Journal of Pathology Clinical Research最新文献

{"title":"Clinical and molecular correlates of digitally quantified anthracosis in lung tissue slides: utility of an automated quantitative workflow","authors":"Lucas C Fung,&nbsp;Brenden Joseph,&nbsp;Kenneth Ofori-Amanfo,&nbsp;Theodora Lo,&nbsp;Peiyao Wang,&nbsp;Mark Trinder,&nbsp;Georgina Barnabas,&nbsp;Taysia Nikaido-Landry,&nbsp;Clinton H Durney,&nbsp;Aadetri Tawara,&nbsp;Sharon Ong,&nbsp;Stephen Lam,&nbsp;Rafael Meza,&nbsp;Renelle Myers,&nbsp;William W Lockwood,&nbsp;Anna McGuire,&nbsp;Julia R Naso,&nbsp;Emilia L Lim","doi":"10.1002/2056-4538.70110","DOIUrl":"10.1002/2056-4538.70110","url":null,"abstract":"<p>Air pollution, such as particulate matter with a diameter of ≤2.5 μm (PM_2.5) is a major contributor to lung cancer in the never-smoking population. Anthracotic pigments (black deposits in the lungs) are physical evidence of environmental exposures. While links between anthracosis and lung disease have been established, anthracosis has not been routinely used as a measure of environmental exposure in research, because there is neither a standard quantitative measure of anthracosis nor an efficient method for quantifying it. We developed ‘Slide-based methods for High-throughput Anthracosis Detection and Estimation’ (SHADE). SHADE is an automated workflow that quantifies anthracotic pigments on scanned images of whole H&amp;E slides. SHADE was optimized to identify anthracosis while avoiding detection of artefacts in images. SHADE scores and manual pathologist rankings of 10-image patches demonstrated high concordance (<i>R</i> = 0.864). Application of SHADE to background lung sections from 140 never-smoking lung cancer patients demonstrated significant associations between high anthracosis and older age, male sex, 30-year residential PM_2.5 estimates, and birthplace in Asia (<i>p</i> &lt; 0.05). Low anthracosis was associated with less aggressive adenocarcinomas (<i>p</i> = 0.052). No significant relationship was identified between anthracosis and 3-year residential PM_2.5 estimates, lobe sampled, ethnicity, <i>EGFR</i> mutation status or pathologic tumor stage. Anthracosis levels in the never-smoking cohort were similar to that of background lung sections from 59 ever-smoking patients. Exploratory analysis of background lung sections of 15 individuals who had bronchoalveolar lavage specimen gene expression data available, SHADE scores were associated with the expression of several immunoregulatory genes (<i>CEACAM6</i>, <i>CXCL6</i>, <i>IL5RA</i>, <i>LCN2</i>, <i>SPA17</i>), the activation of inflammatory response and cytokine gene sets, and suppression of the antigen processing and presentation gene set (false discovery rate <i>&lt;</i> 0.1). SHADE provides an automated workflow for anthracosis quantification and has demonstrated utility in uncovering insight into anthracosis-associated molecular changes in lung cancer.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"12 4","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13382156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148521616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune checkpoint profiling of B7-H proteins predicts survival and treatment response in metastatic clear cell renal cell carcinoma","authors":"Maite Emaldi,&nbsp;Esther Rey-Iborra,&nbsp;Lorena Mosteiro,&nbsp;David Lecumberri,&nbsp;Ane Miren Iturregui,&nbsp;Jon Danel Solano-Iturri,&nbsp;María Armesto,&nbsp;Charles H Lawrie,&nbsp;Rafael Pulido,&nbsp;Javier C Angulo,&nbsp;José I López,&nbsp;Gorka Larrinaga,&nbsp;Caroline E Nunes-Xavier","doi":"10.1002/2056-4538.70108","DOIUrl":"10.1002/2056-4538.70108","url":null,"abstract":"<p>The B7-H family of immune checkpoint proteins plays a central role in tumor immune regulation, yet their prognostic and predictive significance in metastatic clear cell renal cell carcinoma (ccRCC) remains incompletely defined. We analyzed a retrospective