Modern Pathology最新文献

{"title":"Spatial Expression of HER2, NECTIN4, and TROP-2 in Muscle-Invasive Bladder Cancer and Metastases: Implications for Pathological and Clinical Management","authors":"Gabriel Dernbach ,&nbsp;Marie-Lisa Eich ,&nbsp;Mihnea P. Dragomir ,&nbsp;Philipp Anders ,&nbsp;Nadia Jurczok ,&nbsp;Christian Stief ,&nbsp;Philipp Jurmeister ,&nbsp;Thorsten Schlomm ,&nbsp;Frederick Klauschen ,&nbsp;David Horst ,&nbsp;Gerald Bastian Schulz ,&nbsp;Simon Schallenberg","doi":"10.1016/j.modpat.2025.100753","DOIUrl":"10.1016/j.modpat.2025.100753","url":null,"abstract":"<div><div>Muscle-invasive bladder cancer (MIBC) presents significant treatment challenges. Antibody–drug conjugates targeting human epidermal growth factor receptor 2 (HER2), trophoblast cell surface antigen 2 (TROP-2), and nectin cell adhesion molecule 4 (NECTIN4) offer promising therapeutic options. This study examined the spatial expression of HER2, TROP-2, and NECTIN4 in MIBC and metastases, their association with molecular subtypes, and clinical outcomes.</div><div>Formalin-fixed, paraffin-embedded tissue samples from 251 patients with MIBC were analyzed using immunohistochemistry and tissue microarray analysis. Expression patterns between the tumor front and tumor center (TC) were compared, and statistical analyses assessed associations with molecular subtypes and clinical parameters. Additionally, 67 matched lymph node metastases and a secondary cohort comprising 16 distant metastases, including 7 matched primary tumors, were examined to explore the expression patterns in advanced tumor stages.</div><div>In primary tumors, HER2 was predominantly negative (83%) but showed higher positivity in the TC. TROP-2 exhibited high overall expression (58% score 3+), whereas NECTIN4 displayed significant heterogeneity with stronger expression in the TC. Spatial overexpression of TROP-2 and NECTIN4 at the tumor front relative to the TC was associated with a better disease-free survival. Accurate assessment required 4 biopsies for HER2 and NECTIN4 and 3 for TROP-2. HER2 expression was associated with urothelial-like and genomically unstable molecular subtypes, whereas TROP-2 was widely expressed except in the mesenchymal-like subtype. NECTIN4 showed the absence of staining in basal, Mes-like, and Sc/NEC-like subtypes.</div><div>Paired lymph node metastases showed higher expression scores for all 3 markers, whereas distant metastases showed reduced NECTIN4 expression. Additionally, lymph node metastases revealed a considerable heterogeneity for HER2 compared with their matched primary tumors.</div><div>The spatial heterogeneity of HER2, TROP-2, and NECTIN4 expression necessitates multiple biopsies, particularly from the TC, for accurate evaluation. These findings underscore the need for personalized treatment strategies in MIBC, considering the increased risk of relapse associated with HER2 and NECTIN4 overexpression in the TC. Implementing a multibiopsy approach is critical to enhancing diagnostic accuracy.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 7","pages":"Article 100753"},"PeriodicalIF":7.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Deep Learning Model of Histologic Tumor Differentiation as a Prognostic Tool in Hepatocellular Carcinoma","authors":"Ameya Patil ,&nbsp;Bashar Hasan ,&nbsp;Byoung Uk Park ,&nbsp;Lindsey Smith ,&nbsp;Priya Sivasubramaniam ,&nbsp;Rofyda Elhalaby ,&nbsp;Nada Elessawy ,&nbsp;Saadiya Nazli ,&nbsp;Adilson DaCosta ,&nbsp;Abdelrahman Shabaan ,&nbsp;Andrew Cannon ,&nbsp;Chun Lau ,&nbsp;Christopher P. Hartley ,&nbsp;Rondell P. Graham ,&nbsp;Roger K. Moreira","doi":"10.1016/j.modpat.2025.100747","DOIUrl":"10.1016/j.modpat.2025.100747","url":null,"abstract":"<div><div>Tumor differentiation represents an important driver of the biological behavior of various