{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T13:29:41Z","timestamp":1771334981720,"version":"3.50.1"},"reference-count":33,"publisher":"Croatian Society for Medical Biochemistry and Laboratory Medicine","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biochem. med. (Online)"],"published-print":{"date-parts":[[2026,2,15]]},"abstract":"<jats:p>Introduction: Differentiating between malignant pleural effusion (MPE) and tuberculous pleural effusion (TPE) remains challenging in clinical practice. The cancer ratio plus (CR+), a potential diagnostic tool calculated as serum lactate dehydrogenase\/(pleural adenosine deaminase x pleural lymphocyte percentage) has emerged to address this diagnostic challenge. This scoping review maps the available evidence on its diagnostic performance.\nMaterials and methods: We conducted a systematic search of PubMed, Scopus, and Web of Science databases from inception to April 2025. Eligible studies assessed the accuracy of CR+ in distinguishing MPE from TPE. Data on study design, cut-off values, sensitivity, specificity, area under the curve (AUC), and likelihood ratios were extracted and synthesized narratively.\nResults: Six studies comprising 881 patients were included. Reported cut-off values varied widely (5.7 - 41.0), as did sensitivity (74.3 - 97.6%) and specificity (36.6 - 94.1%). Most studies, however, reported good discriminatory power with AUC values generally above 0.80. The highest diagnostic accuracy was observed in one study, which reported a sensitivity of 97.6%, a specificity of 94.1%, and an AUC of 0.86. Differences in cut-off thresholds, study populations, local tuberculosis epidemiology, and laboratory methodology (particularly lymphocyte quantification) likely contributed to this heterogeneity.\nConclusions: The CR+ appears promising as a non-invasive tool using routine parameters for differentiating MPE from TPE, but diagnostic performance varies across settings. The heterogeneity in optimal cut-off values highlights the need for local validation before clinical adoption. Future research should standardize methodology and assess its impact on decision-making and patient outcomes.<\/jats:p>","DOI":"10.11613\/bm.2026.010502","type":"journal-article","created":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T12:28:47Z","timestamp":1765542527000},"page":"32-40","source":"Crossref","is-referenced-by-count":0,"title":["The cancer ratio plus in the differential diagnosis of pleural effusions"],"prefix":"10.11613","volume":"36","author":[{"given":"Malak","family":"Snoussi","sequence":"first","affiliation":[{"name":"Laboratory Medicine, Cheikh Khalifa International University Hospital, Mohammed VI University of Sciences and Health, Casablanca, Morocco; Mohammed VI Faculty of Medicine, Mohammed VI University of Sciences and Health, Casablanca, Morocco"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jalila","family":"El Bakkouri","sequence":"additional","affiliation":[{"name":"Laboratory Medicine, Cheikh Khalifa International University Hospital, Mohammed VI University of Sciences and Health, Casablanca, Morocco; Immunopathology-Immunotherapy-Immunomonitoring Laboratory, Mohammed VI University of Sciences and Health, Casablanca, Morocco"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasmine","family":"Bendimrad","sequence":"additional","affiliation":[{"name":"Mohammed VI Faculty of Pharmacy, Mohammed VI University of Sciences and Health, Casablanca, Morocco; Laboratory Medicine, Cheikh Khalifa International University Hospital, Mohammed VI University of Sciences and Health, Casablanca, Morocco"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lamia","family":"Mellah","sequence":"additional","affiliation":[{"name":"Mohammed VI Faculty of Pharmacy, Mohammed VI University of Sciences and Health, Casablanca, Morocco; Laboratory Medicine, Cheikh Khalifa International University Hospital, Mohammed VI University of Sciences and Health, Casablanca, Morocco"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"4885","published-online":{"date-parts":[[2026,2,15]]},"reference":[{"key":"key20251212122841_r1"},{"key":"key20251212122841_r2","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1111\/j.1440-1843.2010.01723.x","article-title":"Update on tuberculous pleural effusion.","volume":"15","author":"Light","year":"2010","journal-title":"Respirology"},{"key":"key20251212122841_r3","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1378\/chest.109.1.158","article-title":"The Etiology of Pleural Effusions in an Area With High Incidence of Tuberculosis.","volume":"109","author":"Vald\u00e9s","year":"1996","journal-title":"Chest"},{"key":"key20251212122841_r4","article-title":"Etiology of exudative