Lymphoma

LYMPHOMA PENDAHULUAN Limfoma atau disebut juga kanker kelenjar getah bening adalah sejenis kanker yang tumbuhakibat mutasi sel limfosit (sejenis sel darah putih) yang sebelumnya normal. Hal ini berakibat sel abnormal nenjadi ganas. Seperti halnya limfosit normal, limfosit ganas dapat tumbuh pada berbagai organ dalam tubuh termasuk kelenjar getah bening, limpa, sum-sum tulang, darah maupun organ lainnya contoh saluran cerna, paru, kulit dan tulang Limfoma juga sering dikaitkan dengan paparan zat karsinogenik.1. Dalam kepustakaan yang lain disebut bahwa Limfoma adalah setiap kelainan neoplastik jaringan limfoid 2. Limfoma juga disebut sebagai penyakit limfosit yang menyerupai kanker. Disebut penyakit limfosit karena menyerang sel darah putih sehingga berkembang (membelah) abnormal dengan cepat dan menjadi ganas. Limfosit abnormal yang semakin banyak ini (kemudian disebut limfoma) sering terkumpul di kelenjar getah bening dan membuat bengkak.3 Karena sistem limfatik menyerupai peredaran darah yang bersikulasi ke seluruh tubuh membawa getah bening, maka penyakit limfoma juga dapat terbentuk di mana saja. Tak mesti di satu bagian tubuh saja 3. Limfoma pada otak jarang dialami oleh orang dengan kadar sel CD4 yang tinggi. Gejala utama dari limfoma susunan saraf pusat (SSP) adalah sakit kepala dan demam. Perasaan seperti meningkatnya tekanan di dalam kepala atau bahkan serangan sakit kepala yang hebat juga sering terjadi. Sepertiga orang yang mengalami limfoma SSP merasakan gangguan bicara (aphasia), pandangan kabur dan gangguan kepekaan atau pun koordinasi gerakan pada satu sisi tubuh1. Menurut klinik Mayo, tanda awal limfoma SSP bisa dideteksi di mata. 11% dari orang yang belakangan diketahui terserang limfoma SSP ternyata mengalami uveitis (radang pada selaput pelangi mata dan bagian di sekeliling mata) yang didahului dengan gejala lainnya selama berbulan-bulan sampai tahunan. Jika terapi kortikosteroid tidak menyembuhkan uveitis, maka diperlukan sebuah biopsi cairan vitreus pada mata yang akan menunjukkan adanya infiltrasi (radang sel dan puing) sehingga diagnosa limfoma SSP dengan secepatnya diketahui dan dapat segera diobati dengan memeriksakan mata secara rutin. Maka limfoma SSP akan lebih cepat dideteksi dibandingkan dengan pemeriksaan khusus yang bisa saja terlambat. Lagipula pemeriksaan mata tidaklah begitu menakutkan bila dibandingkan dengan biopsi otak3. Menurut Herzberg 2007, pasien Limfoma memiliki peluang untuk sembuh dan produktif, meski tak semua orang mampu dan memiliki akses terhadap pengobatan. Dengan diagnosis yang tepat, pengobatan juga bisa spesifik dan tak makan biaya dibandingkan berobat tanpa arah2,3. Limfoma umumnya dibagi menjadi 2 bagian besar, yaitu : Limfoma non-hodgkin (LNH) dan Limfoma hodgkin. Sekitar 85% dari keganasan tersebut adalah NHL4. SISTEM LIMFATIK Sistem limfatik adalah bagian penting sistem kekebalan tubuh yang memainkan peran kunci dalam pertahanan alamiah tubuh melawan infeksi dan kanker. Pembuluh limfe berisi cairan limfatik putih mirip susu yang mengandung protein, lemak dan limfosit (sel darah putih) yang semuanya mengalir ke seluruh tubuh melalui pembuluh limfatik. Ada dua macam sel limfosit yaitu: Sel B dan Sel T. Sel B membantu melindungi tubuh melawan bakteri dengan jalan membuat antibodi yang menyerang dan memusnahkan bakteri LIMFOMA NON-HODGKIN (LNH) Limfoma non-hodgkin adalah kelompok keganasan primer imfosit yang dapat berasal dari limfosit B, limfosit T dan kadang (amat jarang) berasal dari sel NK (natural killer) yang berada dalam sistem limfe; yang sangat heterogen, baik tipe histologist, gejala, perjalanan klinis, respon terhadap pengobatan, maupun prognosis4,5. Pada LNH sebuah sel limfosit berproliferasi secara tak terkendali yang mengakibatkan terbentuknya tumor. Seluruh sel LNH berasal dari satu sel limfosit, sehingga semua sel dalam tumor pasien LNH sel B memiliki immunoglobulin yang sama pada permukaan selnya5. Kasus LNH terjadi sekitar 50.000 kasus/tahun dengan usia biasanya > 50 tahun dan predominan pada laki-laki. Saat ini sekitar 1,5 juta orang di dunia saat ini hidup dengan LNH dan tiap tahun sekitar 300.000 orang meninggal karena penyakit ini5. Etiologi Etiologi sebagian besar LNH tidak diketahui. Namun terdapat beberapa fakkor resiko terjadinya LNH, antara lain : 1. Imunodefisiensi : 25% kelainan heredier langka yang berhubungan dengan terjadinya LNH antara lain adalah : severe combined immunodeficiency, hypogammaglobulinemia, common variable immunodeficiency, Wiskott Aldrich syndrome dan ataxia-telangiectasia. Limfoma yang berhubungan dengan kelainan-kelainan tersebut seringkali dihubugkan pula dengan Epstein Barr Virus (EBV) dan jenisnya beragam. 2. Agen infeksius : EBV DNA ditemukan pada limfoma Burkit sporadic. Karena tidak pada semua kasus limfoma Burkit ditemukan EBV, hubungan dan mekanisme EBV terhadap terjadinya limfoma Burkit belum diketahui. 3. Paparan lingkungan dan pekerjaan : Beberapa pekerjaan yang sering dihubugkan dengan resiko tinggi adalah peternak serta pekerja hutan dan pertanian. Hal ini disebabkan adanya paparan herbisida dan pelarut organik. 4. Diet dan Paparan lsinya : Risiko LNH meningkat pada orang yang mengkonsumsi makanan tinggi lemak hewani, merokok, dan yang terkena paparan UV4,5. Jenis LNH Terdapat lebih dari 30 sub-tipe NHL yang berbeda (90 persennya dari jenis sel B), yang dapat dikelompokkan menurut beberapa panduan klasifikasi. Klasifikasi tersebut mempertimbangkan beberapa faktor seperti penampakan di bawah mikroskop, ukuran, kecepatan tumbuh dan organ yang terkena. Secara umum dapat dikenali beberapa bentuk NHL yaitu amat agresif (tumbuh cepat), menengah dan indolen (tumbuh lambat). Penentuan ini dilakukan dengan mikroskop oleh dokter patologi di laboratorium2,3. Diagnosis Dimulai dari anamnesis, keadaan penderita secara umum : 1. Pembesaran kelenjar getah bening dan malaise umum : Berat badan menurun 10% dalam waktu 6 bulan, demam tinggi 38oC selama 1 minggu tanpa sebab, keringat malam. 2. Keluhan anemia. 3. Keluhan organ (misalnya lambung, nasofaring). Pada pemeriksaan fisik didapati : Adanya pembesaran kelenjar getah bening, kelainan/pembesaran organ. Tumor LNH dapat terjadi pada tulang, perut, hati, otak atau bagian tubuh yang lain 6. Stadium Penyakit Penetapan stadium penyakit harus selalu dilakukan sebelum pegobatan dan setiap lokasi jangkitan harus didata dengan cermat, digambar secara skematik dan didata tidak hanya jumlah juga ukurannya. Hal ini sangat penting dalam menilai suatu pengobatan. Stadium berdasarkan kesepakatan Ann Arbor :  Stadium I : Pembesaran kelenjar getah bening (KGB) hanya 1 regio.  I E : jika hanya terkena 1 organ ekstra limfatik tidak difus/batas tegas.  Stadium II : Pembesaran 2 regio KGB atau lebih, tetapi masih satu sisi diafragma.  II 2 : pembesaran 2 regio KGB dalam 1 sisi diafragma  II 3 : pembesaran 3 regio KGB dalam 1 sisi diafragma  II E : pembesaran 1 regio atau lebih KGB dalam 1 sisi diafragma dan 1 organ ekstra limfatik tidak difus/batas tegas  Stadium III : Pembesaran KGB di 2 sisi diafragma  Staduium IV : Jika mengenai 1 organ ekstra limfatik atau lebih tetapi secara difus6 Faktor Prognostik LNH dapat dibagi kedalam 2 kelompok prognostik : Indolent Limfoma dan Agresif Limfoma. LNH Indolent memiliki prognosis yang relatif baik, dengan median survival 10 tahun, tetapi biasanya tidak dapat disembuhkan pada stadium lanjut. Tipe Limfoma agresif memiliki perjalanan alamiah yang lebih pendek, namun lebih dapat disembuhkan secara signifikan dengan kemoterapi kombinasi intensif5,6. Pengobatan Pengobatan inti LNH saat ini meliputi kemoterapi, terapi antibodi monoklonal, radiasi, terapi biologik dan cangkok sum-sum tulang. Penentuan jenis terapi yang diambil amat bergantung kondisi individual pasien dan bergantung pada 3 faktor utama : 1. Stadium 2. Ukuran 3. Derajat keganasan Limfoma Agresif (intermediate/derajat keganasan tinggi) cepat tumbuh dan menyebar dalam tubuh dan bila dibiarkan tanpa pengobatan dapat mematikan dalam 6 bulan. Angka harapan hidup rata-rata berkisar 5 tahun dengan sekitar 30-40% sembuh. Pasien yang terdiagnosis dini dan langsung diobati lebih mungkin meraih remisi sempurna dan jarang mengalami kekambuhan. Karena ada potensi kesembuhan, maka biasanya pengobatan lebih agresif. Standar terapi dahulu meliputi kemoterapi standar CHOP dan/atau kemoterapi dosis tinggi dan cangkok sum-sum. Tetapi terapi tersebut dianggap masih memiliki tingkat kekambuhannya 31,5 % sampai 56,8 % dimana Complete Response dan survival rate yang rendah. Pada saat ini sebagai first line treatment digunakan rituximab yang dikombinasi dengan CHOP. Rituximab ( suatu monoklonal antibodi/ antibodi anti CD20 ) yang bisa mengatasi kasus-kasus relaps LNH terhadap agen kemoterapi. Sehingga baru-baru ini, penggunaan rituximab plus kemoterapi standar telah direkomendasikan oleh para peneliti Eropa yang mengobati NHL agresif berdasarkan uji klinisi yang menunjukkan perpanjangan harapan hidup pasien ketika diobati dengan Rituximab ditambah CHOP dibandingkan hanya CHOP6,7. Limfoma Indolen (derajat keganasan rendah) tumbuh lambat sehingga diagnostik awal menjadi lebih sulit. Pasien dapat bertahan hidup selama bertahun-tahun dengan penyakit ini, tetapi standar pengobatan yang ada tidak dapat menyembuhkannya. Biasanya, pasien memberikan respon yang baik pada terapi awal, tetapi sangat mungkin kanker tumbuh kembali. Pasien dengan limfoma indolen bisa mendapatkan terapi sebanyak lima sampai enam kali sepanjang hidup mereka. Meskipun demikian, pasien biasanya memberikan respon terapi yang semakin rendah. Angka harapan hidup pada limfoma jenis ini, dimana seringkali pasien terkalahkan oleh penyakit ini atau komplikasi yang timbul, berkisar antara enam tahun6,7. LIMFOMA HODGKIN (HODGKIN DISEASE) Penyakit Hodgkin termasuk dalam keganasan limforetikular yaitu : limfoma malignum yang terbagi dalam limfoma malignum Hodgkin dan limfoma malignum non Hodgkin. Kedua penyakit tersebut dibedakan secara histopatologis, dimana pada limfoma Hodgkin ditemukan sel Reed Sternberg2,3. virus memperkenalkan gen asing ke dalam sel target.  Stadium I : Keterlibatan suatu region kelenjar geah bening atau struktur jaringan limfoid (limpa. Novak. Pada riwayat penyakit didapati pada penderita umumnya terdapat pembesaran kelenjar getah bening yang tidak nyeri.roche/products/limfoma/. Diagnosis Diagnosis pada penderita dilihat dari riwayat penyakit. 2. Pengobatan Di dalam pengobatan Limfoma Hodgkin langkah pertama yang harus dilakukan adalah penentuan stadium penyakit. terdapat hepatosplenomegali juga adanya neuropati7. yaitu pada usia 15-34 tahun dan usia diatas 55 tahun5. uji fungsi ginjal. hal 638-39.dan dakarbazin)6. Limfoma non Hodgkin. cincin waldeyer) atau keterlibatan satu organ ekstralimfatik.com. Etiologi Penyebab yang pasti dari penyakit ini belum diketahui dengan pasti. Perhimpunan dokter spesialis penyakit dalam Indonesia. dan pruritus. Jakarta. Virus-virus tersebut adalah Epstein-Barr. sedang penyakit lanjut memiliki angka kesembuhan 50-70% 5. infeksi virus onkogenik diduga berperan dalam menimbulkan lesi genetik. Hal 727-33. Diakses pada tanggal 02 September 2008. 