J. Pathol. [JOURNAL]
Sun
200 papers
Clinicopathological significance of loss of Y chromosome in male meningiomas.
Sakaguchi M, Horie M, Ito Y … +5 more , Tanaka S, Ikeda H, Nakada M, Yoshizawa A, Maeda D
J Pathol · 2026 May · PMID 41715910 · Full text
Male meningiomas, comprising approximately 30% of all meningiomas, are more frequently high-grade and associated with poorer clinical outcomes compared to their female counterparts. Although Y chromosome alterations have...
Male meningiomas, comprising approximately 30% of all meningiomas, are more frequently high-grade and associated with poorer clinical outcomes compared to their female counterparts. Although Y chromosome alterations have been studied in various male-predominant tumors, a limited number of studies have evaluated their role in meningiomas. To evaluate the clinicopathological significance of Y chromosome loss in male meningiomas, we assessed the frequency of loss of the Y chromosome (LOY) using droplet digital polymerase chain reaction in combination with multiplex ligation-dependent probe amplification on tumor DNA from 93 male meningioma samples. LOY, detected in nine cases (9.7%), was significantly associated with a higher World Health Organization tumor grade (grade 2: 55.6% versus 14.3%; grade 1: 44.4% versus 85.7%; p = 0.009) and loss of the NF2 gene-encoded protein, moesin-ezrin-radixin-like protein (merlin) (loss: 88.9% versus 50.0%; retained: 11.1% versus 50.0%; p = 0.035). RNA in situ hybridization targeting KDM5D on formalin-fixed paraffin-embedded tissue sections demonstrated a sensitivity of 100% (9/9) and a specificity of 76.2% (64/84) for LOY detection, supporting its utility as a screening modality. Moreover, spatial transcriptomic analysis revealed significant differences in the expression of genes associated with epithelial-mesenchymal transition and extracellular matrix organization between LOY and non-LOY meningioma tumor cells. Our findings emphasize the presence of atypical pathological features and distinct transcriptional profiles in LOY-associated meningiomas. © 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.
Xenium-based spatial transcriptomic analyses uncover prognosis-associated heterogeneity in the tumor microenvironment (TME) of angioimmunoblastic T-cell lymphoma (AITL).
Dong J, Xiao X, Nong L … +5 more , Xue X, Wang L, Sun X, Jiang K, Feng X
J Pathol · 2026 May · PMID 41711078 · Publisher ↗
Angioimmunoblastic T-cell lymphoma (AITL) exemplifies a neoplasm characterized by prominent inflammatory infiltration and robust immune responses in the tumor microenvironment (TME). The pathophysiology of refractory/rec...
Angioimmunoblastic T-cell lymphoma (AITL) exemplifies a neoplasm characterized by prominent inflammatory infiltration and robust immune responses in the tumor microenvironment (TME). The pathophysiology of refractory/recurrent (RR) AITL remains poorly understood due to profound intratumoral heterogeneity and complex TME features, contributing to limited therapeutic efficacy. Using Xenium-based spatial transcriptomics on 10 clinical samples, we compared RR AITL with treatment-responsive [non-refractory/recurrent event in 3 years (NR)] cases to map the TME architecture. We identified a novel cluster of NEIL3+ (Nei Like DNA Glycosylase 3) T-follicular helper (Tfh) cells, which exhibited stem-like characteristics at the transcriptional level, featuring self-renewal and multilineage differentiation capacity, and were highly enriched in RR tumors. Furthermore, we found major differences in immune cell organization between NR and RR microenvironments: RR cases were dominated by B cells primed for adaptive immunity and myeloid cells driving angiogenesis, whereas NR cases exhibited a chemokine-mediated regulatory landscape. These findings provide comprehensive characterization of the TME ecosystem in AITL and reveal potential therapeutic targets for high-risk RR AITL patients. © 2026 The Pathological Society of Great Britain and Ireland.
Fatty acid and cysteine metabolic interplay regulate ferroptosis and highlight xCT as a selenium-chrysin target in breast carcinoma.
Hipólito A, Abreu B, Gonçalves J … +8 more , Silva F, Martins C, Gouveia L, Pereira SA, Bonifácio VDB, André S, Mendes C, Serpa J
J Pathol · 2026 May · PMID 41706708 · Publisher ↗
Cancer metabolic remodeling impacts the entire network of metabolic pathways, and strategies that target various points within this system could contribute to successfully abrogating cancer cell survival. Fatty acids (FA...
