The Journal Of Pathology[JOURNAL]
Sun
200 papers
Identifying therapeutic targets in low-grade serous ovarian carcinomas with no specific molecular profile.
Pishas KI, Cowley KJ, Marinovic E … +18 more , Köbel M, Llaurado-Fernandez M, Kim H, Bao SC, Mizikovsky D, Palpant NJ, Shrestha R, Vary R, Luu J, Meunier L, Semple T, Blancafort P, Golden E, Cohen PA, Carey MS, Campbell IG, Simpson KJ, Cheasley D
J Pathol · 2026 May · PMID 42138099 · Publisher ↗
Low-grade serous ovarian carcinoma (LGSOC) is a rare, indolent ovarian cancer subtype with limited effective therapies. Approximately 40% of cases lack canonical MAPK/ERK or PI3K/AKT/mTOR pathway alterations and are clas...
Low-grade serous ovarian carcinoma (LGSOC) is a rare, indolent ovarian cancer subtype with limited effective therapies. Approximately 40% of cases lack canonical MAPK/ERK or PI3K/AKT/mTOR pathway alterations and are classified as having no specific molecular profile (NSMP). These patients have poor responses to chemotherapy, MEK inhibitors, and hormonal therapies, highlighting the need for alternative strategies. This study aimed to identify novel therapeutic targets in NSMP LGSOC. A high-throughput drug screen of 3,436 compounds (including FDA-approved, clinically tested, and investigational agents) was conducted across 12 LGSOC and one control ovarian epithelial cell line. EGFR inhibitors emerged as selective hits in NSMP cell lines and were further tested in two NSMP and two MAPK-mutant lines in combination with standard-of-care chemotherapy agents, carboplatin and paclitaxel. EGFR expression was assessed using RNA sequencing, DNA methylation profiling, and immunohistochemistry in primary tumors, followed by survival analysis based on expression levels. Unsupervised clustering of drug response data revealed subtype-specific vulnerabilities, with EGFR inhibitors showing marked cytotoxicity in all five NSMP lines (robust Z-score ≤ -2), and minimal activity in MAPK- and USP9X-mutant lines. EGFR inhibitors (avitinib, AV-412) showed selective, low-dose synergy with standard-of-care chemotherapy in NSMP models, with minimal and inconsistent effects in MAPK-mutant lines. NSMP tumors showed elevated EGFR mRNA and EGFR protein expression, associated with poor survival, advanced disease stage, and peritoneal involvement, and inversely correlated with MAPK mutations. These findings position EGFR overexpression as a defining and targetable feature of NSMP LGSOC and support further preclinical validation of EGFR inhibitors as a treatment strategy for this understudied cancer subtype. © 2026 The Pathological Society of Great Britain and Ireland.
The prognostic significance of the IASLC grading system in ALK-positive invasive non-mucinous adenocarcinoma of the lung: correlation with clinicopathological features.
Gu D, Bao J, Chen H … +7 more , Chen S, Shi C, Guo X, Zhou X, Lei Z, Guo L, Yang Q
J Pathol Clin Res · 2026 May · PMID 42117497 · Full text
The prognostic value of the International Association for the Study of Lung Cancer (IASLC) grading system in anaplastic lymphoma kinase (ALK)-positive invasive non-mucinous adenocarcinoma (INMA) remains unclear, particul...
