The Journal Of Pathology[JOURNAL]
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200 papers
Validation of fibroblast activation protein and α-smooth muscle actin as prognostic biomarkers in prostate cancer through AI-assisted image analysis of dual-marker IHC.
Säilä J, Lehto TP, Rannikko A … +3 more , Kallioniemi O, Mirtti T, Pellinen T
J Pathol Clin Res · 2026 Jan · PMID 41410015 · Full text
Prostate cancer (PCa) lacks reliable and accurate tissue-based biomarkers to support prognostic stratification and clinical treatment decisions. Current diagnostic assessment, including Gleason grading, has limitations s...
Prostate cancer (PCa) lacks reliable and accurate tissue-based biomarkers to support prognostic stratification and clinical treatment decisions. Current diagnostic assessment, including Gleason grading, has limitations such as interobserver variability and insufficient granularity for disease aggressiveness. Fibroblast activation protein (FAP) and α-smooth muscle actin (αSMA) have emerged as putative stromal biomarkers, but their prognostic value in localised PCa has not been validated at scale. In this study, we developed a novel artificial intelligence (AI)-augmented image analysis pipeline tailored for dual-marker immunohistochemistry of FAP and αSMA, enabling automated, tissue compartment-specific quantification of biomarker expression. This deep learning model was trained and validated using digitised high-resolution whole-slide images of tissue microarrays from three prostatectomy cohorts, comprising 4,097 cores from 835 patients with comprehensive clinical follow-up data. The AI pipeline demonstrated high accuracy in detecting epithelial, stromal, and immune compartments, as well as in quantifying FAP and αSMA signals. We validated stromal FAP as a robust prognostic marker consistently associated with adverse clinical outcomes, including earlier biochemical recurrence, metastasis, and cancer-specific death. Epithelial FAP and stromal αSMA showed additional prognostic associations in selected analyses, particularly in MRI-visible tumours. Our findings reinforce the biological and clinical relevance of stromal FAP in the prostate tumour microenvironment. By enabling standardised and scalable biomarker quantification, our newly developed AI-assisted workflow advances the clinical utility of FAP and αSMA and demonstrates the power of integrating digital pathology with biomarker quantification. This study represents a critical step toward implementing stromal biomarkers in routine PCa diagnostics and underscores the potential of AI-enhanced histopathology in advancing precision oncology.
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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Systemic and local decorin levels mirror the clinical course of pancreatic cancer.
Svensson M, Lehn S, Jacobsen H … +4 more , Olsson Hau S, Jönsson G, Pietras K, Jirström K
J Pathol Clin Res · 2026 Jan · PMID 41392017 · Full text
Despite significant progress in oncology research, pancreatic cancer remains inherently difficult to treat, and the mechanisms underlying therapeutic resistance remain unresolved. Decorin (DCN), a member of the family of...
Despite significant progress in oncology research, pancreatic cancer remains inherently difficult to treat, and the mechanisms underlying therapeutic resistance remain unresolved. Decorin (DCN), a member of the family of small leucine-rich proteoglycans, has emerged as a versatile actor in various malignant diseases. The aim of this study was to further explore the potential clinical significance of DCN in pancreatic cancer, both regarding its dynamics in serum during chemotherapy and its compartmental and cellular distribution in tumour tissue. To this end, repeated on-treatment levels of soluble DCN were measured using proximity extension assay in 124 patients enrolled in a prospective, observational clinical study, inviting patients diagnosed with pancreatic or other pancreatobiliary-type periampullary adenocarcinoma eligible for adjuvant (n = 30) or first-line palliative (n = 94) chemotherapy. Multiplexed immunofluorescence was applied to map DCN and the associated immune landscape in resected tumours. The results showed increasing levels of DCN in serum after initiation of chemotherapy in palliative, but not in adjuvant, patients. A higher rate of change of serum DCN was an independent adverse prognostic factor in both treatment settings. There was no significant association between systemic levels and local DCN expression. Varying expression of DCN was denoted in both tumour cells, immune cells and stroma, but the prognostic significance was mainly assigned to its expression in B cells. In particular, a higher percentage of DCN positive B cells, overall and in interaction with tumour cells, were independent predictors of shorter survival. In summary, this study is the first to demonstrate the potential clinical utility of on-treatment monitoring of systemic DCN in patients with pancreatic cancer. The findings also provide interesting leads for further research into how DCN may interact with the immune microenvironment to promote tumour development and the emergence of chemoresistance.
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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Epigenetic similarity between adenoid ameloblastoma and dentinogenic ghost cell tumour: DNA methylation analysis in odontogenic tumours.
