The Journal Of Pathology[JOURNAL]
Sun
200 papers
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.
Cribriform pattern and IDC-P in prostate biopsies: prognostic relevance and reporting in metastatic disease.
Okubo Y, Kasajima R, Sato S … +14 more , Yamamoto Y, Suzuki A, Aigase T, Yuguchi S, Hasegawa C, Yoshioka E, Washimi K, Matsuyama R, Hiroshima Y, Nakaigawa N, Narimatsu H, Kishida T, Yokose T, Miyagi Y
J Pathol Clin Res · 2025 Nov · PMID 41063546 · Full text
Cribriform pattern and intraductal carcinoma of the prostate are recognized adverse histological features, yet their prognostic value in treatment-naïve metastatic disease remains uncertain. We conducted a single-center...
Cribriform pattern and intraductal carcinoma of the prostate are recognized adverse histological features, yet their prognostic value in treatment-naïve metastatic disease remains uncertain. We conducted a single-center retrospective study of 183 biopsy-proven prostate carcinomas (105 with metastatic castration-sensitive prostate carcinoma and 78 non-metastatic high-grade cases) diagnosed between 2017 and 2024. Cribriform pattern, intraductal carcinoma of the prostate, and coagulative tumor necrosis were recorded per core and summarized as patient-level binary status and as semiquantitative proportions per cancer-positive core. Two multivariable logistic regression models (binary and semiquantitative) were fitted, and receiver operating characteristic (ROC) analysis evaluated the discriminatory performance of the cribriform proportion. Cribriform pattern and intraductal carcinoma of the prostate were more frequent in metastatic castration-sensitive prostate carcinoma. In the semiquantitative model, the cribriform proportion remained independently associated with metastatic status [odds ratio (OR) 1.29, 95% CI 1.07-1.55, p = 0.008; per 1.0 increase in the proportion, equivalent to OR 1.03 per 10%-point increase], whereas necrosis remained significant only in the binary model. The cancer-positive core rate and a lower total number of biopsy cores were predictive in both models, whereas prostate-specific antigen, intraductal carcinoma of the prostate, and Grade Group composition were not independent predictors. ROC analysis for the cribriform proportion yielded an area under the curve of 0.704, with a Youden Index cut-off of 0.445 (approximately half of cancer-positive cores), corresponding to a sensitivity of 57.1% and a specificity of 75.6%. These findings indicate that semiquantitative reporting of cribriform pattern - expressed as the proportion of cancer-positive cores - adds discriminatory information for metastatic status at presentation and could complement binary reporting in high-grade disease. From a clinical perspective, such evaluation may refine risk stratification at diagnosis and support treatment intensification strategies in very-high-risk patients.
Histopathology-based assessment of the tumour microenvironment in gastrointestinal cancers: practical approaches to prognostication and treatment stratification.
Ni SY, Leung HH, Chan AW
J Pathol Clin Res · 2025 Nov · PMID 41054972 · Full text
The tumour microenvironment (TME) is a key factor in carcinogenesis by affecting tumour growth, invasion, metastasis, and drug resistance. Histopathology and immunohistochemistry provide accessible and reproducible metho...
The tumour microenvironment (TME) is a key factor in carcinogenesis by affecting tumour growth, invasion, metastasis, and drug resistance. Histopathology and immunohistochemistry provide accessible and reproducible methodologies for TME evaluation, with growing evidence supporting their prognostic and predictive significance in gastrointestinal cancers. This commentary examines four papers published in the Journal of Pathology: Clinical Research that illustrate this methodology across various gastrointestinal cancers. The Tumour Microenvironment Score, Combined Immune Checkpoint Stromal Score, Immune Score for Gastric Cancer, and the multicomponent microenvironment and tumour inflammatory features panel have been developed to assess TME characteristics in colorectal cancer, gastric cancer, and gastroenteropancreatic neuroendocrine neoplasm. The reviewed studies demonstrate that basic morphological characteristics together with the expression of immune checkpoint markers and immune cell markers enable the development of effective clinical tools to enhance risk assessment and treatment planning. These practical, cost-effective, and promising methods need to undergo extensive multicentre testing with established protocols, digital pathology, and molecular information integration.
