Modern Pathology最新文献

{"title":"POU4F3 Expression Distinguishes Wnt/Beta-Catenin–Activated Nonpilomatrical Carcinoma From Merkel Cell Carcinoma","authors":"Thibault Kervarrec , Serge Guyétant","doi":"10.1016/j.modpat.2025.100751","DOIUrl":"10.1016/j.modpat.2025.100751","url":null,"abstract":"","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 5","pages":"Article 100751"},"PeriodicalIF":7.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143724355","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":"Methylation Analysis Reveals Epigenetic Congruence Between Bone Sarcomas With H3-3A Mutations and Malignant Giant Cell Tumors of Bone","authors":"Carla Saoud ,&nbsp;Jamal Benhamida ,&nbsp;Laetitia Borsu ,&nbsp;Liliana Villafania ,&nbsp;Konstantinos Linos ,&nbsp;A. Rose Brannon ,&nbsp;Hwang Sinchun ,&nbsp;Carol Morris ,&nbsp;Max Vaynrub ,&nbsp;Meredith Bartelstein ,&nbsp;John Healey ,&nbsp;William Tap ,&nbsp;Tejus A. Bale ,&nbsp;Benjamin A. Nacev ,&nbsp;Marc Ladanyi ,&nbsp;Meera R. Hameed","doi":"10.1016/j.modpat.2025.100763","DOIUrl":"10.1016/j.modpat.2025.100763","url":null,"abstract":"<div><div>Hotspot mutations in <em>H3-3A</em> gene are key drivers in giant cell tumor of bone (GCTB). Rare primary bone sarcomas also harbor this mutation, but their clinicopathologic characteristics and molecular profiles, as well as their relationship to conventional and malignant GCTB (MGCTB) and high-grade conventional osteosarcoma (HGOS), are largely undefined. Herein, we present a series of 10 <em>H3-3A</em> mutated bone sarcomas (BSH3-3A) with a comparative clinicopathologic, mutational, and epigenetic analysis with conventional GCTB, MGCTB, and HGOS. BSH3-3A comprised of 6 high-grade osteosarcomas, 4 undifferentiated pleomorphic sarcoma of bone and occurred in 7 women and 3 men with a mean age of 46 years (28-74 years). The tumors involved femur (n = 4), talus (n = 2), spine (n = 2), pelvis (n = 1), and 1 unknown site. Epiphysis involvement was noted in 2 femoral tumors. In majority of the cases, BSH3-3A showed cellular proliferation of epithelioid and/or spindle cells, hyperchromatic nuclei, and conspicuous pleomorphism with or without osteoid production. One case exhibited both low- and high-grade osteosarcoma components. The mutational profile of BSH3-3A was different than that of conventional HGOS with significantly less frequent <em>TP53</em> mutations. The genomic index, which reflects the degree of genomic complexity, was also significantly lower in BSH3-3A compared with HGOS, yet higher than GCTB. DNA methylation analysis revealed that most BSH3-3A and MGCTB cases form a distinct cluster, positioned near but separate from GCTB, and clearly separated from HGOS. Differential methylation analysis revealed that BSH3-3A exhibited the highest degree of similarity to MGCTB in comparison to HGOS and GCTB. Survival analysis showed that outcomes for BSH3-3A do not differ significantly from those observed in HGOS or MGCTB. Finally, BSH3-3A tumors, although radiologically and histologically identical to high-grade bone sarcomas lacking <em>H3-3A</em> mutations, display epigenetic features similar to MGCTB and have a significantly less complex genomic profile than HGOS, despite comparable clinical outcomes.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 7","pages":"Article 100763"},"PeriodicalIF":7.1,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743180","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":"Nosologic Reappraisal of the Recently Proposed Calcified Chondroid Mesenchymal Neoplasm Concept in a Series of 20 Cases","authors":"Shogo Nishino ,&nbsp;Taisuke Mori ,&nbsp;Hajime Umezu ,&nbsp;Kohtaro Eguchi ,&nbsp;Toshihide Hirai ,&nbsp;Ryouji Yamada ,&nbsp;Shinsuke Ohshima ,&nbsp;Yasushi Yatabe ,&nbsp;Seiichi Yoshimoto ,&nbsp;Akira Kawai ,&nbsp;Toru Motoi ,&nbsp;Akihiko Yoshida","doi":"10.1016/j.modpat.2025.100762","DOIUrl":"10.1016/j.modpat.2025.100762","url":null,"abstract":"<div><div>“Calcified chondroid mesenchymal neoplasm (CCMN)” is a recently proposed term for tumors with hypercellular chondroid histology and fusion genes. However, its impact on the present classification framework has not been extensively investigated. In this study, we analyzed 20 tumors with histology that would