Modern Pathology最新文献

{"title":"Dermal Nerve Sheath Myxomas Harbor Recurrent DPYSL2::CDX1 Fusions and Expand the Spectrum of CDX1-Rearranged Soft Tissue Tumors.","authors":"Carina A Dehner, Laura M Warmke, Sion W Jasmine, Jessica Mercer, Michal Michal, Jiří Soukup, Tomáš Vaněček, Petr Šteiner, Petr Grossmann, Michael Michal","doi":"10.1016/j.modpat.2026.101101","DOIUrl":"https://doi.org/10.1016/j.modpat.2026.101101","url":null,"abstract":"<p><p>Dermal nerve sheath myxoma (DNSM) is a rare benign mesenchymal tumor with presumed nerve sheath differentiation with distinctive morphologic and immunophenotypic features; however, its molecular pathogenesis remains poorly understood. We investigated a series of nine morphologically classic DNSMs and performed molecular testing to identify recurrent genetic alterations. The cohort included five female and four male patients (median age: 56 years; range: 23-75 years). Tumors arose predominantly on the extremities and presented as multinodular dermal-based myxoid neoplasms composed of uniform spindled to epithelioid cells arranged in reticular cords within abundant myxoid stroma. Vacuolated \"signet ring-like\" cells were identified in all tumors. Immunohistochemically, all tested tumors showed diffuse S100, SOX10 and GFAP expression, and a subset focally expressed EMA, keratin AE1/AE3, and GLUT1. RNA-based sequencing identified an identical in-frame DPYSL2::CDX1 fusion in 7 of 9 cases. Fluorescence in situ hybridization testing using CDX1 and DPYSL2 break apart probes as well as DPYSL2/CDX1 dual-fusion probe confirmed rearrangement in 6/7 tested tumors. We herein demonstrate that most DNSM are characterized by recurrent DPYSL2::CDX1 fusions, representing the first recurrent molecular alteration identified in this tumor type. These findings further support the classification of DNSM as a distinct neoplastic entity and highlight the potential utility of molecular testing as a diagnostic adjunct in morphologically challenging cases. Further studies are warranted to clarify the biologic role of CDX1-related fusions and their relationship to other fusion-driven soft tissue neoplasms, particularly those with CDX1/CDX2 fusions.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"101101"},"PeriodicalIF":6.6,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183027","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":"Adamantinoma-like Ewing Sarcoma: An Underrecognized Mimicker in the Head and Neck With Divergent Clinicopathologic Features from Ewing Sarcoma.","authors":"Sara E Amin, Kim O Learned, Komal Ijaz, Michelle D Williams, Mena Mansour","doi":"10.1016/j.modpat.2026.101098","DOIUrl":"https://doi.org/10.1016/j.modpat.2026.101098","url":null,"abstract":"<p><p>Adamantinoma-like Ewing sarcoma (ALES) is a cytokeratin-positive member of the Ewing sarcoma (ES) family with a predilection for the head and neck (HN). Its rarity and overlapping immunophenotype with carcinomas contribute to frequent misclassification, while its biologic behavior and response to standard ES therapy remain incompletely defined. We conducted a 25-year retrospective review to characterize the clinicopathologic spectrum of ALES and compare HN ALES with non-HN ALES and HN ES, incorporating histologic, immunophenotypic, molecular, and clinical outcome data. Twenty-three cases were identified; ALES (n=20) and HN ES (n=3). ALES occurred in older patients (median age 49 vs. 29 years) and demonstrated a marked HN predilection (17/20), with a substantial proportion involving glandular sites. In contrast, HN ES arose in the skull base and sinonasal tract. ALES showed basaloid, epithelioid, or round cell morphology, with occasional palisading and rare squamous differentiation. Diffuse cytokeratin expression was present in all ALES, with frequent p40/p63 positivity, whereas ES showed only focal cytokeratin staining. Nodal metastases occurred in 9/20 ALES cases. EWSR1 rearrangement was identified in all ALES and ES cases, with FLI1 fusion identified in 18/20 ALES and 1/3 ES cases. With a mean follow-up of 60.6 months, outcomes varied by site: salivary gland ALES showed a more favorable course (4/5 in remission), whereas thyroid (6/8) and non-HN ALES (3/3) more often progressed. HN ES demonstrated poor outcomes. ALES is a distinct entity that frequently mimics carcinoma and extends beyond classic morphologic patterns. Site-specific differences observed in our study may aid in diagnosis; however, accurate recognition remains difficult, and a high index of suspicion at specific anatomical sites may be important for diagnosis and management.