Cancer metabolic remodeling impacts the entire network of metabolic pathways, and strategies that target various points within this system could contribute to successfully abrogating cancer cell survival. Fatty acids (FAs) are essential to cancer cells because they support membrane biosynthesis during proliferation and provide energy during metabolic stress. Fatty acid transport protein 1 (FATP1)has been shown to mediate FA uptake in breast carcinoma (BC). The light chain of cysteine/glutamate amino acid exchange transporter system Xc (xCT)is crucial for the uptake of cysteine serving as a carbon and sulfur source that contributes to redox control, bioenergetics, and biosynthesis. In this study, targeting of FA and cysteine metabolic pathways was shown to be a potential strategy for managing BC by inhibiting FATP1 and xCT with arylpiperazine 5k and selenium-chrysin (SeChry), respectively. In BC cell lines, FATP1 expression is controlled by estrogen receptor β (ER-β) and promotes the accumulation of lipid droplets (LDs), which is associated with triple-negative breast carcinoma (TNBC) cells showing increased rates of cell proliferation, two-dimensional directional cell migration, and higher chemoresistance. Expression of xCT was also associated with the TNBC molecular BC subtype. In BC specimens, an association between FATP1 and xCT expression was observed. In vitro, SeChry induced ferroptosis in BC cells by targeting xCT and cysteine reliance and ultimately inducing cell death. In xenograft BC tumors, arylpiperazine 5k abrogated the effects of SeChry encapsulated in polyurea dendrimers functionalized with folate (SeChry@PURE-FA) by reducing intracellular FA and rescuing ferroptosis. In vitro, SeChry sensitized BC cells to cisplatin and may therefore serve as an alternative in combination therapy. Overall, our study confirmed FATP1 as a marker and xCT as both a marker and a target in BC, particularly in TNBC. Induction of ferroptosis by interfering with xCT function may provide an opportunity to improve BC treatment, and a therapeutic approach using SeChry@PURE-FA is a promising strategy. © 2026 The Pathological Society of Great Britain and Ireland.
High-grade endometrial stromal sarcoma is closely related to BCOR-altered sarcomas of the soft tissue and kidney rather than to other uterine sarcomas: implications for uterine sarcoma classification.
Arciuolo D, Patrizi S, Alaggio R … +16 more , Travaglino A, Scaglione G, Vallese S, Santoro A, Pedace L, Nardini C, Milano GM, Locatelli F, Giovannoni I, Barresi S, Pedone Anchora L, Fedeli C, Ciccarone F, Inzani F, Miele E, Zannoni GF
J Pathol · 2026 May · PMID 41706043 · Publisher ↗
High-grade endometrial stromal sarcoma (HGESS), which was not recognized as a distinct entity in the third edition of the World Health Organization (WHO) classification and was therefore included in the undifferentiated...
High-grade endometrial stromal sarcoma (HGESS), which was not recognized as a distinct entity in the third edition of the World Health Organization (WHO) classification and was therefore included in the undifferentiated uterine sarcoma (UUS) category, was reestablished as a separate entity in the fourth edition. HGESS shares BCL-6 corepressor (BCOR) alterations with undifferentiated small round-cell sarcoma (USRCS) of the soft tissue and clear cell sarcoma of the kidney (CCSK). This study aims to perform a comparative morphological, immunohistochemical, and molecular analysis of HGESS, UUS, USRCS, and CCSK. Consecutive uterine sarcomas diagnosed as HGESS or UUS were reviewed and compared to BCOR-altered USRCS (n = 28) and CCSK (n = 10) (including both previously published and new cases). Molecular, DNA methylome (DNAm), and copy number variation (CNV) analyses were performed. DNAm data of 93 previously analyzed uterine and round-cell tumors of several different types were used for clustering analysis. Twenty-five uterine sarcomas (six HGESS and 19 UUS) were included; five of six HGESS cases showed fusions associated with BCOR alterations (YWHAE::NUTM2A/B, EPC1::KDM2B, ZC3H7B::BCOR); UUS showed no fusions (n = 15) or fusions unrelated to BCOR alterations (n = 4). All USRCS and CCSK cases showed either BCOR-ITD or BCOR alteration-related fusions. BCOR-altered HGESS showed broad morphological and immunophenotypic overlap with USRCS and CCSK. DNAm analysis showed that BCOR-altered HGESS, USRCS, and CCSK clustered together, separately from all other tumor types. The non-BCOR-altered HGESS showed a JAZF1::SUZ12 fusion and arose from a low-grade endometrial stromal sarcoma component. CNVs were found in 15/16 uterine sarcomas and in 16/36 USRCS/CCSK cases. BCOR-altered HGESS appeared to be closely related to BCOR-altered USRCS and CCSK rather than to other uterine sarcomas. We suggest that HGESS with BCOR alterations may warrant reclassification as 'BCOR-altered uterine sarcomas'. © 2026 The Pathological Society of Great Britain and Ireland.
The immune-metabolism interactome in efferocytosis: a new paradigm for the central nervous system diseases revealed by single-cell sequencing analysis.
Zhang H, Li W, Xiao P … +3 more , Lu Z, Tian Y, Xu Y
J Pathol · 2026 May · PMID 41693397 · Publisher ↗
Efferocytosis is a process that maintains tissue homeostasis by removing apoptotic cells (ACs) by professional or non-professional phagocytes. The intricate process can be categorized into recognition of ACs, engulfment...