The prognostic value of the International Association for the Study of Lung Cancer (IASLC) grading system in anaplastic lymphoma kinase (ALK)-positive invasive non-mucinous adenocarcinoma (INMA) remains unclear, particularly in relation to the tumor immune microenvironment (TIME). This retrospective study included 108 patients with ALK-positive INMA. Tumors were graded according to the IASLC system. Clinicopathological features, progression-free survival (PFS), and overall survival (OS) were analyzed. Immunohistochemistry was used to assess PD-L1 expression and tumor-infiltrating lymphocytes (TILs), including CD4+, CD8+, and FoxP3+ regulatory T cells. Associations were evaluated using Kaplan-Meier analysis, Cox regression models, and correlation analyses. Higher IASLC grades were significantly associated with more aggressive pathological features, elevated PD-L1 expression, and shorter progression-free survival (PFS). Higher-grade tumors exhibited enhanced T-cell infiltration, predominantly driven by CD8+ T cells, while no significant difference in FoxP3+ Treg density was observed across grades. Notably, the CD4:CD8 ratio decreased, whereas the CD8:FoxP3 ratio increased with tumor grade, indicating a shift toward a CD8-dominant immune microenvironment. Importantly, this cytotoxic predominance occurred in parallel with elevated PD-L1 expression, suggesting an immune context consistent with adaptive immune resistance rather than effective anti-tumor immunity. The IASLC grading system effectively identifies a high-risk subgroup of ALK-positive INMA characterized by aggressive tumor behavior and a dynamically regulated immune microenvironment. High-grade tumors exhibit features of immune engagement coupled with checkpoint-mediated regulation, supporting a model of adaptive immune resistance. These findings underscore the necessity of combination therapeutic strategies that simultaneously target ALK and immune checkpoint modulation in high-grade INMA.
An oncogenic role for EBV-encoded BILF1 in nasopharyngeal carcinoma.
Wong AK, Rajendran V, Mundo L … +14 more , Wei W, Bell AI, Robinson M, Bellan C, Lazzi S, Leahy C, Rajadurai P, Liew YT, Prepageran N, Young LS, Lo KW, Murray PG, Paterson IC, Yap LF
J Pathol · 2026 May · PMID 42099008 · Publisher ↗
It is widely recognized that latent infection is the predominant mode of Epstein-Barr virus (EBV) infection in nasopharyngeal carcinoma (NPC) in which a specific set of latent genes is responsible for driving the develop...
It is widely recognized that latent infection is the predominant mode of Epstein-Barr virus (EBV) infection in nasopharyngeal carcinoma (NPC) in which a specific set of latent genes is responsible for driving the development of the disease. However, the expression of these latent genes does not adequately explain the various transformed phenotypes of NPC cells. Using an established high-throughput quantitative reverse transcription PCR array, we found that several EBV lytic genes were more widely expressed in primary NPC tissues than previously recognized. We focused on a lytic gene, BILF1, which encodes a constitutively active G protein-coupled receptor (GPCR). We showed that BILF1 was expressed in tumour cells from primary NPC tissues at both mRNA and protein levels, and in the absence of BZLF1 expression. RNA sequencing analysis of BILF1-expressing immortalised nasopharyngeal epithelial (NPE) cells demonstrated that the profile of BILF1-regulated genes significantly overlapped with gene signatures of micro-dissected NPC, indicating that the expression of BILF1 is relevant to the pathogenesis of NPC. In accordance with these observations, pathway analysis of the transcriptome of BILF1-expressing cells showed the involvement of BILF1 in key biological processes typically deregulated in NPC. To examine whether BILF1 expression influenced epithelial cell behaviour, functional studies showed that BILF1 enhanced cell proliferation, migration, invasion and colony formation. In addition, BILF1 increased AKT activation in NPE cells, which was responsible for the increase in cell migration. Taken together, our data convincingly point to an oncogenic role for BILF1 in NPC. © 2026 The Pathological Society of Great Britain and Ireland.
Genetic analysis of primary lung interdigitating dendritic cell sarcomas.
Ermakov MS, Filipe JF, Eidenhammer S … +4 more , Ott G, Halbwedl I, Kashofer K, Popper H
J Pathol · 2026 May · PMID 42092301 · Publisher ↗
Interdigitating dendritic cell sarcomas (IDCSs) are rare tumors that commonly arise in the hematopoietic system and rarely outside. The genetic drivers of IDCS carcinogenesis are unknown; therefore, therapeutic options a...
