Neurological Surgery 脳神経外科42巻6号

2014年06月発行

総説

中枢神経系原発悪性リンパ腫の診断と治療―最近の動向

著者： 泉本修一¹

所属機関： ¹近畿大学医学部脳神経外科

ページ範囲：P.507 - P.521

Ⅰ．はじめに

　中枢神経系原発悪性リンパ腫（primary central nervous system lymphoma：PCNSL）は，脳腫瘍全体の3.1%を占め（日本脳腫瘍全国統計1984-2000)²¹⁾，ここ20年の間で増加している⁸⁸⁾．その年齢分布をみると70歳以上の症例が28.1%，60歳以上になると61.8%にのぼり，平均年齢も上昇している²¹⁾．95%以上は非ホジキンリンパ腫で，B細胞由来とされる．しかしPCNSLは，その多様さや稀少さから現在でも診断や最適治療に対する認識に曖昧さが多く残る．

　PCNSLの特徴の1つとして，血液脳関門（blood-brain barrier：BBB）により薬剤の脳内到達に制限があり，また高齢者が多いことで，他臓器のそれに比べて生命予後が不良なことが挙げられる．1994年以降，メトトレキサート大量化学療法/全脳放射線治療（high-dose methotrexate and whole-brain radiotherapy：HD-MTX/WBRT）により生存期間が延長し（Table），現在はそれを基本とした治療が選択されることが多い．本邦で最初のHD-MTX/WBRT 28例の報告では³⁸⁾，全生存期間中央値（median overall survival：mOS）は39.3カ月であった．しかし長期生存者が増えるにつれ，放射線晩期障害としての神経毒性がクローズアップされるようになった．

　本稿では，最近のPCNSLの診断および治療の動向について述べ，HD-MTX/WBRTと高次脳機能障害の問題，さらに，rituximabやtemozolomide（TMZ）を用いた治療，自己血液幹細胞移植併用大量化学療法（high-dose chemotherapy and autologous stem-cell transplantation：HD-CT/ASCT）などの開発途中にある療法を踏まえ，現在のところ推奨できる治療法は何か，また，そのなかで再発時に適した治療法の模索，高齢者や免疫不全患者の治療，髄腔内化学療法の可能性などについて述べる．

参考文献

1) Abrey LE, DeAngelis LM, Yahalom J：Long-term survival in primary CNS lymphoma. J Clin Oncol 16：859-863, 1998

2) Abrey LE, Yahalom J, DeAngelis LM：Treatment for primary CNS lymphoma：the next step. J Clin Oncol 18：3144-3150, 2000

3) Abrey LE, Moskowitz CH, Mason WP, Crump M, Stewart D, Forsyth P, Paleologos N, Correa DD, Anderson ND, Caron D, Zelenetz A, Nimer SD, DeAngelis LM：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 21：4151-4156, 2003

4) Abrey LE, Batchelor TT, Ferreri AJ, Gospodarowicz M, Pulczynski EJ, Zucca E, Smith JR, Korfel A, Soussain C, DeAngelis LM, Neuwelt EA, O'Neill BP, Thiel E, Shenkier T, Graus F, van den Bent M, Seymour JF, Poortmans P, Armitage JO, Cavalli F；International Primary CNS Lymphoma Collaborative Group：Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol 23：5034-5043, 2005

5) Abrey LE, Ben-Porat L, Panageas KS, Yahalom J, Berkey B, Curran W, Schultz C, Leibel S, Nelson D, Mehta M, DeAngelis LM：Primary central nervous system lymphoma：the Memorial Sloan-Kettering Cancer Center prognostic model. J Clin Oncol 24：5711-5715, 2006

6) Al-Mansour Z, Nelson BP, Evens AM：Post-transplant lymphoproliferative disease（PTLD）：risk factors, diagnosis, and current treatment strategies. Curr Hematol Malig Rep 8：173-183, 2013

