J. Pathol. [JOURNAL]
Sun
200 papers
Relative MYC downregulation and RUNX2 upregulation orchestrate partial epithelial-mesenchymal transition in colorectal cancer tumor budding and poorly differentiated clusters.
Koba T, Hibiya T, Shibayama T … +9 more , Kato K, Onizuka H, Satomi K, Nagahama K, Sunami E, Abe N, Kawakami E, Shibahara J, Hayashi A
J Pathol · 2026 Mar · PMID 41511889 · Publisher ↗
Tumor budding and poorly differentiated clusters are key prognostic indicators in colorectal cancer, yet the molecular mechanisms underlying their formation remain incompletely characterized. Using the GeoMx Digital Spat...
Tumor budding and poorly differentiated clusters are key prognostic indicators in colorectal cancer, yet the molecular mechanisms underlying their formation remain incompletely characterized. Using the GeoMx Digital Spatial Profiler, we analyzed gene expression profiles across tubular components, transitional zones, and tumor budding and poorly differentiated cluster regions in 12 colorectal cancer cases. While histopathological assessment revealed no definitive evidence of complete epithelial-mesenchymal transition in tumor budding or poorly differentiated clusters, transcriptional analysis demonstrated significant upregulation of epithelial-mesenchymal transition-related genes (ZEB1, ZEB2, SNAI2) alongside maintained epithelial marker expression, indicating a partial epithelial-mesenchymal transition phenotype. Tumor budding and poorly differentiated cluster regions showed reduced proliferative activity with significant downregulation of MYC and its target genes involved in protein synthesis and cell cycle progression. Conversely, RUNX2 and its targets were significantly upregulated in tumor budding and poorly differentiated cluster regions, particularly genes mediating cell adhesion, migration, and extracellular matrix interactions. KRT80 showed striking upregulation in tumor budding and poorly differentiated cluster regions, correlating with RUNX2 expression. This reciprocal pattern of MYC downregulation and RUNX2 upregulation appears to contribute to maintaining the hybrid epithelial-mesenchymal state characteristic of tumor budding and poorly differentiated cluster regions. Our findings reveal that the formation of these regions involves transcriptional changes preceding morphological alterations, with RUNX2 potentially driving this invasive phenotype while preserving epithelial features. These insights may enhance our understanding of the mechanisms driving colorectal cancer progression and identify potential therapeutic targets for aggressive disease. © 2026 The Pathological Society of Great Britain and Ireland.
Dysregulated proteolytic cascades in Netherton syndrome: from molecular pathology to preclinical drug testing.
Zingkou E, Bisyris E, Pampalakis G … +1 more , Sotiropoulou G
J Pathol · 2026 Mar · PMID 41511866 · Full text
Netherton syndrome (NS) is a rare, severe, and often life-threatening disease for which current therapeutic approaches are limited and show variable effectiveness. NS is characterized by excessive epidermal desquamation...
Netherton syndrome (NS) is a rare, severe, and often life-threatening disease for which current therapeutic approaches are limited and show variable effectiveness. NS is characterized by excessive epidermal desquamation that results in a highly defective epidermal barrier, constitutive skin inflammation, allergies, and hair abnormalities. NS develops due to loss-of-function mutations in the SPINK5 gene, which encodes the LEKTI inhibitor that regulates KLK proteases (KLK5, KLK6, KLK7, KLK13, and KLK14). These findings indicate that dysregulation of proteolytic networks underlies the extensive skin shedding and inflammation characteristic of NS. Spink5 mice recapitulate the major features of the human disease but exhibit neonatal lethality. Several double- and triple-knockout models have been generated to rescue the lethal NS phenotype, and have proved instrumental in studies aiming to elucidate the biological pathways involved in NS, and to identify and validate potential targets for drug development. These studies have established that inhibition of excessive KLK protease activity in LEKTI-deficient epidermis can reverse the cutaneous manifestations of NS. In particular, ablation of KLK5 results in a marked therapeutic response, although KLK7 or TNFα must also be inhibited to rescue the most severe (lethal) form of NS. Murine models have also been essential in proving or disproving putative pathways and/or therapeutic targets proposed from in vitro studies or patient case studies. Collectively, these models have provided a deeper understanding of the epidermal proteolytic cascades involved in NS pathology and in normal skin renewal. Moreover, these models offer a platform in which disease-specific candidate therapeutics can be tested and preclinically validated. © 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.
Uncovering the potential of pathomics: prognostic prediction and mechanistic investigation of pancreatic cancer.
Liu L, Zhao X, Zhang F … +5 more , Huang Y, Wang Q, Fang Z, Zhu Y, Zhang Y
J Pathol · 2026 Mar · PMID 41508286 · Publisher ↗
A machine learning-based pathomics model was investigated for its value and biological significance in predicting overall survival (OS) after surgery in pancreatic cancer patients. Data from 173 patients with pancreatic...