fit with that reported as “CCMN.” With the combined use of RNA sequencing and fluorescence in situ hybridization, 15 tumors were found to have gene fusions, including <em>FN1::FGFR2</em> (n = 4), <em>FN1::TEK</em> (n = 1), <em>FN1::MERTK</em> (n = 1), <em>PDGFRA::USP8</em> (n = 2), <em>FN1</em> rearrangements with undetermined non-<em>FGFR2</em> partners (n = 4), and <em>PDGFRA</em> rearrangements with undetermined partners (n = 3). <em>FN1</em> or <em>PDGFRA</em> rearrangement signals were restricted to epithelioid/polygonal cells, indicating that these were neoplastic elements mixed with abundant reactive cells. The fusion-positive tumors were found in 7 men and 8 women aged 29 to 82 years (median, 57 years), and most involved the temporomandibular joints or digits. Tumors showed a chondroid matrix with grungy calcification and cellular components with epithelioid/polygonal cells and were divided into 2 groups the histology of which corresponded to chondroid tenosynovial giant cell tumor or soft-tissue chondroma. Three fusion-positive tumors harbored calcium pyrophosphate dihydrate crystals. Nuclear atypia was frequent. Gene fusions were not detected in the remaining 5 tumors with abundant crystal/calcium deposition, and some may represent reactive conditions. All 20 tumors followed an indolent clinical course, and 4 patients with temporomandibular joint tumors were successfully followed up without surgery for 9 to 60 months. Using “CCMN” as an entity would entail mixed repercussions in diagnostic practice, and how and whether it should be used in diagnosis requires deliberate discussion. The concept may bring some benefits, but it may arguably cause more confusion because it would substantially restructure the conventional framework by drawing a boundary within the chondroma and conflating the chondroma with chondroid tenosynovial giant cell tumor.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 7","pages":"Article 100762"},"PeriodicalIF":7.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730674","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":"Multiregion Genomic Analysis of Human Pancreatic Mucinous Cystic Neoplasms","authors":"Michael J. Pflüger ,&nbsp;Kohei Fujikura ,&nbsp;Alicia M. Braxton ,&nbsp;Jae W. Lee ,&nbsp;Doreen M. Zucha ,&nbsp;Brian A. Pedro ,&nbsp;Davina Goodman ,&nbsp;Jiayun Lu ,&nbsp;Liping Jiang ,&nbsp;Xiaobing Wang ,&nbsp;Jiarun Zhu ,&nbsp;Marco Dal Molin ,&nbsp;Hao Wang ,&nbsp;Lodewijk A.A. Brosens ,&nbsp;Jin He ,&nbsp;Satomi Kawamoto ,&nbsp;Yuchen Jiao ,&nbsp;Laura D. Wood","doi":"10.1016/j.modpat.2025.100759","DOIUrl":"10.1016/j.modpat.2025.100759","url":null,"abstract":"<div><div>Mucinous cystic neoplasms (MCNs) are precursors to invasive pancreatic cancer. Conflicting clinical management recommendations call for better molecular characterization to improve our understanding of their tumorigenesis and risk assessment. We sampled epithelial tissue from a total of 18 surgically resected MCNs and performed dedicated multiregion analysis of somatic genetic alterations by targeted next-generation sequencing of 25 driver genes. In addition, we performed whole-exome sequencing and immunohistochemistry on selected samples to supplement our analyses. In total, 128 samples of epithelial MCN tissue were sequenced and analyzed, including samples from 13 small MCNs with low-grade (LG) dysplasia, 1 small MCN with high-grade (HG) dysplasia (HGD), and 4 large MCNs with HGD. Eight of 13 (61.5%) comprehensively sampled small LG MCNs lacked somatic driver gene mutations in all tissue blocks. These MCNs were lined by predominantly flat epithelium. In contrast, the majority of MCNs with driver gene mutations were predominantly lined by mucin-rich epithelium. No heterogeneity in <em>KRAS</em> mutations was seen across the sampled regions. Multiregion genetic analysis of 4 large MCNs with HGD provide insights into neoplastic progression, with shared somatic alterations suggesting that HGD arises from LG mucin-rich epithelium. These findings were supported by complementary whole-exome sequencing studies in 26 MCN epithelium samples. The neoplastic epithelium in the majority of small MCNs does not harbor somatic mutations in pancreatic driver genes. The genetic findings from multiregion analysis on MCNs contrast previous investigations in other mucin-producing pancreatic cysts, indicating distinct mechanisms in early tumorigenesis. This calls for a more nuanced risk assessment in MCNs, requiring improved preoperative assessment tools.