2007. uji fungsi hati. Di Amerka Serikat terdapat 7500 kasus baru penyakit Hodgkin setiap tahunnya. Prognosis Pada penyakit ini . Pusat penerbitan departemen ilmu penyakit dalam fakultas kedokteran universitas Indonesia. fungsi ginjal. Klasifikasi WHO mengklasifikasikan limfoma Hodgkin ke dalam 2 jenis yaitu : 1.  Stadium IV : Keterlibatan difus/diseminata pada satu atau lebih organ ekstranodal atau jaringan dengan atau tanpa keterlibatan kelenjar getah bening8. bleomisin. dan pelvis. Buku ajar ilmu penyakit dalam : LNH. Terdapat distribusi umur bimodal. EGC. 6.emedicine. 5. Penyakit Hodgkin. berkeringat malam hari. Kamus kedokteran Dorland. Staging dilakukan menurut Cotswolds (1990) yang merupakan modifikasi dan klasifikasi Ann Arbor (1971).4 berbanding 1. CTscan toraks. Lymphoma. sel ini juga mengandung suatu faktor transkripsi inti sel. Diakses pada tanggal 02 September 2008. 2006. gejala klinis. vinblastin. Stadium I dan IIA: dapat dilakukan radiasi.jurnalnasional/limfoma/44356. rasio kekerapan antara laki-laki dan perempuan adalah 1.8. HIV. www. 2. Anonymous.3-1.  Anamnesis dan pemeriksaan fisik  Evaluasi laboratorium: pemeriksaan darah lengkap.com. juga dilakukan pemeriksaan elektrolit. 2007. Stadium Penyakit Penentuan staging sangat penting untuk terapi dan menilai prognosis. 3. HHV-6. timus. 735-44. penurunan berat badan. misalnya pada pasien transplantasi organ dengan pemberian obat imunosupresif 6. Nodular Lymphobcyte predominance Hodhkin Lymphoma (Nodular LPHL) : Tipe ini mempunyai sel limfosit dan histiosit.  Rontgen foto toraks. www. Pada pemeriksaan penunjang dilakukan pemeriksaan laboratorium berupa darah lengkap. Amori. Limfoma Maligna. Vinjamaran. Sitomegalovirus. . Kedua hal tersebut menyebabkan gangguan apoptosis. Jakarta 4. Non-Hodgkin. Selain itu dilakukan pemeriksaan biopsi sumsum tulang juga pemeriksaan radiologis8. Jurnal Nasional : Pengobatan tepat untuk Limfoma. Faktor yang lain adalah defisiensi imun. abdomen. 1996.  Stadium II : Keterlibatan ≥ 2 regio kelenjar getah bening pada sisi diafragma yang sama. DAFTAR PUSTAKA 1. Anonymous.  Biopsi sumsum tulang  Laparotomi dengan splenektomi untuk menentukan stadium Setelah dilakukan penentuan stadium barulah dilakukan pengobatan sesuai dengan stadium yang ada.Analisis PCR menunjukkan bahwa sel Reed Sternberg berasal dari folikel sel B yang mengalami gangguan struktur pada immunoglobulin.com. stadium III dan IV: kemoterapi (seperti: “ABVD” – doksorubisin [Adriamisin]. www.  Stadium III : Keterlibatan regio kelenjar getah bening pada kedua sisi diafragma. Diakses pada tanggal 02 September 2008. fungsi hati. dan pemeriksaan penunjang.  Dipastikan dengan biopsi eksisi kelenjar getah bening. 2006.7. CD 20 positif tetapi tidak memberikan gambaran sel Reed-Stenberg. Diakses pada tanggal 02 September 2008. urinalisis. 2008. Classic Hodgkin Lymphoma8 . Pada penyakit ini beberapa faktor resiko yang diperkirakan dapat menyebabkan terjadinya limfoma Hodgkin adalah infeksi virus.wordpress.com.jika masih terbatas maka memiliki angka kesembuhan ± 80%. www. Gejala sistenik berupa demam. Current protocols focus on the development of combination chemotherapy programs and reducing the dose of cranial radiotherapy to minimize late neurologic sequelae. GENERAL INFORMATION 1. Anonymous. The addition of chemotherapy to brain irradiation prolongs survival in some patients with AIDS-related disease. producing a response rate of 60% . Diakses pada tanggal 02 September 2008. Incidence and risk factors Primary central nervous system lymphomas (PCNSL) are aggressive malignancies that arise in distinct anatomical sites. Primary central nervous system lymphoma 1. Laperriere 1997). Memorial Sloan-Kettering Cancer Center.nih. discussion 71. with high rates of local relapse and consequent .elearning. Anonymous. However. but only 2 to 5 months in AIDS patients. www. with median survivals of 30 to 45 months.nlm. biological and immunological conditions. 2008.com. www. and spinal cord also are frequently affected. but appropriate neurologic staging is imperative. these malignancies exhibit one of the worst prognoses among all non-Hodgkin lymphomas (NHL) (Reni 1997a. PROGNOSIS 6. In non-AIDS patients. the prognosis of PCNSL is still dismal. but median survival is not significantly improved.7. So far. eyes. Current management of primary central nervous system lymphoma. Abrey 1998. DIAGNOSIS 4. Source Department of Neurology. radiotherapy (RT) has been the standard treatment.mayoclinic. 78. Deangelis LM. Deangelis 1999 ). 8. despite recent therapeutic advances. 1995 Jan. Limfoma. relapse usually occurred within a few months after RT. with a median survival of 14 months and a 5-year survival of approximately 15% . Systemic lymphoma is not present.65% and a notable neurological improvement in most cases (Berry 1981). and comprehensive systemic staging is unnecessary. STAGING 5. Although the introduction of systemic chemotherapy has consistently improved survival (Reni 1997a.com. Abstract Primary CNS lymphoma is rising in incidence in both the AIDS and non-AIDS populations. giving a median survival of 12 to 18 months in non-AIDS patients. TREATMENT References Contributors 1. Diakses pada tanggal 02 September 2008. PATHOLOGY and BIOLOGY 3. For a long time. New York. http://www. GENERAL INFORMATION 2. 75-6. It is a nonHodgkin's lymphoma that usually presents as a brain tumor. New York.24% (Nelson 1992.ncbi. Standard therapy has been whole brain radiotherapy. but the leptomeninges. USA. the addition of chemotherapy to radiotherapy has improved the prognosis. 2008. Ferreri 1995a).gov/pubmed/7718442 Oncology (Williston Park).blogspot. which display unique structural.9(1):63-71. Hodgkin Disease. The histological margins are cloudy and lymphomatous cells can be found at a distance from the macroscopic margins of the lesion. Schaumburg 1972). Most PCNSL have Bimmunophenotype ( Ferreri 1995a.Hochberg 1988) that can be confirmed by immunoglobulin light or heavy chains gene rearrangement (most frequently lg M/k). No immunophenotypical or genotypical differences have been observed between PCNSL and all other NHLs. Jellinger 1995). A histological characteristic of PCNSL is the multiplication of the basal membranes of the blood vessels encased by the neoplasm (Henry 1974). Frequently. few immunocompetent patients are affected by PCNSL in which the Epstein-Barr virus genome is present in the neoplastic cells. Methods of molecular biology could be useful to differentiate tumour cells from non- .death. the most significant series on PCNSL showed a positivity of CSF in 0-50% of the patients ( Reni 1997a). The latter. Only 15 cases of the former have been reported. In 85% of the cases protein concentration is increased (Henry 1974. In contrast to immunodeficient patients (Bashir 1994). also named malignant angioendoteliosis. plasmacytic or plasmacytoid (Henry 1974). even though they are not specific and are variable. but it often presents some difficulties due to the site of involvement and the patient's poor performance status. By contrast to the situation in systemic lymphomas involving the CNS. are very useful for diagnosis orientation. including those of the CNS. Moreover. When the neoplastic cells cannot be detected by classical histological techniques. immunoblastic. Some extremely rare histological forms of PCNSL such as solitary intracranial plasmacytoma and angiotropic lymphoma (Hacker 1992) have been described. PCNSL are predominantly diffuse large-cell. histological appearance consists of vasocentric proliferation with infiltration of the cerebral parenchyma among the involved vessels. Defining the optimum therapeutic management is difficult because of potential selection biases in large retrospective reviews and the limited number of prospective studies (Reni 1997a). The follicular pattern of growth is rare: the most significant published series ( Jellinger 1995) reported a 14% incidence of indolent lymphomas. a certain degree of infiltration of macrophages and an intense astrocytic reaction can be observed.90% of cases. which has potential prognostic and therapeutic implications. while other authors observed low-grade PCNSL in 3 . Unfortunately. in which the cytological examination of the CSF is positive in 70-95% of the cases. Modern immunohistochemical methods. In 80% of cases. several therapeutic questions still remain unanswered after a decade of research. The alterations of cerebrospinal fluid (CSF). modern immunohistochemical and molecular techniques make a diagnosis possible with a minimum of tissue sampled by stereotactic biopsy. it seems that the histotype has no prognostic value and therefore would not influence therapeutic choice or treatment response ( Jellinger 1992. these structures are highlighted like a network that has given rise to the name "reticular sarcoma". CSF cytology examination is very important to allow diagnosis of PCNSL in patients that cannot be biopsied due to their poor clinical condition. PATHOLOGY and BIOLOGY The histological confirmation of PCNSL diagnosis is extremely important.Lachance 1991). Although studies published on PCNSL are increasing.g. An extended necrosis can be observed occasionally (O'Neill 1993). even though an increase in incidence among immunocompetent patients has been observed (Bergmann 1994) mostly in meningeal localisations (Marshall 1998): their clinical characteristics seem identical to B-cell PCNSL and would need the same therapeutic approach. the study of lymphocytic pleiocytosis that is noticed in the CSF in half of the patients assumes an important role. lymphoblastic or Burkitt's lymphomas. is a fatal neoplasm characterized by the intravascular multifocal proliferation of large cells that can strike any vessel. being reduced only in the case of diffuse meningeal infiltration. it seems to have a fundamental value in staging.50% of cases (Fine 1993. while glucose concentration is generally normal. all of them with a prevalently meningeal localization. and techniques of molecular biology should soon extend the diagnostic potential of this technique. When stained with silver salts. In 60 . T-cell PCNSL are rare (1-2%). Unlike PCNSL in the presence of immunodeficiency. Even though retrospective studies with sufficient numbers of cases are not available. Several models of cellular differentiation have been described. e. 2. Only 20 30% of immunocompetent patients are affected by aggressive lymphomas. Hochberg 1988). it is not possible to identify lymphomatous cells in every case and sometimes not even in the presence of an extended meningeal infiltration. in the immunocompetent individuals these neoplasms show monoclonal proliferation in 90% of cases (Hochberg 1988. However. deeply localized. the optic nerve. the choroides and less frequently. clinical presentation is nonspecific and consistent with that of an intracranial mass. mainly due to a late diagnosis. Therefore. cerebellar and the brain stem parenchyma. The peak of incidence is between 60 and 70 years of age for immunocompetent individuals (Deangelis 1994. However. The initial symptoms are similar to those of neuropathies or lumbosacral radiculopathies with radicular pain. and radicular symptoms associated with sensory damage. Often headaches (56%) and other signs of intracranial hypertension such as nausea (35%). It is probable that the development of new diagnostic techniques of molecular biology will reveal an increased percentage