Efferocytosis is a process that maintains tissue homeostasis by removing apoptotic cells (ACs) by professional or non-professional phagocytes. The intricate process can be categorized into recognition of ACs, engulfment of ACs, and degradation of efferosomes. Aberrations in efferocytosis result in inadequate clearance of ACs, leading to prolonged inflammation that is implicated in the development and progression of various human diseases. Most central nervous system (CNS) diseases are associated with dysregulation of inflammatory homeostasis. Microglia, the resident immune cells of the CNS, play a primary role in efferocytosis in the brain, which is essential for maintaining the homeostasis of the internal environment. In this review, we summarize the current knowledge of the basic processes of efferocytosis and its indispensable role in the developing and aging brain. Additionally, we discuss the regulatory role of immune-metabolism crosstalk and the insights from single-cell sequencing analysis in dissecting microglial heterogeneity during efferocytosis. We also focus on recent discoveries regarding the critical role of efferocytosis in several CNS diseases, including cerebral ischemia, intracerebral hemorrhage, traumatic brain injury, major depressive disorder, glioblastoma multiforme, Alzheimer's disease, and Parkinson's disease. Finally, we outline potential therapeutic strategies and existing challenges, emphasizing the need for context-specific targeting to improve CNS disease outcomes. © 2026 The Pathological Society of Great Britain and Ireland.
Mitochondrial reprogramming in lung cancer: a therapeutic vulnerability and a strategy for reversing drug resistance.
Park WH
J Pathol · 2026 Jun · PMID 41693386 · Publisher ↗
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 metaboli...
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.
Exploring adenoid basal carcinoma to squamous cell carcinoma of the uterine cervix transformation using spatial transcriptomics.
Ma R, Jin Y, Lei Z … +6 more , Sun P, Wang J, Yang H, Cheng Y, Guo T, Guo L
J Pathol · 2026 May · PMID 41670056 · Publisher ↗
Adenoid basal carcinoma (ABC) is a rare cervical tumor that generally carries a favorable prognosis. However, when ABC is mixed with an invasive carcinoma, particularly squamous cell carcinoma (SCC), the prognosis is poo...
Adenoid basal carcinoma (ABC) is a rare cervical tumor that generally carries a favorable prognosis. However, when ABC is mixed with an invasive carcinoma, particularly squamous cell carcinoma (SCC), the prognosis is poor. Moreover, transitional nests (TNs), which are frequently observed in mixed tumors, likely represent an intermediate stage between ABC and SCC. Therefore, elucidating the relationship between these subtypes through histomorphological and molecular biological analysis is essential for guiding effective therapeutic strategies. To this end, we conducted a retrospective study involving 20 cases of ABC, most of which were accompanied by one or more of the three subtypes of SCC, TN, and high-grade squamous intraepithelial lesion (HSIL). Histomorphological analysis revealed that TN were frequently located in the transitional zones between classic ABC and SCC, while maintaining a distinct spatial separation from classic HSIL regions. The central areas of TNs exhibit cytological atypia resembling that of SCC, often surrounded by a cuff-like arrangement of basaloid cells, which express the basal cell marker BCL-2. We performed digital spatial profiling (DSP) analysis on four cases exhibiting concurrent ABC, TN, SCC, and HSIL. We identified the differentially expressed genes CK13 and SCCA2, which distinguish TN from ABC, SCC, and HSIL, and validated these findings by immunohistochemistry. This study investigates the relationship between ABC and SCC and demonstrates the disease spectrum of ABC progressing to SCC through a transitional phase represented by TNs. This finding provides novel insights into the pathogenesis of SCC. In addition, we believe that total hysterectomy may be an appropriate strategy when ABC is accompanied by a TN. However, larger-scale studies will still be needed in the future to guide clinical decisions because of the limited sample size. © 2026 The Pathological Society of Great Britain and Ireland.
Crohn's lymphoid aggregates with endothelial clusters colocalise with submucosal fibrosis in fibrostenosing Crohn's disease.
Glinka M, Wickham GJ, Nadalin F … +15 more , Kirkwood KJ, Caldwell H, Wicks M, Hill B, Houghton D, Sharghi M, Kefayat A, Haggarty B, Burger A, Baldock RA, Adams DJ, Papatheodorou I, Bankhead P, Din S, Arends MJ
J Pathol · 2026 Apr · PMID 41645585 · Full text
Crohn's disease (CD) involves chronic transmural inflammation of the intestines, leading to progressive wall fibrosis with stenosis and luminal obstruction, predominantly in the terminal ileum. Fibrosis is a significant...
Crohn's disease (CD) involves chronic transmural inflammation of the intestines, leading to progressive wall fibrosis with stenosis and luminal obstruction, predominantly in the terminal ileum. Fibrosis is a significant therapeutic challenge, thus improved understanding of localisation, cellular composition, and cell-cell interactions in CD fibrostenosing lesions (FSLs) may identify potential targetable pathways. Using CD FSL patient resection samples, we identify and quantify novel pathological changes in structure, collagen, and cell numbers for each ileal layer (mucosa, muscularis mucosae, submucosa, muscularis propria, serosa). In addition, fresh resection ileal samples were single-cell RNA (scRNA)-sequenced, validating the cell types and cell-cell interactions. We found significantly increased collagenous fibrosis expansion, significantly increased infiltration of lymphocytes, macrophages, endothelium, and Crohn's lymphoid aggregates (CLAs) in all layers, except for the ulcerated mucosa. Importantly, endothelial cells accumulate in clusters around CLAs, and scRNA-seq data demonstrated ligand-receptor intercellular signalling interactions between endothelium, B and T lymphocytes, macrophages, and myofibroblasts via multiple pathways that included GAS, SELL, and SELPLG, among many others. The highest levels of fibrotic collagen and CLAs with accumulated endothelium were observed in submucosa, followed by serosa, demonstrating colocalisation and correlation of endothelial-CLAs with collagen that is consistent with CLAs having a role in promoting collagenous fibrosis that requires further investigation. © 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.