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 7","pages":"Article 100759"},"PeriodicalIF":7.1,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692884","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":"Lower Degree of Microsatellite Instability in Colorectal Carcinomas From MSH6-Associated Lynch Syndrome Patients","authors":"Noah C. Helderman ,&nbsp;Fabian Strobel ,&nbsp;Lena Bohaumilitzky ,&nbsp;Diantha Terlouw ,&nbsp;Anne-Sophie van der Werf - ’t Lam ,&nbsp;Tom van Wezel ,&nbsp;Hans Morreau ,&nbsp;Magnus von Knebel Doeberitz ,&nbsp;Maartje Nielsen ,&nbsp;Matthias Kloor ,&nbsp;Aysel Ahadova","doi":"10.1016/j.modpat.2025.100757","DOIUrl":"10.1016/j.modpat.2025.100757","url":null,"abstract":"<div><div>Numerous observational and molecular studies focusing on Lynch syndrome (LS) have revealed significant variation in the phenotype and molecular characteristics among carriers of pathogenic variants in mismatch repair genes (<em>path_MMR</em>). Recently, we demonstrated that colorectal carcinomas in <em>path_MSH6</em> carriers exhibit fewer insertion/deletion mutations compared with cumulative colorectal cancers (CRCs) from other MMR groups, raising the question of whether <em>MSH6</em>-mutated CRCs might display a relatively lower degree of microsatellite instability (MSI). Mutations at 20 coding microsatellites (cMS) were analyzed in 39 <em>MSH6</em>-, 18 <em>MLH1</em>-, 16 <em>MSH2</em>-, and 22 <em>PMS2</em>-mutated CRCs and 35 sporadic MSI CRCs, and mutation frequencies and mutant allele ratios were compared among the different MMR-deficient groups. Considering factors such as <em>HLA-A</em>∗02:01 type, <em>B2M</em> status, and the anticipated immunogenicity of frameshift peptides derived from cMS mutations, the identified cMS mutation profiles of <em>MSH6</em>-mutated CRCs were further investigated to assess their potential impact on immunotherapeutic strategies. <em>MSH6</em>-mutated CRCs exhibited lower mutation frequencies and mutant allele ratios across most cMS. Variation in cMS mutation patterns was observed both between different tumor regions and between tumor tissue and adjacent adenomatous tissue. The cMS mutations in <em>MSH6</em>-mutated CRCs demonstrated inverse correlations with the predicted immunogenicity of the resulting frameshift peptides, which may suggest a negative selection of cell clones bearing highly immunogenic frameshift peptides. Overall, <em>MSH6</em>-mutated CRCs display a relatively lower degree of MSI and represent a biologically distinct subgroup of LS-associated CRCs. This lower MSI level may implicate an altered immune response compared with other MSI CRCs, which could have theoretical implications for the success of immunotherapy in <em>MSH6</em>-mutated CRCs. Future studies should carefully evaluate this possibility. If confirmed, these results would reinforce the notion of classifying LS as distinct syndromes associated with specific MMR genes.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 7","pages":"Article 100757"},"PeriodicalIF":7.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA In Situ Hybridization Detection of CRTC1/3::MAML2 Fusions and LINC00473 in Mucoepidermoid Carcinomas and Hidradenomas of Breast, Salivary Glands, and Skin","authors":"Cooper D. Rutland ,&nbsp;Leandra Kingsley ,&nbsp;Aihui Wang ,&nbsp;Sabrina Zdravkovic ,&nbsp;Ishani Das ,&nbsp;Ryan Bremer ,&nbsp;Jordan S. Laser ,&nbsp;Julia A. Bridge ,&nbsp;Justin A. Bishop ,&nbsp;Gregor Krings ,&nbsp;Yunn-Yi Chen ,&nbsp;Gregory R. Bean","doi":"10.1016/j.modpat.2025.100756","DOIUrl":"10.1016/j.modpat.2025.100756","url":null,"abstract":"<div><div>Genomic rearrangements involving <em>MAML2</em> have been reported in mucoepidermoid carcinoma (MEC) arising in various anatomical sites, as well as the benign counterpart of hidradenoma (HA). Depending on the location, <em>MAML2</em>-rearranged neoplasms may share morphologic overlap with additional diagnostic entities, including other salivary gland malignancies and cutaneous