Interdigitating dendritic cell sarcomas (IDCSs) are rare tumors that commonly arise in the hematopoietic system and rarely outside. The genetic drivers of IDCS carcinogenesis are unknown; therefore, therapeutic options are limited. We investigated somatic gene mutations and copy-number alterations (CNAs) in nine IDCSs arising in the lung by whole-exome sequencing (WES) paired with shallow whole-genome sequencing (sWGS). Using a panel of immunohistochemical markers, follicular dendritic sarcomas and Langerhans cell sarcomas were excluded, and inflammatory myofibroblastic tumors were excluded based on morphology. The Ki-67 score was used to stratify the tumors into low-grade (≤ 20%) and high-grade (> 20%) tumors. The main question addressed by the study was whether genetic aberrations can be identified in IDCSs and whether these are druggable. High-grade IDCSs showed a higher fraction of genome altered by CNA (48.42%) than low-grade IDCSs (18.15%) and tended to have greater tumor mutation burden (7.56 versus 0.88 mut/Mb; not significant). Heterogeneous gains on chromosome 17 were characteristic of almost all IDCS cases (eight of nine cases, 89%), independent of grade. CNA in cancer-actionable genes was independent of clinicopathological characteristics and included amplifications in EGFR, MYC, MDM4, ERBB2, CCNE1, and BRAF and losses in MTAP, CDKN2A, CDKN2B, MLH1, and VHL, as well as homozygous losses in SMAD2/4, ATM, and TP53. Somatic gene mutations in cancer-related genes were identified in seven of nine IDCSs. No common driver mutations were identified. The heterogeneous genetic landscape suggests a mixed etiology of IDCS carcinogenesis and genomic instability in high-grade tumors. Distinct druggable biomarkers have been identified in almost all tumors, providing novel therapeutic options. © 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.
Unraveling the spatial landscape of dystrophinopathies: a transcriptomic approach to Becker and Duchenne muscular dystrophies.
Heezen LG, Mao Q, Nicolau S … +12 more , Rausell CN, van der Weerd J, Kueckelhaus J, Gokul Nath R, Diaz-Manera J, Kan HE, Niks EH, van Putten M, Aartsma-Rus A, Flanigan KM, Mahfouz A, Spitali P
J Pathol · 2026 Jul · PMID 42067897 · Full text
Dystrophinopathies are caused by pathogenic variants in the DMD gene, resulting in partial (Becker) or complete loss (Duchenne) of dystrophin. Becker (BMD) and Duchenne muscular dystrophy (DMD) are characterized by progr...
Dystrophinopathies are caused by pathogenic variants in the DMD gene, resulting in partial (Becker) or complete loss (Duchenne) of dystrophin. Becker (BMD) and Duchenne muscular dystrophy (DMD) are characterized by progressive muscle wasting, fatty replacement, fibrosis, and loss of function. To study histopathological changes, we used Visium spatial transcriptomics to profile skeletal muscle biopsies of patients affected by dystrophinopathy (n = 8) and healthy controls (n = 4). We estimated the proportion of cell types and their spatial localization across samples applying a deconvolution strategy using previously published single-nucleus RNA-sequencing data. We identified genes enriched in fat patches and cell types such as fibroadipogenic progenitors (FAPs) in areas of active pathology. Using expression data of ligand-receptor pairs, we highlight cell-cell communications leading to fibrotic and adipogenic lesions. Finally, analysis of gene expression gradients in areas of adjacent muscle and fat, allowed the identification of genes associated with muscle areas committed to becoming fat. © 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.
Transcriptomic comparative study between canalicular adenoma and HMGA2::WIF1 canalicular-like pleomorphic adenoma.
Alsugair Z, Champagnac A, Fieux M … +6 more , Philouze P, Ceruse P, Thamphya B, Pissaloux D, Tirode F, Benzerdjeb N
J Pathol · 2026 Apr · PMID 42052924 · Publisher ↗
Canalicular adenoma (CA) is a benign salivary gland tumor predominantly affecting the upper lip and is characterized by monomorphic epithelial cells arranged in branching cords within a loose and vascularized stroma. Unl...
