Modern Pathology最新文献

{"title":"Computational Pathology for Accurate Prediction of Breast Cancer Recurrence: Development and Validation of a Deep Learning-based Tool.","authors":"Ziyu Su, Yongxin Guo, Robert Wesolowski, Gary Tozbikian, Nathaniel S O'Connell, M Khalid Khan Niazi, Metin N Gurcan","doi":"10.1016/j.modpat.2025.100847","DOIUrl":"https://doi.org/10.1016/j.modpat.2025.100847","url":null,"abstract":"<p><p>Accurate recurrence risk stratification is crucial for optimizing treatment plans for breast cancer patients. Current prognostic tools like Oncotype DX (ODX) offer valuable genomic insights for HR+/HER2- patients but are limited by cost and accessibility, particularly in underserved populations. In this study, we present Deep-BCR-Auto, a deep learning-based computational pathology approach that predicts breast cancer recurrence risk from routine H&E-stained whole slide images (WSIs). Our methodology was validated on two independent cohorts: the TCGA-BRCA dataset and an in-house dataset from The Ohio State University (OSU). Deep-BCR-Auto demonstrated robust performance in stratifying patients into low- and high-recurrence risk categories. On the TCGA-BRCA dataset, the model achieved an area under the receiver operating characteristic curve (AUROC) of 0.827, significantly outperforming existing weakly supervised models (p=0.041). In the independent OSU dataset, Deep-BCR-Auto maintained strong generalizability, achieving an AUROC of 0.832, along with 82.0% accuracy, 85.0% specificity, and 67.7% sensitivity. These findings highlight the potential of computational pathology as a cost-effective alternative for recurrence risk assessment, broadening access to personalized treatment strategies. This study underscores the clinical utility of integrating deep learning-based computational pathology into routine pathological assessment for breast cancer prognosis across diverse clinical settings.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"100847"},"PeriodicalIF":7.1,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668002","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 Four Cases of an Underrecognized Neoplasm That May Mimic Sex Cord-Stromal Tumors.","authors":"Kyle M Devins, Adam S Fisch, Robert H Young, Dora Dias-Santagata, Esther Oliva","doi":"10.1016/j.modpat.2025.100848","DOIUrl":"https://doi.org/10.1016/j.modpat.2025.100848","url":null,"abstract":"<p><p>GLI1-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 four ovarian neoplasms with GLI1 gene fusions; all were initially diagnosed as unusual sex cord stromal tumors (n=3) or endometrioid adenocarcinoma with sex cord-like morphology (n=1). Patients ranged from 11-70 years and tumors from 3-15 cm; all were confined to the ovary. Three 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 (n=3), trabeculae (n=2), follicle-like macrocysts (n=2), cords (n=1), microcysts (n=1), and rosette-like formations (n=1). Mitotic activity was minimal (<1-2/10 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 PTCH1::GLI1 fusions in all three tumors with round cells and an ACTB::GLI1 fusion in the predominantly spindled tumor. Our experience with these tumors, particularly the discovery of three of the cases in a relatively short time frame, suggests 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 greater understanding of these rare neoplasms.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"100848"},"PeriodicalIF":7.1,"publicationDate":"2025-07-16","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":"Comparative analysis of somatic and germline polymerase proofreading deficiencies in cancer: molecular and clinical implications.","authors":"Julen Viana-Errasti, Raúl Marín, Sandra García-Mulero, Tirso Pons, Mariona Terradas, Gabriel Capellá, Victor Moreno, Pilar Mur, Laura Valle","doi":"10.1016/j.modpat.2025.100843","DOIUrl":"https://doi.org/10.1016/j.modpat.2025.100843","url":null,"abstract":"<p><p>Polymerases ε and δ maintain genome integrity through exonuclease proofreading. Germline and somatic pathogenic variants (PVs) in the exonuclease domain (ED) of POLE and POLD1 impair proofreading, causing hypermutated tumors. Despite shared mutational features that make these tumors highly immunogenic, molecular and clinical distinctions between POLE and POLD1 mutations, and between somatic and germline variants, remain incompletely understood. We compared molecular and clinical characteristics of POLE and POLD1 ED PVs (n=31), assessing their location, pathogenicity, clinical phenotypes, mismatch repair (MMR) status, tumor mutational burden (TMB) and signatures. We analyzed 360 proofreading-deficient tumors (TCGA/COSMIC) and 70 families (249 individuals) with polymerase proofreading-associated polyposis (PPAP). All germline and