The Journal Of Pathology[JOURNAL]
Sun
200 papers
Cancer-associated fibroblast subtypes in the tumor microenvironment of prostate cancer and associations to patient outcomes.
Blanke ML, Salachan PV, Georgsen JB … +4 more , Fredsøe J, Ulhøi B, Borre M, Sørensen KD
J Pathol · 2026 Apr · PMID 41588654 · Publisher ↗
Prostate cancer (PC) is a prevalent malignancy, and outcomes range from indolent disease to terminal illness. Prostate-specific antigen-based diagnostics lack specificity and correlation with tumor aggressiveness, leadin...
Prostate cancer (PC) is a prevalent malignancy, and outcomes range from indolent disease to terminal illness. Prostate-specific antigen-based diagnostics lack specificity and correlation with tumor aggressiveness, leading to overdiagnosis and undertreatment. Recent studies on cancer-associated fibroblasts (CAFs) have identified antigen presenting CAFs (apCAF), inflammatory CAFs (iCAF), and myofibrillar CAFs (myCAF) in pancreatic ductal adenocarcinoma, non-small-cell lung cancer, and breast cancer. However, their significance in PC is not yet understood. This study employs publicly available single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) data combined with multiplex immunofluorescence (mIF) and digital pathology analyses of radical prostatectomy (RP) specimens from two cohorts (cohort 1, n = 235; cohort 2, n = 240) to identify CAF subtypes in localized PC and their association with biochemical recurrence (BCR) by uni- and multivariable [adjusted for Cancer of the Prostate Risk Assessment postsurgical (CAPRA-S) score] Cox regression analyses. We identified myCAFs, iCAFs, and apCAFs in PC by analyzing scRNA-seq and ST data. We also identified the three CAF subtypes by mIF staining of RP specimens from cohorts 1 and 2. In prostate tumors, higher numbers of apCAFs and myCAFs were present close to malignant versus adjacent nonmalignant (AN) glands (p < 0.001, Wilcoxon test), whereas we saw no significant difference for iCAFs. In univariable Cox regression analyses, high levels of apCAFs and iCAFs were associated with increased risk of BCR in cohort 1 [apCAF: hazard ratio (HR): 1,78, p < 0.05, iCAF: HR: 1,76, p < 0.05] and confirmed in cohort 2 (apCAF: HR: 1.85, p < 0.05, iCAF: HR: 2.06, p < 0.05). In multivariable Cox regression analyses, both apCAF and iCAF levels remained independently associated with BCR after adjustment for CAPRA-S score. Our findings imply the potential of CAF subtypes as biomarkers for risk stratification in PC. © 2026 The Pathological Society of Great Britain and Ireland.
Uncoupling TGFβ1 signalling from collagen protein synthesis in Dupuytren's disease.
Cooper G, Gumbs JA, Alkharabsheh S … +10 more , Lee KJ, Carter A, Coleman H, O'Heneghan-Yates NS, Ijaz R, Beamish E, Menezes LA, Liloglou T, Clegg PD, Canty-Laird EG
J Pathol · 2026 Apr · PMID 41588641 · Full text
Dupuytren's disease is a fibroproliferative disorder of the palmer fascia (PF) characterised by flexion contractures in the hand. Dupuytren's disease can be treated surgically, but disease recurrence rates are high, pote...