7) Angelov L, Doolittle ND, Kraemer DF, Siegal T, Barnett GH, Peereboom DM, Stevens G, McGregor J, Jahnke K, Lacy CA, Hedrick NA, Shalom E, Ference S, Bell S, Sorenson L, Tyson RM, Haluska M, Neuwelt EA：Blood-brain barrier disruption and intra-arterial methotrexate-based therapy for newly diagnosed primary CNS lymphoma：a multi-institutional experience. J Clin Oncol 27：3503-3509, 2009

8) Arita H, Izumoto S, Kinoshita M, Okita Y, Hashimoto N, Fujita T, Ichimaru N, Takahara S, Yoshimine T：Posttransplant lymphoproliferative disorders of the central nervous system after kidney transplantation：single center experience of 40 years. Two case reports. Neurol Med Chir（Tokyo）50：1079-1083, 2010

9) Baraniskin A, Kuhnhenn J, Schlegel U, Chan A, Deckert M, Gold R, Maghnouj A, Zöllner H, Reinacher-Schick A, Schmiegel W, Hahn SA, Schroers R：Identification of microRNAs in the cerebrospinal fluid as marker for primary diffuse large B-cell lymphoma of the central nervous system. Blood 117：3140-3146, 2011

10) Batchelor T, Carson K, O'Neill A, Grossman SA, Alavi J, New P, Hochberg F, Priet R：Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy：a report of NABTT 96-07. J Clin Oncol 21：1044-1049, 2003

11) Batchelor T, Loeffler JS：Primary CNS lymphoma. J Clin Oncol 24：1281-1288, 2006

12) Batchelor TT, Grossman SA, Mikkelsen T, Ye X, Desideri S, Lesser GJ：Rituximab monotherapy for patients with primary CNS lymphoma. Neurology 76：929-930, 2011

13) Birnbaum T, Stadler EA, von Baumgarten L, Straube A：Rituximab significantly improves complete response rate in patients with primary CNS lymphoma. J Neurooncol 109：285-291, 2012

14) Birnbaum T, Bochmann K, von Baumgarten L, Straube A：Early relapses in patients with primary CNS lymphoma treated with methotrexate-based chemotherapy without consolidating whole brain irradiation. J Neurooncol 112：233-239, 2013

15) Brück W, Brunn A, Klapper W, Kuhlmann T, Metz I, Paulus W, Deckert M；Netzwerk Lymphome und Lymphomatoide Läsionen des Nervensystems：Differential diagnosis of lymphoid infiltrates in the central nervous system：experience of the network lymphomas and lymphomatoid lesions in the nervous system. Pathologe 34：186-197, 2013

16) Cabanillas F：How important is whole brain radiotherapy for treatment of primary CNS lymphoma? Lancet Oncol 11：1011-1012, 2010

17) Cady FM, O'Neill BP, Law ME, Decker PA, Kurtz DM, Giannini C, Porter AB, Kurtin PJ, Johnston PB, Dogan A, Remstein ED：Del(6)(q22）and BCL6 rearrangements in primary CNS lymphoma are indicators of an aggressive clinical course. J Clin Oncol 26：4814-4819, 2008

18) Cavaliere R, Petroni G, Lopes MB, Schiff D；International Primary Central Nervous System Lymphoma Collaborative Group：Primary central nervous system post-transplantation lymphoproliferative disorder：an International Primary Central Nervous System Lymphomas Collaborative Group report. Cancer 116：863-870, 2010

19) Chamberlain MC, Johnston SK：High-dose methotrexate and rituximab with deferred radiotherapy for newly diagnoses primary B-cell CNS lymphoma. Neuro Oncol 12：736-744, 2010

20) Chan CC, Rubenstein JL, Coupland SE, Davis JL, Harbour JW, Johnston PB, Cassoux N, Touitou V, Smith JR, Batchelor TT, Pulido JS：Primary vitreoretinal lymphoma：a report from an International Primary Central Nervous System Lymphoma Collaborative Group symposium. Oncologist 16：1589-1599, 2011