forms of cancer. Histologic features of tumor differentiation in hepatocellular carcinoma (HCC) include cytoarchitecture, immunohistochemistry profile, and reticulin framework. In this study, we evaluate the performance of an artificial intelligence (AI)–based model in quantifying features of HCC tumor differentiation and predicting cancer-related outcomes. We developed a supervised AI model using a cloud-based, deep learning platform to quantify histologic features of HCC differentiation, including various morphologic parameters (nuclear density, area, circularity, chromatin pattern, and pleomorphism), mitotic figures, immunohistochemistry markers (HepPar 1 and glypican-3), and reticulin expression. We applied this AI model to patients undergoing HCC curative resection and assessed whether AI-based features added value to standard clinical and pathologic data in predicting HCC-related outcomes. Ninety-nine HCC resection specimens were included. Three AI-based histologic variables were most relevant to HCC prognostic assessment: (1) percentage of tumor occupied by neoplastic nuclei (nuclear area percent), (2) quantitative reticulin expression in the tumor, and (3) HepPar 1 low (ie, expressed in &lt;50% of the tumor)/glypican-3–positive immunophenotype. Statistical models that included these AI-based variables outperformed models with combined clinical pathologic features for overall survival (C-indexes of 0.81 vs 0.68), disease-free survival (C-indexes of 0.73 vs 0.68), metastasis (C-indexes of 0.78 vs 0.65), and local recurrence (C-indexes of 0.72 vs 0.68) for all cases, with similar results in the subgroup analysis of World Health Organization grade 2 HCCs. Our AI model serves as a proof of concept that HCC differentiation can be objectively quantified digitally by assessing a combination of biologically relevant histopathologic features. In addition, several AI-derived features were independently predictive of HCC-related outcomes in our study population, most notably nuclear area percent, hepar-low/glypican-3–negative phenotype, and decreasing levels of reticulin expression, highlighting the relevance of quantitative analysis of tumor differentiation features in this context.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 7","pages":"Article 100747"},"PeriodicalIF":7.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pan-Cancer Molecular Biomarkers: Practical Considerations for the Surgical Pathologist","authors":"Pari Jafari,&nbsp;Megan Forrest,&nbsp;Jeremy Segal,&nbsp;Peng Wang,&nbsp;Melissa Yuwono Tjota","doi":"10.1016/j.modpat.2025.100752","DOIUrl":"10.1016/j.modpat.2025.100752","url":null,"abstract":"<div><div>Traditional anatomic pathologic classification of cancer is based on tissue of origin and morphologic and immunohistochemical characterization of the malignant cells. With the technological improvements of massively parallel or next-generation sequencing, oncogenic drivers that are shared across different tumor types are increasingly being identified and used as pan-cancer biomarkers. This approach is reflected in the growing list of Food and Drug Administration-approved tumor-agnostic therapies, including pembrolizumab in the setting of microsatellite instability and high tumor mutational burden, larotrectinib and entrectinib for solid tumors with <em>NTRK</em> fusions, and combined dabrafenib-trametinib for <em>BRAF</em> V600E-mutated neoplasms. Several other biomarkers are currently under investigation, including fibroblast growth factor receptor (<em>FGFR</em>), <em>RET</em>, and <em>ROS1</em> fusions; <em>ERBB2</em> amplification; and mutations in the <em>AKT1/2/3</em>, <em>NF1</em>, <em>RAS</em> pathway and (mitogen-activated protein kinase (<em>MAPK</em>) pathway. As molecular assays are increasingly incorporated into routine tumor workup, the emergence of additional pan-cancer biomarkers is likely to be a matter more of “when” than “if.” In this review, we first explore some of the conceptual and technical considerations at the intersection of surgical and molecular pathology, followed by a brief overview of both established and emerging molecular pan-cancer biomarkers and their diagnostic and clinical applications.