{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T10:29:15Z","timestamp":1794047355707,"version":"4.8.0"},"reference-count":34,"publisher":"Ferrata Storti Foundation (Haematologica)","issue":"6","license":[{"start":{"date-parts":[[2020,5,7]],"date-time":"2020-05-07T00:00:00Z","timestamp":1588809600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/legalcode"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["haematol"],"abstract":"<jats:p>A subset of patients with advanced-stage classical Hodgkin Lymphoma (cHL) relapse or progress following standard treatment. Given their dismal prognosis, identifying this group of patients upfront represents an important medical need. While prior research has identified characteristics of the tumor microenvironment, which are associated with cHL outcomes, biomarkers that are developed and validated in this high-risk group are still missing. Here, we applied whole-slide image analysis (WSI), a quantitative, large-scale assessment of tumor composition that utilizes conventional histopathology slides. We conducted WSI on a study cohort with pre-treatment biopsies of 340 advanced-stage cHL patients enrolled in the HD12 and HD15 trials of the German Hodgkin Study Group (GHSG), and tested our results in in a validation cohort of 147 advanced-stage cHL patients within the GHSG HD18 trial. All patients were treated with BEACOPP-based regimens. By quantifying T cells, B cells, Hodgkin-Reed-Sternberg-cells and macrophages with WSI, 80% of all cells in the tumor tissue were identified. Crucially, low B cell count was associated with significantly reduced progression-free survival (PFS) and overall survival (OS), while T cell-, macrophage- and Hodgkin-Reed-Sternberg-cell content was not associated with the risk of progression or relapse in the study cohort. We further validated low B cell content as a prognostic factor of PFS and OS in the validation cohort and demonstrate good inter-observer agreement of WSI. WSI may represent a key tool for risk stratification of advanced-stage cHL that can easily be added to the standard diagnostic histopathology work-up.<\/jats:p>","DOI":"10.3324\/haematol.2019.243287","type":"journal-article","created":{"date-parts":[[2020,5,7]],"date-time":"2020-05-07T14:06:32Z","timestamp":1588860392000},"page":"1684-1692","source":"Crossref","is-referenced-by-count":26,"title":["Whole-slide image analysis of the tumor microenvironment identifies low B-cell content as a predictor of adverse outcome in patients with advanced-stage classical Hodgkin lymphoma treated with BEACOPP"],"prefix":"10.3324","volume":"106","author":[{"family":"Ron Daniel Jachimowicz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Luise Pieper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Sarah Reinke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Artur Gontarewicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Annette Pl\u00fctschow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Heinz Haverkamp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Leonie Frauenfeld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Falko Fend","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Mathis Overkamp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Franziska Jochims","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Christoph Thorns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Martin Leo Hansmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Peter M\u00f6ller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Andreas Rosenwald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Harald Stein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Hans Christian Reinhardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Peter Borchmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Bastian von Tresckow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Andreas Engert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Wolfram Klapper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1856","published-online":{"date-parts":[[2020,5,7]]},"reference":[{"key":"26268","doi-asserted-by":"crossref","unstructured":"Diehl V, Franklin J, Pfreundschuh M. 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Tumor-associated macrophages and survival in classic Hodgkin's lymphoma. N Engl J Med. 2010; 362(10):875-885.","DOI":"10.1056\/NEJMoa0905680"},{"key":"26280","doi-asserted-by":"crossref","unstructured":"Tzankov A, Matter MS, Dirnhofer S. Refined prognostic role of CD68-positive tumor macrophages in the context of the cellular micromilieu of classical Hodgkin lymphoma. Pathobiology. 2010; 77(6):301-308.","DOI":"10.1159\/000321567"},{"key":"26281","doi-asserted-by":"crossref","unstructured":"Kamper P, Bendix K, Hamilton-Dutoit S. Tumor-infiltrating macrophages correlate with adverse prognosis and Epstein-Barr virus status in classical Hodgkin's lymphoma. Haematologica. 2011; 96(2):269-276.","DOI":"10.3324\/haematol.2010.031542"},{"key":"26282","doi-asserted-by":"crossref","unstructured":"Panico L, Ronconi F, Lepore M. Prognostic role of tumor-associated macrophages and angiogenesis in classical Hodgkin lymphoma. Leuk Lymphoma. 2013; 54(11):2418-2425.","DOI":"10.3109\/10428194.2013.778405"},{"key":"26283","doi-asserted-by":"crossref","unstructured":"Chetaille B, Bertucci F, Finetti P. Molecular profiling of classical Hodgkin lymphoma tissues uncovers variations in the tumor microenvironment and correlations with EBV infection and outcome. Blood. 