21) The Committee of Brain Tumor Registry of Japan：Report of Brain Tumor Registry of Japan（1984-2000）12th edition. Neurol Med Chir（Tokyo）Suppl 49, 2009

22) Correa DD, Shi W, Abrey LE, DeAngelis LM, Omuro AM, Deutsch MB, Thaler HT：Cognitive functions in primary CNS lymphoma after single or combined modality treatments. Neuro Oncol 14：101-108, 2012

23) DeAngelis LM, Seiferheld 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 20：4643-4648, 2002

24) Deckert M, Brunn A, Montesinos-Rongen M, Terreni MR, Ponzoni M：Primary lymphoma of the central nervous system―a diagnostic challenge. Hematol Oncol, DOI：10.1002/hon.2087, 2013

25) Dietrich J, Monje M, Wefel J, Meyers C：Clinical patterns and biological correlates of cognitive dysfunction associated with cancer therapy. Oncologist 13：1285-1295, 2008

26) Doolittle ND, Korfel A, Lubow MA, Schorb E, Schlegel U, Rogowski S, Fu R, Dósa E, Illerhaus G, Kraemer DF, Muldoon LL, Calabrese P, Hedrick N, Tyson RM, Jahnke K, Maron LM, Butler RW, Neuwelt EA：Long-term cognitive function, neuroimaging, and quality of life in primary CNS lymphoma. Neurology 81：84-92, 2013

27) Enting RH, Demopoulos A, DeAngelis LM, Abrey LE：Salvage therapy for primary CNS lymphoma with a combination of rituximab and temozolomide. Neurology 63：901-903, 2004

28) Evens AM, Choquet S, Kroll-Desrosiers AR, Jagadeesh D, Smith SM, Morschhauser F, Leblond V, Roy R, Barton B, Gordon LI, Gandhi MK, Dierickx D, Schiff D, Habermann TM, Trappe R：Primary CNS posttransplant lymphoproliferative disease（PTLD）：an international report of 84 cases in the modern era. Am J Transplant 13：1512-1522, 2013

29) Ferreri AJ, Blay JY, Reni M, Pasini F, Spina M, Ambrosetti A, Calderoni A, Rossi A, Vavassori V, Conconi A, Devizzi L, Berger F, Ponzoni M, Borisch B, Tinguely M, Cerati M, Milani M, Orvieto E, Sanchez J, Chevreau C, Dell'Oro S, Zucca E, Cavalli F：Prognostic scoring system for primary CNS lymphomas：the International Extranodal Lymphoma Study Group experience. J Clin Oncol 21：266-272, 2003

30) Ferreri AJ, Reni M, Foppoli M, Martelli M, Pangalis GA, Frezzato M, Cabras MG, Fabbri A, Corazzelli G, Ilariucci F, Rossi G, Soffietti R, Stelitano C, Vallisa D, Zaja F, Zoppegno L, Aondio GM, Avvisati G, Balzarotti M, Brandes AA, Fajardo J, Gomez H, Guarini A, Pinotti G, Rigacci L, Uhlmann C, Picozzi P, Vezzulli P, Ponzoni M, Zucca E, Caligaris-Cappio F, Cavalli F；International Extranodal Lymphoma Study Group（IELSG）：High dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma：a randomized phase 2 trial. Lancet 374：1512-1520, 2009

31) Ferreri AJ, DeAngelis L, Illerhaus G, O'Neill BP, Reni M, Soussain C, Yahalom J：Whole-brain radiotherapy in primary CNS lymphoma. Lancet Oncol 12：118-119, 2011

32) Fischer L, Martus P, Weller M, Klasen HA, Rohden B, Röth A, Storek B, Hummel M, Nägele T, Thiel E, Korfel A：Meningeal dissemination in primary CNS lymphoma：prospective evaluation of 282 patients. Neurology 71：1102-1108, 2008