somatic PVs had high AlphaMissense scores (0.87-1), and clustered within or near Exo motifs. Recurrent, non-founder germline PVs, POLE L424V and POLD1 S478N, showed low/modest REVEL scores. Somatic variants occurred mainly in endometrial cancers (75% of proofreading-deficient TCGA cancers), while colorectal cancer predominated in PPAP (56% of carriers). Cancer risks and tumor spectra differed between POLE and POLD1 PV carriers. Aggressive hereditary phenotypes were linked to either specific POLE PVs (e.g., S297F, V411L, P436R, M444K, A456P, S4611T) or to 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 TMB and a shift in the associated mutational spectra. Unlike POLE, POLD1 ED PVs exhibited haplosufficiency, typically requiring a somatic second hit (e.g., loss of heterozygosity) or MMR deficiency to drive hypermutation. In conclusion, differences between POLE and POLD1, 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.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"100843"},"PeriodicalIF":7.1,"publicationDate":"2025-07-16","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":"A Genomic Alteration in GATA3 Affects Treatment Responses with a CDK4/6 Inhibitor Collaborating with p18INK4C Expression in Advanced Breast Carcinoma.","authors":"Xiao Huang, Sooryanarayana Varambally, Sarah A Anderson, Brooke B Bartow, Shuko Harada, Shi Wei, Gene P Siegal, Katia Khoury, Ceren Yalniz","doi":"10.1016/j.modpat.2025.100841","DOIUrl":"https://doi.org/10.1016/j.modpat.2025.100841","url":null,"abstract":"<p><p>Cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6i) with endocrine therapy benefits patients with hormone receptor (HR)-positive, human epidermal growth receptor 2 (HER2)-negative breast carcinomas. However, most tumors develop resistance to CDK4/6i during the course of therapy. Although preclinical studies have proposed molecular mechanisms for the resistance, predictive markers are yet to be discovered. We investigated the tumor molecular profiling in 42 patients with advanced stage breast carcinoma who received CDK4/6i therapy. The tumors carrying a GATA3 gene mutation, mainly a frameshift variant, showed a better treatment response compared to other tumors. Furthermore, we explored the potential underlining mechanism of this association. To that end, nuclear expression of p18, one of the INK family proteins, was found to be positively associated with the GATA3 mutation, as well as a CDK4/6i treatment response. Therefore, our study suggests that a GATA3 gene mutation, collaborating with p18 protein expression in tumor nuclei, may have a predictive value for CDK4/6i therapy in breast carcinoma.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"100841"},"PeriodicalIF":7.1,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667999","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":"Analytical and Clinical Performance of the VENTANA CLDN18 (43-14A) RxDx Assay in Gastric and Gastroesophageal Junction Adenocarcinoma Tissue Samples in SPOTLIGHT and GLOW.","authors":"Steven P Stratton, Lizhen Pang, Judith Pugh, Margarita Kouzova, Drew Baldwin, Jannine McDonald, Rebecka Lawrence-Glaze, Sean Moran, Abraham Guerruero, Diarmuid Moran","doi":"10.1016/j.modpat.2025.100844","DOIUrl":"https://doi.org/10.1016/j.modpat.2025.100844","url":null,"abstract":"<p><p>New therapies are needed to treat patients with human epidermal growth factor receptor 2 (HER2)-negative, locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. Zolbetuximab is a monoclonal antibody that targets the tight junction protein claudin 18 isoform 2 (CLDN18.2) in G/GEJ adenocarcinoma cells. We describe the analytical and clinical performance of the VENTANA CLDN18 (43-14A) RxDx Assay (Roche Diagnostics Solutions, Tucson, AZ, USA) as a companion diagnostic immunohistochemistry assay for treatment with zolbetuximab. Analytical performance was assessed in commercially available G/GEJ adenocarcinoma samples. Clinical performance was assessed in the context of two phase 3 trials (SPOTLIGHT, NCT03504397; GLOW, NCT03653507) of first-line zolbetuximab plus chemotherapy in patients with HER2-negative, LA unresectable or mG/GEJ adenocarcinoma whose tumors were CLDN18.2-positive (≥75% of viable tumor cells demonstrating moderate-to-strong membrane CLDN18 staining). Staining acceptability rates were assessed in patients whose tumors were tested for CLDN18.2 status using the VENTANA CLDN18 (43-14A) RxDx Assay and who met enrollment eligibility criteria not related to CLDN18.2 status. Progression-free survival and overall survival were evaluated in enrolled patients. Analytical performance: Positive and negative percent agreement (PPA, NPA) compared with immunohistochemistry reference scoring was 100% for between-antibody, between-detection