Modern Pathology最新文献

{"title":"Phenotypic Characterisation of Richter Transformation and De Novo Diffuse Large B-Cell Lymphoma With or Without Monoclonal B-cell Lymphocytosis.","authors":"Fernando Martin-Moro, Miguel Alcoceba, Samuel Romero, Juan Marquet-Palomanes, David Alonso-Castronuño, Beatriz Astibia-Mahillo, Rafael Andreu, Rocio Perez-Alonso, Eulalia Rodriguez-Martin, Cristina De Ramon, Irene Solano, Alejandro Martin Garcia-Sancho, Miguel Piris-Villaespesa, Oscar Blanco, Ernesto Roldan-Santiago, Jose A Garcia-Marco, Dolores Subira, Almudena Navarro-Bailon, Monica Garcia-Cosio, Jose A Garcia-Vela, Javier Lopez-Jimenez","doi":"10.1016/j.modpat.2026.101009","DOIUrl":"https://doi.org/10.1016/j.modpat.2026.101009","url":null,"abstract":"<p><p>Richter transformation diffuse large B-cell lymphoma type (DLBCL-RT) is a biologically complex process that requires a comprehensive work-up for an accurate diagnosis. Detailed information regarding DLBCL-RT immunophenotype is limited. We used multiparametric flow cytometry and immunohistochemistry to assess the phenotypic profile of 63 patients diagnosed with DLBCL-RT. Cases partially retained the immunophenotype of the previous chronic lymphocytic leukemia (CLL), although modulation of markers such as CD43, CD5, CD200, CD23, and CD38 was common. Moreover, the phenotype of DLBCL-RT differed according to prior exposure or not to CLL therapy, with treatment-naïve patients showing more immunophenotypic variations against prior CLL compared to those who received therapy before transformation. With respect to the prognostic impact of antigenic markers, cases expressing CD20 exhibited higher overall survival compared to those CD20-negative, whereas CD43 expression was associated with worse prognosis. DLBCL-RT cases exhibited several antigenic differences in CLL-associated markers compared with an independent cohort of non-transformed DLBCL without concurrent CLL-like monoclonal B-cell lymphocytosis (MBL) (n = 28). In contrast, a separate cohort of patients with de novo DLBCL and concomitant CLL-like MBL (n = 25) exhibited biological similarities to DLBCL-RT, including comparable phenotypic profiles and a high rate of clonal relatedness between MBL and DLBCL. We conclude that DLBCL-RT is associated with a CLL-like immunophenotype influenced by pre-existing CLL characteristics, and we propose that, in some cases, de novo DLBCL with concomitant MBL may be considered as RT.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"101009"},"PeriodicalIF":5.5,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NTRK Fusion Landscape in 195 Positive Cases of 17 Tumors: A Chinese Multicenter Retrospective Study with Optimized Pan-TRK IHC Screening.","authors":"Shafei Wu, Jian Wang, Wentao Yang, Yuchen Han, Zhihong Zhang, Gang Chen, Bin Meng, Yan Sun, Yang Liu, Wencai Li, Shenglei Li, Lifeng Wang, Hongying Zhang, Lingchuan Guo, Yueping Liu, Xiaoding Liu, Ruping Hong, Kaimi Li, Junyi Pang, Zhiyong Liang","doi":"10.1016/j.modpat.2026.101007","DOIUrl":"https://doi.org/10.1016/j.modpat.2026.101007","url":null,"abstract":"<p><p>Neurotrophic tyrosine receptor kinase (NTRK) fusions are crucial in tumorigenesis and in guiding targeted therapy with TRK inhibitors. However, their rarity, fusion heterogeneity, and limitations of conventional pan-TRK immunohistochemistry (IHC) impede accurate clinical detection. This multicenter retrospective study analyzed 374 NGS/FISH-validated samples (195 NTRK - positive and 179 NTRK - negative) collected from 12 Chinese centers to investigate fusion heterogeneity and refine the interpretation of pan-TRK IHC. We developed an amplified protocol by combining the traditional pan-TRK IHC (EPR17341) with the OptiView Amplification kit and established new interpretation criteria. A total of 40 solid tumor types were included, and 23 unique fusion partners were identified. Papillary thyroid cancer was the most common NTRK-positive tumor (49.74 %) and harbored all three NTRK subtypes. Among NTRK-positive samples, NTRK3 (74.87 %) was the most prevalent subtype, followed by NTRK1 (23.59 %). ETS variant transcription factor 6 (ETV6) was the most frequent fusion partner, identified in 122 out of 195 cases. It was uniquely shared