J. Pathol. [JOURNAL]
Sun
200 papers
Hypoxia-induced regional heterogeneity in proliferative vitreoretinopathy: implications for targeted therapies.
Yin W, Xu M, Gao Y … +6 more , Niu Z, Wu X, Song Y, Liu Q, Mao X, Yuan S
J Pathol · 2026 Jan · PMID 41215615 · Publisher ↗
Proliferative vitreoretinopathy (PVR) represents a common and challenging complication leading to blindness following ocular injury. The prevailing view, which guides current drug development efforts, posits that the mes...
Proliferative vitreoretinopathy (PVR) represents a common and challenging complication leading to blindness following ocular injury. The prevailing view, which guides current drug development efforts, posits that the mesenchymal transition of retinal pigment epithelium (RPE) underlies the pathogenesis of PVR. However, in our study, by employing single-cell sequencing and immunofluorescence staining on surgically excised PVR membranes, we demonstrate that PVR exhibits distinct cytopathological characteristics depending on their retinal location. Specifically, epiretinal PVR predominantly comprises macrophages, whereas subretinal PVR is primarily constituted of PMEL RPE-derived cells. Both molecular pathological phenotypes are unified by retinal hypoxia following injury, yet they diverge in their downstream hypoxic pathway selection. Targeting HIF1α-regulated glycolysis selectively reduced epiretinal PVR formation, while inhibiting reactive oxygen species production specifically abrogated subretinal PVR. Furthermore, the application of hyperoxia chamber in a mouse model of dispase-induced retinal injury effectively eradicated PVR across all retinal regions and restored retinal morphology. Our findings establish hypoxia-induced regional heterogeneity as a pathological mechanism in PVR progression and advocate for anatomically targeted therapeutic strategies. © 2025 The Pathological Society of Great Britain and Ireland.
Molecular evidence of a clonal relationship of synchronous/multifocal gastric-type lesions of the female genital tract.
Shi M, Yang H, Zhang F … +12 more , Hou T, Huang H, Lu Y, Zhou Y, Lan T, Ji J, Hou J, Zhou C, Zhang Z, Qin S, Huang Z, Liu Y
J Pathol · 2026 Jan · PMID 41208479 · Publisher ↗
Synchronous/multifocal gastric-type lesions (SMGLs) of the female genital tract are heterogeneous diseases that are rare and challenging to diagnose. The core issue is distinguishing between multiple primaries and multif...
Synchronous/multifocal gastric-type lesions (SMGLs) of the female genital tract are heterogeneous diseases that are rare and challenging to diagnose. The core issue is distinguishing between multiple primaries and multifocal metastases from a single lesion. This is vital for staging, prognosis, and treatment decisions, especially when metastases mimic primary and early lesions at the relevant sites. Traditional morphological diagnosis often faces a paradoxical situation on this key issue and cannot quantitatively evaluate the correlations among multiple foci. Here, six cases of SMGL were collected, two of which exhibited pagetoid dissemination within the genital tract, with all lesions being noninvasive. A total of 24 samples were subjected to whole-exome sequencing. By inference based on overlapping genetic variations, base substitution mutation patterns, composition and similarity of COSMIC signatures, clonality indices, and the construction of evolutionary trees, it was inferred that the multiple foci in each patient were clonally related, indicating that all cases were metastatic. The follow-up duration ranged from 7 to 62 months (median: 24.5 months). Four patients died of disease (median survival time: 24.5 months, range: 8-47 months), including one patient who had no invasive lesions at initial diagnosis; two patients experienced recurrences at 17 and 40 months, respectively. These results imply that even if all foci exhibit the appearance of in situ or premalignant changes histologically, they may actually be aggressive. Hence, for SMGLs, before opting for conservative treatment, comprehensive clinical assessment, appropriate surgical extent, adequate sampling, and careful microscopic examination are crucial. Clonal analysis should also be conducted where necessary to avoid undertreatment due to understaging. The study further explored the genomic traits of SMGLs involving more than two sites. © 2025 The Pathological Society of Great Britain and Ireland.
Transcriptomic profiling reveals the role of Hedgehog signaling as a biomarker and in the pathogenesis of Ménétrier's disease.
Shin M, Gabriel TT, Ofosu FK … +5 more , Zhang J, Wang TT, Bechard ME, Coffey RJ, Huh WJ
J Pathol · 2026 Jan · PMID 41199529 · Full text
Both Ménétrier's disease (MD) and juvenile polyposis syndrome (JPS) are rare premalignant conditions that can lead to gastric cancer. MD is an acquired disease without known causative mutations that is characterized by i...