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"101098"},"PeriodicalIF":6.6,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183099","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":"MAP2K1-mutated melanocytic tumors: correlation of histological features with their molecular functional class based on a study of 114 cases.","authors":"Laura Gadeyne, Silvia M Rossi, Boulos Mansour, Daniel Nosek, Pia Waldenbäck, Siebe Loontiens, Joni Van der Meulen, Nadine Van Roy, Marjolein Vandekerckhove, Ella De Ryck, David Creytens, Fleur Cordier, Julie Lemahieu, Assia Bassarova, Saleem Taibjee, Maged Daruish, Vasiliki Siozopoulou, Dimitrios Goutas, Daniel Pissaloux, Arnaud De la Fouchardière, Shantel Olivares, Pedram Gerami, Dmitry V Kazakov, Ahmed K Alomari, Michele Donati","doi":"10.1016/j.modpat.2026.101100","DOIUrl":"https://doi.org/10.1016/j.modpat.2026.101100","url":null,"abstract":"<p><p>MAP2K1: mutated melanocytic tumors are relatively recently described and show diverse morphological features and complex genetic aberrations which require further characterization. In this study we describe the clinical, histomorphological, immunohistochemical and genetic characteristics of a cohort of 114 MAP2K1-mutated melanocytic neoplasms, including benign (n = 55), intermediate (n = 34) and malignant (n = 25) tumors, collected from different institutions, harboring Class I (RAF-dependent) (n = 16), Class II (RAF-regulated) (n = 59) and/or Class III (RAF-independent) (n = 44) MAP2K1 mutations. Five lesions exhibited dual MAP2K1 mutations, all involving 2 different functional classes. Benign melanocytic lesions with Class II/III MAP2K1 mutations show reproducible morphologic patterns, compatible with the assumption that the MAP2K1 variant is the molecular driver mutation in these lesions. These melanocytic lesions fall into a morphological spectrum which include either mainly dermal-based lesions with combined (nevoid to spitzoid) cytonuclear characteristics and associated desmoplastic stroma (22%), or mainly junctionally-located lesions with spitzoid Clark (SPARK) morphology (18%), as well as lesions with overlapping features (6%). A minority of lesions show a dysplastic nevus (4%) or desmoplastic Spitz nevus morphology (3%), that could represent the ends of this morphologic spectrum. Chromosome 15 amplifications and dual MAP2K1 mutations were demonstrated in a subset of lesions with the combined desmoplastic morphology. Furthermore, we describe MAP2K1-driven melanocytic lesions with secondary well-recognized pathogenic mutations, including WNT-activated melanocytomas (12%), but also a new, genetically and morphologically heterogenous group of melanocytomas, most often harboring Class II MAP2K1 mutations in conjunction with RAF-activating co-mutations (11%). In MAP2K1-driven melanoma, we demonstrate the presence of secondary mutations in classical progression genes, such as TERT promoter and CDKN2A, and a plexiform dermal, superficial spreading or desmoplastic melanoma morphology. Lastly, lesions harboring only Class I MAP2K1 mutations are mostly melanoma, commonly have RAF-activating co-mutations and show a heterogeneous morphological phenotype.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"101100"},"PeriodicalIF":6.6,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183032","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":"Routine H&E Histology Encodes Postoperative Risk Heterogeneity in Resected Pancreatic Ductal Adenocarcinoma: A Multicohort Evaluation of TIGERS.","authors":"Yixuan Shen, Chengwei Chen, Hui Jiang, Wenbin Liu, Yunshuo Zhang, Yelin Yang, Ming Yang, Danqun Zheng, Jieyu Yu, Fang Liu, Jing Li, Yilun Zheng, Xiaomu Hu, Jianping Lu, Chengwei Shao, Yun Bian","doi":"10.1016/j.modpat.2026.101099","DOIUrl":"https://doi.org/10.1016/j.modpat.2026.101099","url":null,"abstract":"<p><p>Patients with resected pancreatic ductal adenocarcinoma (PDAC) can have different outcomes despite similar TNM stage. We developed