Modern Pathology最新文献

{"title":"Replacing molecular testing with next-generation immunohistochemistry: I can diagnose that soft tissue tumor with a single antibody!","authors":"Jason L Hornick","doi":"10.1016/j.modpat.2025.100912","DOIUrl":"https://doi.org/10.1016/j.modpat.2025.100912","url":null,"abstract":"<p><p>Immunohistochemistry plays a central role in the diagnosis of soft tissue tumors. Conventional immunohistochemistry employs antibodies directed against lineage-restricted antigens, in an attempt to identify a line of differentiation and narrow down the differential diagnosis. However, in most cases, such markers are inadequate to reach a specific diagnosis. Many soft tissue tumors harbor recurrent, often disease-defining molecular genetic alterations. Increasingly, fluorescence in situ hybridization analysis or next-generation sequencing is employed for identification of such alterations as a diagnostic adjunct. In recent years, immunohistochemistry has been used as a surrogate for such molecular genetic or cytogenetic analysis; this approach can identify the protein correlates of genetic alterations. Numerous \"next-generation\" antibodies directed against the protein products of a wide range of genetic alterations (such as gene fusions, amplifications, deletions, and point mutations) have entered our diagnostic armamentarium. In addition, gene expression profiling has uncovered diagnostically useful markers for immunohistochemistry. Finally, epigenetic alterations (e.g., methylation) can also be assessed by immunohistochemistry. This review will provide examples of the application of contemporary molecular immunohistochemistry for soft tissue tumor diagnosis.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"100912"},"PeriodicalIF":5.5,"publicationDate":"2025-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145292980","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":"Giant Cell Rich Tumors of Bone and Soft Tissue.","authors":"Robert M van der Linde, David G P van IJzendoorn, Matt van de Rijn, Judith V M G Bovée","doi":"10.1016/j.modpat.2025.100915","DOIUrl":"https://doi.org/10.1016/j.modpat.2025.100915","url":null,"abstract":"<p><p>Many benign and malignant bone and soft tissue tumors can contain giant cells, in variable amounts. In some tumors, such as tenosynovial giant cell tumor (TGCT) and giant cell tumor of bone (GCTB), these osteoclast-like giant cells are so prominent and characteristic, that their presence has defined the entity. Other examples of bone tumors in which the presence of osteoclast-like giant cells is characteristic include chondroblastoma, aneurysmal bone cyst, non-ossifying fibroma and central giant cell granuloma. These tumors have a distinct pathogenesis, though some parallels can be identified. The osteoclast-like giant cells within these tumors are not the neoplastic component, but are non-neoplastic bystanders and part of the tumor microenvironment. Notably, the activation of the CSF1-CSF1R and/or the RANKL-RANK signaling pathways, best studied in TGCT and GCTB, respectively, appears to be key in attracting macrophages and formation of osteoclast-like giant cells within the tumor. Among soft tissue tumors, a plethora of tumors have been described to contain variable amounts of giant cells, and the underlying mechanisms are so far less well understood. One exception is the recently described keratin-positive giant cell-rich tumor of soft tissue, which also seems to rely on CSF1-CSF1R signaling to attract giant cells. The CSF1-CSF1R and RANKL-RANK pathways are suitable targets for non-surgical interventions and inhibitors of these pathways are already being used for some entities in clinical practice. These inhibitors inhibit tumor growth and may induce bone formation, though pathologists should be aware when evaluating post treatment specimens that the neoplastic cells remain unaffected.