Modern Pathology最新文献

{"title":"Multimodal Explainable Artificial Intelligence for Prognostic Stratification of Patients With Glioblastoma","authors":"Bhakti Baheti ,&nbsp;Sunny Rai ,&nbsp;Shubham Innani ,&nbsp;Garv Mehdiratta ,&nbsp;William Robert Bell ,&nbsp;Sharath Chandra Guntuku ,&nbsp;MacLean P. Nasrallah ,&nbsp;Spyridon Bakas","doi":"10.1016/j.modpat.2025.100797","DOIUrl":"10.1016/j.modpat.2025.100797","url":null,"abstract":"<div><div>Glioblastoma (GBM) is the most common and aggressive malignant adult tumor of the central nervous system, with a grim prognosis and heterogeneous morphologic and molecular profiles. Since the adoption of the current standard-of-care treatment in 2005, no substantial prognostic improvement has been noticed. In this study, we seek the identification of prognostically relevant GBM characteristics from routinely acquired hematoxylin and eosin–stained whole slide images (WSIs) and clinical data, which when integrated via advanced computational methods could yield improved patient prognostic stratification and hence optimize clinical decision making and patient management. The proposed WSI analysis capitalizes on a comprehensive curation of apparent artifactual content and an interpretability mechanism via a weakly supervised attention-based multiple-instance learning approach that further utilizes clustering to constrain the search space. Patterns automatically identified by our approach as of high prognostic value classify each WSI as representative of short or long survivors. Further assessments of the prognostic relevance of the associated clinical patient data are performed both in isolation and in an integrated manner, using XGBoost and SHapley Additive exPlanations. The multimodal integration of WSI with clinical data yields enhanced stratification performance when compared with using either one of the modalities. Identifying tumor morphologic and clinical patterns associated with short and long survival will enable the clinical neuropathologist to provide additional relevant prognostic information to the treating team and suggest avenues of biological investigation for further understanding and potentially treating GBM.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 9","pages":"Article 100797"},"PeriodicalIF":7.1,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144151193","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":"Concordance Between the PD-L1 Tumor Area Positivity Score and Combined Positive Score for Gastric or Esophageal Cancers Treated With Tislelizumab","authors":"Markus Moehler ,&nbsp;Harry H. Yoon ,&nbsp;Daniel-Christoph Wagner ,&nbsp;Silu Yang ,&nbsp;Jingwen Shi ,&nbsp;Yun Zhang ,&nbsp;Han Hu ,&nbsp;Christopher La Placa ,&nbsp;Yanyan Peng ,&nbsp;Wenting Du ,&nbsp;Adrienne McCampbell ,&nbsp;Wenjie Xu ,&nbsp;Zhirong Shen ,&nbsp;Hui Xu ,&nbsp;Ruiqi Huang ,&nbsp;Ken Kato","doi":"10.1016/j.modpat.2025.100793","DOIUrl":"10.1016/j.modpat.2025.100793","url":null,"abstract":"<div><div>Tumor Area Positivity (TAP) score is an emerging score measuring programmed death-ligand 1 (PD-L1) expression in tumors. However, the availability of concordance data between TAP score and other immunohistochemistry scoring methods is limited. We investigated concordance between TAP score and combined positive score (CPS) and the relationship between PD-L1 status and clinical outcomes using gastric/gastroesophageal junction adenocarcinoma (GC/GEJC) and esophageal squamous cell carcinoma (ESCC) samples from patients subsequently treated with tislelizumab. Baseline tissue samples from RATIONALE-305 (GC/GEJC; NCT03777657), RATIONALE-302 (ESCC; NCT03430843), and RATIONALE-306 (ESCC; NCT03783442) were assessed for PD-L1 expression using an investigational use-only version