The Journal of Pathology最新文献

A significant proportion of gastric diffuse large B-cell lymphoma with mucosa-associated lymphoid tissue [DLBCL(MALT)] and without MALT (‘pure’ DLBCL) can be resolved by Helicobacter pylori eradication (HPE). Gastric MALT lymphoma is an indolent lymphoma derived from memory B cells in the marginal zone. In the present study, we aimed to explore the origin of large cells in HPE-responsive gastric DLBCLs (complete remission after HPE). We investigated gastric lymphoma biopsies from 31 patients with HPE-responsive DLBCLs [15 ‘pure’ DLBCLs, 16 DLBCL(MALT)s]. We used the Hans algorithm (CD10, BCL-6, and MUM1) to define the origins of germinal center B cell (GCB) and non-GCB. To further ascertain the cellular origin, 11 ‘pure’ DLBCLs were examined using an Agilent whole-human genome microarray. Eleven DLBCLs [eight with ‘pure’ DLBCL and three with DLBCL(MALT)] were also assessed using Lymph2Cx. Specific GCB markers, including BACH2, AID, and BCL2 rearrangement and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) codon 641 mutations, were evaluated in 31 patients with HPE-responsive gastric DLBCLs. According to the Hans algorithm, 53% (8/15) of gastric ‘pure’ DLBCLs and 50% (8/16) of DLBCL(MALT)s were of the GCB phenotype. Gene expression assays revealed that five of six patients with ‘Hans’ GCB had GCB genetic signatures, whereas four of five patients with ‘Hans’ non-GCB had activated B-cell genetic signatures. The Lymph2Cx assay revealed the GCB subtype in seven of eight patients with ‘Hans’ GCB. The expression patterns of BACH2 (p = 0.005) and AID (p = 0.038) closely correlated with the ‘Hans’ GCB phenotype. BCL2 rearrangements and EZH2 codon 641 mutations were detected in 44% (7/16) and 13% (2/16) of patients with ‘Hans’ GCB, respectively. In another cohort of 29 HPE-unresponsive gastric DLBCLs [19 ‘pure’ DLBCLs and 10 DLBCL(MALT)s], we found a close association between the ‘Hans’ GCB subtype and the GCB subtype as determined by the Agilent whole-human genome microarray and Lymph2Cx in lymphoma cells of these patients. In conclusion, more than half of HPE-responsive large cell lymphoma cases in the stomach were of GCB origin. © 2026 The Pathological Society of Great Britain and Ireland.

Bronchiolar adenoma (BA) is a rare benign pulmonary neoplasm defined by a bilayered architecture with a continuous basal cell layer. Increasingly, BA-like lesions with atypical features have been recognized, challenging established diagnostic boundaries and raising questions regarding their malignant potential. In this study, we investigated the clinicopathological and molecular characteristics of such lesions. We retrospectively analyzed 19 BA-like lesions that retained at least focal classic BA morphology and exhibited one or more predefined atypical features, including basal cell hyperplasia (with or without squamous dysplasia), partial-to-complete loss of the basal cell layer, stromal-like growth, cytological atypia exceeding classic BA, or morphologically contiguous carcinoma components. Patients showed a broad age distribution with a slight female predominance, and all cases with available follow-up remained disease-free following complete surgical resection (median 29.6 months; range 5–64 months). Histologically, atypical changes involved both basal and luminal compartments, resulting in mixed biphasic and monolayered areas, stromal-like growth, squamous metaplasia or dysplasia, and variable degrees of cytological atypia. Whole-exome sequencing (10 cases) and targeted profiling (two cases) revealed heterogeneous genetic alterations, including driver events involving BRAF, EGFR, and MET, as well as recurrent mutations affecting HRAS, PIK3CA, MTOR, DNA repair genes, and epigenetic regulators. Pathogenic TP53 mutations were confined to lesions with marked epithelial atypia. At the pathway level, MAPK alterations, including HRAS mutations, were enriched in basal-hyperplasia lesions, whereas PI3K/AKT/mTOR alterations were more frequent in basal-deficient lesions. These findings support the concept that BA-like lesions with atypical features represent a morphological continuum ranging from benign BA to malignant lesions. We further propose a pragmatic framework for diagnosis and clinical management, although validation in larger cohorts with longer follow-up is required. © 2026 The Pathological Society of Great Britain and Ireland.

