{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:44:43Z","timestamp":1760060683023,"version":"build-2065373602"},"reference-count":38,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T00:00:00Z","timestamp":1757635200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/NCI","award":["5R01CA293380"],"award-info":[{"award-number":["5R01CA293380"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Effusion-based lymphoma (EBL) is a rare and aggressive large B-cell lymphoma. It presents as a body cavity effusion without a solid mass, lacks HHV-8 association, and typically expresses CD20. Objectives: To better understand the biology of this entity, we performed transcriptomic profiling of eight EBL cases. Methods: We analyzed the cases with the NanoString PanCancer Immune Profiling Panel and compared the results with publicly available datasets representing follicular lymphoma (FL), mantle cell lymphoma (MCL), and large B-cell lymphoma (LBCL) subtypes. Results: Unsupervised clustering and differential expression analysis revealed that EBL cases cluster transcriptionally with the LBCL group. Lymphoma-specific signaling pathway enrichment (SignatureDB) predominantly identified non-germinal center (activated B-cell-type) pathways. In addition, KEGG pathway analyses revealed enrichment in specific inflammatory and immune response pathways that are associated with B-cell lymphoma development in the setting of chronic inflammation, including those linked to Toll-like receptor and NF-\u03baB signaling. Conclusions: These findings support a post-germinal center origin for EBL, which arises in a background of chronic inflammation and persistent antigen stimulation.<\/jats:p>","DOI":"10.3390\/cancers17182978","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T07:52:28Z","timestamp":1757663548000},"page":"2978","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Transcriptional Analysis of Effusion-Based Lymphoma Supports a Post-Germinal Center Origin and Specific Inflammatory Signal Background"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9129-3221","authenticated-orcid":false,"given":"Vanessa","family":"Perez-Silos","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Illinois Chicago, Chicago, IL 60607, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2713-4207","authenticated-orcid":false,"given":"Hojung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Illinois Chicago, Chicago, IL 60607, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9082-2117","authenticated-orcid":false,"given":"Chenguang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5314-8469","authenticated-orcid":false,"given":"Alejandro","family":"Zevallos-Morales","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Illinois Chicago, Chicago, IL 60607, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony","family":"Tipton","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Illinois Chicago, Chicago, IL 60607, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9093-4303","authenticated-orcid":false,"given":"Pierina","family":"Danos-Diaz","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Illinois Chicago, Chicago, IL 60607, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6420-0760","authenticated-orcid":false,"given":"Ryan","family":"Wilcox","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6747-680X","authenticated-orcid":false,"given":"Nathanael","family":"Bailey","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nidhi","family":"Aggarwal","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Savanah Dior","family":"Gisriel","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Wisconsin, Madison, WI 53705, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8814-5660","authenticated-orcid":false,"given":"Alexandria","family":"Smith-Hannah","sequence":"additional","affiliation":[{"name":"Department of Pathology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mina","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yale University, New Haven, CT 06520, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2394-7323","authenticated-orcid":false,"given":"John Karl","family":"Frederiksen","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Illinois Chicago, Chicago, IL 60607, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2238-5066","authenticated-orcid":false,"given":"Carlos","family":"Murga-Zamalloa","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Illinois Chicago, Chicago, IL 60607, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1038\/s41379-022-01091-x","article-title":"Human herpesvirus 8-negative effusion-based large B-cell lymphoma: A distinct entity with unique clinicopathologic characteristics","volume":"35","author":"Gisriel","year":"2022","journal-title":"Mod. Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.jasc.2014.10.002","article-title":"HHV8-negative effusion based lymphoma: A series of 17 cases at a single institution","volume":"4","author":"Usmani","year":"2015","journal-title":"J. Am. Soc. Cytopathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1182\/blood-2013-11-536433","article-title":"Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue","volume":"123","author":"Scott","year":"2014","journal-title":"Blood"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1159\/000097460","article-title":"Comparison of Human Herpes Virus 8 Related Primary Effusion Lymphoma with Human Herpes Virus 8 Unrelated Primary Effusion Lymphoma-Like Lymphoma on the Basis of HIV: Report of 2 Cases and Review of 212 Cases in the Literature","volume":"117","author":"Kobayashi","year":"2006","journal-title":"Acta Haematol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4442","DOI":"10.1182\/bloodadvances.2020002293","article-title":"Primary human herpesvirus 8\u2013negative effusion-based lymphoma: A large B-cell lymphoma with favorable prognosis","volume":"4","author":"Kaji","year":"2020","journal-title":"Blood Adv."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1097\/PAS.0000000000001168","article-title":"Age and CD20 Expression Are Significant Prognostic Factors in Human Herpes Virus-8-negative Effusion-based Lymphoma","volume":"42","author":"Kubota","year":"2018","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1309\/AJCPHZ3CHO4HUWET","article-title":"Human Herpesvirus 8\u2013Unrelated Primary Effusion Lymphoma\u2013Like Lymphoma","volume":"140","author":"Wu","year":"2013","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1097\/PAS.0b013e318267fabc","article-title":"KSHV\/HHV8-negative Effusion-based Lymphoma, a Distinct Entity Associated With Fluid Overload States","volume":"37","author":"Alexanian","year":"2013","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1182\/blood-2017-12-822171","article-title":"Aggressive genomic features in clinically indolent primary HHV8-negative effusion-based lymphoma","volume":"133","author":"Mendeville","year":"2019","journal-title":"Blood"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"102656","DOI":"10.1155\/2015\/102656","article-title":"Molecular Pathogenesis of MALT Lymphoma","volume":"2015","author":"Troppan","year":"2015","journal-title":"Gastroenterol. Res. Pract."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.3324\/haematol.2009.005983","article-title":"Chronic inflammatory disease, lymphoid tissue neogenesis and extranodal marginal zone B-cell lymphomas","volume":"94","author":"Bende","year":"2009","journal-title":"Haematologica"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"110476","DOI":"10.1016\/j.clim.2025.110476","article-title":"Diffuse large B cell lymphoma in rheumatoid arthritis patients is associated with elevated B-cell driving factors including CXCL13","volume":"275","author":"Euler","year":"2025","journal-title":"Clin. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3774","DOI":"10.1002\/art.22277","article-title":"Characteristics of diffuse large B cell lymphomas in rheumatoid arthritis","volume":"54","author":"Baecklund","year":"2006","journal-title":"Arthritis Rheum."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1002\/art.21675","article-title":"Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis","volume":"54","author":"Baecklund","year":"2006","journal-title":"Arthritis Rheum."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"156289","DOI":"10.1016\/j.cyto.2023.156289","article-title":"Cytokine profiles in patients with newly diagnosed diffuse large B-cell lymphoma: IL-6 and IL-10 levels are associated with adverse clinical features and poor outcomes","volume":"169","author":"Bao","year":"2023","journal-title":"Cytokine"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"185","DOI":"10.3109\/10428190109057969","article-title":"Primary Effusion Lymphoma in an Hiv-Negative Patient with No Serologic Evidence of Kaposi's Sarcoma Virus","volume":"41","author":"Rodriguez","year":"2001","journal-title":"Leuk. Lymphoma"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1007\/BF02982069","article-title":"Human Herpes Virus 8-Negative Primary Effusion Lymphoma in a Patient With a Ventriculoperitoneal Shunt Tube","volume":"74","author":"Ashihara","year":"2001","journal-title":"Int. J. Hematol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.cell.2017.09.027","article-title":"Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma","volume":"171","author":"Reddy","year":"2017","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1200\/JCO.18.01583","article-title":"Double-Hit Gene Expression Signature Defines a Distinct Subgroup of Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma","volume":"37","author":"Ennishi","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/j.ccell.2020.03.015","article-title":"A Probabilistic Classification Tool for Genetic Subtypes of Diffuse Large B Cell Lymphoma with Therapeutic Implications","volume":"37","author":"Wright","year":"2020","journal-title":"Cancer Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1038\/s41375-023-02120-7","article-title":"Genetic and transcriptomic analyses of diffuse large B-cell lymphoma patients with poor outcomes within two years of diagnosis","volume":"38","author":"Ren","year":"2023","journal-title":"Leukemia"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"9991","DOI":"10.1073\/pnas.1732008100","article-title":"A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma","volume":"100","author":"Wright","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"EdgeR: A Bioconductor package for differential expression analysis of digital gene expression data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"D\u2019aNgelo, A., Kilili, H., Chapman, R., Generali, D., Tinhofer, I., Luminari, S., Donati, B., Ciarrocchi, A., Giannini, R., and Moretto, R. (2023). Immune-related pan-cancer gene expression signatures of patient survival revealed by NanoString-based analyses. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0280364"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3292","DOI":"10.1038\/s41596-024-01020-z","article-title":"Using clusterProfiler to characterize multiomics data","volume":"19","author":"Xu","year":"2024","journal-title":"Nat. Protoc."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"102030","DOI":"10.1016\/j.xcrm.2025.102030","article-title":"Practical microenvironment classification in diffuse large B cell lymphoma using digital pathology","volume":"6","author":"Wang","year":"2025","journal-title":"Cell Rep. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2202","DOI":"10.1182\/blood.2020010527","article-title":"SOX11, CD70, and Treg cells configure the tumor immune microenvironment of aggressive mantle cell lymphoma","volume":"138","author":"Balsas","year":"2021","journal-title":"Blood"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Care, M.A., Barrans, S., Worrillow, L., Jack, A., Westhead, D.R., Tooze, R.M., and Richards, K.L. (2013). A Microarray Platform-Independent Classification Tool for Cell of Origin Class Allows Comparative Analysis of Gene Expression in Diffuse Large B-cell Lymphoma. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0055895"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1158\/2159-8290.CD-22-0561","article-title":"An Aged\/Autoimmune B-cell Program Defines the Early Transformation of Extranodal Lymphomas","volume":"13","author":"Venturutti","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Zhou, X., Guo, S., and Shi, Y. (2022). Comprehensive analysis of the expression and significance of CXCLs in human diffuse large B-cell lymphoma. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-06877-2"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1007\/s00296-020-04524-5","article-title":"Serum CXCL13 levels are associated with lymphoma risk and lymphoma occurrence in primary Sj\u00f6gren\u2019s syndrome","volume":"40","author":"Registry","year":"2020","journal-title":"Rheumatol. Int."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/j.biopha.2018.07.171","article-title":"CXCL9 promotes the progression of diffuse large B-cell lymphoma through up-regulating \u03b2-catenin","volume":"107","author":"Ruiduo","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"8872","DOI":"10.1080\/21655979.2021.1987820","article-title":"Neutrophils correlate with hypoxia microenvironment and promote progression of non-small-cell lung cancer","volume":"12","author":"Zhang","year":"2021","journal-title":"Bioengineered"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4413","DOI":"10.1007\/s10238-023-01152-8","article-title":"CXCL6: A potential therapeutic target for inflammation and cancer","volume":"23","author":"Dai","year":"2023","journal-title":"Clin. Exp. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1158\/0008-5472.CAN-16-0786","article-title":"CXCL-8\/IL8 Produced by Diffuse Large B-cell Lymphomas Recruits Neutrophils Expressing a Proliferation-Inducing Ligand APRIL","volume":"77","author":"Manfroi","year":"2017","journal-title":"Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1038\/s41408-018-0099-y","article-title":"Tumor-associated neutrophils correlate with poor prognosis in diffuse large B-cell lymphoma patients","volume":"8","author":"Manfroi","year":"2018","journal-title":"Blood Cancer J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.ajpath.2023.10.008","article-title":"Specific Polo-Like Kinase 1 Expression in Nodular Lymphocyte-Predominant Hodgkin Lymphoma Suggests an Intact Immune Surveillance Program","volume":"194","author":"Weiss","year":"2023","journal-title":"Am. J. Pathol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1038\/nm.2328","article-title":"Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression","volume":"17","author":"Bissell","year":"2011","journal-title":"Nat. Med."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/18\/2978\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:44:17Z","timestamp":1760035457000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/18\/2978"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,12]]},"references-count":38,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["cancers17182978"],"URL":"https:\/\/doi.org\/10.3390\/cancers17182978","relation":{},"ISSN":["2072-6694"],"issn-type":[{"type":"electronic","value":"2072-6694"}],"subject":[],"published":{"date-parts":[[2025,9,12]]}}}