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Insights into the biology of primary central nervous system lymphoma

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Abstract

Primary central nervous system lymphoma (PCNSL) is a rare variant of non-Hodgkin lymphoma that is confined to the central nervous system. Biologic studies of PCNSL are challenging to conduct because the disease is rare and available tissue material is sparse. However, in recent years there has been progress in the understanding of PCNSL biology, largely as the result of multicenter studies using modern molecular techniques. Recent studies may improve insight into the pathogenesis of PCNSL and increase the chances of identifying prognostic factors and novel therapeutic targets. This review discusses recent advances in PCNSL biology, including immunologic and genetic risk factors, and focuses on the molecular alterations important in central nervous system lymphomagenesis.

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References and Recommended Reading

  1. Pfannl R, Harris FJ: Pathology of primary central nervous system lymphoma and related conditions. In Lymphoma of the Nervous System. Edited by Batchelor TT. Boston: Butterworth-Heinemann; 2004:29–41.

    Google Scholar 

  2. Eby NL, Grufferman S, Flannelly CM, et al.: Increasing incidence of primary brain lymphoma in the US. Cancer 1988, 62:2461–2465.

    Article  PubMed  CAS  Google Scholar 

  3. O’Neill BP: Epidemiology of PCNSL. In Lymphoma of the Nervous System. Edited by Batchelor TT. Boston: Butterworth-Heinemann; 2004:43–51.

    Google Scholar 

  4. Kadan-Lottick NS, Skluzacek MC, Gurney JG: Decreasing incidence rates of primary central nervous system lymphoma. Cancer 2002, 95:193–202.

    Article  PubMed  Google Scholar 

  5. CBTRUS, Statistical Report: Primary Brain Tumors in the United States 1998–2002. Chicago: Central Brain Tumor Registry of the United States; 2005–2006.

    Google Scholar 

  6. Fine HA, Mayer RJ: Primary central nervous system lymphoma. Ann Intern Med 1993, 119:1093–1104.

    PubMed  CAS  Google Scholar 

  7. Schabet M: Epidemiology of primary CNS lymphoma. J Neurooncol 1999, 43:199–201.

    Article  PubMed  CAS  Google Scholar 

  8. Coté TR, Manns A, Hardy CR, et al.: Epidemiology of brain lymphoma among people with or without acquired immunodeficiency syndrome. AIDS/Cancer Study Group. J Natl Cancer Inst 1996, 88:675–679.

    Article  PubMed  Google Scholar 

  9. Bashir R, Chamberlain M, Ruby E, Hochberg FH: T-cell infiltration of primary CNS lymphoma. Neurology 1996, 46:440–444.

    PubMed  CAS  Google Scholar 

  10. Ferry J, Harris N: Pathology of post-transplant lymphoproliferative disorders. In Pathology and Rejection Diagnosis in Solid Organ Transplantation. Edited by Solez K, Racusen LC, Billingham ME. New York: Marcel Dekker; 1994:277–301.

    Google Scholar 

  11. Linnebank M, Schmidt S, Kölsch H, et al.: The methionine synthase polymorphism D919G alters susceptibility to primary central nervous system lymphoma. Br J Cancer 2004, 90:1969–1971.

    Article  PubMed  CAS  Google Scholar 

  12. Riemersma SA, Oudejans JJ, Vonk MJ, et al.: High numbers of tumour-infiltrating activated cytotoxic T lymphocytes, and frequent loss of HLA class I and II expression, are features of aggressive B cell lymphomas of the brain and testis. J Pathol 2005, 206:328–336.

    Article  PubMed  CAS  Google Scholar 

  13. Lossos IS: Molecular pathogenesis of diffuse large B-cell lymphoma. J Clin Oncol 2005, 23:6351–6357.

    Article  PubMed  CAS  Google Scholar 

  14. Thompsett AR, Ellison DW, Stevenson FK, Zhu D: V(H) gene sequences from primary central nervous system lymphomas indicate derivation from highly mutated germinal center B cells with ongoing mutational activity. Blood 1999, 94:1738–1746.