Roles of THBS2 fibroblasts in malignant transformation of colorectal polyp to cancer.
Han Q, Liu L, Wang J … +7 more , Deng J, Tang J, Lu Y, Lai X, E F, Lai M, Zhang H
J Pathol · 2026 Apr · PMID 41640327 · Publisher ↗
Colorectal cancer (CRC) typically originates from benign polyps within the colorectum. However, the mechanisms driving this transformation remain poorly understood. In this study, we employed a comprehensive multi-omics...
Colorectal cancer (CRC) typically originates from benign polyps within the colorectum. However, the mechanisms driving this transformation remain poorly understood. In this study, we employed a comprehensive multi-omics approach, incorporating multiplex immunostaining and adeno-associated virus (AAV)-mediated mouse models, to systematically dissect the key drivers of malignant transformation in CRC. Our investigations revealed a dynamic and stage-specific expression pattern of thrombospondin 2 (encoded by the gene THBS2), characterized by significantly downregulated expression during the polyp stage, followed by markedly upregulated expression in malignant CRC tissues compared to healthy colon tissue. Intriguingly, THBS2 expression was primarily localized within a distinct fibroblast subpopulation, with THBS2 fibroblasts exhibiting a tumor-tropic infiltration pattern. Through a series of analyses, we hypothesized that THBS2 fibroblasts may play a role in coordinating CRC progression via the THBS2-CD36 and THBS2-SDC1 pathways. Furthermore, depletion of THBS2 fibroblasts enhanced polyp formation but suppressed tumor formation in a thymidine kinase 1/ganciclovir/azoxymethane/dextran sulfate sodium mouse model. The comprehensive multi-omics atlas and complementary data presented here will advance our understanding of the mechanisms underlying CRC malignant transformation and may provide a potential therapeutic target. © 2026 The Pathological Society of Great Britain and Ireland.
Characterisation of bacteria-induced colitis and its modulation by probiotics in naked mole rats: a new mammalian model for acute inflammatory disease.
Hart DW, Ng AS, Gazińska P … +12 more , Goldin R, Gopal P, O'Dell N, Zargar A, Pytowski L, Montazid S, Bardella C, East JE, Tomlinson IP, Koch N, Bennett NC, Irshad S
J Pathol · 2026 Apr · PMID 41640304 · Full text
Enteropathogenic bacteria are a major cause of morbidity and mortality globally. While mouse models have been indispensable in advancing our understanding of infectious enteric diseases, key differences in intestinal mic...
Enteropathogenic bacteria are a major cause of morbidity and mortality globally. While mouse models have been indispensable in advancing our understanding of infectious enteric diseases, key differences in intestinal microbiota and immunobiology between mice and humans underscore the need for alternative mammalian models that better recapitulate human disease states. The naked mole rat (NMR), the longest-lived rodent and a model of healthy ageing, presents a unique opportunity. It possesses an exceptionally robust intestinal barrier, an abundance of goblet cells, a thicker mucin layer, and reduced gut permeability compared to mice. Additionally, the NMR gut microbiome exhibits compositional and functional features shared with human centenarians and traditional-lifestyle populations (e.g. Hadza hunter-gatherers), including an enrichment of health-associated taxa and metabolic pathways. Here, we leverage this model to show that systemic Citrobacter braakii infection is associated with colonic inflammation and epithelial injury that closely mimics human haemorrhagic colitis. Infected NMRs develop mucosal erosions, ulcerations, depletion of goblet cells, expansion of proliferative compartments, and active inflammation in the lamina propria. Without intervention, systemic inflammation associated with sepsis ensues and results in high mortality. Furthermore, we demonstrate the utility of this model for therapeutic testing by showing a strong effect of a probiotic cocktail comprising lactobacilli, bifidobacteria, streptococci, and enterococci. Treatment with this cocktail promoted mucosal healing, restored intestinal homeostasis, and exerted an anti-inflammatory effect. Taken together, we establish the NMR as a translatable model for investigating disease mechanisms in infectious colitis, including disruptions in mucosal barrier permeability, gut microbial ecology, and local and systemic immune regulation, as well as for testing functional probiotic strains as potential therapeutics. © 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.
Lymphatic topology reveals a novel intranodal lympho-venous shunt.
Sukhbaatar A, Mishra R, Nakamura A … +3 more , Mori S, Sugiura T, Kodama T
J Pathol · 2026 Apr · PMID 41635937 · Full text
Understanding the lymphatic network is crucial for immunological research. Currently, a complete map of lymphatic drainage in mice is lacking. We present a detailed lymphatic system flow dynamic of two mouse strains with...