kit, between-instrument, between-day, and within-run precision studies. Interlaboratory reproducibility exceeded 90% average positive and negative agreement (APA, ANA) between sites and 94% APA and ANA between readers across three sites. Clinical performance: Among 3783 patient tumor samples, staining acceptability rates exceeded 94%. Patients identified for eligibility using the VENTANA CLDN18 (43-14A) RxDx Assay demonstrated statistically significant improvement in progression-free survival and overall survival with zolbetuximab plus chemotherapy in both phase 3 trials. The VENTANA CLDN18 (43-14A) RxDx Assay demonstrated robust, reproducible analytical performance and clinical utility as a companion diagnostic for first-line zolbetuximab plus chemotherapy in patients with HER2-negative, LA unresectable or mG/GEJ adenocarcinoma whose tumors are CLDN18.2-positive.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"100844"},"PeriodicalIF":7.1,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668000","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 Predicts Survival Across Squamous Tumor Entities From Routine Pathology: Insights from Head and Neck, Esophagus, Lung and Cervical Cancer.","authors":"Verena Bitto, Xiaofeng Jiang, Michael Baumann, Jakob Nikolas Kather, Ina Kurth","doi":"10.1016/j.modpat.2025.100845","DOIUrl":"https://doi.org/10.1016/j.modpat.2025.100845","url":null,"abstract":"<p><p>Computational pathology-based models are becoming increasingly popular for extracting biomarkers from images of cancer tissue. However, their validity is often only demonstrated on a single unseen validation cohort, limiting insights into their generalizability and posing challenges for explainability. In this study, we developed models to predict overall survival using haematoxylin and eosin (H&E) slides from formalin-fixed paraffin-embedded (FFPE) samples in head and neck squamous cell carcinoma (HNSCC). By validating our models across diverse squamous tumor entities, including head and neck (hazard ratio [HR] = 1.58, 95% CI = 1.17-2.12, p = 0.003), esophageal (non- significant), lung (HR = 1.31, 95% CI = 1.13-1.52, p < 0.001) and cervical (HR = 1.39, 95% CI = 1.10-1.75, p = 0.005) squamous cell carcinomas, we showed that the predicted risk score captures relevant information for survival beyond HNSCC. Correlation analysis indicated that the predicted risk score is strongly associated with various clinical factors, including human papillomavirus status, tumor volume and smoking history, although the specific factors vary across cohorts. These results emphasize the relevance of comprehensive validation and in-depth assessment of computational pathology-based models to better characterize the underlying patterns they learn during training.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"100845"},"PeriodicalIF":7.1,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668003","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":"Ossifying Spindled and Epithelioid Tumor: A Novel Soft Tissue Tumor.","authors":"John M Gross, Ying S Zou, Michael Michal, Abbas Agaimy, Roberto A Garcia, Christopher Hysell, Karen J Fritchie, Josephine K Dermawan, Brian P Rubin, Melanie Klausner, Laura Morsberger, Jonathan Dudley, Alyza Skaist, Yan Zhang, Kornel Schuebel, Jennifer Meyers, Srinivasan Yegnasubramanian, Leslie Cope, Nasir Ud Din, Ali Alani, David I Suster, Lisa Rooper, Pedram Argani, Ezra G Baraban, Daniel Baumhoer, Baptiste Ameline, Gregory W Charville, Andrew E Rosenberg","doi":"10.1016/j.modpat.2025.100840","DOIUrl":"https://doi.org/10.1016/j.modpat.2025.100840","url":null,"abstract":"<p><p>This investigation describes the clinicoradiologic, pathologic, and molecular features of a unique soft tissue tumor characterized by a peripheral shell of bone and composed of bland myoid spindle and epithelioid cells that are keratin-positive. Our study cohort consists of 6 males and 6 females with a mean age of 32 years. The tumors arose in the extremities (n=9) and proximal limb girdle (n=3) and were equally distributed between deep and superficial soft tissues. Patients reported dull painless masses of several months to greater than 10 years duration (mean: 2.9 yrs). Imaging demonstrated a complete or partial peripheral shell of bone that could extend centrally, and the tumor mean size was 5.7 cm. Histologically, the tumors were composed of uniform eosinophilic myoid spindled cells growing in sheets and intersecting fascicles surrounded by mature lamellar and/or woven bone. Also present was an admixed component of intermediate-sized epithelioid cells with eosinophilic cytoplasm. Mitotic activity was consistently low. Immunohistochemistry showed strong multifocal staining for keratins and 50% (5/10) showed