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.
Reduced GATA3 expression associates with immuno-metabolic alterations and aggressive features in breast cancer.
Sæle AK, Svanøe AA, Askeland C … +11 more , Knutsvik G, Ingebriktsen LM, Humlevik RO, Heie A, Aas T, Winge I, Collett K, Stefansson IM, Hoivik EA, Akslen LA, Wik E
J Pathol Clin Res · 2025 Nov · PMID 41024411 · Full text
In breast cancer (BC), the transcription factor GATA3 is linked to estrogen receptor (ER) alpha biology, and its loss is associated with aggressive tumor features. Little is reported about potential roles and implication...
In breast cancer (BC), the transcription factor GATA3 is linked to estrogen receptor (ER) alpha biology, and its loss is associated with aggressive tumor features. Little is reported about potential roles and implications of GATA3 independent of ER, and possible relationships to the BC tumor microenvironment (TME) have not been much explored. Thus, the discovery of novel biomarkers potentially linked to ER and GATA3 functions and predicting aspects of the TME could significantly improve precision in the management of patient subgroups. We examined GATA3 protein and mRNA expression in a large in-house population-based BC series (n = 837), and in the METABRIC datasets (METABRIC Discovery, n = 997 and METABRIC Validation, n = 995). Associations with primary BC phenotypes, transcriptional programs, TME features, clinical outcomes, and potentially independent roles of GATA3 are reported. We find that low GATA3 expression associates with aggressive features like increased tumor diameter, higher histological grade, triple negative BC, and a basal-like (CK5/6 positive) phenotype. Low GATA3 mRNA expression associated with downregulation of ER-related genes, upregulation of transcriptional signatures reflecting hypoxia, and enrichment of gene sets reflecting tumor cell proliferation, epithelial-mesenchymal transition, and stemness. Low GATA3 protein and mRNA expression both associated with overall reduced BC-specific survival. Notably, low GATA3 expression strongly associated with upregulation of immune checkpoint markers, T-cell activation, and metabolic alterations not previously described in BC. Gene expression patterns underlying GATA3-low tumors, independent of ER status, reflected activation of immunological and metabolic processes. This study suggests that GATA3 might influence the TME independent of ER status. Our results point to metabolic and immunophenotypic alterations in GATA3-low BCs, in particular with T-cell activation and increased expression of immune checkpoints. These findings could be relevant for patient selection in the context of immunotherapies and potential targeting of metabolic pathways.
Advancing homebrew AI in diagnostic practice: opportunities and barriers.
Khoury ZH, Sultan AS
J Pathol · 2025 Dec · PMID 40999996 · Full text
In a recent issue of The Journal of Pathology, Calderaro et al present a timely and persuasive argument advocating for the integration of homebrew artificial intelligence (AI) models in diagnostic pathology. Their articl...
In a recent issue of The Journal of Pathology, Calderaro et al present a timely and persuasive argument advocating for the integration of homebrew artificial intelligence (AI) models in diagnostic pathology. Their article is a robust defense of local model development within pathology departments as a pathway to democratizing digital diagnostics. This commentary expands on their premise, critically examining the real-world implications, practical limitations, and unmet needs of practicing pathologists. The commentary outlines both the opportunities and challenges for the widespread adoption of homebrew AI in pathology practice. Without institutional backing, digital infrastructure, and sustained training efforts, the promise of homebrew AI may falter. © 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.
Dysregulated mitochondrial energy metabolism drives the progression of mucosal field effects to invasive bladder cancer.
Lee S, Jung SY, Kuś P … +18 more , Bondaruk J, Lee JG, Jaksik R, Putluri N, Dinh KN, Cogdell D, Chen H, Wang Y, Chen J, Navai N, Dinney C, Mendelsohn C, McConkey D, Behringer RR, Guo CC, Wei P, Kimmel M, Czerniak B
J Pathol · 2025 Nov · PMID 40996337 · Full text
Multiplatform mutational and gene expression profiling complemented with proteomic and metabolomic spatial mapping were used on the whole-organ scale to identify the molecular profile of bladder cancer evolution from fie...