TIGERS (Tumor Intelligence Grading and Evaluation Risk Score), a nine-feature prognostic biomarker derived from routine hematoxylin and eosin (H&E) whole-slide images. TIGERS quantifies tumor burden, glandular and nuclear morphology, chromatin texture, and tumor-stroma topology. The score was trained in 644 treatment-naive cases and evaluated in an internal validation cohort (n = 385), a separate post-neoadjuvant cohort (n = 275), two external cohorts (n = 260 and n = 235), the TCGA-PAAD cohort (n = 133), and a prospectively accrued external cohort (n = 155) with subsequent offline inference. Overall survival was the primary endpoint; the same formula and locked cutoff were applied throughout. The cutoff stratified survival in the internal validation cohort and three of four retrospective test cohorts. In the remaining external cohort, 226 of 235 patients (96.2%) were classified as high risk, showing limited transportability of the fixed threshold. Adding TIGERS to the clinicopathologic model increased Harrell's C-index in all six retrospective cohorts (range 0.015-0.047). In the prospectively accrued cohort, mortality was 47.5% in the high-risk group and 22.7% in the low-risk group; high risk remained associated with worse survival after adjustment (hazard ratio, 4.45; 95% confidence interval, 2.28-8.70; P < .001). Automated quality control passed 92.3% of screened cases, and scoring was completed in all included cases with a median turnaround time of 13.5 minutes. TIGERS assigned 43.2% of patients to a different risk category than the prespecified stage-based definition. Higher TIGERS correlated with a more basal-like proteomic profile in both the training and internal validation cohorts, supporting a molecular basis for its prognostic value. Routine H&E histology may therefore provide prognostic information complementary to conventional clinicopathologic assessment. Prospective interventional studies are needed before TIGERS can guide treatment or surveillance.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"101099"},"PeriodicalIF":6.6,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183155","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":"Genomic and Transcriptomic Characterization of Angiosarcomas: Focus on Cardiac Origin.","authors":"Tao Lu, Yuan Liu, Mingming Yuan, Rongrong Chen, Guotao Ma, Yingyi Wang","doi":"10.1016/j.modpat.2026.101102","DOIUrl":"https://doi.org/10.1016/j.modpat.2026.101102","url":null,"abstract":"<p><p>Cardiac angiosarcoma is a rare and aggressive malignancy with limited therapeutic options, and its molecular features remain poorly defined. This study sought to characterize the genomic and transcriptomic landscape of cardiac angiosarcoma and to explore molecular features associated with clinical outcomes, chemotherapy response, and potential therapeutic vulnerabilities. We retrospectively analyzed 35 patients with cardiac angiosarcoma who underwent whole-exome sequencing (n = 11) and/or whole-transcriptome sequencing (n = 33). An additional 35 patients with angiosarcoma from noncardiac or unknown primary sites were included for comparative genomic analyses. Cardiac angiosarcoma frequently harbored alterations in KDR (55%), PLCG1 (45%), and CCND1 (36%), with recurrent amplifications at 8p23.1, 8p23.2, and 4q12 and recurrent deletions at 17q21.31, 15q13.2, 8p23.1, and 2q11.2. Transcriptomic analyses identified differential expression patterns associated with relapse, mortality, and chemotherapy response. Tumors from the low-relapse-risk group were enriched for axon guidance, whereas those from the high-relapse-risk group were enriched for cytokine-cytokine receptor interaction. Approximately one-third of patients exhibited high infiltration of most immune cell populations. Potentially actionable genomic alterations were identified in 71.7% of angiosarcomas. Compared with noncardiac angiosarcomas, cardiac tumors showed higher frequencies of KDR, CCND1, MCL1, and PLCG1 alterations and unique enrichment of the apelin signaling and vascular smooth muscle contraction pathways. Genomic and transcriptomic profiling of cardiac angiosarcoma revealed a distinct molecular landscape with candidate prognostic and therapeutic markers, providing a foundation for future precision oncology strategies in this rare disease.