{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T05:16:19Z","timestamp":1788066979236,"version":"build-2784847793"},"reference-count":32,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background\/Objectives: Intravascular large B-cell lymphoma (IVLBCL) is a rare and diagnostically challenging disease, often presenting as fever of unknown origin (FUO). This study aimed to develop and validate diagnostic predictive models and scoring systems to distinguish IVLBCL from other causes of FUO in hospitalized patients. Methods: A retrospective analysis was conducted in patients with IVLBCL or other causes of FUO who were treated between February 2015 and October 2023. Two multivariable logistic regression models and corresponding integer-based scoring systems were developed in a training cohort comprising 42 patients with IVLBCL and 45 FUO controls. Internal validation was performed using leave-one-out cross-validation and bootstrap resampling, followed by temporal validation in an independent cohort of 18 patients with IVLBCL and 21 FUO controls. Model 1 was additionally evaluated for sensitivity in an external case-only cohort comprising 40 patients with IVLBCL from eight hospitals. Results: Model 1 incorporated peripheral edema, hypoxemia, neurological symptoms, hemophagocytic lymphohistiocytosis, and interstitial lung abnormalities on computed tomography and achieved an area under the receiver operating characteristic curve (AUC) of 0.916 in the training cohort. Model 2 combined the interleukin-10\/interleukin-6 (IL-10\/IL-6) ratio with peripheral edema, hypoxemia, and neurological symptoms and demonstrated significantly improved discrimination (AUC = 0.982, p = 0.021 vs. Model 1). In the temporal validation cohort, the AUCs of Models 1 and 2 were 0.975 and 0.997, respectively. The corresponding integer-based scoring systems achieved AUCs of 0.903 and 0.952 in the training cohort and 0.926 and 0.992 in the temporal validation cohort. In the external case-only cohort, both Model 1 and its integer-based score identified 32 of 40 patients, yielding a sensitivity of 80.0%. Random skin biopsy provided the histological diagnosis in 58% of cases, with a positivity rate of 79.5%. Conclusions: Two diagnostic models and their simplified scoring systems were developed and internally and temporally validated to aid the diagnosis of IVLBCL in hospitalized patients with FUO. These models may assist in the diagnostic workup of hospitalized FUO patients, especially when IL-10\/IL-6 testing is unavailable. Their performance in outpatient or community settings remains uncertain, and prospective multicenter validation with appropriate FUO controls is warranted.<\/jats:p>","DOI":"10.3390\/diagnostics16172768","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T18:33:52Z","timestamp":1787942032000},"page":"2768","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Diagnostic Predictive Model for Distinguishing Intravascular Large B-Cell Lymphoma Among Patients with Fever of Unknown Origin"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5381-5850","authenticated-orcid":false,"given":"Min","family":"Lang","sequence":"first","affiliation":[{"name":"Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Wangfujing Dongcheng District, Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Chao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Wangfujing Dongcheng District, Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Yiao","family":"Di","sequence":"additional","affiliation":[{"name":"Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Wangfujing Dongcheng District, Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8049-1166","authenticated-orcid":false,"given":"Zhe","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Wangfujing Dongcheng District, Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Zepeng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Congwei","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Ximin","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Danqing","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Wangfujing Dongcheng District, Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1192-4896","authenticated-orcid":false,"given":"Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Wangfujing Dongcheng District, Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Wangfujing Dongcheng District, Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"supervision","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]},{"given":"Daobin","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Wangfujing Dongcheng District, Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Wangfujing Dongcheng District, Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"ref_1","unstructured":"Nakamura, S. (2008). Intravascular large B-cell lymphoma. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, IARC Press."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3168","DOI":"10.1200\/JCO.2006.08.2313","article-title":"Definition, diagnosis, and management of intravascular large B-cell lymphoma: Proposals and perspectives from an international consensus meeting","volume":"25","author":"Ponzoni","year":"2007","journal-title":"J. Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/S1470-2045(09)70140-8","article-title":"Presentation and management of intravascular large B-cell lymphoma","volume":"10","author":"Shimada","year":"2009","journal-title":"Lancet Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.amjmed.2021.07.038","article-title":"Fever of Unknown Origin (FUO): A Call for New Research Standards and Updated Clinical Management","volume":"135","author":"Wright","year":"2022","journal-title":"Am. J. Med."},{"key":"ref_5","first-page":"137","article-title":"Fever of Unknown Origin in Adults","volume":"105","author":"David","year":"2022","journal-title":"Am. Fam. Physician"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1111\/bjh.16081","article-title":"Diagnosis of intravascular large B cell lymphoma: Novel insights into clinicopathological features from 42 patients at a single institution over 20 years","volume":"187","author":"Matsue","year":"2019","journal-title":"Br. J. Haematol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"946","DOI":"10.3904\/kjim.2018.396","article-title":"Asian variant of intravascular large B-cell lymphoma: A comparison of clinical features based on involvement of the central nervous system","volume":"35","author":"Yoon","year":"2020","journal-title":"Korean J. Intern. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1016\/S0025-6196(11)61097-5","article-title":"Use of random skin biopsy for diagnosis of intravascular large B-cell lymphoma","volume":"82","author":"Asada","year":"2007","journal-title":"Mayo Clin. Proc."