Understanding the lymphatic network is crucial for immunological research. Currently, a complete map of lymphatic drainage in mice is lacking. We present a detailed lymphatic system flow dynamic of two mouse strains with swollen lymph nodes (LNs), using region-specific tracer injection and high-resolution micro-CT imaging to characterize LN volume, weight, density, and spatial topology. No significant differences were observed in LN localization or numbers by strain or sex. Notably, we identified previously unreported drainage pathways and asymmetries, including distinct right and left lymphatic flows. We also discovered intranodal lympho-venous shunts in LNs, which facilitate unidirectional fluid transport and prevent interstitial fluid buildup and edema. Our findings suggest that these shunts may play a significant role in the delivery of therapeutics within LNs and highlight the need for further research into lymphatic structure-function relationships. © 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.
Bile duct tumor thrombus (intraductal polypoid growth)-positive intrahepatic cholangiocarcinoma: clinicopathologic and genomic analysis.
Mitsui A, Esaki M, Nara S … +6 more , Arai Y, Nakamura H, Shibata T, Ban D, Mizui T, Hiraoka N
J Pathol · 2026 May · PMID 41618619 · Publisher ↗
Bile duct tumor thrombus (BDTT), a tumor cluster occupying the luminal space in the large bile duct, is rare in intrahepatic cholangiocarcinoma (iCCA). Most studies on BDTT in iCCA to date are case reports, and the clini...
Bile duct tumor thrombus (BDTT), a tumor cluster occupying the luminal space in the large bile duct, is rare in intrahepatic cholangiocarcinoma (iCCA). Most studies on BDTT in iCCA to date are case reports, and the clinicopathological characteristics remain unknown. This study aimed to characterize iCCA with BDTT clinicopathologically and genetically. We analyzed 223 surgically resected iCCA cases, including 102 small duct type (SDT) and 121 large duct type (LDT) cases. BDTT was found in 19.6% (20/102) of SDT cases. Histological and immunohistochemical features of BDTT-positive SDT were comparable with those of conventional SDT (MUC1MUC2MUC5ACMUC6CDX-2). BDTT-positive SDT showed female predominance and higher T factors compared with conventional SDT. SDT was associated with a significantly longer survival in iCCA. SDT patients with BDTT had significantly shorter survival than those without BDTT and survival rates similar to those of LDT patients; the presence of BDTT in SDT was an independent unfavorable prognostic factor (HR = 2.601, p = 0.006). Whole-exome sequencing analysis revealed recurrent altered gene expression: those more frequent in SDT compared with LDT (BAP1, IDH1/2, ZNF717, FGFR2, NRAS); those more frequent in LDT (KRAS, TP53, SMAD4, MUC6, CACNA1A, MLL2, MDM2, TGFBR1/2); and those found comparably in both SDT and LDT (MUC4, ARID1A, EPHA2, PIK3CA, MUC17, MAP3K4, MUC2, BRAF, NF1). Genetic landscapes were similar in SDT iCCA with and without BDTT; recurrent mutations in MUC2 and MUC17 and FGFR2 fusion genes were more frequent in BDTT-positive SDTs. PTPRK::RSPO3 fusion gene was found in one LDT case. Intraglandular papillary and tubular proliferation is a unique and rare histology of SDT. BDTT was frequently found in SDT with this pattern, and FGFR2 gene rearrangement was frequent. These results highlight the importance of evaluating BDTT in SDT, as it may be the main route of hilar extension in aggressive cases. © 2026 The Pathological Society of Great Britain and Ireland.
Correction to 'Recombinant Klotho administration after myocardial infarction reduces ischaemic injury and arrhythmias by blocking intracellular calcium mishandling and CaMKII activation'.
J Pathol · 2026 Mar · PMID 41591315 · Full text
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Utility of pancreatic tumor scrapings for organoid development and precision medicine strategies.
Tsang CF, Patel H, Kouassi FM … +16 more , Khandakar B, St Surin LG, Rouse JA, Utama R, Budagavi D, Hohenleitner JT, Chunton A, Zhao Z, Fox SS, Valente CC, Weiss MJ, Rishi A, King DA, Crawford JM, Habowski AN, Tuveson DA
J Pathol · 2026 Apr · PMID 41588864 · Publisher ↗
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers due to late diagnosis and chemoresistance. Patient-derived organoids (PDOs) hold promise for predicting individualized drug responses, but their est...
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers due to late diagnosis and chemoresistance. Patient-derived organoids (PDOs) hold promise for predicting individualized drug responses, but their establishment is often constrained by the limited availability of tumor material and prior neoadjuvant treatment. Standard PDO generation relies on dissected tissue slices from the cut surface of the tumor, which may include both the invasive front, where it is postulated that more aggressive cancer cells reside, and potentially fewer viable neoplastic cells in the tumor center. This study investigated whether scraping the cut surface of the PDAC enhanced PDO establishment compared to standard tissue samples, to take advantage of potential harvesting of viable neoplastic cells from the invasive front. Tumor scrapings from 26 patients and matched tissue slices from 20 patients were collected. PDOs were successfully established from 10 tumor scrapings and eight matched tissue slices, including three neoadjuvant-treated cases. Organoid histological architecture was comparable to the surgical tumor specimens, with paired scraping PDOs and tissue slice PDOs showing genomic and transcriptomic concordance. Pharmacotyping demonstrated that scraping PDOs reliably captured patient-specific chemosensitivity, highlighting the potential for a viable alternative method to standard tissue-slice PDOs. As proliferative and treatment-resistant neoplastic cells often originate from tumor edges, increasing representation of the periphery and across the tumor may offer a more clinically relevant model of PDAC biology, improving therapeutic decision-making and patient outcomes. © 2026 The Pathological Society of Great Britain and Ireland.