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"101102"},"PeriodicalIF":6.6,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183019","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":"Ex vivo fluorescence confocal microscopy for real-time margin assessment of nonmelanoma skin cancer in Mohs surgery: A prospective interventional study.","authors":"Marco Spadafora, Serena Morsia, Margherita Raucci, Shaniko Kaleci, Johanna Chester, Cinzia Ricci, Simonetta Piana, Giovanni Pellacani, Moira Ragazzi, Caterina Longo","doi":"10.1016/j.modpat.2026.101095","DOIUrl":"https://doi.org/10.1016/j.modpat.2026.101095","url":null,"abstract":"<p><p>New-generation ex vivo fluorescence confocal microscopy (EVFCM) generates hematoxylin-eosin-like images directly comparable to conventional histopathology. Its interobserver performance with a novel acquisition mode in non-melanoma skin cancer (NMSC) micrographically controlled surgery remains to be defined. In this prospective interventional study, 42 tumors from 39 patients undergoing Mohs surgery between January and October 2025 were examined with EVFCM. Specimens were orthogonally sectioned, stained, and acquired in digital-stain mode. Peripheral and deep margins were independently and blindly reviewed by a dermatologist and a pathologist, both trained in EVFCM interpretation. Concordant negative margins were considered tumor-free, whereas positive, discordant, or equivocal findings prompted re-excision and re-evaluation. Diagnostic agreement with histopathology was assessed using Cohen's κ statistic. A total of 261 margins were evaluated. Inter-reader agreement between the dermatologist and pathologist was almost perfect for both margin assessment (κ=0.863; SE 0.067; p<0.001; observed agreement 98.6%) and histotype assessment (κ=0.882; SE 0.031; p<0.001; observed agreement 97.6%). Compared with histopathology, EVFCM showed high performance, with an overall diagnostic accuracy of 96.4%. The AUC for the combined assessment was 0.875 (SE 0.074; 95% CI 0.730-1.000). Only two discrepancies were observed between EVFCM and histopathology: one false-negative margin assessment and one discordance attributable to differences in sample processing. These findings support EVFCM as a reliable tool for intraoperative margin assessment in NMSC. Comparable performance between dermatologist and pathologist readers supports its potential integration into Mohs surgery workflows; however, potential workflow advantages of the standardized sample-processing approach require prospective validation using quantitative time metrics.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"101095"},"PeriodicalIF":6.6,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149148507","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":"Parathyroid Pathology Uncovered: Tiny Glands, Big Questions.","authors":"C Christofer Juhlin, Anthony J Gill","doi":"10.1016/j.modpat.2026.101097","DOIUrl":"https://doi.org/10.1016/j.modpat.2026.101097","url":null,"abstract":"<p><p>Parathyroid neoplasms encountered in routine practice are most often diagnostically straightforward and can usually be classified on the basis of conventional histomorphology without the need for extensive biomarker work-up. This relative simplicity has contributed to the perception that pathologic assessment of parathyroid tumors is largely uncomplicated. Yet this view rapidly changes when a lesion exhibits atypical features beyond those expected in a conventional adenoma, particularly when the differential diagnosis includes parathyroid carcinoma, an exceptionally rare but potentially fatal malignancy. In these difficult cases, the endocrine pathologist carries substantial responsibility in separating misleading and overinterpreted atypical findings from lesions that truly harbor malignant potential or an increased risk of recurrence. Beyond classification, pathology also has a central role in identifying molecular abnormalities of diagnostic or therapeutic relevance in parathyroid carcinoma, as well as recognizing morphologic or immunophenotypic clues that may point to an underlying hereditary syndrome. In some cases, the pathologist may be the first to raise suspicion of a germline disorder and thereby initiate further genetic investigation. This review provides a focused analysis of the major histopathologic challenges in primary hyperparathyroidism. Particular emphasis is placed on distinguishing ordinary adenoma from normal glands, identifying atypical parathyroid tumors and parathyroid carcinoma while avoiding overdiagnosis, integrating immunohistochemical and molecular findings into diagnostic practice, and identifying features suggestive of hereditary disease. Our aim is to provide a practical framework that supports more accurate, reproducible, and clinically relevant pathologic assessment of parathyroid tumors.