Oh KY
J Pathol Clin Res · 2026 Jan · PMID 41334583 · Full text
Although adenoid ameloblastoma (AA) has recently been included in the WHO classification as a separate tumour type, its clinical, histological, immunohistochemical, and molecular similarities to dentinogenic ghost cell t...
Although adenoid ameloblastoma (AA) has recently been included in the WHO classification as a separate tumour type, its clinical, histological, immunohistochemical, and molecular similarities to dentinogenic ghost cell tumour (DGCT) raise questions about the current classification system. The aim of this study was to investigate the epigenetic similarity between AA and DGCT. A total of 35 odontogenic tumours consisting of 6 types, including 3 AAs and 4 DGCTs, were collected for this study. DNA methylation analysis was performed using the Infinium MethylationEPIC v2.0 BeadChip. Unsupervised clustering analysis was performed using t-distributed stochastic neighbour embedding (t-SNE) and Uniform Manifold Approximation and Projection (UMAP). No differentially methylated regions were identified between AA and DGCT. Both t-SNE and UMAP plots demonstrated that AAs clustered together with DGCTs, clearly separated from the other types of odontogenic tumour. Within the AA and DGCT methylation class, no subclasses were identified by the presence of the so-called AA-like histology, characterised by cribriform architecture and duct-like structures. These findings suggest a clear epigenetic similarity between AA and DGCT, further supporting the notion that the two tumours represent a spectrum of the same entity and may be better classified on a molecular basis as 'WNT pathway-altered odontogenic tumours'.
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.
Decoding UTROSCT heterogeneity: systematic clinicopathological evaluation combined with molecular profiling.
Yang J, Zhang J, Li J … +4 more , Liu Y, Wang Y, Hu A, Liu C
J Pathol Clin Res · 2026 Jan · PMID 41317331 · Full text
Uterine tumor resembling ovarian sex cord tumor (UTROSCT) constitutes an exceptionally rare histological subset of uterine mesenchymal neoplasms. While most cases have benign clinical behavior, a subset of UTROSCTs exhib...
Uterine tumor resembling ovarian sex cord tumor (UTROSCT) constitutes an exceptionally rare histological subset of uterine mesenchymal neoplasms. While most cases have benign clinical behavior, a subset of UTROSCTs exhibits clinically aggressive behavior characterized by recurrence and metastasis. Here, we present a cohort of 25 UTROSCT cases molecularly confirmed by recurrent fusion gene detection, including ESR1::NCOA3 (n = 12), GREB1::NCOA1 (n = 6), ESR1::NCOA2 (n = 3), GREB1::NCOA2 (n = 2), GREB1::SS18 (n = 1), and GREB1::CTNNB1 (n = 1). Notably, six cases (6/25, 24%) demonstrated recurrence/metastasis: two cases showed intrauterine recurrence (harboring ESR1::NCOA3 and GREB1::NCOA1 fusions), while four developed extrauterine metastases (carrying ESR1::NCOA3, ESR1::NCOA2, GREB1::NCOA1, and GREB1::NCOA2 fusions), with one fatality. To dissect the biological basis of UTROSCT aggressiveness, we performed integrated clinicopathologic, immunohistochemical, and molecular profiling. Multivariate analysis identified tumor size >5 cm, FIGO stage IB, and lymphovascular space invasion (LVSI) as independent predictors of recurrence/metastasis, whereas histologic features, proliferation index, and fusion gene subtypes lacked prognostic significance. Multi-omics analysis of primary versus metastatic tumors revealed striking copy number variations (CNVs) exclusively in metastatic lesions. Specifically, heterozygous losses of SMARCB1 (2/4 metastatic cases) and ATRX (1/4 metastatic cases) were identified; both play critical roles in chromatin remodeling. These genetic alterations were conspicuously absent in primary tumors, suggesting their potential role in metastatic progression. Our findings represent the first demonstration of CNV-driven oncogenic evolution in UTROSCTs, particularly implicating SWI/SNF complex dysregulation in metastatic competence.
A membranous nephropathy variant mimicking minimal change disease.
Pan C, Xiang S, Jiang M … +6 more , Li Y, Huang B, Ye T, Du Y, Tang X, Yuan Y
J Pathol Clin Res · 2026 Jan · PMID 41317330 · Full text
This study characterizes a novel disease pattern of membranous nephropathy (MN) that exhibits overlapping clinicopathological features with minimal change disease (MCD), termed 'MCD-like MN'. Patients with histologically...
