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Methotrexate-associated lymphoproliferative disorders of T-cell phenotype: clinicopathological analysis of 28 cases



Methotrexate-associated lymphoproliferative disorders are categorized as “other immunodeficiency-associated lymphoproliferative disorders in the WHO classification. Methotrexate-associated lymphoproliferative disorder is mainly a B-cell lymphoproliferative disorders or Hodgkin lymphoma type, whereas T-cell lymphoproliferative disorders are relatively rare (4–8%). Only a small number of methotrexate-associated T-cell lymphoproliferative disorders have been detailed thus far. Because of the rarity, methotrexate-associated T-cell lymphoproliferative disorder has not been well studied and its clinicopathological characteristics are unknown. A total of 28 cases of methotrexate-associated T-cell lymphoproliferative disorders were retrospectively analyzed. Histologically and immunohistochemically, they were divided into three main types: angioimmunoblastic T-cell lymphoma (n = 19), peripheral T-cell lymphoma, NOS (n = 6), and CD8+ cytotoxic T-cell lymphoma (n = 3). Among the 28 cases, only one CD8+ cytotoxic T-cell lymphoma case was Epstein-Barr virus-positive. The other 27 cases were negative for Epstein-Barr virus on tumor cells, but scattered Epstein-Barr virus-infected B-cells were detected in 24 cases (89%), implying the reactivation of Epstein-Barr virus caused by immunodeficient status of the patients. After the diagnosis of methotrexate-associated T-cell lymphoproliferative disorder, methotrexate was immediately withdrawn in 26 cases. Twenty (77%) cases presented with spontaneous regression. Compared to methotrexate-associated B-cell lymphoproliferative disorder, patients with methotrexate-associated T-cell lymphoproliferative disorder had a significantly higher proportion of males (p = 0.035) and presence of B-symptoms (p = 0.036), and lower proportion of Epstein-Barr virus+ tumor cells (p < 0.001). Although the difference was not significant, the methotrexate-associated T-cell lymphoproliferative disorder also had more frequent spontaneous regression (p = 0.061). In conclusion, methotrexate-associated T-cell lymphoproliferative disorder was divided into three main types: angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, NOS, and CD8+ cytotoxic T-cell lymphoma. Angioimmunoblastic T-cell lymphoma was the most common type. Methotrexate-associated T-cell lymphoproliferative disorder was characterized by a high rate of spontaneous regression after methotrexate cessation. Epstein-Barr virus positivity was relatively rare in methotrexate-associated T-cell lymphoproliferative disorder, significantly less frequent than methotrexate-associated B-cell lymphoproliferative disorder, suggesting different pathogenesis.

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  1. 1.

    Rath T, Rubbert A. Drug combinations with methotrexate to treat rheumatoid arthritis. Clin Exp Rheumatol. 2010;28:S52–7.

  2. 2.

    Bernatsky S, Clarke AE, Suissa S. Hematologic malignant neoplasms after drug exposure in rheumatoid arthritis. Arch Intern Med. 2008;168:378–81.

  3. 3.

    Gaulard P, Swerdlow SH, Harris NL, et al. Other iatrogenic immunodeficiency-associated lymphoproliferative disorders. In: Swerdlow SH, Campo E, Harris NL, et al. editors. World Health Organization classification of tumours of hematopoietic and lymphoid tissue. Revised 4th edn. Lyon, France: International Agency of Research on Cancer; 2017. p. 462–4.

  4. 4.

    Thomas E, Brewster DH, Black RJ, Macfarlane GJ. Risk of malignancy among patients with rheumatic conditions. Int J Cancer. 2000;88:497–502.

  5. 5.

    Mellemkjaer L, Linet MS, Gridley G, et al. Rheumatoid arthritis and cancer risk. Eur J Cancer. 1996;32a:1753–7.

  6. 6.

    Gridley G, McLaughlin JK, Ekbom A, et al. Incidence of cancer among patients with rheumatoid arthritis. J Natl Cancer Inst. 1993;85:307–11.

  7. 7.

    Hoshida Y, Xu JX, Fujita S, et al. Lymphoproliferative disorders in rheumatoid arthritis: clinicopathological analysis of 76 cases in relation to methotrexate medication. J Rheumatol. 2007;34:322–31.

  8. 8.

    Ichikawa A, Arakawa F, Kiyasu J, et al. Methotrexate/iatrogenic lymphoproliferative disorders in rheumatoid arthritis: histology, Epstein-Barr virus, and clonality are important predictors of disease progression and regression. Eur J Haematol. 2013;91:20–8.

  9. 9.

    Mariette X, Cazals-Hatem D, Warszawki J, et al. Lymphomas in rheumatoid arthritis patients treated with methotrexate: a 3-year prospective study in France. Blood. 2002;99:3909–15.

  10. 10.

    Yamakawa N, Fujimoto M, Kawabata D, et al. A clinical, pathological, and genetic characterization of methotrexate-associated lymphoproliferative disorders. J Rheumatol. 2014;41:293–9.

  11. 11.

    Gion Y, Iwaki N, Takata K, et al. Clinicopathological analysis of methotrexate-associated lymphoproliferative disorders: Comparison of diffuse large B-cell lymphoma and classical Hodgkin lymphoma types. Cancer Sci. 2017;108:1271–80.