pleural effusion among adults: differentiating between tuberculous and other causes, a multicenter prospective cohort study.","volume":"12","author":"Hussein","year":"2024","journal-title":"IJID Reg"},{"key":"key20251212122841_r5","first-page":"157","article-title":"Discriminating Tuberculous Pleural Effusion from Malignant Pleural Effusion Based on Routine Pleural Fluid Biomarkers, Using Mathematical Methods.","volume":"16","author":"Darooei","year":"2017","journal-title":"Tanaffos"},{"key":"key20251212122841_r6","doi-asserted-by":"crossref","DOI":"10.1177\/1753466618808660","article-title":"Biomarkers in the diagnosis of pleural diseases: a 2018 update.","volume":"12","author":"Porcel","year":"2018","journal-title":"Ther Adv Respir Dis"},{"key":"key20251212122841_r7","doi-asserted-by":"crossref","first-page":"31","DOI":"10.2147\/OAEM.S29942","article-title":"Pleural effusion: diagnosis, treatment, and management.","volume":"4","author":"Karkhanis","year":"2012","journal-title":"Open Access Emerg Med"},{"key":"key20251212122841_r8","first-page":"208","article-title":"Thoracentesis for the Diagnosis and Management of Pleural Effusions: The Current State of a Centuries-Old Procedure.","volume":"3","author":"Nicholson","year":"2023","journal-title":"J Respir."},{"key":"key20251212122841_r9","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1111\/imj.15725","article-title":"Evaluation of pleural fluid cytology for the diagnosis of malignant pleural effusion: a retrospective cohort study.","volume":"52","author":"Pairman","year":"2022","journal-title":"Intern Med J"},{"key":"key20251212122841_r10","doi-asserted-by":"crossref","DOI":"10.3389\/fcimb.2021.704169","article-title":"Time to Detection of Growth for Mycobacterium tuberculosis in a Low Incidence Area.","volume":"11","author":"Vongthilath-Moeung","year":"2021","journal-title":"Front Cell Infect Microbiol"},{"key":"key20251212122841_r11","doi-asserted-by":"crossref","DOI":"10.1016\/j.rmed.2021.106607","article-title":"Diagnosis of tuberculous pleural effusions: A review.","volume":"188","author":"Lo Cascio","year":"2021","journal-title":"Respir Med"},{"key":"key20251212122841_r12","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1186\/s12879-023-08781-0","article-title":"Biomarkers for distinguishing tuberculous pleural effusion from non-tuberculosis effusion: a retrospective study.","volume":"23","author":"Fei","year":"2023","journal-title":"BMC Infect Dis"},{"key":"key20251212122841_r13","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0213728","article-title":"Adenosine deaminase for diagnosis of tuberculous pleural effusion: A systematic review and meta-analysis.","volume":"14","author":"Aggarwal","year":"2019","journal-title":"PLoS One"},{"key":"key20251212122841_r14","doi-asserted-by":"crossref","first-page":"213","DOI":"10.7861\/clinmedicine.19-3-213","article-title":"Interpreting pleural fluid results.","volume":"19","author":"Mercer","year":"2019","journal-title":"Clin Med (Lond)"},{"key":"key20251212122841_r15","doi-asserted-by":"crossref","first-page":"265","DOI":"10.3389\/fimmu.2012.00265","article-title":"Autoimmune Dysregulation and Purine Metabolism in Adenosine Deaminase Deficiency.","volume":"3","author":"Sauer","year":"2012","journal-title":"Front Immunol"},{"key":"key20251212122841_r16","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1189\/jlb.1009696","article-title":"Adenosine deaminase potentiates the generation of effector, memory, and regulatory CD4+ T cells.","volume":"89","author":"Martinez-Navio","year":"2011","journal-title":"J Leukoc Biol"},{"key":"key20251212122841_r17","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0213728","article-title":"Adenosine deaminase for diagnosis of tuberculous pleural effusion: A systematic review and meta-analysis.","volume":"14","author":"Aggarwal","year":"2019","journal-title":"PLoS One"},{"key":"key20251212122841_r18","article-title":"Tuberculous and Malignant Pleural Effusions With Adenosine Deaminase Levels of 40-70 IU\/L: Trends in New Cases Over Time and Differentiation Between Groups.","volume":"40","author":"Lee","year":"2025","journal-title":"J Korean Med Sci"},{"key":"key20251212122841_r19","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/978-1-62703-290-2_7","article-title":"Detection of Necrosis by Release of Lactate Dehydrogenase (LDH) Activity.","volume":"979","author":"Chan","year":"2013","journal-title":"Methods Mol Biol"},{"key":"key20251212122841_r20","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1007\/s00277-025-06321-1","article-title":"The metabolic role of lactate dehydrogenase in the growth of diffuse large B cell lymphoma.","volume":"104","author":"Zhang","year":"2025","journal-title":"Ann