across all three NTRK subtypes, with its fusion to NTRK1 being reported for the first time. NTRK1 and NTRK3 exhibited marked fusion partner specificity, with no overlap in their associated partners except for ETV6. The optimized pan-TRK IHC protocol significantly improved staining efficiency by enhancing intensity and clarity. Consequently, the newly established criteria (cytoplasmic intensity ≥1 in ≥50% of tumor cells or any nuclear intensity ≥1) exhibited outstanding detection performance, achieving an overall sensitivity of 94.36% and increasing specificity to 79.89%, compared to 60.22% under the conventional one. Particularly, the detection sensitivity for NTRK3 fusions was significantly enhanced and reached 95.89 %. This study contributes to clarifying NTRK fusion distribution in patients and validates a standardized, sensitive pan-TRK IHC strategy for clinical screening.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"101007"},"PeriodicalIF":5.5,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147817580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Copy Number-Low/TP53 Mutated Endometrial Cancer With Wild Type p53 Immunoexpression: Implications for Risk Stratification and Management When Using Next Generation Sequencing for Molecular Classification.","authors":"Joseph T Rabban, Rebecca J Wolsky, Neslihan Kayraklioglu, Kurtis D Davies, Dara L Aisner, W Patrick Devine","doi":"10.1016/j.modpat.2026.101005","DOIUrl":"https://doi.org/10.1016/j.modpat.2026.101005","url":null,"abstract":"<p><p>Endometrial cancers with a Cancer Genome Atlas (TCGA) molecular profile of TP53-mutated, POLE-wild type, and microsatellite-stable generally exhibit a high burden of copy number (CN) alterations and carry an increased risk for adverse outcome, meriting maximal adjuvant therapy. In contrast, the prognosis associated with a TP53 mutation that co-exists with a POLE mutation or microsatellite instability aligns with that of ultramutated or hypermutated cancers, respectively. Herein we characterize a rare molecular sub-class of endometrial cancers defined by TP53 mutation but low burden of CN alterations, wild type p53 immunoexpression (IHC) and low TP53 variant allele frequency (VAF, median 13%, maximum 47%). Among 723 consecutive endometrial cancers prospectively classified using next generation sequencing (NGS), 16 (2.2%) were CN-Low/TP53-mutated / p53 wild type IHC. Two additional cases were identified in a separate retrospective cohort of 32 recurrent low grade early-stage endometrial cancers, bringing the total to 18 cases. They affected post-menopausal patients, exhibited low grade endometrioid histotype and were mostly confined to the uterus without lymphovascular space invasion. The recurrence rate was 6.25% (1/16) in the prospective cohort and none died, placing their prognosis closer to that of CN-Low than CN-High cancers. We conclude that NGS-based TCGA classification of TP53-mutated, POLE-wild type, microsatellite stable endometrial cancers with TP53 VAF <50% requires further evaluation by CN analysis and/or p53 IHC to detect this rare molecular category. Immunohistochemistry-based TCGA classification, such as the ProMisE protocol, will not be able to detect these cases as the p53 IHC pattern is wild type and there are no distinguishing morphological features; this may be of relevance for analyzing ProMisE protocol-based clinical trials and outcomes studies. Long term outcome studies are needed to refine risk stratification and treatment decisions for this unique molecular class of endometrial cancers that further contributes to the evolving understanding that the clinical significance of TP53 mutation in endometrial cancer is complex and depends on co-existing molecular alterations.