2009; 113(12):2765-3775.","DOI":"10.1182\/blood-2008-07-168096"},{"key":"26284","doi-asserted-by":"crossref","unstructured":"Greaves P, Clear A, Coutinho R. Expression of FOXP3, CD68, and CD20 at diagnosis in the microenvironment of classical Hodgkin lymphoma is predictive of outcome. J Clin Oncol. 2013; 31(2):256-262.","DOI":"10.1200\/JCO.2011.39.9881"},{"key":"26285","doi-asserted-by":"crossref","unstructured":"Tudor CS, Distel LV, Eckhardt J. B cells in classical Hodgkin lymphoma are important actors rather than bystanders in the local immune reaction. 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PET-guided treatment in patients with advanced-stage Hodgkin's lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group. Lancet. 2018; 390(10114):2790-2802.","DOI":"10.1016\/S0140-6736(17)32134-7"},{"key":"26289","doi-asserted-by":"crossref","unstructured":"Hutchings M, Loft A, Hansen M. FDGPET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma. Blood. 2006; 107(1):52-59.","DOI":"10.1182\/blood-2005-06-2252"},{"key":"26290","doi-asserted-by":"crossref","unstructured":"Scott DW, Chan FC, Hong F. Gene expression-based model using formalinfixed paraffin-embedded biopsies predicts overall survival in advanced-stage classical Hodgkin lymphoma. J Clin Oncol. 2013; 31(6):692-700.","DOI":"10.1200\/JCO.2012.43.4589"},{"key":"26291","doi-asserted-by":"crossref","unstructured":"Tan KL, Scott DW, Hong F. Tumorassociated macrophages predict inferior outcomes in classic Hodgkin lymphoma: a correlative study from the E2496 Intergroup trial. Blood. 2012; 120(16):3280-3287.","DOI":"10.1182\/blood-2012-04-421057"},{"key":"26292","doi-asserted-by":"crossref","unstructured":"Azambuja D, Natkunam Y, Biasoli I. Lack of association of tumor-associated macrophages with clinical outcome in patients with classical Hodgkin's lymphoma. Ann Oncol. 2012; 23(3):736-742.","DOI":"10.1093\/annonc\/mdr157"},{"key":"26293","doi-asserted-by":"crossref","unstructured":"Sanchez-Espiridion B, Martin-Moreno AM, Montalban C. Immunohistochemical markers for tumor associated macrophages and survival in advanced classical Hodgkin's lymphoma. Haematologica. 2012; 97(7):1080-1084.","DOI":"10.3324\/haematol.2011.055459"},{"key":"26294","doi-asserted-by":"crossref","unstructured":"Diefenbach CS, Li H, Hong F. Evaluation of the International Prognostic Score (IPS-7) and a Simpler Prognostic Score (IPS-3) for advanced Hodgkin lymphoma in the modern era. Br J Haematol. 2015; 171(4):530-538.","DOI":"10.1111\/bjh.13634"},{"key":"26295","doi-asserted-by":"crossref","unstructured":"Guisado-Vasco P, Arranz-Saez R, Canales M. Stage IV and age over 45 years are the only prognostic factors of the International Prognostic Score for the outcome of advanced Hodgkin lymphoma in the Spanish Hodgkin Lymphoma Study Group series. Leuk Lymphoma. 2012; 53(5):812-819.","DOI":"10.3109\/10428194.2011.635861"},{"key":"26296","doi-asserted-by":"crossref","unstructured":"Sanchez-Aguilera A, Montalban C, de la Cueva P. Tumor microenvironment and mitotic checkpoint are key factors in the outcome of classic Hodgkin lymphoma. Blood. 2006; 108(2):662-668.","DOI":"10.1182\/blood-2005-12-5125"},{"key":"26297","doi-asserted-by":"crossref","unstructured":"Panico L, Tenneriello V, Ronconi F. High CD20+ background cells predict a favorable outcome in classical Hodgkin lymphoma and antagonize CD68+ macrophages. Leuk Lymphoma. 2015; 56(6):1636-1642.","DOI":"10.3109\/10428194.2014.951849"},{"key":"26298","doi-asserted-by":"crossref","unstructured":"Sanchez-Espiridion B, Montalban C, Lopez A. A molecular risk score based on 4 functional pathways for advanced classical Hodgkin lymphoma. Blood. 2010; 116(8):e12-17.","DOI":"10.1182\/blood-2010-02-270009"},{"key":"26299","doi-asserted-by":"crossref","unstructured":"Griss J, Bauer W, Wagner C. B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma. Nat Commun. 2019; 10(1):4186.","DOI":"10.1038\/s41467-019-12160-2"},{"key":"26300","doi-asserted-by":"crossref","unstructured":"Cader FZ, Schackmann RCJ, Hu X. Mass cytometry of Hodgkin lymphoma reveals a CD4(+) regulatory T-cell-rich and exhausted T-effector microenvironment. Blood. 2018; 132(8):825-836.","DOI":"10.1182\/blood-2018-04-843714"},{"key":"26301","doi-asserted-by":"crossref","unstructured":"Carey CD, Gusenleitner D, Lipschitz M. Topological analysis reveals a PD-L1- associated microenvironmental niche for Reed-Sternberg cells in Hodgkin lymphoma. Blood. 2017; 130(22):2420-2430.","DOI":"10.1182\/blood-2017-03-770719"}],"container-title":["Haematologica"],"original-title":[],"link":[{"URL":"https:\/\/haematologica.org\/article\/download\/9746\/70859","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/haematologica.org\/article\/download\/9746\/70860","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/haematologica.org\/article\/download\/9746\/70859","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T09:57:03Z","timestamp":1794045423000},"score":1,"resource":{"primary":{"URL":"https:\/\/haematologica.org\/article\/view\/9746"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,7]]},"references-count":34,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6,1]]}},"URL":"https:\/\/doi.org\/10.3324\/haematol.2019.243287","relation":{},"ISSN":["1592-8721","0390-6078"],"issn-type":[{"value":"1592-8721","type":"electronic"},{"value":"0390-6078","type":"print"}],"subject":[],"published":{"date-parts":[[2020,5,7]]}}}