Both Ménétrier's disease (MD) and juvenile polyposis syndrome (JPS) are rare premalignant conditions that can lead to gastric cancer. MD is an acquired disease without known causative mutations that is characterized by increased expression of an EGF receptor (EGFR) ligand, transforming growth factor-alpha (TGFα), in the stomach. JPS is inherited in an autosomal dominant pattern and is caused by BMPR1A or SMAD4 mutations. Although there are distinct clinico-pathological features that differ between the two diseases, they also share similar features that often lead to misdiagnosis. To identify diagnostic markers for MD and to better understand the pathogenesis of the disease, we performed transcriptomic profiling of stomach tissues from normal (NL), MD, and JPS patients. Comparative analysis between MD and JPS revealed both common and differential gene signatures. Common gene signatures included estrogen receptor signaling, integrin signaling, mTOR signaling, and others, which may be responsible for histopathological similarities. Among differential gene signatures, we found that Hedgehog (Hh) signaling is upregulated in MD and confirmed that protein expression of Hh signaling downstream targets, GLI1 (glioma-associated oncogene homolog 1) and HHIP (Hedgehog-interacting protein), is higher in MD than in JPS, particularly in foveolar cells by immunohistochemistry. We also demonstrated that treatment with an Hh pathway inhibitor partially rescued the histopathological phenotypes in an MD mouse model. This study provides valuable insights into the potential mechanisms underlying the similar clinico-pathological features observed in MD and JPS. We also identified GLI1 and HHIP as diagnostic markers that can help to distinguish MD from JPS. Furthermore, Hh signaling was shown to play an important role in the pathogenesis of MD and may serve as a potential therapeutic target. © 2025 The Pathological Society of Great Britain and Ireland.
Contrastive virtual staining enhances deep learning-based PDAC subtyping from H&E-stained tissue cores.
Fischer M, Muckenhuber A, Peretzke R … +17 more , Farah L, Ulrich C, Ziegler S, Schader P, Feineis L, Gao H, Xiao S, Götz M, Nolden M, Steiger K, Sieveke JT, Endrös L, Braren R, Kleesiek J, Schüffler P, Neher P, Maier-Hein K
J Pathol · 2026 Jan · PMID 41188199 · Full text
Pancreatic ductal adenocarcinoma (PDAC) subtyping typically relies on immunohistochemistry (IHC) staining for critical markers like HNF1A and KRT81, a labor-intensive manual staining process that introduces variability....
Pancreatic ductal adenocarcinoma (PDAC) subtyping typically relies on immunohistochemistry (IHC) staining for critical markers like HNF1A and KRT81, a labor-intensive manual staining process that introduces variability. Virtual staining methods offer promising alternatives by generating synthetic IHC images from routine hematoxylin and eosin (H&E) slides. However, most current approaches evaluate success by image quality measures rather than assessing diagnostically relevant features. Here, we introduce a novel cycleGAN framework utilizing a contrastive-inspired approach trained on semipaired datasets derived from consecutive tissue sections. Our method significantly enhances PDAC subtyping accuracy based on synthetic IHC images generated from standard H&E inputs, improving the classification F1-score from 0.66 to 0.77 for KRT81 and from 0.61 to 0.73 for HNF1A, compared with classification directly on H&E images. This approach also substantially outperforms baseline CycleGAN models. These results underscore the clinical potential of contrastive virtual staining to streamline PDAC diagnostics and improve their robustness. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
mTOR-mediated upregulation of B7-H3 in MiT/TFE translocation renal cell carcinoma.
Li H, Amaral A, Vidotto T … +11 more , Woo J, Liu HB, Oliveira LD, Dairo O, Feng K, Shenderov E, Argani P, Schmidt LS, Linehan WM, Lotan TL, Asrani K
J Pathol · 2026 Jan · PMID 41178060 · Publisher ↗
Clinical trials targeting B7-H3 (CD276), a membranous immunomodulatory molecule in the B7 superfamily, have shown promise in prostate cancer and may be expanded to additional tumor types with high expression, such as tho...
Clinical trials targeting B7-H3 (CD276), a membranous immunomodulatory molecule in the B7 superfamily, have shown promise in prostate cancer and may be expanded to additional tumor types with high expression, such as those with mTOR signaling activation. MiT/TFE-rearranged translocation renal cell carcinoma (tRCC) is a rare, aggressive subtype that is relatively immune-depleted, with high levels of mTOR activity. Thus, we assessed B7-H3 expression in preclinical tRCC models and human tRCC samples. As hypothesized, we found that induction of TFE3 fusion proteins, including SFPQ-TFE3, PRCC-TFE3, ASPSCR1-TFE3, and NONO-TFE3, is associated with upregulation of B7-H3 in multiple human preclinical tRCC cell line systems and transgenic mouse models. Pharmacologic or genetic inhibition of mTOR signaling is sufficient to downregulate B7-H3 expression in inducible and patient-derived, human cell line models of tRCC. In keeping with these preclinical results, human tRCC demonstrated significantly higher gene expression of CD276 than normal kidney, across five of the six fusions studied. At the protein level, tRCC had higher tumor cell B7-H3 intensity and proportion scores than normal kidney or clear cell RCC (ccRCC). B7-H3 expression in tumor vasculature was similar in tRCC and ccRCC, both of which showed significantly higher expression than normal kidney. Within tRCC cases, higher CD276 expression was observed in metastatic compared to localized tumors and was associated with lower tumoral CD4 T-cell content by bulk RNAseq deconvolution. Taken together, tRCC fusion proteins upregulate B7-H3 expression via increased mTOR signaling, resulting in a higher tumoral B7-H3 expression compared to normal kidney or conventional RCC, suggesting that B7-H3 may be a promising therapeutic target in tRCC. © 2025 The Pathological Society of Great Britain and Ireland.