of positive exams. signs of impairment of the brain stem and the cerebellum and extrapyramidal syndromes. in the most numerous series CSF examination demonstrated lymphomatous cells in less than half of the cases examined. the retina. and associated with floaters or campimeter deficit. Therefore both the study of clonogenicity and immunophenotype allows the reactive or neoplastic character of the lymphocytic pleiocytosis to be defined ( Kranz 1992). As described in the paragraph dedicated to histopathology. uveitis from lymphoma rapidly becomes resistant to this treatment. the leptomeninges and the spinal cord. While common uveitis shows a hightened sensitivity to topical or systemic corticosteroids. the fact that in some cases a monoclonal proliferation of T-lymphocytes can be observed must be emphasized. personality changes are frequent. PCNSL displays two fundamental characteristics that assume a great importance in this situation. its involvement is not considered a systemic dissemination. PCNSL begins in an intraocular location.5:1 (Ferreri 1995a). The male:female ratio is 1. Finally. Also if clinically silent.malignant reactive cells. a persistent uveitis that becomes resistant to corticotherapy should suggest an intraocular localization from PCNSL. most of all in the legs. coming into close contact with the ventricular system and disseminating through the cerebrospinal fluid (CSF) to the meninges ( Shibata 1989). At the onset. in some cases. In these cases the prognosis is very poor with a median survival of few months. The neoplastic cells can infiltrate the vitreous humor. with signs of both motor and sensory focal deficits in about 50% of cases. However. PCNSL can arise in the cerebral. their monoclonal proliferation and their prevalently B-immunophenotype. At least 80% of the patients with primitive lymphoma of the eye will develop a cerebral lymphoma sometimes after a prolonged latency. Sometimes the neoplasm symmetrically infiltrates both the cerebral hemispheres. usually in the periventricular regions infiltrating the corpus callosum and the basal ganglia. more often in the multifocal forms. In 5-20% of cases. Only 10-15% of the lesions are localized in subtentorial fossa. giving origin to the typical radiographic "butterfly" image. The patient generally complains of pain in the limbs. DIAGNOSIS 3. In fact. A leptomeningeal localization in the absence of a parenchymal mass occurs in less than 10% of cases (Hochberg 1988). its onset is similar to a non-specific monolateral uveitis refractory to conventional ophthalmologic treatment. These neoplasms are associated with a polyclonal proliferation of reactive T-lymphocytes in more than half of the cases (Ng 1998). Ferreri 1995a). PCNSL present with a single lesion.1 Clinical presentations PCNSL occur in all age groups. PCNSL tend to infiltrate the subependimal tissues. PCNSL are by definition limited to the CNS and therefore considered a stage IEdisease. Since the eye is an extension of the CNS. even when it is bilateral. This localisation presents the greatest diagnostic difficulties. The symptoms resulting from the involvement of the eye precede cerebral symptoms by months or years. the use of electron microscopy could facilitate the definitive diagnosis (Hu 1996). 3. in the eye. some cases have been described . A study based on autopsy findings demonstrated a meningeal involvement in 100% of cases (Schaumburg 1972). The rapid growth of PCNSL produces a progressive worsening of the neurological performance status: an average of 2-3 months usually elapses between the clinical onset and the radiological diagnosis. increase of intrarachidian pressure or confusion. Less frequently there are generalized seizures. Rarely PCNSL affect the spinal cord (Ferreri 1995a). Even though extremely rare. Systemic symptoms are rarely associated. the involvement of both eyes occurs in almost 80% of cases. In more than half of immunocompetent patients. Since these neoplasms show a predilection for localization in the frontal lobe. vomiting (11%) and papilloedema (32%) are present ( Fine 1993). At least 80% of patients with primitive lymphoma of the eye will develop a cerebral lymphoma. usually in the periventricular regions infiltrating the corpus callosum and the basal ganglia. some cases have been described occurring at the level of the cauda equina and the sciatic nerve. computerized tomography scans (CT) and magnetic resonance (MR) images suggest that it is appropriate to be suspicious of a lymphomatous nature of a cerebral mass. its involvement is not considered a systemic dissemination. increase of intrarachidian pressure or confusion. and genetic features are common to all other NHLs. Even though extremely rare. Rarely they are associated with systemic symptoms. this location presents the greatest diagnostic difficulties. The patient generally complains of pain in the limbs. most of all in the legs. Only 10-15% of the lesions are localized in subtentorial fossa.A study based on autopsy findings demonstrated a meningeal involvement in 100% of cases (Schaumburg 1972). when the condition is clinically silent. In these cases the prognosis is very poor with a median survival of few months. A leptomeningeal localization in the absence of a parenchymal mass occurs in less than 10% of cases (Hochberg 1988). the pre-contrast CT . At the onset.2 Neuroimaging The main diagnostic criteria for PCNSL include clinical and radiological examinations. the involvement of both eyes occurs in almost 80% of cases. in the most numerous series CSF examination demonstrated lymphomatous cells in less than half of the cases examined. to distinguish it from the infiltration of the nerves by a systemic lymphoma.occurring at the level of the cauda equina and the sciatic nerve. PCNSL can arise in the cerebral. Some authors have described a form of PCNSL that infiltrates the spinal nerves and their ganglia. and associated with floaters or campimeter deficit. It is probable that the development of new diagnostic techniques of molecular biology will reveal an increased percentage of positive exams. while morphological. Sometimes the neoplasm symmetrically infiltrates both cerebral hemispheres. Ferreri 1995a). the choroides and less frequently. coming into close contact with the ventricular system and disseminating through the cerebrospinal fluid (CSF) to the meninges ( Shibata 1989). cerebellar and the brain stem parenchyma. While common uveitis shows an increased sensitivity to topical or systemic corticosteroids. more often in the multifocal forms. Some authors have described a form of PCNSL that infiltrates the spinal nerves and their ganglia. The symptoms resulting from the involvement of the eye precede cerebral symptoms by months or even years. PCNSL tends to infiltrate the subependimal tissues. In spite of the fact that pathognomonic radiological patterns of PCNSL do not exist. immunophenotypic.5:1 (Ferreri 1995a). but the peak of incidence is between 60 and 70 years of age for immunocompetent individuals ( Deangelis 1994. However. to distinguish it from the infiltration of the nerves by a systemic lymphoma. The rapid growth of PCNSL produces a progressive worsening of the neurological performance status: an average of 23 months usually elapses between the clinical onset and the radiological diagnosis. mainly due to a late diagnosis. the leptomeninges and the spinal cord. uveitis from lymphoma becomes rapidly resistant to this treatment. It has been termed neurolymphomatosis. It has been termed neurolymphomatosis. consisting of signs of both motor and sensory focal deficits in about 50% of cases. Since the eye is an extension of the CNS. and extrapyramidal syndromes. clinical presentation is non-specific and consistent with those of an intracranial mass. When it does so. 3. signs of impairment of the brain stem and the cerebellum. vomiting (11%) and papilloedema (32%) (Fine 1993). deeply localized. PCNSL begins in an intraocular location. even when it is bilateral. Therefore. PCNSL occur in all age groups. In fact. PCNSL presents as a single lesion. In 5-20% of cases. sometimes after a prolonged latency. the optic nerve. in the eye. Also. Since these neoplasms show a predilection for localization in the frontal lobe. Rarely PCNSL affects the spinal cord (Ferreri 1995a). In more than half of immunocompetent patients. the retina. PCNSL are by definition limited to the CNS and therefore considered a stage IEdisease. The male: female ratio is 1. The neoplastic cells can infiltrate the vitreous humor. and radicular symptoms associated with sensory damage. In 90% of cases. a persistent uveitis that becomes resistant to corticotherapy should suggest an intraocular localization from PCNSL. The initial symptoms are similar to those of neuropathies or lumbosacral radiculopathies with radicular pain. giving rise to the typical radiographic "butterfly" image. Often there are headaches (56%) and other signs of intracranial hypertension such as nausea (35%). it generally presents in a way similar to a non-specific monolateral uveitis refractory to conventional ophthalmologic treatment. Less frequently there are generalized seizures. personality changes are frequent. PCNSL lesions do not have a prominent neovascularization and discrepancies between the intense enhancement of the CT and the absence of vascular neoformation in the angiogram have been explained by using positron-emission tomography. several authors reported cases of systemic lymphoma which . A lesion with scarce enhancement is generally associated with an intact BBB that could hamper the antineoplastic drug reaching the lymphomatous cells. most gliomas. Proton magnetic resonance spectroscopy imaging seems to be a useful tool in diagnostic suspicion. are generally hypodense. Fine 1993. while the natural history of prior or concomitant neoplasm as well as the location could suggest metastatic disease. In some cases. that are not visible by CT scan. tend to localize in the deep regions of the brain ( Ferreri 1995a). 