cohort of primary tumor specimens from 145 patients with synchronous or metachronous metastatic ccRCC to evaluate the expression of B7-H3, B7-H4, B7-H5, and B7-H7 and their association with tumor aggressiveness, treatment response, and long-term survival. Immunohistochemistry revealed marked intratumoral heterogeneity and distinct compartmentalized expression patterns, with B7-H3 detected in both tumor cells and stromal compartments, B7-H4 exclusively expressed in tumor cells, B7-H5 localized to tumor cells and tumor-infiltrating lymphocytes (TILs), and B7-H7 detected in both tumor cells and TILs. We did not detect any overlap in expression between B7-H proteins and PD-L1 positivity in TILs. High B7-H3 expression in tumor and stroma was significantly associated with higher histological grade, increased local invasion, lymph node involvement, and advanced stage. B7-H5 expression in TILs correlated with impaired Eastern Cooperative Oncology Group performance status. Elevated B7-H3 predicted unfavorable response to tyrosine kinase inhibitors, mechanistic target of rapamycin inhibitors, and immune checkpoint inhibitors, whereas B7-H5 negativity in tumor cells associated with more favorable treatment outcomes. B7-H4 and B7-H7 expression in tumor cells were associated with features of tumor aggressiveness and immune suppression, further highlighting the potential role of multiple B7-H family checkpoints in metastatic ccRCC. In multivariable Cox regression models, B7-H3 expression in tumor and stroma independently predicted shorter disease-free and overall survival. B7-H5 expression in TILs independently predicted reduced overall survival. These findings identify B7-H3 as a robust biomarker of tumor aggressiveness, therapeutic resistance, and adverse prognosis in metastatic ccRCC, while B7-H5 in TILs provides complementary prognostic information. Integrated profiling of B7-H immune checkpoints in primary tumors may refine clinical risk stratification and support the development of biomarker-guided immunotherapeutic strategies.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"12 4","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13382381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148521534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanosensitive TRPV4 immunohistochemistry improves deep learning-based classification of ductal carcinoma in situ beyond H&E morphology","authors":"Janghyun Yoo,&nbsp;Raghav Karthikeyan,&nbsp;Kashi Kamat,&nbsp;Christopher Chan,&nbsp;Shabnam Samankan,&nbsp;Elham Arbzadeh,&nbsp;Arnold Schwartz,&nbsp;Patricia S Latham,&nbsp;Inhee Chung","doi":"10.1002/2056-4538.70106","DOIUrl":"10.1002/2056-4538.70106","url":null,"abstract":"<p>Ductal carcinoma <i>in situ</i> (DCIS) spans a biologic continuum from atypical ductal hyperplasia (ADH) to high-grade lesions with variable risk of progression to invasive ductal carcinoma (IDC), yet morphologic assessment by hematoxylin and eosin (H&amp;E) remains diagnostically limited, particularly at the benign versus ADH/low-grade DCIS boundary. TRPV4, a mechanosensitive ion channel with pathology-dependent subcellular localization in DCIS, offers a biologically motivated immunohistochemical (IHC) marker that may refine classification beyond routine H&amp;E assessment. We tested whether deep learning models trained on TRPV4 IHC outperform H&amp;E-based models across the DCIS progression spectrum. We assembled a multi-institutional cohort of H&amp;E and TRPV4 IHC whole-slide images from 108 patients, comprising an internal development cohort (<i>n</i> = 69), an external test cohort (<i>n</i> = 39), yielding 24,248 annotated tiles. Histopathological tiles from annotated regions were grouped into four ordered classes: normal/benign, ADH/low-grade DCIS, high-grade DCIS, and IDC. Xception and EfficientNet-B0 convolutional neural networks were trained with patient-level three-fold cross-validation on the development