Phylogenetic analysis of paired breast carcinomas identifies genetic events associated with clonal recurrence and invasive progression.
Kader T, Zethoven M, Mahale S … +30 more , Saunders H, Tjoeka L, Lehmann R, Jayawardana MW, Pang JM, Lesche D, Rajan N, Semple T, Lee JEA, Lupat R, Byrne DJ, Hughes S, Nguyen H, Lai S, Pechlivanis M, Craig O, Devereux L, House E, Jayasinghe SI, Kaufmann TL, Schwarz RF, Green AR, Miligy IM, Cummings M, Lakhani S, Campbell IG, Rakha E, Fox SB, Mann GB, Gorringe KL
J Pathol · 2026 Jan · PMID 41165701 · Full text
Development of ipsilateral breast carcinoma following a diagnosis of breast ductal carcinoma in situ (DCIS) has been assumed to represent recurrence of the primary tumour. However, this may not always be the case, and it...
Development of ipsilateral breast carcinoma following a diagnosis of breast ductal carcinoma in situ (DCIS) has been assumed to represent recurrence of the primary tumour. However, this may not always be the case, and it is important to determine how often such recurrences represent new tumours. Ipsilateral primary-recurrence pairs (n = 78) were sequenced to test their clonal relatedness. Shared genetic events were identified from whole exome sequencing (n = 54 pairs) using haplotype-specific copy number and phylogenetic analysis. The remaining pairs were sequenced using a targeted panel or low-coverage whole genome sequencing. We included 32 non-recurrent DCIS to compare recurrent and non-recurrent disease. We found that 7% of DCIS recurrences were non-clonal by whole exome sequencing, indicative of a new breast carcinoma. Lower resolution methods detected a higher non-clonality rate (29%). By comparing primary DCIS with their recurrence, we found that the evolution of DCIS to invasive disease was associated with increased ploidy and copy number events. TP53 mutations were enriched in DCIS with clonal recurrence compared with non-recurrent DCIS. Our results verify that de novo 'recurrent tumours' of independent origin occur in patients who may be at high risk. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
MicroRNA profiling of testicular Leydig cell tumors identifies a microRNA signature associated with malignancy and miR-196b-5p as a potentially useful biomarker.
Lobo J, Tavares NT, Fernandes-Pontes F … +20 more , Constâncio V, Marques AT, Oliveira-Lopes B, Fonseca D, Jerónimo C, Henrique R, Michalova K, Cornejo KM, Colecchia M, Ricci C, Idrees MT, Contreras F, Gonzalez IMF, Anderson WJ, MacLean F, Osunkoya AO, Kao CS, Sangoi AR, Ulbright TM, Acosta AM
J Pathol · 2026 Jan · PMID 41152570 · Full text
Approximately 10% of testicular Leydig cell tumors (LCTs) are clinically malignant and unresponsive to systemic treatment. Predicting their clinical behavior can be problematic because there are no biomarkers that can co...
Approximately 10% of testicular Leydig cell tumors (LCTs) are clinically malignant and unresponsive to systemic treatment. Predicting their clinical behavior can be problematic because there are no biomarkers that can consistently discriminate between benign and malignant LCTs. We assessed microRNA expression profiles of LCTs to identify differentially expressed microRNAs that could potentially distinguish benign from malignant neoplasms. The study consisted of two phases. In the first (discovery) phase, we interrogated 768 microRNAs in a series of 11 LCTs (six malignant and five benign) using Taqman Low-Density Array (TLDA) microRNA profiling. In the second phase, we validated the top differentially expressed microRNA targets with real-time quantitative PCR on a series of 35 LCTs (17 malignant and 18 benign), assessing their clinical performance for distinguishing malignant from benign LCTs. Target biologic pathways were analyzed using the miRTargetLink 2.0 tool. A total of 50 microRNAs were differentially regulated in malignant LCTs (27 upregulated, 23 downregulated). The top six microRNA candidates (top three upregulated and top three downregulated) were validated, showing good performance for discriminating between malignant and benign LCTs, with an area under the curve (AUC) ranging between 0.69 and 0.87. MiR-196b-5p showed the best performance, with sensitivity, specificity, negative predictive value, positive predictive value, and accuracy of 82%, 83%, 83%, 82%, and 83%, respectively. A panel (i.e. combined) analysis reached 100% sensitivity and 83% specificity. Pathway analysis revealed significant overlap in the biological process targeted by the upregulated microRNAs in malignant LCTs, including proliferation, development, metabolism, hormone synthesis, and cell death. Our results support the idea that malignant LCTs are associated with a distinct microRNA signature. MiR-196b-5p was identified as a potentially useful biomarker to distinguish benign from malignant tumors. The shared downstream targets of the top upregulated microRNAs suggest that dysregulation of cell proliferation and apoptosis underlie aggressive biologic behavior in LCTs and may offer opportunities for targeted therapies. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Identification of actionable targets using DEPArray-based sorting of pure carcinoma and stromal populations from formalin-fixed paraffin-embedded tissues followed by shallow whole-genome sequencing.