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"101097"},"PeriodicalIF":6.6,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147625","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":"Reproducible and Interpretable H&E-based Histopathological Subtypes of Non-metastatic Lymph Nodes Refine Risk Stratification in Colorectal Cancer.","authors":"Zhen Zhang, Yueyang Zhang, Xu Liu, Yafang Li, Wei Cui, Hong Su, Shuai Jiao, Jian Ma, Zhongyuan Bai, Yongsheng Meng, Haipeng Chen, Haitao Zhou, Xu Guan, Yanfeng Xi","doi":"10.1016/j.modpat.2026.101096","DOIUrl":"https://doi.org/10.1016/j.modpat.2026.101096","url":null,"abstract":"<p><p>Lymph node status is fundamental for staging, prognostic assessment, and treatment decision-making in colorectal cancer (CRC); however, current pathological evaluation largely focuses on metastatic involvement and overlooks the biological heterogeneity of non-metastatic lymph nodes (LNs). Here, we developed a reproducible histopathological classification system for non-metastatic LNs and established an interpretable machine-learning model for patient-level risk stratification in CRC. In this multicentre cohort study, we analyzed H&E-stained whole-slide images of non-metastatic LNs from patients with CRC undergoing curative-intent surgery across three independent cohorts. Non-metastatic LNs were classified into stimulated, unstimulated, and depleted subtypes based on semiquantitative assessment of proliferative and depletion-related morphological features. The biological characteristics of these subtypes were investigated using immunohistochemistry, transcriptomic profiling, and clinicopathological correlation analyses. Patient-level distributions of lymph node histopathological subtypes were integrated into multiple machine-learning algorithms, with model performance evaluated in internal and external validation cohorts. A total of 754 patients and 11,678 LN whole-slide images were included, comprising 10,410 non-metastatic and 1,268 metastatic LNs. Histopathological subtype assignment showed high interobserver reproducibility (Fleiss' κ=0.879, 95% CI 0.810-0.938). Stimulated LNs demonstrated enhanced immune activation features, whereas depleted LNs exhibited stromal remodeling, innate inflammatory activation, and impaired adaptive immune signaling. These histopathological subtypes were strongly associated with previously defined molecular LN subtypes. Among 12 machine-learning approaches, the random survival forest model achieved the best prognostic performance, with C-indices of 0.877 in the training cohort, 0.777 in cross-validation, 0.744 in temporal validation, and 0.748 in geographic validation. The resulting risk stratification system consistently discriminated overall survival across independent cohorts and clinically relevant subgroups. We established a reproducible H&E-based histopathological classification of non-metastatic LNs in CRC and developed an interpretable machine-learning model that captures lymph node immune-stromal heterogeneity and provides additional prognostic information beyond conventional staging parameters.