mimics. In some cases, detection of a <em>CRTC1::MAML2</em> or less common <em>CRTC3::MAML2</em> rearrangement by fluorescence in situ hybridization (ISH) or next-generation sequencing may be necessary to help confirm the diagnosis. However, such testing can be time consuming, relatively expensive, and unavailable in many pathology laboratories. We describe the development and validation of an ISH custom BaseScope assay targeting the recurrent breakpoints of <em>CRTC1::MAML2</em> and <em>CRTC3::MAML2</em> rearrangements. Moreover, we investigated the diagnostic utility of <em>LINC00473</em> RNAscope as a surrogate marker for <em>MAML2</em> fusion status. <em>LINC00473</em> is a long noncoding RNA reportedly downstream of the <em>CRTC1::MAML2</em> oncoprotein. We evaluated 227 patient cases, including 30 salivary gland and 2 breast MEC, 14 cutaneous and 8 breast HA, and 173 cases representing &gt;20 potential histologic entities in the differential diagnosis for the presence of each fusion transcript by BaseScope, and a subset of cases (n = 205) for the detection of <em>LINC00473</em> by RNAscope. RNA ISH was directly visualized by chromogenic signal, and the <em>MAML2</em> fusion partner could be positively identified in the majority of cases. Overall, RNA ISH demonstrates high concordance with orthogonal testing, with <em>CRTC1/3::MAML2</em> BaseScope showing 93% sensitivity and 100% specificity and <em>LINC00473</em> RNAscope showing 92% sensitivity and 99% specificity. RNA ISH for <em>CRTC1/3::MAML2</em> rearrangements and <em>LINC00473</em> represent reasonable timely and cost-effective alternatives to fluorescence ISH and next-generation sequencing. Such markers may provide the means for accurate diagnosis to ensure appropriate therapy of MEC and HA—neoplasms that can arise in multiple anatomical sites and be encountered by a wide range of pathologists.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 7","pages":"Article 100756"},"PeriodicalIF":7.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663952","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":"Spatial Expression of HER2, NECTIN4, and TROP-2 in Muscle-Invasive Bladder Cancer and Metastases: Implications for Pathological and Clinical Management","authors":"Gabriel Dernbach ,&nbsp;Marie-Lisa Eich ,&nbsp;Mihnea P. Dragomir ,&nbsp;Philipp Anders ,&nbsp;Nadia Jurczok ,&nbsp;Christian Stief ,&nbsp;Philipp Jurmeister ,&nbsp;Thorsten Schlomm ,&nbsp;Frederick Klauschen ,&nbsp;David Horst ,&nbsp;Gerald Bastian Schulz ,&nbsp;Simon Schallenberg","doi":"10.1016/j.modpat.2025.100753","DOIUrl":"10.1016/j.modpat.2025.100753","url":null,"abstract":"<div><div>Muscle-invasive bladder cancer (MIBC) presents significant treatment challenges. Antibody–drug conjugates targeting human epidermal growth factor receptor 2 (HER2), trophoblast cell surface antigen 2 (TROP-2), and nectin cell adhesion molecule 4 (NECTIN4) offer promising therapeutic options. This study examined the spatial expression of HER2, TROP-2, and NECTIN4 in MIBC and metastases, their association with molecular subtypes, and clinical outcomes.</div><div>Formalin-fixed, paraffin-embedded tissue samples from 251 patients with MIBC were analyzed using immunohistochemistry and tissue microarray analysis. Expression patterns between the tumor front and tumor center (TC) were compared, and statistical analyses assessed associations with molecular subtypes and clinical parameters. Additionally, 67 matched lymph node metastases and a secondary cohort comprising 16 distant metastases, including 7 matched primary tumors, were examined to explore the expression patterns in advanced tumor stages.</div><div>In primary tumors, HER2 was predominantly negative (83%) but showed higher positivity in the TC. TROP-2 exhibited high overall expression (58% score 3+), whereas NECTIN4 displayed significant heterogeneity with stronger expression in the TC. Spatial overexpression of TROP-2 and NECTIN4 at the tumor front relative to the TC was associated with a better disease-free survival. Accurate assessment required 4 biopsies for HER2 and NECTIN4 and 3 for TROP-2. HER2 expression was associated with urothelial-like and genomically unstable molecular subtypes, whereas TROP-2 was widely expressed except in the mesenchymal-like subtype. NECTIN4 showed the absence of staining in basal, Mes-like, and Sc/NEC-like subtypes.