A machine learning-based pathomics model was investigated for its value and biological significance in predicting overall survival (OS) after surgery in pancreatic cancer patients. Data from 173 patients with pancreatic ductal adenocarcinoma (PDAC) who underwent surgery and continued follow-up in two centers were retrospectively analyzed. Pathomics parameters of both the tumor and peritumor were measured in all patients, and the optimal pathomics score (Pathscore) was calculated using five machine learning methods. The best Pathscore was then combined with multiple clinical parameters to analyze its incremental value and to construct a comprehensive nomogram. TCGA data, multiplex immunofluorescence, spatial analysis, and single-cell sequencing were used to explore the biological mechanisms of pathomics. In predicting OS, pathomics parameters from the tumor and peritumoral regions provided complementary prognostic information. The LASSO-based combined model achieved the best predictive accuracy. Multivariate Cox regression analysis identified T-stage, N-stage, CA19-9, and Pathscore as independent predictors of OS in patients with PDAC. The integrated nomogram demonstrated superior and more stable predictive performance. Analysis of the TCGA dataset suggested that the pathomics model was associated with the immune status of pancreatic cancer, a finding supported by trends in the validation cohort. Spatial analysis and single-cell analysis further revealed a strong association between the Pathscore and immune cell infiltration, in particular CD8+ T cells. Machine learning-based pathomics models can help to predict the immune status and OS of patients with PDAC. The integration of pathomics with clinical parameters provides a robust basis for immune evaluation, prognostic prediction, and therapeutic decision-making in PDAC. © 2026 The Pathological Society of Great Britain and Ireland.
Integrated morphological, immunohistochemical, and genomic profiling identifies uterine leiomyoma patients with hereditary leiomyomatosis and renal cell cancer syndrome: a comprehensive analysis of 252 cases.
Liu Y, Wang X, Wang Y … +5 more , Ting X, Yang J, Hu A, Song Z, Liu C
J Pathol · 2026 Mar · PMID 41496563 · Publisher ↗
Fumarate hydratase-deficient uterine leiomyomas (FHd-ULMs) represent a molecularly distinct subgroup of smooth muscle tumours associated with hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. This study d...
Fumarate hydratase-deficient uterine leiomyomas (FHd-ULMs) represent a molecularly distinct subgroup of smooth muscle tumours associated with hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. This study determined the detection rate of germline pathogenic FH variants in FHd-ULMs using paired tumour-normal sequencing and assessed the utility of integrated morphological, immunohistochemical (FH/2SC), genomic, and clinical features for selecting cases suspected of HLRCC. Histopathological assessment of the 252 FHd-ULMs revealed consistent morphological features, whereas molecular profiling identified three biologically distinct categories. Germline FH-mutated (hereditary) cases constituted 35.7% (74/207) of this FHd-ULM cohort, four of which showed concomitant somatic copy-number alterations. This contrasted with the somatic-mutated subgroup, which comprised 50.7% (105/207), including 18.4% (38/207) with isolated somatic copy-number losses. The remaining 13.6% (28/207), though lacking detectable FH mutations, were classified with somatic-mutated cases as sporadic FHd-ULMs based on shared clinicopathological features. Molecular analysis identified shared variant distributions across exons 2-10, with exons 5 and 7 in the fumarate lyase domain emerging as the predominant mutational hotspots. Notably, truncating mutations showed significantly higher prevalence in hereditary cases versus somatic variants (p < 0.01). Clinically, hereditary FHd-ULMs presented at younger ages (< 45 years) and manifested more aggressive phenotypes, including elevated rates of infertility (54.1% versus 26.4%), multifocal tumour development (86.5% versus 53.4%), increased surgical interventions (44.6% versus 11.5%), and familial leiomyoma clustering (51.4% versus 24.2%). Our results identify germline FH mutations, which confer significant HLRCC risk, in 35.7% of FHd-ULMs, while somatic alterations account for the majority of cases. To ensure efficient resource allocation, we propose a stratified diagnostic approach: initial universal FH/2SC immunohistochemical screening for ULMs displaying ≥ 3 FH-deficient morphological features, followed by confirmatory genetic testing in high-risk individuals, defined by either aberrant FH/2SC immunoreactivity or, in immunohistochemically normal cases, age < 45 years together with a personal/family history of multiple symptomatic leiomyomas or HLRCC-associated neoplasms. © 2026 The Pathological Society of Great Britain and Ireland.
Delta-like 1 homolog (DLK1) regulates cancer stemness and chemoresistance of ovarian cancer by CD44/CD133 upregulation.
Huang CC, Wu JC, Chen PC … +7 more , Cheng SH, Kung ML, Wu MH, Wu CH, Li WY, Wu CS, Tai MH
J Pathol · 2026 Mar · PMID 41496518 · Publisher ↗
Ovarian cancer is a heterogeneous gynecologic malignancy, with most cases diagnosed at an advanced stage. Despite the availability of effective treatments such as surgery and platinum/taxane-based chemotherapy, advanced...
