Modern Pathology最新文献

{"title":"An Integrated Clinical Genomic and Transcriptomic Subgrouping of Central Chondrosarcoma","authors":"Debora M. Meijer ,&nbsp;Sanne Venneker ,&nbsp;Baptiste Ameline ,&nbsp;Zeynep Erdem ,&nbsp;Sara Cardoso ,&nbsp;Dina Ruano ,&nbsp;Inge H. Briaire-de Bruijn ,&nbsp;Brendy E. van den Akker ,&nbsp;Pauline M. Wijers-Koster ,&nbsp;Claire H.J. Scholte ,&nbsp;Veroniek M. van Praag ,&nbsp;Michiel A.J. van de Sande ,&nbsp;Marieke L. Kuijjer ,&nbsp;Daniel Baumhoer ,&nbsp;Noel F.C.C. de Miranda ,&nbsp;Judith V.M.G. Bovée","doi":"10.1016/j.modpat.2025.100894","DOIUrl":"10.1016/j.modpat.2025.100894","url":null,"abstract":"<div><div>Central conventional chondrosarcoma, a malignant cartilage-producing bone tumor, is the second most common bone sarcoma. Chondrosarcomas are histologically graded, which is so far the best predictor of survival. Early mutations in isocitrate dehydrogenase 1 (<em>IDH1</em>) and <em>IDH2</em> genes are frequent, leading to the production of the oncometabolite D-2-hydroxyglutarate, which affects DNA methylation, resulting in a preferred chondrogenic differentiation over osteogenic differentiation of mesenchymal stem cells, which are currently considered the precursor cells of chondrosarcoma. DNA methylation profiling has previously revealed distinct profiles between <em>IDH</em>-mutant and <em>IDH</em>–wild-type chondrosarcomas, but the presence of further DNA methylation subgroups indicates that classification based solely on <em>IDH</em> status is too simplistic. In this study, we aim to identify biological subgroups in a total of 116 chondrosarcomas by integrating clinical data, <em>IDH</em> mutation status, gene expression, and genome-wide loss of heterozygosity (LOH). Clinical associations were observed between several factors, including sex and histological grade, as well as tumor site and <em>IDH</em> mutation status. RNA sequencing and genome-wide LOH confirmed the distinction between <em>IDH</em>–wild-type and <em>IDH</em>-mutant chondrosarcomas, where the number of chromosome arms affected by LOH was significantly higher in <em>IDH</em>–wild-type tumors than in <em>IDH</em>-mutant tumors. However, no clear subgroups emerged within each <em>IDH</em> group. Further clustering on RNA expression of differentiation markers identified subgroups characterized by chondrogenic, osteogenic, resting chondrocyte, or dedifferentiated profiles. These different subgroups showed a specific clinical presentation and suggest different precursor cells. Instead of a simple dichotomy between <em>IDH</em>-mutant and <em>IDH</em>–wild-type, our integrated approach highlights interconnected clinical, genomic, and transcriptomic patterns that offer a more nuanced view of chondrosarcoma biology and might potentially guide treatment stratification.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 12","pages":"Article 100894"},"PeriodicalIF":5.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145113777","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":"Non–neoplastic Orthopedic Pathology Updates: Common Problems and Pitfalls and How to Avoid Them","authors":"Scott E. Kilpatrick","doi":"10.1016/j.modpat.2025.100911","DOIUrl":"10.1016/j.modpat.2025.100911","url":null,"abstract":"<div><div>Despite representing &lt;1% of all musculoskeletal surgical pathology cases, primary musculoskeletal neoplasms are disproportionately emphasized in the surgical pathology literature, compared with non–neoplastic orthopedic pathology. Yet, there remains significant interest among practicing pathologists and their clinical colleagues to maintain expertise in the non–neoplastic arena, as evidenced by increasing volumes of non–neoplastic orthopedic diseases, often reflected in consult cases. Recent literature has renewed the discussion of arthroplasty, emphasized the clinical importance of pathologic examination, and provided updated diagnostic clarification for separating avascular necrosis from degenerative joint disease (DJD)/osteoarthritis (OA) with secondary osteonecrosis, acute infectious osteomyelitis from pseudoabscesses of DJD/OA, and revisited the diagnoses of subchondral insufficiency fracture and rapidly destructive arthropathy. Providing accurate neutrophil counts to help determine periprosthetic joint infection has rapidly become one of the most common sources of frozen section evaluation in the United States. Distinguishing periprosthetic joint infection from aseptic loosening has significant intraoperative implications. In addition to acute arthritis and mass effect, calcium pyrophosphate dihydrate (CPPD) deposition disease may lead to DJD/OA. However, most histologically confirmed examples of CPPD, involving the large extremity joints, are not identified preoperatively or radiologically, requiring pathologic evaluation to reliably establish the diagnosis. The incidence of CPPD deposits appears highest in the humeral head/shoulder, followed by the knees and hips/femoral head. Recent evidence has documented infrequent examples of combined gout and CPPD/pseudogout within the same tophi, associated with unique clinicopathologic features compared with those with gout alone. Carpal tunnel syndrome, trigger finger, and lumbar stenosis represent potential early red flags for the development of transthyretin (TR) cardiac amyloidosis. Although previously discarded at many institutions, excised tissue removed from such specimens, particularly tenosynovium from the carpal tunnel flexor retinaculum, are now routinely evaluated histologically with Congo red staining and, when positive, followed by mass spectrometry for confirmatory amyloid subtyping. With the use of a recently developed TR stabilizer, such as tafamidis, early histologic detection and treatment of TR cardiac amyloidosis has improved clinical outcomes. Herein is a summary of recent relevant developments in non–neoplastic orthopedic surgical pathology, updated diagnostic criteria and pitfalls, and the resulting clinical impact, where applicable.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 12","pages":"Article 100911"},"PeriodicalIF":5.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145301910","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 Human Papillomavirus 6 and Human Papillomavirus 11-Associated Squamous Cell Carcinoma of the Uterine Cervix and Vulva","authors":"Ying Sun ,&nbsp;Colton Smith ,&nbsp;Jason Murray ,&nbsp;Jing Zhu ,&nbsp;Aparna Pallavajjala ,&nbsp;Sichen Liang ,&nbsp;Melanie Klausner ,&nbsp;Ya-Chea Tsai ,&nbsp;Chien-Fu Hung ,&nbsp;Tzyy-Choou Wu ,&nbsp;Ying S. Zou ,&nbsp;Deyin Xing","doi":"10.1016/j.modpat.2025.100909","DOIUrl":"10.1016/j.modpat.2025.100909","url":null,"abstract":"<div><div>Although the association between human papillomavirus (HPV) 6 and HPV11 and 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 17 cases were successfully analyzed using deep next-generation sequencing. Recurrent molecular alterations in the SCCs included mutations in the <em>TERT</em> promoter (<em>pTERT</em>, 71%), <em>NOTCH1</em> (57%), <em>NFE2L2</em> (57%), <em>NOTCH3</em> (29%), and <em>CDKN2A</em> (29%). Mutations in <em>NOTCH1</em> and <em>NFE2L2</em> tended to be mutually exclusive. Less common somatic mutations were each detected in the following genes: <em>AR</em>, <em>ARID1A</em>, <em>ASXL1</em>, <em>BCORL1</em>, <em>DAZAP1</em>, <em>FNDC1</em>, <em>HRAS, KMT2B</em>, <em>NOTCH2</em>, <em>NRAS</em>, <em>PIK3R1</em>, and <em>TP53</em>. Etiologically similar to the SCCs, the vast majority of vulvar and cervical condylomas (7/9, 78%) were infected with HPV6 rather than HPV11. Unlike the SCCs, condylomas rarely harbored recurrent pathogenic somatic mutations. <em>NOTCH1</em> and <em>NOTCH2</em> 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 <em>NOTCH1</em>, <em>NOTCH2</em>, <em>ERBB3</em>, <em>ATRX</em>, <em>FGFR2</em>, <em>EPHA5</em>, <em>CARD11, STAG2,</em> and <em>TSC2</em> 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 <em>pTERT</em> and <em>NOTCH1</em> 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.