This study characterizes a novel disease pattern of membranous nephropathy (MN) that exhibits overlapping clinicopathological features with minimal change disease (MCD), termed 'MCD-like MN'. Patients with histologically confirmed MN showing sparse and segmental subepithelial electron-dense deposits (EDD) but clinically resembling MCD were enrolled, alongside age- and gender-matched classic MCD and MN controls. Clinicopathological parameters were compared across groups. MN-associated antigens and MCD-related podocyte antigens were analyzed in renal tissues and serum. Among 107 archival MCD cases re-evaluated, 16 were reclassified as MCD-like MN based on EDD presence. Pathologically, these cases demonstrated IgG deposition in podocytes (62.5%), significantly higher than classic MCD (6.2%), but lacked complement activation and showed milder interstitial fibrosis compared to MN. Clinically, MCD-like MN patients presented a shorter disease duration and higher complete remission rates compared to MN (p < 0.01), resembling classical MCD. Additionally, they had lower serum creatinine levels than MCD patients (p < 0.01), which were more similar to MN levels. Furthermore, MN-associated antigens were detected in MCD-like MN cases and some of the serum antibodies' levels were increased, suggesting shared pathogenesis with MN, albeit with distinct immune features. Besides, spectrometry counts of podocyte antigens were not increased, and serum anti-podocyte antibodies were either absent or not elevated compared to MCD patients, ruling out antibody-mediated podocytopathy. Collectively, MCD-like MN represents a distinct MN subtype with atypical MCD-like clinicopathological features, likely driven by a unique immune mechanism divergent from both classic MN and MCD.
Characterisation and impact of intratumoural stroma in melanoma and carcinoma brain metastases.
Bandke D, Weis S, Gruber A … +4 more , Noack P, Kalev O, Ornig K, Langer R
J Pathol Clin Res · 2026 Jan · PMID 41317317 · Full text
Research on the tumour microenvironment in brain metastases (BM) has predominantly focused on the immune response, while the presence, morphological patterns, and potential clinical relevance of intratumoural stroma rema...
Research on the tumour microenvironment in brain metastases (BM) has predominantly focused on the immune response, while the presence, morphological patterns, and potential clinical relevance of intratumoural stroma remain less intensively investigated. We retrospectively analysed 604 BM (529 carcinomas, 75 melanomas) from 556 patients. Intratumoural stroma was histomorphologically classified into absent/unclear (Group 0), present without desmoplasia (Group 1) or with desmoplasia (Group 2). Associations with histological features, clinical parameters, and survival were evaluated. Intratumoural stroma was absent in 63.2% of tumours (n = 382), was present without desmoplasia in 14.9% (n = 90), and was desmoplastic in 21.9% (n = 132). Desmoplasia was most frequent in metastases from breast carcinomas and pulmonary squamous cell carcinomas. No significant associations were found between stroma groups and age, sex, brain location, PD-L1 expression, oncogenic mutations in lung carcinoma, or breast-cancer molecular subtype. Independent predictors of poorer survival were increasing age (HR = 1.029, 95% CI: 1.018-1.039, p < 0.001), male sex (HR = 1.492, 95% CI: 1.204-1.849, p < 0.001), and infratentorial location (HR = 1.402, 95% CI: 1.125-1.748, p = 0.003). Stroma groups showed no independent prognostic value in the overall cohort. However, subgroup analysis of non-small cell lung cancer revealed a U-shaped relationship, with Group 1 stroma linked to better survival (p = 0.020). In summary, intratumoural stroma in BM is a carcinoma-specific phenomenon, absent in melanoma. Patient outcomes, however, were primarily determined by demographic and anatomical factors rather than stromal morphology in the overall cohort but may have clinical relevance in particular tumour subgroups.
Development of a decision tree diagram for classifying study designs in tumour pathology research: a multidisciplinary approach.
Craciun OM, García-Ovejero E, Campbell F … +23 more , Montes-Mota M, Holdenrieder S, Trulson I, Worf K, Gabriel S, Kowalewska M, Michalek I, Maslova K, Taraszkiewicz L, Del Águila J, Colling R, Tan PH, Goldman-Lévy G, Giesen C, Cierco Jimenez R, Lokuhetty D, Cree IA, Indave I, Pérez Gómez B, Chechlińska M, Pollán Santamaría M, Plans-Beriso E, WCT EVI MAP Project Team
J Pathol Clin Res · 2026 Jan · PMID 41317315 · Full text
The World Health Organization (WHO) Classification of Tumours: A Living Evidence Gap Map by Tumour Type (WCT EVI MAP) project aims to develop Evidence Gap Maps of the available evidence, primarily to inform the WHO Class...