Canalicular adenoma (CA) is a benign salivary gland tumor predominantly affecting the upper lip and is characterized by monomorphic epithelial cells arranged in branching cords within a loose and vascularized stroma. Unlike pleomorphic adenoma (PA), CA lacks a chondroid matrix and exhibits specific histological features, such as high cuboidal to columnar cells arranged in one to two cell layers. A recently identified PA subtype, named 'HMGA2-canalicular-like PA', mimics the morphology of CA but affects major salivary glands, and harbors the HMGA2::WIF1 fusion. Immunohistochemical markers including SOX10 positivity and p40/p63 negativity are shared between these entities, raising questions about their molecular differences. Therefore, the current study aimed to extensively compare the molecular profiles of CAs and HMGA2-canalicular-like PAs to better understand the mechanisms underlying their oncogenesis. In the present study, CAs and the HMGA2-canalicular-like PAs mostly shared similar histology and immunostaining, while the clinical presentations regarding tumor site and transcriptomic profiles were different. A novel finding was the overexpression of SOX2 in patients diagnosed with CA, in comparison to those diagnosed with HMGA2-canalicular-like PA. The CAs displayed significantly higher enrichment of hallmarks for Hedgehog signaling, IL2/STAT5 signaling, and apical surface, and significantly lower enrichment of hallmarks for apoptosis and mitotic spindle. Additionally, Gene Ontology enrichment analysis displayed significant enrichment of biological process for CAs in comparison to HMGA2-canalicular-like PAs for myofibril assembly, muscle filament sliding, actin-myosin filament sliding, and sarcomere organization. CAs and HMGA2-canalicular-like PAs exhibited similar histology and immunostaining but differed significantly in tumor site and transcriptomic profiles. The latter revealed significant activation of muscle-related transcriptional pathways, and overexpression of SOX2 in CAs. © 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.
Immunological mechanisms underlying the clinical heterogeneity of Kikuchi disease: the potential role of atypical memory B cells.
Yu SC, Chang KC, Chen TC … +2 more , Chen CN, Yang TL
J Pathol · 2026 Apr · PMID 42052902 · Publisher ↗
Building on our previous research, which classified Kikuchi disease into three subtypes based on predominant symptoms and fever status - febrile type, febrile lymphadenopathy (FebLAP), and afebrile lymphadenopathy (aLAP)...
Building on our previous research, which classified Kikuchi disease into three subtypes based on predominant symptoms and fever status - febrile type, febrile lymphadenopathy (FebLAP), and afebrile lymphadenopathy (aLAP) - we further investigated the underlying mechanisms contributing to their distinct clinical differences. Using NanoString nCounter technology, we analyzed the gene expression profiles of 35 Kikuchi disease lymph node specimens and compared them across the subtypes. Compared with the febrile type, aLAP exhibited higher AICDA expression, a trend observed in both germinal center positive and negative cases. The aLAP specimens also showed higher expression of B-cell markers; however, CD20 immunohistochemical staining did not reveal an increased number of B cells in aLAP. We therefore hypothesize that aLAP contains a higher proportion of atypical memory B cells, characterized by elevated AICDA and B-cell marker expression compared with other B-cell subsets. Immunohistochemical staining demonstrated that IRTA1+ atypical memory B cells were present in 64% (23/36) of aLAP cases, significantly higher than in FebLAP (0/8, 0%) and the febrile type (2/11, 18%) (p < 0.001). This finding confirms that aLAP is more likely to contain atypical memory B cells compared with the other subtypes. Pathway analysis revealed that the febrile type upregulates pathways associated with TLR2 and TLR4 signaling and neutrophil degranulation, while aLAP upregulates the TNFR2 non-canonical NF-κB pathway. RNAscope in situ hybridization demonstrated higher TLR4 expression in the febrile type compared with the aLAP type. These findings suggest that the triggering microbes for each subtype may differ, leading to distinct immune responses and clinical presentations. Overall, these results provide new insights into the immunopathogenesis of Kikuchi disease and highlight the potential role of atypical memory B cells in shaping its distinct clinical presentations. © 2026 The Pathological Society of Great Britain and Ireland.
Tubal ligation exacerbates ovulation-driven TP53 mutagenesis and p53 signatures by depleting protective menstrual hemoglobin.