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 6","pages":"Article 100752"},"PeriodicalIF":7.1,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Multicenter Study on Intraoperative Glioma Grading via Deep Learning on Cryosection Pathology","authors":"Xi Liu ,&nbsp;Tianyang Sun ,&nbsp;Hong Chen ,&nbsp;Shuai Wu ,&nbsp;Haixia Cheng ,&nbsp;Xiaojia Liu ,&nbsp;Qi Lai ,&nbsp;Kun Wang ,&nbsp;Lin Chen ,&nbsp;Junfeng Lu ,&nbsp;Jun Zhang ,&nbsp;Yaping Zou ,&nbsp;Yi Chen ,&nbsp;Yingchao Liu ,&nbsp;Feng Shi ,&nbsp;Lei Jin ,&nbsp;Dinggang Shen ,&nbsp;Jinsong Wu","doi":"10.1016/j.modpat.2025.100749","DOIUrl":"10.1016/j.modpat.2025.100749","url":null,"abstract":"<div><div>Intraoperative glioma grading remains a significant challenge primarily due to the diminished diagnostic attributable to the suboptimal quality of cryosectioned slides. Precise intraoperative diagnosis is instrumental in guiding the surgical strategy to balance resection extent and neurologic function preservation, thereby optimizing patient prognoses. This study developed a model for intraoperative glioma grading via deep learning on cryosectioned images, termed intraoperative glioma grading on cryosection (IGGC). The model was trained and validated on The Cancer Genome Atlas data sets and 1 cohort (<span><math><mrow><msub><mi>n</mi><mrow><mi>t</mi><mi>r</mi><mi>a</mi><mi>i</mi><mi>n</mi></mrow></msub></mrow></math></span> = 1603 and <span><math><mrow><msub><mi>n</mi><mrow><mi>v</mi><mi>a</mi><mi>l</mi><mi>i</mi><mi>d</mi><mi>a</mi><mi>t</mi><mi>e</mi></mrow></msub></mrow></math></span> = 628), and tested on 5 cohorts (<span><math><mrow><msub><mi>n</mi><mrow><mi>t</mi><mi>e</mi><mi>s</mi><mi>t</mi></mrow></msub></mrow></math></span> = 213). The IGGC model achieved an area under the receiver operating characteristic curve value of 0.99 in differentiating between high-grade glioma and low-grade glioma, and an area under the receiver operating characteristic curve value of 0.96 in identifying grade 4 glioma. Integrated into the clinical workflow, the IGGC model-assisted pathologists of varying experience levels in reducing interobserver variability and enhancing diagnostic consistency. This integrated diagnostic model possesses the potential for clinical implementation, offering a time-efficient and highly accurate method for the 3-grade classification of adult-type diffuse gliomas based on intraoperative cryosectioned slides.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 7","pages":"Article 100749"},"PeriodicalIF":7.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The MEF2D::NCOA2 Fusion Defines a Distinct Emerging Vulvovaginal Myxoid Epithelioid Tumor With Smooth Muscle Differentiation","authors":"Alexis Trecourt ,&nbsp;Guillaume Bataillon ,&nbsp;François Le Loarer ,&nbsp;Marie Donzel ,&nbsp;Eudeline Alix ,&nbsp;Françoise Descotes ,&nbsp;Jonathan Lopez ,&nbsp;Brice Thamphya ,&nbsp;Daniel Pissaloux ,&nbsp;Isabelle Treilleux ,&nbsp;Sabrina Croce ,&nbsp;Mojgan Devouassoux-Shisheboran","doi":"10.1016/j.modpat.2025.100750","DOIUrl":"10.1016/j.modpat.2025.100750","url":null,"abstract":"<div><div>Myocyte-specific enhancer factor 2D gene and nuclear receptor coactivator 2 gene fusion (<em>MEF2D::NCOA2</em>) was recently reported in 2 vulvovaginal myxoid epithelioid smooth muscle tumors. We aimed to perform an integrated approach combining clinical, morphologic, immunohistochemical, and molecular profiling