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"101005"},"PeriodicalIF":5.5,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and Molecular Evaluation of HER2-Low and Ultralow Breast Cancer in the PENELOPE-B Clinical Trial Cohort.","authors":"Carsten Denkert, Sivaramakrishna Rachakonda, Anika Pehl, Frederik Marmé, Miguel Martin, Thomas Karn, Michael Untch, Hervé Bonnefoi, Sung-Bae Kim, Nader Hirmas, Harry Bear, Agnieszka K Witkiewicz, Seock-Ah Im, Angela DeMichele, Laura Van't Veer, Nicole McCarthy, Thorsten Stiewe, Paul Jank, Karen A Gelmon, José A García-Sáenz, Christina Westhoff, Catherine M Kelly, Toralf Reimer, Mireia Melé Olivé, Erik S Knudsen, Marion van Mackelenbergh, Federico Rojo, Nadine Frickel, Peter A Fasching, Julia Teply-Szymanski, Masakazu Toi, Hope S Rugo, Michael Gnant, Andreas Makris, Bärbel Felder, Valentina Nekljudova, Sibylle Loibl","doi":"10.1016/j.modpat.2026.101006","DOIUrl":"https://doi.org/10.1016/j.modpat.2026.101006","url":null,"abstract":"<p><p>The DestinyBreast-(DB)-04 and DB06-trials have shown clinical activity of Trastuzumab-Deruxtecan (T-DXd) in HER2-low and HER2-ultralow metastatic breast cancer (BC). The identification of HER2-low and -ultralow BC is therefore essential for personalized therapy with T-DXd. We evaluated 723 residual tumors from the PENELOPE-B trial (NCT01864746) and correlated different levels of HER2 protein expression with prognosis and mRNA profiles, including HER2 transcripts. In PENELOPE-B, 57.68% (n=417) of 723 residual tumors were HER2-low. The HER2-ultralow category was assigned to 109 tumors (15.08%), and 197 tumors (27.25%) were completely HER2 negative (HER2-zero). In Kaplan-Meier analysis, there were no survival differences among these three subgroups. There was no significant difference in HER2 mRNA expression between HER2-zero and HER2-ultralow tumors (p=0.08). In contrast, there was a highly significant difference in HER2 mRNA expression between HER2-ultralow and HER2-low tumors (p<0.0001) and between HER2-low and HER2-positive tumors (p<0.0001). The extracellular protease Cathepsin-L, which has been suggested as a biomarker for extracellular cleavage of T-DXd, was detectable in all HER2-related subgroups, and was a negative prognostic factor for iDFS and OS (p=0.0001) in pre-neoadjuvant core biopsies. In our study, we were able to characterize HER2-low as a clinically relevant and molecular defined tumor group with significantly increased HER2-expression. In contrast, for HER2-ultralow we did not observe a defined molecular phenotype, despite the clinically relevant regulatory approval of T-DXd also in the ultra-low subgroup. Additional investigations are needed to identify biomarkers beyond HER2 for T-DXd response as a basis for refined criteria for treatment eligibility.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"101006"},"PeriodicalIF":5.5,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mature Tertiary Lymphoid Structures in Breast Cancers Are Associated With Anti-Tumor Immunity and Better Prognosis.","authors":"Shibo Yu, Mirte Dekker, Mieke C Zwager, Lorian Slagter-Menkema, Tineke van der Sluis, Carolina P Schröder, Marcel A T M van Vugt, Bert van der Vegt","doi":"10.1016/j.modpat.2026.101004","DOIUrl":"https://doi.org/10.1016/j.modpat.2026.101004","url":null,"abstract":"<p><p>Tertiary lymphoid structures (TLSs) are immune cells accumulated in non-lymphoid tissues, with an inner core of B cells encompassed by T cells. The aim of this study was to evaluate the clinical importance of mature TLSs in breast cancer, including their association with immunotherapy response and their role in modulating the tumor immune microenvironment. We analyzed histopathological data of 726 consecutive primary breast cancers and transcriptomic data of 824 breast cancer samples from the publicly available TCGA database to estimate the clinical and immunological value of mature TLSs in breast cancer. Additionally, we utilized pretreatment transcriptomic data of 69 breast cancer patients from the publicly available I-SPY2 clinical trial to investigate the relation between TLS-related gene signatures and patient responses to immune checkpoint inhibitors (ICIs). The existence of mature TLSs was identified in approximately 5.6% (41/726) of all breast cancer patients (HR+HER2-: 0.92%; TNBC: 14.96%; HER2+: 10.98%) and was independently associated with improved recurrence-free survival (RFS) after adjusting for subtypes, tumor-infiltrating lymphocyte (TIL) levels, and tumor stage after the multivariable Cox regression analysis in our patient cohort. Notably, the presence of mature TLSs was related to immune cell infiltration in our breast cancer patient cohort. In line with these findings, TLS-related gene signatures analyzed through transcriptomic data reliably reflected the existence of mature TLSs and were related to better clinical responses to ICIs in breast cancer patients. In conclusion, our findings show that mature TLS formation is linked with immune cell infiltration, contributes to a favorable prognosis, and may function as a potential complementary biomarker for immunotherapy response in breast cancer.