</div><div>Paired lymph node metastases showed higher expression scores for all 3 markers, whereas distant metastases showed reduced NECTIN4 expression. Additionally, lymph node metastases revealed a considerable heterogeneity for HER2 compared with their matched primary tumors.</div><div>The spatial heterogeneity of HER2, TROP-2, and NECTIN4 expression necessitates multiple biopsies, particularly from the TC, for accurate evaluation. These findings underscore the need for personalized treatment strategies in MIBC, considering the increased risk of relapse associated with HER2 and NECTIN4 overexpression in the TC. Implementing a multibiopsy approach is critical to enhancing diagnostic accuracy.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 7","pages":"Article 100753"},"PeriodicalIF":7.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Deep Learning Model of Histologic Tumor Differentiation as a Prognostic Tool in Hepatocellular Carcinoma","authors":"Ameya Patil ,&nbsp;Bashar Hasan ,&nbsp;Byoung Uk Park ,&nbsp;Lindsey Smith ,&nbsp;Priya Sivasubramaniam ,&nbsp;Rofyda Elhalaby ,&nbsp;Nada Elessawy ,&nbsp;Saadiya Nazli ,&nbsp;Adilson DaCosta ,&nbsp;Abdelrahman Shabaan ,&nbsp;Andrew Cannon ,&nbsp;Chun Lau ,&nbsp;Christopher P. Hartley ,&nbsp;Rondell P. Graham ,&nbsp;Roger K. Moreira","doi":"10.1016/j.modpat.2025.100747","DOIUrl":"10.1016/j.modpat.2025.100747","url":null,"abstract":"<div><div>Tumor differentiation represents an important driver of the biological behavior of various forms of cancer. Histologic features of tumor differentiation in hepatocellular carcinoma (HCC) include cytoarchitecture, immunohistochemistry profile, and reticulin framework. In this study, we evaluate the performance of an artificial intelligence (AI)–based model in quantifying features of HCC tumor differentiation and predicting cancer-related outcomes. We developed a supervised AI model using a cloud-based, deep learning platform to quantify histologic features of HCC differentiation, including various morphologic parameters (nuclear density, area, circularity, chromatin pattern, and pleomorphism), mitotic figures, immunohistochemistry markers (HepPar 1 and glypican-3), and reticulin expression. We applied this AI model to patients undergoing HCC curative resection and assessed whether AI-based features added value to standard clinical and pathologic data in predicting HCC-related outcomes. Ninety-nine HCC resection specimens were included. Three AI-based histologic variables were most relevant to HCC prognostic assessment: (1) percentage of tumor occupied by neoplastic nuclei (nuclear area percent), (2) quantitative reticulin expression in the tumor, and (3) HepPar 1 low (ie, expressed in &lt;50% of the tumor)/glypican-3–positive immunophenotype. Statistical models that included these AI-based variables outperformed models with combined clinical pathologic features for overall survival (C-indexes of 0.81 vs 0.68), disease-free survival (C-indexes of 0.73 vs 0.68), metastasis (C-indexes of 0.78 vs 0.65), and local recurrence (C-indexes of 0.72 vs 0.68) for all cases, with similar results in the subgroup analysis of World Health Organization grade 2 HCCs. Our AI model serves as a proof of concept that HCC differentiation can be objectively quantified digitally by assessing a combination of biologically relevant histopathologic features. In addition, several AI-derived features were independently predictive of HCC-related outcomes in our study population, most notably nuclear area percent, hepar-low/glypican-3–negative phenotype, and decreasing levels of reticulin expression, highlighting the relevance of quantitative analysis of tumor differentiation features in this context.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 7","pages":"Article 100747"},"PeriodicalIF":7.