cohort and evaluated as ensembles on the external test cohort. On external patient-level testing, H&amp;E ensembles achieved macro-F1 values of 0.43–0.44 and macro-AUC values of 0.73–0.80, whereas TRPV4 IHC ensembles improved performance to macro-F1 values of 0.68–0.72 and macro-AUC values of 0.91–0.92, corresponding to a 54.5–67.4% relative improvement in patient-level macro-F1. Patient-level per-class analyses showed the largest AUC gains with TRPV4 IHC versus H&amp;E for ADH/low-grade DCIS (0.94–0.95 versus 0.61–0.70) and IDC (0.77–0.85 versus 0.61–0.69). Per-class analyses showed the largest gains with TRPV4 IHC versus H&amp;E for ADH/low-grade DCIS (AUC, 0.83–0.84 versus 0.70–0.81) and IDC (AUC, 0.74–0.79 versus 0.65–0.66). These findings support TRPV4 IHC as a mechanistically grounded complement to H&amp;E that improves patient-level discrimination across the DCIS progression spectrum, with the strongest gains for ADH/low-grade DCIS and IDC, in a pilot multi-institutional setting.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"12 4","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.70106","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148406568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MET-amplified gastric cancers exhibit co-amplifications of BRAF, CDK6, and EGFR","authors":"Silke Lüschen,&nbsp;Ulrike Ebert,&nbsp;Hans-Michael Behrens,&nbsp;Sandra Krüger,&nbsp;Dita Ulase,&nbsp;Anu Amallraja,&nbsp;Steffen M. Heckl,&nbsp;Thomas Becker,&nbsp;Philip Rosenstiel,&nbsp;Tobias Meißner,&nbsp;Christoph Röcken","doi":"10.1002/2056-4538.70104","DOIUrl":"10.1002/2056-4538.70104","url":null,"abstract":"<p>MET-positive gastric cancer (GC) has a poor prognosis. In addition, targeting MET with monoclonal antibodies or tyrosine kinase inhibitors had limited success. We searched for additional genetic alterations that might explain the poor outcome of MET-positive GC and lack of response to MET-targeted therapies. Multiregional whole-exome sequencing was performed on primary tumor and lymph node metastasis samples from two <i>MET</i>-amplified discovery cases. Immunohistochemistry, <i>in situ</i> hybridization, and digital droplet polymerase chain reaction were performed in a validation cohort of 24 <i>MET</i>-amplified GCs. Whole-exome sequencing found 191 and 166 non-synonymous mutations, respectively. Only eight genes showed non-synonymous mutations in both cases, including <i>TP53</i>. Copy number variations (CNVs) were found in 18 and 14 autosomes, respectively, most commonly affecting chromosome 7. Since <i>BRAF</i>, <i>CDK6</i>, and <i>EGFR</i> are also localized on chromosome 7, validation studies were performed by fluorescence or chromogenic <i>in situ</i> hybridization, and co-amplification was found in 54% of the cases, including two discovery and 24 validation cases. Different combinations were found, for example, <i>CDK6 + MET</i>, <i>EGFR + MET</i>, <i>CDK6 + EGFR + MET</i>, <i>BRAF + CDK6 + EGFR + MET</i>, or <i>BRAF + EGFR + MET</i>. A database search using cBioPortal confirmed our findings. However, marked intra- and intertumoral heterogeneity was observed, and CNVs were highly variable and spatially separated. <i>MET</i> amplification in GC is accompanied by amplification of other oncogenes located on chromosome 7, that is, <i>BRAF</i>, <i>CDK6</i>, and <i>EGFR</i>, in a highly heterogeneous manner leading to substantial intra- and intertumoral heterogeneity. This may cause diagnostic and therapeutic challenges, provoke subclonal evolution, and lead to poor prognosis of <i>MET</i>-amplified GC and the failure of targeted therapies.