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"100915"},"PeriodicalIF":5.5,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145286598","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":"Comparative analysis reveals recurrent molecular alterations in low-risk HPV6 and HPV11-associated squamous cell carcinoma of the uterine cervix and vulva.","authors":"Ying Sun, Colton Smith, Jason Murray, Jing Zhu, Aparna Pallavajjala, Sichen Liang, Melanie Klausner, Ya-Chea Tsai, Chien-Fu Hung, Tzyy-Choou Wu, Ying S Zou, Deyin Xing","doi":"10.1016/j.modpat.2025.100909","DOIUrl":"https://doi.org/10.1016/j.modpat.2025.100909","url":null,"abstract":"<p><p>While the association of HPV6 and HPV11 with squamous cell carcinomas (SCCs) has been well documented, the molecular alterations and mechanisms by which these low-risk HPVs contribute to carcinogenesis remain largely unknown. In this study, we comparatively elucidated the molecular landscape of HPV6/11-associated condylomas (9 cases) and SCCs (8 cases) of the uterine cervix and vulva. Sixteen of seventeen cases were successfully analyzed using deep next-generation sequencing. Recurrent molecular alterations in the SCCs included mutations in the TERT promoter (pTERT, 71%), NOTCH1 (57%), NFE2L2 (57%), NOTCH3 (29%), and CDKN2A (29%). Mutations in NOTCH1 and NFE2L2 tended to be mutually exclusive. Less common somatic mutations were each detected in the following genes: AR, ARID1A, ASXL1, BCORL1, DAZAP1, FNDC1, HRAS, KMT2B, NOTCH2, NRAS, PIK3R1, and TP53. Etiologically similar to the SCCs, the vast majority of vulvar and cervical condylomas (7 of 9, 78%) were infected with HPV6 rather than HPV11. Unlike the SCCs, condylomas rarely harbored recurrent pathogenic somatic mutations. NOTCH1 and NOTCH2 were the only mutant genes detected in both SCCs and condylomas in this series, suggesting a critical role for the NOTCH pathway in the initiation and maintenance of HPV6/11-related early squamous lesions. Although pathogenic mutations in NOTCH1, NOTCH2, ERBB3, ATRX, FGFR2, EPHA5, CARD11, STAG2 and TSC2 were detected in condylomas, none were recurrent, indicating diverse genetic alterations involved in the development of these lesions. Case 8 illustrated a stepwise progression from condyloma to invasive SCC, in which pathogenic mutations in pTERT and NOTCH1 were detected in the SCC (age 58) and the condyloma at age 55, but not in the condyloma at age 44. Our study presents the first report on the molecular landscape of HPV6/11-associated SCCs of the uterine cervix and vulva. We provide evidence that SCCs associated with low-risk HPV are distinct entities, differing from those related to high-risk HPV and more closely resembling HPV-independent neoplasms. Given that low-risk HPV-associated SCCs of the cervix and vulva exhibit unique morphological and molecular features, they should either be described separately within existing classification systems or classified as a distinct new entity.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"100909"},"PeriodicalIF":5.5,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280708","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":"Deep Learning-Based Segmentation of Lung Adenocarcinoma Whole Slide Images for Objective Grading, STAS Identification, and Mutation Prediction.","authors":"David Joon Ho, Jason C Chang, Rania G Aly, Hai Cao Truong Nguyen, Prasad S Adusumilli, Thomas J Fuchs, William D Travis, Chad M Vanderbilt","doi":"10.1016/j.modpat.2025.100907","DOIUrl":"https://doi.org/10.1016/j.modpat.2025.100907","url":null,"abstract":"<p><p>Manual quantification of morphologic patterns in lung adenocarcinoma is subject to reproducibility issues due to inter-pathologist variability. In this study, we developed a deep learning-based multi-class segmentation model providing a modality for objective and quantitative grading of digitized lung adenocarcinoma images from resected specimens. Additionally, the model can detect tumor spread through air spaces (STAS) and show enrichment of specific morphologic patterns in tumors with different genomic alterations. The study was based on 766 resected nonmucinous lung adenocarcinomas. Deep Multi-Magnification Network was trained to segment 14 tissue subtypes based on annotations of 108 internal whole slide images at pixel-level by thoracic pathologists. The trained model was validated on an external cohort of 130 cases for determining predominant patterns and on the remaining 528 internal cases for the three clinical tasks. The model graded nonmucinous lung adenocarcinomas based on the International Association for the Study of Lung Cancer Pathology Committee recommendation and successfully stratified patients into well, moderately and poorly differentiated morphologies (p<1×10^-4). Pixels categorized as STAS significantly