analyses, including targeted RNA sequencing, targeted gene expression analysis profiling with clustering, DNA mutational analysis, and array comparative genomic hybridization in a series of 3 <em>MEF2D::NCOA2</em> fusion–associated vulvovaginal tumors, to better describe this entity. The median age at diagnosis was 45 years. Tumors were well circumscribed and located deeply within the vulva, vaginal wall, or between the bladder and the vagina (1/3, 33.3% each). The median size of tumors was 2.5 cm. All tumors had a similar morphology, reminiscent of smooth muscle tumor with prominent myxoid stromal changes (3/3, 100%). Tumor cells were haphazardly arranged in short fascicles and were mostly spindle cells. Microcystic spaces lined by epithelioid cells and/or sheets of epithelioid cells were observed in all tumors (3/3, 100%), associated with a myxoid background. Cytologic atypia was none to mild, and the mitotic counts were always low (≤1 mitosis/high-power fields). Immunohistochemistry found smooth muscle actin, desmin, h-caldesmon, estrogen receptors, and CD34 to be intensely and diffusely expressed in all tumors (3/3, 100%). A <em>MEF2D::NCOA2</em> transcript was observed in all tumors (3/3, 100%), which was the driver of molecular alteration. No pathogenic variants were found, and array comparative genomic hybridization found simple genomic profiles for all tumors (3/3, 100%). On targeted gene expression analysis, <em>MEF2D::NCOA2</em> fusion–associated tumors clustered distinctly from other gynecologic mimickers and neoplasms with myxoid stromal changes (vulvovaginal leiomyomas, myxoid vulvovaginal leiomyomas, deep angiomyxomas, myxoid leiomyosarcomas, myxoid endometrial stromal sarcomas, and inflammatory myofibroblastic tumors). The signaling pathways involved in this entity included the expression of genes encoding smooth muscle phenotype proteins, favoring a smooth muscle (myoid) differentiation. All patients were alive and free of disease at the last follow-up. To conclude, vulvovaginal <em>MEF2D::NCOA2</em> fusion–associated tumors are distinct and emerging entities, with a rather indolent behavior.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 6","pages":"Article 100750"},"PeriodicalIF":7.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Characterization of TFE3-Rearranged Renal Cell Carcinoma in Children and Adolescents","authors":"Haoyang Liu ,&nbsp;Haolin Liu ,&nbsp;Junru Chen ,&nbsp;Xiaoxue Yin ,&nbsp;Sha Zhu ,&nbsp;Xu Hu ,&nbsp;Yanfeng Tang ,&nbsp;Sike He ,&nbsp;Junjie Zhao ,&nbsp;Xingming Zhang ,&nbsp;Jiayu Liang ,&nbsp;Jinge Zhao ,&nbsp;Jingjing Guo ,&nbsp;Nanshan Yang ,&nbsp;Ling Nie ,&nbsp;Zhenhua Liu ,&nbsp;Ni Chen ,&nbsp;Pengfei Shen ,&nbsp;Xiaoxi Zeng ,&nbsp;Yuntian Chen ,&nbsp;Guangxi Sun","doi":"10.1016/j.modpat.2025.100748","DOIUrl":"10.1016/j.modpat.2025.100748","url":null,"abstract":"<div><div><em>TFE</em>3-rearranged renal cell carcinoma (<em>TFE3</em>-RCC) is a rare but aggressive subtype of kidney cancer that mainly affects young patients. However, the molecular characteristics of <em>TFE3</em>-RCCs in children and adolescents remain poorly understood. To this end, we performed a comprehensive study to characterize the genomic and transcriptional profiles of pediatric/adolescent <em>TFE3</em>-RCCs and compare them with those of adult tumors. In this study, 17 pediatric/adolescent patients with <em>TFE3</em>-RCC who underwent kidney surgery between 2009 and 2023 were selected from our multicenter <em>TFE3</em>-RCC database (n = 118). Whole-exome and RNA sequencing were performed on untreated primary tumor tissues. Detailed clinicopathological data and patient follow-up information were collected for analysis. <em>ASPSCR1::TFE3</em> fusion was the most common fusion subtype in pediatric/adolescent patients. Tumors with <em>ASPSCR1::TFE3</em> fusion developed at a younger age compared with those with other fusion subtypes (median age: 21 years vs 39 years, <em>P</em> &lt; .001). Pediatric/adolescent <em>TFE3</em>-RCCs demonstrated similar genomic features and survival outcomes to those in adults. Similar to adult tumors, pediatric/adolescent <em>TFE3</em>-RCCs with <em>ASPSCR1::TFE3</em> fusion displayed higher expression of angiogenesis, proliferation, and stroma gene signatures and responded favorably to anti-PD1 plus tyrosine kinase inhibitor combination therapy. This study provides comprehensive insights into the genomic and transcriptional features of pediatric/adolescent <em>TFE3</em>-RCCs, suggesting the importance of transcriptional signatures and the potential therapeutic strategies tailored for this population.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 6","pages":"Article 100748"},"PeriodicalIF":7.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586305","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":"Cover","authors":"","doi":"10.1016/j.modpat.2025.100745","DOIUrl":"10.1016/j.modpat.2025.100745","url":null,"abstract":"","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 3","pages":"Article 100745"},"PeriodicalIF":7.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143643228","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":"Clinicopathological Predictors of the Presence of Blood Circulating Tumor DNA in Early-Stage Non–Small Cell Lung Cancers","authors":"Arnaud Driussi ,&nbsp;Fabien C. Lamaze ,&nbsp;Manal Kordahi ,&nbsp;Victoria Saavedra Armero ,&nbsp;Nathalie Gaudreault ,&nbsp;Michèle Orain ,&nbsp;William Enlow ,&nbsp;Chris Abbosh ,&nbsp;Darren Hodgson ,&nbsp;Abhijit Dasgupta ,&nbsp;Andréanne Gagné ,&nbsp;Yohan Bossé ,&nbsp;Philippe Joubert","doi":"10.1016/j.modpat.2025.100744","DOIUrl":"10.1016/j.modpat.2025.100744","url":null,"abstract":"<div><div>The implementation of lung cancer screening programs across the world has drawn considerable attention to improving early-stage lung cancer detection and prognostication. Several blood-based assays detecting circulating tumor DNA (ctDNA) recently emerged as noninvasive methods to detect malignancies. However, their limited sensitivity and predictive value remain a hurdle to their clinical use. We aimed to evaluate the association between clinicopathological parameters and presurgical ctDNA detection in clinical stage I non–small cell lung cancer patients to further understand ctDNA shedding biology. The cohort included 180 adenocarcinomas (LUAD) and 80 squamous cell carcinomas (LUSC) stage I patients who underwent lung cancer resection. Patients’ clinical and pathological features were collected. A multicancer early-detection test (GRAIL LLC) was used to detect ctDNA using targeted methylation patterns. The association between the cell-free DNA tumor methylated fraction (TMeF) and the clinicopathological predictors was evaluated using univariate and multivariate modeling. LUSC was associated with a higher TMeF than LUAD. Pathological stage, tumor grade, and tumor volume were key determinants of ctDNA detection in both LUSC and LUAD. In LUAD, ctDNA detection also correlated with histologic pattern composition, necrosis, acute inflammation, and, to a lesser degree, spread through alveolar spaces and lymphovascular invasion. Based on our results, we propose classification methods for both LUAD (using histologic pattern composition) and LUSC (using tumor grade and pathological stage) to identify patients likely to have high ctDNA levels. These results confirm previous findings and suggest that previously unidentified factors, including histologic pattern composition and acute inflammation, influence ctDNA levels. These results will help in understanding the ctDNA shedding process and may allow identification of patients eligible for ctDNA detection–based follow-up.