Multiplatform mutational and gene expression profiling complemented with proteomic and metabolomic spatial mapping were used on the whole-organ scale to identify the molecular profile of bladder cancer evolution from field effects. Analysis of the mutational landscape identified three types of mutations, referred to as α, β, and γ. Time modeling of the mutations revealed that carcinogenesis may span 30 years and can be divided into dormant and progressive phases. The α mutations developed in the dormant phase. The progressive phase lasted 5 years and was signified by expanding β mutations, but it was driven to invasive cancer by γ mutations. The mutational landscape emerged on a background of disorganized urothelial differentiation, activated epithelial-mesenchymal transition, and enhanced immune infiltration with T-cell exhaustion. Complex dysregulation of mitochondrial energy metabolism with downregulation of oxidative phosphorylation emerged as the leading mechanism driving the progression of mucosal field effects to invasive cancer. © 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.
Tracing metastatic spread in pediatric solid tumors using copy number and targeted deep sequencing.
Andersson N, Ferro M, Jansson C … +3 more , Chattopadhyay S, Karlsson J, Gisselsson D
J Pathol · 2025 Nov · PMID 40985487 · Full text
The most common cause of death in pediatric cancer patients is a treatment-resistant tumor, compounded by metastatic spread, making surgery, radiation therapy, and chemotherapy unfeasible as curative treatment options. H...
The most common cause of death in pediatric cancer patients is a treatment-resistant tumor, compounded by metastatic spread, making surgery, radiation therapy, and chemotherapy unfeasible as curative treatment options. However, the mechanisms behind metastatic spread in pediatric tumors remain largely unexplored. We conducted whole-genome copy number profiling on 171 primary tumor and metastases samples from 17 patients with neuroblastoma, Wilms tumor, or gonadal tumors, and performed targeted deep sequencing on a subset. Phylogenetic reconstruction enabled spatiotemporal tracking of subclones. In total, 11 of 17 patients displayed at least one metastasis arising earlier, defined as occurring before the most recent common ancestor in the primary tumor. In eight patients, metastatic spread was observed several times during tumor evolution, with different subclones from the same primary tumor having metastatic capability, even colonizing the same site. Strikingly, dissemination between metastases (intermetastatic spread) occurred in eight of nine patients with metastases in at least two different sites, indicating that this is a common phenomenon in pediatric malignancy. © 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.
Computational pathology in the age of artificial intelligence - embrace not fear.
Tan-Garcia A, Chua TH, Leow WQ
J Pathol Clin Res · 2025 Sep · PMID 40981474 · Full text
Anatomical pathology has traditionally relied on the interpretation of histomorphological features under a light microscope by trained pathologists for diagnosis. Technological advancements have enabled the digitisation...
Anatomical pathology has traditionally relied on the interpretation of histomorphological features under a light microscope by trained pathologists for diagnosis. Technological advancements have enabled the digitisation of tissue slides to produce high-resolution whole slide images, heralding the era of digital pathology (DP). Many laboratories around the world have incorporated DP into their routine workflows owing to the myriad applications it offers in facilitating tumour board discussions, remote reporting, teaching, and research. Most significantly, DP has engendered the field of computational pathology, a novel branch of histopathology incorporating artificial intelligence (AI) models. Computational pathology has been utilised in histomorphological quantification and diagnostic, predictive, and prognostic applications due to its potential to improve diagnostic accuracy, personalise treatment, and streamline workflows. Here, we highlight the work of Meier et al, Shen et al, and Lee et al, published in this journal in recent years, as they apply AI models to predict survival and treatment responses in gastric cancer, breast cancer, and diffuse large B-cell lymphoma, respectively. Collectively, these studies illustrate various approaches to incorporating AI into the DP pipeline and their potential clinical applications. Issues related to diagnostic accuracy, cost, patient confidentiality, and regulatory ethics still need to be addressed within the field. Despite this, the overall sentiment among pathologists is one of cautious optimism.