of the VENTANA PD-L1 (SP263) CDx Assay. PD-L1 status was scored by TAP score and CPS. Concordance and correlation of both scores with clinical and safety outcomes were analyzed. Across all trials, agreement between TAP score and CPS was significant at PD-L1 cutoffs of ≥1%/≥1, ≥5%/≥5, and ≥10%/≥10 (Cohen’s κ, 0.64-0.85). Similar outcomes for overall survival (OS), progression-free survival, objective response rate, and duration of response were observed between TAP score- and CPS-defined PD-L1–positive subgroups at analogous PD-L1 cutoffs. OS hazard ratios in the PD-L1–high subgroups were similar between protocol-defined TAP score and the same numeric CPS value (OS hazard ratio [95% CI]: RATIONALE-305, 0.72 [0.59-0.88] and 0.73 [0.60-0.89]; RATIONALE-302, 0.52 [0.35-0.76] and 0.54 [0.37-0.78]; and RATIONALE-306, 0.63 [0.45-0.89] and 0.58 [0.42-0.81], respectively). Safety outcomes were generally comparable between all PD-L1 subgroups. In conclusion, TAP score and CPS are clinically comparable immunohistochemistry measures of tumor PD-L1 expression in tislelizumab-treated patients with GC/GEJC or ESCC.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 9","pages":"Article 100793"},"PeriodicalIF":7.1,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079113","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":"Differential Localization of β-Catenin Protein in CTNNB1 Mutant Endometrial Cancers Results in Distinct Transcriptional Profiles","authors":"Molly L. Parrish ,&nbsp;Macy L. Osborne-Frazier ,&nbsp;Russell R. Broaddus ,&nbsp;Andrew B. Gladden","doi":"10.1016/j.modpat.2025.100791","DOIUrl":"10.1016/j.modpat.2025.100791","url":null,"abstract":"<div><div><em>CTNNB1</em> exon 3 mutation is a well-established driver of nearly 30% of endometrioid endometrial cancers (EECs), and this is associated with worse patient survival. Paradoxically, we have previously demonstrated that mutant β-catenin protein does not robustly localize to the nucleus in these cancers. The purpose of this study was to determine downstream gene expression in these cancers with nuclear or membrane/cytoplasmic mutant β-catenin protein localization. Spatial transcriptomics was performed on tumors with intratumor nuclear and nonnuclear mutant β-catenin, using the protein localization to select for regions of interest (ROIs). Differential expression analysis of all nuclear and nonnuclear ROIs yielded distinct transcriptional profiles based on the localization of β-catenin. Analysis revealed enrichment for Wnt signaling and epithelial-to-mesenchymal transition pathways in nuclear ROIs and hormone signaling in nonnuclear ROIs. Hierarchical clustering yielded 2 clusters comprised of almost entirely nuclear or nonnuclear ROIs. A novel therapeutic target, TROP2, encoded by the <em>TACSTD2</em> gene, was identified to be altered by Wnt/β-catenin signaling. These data provide evidence for highly heterogeneous intratumor transcriptional profiles dependent on β-catenin protein localization in EEC with <em>CTNNB1</em> driver mutations. Therefore, reporting of β-catenin immunohistochemistry should include an estimated percentage of tumor with nuclear localization in EEC tumors with exon 3 <em>CTNNB1</em> mutations.