Biology and treatment of primary central nervous system lymphoma Authors
Cite this article as: Algazi, A.P., Kadoch, C. & Rubenstein, J.L. Neurotherapeutics (2009) 6: 587. doi:10.1016/j.nurt.2009.04.013 Summary
Primary central nervous system lymphoma (PCNSL) is a rare variant of extranodal non-Hodgkin lymphoma that is restricted in distribution to the brain, leptomeninges, spinal cord, and intraocular compartments. Although PCNSL shares overlapping features with systemic lymphoma, recent studies also reveal a unique pattern of gene and protein expression in PCNSL. These findings have yielded new insights into the pathophysiology of the disease, as well as the identification of novel prognostic biomarkers. Immune system compromise, such as is seen in acquired immune deficiency syndrome (AIDS), is the best established known risk factor for PCNSL. Like other lesions of the brain, meninges, and eye, the presenting symptoms associated with PCNSL typically include focal neurological deficits related to the site of disease or more global consequences of increased intracranial pressure. Diagnosis of PCNSL typically includes gadolinium-enhanced MRI and pathologic tissue analysis, as well as additional studies aimed at excluding concurrent systemic disease. PCNSL typically has a worse overall prognosis than systemic lymphoma. High-dose chemotherapy, particularly with methotrexate-based regimens, is the backbone of therapy for most patients, and chemotherapy is associated with much lower rates of treatment-related morbidity and mortality than whole-brain irradiation. Autologous stem cell transplantation is an emerging treatment modality, particularly in younger patients with relapsed disease, but high rates of treatment-related mortality are observed in older patients. Immunotherapy, including treatment with intrathecal rituximab, is another area of active research that may have promise in refractory or relapsed disease. Treatment options for intraocular lymphoma parallel those for PCNSL elsewhere in the brain: systemic chemotherapy, radiation, and local delivery of cytotoxic and immunologically active agents such as anti-CD20 antibody.
Key Words Brain tumor treatment gene expression pathobiology immunotherapy Download to read the full article text References
Hochberg FH, Baehring JM, Hochberg EP. Primary CNS lymphoma. Nat Clin Pract Neurol 2007;3: 24–35.
Fine HA, Mayer RJ. Primary central nervous system lymphoma. Ann Intern Med 1993;119: 1093–1104.
Cote TR, Manns A, Hardy CR, Yellin FJ, Hartge P; AIDS/Cancer Study Group. Epidemiology of brain lymphoma among people with or without acquired immunodeficiency syndrome. J Natl Cancer Inst 1996;88: 675–679.
Diamond C, Taylor TH, Aboumrad T, Anton-Culver H. Changes in acquired immunodeficiency syndrome-related non-Hodgkin lymphoma in the era of highly active antiretroviral therapy: incidence, presentation, treatment, and survival. Cancer 2006;106: 128–135.
Kadoch C, Treseler P, Rubenstein JL. Molecular pathogenesis of primary central nervous system lymphoma. Neurosurg Focus 2006;21(5): E1.
Montesinos-Rongen M, Kuppers R, Schluter D, et al. Primary central nervous system lymphomas are derived from germinal-center B cells and show a preferential usage of the V4-34 gene segment. Am J Pathol 1999;155: 2077–2086.
Camilleri-Broët S, Crinière E, Broët P, et al. A uniform activated B-cell-like immunophenotype might explain the poor prognosis of primary central nervous system lymphomas: analysis of 83 cases. Blood 2006;107: 190–196.
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.
Rubenstein JL, Fridlyand J, Shen A, et al. Gene expression and angiotropism in primary CNS lymphoma. Blood 2006;107: 3716–3723.
Montesinos-Rongen M, Van Roost D, Schaller C, Wiestler OD, Deckert M. Primary diffuse large B-cell lymphomas of the central nervous system are targeted by aberrant somatic hypermutation. Blood 2004;103: 1869–1875.
Rubenstein JL, Shen A, Fridlyand J, et al. Gene expression profile analysis of primary CNS lymphoma: class distinction and outcome prediction. Proc Am Assoc Cancer Res 2004;45:abstract 4433.
Tun HW, Personett D, Baskerville KA, et al. Pathway analysis of primary central nervous system lymphoma. Blood 2008;111: 3200–3210.