    PubMed  CAS  Google Scholar 

  15. Alizadeh AA, Eisen MB, Davis RE, et al.: Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000, 403:503–511.

    Article  PubMed  CAS  Google Scholar 

  16. Rosenwald A, Wright G, Chan WC, et al.; Lymphoma/Leukemia Molecular Profiling Project: The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 2002, 346:1937–1947.

    Article  PubMed  Google Scholar 

  17. Lossos IS, Alizadeh AA, Eisen MB, et al.: Ongoing immunoglobulin somatic mutation in germinal center B cell-like but not in activated B cell-like diffuse large cell lymphomas. Proc Natl Acad Sci U S A 2000, 97:10209–10213.

    Article  PubMed  CAS  Google Scholar 

  18. Larocca LM, Capello D, Rinelli A, et al.: The molecular and phenotypic profile of primary central nervous system lymphoma identifies distinct categories of the disease and is consistent with histogenetic derivation from germinal center-related B cells. Blood 1998, 92:1011–1019.

    PubMed  CAS  Google Scholar 

  19. Montesinos-Rongen M, Küppers R, Schlüter D, et al.: Primary central nervous system lymphomas are derived from germinalcenter B cells and show a preferential usage of the V4-34 gene segment. Am J Pathol 1999, 155:2077–2086.

    PubMed  CAS  Google Scholar 

  20. Braaten KM, Betensky RA, de Leval L, et al.: BCL-6 expression predicts improved survival in patients with primary central nervous system lymphoma. Clin Cancer Res 2003, 9:1063–1069.

    PubMed  CAS  Google Scholar 

  21. Roychowdhury S, Peng R, Baiocchi RA, et al.: Experimental treatment of Epstein-Barr virus-associated primary central nervous system lymphoma. Cancer Res 2003, 63:965–971.

    PubMed  CAS  Google Scholar 

  22. Tanner JE, Alfieri C: The Epstein-Barr virus and posttransplant lymphoproliferative disease: interplay of immunosuppression, EBV, and the immune system in disease pathogenesis. Transpl Infect Dis 2001, 3:60–69.

    Article  PubMed  CAS  Google Scholar 

  23. Thomas JA, Crawford DH, Burke M: Clinicopathologic implications of Epstein-Barr virus related B cell lymphoma in immunocompromised patients. J Clin Pathol 1995, 48:287–290.

    Article  PubMed  CAS  Google Scholar 

  24. Penn I: The role of immunosuppression in lymphoma formation. Springer Semin Immunopathol 1998, 20:343–355.

    Article  PubMed  CAS  Google Scholar 

  25. Cingolani A, Gastaldi R, Fassone L, et al.: Epstein-Barr virus infection is predictive of CNS involvement in systemic AIDSrelated non-Hodgkin’s lymphomas. J Clin Oncol 2000, 18:3325–3330.

    PubMed  CAS  Google Scholar 

  26. Meeker TC, Shiramizu B, Kaplan L, et al.: Evidence for molecular subtypes of HIV-associated lymphoma: division into peripheral monoclonal, polyclonal and central nervous system lymphoma. AIDS 1991, 5:669–674.

    Article  PubMed  CAS  Google Scholar 

  27. Rubin N, Chamberlain M: Primary central nervous system lymphoma in acquired immune deficiency syndrome. In Lymphoma of the Nervous System. Edited by Batchelor TT. Boston: Butterworth-Heinemann; 2004:97–103.

    Google Scholar 

  28. Del Valle L, Enam S, Lara C, et al.: Primary central nervous system lymphoma expressing the human neurotropic polyomavirus, JC virus, genome. J Virol 2004, 78:3462–3469.

    Article  PubMed  CAS  Google Scholar 

  29. Montesinos-Rongen M, Besleaga R, Heinsohn S, et al.: Absence of simian virus 40 DNA sequences in primary central nervous system lymphoma in HIV-negative patients. Virchows Arch 2004, 444:436–438.