Automated multi-regional IHC scoring enhances prognostication in colorectal cancer.
Cheng J, Han Y, Yuan Y … +11 more , Huang S, Xiao B, Kong Y, Xue W, Yuan R, Liu H, Lan P, Wu X, Qian Y, Ni D, Chen Y
J Pathol Clin Res · 2025 Sep · PMID 40966320 · Full text
The tumor immune microenvironment plays a critical role in colorectal cancer (CRC) prognosis. However, most studies assess a limited set of immune markers manually in the tumor region, without considering immune heteroge...
The tumor immune microenvironment plays a critical role in colorectal cancer (CRC) prognosis. However, most studies assess a limited set of immune markers manually in the tumor region, without considering immune heterogeneity across multiple tissue regions. This study aims to enhance CRC prognostic assessment by developing an automated multi-regional immunohistochemistry (IHC) scoring system for 15 immune markers. Two representative tissue cores were extracted from CRC surgical specimens (n = 154) across four regions: tumor center, invasive margin, paracancerous tissues, and normal tissues. IHC staining was performed for 15 immune markers, and digitized slides were analyzed using computational algorithms to classify tissue types (e.g., glands, tumor, and stroma) and identify stained pixels. Immune infiltration was quantified in different tissue types across regions, and a tumor-to-healthy immune ratio (THIR) score was introduced to compare immune marker expression in tumor versus healthy stroma. Associations between IHC scores and overall survival (OS) and relapse-free survival (RFS) were evaluated. Computational models achieved 95.19% accuracy in tissue classification and 97.90% in staining identification. Analysis of 120 IHC scores (15 markers × 8 tissue types) revealed significant immune heterogeneity, with 56 scores correlating with OS and 54 with RFS. Notably, markers such as Granzyme B and CD4 had higher prognostic relevance at the invasive margin than the tumor center, while markers like S100 and CD20 exhibited opposing prognostic effects across regions. Integrating multiple markers significantly improved prognostic accuracy, with the combined marker score in normal stroma providing the most significant risk stratification (log-rank test, p = 1.56e-7, OS). The THIR score also strongly correlated with patient outcomes. This study advances CRC prognostication through automated multi-regional IHC scoring, highlighting the importance of immune heterogeneity across tissue regions. These findings support integrating region-specific immune profiling into clinical workflows for more personalized and precise patient care.
Histological types of invasive breast cancer in 830,000 women diagnosed in England during 1988-2016.
Probert J, Broggio J, Darby SC … +4 more , Dodwell D, McGale P, Taylor C, Gaitskell K
J Pathol Clin Res · 2025 Sep · PMID 40965430 · Full text
Breast cancer can be categorised into a number of histological types, based on microscopic appearances. There is some evidence that the different breast cancer histological types are associated with different patient and...
Breast cancer can be categorised into a number of histological types, based on microscopic appearances. There is some evidence that the different breast cancer histological types are associated with different patient and tumour characteristics, but few previous studies have been large enough to investigate this systematically, especially for rare histological types. National cancer registration data were used to describe trends in the incidence of specific histological types of invasive breast cancer in women diagnosed when aged 18-89 years in England from January 1988 to December 2016, and to investigate associations between breast cancer histological types and patient and tumour characteristics. There were 838,776 women diagnosed with a first primary invasive breast cancer in this 29-year period, including 614,698 (73%) cases of ductal carcinoma NST [no special type (NST)], 90,028 (11%) cases of lobular carcinoma, and more than 16,000 (2%) cases each of tubular and mucinous carcinomas. Rarer histological types included medullary, papillary, metaplastic, and cribriform carcinomas, with >1000 cases of each type. Data quality and completeness improved substantially during the study period. The different histological types of breast cancer showed different patterns in incidence by calendar period of diagnosis, age at diagnosis, and screen-detection status, as well as different associations with tumour characteristics such as grade, stage at diagnosis, and molecular subtype. This large nationwide study provides an overview of the changing incidence of the different histological types of invasive breast cancer in England over almost 30 years. It also gives an opportunity to investigate the characteristics of rare histological types, which smaller studies have been unable to explore. In addition, the results demonstrate the continuing value of histological types defined by microscopic morphology, alongside newer molecular classifications.