Dupuytren's disease is a fibroproliferative disorder of the palmer fascia (PF) characterised by flexion contractures in the hand. Dupuytren's disease can be treated surgically, but disease recurrence rates are high, potentially due to continual production of matrisomal proteins. Here, metabolic labelling and proteomics identified differences in the new synthesis and composition of matrisomal proteins between Dupuytren's tissue and normal PF. Dupuytren's tissue actively synthesised type I collagen, fibronectin (FN1), matrix metalloproteinases-2 and -3 (MMP2, MMP3) and tissue inhibitor of metalloproteinases 2 (TIMP2). Both tissues actively synthesised insulin-like growth factor binding protein 7 (IGFBP7). Label-free analysis implicated the transforming growth factor-β (TGFβ) pathway in the matrisomal profile of Dupuytren's tissue. The effect of TGFβ isoforms on COL1 mRNA expression was first tested in cultured young and aged equine tenocytes. COL1A1 mRNA responded to treatment with all TGFβ isoforms and was more highly expressed in cells from aged samples. In aged human cells, COL1A1 and COL1A2 mRNA was higher in cells derived from Dupuytren's tissue than normal PF and in response to TGFβ1, but no changes in COL1A1 or COL1A2 CpG methylation were detected. TGFβ1 treatment only resulted in increased type I collagen protein accumulation in the media of Dupuytren's nodule cells. In three-dimensional cultures, COL1A1 mRNA was lower in normal PF than in Dupuytren's cells, but TGFβ1 treatment only increased type I collagen accumulation in the media of normal PF cultures, and TGFβ1 inhibition did not alter new collagen protein synthesis. TGFβ1 inhibition in Dupuytren's tissue explants did not alter the proportion of homotrimeric type I collagen, nor was this changed in skin or tendon of the tight-skin (TSK) mouse, a naturally occurring model of indirect TGFβ1 activation. Therefore, the role of TGFβ in Dupuytren's disease may be predominantly related to myofibroblast phenoconversion and contractility rather than directly altering collagen protein synthesis. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
AI for pathologists: a universal lymph node metastasis detection app that enhances efficiency while preserving diagnostic accuracy.
Vazzano J, Challa B, Arole V … +13 more , Shilo K, Reuss S, Kobalka P, Satturwar S, Xie J, Chung D, Shafi S, Kellough D, Palermini E, Li Z, Chen W, Parwani A, Sun S
J Pathol Clin Res · 2026 Jan · PMID 41560478 · Full text
Increasing workload combined with the shortage of pathologists is the leading cause of diagnostic errors and delays. Nonetheless, in clinical practice, pathologists often spend hours on tedious tasks such as counting mit...
Increasing workload combined with the shortage of pathologists is the leading cause of diagnostic errors and delays. Nonetheless, in clinical practice, pathologists often spend hours on tedious tasks such as counting mitoses and searching for lymph node micro-metastasis, which may yield unreliable results. The advent of digital pathology and the development of artificial intelligence (AI) applications (app) for image analysis have opened new possibilities for improving the efficiency and accuracy of pathologists. However, the perceived black box nature of AI has led to skepticism among many pathologists about its diagnostic capabilities, resulting in a lack of trust in AI. In addition, it is a common belief that AI applications should be limited to the areas they were trained in, which has significantly limited their generalizability. Given the homogeneous cell population of lymph nodes and overlapping of tumor morphology across different organs, we hypothesized that a lymph node metastasis detection application trained on a few organs could potentially recognize metastasis from multiple organs. We used the commercially available Visiopharm app (AI tool), initially trained on lymph node metastases from breast and colon cancer, to detect metastasis of 12 distinct types of cancer from 15 organ systems based on the analysis of 172 slides (all with corresponding immunohistochemical staining confirmation). Furthermore, by using the annotation map generated by the app as a guide, pathologists were also able to reduce the time spent searching for metastasis substantially (from 54.7 to 42.1 s per slide on average) without compromising diagnostic accuracy. With pathologists serving as the trusted gatekeepers and the development of more sophisticated image analysis applications, the use of AI can help to address the shortage of pathologists, enhance their performance and eventually improve patient care.
Alcian blue-positive stromal phenotype in basal cell carcinoma is associated with progression on first-line hedgehog inhibitors.