correlated with pathologists' interpretations. For molecular analysis, solid pattern was enriched with TP53 mutations and depleted of EGFR kinase domain mutations. Lepidic pattern was inversely associated with TP53 mutations. Acinar was enriched with EGFR mutations, while papillary was associated with RET fusions. Our study demonstrated that deep learning-based segmentation can accurately quantify histological patterns in lung adenocarcinoma and identify additional prognostic features. By simultaneously providing objective assessment of various tasks, our comprehensive methodology in lung adenocarcinoma paves way for deep learning-assisted pathological diagnosis and treatment guidance.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"100907"},"PeriodicalIF":5.5,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145275333","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":"Clinicopathologic and Molecular Genetic Features of Spindle Cell Rhabdomyosarcoma harboring ZFP64::NCOA2/3 fusions: A Series of 14 Cases.","authors":"Carina A Dehner, Baptiste Ameline, Fernanda Amary, John Gross, Ying Zou, Michael Michal, Zdenek Kinkor, Jorge Torres-Mora, Faizan Malik, Erica Kao, Robert Ricciotti, Nasir Ud Din, Ivy John, Brendan C Dickson, Elizabeth G Demicco, Abbas Agaimy, Konstantinos Linos, Meera R Hameed, Andrew L Folpe, Daniel Baumhoer","doi":"10.1016/j.modpat.2025.100906","DOIUrl":"https://doi.org/10.1016/j.modpat.2025.100906","url":null,"abstract":"<p><p>Spindle cell rhabdomyosarcomas (SCRMS), recognized by the 2020 WHO Classification of Tumors of Soft Tissue and Bone as a distinct entity, comprise a family of malignant skeletal muscle tumors sharing spindle cell morphology. To date, members of this family include 1) MyoD1-mutated spindle cell/sclerosing RMS (SCRMS/SRMS), 2) intraosseous SCRMS with FET::TFCP2 or MEIS1::NCOA2 fusions and 3) infantile congenital SCRMS harboring NCOA1/2 or VGLL3 rearrangements. A rare, emerging subtype of SCRMS has been reported to harbor recurrent ZFP64::NCOA3 fusions. We studied 14 cases of this rare SCRMS subtype. The tumors presented in 11 men and 3 women (median age: 39.5 years; range: 22-69) and involved the thigh (4), lower leg (2), gluteal soft tissues (2), abdominal wall (1), mediastinum (1), subperiosteal surface of 3^rd rib (1), glottis (1), prostate (1), and pelvis (1). Morphologically, 11 tumors showed uniform spindle cell morphology with a fascicular architecture, while the remaining 3 tumors demonstrated focal or predominant round cell morphology. Extensive chondro-osseous differentiation was seen in 2 cases. By immunohistochemistry, tumors were variably positive for both desmin and MyoD1 (6 tumors), desmin, MyoD1 and myogenin (1 tumor), desmin alone (3 tumors of which only one was also tested for MyoD1), or MyoD1 alone (3 tumors). Smooth muscle actin was noted in 6 of 10 tested cases, and 2 of 5 tested cases showed ALK expression. A ZFP64::NCOA3 fusion was detected in 8 tumors, and a ZFP64::NCOA2 fusion in 6. Methylation studies showed all but one tested tumor to form a tight cluster, clearly separate from other RMS subtypes and non-RMS morphologic mimics. Clinical follow-up (10 of 14 cases; median: 35 months; range: 3-108 months) demonstrated local recurrence in 2 patients and distant metastases in 5 (median: 12 months; range: at presentation - 106 months). At the time of last follow-up, 5 patients were alive without evidence of disease, 3 patients were alive with disease, and 2 patients died of disease at 34 and 108 months. We conclude that SCRMS with ZFP64::NCOA2/3 fusions represent a distinct, clinically aggressive sarcoma, characterized by fascicular and sometimes round cell morphology, occasional chondro-osseous differentiation and variable skeletal muscle marker expression. Recognition of this emerging subtype of SCRMS may have prognostic and therapeutic implications.