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 12","pages":"Article 100909"},"PeriodicalIF":5.5,"publicationDate":"2025-12-01","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":"Methylation Profiles in Bone and Soft Tissue Tumors: Do They Help Classify the Unclassifiable?","authors":"Josephine K. Dermawan","doi":"10.1016/j.modpat.2025.100910","DOIUrl":"10.1016/j.modpat.2025.100910","url":null,"abstract":"<div><div>Methylation profiling offers a promising avenue for improving the diagnosis and classification of bone and soft tissue tumors, particularly in cases where traditional methods fall short. Through examining tissue- and lineage-specific DNA methylation patterns, this approach can augment the classification of morphologically similar tumors with different genetics (genetic heterogeneity) or tumors that share genetic drivers but diverge phenotypically (phenotypic heterogeneity). This tool can also help clarify previously unclassifiable, poorly differentiated or transdifferentiated nonmesenchymal tumors that mimic sarcomas. By adopting an unbiased approach to grouping and subtyping using unsupervised clustering on methylomes, methylation profiling could potentially revise how we classify sarcomas. There is a need clinically to develop a methylation classifier that accurately predicts sarcoma class based on methylation profile, specifically in sarcomas that are challenging to differentiate due to overlapping morphologic or molecular features. However, current classifiers are limited by the diversity and size of their reference cohorts, dilution of signal by nonneoplastic tissue, and alteration of the methylomic landscape by histone modifications and oncometabolite-related mutations. Key considerations include the importance of quality control for tissue-based methylation profiling, transparent and reproducible pipelines, and open data sharing. Future advancements include continued refinement of methylation-based classifiers with a broader spectrum of rare and ultrarare tumor types and adopting new biological insights from methylome-driven analyses and integration of multiomic approaches. Although methylation profiling emerges as a valuable adjunct to existing diagnostic modalities, clinicopathologic considerations should always be incorporated for a more nuanced, management-based tumor classification system.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 12","pages":"Article 100910"},"PeriodicalIF":5.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145301951","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":"2025-12-01","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":"A Rational Approach to the Diagnosis of Liver Metastases","authors":"Shaomin Hu,&nbsp;Daniela S. Allende","doi":"10.1016/j.modpat.2025.100903","DOIUrl":"10.1016/j.modpat.2025.100903","url":null,"abstract":"<div><div>The diagnosis of liver metastases encompasses a broad spectrum of entities and relies on clinicopathological correlation, with some cases being 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 the classification of these tumors. It underscores the importance of careful consideration and prioritizing site-agnostic biomarkers and tumor lineage classification (eg, carcinoma, sarcoma, lymphoma, or melanoma) when choosing ancillary stains in challenging cases with limited material.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 12","pages":"Article 100903"},"PeriodicalIF":5.5,"publicationDate":"2025-12-01","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}