    Article  PubMed  Google Scholar 

  30. Rubenstein JL, Shen A, Fridlyand J, et al.: Gene expression profile analysis of primary CNS lymphoma: class distinction and outcome prediction. Presented at the Eighth Annual Meeting of the Society for Neuro-Oncology. Keystone, CO; November 13–16, 2003.

  31. Rubenstein JL, Fridlyand J, Shen A, et al.: Gene expression and angiotropism in primary CNS lymphoma. Blood 2006, 107:3716–3723.

    Article  PubMed  CAS  Google Scholar 

  32. Park HR, Tomida A, Sato S, et al.: Effect on tumor cells of blocking survival response to glucose deprivation. J Natl Cancer Inst 2004, 96:1300–1310.

    Article  PubMed  CAS  Google Scholar 

  33. Kadoch C, Treseler P, Rubenstein JL: Molecular pathogenesis of primary central nervous system lymphoma. Neurosurg Focus 2006, 21:E1.

    Article  PubMed  Google Scholar 

  34. Tun HW, Personett D, Baskerville KA, et al.: Pathway analysis of primary central nervous system lymphoma. Blood 2008, 111:3200–3210.

    Article  PubMed  CAS  Google Scholar 

  35. El-Tanani MK, Campbell FC, Kurisetty V, et al.: The regulation and role of osteopontin in malignant transformation and cancer. Cytokine Growth Factor Rev 2006, 17:463–474.

    Article  PubMed  CAS  Google Scholar 

  36. Chabas D, Baranzini SE, Mitchell D, et al.: The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 2001, 294:1731–1735.

    Article  PubMed  CAS  Google Scholar 

  37. Johansen JS, Jensen BV, Roslind A, Price PA: Is YKL-40 a new therapeutic target in cancer? Expert Opin Ther Targets 2007, 11:219–234.

    Article  PubMed  CAS  Google Scholar 

  38. Kim SH, Das K, Noreen S, et al.: Prognostic implications of immunohistochemically detected YKL-40 expression in breast cancer. World J Surg Oncol 2007, 5:17.

    Article  PubMed  Google Scholar 

  39. Karabatsou K, Pal P, Dodd S, et al.: Expression of survivin, platelet-derived growth factor A (PDGF-A) and PDGF receptor alpha in primary central nervous system lymphoma. J Neurooncol 2006, 79:171–179.

    Article  PubMed  CAS  Google Scholar 

  40. Lossos IS, Czerwinski DK, Alizadeh AA, et al.: Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. N Engl J Med 2004, 350:1828–1837.

    Article  PubMed  CAS  Google Scholar 

  41. Courts C, Montesinos-Rongen M, Brunn A, et al.: Recurrent inactivation of the PRDM1 gene in primary central nervous system lymphoma. J Neuropathol Exp Neurol 2008, 67:720–727.

    Article  PubMed  CAS  Google Scholar 

  42. Montesinos-Rongen M, Van Roost D, Schaller C, et al.: Primary diffuse large B-cell lymphomas of the central nervous system are targeted by aberrant somatic hypermutation. Blood 2004, 103:1869–1875.

    Article  PubMed  CAS  Google Scholar 

  43. Nakamura M, Sakaki T, Hashimoto H, et al.: Frequent alterations of the p14(ARF) and p16(INK4a) genes in primary central nervous system lymphomas. Cancer Res 2001, 61:6335–6339.

    PubMed  CAS  Google Scholar 

  44. Kamijo T, Bodner S, van de Kamp E, et al.: Tumor spectrum in ARF-deficient mice. Cancer Res 1999, 59:2217–2222.

    PubMed  CAS  Google Scholar 

  45. Rubenstein JL, Treseler P, O’Brien JM: Pathology and genetics of primary central nervous system and intraocular lymphoma. Hematol Oncol Clin North Am 2005, 19:705–717, vii.