DeTemple VK, Stadler R, Bredemeier S … +15 more , Chung S, Schaper-Gerhardt K, Alter M, Angela Y, Stege H, Leiter U, Ohletz J, Livingstone E, von Wasielewski I, Hassel JC, Huynh J, Gebhardt C, Pföhler C, Gutzmer R, Scheel CH
J Pathol Clin Res · 2026 Jan · PMID 41543881 · Full text
Basal cell carcinoma (BCC) is the most frequent malignancy in fair-skinned populations. Although curable in most cases, approximately 4% of patients develop locally advanced or metastatic disease (advBCC) requiring syste...
Basal cell carcinoma (BCC) is the most frequent malignancy in fair-skinned populations. Although curable in most cases, approximately 4% of patients develop locally advanced or metastatic disease (advBCC) requiring systemic therapy. Hedgehog pathway inhibitors (HHIs; vismodegib/sonidegib) constitute standard first-line treatment, yet individual responses vary and no histopathological biomarker predicting therapeutic outcome exists. We conducted a retrospective, multicenter analysis of 70 BCCs encompassing clinically common and advanced stages. Routine hematoxylin and eosin and Alcian blue (AB; pH 2.5) staining was evaluated using a 17-parameter, numerically encoded histopathology matrix spanning tumor morphology, stromal composition, and immune contexture. Data were mapped by unsupervised hierarchical clustering. Distinct AB staining patterns were observed: superficial and nodular BCCs typically exhibited an AB-positive peritumoral border, whereas infiltrative and sclerosing subtypes displayed a diffuse AB-positive desmoplastic stroma. The latter also correlated with advanced EADO clinical stages (correlation coefficients 0.46-0.48; p < 0.001). In a subset of 30 advBCCs obtained before or during HHI therapy, AB-positive stroma was the only parameter independently associated with shorter progression-free survival (multivariable hazard ratio = 23.8; 95% CI 4.02-141.3; p < 0.001). Established clinical or histological features failed to associate with outcome. Our findings identify diffuse AB-positive stroma as a readily detectable feature of histologically aggressive BCC and as a candidate biomarker associated with progression under HHI treatment. Because AB staining is routine, inexpensive, and easily standardized, this phenotype represents an immediately implementable readout for prospective validation and a potential link between extracellular-matrix remodeling and therapy resistance in BCC.
Single-nucleus RNA sequencing identifies a novel tenogenic heterologous differentiation in endometrial carcinosarcomas: implications for diagnosis and tumor classification.
González-Martínez S, Palacios J, Carretero-Barrio I … +7 more , Fernández-Lanza V, Cortés-Salgado A, Román J, Matias-Guiu X, Gatius S, Cortés J, Pérez-Mies B
J Pathol · 2026 Feb · PMID 41537454 · Full text
Carcinosarcomas (CSs) are aggressive biphasic tumors characterized by epithelial and mesenchymal components, whose histogenesis and differentiation dynamics remain poorly understood. We present single-nucleus RNA sequenc...
Carcinosarcomas (CSs) are aggressive biphasic tumors characterized by epithelial and mesenchymal components, whose histogenesis and differentiation dynamics remain poorly understood. We present single-nucleus RNA sequencing (snRNA-seq) analysis of six CSs (five endometrial and one ovarian) and two normal endometrial samples, profiling over 96,298 cells. By integrating transcriptomic data with inferred copy number variations (CNVs), immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and in situ hybridization (ISH) validation, we resolved the complex cellular architecture of these tumors, identified lineage-specific programs, and revealed unexpected differentiation trajectories. snRNA-seq was used to further refine the histopathological classification of three cases by uncovering heterologous differentiation not previously recognized: one rhabdomyogenic, one osteogenic, and, notably, one exhibiting a novel tenogenic program, defined by the expression of SCX, MKX, and TNMD. All CSs displayed a prominent mesenchymal compartment comprising both undifferentiated fibroblast-like cells and distinct lineage committed populations, including rhabdomyoblasts (Rhab), tenoblasts (Teno), osteoblasts (Osteo), and chondroblasts (Chond). In some tumors, multiple mesenchymal identities co-existed, and in others, differentiation gradients (e.g. immature versus mature rhabdomyoblasts) were observed. These patterns underscore the cellular plasticity and multilineage potential of the sarcomatous component. Furthermore, the expression of specialized interface markers (COL22A1, NCAM1, ACAN, CHRNG, MUSK) suggests that some tumors use structured developmental programs reminiscent of the muscle-tendon junction, enthesis, or neuromuscular junction. CNV analysis revealed tumor-specific genomic alterations with clonal and subclonal patterns linked to differentiation state, which were validated by FISH. Altogether, this study demonstrates that CSs are not static biphasic tumors but rather complex ecosystems with extensive developmental plasticity. Our findings redefine their classification and support the use of single-nucleus approaches to uncover hidden differentiation trajectories in highly heterogeneous cancers, including the discovery of a previously unreported tenogenic lineage. Our results challenge the diagnosis of homologous CS when only morphological criteria are applied. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Assessing the association between homologous recombination deficiency scores and treatment response in localized and metastatic prostate cancer.