Nteliopoulos G, Wren E, Rushton A … +18 more , Wadsley MK, Fernandez-Garcia D, Manodoro F, Agbaimoni O, Chauhan R, Cheng Z, Ennis DP, Page K, Allsopp RC, Bautista J, Puccio I, Matthews N, Gleason KL, Farah R, Kenny L, McNeish IA, Shaw JA, Coombes RC
J Pathol · 2026 Jan · PMID 41144934 · Full text
Formalin-fixed paraffin-embedded (FFPE) tissue specimens represent precious resources for clinical genomic profiling studies, especially when coupled with comprehensive medical records. Even though next-generation sequen...
Formalin-fixed paraffin-embedded (FFPE) tissue specimens represent precious resources for clinical genomic profiling studies, especially when coupled with comprehensive medical records. Even though next-generation sequencing (NGS) is an effective tool to detect somatic mutations and somatic copy number alterations (sCNA), the biggest challenges in unlocking clinically translatable genomic information from FFPE tissue are low DNA yields and degraded DNA, affected by variable formalin fixation. Another issue is that the proportion of carcinoma and other noncarcinoma cells is variable and can be confounded by intratumoral heterogeneity. To explore these challenges, we isolated pure carcinoma and stromal cells using the DEPArray™ NxT system, a microchip-based digital sorter that allows isolation of pure, homogeneous subpopulations of cells from FFPE samples. We isolated pure carcinoma and stromal cell populations from 12 FFPE tissues, including tissues from nine primary and metastatic breast cancer and three primary ovarian high-grade serous carcinomas. This was followed by downstream shallow whole-genome sequencing (WGS) for copy number landscape profiling (10 samples) and/or a targeted panel for somatic mutation and sCNA analysis (seven samples), subject to cell availability. Seven out of 10 samples (even some with low tumour content or of old age) produced good-quality genomic data, detecting sCNA in all carcinoma population samples but not in the stromal populations. Mutation analysis was performed successfully in 6/7 samples and somatic mutations were detected in all of them. Our workflow enabled the identification of clinically actionable targets, including PIK3CA, ERBB2, FGFR1/2, CDK6, CCNE1, KRAS amplifications and RB, BRCA1/2 losses in patients that would direct therapy. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Issues and missed opportunities in lymph node assessment after neoadjuvant chemotherapy.
Ryan L, Provenzano E, Grigoriadis A … +1 more , Pinder SE
J Pathol · 2025 Dec · PMID 41132035 · Full text
Assessment of axillary lymph nodes in breast cancer patients following neoadjuvant chemotherapy (NACT) is a crucial part of the clinical and pathological assessment of the disease and has prognostic and management implic...
Assessment of axillary lymph nodes in breast cancer patients following neoadjuvant chemotherapy (NACT) is a crucial part of the clinical and pathological assessment of the disease and has prognostic and management implications. This, however, currently lacks standardisation and focuses only on the number of lymph nodes with metastases still present, the largest metastasis, and the presence of pathological complete response. Potential changes in any residual disease or within the lymph node parenchyma are not examined. Novel methods of more nuanced approaches are rare in the literature, even when considering multiple cancer types, but can offer an insight into the potential additional information to be gained and improvement in patient stratification. Given how common NACT is as the backbone of cancer therapy, there is a surprising lack of research into the lymph node response and determination of the biological factors driving what is seen histologically. Furthermore, with NACT now being administered alongside immunotherapy, there is an increasing need to understand the functional and architectural changes induced in the lymph nodes by metastatic tumour and systemic therapies. This review summarises current approaches, with breast cancer as an exemplar, and discusses the literature investigating a possible more granular approach to lymph node assessment after NACT. Translating these multiple carcinoma studies to breast cancer patients may prompt tissue-based research and, with clinical validation studies, changes to the reporting of lymph node response, for example percentage of viable tumour and immunological architectural features such as germinal centres. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Genetic landscape of non-UV-induced cutaneous squamous cell carcinomas.
Al Youssef C, Alkobtawi M, Safi R … +18 more , Chanal J, Sohier P, Leclerc-Mercier S, Zehou O, Ortonne N, Moguelet P, Senet P, Adoux L, Letourneur F, Bergqvist C, Abbas O, Kibbi AG, Bodemer C, Ferré VM, Guégan S, Oulès B, Aractingi S, Nassar D
J Pathol · 2025 Dec · PMID 41132030 · Publisher ↗
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and is most often caused by cumulative UV exposure. However, cSCC may also arise independently of UV exposure, on sites of sustained skin dam...