Subramani K, Su CC, Wang JH … +4 more , Huang HS, Hsu CS, Chen PC, Chu TY
J Pathol · 2026 Jul · PMID 42052633 · Publisher ↗
The fallopian tube epithelium (FTE) is the primary tissue of origin for ovarian high-grade serous carcinoma (HGSC), with ovulation implicated as a key risk factor. TP53 mutations, a hallmark of HGSC and its precursor les...
The fallopian tube epithelium (FTE) is the primary tissue of origin for ovarian high-grade serous carcinoma (HGSC), with ovulation implicated as a key risk factor. TP53 mutations, a hallmark of HGSC and its precursor lesions, such as p53 signature, are predominantly CG>TA substitutions attributed to cytidine deamination. We previously demonstrated that ovulatory follicular fluid (FF) released reactive oxygen species (ROS), which activate activation-induced cytidine deaminase (AID) and promote TP53 mutagenesis in FTE. Here, we demonstrate that hemoglobin (Hb) originating from retrograde menstruation acts as an extracellular ROS scavenger, attenuating AID-mediated TP53 deamination in fallopian tube fimbriae, both in vitro and in vivo. Peritoneal fluid from tubal-ligated women exhibited significantly lower Hb, higher ROS, and elevated hypoxanthine phosphoribosyl transferase (HPRT) mutagenic activity compared to nonligated controls (p < 0.004). Histopathological analysis of 206 fallopian tubes from 119 women undergoing opportunistic salpingectomy further revealed a significantly higher frequency of p53 signatures in ligated tubes (0.22 ± 0.64 lesions per fimbria) than in nonligated tubes (0.07 ± 0.31 lesions per fimbria) (p = 0.017). Multivariate analysis identified tubal ligation as the sole reproductive factor independently associated with p53 signatures [odds ratio (OR) = 3.32; 95% CI: 1.15-9.57]. Our findings indicate that retrograde menstrual Hb mitigates ovulation-associated ROS stress, thereby reducing AID-mediated TP53 mutagenesis in the FTE. This study uncovers a physiological, protective role for menstruation against ovulatory oxidative damage and its mutagenic consequences, while demonstrating that tubal ligation disrupts this endogenous antioxidant mechanism, resulting in an increased burden of p53 signature lesions. © 2026 The Pathological Society of Great Britain and Ireland.
Reduced folate receptor alpha (FOLR1) protein expression in fallopian tubes from premenopausal women: implications for the FOLR1 CDx assay for mirvetuximab-soravtansine therapy.
Nasdala A, Kandt LD, Radner M … +8 more , Schaumann N, Gronewold M, Hillmann P, Christgen H, Hachenberg J, Kuehnle E, Hartmann C, Christgen M
J Pathol Clin Res · 2026 May · PMID 42023640 · Full text
Mirvetuximab-soravtansine (MIRV-S) is an antibody-drug conjugate targeting folate receptor alpha (FOLR1). MIRV-S is approved for the treatment of FOLR1-positive, platinum-resistant ovarian carcinoma. Patient eligibility...
Mirvetuximab-soravtansine (MIRV-S) is an antibody-drug conjugate targeting folate receptor alpha (FOLR1). MIRV-S is approved for the treatment of FOLR1-positive, platinum-resistant ovarian carcinoma. Patient eligibility is determined by immunohistochemistry (IHC) using a companion diagnostic (CDx) assay (FOLR1-2.1, Ventana). This assay requires on-slide positive controls (OPCs) to aid FOLR1 evaluation. The manufacturer recommends normal fallopian tube (NFT) tissue for OPCs. Estrogen receptor signaling represses FOLR1 in cell culture models. It is unknown whether hormonal factors, such as menopausal status, also impact on FOLR1 immunoreactivity in NFTs used as OPCs. To address this question, we studied FOLR1 protein expression in NFTs (n = 51) from women aged 26-83 years. IHC was performed with the FOLR1-2.1 CDx assay. Immunoreactivity at apical and basolateral cell membranes was assessed using H-scores (aH-score and bH-score respectively). Overall FOLR1 expression was evaluated using a combined H-score (cH-score; i.e. aH- and bH-scores added together). Immunoreactivity scores in pre-, peri-, and postmenopausal age groups were compared with the chi-square test for trends. NFTs showed variable FOLR1 protein expression [median aH-score: 152.5, interquartile range (IQR): 120-175; median bH-score: 35, IQR: 7-85; median cH-score: 195, IQR: 140-245]. Apical immunoreactivity was age-independent (p = 0.619), but low or absent basolateral immunoreactivity (bH-score <35) was associated with premenopausal age (p = 0.018). Low overall FOLR1 expression (cH-score <195) was also associated with premenopausal age (p = 0.037). In conclusion, NFTs show an age-dependent FOLR1 expression pattern, which likely reflects hormonal repression of FOLR1 in premenopausal women. NFT tissue from postmenopausal women is appropriate and meets the requirements for the current FOLR1 CDx assay.