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"101004"},"PeriodicalIF":5.5,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147717332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MetAssist 2.0: A Generalizable AI Framework for Lymph Node Metastasis Detection Across Multiple Cancer Types.","authors":"Javier Garcia-Baroja, Bastian Dislich, Philipp Zens, Branislav Zagrapan, Fammi Maria Parokkaran, Léo Wütschert, Synes Elias Weber, Lucine Christe, Christina Neppl, Tilman Rau, Aurel Perren, Yuri Tolkach, Inti Zlobec, Amjad Khan","doi":"10.1016/j.modpat.2026.101003","DOIUrl":"https://doi.org/10.1016/j.modpat.2026.101003","url":null,"abstract":"<p><p>Lymph node metastasis assessment is critical for cancer staging, yet the process is labor-intensive and prone to variability, particularly when evaluating micro-metastases or isolated tumor cells that can directly alter treatment decisions. We present MetAssist 2.0, a modular AI system that combines a pathology foundation model with transformer-based segmentation to automate metastasis detection across cancer types. Trained on colorectal and upper gastrointestinal cancers, it was validated on 8,144 slides spanning seven cancer types and 14 multi-institutional cohorts. MetAssist 2.0 achieved at least 90% sensitivity in 13 cohorts and 91% specificity in 11, including challenging subtypes such as mucinous adenocarcinoma and tumor deposits. With only 10 annotated slides, the system adapted to unseen cancer types via few-shot fine-tuning. As a triage tool for colorectal cancer, it could reduce pathologist workload by up to 72% with a 98% sensitivity and revealed metastases missed in routine reporting. These results demonstrate broad generalizability and near clinical-grade performance, positioning MetAssist 2.0 for integration into the pathology workflows.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"101003"},"PeriodicalIF":5.5,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147717406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Histopathologic evaluation and reporting in inflammatory bowel disease A consensus paper sponsored by the Rodger C. Haggitt Gastrointestinal Pathology Society.","authors":"Alexandros D Polydorides, Xiuli Liu, Shaomin Hu, Michael G Drage, Jean-Frederic Colombel, Dermot P B McGovern, Gert De Hertogh, Vikram Deshpande, Michael Vieth, Nicole C Panarelli","doi":"10.1016/j.modpat.2026.101002","DOIUrl":"https://doi.org/10.1016/j.modpat.2026.101002","url":null,"abstract":"<p><p>The histopathologic evaluation and diagnosis of specimens from patients with inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn disease (CD), is complicated, yet clinically important. Therefore, formalized recommendations about appropriate terminology and necessary elements to include in the corresponding report are likely to benefit practicing pathologists. This consensus paper was initiated and sponsored by the Rodger C. Haggitt Gastrointestinal Pathology Society (GIPS) after the majority of respondents in a survey indicated that IBD reporting guidelines would inform their daily practice. The document presented herein provides recommendations for the macroscopic and histologic examination of samples from patients with suspected or confirmed IBD at three distinct tiers of disease evolution: initial diagnosis with endoscopic biopsies, disease activity assessment during colonoscopic surveillance, and evaluation of long-term prognosis after surgery. Given its complexity and importance, IBD-related neoplasia will be considered in a separate, forthcoming document. These recommendations, presented in the form of 20 main position statements, each following a brief review of the pertinent literature and some with additional supplemental statements, reflect the strength of available published evidence. They were subjected to review, vote, and approval by all authors and, in addition, by a group of surgical pathologists and gastroenterologist clinicians with documented interest and experience in the diagnosis and treatment of patients with IBD. We hope this document is the first in a dynamic series with subsequent iterations and revisions incorporating emerging data and evolving approaches to management.