{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T02:53:02Z","timestamp":1790909582967,"version":"4.1.0"},"reference-count":23,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["European J of Haematology"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Extranodal (EN) involvement is common in diffuse large B\u2010cell lymphoma (DLBCL), but current prognostic models inadequately capture the anatomical complexity of EN dissemination. We evaluated primary multifocal extranodal DLBCL (PMEN\u2010DLBCL) as a distinct clinical and anatomical phenotype using a standardized lesion\u2010level classification framework.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We retrospectively analyzed 393 adults with newly diagnosed DLBCL treated with rituximab\u2010based chemoimmunotherapy between 2003 and 2025. Patients were classified as primary nodal (PN;\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009231), primary focal extranodal (PFEN;\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009115), or primary multifocal extranodal (PMEN;\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200947) DLBCL according to predefined anatomical criteria. Clinical characteristics, organ involvement patterns, treatment response, survival outcomes, CNS relapse, and patterns of extranodal dissemination were evaluated. Exploratory co\u2010occurrence analyses and unsupervised hierarchical clustering were performed within the PMEN cohort.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>PMEN accounted for 12.0% of all DLBCL cases and was enriched for adverse clinical features, including impaired performance status, elevated lactate dehydrogenase, and high\u2010risk IPI categories. PMEN demonstrated preferential involvement of axial and appendicular bones, liver, muscle, adrenal glands, lung, and kidney, whereas PFEN was enriched for gastric and head\u2010and\u2010neck disease. Although overall response rates were comparable across groups, PMEN exhibited lower complete response rates (60.5% vs. 78.3% in PFEN) and more frequent early treatment failure. Five\u2010year progression\u2010free survival was 52.3% in PMEN compared with 71.2% in PFEN. In univariable analysis, PMEN was associated with inferior PFS relative to PFEN (HR 1.86, 95% CI 1.08\u20133.20), but this association lost significance after adjustment for established prognostic factors. Within PMEN, adrenal involvement independently predicted inferior PFS and overall survival. Exploratory clustering identified skeletal\u2010dominant and visceral\u2010dominant phenotypes, with markedly lower complete response rates in visceral\u2010dominant disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>PMEN\u2010DLBCL represents a distinct anatomical and clinical phenotype characterized by multifocal extranodal dissemination, preferential skeletal and deep visceral organ involvement, adverse baseline features, and inferior response quality. Specific organ involvement and spatial dissemination patterns appear more informative than extranodal site count alone, supporting further investigation of anatomical disease architecture in risk stratification of extranodal DLBCL.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/ejh.70335","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T01:53:29Z","timestamp":1790906009000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond Extranodal Site Count: Clinical and Anatomical Characterization of Primary Multifocal Extranodal Diffuse Large B\u2010Cell Lymphoma"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8519-8188","authenticated-orcid":false,"given":"Thomas P.","family":"Thomopoulos","sequence":"first","affiliation":[{"name":"Second Propaedeutic Department of Internal Medicine, &amp; Research Institute, Hematology Unit, School of Medicine National and Kapodistrian University of Athens, University General Hospital \u201cAttikon\u201d  Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Apostolopoulou","sequence":"additional","affiliation":[{"name":"Second Propaedeutic Department of Internal Medicine, &amp; Research Institute, Hematology Unit, School of Medicine National and Kapodistrian University of Athens, University General Hospital \u201cAttikon\u201d  Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9892-8787","authenticated-orcid":false,"given":"Pinelopi","family":"Vryttia","sequence":"additional","affiliation":[{"name":"Second Propaedeutic Department of Internal Medicine, &amp; Research Institute, Hematology Unit, School of Medicine National and Kapodistrian University of Athens, University General Hospital \u201cAttikon\u201d  Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9234-7073","authenticated-orcid":false,"given":"Anthi","family":"Bouchla","sequence":"additional","affiliation":[{"name":"Second Propaedeutic Department of Internal Medicine, &amp; Research Institute, Hematology Unit, School of Medicine National and Kapodistrian University of Athens, University General Hospital \u201cAttikon\u201d  Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8303-6513","authenticated-orcid":false,"given":"Artemis","family":"Zormpa","sequence":"additional","affiliation":[{"name":"Second Propaedeutic Department of Internal Medicine, &amp; Research Institute, Hematology Unit, School of Medicine National and Kapodistrian University of Athens, University General Hospital \u201cAttikon\u201d  Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioulia","family":"Markaki","sequence":"additional","affiliation":[{"name":"Second Propaedeutic Department of Internal Medicine, &amp; Research Institute, Hematology Unit, School of Medicine National and Kapodistrian University of Athens, University General Hospital \u201cAttikon\u201d  Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgia","family":"Karamanou","sequence":"additional","affiliation":[{"name":"Second Propaedeutic Department of Internal Medicine, &amp; Research Institute, Hematology Unit, School of Medicine National and Kapodistrian University of Athens, University General Hospital \u201cAttikon\u201d  Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Periklis G.","family":"Foukas","sequence":"additional","affiliation":[{"name":"Second Department of Pathology School of Medicine, National and Kapodistrian University of Athens, University General Hospital \u201cAttikon\u201d  Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0421-9424","authenticated-orcid":false,"given":"Vasiliki","family":"Pappa","sequence":"additional","affiliation":[{"name":"Second Propaedeutic Department of Internal Medicine, &amp; Research Institute, Hematology Unit, School of Medicine National and Kapodistrian University of Athens, University General Hospital \u201cAttikon\u201d  Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3376-837X","authenticated-orcid":false,"given":"Sotirios G.","family":"Papageorgiou","sequence":"additional","affiliation":[{"name":"Second Propaedeutic Department of Internal Medicine, &amp; Research Institute, Hematology Unit, School of Medicine National and Kapodistrian University of Athens, University General Hospital \u201cAttikon\u201d  Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"issue":"6","key":"e_1_2_11_2_1","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1182\/blood-2013-09-524108","article-title":"An Enhanced International Prognostic Index (NCCN\u2010IPI) for Patients With Diffuse Large B\u2010Cell Lymphoma Treated in the Rituximab Era","volume":"123","author":"Zhou Z.","year":"2014","journal-title":"Blood"},{"issue":"14","key":"e_1_2_11_3_1","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1056\/NEJM199309303291402","article-title":"A Predictive Model for Aggressive Non\u2010Hodgkin's Lymphoma","volume":"329","year":"1993","journal-title":"New England Journal of Medicine"},{"issue":"9","key":"e_1_2_11_4_1","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1634\/theoncologist.10-9-734","article-title":"Multifocal Extranodal Non\u2010Hodgkin Lymphoma: A Clinicopathologic Study of 37 Cases in Greece, a Hellenic Cooperative Oncology Group Study","volume":"10","author":"Economopoulos T.","year":"2005","journal-title":"Oncologist"},{"issue":"3","key":"e_1_2_11_5_1","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1002\/ajh.23638","article-title":"Sites of Extranodal Involvement Are Prognostic in Patients With Diffuse Large B\u2010Cell Lymphoma in the Rituximab Era: An Analysis of the Surveillance, Epidemiology and End Results Database","volume":"89","author":"Castillo J. J.","year":"2014","journal-title":"American Journal of Hematology"},{"issue":"2","key":"e_1_2_11_6_1","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1046\/j.1365-2141.2003.04749.x","article-title":"Diffuse Large B\u2010Cell Lymphoma: Clinical Implications of Extranodal Versus Nodal Presentation \u2013 A Population\u2010Based Study of 1575 Cases","volume":"124","author":"M\u00f8ller M. B.","year":"2004","journal-title":"British Journal of Haematology"},{"issue":"8","key":"e_1_2_11_7_1","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1007\/s11864-018-0555-8","article-title":"Extranodal Diffuse Large B Cell Lymphoma: Molecular Features, Prognosis, and Risk of Central Nervous System Recurrence","volume":"19","author":"Ollila T. A.","year":"2018","journal-title":"Current Treatment Options in Oncology"},{"issue":"8","key":"e_1_2_11_8_1","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1002\/cac2.70033","article-title":"Extranodal Diffuse Large B\u2010Cell Lymphoma: Clinical and Molecular Insights With Survival Outcomes From the Multicenter EXPECT Study","volume":"45","author":"Chen S. Y.","year":"2025","journal-title":"Cancer Commun (Lond)"},{"key":"e_1_2_11_9_1","unstructured":"T. M.Therneau \u201cA Package for Survival Analysis in R \u201d2026 3.8(6)."},{"key":"e_1_2_11_10_1","unstructured":"Z.Gu \u201cComplexHeatmap: Make Complex Heatmaps \u201d2024."},{"key":"e_1_2_11_11_1","unstructured":"R.Kolde \u201cpheatmap: Pretty Heatmaps \u201d2019."