Ovarian cancer is a heterogeneous gynecologic malignancy, with most cases diagnosed at an advanced stage. Despite the availability of effective treatments such as surgery and platinum/taxane-based chemotherapy, advanced ovarian cancer frequently recurs, highlighting the need to investigate mechanisms of chemotherapy resistance. Delta-like non-canonical Notch ligand 1 (DLK1), a transmembrane protein of the EGF-like family, is aberrantly expressed in several cancers. Our previous study demonstrated that DLK1 promotes oncogenic behaviors and epithelial-mesenchymal transition in ovarian high-grade serous carcinoma. In this study, we observed a positive correlation between DLK1 and stemness markers CD44 and CD133 in human epithelial ovarian cancer using tissue microarray analysis. Overexpression of DLK1 by an adenovirus vector accelerated sphere-forming capability and upregulated CD44, CD133, and ABCG2 expression in human ovarian cancer cell lines. Conversely, DLK1 silencing by siRNA abolished the stimulatory effects on the stem cell-like properties and reduced CD44 and CD133 expression in ovarian cancer cells. Furthermore, DLK overexpression by an adenovirus vector enhanced colony formation and suppressed the cisplatin- and taxol-induced death in human ovarian cancer cells. Conversely, DLK1 siRNA reversed cell death and colony formation induced by these chemotherapeutic agents. Finally, we demonstrated that DLK1 regulates CD44, CD133, and ABCG2 expression through the Notch1/AKT/STAT3 signaling pathway, involving the phosphorylation and translocation of STAT3. Collectively, these results suggest that targeting DLK1 may represent a potential therapeutic strategy to improve outcomes in recurrent ovarian cancer following chemotherapy. © 2026 The Pathological Society of Great Britain and Ireland.
ERBB2 amplification is a late event in the pathogenesis of high-grade endometrial carcinomas with heterogeneous HER2 expression.
Chui MH, Brown DN, Reis-Filho JS … +2 more , Ellenson LH, Weigelt B
J Pathol · 2026 Mar · PMID 41496508 · Publisher ↗
Intratumor heterogeneity of ERBB2 amplification/HER2 overexpression is frequently observed in ERBB2-amplified high-grade endometrial carcinoma (HG-EC) and contributes to anti-HER2 therapy resistance. To elucidate the mol...
Intratumor heterogeneity of ERBB2 amplification/HER2 overexpression is frequently observed in ERBB2-amplified high-grade endometrial carcinoma (HG-EC) and contributes to anti-HER2 therapy resistance. To elucidate the molecular pathogenesis and evolutionary trajectory of HER2-heterogeneous HG-ECs, we performed next-generation sequencing of spatially distinct HER2-negative (HER2-) and HER2-positive (HER2+) tumor areas from nine tumors (whole exome, n = 7; targeted panel, n = 2). HER2- and HER2+ components shared a high proportion of somatic mutations, particularly clonal mutations, including known EC driver genetic alterations. The 17q12 amplicon, containing the ERBB2 gene, was the only significant recurrent copy number alteration that differed between HER2- and HER2+ components. By unsupervised hierarchical clustering of genome-wide copy number alterations, samples clustered together at the patient level rather than by HER2 status. Intra- and intertumor heterogeneity in ERBB2 amplification/HER2 expression was also observed in metastatic lesions, which likely originated from different tumor subpopulations within the primary tumor. Exploratory spatial transcriptomics analyses revealed gene expression differences associated with HER2 status, including a shift from 'mesenchymal-like' toward epithelial differentiation in HER2+ components for a subset of cases, a finding that warrants further investigation. Our results suggest that HER2 heterogeneity in HG-EC reflects late acquisition of ERBB2 amplification during tumor evolution. ERBB2 does not appear to drive tumor initiation in HER2-heterogeneous HG-EC but likely serves a context-dependent role in the progression of established tumors. © 2026 The Pathological Society of Great Britain and Ireland.
Integration of histopathological characteristics by machine learning improves the prediction of neoadjuvant immunochemotherapy response in triple-negative breast cancer.
Lu X, Luo B, Wei Y … +8 more , Zhang W, Wu X, Chen J, Shi H, Yuan J, Bu H, Yi Y, Gou Z
J Pathol · 2026 Mar · PMID 41496443 · Publisher ↗
Neoadjuvant immunochemotherapy (NAIC) is a standard treatment for triple-negative breast cancer (TNBC), but there is no reliable biomarker to identify potential responders and optimize patient care. In this study, we dev...
Neoadjuvant immunochemotherapy (NAIC) is a standard treatment for triple-negative breast cancer (TNBC), but there is no reliable biomarker to identify potential responders and optimize patient care. In this study, we developed a model named Immunotherapy Prediction based on Pathological Images (IPPI) by machine learning. The IPPI model performed well in the discovery cohort and two validation cohorts, which included a total of 209 patients, and its predictive power was significantly improved compared to clinical factors and the combined positive score for programmed death-ligand 1. TNBC patients predicted to achieve a pathological complete response had a better prognosis than those predicted to have residual disease. Moreover, we elucidated the relationship between histopathological features and biological characteristics, thereby improving the interpretability of the IPPI model. This study proposes a novel and efficient model to facilitate the prediction of NAIC response in TNBC patients, highlights key histopathological features associated with treatment response, and presents new evidence for precision immuno-oncology through the integration of machine learning and digital pathology. © 2026 The Pathological Society of Great Britain and Ireland.