WINTER MEETING, The Microenvironment & Disease, 8th Joint Meeting with the Royal Society of Medicine, 217th Scientific Meeting of the Pathological Society of Great Britain & Ireland, 20-21 January 2026.
J Pathol · 2026 Apr · PMID 42008097 · Publisher ↗
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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.
HISTAI: a valuable dataset with a valuable lesson.
Hewitt KJ, Reitsam NG, Foersch S … +3 more , Erber R, Zeng Q, Kather JN
J Pathol Clin Res · 2026 May · PMID 41986917 · Full text
The application of artificial intelligence in computational pathology depends on both robust algorithms and high-quality, clinically reliable data. Progress in this field has been limited by the scarcity of large, divers...
The application of artificial intelligence in computational pathology depends on both robust algorithms and high-quality, clinically reliable data. Progress in this field has been limited by the scarcity of large, diverse, and well-validated whole slide image (WSI) datasets. To address this gap, HISTAI introduced an open-source resource comprising over 112,000 WSIs across multiple organ systems with associated clinical metadata. Here, we present a pathologist-led evaluation of label accuracy, metadata completeness, and dataset composition across 328 selected cases from this resource. Although HISTAI reports 47,279 cases, we identified only 44,564 unique cases after accounting for missing entries and duplicate records. Basic demographic information, including age and sex, was available for only 55% of cases. Dataset composition was uneven, with dermatopathology accounting for 47.1% of cases and gastrointestinal pathology for 24.0%; however, primary specialty was explicitly reported for only 39.6% of cases, obscuring this imbalance within the provided metadata. Notably, clinical ground truth is recorded in the Conclusion column. Concordance between the dataset's Conclusion and Diagnosis fields was observed in only 20.7% of cases, while 27.1% contained conflicting diagnoses. In a focused review of 198 cases, 30.3% were found to contain unclear or ambiguous diagnostic conclusions, including eight cases in which the diagnosis was incorrect. Assessment of molecular annotation revealed that only 18.9% of analyzed lung and colorectal cancer cases included molecular information. Furthermore, among adult-type diffuse gliomas, none of the 55 cases met current World Health Organisation Classification of Tumors of the Central Nervous System 5th Edition (WHO CNS5) diagnostic criteria, with IDH mutation status reported in only 15 cases. Together, these findings highlight substantial ambiguities in ground-truth labeling, incomplete molecular annotation, and limited documentation of dataset provenance and ethical oversight. While HISTAI represents a valuable open-source resource, its effective and responsible use requires careful clinical validation and close collaboration between computational researchers and pathologists.
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.
MET fusions and splicing variants in glioma: a landscape integrating clinical, pathological, and survival features.
Fang Z, Zheng C, Wang P … +9 more , Liu X, Liu L, Li G, Dong J, Chen Q, Zhang D, Feng Y, Zhang Y, Bao Z
J Pathol Clin Res · 2026 May · PMID 41910014 · Publisher ↗
MET alterations, including MET fusions and splicing variants (F/SVs), are linked to glioma progression, but the clinical features remain underexplored since the 2021 WHO classification of tumors of the CNS. We aimed to s...