Zhu Q, Shi Y, Wang T … +9 more , Zheng Q, Zhou X, Tan Z, Chen J, Guo J, Liu H, Shen P, Zeng H, Zhao J
J Pathol Clin Res · 2026 Jan · PMID 41532774 · Full text
The aim of this study was to evaluate the predictive value of homologous recombination deficiency scores for therapeutic efficacy in prostate cancer across various disease stages under different regimens. We collected ti...
The aim of this study was to evaluate the predictive value of homologous recombination deficiency scores for therapeutic efficacy in prostate cancer across various disease stages under different regimens. We collected tissue samples from 167 prostate cancer patients and performed genomic sequencing to assess homologous recombination deficiency scores. Among them, 67 patients with localized disease received radical prostatectomy, and 100 patients with metastatic disease received androgen receptor target inhibitor treatment. We examined the predictive value of homologous recombination deficiency scores in forecasting the therapeutic efficacy of standard-of-care treatment of prostate cancer under different disease stages. Among patients who underwent radical prostatectomy, those with higher homologous recombination deficiency scores experienced notably shorter biochemical progression-free survival and overall survival than those with lower scores (median biochemical progression-free survival: 50.6 versus 148.4 months, p = 0.037; median overall survival: 149.0 months versus not reached, p = 0.0018). In patients receiving androgen receptor pathway inhibitor treatment, men with higher homologous recombination deficiency scores exhibited reduced prostate-specific antigen progression-free survival, radiographic progression-free survival, and overall survival compared to the lower score group at the metastatic castration-resistant stage (median prostate-specific antigen progression-free survival: 8.17 versus 24.17 months, p = 0.032; median radiographic progression-free survival: 11.8 versus 24.8 months, p = 0.015; median overall survival: 36.5 months versus not reached, p = 0.056) and a deteriorating trend in the metastatic hormone-sensitive stage. Molecular characterization showed that higher homologous recombination deficiency scores were associated with higher alteration rates in genes such as BRCA2, CDK12, MYC, and PTEN. This study reveals that higher homologous recombination deficiency scores are associated with unfavorable treatment efficacy of radical prostatectomy in localized prostate cancer and of androgen receptor target inhibitor treatment in metastatic prostate cancer.
Mining bulk transcriptomic datasets identifies inflammasome activation and antigen presentation as key novel mechanisms of BK polyomavirus-associated nephropathy.
Davidson LA, Niessen NM, Rowlandson M … +9 more , Hibberd AD, Heer MK, Hsu AC, Kaiko GE, Reid AT, Mayall JR, Horvat JC, Trevillian PR, Baines KJ
J Pathol · 2026 Mar · PMID 41527905 · Publisher ↗
BK polyomavirus (BKPyV) is a viral infection experienced by kidney transplant recipients that can lead to the development of BKPyV-associated nephropathy (BKPyVAN), graft dysfunction, and loss. There are no BKPyV-specifi...