Fibroblast-derived neuropilin 1 alleviates renal fibrosis progression.
Shen Y, Placier S, Louedec L … +8 more , Frère P, Vandermeersch S, Figueroa S, François H, Chadjichristos CE, Cohen C, Chatziantoniou C, Calmont A
J Pathol · 2026 Feb · PMID 41432227 · Full text
Chronic kidney disease (CKD) is a major global health challenge affecting over 10% of the adult population. A hallmark of CKD progression is the transdifferentiation of kidney fibroblasts into extracellular matrix-produc...
Chronic kidney disease (CKD) is a major global health challenge affecting over 10% of the adult population. A hallmark of CKD progression is the transdifferentiation of kidney fibroblasts into extracellular matrix-producing myofibroblasts, a key mechanism involved in the decline of kidney function and the development of kidney failure. Fibroblasts maintain the structural integrity of the kidney and support epithelial survival, repair, and regeneration after acute kidney injury. Maladaptive repair is a failure to resolve fibroblast activation, which ultimately progresses to chronic injury and CKD. In this study, we showed that the membrane-bound coreceptor neuropilin 1 (NRP1) was essential to maintain fibroblast function and prevent their transdifferentiation into myofibroblasts. We used the myelin protein zero-Cre (P0-Cre) to specifically abrogate Nrp1 in kidney resident fibroblasts during fibrosis progression. We employed kidney-induced interstitial fibrosis models combined with a lineage-tracing strategy, single-cell RNA sequencing analysis, and ex vivo explant cultures to reveal a cell autonomous protective role for NRP1 in limiting fibrosis. Furthermore, we extended the analysis by showing that Nrp1 conditional mutants were more prone to develop cardiac fibrosis in a mouse model of heart failure. Collectively, these findings provide new insights into the signalling pathways controlling the transition from acute to chronic kidney disease conversion and identify NRP1 as a novel regulator of fibroblast supportive function. © 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.
Truncated FOS impairs osteogenic differentiation and induces prostaglandin and NFκB signalling in an in vitro cell-of-origin model for osteoid osteoma and osteoblastoma.
Lam SW, Belova T, Franceschini N … +8 more , van den Akker B, van IJzendoorn DG, Mikkers HM, Mei H, Cleton-Jansen AM, Kuijjer ML, Szuhai K, Bovée JV
J Pathol · 2026 Mar · PMID 41424327 · Full text
Osteoid osteoma and osteoblastoma are non-malignant bone-forming tumours of the skeleton, characterised by the presence of irregular trabeculae of woven bone. Rearrangements in FOS, and less frequently FOSB, have recentl...
Osteoid osteoma and osteoblastoma are non-malignant bone-forming tumours of the skeleton, characterised by the presence of irregular trabeculae of woven bone. Rearrangements in FOS, and less frequently FOSB, have recently been identified in osteoid osteoma and osteoblastoma. Identical rearrangements in FOS were previously detected in epithelioid haemangioma, where these led to truncation of the FOS protein in the C-terminal domain, causing increased protein stability due to impaired degradation. Since FOS plays a role in osteogenic differentiation, the effect of FOS truncation on osteogenic differentiation and proliferation was investigated in an in vitro model for osteoid osteoma and osteoblastoma. In this model, truncated FOS (FOSΔ) was overexpressed in human foetal mesenchymal stem cells through a lentiviral vector. Osteogenic differentiation - assessed by measuring mineralisation, ALPL expression, and ALP activity - and proliferation rate were reduced in cells overexpressing FOSΔ compared to mesenchymal stem cells with an empty lentiviral vector (pLV). Transcriptome-sequencing and differential gene expression analysis revealed decreased gene expression of genes in pathways involving cell cycling and mitosis and osteogenic differentiation, including WNT signalling, extracellular matrix organisation, and matrix metalloproteinases (MMPs), in FOSΔ as compared to empty vector cells, indicating decreased proliferation and osteogenesis. Instead, FOSΔ cells showed upregulation of genes involved in prostaglandin signalling and NF-kB inflammatory pathways. These findings highlight that FOSΔ compromises cellular growth and osteogenesis, which is in line with the morphological features of osteoid osteoma and osteoblastoma with woven bone formation instead of mature lamellar bone, as well as the indolent clinical behaviour. Additionally, FOSΔ promotes inflammatory signalling instead, which correlates with clinically exquisite response to non-steroid anti-inflammatory drugs. © 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.
Molecular alterations in high-grade neuroendocrine tumors of the small intestine.
Hercent A, Masliah-Planchon J, Cohen D … +7 more , Nicolle R, Scoazec JY, Ruszniewski P, Bièche I, de Mestier L, Couvelard A, Cros J
J Pathol · 2026 Feb · PMID 41416936 · Full text
High-grade neuroendocrine tumors of the small intestine are separated into two groups: well-differentiated neuroendocrine tumors (NETs, high-grade) and poorly differentiated neuroendocrine carcinomas (NECs). They represe...