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and is most often caused by cumulative UV exposure. However, cSCC may also arise independently of UV exposure, on sites of sustained skin damage like chronic ulcers, scars, Recessive Dystrophic Epidermolysis Bullosa (RDEB), and inflammatory skin diseases such as hidradenitis suppurativa (HS). Little is known about non-UV-induced skin carcinomas. We aimed to describe the clinical, pathological, and genetic features, of non-UV-induced cSCC. We collected clinical and pathologic data corresponding to 31 patients with non-UV-induced cSCC, including 5 cSCC on HS, 4 on chronic leg ulcers and 8 on RDEB. DNA was extracted from FFPE samples and analysed using a NGS assay targeting 523 cancer genes. A comparison was performed with published genetic data obtained in non-UV-induced and UV-induced cSCC. We found that the Tumour Mutational Burden (TMB) of non-UV-induced cSCC was 6-times lower than the published TMB of UV-induced cSCC. The predominant mutational signature was a clock-wise signature. By comparing the frequency of driver mutations, we found TP53 and NOTCH1 to be significantly less frequently mutated than in UV-mutated cSCC. Interestingly, KMT2B (a histone methyl transferase) was mutated in 11/31 non-UV-induced cSCC and this proportion was significantly higher than in UV-mutated cSCC. These mutations were high impact loss-of-function mutations. We found that knocking down KMT2B expression using siRNA did not affect cell proliferation of SCC-13 and A-431 cell lines, however, it significantly increased cell migration in vitro. Taken together, this study provides a comprehensive description of non-UV-induced cSCC and identifies that KMT2B is mutated and involved in non-UV-induced cSCC carcinogenesis. © 2025 The Pathological Society of Great Britain and Ireland.
Fibroblast-specific palladin drives kidney fibrosis via MRTF-SRF signaling.
Yamamoto N, Sakai N, Yamamura Y … +25 more , Kaikoi D, Hayashi D, Matsuno T, Koshino A, Sako K, Horikoshi K, Yuasa T, Tamai A, Minami T, Oshima M, Nakagawa S, Kitajima S, Hara A, Shimizu M, Terakawa J, Horike SI, Daikoku T, Mizokami A, Ikeda H, Kadoguchi M, Arakawa H, Ohtsuki S, Lagares D, Wada T, Iwata Y
J Pathol · 2026 Jan · PMID 41131992 · Full text
Fibrosis is a common end-stage pathway of progressive chronic kidney diseases. Previously we demonstrated that myocardin-related transcription factor (MRTF)-serum response factor (SRF) signaling drives the expression of...
Fibrosis is a common end-stage pathway of progressive chronic kidney diseases. Previously we demonstrated that myocardin-related transcription factor (MRTF)-serum response factor (SRF) signaling drives the expression of fibrosis-related molecules through actin cytoskeleton dynamics in renal fibroblasts. However, it has not been elucidated whether actin-associated proteins relate to the pathogenesis of fibrosis. Here, we reveal that the actin cytoskeleton-regulating pathway is significantly correlated with estimated glomerular filtration rate (eGFR) and collagen type 1 alpha 1 expression in human proteome analysis. We found that palladin was one of the TGF-β1-dependent actin-associated proteins in renal fibroblasts. Our mechanistic studies demonstrated that palladin activates MRTF-SRF signaling via actin cytoskeleton rearrangement upon TGF-β1 stimulation. In addition, palladin expression itself was enhanced by MRTF-SRF signaling, indicating a positive feedback loop. In vitro, genetic silencing of the palladin-MRTF-SRF axis suppressed extracellular matrix production and myofibroblast differentiation. In preclinical models in vivo, fibroblast-specific palladin-deficient mice (palladin) were protected from kidney dysfunction and fibrosis that developed in adenine-induced nephropathy, which was associated with reduced numbers of myofibroblasts compared to wild type (palladin) mice. In patients with renal disease, palladin was significantly upregulated in the renal interstitium of patients with low eGFR and kidney fibrosis. Moreover, upregulation of the palladin-MRTF-SRF axis correlated with kidney function and fibrosis in patients with various kidney diseases, including IgA nephropathy, diabetic nephropathy, and nephrosclerosis. Taken together, we consider palladin to be a novel regulator of actin cytoskeleton signaling in fibrotic fibroblasts and represents a novel therapeutic target for the treatment of progressive kidney diseases. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Lactate-mediated activation of GPR81 regulates BCR/Abl protein expression in chronic myeloid leukemia cells selected under low oxygen tension.
Menegazzi G, Desideri D, Biagioni A … +3 more , Rovida E, Dello Sbarba P, Peppicelli S
J Pathol · 2025 Dec · PMID 41128634 · Full text
Chronic myeloid leukemia (CML) is a stem cell-driven neoplasia characterized by the expression of the constitutively active tyrosine kinase (TK) BCR/Abl. Under low oxygen, a condition that characterizes stem cell niches...
Chronic myeloid leukemia (CML) is a stem cell-driven neoplasia characterized by the expression of the constitutively active tyrosine kinase (TK) BCR/Abl. Under low oxygen, a condition that characterizes stem cell niches (SCNs) in vivo, the oncogenic BCR/Abl is suppressed. Consequently, leukemia stem cells (LSCs) residing within SCNs show resistance to TK inhibitors (TKIs), the first-line therapy for CML, due to the lack of their molecular target. It is therefore important to deepen understanding of the mechanisms driving BCR/Abl suppression to design new strategies able to repress TKI-resistant LSCs. Our previous studies showed that BCR/Abl suppression occurred when glucose approaches completed exhaustion in culture medium. As lactate is the main byproduct of glucose catabolism in low oxygen, in this study we addressed the role of lactate in regulating BCR/Abl expression. We found that treatment of CML cells with 2-DG, which blocks glycolysis and thereby lactate production, or monocarboxylate transporter (MCT) inhibitors, which reduce lactate excretion, enhanced BCR/Abl expression and promoted maintenance of a BCR/Abl-dependent/TKI-sensitive stem cell phenotype. The effects of MCT inhibition were abolished when exogenous lactate was added to culture medium, resulting in the suppression of BCR/Abl expression. Treatment with 3-hydroxy-butyrate acid, an antagonist of the GPR81 plasma membrane 'lactate' receptor, prevented lactate-driven BCR/Abl suppression, while the selective GPR81 agonist 3-chloro-5-hydroxy-BA counteracted the maintenance of BCR/Abl induced by MCT inhibition. Our results indicate that GPR81 engagement by extracellular lactate determines BCR/Abl suppression in low oxygen environments. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Metamorphoses in pancreatic cancer precursors: the role of simple mucinous cysts.