Han JI, Huang NN, Kim DU, Kehrl JH. RGS1 and RGS13 mRNA silencing in a human B lymphoma line enhances responsiveness to chemoattractants and impairs desensitization. J Leukoc Biol 2006;79: 1357–1368.
Cobbers JM, Wolter M, Reifenberger J, et al. Frequent inactivation of
and rare mutation of
in PCNSL. Brain Pathol 1998;8: 263–276.
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.
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.
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.
Mazzucchelli L, Blaser A, Rappeler A, et al. BCA-1 is highly expressed in
-induced mucosa-associated lymphoid tissue and gastric lymphoma. J Clin Invest 1999;104: R49-R54.
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.
Antinori A, De Rossi G, Ammassari A, et al. Value of combined approach with thallium-201 single-photon emission computed tomography and Epstein-Barr viras DNA polymerase chain reaction in CSF for the diagnosis of AIDS-related primary CNS lymphoma. J Clin Oncol 1999;17: 554–560.
Bossolasco S, Cinque P, Ponzoni M, et al. Epstein-Barr virus DNA load in cerebrospinal fluid and plasma of patients with AIDS-related lymphoma. J Neurovirol 2002;8: 432–438.
Klemschmidt-DeMasters BK, Damek DM, Lillehei KO, Dogan A, Giannini C. Epstein Barr virus-associated primary CNS lymphomas in elderly patients on immunosuppressive medications. J Neuropathol Exp Neurol 2008;67: 1103–111.
Penn I. The role of immunosuppression in lymphoma formation. Springer Semin Immunopathol 1998;20: 343–355.
Cingolani A, Gastaldi R, Fassone L, et al. Epsteiu-Barr virus infection is predictive of CNS involvement in systemic AIDS-related non-Hodgkin’s lymphomas. J Clin Oncol 2000: 18: 3325–3330.
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.
Kadan-Lottick NS, Skluzacek MC, Gurney JG. Decreasing incidence rates of primary central nervous system lymphoma. Cancer 2002;95: 193–202.
Schabet M. Epidemiology of primary CNS lymphoma. J Neurooncol 1999;43: 199–201.
Penu I, Porat G. Central nervous system lymphomas in organ allograft recipients. Transplantation 1995;59: 240–244.
Olson JE, Janney CA, Rao RD, et al. The continuing increase in the incidence of primary central nervous system non-Hodgkin lymphoma: a Surveillance. Epidemiology, and End Results analysis. Cancer 2002;95: 1504–1510.
Hochberg FH, Batchelor T, Loeffler JS. Clinical presentation, pathologic features, and diagnosis of primary central nervous system lymphoma. Available at: http://www.uptodate.com. Last updated: Nov. 13, 2008; last literature review version 17.1: January 2009. Accessed April 24, 2009.
Hormigo A, Abrey L, Heinemann MH, DeAngelis LM. Ocular presentation of primary central nervous system lymphoma: diagnosis and treatment. Br J Haematol 2004;126: 202–208.
Park S, Abad S, Tulliez M, et al. Pseudouveitis: a clue to the diagnosis of primary central nervous system lymphoma in immunocompetent patients. Medicine (Baltimore) 2004;83: 223–232.
Buhring U, Herrlinger U, Krings T, Thiex R, Weller M, Küker W. MRI features of primary central nervous system lymphomas at presentation. Neurology 2001;57: 393–396.
Cha S, Knopp EA, Johnson G, et al. Intracranial mass lesions: dynamic contrast-enhanced susceptibility-weighted echo-planar perfusion MR imaging. Radiology 2002;223: 11–29.
Guo AC, Cummings TJ, Dash RC, Provenzale JM. Lymphomas and high-grade astrocytomas: comparison of water diffusibility and histologic characteristics. Radiology 2002;224: 177–183.
Huang MQ, Pickup S, Nelson DS, et al. Monitoring response to chemotherapy of non-Hodgkin’s lymphoma xenografts by T
-weighted and diffusion-weighted MRI. NMR Biomed 2008;21: 1021–1029.
Balmaceda C, Gaynor JJ, Sun M, Gluck JT, DeAngelis LM. Leptomeningeal tumor in primary central nervous system lymphoma: recognition, significance, and implications. Ann Neurol 1995;38: 202–209.