{"title":"Comparative Analysis of Somatic and Germline Polymerase Proofreading Deficiencies in Cancer: Molecular and Clinical Implications","authors":"Julen Viana-Errasti ,&nbsp;Raúl Marín ,&nbsp;Sandra García-Mulero ,&nbsp;Tirso Pons ,&nbsp;Mariona Terradas ,&nbsp;Gabriel Capellá ,&nbsp;Victor Moreno ,&nbsp;Pilar Mur ,&nbsp;Laura Valle","doi":"10.1016/j.modpat.2025.100843","DOIUrl":"10.1016/j.modpat.2025.100843","url":null,"abstract":"<div><div>Polymerases ε and δ maintain genome integrity through exonuclease proofreading. Germline and somatic pathogenic variants (PVs) in the exonuclease domain (ED) of <em>POLE</em> and <em>POLD1</em> impair proofreading, causing hypermutated tumors. Despite shared mutational features that make these tumors highly immunogenic, molecular and clinical distinctions between <em>POLE</em> and <em>POLD1</em> mutations and between somatic and germline variants remain incompletely understood. We compared the molecular and clinical characteristics of <em>POLE</em> and <em>POLD1</em> ED PVs (n = 31), assessing their location, pathogenicity, clinical phenotypes, mismatch repair (MMR) status, tumor mutational burden, and signatures. We analyzed 360 proofreading-deficient tumors (source: The Cancer Genome Atlas [TCGA] and Catalogue Of Somatic Mutations In Cancer [COSMIC]) and 70 families (249 individuals) with polymerase proofreading-associated polyposis. All germline and somatic PVs had high AlphaMissense scores (0.87-1) and clustered within or near Exo motifs. Recurrent, nonfounder germline PVs, <em>POLE</em> L424V and <em>POLD1</em> S478N, showed low/modest REVEL scores. Somatic variants occurred mainly in endometrial cancers (75% of proofreading-deficient TCGA cancers), whereas colorectal cancer predominated in polymerase proofreading-associated polyposis (56% of carriers). Cancer risks and tumor spectra differed between <em>POLE</em> and <em>POLD1</em> PV carriers. Aggressive hereditary phenotypes were linked to either specific <em>POLE</em> PVs (eg, S297F, V411L, P436R, M444K, A456P, and S461T) or the co-occurrence of germline ED PVs with germline MMR gene PVs. Distinct hypermutator profiles were confirmed for polymerase ε and polymerase δ proofreading deficiencies via unique mutational signatures (Polymerase ε: SBS10a/b, SBS28; Polymerase δ: SBS10c/d). Tumors with combined proofreading and MMR deficiencies had significantly higher tumor mutational burden and a shift in the associated mutational spectra. Unlike <em>POLE</em>, <em>POLD1</em> ED PVs exhibited haplosufficiency, typically requiring a somatic second hit (eg, loss of heterozygosity) or MMR deficiency to drive hypermutation. In conclusion, differences between <em>POLE</em> and <em>POLD1</em> and between somatic and germline mutations influence clinical presentation, mutagenic potential, and reliance on cooperating defects in tumorigenesis. These insights advance the understanding of proofreading-deficient cancers, with implications for diagnostics, genetic counseling, and precision oncology.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 12","pages":"Article 100843"},"PeriodicalIF":5.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668001","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":"GLI1-Altered Tumors of the Ovary: A Report of 4 Cases of an Underrecognized Neoplasm That May Mimic Sex Cord–Stromal Tumors","authors":"Kyle M. Devins,&nbsp;Adam S. Fisch,&nbsp;Robert H. Young,&nbsp;Dora Dias-Santagata,&nbsp;Esther Oliva","doi":"10.1016/j.modpat.2025.100848","DOIUrl":"10.1016/j.modpat.2025.100848","url":null,"abstract":"<div><div><em>GLI1</em> (glioma-associated oncogene homologue 1) altered neoplasms are an emerging group of tumors of presumed mesenchymal derivation, which occur mostly in the head and neck or soft tissues of the trunk and extremities. We have recently identified 4 ovarian neoplasms with <em>GLI1</em> gene fusions; all were initially diagnosed as unusual sex cord–stromal tumors (<em>n</em> = 3) or endometrioid adenocarcinoma with sex cord-like morphology (<em>n</em> = 1). Patients’ age ranged from 11 to 70 years and tumor size from 3 to 15 cm; all were confined to the ovary. Three tumors displayed dominant patterns of large irregular aggregates and smaller well-delineated nests of round cells with minimal to moderate amounts of clear to eosinophilic cytoplasm and monotonous round to ovoid nuclei divided by collagenous