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"100906"},"PeriodicalIF":5.5,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145275323","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":"Head-to-head comparison of two artificial intelligence tools for detecting lymph-node metastases in whole slide pathology images within and beyond their intended use.","authors":"Rachel N Flach, Milan Samuels, Natalie D Ter Hoeve, Nikolas Stathonikos, Trudy G N Jonges, Jan Erik Freund, Gerben E Breimer, Willeke A M Blokx, Frans Schutgens, Tri Q Nguyen, Paul J van Diest, Carmen van Dooijeweert","doi":"10.1016/j.modpat.2025.100905","DOIUrl":"https://doi.org/10.1016/j.modpat.2025.100905","url":null,"abstract":"<p><p>The increasing diagnostic workload in pathology, driven by rising cancer incidences, highlights the need for scalable, cost-effective solutions. Artificial intelligence (AI) has shown promise in supporting lymph node (LN) metastasis detection, a key prognostic factor in cancer staging. However, current CE-IVD certified AI-tools are often limited to specific tumor types, reducing their cost-efficiency and clinical utility. This study evaluates the performance of two CE-IVD certified AI tools-Visiopharm Metastasis Detection App (VMD) and DeepPath LYDIA (DPL)-for multipurpose LN metastasis detection across six tumor types, both within and beyond their intended use. We retrospectively analyzed whole slide images from 455 patients with LN-metastases from melanoma, colorectal, head and neck, lung, vulvar, and breast cancer. Both sentinel and non-sentinel LNs were included, with expert pathologists establishing the reference standard, according to clinical practice. Sensitivity was calculated per case and stratified by metastasis size. False positive alerts (FPAs) were assessed in 1,012 tumor-negative slides. Both applications demonstrated excellent sensitivity for macro-metastases across tumor types. DPL showed slightly higher sensitivity for micro-metastases and isolated tumor cells (ITCs) compared to VMD, particularly in lung cancer and melanoma. FPA rates were substantial for both tools, with VMD generally producing more alerts, especially in lung- and breast cancer. Our findings suggest that a single AI tool may be suitable for LN metastasis detection across multiple tumor types, even beyond its intended use. However, high FPA rates-particularly in lung cancer (inside intended use for DPL)-may limit practical usability. Prospective studies are needed to confirm workflow efficiency gains and define optimal implementation strategies. These results support a broader, pragmatic approach to AI validation and regulatory approval, potentially improving the business case for AI adoption in pathology laboratories.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"100905"},"PeriodicalIF":5.5,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145275388","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 profiling of pediatric mycosis fungoides, lymphomatoid papulosis z, and primary cutaneous anaplastic large cell lymphoma identifies recurrent tyrosine kinase gene fusions.","authors":"Grant M Fischer, Harrison K Tsai, Jennifer Huang, Mark C Mochel, Sam Sadigh, Zenggang Pan, Meagan Montesion, Erik A Williams, Mark Sabbagh, Paolo Chetta, Va Lip, Judith A Ferry, Julie D R Reimann, Lyn Duncan, Steven Chen, Thomas Kupper, Marilyn G Liang, Lynda M Vrooman, Jessica Pollard, Dimitra Pouli, Mark D Fleming, Birgitta Schmidt, Marian H Harris, Jacob R Bledsoe","doi":"10.1016/j.modpat.2025.100908","DOIUrl":"https://doi.org/10.1016/j.modpat.2025.100908","url":null,"abstract":"<p><p>Pediatric cutaneous T-cell lymphoproliferative disorders encompass a diagnostically complex set of rare diseases of undefined pathogenesis, including mycosis fungoides (MF), lymphomatoid papulosis (LyP), and primary cutaneous anaplastic large cell lymphoma (pcALCL). In the pediatric population these disorders are much less common than in adults, which has precluded systematic evaluation of their molecular pathogenesis. We report the clinicopathologic and molecular features of pediatric MF (n=14, ages 5-17 years at diagnosis), LyP (n=8, ages 4-17 years), and pcALCL (n=2). Next-generation sequencing analysis (targeted 72-gene fusion panel, targeted 447-gene exome sequencing panel, and/or FoundationOneHeme) was performed. JAK2 fusions were detected in 64% (7/11) MF [PCM1::JAK2, ILF3::JAK2 (n=2), ATXN2L::JAK2 (n=2), and NUP214::JAK2 (n=2)] by next generation sequencing of available cases. TYK2 fusions were identified in 1/11 MF [novel LMNA::TYK2], 3/5 LyP [NPM1::TYK2 (n=2) and novel RAN::TYK2], and 1/2 pcALCL [RAN::TYK2] cases tested. A novel NUP214::FRK fusion was observed in the other pcALCL. Fusions were in-frame and retained the kinase domain of the 3' partner in all cases. MF cases demonstrated clonal TCR gene rearrangements (12/12 tested). Treatment was heterogeneous, although usually included narrowband UVB phototherapy for MF, and topical steroids for MF and LyP. We demonstrate that pediatric MF, LyP, and pcALCL harbor frequent tyrosine kinase gene fusions with enrichment of JAK2 and TYK2 fusions, genomic alterations that are diagnostically useful and may be amenable to targeted therapy.