33) Fischer L, Korfel A, Pfeiffer S, Kiewe P, Volk HD, Cakiroglu H, Widmann T, Thiel E：CXCL13 and CXCL12 in central nervous system lymphoma patients. Clin Cancer Res 15：5968-5973, 2009

34) Fritsch K, Kasenda B, Hader C, Nikkhah G, Prinz M, Haug V, Haug S, Ihorst G, Finke J, Illerhaus G：Immunochemotherapy with rituximab, methotrexate, procarbazine, and lomustine for primary CNS lymphoma（PCNSL）in the elderly. Ann Oncol 22：2080-2085, 2011

35) Gregory G, Arumugaswamy A, Leung T Chan KL, Abikhair M, Tam C, Bajel A, Cher L, Grigg A, Ritchie D, Opat S：Rituximab is associated with improved survival for aggressive B cell CNS lymphoma. Neuro Oncol 15：1068-1073, 2013

36) Grimm SA, McCannel CA, Omuro AM, Ferreri AJ, Blay JY, Neuwelt EA, Siegal T, Batchelor T, Jahnke K, Shenkier TN, Hall AJ, Graus F, Herrlinger U, Schiff D, Raizer J, Rubenstein J, Laperriere N, Thiel E, Doolittle N, Iwamoto FM, Abrey LE：Primary CNS lymphoma with intraocular involvement：International PCNSL Collaborative Group Report. Neurology 71：1355-1360, 2008

37) Herrlinger U, Küker W, Uhl M, Blaicher HP, Karnath HO, Kanz L, Bamberg M, Weller M；Neuro-Oncology Working Group of the German Society：NOA-03 trial of high-dose methotrexate in primary central nervous system lymphoma：final report. Ann Neurol 57：843-847, 2005

38) Hiraga S, Arita N, Ohnishi T, Kohmura, E, Yamamoto K, Oku Y, Taki T, Sato M, Aozasa K, Yoshimine T：Rapid infusion of high-dose methotrexate resulting in enhanced penetration into cerebrospinal fluid and intensified tumor response in primary central nervous system lymphomas. J Neurosurg 91：221-230, 1999

39) Hoang-Xuan K, Taillandier L, Chinot O, Soubeyran P, Bogdhan U, Hildebrand J, Frenay M, De Beule N, Delattre JY, Baron B；European Organization for Research and Treatment of Cancer Brain Tumor Group：Chemotherapy alone as initial treatment for primary CNS lymphoma in patients older than 60 years：a multicenter phase II study（26952）of the European Organization for Research and Treatment of Cancer Brain Tumor Group. J Clin Oncol 21：2726-2731, 2003

40) Hottinger AF, DeAngelis LM, Yahalom J, Abrey LE：Salvage whole brain radiotherapy for recurrent or refractory primary CNS lymphoma. Neurology 69：1178-1182, 2007

41) Illerhaus G, Marks R, Ihorst G, Guttenberger R, Ostertag C, Derigs G, Frickhofen N, Feuerhake F, Volk B, Finke J：High-dose chemotherapy with autologous stem-cell transplantation and hyperfractionated radiotherapy as first-line treatment of primary CNS lymphoma. J Clin Oncol 24：3865-3870, 2006

42) Illerhaus G, Marks R, Müller F, Ihorst G, Feuerhake F, Deckert M, Ostertag C, Finke J：High-dose methotrexate combined with procarbazine and CCNU for primary CNS lymphoma in the elderly：results of a prospective pilot and phase II study. Ann Oncol 20：319-325, 2009

43) 泉本修一，丸野元彦，吉峰俊樹：悪性リンパ腫再発時の治療．脳外誌14：772-777, 2005

44) 泉本修一，森　鑑二，有田憲生；中枢神経系悪性リンパ腫研究会：悪性リンパ腫に対するHD-MTX療法の長期治療成績と問題点―多施設共同臨床研究から．第26回日本脳腫瘍学会抄録集．2008, p130

