INTRODUCTION

Non-Hodgkin's lymphoma invades the brain, the vitreous body and nerves of the eye, the meninges, and the nerve roots of brain and spine, leading to the development of a primary CNS lymphoma. The mechanism of involvement of these locations by malignant B lymphocytes is unknown, but it might involve molecular targeting of lymphoma cells generated at cryptic systemic sites. The diagnosis of primary CNS lymphoma has been facilitated by advances in imaging techniques and the discovery of molecular markers. Methotrexate-based regimens, even when radiation is deferred, prolong overall survival to over 5 years, but relapses eventually occur in most cases. Better tools for earlier diagnosis and monitoring of treatment response will emerge from molecular studies of therapeutic targets.

Primary CNS lymphoma (PCNSL) is a nervous-system-seeking extranodal non-Hodgkin's lymphoma (NHL). Microscopically, PCNSL resembles systemic diffuse large B-cell lymphoma (DLBCL) and the two disorders share common molecular features; however, the underlying molecular mechanisms of PCNSL,

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INTRODUCTION

including the causative role of somatic gene alterations, remain uncertain. Survival and functional outcome in patients with PCNSL have improved markedly since the deferral of cranial irradiation and the provision of methotrexate-based chemotherapy became standard of care, but most patients relapse, and the 5-year survival rate remains inferior to that of patients over 60 years of age with DLBCL outside the nervous system. This Review highlights advances in our understanding of PCNSL, as well as current approaches to its diagnosis and therapy.

Epidemiology and risk factors

Immunocompetent Host

PCNSL represents 3.1% of all primary brain tumors and 2–3% of NHLs.[1,2] After a three-fold rise observed two decades ago, the incidence of PCNSL has increased only slightly in the past 10 years in individuals above the age of 60, and now stands at 0.46 per 100,000 patient-years.[1,3] A slight male predominance is observed. In our experience, a larger than expected number of patients with PCNSL have experienced prior 'autoimmune' disease of systemic or neurologic sites (e.g. conditions resembling chronic inflammatory demyelinating polyneuropathy or multiple sclerosis) or have had therapy with corticosteroids or immunosuppressive agents.

Immunocompromised Host

Patients with acquired or congenital immunodeficiency are highly predisposed to develop PCNSL, and the disease represents the most frequent brain tumor in this patient population. Epstein–Barr virus (EBV) infection increases the risk of brain involvement in PCNSL.[4] The introduction, in 1995, of highly active antiretroviral therapy (HAART) to treat HIV infection dramatically reduced the occurrence of PCNSL in the immunocompromised population. According to one study, the incidence rate of primary and secondary brain lymphomas dropped from 2.8 per 1,000 patient-years in 1990 to 0.4 per 1,000 patient-years in 1998.[5] In general, PCNSL patients with AIDS are younger than those with an intact immune system, and they present with a CD4+ T-cell count below 50 cells/µl. Recipients of HAART tend to have had fewer AIDS-defining illnesses and are diagnosed with PCNSL later than patients with HIV were in the pre-HAART era.[6] Congenital immunodeficiency syndromes that predispose to lymphoma include ataxia-telangiectasia, Wiskott–Aldrich syndrome, and common-variable or severe-combined immunodeficiency.[7]

The rise in solid organ transplantation has increased the incidence of post-transplant lymphoproliferative disorder (PTLD), although this lymphoma still arises in fewer than 2% of organ transplant recipients. PTLD tends to involve the donor organ and multiple extranodal sites, and is rarely confined to the nervous system.[8] The main risk factors for PTLD are EBV mismatch (a seronegative host receiving a seropositive organ), and the extent of therapeutic immunosuppression (antithymocyte globulin causes a significant increase in risk). The risk of PCNSL is highest amongst heart–lung transplant recipients. In over three-quarters of transplant patients, PTLD reflects reactivated or newly acquired EBV infection. EBV-negative PTLD occurs later after transplantation than EBV-positive PTLD (4–5 years versus 6 months after transplantation).[9]