4. a dramatic response to corticosteroids should raise the suspicion of PCNSL.Hochberg 1988). they are commonly located at the corticomedullar junction area rather than in the periventricular regions. but which cannot be revealed by angiography.scan shows an iso. both high. in contrast to PCNSL.or hypo-dense. Hochberg 1988). These tests should be used as appropriate. In some cases. recent reviews have challenged the actual usefulness of an extensive systemic evaluation in the staging work-up of PCNSL. based on the histological subtype of the PCNSL. as well as diagnostic information. metastasis. and early detection of relapse ( Raizer 2005). periventricular lesions that involve the median deep structures of the brain can present with a "butterfly" image that suggests a malignant glioma. Enhancement is also observed with MR. 3. which in general are poorly delimited with scarce perilesional oedema. lesion. This differential diagnosis is very difficult. The use of MR allows the identification of some lesions.3 Additional useful tests Additional tests such as specialised techniques of molecular biology may be useful in diagnosis and staging of PCNSL. Additionally. Although cerebral metastasis can be hyper. PCNSL can also present on a CT scan like a diffuse and hyperdense meningeal infiltration which is rare and difficult to distinguish from other meningeal lesions. STAGING Since PCNSL tend to remain localized in the CNS. Only in 12% of patients with PCNSL enhancement is not observed (Deangelis 1994). not only because the radiographic images are similar. but also because both show a dramatic response to steroids administration. PCNSL have an intense proliferation of small calibre vessels that allows an abundant tissue perfusion. meningiomas. This conclusion is supported by the fact that in the larger series of PCNSL no case of systemic lymphoma has been found which presented solely with a symptomatic cerebral mass lesion (Deangelis 1994. response assessment. In the case of a multifocal presentation or of patients with a prior or concomitant history of malignancy the differential diagnosis between PCNSL and metastasis can be especially difficult (Reni 1997b). In spite of the efforts of several authors to find a direct relationship between the radiological and histopathological diagnosis. It allows to distinguish an avascular tumour in 70% of cases (Fine 1993). The lesions. Enhancement might predict. a diffuse infiltration of the white matter accompanied by a slight enhancement can be observed. while the preGadolinium T1 MR image shows an isointense lesion. The radiographic aspect of brain lesions is common to all PCNSL histotypes and it is useful in the differential diagnosis with demyelination diseases. none of the radiological patterns described corresponds to a particular histotype. in particular those in the spinal cord. The calcifications that are frequently observed in oligodendrogliomas and lowgrade astrocytomas are usually absent in PCNSL. response to chemotherapy since this depends on the grade of integrity of the blood-brain barrier (BBB). single or multiple. The use of contrast media produces an intense and homogeneous enhancement of the image. having an appearance similar to that of meningioma (Ferreri 1995a).and lowgrade. Moreover. FDG-PET displays a high sensitivity in PCNSL diagnosis and it may be suitable for therapeutic monitoring (Palmedo 2005). In a third of the cases a diffuse and homogeneous colouration or "blush" that persists from the capillary phase to the venous phase can be observed. In contrast. sarcoidosis and toxoplasmosis (Ferreri 1995a . gliomas. Contrary to what happens in gliomas.or iso-dense. Angiography has a complementary role and is rarely used in PCNSL diagnosis. This pattern should be distinguished from that of multiple sclerosis and of other leucoencephalopathies. chest x-ray. testicular ultrasound. Different from most other extranodal lymphomas. Moreover. PCNSL are. half of the 5-year survivors experience a relapse between 5 and 13 years from diagnosis ( O'Neill 1993).4 Restaging procedures Restaging should include all the diagnostic procedures which were positive at time of diagnosis and initial staging. while meningeal. the prognosis of PCNSL is ominous. Deangelis 1992b). with a 5-year survival rate of 4% ( Reni 1997a). gastrointestinal contrast study or gastroscopy. In 93% of cases the relapse is local. spread consists of a single and asymptomatic lesion. prognosis and survival are extremely different from those of other stage-I NHLs. while it has produced in many cases a clear worsening of the quality of life. spinal and intraocular relapses are less frequent (Socie 1990. Because current experience suggests that extensive staging might detect systemic disease in some patients initially considered as having PCNSL (Ferreri 1996). Loeffler 1985. Surgery has not improved survival. after a brief course inevitably lead to death. there is no established consensus on the most appropriate extent of staging work-up. and overall survival has not improved consistently . Treatment with radiotherapy and corticosteroids has been the standard therapy for several years. Thanks to the elevated sensitivity of PCNSL to both steroids and radiotherapy. almost all patients relapse in just a few months from the end of treatment. The addition of chemotherapy to radiation therapy has improved survival. ophthalmologic evaluation (slitlamp). However.2 Staging system The standard staging system used for PCNSL is the same as that proposed for Hodgkin's disease at the Ann Arbor Conference in 1971 ( Carbone 1971). 5. Laperriere 1997). the prognosis of PCNSL remains ominous with a great number of local relapses that. in spite of the elevated percentage of initial complete responses. Treatment of relapses sometimes achieves a complete remission with a lengthening of survival and an improvement in the patient's quality of life (Reni 1999). Therefore. but their biological behaviour and prognosis are completely different from other lymphomas at the same stage. whole-body CT scan. Nelson 1992. these extranodal lymphomas are considered as stage IE-disease. 4.only became evident after complete staging work-up in patients who were initially diagnosed as affected by PCNSL ( O'Neill 1995b. staging work-up should include physical examination. stage IE. While other lymphomas have a 10-year survival rate of 70%. giving survival rates of 3. Although results from prospective trials suggest progress in the treatment of PCNSL. In spite of this improvement. and bilateral bone marrow aspirate and biopsy. even within the radiation field (Deangelis 1994). PCNSL show systemic dissemination in only 7-8% of cases. The clinical evolution is rapidly fatal if correct treatment is not started immediately and the median survival with only supportive therapy is less than 3 months. which can be diagnosed only at autopsy (Henry 1974). survival improvements are not reflected in studies on population-based cohort. blood count and biochemical profile. Ferreri 1996). In general. As described above. 4. most patients have a complete radiological remission and a significant improvement in neurological performance status and quality of life (Berry 1981) after corticosteroids and adequate irradiation. but their clinical behaviour.5-5 months (Reni 1997a). with a median survival of 12-18 months (Henry 1974.3 Molecular analysis of minimal residual disease Molecular markers have not been used for monitoring the minimal residual disease in PCNSL. 4. PROGNOSIS 5. Hayakawa 1994. by definition.1 Natural history PCNSLs are characterized by a rapid growth that is almost always limited to the CNS. which can be achieved by spinal-cord irradiation. has allowed to develop a prognostic scoring system that distinguishes three different risk groups based on the presence of 0-1.90%. Brada 1998. In the vast majority of prospective trials.in the past three decades ( Panageas 2005). 6.G.S. while WBRT with 30 Gy which may or may not be followed by a tumour-bed boost to reach 36 Gy appears suitable for patients in complete remission after chemotherapy.35% ( Glass 1994. Therefore.E. WBRT with 30 . It is noteworthy that treatment sequence is strongly influenced by the choice of drugs used. There are no prospective trials providing therapeutic results obtained with chemotherapy followed by RT versus the inverse sequence (radiotherapy. high-dose systemic chemotherapy or by intrathecal drug delivery. There are 3 major aspects limiting the widely use of intrathecal chemotherapy: the increased risk of severe neurotoxicity. radiotherapy doses should be decided on the basis of response to primary chemotherapy. TREATMENT 6. which is not useful to discriminate among risk groups in PCNSL series (Blay 1998). and in 100% of cases at autopsy (Schaumburg 1972).L. Laperriere 1997). serum lactate dehydrogenase level. These findings seem to support the necessity for meningeal treatment. Several authors have tried to improve survival by adding other drugs to methotrexate. Cher 1996. The first strategy is associated with relevant marrow toxicity (Reni 1997a. age. Then.2 Prognostic factors The identification of clinically relevant prognostic factors constitutes an important step forward in the fight against PCNSL. In combined treatment. Blay 1998) data support the use of chemotherapy-radiotherapy as the optimal sequence. Cher 1996). (International Extranodal Lymphoma Study Group) score. High-dose methotrexate as monochemotherapy followed by radiotherapy is associated with a response rate of 80% .15 Gy may be advisable in cases with residual disease. and the involvement of deep structures of the brain. . chemotherapy . Retrospective series have inconsistently shown a survival advantage for combinations of chemotherapy and radiotherapy over radiotherapy alone. 5. Bessell 1996). choosing primary chemotherapy followed by radiation therapy. PS. Ferreri 2003). Abrey 1998) in comparison to the 3% . This strategy produced a 5-year survival of 25% .1 First-line treatment The standard treatment for PCNSL has not yet been defined due to the lack of adequate randomized trials. 2-3 or 4-5 unfavourable features (Ferreri 2002.40% ( Glass 1994. will allow the separation of patients into risk groups. in more than 20% of cases at relapse (Glass 1994. cerebrospinal fluid protein concentration.36 Gy followed by a tumour bed boost of 10 . primary chemotherapy containing high-dose methotrexate followed by radiation therapy is suitable for individual clinical use on a type a type 3 level of evidence (Abrey 1998). and.24% reported with RT alone (Nelson 1992. Ferreri 1995a). a 2-year survival of 60% . the combination of five independent predictors of response and survival.radiotherapy should be considered as the only acceptable sequence for high dose methotrexate delivery. A diffused use of this prognostic index. the addition of other drugs at conventional doses did not consistently improve outcome when compared with high-dose methotrexate monochemotherapy (Blay 1995. which could result in the application of risk-adjusted therapeutic strategies. Conversely to those observed for the International Prognostic Index. Considering that the use of high-dose methotrexate (the main drug in PCNSL management) after radiotherapy has been associated with a high incidence of severe neurotoxicity (Blay 1998).e.chemotherapy). Meningeal involvement has been demonstrated by a positive CSF cytology examination in up to 50% of cases at diagnosis (Sandor 1998). However. while the indications for and efficacy of different doses of systemic methotrexate and intrathecal chemotherapy are unclear. experimental and clinical (Reni 1997a. O'Brien 1996. and the comparison of therapeutic results from prospective studies. but this difference could actually be due to selection bias considering the strong prognostic impact of some variables such as age and PS (Nelson 1992). general criteria for treatment of aggressive NHL were adopted. until definitive conclusions from well-designed trials are available. i.Bessell 1996) and has produced a remarkably higher morbidity and mortality (Blay 1995).70% and a 5-year survival of 25% . named I. to date. radiotherapy parameters should follow the widely accepted principles used for other aggressive NHLs (Glick 1995). However. In other small series. Age > 60 years. high-dose radiotherapy and hyperfractionation have been proposed as risk factors (Deangelis 1994. Herrlinger 2002. IOL is exquisitely sensitive to corticosteroids and radiotherapy. 