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 9","pages":"Article 100791"},"PeriodicalIF":7.1,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143971654","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":"Malignant Chondroblastoma: An Epigenetically Distinct Subtype of Chondroblastoma With a Predilection for the Skeletally Mature","authors":"Karen Fritchie ,&nbsp;Baptiste Ameline ,&nbsp;Vanghelita Andrei ,&nbsp;Greg Charville ,&nbsp;Jason L. Hornick ,&nbsp;David M. Meredith ,&nbsp;Ivy John ,&nbsp;Michael Michal ,&nbsp;Tamas Pancsa ,&nbsp;Scott E. Kilpatrick ,&nbsp;John Reith ,&nbsp;Zhen Wang MD, PhD ,&nbsp;Andrew Horvai ,&nbsp;John Gross ,&nbsp;Vaiyapuri Sumathi ,&nbsp;Jessica L. Davis ,&nbsp;Bibianna Purgina ,&nbsp;Daniel P. Raymond ,&nbsp;Hakan Ilaslan ,&nbsp;John Chrisinger ,&nbsp;Daniel Baumhoer","doi":"10.1016/j.modpat.2025.100790","DOIUrl":"10.1016/j.modpat.2025.100790","url":null,"abstract":"<div><div>Malignant chondroblastoma is a recently described variant of chondroblastoma showing a distinct age/site distribution and morphology along with the typical <em>H3-3B</em> p.K36M mutation. We sought to further compare conventional and malignant chondroblastoma. Malignant chondroblastomas were collected. H3-3 K36M immunohistochemistry, as well as DNA methylation and copy number profiling, were performed and compared with conventional chondroblastoma. Forty-one samples from 26 patients were identified (20 males, 6 females; age: 19-62 years; median: 39 years). Anatomical sites included rib (7), pelvis (4), acromion (4), scapula (4), spine (2), long bone (3), calcaneus (1), and talus (1). Imaging showed an expansile mass with variable cortical erosion and/or breakthrough. Most patients (n = 17) showed sheets of atypical ovoid cells deposited in a myxoid stroma. Osteoclast-like giant cells/matrix formation was scarce. Six patients had tumors with features of conventional chondroblastoma but significant cytologic atypia. Three tumors demonstrated a morphology indistinguishable from conventional chondroblastoma except for extensive permeation, and one of these cases showed a transition to high-grade sarcoma. The final case was composed only of high-grade pleomorphic sarcoma that harbored an <em>H3F3A</em> p.K36M mutation. When an adjacent host bone was present, permeative growth through the cortex and native trabeculae was noted. All samples tested positive for the H3-3 K36M-specific antibody (26 of 26). Methylome profiling of 28 specimens from 24 patients revealed that 26 of these specimens formed a distinct cluster on a uniform manifold approximation and projection dimension reduction plot separate from conventional chondroblastoma and high-grade osteosarcoma. Of 26 methylomes from which interpretable copy number profiles can be derived, 12 had no variations, whereas 14 had copy number changes. Of 22 patients, 11 experienced local recurrence, 8 patients developed metastasis, and 3 patients died of disease. Malignant chondroblastoma is a rare, clinically and epigentically distinct variant of chondroblastoma with a predilection for the flat bones of skeletally mature individuals and high rates of local recurrence and distant metastases. A subset transforms into high-grade pleomorphic sarcoma, either de novo or in subsequent recurrences. Malignant chondroblastoma with high-grade features and/or copy number variations appears to have a higher propensity for adverse events, including death from disease.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 9","pages":"Article 100790"},"PeriodicalIF":7.1,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143971050","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":"Comprehensive Clinicopathological and Multiomics Characterization of Dermatofibrosarcoma Protuberans Revealed PDGFD Fusion as Distinct Molecular Subtype With Better Survival","authors":"Maximus C.F. Yeung ,&nbsp;Tsun Fong ,&nbsp;Anthony P.Y. Liu ,&nbsp;Ronald C.K. Chan ,&nbsp;Angela Z. Chan ,&nbsp;W.H. Lau ,&nbsp;Johann Lok ,&nbsp;Gloria Y. Gao ,&nbsp;S.Y. Leung ,&nbsp;Tony W.H. Shek","doi":"10.1016/j.modpat.2025.100792","DOIUrl":"10.1016/j.modpat.2025.100792","url":null,"abstract":"<div><div>Dermatofibrosarcoma protuberans (DFSP) is a locally aggressive superficial mesenchymal neoplasm characterized by <em>COL1A1::PDGFB</em> fusion. Recently, <em>PDGFD</em> has been identified as a less common fusion partner. However, the clinicopathological and molecular differences between <em>PDGFD</em>-fusion and <em>PDGFB</em>-fusion DFSP remain largely unknown. In this study of 363 DFSP, we found 10 cases with <em>PDGFD</em> fusion, including 2 with a previously undescribed partner involving the <em>EMILIN1</em> gene. Multiomics analysis showed distinct transcriptomics, epigenomics, and copy number features for <em>PDGFD</em>-fusion DFSP versus <em>PDGFB</em>-fusion DFSP. <em>PDGFD</em>-fusion DFSP had higher <em>PDGFD</em> expression and virtually no <em>PDGFB</em> expression. Both clustered into the DFSP epigenomic cluster but formed a distinct subcluster with differential methylation affecting fibroblast migration genes. Copy number analysis revealed that <em>PDGFD</em>-fusion DFSP formed a distinct subgroup with a generally copy number–neutral profile and better survival than <em>PDGFB</em>-fusion DFSP that was dominated by amplification at translocation sites in chromosomes 17 and 22. Pooled analysis of 39 cases (incorporating 29 from the literature) revealed that <em>PDGFD</em>-fusion DFSP was more common in women (71.8% vs 42.4%, <em>P</em> &lt; .001), occurred at a lower age (median, 37 years vs 45 years, <em>P</em> &lt; .01), and had a higher chance of occurrence at the breast (25.6% vs 2.3%, <em>P</em> &lt; .001). <em>PDGFD</em>-fusion DFSP also tended to center predominantly in the subcutis (63.6% vs 30%, <em>P</em> &lt; .001), had a circumscribed border (50% vs 19.2%, <em>P</em> &lt; .001), was smaller in size (3 cm vs 3.5 cm, <em>P</em> = .017), and had a lower mitotic count (median, 1 vs 3 per 10 high-power fields, <em>P</em> = .03). Overall, our study provided detailed multiomics characterization of <em>PDGFD</em>-fusion DFSP with significant clinicopathological and diagnostic implications.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 9","pages":"Article 100792"},"PeriodicalIF":7.1,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027197","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":"Molecular Landscape, Genomic Shift, and Prediction in the Neoadjuvant Setting of Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer","authors":"Laura Pons ,&nbsp;Laura Hernandez ,&nbsp;Aintzane Urbizu ,&nbsp;Laura Arnaldo ,&nbsp;Paula Rodriguez-Martinez ,&nbsp;Carolina Sanz ,&nbsp;Ana M. Muñoz-Mármol ,&nbsp;Eva Fernandez ,&nbsp;Eudald Felip ,&nbsp;Vanesa Quiroga ,&nbsp;Mireia Margelí ,&nbsp;Pedro L. Fernandez","doi":"10.1016/j.modpat.2025.100787","DOIUrl":"10.1016/j.modpat.2025.100787","url":null,"abstract":"<div><div>The amplification or overexpression of human epidermal growth factor receptor 2 (HER2) defines a breast cancer subtype, which benefits from neoadjuvant HER2-targeted therapy. However, at least 40% of patients respond poorly or do not respond to treatment. We analyzed the main genomic alterations of 64 HER2+ patients by next-generation sequencing to identify new predictors of response and correlate them with clinicopathological parameters. We also compared the genomic alterations between primary and residual tumors after neoadjuvant treatment. The <em>TP53</em> gene was the most frequently mutated gene, and in combination with <em>ERBB2</em> overexpression, the 2 were predictive of residual cancer burden (<em>P</em> = .001). Furthermore, the combination of their immunohistochemical counterpart (p53 mutant and score 3+ for HER2) can predict complete pathological response and the grade of response (<em>P</em> = .038 and <em>P</em> = .031, respectively). Therefore, p53 could be included in the initial panel of breast cancer biomarkers to help therapeutic decision-making in HER2+ cases.