BK polyomavirus (BKPyV) is a viral infection experienced by kidney transplant recipients that can lead to the development of BKPyV-associated nephropathy (BKPyVAN), graft dysfunction, and loss. There are no BKPyV-specific treatments available to prevent this significant cause of transplant failure. This bioinformatic study aims to characterise the cellular networks and pathways involved in BKPyVAN to identify novel therapeutic targets. Four publicly available bulk transcriptomic datasets containing BKPyVAN post-transplant biopsy tissue were identified in the National Centre for Biotechnology Information Gene Expression Omnibus (NCBI GEO). Differentially expressed genes (DEGs) (adjusted p < 0.05, fold change ≥ 1.5) were identified and dataset comparisons made between BKPyVAN versus stable grafts and acute rejection versus stable grafts. Canonical pathways were investigated using QIAGEN Ingenuity Pathway Analyses and protein interaction networks using STRING v12.0. There were 226 genes identified as differentially expressed in BKPyVAN compared with stable graft function that were conserved across all four datasets. This gene signature was associated with three cellular networks and 201 significantly enriched pathways. The cellular networks identified included 67 immune-related proteins; eight proteins associated with the absent in melanoma 2 (AIM2) inflammasome; and four HLA class II proteins. The most notable pathways significantly increased in BKPyVAN included HLA class II antigen presentation (p < 0.001), inflammasome (p < 0.001), and interleukin 6 signalling (p < 0.01). There were seven DEGs that were observed as common to all BKPyVAN versus acute rejection comparisons. The TUBB3 gene was the only gene that was consistently upregulated in all datasets. Several pathways and potential treatment targets were identified using a bulk RNA mining strategy, including HLA class II antigen presentation, AIM2 inflammasome, and IL-6 signalling in BKPyVAN pathology. Such tools provide an important first step in identifying novel mediators of disease pathogenesis and likely hold the key for the discovery of potential treatment targets for BKPyVAN in the future. © 2026 The Pathological Society of Great Britain and Ireland.
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.
Prognostic significance of beta-adrenergic receptor expression in oesophageal adenocarcinoma.
Oliveira T, Sasi S, Trainor J … +7 more , McManus DT, McQuaid S, Lewis C, James JA, Coleman HG, McMenamin ÚC, Turkington RC
J Pathol Clin Res · 2026 Jan · PMID 41486075 · Full text
Expression of the β-adrenergic receptors' family has been associated with survival outcomes in multiple different cancer types, showing their potential to act as prognostic factors. No previous work has evaluated these r...
Expression of the β-adrenergic receptors' family has been associated with survival outcomes in multiple different cancer types, showing their potential to act as prognostic factors. No previous work has evaluated these receptors in relation to survival in oesophageal adenocarcinoma. We sought to analyse the expression of β and β adrenergic receptors in oesophageal adenocarcinoma and their association with survival outcomes. The expression of β and β adrenergic receptors was evaluated in a cohort of oesophageal adenocarcinoma patients treated with neo-adjuvant chemotherapy prior to surgical resection at the Northern Ireland Cancer Centre between 2004 and 2012. Immunohistochemical staining for was assessed using a Tissue Microarray with triplicate tumour cores. Cox proportional hazards regression was used to investigate the association of β and β adrenergic receptor expression with survival outcomes, including adjustment for clinical factors. In total, 115 and 122 patients were assessed for β and β adrenergic receptor expression, respectively. In adjusted analysis, high β adrenergic receptor expression was associated with improved recurrence-free [hazard ratio [HR] 0.57, 95% CI 0.33-0.97] and overall survival (HR 0.53, 95% CI 0.30-0.94) with restriction to gastro-oesophageal junction tumours showing a stronger association with improved overall survival (HR 0.27, 95% CI 0.13-0.59). No significant association was observed for β adrenergic receptor expression and any survival outcome. In summary, we found that higher expression of the β adrenergic receptor was associated with a significant improvement in survival in oesophageal adenocarcinoma patients, and gastro-oesophageal junction tumours in particular, treated with neoadjuvant chemotherapy followed by surgical resection.