Somatic whole exome sequencing of colorectal carcinoma in young patients from sub-Saharan Africa reveals novel insights.
Aldera AP, Owusu D, Biral L … +4 more , Pillay K, Boutall A, Dave S, Ramesar R
J Pathol Clin Res · 2025 Sep · PMID 40958358 · Full text
Colorectal carcinoma (CRC) is a frequent cause of morbidity and mortality in sub-Saharan Africa. The incidence of early-onset, microsatellite stable (MSS) CRC is on the rise, and the tumour biology of these lesions is po...
Colorectal carcinoma (CRC) is a frequent cause of morbidity and mortality in sub-Saharan Africa. The incidence of early-onset, microsatellite stable (MSS) CRC is on the rise, and the tumour biology of these lesions is poorly categorised. Preliminary data from one centre in Nigeria found differences in the frequencies of mutations in driver genes and altered signalling pathways. We sought to investigate potential alternative driver genes and signalling pathways by whole exome sequencing. Eighty-three cases passed quality control filters and were included in the analysis (77 MSS, 4 microsatellite instability-high, and 2 POLE mutant). APC, TP53, and KRAS were among the most frequently mutated driver genes, although at a lower frequency than expected. BRAF V600E mutations were absent in our cohort. Although there were differences in the frequencies of mutations in the major driver genes, the frequencies of oncogenic pathway alterations were found to be similar. FAT4 (26%) and TET2 (15%) emerged as important mutated driver genes and potential therapeutic targets for further investigation. We have highlighted distinct differences in driver gene mutations in our cohort of young CRC from sub-Saharan Africa and have identified FAT4 and TET2 as potential drivers that are more common and are potential therapeutic targets.
Chromosomal instability and genomic alterations in cholangiocarcinoma from Northeastern Thailand.
Deenonpoe R, Guscott MA, Watcharadetwittaya S … +4 more , McNeill IL, Moralli D, Shaikh N, McClelland SE
J Pathol · 2025 Nov · PMID 40952339 · Full text
Cholangiocarcinoma (CCA) is a lethal cancer of the bile duct and is a major health concern in several parts of the world, including northeastern Thailand, where CCA incidence is the highest due to the endemic liver fluke...
Cholangiocarcinoma (CCA) is a lethal cancer of the bile duct and is a major health concern in several parts of the world, including northeastern Thailand, where CCA incidence is the highest due to the endemic liver fluke Opisthorchis viverrini. Multiple studies have characterised genomic alterations in CCA tumours, and specific chromosomal alterations can predict prognosis. However, it is not known whether chromosomal instability (CIN), ongoing genomic alteration characteristic of most cancer types, is present in CCA tumours. In this study we leveraged a panel of cancer cell lines derived from fluke-positive CCA patients, as well as a matched normal cholangiocyte line as a control, to characterise CIN in CCA. We observed elevated rates of chromosome segregation errors compared to normal cells, although overall CIN rates were lower than those for highly genomically unstable cancers, such as colorectal or ovarian cancer. Chromosome segregation errors in CCA cell lines were potentially driven by elevated DNA replication stress and centrosome duplication. Single-cell genome sequencing and karyotyping of the cell lines showed extensive structural and numerical chromosomal aberrations, as well as copy number alterations that were heterogeneous between individual cells, supporting the presence of ongoing CIN in these cell line models. Low-pass whole-genome sequencing of 33 CCA tumour samples with matched normal tissue from northeastern Thailand, a liver fluke-endemic region showed increased whole and subchromosomal level alterations, with a higher extent of genomic alterations in intrahepatic tumours compared to extrahepatic. Eight tumours carried focal amplifications and/or deletions involving known cancer genes, as well as potential chromosomal instability-associated genes, including CCNE1 amplifications and a rare amplification of BRCA1. This study provides increased understanding of the rate and potential mechanisms of CIN in CCA that may inform new therapeutic strategies that synergise with specific ongoing CIN mechanisms. © 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.