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"12 4","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.70104","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148406481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SOX10 distinguishes oligodendrogliomas from low-grade glioneuronal tumors/low-grade gliomas with oligodendrocyte-like features","authors":"Danmei Zhou,&nbsp;Xiaomu Hu,&nbsp;Yin Wang,&nbsp;Feng Tang,&nbsp;Zunguo Du,&nbsp;Ji Xiong","doi":"10.1002/2056-4538.70103","DOIUrl":"10.1002/2056-4538.70103","url":null,"abstract":"<p>Oligodendrogliomas exhibit significant morphological overlap with low-grade glioneuronal tumors/low-grade gliomas with oligodendrocyte-like features, posing challenges in histopathological diagnosis. SOX10, a transcription factor critical for oligodendrocyte maturation and central nervous system myelination, may serve as a diagnostic marker. We evaluated the diagnostic utility of SOX10 immunohistochemical expression in 300 oligodendrogliomas versus 52 low-grade glioneuronal tumors/low-grade gliomas with oligodendrocyte-like features. Notably, SOX10 was negative in 251/300 (83.7%) oligodendrogliomas but diffusely positive in 47/52 (90.4%) low-grade glioneuronal tumors/low-grade gliomas with oligodendrocyte-like features (except polymorphous low-grade neuroepithelial tumors of the young, PLNTY). SOX10 expression was significantly higher in the latter group (<i>p</i> &lt; 0.001) and showed a WHO grade dependent up-regulation in oligodendrogliomas (<i>p</i> &lt; 0.001). The diagnostic utility of SOX10 was evident in IDH1-immunonegative cases, yielding 72% sensitivity, 90.4% specificity, and a 78.3% positive predictive value for oligodendroglioma. Combining H3K27me3 loss with SOX10 negativity markedly improved diagnostic sensitivity for oligodendroglioma to 88.5%, substantially surpassing the 35% sensitivity achieved with H3K27me3 loss alone. Additionally, an immunohistochemical panel comprising SOX10, Olig2, and IDH1 aided in discriminating non-neoplastic oligodendrocyte hyperplasia from oligodendroglioma and evaluating the presence of peritumoral tumor residue, particularly in IDH1-immunonegative oligodendroglioma. In conclusion, SOX10 negativity effectively excludes low-grade glioneuronal tumors/low-grade gliomas with oligodendrocyte-like features (except PLNTY) and non-neoplastic oligodendrocyte hyperplasia from oligodendrogliomas. SOX10 serves as a specific diagnostic marker, enhancing pathological diagnostic accuracy.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"12 4","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.70103","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148363124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pan-TRK expression and NTRK gene aberrations in meningiomas: association with tumor grade and proliferative activity","authors":"Yinan Zhu,&nbsp;Mingfang Sun,&nbsp;Wanchen Lu,&nbsp;Ziyue Wang,&nbsp;Haiyan Xi,&nbsp;Yan Song,&nbsp;Hongtao Xu,&nbsp;Xuyong Lin","doi":"10.1002/2056-4538.70105","DOIUrl":"10.1002/2056-4538.70105","url":null,"abstract":"<p>Tropomyosin receptor kinase (TRK) fusions are actionable oncogenic drivers, and pan-TRK immunohistochemistry (IHC) serves as a reliable screening tool for <i>NTRK gene</i> aberrations. However, the expression profile and clinical significance of pan-TRK in meningiomas remain unclear. This study aimed to characterize pan-TRK expression, its correlation with clinicopathological features, and underlying NTRK rearrangement status in meningiomas. We retrospectively analyzed 70 primary intracranial tumor specimens, including 50 meningiomas (21 WHO grade 1, 26 grade 2, and 3 grade 3) and 20 non-meningioma CNS tumors (9 solitary fibrous tumors, 6 hemangioblastomas, and 5 schwannomas) from the First Affiliated Hospital of China Medical University (2020–2022). Pan-TRK IHC was performed using the Ventana EPR17341 antibody, with fluorescence <i>in situ</i> hybridization (FISH) validating <i>NTRK gene</i> aberrations in positive cases. Clinicopathological correlations were analyzed using chi-square/Fisher's exact tests and Spearman's rank correlation. Pan-TRK immunoreactivity was detected in 12/50 (24.0%) meningiomas, predominantly with cytoplasmic staining (75.0%). Positivity was significantly higher in high-grade (WHO 2/3) meningiomas (7/29, 46.7% versus 3/21, 14.3% in grade 1; <i>p</i> = 0.031) and tumors with Ki-67 index ≥5% (7/15, 46.7% versus 5/35, 14.3% in Ki-67 &lt;5%; <i>p</i> = 0.027). No pan-TRK expression was observed in non-meningioma tumors (0/20). FISH confirmed <i>NTRK gene</i> aberrations in 2/12 (16.7%) pan-TRK-positive cases (both WHO 3 anaplastic meningiomas), with strong/moderate IHC staining correlating with aberrations. Pan-TRK is frequently expressed in meningiomas, particularly in high-grade and proliferative tumors, and may have preliminary utility in differentiating meningiomas from other CNS tumors. However, <i>NTRK gene</i> aberrations are rare, necessitating FISH or next-generation sequencing confirmation for pan-TRK-positive cases to identify candidates for TRK-targeted therapy. Further studies are needed to clarify the biological role of non-fusion-mediated pan-TRK overexpression in meningioma progression.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"12 4","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.70105","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148363154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ectonucleotidases CD39 and CD73 expression levels are independent and inverse predictors of survival in muscle-invasive bladder cancer","authors":"Stephan Ledderose,&nbsp;Julia Schwenke,&nbsp;Lennert Eismann,&nbsp;Severin Rodler,&nbsp;Martina Rudelius,&nbsp;Carola Ledderose","doi":"10.1002/2056-4538.70102","DOIUrl":"10.1002/2056-4538.70102","url":null,"abstract":"<p>Bladder cancer is one of the leading causes of cancer-related mortality worldwide. Long-term survival is particularly poor in patients with muscle-invasive bladder cancer (MIBC). Modulation of purinergic signaling through the ectonucleotidases CD39 and CD73 has emerged as a promising therapeutic strategy in cancer medicine. Altered expression patterns of these molecules have been linked to prognosis in various malignancies. In this study, we assessed the value of CD39 and CD73 expression as prognostic markers and potential therapeutic targets in MIBC. CD39 and CD73 expression was determined by immunohistochemistry using tissue microarrays from 180 patients with MIBC. Associations between tumoral and stromal expression and clinicopathological variables, including overall survival (OS), tumor-specific survival (TSS) and disease-free survival (DFS), were analyzed. Tumor cells did not express CD39. High stromal CD39 expression was significantly associated with a lower T category and UICC stage as well as prolonged median OS, TSS, and DFS. High CD73 expression by tumor cells was significantly associated with poorer OS and TSS. Stromal CD73 expression was not significantly correlated with survival outcomes. Our findings indicate distinct and compartment-specific roles for CD39 and CD73 in MIBC. They suggest that high CD73 expression in tumor cells and low CD39 expression in stromal cells are negative prognostic indicators and potential therapeutic targets in MIBC.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"12 4","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.70102","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148303587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oestrogen receptor phosphorylation profiles and in silico PAM50 subtyping reflect sexual dimorphism in breast cancer","authors":"Subarnarekha Chatterji,&nbsp;Aimee Diack,&nbsp;Marcin Szostok,&nbsp;Michael D Morgan,&nbsp;Valentina Silvestri,&nbsp;Laura Ottini,&nbsp;Cathy B Moelans,&nbsp;Paul J van Diest,&nbsp;Cigdem Selli,&nbsp;Andrew H Sims,&nbsp;Rasha Abu-Eid,&nbsp;Valerie Speirs","doi":"10.1002/2056-4538.70101","DOIUrl":"10.1002/2056-4538.70101","url":null,"abstract":"<p>Breast cancer (BC) is most prevalent in females but also accounts for &lt;1% of male cancer cases and 0.2% of male cancer-related deaths. Distribution