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"101096"},"PeriodicalIF":6.6,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149148514","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":"Dual-Foundation-Model Ensemble Predicts Gene Expression in Muscle-Invasive Bladder Cancer for Patient Outcome Stratification.","authors":"Ingvild Frøberg Mathisen, Florestan J Koll, Robin Sebastian Mayer, Marcel H Schulz, Julia Bein, Felix Chun, Markus Eckstein, Anne Fassl, Jens Köllermann, Mike Wenzel, Nadine Flinner, Peter J Wild","doi":"10.1016/j.modpat.2026.101092","DOIUrl":"https://doi.org/10.1016/j.modpat.2026.101092","url":null,"abstract":"<p><p>Muscle-invasive bladder cancer (MIBC) exhibits significant heterogeneity in clinical outcomes and treatment responses. While gene expression profiling has provided important biological and prognostic insight, transcriptomic assays are not routinely incorporated into standard clinical practice, in part due to cost. AI models have been demonstrated to predict gene expression from H&E-stain whole-slide images (WSIs) potentially offering a scalable approach for gathering transcriptomic information for patient stratification and biomarker discovery. We developed and tested models to predict expression of 857 genes directly from H&E-stained whole-slide images (WSI). The best performing final model was a dual-ensemble combining predictions from models trained on features extracted with different foundation models. The dual-ensemble reached 776/857 predictable genes with an average correlation of 0.43 (cross-validation), 0.45 (holdout) and 0.40 (external Frankfurt cohort). Predicted expression strongly correlates with expression of clinically relevant markers (like NECTIN4). Estimated hazard ratios of predicted expression correlated strongly with those of measured expression and genes associated with overall survival for both predicted and measured expression in both cohorts were identified. AI-predicted basal vs. luminal subtypes were associated with overall survival and aligned with the ground-truth (accuracies > 0.8). Findings demonstrate that gene expressions inferred from routine staining can support biomarker discovery and patient stratification in MIBC.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"101092"},"PeriodicalIF":6.6,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112095","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":"A Complementary Role for Immunohistochemistry and NGS for Detection of MTAP Loss in Patients with Non-Small Cell Lung Cancer.","authors":"Sanna Laaksonen, Igor Odintsov, Alice T Shaw, Lynette M Sholl","doi":"10.1016/j.modpat.2026.101093","DOIUrl":"https://doi.org/10.1016/j.modpat.2026.101093","url":null,"abstract":"<p><p>Methylthioadenosine phosphorylase (MTAP) is an enzyme encoded by MTAP gene on chromosome 9p21. MTAP inactivation introduces a metabolic vulnerability with implications for targeted therapy. MTAP loss may be detected at the protein or DNA level, but characterization of clinical assays for detection of this event in non-small cell lung carcinoma (NSCLC) is limited. Clinicopathologic and genomic correlates of MTAP gene deletion were examined via retrospective review of an institutional cohort of 5,233 NSCLC cases with available next generation sequencing (NGS) data for 447 genes, including full coverage of the MTAP coding sequence. A subset of 105 cases were examined to assess the correlation between MTAP deletion by NGS and MTAP expression by immunohistochemistry (IHC). Homozygous deletion of MTAP was detected in 5.6% of NSCLC by NGS and was significantly more common in lung adenocarcinomas from patients with never/light smoking history (34.8%), and concurrent ALK fusions (8.2%) or EGFR mutations (45.9%). Approximately 13% of MTAP \"loss\" cases showed a heterogenous staining pattern by IHC. Concordance of NGS and IHC for detection of MTAP deficiency in NSCLC was 97.3%, following careful quality control (including recognition of a single case with partial deletion of 3' MTAP) and exclusion of NGS results from tumors with ≤30% tumor content. The remaining two discordant cases included one case with non-diploid genome and multiple copy states resulting in an incorrect NGS interpretation and one case with copy neutral NGS result and complete loss of protein expression by IHC. MTAP protein loss was therefore observed in the absence of a sequencing alteration in <1% of cases. MTAP gene deletion appears enriched in NSCLC with certain molecular drivers. NGS and IHC can show excellent concordance for detection of MTAP loss in NSCLC, with IHC showing superior sensitivity in the context of low tumor content or subclonal events.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"101093"},"PeriodicalIF":6.6,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112092","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}