High-grade neuroendocrine tumors of the small intestine are separated into two groups: well-differentiated neuroendocrine tumors (NETs, high-grade) and poorly differentiated neuroendocrine carcinomas (NECs). They represent very rare entities, with few molecular data available, and are very challenging to treat. In this study we aimed to describe the molecular profile of these tumors and their spatial and temporal heterogeneity. We collected a national multicenter cohort of high-grade NETs (14 patients) and NECs (11 patients). DNA and RNA were extracted and somatic point mutations, copy number variations, and gene expression levels were studied using high-throughput sequencing of a panel of 571 genes and RNA sequencing, respectively. Additional samples to study spatial or temporal heterogeneity were available for 12 patients, leading to a total of 42 samples analyzed. Differential diagnostic markers were confirmed by immunohistochemistry. NECs resemble their counterparts in other organs, with a relatively high tumor mutational burden (TMB) and frequent alteration of TP53 and RB1, together with organ-specific alterations such as APC. In contrast, high-grade NETs resemble low-grade NETs, with a low TMB but frequent chromosomic alterations. Transcriptomic analysis confirmed that high-grade NETs and NECs are two distinct entities, with specific drivers. Serotonin pathway markers were the most efficient to discriminate high-grade ileal NETs from NECs. Despite variations in the proliferation index, NETs showed little spatial and temporal heterogeneity, suggesting that epigenetic mechanisms play a crucial role in tumor progression. © 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.
Ghent Pathology 2025. 15th Joint Meeting of the BDIAP and The Pathological Society joint with the Belgian Society of Pathology, 24-26 June 2025.
J Pathol · 2025 Dec · PMID 41404921 · Publisher ↗
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Spatial analysis of HPV-associated cervical intraepithelial neoplastic tissues demonstrate distinct immune signatures associated with cervical cancer progression.
Pavilion G, Vu H, Xiong Z … +7 more , Dang TVT, O'Brien B, Walsh M, Causer A, Chandra J, Nguyen Q, Frazer IH
J Pathol · 2026 Feb · PMID 41362277 · Full text
Cervical cancer remains the fourth most common cancer affecting women worldwide, and incidences of other HPV-related cancers continue to rise. For the development of effective prevention strategies in high-risk patients,...
Cervical cancer remains the fourth most common cancer affecting women worldwide, and incidences of other HPV-related cancers continue to rise. For the development of effective prevention strategies in high-risk patients, we aimed to better understand the roles of inflammatory pathways and the tumour microenvironment as the main driver of progression to malignancy in HPV-infected tissues. We analysed the spatial organisation of seven samples of HPV+ high-grade squamous intraepithelial lesion (HSIL) and cervical intraepithelial neoplasia 3 (CIN3), comparing tumour heterogeneity and immune microenvironments between premalignant (neoplastic) and adjacent cervical tissues. We observed evidence of immune suppression within the neoplastic regions across all samples and identified distinct immune clusters for each dysplastic lesion. Previous single-cell data analyses in an HPV16 E7 oncoprotein-driven transgenic mouse model suggested a potential role for IL34-CSF1R signalling in immune modulation, where low IL34 expression was associated with Langerhans cell dysfunction, and, in cervical cancer, with poor patient outcome. Here we observed that IL34-CSF1R coexpression was absent within HPV-associated neoplastic regions, but present in adjacent normal tissue regions. Additionally, we identified enrichment of an M2 gene signature in neoplastic regions, while adjacent tissue was enriched with a proinflammatory M1 gene signature. Our findings provide biopathological insights into the spatial cellular and molecular mechanisms underlying HPV-associated cervical cancer immune regulation and suggest a strategy to modulate the immune system in HPV-positive neoplastic cervical and other tissues. © 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.
Genome-wide analysis of somatic noncoding mutation patterns and mitochondrial heteroplasmic shift in type B1 and B2 thymomas.
Fujikura K, Correa I, Heck S … +8 more , Watanabe K, King J, McLean E, Ndagire S, Takahashi Y, Kuroda M, Bille A, Nonaka D
J Pathol · 2026 Feb · PMID 41344988 · Full text
Type B1 and B2 thymomas are lymphocyte-rich malignant tumours with few somatic mutations in protein-coding regions of the nuclear genome; nonetheless, noncoding regions remain uncharacterized. Here, we developed a method...