Pathogenesis

Cellular Origin of Primary CNS Lymphoma

PCNSL is classified as a diffuse large B-cell lymphoma (World Health Organization classification). It has been suggested that clonal proliferation might occur among normal B lymphocytes drawn to the CNS, a theory that is supported by the occurrence of white matter brain lesions that herald brain lymphoma.[10] Alternatively, a clone of malignant systemic lymphocytes displaying specific adhesion molecules might traffic to the brain.[11,12,13] We have implicated cellular adhesion molecules in this homing process by demonstrating that lymphocyte function-associated antigen (LFA)1a, LFA1b and intercellular adhesion

molecule 1 (ICAM1) mediate interaction between lymphoma cells and tumor endothelial cells.[14] The adhesion of clonal cells to the nervous system also involves the family of N-cadherins and the adhesion molecule CD44.[15] In rare cases, patients with the indolent NHL chronic lymphocytic leukemia develop PCNSL in the absence of systemic DLBCL and without exhibiting evidence of chronic lymphocytic leukemia in the CNS. These cases support the concept that transformation of a malignant clone of aggressive lymphoma can be accompanied by the expression of chemokine receptors that drive phenotypic presentation as a disease of the CNS only. Intriguingly, immunoglobulin heavy chain (IgH) gene rearrangement analysis revealed presence of B lymphocytes clonally related to the brain tumor in peripheral blood and bone marrow of two patients with PCNSL.[16]

Molecular Features

Our knowledge of PCNSL reflects insights learned from the molecular pathology of extraneural DLBCL, as anatomic constraints on the amount of accessible tissue hinder PCNSL-specific research. PCNSL probably originates from cells that have undergone maturation in germinal centers of lymph nodes. PCNSL and systemic DLBCL share many molecular features. Both have clonal rearrangement and somatic hypermutation (SHM) of immunoglobulin genes,[17,18,19] and complementary DNA expression profiling experiments support the existence of similar molecular subtypes for PCNSL and systemic DLBCL, including germinal center B-cell-type (GCB), activated B-cell-type (ABC) and 'type 3' gene expression profiles.[20,21] For PCNSL, however, an overlapping state of differentiation is characterized by expression of both GCB and ABC genes.[22] Aberrant SHM targeting the regulatory or coding regions of proto-oncogenes such as c-MYC, PIM1, RhoH/TTF and PAX5 has been described in both systemic lymphoma and PCNSL.[23,24] Intriguingly, these mutations occur in some of the same chromosomal breakpoint regions that are affected by translocation events. It is tempting to think of PCNSL and systemic DLBCL as disorders reflecting faulty class-switch recombination or SHM.[25] This hypothesis is further corroborated by the recent finding in patients with PCNSL of reciprocal chromosomal translocations involving the BCL6 locus on chromosome 3q27 at a frequency (38%) comparable to that of extracerebral DLBCL.[26] In general, translocations can result in upregulation of a growth-promoting gene (such as BCL6) from a heterologous promotor on the derivative chromosome. The breakpoints identified in BCL6 are all located within the major translocation cluster, raising the possibility that erroneous SHM is the underlying pathogenetic mechanism. Translocation partners include the IgH and immunoglobulin light chain (IgL) loci. In one case, the breakpoint in the IgH locus was found within the switch µ region, indicating faulty class switch recombination.[26]

At the cytogenetic level, a functional role for undiscovered oncogenes and tumor suppressor genes is indicated by reported gains of genomic material on chromosomes 12q, 18q and 22q, and losses on 6q.[27] For example, loss of human leukocyte antigen expression might help tumor cells to evade elimination by the immune system.[28]

The Role of Infectious Agents

Infectious agents promote lymphomagenesis through direct transforming properties or sustained antigenic stimulation. EBV genomic material is identified in over 90% of PCNSL tissue from immunocompromised patients.[29] An insight into the role of EBV was gleaned from the finding that early PTLD contains spatially distinct masses originating from different EBV-transformed B-cell clones.[30] Although nervous system PTLD is monomorphic and clonal, this tumor, like systemic PTLD, probably evolves from polyclonal to oligoclonal and then a clonal cell population. EBV episomes are not found in PCNSL occurring in immunocompetent patients, and the notion that EBV might still be involved in B-cell oncogenesis in this population (the 'hit-and-run' hypothesis[31]) remains speculative. Intriguingly, it has been shown that EBV infection of B cells results in expression of activation-induced cytidine deaminase and polymerase ?, both of which are crucial enzymes for SHM. Aberrant SHM involving growth-regulatory genes might provide B cells with a survival advantage independent from EBV infection, which might be eradicated in immunocompetent hosts.[32] Other viruses have been directly implicated in the pathogenesis of primary effusion lymphoma and multicentric Castleman disease (human herpesvirus 8), as

well as adult T-cell leukemia/lymphoma (human T-lymphotropic virus 1). The mechanism of viral oncogenesis might involve virally induced activation of human oncogenes or expression of oncogenes encoded by the virus that alter cell growth and prolong cell survival.

