Immunophenotypic analysis of cerebrospinal fluid reveals concurrent development of ATL in the CNS of a HAM/TSP patient


Both adult T-cell leukemia/lymphoma (ATL) and human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) can be induced by HTLV-1, but concurrent development has been rarely reported. We present the case of a 55-year-old female who developed cranial nerve symptoms after a 20-year history of HAM/TSP. Although multiple white matter lesions were observed on brain magnetic resonance imaging, no abnormalities were seen on a systemic computed tomography scan. Quantitative flow-cytometric analysis of cell populations in the cerebrospinal fluid (CSF) revealed that most of the infiltrating cells were not inflammatory cells, but HTLV-1-infected CD4+ CADM-1+ T-cells completely lacking CD7 expression. As stepwise downregulation of CD7 is correlated with disease progression from HTLV-1 carrier to aggressive ATL, the CSF cells were classified as aggressive ATL; these cells exhibited a more progressed phenotype than those in peripheral blood (PB). HAM/TSP disease activity was estimated to be low. From these and other examinations, we made a diagnosis of acute-type ATL, which unusually developed in the central nervous system at initial onset prior to systemic progression. In ATL cases with a challenging diagnosis, immunophenotypic characterization of CSF and PB is valuable for differential diagnosis and understanding disease status.

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  1. 1.

    Gessain A, Cassar O. Epidemiological aspects and world distribution of HTLV-1 infection. Front Microbiol. 2012;3:388.

  2. 2.

    Yamano Y, Sato T. Clinical pathophysiology of human T-lymphotropic virus-type 1-associated myelopathy/tropical spastic paraparesis. Front Microbiol. 2012;3:389.

  3. 3.

    Nosaka K, Iwanaga M, Imaizumi Y, Ishitsuka K, Ishizawa K, Ishida Y, et al. Epidemiological and clinical features of adult T-cell leukemia-lymphoma in Japan, 2010–2011: a nationwide survey. Cancer Sci. 2017;108:2478–86.

  4. 4.

    Araya N, Sato T, Yagishita N, Ando H, Utsunomiya A, Jacobson S, et al. Human T-lymphotropic virus type 1 (HTLV-1) and regulatory T cells in HTLV-1-associated neuroinflammatory disease. Viruses. 2011;3:1532–48.

  5. 5.

    Araya N, Sato T, Ando H, Tomaru U, Yoshida M, Coler-Reilly A, et al. HTLV-1 induces a Th1-like state in CD4 + CCR4 + T cells. J Clin Investig. 2014;124:3431–42.

  6. 6.

    Furukawa Y, Okadome T, Tara M, Niina K, Izumo S, Osame M. Human T-cell lymphotropic virus type-I (HTLV-I)-associated myelopathy/tropical spastic paraparesis with acute type of adult T-cell leukemia. Intern Med. 1995;34:1130–3.

  7. 7.

    Ishigaki T, Kobayashi S, Zaike Y, Watanabe E, Sato N, Ohno N, et al. Establishment of flow cytometric methods for evaluation of adult T-cell leukemia and their clinical application. Cytom Res. 2014;24(2):33–9 (Japanese).

  8. 8.

    Kobayashi S, Tian Y, Ohno N, Yuji K, Ishigaki T, Isobe M, et al. The CD3 versus CD7 plot in multicolor flow cytometry reflects progression of disease stage in patients infected with HTLV-I. PLoS ONE. 2013;8:e53728.

  9. 9.

    Kobayashi S, Nakano K, Watanabe E, Ishigaki T, Ohno N, Yuji K, et al. CADM1 expression and stepwise downregulation of CD7 are closely associated with clonal expansion of HTLV-I-infected cells in adult T-cell leukemia/lymphoma. Clin Cancer Res. 2014;20:2851–61.

  10. 10.

    Kobayashi S, Watanabe E, Ishigaki T, Ohno N, Yuji K, Nakano K, et al. Advanced human T-cell leukemia virus type 1 carriers and early-stage indolent adult T-cell leukemia-lymphoma are indistinguishable based on CADM1 positivity in flow cytometry. Cancer Sci. 2015;106:598–603.

  11. 11.

    Shimoyama M. Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984–1987). Br J Haematol. 1991;79:428–43718.

  12. 12.

    Kitajima M, Korogi Y, Shigematsu Y, Liang L, Matsuoka M, Yamamoto T, et al. Central nervous system lesions in adult T-cell leukaemia: MRI and pathology. Neuroradiology. 2002;44:559–67.

  13. 13.

    Dungerwalla M, Osuji N, Waldman AD, Al Jehani F, Mehta A, Tailor R, et al. Isolated central nervous system involvement in adult T-cell lymphoma/leukaemia. Br J Haematol. 2005;130:511–5.

  14. 14.

    Tsukasaki K, Tobinai K. Clinical trials and treatment of ATL. Leuk Res Treat. 2012;2012:101754.

  15. 15.

    Sato T, Coler-Reilly A, Utsunomiya A, Araya N, Yagishita N, Ando H, et al. CSF CXCL10, CXCL9, and neopterin as candidate prognostic biomarkers for HTLV-1-associated myelopathy/tropical spastic paraparesis. PLoS Negl Trop Dis. 2013;7:e2479.

  16. 16.

    Sato T, Yagishita N, Tamaki K, Inoue E, Hasegawa D, Nagasaka M, et al. Proposal of classification criteria for HTLV-1-associated myelopathy/tropical spastic paraparesis disease activity. Front Microbiol. 2018;9:1651.

  17. 17.

    van Westrhenen A, Smidt LCA, Seute T, Nierkens S, Stork ACJ, Minnema MC, et al. Diagnostic markers for CNS lymphoma in blood and cerebrospinal fluid: a systematic review. Br J Haematol. 2018;182(3):384–403.

  18. 18.

    Uozumi K, Ishitsuka K, Ohno N, Nakahara K, Utsunomiya A, Hanada S, et al. Significance of elevated levels of soluble factors in the cerebrospinal fluid in patients with adult T-cell leukemia. Leuk Lymphoma. 1995;19:437–45.

  19. 19.

    Haldorsen IS, Espeland A, Larsson EM. Central nervous system lymphoma: characteristic findings on traditional and advanced imaging. AJNR Am J Neuroradiol. 2011;32:984–92.

  20. 20.

    Hu X, Laguerre V, Packert D, Nakasone A, Moscinski L. A simple and efficient method for preparing cell slides and staining without using cytocentrifuge and cytoclips. Int J Cell Biol. 2015;2015:813216.

  21. 21.

    Scott BJ, Douglas VC, Tihan T, Rubenstein JL, Josephson SA. A systematic approach to the diagnosis of suspected central nervous system lymphoma. JAMA Neurol. 2013;70(3):311–9.

  22. 22.

    Makiyama J, Kobayashi S, Watanabe E, Ishigaki T, Kawamata T, et al. CD4 + CADM1 + cell percentage predicts disease progression in HTLV-1 carriers and indolent adult T-cell leukemia/lymphoma. Cancer Sci. 2019;110(12):3746–53.

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Correspondence to Tomohiro Ishigaki.

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Takeda, R., Ishigaki, T., Ohno, N. et al. Immunophenotypic analysis of cerebrospinal fluid reveals concurrent development of ATL in the CNS of a HAM/TSP patient. Int J Hematol (2020).

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  • Adult T-cell leukemia/lymphoma (ATL)
  • HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP)
  • Multi-color flow cytometry
  • Central nervous system involvement