Type B1 and B2 thymomas are lymphocyte-rich malignant tumours with few somatic mutations in protein-coding regions of the nuclear genome; nonetheless, noncoding regions remain uncharacterized. Here, we developed a method to isolate pure thymoma cells from lymphocyte-rich tissues, and then performed genome-wide deep sequencing. The total number of somatic mutations was ~80 times higher in noncoding regions than in coding regions in type B12 thymomas (1,671.3 versus 21.1 per case). Coding mutations were identified in epigenetic regulators, DNA repair genes, and some other genes. Nevertheless, 40% of the cases exhibited fewer than four nonsynonymous mutations in coding regions. A systematic noncoding analysis identified 405.0 mutations per case in cis-regulatory elements and detected six recurrent mutations: one interferon regulatory factor (IRF8), two E3 ubiquitin ligases (UBR2 and RNF213), and three intergenic regions. Tumour-specific/enriched mitochondrial heteroplasmic shift was observed in 90% of cases, with a significant proportion of mutations located in the D-loop region. When tracing the evolutionary lineage of mtDNA mutation, the majority of cases can be explained by a linear evolutionary model. This suggests that positive selection may be operating on the mitochondrial genome during thymoma development. In summary, numerous noncoding mutations and mitochondrial heteroplasmic shift were detected in type B1 and B2 thymomas, some of which may be functional. Given the paucity of coding mutations observed in this disease entity, other factors such as disruption of the noncoding landscape and tumour-specific/enriched mitochondrial heteroplasmic shift, may contribute to the development of thymoma. © 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.
WINTER MEETING, The Microenvironment & Disease, 7th Joint Meeting with the Royal Society of Medicine, 216th Scientific Meeting of the Pathological Society of Great Britain & Ireland, 21-22 January 2025.
J Pathol · 2025 Dec · PMID 41339118 · Publisher ↗
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Small cell neuroendocrine carcinoma of the cervix: diagnostic challenges and emerging molecular insights.
Charbel A, Akiki G, Diwan SS … +3 more , Leung SOA, Kommoss FK, Tessier-Cloutier B
J Pathol · 2026 Feb · PMID 41320640 · Publisher ↗
Small cell neuroendocrine carcinoma of the cervix (SCNECC) is a rare and highly aggressive malignancy with poor prognosis that predominantly affects premenopausal women. Histopathological evaluation is central to diagnos...
Small cell neuroendocrine carcinoma of the cervix (SCNECC) is a rare and highly aggressive malignancy with poor prognosis that predominantly affects premenopausal women. Histopathological evaluation is central to diagnosis and clinical management; however, distinguishing SCNECC from other 'small blue round cell' malignancies often requires a multimodal approach that integrates morphology, immunohistochemistry, and advanced molecular testing. In the absence of specific and sensitive biomarkers, SCNECC largely remains a diagnosis of exclusion, underscoring the need for comprehensive diagnostic algorithms. A study by Pan, Yan, Yuan et al employed whole transcriptome profiling and identified three molecular subgroups within SCNECC. Importantly, one subgroup displayed an inflamed phenotype, characterized by high expression of MHC-II complex and IFN-α/β-related genes, suggesting potential susceptibility to immunotherapy, a finding that mirrors observations in small cell lung cancer. These findings highlight the biological heterogeneity of SCNECC and reinforce the importance of integrating molecular data to refine diagnostic accuracy and guide therapeutic decision-making. This commentary emphasizes the pressing need for comprehensive diagnostics and further research to advance treatment strategies for this rare and challenging malignancy. © 2025 The Pathological Society of Great Britain and Ireland.
Estrogen regulation in the prostate underlies racial disparity in men with benign prostatic hyperplasia.
Liu TT, Pascal LE, Ricke EA … +7 more , Bautista-Ruiz AL, Townsend J, Allen GO, Dhir R, Strand DW, DeFranco DB, Ricke WA
J Pathol · 2026 Feb · PMID 41318954 · Full text
Lower urinary tract symptoms (LUTS), associated with benign prostatic hyperplasia (BPH), are an aging-related disease, with more than 210 million cases worldwide. Estrogen exposure and estrogen regulation have been impli...
Lower urinary tract symptoms (LUTS), associated with benign prostatic hyperplasia (BPH), are an aging-related disease, with more than 210 million cases worldwide. Estrogen exposure and estrogen regulation have been implicated in a variety of disease processes, with estrogen receptor (ER)-α pathways associated with disease progression and ERβ pathways considered to be disease-protective through enhanced apoptosis and reduced cellular proliferation. Preclinical models of LUTS/BPH have shown that ERα activation contributes to disease initiation and progression. Self-identified African American (AA) men have a high incidence of LUTS/BPH, with increased incidence of non-surgical treatment failure, larger prostates at time of surgery, and surgery occurring at a younger age compared with self-identified European American (EA) men. While circulating estrogen levels are higher in AA individuals, regulation of ERs, particularly ERβ, in normal and LUTS/BPH human prostate has not been well characterized. In this study, we examined differences in ER expression between peripheral zone (PZ) and transition zone (TZ) prostate tissues using multiplex, multispectral imaging. Additionally, we assessed changes in ERs and steroid metabolism genes involved in ERβ signaling between normal and LUTS/BPH prostate samples. Our study revealed underlying differences in steroid metabolism gene expression between normal AA and EA prostates, which were further altered with LUTS/BPH. Importantly, the contribution of ERα to LUTS/BPH was more pronounced in EA prostate samples, whereas AA prostate samples exhibited an overall increase in the expression of both ER and estrogen metabolism-related genes. Although estrogens have also been implicated in collagen deposition in the prostate of LUTS/BPH patients, we did not observe significant differences in collagen deposition between AA and EA samples. These results suggest that racial differences in steroid hormone signaling pathways within the benign prostate represent a promising area for the development of precision-based therapies to reduce LUTS in aging men. © 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.