focal staining for S100; however, all were negative for SMA, desmin, SOX10, ERG, and CD34. Genetic analysis by multiple targeted RNA sequencing panels was negative (n=10); however, whole transcriptome sequencing (WTS) (n=8) revealed a recurrent and novel in-frame SRSF7::NFATC3 fusion in four tumors. Dual FISH probes for SRSF7::NFATc3 successfully confirmed this fusion and identified a 5^th case which had not undergone WTS but was negative by a targeted RNA fusion panel. Methylation profiling (n=8) demonstrated a shared epigenetic profile distinct from other entities. Clinical follow-up (n=11) showed no evidence of recurrence after primary excision with a mean of 41.6 months. In summary, we describe a novel soft tissue tumor designated 'ossifying spindled and epithelioid tumor' (OSET) as a descriptive histologic term that also emphasizes its close radiologic mimic, ossifying fibromyxoid tumor (OFMT). All cases have behaved in a benign fashion without recurrence following simple excision. Awareness of this entity is important so it can be distinguished from other neoplasms that have more aggressive biological potential.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"100840"},"PeriodicalIF":7.1,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667984","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":"Exploring the genetic landscape of primary marginal zone lymphoma of the urinary bladder.","authors":"Ilaria Balestri, Vanesa-Sindi Ivanova, Gorana Gašljević, Michael von Gunten, Metka Volavšek, Baptiste Hamelin, Stefan Dirnhofer, Kirsten Mertz, Thomas Menter, Alexandar Tzankov","doi":"10.1016/j.modpat.2025.100838","DOIUrl":"https://doi.org/10.1016/j.modpat.2025.100838","url":null,"abstract":"<p><p>Extranodal marginal zone B-cell lymphoma (MZL) of mucosa-associated lymphoid tissue is the most frequent primary lymphoma of the urinary bladder. While MZLs from various anatomical sites are often associated with autoimmune disorders, infections, and site-characteristic genetic alterations, the molecular foundations and potential infectious triggers of urinary bladder MZL remain poorly understood. To elucidate the disease etiology and correlation with MZLs arising in other locations, we examined a cohort of 17 cases (11 female and 6 male) diagnosed with primary bladder MZL between 2005 and 2025. Immunohistochemical analysis confirmed literature, with all samples testing positive for the pan B-cell markers CD20 and CD79a, and negative for CD5 (except one), cyclin D1, and SOX11. Thirteen samples exhibited secretory differentiation and displayed immunoglobulin light chain restriction (9 κ, 4 λ). No gene rearrangements in BCL2, BCL6, BCL10, IRF4, MALT1, and MYC were detected. High-throughput sequencing identified 31 pathogenic/likely pathogenic somatic mutations across 18 genes, with TBL1XR1 (n = 8), MAP2K1 (n = 4), and TNFAIP3 (n = 2) being the most frequently mutated ones. Additionally, all cases included variants of unknown significance. The sample of one patient tested positive for Chlamydia trachomatis, human betaherpesvirus 6B and Epstein-Barr virus. Escherichia coli was detected in 5 samples. We provide compelling evidence that urinary bladder MZL is a mutation-driven rather than gene fusion-driven disease, and that Escherichia coli was present in approximately one-third of tumor biopsies. These tumors frequently harbored pathogenic mutations in genes encoding components regulating plasma cell differentiation and the pleiotropic MAPK/ERK signaling pathway. TBL1XR1, which resulted unexpectedly frequently mutated, is generally linked to more aggressive variants of MZL and diffuse large B-cell lymphoma, however, its prognostic significance in urinary bladder MZL remains to be determined. Comparative analysis highlighted partial overlap of urinary bladder MZL mutational profiles with those found in salivary gland MZL.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"100838"},"PeriodicalIF":7.1,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144619080","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":"Pitfalls in the histological diagnosis of morphologic variants of invasive lobular carcinoma of the breast.","authors":"Giuseppe Floris, Lounes Djerroudi, Gitte Zels, Maxim De Schepper, François Richard, Rigleta Brahimaj, Patrick W B Derksen, Matthias Christgen, Sunil R Lakhani, Paul J Van Diest, Edi Brogi, Christine Desmedt, Stuart J Schnitt, Anne Vincent-Salomon","doi":"10.1016/j.modpat.2025.100837","DOIUrl":"https://doi.org/10.1016/j.modpat.2025.100837","url":null,"abstract":"<p><p>Invasive lobular carcinoma (ILC) is the second most frequent histological type of breast cancer and the most frequent special type. Disruption of cell-to-cell adhesion, caused most often by E-cadherin loss