The World Health Organization (WHO) Classification of Tumours: A Living Evidence Gap Map by Tumour Type (WCT EVI MAP) project aims to develop Evidence Gap Maps of the available evidence, primarily to inform the WHO Classification of Tumours. The project, covering all tumour types, faces the challenge of reviewing a huge number of studies by reviewers from multiple backgrounds. The aim was to develop a decision tree (DT) diagram for classifying study designs reporting on tumour pathology studies, in order to support the decision-making process when assigning evidence levels across various disciplines. A modified consensus process, incorporating stakeholder workshops, was conducted in three phases: (1) development of the initial DT diagram draft (literature review and expert evaluation); (2) iterative reviews with project partners; and (3) testing the advanced DT diagram version with several sets of references to refine critical points. A total of 368 records were used for training throughout the entire process. Consensus was achieved when classifications could categorise studies consistently without causing discordance in new example sets. A DT diagram and its Glossary of Operational Definitions with 27 decision nodes and 26 categories were developed. The DT diagram is organised into six sections: WCT EVI MAP selection criteria, evidence synthesis, basic research related studies, descriptive studies, observational and experimental studies, and diagnostic test studies. The DT diagram is a valuable tool for the project's needs, successfully integrating diverse disciplinary perspectives for classifying evidence in tumour pathology research according to study design. It lays the foundation for future advancements in evidence mapping and classification within tumour pathology and related disciplines.
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.
The road to therapy for myeloid sarcoma: navigating the complexities of subclonal MAPK/ERK mutations and clonal evolution.
Yang D, Yang J, Wang G
J Pathol Clin Res · 2025 Nov · PMID 41251399 · Full text
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Authors' reply: Re: Yang et al. The road to therapy for myeloid sarcoma: navigating the complexities of subclonal MAPK/ERK mutations and clonal evolution.
Nann D, Fend F
J Pathol Clin Res · 2025 Nov · PMID 41250646 · Full text
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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.
B lymphocytes and tertiary lymphoid structures have a prognostic impact on penile squamous cell carcinoma.
Zavillová N, Waldauf P, Kendall Bártů M … +6 more , Čapka D, Hojný J, Prouzová Z, Matěj R, Zachoval R, Hrudka J
J Pathol Clin Res · 2025 Nov · PMID 41235705 · Full text
Several prognostic markers, including tumor-infiltrating lymphocytes, which have been recently identified in penile squamous cell carcinoma (pSCC), have focused mostly on T cells. The prognostic role of B cells and terti...
Several prognostic markers, including tumor-infiltrating lymphocytes, which have been recently identified in penile squamous cell carcinoma (pSCC), have focused mostly on T cells. The prognostic role of B cells and tertiary lymphoid structures (TLSs) has not yet been sufficiently described. We examined whole tissue sections histopathologically for TLSs and immunohistochemically for CD20 and CD138. The B-cell immunoscore (B-IS) divided the cohort into five categories based on the expression of these two B-cell/plasma cell markers (CD20 and CD138, respectively). Patients with fewer TLSs had worse overall survival (OS) [hazard ratio (HR) = 2.17; 95% CI: 0.94-5; p = 0.069]. A significant association was identified between a high TLS diameter and the presence of a lymphocytic infiltrate [odds ratio (OR) = 2.2442; 95% CI: 1.1022-4.55; p = 0.0208]. Patients with low B-IS (HR = 1.89, 95% CI: 1.18-3.03, p = 0.008), a low number of CD20 cells in the tumor center (HR = 1.67, 95% CI: 1.04-2.7, p = 0.035), and a low number of CD20 cells at the tumor invasion front (HR = 1.69, 95% CI: 1.06-2.78; p = 0.028) had significantly worse OS. High B-ISs were strongly associated with a mutated p53 profile detected by immunohistochemistry (OR = 4.76, 95% CI: 1.32-25, p = 0.011), low T-cell immunoscores (OR = 0.49; 95% CI: 0.23-1.03; p = 0.051), and brisk lymphocytic infiltration (OR = 2.0417, 95% CI: 1.01-4.76; p = 0.037). High CD20 cell counts at the invasion front were associated with histological grade 3 disease (OR = 2.44, 95% CI 1.15-5.26, p = 0.015). An association was also observed between low B-IS and mutations in KMT2D (OR 0.31, 95% CI: 0.07-1.21, p = 0.057) and EGFR (OR = ∞, 95% CI: 0.86-∞, p = 0.053). In conclusion, high numbers of tumor-infiltrating B cells within TLSs represent a favorable prognostic marker in pSCC. These findings emphasize the need to identify novel microscopic prognostic markers during pathological assessment to guide early and appropriate therapeutic strategies.
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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