Camisa PR, Campa D, Esposito I … +1 more , Crippa S
J Pathol · 2026 Mar · PMID 41122920 · Publisher ↗
Pancreatic cystic lesions present a unique opportunity to identify and potentially prevent pancreatic ductal adenocarcinoma (PDAC), one of the deadliest solid tumors. Until now, research has primarily focused on intraduc...
Pancreatic cystic lesions present a unique opportunity to identify and potentially prevent pancreatic ductal adenocarcinoma (PDAC), one of the deadliest solid tumors. Until now, research has primarily focused on intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs), whose potential for malignant transformation is well established. In recent years, however, a new pathological entity has emerged: the simple mucinous cyst (SMC). SMCs are distinct from other cystic lesions, as they lack both communication with the pancreatic ductal system (a hallmark of IPMNs), and the ovarian-like stroma, characteristic of MCNs. The recent work by Pea et al, published in The Journal of Pathology, suggests that these lesions can progress to PDAC, underscoring the need for further characterization. In this commentary, we review the key findings of this study and discuss the potential next steps required to translate these discoveries into actionable clinical practice. © 2025 The Pathological Society of Great Britain and Ireland.
Super resolution of pathology images with hierarchical feature integration and local image patterns.
Xu F, Li L, Wang S … +6 more , Ling R, Zhang X, Deng X, Zhou M, Ling J, Gao C
J Pathol · 2025 Dec · PMID 41081336 · Publisher ↗
Recent advancements in pathological imaging have facilitated single-cell and subcellular-level analysis based on high-resolution images for tumor subtyping, cytomorphological assessment, and infection detection. As high-...
Recent advancements in pathological imaging have facilitated single-cell and subcellular-level analysis based on high-resolution images for tumor subtyping, cytomorphological assessment, and infection detection. As high-resolution imaging is often limited by cost, super-resolution methods provide a practical alternative with only low-resolution data. However, existing methods generally suffer from artifacts, oversmoothing, and slow inference speed. In this study, we developed a hierarchal deep learning framework based on local pathological image patterns, named Hierarchical Local Image Patterns (HLIP), to achieve accurate, high-fidelity, and real-time super resolution with flexible magnifications. HLIP integrates semantic features with both pixel- and morphology-level features and reconstructs super-resolution images by the recognized local pathological image patterns. Benchmark analysis showed HLIP achieved the best performance and robustness on both internal and external test datasets. The generated super-resolution images contain abundant pathological details and maintain high fidelity. HLIP can be used for the enhancement of other models across multiple clinical scenarios, including gland segmentation, cell segmentation, Helicobacter pylori detection, and therapy response prediction. With its superior performance in pathology image super resolution, HLIP offers a versatile tool for image preprocessing in computer-aided systems, thereby supporting accurate diagnosis in clinical practice. © 2025 The Pathological Society of Great Britain and Ireland.
Correction to 'Development and characterization of improved unifocal primary mouse lung cancer models with metastatic potential'.
J Pathol · 2025 Nov · PMID 41077781 · Full text
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DNA-hypermethylated human gastric cancer circumvents apoptosis in the absence of TP53 mutation.
Mano Y, Matsusaka K, Seki M … +12 more , Kita K, Fukuyo M, Rahmutulla B, Usui G, Fujiki R, Urabe M, Abe H, Matsubara H, Ushiku T, Seto Y, Fukayama M, Kaneda A
J Pathol · 2025 Dec · PMID 41065300 · Publisher ↗
p53 is one of the most important tumour suppressors exerting antitumour effects primarily via apoptosis. TP53 mutations are common in gastric tumorigenesis; however, nearly half of the gastric cancers (GCs) remain wildty...