Periostin-IHH feedforward loop promotes hepatocellular carcinoma development by enhancing hepatic fibrosis and tumor cell proliferation.
Liu B, Li X, Zhang M … +5 more , Liu X, Sun J, Deng M, Ouyang G, Wu T
J Pathol · 2025 Nov · PMID 40936244 · Publisher ↗
The extracellular matrix protein periostin plays a critical role in the progression of hepatic fibrosis and hepatocellular carcinoma (HCC). However, little is known about how periostin regulates both hepatic fibrosis and...
The extracellular matrix protein periostin plays a critical role in the progression of hepatic fibrosis and hepatocellular carcinoma (HCC). However, little is known about how periostin regulates both hepatic fibrosis and tumor growth in the progression of HCC. Here we demonstrate that periostin deficiency impairs HCC development and decreases tissue stiffness of liver tumors in DEN/CCl-treated mice. Increased matrix stiffness enhanced periostin expression in hepatic stellate cells (HSCs). The combination of periostin and increased stiffness synergistically promoted HCC cell proliferation in vitro. Moreover, periostin deficiency in HSCs impaired both HSC-promoted and stiffness-increased HCC cell proliferation in vivo. We further demonstrated that periostin promotes Indian hedgehog (IHH) expression in HCC cells through the integrin-PYK2-TAZ pathway. Conversely, IHH increased the expression of periostin in HSCs via GLI2. Periostin expression positively correlates with fibrotic features and IHH signaling in clinical HCC tissues. Collectively, these findings indicate that periostin and IHH cooperatively contribute to the development of HCC by regulating the tumor-stroma crosstalk via the periostin-integrin-PYK2-TAZ-IHH pathway in tumor cells and IHH-GLI2-periostin signaling in HSCs. © 2025 The Pathological Society of Great Britain and Ireland.
Investigating the mechanisms of indocyanine green tumour uptake in sarcoma cell lines and ex vivo human tissue.
Chan CD, Brookes MJ, Pringle TA … +6 more , Pal R, Tanwani R, Burt AD, Knight JC, Kumar AT, Rankin KS
J Pathol · 2025 Nov · PMID 40928629 · Full text
Indocyanine green (ICG) is a well-established near-infrared dye which has been used clinically for several decades. Recently, it has been utilised for fluorescence-guided surgery in a range of solid cancer types, includi...
Indocyanine green (ICG) is a well-established near-infrared dye which has been used clinically for several decades. Recently, it has been utilised for fluorescence-guided surgery in a range of solid cancer types, including sarcoma, with the aim of reducing the positive margin rate. The increased uptake and retention of ICG within tumours, compared with normal tissue, gives surgeons a visual reference to aid resection when viewed through a near-infrared camera. However, the mechanisms of this process are poorly understood. We performed in vitro ICG cellular uptake studies across a panel of sarcoma cell lines exhibiting varying proliferation rates and phenotypes. The effects of ICG concentration, incubation time, inhibition of clathrin-mediated endocytosis, and cell line proliferation rate on the cellular uptake of ICG were investigated using fluorescence microscopy and flow cytometry. Subcellular localisation of intracellular ICG was assessed via colocalization with a lysosomal marker. The spatial distribution of ICG in patient tumour tissue following fluorescence-guided surgery was assessed by high-resolution tissue imaging and quantified using fluorescence lifetime imaging. In vitro results showed that the cell line proliferation rate correlated significantly with ICG uptake (Spearman's rank correlation coefficient = 1.00, p < 0.001), and maximum ICG uptake was observed after 24 h incubation. ICG cellular uptake was significantly reduced by inhibition of clathrin-mediated endocytosis (p = 0.0004), and intracellular ICG significantly colocalized with a lysosomal marker within 30 min (Pearson's r = 0.8). On histological analysis of tumour tissue from three different sarcoma subtypes, ICG was observed within sarcoma cells as well as accumulating in paucicellular areas of haemorrhage and necrosis within the tumour microenvironment. Through quantification of fluorescence lifetime imaging of ICG, we were able to differentiate sarcoma cells from haemorrhage and necrosis within tumour tissue. Combining in vitro data with analysis of patient tissue, we propose that the uptake and accumulation of ICG in sarcomas is driven by a synergistic mechanism involving the enhanced permeability and retention effect combined with active tumour cell endocytosis of the dye. © 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.