25% and 9% for patients aged 60. the impossibility of performing a lumbar puncture or using an Ommaya's reservoir in up to one third of patients due to elevated intracranial pressure ( Ferreri 1995a). and 25% to 35% at 5 years (Blay 1998). Some authors assert that meningeal recurrence only occurs in patients with positive CSF cytology at diagnosis. The appearance of late toxicity seems to reflect a predisposition to vascular injury at the site of the original lymphoma. which are not well understood ( Batchelor 2003a). the real efficacy of this strategy has not yet been defined. These data seem to indicate that it is feasible to treat PCNSL using chemotherapy alone. but showing an extremely variable actuarial survival. Schultz 1996). the vast majority of meningeal relapses were actually observed in CSF-positive patients. Treatment-related neurotoxicity in PCNSL patients has not been clearly defined due to the small number of long-term survivors reported in the literature. there is no evidence that intraocular lymphomas should be treated in a different way with respect to PCNSL without intraocular disease. This is also supported by some prospective trials that evaluated protocols using a methotrexate dose > 3 g/m2 without intrathecal chemotherapy. The efficacy of cytostatics is dependent on intraocular pharmacokinetics. and a complete remission rate > 75%. post-radiotherapy chemotherapy.Batchelor 2003b). Presently. In a retrospective analysis of 378 patients. Since only a few prospective non-randomized trials assessing the impact on survival and toxicity of chemotherapy alone have been reported. as well as other strategies to dose intensify chemotherapy and eliminate the need for WBRT. perhaps in the randomised phase II setting. Given the extremely high risk of treatment-related neurotoxicity. Systemic administration of MTX and cytarabine can yield therapeutic levels of drug in the intraocular fluids and clinical responses have been documented. included a few relapsed or histologically unproved cases. Cher 1996). however. There is no standard treatment approach to isolated IOL. A direct relationship between age and severe neurotoxicity has been reported. < 60 and < 40 years. there was no difference in survival (median 32 months) between these two subgroups. should validate the chemotherapy alone strategy. In a comparison of older patients treated with or without WBRT following HDMTX-based chemotherapy ( Abrey 2000). Primary chemotherapy consisted of a high dose-methotrexate-containing regimen alone (Cher 1996) or in combination (Sandor 1998. chemotherapy alone should be considered in patients over the age of 60. Even though these trials reported response and survival data similar to those obtained in series entirely treated with intrathecal drug delivery (Glass 1994. Future studies. In practice. with a 5-year risk of 48%. Ferreri 1995a). Weigel 2004). and patients who relapsed were effectively salvaged with additional chemotherapy or radiotherapy (Freilich 1996). delaying radiotherapy at time of relapse in complete responders. while results with HD-MTX-based polychemotherapy were 65%-100% and 65%-78%. Cheng 1998). it was observed that WBRT did not improve survival in patients achieving complete remission after HD-MTX (Ferreri 2002). In published prospective trials. 6. HD-MTX alone produced a 52%-100% response rate and a 2-yr survival of 61%-63% (Cher 1996.100%.especially in patients treated with high-dose methotrexate and WBRT (Glass 1994. in larger series. as a major strategy to minimize neurotoxicity (Sandor 1998). achieving a response rate of 85% . The cumulative incidence varies from 5 to 10% at one-year .2 Chemotherapy as exclusive treatment Chemotherapy as exclusive treatment for PCNSL is an interesting but still investigational strategy. and although there was a higher relapse rate in patients treated without WBRT.3 Treatment of elderly patients . this strategy has produced response rates in excess of 90%. half the patients develop a recurrence of their original symptoms without evidence of relapsed lymphoma. Some authors have proposed to treat patients with chemotherapy alone. respectively (Schlegel 2001). and had a short follow-up (Sandor 1998 . and the lack of a prospective assessment of its survival effect. 6. and that intrathecal chemotherapy should be reserved to these patients (Glass 1994. Furthermore these studies had a small sample size. Guha-Thakurta 1999. chemotherapy alone markedly reduced the risk of neurotoxicity. relapse is common. respectively (Camilleri-Broet 1998). Cheng 1998). One third of these patients died of complications related to the neurotoxicity (Abrey 1998). relapses in the brain or spinal cord after combined treatment necessitate further chemotherapy.3. Re-induction with HD-MTX resulted in a response in approximately . Ocular recurrence can be treated with RT or with HD-araC which gives a survival lightly longer than that obtained with recurrences at other sites (Deangelis 1994). the time to relapse (cut-off: 12 months) being the main independent indicator of survival. but follow-up is too short to draw firm conclusions. However. these patients were referred for radiation therapy. Median survival after relapse for patients responding to second-line treatment is 14 months. In these cases.5 g/m2) alone or in combination with thiotepa. cisplatin. temozolomide and several other drugs have also been used. Higher doses and larger radiation volumes or hyperfractionation increased treatment-related toxicity without any improvement in outcome. 74 years) treated with a variable chemotherapy regimen. In some cases. a complete remission rate of 72% was achieved with a remarkable improvement in Karnofsky PS and cognitive functions. In a group of 13 elderly patients (median age. Salvage therapy achieves a further complete remission in many cases. Regression after steroid therapy. 6. 4 of them were irradiated as part of salvage therapy. Salvage WBRT has been associated with an overall response rate of 60-74% and a median survival after relapse of 11-19 months in patients who experienced failure after initial HD-MTX ( Herrlinger 2005. Confirmatory biopsy is thus mandatory. vincristine and cytarabine. Treating a patient with unconfirmed PCNSL generates ethical and medical problems. However. including mostly high-dose methotrexate (1 . Conclusions regarding the optimum second-line treatment cannot be made due to the extremely heterogeneous treatment modalities used in published series. but procarbazine.5 Treatment of relapsed patients The median survival of untreated patients with PCNSL after first-line treatment failure is 2 months. vincristine. This decision is still valid since there is a lack of randomized trials demonstrating the superiority of combined treatment compared with radiotherapy alone. mainly in young patients with good PS. that is lesions regressing after steroids are actually PCNSL (Bromberg 2002). High-dose methotrexate-containing chemotherapy followed by radiation therapy is suitable for individual clinical use in histologically unproven PCNSL on a type 3 level of evidence for patients medically fit to undergo systemic chemotherapy. or to the presence of intracranial hypertension.20 months). patients in whom radiological assessment has risen suspicion of PCNSL are not referred for histological assessment due to the frequent involvement of vital 'untouchable' structures. with consequent symptomatic and survival improvement (Deangelis 1994. chemotherapy alone appears an efficient and safe therapeutic alternative for elderly patients. In the past. WBRT using 40-45 Gy followed by a boost to the tumour bed of 10 Gy was suggested as the optimum treatment ( Reni 1997a). In general. Six patients were alive with a median follow-up of 13 months. Blay 1998) and prospective (Abrey 1998) experiences suggest that the addition of chemotherapy significantly improves outcome. A very preliminary experience showed that temozolomide could be active against PCNSL in elderly patients in whom HD-MTX-based chemotherapy is contraindicated. retrospective ( Reni 1997a. re-irradiation of relapsed lesions has also been indicated. achieving 3 complete responses. In elderly patients with a good performance status. use of radiotherapy and severe neurotoxicity. Six patients relapsed (5 . Boiardi 1999). Nguyen 2005). The most used cytostatic in patients who have relapsed after high-dose methotrexate is cytarabine. some authors have suggested that chemotherapy is used again as salvage strategy (Sandor 1998. localized deeply into the brain. deep location of disease and neuroimaging appearance strongly support PCNSL diagnosis. which may or may not be followed by irradiation if this is still feasible. No cases of treatment-related neurotoxicity were observed in complete responders. There is no standard approach to patients with relapsed CNS lymphoma who have already received upfront systemic chemotherapy. Meningeal relapse can be treated with spinal cord irradiation or intrathecal chemotherapy. Considering these findings and the relation between age.4 Treatment of histologically unproved PCNSL Occasionally. 6. only half of patients with "vanishing tumors".Radiation therapy is the conventional choice in elderly patients who cannot receive up-front chemotherapy. Reni 1999). In patients relapsed after chemotherapy as exclusive first-line treatment. chemotherapy alone is suitable for individual clinical use on a type R basis (Freilich 1996). and only a 14% loss of cognitive function at one year (Doolittle 2000). However. there have been two small APBSCT phase II trials. this strategy is a procedurally intensive treatment.5 g/m2 and two cycles of cytarabine 3 g/m2 daily for two days. Preliminary data suggest that rituximab . Significant treatment related toxicity was rare. As with conventional therapy. however. high tumor response and survival rates. maintenance or radiomimetic treatment against PCNSL. in a multicentre phase II trial on PCNSL relapsed or refractory to HDMTX (Reni 2004). monthly. but attractive preliminary results were achieved in small pilot studies (Galetto 1993. upfront BBBD plus HD-MTX has been associated with acceptable morbidity. the sole experience with radiomimetic in PCNSL patients (infusional 5 bromo-2?-deoxyuridine) has been associated with unacceptable neurotoxicity (Dabaja 2003). however. Reversible blood-brain barrier disruption (BBBD) by intra-arterial infusion of hypertonic mannitol followed by intra-arterial chemotherapy is a strategy that leads to increased drug concentrations in the lymphoma-infiltrated brain and may thus improve survival. induction cytarabine and etoposide followed by high dose chemotherapy with thiotepa. 