Benign prostatic hyperplasia (BPH) is the most common urologic disease in aging men, resulting in significant morbidity. The etiologies of BPH are unknown, though chronic prostatic inflammation is known to promote hyperplasia, fibrotic remodeling, and therapeutic resistance in BPH. BPH is highly complex and heterogeneous, presenting with varying degrees of stromal and epithelial proliferation, fibrosis, inflammation, and associated lower urinary tract symptoms. This complexity poses challenges in developing models. Here, we characterize an Aire transcription factor-deficient nonresolving (chronic) inflammation model in a C57BL/6J background for the study of the prostatic inflammation present in BPH. This chronic inflammatory model exhibits a lack of central tolerance but retains an otherwise intact and functional immune system. C57BL/6^Aire−/− mice were subcutaneously injected with prostate homogenate protein and Freund's Complete Adjuvant and boosted after 10 days. After 21 and 35 days, whole prostates were collected for histology, flow cytometry, and single-cell RNA sequencing (scRNA-seq), which were then compared to human BPH data. Inflammation was confined to the prostate in C57BL/6^Aire−/− mice. Histological and scRNA-seq data show that the dominant leukocyte phenotypes in the prostates of C57BL/6^Aire−/− mice are B and T lymphocytes. Macrophages in C57BL/6^Aire−/− mouse prostates express signatures associated with an array of phenotypes, as also seen in BPH. We identify a Trem2⁺ population of macrophages and aging-associated Cd8⁺ GZMK hi GZMB low T cells in C57BL/6^Aire−/− prostates similar to those seen in human BPH. Further, fibroblast clusters in C57BL/6^Aire−/− are similar to fibroblasts identified from the prostates of patients diagnosed with BPH, and these clusters also express markers associated with aging. Overall, the inflammation and predicted leukocyte--stromal interactions observed in the prostates of C57BL/6^Aire−/− mice resemble human BPH, likely at the early stages of the disease, making this model useful for studying the impact of inflammation-driven prostatic hyperplasia. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Human tumors likely differ in their mitotic ages, reflecting how many divisions elapse between the final tumor progenitor cell and surgical removal. We used a rapidly fluctuating CpG (fCpG) methylation clock to infer relative endometrial adenocarcinomas (EAC) mitotic ages. Experimentally, young tumors initiated from single cells show low-diversity, high-variance fCpG distributions with trimodal peaks near 0%, 50%, and 100%, reflecting inherited progenitor methylation states. fCpG methylation becomes polymorphic with divisions, and older tumors exhibit higher diversity, lower variance, and unimodal distributions centered around 50%. Mitotic ages varied across EAC samples. Synchronous hyperplasia and invasive regions generally shared similar ages, and primary–metastatic EAC pairs showed both synchronous and stepwise progression. The Cancer Genome Atlas (TCGA) EACs also showed variable mitotic ages: younger tumors were enriched for proliferation pathways, whereas older tumors showed more immune infiltration, immune-pathway activation, and evidence of T-cell exhaustion. These results show that human tumors can be ranked by mitotic age and suggest that the growth of older cancers is restrained by immune surveillance. © 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.

Platelet-derived microparticles (PMPs) constitute the majority of circulating microparticles in blood. PMPs carry cargo including RNA, protein, and miRNA, and play key pathophysiologic intercellular signaling roles in cardiovascular, autoimmune, and liver diseases. Most methods use fresh platelets treated with an agonist to generate PMPs, which has restricted the size and feasibility of human studies. With the rise of large biobanks, such as the UK Biobank (https://www.ukbiobank.ac.uk/), and because microparticles are retained in cryopreserved plasma, this study aimed to develop an efficient and reproducible method to isolate PMPs from banked cryopreserved human plasma to investigate their communication with target cells. We employed flow cytometry using 180–1,300 nm size calibration beads and the platelet-specific marker CD41 to identify and sort PMPs based on size and CD41 positivity. Following isolation, microparticle size and morphology were validated by electron microscopy and nanoparticle tracking analysis. To assess the utility of the microparticles for studies of cell–cell interactions, we visualized microparticle uptake into human umbilical vein endothelial cells and THP-1 cells. Our method enables the isolation and downstream analysis of human PMPs in cell–cell interactions, facilitating translational studies in large populations and rare diseases. © 2026 The Pathological Society of Great Britain and Ireland.

