The Journal of Pathology最新文献

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.

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.

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.

The conceptualization of mitochondria, previously restricted to their function as cellular 'powerhouses', has evolved to recognize their function as central coordinating hubs for the orchestration of cancer cell metabolism, signaling, and fate determination. Within the context of lung cancer, encompassing both non-small cell lung cancer and small cell lung cancer, these organelles undergo profound functional and structural dysregulation integral to tumor initiation, progression, and most critically, therapeutic resistance. This review presents a synthesis of the burgeoning field of mitochondrial inhibitors as a strategic approach for lung cancer treatment, achieved by synthesizing detailed mechanistic and preclinical data into an evidence-graded framework. This document first provides a delineation of the fundamental dysregulation of mitochondrial functions in lung cancer, inclusive of metabolic reprogramming toward oxidative phosphorylation dependency, particularly in distinct genetic contexts (e.g., LKB1, SWI/SNF-mutant). Subsequent sections systematically categorize and analyze the major classes of mitochondrial inhibitors predicated upon their mechanisms of action, including electron transport chain inhibitors, pro-apoptotic agents (e.g., B-cell lymphoma 2/B-cell lymphoma xL inhibitors), and modulators of metabolism and dynamics. A critical focus is applied to the role of these agents in the supersession of acquired resistance to established therapies, such as epidermal growth factor receptor-tyrosine kinase inhibitors, chemotherapy, and immunotherapy. The translational landscape is consolidated herein by summarizing key clinical trials (including terminations precipitated by toxicity) and distinguishing small cell lung cancer specific vulnerabilities. Finally, the significant challenges of on-target, off-tumor toxicity and the crucial necessity for predictive biomarkers are addressed. Through the synthesis of these disparate fields into a unified, clinically oriented framework, it is posited that targeting mitochondrial vulnerabilities possesses the potential to overcome longstanding therapeutic hurdles in lung cancer. © 2026 The Pathological Society of Great Britain and Ireland.

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.

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.

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.

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.

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.