Batchelor T, Loeffler JS. Primary CNS lymphoma. J Clin Oncol 2006;24: 1281–1288.
Fitzsimmons A, Upchurch K, Batchelor T. Clinical features and diagnosis of primary central nervous system lymphoma. Hematol Oncol Clin North Am 2005;19: 689–703, vii.
Pierce MA, Johnson MD, Maciunas RJ, et al. Evaluating contrast-enhancing brain lesions in patients with AIDS by using positron emission tomography. Ann Intern Med 1995;123: 594–598.
Kulkarni AV, Guha A, Lozano A, Bernstein M. Incidence of silent hemorrhage and delayed deterioration after stereotactic brain biopsy. J Neurosurg 1998;89: 31–35.
Boviatsis EJ, Kouyialis AT, Stranjalis G, Korfias S, Sakas DE. CT-guided stereotactic biopsies of brain stem lesions: personal experience and literature review. Neurol Sci 2003;24: 97–102.
Soo TM, Bernstein M, Provias J, et al. Failed stereotactic biopsy in a series of 518 cases. Stereotact Funct Neurosurg 1995;64: 183–196.
Weller M. Glucocorticoid treatment of primary CNS lymphoma. J Neurooncol 1999;43: 237–239.
National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: central nervous system cancers. Available at: http://www.nccn.org/professionals/physician_gls/f_guidelines. asp. Accessed April 24, 2009.
Jahnke K, Hummel M, Korfel A, et al. Detection of subclinical systemic disease in primary CNS lymphoma by polymerase chain reaction of the rearranged immunoglobulin heavy-chain genes. J Clin Oncol 2006;24: 4754–4757.
Ferreri AJ, Blay JY, Reni M, et al. Prognostic scoring system for primary CNS lymphomas: the International Extranodal Lymphoma Study Group experience. J Clin Oncol 2003;21: 266–272.
Abrey LE, DeAngelis LM, Yahalom J. Long-term survival in primary CNS lymphoma. J Clin Oncol 1998;16: 859–863.
Bellinzona M, Roser F, Ostertag H, Gaab RM, Saint M. Surgical removal of primary central nervous system lymphomas (PCNSL) presenting as space occupying lesions: a series of 33 cases. Eur J Surg Oncol 2005;31: 100–105.
Henry JM, Heffner RR Jr, Dillard SH, Earle KM, Davis RL. Primary malignant lymphomas of the central nervous system. Cancer 1974;34: 1293–1302.
Murray K, Kun L, Cox J. Primary malignant lymphoma of the central nervous system: results of treatment of 11 cases and review of the literature. J Neurosurg 1986;65: 600–607.
DeAngelis LM. Current management of primary central nervous system lymphoma. Oncology (Williston Park) 1995;9: 63–71; discussion 71, 75–76, 78.
Nelson DF, Martz KL, Bonner H, et al. Non-Hodgkin’s lymphoma of the brain: can high dose, large volume radiation therapy improve survival? Report on a prospective trial by the Radiation Therapy Oncology Group (RTOG): RTOG 8315. Int J Radiat Oncol Biol Phys 1992;23: 9–17.
Harder H, Holtel H, Bromberg JE, et al. Cognitive status and quality of life after treatment for primary CNS lymphoma. Neurology 2004;62: 544–547.
Bessell EM, López-Guillermo A, Villa S, et al. Importance of radiotherapy in the outcome of patients with primary CNS lymphoma: an analysis of the CHOD/BVAM regimen followed by two different radiotherapy treatments. J Clin Oncol 2002;20: 231–236.
DeAngelis LM, Yahalom J, Thaler HT, Kher U. Combined modality therapy for primary CNS lymphoma. J Clin Oncol 1992;10: 635–643.
Omuro AM, Ben-Porat LS, Panageas KS, et al. Delayed neurotoxicity in primary central nervous system lymphoma. Arch Neurol 2005;62: 1595–1600.
DeAngelis LM, Sciferheld W, Schold SC, Fisher B, Schultz CJ; Radiation Therapy Oncology Group Study 93-10. Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10. J Clin Oncol 2002;20: 4643–4648.
Shah GD, Yahalom J, Correa DD, et al. Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol 2007;25: 4730–4735.
Correa DD, Rocco-Donovan M, DeAngelis LM, et al. Prospective cognitive follow-up in primary CNS lymphoma patients treated with chemotherapy and reduced-dose radiotherapy. J Neurooncol 2009;91: 315–321.