28 patients received five cycles of MTX 3. with vascular interventions. efficacy against systemic lymphomas and ability to cross the BBB. with a median duration of 7 months (Tyson 2003). The experience is still very limited. In one study. It is possible that the patients treated at relapse who previously received WBRT will have a higher risk of neurotoxicity. resulting in 0-6 methylguanine-DNA methyltransferase depletion. followed by BEAM (carmustine. mostly complete remissions. under general anaesthesia. this strategy can be used to replace WBRT in an effort to avoid treatment-related neurotoxicity. This drug displayed excellent tolerability and a 26% response rate. etoposide. In institutions with adequate expertise.6 New active drugs and therapeutic options High-dose chemotherapy with autologous peripheral blood stem cells transplantation (PBSCT) is an investigational therapeutic alternative. Fourteen patients completed the planned therapy and 5 remained in remission at a median of 26 months after transplant. cytarabine and melphalan) consolidation chemotherapy in those patients with chemosensitive disease (Abrey 2003). In relapsed patients. The preliminary results from these trials using high dose chemotherapy with APBSCT clearly indicate that this strategy is feasible in patients with PCNSL. even in elderly patients. such as unconjugated or radiolabeled monoclonal antibodies. The lack of cross-resistance with MTX has been an advantage when this strategy has been used as salvage therapy. The therapeutic benefit of graft-versus-lymphoma (GVL) effect after allogeneic PBSCT has been also reported in a case of PCNSL relapsed after high-dose methotrexate-containing chemotherapy and radiotherapy and after second-line conventional chemotherapy ( Varadi 1999). 6.temozolomide . Temozolomide is an oral alkylating agent that spontaneously undergoes chemical conversion to MTIC (5-(3methyl-1-triazeno) imidaxole-4-carboxamide). cytostatic drugs for induction and conditioning chemotherapy have been selected on the basis of their safety. it is well tolerated. The role of high-dose chemotherapy and APBSCT in PCNSL is still to be defined considering that worldwide experience is still limited. In patients with newly diagnosed PCNSL. In a study on 22 patients with recurrent or refractory primary CNS or intraocular lymphoma. carboplatin based chemotherapy plus BBBD produced a 36% response rate.50% of patients with a median PFS of 10 months (Plotkin 2004). Considering that it permeates the BBB. Khalfallah 1996). However. over one year. and it exhibits additive cytotoxic activity with radiotherapy. In another still ongoing study. Theoretically. Nineteen of 24 patients enrolled to date have achieved a complete remission and there have not been any unexpected acute toxicities. a combination of MTX. only 50% of patients had chemosensitive disease and a significant proportion relapsed after transplant. with a 3-year overall survival of 64% (Soussain 2001). there was a significant incidence of neurotoxicity as well as significant treatment-related morbidity/mortality in patients over the age of 60. BBBD may prove most useful in the delivery of agents unlikely to traverse an intact BBB. The latter application is supported by the positive experience in high-grade gliomas. temozolomide may be used as induction. busulfan and cyclophosphamide produced a complete remission rate of 72%. and its role needs further investigations in PCNSL. and further studies are needed to identify the optimal induction and high dose chemotherapy regimens. thiotepa and cytarabine is used as induction regimen followed by high dose chemotherapy with BCNU and thiotepa and hyperfractionated radiotherapy ( Illerhaus 2001). High dose chemotherapy supported by APBSCT has been used as a strategy to dose intensify chemotherapy given to patients with newly diagnosed or relapsed PCNSL. Primary anaplastic large cell lymphoma of the central nervous system. a camptothecin derivative that inhibits the enzyme topoisomerase I. Major P. Dryja TP. J Clin Oncol 2005. J Clin Oncol 2000. remains to be defined considering that treatment patients died early due to intraparenchymal progression. Moskowitz CH. top References Abdulkader I. Skarin AT. 18: 3144-3150 [ Medline] Agarwal S. 23: 5034-5043 [ Medline] Abrey LE. Allut AG. Gospodarowicz M. while promising effects have been reported in a few cases of leptomeningeal lymphoma treated with intraventricular rituximab (Schulz 2004). Primary central nervous system lymphoma. 86: 71-76 [Medline] Akpek EK. et al. Lozano A. Zucca E. Deangelis LM. and outcomes. High doses of this drug can be safely infused to attain higher CSF concentrations. Hum Pathol 1999. Crump M. Ekfors T.combination is well tolerated and active ( Enting 2004). Stewart D. Swaim MW. Kalimo H. Pathogenesis of primary central nervous system lymphoma: invasion of malignant lymphoid cells into and within the brain parenchyme. Haltia M. Ahmed I. Anecdotal experience with intravenous rituximab showed disappointing results. however. Forsyth P. presenting as diabetes insipidus. 107: 303-304 [Medline] Aho R. 21: 4151-4156 [Medline] Abrey LE. Deangelis LM. Forteza J. J . Hochberg FH. produces an objective response in one third of patients with refractory or relapsed PCNSL. Bernstein M. Rituximab. a chimeric monoclonal antibody directed against the B-cell specific antigen CD20. 106: 1805-1810 [Medline ] Al-Yamany M. Duration of response. Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. with a one-year PFS of 13% (Fischer 2004). Topotecan. Ophthalmology 1999. Spontaneous remission of primary central nervous system lymphoma: report of 3 cases and discussion of pathophysiology. Fraga M. Reni 2001 ). 65 Suppl 1:137-40: 137-140 [Medline] Abrey LE. Pulczynski EJ. Am J Med 1999. Treatment for primary CNS lymphoma: the next step. Batchelor TT. Cameselle-Teijeiro J. J Clin Oncol 1998. Aldous MD. et al. Long-term survival in primary CNS lymphoma. diagnosis. et al. 16: 859-863 [Medline] Abrey LE. Laperriere N. Beardsley GP. 30: 978-981 [Medline] Abelson HT. Intraocular-central nervous system lymphoma: clinical features. Ensminger W. et al. Yahalom J. is an intriguing investigational drug. Cancer Treat Rep 1981. The latter observation constitutes the primary endpoint of one of the only two ongoing randomized trials in PCNSL. Treatment of central nervous system tumors with methotrexate. Some retrospective evidence suggests a positive impact of the addition of high-dose cytarabine to HD-MTX (Ferreri 2002. Acta Neuropathol (Berl ) 1993. Kufe DW. Jakobiec FA. Soheilian M. Nag S. Gockerman JP. Ferreri AJ. J Clin Oncol 2003. Yahalom J. as a sequela of hepatitis C. Mason WP. Rodriguez-Nunez A. 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. Epstein-Barr virus in monitoring the response to therapy of acquired immunodeficiency syndrome-related primary central nervous system lymphoma. Firth J. 45: 259-261 [Medline ] Bashir R. Broggi G. Blood 1995. Salmaso R. Late neurological toxicity after the treatment of primary cerebral lymphoma: multivariate analysis on 208 patients (Meeting abstract). 21: 1044-1049 [Medline] Batchelor TT. Pozzi A. Primary central nervous system lymphomas: clinico-pathologic and immunohistochemical analysis of 30 cases. Conroy T. 16: A86 [Medline] Blay JY. 9: 711-715 [Medline ] Bergmann M. J Clin Oncol 2003b. J Clin Oncol 1998. Eghbali H. Rosenblum MK. Lowe J. J Neurol 1999. High-dose methotrexate for intraocular lymphoma. High-dose methotrexate for the treatment of primary cerebral lymphomas: analysis of survival and late neurologic toxicity in a retrospective series. Kryne-Kubat B. Hochberg F. Cingolani A. Graus F. Philip T. J Neurooncol 1994. Kolak G. New P. Clin Oncol (R Coll Radiol ) 1991. 96: 236-243 [Medline] Berry MP.Neurooncol 1999. Brunat-Mentigny M. Ammassari A. 246: 31-37 [Medline ] . et al. Punt JA. De Luca A. 52: 1648-1651 [Medline] Boiardi A. Detection of Eber-1 RNA in primary brain lymphomas in immunocompetent and immunocompromised patients. Terzija-Wessel U. 42: 151-159 [Medline] Altavilla G. Conroy T. Chevreau C. Carrie C. Hope T. Carson K. Foster CS. Int J Radiat Oncol Biol Phys 1981. Primary non-Hodgkin's lymphoma of the CNS treated with BVAM or CHOD/BVAM chemotherapy before radiotherapy. Grossman SA. Firth JL. et al. Thyss A. et al. Hariharan S. Larocca LM. Primary intracranial neoplasms in patients with HIV. Bouabdallah R. Radiation therapy in the management of primary malignant lymphoma of the brain. 85: 19-27 [Medline] Antinori A. 86: 2922-2929 [Medline ] Blay JY. 14: 945-954 [Medline ] Bessell EM. Bouhour D. Kuchelmeister K. Cunningham C. Cusatelli P. Thyss A. Ann Neurol 1999. 20: 47-53 [Medline] Batchelor T. Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-07. The C5R protocol: a regimen of high-dose chemotherapy and radiotherapy in primary cerebral non-Hodgkin's lymphoma of patients with no known cause of immunosuppression. Chemotherapy is effective as early treatment for primary central nervous system lymphoma. Salmaggi A. J Clin Oncol 1996. et al. Gerhard L. Fariselli L. Holland I. Alavi J. Henson JW. Weisenburger D. O'Neill A. Clin Neurol Neurosurg 1994. Hope DT. Tumori 1999. Abrey LE. et al. 7: 55-59 [Medline] Bessell EM. et al. Proc Annu Meet Am Soc Clin Oncol 1997. Gardiman M. Gaidano G. et al. Bilsky MH. Silvani A. Simpson WJ. Punt J. Intravascular lymphomatosis of the CNS: clinicopathologic study and search for expression of oncoproteins and Epstein-Barr virus. McManus B. Moloney AJ. Ciordia R. Quesnel N. Bouffet E. Primary non-Hodgkin's lymphoma of the central nervous system: phase II study of chemotherapy (BVAM) prior to radiotherapy. 16: 864-871 [Medline] Blumenthal DT. Eghbali H. 3: 193-198 [Medline] Blay J-Y. Chevreau C. Blasius S. Raizer JJ. Clin Cancer Res 2003a. Neurology 1999. 241: 96-100 [Medline] Boiardi A. 110: 607-612 [Medline] Carbone PP. 47: 1113-1116 [Medline] Chamberlain MC. Arch Neurol 1990. Hochberg FH. Gontier MF. Brion A. Wang CH. 22: 88-93 [Medline ] Cheng AL. High-dose chemotherapy with autologous stem cell transplantation as first-line therapy for primary CNS lymphoma in patients younger than 60 years: a multicenter phase II study of the GOELAMS group. Neurology 1995b. Kormanik P. Wang CJ. Ital J Neurol Sci 1997. Salmaggi A. Primary central nervous system lymphomas in 72 immunocompetent patients: pathologic findings and clinical correlations. Criniere E. 18: 787-792 [Medline ] Brada M. Yeh KH. Siemers MD. Recurrent primary central nervous system lymphoma complicated by lymphomatous meningitis. Adjuvant chemotherapy for primary lymphoma of the central nervous system. et al. Huang EY. Chang Keng I Hsueh Tsa Chih 1999. Henin D. 46: 17571759 [Medline] Colombat P. Smithers DW. A uniform activated B-cell-like immunophenotype might explain the poor prognosis of primary central nervous system lymphomas: analysis of 83 cases. 107: 190-196 [Medline ] Camilleri-Broet S. Moreau A. Valentini S. Hines F. CNS lymphoma. et al. Silvani A. Liu MY. Broggi G. Am J Clin Pathol 1998. Uen WC. Therapy of primary CNS lymphoma with methotrexatebased chemotherapy and deferred radiotherapy: preliminary results. et al. Hjiyiannakis D. Rachieru P. Dearnaley D. 82: 1946-1951 [Medline] Cher L. Taphoorn MJ. Martin A. Bone . Silvani A. 45: 1031-1032 [Medline] Chen HC. Delwail V. Kaplan HS. Neurology 1996. Int J Radiat Oncol Biol Phys 1998. 31: 1860-1861 [Medline] Chamberlain MC. Tubiana M. Angonin R. Int J Radiat Oncol Biol Phys 1990. Horwich A.Boiardi A. Sun LM. Primary cerebral non-Hodgkin's lymphoma (PCNSL): a review of new trends in management. Leung SW. Management of primary cerebral lymphoma with initial chemotherapy: preliminary results and comparison with patients treated with radiotherapy alone. et al. Bertrand P. Radiation therapy in primary central nervous system lymphoma. Is a "vanishing tumor" always a lymphoma? Neurology 2002. Cancer 1998. Systemic chemotherapy alone for patients with non-acquired immunodeficiency syndrome-related central nervous system lymphoma: a pilot study of the BOMES protocol. Ashley S. J Neurol 1993. 