septae and focal myxoid areas. The final tumor showed alternating hypocellular and cellular areas composed of a loose, haphazard arrangement of spindled cells associated with myxoid stroma, imparting a “lace-like” reticular appearance, with only focal nested round cell morphology (20%). Additional minor patterns included tubules (<em>n</em> = 3), trabeculae (<em>n</em> = 2), follicle-like macrocysts (<em>n</em> = 2), cords (<em>n</em> = 1), microcysts (<em>n</em> = 1), and rosette-like formations (<em>n</em> = 1). Mitotic activity was minimal (&lt;1 to 2/10 high-power fields). All tumors had a network of numerous capillary-sized vessels. Two tumors had some positivity for markers of sex cord–stromal differentiation, with focal, strong calretinin expression in one and diffuse, weak SF1 in another. RNA-based next-generation sequencing revealed <em>PTCH1::GLI1</em> fusions in all 3 tumors with round cells and an <em>ACTB::GLI1</em> fusion in the predominantly spindled tumor. Our experience with these tumors, particularly the discovery of 3 of the cases in a relatively short time frame, suggests that they are underrecognized in the ovary, where their morphologic features often mimic those of sex cord–stromal neoplasms. Awareness of their morphologic features and appropriate use of genetic testing will ensure accurate diagnosis and lead to a greater understanding of these rare neoplasms.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 12","pages":"Article 100848"},"PeriodicalIF":5.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667983","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":"Apolipoprotein E Immunostaining Has Diagnostic Utility in Differentiating Dense Deposit Disease and C3 Glomerulonephritis: Clone-Based Evaluation of D719N, EP1373Y, and 1B2C9","authors":"Ozge Hurdogan ,&nbsp;Safak Mirioglu ,&nbsp;Ahmet Burak Dirim ,&nbsp;Muge Doksan ,&nbsp;Zeynep Nagehan Yuruk Yildirim ,&nbsp;Aydin Turkmen ,&nbsp;Isin Kilicaslan ,&nbsp;Yasemin Ozluk","doi":"10.1016/j.modpat.2025.100874","DOIUrl":"10.1016/j.modpat.2025.100874","url":null,"abstract":"<div><div>Electron microscopy (EM) has been essential for the diagnosis of dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). Recent research showed significantly higher accumulation of apolipoprotein E (ApoE) in DDD compared with C3GN and tested the use of ApoE immunohistochemistry for DDD diagnosis. We aimed to investigate the diagnostic value of ApoE in DDD and C3GN using 3 distinct ApoE clones—D719N, EP1373Y, and 1B2C9. Kidney biopsies of 26 DDD and 18 C3GN, diagnosed based on EM findings, were subjected to immunohistochemical analyses using ApoE clones D719N, EP1373Y, and 1B2C9. Kidney biopsies of 8 immune complex-mediated membranoproliferative glomerulonephritis, 13 acute postinfectious glomerulonephritis, 13 focal segmental glomerulosclerosis, 6 minimal change disease, 13 membranous nephropathy, 11 lupus nephritis, and 9 fibrillary glomerulonephritis constituted the control group. The staining pattern, intensity, and distribution were evaluated in each renal compartment. Linear/predominantly linear staining of score 2 to 3 intensity in a diffuse/global distribution was interpreted as diagnostic for DDD. DDD and C3GN cases were reclassified using each clone individually. D719N confirmed the diagnosis of DDD in 76.9% of the cases, whereas EP1373Y and 1B2C9 in 84.6%. All 3 clones confirmed C3GN diagnosis in 94.4% of the cases. EP1373Y and 1B2C9 demonstrated superior sensitivity (85% vs 77%) and overall diagnostic accuracy compared with D719N (89% vs 85%). Clone 1B2C9 showed significantly more intense background staining compared with D719N and EP1373Y in all cases (<em>P</em> &lt; .001). No cases in the control group showed false-positive staining, except for 66.7% of fibrillary glomerulonephritis. Notably, 2 among 6 D719N-negative DDDs were transplant biopsies, and 2 belonged to the same patient with Barraquer-Simons syndrome. All 3 ApoE clones, D719N, EP1373Y, and 1B2C9, can be used for routine diagnosis in the absence of EM or as an adjunct to EM to increase diagnostic accuracy in differentiating DDD and C3GN.