of histological subtypes, receptor status, and age of diagnosis varies based on sex, and a growing body of evidence supports sex-specific molecular differences in BC. However, this is limited by the smaller number of male cases available for study compared to the thousands of cases of female BC. We combined publicly available male BC gene expression datasets for 195 patients from 4 studies and split randomly into discovery and validation sets. Clustering and gene expression analysis were performed. Two stable clusters were identified initially, confirmed in the validation set. Cluster C1 was enriched for genes associated with MAPK signalling and arylesterase activity. Cluster C2 showed enrichment of genes associated with proliferation, invasion, and metastasis, along with enrichment of gene ontology and pathway terms related to ECM regulation, particularly collagen-containing ECM. Of note, when stratified by ERα and PR status, no enrichment was observed with the predicted PAM50 classification. ERα and MAPK signalling were enriched in both clusters, albeit through different gene sets. Since these pathways were enriched, we investigated the signalling regulation of ERα based on immunohistochemical expression of phosphorylated ERα (S104, S118, S167, S294) and their prognostic roles. This analysis also revealed distinctions from female BC, showing a lack of prognostic outcome for any of these biomarkers. We show that male BC does not align with female BC in the same way that intrinsic subtypes of female BC are not identical. As BC heterogeneity is well recognised, we propose that male BC should be considered as a potentially unique clinical subtype of BC.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"12 4","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.70101","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148303584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinicopathological and molecular characterization of HPV-associated cervical poorly cohesive carcinoma: a rare aggressive entity","authors":"Wei Liu,&nbsp;Xiao-jiang Wang,&nbsp;Yan-mei Cui,&nbsp;Jing-cheng Liu,&nbsp;Jiajie Zhang,&nbsp;Li-bin Zhang,&nbsp;Xi Lei,&nbsp;Xiuqin Weng,&nbsp;Wucheng Shen,&nbsp;Wen-xiu Miao,&nbsp;Jun-cheng Ye,&nbsp;Tong-mei He,&nbsp;Qin Xu,&nbsp;Yi Shi,&nbsp;Dan Hu","doi":"10.1002/2056-4538.70100","DOIUrl":"10.1002/2056-4538.70100","url":null,"abstract":"<p>Primary signet-ring cell carcinoma and poorly differentiated adenocarcinoma with poorly cohesive morphology in the cervix are rare conditions, and their clinicopathological features remain poorly described. This study defines primary cervical poorly differentiated adenocarcinomas meeting the diagnostic criteria for poorly cohesive carcinoma as outlined in the 2019 WHO Classification of Digestive System Tumors as ‘HPV-associated cervical poorly cohesive carcinomas’ (HPV-associated CPCC) and describe their clinicopathological and molecular features. Sixteen HPV-associated CPCC cases were analyzed and classified into three histological subtypes: signet-ring cell carcinoma (<i>n</i> = 4), not otherwise specified (<i>n</i> = 6), and mixed types (<i>n</i> = 6). All patients were Chinese (median age: 46 years; range: 30–66). Vaginal bleeding was the primary presenting symptom (100.0%). High-risk human papillomavirus (HPV) was identified in all tumors, with HPV-18 as the predominant genotype (<i>n</i> = 13), HPV-16 in two cases, and a single case exhibiting concurrent infection with HPV-16, -18, and -58. Overall, 56.3% presented with advanced-stage disease (International Federation of Gynecology and Obstetrics [FIGO] IIIB–IVB), frequently involving regional lymph nodes (56.3%) and distant sites (18.8%). Histopathological examination revealed diffuse stromal infiltration (100%), lymphovascular invasion (75.0%), necrosis (75.0%), and desmoplasia. Immunohistochemically, all cases showed p16 block positivity. Variable