{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:23:36Z","timestamp":1760059416390,"version":"build-2065373602"},"reference-count":19,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,6,14]],"date-time":"2025-06-14T00:00:00Z","timestamp":1749859200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Tungs\u2019 Taichung MetroHarbor Hospital","award":["#TTMHH-R1140057","#TTMHH-R1130008"],"award-info":[{"award-number":["#TTMHH-R1140057","#TTMHH-R1130008"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background and Clinical Significance: Methotrexate is widely used as a disease-modifying antirheumatic drug for rheumatoid arthritis (RA), yet prolonged immunosuppression may lead to rare complications, including Epstein\u2013Barr virus (EBV)-positive lymphoproliferative disorders (LPDs). Case Presentation: We present the case of a 70-year-old woman with RA on chronic immunosuppressive therapy who developed symptoms resembling recurrent tonsillitis. CT imaging revealed bilateral necrotic palatine tonsils and extensive necrotic lymphadenopathy involving the cervical, mediastinal, and axillary regions. Bilateral tonsillectomy was performed due to concerns about malignancy or infection, and histopathology confirmed a polymorphic EBV-positive LPD with Hodgkin-like features, consistent with iatrogenic immunodeficiency-associated LPD. Methotrexate was subsequently discontinued, and the patient was managed conservatively without systemic chemotherapy. Clinical recovery was observed during follow-up. Conclusions: This case highlights the importance of considering methotrexate-associated LPDs in the differential diagnosis of atypical tonsillar infections in immunosuppressed patients, particularly when necrotic features or systemic lymphadenopathy are present. The pathogenesis may involve EBV reactivation under impaired immune surveillance due to methotrexate, leading to abnormal B-cell proliferation and clonal expansion. This case is contextualized through a comparative analysis of published reports, highlighting clinical features and treatment responses of methotrexate-associated EBV-positive LPDs in the form of a focused literature review.<\/jats:p>","DOI":"10.3390\/diagnostics15121517","type":"journal-article","created":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T04:06:24Z","timestamp":1750046784000},"page":"1517","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Protracted Tonsillitis as an Atypical Initial Manifestation of Methotrexate-Induced EBV-Positive Lymphoproliferative Disorder in Rheumatoid Arthritis: A Case Report and Literature Review"],"prefix":"10.3390","volume":"15","author":[{"given":"Ting-Shen","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Otolaryngology, Tungs\u2019 Taichung MetroHarbor Hospital, Taichung 435, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tang-Yi","family":"Tsao","sequence":"additional","affiliation":[{"name":"Department of Pathology, Tungs\u2019 Taichung MetroHarbor Hospital, Taichung 435, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shih-Wei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Tungs\u2019 Taichung MetroHarbor Hospital, Taichung 435, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min-Cheng","family":"Ko","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Tungs\u2019 Taichung MetroHarbor Hospital, Taichung 435, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2694-1207","authenticated-orcid":false,"given":"Stella Chin-Shaw","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Tungs\u2019 Taichung MetroHarbor Hospital, Taichung 435, Taiwan"},{"name":"Superintendent Office, Tungs\u2019 Taichung MetroHarbor Hospital, Taichung 435, Taiwan"},{"name":"Department of Post-Baccalaureate Medicine, National Chung Hsing University, Taichung 402, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1007\/BF00290296","article-title":"Long-term experience with low dose methotrexate in rheumatoid arthritis","volume":"13","author":"Tishler","year":"1993","journal-title":"Rheumatol. Int."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1097\/PAS.0b013e3181cf8622","article-title":"EBV positive mucocutaneous ulcer\u2014A study of 26 cases associated with various sources of immunosuppression","volume":"34","author":"Dojcinov","year":"2010","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1007\/s12105-010-0202-6","article-title":"Methotrexate-related Epstein-Barr Virus (EBV)-associated lymphoproliferative disorder\u2014So-called \u201cHodgkin-like lesion\u201d\u2014Of the oral cavity in a patient with rheumatoid arthritis","volume":"4","author":"Kikuchi","year":"2010","journal-title":"Head Neck Pathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"159","DOI":"10.3960\/jslrt.20041","article-title":"Clinicopathological evaluation of methotrexate-associated lymphoproliferative disorders with special focus on Epstein-Barr virus-positive mucocutaneous lesions","volume":"60","author":"Shiraiwa","year":"2020","journal-title":"J. Clin. Exp. Hematop."