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630469","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":"Pan-Cancer Molecular Biomarkers: Practical Considerations for the Surgical Pathologist","authors":"Pari Jafari,&nbsp;Megan Forrest,&nbsp;Jeremy Segal,&nbsp;Peng Wang,&nbsp;Melissa Yuwono Tjota","doi":"10.1016/j.modpat.2025.100752","DOIUrl":"10.1016/j.modpat.2025.100752","url":null,"abstract":"<div><div>Traditional anatomic pathologic classification of cancer is based on tissue of origin and morphologic and immunohistochemical characterization of the malignant cells. With the technological improvements of massively parallel or next-generation sequencing, oncogenic drivers that are shared across different tumor types are increasingly being identified and used as pan-cancer biomarkers. This approach is reflected in the growing list of Food and Drug Administration-approved tumor-agnostic therapies, including pembrolizumab in the setting of microsatellite instability and high tumor mutational burden, larotrectinib and entrectinib for solid tumors with <em>NTRK</em> fusions, and combined dabrafenib-trametinib for <em>BRAF</em> V600E-mutated neoplasms. Several other biomarkers are currently under investigation, including fibroblast growth factor receptor (<em>FGFR</em>), <em>RET</em>, and <em>ROS1</em> fusions; <em>ERBB2</em> amplification; and mutations in the <em>AKT1/2/3</em>, <em>NF1</em>, <em>RAS</em> pathway and (mitogen-activated protein kinase (<em>MAPK</em>) pathway. As molecular assays are increasingly incorporated into routine tumor workup, the emergence of additional pan-cancer biomarkers is likely to be a matter more of “when” than “if.” In this review, we first explore some of the conceptual and technical considerations at the intersection of surgical and molecular pathology, followed by a brief overview of both established and emerging molecular pan-cancer biomarkers and their diagnostic and clinical applications.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 6","pages":"Article 100752"},"PeriodicalIF":7.1,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586308","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 Multicenter Study on Intraoperative Glioma Grading via Deep Learning on Cryosection Pathology","authors":"Xi Liu ,&nbsp;Tianyang Sun ,&nbsp;Hong Chen ,&nbsp;Shuai Wu ,&nbsp;Haixia Cheng ,&nbsp;Xiaojia Liu ,&nbsp;Qi Lai ,&nbsp;Kun Wang ,&nbsp;Lin Chen ,&nbsp;Junfeng Lu ,&nbsp;Jun Zhang ,&nbsp;Yaping Zou ,&nbsp;Yi Chen ,&nbsp;Yingchao Liu ,&nbsp;Feng Shi ,&nbsp;Lei Jin ,&nbsp;Dinggang Shen ,&nbsp;Jinsong Wu","doi":"10.1016/j.modpat.2025.100749","DOIUrl":"10.1016/j.modpat.2025.100749","url":null,"abstract":"<div><div>Intraoperative glioma grading remains a significant challenge primarily due to the diminished diagnostic attributable to the suboptimal quality of cryosectioned slides. Precise intraoperative diagnosis is instrumental in guiding the surgical strategy to balance resection extent and neurologic function preservation, thereby optimizing patient prognoses. This study developed a model for intraoperative glioma grading via deep learning on cryosectioned images, termed intraoperative glioma grading on cryosection (IGGC). The model was trained and validated on The Cancer Genome Atlas data sets and 1 cohort (<span><math><mrow><msub><mi>n</mi><mrow><mi>t</mi><mi>r</mi><mi>a</mi><mi>i</mi><mi>n</mi></mrow></msub></mrow></math></span> = 1603 and <span><math><mrow><msub><mi>n</mi><mrow><mi>v</mi><mi>a</mi><mi>l</mi><mi>i</mi><mi>d</mi><mi>a</mi><mi>t</mi><mi>e</mi></mrow></msub></mrow></math></span> = 628), and tested on 5 cohorts (<span><math><mrow><msub><mi>n</mi><mrow><mi>t</mi><mi>e</mi><mi>s</mi><mi>t</mi></mrow></msub></mrow></math></span> = 213). The IGGC model achieved an area under the receiver operating characteristic curve value of 0.99 in differentiating between high-grade glioma and low-grade glioma, and an area under the receiver operating characteristic curve value of 0.96 in identifying grade 4 glioma. Integrated into the clinical workflow, the IGGC model-assisted pathologists of varying experience levels in reducing interobserver variability and enhancing diagnostic consistency. This integrated diagnostic model possesses the potential for clinical implementation, offering a time-efficient and highly accurate method for the 3-grade classification of adult-type diffuse gliomas based on intraoperative cryosectioned slides.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 7","pages":"Article 100749"},"PeriodicalIF":7.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}