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"101002"},"PeriodicalIF":5.5,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147691127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Desert Immune Phenotype in Endometrial Carcinoma: A Distinct Subgroup With Poor Prognosis and Targetable Mutations.","authors":"Merve Kaya, Lawrence H Lin, Jan Oosting, Melanie E Powell, Emma J Crosbie, Alexandra Leary, Linda R Mileshkin, Lois Shepherd, Marco de Bruyn, Jan Jobsen, Judith R Kroep, Carien L Creutzberg, Nanda Horeweg, Alicia Léon-Castillo, Carlos Parra-Herran, Vincent T H B M Smit, Marisa R Nucci, Tjalling Bosse","doi":"10.1016/j.modpat.2026.101000","DOIUrl":"https://doi.org/10.1016/j.modpat.2026.101000","url":null,"abstract":"<p><p>Accurate assessment of the tumor immune microenvironment is increasingly important for risk stratification in endometrial carcinoma (EC). Existing immune profiling methods often rely on immunohistochemistry or digital quantification to distinguish inflamed and excluded phenotypes, whereas the desert phenotype-marked by minimal immune infiltration-may be identifiable on routine hematoxylin and eosin (H&E) slides. Therefore, we developed a qualitative histological scoring system to define the Desert phenotype on H&E slides and used it to examine clinicopathologic and molecular associations, evaluate prognostic relevance, and assess interobserver reproducibility. Five expert gynecologic pathologists defined consensus criteria for the Desert phenotype in a molecularly classified development cohort (n = 20) and applied them to a testing cohort from the randomized PORTEC-3 trial (n = 380), which included patients with high-risk EC randomized to radiotherapy or chemoradiotherapy. In the PORTEC-3 cohort, 28% of tumors displayed the Desert phenotype. Desert EC were enriched for No Specific Molecular Profile (NSMP) and p53-abnormal (p53abn) subtypes and exhibited a distinct mutational profile, including a higher prevalence of CTNNB1 and AKT1 mutations, an effect that was driven by the NSMP subtype. Desert EC had worse recurrence-free survival compared with Non-Desert EC. Across molecular classes, worse overall survival was only observed in desert p53abn EC compared to non-desert p53abn EC. Interobserver agreement was moderate (κ = 0.57). CONCLUSION: The Desert immune phenotype, as identified on routine H&E-slides with moderate agreement, is a biologically distinct and prognostically significant subset of EC. Future work to improve reproducibility is essential to validate its potential for clinical use, both for risk stratification and for guiding immunotherapy.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"101000"},"PeriodicalIF":5.5,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147675095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"p62/SQSTM1 Accumulation Defines an EMT/Twist1-Associated Infiltrative Phenotype in Pancreatic Neuroendocrine Tumors.","authors":"Takashi Matsumoto, Takeo Yamamoto, Satoru Osajima, Yoshiyuki Nakanishi, Shoko Noguchi, Yusuke Mizuuchi, Masatoshi Murakami, Keijiro Ueda, Ken Takigawa, Masatoshi Shimo, Kohta Miyawaki, Koji Kato, Nao Fujimori, Kohei Nakata, Shinichi Aishima, Yoshinao Oda","doi":"10.1016/j.modpat.2026.101001","DOIUrl":"https://doi.org/10.1016/j.modpat.2026.101001","url":null,"abstract":"<p><p>Pancreatic neuroendocrine tumors (PNETs) lack clinically validated biomarkers for risk stratification and treatment selection. p62 (also known as SQSTM1)-a multifunctional adaptor protein degraded by autophagy-has been associated with adverse outcomes, but its correlation with invasion and metastasis in PNETs remains unclear. We retrospectively analyzed 194 PNETs resected between January 1994 and December 2022. The expression of p62, LC3B, E-cadherin, and Twist1 was