  12. 12.

    Hatanaka K, Nakamura N, Kojima M, et al. Methotrexate-associated lymphoproliferative disorders mimicking angioimmunoblastic T-cell lymphoma. Pathol Res Pract. 2010;206:9–13.

  13. 13.

    Ishibuchi H, Motegi S, Yamanaka M, Amano H, Ishikawa O. Methotrexate-associated lymphoproliferative disorder: Sequential development of angioimmunoblastic T-cell lymphoma-like lymphoproliferation in the lymph nodes and diffuse large B-cell lymphoma in the skin in the same patient. Eur J Dermatol. 2015;25:361–2.

  14. 14.

    Claudino WM, Gibson B, Tse W, Krem M, Grewal J. Methotrexate-associated primary cutaneous CD30-positive cutaneous T-cell lymphoproliferative disorder: a case illustration and a brief review. Am J Blood Res. 2016;6:1–5.

  15. 15.

    Saleh JZ, Lee LH, Schieke SM, Hosking PR, Hwang ST. Methotrexate-induced CD30(+) T-cell lymphoproliferative disorder of the oral cavity. JAAD Case Rep. 2016;2:354–6.

  16. 16.

    Nemoto Y, Taniguchi A, Kamioka M, et al. Epstein-Barr virus-infected subcutaneous panniculitis-like T-cell lymphoma associated with methotrexate treatment. Int J Hematol. 2010;92:364–8.

  17. 17.

    Koji H, Yazawa T, Nakabayashi K, et al. CD8-positive T-cell lymphoproliferative disorder associated with Epstein-Barr virus-infected B-cells in a rheumatoid arthritis patient under methotrexate treatment. Mod Rheumatol. 2016;26:271–5.

  18. 18.

    Hatachi S, Kunitomi A, Aozasa K, Yagita M. CD8(+) T-cell lymphoproliferative disorder associated with Epstein-Barr virus in a patient with rheumatoid arthritis during methotrexate therapy. Mod Rheumatol. 2010;20:500–5.

  19. 19.

    Takajo I, Umekita K, Ikei Y, Oshima K, Okayama A. Adult T-cell leukemia/lymphoma as a methotrexate-associated lymphoproliferative disorder in a patient with rheumatoid arthritis. Intern Med. 2018;57:2071–5.

  20. 20.

    Tokunaga T, Shimada K, Yamamoto K, et al. Retrospective analysis of prognostic factors for angioimmunoblastic T-cell lymphoma: a multicenter cooperative study in Japan. Blood. 2012;119:2837–43.

  21. 21.

    Asano N, Suzuki R, Kagami Y, et al. Clinicopathologic and prognostic significance of cytotoxic molecule expression in nodal peripheral T-cell lymphoma, unspecified. Am J Surg Pathol. 2005;29:1284–93.

  22. 22.

    van Dongen JJ, Langerak AW, Bruggemann M, et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia. 2003;17:2257–317.

  23. 23.

    Attygalle AD, Kyriakou C, Dupuis J, et al. Histologic evolution of angioimmunoblastic T-cell lymphoma in consecutive biopsies: clinical correlation and insights into natural history and disease progression. Am J Surg Pathol. 2007;31:1077–88.

  24. 24.

    Willenbrock K, Brauninger A, Hansmann ML. Frequent occurrence of B-cell lymphomas in angioimmunoblastic T-cell lymphoma and proliferation of Epstein-Barr virus-infected cells in early cases. Br J Haematol. 2007;138:733–9.

  25. 25.

    Feng WH, Cohen JI, Fischer S, et al. Reactivation of latent Epstein-Barr virus by methotrexate: a potential contributor to methotrexate-associated lymphomas. J Natl Cancer Inst. 2004;96:1691–702.

  26. 26.

    Landais E, Saulquin X, Houssaint E. The human T cell immune response to Epstein-Barr virus. Int J Dev Biol. 2005;49:285–92.

  27. 27.

    Dunleavy K, Wilson WH. Angioimmunoblastic T-cell lymphoma: immune modulation as a therapeutic strategy. Leuk Lymphoma. 2007;48:449–51.

  28. 28.

    Dunleavy K, Wilson WH, Jaffe ES. Angioimmunoblastic T cell lymphoma: pathobiological insights and clinical implications. Curr Opin Hematol. 2007;14:348–53.

  29. 29.

    Masucci MG, Ernberg I. Epstein-Barr virus: adaptation to a life within the immune system. Trends Microbiol. 1994;2:125–30.

  30. 30.

    Callan MF, Steven N, Krausa P, et al. Large clonal expansions of CD8+ T cells in acute infectious mononucleosis. Nat Med. 1996;2:906–11.

  31. 31.

    Sandhu A, Ahmad S, Kaur P, et al. Methotrexate preferentially affects Tc1 and Tc17 subset of CD8 T lymphocytes. Clinical Rheumatol. 2019;38:37–44.

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This work was supported in part by grants from the Grants-in-Aid for Scientific Research, grant number 18K15104.

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The authors declare that they have no conflict of interest.

Correspondence to Akira Satou.

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