Colon cancer progression is closely associated with the tumor microenvironment, where cancer-associated fibroblasts (CAFs) play a pivotal role. Exosomal long non-coding RNAs (lncRNAs) are known to modulate the tumor stroma, but the role of lncRNA PVT1 (plasmacytoma variant translocation 1) in exosome-mediated fibroblast activation in colon cancer remains poorly understood. This study demonstrated significantly elevated PVT1 levels in colon cancer tissues. Mechanistically, hypoxia/reoxygenation (H/R) induced the recruitment of HIF-1α to the PVT1 promoter, directly activating its transcription and subsequent exosomal loading. Exosomes derived from H/R-treated colon cancer cells promoted fibroblast activation into a CAF phenotype. PVT1 was found to sponge miR-23b-5p, thereby upregulating a network of target genes. Importantly, silencing of MAPK13, a key downstream target, significantly abrogated the PVT1-mediated fibroblast-to-CAF transformation. In vivo experiments confirmed that exosomal PVT1 enhanced CAF infiltration and tumor growth, whereas these effects were reversed by either restoring miR-23b-5p expression or knocking out PVT1. These findings uncover a novel mechanism whereby H/R-induced exosomal PVT1 promotes fibroblast activation and CAF transformation via the miR-23b-5p signaling axis, providing potential diagnostic biomarkers and therapeutic targets for modulating the tumor stroma in colon cancer. © 2026 The Pathological Society of Great Britain and Ireland.

Prostate cancer (PCa) is the second most common type of neoplasm, currently treated with a variety of therapeutic agents. Although advances in treatment over the past decade have improved overall survival, patients with advanced PCa eventually progress from hormone-sensitive PCa to metastatic castration-resistant PCa. For this reason, other therapeutic strategies, including immunotherapy, are being investigated. Despite initial enthusiasm, these approaches have not yet produced significant improvements in either progression free survival or overall survival. Several factors may have contributed to the consistently disappointing results of immune checkpoint inhibitors in PCa, despite their more successful results in other tumor types. In this review, we discuss the potential reasons for these disappointing clinical results. © 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.