MET alterations, including MET fusions and splicing variants (F/SVs), are linked to glioma progression, but the clinical features remain underexplored since the 2021 WHO classification of tumors of the CNS. We aimed to systematically depict the MET F/SVs and patient characteristics in a multicenter cohort focusing on clinical, pathological, and survival features. We studied data from 1,041 patients with MET F/SVs data from the public Chinese Glioma Genome Atlas database and the TruSight Tumor 170 study. Clinical outcomes were evaluated based on the RANO criteria. We used chi-square and Fisher's exact tests for variable analysis. Kaplan-Meier analysis was used to assess survival trends, while univariate and multivariate analyses revealed the prognostic value of MET F/SVs. Immunohistochemical staining was performed to demonstrate the MET expression level. Among the 1,041 patients, 49 patients had F/SVs (4.70%), and 23 had ZM fusion (PTPRZ1-MET fusion gene; 2.21%). Among the 67 recurrent grade 4 astrocytomas, the proportions of F/SVs (11.94%, n = 8) and ZMs (5.97%, n = 4) were the highest. MET F/SVs were significantly associated with malignant clinical outcomes in the IDH-mutant astrocytoma cohort, with a frequency of 5.04% (18/357) across all WHO grades. Multivariate analysis revealed that the MET F/SVs were independently associated with worse survival in astrocytoma patients [overall survival (OS): p = 0.0011; progression-free survival (PFS): p = 0.004]. ZM fusion was associated with a worse prognosis in both astrocytoma (OS p < 0.001, PFS p < 0.001) and glioblastoma (OS, p = 0.252; PFS, p = 0.010) patients. We highlight the utmost relevance of ZM fusion as an adverse prognostic factor in astrocytoma (11/382, 2.88%) and glioblastoma grade 4 (11/401, 2.74%) patients and suggest that the grading of these tumors should be refined.
Molecular subtype concordance and metastatic patterns in muscle-invasive bladder cancer.
Olah C, Juhász D, Váradi M … +8 more , Reis H, Al-Nader M, Mahmoud O, Grünwald BT, Grünwald V, Hadaschik B, Nyirády P, Szarvas T
J Pathol Clin Res · 2026 May · PMID 41896709 · Publisher ↗
Molecular subtypes are potential prognostic and predictive tools in muscle-invasive bladder cancer (MIBC). However, subtype concordance between primary tumors and metastases, as well as subtype-specific differences in me...
Molecular subtypes are potential prognostic and predictive tools in muscle-invasive bladder cancer (MIBC). However, subtype concordance between primary tumors and metastases, as well as subtype-specific differences in metastatic patterns, remain poorly characterized. The present study aimed to evaluate the concordance of molecular subtypes between primary tumors and matched lymph node (LN) metastases and to explore their association with metastatic patterns. Gene expression-based molecular subtypes were determined according to the five-tiered Lund Taxonomy in 182 primary tumor samples and 34 matched LN metastases from patients with MIBC who underwent upfront radical cystectomy. Subtypes identified in the primary tumors were compared with those in matched positive LNs and patterns of distant metastasis were analyzed. In addition, the association between molecular and histological subtypes was also investigated. We found an overall 62% subtype concordance between primary tumors and corresponding LN metastases, with complete concordance in the basal/squamous subtype, lower concordance in the luminal subtypes (genomically unstable: 67%; urothelial-like: 57%), and low concordance (33%) in the mesenchymal-like (Mes) subtype. Luminal subtypes were associated with LN-only metastases and less frequent distant metastases. In contrast, the Mes subtype was associated with a higher rate of distant metastases (43%), and more frequent multiorgan involvement (≥3 organs: 40%). Higher expression of the mesenchymal gene CDH2 and the neuronal-differentiation genes GNG4 and ENO2 was associated with a higher number of metastatic sites. Gene expression-based molecular subtypes may change between primary MIBCs and matched LN metastases, and these differences appear to be subtype-dependent. Mes subtype and the expression of CDH2 as well as GNG4 and ENO2 are associated with more frequent and extensive metastases, indicating highly aggressive forms of MIBC.
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