45) Jahnke K, Korfel A, Komm J, Bechrakis NE, Stein H, Thiel E, Coupland SE：Intraocular lymphoma 2000-2005：results of a retrospective multicentre trial. Graefes Arch Clin Exp Ophthalmol 244：663-669, 2006

46) Jagadeesh D, Woda BA, Draper J, Evens AM：Post transplant lymphoproliferative disorders：risk, classification, and therapeutic recommendations. Curr Treat Options Oncol 13：122-136, 2012

-methylguanine-DNA methyltransferase（MGMT）immunohistochemistry as a predictor of resistance to temozolomide in primary CNS lymphoma. J Neurooncol 114：135-140, 2013

48) Juergens A, Pels H, Rogowski S, Fliessbach K, Glasmacher A, Engert A, Reiser M, Diehl V, Vogt-Schaden M, Egerer G, Schackert G, Reichmann H, Kroschinsky F, Bode U, Herrlinger U, Linnebank M, Deckert M, Fimmers R, Schmidt-Wolf IG, Schlegel U：Long-term survival with favorable cognitive outcome after chemotherapy in primary central nervous system lymphoma. Ann Neurol 67：182-189, 2010

49) Kadoch C, Li J, Wong VS, Chen L, Cha S, Munster PN, Lowell CA, Shuman MA, Rubenstein JL：Complement activation and intraventricular rituximab distribution in recurrent central nervous system lymphoma. Clin Cancer Res 20：1029-1041, 2014

50) Kinoshita M, Hashimoto N, Izumoto S, Okita Y, Kagawa N, Maruno M, Ohnishi T, Arita N, Yoshimine T：Immunohistological profiling by B-cell differentiation status of primary central nervous system lymphoma treated by high-dose methotrexate chemotherapy. J Neurooncol 99：95-101, 2010

51) Korfel A, Weller M, Martus P, Roth P, Klasen HA, Roeth A, Rauch M, Hertenstein B, Fischer T, Hundsberger T, Leithäuser M, Birnbaum T, Kirchen H, Mergenthaler HG, Schubert J, Berdel W, Birkmann J, Hummel M, Thiel E, Fischer L：Prognostic impact of meningeal dissemination in primary CNS lymphoma（PCNSL）：experience from the G-PCNSL-SG1 trial. Ann Oncol 23：2374-2380, 2012

52) Kurzwelly D, Glas M, Roth P, Weimann E, Lohner H, Waha A, Schabet M, Reifenberger G, Weller M, Herrlinger U：Primary CNS lymphoma in the elderly：temozolomide therapy and MGMT status. J Neurooncol 97：389-392, 2010

53) Lai R, Abrey LE, Rosenblum MK, DeAngelis LM：Treatment-induced leukoencephalopathy in primary CNS lymphoma. Neurology 62：451-456, 2004

54) Laperriere NJ, Cerezo L, Milosevic MF, Wong CS, Patterson B, Panzarella T：Primary lymphoma of brain：results of management of a modern cohort with radiation therapy. Radiother Oncol 43：247-252, 1997

55) Linnebank M, Moskau S, Kowoll A, Semmler A, Bangard C, Vogt-Schaden M, Egerer G, Schackert G, Reichmann H, Schmidt-Wolf IG, Pels H, Schlegel U：Association of transcobalamin c. 776C＞G with overall survival in patients with primary central nervous system lymphoma. Br J Cancer 107：1840-1843, 2012

56) Mappa S, Marturano E, Licata G, Frezzato M, Frungillo N, Ilariucci F, Stelitano C, Ferrari A, Sorarú M, Vianello F, Baldini L, Proserpio I, Foppoli M, Assanelli A, Reni M, Caligaris-Cappio F, Ferreri AJ：Salvage chemoimmunotherapy with rituximab, ifosfamide and etoposide（R-IE regimen）in patients with primary CNS lymphoma relapsed or refractory to high-dose methotrexate-based chemotherapy. Hematol Oncol 31：143-150, 2013