Poortmans PM, Kluin-Nelemans HC, Haaxma-Reiche H, et al. High-dose methotrexate-based chemotherapy followed by consolidating radiotherapy in non-AIDS-related primary central nervous system lymphoma: European Organization for Research and Treatment of Cancer Lymphoma Group Phase II Trial 20962. J Clin Oncol 2003;21: 4483–4488.
Ervin T, Canellos GP. Successful treatment of recurrent primary central nervous system lymphoma with high-dose methotrexate. Cancer 1980;45: 1556–1557.
Herbst KD, Corder MP, Justice GR. Successful therapy with methotrexate of a multicentric mixed lymphoma of the central nervous system. Cancer 1976;38: 1476–1478.
O’Neill BP, O’Fallon JR, Earle JD, et al. Primary central nervous system non-Hodgkin’s lymphoma: survival advantages with combined initial therapy? Int J Radiat Oncol Biol Phys 1995;33: 663–673.
Schultz C, Scott C, Sherman W, et al. Preirradiation chemotherapy with cyclophosphamide, doxorubicin, vincristine, and dexamethasone for primary CNS lymphomas: initial report of radiation therapy oncology group protocol 88-06. J Clin Oncol 1996;14: 556–564.
Shapiro WR, Young DF, Mehta BM. Methotrexate: distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections. N Engl J Med 1975;293: 161–166.
Glantz MJ, Cole BF, Recht L, et al. High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary? J Clin Oncol 1998;16: 1561–1567.
Khan RB, Shi W, Thaler HT, DeAngelis LM, Abrey LE. Is intrathecal methotrexate necessary in the treatment of primary CNS lymphoma? J Neurooncol 2002;58: 175–178.
Doolittle ND, Miner ME, Hall WA, et al. Safety and efficacy of a multicenter study using intraarterial chemotherapy in conjunction with osmotic opening of the blood-brain barrier for the treatment of patients with malignant brain tumors. Cancer 2000;88: 637–647.
McAllister LD, Doolittle ND, Guastadisegni PE, et al. Cognitive outcomes and long-term follow-up results after enhanced chemotherapy delivery for primary central nervous system lymphoma. Neurosurgery 2000;46: 51–60; discussion 60-51.
Cher L, Glass J, Harsh GR, Hochberg FH. Therapy of primary CNS lymphoma with methotrexate-based chemotherapy and deferred radiotherapy: preliminary results. Neurology 1996;46: 1757–1759.
Guha-Thakurta N, Damek D, Pollack C, Hochberg FH. Intravenous methotrexate as initial treatment for primary central nervous system lymphoma: response to therapy and quality of life of patients. J Neurooncol 1999;43: 259–268.
Batchelor T, Carson K, O’Neill A, et al. Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-07. J Clin Oncol 2003;21: 1044–1049.
Herrlinger U, Küker W, Uhl M, et al. NOA-03 trial of high-dose methotrexate in primary central nervous system lymphoma: final report. Ann Neurol 2005;57: 843–847.
Reni M, Mason W, Zaja F, et al. Salvage chemotherapy with temozolomide in primary CNS lymphomas: preliminary results of a phase II trial. Eur J Cancer 2004;40: 1682–1688.
Reni M, Zaja F, Mason W, et al. Temozolomide as salvage treatment in primary brain lymphomas. Br J Cancer 2007;96: 864–867.
Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002;346: 235–242.
Rubenstein JL, Combs D, Rosenberg J, et al. Rituximab therapy for CNS lymphomas: targeting the leptomeningeal compartment. Blood 2003;101: 466–468.
Stemmler HJ, Schmitt M, Willems A, et al. Ratio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2-positive breast cancer patients with brain metastases and impairment of blood-brain barrier. Anticancer Drugs 2007;18: 23–28.
Issa S, Shen A, Karch J, et al. Treatment of primary CNS lymphoma with induction high-dose methotrexate, temozolomide, rituximab followed by consolidation cytarabine/etoposide: a pilot study with biomarker analysis. Presented at the American Society of Hematology 2008 Annual Meeting; December 8, 2008; Atlanta, GA. Abstract 1364.