    Article  PubMed  Google Scholar 

  46. Nakamura M, Shimada K, Ishida E, Konishi N: Histopathology, pathogenesis and molecular genetics in primary central nervous system lymphomas. Histol Histopathol 2004,19:211–219.

    PubMed  CAS  Google Scholar 

  47. Harada K, Nishizaki T, Kubota H, et al.: Distinct primary central nervous system lymphoma defined by comparative genomic hybridization and laser scanning cytometry. Cancer Genet Cytogenet 2001, 125:147–150.

    Article  PubMed  CAS  Google Scholar 

  48. Montesinos-Rongen M, Zühlke-Jenisch R, Gesk S, et al.: Interphase cytogenetic analysis of lymphoma-associated chromosomal breakpoints in primary diffuse large B-cell lymphomas of the central nervous system. J Neuropathol Exp Neurol 2002, 61:926–933.

    PubMed  CAS  Google Scholar 

  49. Fujii A, Ohshima K, Hamasaki M, et al.: Differential expression of chemokines, chemokine receptors, cytokines and cytokine receptors in diffuse large B cell malignant lymphoma. Int J Oncol 2004, 24:529–538.

    PubMed  CAS  Google Scholar 

  50. Smith JR, Braziel RM, Paoletti S, et al.: Expression of B-cell-attracting chemokine 1 (CXCL13) by malignant lymphocytes and vascular endothelium in primary central nervous system lymphoma. Blood 2003, 101:815–821.

    Article  PubMed  CAS  Google Scholar 

  51. Roy S, Josephson SA, Fridlyand J, et al.: Protein biomarker identification in the CSF of patients with CNS lymphoma. J Clin Oncol 2008, 26:96–105.

    Article  PubMed  CAS  Google Scholar 

  52. Falini B, Fizzotti M, Pileri S, et al.: Bcl-6 protein expression in normal and neoplastic lymphoid tissues. Ann Oncol 1997, 8(Suppl 2):101–104.

    Article  PubMed  Google Scholar 

  53. Dogan A, Bagdi E, Munson P, Isaacson PG: CD10 and BCL-6 expression in paraffin sections of normal lymphoid tissue and B-cell lymphomas. Am J Surg Pathol 2000, 24:846–852.

    Article  PubMed  CAS  Google Scholar 

  54. Levy O, Deangelis LM, Filippa DA, et al.: Bcl-6 predicts improved prognosis in primary central nervous system lymphoma. Cancer 2008, 112:151–156.

    Article  PubMed  Google Scholar 

  55. Lin CH, Kuo KT, Chuang SS, et al.: Comparison of the expression and prognostic significance of differentiation markers between diffuse large B-cell lymphoma of central nervous system origin and peripheral nodal origin. Clin Cancer Res 2006, 12:1152–1156.

    Article  PubMed  CAS  Google Scholar 

  56. Ponzoni M, Berger F, Chassagne-Clement C, et al.; International Extranodal Lymphoma Study Group: Reactive perivascular T-cell infiltrate predicts survival in primary central nervous system B-cell lymphomas. Br J Haematol 2007, 138:316–323.

    Article  PubMed  CAS  Google Scholar 

  57. Weber T, Weber RG, Kaulich K, et al.: Characteristic chromosomal imbalances in primary central nervous system lymphomas of the diffuse large B-cell type. Brain Pathol 2000, 10:73–84.

    PubMed  CAS  Google Scholar 

  58. Nakamura M, Kishi M, Sakaki T, et al.: Novel tumor suppressor loci on 6q22–23 in primary central nervous system lymphomas. Cancer Res 2003, 63:737–741.

    PubMed  CAS  Google Scholar 

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Correspondence to Tracy T. Batchelor.

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Mrugala, M.M., Rubenstein, J.L., Ponzoni, M. et al. Insights into the biology of primary central nervous system lymphoma. Curr Oncol Rep 11, 73–80 (2009). https://doi.org/10.1007/s11912-009-0012-8

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