57) Maza S, Buchert R, Brenner W, Munz DL, Thiel E, Korfel A, Kiewe P：Brain and whole-body FDG-PET in diagnosis, treatment monitoring and long-term follow-up of primary CNS lymphoma. Radiol Oncol 47：103-110, 2013

58) Mead GM, Bleehen NM, Gregor A, Bullimore J, Shirley D, Rampling RP, Trevor J, Glaser MG, Lantos P, Ironside JW, Moss TH, Brada M, Whaley JB, Stenning SP：A medical research council randomized trial in patients with primary cerebral non-Hodgkin lymphoma：cerebral radiotherapy with and without cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy. Cancer 89：1359-1370, 2000

59) Morris PG, Correa DD, Yahalom J, Raizer JJ, Schiff D, Grant B, Grimm S, Lai RK, Reiner AS, Panageas K, Karimi S, Curry R, Shah G, Abrey LE, DeAngelis LM, Omuro A：Rituximab, methotrexate, procarbazine, and vincristine followed by consolidation reduced-dose whole-brain radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma：final results and long-term outcome. J Clin Oncol 31：3971-3979, 2013

60) Nayak L, Abrey LE, Drappatz J, Gilbert MR, Reardon DA, Wen PY, Prados M, DeAngelis LM, Omuro A；North American Brain Tumor Consortium：Multicenter phase II study of rituximab and temozolomide in recurrent primary central nervous system lymphoma. Leuk Lymphoma 54：58-61, 2013

61) Nelson DF, Martz KL, Bonner H, Nelson JS, Newall J, Kerman HD, Thomson JW, Murray KJ：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 23：9-17, 1992

62) Ng S, Rosenthal MA, Ashley D, Cher L：High-dose methotrexate for primary CNS lymphoma in the elderly. Neuro Oncol 2：40-44, 2000

63) Nguyen PL, Chakravarti A, Finkelstein DM, Hochberg FH, Batchelor TT, Loeffler JS：Results of whole-brain radiation as salvage of methotrexate failure for immunocompetent patients with primary central nervous system lymphoma. J Clin Oncol 23：1507-1513, 2005

64) Omuro AM, Ben-Porat LS, Panageas KS, Kim AK, Correa DD, Yahalom J, DeAngelis LM, Abrey LE：Delayed neurotoxicity in primary central nervous system lymphoma. Arch Neurol 62：1595-1600, 2005

65) Omuro AM, Taillandier L, Chinot O, Carnin C, Barrie M, Hoang-Xuan K：Temozolomide and methotrexate for primary central nervous system lymphoma in the elderly. J Neurooncol 85：207-211, 2007

66) Omuro AM, Chinot OL, Taillandier L, Ghesquieres H, Soussain C, Delwail V, Lamy T, Gressin R, Choquet S, Soubeyran PL, Maire JP, Amiel AB, Lebouvier-Sadot S, Gyan E, Barrie M, del Rio MS, Gonzalez A, Houillie C, Tanguy ML, Hoang-Xuan K：Multicenter randomized Phase 2 trial of methotrexate（MTX）and temozolomide（TMZ）versus MTX, procarbazine, vincristine and cytarabine for primary CNS lymphoma in the elderly：an Anocef and Goelams intergroup study. J Clin Oncol 31（suppl), Abstract 2032, 2013

67) Pels H, Schmidt-Wolf IG, Glasmacher A, Schulz H, Engert A, Diehl V, Zellner A, Schackert G, Reichmann H, Kroschinsky F, Vogt-Schaden M, Egerer G, Bode U, Schaller C, Deckert M, Fimmers R, Helmstaedter C, Atasoy A, Klockgether T, Schlegel U：Primary central nervous system lymphoma：results of a pilot and phase II study of systemic and intraventricular chemotherapy with deferred radiotherapy. J Clin Oncol 21：4489-4495, 2003