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 6","pages":"Article 100744"},"PeriodicalIF":7.1,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Consistent Patterns of Immune-Related Adverse Events in Postmortem and Real-World Data on Immune Checkpoint Inhibitors","authors":"Connor Frey","doi":"10.1016/j.modpat.2025.100730","DOIUrl":"10.1016/j.modpat.2025.100730","url":null,"abstract":"","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 4","pages":"Article 100730"},"PeriodicalIF":7.1,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143480264","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":"Prostate Ductal Adenocarcinoma Revisited: Clinicopathological and Genomic Characterization Identifies Heterogenous Group of Diseases with Implications for Patient Management","authors":"Qi Cai ,&nbsp;Xiaosong Meng ,&nbsp;Jing Sun ,&nbsp;Jeffrey Gagan ,&nbsp;Aditi Aggarwal ,&nbsp;Anas M. Khanshour ,&nbsp;Raj Bhanvadia ,&nbsp;Jing Xu ,&nbsp;Sambit K. Mohanty ,&nbsp;Rajal B. Shah","doi":"10.1016/j.modpat.2025.100743","DOIUrl":"10.1016/j.modpat.2025.100743","url":null,"abstract":"<div><div>Prostate ductal adenocarcinoma (PDA) is an aggressive subtype of prostate adenocarcinoma (PA). It can be found either in the peripheral zone, typically associated with acinar PA, or centrally in or around the verumontanum as a urethral polyp. Whether centrally occurring PDAs are biologically and genetically different compared with peripheral PDA remains unknown. Thirty-five PDAs diagnosed on resection specimens were categorized into 3 groups based on PDA location (central [urethra] involvement only [PDA-C], both central and peripheral involvement [PDA-C&amp;P], peripheral involvement only [PDA-P]) and analyzed for clinicopathological, genomic characteristics, and outcomes. Targeted next-generation DNA and RNA sequencing with full exon coverage of 1425 cancer-related genes was performed on 2 PDA-C, 8 PDA-C&amp;P, and 12 PDA-P with a grossly dissectible population of viable PDA. In 11 PDA-P, the same patients' ductal and associated acinar components were sequenced separately. Of 35 PDAs, 2 (6%), 11 (31%), and 22 (63%) were PDA-C, PDA-C&amp;P, and PDA-P, respectively. PDA-C&amp;P compared with PDA-P presented with larger tumor size (median 45 mm vs 25 mm), % ductal component (100% vs 30%), ≥ pT3 disease (100% vs 64%), visceral metastasis (36% vs 0%), and cancer-specific mortality (27% vs 0%) (<em>P</em> &lt; .05) and enrichment for at least 1 DNA damage and repair (DDR)-related gene alterations (<em>BRCA2</em>, <em>ATM</em>, <em>CDK12</em>, <em>ERCC2</em>) (63% vs 8%), and PI3K pathway alterations (37% vs none). PDA-Ps were enriched in <em>FOXA1</em> alterations compared with PDA-C&amp;P (75% vs 25%) including 5 (56%) having <em>FOXA1</em> mutation in only ductal components. <em>TMPRSS2::ERG</em> fusion was present in only 1 patient with PDA-P in both ductal and acinar components. One patient with PDA-C and 3 with PDA-C&amp;P exhibited novel gene fusion <em>ACPP::FGFR2</em> and <em>NF1::ADAP</em>, <em>FGFR2::POC1B</em>, and <em>RB1:TT</em><em>T</em><em>Y3</em>, respectively. In 2 patients with PDA-C, PDA was eradicated in transurethral resection with no residual disease in follow-up radical prostatectomy. PDA-C lacked alterations in DDR genes. Our findings suggest that PDAs are clinically and genetically heterogeneous diseases. Understanding the heterogeneity of PDA is critically important in determining its biological potential and facilitating optimal patient management.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 6","pages":"Article 100743"},"PeriodicalIF":7.1,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523849","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}