue (AT), collagen VI, was associated with increased production of endotrophin, a signaling peptide derived from AT that was also elevated in the urine of patients with abundant PPAT confirming the clinical relevance of our results. These results highlight a unique mechanism of expansion of an adipose depot and open new mechanistic avenues to explain its role in prostate-related disorders. © 2026 The Pathological Society of Great Britain and Ireland.
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