68) Pels H, Schlegel U：Primary central nervous system lymphoma. Curr Treat Options Neurol 8：346-357, 2006

69) Pels H, Juergens A, Schirgens I, Glasmacher A, Schulz H, Engert A, Schackert G, Reichmann H, Kroschinsky F, Vogt-Schaden M, Egerer G, Bode U, Deckert M, Fimmers R, Urbach H, Schmidt-Wolf IG, Schlegel U：Early complete response during chemotherapy predicts favorable outcome in patients with primary CNS lymphoma. Neuro Oncol 12：720-724, 2010

70) Plotkin SR, Betensky RA, Hochberg FH, Grossman SA, Lesser GJ, Nabors LB, Chon B, Batchelor TT：Treatment of relapsed central nervous system lymphoma with high-dose methotrexate. Clin Cancer Res 10：5643-5646, 2004

71) Poortmans PM, Kluin-Nelemans HC, Haaxma-Reiche H, Van't Veer M, Hansen M, Soubeyran P, Taphoorn M, Thomas J, Van den Bent M, Fickers M, Van Imhoff G, Rozewicz C, Teodorovic I, van Glabbeke M；European Organization for Research and Treatment of Cancer Lymphoma Group：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 21：4483-4488, 2003

72) Preusser M, Woehrer A, Koperek O, Rottenfusser A, Dieckmann K, Gatterbauer B, Roessler K, Slavc I, Jaeger U, Streubel B, Hainfellner JA, Chott A：Primary central nervous system lymphoma：a clinicopathological study of 75 cases. Pathology 42：547-552, 2010

73) Reni M, Zaja F, Mason W, Perry J, Mazza E, Spina M, Bordonaro R, Ilariucci F, Faedi M, Corazzelli G, Manno P, Franceschi E, Pace A, Candela M, Abbadessa A, Stelitano C, Latte G, Ferreri AJ：Temozolomide as salvage treatment in primary brain lymphomas. Br J Cancer 96：864-867, 2007

74) Reni M, Mazza E, Foppoli M, Ferreri AJ：Primary central nervous system lymphomas：salvage treatment after failure to high-dose methotrexate. Cancer Lett 258：165-170, 2007

75) Roth P, Martus P, Kiewe P, Möhle R, Klasen H, Rauch M, Röth A, Kaun S, Thiel E, Korfel A, Weller M：Outcome of elderly patients with primary CNS lymphoma in the G-PCNSL-SG-1 trial. Neurology 79：890-896, 2012

76) Rubenstein JL, Combs D, Rosenberg J, Levy A, McDermott M, Damon L, Ignoffo R, Aldape K, Shen A, Lee D, Grillo-Lopez A, Shuman MA：Rituximab therapy for CNS lymphomas：targeting the leptomeningeal compartment. Blood 101：466-468, 2003

77) Rubenstein JL, Fridlyand J, Shen A, Aldape K, Ginzinger D, Batchelor T, Treseler P, Berger M, McDermott M, Prados M, Karch J, Okada C, Hyun W, Parikh S, Haqq C, Shuman M：Gene expression and angiotropism in primasry CNS lymphoma. Blood 107：3716-3723, 2006

78) Rubenstein JL, Hsi ED, Johnson JL, Jung SH, Nakashima MO, Grant B, Cheson BD, Kaplan LD：Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma：CALGB 50202（Alliance 50202). J Clin Oncol 31：3061-3068, 2013

79) Rubenstein JL, Wong VS, Kadoch C, Gao HX, Barajas R, Chen L, Josephson SA, Scott B, Douglas V, Maiti M, Kaplan LD, Treseler PA, Cha S, Hwang JH, Cinque P, Cyster JG, Lowell C：CXCL13 plus interleukin 10 is highly specific for the diagnosis of CNS lymphoma. Blood 121：4740-4748, 2013