p53 is one of the most important tumour suppressors exerting antitumour effects primarily via apoptosis. TP53 mutations are common in gastric tumorigenesis; however, nearly half of the gastric cancers (GCs) remain wildtype TP53 (TP53_WT). We investigated epigenetic/genetic profiles of GCs and the carcinogenic mechanisms underlying GCs with TP53_WT. Comprehensive DNA methylation analysis revealed four DNA methylation epigenotypes (MEs) in GCs, namely, high ME (HME), extremely HME (E-HME), low ME (LME), and extremely LME (E-LME). E-HME matched Epstein-Barr virus (EBV)-positive GC (E-HME/EBV). HME can be further categorised into MLH1-deficient (HME_MLH1(-)) and -proficient cases. The Cancer Genome Atlas data confirmed that HME_MLH1(-)/microsatellite instability (MSI) and E-HME/EBV cases significantly retained TP53_WT and had higher MDM2 expression levels than other MEs. We hypothesised that apoptosis pathways in TP53_WT GC may be suppressed post-transcriptionally by activated MDM2. Short hairpin RNA-mediated MDM2 knockdown and the p53-MDM2 inhibitors, nutlin-3 and RG7388, induced apoptosis in TP53_WT GC cells, indicating that activated MDM2 suppressed p53 protein levels and thereby attenuated the downstream p53 pathway activation, which was restored upon MDM2 knockdown or inhibitor treatment. Collectively, DNA-hypermethylated GC cases, HME_MLH1(-)/MSI and E-HME/EBV, follow a unique carcinogenic pathway to evade apoptosis in the absence of TP53 mutation, potentially making them responsive to therapeutic strategies that function primarily through the p53 pathway. © 2025 The Pathological Society of Great Britain and Ireland.
Expression of SARS-CoV-2 entry-associated proteins in COPD airways: an immunohistochemical study.
Vlaming-van Eijk LE, Sarsam Z, Bakker J … +3 more , Reinders-Luinge M, Brandsma CA, Timens W
J Pathol · 2025 Dec · PMID 41047996 · Full text
Coronavirus disease 2019 (COVID-19) is of special concern to patients with chronic obstructive pulmonary disease (COPD), given their susceptibility to exacerbations caused by respiratory tract infections. As the suscepti...
Coronavirus disease 2019 (COVID-19) is of special concern to patients with chronic obstructive pulmonary disease (COPD), given their susceptibility to exacerbations caused by respiratory tract infections. As the susceptibility of acquiring a SARS-CoV-2 infection in COPD remains unclear, this study explored the airway expression of SARS-CoV-2 entry-associated proteins in the lungs of COPD patients in comparison to non-COPD controls. Immunohistochemical staining of lung tissue was performed to investigate the expression profiles of SARS-CoV-2 entry-associated proteins in the bronchial epithelium of 27 COPD patients and 40 non-COPD controls. In addition, the associations between these expression profiles with lung function in COPD patients and smoking status in non-COPD controls were examined. COPD patients demonstrated smoking-independent lower expression of HSPA5, NRP1, BSG, TMPRSS2, and ITGB6 in airway epithelium as compared to non-COPD controls. No significant differences were observed for Furin, CTSL, ADAM17, and ITGA5. BSG percentage area expression was significantly negatively associated with lung function in COPD patients. Moreover, the study revealed smoking-associated differences for Furin, HSPA5, ADAM17, BSG, ITGA5, and ITGB6 within non-COPD controls, with lower airway epithelial expression (except for Furin) in ever-smokers than in never-smokers. To conclude, this study showed a lower expression of a specific set of SARS-CoV-2 entry-associated proteins in the bronchial epithelium of COPD patients compared with non-COPD controls, while other factors showed similar expression levels. The consequences of these findings on COVID-19 susceptibility remain uncertain. Although reduced expression of entry factors may suggest less cellular availability for viral entry, it could be speculated that the similar expression levels of other factors, together with impaired airway clearance in COPD, may still facilitate infection, thereby providing potential mechanistic insight into COVID-19 susceptibility in this patient population. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
KMT2D deficiency potentiates antitumor immunity and sensitizes immune checkpoint blockade in urologic cancers.
Ye Y, Liao Y, Zhang Y … +11 more , Zhang J, Luo M, Yang Q, Zhai Q, Xu Z, Wang Y, Wen H, Wu C, Qiu Y, Lv S, Wei Q
J Pathol · 2025 Dec · PMID 41047992 · Publisher ↗
Immune checkpoint blockade (ICB) therapy has made remarkable advances in cancer treatment. However, the overall response rate remains limited. Here, we aim to explore the role of histone 3 lysine 4 mono-methyltransferase...
Immune checkpoint blockade (ICB) therapy has made remarkable advances in cancer treatment. However, the overall response rate remains limited. Here, we aim to explore the role of histone 3 lysine 4 mono-methyltransferase KMT2D in tumor immune response and improve the efficacy of ICB. We developed a patient-derived urologic tumor fragment (PDUTF) platform comprising 56 tumors and constructed three major urological tumor tissue microarrays from 356 patients. Analyzed using the PDUTF platform and tissue microarrays (TMAs), we found that tumors with KMT2D deficiency were associated with enhanced T-cell activation in response to anti-PD-1 therapy and exhibited increased T-cell infiltration. Subsequently, T-cell migration and T-cell-mediated tumor cell killing assays revealed that the deletion of KMT2D in cancer cells promoted CD8 T-cell migration and cytotoxicity against tumor cells. Mechanistically, the loss of KMT2D enhanced antitumor immunity by promoting chemokine-mediated recruitment of T cells both in vitro and in vivo. Finally, the small-molecule inhibitor MI-503 combined with anti-PD-1 therapy suppressed tumor growth on the PDUTF platform. Collectively, KMT2D deficiency sensitizes tumor cells to ICB, and inhibiting KMT2D may represent a promising approach in combination with ICB to improve patient prognosis. © 2025 The Pathological Society of Great Britain and Ireland.