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1182\/blood-2006-01-021253","article-title":"Intravascular large B-cell lymphoma (IVLBCL): A clinicopathologic study of 96 cases with special reference to the immunophenotypic heterogeneity of CD5","volume":"109","author":"Murase","year":"2007","journal-title":"Blood"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.5858\/arpa.2021-0165-RA","article-title":"Intravascular Large B-Cell Lymphoma: A Brief Review of Current and Historic Literature and a Cautionary Tale of Pertinent Pitfalls","volume":"146","author":"Davis","year":"2022","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e5985","DOI":"10.1097\/MD.0000000000005985","article-title":"Retrospective study of intravascular large B-cell lymphoma cases diagnosed in Quebec: A retrospective study of 29 case reports","volume":"96","author":"Brunet","year":"2017","journal-title":"Medicine"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1182\/blood-2017-04-737445","article-title":"Intravascular large B-cell lymphoma: A chameleon with multiple faces and many masks","volume":"132","author":"Ponzoni","year":"2018","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e6925","DOI":"10.1097\/MD.0000000000006925","article-title":"Intravascular large b-cell lymphoma diagnosed via transjugular liver biopsy in a patient with liver dysfunction and thrombocytopenia: A Case Report","volume":"96","author":"Kim","year":"2017","journal-title":"Medicine"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1620\/tjem.238.197","article-title":"Reversible Hypopituitarism Associated with Intravascular Large B-Cell Lymphoma: Case Report of Successful Immunochemotherapy","volume":"238","author":"Sawada","year":"2016","journal-title":"Tohoku J. Exp. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"486","DOI":"10.3324\/haematol.10829","article-title":"Variations in clinical presentation, frequency of hemophagocytosis and clinical behavior of intravascular lymphoma diagnosed in different geographical regions","volume":"92","author":"Ferreri","year":"2007","journal-title":"Haematologica"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e131","DOI":"10.1002\/ctm2.131","article-title":"Serum interleukin-10 as a valuable biomarker for early diagnosis and therapeutic monitoring in intravascular large B-cell lymphoma","volume":"10","author":"Zhang","year":"2020","journal-title":"Clin. Transl. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1002\/pbc.21039","article-title":"HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis","volume":"48","author":"Henter","year":"2007","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1016\/S2213-2600(20)30168-5","article-title":"Interstitial lung abnormalities detected incidentally on CT: A Position Paper from the Fleischner Society","volume":"8","author":"Hatabu","year":"2020","journal-title":"Lancet Respir. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"55","DOI":"10.7326\/M14-0697","article-title":"Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD): The TRIPOD Statement","volume":"162","author":"Collins","year":"2015","journal-title":"Ann. Intern. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"558","DOI":"10.4097\/kja.19087","article-title":"Multicollinearity and misleading statistical results","volume":"72","author":"Kim","year":"2019","journal-title":"Korean J. Anesthesiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2302","DOI":"10.1002\/sim.7273","article-title":"Firth\u2019s logistic regression with rare events: Accurate effect estimates and predictions?","volume":"36","author":"Puhr","year":"2017","journal-title":"Stat. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"837","DOI":"10.2307\/2531595","article-title":"Comparing the areas under two or more correlated receiver operating characteristic curves: A nonparametric approach","volume":"44","author":"DeLong","year":"1988","journal-title":"Biometrics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1016\/S0895-4356(01)00341-9","article-title":"Internal validation of predictive models: Efficiency of some procedures for logistic regression analysis","volume":"54","author":"Steyerberg","year":"2001","journal-title":"J. Clin. Epidemiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1097\/PAS.0b013e31815d29c9","article-title":"Intravascular large T-cell or NK-cell lymphoma: A rare variant of intravascular large cell lymphoma with frequent cytotoxic phenotype and association with Epstein-Barr virus infection","volume":"32","author":"Cerroni","year":"2008","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1097\/DAD.0000000000000321","article-title":"Usefulness of Random Skin Biopsy as a Diagnostic Tool of Intravascular Lymphoma Presenting with Fever of Unknown Origin","volume":"37","author":"Pongpudpunth","year":"2015","journal-title":"Am. J. Dermatopathol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1007\/s00277-023-05525-7","article-title":"Distinct FDG PET\/CT avidity among newly diagnosed intravascular large B-cell lymphoma patients: A descriptive observational study","volume":"103","author":"Zhao","year":"2024","journal-title":"Ann. Hematol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1007\/BF02983788","article-title":"The serum cytokine profiles of lymphoma-associated hemophagocytic syndrome: A comparative analysis of B-cell and T-cell\/natural killer cell lymphomas","volume":"77","author":"Ohno","year":"2003","journal-title":"Int. J. Hematol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.jdin.2022.09.005","article-title":"Probability scoring system of intravascular large B-cell lymphoma for the application of random skin biopsy: A retrospective cohort study","volume":"9","author":"Takigawa","year":"2022","journal-title":"JAAD Int."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1111\/ijd.16907","article-title":"Predictive factors and scoring system for intravascular large B-cell lymphoma among suspected cases: A single-center retrospective analysis","volume":"63","author":"Tanaka","year":"2024","journal-title":"Int. J. Dermatol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Yin, Y., Zhang, W., Zhao, L., Li, Y., Huang, M., Han, Y., and Wu, X. (2025). Development and validation of a predictive model for diagnosing EBER-positive lymphoma-associated hemophagocytic lymphohistiocytosis. BMC Cancer, 25.","DOI":"10.1186\/s12885-025-13788-8"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1177\/12034754221130257","article-title":"Recommendations for an Approach to Random Skin Biopsy in the Diagnosis of Intravascular B-Cell Lymphoma","volume":"27","author":"MacGillivary","year":"2023","journal-title":"J. Cutan. Med. Surg."},{"key":"ref_32","first-page":"003497","article-title":"Early Diagnosis of Intravascular Large B-Cell Lymphoma by Random Skin Biopsy","volume":"9","author":"Sakaguchi","year":"2022","journal-title":"Eur. J. Case Rep. Intern. Med."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/17\/2768\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T04:28:36Z","timestamp":1788064116000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/17\/2768"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,28]]},"references-count":32,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["diagnostics16172768"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics16172768","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,28]]}}}