evaluated using immunohistochemistry, and targeted transcriptomic profiling (nCounter) was performed to compare p62-high and p62-low groups. High p62 expression was associated with shorter overall and disease-free survival and higher frequencies of lymph node metastasis and an infiltrating growth pattern. In tumors with an infiltrating growth pattern, p62 expression was higher at the invasive front than in the tumor center, supporting a spatial association with histopathologic invasion. Transcriptomic profiling showed enrichment of epithelial-mesenchymal transition (EMT) pathways in the p62-high group, including upregulation of TWIST1, a key EMT-related transcription factor. Consistently, p62-high tumors showed reduced membranous E-cadherin and increased cytoplasmic and nuclear Twist1 expression. In a subgroup of small tumors (≤ 20 mm), p62-high status was not associated with significantly different survival, but it remained associated with infiltrative histopathologic features. Collectively, high p62 expression was associated with an aggressive, infiltrative PNET phenotype and an EMT/Twist1-associated signature, suggesting that p62 may capture a biologic state characterized by infiltrative behavior and complement risk stratification within current WHO frameworks.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"101001"},"PeriodicalIF":5.5,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147675051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stage-independent real-time subtype classification and comprehensive biopsy profiling of urothelial carcinomas by the Lund Taxonomy system.","authors":"Pontus Eriksson, Elena Aramendía Cotillas, Carl-Adam Mattsson, Aymeric Zadoroznyj, Carina Bernardo, Gottfrid Sjödahl, Anders Edsjö, Markus Heidenblad, Fredrik Liedberg, Mattias Höglund","doi":"10.1016/j.modpat.2026.100997","DOIUrl":"https://doi.org/10.1016/j.modpat.2026.100997","url":null,"abstract":"<p><p>Bladder cancer is a heterogeneous malignancy with diverse clinical outcomes, and conventional pathological assessment alone is insufficient to capture its underlying biology. Gene expression profiling can stratify tumors into molecular subtypes with prognostic and predictive potential, but the reliability of transcriptomic classification and its clinical utility remains to be established. The translational/observational UROSCANSEQ study (ISRCTN15459149) prospectively evaluates RNA-based Lund Taxonomy (LundTax) molecular subtype classification in a clinical setting. Among 784 consecutive biopsies collected between 2018 and 2022, RNA sequencing was successful for 90% of all biopsies, encompassing 662 bladder cancer patients with a stage distribution of 48% Ta, 27% T1, 24% ≥T2, and 1% CIS. We demonstrate that the LundTax subtype classification algorithm, applied to individual samples, accurately identifies cancer cell phenotypes with characteristic gene and protein expression patterns in a manner robust to RNA quality, data preprocessing strategies, and batch effects, supporting its clinical feasibility across both non-muscle-invasive and muscle-invasive disease. We further extend the LundTax framework by incorporating single-sample molecular risk-scores reflecting tumor grade, proliferation, and progression-risk, as well as tumor microenvironment (TME) signatures. Both risk scores and overall immune and stromal content in biopsies were significantly associated with an increased risk of clinical progression in non-invasive disease. In a separate analysis of the relative cellular composition of the TME, however, only the fraction of natural killer (NK) cells remained significant. Together, the expanded LundTax system provides a comprehensive molecular portrait of individual tumor biopsies. By explicitly separating cancer cell-intrinsic phenotypes, prognostic indices, and microenvironmental signals, the framework minimizes biological confounding and establishes a strong foundation for future studies evaluating clinical outcomes and treatment responses.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"100997"},"PeriodicalIF":5.5,"publicationDate":"2026-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147623505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}