Hierarchical image pyramid transformer framework for automated breast cancer molecular subtyping using tissue microarrays.
Li B, Zhong Y, Xing Z … +4 more , Zhou J, Li H, Yang L, Chen W
J Pathol · 2026 Apr · PMID 41588712 · Publisher ↗
The heterogeneity of breast cancer at molecular and histological levels poses significant challenges for precise diagnosis and treatment. Current molecular subtyping, crucial for guiding personalized therapy, relies on i...
The heterogeneity of breast cancer at molecular and histological levels poses significant challenges for precise diagnosis and treatment. Current molecular subtyping, crucial for guiding personalized therapy, relies on immunohistochemistry, which is often limited by intratumoral heterogeneity and potential sampling bias. While deep learning shows promise in digital pathology, existing models face computational and technical hurdles in capturing multiscale morphological features and long-range dependencies from high-resolution images, particularly in the context of tissue microarrays (TMAs). To address this, we developed and validated the pathomics breast cancer hierarchical image pyramid transformer (PBC-HIPT), a novel deep learning framework designed for automated molecular subtyping from standard H&E-stained images. The PBC-HIPT model utilizes a multilevel transformer-based architecture to hierarchically aggregate histopathological features from the cellular to the tissue scale, enabling a comprehensive analysis. We trained and validated the model on a multi-institutional cohort comprising 252 TMA cases and 46 independent whole-slide images (WSIs), assessing its performance via five-fold cross-validation on three-, four-, and five-class molecular subtyping tasks, as well as key biomarker [estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), Ki-67] prediction, comparing it against several established multiple instance learning methods. PBC-HIPT demonstrated superior performance, achieving a mean accuracy of 84.3% and a mean area under the curve (AUC) of 0.91 in the clinically critical three-class subtyping task (luminal, HER2-enriched, triple-negative breast cancer), significantly outperforming baseline models. The framework excelled in biomarker prediction, attaining accuracies of 91.8% (AUC: 0.97) for ER status and 92.0% (AUC: 0.96) for PR status. It also achieved an accuracy of 73.8% (AUC: 0.81) for Ki-67 proliferation status and 84.6% (AUC: 0.85) for binary HER2 status classification. While the model showed robust intramodality generalization on TMAs (ER AUC > 0.96), its performance dropped in WSI cross-modality validation. In conclusion, the PBC-HIPT model provides a robust, automated solution for accurate molecular subtyping and biomarker assessment from H&E-stained TMAs. © 2026 The Pathological Society of Great Britain and Ireland.
Integrating artificial intelligence (AI) into colorectal cancer reporting.
Bräutigam K, Baker AM, Koelzer VH … +2 more , Kather JN, Graham TA
J Pathol · 2026 Apr · PMID 41588707 · Full text
Artificial intelligence (AI) and deep learning (DL) are transforming cancer research and clinical care, with histopathology playing a central role in this transformation. In colorectal cancer (CRC), the second leading ca...
Artificial intelligence (AI) and deep learning (DL) are transforming cancer research and clinical care, with histopathology playing a central role in this transformation. In colorectal cancer (CRC), the second leading cause of cancer mortality world-wide, multimodal and vision-language models (VLMs) hold particular promise for enhancing the standardisation of histopathology reporting, the understanding of disease biology, and the discovery of novel prognostic indicators. Despite the availability of guidelines and reporting templates for essential prognostic indicators, variability remains in how key features such as TNM staging or tumour deposits are assessed and reported in routine clinical practice. AI-based tools have the potential to support refined extraction of established and extended features directly from whole-slide images. In parallel, recent studies have shown that DL models applied to pathology slides and associated AI-based biomarkers can outperform traditional histopathological prognostic indicators and uncover novel parameters, including tumour-adipocyte interactions, tumour-stroma ratio, and immune cell patterns at the invasive margin. Here, we review recent advances in both domains: AI-assisted standardisation of CRC pathology reporting and AI-driven identification of novel prognostic biomarkers. We highlight the need to refine and standardise CRC reporting practices and propose that a harmonised approach combining established pathology features with AI-derived prognostic indicators could refine risk assessment and improve outcomes for CRC patients. © 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.
Cancer-associated fibroblast subtypes in the tumor microenvironment of prostate cancer and associations to patient outcomes.
Blanke ML, Salachan PV, Georgsen JB … +4 more , Fredsøe J, Ulhøi B, Borre M, Sørensen KD
J Pathol · 2026 Apr · PMID 41588654 · Publisher ↗
Prostate cancer (PC) is a prevalent malignancy, and outcomes range from indolent disease to terminal illness. Prostate-specific antigen-based diagnostics lack specificity and correlation with tumor aggressiveness, leadin...