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/j.pathol.2020.10.019","article-title":"Primary cutaneous methotrexate-associated B-cell lymphoproliferative disorders other than EBV-positive mucocutaneous ulcer: Clinical, pathological, and immunophenotypic features","volume":"53","author":"Satou","year":"2021","journal-title":"Pathology"},{"key":"ref_6","first-page":"35","article-title":"Tonsillitis and Tonsilloliths: Diagnosis and Management","volume":"107","author":"Smith","year":"2023","journal-title":"Am. Fam. Physician"},{"key":"ref_7","first-page":"uaae002","article-title":"The first case of methotrexate-associated lymphoproliferative disorder in the sacrum: A case report","volume":"10","author":"Yamaguchi","year":"2024","journal-title":"BJR Case Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1023\/A:1008363805242","article-title":"Discrepancies in Epstein-Barr virus association at presentation and relapse of classical Hodgkin\u2019s disease: Impact on pathogenesis","volume":"11","author":"Nerurkar","year":"2000","journal-title":"Ann. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1002\/(SICI)1096-9896(199708)182:4<475::AID-PATH878>3.0.CO;2-6","article-title":"Disappearance of the Epstein-Barr virus in a relapse of Hodgkin\u2019s disease","volume":"182","author":"Delecluse","year":"1997","journal-title":"J. Pathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1943","DOI":"10.1200\/JCO.1996.14.6.1943","article-title":"Spontaneous regression of lymphoproliferative disorders in patients treated with methotrexate for rheumatoid arthritis and other rheumatic diseases","volume":"14","author":"Salloum","year":"1996","journal-title":"J. Clin. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1089\/vim.2022.0200","article-title":"Immunity and Immune Evasion Mechanisms of Epstein-Barr Virus","volume":"36","author":"Yao","year":"2023","journal-title":"Viral Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Pociupany, M., Snoeck, R., Dierickx, D., and Andrei, G. (2024). Treatment of Epstein-Barr Virus infection in immunocompromised patients. Biochem. Pharmacol., 225.","DOI":"10.1016\/j.bcp.2024.116270"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Zhao, Y., Zhang, Q., Zhang, B., Dai, Y., Gao, Y., Li, C., Yu, Y., and Li, C. (2024). Epstein-Barr Viruses: Their Immune Evasion Strategies and Implications for Autoimmune Diseases. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25158160"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"255","DOI":"10.4103\/IJPM.IJPM_135_16","article-title":"Methotrexate-associated Epstein-Barr virus mucocutaneous ulcer: A case report and review of literature","volume":"61","author":"Ravi","year":"2018","journal-title":"Indian J. Pathol. Microbiol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Saito, S., Suzuki, K., Yoshimoto, K., Kaneko, Y., Yamaoka, K., Shimizu, T., Mori, T., Okamoto, S., Kameyama, K., and Amano, K. (2018). Restoration of Decreased T Helper 1 and CD8+ T Cell Subsets Is Associated With Regression of Lymphoproliferative Disorders Developed During Methotrexate Treatment. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.00621"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1007\/s12026-024-09531-3","article-title":"EBV\u2009+\u2009B cell-derived exosomes promote EBV-associated T\/NK-cell lymphoproliferative disease immune evasion by STAT3\/IL-10\/PD-L1 pathway","volume":"72","author":"Chen","year":"2024","journal-title":"Immunol. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1002\/bab.1856","article-title":"Viral IL-10 promotes cell proliferation and cell cycle progression via JAK2\/STAT3 signaling pathway in nasopharyngeal carcinoma cells","volume":"67","author":"Ren","year":"2020","journal-title":"Biotechnol. Appl. Biochem."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Chakravorty, S., Afzali, B., and Kazemian, M. (2022). EBV-associated diseases: Current therapeutics and emerging technologies. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1059133"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Ferrari, S., Weber, A., Marra, P., Tebaldi, P., Pavoni, C., Barbui, A.M., Gritti, G., Dulcetta, L., Carbone, F.S., and Muglia, R. (Radiol. Med., 2025). Enhancing the diagnostic accuracy of core needle biopsy in patients with lymphoproliferative disorders by an optimized protocol, Radiol. Med., in press.","DOI":"10.1007\/s11547-025-01976-2"}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/15\/12\/1517\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:52:12Z","timestamp":1760032332000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/15\/12\/1517"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,14]]},"references-count":19,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["diagnostics15121517"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics15121517","relation":{},"ISSN":["2075-4418"],"issn-type":[{"type":"electronic","value":"2075-4418"}],"subject":[],"published":{"date-parts":[[2025,6,14]]}}}