Pels H, Schmidt-Wolf IG, Glasmacher A, et al. Primary central nervous system lymphoma: results of a pilot and phase II study of systemic and intraventricular chemotherapy with deferred radiotherapy. J Clin Oncol 2003;21: 4489–4495.
Pels H, Juergens A, Glasmacher A, et al. Early relapses in primary CNS lymphoma after response to polychemotherapy without intraventricular treatment: results of a phase II study. J Neurooncol 2009;91: 299–305.
Abrey LE, Moskowitz CH, Mason WP, et al. Intensive methotrexate and cytarabine followed by high-dose chemotherapy with autologous stem-cell rescue in patients with newly diagnosed primary CNS lymphoma: an intent-to-treat analysis. J Clin Oncol 2003;21: 4151–4156.
Montemurro M, Kiefer T, Schüler F, et al. Primary central nervous system lymphoma treated with high-dose methotrexate, high-dose busulfan/thiotepa, autologous stem-cell transplantation and response-adapted whole-brain radiotherapy: results of the multi-center Ostdeutsche Studiengruppe Hämato-Onkologie OSHO-53 phase II study. Ann Oncol 2007;18: 665–671.
Soussain C, Hoang-Xuan K, Taillandier L, et al; Société Française de Greffe de Moëlle Osseuse-Thérapie Cellulaire. Intensive chemotherapy followed by hematopoietic stem-cell rescue for refractory and recurrent primary CNS and intraocular lymphoma: Société Française de Greffe de Moelle Osseuse-Thérapie Cellulaire. J Clin Oncol 2008;26: 2512–2518.
Plotkin SR, Betensky RA, Hochberg FH, et al. Treatment of relapsed central nervous system lymphoma with high-dose methotrexate. Clin Cancer Res 2004;10: 5643–5646.
Herrlinger U, Brugger W, Bamberg M, Küker W, Dichgans J, Weller M. PCV salvage chemotherapy for recurrent primary CNS lymphoma. Neurology 2000;54: 1707–1708.
Nguyen PL, Chakravarti A, Finkelstein DM, et al. Results of whole-brain radiation as salvage of methotrexate failure for immunocompetent patients with primary CNS lymphoma. J Clin Oncol 2005;23: 1507–1513.
Sakamoto M, Oya N, Mizowaki T, et al. Initial experiences of palliative stereotactic radiosurgery for recurrent brain lymphomas. J Neurooncol 2006;77: 53–58.
Rubenstein JL, Fridlyand J, Abrey L, et al. Phase I study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma. J Clin Oncol 2007;25: 1350–1356.
Chamberlain MC, Johnston SK, Van Horn A, Glantz MJ. Recurrent lymphomatous meningitis treated with intra-CSF rituximab and liposomal ara-C. J Neurooncol 2009;91: 271–277.
de Smet MD, Stark-Vancs V, Kohler DR, Smith J, Wittes R, Nussenblatt RB. Intraocular levels of methotrexate after intravenous administration. Am J Ophthalmol 1996;121: 442–444.
Batchelor TT, Kolak G, Ciordia R, Foster CS, Henson JW. High-dose methotrexate for intraocular lymphoma. Clin Cancer Res 2003;9: 711–715.
Baumann MA, Ritch PS, Hande KR, et al. Treatment of intraocular lymphoma with high-dose Ara-C. Cancer 1986;57: 1273–1275.
Grimm SA, McCannel CA, Omuro AM, et al. Primary CNS lymphoma with intraocular involvement: International PCNSL Collaborative Group Report. Neurology 2008;71: 1355–1360.
Itty S, Pulido JS. Rituximab for intraocular lymphoma. Retina 2009;29: 129–132.
Kim H, Csaky KG, Chan CC, et al. The pharmacokinetics of rituximab following an intravitreal injection. Exp Eye Res 2006;82: 760–766.
Ohguro N, Hashida N, Tano Y. Effect of intravitreous rituximab injections in patients with recurrent ocular lesions associated with central nervous system lymphoma. Arch Ophthalmol 2008;126: 1002–1003.
Rubenstein JL, Shen A, Batchelor TT, Kadoch C, Treseler P, Shuman MA. Differential gene expression in central nervous system lymphoma. Blood 2009;113: 266–267.
CrossRef PubMed Copyright information
© The American Society for Experimental NeuroTherapeutics, Inc. 2009