Prostate cancer (PC) is a prevalent malignancy, and outcomes range from indolent disease to terminal illness. Prostate-specific antigen-based diagnostics lack specificity and correlation with tumor aggressiveness, leading to overdiagnosis and undertreatment. Recent studies on cancer-associated fibroblasts (CAFs) have identified antigen presenting CAFs (apCAF), inflammatory CAFs (iCAF), and myofibrillar CAFs (myCAF) in pancreatic ductal adenocarcinoma, non-small-cell lung cancer, and breast cancer. However, their significance in PC is not yet understood. This study employs publicly available single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) data combined with multiplex immunofluorescence (mIF) and digital pathology analyses of radical prostatectomy (RP) specimens from two cohorts (cohort 1, n = 235; cohort 2, n = 240) to identify CAF subtypes in localized PC and their association with biochemical recurrence (BCR) by uni- and multivariable [adjusted for Cancer of the Prostate Risk Assessment postsurgical (CAPRA-S) score] Cox regression analyses. We identified myCAFs, iCAFs, and apCAFs in PC by analyzing scRNA-seq and ST data. We also identified the three CAF subtypes by mIF staining of RP specimens from cohorts 1 and 2. In prostate tumors, higher numbers of apCAFs and myCAFs were present close to malignant versus adjacent nonmalignant (AN) glands (p < 0.001, Wilcoxon test), whereas we saw no significant difference for iCAFs. In univariable Cox regression analyses, high levels of apCAFs and iCAFs were associated with increased risk of BCR in cohort 1 [apCAF: hazard ratio (HR): 1,78, p < 0.05, iCAF: HR: 1,76, p < 0.05] and confirmed in cohort 2 (apCAF: HR: 1.85, p < 0.05, iCAF: HR: 2.06, p < 0.05). In multivariable Cox regression analyses, both apCAF and iCAF levels remained independently associated with BCR after adjustment for CAPRA-S score. Our findings imply the potential of CAF subtypes as biomarkers for risk stratification in PC. © 2026 The Pathological Society of Great Britain and Ireland.
Uncoupling TGFβ1 signalling from collagen protein synthesis in Dupuytren's disease.
Cooper G, Gumbs JA, Alkharabsheh S … +10 more , Lee KJ, Carter A, Coleman H, O'Heneghan-Yates NS, Ijaz R, Beamish E, Menezes LA, Liloglou T, Clegg PD, Canty-Laird EG
J Pathol · 2026 Apr · PMID 41588641 · Full text
Dupuytren's disease is a fibroproliferative disorder of the palmer fascia (PF) characterised by flexion contractures in the hand. Dupuytren's disease can be treated surgically, but disease recurrence rates are high, pote...
Dupuytren's disease is a fibroproliferative disorder of the palmer fascia (PF) characterised by flexion contractures in the hand. Dupuytren's disease can be treated surgically, but disease recurrence rates are high, potentially due to continual production of matrisomal proteins. Here, metabolic labelling and proteomics identified differences in the new synthesis and composition of matrisomal proteins between Dupuytren's tissue and normal PF. Dupuytren's tissue actively synthesised type I collagen, fibronectin (FN1), matrix metalloproteinases-2 and -3 (MMP2, MMP3) and tissue inhibitor of metalloproteinases 2 (TIMP2). Both tissues actively synthesised insulin-like growth factor binding protein 7 (IGFBP7). Label-free analysis implicated the transforming growth factor-β (TGFβ) pathway in the matrisomal profile of Dupuytren's tissue. The effect of TGFβ isoforms on COL1 mRNA expression was first tested in cultured young and aged equine tenocytes. COL1A1 mRNA responded to treatment with all TGFβ isoforms and was more highly expressed in cells from aged samples. In aged human cells, COL1A1 and COL1A2 mRNA was higher in cells derived from Dupuytren's tissue than normal PF and in response to TGFβ1, but no changes in COL1A1 or COL1A2 CpG methylation were detected. TGFβ1 treatment only resulted in increased type I collagen protein accumulation in the media of Dupuytren's nodule cells. In three-dimensional cultures, COL1A1 mRNA was lower in normal PF than in Dupuytren's cells, but TGFβ1 treatment only increased type I collagen accumulation in the media of normal PF cultures, and TGFβ1 inhibition did not alter new collagen protein synthesis. TGFβ1 inhibition in Dupuytren's tissue explants did not alter the proportion of homotrimeric type I collagen, nor was this changed in skin or tendon of the tight-skin (TSK) mouse, a naturally occurring model of indirect TGFβ1 activation. Therefore, the role of TGFβ in Dupuytren's disease may be predominantly related to myofibroblast phenoconversion and contractility rather than directly altering collagen protein synthesis. © 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.
Single-nucleus RNA sequencing identifies a novel tenogenic heterologous differentiation in endometrial carcinosarcomas: implications for diagnosis and tumor classification.