Androgen receptor-mediated regulation of BRCA1 modulates the antioxidant defense in prostate cancer.
Sriraman S, Virtanen V, Kukkula A … +6 more , Toriseva M, Lumiainen A, West G, Poutanen M, Taimen P, Sundvall M
J Pathol · 2025 Dec · PMID 41047927 · Full text
Lethal prostate cancer (PCa) is a genetically heterogeneous disease characterized by evolving androgen receptor (AR) signaling, eventually culminating in castration resistance. The tumor suppressor gene BRCA1 has multipl...
Lethal prostate cancer (PCa) is a genetically heterogeneous disease characterized by evolving androgen receptor (AR) signaling, eventually culminating in castration resistance. The tumor suppressor gene BRCA1 has multiple functions that include secondary processes cooperating with its main function as a caretaker of genomic integrity. BRCA1 is often mutated in breast and ovarian cancer, but BRCA1 mutations are also associated with PCa, although they are less frequently observed. Most PCa patients do not, however, carry BRCA1 mutations, and interestingly, it has been shown that BRCA1 expression is enriched in castration-resistant PCa. In this study we elucidated the prostate tissue-specific role of the BRCA1 protein. Although the regulation of DNA damage response genes has been studied in PCa, comprehensive analyses of BRCA1 regulation in the context of androgen signaling are lacking. Our results indicate that BRCA1 is dynamically regulated by AR signaling and that activation of AR via its natural ligand, dihydrotestosterone, represses BRCA1 expression. Our analyses both in vitro and of patient samples and mouse xenografts showed that BRCA1 expression was induced and sustained after androgen deprivation. Moreover, we observed that oxidative stress-related pathways were regulated by BRCA1 in PCa cells and that androgen deprivation therapy-induced activation of BRCA1 supported the function of NRF2, the master regulator of antioxidant defense, and a known interactor of BRCA1. Impaired NRF2 activity, in the absence of BRCA1, decreased growth in a 3D environment. Our findings shed light on the functional role of BRCA1 protein in PCa and suggest that BRCA1 is regulated by the evolving AR signaling state during PCa progression. Thus, AR-mediated suppression of BRCA1 accumulates oncogenic alterations in the early phases of PCa tumor progression and safeguards from excessive reactive oxygen species (ROS) when upregulated during androgen deprivation therapy. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Mutation profiling in differential diagnosis between TdT-positive high-grade/large B-cell lymphoma and B-lymphoblastic leukaemia/lymphoma.
Tzioni MM, Cucco F, Rásó-Barnett L … +25 more , Chen Z, Wotherspoon A, Kurz KS, Madej E, Makker J, Strazda AE, Guo F, Egan C, Soilleux E, Hook L, Krenacs L, Geyer JT, Laurent C, Xerri L, Mescam L, Plank L, Rahbek Gjerdrum LM, Lopez-Hisijos N, Greiner T, Khoury J, Klapper W, Oschlies I, Rosenwald A, Ott G, Du MQ
J Pathol · 2025 Dec · PMID 41047873 · Full text
Terminal deoxynucleotidyl transferase (TdT) is occasionally expressed in large B-cell lymphoma (LBCL), and this causes difficulty in differential diagnosis from B-lymphoblastic leukaemia/lymphoma (B-ALL/LBL). We reviewed...
Terminal deoxynucleotidyl transferase (TdT) is occasionally expressed in large B-cell lymphoma (LBCL), and this causes difficulty in differential diagnosis from B-lymphoblastic leukaemia/lymphoma (B-ALL/LBL). We reviewed 31 cases of TdT-positive LBCL and B-ALL/LBL, and their final diagnosis included 19 diffuse large/high-grade BCLs with MYC and BCL2 rearrangements (five DLBCL-MYC/BCL2, 14 HGBCL-MYC/BCL2), three DLBCL not otherwise specified (NOS), three HGBCL-NOS, four B-ALL/LBL, and two unclassifiable cases. TdT was variably expressed in all these cases, without any clear demarcation among different groups. Loss or partial loss of CD20 expression was seen in 13/17 DLBCL/HGBCL-MYC/BCL2, 2/3 HGBCL-NOS, and 2/2 unclassified, albeit not in DLBCL-NOS. Expression of BCL6 and/or MUM1 was seen in 3/4 B-ALL/LBLs and 2/2 unclassified. Next-generation sequencing revealed characteristic mutations associated with follicular lymphoma and its high-grade transformation in each DLBCL/HGBCL-MYC/BCL2, and also frequent variants in genes targeted by somatic hypermutation (SHM) in almost all DLBCL/HGBCL-MYC/BCL2, DLBCL-NOS, and HGBCL-NOS but one case. In contrast, such mutations were absent in B-ALL/LBL. There were no pathognomonic mutations in the two unclassifiable cases, although one showed a moderate level of somatic mutations in its rearranged IGHV. Furthermore, in three cases of TdT-positive HGBCL-MYC/BCL2, studies of previous or concurrent follicular lymphoma demonstrated their divergent evolution from an IGH::BCL2-positive cell population following acquisition of MYC translocation. In conclusion, mutation profiling analysis including the SHM target genes is highly valuable in the differential diagnosis between TdT-positive LBCL and B-ALL/LBL. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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