of function, results in the distinctive histomorphology of ILC which is characterized by single threads of monotonous, dyscohesive neoplastic epithelial cells infiltrating the breast parenchyma with little or no stromal reaction, referred to as classic ILC. In the past four decades, ILC variants that differ from classic ILC with regard to architectural, cytological, and/or nuclear features have been described. The recognition and correct characterization of ILC, including its variant forms, is essential to avoid misdiagnosis and its possible treatment implications. Some ILC variants may be associated with more aggressive clinical behavior as compared to classic ILC, independent of standard predictive and prognostic parameters. Additionally, the distinctive biological and clinical features of ILC are increasingly being investigated as therapeutic targets in ILC-tailored clinical trials. In this manuscript, we have undertaken an in-depth review of the current state of knowledge about ILC variants. Evidence gained from molecular analysis of ILC and its microenvironment suggests that ILC variants are biologically distinct from classic ILC. However, this conclusion is undermined by the imprecise histopathological identification of ILC variants. In the absence of standardized and simplified criteria for the diagnosis of ILC, under-recognition of ILC variants may translate into missed opportunities for tailored treatment of ILC patients. Therefore, we propose steps toward the development of a roadmap that will ultimately lead to a more reproducible classification of ILC variants and improve our knowledge of these challenging tumors.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"100837"},"PeriodicalIF":7.1,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567545","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":"Hyalinizing Clear Cell Carcinoma (HCCC) of the Head and Neck: A Multicenter Retrospective Study of 87 Cases Focusing on Prognostic Pathologic Features and Grading scheme.","authors":"Bin Xu, Kartik Viswanathan, Marie Barbesier, Alexander Ladenheim, Cristina R Antonescu, Ronald Ghossein, Dan Lubin, Kelly Magliocca, Sayed Matar, Michael W Mikula, Isabella Tondi Resta, Dibisha Roy, Soo Yeon Sohn, Anuj Verma, Manju L Prasad, Lisa Rooper, Margaret Brandwein-Weber, Zubair Baloch, Nora Katabi","doi":"10.1016/j.modpat.2025.100834","DOIUrl":"https://doi.org/10.1016/j.modpat.2025.100834","url":null,"abstract":"<p><p>Hyalinizing clear cell carcinoma (HCCC) is a salivary gland carcinoma characterized by the presence of clear and eosinophilic cells within a hyalinized stroma and the EWSR1 rearrangement. Aiming to identify prognostic factors and establish a grading system, we herein conducted a detailed clinicopathology review of a large retrospective cohort of 87 HCCCs from seven tertiary centers. Most HCCCs (91%) originated from minor salivary glands, although major salivary glands were affected in 8%. The most common sites were base of tongue, palate, nasopharynx, and maxilla . Eosinophilic cells were more prevalent than clear cells. Histologic features included Intraosseous component (19%), perineural invasion (48%), lymphovascular invasion (LVI, 16%), nuclear pleomorphism (14%), tumor necrosis (26%), and a mitotic index (MI) ≥5/2 mm², 9%). Factors associated with increased risk of nodal metastasis at presentation included LVI, high MI, and tumor necrosis. The 10-year disease-specific survival (DSS), disease-free survival (DFS), and distant metastasis-free survival (DMFS) were 80%, 51%, and 87%, respectively. Significant prognostic factors identified on univariate survival analysis included MI≥5/2 mm², tumor necrosis, atypical mitosis, and nuclear pleomorphism for DSS; LVI, MI≥5/2 mm², and percentage of clear cells for DFS; and nodal metastasis, LVI, MI≥5/2 mm², tumor necrosis, and atypical mitosis for DMFS. The only independent prognostic factor for DFS identified on multivariate survival analysis was MI≥5/2 mm². High grade HCCCs, defined as tumors with MI≥5/2 mm² and/or tumor necrosis, were associated with increased risk of nodal metastasis at presentation and shortened DSS and DMFS. Among 67 HCCCs examined for EWSR1 rearrangement, 65 (97%) harbored EWSR1 translocation. In conclusion, we identified multiple prognostic factors in HCCC, including MI, necrosis, atypical mitosis, nuclear pleomorphism, lymphovascular invasion, and percentage of clear cells. We herein proposed a prognostically relevant two-tiered grading system, classifying HCCC with a MI≥5/10 2 mm² and/or tumor necrosis as high grade.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"100834"},"PeriodicalIF":7.1,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567544","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}