González-Martínez S, Palacios J, Carretero-Barrio I … +7 more , Fernández-Lanza V, Cortés-Salgado A, Román J, Matias-Guiu X, Gatius S, Cortés J, Pérez-Mies B
J Pathol · 2026 Feb · PMID 41537454 · Full text
Carcinosarcomas (CSs) are aggressive biphasic tumors characterized by epithelial and mesenchymal components, whose histogenesis and differentiation dynamics remain poorly understood. We present single-nucleus RNA sequenc...
Carcinosarcomas (CSs) are aggressive biphasic tumors characterized by epithelial and mesenchymal components, whose histogenesis and differentiation dynamics remain poorly understood. We present single-nucleus RNA sequencing (snRNA-seq) analysis of six CSs (five endometrial and one ovarian) and two normal endometrial samples, profiling over 96,298 cells. By integrating transcriptomic data with inferred copy number variations (CNVs), immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and in situ hybridization (ISH) validation, we resolved the complex cellular architecture of these tumors, identified lineage-specific programs, and revealed unexpected differentiation trajectories. snRNA-seq was used to further refine the histopathological classification of three cases by uncovering heterologous differentiation not previously recognized: one rhabdomyogenic, one osteogenic, and, notably, one exhibiting a novel tenogenic program, defined by the expression of SCX, MKX, and TNMD. All CSs displayed a prominent mesenchymal compartment comprising both undifferentiated fibroblast-like cells and distinct lineage committed populations, including rhabdomyoblasts (Rhab), tenoblasts (Teno), osteoblasts (Osteo), and chondroblasts (Chond). In some tumors, multiple mesenchymal identities co-existed, and in others, differentiation gradients (e.g. immature versus mature rhabdomyoblasts) were observed. These patterns underscore the cellular plasticity and multilineage potential of the sarcomatous component. Furthermore, the expression of specialized interface markers (COL22A1, NCAM1, ACAN, CHRNG, MUSK) suggests that some tumors use structured developmental programs reminiscent of the muscle-tendon junction, enthesis, or neuromuscular junction. CNV analysis revealed tumor-specific genomic alterations with clonal and subclonal patterns linked to differentiation state, which were validated by FISH. Altogether, this study demonstrates that CSs are not static biphasic tumors but rather complex ecosystems with extensive developmental plasticity. Our findings redefine their classification and support the use of single-nucleus approaches to uncover hidden differentiation trajectories in highly heterogeneous cancers, including the discovery of a previously unreported tenogenic lineage. Our results challenge the diagnosis of homologous CS when only morphological criteria are applied. © 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.
Mining bulk transcriptomic datasets identifies inflammasome activation and antigen presentation as key novel mechanisms of BK polyomavirus-associated nephropathy.
Davidson LA, Niessen NM, Rowlandson M … +9 more , Hibberd AD, Heer MK, Hsu AC, Kaiko GE, Reid AT, Mayall JR, Horvat JC, Trevillian PR, Baines KJ
J Pathol · 2026 Mar · PMID 41527905 · Publisher ↗
BK polyomavirus (BKPyV) is a viral infection experienced by kidney transplant recipients that can lead to the development of BKPyV-associated nephropathy (BKPyVAN), graft dysfunction, and loss. There are no BKPyV-specifi...
BK polyomavirus (BKPyV) is a viral infection experienced by kidney transplant recipients that can lead to the development of BKPyV-associated nephropathy (BKPyVAN), graft dysfunction, and loss. There are no BKPyV-specific treatments available to prevent this significant cause of transplant failure. This bioinformatic study aims to characterise the cellular networks and pathways involved in BKPyVAN to identify novel therapeutic targets. Four publicly available bulk transcriptomic datasets containing BKPyVAN post-transplant biopsy tissue were identified in the National Centre for Biotechnology Information Gene Expression Omnibus (NCBI GEO). Differentially expressed genes (DEGs) (adjusted p < 0.05, fold change ≥ 1.5) were identified and dataset comparisons made between BKPyVAN versus stable grafts and acute rejection versus stable grafts. Canonical pathways were investigated using QIAGEN Ingenuity Pathway Analyses and protein interaction networks using STRING v12.0. There were 226 genes identified as differentially expressed in BKPyVAN compared with stable graft function that were conserved across all four datasets. This gene signature was associated with three cellular networks and 201 significantly enriched pathways. The cellular networks identified included 67 immune-related proteins; eight proteins associated with the absent in melanoma 2 (AIM2) inflammasome; and four HLA class II proteins. The most notable pathways significantly increased in BKPyVAN included HLA class II antigen presentation (p < 0.001), inflammasome (p < 0.001), and interleukin 6 signalling (p < 0.01). There were seven DEGs that were observed as common to all BKPyVAN versus acute rejection comparisons. The TUBB3 gene was the only gene that was consistently upregulated in all datasets. Several pathways and potential treatment targets were identified using a bulk RNA mining strategy, including HLA class II antigen presentation, AIM2 inflammasome, and IL-6 signalling in BKPyVAN pathology. Such tools provide an important first step in identifying novel mediators of disease pathogenesis and likely hold the key for the discovery of potential treatment targets for BKPyVAN in the future. © 2026 The Pathological Society of Great Britain and Ireland.
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