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"100908"},"PeriodicalIF":5.5,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145275383","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":"Corrigendum to “Spatial Evaluation and Prognostic Significance of V-Domain Immunoglobulin Suppressor of T-Cell Activation (VISTA) in Human Resectable Cervical Carcinoma: Implications for Immune Activation and Suppression” [Modern Pathology 2025;38(12):100851]","authors":"Qingsheng Xie ,&nbsp;Jinqing Li ,&nbsp;Jieyao Li ,&nbsp;Chaoqun Liu ,&nbsp;Yangyang Li ,&nbsp;Hong Zeng ,&nbsp;Jingwei Yu ,&nbsp;Yingchen Wu ,&nbsp;Kaiqian Chen ,&nbsp;Zhaonan Zhang ,&nbsp;Bo Wang","doi":"10.1016/j.modpat.2025.100892","DOIUrl":"10.1016/j.modpat.2025.100892","url":null,"abstract":"","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 12","pages":"Article 100892"},"PeriodicalIF":5.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251874","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":"Corrigendum to “Magnetic Resonance Imaging (MRI)–Adapted Prostate Cancer Risk Tool Incorporating Cribriform and Intraductal Carcinoma” (Modern Pathology 2025 Dec;38(12):100852)","authors":"Ngoc-Nhu Jennifer Nguyen ,&nbsp;Kristen Liu ,&nbsp;Katherine Lajkosz ,&nbsp;Rui Bernardino ,&nbsp;Leyi Bellinda Yin ,&nbsp;Eva Hollemans ,&nbsp;Lisa J. Kroon ,&nbsp;Neil Fleshner ,&nbsp;Geert J.L.H. van Leenders ,&nbsp;Kenneth A. Iczkowski ,&nbsp;Theodorus H. van der Kwast ,&nbsp;Michelle R. Downes","doi":"10.1016/j.modpat.2025.100893","DOIUrl":"10.1016/j.modpat.2025.100893","url":null,"abstract":"","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 12","pages":"Article 100893"},"PeriodicalIF":5.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251822","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 rational approach to the diagnosis of liver metastases.","authors":"Shaomin Hu, Daniela S Allende","doi":"10.1016/j.modpat.2025.100903","DOIUrl":"https://doi.org/10.1016/j.modpat.2025.100903","url":null,"abstract":"<p><p>The diagnosis of liver metastases encompasses a broad-spectrum of entities and relies on clinicopathological correlation, with some cases be diagnosable using hematoxylin and eosin staining alone. For more challenging cases, ancillary testing is often required, with a focus on maximizing diagnostic yield while preserving tissue. This review draws on years of experience at a high-volume, tertiary referral center and incorporates an in-depth analysis of the existing literature in the field. When evaluating a liver lesion, the first step is to determine whether it represents a primary hepatic tumor or a metastasis. This review discusses a practical panel of immunohistochemical stains valuable in making this distinction. Next, it outlines a morphologic pattern-based approach to metastatic liver tumors, categorized by epithelioid, spindle, undifferentiated, and small round blue cell morphology. For each category, readers will find a proposed list of differentials based on the morphologic pattern, a suggested screening immunohistochemical panel, a focused discussion of potential pitfalls and practical tips for ancillary testing (\"important aspects of ancillary testing\"), and additional insights on specific entities within each group (\"special diagnostic considerations\").\" This review provides a comprehensive overview of the diagnosis of liver metastases along with a current guide to immunohistochemical and molecular testing for classification of these tumors. It underscores the importance of careful consideration and prioritizing site-agnostic biomarkers and tumor lineage classification (e.g., carcinoma, sarcoma, lymphoma, or melanoma) when choosing ancillary stains in challenging cases with limited material.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"100903"},"PeriodicalIF":5.5,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228671","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}