Papillary renal cell carcinoma with high-ABCC2 shows an immune-evasive profile associated with favorable response to immunotherapy.
Castillo VF, Zakhary A, Rotondo F … +6 more , Di Ciano-Oliveira C, Hamdani M, Adona E, van der Kwast T, Trpkov K, Saleeb R
J Pathol · 2026 Feb · PMID 41259021 · Full text
The use of immune checkpoint inhibitors is a promising therapeutic strategy for metastatic papillary renal cell carcinoma (PRCC); however, predictive biomarkers remain limited. PRCCs with high ABCC2 expression represent...
The use of immune checkpoint inhibitors is a promising therapeutic strategy for metastatic papillary renal cell carcinoma (PRCC); however, predictive biomarkers remain limited. PRCCs with high ABCC2 expression represent an aggressive subset frequently associated with metastasis. The tumor microenvironment (TME) profile of these tumors remains poorly defined. This study aims to characterize the TME of PRCC in relation to its ABCC2 status. A discovery cohort of 157 ABCC2-high PRCCs, 156 ABCC2-low PRCCs, and 72 normal kidneys was evaluated. Using RNA sequencing data, immune cell composition, immune checkpoint markers, and immune signature scores were assessed. Validation was performed in an independent cohort (31 ABCC2-high, 36 ABCC2-low, and 15 normal kidneys) using RNA in situ hybridization (RNA-ISH) and immunohistochemistry (IHC). ABCC2-high PRCCs demonstrated increased infiltration of cytotoxic T cells (p < 0.001), M2 macrophages (p = 0.021), and regulatory T cells (p < 0.001) compared to ABCC2-low tumors. ABCC2-high PRCCs also had higher expression of immune checkpoint biomarkers including programmed cell death ligand 1 (PD-L1) (p < 0.001). The validation cohort showed this similar TME profile. Additionally, ABCC2-high PRCCs had higher PD-L1 IHC positivity (combined positive score ≥ 1, p = 0.035; tumor proportion score ≥ 1%, p = 0.006) and immune predictive signature score (p = 0.029). NRF2-Antioxidant Response Element signaling pathway was enriched in ABCC2-high PRCCs as evidenced by overrepresentation in pathway analysis, higher gene signature score (p < 0.001), and elevated transcript signals (NFE2L2, p < 0.001; NQO1, p < 0.001), compared to ABCC2-low PRCCs. In conclusion, ABCC2-high PRCCs are immune-infiltrated tumors with a suppressive phenotype potentially responsive to immune checkpoint inhibitors. ABCC2 IHC may serve as a predictive biomarker to help identify patients likely to benefit from such 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.
Novel growth pattern-specific digital marker of TILs improves stratification of lung adenocarcinoma patients.
AlRubaian A, Azam A, Rajpoot NM … +1 more , Raza SEA
J Pathol · 2026 Feb · PMID 41240064 · Full text
Lung adenocarcinoma (LUAD) is one of the most prevalent forms of cancer and continues to be associated with high mortality rates, despite recent advances in cancer therapy. Effective risk stratification is critical for g...
Lung adenocarcinoma (LUAD) is one of the most prevalent forms of cancer and continues to be associated with high mortality rates, despite recent advances in cancer therapy. Effective risk stratification is critical for guiding treatment decisions and improving our understanding of disease mechanisms. However, current prognostic approaches face considerable limitations. Growth pattern-based grading serves as a prognostic indicator of tumour aggressiveness, but is inherently subjective and prone to a high degree of variability among observers. Other well-established prognostic indicators, such as tumour infiltrating lymphocytes (TILs) and stromal TILs (sTILs) scores, provide valuable prognostic information but require labour-intensive assessment. The pronounced heterogeneity of LUAD further complicates prognosis and underscores the need for robust, integrative biomarkers that capture both the morphological and immunological characteristics of the tumour. To address this need, we propose an AI-based growth-pattern-specific TILs (GPS-TILs) marker that quantifies TILs and sTILs within each growth pattern separately. By integrating morphological information from the tumour growth patterns and immune microenvironment data from TILs, we demonstrate that the proposed GPS-TILs marker improves patient stratification. We evaluated the prognostic utility of GPS-TILs using survival analysis with Cox proportional hazards models in a cross-validation setting using The Cancer Genome Atlas LUAD (TCGA-LUAD) cohort. Our findings revealed that GPS-TILs offers strong prognostic value for overall survival (p < 0.0001, C-index = 0.59), outperforming conventional TIL-based measures and morphology-based stratification approaches. These results highlight the potential of GPS-TILs as a more objective and effective tool for improving patient risk stratification in LUAD. © 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.
Generation of functional noncanonical donor splice sites by +2T variants in breast cancer susceptibility genes: impact on clinical interpretation.