Sparking malignancy: nicotine as a driver of stemness and metastasis in triple-negative breast cancer.
Simpkins C, Toska E
J Pathol · 2025 Dec · PMID 40923665 · Publisher ↗
Triple-negative breast cancer (TNBC) lacks expression of estrogen receptor (ER), progesterone receptor (PR), and HER2, and remains one of the most aggressive and therapeutically challenging breast cancer subtypes, marked...
Triple-negative breast cancer (TNBC) lacks expression of estrogen receptor (ER), progesterone receptor (PR), and HER2, and remains one of the most aggressive and therapeutically challenging breast cancer subtypes, marked by early relapse, metastasis, and limited targeted treatment options. In a recent study published in The Journal of Pathology, Kuo et al provide compelling evidence that nicotine exposure, whether from tobacco smoke or e-cigarette vapor, drives TNBC progression by promoting stem-like and metastatic phenotypes. Integrating clinical datasets, patient tissues, cell lines, and in vivo models, the authors demonstrate that nicotine enhances tumor aggressiveness via coordinated upregulation of CHRNA9 and IGF1R. Silencing either receptor attenuates nicotine-induced stemness, invasion, and metastasis, revealing a therapeutically actionable axis. High expression of CHRNA9 and IGF1R correlates with poor clinical outcomes and may define a nicotine-exposed TNBC subgroup that could benefit from IGF1R-targeted therapy or repurposed nicotinic receptor antagonists. These findings underscore the role of environmental exposures in shaping tumor biology and offer a mechanistic basis for the poorer prognosis observed in smokers with breast cancer. © 2025 The Pathological Society of Great Britain and Ireland.
Impact of NLRP1 Met1154Val and IL1B variants on gestational malaria: an unexplored role of NLRP1 in inflammasome activation by Plasmodium spp.
Leal VN, Ribeiro JA, Marra LG … +6 more , Rio AT, Reis EC, Wunderlich G, Dombrowski JG, Marinho CR, Pontillo A
J Pathol · 2025 Nov · PMID 40923647 · Full text
We hypothesized that variants in inflammasome-related genes could influence susceptibility to gestational malaria (GM). To test this, we conducted an association study in a cohort of pregnant women from a malaria-endemic...
We hypothesized that variants in inflammasome-related genes could influence susceptibility to gestational malaria (GM). To test this, we conducted an association study in a cohort of pregnant women from a malaria-endemic region in northern Brazil, assessing whether specific functional single nucleotide variants (SNVs) in inflammasome genes affect (1) the response to Plasmodium infection and (2) the development of placental malaria. Our findings revealed that the NLRP1 p.Met1154Val variant was associated with a protective effect against Plasmodium infection. Moreover, IL1B SNVs appeared more prevalent in severe cases. Additionally, multivariate analyses incorporating placental blood cytokines, growth factors, and immunohistochemical features revealed that the NLRP1 p.Met1154Val variant correlated with a healthier placental state, highlighting a potential protective role of the NLRP1 inflammasome in GM. For the first time, we showed that infected red blood cells induce NLRP1- and caspase-1-dependent pyroptosis in BeWo trophoblast cells, identifying a novel inflammasome pathway involved in GM pathogenesis. Our study identifies a genetic variant underlying NLRP1 contribution to GM and suggests that NLRP1 may be an under-explored inflammasome receptor in malaria and infected erythrocytes' sensing. © 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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