Hematol"},{"key":"key20251212122841_r21","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/s00408-015-9831-6","article-title":"Identifying Malignant Pleural Effusion by A Cancer Ratio (Serum LDH: Pleural Fluid ADA Ratio).","volume":"194","author":"Verma","year":"2016","journal-title":"Lung"},{"key":"key20251212122841_r22","article-title":"Differentiating Malignant from Tubercular Pleural Effusion by Cancer Ratio Plus (Cancer Ratio: Pleural Lymphocyte Count).","volume":"2016","author":"Verma","year":"2016","journal-title":"Can Respir J"},{"key":"key20251212122841_r23","doi-asserted-by":"crossref","first-page":"467","DOI":"10.7326\/M18-0850","article-title":"PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation.","volume":"169","author":"Tricco","year":"2018","journal-title":"Ann Intern Med"},{"key":"key20251212122841_r24","unstructured":"Sai BRC, Rao R. Adarsha G K et al. Utility of Cancer Ratio (Serum LDH\/Pleural Fluid ADA) and Cancer Plus Ratio (Cancer Ratio\/Pleural Fluid Lymphocytic Percentage) in Differentiating Malignant Pleural Effusion and Tubercular Pleural Effusion: A Prospective Observational Study. Research Square [Preprint]. 2025 [cited 2025 Nov 3]. Available from: https:\/\/www.researchsquare.com\/article\/rs-7264543\/v1"},{"key":"key20251212122841_r25","unstructured":"World health organization. Global tuberculosis report. 1.1 TB incidence. Available from: https:\/\/www.who.int\/teams\/global-programme-on-tuberculosis-and-lung-health\/tb-reports\/global-tuberculosis-report-2024\/tb-disease-burden\/1-1-tb-incidence. Accessed November 3rd, 2025."},{"key":"key20251212122841_r26","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.jclinepi.2011.07.004","article-title":"Three principles to define the success of a diagnostic study could be identified.","volume":"65","author":"Vach","year":"2012","journal-title":"J Clin Epidemiol"},{"key":"key20251212122841_r27","first-page":"DC04","article-title":"First Line Anti-TB Drug Resistance in an Urban Area of Odisha, India.","volume":"10","author":"Das","year":"2016","journal-title":"J Clin Diagn Res"},{"key":"key20251212122841_r28","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1159\/000543522","article-title":"Understanding the Growing Burden of Malignant Pleural Effusion \u2013 Epidemiology, Healthcare Utilization, and Cost: A Canadian Perspective.","volume":"104","author":"Czarnecka-Kujawa","year":"2025","journal-title":"Respiration."},{"key":"key20251212122841_r29","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s43168-020-00004-3","article-title":"Relations between serum and pleural fluid biomarkers: a new look of an old concept.","volume":"14","author":"Hussein","year":"2020","journal-title":"Egypt J Bronchol"},{"key":"key20251212122841_r30","doi-asserted-by":"crossref","DOI":"10.6061\/clinics\/2021\/e2515","article-title":"Role of cancer ratio and other new parameters in the differential diagnosis of malignant pleural effusion.","volume":"76","author":"Ren","year":"2021","journal-title":"Clinics (Sao Paulo)."},{"key":"key20251212122841_r31","article-title":"Age\u202f: pleural fluid ADA ratio and other indicators for differentiating between tubercular and malignant pleural effusions.","volume":"101","author":"Zhou","year":"2022","journal-title":"Medicine (Baltimore)"},{"key":"key20251212122841_r32","first-page":"221","article-title":"Value of Cancer Ratio plus and Cancer Ratio Formulation in Distinguishing Malignant Pleural Effusion from Tuberculosis and Parapneumonic Effusion.","volume":"20","author":"Gayaf","year":"2021","journal-title":"Tanaffos"},{"key":"key20251212122841_r33","first-page":"13","article-title":"Diagnostic role of Cancer Ratio and Cancer Ratio Plus differentiability of Tubercular PLEF and Malignant pleural effusion in Tertiary care Hospital, Odisha.","volume":"17","author":"Parida","year":"2025","journal-title":"CME J Geriatr Med"}],"container-title":["Biochemia medica"],"original-title":[],"link":[{"URL":"https:\/\/biochemia-medica.com\/en\/journal\/36\/1\/10.11613\/BM.2026.010502\/fullArticle","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T12:43:02Z","timestamp":1771332182000},"score":1,"resource":{"primary":{"URL":"https:\/\/biochemia-medica.com\/en\/journal\/36\/1\/10.11613\/BM.2026.010502"}},"subtitle":["a scoping review of current evidence"],"short-title":[],"issued":{"date-parts":[[2026,2,15]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,2,17]]},"published-print":{"date-parts":[[2026,2,15]]}},"URL":"https:\/\/doi.org\/10.11613\/bm.2026.010502","relation":{},"ISSN":["1846-7482","1330-0962"],"issn-type":[{"value":"1846-7482","type":"electronic"},{"value":"1330-0962","type":"print"}],"subject":[],"published":{"date-parts":[[2026,2,15]]}}}