Llinares-Burguet I, Sanoguera-Miralles L, Bueno-Martínez E … +5 more , García-Álvarez A, Valenzuela-Palomo A, Pérez-Segura P, de la Hoya M, Velasco-Sampedro EA
J Pathol · 2026 Feb · PMID 41230741 · Full text
Splicing dysregulation is a relevant mechanism of pathogenicity for variants in disease susceptibility genes. Variants affecting the critical intronic +1 and +2 GT nucleotides of the 5' splice sites (5'ss) are generally...
Splicing dysregulation is a relevant mechanism of pathogenicity for variants in disease susceptibility genes. Variants affecting the critical intronic +1 and +2 GT nucleotides of the 5' splice sites (5'ss) are generally strong indicators of pathogenicity. However, some +2 T variants create functional noncanonical 5'ss that generate wildtype transcripts, hampering accurate variant interpretation and genetic counseling. We previously showed that variants PALB2 c.108+2T > C and ATM c.1898+2T > G generated significant levels of full-length (FL) transcripts by creating functional atypical GC and GG donor sites, respectively. In this study, we aimed to investigate the splicing impact of +2T variants in the breast cancer susceptibility genes ATM, BRCA1, and PALB2. For this purpose, five minigenes encompassing 29 exons of ATM, BRCA1, and PALB2 were employed. A total of 30 +2T > C/G/A variants were introduced into these constructs by site-directed mutagenesis and analyzed in MCF-7 cells. Four +2T > C variants (ATM c.6347+2T > C, BRCA1 c.5193+2T > C and c.5277+2T > C, and PALB2 c.2748+2T > C) and ATM variants c.6347+2T > A/G produced FL-transcripts (4%-81% of the overall expression). All +2T > C leaky variants conserved a central core of 6 nucleotides (AGgcaa). Variants were assessed according to the ClinGen specifications of the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) interpretation guidelines. Two variants (ATM c.6347+2T > C and BRCA1 c.5193+2T > C) were classified as likely benign, consistent with predictions based on their respective ACMG/AMP-based gene specifications. Conversely, two variants (ATM c.6347+2T > G and BRCA1 c.4675+2T > C), initially predicted as likely pathogenic, were reclassified as variant of uncertain significance (VUS). In conclusion, a significant proportion of +2T variants can create functional noncanonical 5'ss, resulting in the production of FL-transcripts that may preserve gene function. Variant-splicing assays provide essential data for accurate clinical classification and for the development of effective clinical management strategies for patients and their families. © 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.
Clinical outcomes and immune contexture in SMARCA4-deficient gastric cancer patients.
Sun M, Gu Y, Wang J … +8 more , Zhang Z, Ling Z, Lin C, Liu H, Li R, Shao F, He H, Xu J
J Pathol · 2026 Jan · PMID 41217429 · Publisher ↗
Exploiting vulnerabilities in switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complexes for cancer therapy is a promising therapeutic strategy. The SWI/SNF chromatin remodeling complex acts as a regulatory c...
Exploiting vulnerabilities in switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complexes for cancer therapy is a promising therapeutic strategy. The SWI/SNF chromatin remodeling complex acts as a regulatory component of transcription, and our previous study found an immune-active microenvironment and better response to immunotherapy of gastric cancer with ARID1A loss. However, little is known about the clinical significance of SMARCA4, which encodes for another subunit of the SWI/SNF complex, in gastric cancer (GC) patients. This study analyzed the association of SMARCA4 status with clinicopathological features, survival outcomes, therapeutic response, and immune microenvironment characteristics in three independent cohorts: Zhongshan Hospital (ZSHS) cohort (n = 442), Zhongshan Hospital immune checkpoint blockade (ZSHS-ICB) cohort (n = 41), and Samsung Medical Center cohort (SMC, n = 51). SMARCA4-deficient GC patients exhibit clinicopathological features associated with enhanced tumor aggressiveness, including a higher prevalence of poorly differentiated disease (p = 0.034), pN3 stage at diagnosis (p = 0.059), E-cadherin negative expression (p < 0.001), and genomically stable (GS) and microsatellite stable/epithelial-mesenchymal transition molecular subtype (MSS/EMT) (p < 0.001 and p < 0.001, respectively). Kaplan-Meier analysis revealed that SMARCA4 deficiency indicated poor prognosis in GC (p < 0.001). Moreover, SMARCA4 deficiency identified a subgroup of GC patients who exhibited poor outcomes despite receiving adjuvant chemotherapy in the GS subtype (p = 0.029). In contrast, these patients demonstrated increased sensitivity to anti-PD-1 therapy in both the ZSHS-ICB (p = 0.039) and SMC (p = 0.062) cohorts. Immunological analysis revealed a distinct immune profile characterized by abundant but exhausted CD8 T cells in SMARCA4-deficient GC. In conclusion, patients with SMARCA4-deficient GC patients demonstrated poor prognosis but improved response to immunotherapy. These observed clinical outcomes may be attributed to the immunosuppressive microenvironment, highlighting the potential for developing novel therapeutic approaches. © 2025 The Pathological Society of Great Britain and Ireland.
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