Uveal melanoma (UM) is a deadly ocular malignancy with well-described genetic alterations that predict disease outcome. However, our current understanding of the biological underpinnings of high-risk uveal melanoma progression remains relatively limited. Using RNA expression profiles from 250 patients with UM, we identified 12 novel biomarkers associated with high-risk UM, with protein expression level validation of the top two candidates: the transcriptional regulator RBFOX2 and matrix protein COL9A3. Moreover, we investigated the functional contribution of COL9A3 via its overexpression in EIF1AX^mut and BAP1^mut UM cell lines. Our data suggest that COL9A3 enhances cell motility and cell proliferation and alters morphology specifically in BAP1^mut UM cells. Furthermore, zebrafish xenograft studies revealed increased cell dissemination in a EIF1AX^mut UM cell line upon overexpression of COL9A3, whereas a BAP1^mut UM cell line remained unchanged under wild-type conditions. Interestingly, RNA sequencing revealed a high-stress profile by upregulated metabolic activity and loss of protein translation due to COL9A3 overexpression. BAP1^mut UM appears to adapt to this stress by upregulation of plasticity markers, such as CD44, Nestin, EZH2, ABCB5, PAX3 and CD166, as a coping mechanism. These markers are known as differentiation markers during the development of melanocyte biogenesis and are implicated in plasticity in other high-risk cancers. The relationship between COL9A3 and plasticity was validated by multiplex immunohistochemistry of formalin-fixed paraffin-embedded (FFPE) tissue, which demonstrated colocalization of COL9A3, CD44 and Nestin. BAP1^mut-UM samples presented higher levels of COL9A3, CD44 and Nestin expression than EIF1AX^mut or SF3B1^mut UM samples based on the mean fluorescent intensity of each marker. A positive correlation between COL9A3 and Nestin expression in triple-positive cells, irrespective of the UM subtype, was observed. Collectively, our findings suggest that COL9A3 is a novel high-risk biomarker that may contribute to UM cell plasticity and is most prevalent in BAP1^mut UM. © 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 cellular composition and disease susceptibilities of the distinct zones of the human prostate remain incompletely understood. Benign prostatic hyperplasia (BPH) is a common condition that causes widespread morbidity and is nearly exclusively localized to the transition zone (TZ). Through extensive single-cell RNA sequencing (scRNA-seq) of benign regions from prostatectomy specimens, we identified a basal cell population expressing WIF1, VCAN, and NRG1, among other genes, that was significantly enriched in the TZ. Analysis of previously published scRNA-seq datasets further confirmed that WIF1⁺ basal cells were significantly enriched in BPH compared with normal prostate. Pathway and cell-cell communication analyses revealed that this basal subtype is associated with programs related to cell proliferation, epithelial-mesenchymal transition, immune regulation, angiogenesis, and hormone response. Together, the molecular signature, zonal distribution, and pathway enrichment suggest that TZ-enriched WIF1⁺ basal cells may contribute to BPH pathogenesis by promoting epithelial and stromal remodeling. © 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.

Fibroblast growth factor receptor 1 (FGFR1) amplification, a significant cancer alteration with both prognostic and therapeutic relevance, lacks a standardized definition. The relationship between FGFR1 copy number (CN) variations and tumour microenvironment (TME) characteristics also remains poorly understood. This study defined FGFR1 amplification and investigated TME features across FGFR1 CN subtypes in triple-negative breast cancer (TNBC) to guide precise treatment. We analysed 182 TNBC tumour specimens. FGFR1 CN status was assessed using fluorescence in situ hybridization (FISH). Next-generation sequencing (NGS) was performed on 88 samples to explore biological differences. Immunohistochemical (IHC) results for CD3, CD4, and CD8 along with clinical data were analysed. Samples were categorized into four groups based on the FGFR1/CEN8 ratio and the mean FGFR1 signals per cell. Groups 1 (ratio ≥ 2.0, signals ≥ 4.0) and 2 (ratio ≥ 2.0, signals < 4.0) exhibited robust tumour proliferation, increased FGFR signalling, and an immunosuppressive TME. Conversely, group 4 (ratio < 2.0, signals < 4.0) showed significantly enhanced immune cell infiltration (e.g. CD8⁺ T cells, NK cells), supported by elevated CD3⁺/CD8⁺ T-cell densities. Group 3 (ratio < 2.0, signals ≥ 4.0) was heterogeneous: tumours with FGFR1 CN ≥ 5 resembled groups 1/2, while those with CN < 5 mirrored group 4. Thus, FGFR1 amplification (FGFR1-Amp) was defined as FGFR1/CEN8 ratio ≥ 2.0 or CN ≥ 5.0 (14.29% prevalence, 26/182). Remaining cases were FGFR1-neutral (FGFR1-Neu). Immune profiling revealed that FGFR1-Amp & HER2-low TNBC had reduced immune cell infiltration but heightened oncogenic signalling (including epithelial-mesenchymal transition, angiogenesis) compared with other subgroups. In contrast, FGFR1-Neu tumours, especially HER2-zero, displayed increased immune cell infiltration (NK cells, effector cells), MHC I/II molecules, activation markers, and elevated immune checkpoint expression (e.g. PD-L1, CTLA4, LAG3). This study defines FGFR1 amplification in TNBC and characterizes its TME. FGFR1-Amp in HER2-low TNBC correlates with an immunosuppressive environment, potentially hindering HER2-ADC efficacy and suggesting combined FGFR inhibition. Conversely, FGFR1-Neu & HER2-zero tumours with immune activation may respond better to immunotherapy. © 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.