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 9","pages":"Article 100787"},"PeriodicalIF":7.1,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143990216","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":"Malignant Transformation in Pleomorphic Adenoma: The Impact of DNA Methylation Profiling and Pathogenic Mutations","authors":"Emmanuelle Uro-Coste ,&nbsp;Yvan Nicaise ,&nbsp;Béatrice Akiki ,&nbsp;Clementine Decamps ,&nbsp;Léonor Chaltiel ,&nbsp;Aurore Siegfried ,&nbsp;Beatrice Herbault-Barres ,&nbsp;Hadrien Reboul ,&nbsp;Emmanuella Bassey ,&nbsp;Anouchka Modesto ,&nbsp;Valentine Poissonnet ,&nbsp;Caroline Even ,&nbsp;Benjamin Verillaud ,&nbsp;Valérie Costes-Martineau ,&nbsp;François-Regis Ferrand ,&nbsp;Sebastien Vergez ,&nbsp;Elizabeth Cohen-Jonathan-Moyal","doi":"10.1016/j.modpat.2025.100786","DOIUrl":"10.1016/j.modpat.2025.100786","url":null,"abstract":"<div><div>Salivary gland tumors are a rare and heterogeneous group of lesions with diverse microscopic appearances and variable clinical behavior. The most common salivary gland tumor subtype, pleomorphic adenoma (PA), can undergo malignant transformation into carcinoma ex pleomorphic adenoma (CXPA). Carcinomatous transformation from PA to CXPA is a highly progressive and multistep process. Distinguishing a PA with some atypia from a low-grade intracapsular or minimally invasive CXPA is primarily subjective as no mitotic count thresholds exist to help pathologists distinguish between them in difficult cases. In this prospective study, we collected 140 cases encompassing both PA and CXPA to study their molecular signatures. The primary objective was to investigate the use of DNA methylation profiling as a potential molecular tool for differentiating between these 2 entities. Methylation analysis was performed on 33 PA cases and 33 CXPA cases. We were able to demonstrate that based on their methylation profiles, PA and CXPA could be classified into 3 distinct clusters that we called benign, intermediate, and malignant. We also revealed that the presence of <em>TP53</em>, <em>HRAS</em>, <em>PTEN</em>, and/or <em>TERT</em> pathogenic mutations were exclusively present in CXPA cases and that chromosomal alteration on chromosomes 5 and 8 are potentially associated with malignant transformation. In conclusion, our study provides a comprehensive molecular framework for PA and CXPA. The presence of a pathogenic mutation in <em>TP53</em>, <em>HRAS</em>, <em>PTEN</em>, or <em>pTERT</em> or <em>HER2</em> amplification could be integrated into a molecular diagnosis of CXPA for tumors within the PA–CXPA spectrum. In the future, we aim to improve our methylomic classification to make it a precision medicine diagnostic tool for the treatment management of tumors within the PA–CXPA spectrum.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 9","pages":"Article 100786"},"PeriodicalIF":7.1,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144033521","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":"Not All HER2-Positive Breast Cancers Are the Same: Intratumoral Heterogeneity, Low-Level HER2 Amplification, and Their Impact on Neoadjuvant Therapy Response","authors":"Wenli Dai ,&nbsp;Olga Navolotskaia ,&nbsp;Jeffrey L. Fine ,&nbsp;Lakshmi Harinath ,&nbsp;Samaneh A. Motanagh ,&nbsp;Tatiana M. Villatoro ,&nbsp;Rohit Bhargava ,&nbsp;Beth Z. Clark ,&nbsp;Jing Yu","doi":"10.1016/j.modpat.2025.100785","DOIUrl":"10.1016/j.modpat.2025.100785","url":null,"abstract":"<div><div>Human epidermal growth factor receptor 2 (HER2)-positive breast cancers are frequently treated with neoadjuvant anti-HER2 and chemotherapy (NACT). However, treatment response varies, with a subset of tumors showing high residual cancer burden (RCB). This study investigates the relationship between