},{"key":"e_1_2_11_12_1","unstructured":"D. D.SjobergandT.Fei \u201ctidycmprsk: Competing Risks Estimation \u201dVersion 1.1.27UR https:\/\/mskcc\u2010epi\u2010bio.github.io\/tidycmprsk\/ed2026."},{"issue":"1","key":"e_1_2_11_13_1","first-page":"1","article-title":"FactoMineR: An R Package for Multivariate Analysis","volume":"25","author":"L\u00ea S.","year":"2008","journal-title":"Journal of Statistical Software"},{"key":"e_1_2_11_14_1","unstructured":"A.KassambaraandF.Mundt \u201cfactoextra: Extract and Visualize the Results of Multivariate Data Analyses \u201dR package version 2.1.0 ed2026."},{"issue":"1","key":"e_1_2_11_15_1","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1093\/annonc\/mdg004","article-title":"Primary Extranodal Non\u2010Hodgkin's Lymphoma (NHL): The Impact of Alternative Definitions Tested in the Comprehensive Cancer Centre West Population\u2010Based NHL Registry","volume":"14","author":"Krol A. D.","year":"2003","journal-title":"Annals of Oncology"},{"issue":"3","key":"e_1_2_11_16_1","doi-asserted-by":"crossref","first-page":"301","DOI":"10.3904\/kjim.2010.25.3.301","article-title":"Modified Number of Extranodal Involved Sites as a Prognosticator in R\u2010CHOP\u2010Treated Patients With Disseminated Diffuse Large B\u2010Cell Lymphoma","volume":"25","author":"Yoo C.","year":"2010","journal-title":"Korean Journal of Internal Medicine"},{"issue":"10","key":"e_1_2_11_17_1","first-page":"e13594","article-title":"Extranodal Site of Diffuse Large B\u2010Cell Lymphoma and the Risk of R\u2010CHOP Chemotherapy Resistance and Early Relapse","volume":"74","author":"Ting C. Y.","year":"2020","journal-title":"International Journal of Clinical Practice"},{"issue":"1","key":"e_1_2_11_18_1","doi-asserted-by":"crossref","first-page":"57","DOI":"10.21147\/j.issn.1000-9604.2017.01.07","article-title":"Extranodal Involvement in Young Patients With Diffuse Large B\u2010Cell Lymphoma: Distribution, Prognostic Value and Treatment Options","volume":"29","author":"Yao S.","year":"2017","journal-title":"Chinese Journal of Cancer Research"},{"issue":"17","key":"e_1_2_11_19_1","doi-asserted-by":"crossref","first-page":"4166","DOI":"10.1002\/cncr.27381","article-title":"Prognostic Impact of Extranodal Involvement in Diffuse Large B\u2010Cell Lymphoma in the Rituximab Era","volume":"118","author":"Ishigatsubo Y.","year":"2012","journal-title":"Cancer"},{"issue":"1","key":"e_1_2_11_20_1","doi-asserted-by":"crossref","first-page":"152","DOI":"10.21147\/j.issn.1000-9604.2019.01.10","article-title":"Clinical Features and Outcomes of Diffuse Large B\u2010Cell Lymphoma Based on Nodal or Extranodal Primary Sites of Origin: Analysis of 1,085 WHO Classified Cases in a Single Institution in China","volume":"31","author":"Shi Y.","year":"2019","journal-title":"Chinese Journal of Cancer Research"},{"issue":"7","key":"e_1_2_11_21_1","doi-asserted-by":"crossref","first-page":"2047","DOI":"10.3109\/10428194.2014.982636","article-title":"Diffuse Large B\u2010Cell Lymphoma: Sites of Extranodal Involvement Are a Stronger Prognostic Indicator Than Number of Extranodal Sites in the Rituximab Era","volume":"56","author":"Lu C.\u2010S.","year":"2015","journal-title":"Leukemia & Lymphoma"},{"issue":"1","key":"e_1_2_11_22_1","doi-asserted-by":"crossref","first-page":"e70565","DOI":"10.1002\/cam4.70565","article-title":"Influence of Organ\u2010Specific Extranodal Involvement on Survival Outcomes in Stage IV Diffuse Large B\u2010Cell Lymphoma","volume":"14","author":"Kim T.\u2010Y.","year":"2025","journal-title":"Cancer Medicine"},{"issue":"4","key":"e_1_2_11_23_1","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 G. W.","year":"2020","journal-title":"Cancer Cell"},{"issue":"7","key":"e_1_2_11_24_1","doi-asserted-by":"crossref","first-page":"e221","DOI":"10.1002\/ctm2.221","article-title":"Influence of Oncogenic Mutations and Tumor Microenvironment Alterations on Extranodal Invasion in Diffuse Large B\u2010Cell Lymphoma","volume":"10","author":"Shen R.","year":"2020","journal-title":"Clinical and Translational Medicine"}],"container-title":["European Journal of Haematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/ejh.70335","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/ejh.70335","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/ejh.70335","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T01:53:38Z","timestamp":1790906018000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/ejh.70335"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,1]]},"references-count":23,"alternative-id":["10.1111\/ejh.70335"],"URL":"https:\/\/doi.org\/10.1111\/ejh.70335","archive":["Portico"],"relation":{},"ISSN":["0902-4441","1600-0609"],"issn-type":[{"value":"0902-4441","type":"print"},{"value":"1600-0609","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,1]]},"assertion":[{"value":"2026-08-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-01","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"ejh.70335"}}