80) Schorb E, Kasenda B, Atta J, Kaun S, Morgner A, Hess G, Elter T, von Bubnoff N, Dreyling M, Ringhoffer M, Krause SW, Derigs G, Klimm B, Niemann D, Fritsch K, Finke J, Illerhaus G：Prognosis of patients with primary central nervous system lymphoma after high-dose chemotherapy followed by autologous stem cell transplantation. Haematologica 98：765-70, 2013

81) Schroers R, Baraniskin A, Heute C, Kuhnhenn J, Alekseyev A, Schmiegel W, Schlegel U, Pels HJ：Detection of free immunoglobulin light chains in cerebrospinal fluids of patients with central nervous system lymphomas. Eur J Haematol 85：236-242, 2010

82) Schroers R, Baraniskin A, Heute C, Vorgerd M, Brunn A, Kuhnhenn J, Kowoll A, Alekseyev A, Schmiegel W, Schlegel U, Deckert M, Pels H：Diagnosis of leptomeningeal disease in diffuse large B-cell lymphomas of the central nervous system by flow cytometry and cytopathology. Eur J Haematol 85：520-528, 2010

83) Shah GD, Yahalom J, Correa DD, Lai RK, Raizer JJ, Schiff D, LaRocca R, Grant B, DeAngelis LM, Abrey LE：Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed CNS lymphoma. J Clin Oncol 25：4730-4735, 2007

84) Shapiro WR, Young DF, Mehta BM：Methotrexate：distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections. N Engl J Med 293：161-166, 1975

85) Soussain C, Hoang-Xuan K, Taillandier L, Fourme E, Choquet S, Witz F, Casasnovas O, Dupriez B, Souleau B, Taksin AL, Gisselbrecht C, Jaccard A, Omuro A, Sanson M, Janvier M, Kolb B, Zini JM, Leblond V；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 Moëlle Osseuse-Thérapie Cellulaire. J Clin Oncol 26：2512-2518, 2008

86) Swerdlow SH, Harris NL：WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. International Agency for Research on Cancer, Lyon, 2008

87) Thiel E, Korfel A, Martus P, Kanz L, Griesinger F, Rauch M, Röth A, Hertenstein B, von Toll T, Hundsberger T, Mergenthaler HG, Leithäuser M, Birnbaum T, Fischer L, Jahnke K, Herrlinger U, Plasswilm L, Nägele T, Pietsch T, Bamberg M, Weller M：High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma（G-PCNSL-SG-1）：a phase 3, randomised, non-inferiority trial. Lancet Oncol 11：1036-1047, 2010

88) Villano JL, Koshy M, Shaikh H, Dolecek TA, McCarthy BJ：Age, gender, and racial differences in incidence and survival in primary CNS lymphoma. Br J Cancer 105：1414-1418, 2011

89) Weller M, Martus P, Roth P, Thiel E, Korfel A；German PCNSL Study Group：Surgery for primary CNS lymphoma? Challenging a paradigm. Neuro Oncol 14：1481-1484, 2012

90) Westwood TD, Hogan C, Julyan PJ, Coutts G, Bonington S, Carrington B, Taylor B, Khoo S, Bonington A：Utility of FDG-PETCT and magnetic resonance spectroscopy in differentiating between cerebral lymphoma and non-malignant CNS lesions in HIV-infected patients. Eur J Radiol 82：e274-e379, 2013

91) Wieduwilt MJ, Valles F, Issa S, Behler CM, Hwang J, McDermott M, Treseler P, O'Brien J, Shuman MA, Cha S, Damon LE, Rubenstein JL：Immunochemotherapy with intensive consolidation for primary CNS lymphoma：a pilot study and prognostic assessment by diffusion-weighted MRI. Clin Cancer Res 18：1146-1155, 2012

92) Zhu JJ, Gerstner ER, Engler DA, Mrugala MM, Nugent W, Nierenberg K, Hochberg FH, Betensky RA, Batchelor TT：High-dose methotrexate for elderly patients with primary CNS lymphoma. Neuro Oncol 11：211-215, 2009