Diagnostic utility and pitfalls of human T-lymphotropic virus serology in adult T-cell leukemia/lymphoma: evidence from a 25-year pathology-based nonendemic cohort.
Yuan CT, Sun LY, Chuang SS … +8 more , Karube K, Yang HB, Lee SH, Wang RC, Chang KC, Kao CJ, Huang HH, Chou WC
J Pathol Clin Res · 2026 Jan · PMID 41466159 · Full text
Adult T-cell leukemia/lymphoma (ATLL) is a distinct type of peripheral T-cell lymphoma (PTCL) driven by human T-lymphotropic virus type I (HTLV-1)-infected T cells, but diagnosis can be confounded by histological overlap...
Adult T-cell leukemia/lymphoma (ATLL) is a distinct type of peripheral T-cell lymphoma (PTCL) driven by human T-lymphotropic virus type I (HTLV-1)-infected T cells, but diagnosis can be confounded by histological overlap with non-ATLL PTCL. While molecular testing is the diagnostic gold standard in endemic areas, HTLV-1/2 serology is often used as a surrogate in nonendemic settings, yet its accuracy and limitations remain unclear. We retrospectively analyzed 881 PTCL cases over 25 years at two tertiary referral hospitals in Taiwan, where HTLV-1 is nonendemic. Serology was available in 48.2% of cases. Molecular confirmation was performed using HBZ in situ hybridization and tax quantitative polymerase chain reaction. Among the 44 seropositive PTCL patients with tissue available, 37 were diagnosed and molecularly confirmed as ATLL. Of the seven initially diagnosed as non-ATLL PTCL, three were reclassified as ATLL, while four showed no molecular evidence, including three likely false seropositives with borderline signal-to-cutoff (S/CO) values in serology assay and T follicular helper cell phenotype. In seropositive PTCL, clinicopathologic interpretation without molecular testing yielded 100% positive predictive value, 93% sensitivity, and 93% accuracy, compared with 91% positive predictive value by serology alone. In addition, retrospective molecular screening in 59 PTCL without prior serologic data revealed one case of ATLL that had initially been overlooked. In conclusion, our findings support routine HTLV-1/2 serologic testing in all newly diagnosed PTCLs. However, interpretation should be guided by clinicopathological correlation and serology index values. Borderline index results warrant molecular confirmation.
Implementing Immunoscore in colorectal cancer: lessons from cohort studies, limitations and barriers to adoption.
Hsu MS, Leung SY
J Pathol Clin Res · 2026 Jan · PMID 41459996 · Full text
The Immunoscore (IS) quantifies the immune contexture of colorectal cancer (CRC) by measuring CD3 and CD8 T-cell densities in the tumour centre and invasive margin, providing superior prognostic performance compared with...
The Immunoscore (IS) quantifies the immune contexture of colorectal cancer (CRC) by measuring CD3 and CD8 T-cell densities in the tumour centre and invasive margin, providing superior prognostic performance compared with TNM staging and mismatch-repair (MMR) status alone. Large international cohort studies have validated its ability to predict benefit from adjuvant chemotherapy in stage III colon cancer. More recently, Immunoscore-IC - a refined version that incorporates PD-L1 cell density and spatial interactions - has emerged as the first biomarker capable of identifying the subset of patients with proficient-MMR (pMMR/MSS) metastatic CRC who derive significant benefit from immune checkpoint inhibitors. Despite these advances, technical requirements, biological limitations, and reliance on retrospective data continue to hinder widespread clinical adoption. Addressing some of these challenges could enhance its utility and facilitate broader integration into routine pathology practice. In this commentary, we place landmark IS publications within the evolving research landscape, including papers published in The Journal of Pathology Clinical Research; integrate findings from recent international validation cohorts and adjuvant trials; and highlight the growing evidence supporting IS as a robust prognostic tool with clear predictive implications for both chemotherapy and immunotherapy in CRC.
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.
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