expression of antibody-drug conjugate targets was observed, with HER2-low expression (33.3%), and positive staining for Trop-2 (85.7%), nectin-4 (42.9%), and tissue factor (92.3%). During follow-up, disease-specific mortality was 50.0%. The 3-year overall survival rate was 56.3%, which was significantly lower in advanced-stage disease (45.0%) than in early-stage disease (75.0%). Whole-exome sequencing revealed low tumor mutational burden (median 1.28 Muts/Mb), recurrent mutations in AK1, ARHGAP39, KRT24, MICAL3, SLC6A9 (27.3%), KRAS, and KMT2C (18.2%), alongside MUC2 copy gain (63.6%) and bidirectional Y_RNA alterations (gain 54.5%/loss 45.5%). Collectively, HPV-associated CPCC represents a distinct and aggressive subtype characterized by distinctive histopathological features, a predominant association with HPV18, frequent presentation at advanced stages, and marked molecular and biomarker heterogeneity.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"12 4","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.70100","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148253751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"YAP-activated lymph node fibroblasts contribute to extracellular matrix remodeling associated with extranodal extension of oral squamous cell carcinoma","authors":"Qian Zhang,&nbsp;Shanben Jiang,&nbsp;Ansardin Abliz,&nbsp;Sheng Chen,&nbsp;Qingang Hu,&nbsp;Liang Ding,&nbsp;Yuxin Wang","doi":"10.1002/2056-4538.70095","DOIUrl":"10.1002/2056-4538.70095","url":null,"abstract":"<p>Desmoplasia, characterized by excessive expansion of cancer-associated fibroblasts (CAFs) and aberrant extracellular matrix (ECM) deposition, is widely present especially in invasive cancers. The extranodal extension (ENE) of nodal metastasis involves the extension of invasive tumor cells through the lymph node capsule into the perinodal adipose tissue, leading to systemic metastasis. Thus, the specific roles of desmoplasia in ENE formation need to be identified. This study aimed to investigate the association between desmoplasia and its role in ENE formation of oral squamous cell carcinoma, with a focus on Yes-associated protein (YAP)-mediated fibroblast activation and ECM remodeling. Transcriptome profiling and histopathology study based on tissue microarrays were performed to explore the association of metastasis-associated CAFs (MAFs) in ECM remodeling with ENE formation. Primary MAFs were isolated from ENE-positive (ENE⁺) and ENE-negative (ENE⁻) lymph nodes for functional characterization. The regulatory role of YAP in MAF-mediated ECM remodeling was investigated through immunohistochemistry, gene knockdown, and co-culture assays with HSC-3 tumor cells. A high degree of desmoplasia and rich collagen remodeling in lymph nodes was associated with higher ENE risk. ENE⁺ MAFs exhibited superior proliferative capacity, enhanced migration, and increased ECM remodeling activity compared to ENE⁻ MAFs. Co-culture experiments demonstrated that ENE⁺ MAFs significantly promoted HSC-3 cell invasion through Matrigel. Exploratory RNA sequencing revealed enrichment of ECM receptor interaction and Hippo-YAP pathway in ENE⁺ lymph nodes. Nuclear YAP localization in MAFs correlated with elevated expression of ECM components (collagen type I alpha 1 [COL1A1], fibronectin 1 [FN1], Tenascin C) and matrix metalloproteinase-2. YAP knockdown in ENE⁺ MAFs significantly attenuated both ECM remodeling capacity and pro-invasion ability <i>in vitro</i>. These findings suggest that YAP-activated MAFs contribute to ECM remodeling that may create a stromal environment permissive for ENE formation, though direct <i>in vivo</i> validation is needed to establish causality.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"12 4","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.70095","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148158606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}