59: 762-764 [Medline] Camilleri-Broet S. Moreau A. Lemevel A. Allegranza A. Chemotherapy as first treatment for primary malignant non-Hodgkin's lymphoma of the central nervous system preliminary data. Report of the Committee on Hodgkin's Disease Staging Classification. Bloom HJ. 5: 521-525 [Medline ] Chamberlain MC. 18: 1-7 [Medline] Brada M. Glantz M. Primary CNS lymphoma. Delwail V. Traish D. Neurology 1995a. Broet P. Oncol Rep 1998. Levin VA. Hung RL. 40: 1157-1162 [Medline] Bromberg JE. Short intensive primary chemotherapy and radiotherapy in sporadic primary CNS lymphoma (PCL). Mokhtari K. Glass J. Harsh GR. Fang FM. Groupe Ouest Est d'etude des Leucenies et Autres Maladies du Sang (GOELAMS). 45: 1233 [Medline] Chamberlain MC. Musshoff K. Blood 2006. Cancer Res 1971. Neurology 1990. 10: 635-643 [Medline] Deangelis LM. 38: 417-420 [ Medline] Dabaja BS. et al. Cancer 2003. Spina M. Primary central nervous system lymphoma. PPO Updates 1992a. Primary central nervous system lymphoma. 8: 419-423 [ Medline] Deangelis LM. Osztie E. 63: 901-903 [Medline] Ervin T. Primary central nervous system lymphoma. Canellos GP. Yahalom J. Ambrosetti A. Grufferman S. Salvage therapy for primary CNS lymphoma with a combination of rituximab and temozolomide. Vogel FS. 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. Successful treatment of recurrent primary central nervous system lymphoma with high-dose methotrexate. Combined modality therapy for primary CNS lymphoma. Cancer J Sci Am 1996. 66: 699-701 [Medline] Deangelis LM. Kher U. 2: 166 [Medline ] Deangelis LM. 6: 1-13 [Medline] Deangelis LM. Hall WA.Marrow Transplant 2006. Increasing incidence of primary brain lymphoma in the US. Heinemann MH. et al. Tableman M. Oncology (Huntingt ) 1995b. Primary central nervous system lymphoma: Phase I evaluation of infusional bromodeoxyuridine with whole brain accelerated fractionation radiation therapy after chemotherapy. J Clin . Primary Central Nervous System Lymphoma: Curable Without Toxicity? Cancer J Sci Am 1996. Pro B. Curr Opin Neurol 1995a. Petrillo A. Primary brain tumors in the acquired immunodeficiency syndrome. et al. Flannelly CM. 135:155-69: 155-169 [Medline] Deangelis LM. 67: 1431-1435 [Medline] Deangelis LM. Abrey LE. Thaler HT. Braziel R. Pasini F. Siegal T. Prognostic scoring system for primary CNS lymphomas: the International Extranodal Lymphoma Study Group experience. 45: 1556-1557 [Medline] Ferreri AJ. Meyers CA. Primary central nervous system lymphoma as a secondary malignancy. Yahalom J. Non-AIDS Primary CNS Lymphoma: First Example of a Durable Response in a Primary Brain Tumor using Enhanced Chemotherapy Delivery without Cognitive Loss and without Radiotherapy. J Clin Oncol 1992b. Jerome E. Reni M. Thaler HT. Schold SCJ. Henner WD. 40: 80-86 [Medline] Deangelis LM. Neurology 2004. Cirrincione C. 9: 63-71 [Medline] Deangelis LM. Krol G. Ha CS. Cancer 2000. Crossen JR. Recent Results Cancer Res 1994. Cancer 1980. Seabrooke LF. Blay JY. McLaughlin P. Cancer 1991. Cancer 1988. 98: 1021-1028 [Medline] Dahlborg SA. J Neurol Neurosurg Psychiatry 1999. Miner ME. Current management of primary central nervous system lymphoma. Burger PC. 62: 2461-2465 [Medline ] Enting RH. Deangelis LM. 88: 637-647 [Medline] Eby NL. Primary CNS lymphoma: combined treatment with chemotherapy and radiotherapy. Demopoulos A. 2: 137 [Medline] Doolittle ND. et al. Hotleman K. Biberfeld P. 62: 1885-1887 [Medline] Freilich RJ. Increasing annual incidence of primary malignant brain . Blood 1995. 21: 415-446 [Medline] Ferreri AJ. 119: 10931104 [Medline] Fine HA. 86: 2873-2875 [Medline] Fischer L. Kirchen H. Terreni MR. vincristine. Monjour A. JAMA 1993. Chemotherapy without radiation therapy as initial treatment for primary CNS lymphoma in older patients. 21: 266-272 [Medline ] Ferreri AJ. 77: 827-833 [ Medline] Fine HA. CHOP + radiotherapy (XRT) for intermediate grade early stage non-Hodgkin's lymphoma (NHL). Primary central nervous system lymphoma in immunocompetent patients. Reni M. Cancer Treat Rev 1995a. High-dose methotrexate for nonAIDS primary central nervous system lymphoma. Bashir R. Cher L. Pasini F. J Neurosurg 1994. Bolognesi A. Levine A. Klasen HA. 81: 188-195 [Medline] Glass J. Neurology 2002. 58: 1513-1520 [Medline] Ferreri AJ. J Neurooncol 1996. Preirradiation methotrexate chemotherapy of primary central nervous system lymphoma: long-term outcome. Importance of complete staging in nonHodgkin's lymphoma presenting as a cerebral mass lesion. Zoldan MC. 16: 8-12 [ Medline] Galetto G. O'Connell MJ. An ecog randomized phase III trial of CHOP vs. 30: 257-265 [ Medline] Glick JH. Proc Annu Meet Am Soc Clin Oncol 1995. Deangelis LM. Reni M. Verusio C. 31A: 2008-2012 [Medline] Ferreri AJ. Shustik C. Kim K. Villa E. Castanos-Velez E. Reni M. Analysis of human herpesvirus type 8 infection in AIDS-related and AIDS. Hochberg FH. Eur J Cancer 1995b. Med Oncol 1999. AIDS Clinical Trials Group. and dexamethasone (MCHOD). Linggood RM. A multicenter study of treatment of primary CNS lymphoma. Delattre JY. et al. Hochberg FH. Gloghini A. Gruber ML. Pivnik A. Report of 13 cases. 46: 435-439 [ Medline] Gabbai AA. Thiel E. Villa E. Combined therapy for primary central nervous system lymphoma in immunocompetent patients. Oncology Core Committee. Villa E. Jahnke K. Primary central nervous system lymphoma. cyclophosphamide. Treatment of primary central nervous system lymphoma: still more questions than answers. Korfel A.Oncol 2003. Gruber ML. J Neurosurg 1989. 70: 190194 [Medline] Gaidano G. Response of relapsed or refractory primary central nervous system lymphoma (PCNSL) to topotecan. Neurology 2004. Pastore C. 175: 1193-1197 [Medline] Gaidano G. J Infect Dis 1997. Ries LG. Calderoni A. Neurology 1996. Cher L. Therapy of primary central nervous system lymphoma with pre-irradiation methotrexate. Earle J. 14: 391 [Medline] Greig NH. doxorubicin. Lymphoid disorders associated with HHV-8/KSHV infection: facts and contentions.unrelated primary central nervous system lymphoma. Yancik R. AIDS-associated primary central nervous system lymphoma. Tirelli U. Reni M. Capello D. et al. Antinori A. Ann Intern Med 1993. Cancer 1996. Mayer RJ. Rapoport SI. 269: 92-93 [Medline] Glass J. Hochberg FH. Carbone A. J Natl Cancer Inst 1990. 24: 3865-3870 [Medline] Jahnke K. Primary central nervous system lymphoma in Japan--a retrospective. et al. Schabet M. Cancer Treat Res 1993. Guttenberger R. High-DoseChemotherapy with Autologous PBSCT and Hyperfractionated Radiotherapy as First-Line Treatment for Primary CNS Lymphoma (PCNSL) . J Neurooncol 1991. et al. Hochberg FH. Kuker W. Uhl M. et al. Burmeister T. A primary central nervous system T cell lymphoma in a renal transplant patient. Ostertag C. Gratiot-Deans J. Petersen D. Prados M. Loeffler JS. Derigs G. 34: 1293-1302 [ Medline] Herrlinger U.operative study by CNS-Lymphoma Study Group in Japan. 53: 691-692 [Medline] Hayakawa T. et al. Derigs G. et al. Primary central nervous system lymphoma. Deckert M. Dillard SH. Kuker W. Primary central nervous system lymphoma. Guttenberger R. Knight BP. 68: 835853 [Medline] Hu X. Ihorst G.tumors in the elderly. German Cancer Society Neuro-Oncology Working Group NOA-03 multicenter trial of single-agent high-dose methotrexate for primary central nervous system lymphoma. co. Ann Neurol 2002. Lunde NM. Pollack C. Davis RL. Earle KM. Schabet M. 19: 197-215 [Medline] Henry JM. J Clin Oncol 2006. Chin Med J (Engl ) 1996. Kanz L. Cancer 1974. Heffner RRJ. Leichtman AB. Neuwelt EA. Sandler H. J Clin Oncol 2006. 43: 259-268 [Medline ] Gumerlock MK. Transplantation 1992. Blaicher HP. Brugger W. Detection of subclinical systemic disease in primary CNS lymphoma by polymerase chain reaction of the rearranged immunoglobulin heavy-chain genes. Primary cerebral lymphoma. 109: 414-416 [Medline] Illerhaus G. Korfel A. Tanaka R. J Neurooncol 1994. Abe H. Kiewe P. 97: 257-264 [ Medline] Hochberg FH.Update of a Multicenter Phase II Study. 51: 247-252 [Medline] Herrlinger U. Sugita K. Frickhofen N. Primary malignant lymphomas of the central nervous system. 57: 843-847 [Medline] Herrlinger U. Kortmann RD. Takakura K. J Neurosurg 1988. Karnath HO. NOA-03 trial of high-dose methotrexate in primary central nervous system lymphoma: final report. Hirsch F. Acta Neurol Scand 1998. Lu H. 82: 1621-1624 [Medline] Guha-Thakurta N. Marks R. Miller DC. Onkologie 2001. 54 (Suppl 6): 16 [ Medline] Illerhaus G. et al. Ann Neurol 2005. 10: 191-201 [Medline] Hochberg FH. 24: 4754-4757 [Medline] . J Neurooncol 1999. Intravenous methotrexate as initial treatment for primary central nervous system lymphoma: response to therapy and quality of life of patients [In Process Citation]. et al. Marks R. Will BE. High-dose chemotherapy with autologous stem-cell transplantation and hyperfractionated radiotherapy as first-line treatment of primary CNS lymphoma. Klasen HA. Yoshimoto T. Hummel M. Kortmann RD. Wang W. Clemens M. Hong B. The therapy of primary brain lymphoma. 66:111-26: 111126 [Medline] Hacker SM. Damek D. Clinical presentation and therapeutic outcome in 26 patients with primary CNS lymphoma. A changeable tumor. HTLV-I associated primary CNS T-cell lymphoma. Scaravilli F. Skluzacek MC. et al. 44: 1721-1727 [ Medline] Lachance DH. Primary CNS lymphoma. Ki-67 proliferation index. Semin Oncol 1999. Skarin A. Fruchart C. Proust F. Nussenblatt RB. Johansen P. Asari S. Patterson B. Nishimoto A. Thom M. Kase E. Schulz TF. Primary leptomeningeal lymphoma: report of 9 cases. Bone Marrow Transplant 1996. Delangre T. 30: 131-142 [Medline] Lachance DH. Tilly H. 24: 33-36 [Medline] Kadan-Lottick NS. Diagnosis and management of primary intraocular lymphoma. Decreasing incidence rates of primary central nervous system lymphoma.Jellinger KA. O'Neill BP. Milosevic MF. 43: 247-252 [Medline] Laperriere NJ. Primary central nervous system lymphoma. Hematol Oncol Clin North Am 2005. et al. Milosevic MF. Gockerman JP. Tabuchi K. 47: 191-195 [ Medline] Levy-Clarke GA. 18: 1021-1023 [ Medline] Kranz BR. Cerezo L. Primary central nervous system lymphoma: analysis of prognostic variables and patterns of treatment failure. J Cancer Res Clin Oncol 1992. J Neurosurg 1985. Halperin EC. Mauch P. Gerl A. Simpson JR. 176: 855-860 [Medline] . Ohnishi R. Li CY. Jaeckle KA. Primary central nervous system lymphomas--an update. Panzarella T. Witzig TE. Lancet 1992. viii [Medline] Loeffler JS. Whitton AC. doxorubicin. vincristine. Primary lymphomas of the central nervous system: patterns of failure and factors that influence survival. Grigsby PW. Epstein-Barr virus genome. J Clin Oncol 1985. J Neurol Sci 1998. Brizel DM. 119: 7-27 [ Medline] Jellinger KA. Weinstein HJ. Patterson B. 41: 95-100 [Medline] Laperriere NJ. J Neurooncol 1995. 340: 727 [Medline] Krogh-Jensen M. Paulus W. Wells WA. Boyko OB. et al. Leuk Lymphoma 1998. et al. Cyclophosphamide. 19: 739-49. 