HER2 immunohistochemical (IHC) intratumoral heterogeneity (ITH), low-level <em>HER2</em> amplification, and tumor response to NACT. A total of 205 post-NACT HER2-positive breast carcinomas with available RCB results were classified into the following 5 HER2 groups: (1) IHC 3+ (HER2 IHC positive, no fluorescence in situ hybridization performed), (2) Group 1-High (fluorescence in situ hybridization <em>HER2</em> copies &gt; 8 or <em>HER2/CEP17</em> ratio &gt; 4), (3) Group 1-Intermediate (<em>HER2</em> copies &gt; 6-8 or <em>HER2/CEP17</em> ratio &gt; 3-4), (4) Group 1-Low (<em>HER2</em> copies 4-6 and <em>HER2/CEP17</em> ratio 2-3), and (5) Group 3 (<em>HER2</em> copies ≥ 6 and <em>HER2/CEP17</em> ratio &lt; 2). Low-level <em>HER2</em> amplification, collectively designated as <em>HER2</em> copies 4 to 8 or <em>HER2/CEP17</em> ratio &lt; 4, was associated with reduced response to HER2-targeted therapy and higher RCB post-NACT. HER2 IHC ITH, defined as the presence of at least 3 distinct staining intensities, with at least 10% of tumor cells exhibiting weak or no staining, was significantly more prevalent in low-level <em>HER2</em> amplification groups (Group 1-Intermediate: 93.3%, Group 1-Low: 87.5%, and Group 3: 80.0%) compared with high-level amplification groups (IHC 3+: 24.7% and Group 1-High: 28.6%) (<em>P</em> &lt; .001). Both low-level <em>HER2</em> amplification and HER2 IHC ITH, regardless of hormone receptor status, were independently associated with poor treatment response, and tumors demonstrating both features had the highest likelihood of low therapeutic efficiency. These findings suggest that both low-level <em>HER2</em> amplification and HER2 IHC ITH contribute to poor NACT response and may warrant alternative therapeutic strategies. Further prospective studies are needed to refine the clinical significance of low-level <em>HER2</em> amplification and IHC ITH, particularly in the context of novel HER2-targeted therapies such as antibody-drug conjugates.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 7","pages":"Article 100785"},"PeriodicalIF":7.1,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144001964","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":"The Involvement of PI3K–Akt Signaling in the Clinical and Pathological Findings of Idiopathic Multicentric Castleman Disease–Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis, and Organomegaly and Not Otherwise Specified Subtypes","authors":"Tomoka Haratake ,&nbsp;Midori Filiz Nishimura ,&nbsp;Asami Nishikori ,&nbsp;Michael V. Gonzalez ,&nbsp;Daisuke Ennishi ,&nbsp;You Cheng Lai ,&nbsp;Sayaka Ochi ,&nbsp;Manaka Tsunoda ,&nbsp;David C. Fajgenbaum ,&nbsp;Frits van Rhee ,&nbsp;Shuji Momose ,&nbsp;Yasuharu Sato","doi":"10.1016/j.modpat.2025.100782","DOIUrl":"10.1016/j.modpat.2025.100782","url":null,"abstract":"<div><div>Idiopathic multicentric Castleman disease is a rare lymphoproliferative disorder that is clinically classified into idiopathic plasmacytic lymphadenopathy (IPL); thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO); and not otherwise specified (NOS). Although each subtype shows varying degrees of hypervascularity, no statistical data on the degree of vascularization have been reported. Additionally, the mechanisms underlying vascularization in each clinical subtype are poorly understood. Here, we aimed to clarify these mechanisms by evaluating the histopathological characteristics of each clinical subtype across 37 patients and performing a whole-transcriptome analysis focusing on angiogenesis-related gene expression. Histologically, TAFRO and NOS exhibited a significantly higher degree of vascularization than IPL (IPL vs TAFRO, <em>P</em> &lt; .001; IPL vs NOS, <em>P</em> = .002). In addition, the germinal