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 12","pages":"Article 100874"},"PeriodicalIF":5.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961580","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":"Artificial Intelligence (AI)-Driven Screening of Equivocal Prostate Immunohistochemistry (IHC) Cases: Development and Validation of a Screening and Cancer Detection Framework","authors":"Ramin Nateghi ,&nbsp;Ruoji Zhou ,&nbsp;Madeline Saft ,&nbsp;Marina Schnauss ,&nbsp;Clayton Neill ,&nbsp;Ridwan Alam ,&nbsp;Nicole Handa ,&nbsp;Mitchell Huang ,&nbsp;Eric V. Li ,&nbsp;Jeffery A. Goldstein ,&nbsp;Hiten D. Patel ,&nbsp;Edward M. Schaeffer ,&nbsp;Menatalla Nadim ,&nbsp;Fattaneh Pourakpour ,&nbsp;Bogdan Isaila ,&nbsp;Christopher Felicelli ,&nbsp;Vikas Mehta ,&nbsp;Behtash G. Nezami ,&nbsp;Ashley E. Ross ,&nbsp;Ximing J. Yang ,&nbsp;Lee A.D. Cooper","doi":"10.1016/j.modpat.2025.100904","DOIUrl":"10.1016/j.modpat.2025.100904","url":null,"abstract":"<div><div>Artificial intelligence (AI) has been proposed as a solution to meet increasing demand for the diagnostic services of pathologists (B.I., C.F., V.M., B.G.N., X.J.Y.). Prostate biopsies are a significant source of this demand, and a substantial fraction of these biopsies require immunohistochemistry (IHC) staining, which adds work, time, and cost to the diagnostic process. Equivocal cases, which often prompt the use of IHC, not only present the greatest challenge to AI cancer detection tools but also represent the area where properly trained systems could offer the most clinical value by reducing the need for ancillary testing for cancer confirmation. From August 2021 to April 2023, we scanned 25,570 slides from 1641 patients. We investigated the performance of institutionally developed models for prostate cancer detection using digital pathology images, with an aim for reducing work, turnaround time, and costs related to the ordering of IHC equivocal cases. We advanced complementary sensitive and specific models to screen these challenging cases, aiming to identify slides that could be confidently diagnosed without any ancillary IHC tests. Additionally, we compared the performance of a prostate-specific model to a general-purpose foundation model for screening and cancer detection. Our screening models correctly classified 55% of challenging equivocal blocks where IHC was ordered with a 1.4% error rate. We found that the foundation model achieved higher screening rates (ie, percentage of cases where IHC could be avoided), but this came at the cost of uniformly higher error rates and significantly greater computational demands. When trained as a standalone prostate cancer detection system, our model demonstrated high concordance with pathologist ground truth, achieving an area under the curve of 98.5%, sensitivity of 95.0%, and specificity of 97.8%. Computational models can aid in the diagnosis of prostate cancer and can effectively screen challenging prostate biopsy cases, reducing unnecessary IHC utilization and helping to optimize pathology workflows.</div><div><strong>Plain language summary</strong></div><div>Traditional pathologic diagnosis of prostate cancer can be labor intensive. Equivocal cases in particular often require special testing (immunohistochemistry [IHC]) to establish a diagnosis, which introduces further delay and cost. This study develops an artificial intelligence system specifically designed to screen equivocal cases and reduce the need for IHC. Our model serves as a second-read tool to help optimize pathology workflow and reduce turnaround time and costs by flagging cases where IHC can be safely avoided.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 12","pages":"Article 100904"},"PeriodicalIF":5.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225603","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}