62: 522-527 [Medline] Khalfallah S. Neurology 1994. Radiology 1990. Rudge P. Cerebrospinal fluid immunocytology in primary central nervous system lymphoma. Burger PC. Wilmanns W. Ervin TJ. Macdonald DR. Wong CS. Stamatoullas A. Thierfelder S. Radiother Oncol 1998. Canellos G. Primary central nervous system lymphomas--new pathological developments. diagnosis with immunocytochemical analysis. Fine HA. and prednisone for primary central nervous system lymphoma: short-duration response and multifocal intracerebral recurrence preceding radiotherapy. Paulus W. 26: 346-356 [Medline ] Marshall AG. D'Amore F. Garcia DM. Primary lymphoma of brain: results of management of a modern cohort with radiation therapy. 158: 226-231 [Medline] Michalski JM. 95: 193-202 [Medline] Kawakami Y. Accelerated radiation therapy for primary lymphoma of the brain. Primary central nervous system lymphomas in immunocompetent individuals: histology. Gurney JG. p53 and bcl-2 gene expression. Durable remission of a relapsing primary central nervous system lymphoma after autologous bone marrow transplantation. Wong CS. 3: 490-494 [Medline] Maher EA. Radiother Oncol 1997. Pawson R. Chan CC. and review of the literature. Cancer 2002. Neurology 1991. Schlegel U. 23: 1507-1513 [Medline] O'Brien PC. Crossen J. Hill S. et al. Rodriguez M. Urbach H. 1993. Frenkel EP. Roos DE. Schuler F. Kurtin PJ. p. Immunol Rev 1998. Hill SA. O'Fallon JR. Walker QJ. 25: 67-71 [Medline] O'Neill BP. et al. 106: 934a [Medline] Nelson DF. et al. Barton MB. et al. Osmotic blood-brain barrier modification and combination chemotherapy: concurrent tumor regression in areas of barrier opening and progression in brain regions distant to barrier opening. Preliminary results of combined chemotherapy and radiotherapy for non-AIDS primary central nervous system lymphoma. Martz KL. France. Bender H. Frenkel E. Medical Journal of Australia 1996. 119 [ Medline] O'Neill BP. Wang CH. Primary central nervous system non-Hodgkin's lymphoma (PCNSL): survival advantages with combined initial therapy? A final report of the North Central Cancer Treatment Group (NCCTG) Study 86-72-52. Krigel RL. 33: 663-673 [Medline] O'Neill BP. Trans-Tasman Radiation Oncology Group (TROG). Int J Radiat Oncol Biol Phys 1999a. Witzig TE. McGrath MS. 9: 1580-1590 [Medline] Neuwelt EA. Brown LD. HD-Busulfan/Thiotepa. Diehl J. 162:293-8: 293-298 [Medline] Nguyen PL. Liew KH. Finkelstein DM. February 2-5. Fourth International Congress on Anti-cancer Chemotherapy 1993. et al. The immunology of AIDS-associated lymphomas. Neurosurgery 1983. Primary CNS lymphoma treated with osmotic blood-brain barrier disruption: prolonged survival and preservation of cognitive function. Occult systemic non-Hodgkin's lymphoma (NHL) in patients initially diagnosed as primary central nervous system lymphoma (PCNSL): how much staging is enough? J Neurooncol 1995b. 16: 211-215 [Medline] O'Neill BP. Loeffler JS. Chakravarti A. FDG-PET in . Colgan JD. Earle JD. Dahlborg SA. Int J Radiat Oncol Biol Phys 1992. Earle JD. J Clin Oncol 1991. large volume radiation therapy improve survival? Report on a prospective trial by the Radiation Therapy Oncology Group (RTOG): RTOG 8315. 12: 662-671 [Medline] Neuwelt EA. Ramsey F. Neurosurgery 1984. Newall J. O'Fallon JR. Paris. Habermann TM. Trotter GE. Habermann TM. Kiefer T. Primary CNS Lymphoma Treated with HD-Methotrexate. Dinapoli RP. Nelson JS. Earle JD. Kerman HD. Matthies A. Primary CNS non-Hodgkin's lymphoma (PCNSL): survival advantage with combined initial therapy? (Meeting abstract). Krigel RL. Colgan JP.Montemurro M. Bonner H. 15: 362-366 [ Medline] Ng VL. Blood 2005. 165: 424-427 [Medline] O'Neill BP. Successful treatment of primary central nervous system lymphomas with chemotherapy after osmotic blood-brain barrier opening. J Clin Oncol 2005. Hochberg FH. Int J Radiat Oncol Biol Phys 1995a. Med Oncol 1999b. Goldman DL. Autologous Stem Cell Transplantation and Response-Adapted Whole-Brain Radiotherapy: Results of the Multicenter OSHO-53 Phase II. Non-Hodgkin's lymphoma of the brain: can high dose. O'Fallon JR. Schmidt-Wolf IG. Results of whole-brain radiation as salvage of methotrexate failure for immunocompetent patients with primary CNS lymphoma. Primary central nervous system non-Hodgkin's lymphoma: survival advantages with combined initial therapy?. Batchelor TT. Prevention of recurrence and prolonged survival in primary central nervous system lymphoma (PCNSL) patients treated with adjuvant highdose methylprednisolone. et al. Roman-Goldstein S. 23: 9-17 [ Medline] Neuwelt EA. Colgan JP. 43: 559-563 [Medline] Palmedo H. Balaban E. et al. Ferreri AJ. J Neurooncol 1997b. et al. Lesser GJ. Prognostic factors in the diagnosis and treatment of primary central nervous system lymphoma. 14: 556-564 . Clinical relevance of consolidation radiotherapy and other main therapeutic issues in primary central nervous system lymphomas treated with upfront high-dose methotrexate. Ferreri AJ. Nabors LB. 8: 227-234 [Medline] Reni M. Blay JY. J Clin Oncol 1998. Zoldan MC. vincristine. Treatment of relapsed central nervous system lymphoma with high-dose methotrexate. Hochberg FH. Abrey LE. Phase II trial of chemotherapy alone for primary CNS and intraocular lymphoma. Primary central nervous system lymphoma: treatment with chemotherapy and radiotherapy. Monjour A. Ferreri AJ. Whitcup SM. Lunsford LD. Pearson D. Cancer 2005. Panageas KS. J Neurol Neurosurg Psychiatry 2001. 104: 2466-2472 [Medline] Plotkin SR. Betensky RA. Adams RD. 71: 173-180 [Medline] Reni M. Garancini MP. Zaja F. et al. 95: 199-212 [Medline] Schlegel U. 40: 1682-1688 [Medline ] Sandor V. Delattre JY. Deangelis LM. Salvage chemotherapy with temozolomide in primary CNS lymphomas: preliminary results of a phase II trial. Scott C. 51: 419-425 [ Medline] Reni M. Murray K. Pels H. Ferreri AJ. 63: 939-947 [ Medline] Raizer JJ. Perry J. Proton magnetic resonance spectroscopy in immunocompetent patients with primary central nervous system lymphoma. Second-line treatment for primary central nervous system lymphoma. Primary brain lymphomas in patients with a prior or concomitant malignancy. J Neurooncol 2005. Villa E. Eur J Nucl Med Mol Imaging 2005 [ Medline] Panageas KS. Br J Cancer 1999. Guha-Thakurta N. 79: 530-534 [Medline] Reni M. Biron P. Nussenblat R. Schmidt-Wolf I. 31A: 2003-2007 [Medline] Schaumburg HH. Stark-Vancs V. A consideration of their clinical features and therapy. Ben Porat L. The reticulum cell sarcoma--microglioma group of brain tumours. Lis E. Abrey LE. Dell'Oro S. 10: 5643-5646 [Medline] Pollack IF. Eur J Cancer 2004. Clin Cancer Res 2004. Eur J Cancer 1995. et al. et al. J Clin Oncol 1996. Deangelis LM. Int J Radiat Oncol Biol Phys 2001. and dexamethasone for primary CNS lymphomas: initial report of radiation therapy oncology group protocol 88-06. Combined systemic and intraventricular chemotherapy in primary CNS lymphoma: a pilot study. doxorubicin. 1975-1999. Ann Oncol 1997a. Kleinschmidt R. Plank CR. Flickinger JC. Trends in survival from primary central nervous system lymphoma. 16: 3000-3006 [Medline] Sarazin M. 71: 118-122 [Medline] Schultz C. Villa E. Therapeutic management of primary central nervous system lymphoma in immunocompetent patients: results of a critical review of the literature. Nibio A. Grossman SA. Brouwers P. Franceschi E. et al. 32: 135-142 [Medline] Reni M. Dameshek HL. Mason W. Fields J. Donahue B. Brain 1972. Ameri A. Poisson M. Koutcher JA. Sherman W. et al. Glasmacher A. Villa E.immunocompetent patients with primary central nervous system lymphoma: correlation with MRI and clinical follow-up. Cancer 1989. Elkin EB. Bernardi D. Preirradiation chemotherapy with cyclophosphamide. Helmstaedter C. O'Neill BP. Levy V. 104: 901 [Medline] Tyson RM. Mehta BM. 19: 742-749 [Medline] Stewart DA. Horten BC. Chaudhry A. Primary lymphoma of the central nervous system. High Dose Thiotepa. ventricular and lumbar injections. Voorhies RM. 65: 322-326 [Medline] Soussain C. 65: 1907-1912 [ Medline] Shibata S. Yamabe H. Zeelen U. Piprot-Chauffat C. Jahnke K. Legars D. Schmidt-Wolf I. A single-center study of 11 patients with intraocular lymphoma treated with conventional chemotherapy followed by high-dose chemotherapy and autologous bone marrow transplantation in 5 cases. Reux I. Sasai K. Pharmacokinetics of tumor cell exposure to [14C]methotrexate after intracarotid administration without and with hyperosmotic opening of the blood-brain and blood-tumor barriers in rat brain tumors: a quantitative autoradiographic study. Thiel E. Tsutsui K. Sites of origin of primary intracerebral malignant lymphoma. Hiraoka M. Systemic chemotherapy with vincristine. Leuk Lymphoma 1996. Intraventricular treatment of relapsed central nervous system lymphoma with the anti-CD20 antibody rituximab. 293: 161-166 [ Medline] Shenkier TN. Results of intensive chemotherapy followed by hematopoietic stem-cell rescue in 22 patients with refractory or recurrent primary CNS lymphoma or intraocular lymphoma. Abe M. Leuk Lymphoma 2003. Basler GA. Merle-Beral H. et al. 10: 49-52 [Medline] Shapiro WR. Current status and future of relapsed primary central nervous system lymphoma (PCNSL). Neutwelt EA. et al. Pels H. Hiesiger EM. Engert A. Primary CNS lymphoma of T-cell origin: a descriptive analysis from the international primary CNS lymphoma collaborative group. doxorubicin and prednisolone following radiotherapy for primary central nervous system lymphoma: a phase II study. Mikol J. 23: 339-345 [ Medline] Soussain C. 23: 2233-2239 [Medline] Shibamoto Y. Siegal T. Young DF. J Neurooncol 1999. Cancer Res 1988.prednisolone chemotherapy.[Medline] Schulz H. cyclophosphamide. Blay JY. Lacy C. et al. Thurel C. Neurosurgery 1989. Poortmans P. Methotrexate: distribution in cerebrospinal fluid after intravenous. Fardeau C. Lipschutz LE. An unresolved therapeutic problem. Cancer 1990. Oya N. J Clin Oncol 2001. N Engl J Med 1975. Doolittle ND. Busulfan. 89: 753-754 [ Medline] Shapiro WR. Shima N. 25: 14-19 [Medline] Socie G. Sutton L. Haematologica 2004. Gerber S. Forsyth P. Blood 2004. Clin Bull 1980. et al. Hoang-Xuan K. Cassoux N. J Clin Oncol 2005. Dodo Y. Schlienger M. et al. Cancer 1990. 48: 694-701 [Medline] Shapiro WR. Azar N. Kraemer DF. Chronic methotrexate toxicity to the central nervous system. Cyclophosphamide (TBC) and Autologous Hematopoietic Stem Cell Transplantation (ASCT) without Whole Brain Radiotherapy (WBRT) for Primary Central Nervous System Lymphoma (PCNSL). 44: 627-633 [Medline] . Allen JC.dose radiation and systemic vincristine-doxorubicincyclophosphamide. 42: 161-167 [Medline] Shibamoto Y. Suzan F. Improved survival rate in primary intracranial lymphoma treated by high. Germing U. Sher PB. Kapelushnik J.Varadi G. 34: 185-190 [Medline] Velasquez WS. Weis J. 31: 545-550 [ Medline] Weigel R. Or R. 20: 177-185 [Medline] Watne K. J Neurooncol 1994. Primary malignant lymphoma of the brain. Krauss JK. Brautbar C. Graft-versus-lymphoma effect after allogeneic peripheral blood stem cell transplantation for primary central nervous system lymphoma. Hager B. A report of 24 cases from the Norwegian Radium Hospital. et al. Nome O. et al. 106: 82-87 [Medline] . Scott H. Nagler A. Lindegaard MW. Primary central nervous system lymphoma. Severe complications after intrathecal methotrexate (MTX) for treatment of primary central nervous system lymphoma (PCNSL). Naparstek E. Clin Neurol Neurosurg 2004. Abrahamsen AF. Leuk Lymphoma 1999. Acta Oncol 1992. Senn P.