centers (GCs) were significantly more atrophic in TAFRO than in IPL. In TAFRO and NOS, “whirlpool vessels” in GCs were seen in most cases (TAFRO, 9/9, 100%; NOS, 6/8, 75%) but not in IPL (IPL vs TAFRO, <em>P</em> &lt; .001; IPL vs NOS, <em>P</em> = .007). Likewise, immunostaining for Ets-related gene revealed higher levels in endothelial cells of GCs in TAFRO than in IPL (<em>P</em> = .014), and TAFRO and NOS were associated with a significantly higher number of endothelial cells in interfollicular areas compared with that in IPL (TAFRO vs IPL, <em>P</em> &lt; .001; NOS vs IPL, <em>P</em> = .002). Gene expression analysis revealed that the PI3K–Akt signaling pathway was significantly enriched in the TAFRO and NOS (TAFRO/NOS) groups. This pathway, which may be activated by vascular endothelial growth factor A and some integrins, is known to affect angiogenesis by increasing vascular permeability, which may explain the clinical manifestations of anasarca and/or fluid retention in TAFRO/NOS. These results suggest that the PI3K–Akt pathway plays an important role in the pathogenesis of TAFRO/NOS.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 8","pages":"Article 100782"},"PeriodicalIF":7.1,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143941834","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":"Incidence, Clinicopathologic Features, and Follow-Up Results of human epidermal growth factor receptor-2–Ultralow Breast Carcinoma","authors":"Yan Hu,&nbsp;Daniel Jones,&nbsp;Weiqiang Zhao,&nbsp;Gary Tozbikian,&nbsp;Anil V. Parwani,&nbsp;Zaibo Li","doi":"10.1016/j.modpat.2025.100783","DOIUrl":"10.1016/j.modpat.2025.100783","url":null,"abstract":"<div><div>The preliminary result of DESTINY-Breast06 trial demonstrated the effectiveness of antibody-drug conjugate in patients with human epidermal growth factor receptor-2 (HER2)–ultralow breast carcinoma (BC), defined by the presence of ≤10% of infiltrating cancer cells showing incomplete and faint/weak membrane staining on HER2 immunohistochemistry. In this study, we investigated the pathologic features and clinical outcomes in patients with HER2-ultralow, HER2-null, and HER2-low expression. The incidence of HER2 ultralow was 17.5% (260/1486). The incidence of other groups is as follows: 7.7% for HER2 null, 56.8% for HER2 low, and 18% for HER2 positive. HER2-ultralow cases showed similarity to HER2-low cases but a significant difference from HER2-null cases, including older age (61.1 vs 57.3 years; <em>P</em> = .0099), fewer grade 3 BCs (18.1% vs 53.9%; <em>P</em> &lt; .0001), triple-negative BCs (16.2% vs 42.6%; <em>P</em> &lt; .0001), estrogen receptor (ER)–negative BCs (16.5% vs 47.8%; <em>P</em> &lt; .0001), and progesterone receptor–negative BCs (26.2% vs 54.8%; <em>P</em> &lt; .0001). When cases were stratified based on ER positivity, these differences between HER2-null and HER2-ultralow groups were confined to ER+ but not ER− cases. There were no discernible differences in response to neoadjuvant chemotherapy (n = 125) among HER2-null, HER2-ultralow, and HER2-low BCs. HER2-null/ER−BCs displayed a lower probability of overall survival than HER2-ultralow and HER2-low/ER−BCs, but no statistically significant difference was observed in disease-free survival among the 3 groups. HER2-ultralow BCs exhibit distinct features that align more closely with HER2-low BCs than HER2-null BCs. These findings contribute to the evolving classification of HER2 expression in BC and may have implications for refining treatment strategies in this subgroup.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 8","pages":"Article 100783"},"PeriodicalIF":7.1,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143941835","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}