Another important mechanism of pathogenesis in systemic lymphoma is chronic antigenic stimulation. Relatively strong evidence for this mechanism exists for Borrelia burgdorferi-associated cutaneous marginal zone lymphoma and Helicobacter pylori-related gastric mucosa-associated lymphoid tissue (MALT) lymphoma.

Autoimmune Disease and Pharmacologic Immunosuppression

Chronic immune activation has been epidemiologically associated with systemic lymphoma in disorders such as Sjögren's syndrome, rheumatoid arthritis, systemic lupus erythematosus and celiac disease.[33] Clearly the increased risk reflects the underlying disorder as well as therapy with agents targeting tumor necrosis factor (etanercept, infliximab) and immunosuppressive agents (methotrexate, azathioprine, cyclophosphamide, chlorambucil).[34] The contribution to PCNSL of pharmacologic immunosuppression after organ transplantation is best demonstrated by the occurrence of PTLD of the nervous system following therapy with tacrolimus or ciclosporin, as well as its regression following reduction of these agents.

Clinical Presentation

In our experience, patients' histories often note a neurologic prodrome years before PCNSL. These lingering illnesses, suggestive of multiple sclerosis or vitritis, might reflect polyclonal lymphoid proliferates that are still subject to T-cell regulation. Lymphoma can infiltrate white matter tracts of the corpus callosum and internal capsule to produce personality change, cognitive decline and weakness. The edematous masses, which are seldom hemorrhagic, produce language deficits, paresis of extremities, and signs of brain swelling including headache, hiccups, and emesis. Seizures are seen more often in patients with AIDS, afflicting 2–33% of this group. Infiltration of the walls of the third ventricle produces inappropriate secretion of antidiuretic hormone, diabetes insipidus, hyposexuality, hyperphagia, and psychotic thought changes. Less common is tumor infiltration of the brainstem and walls of the fourth ventricle, presenting as dysconjugate gaze, vertigo, ataxia and intractable vomiting. Fewer than 40 examples exist of spinal cord lymphoma causing myelopathy.

Meningeal lymphoma with confusion, psychomotor slowing, cranial neuropathies and cauda equina syndrome can accompany PCNSL. Lymphoma of the dura, indistinguishable from meningioma, might be limited to the extradural space or invade the arachnoid membrane through microscopic holes or after surgical intervention.

Intravascular lymphoma, a systemic NHL, involves the nervous system as malignant lymphocytes adhere to the intima of brain arterioles. Small-vessel strokes occur in patients with fatigue and weight loss, and nocturnal perspiration, hepatosplenomegaly or unexplained pancytopenia. The multivessel involvement produces 'lacunar stroke' syndromes with subcortical dementia, myelopathies and lymphocytic infiltrates in the spinal fluid.[35]

When lymphoma invades the cranial or peripheral nerve roots ('neurolymphomatosis'), migratory pain syndromes emerge. Isolated disorders of the fifth or seventh cranial nerves are often confused with trigeminal neuralgia or Bell's palsy. Painless polyneuropathies or involvement of a single nerve are rare.[36]

Intraocular lymphoma (IOL) is not easily distinguished from therapy-resistant vitritis attributable to sarcoidosis, cytomegalovirus infection or Behçet's syndrome. Ocular 'floaters' and blurred vision progress to involve both eyes, with clumped cellular infiltrates being seen on slit lamp examination, followed by retinal infiltrates.[37] The risk of brain involvement approaches 50% in primary IOL patients, and 15% of

PCNSL is associated with concurrent or subsequent eye involvement.

Systemic dissemination, suspected in the setting of 'B symptoms' (weight loss, fever and night sweats), is rare in PCNSL, as is a presentation of PCNSL as the sole form of an occult systemic primary neoplasm.

Diagnosis

Neuroimaging Studies

A feature that PCNSL shares with other infiltrative brain tumors is preferential spread along white matter tracts and the subependymal space. Three-quarters of PCNSL patients present with supratentorial masses. The most frequent location of PCNSL is the cerebral hemispheres, followed by the basal ganglia, corpus callosum, and cerebellum; only rarely are these tumors located in deep brain structures, the brainstem, or the spinal cord. Lesions are typically in contact with cerebrospinal fluid spaces, either ventricular or subarachnoid.[38] Multiple lesions are seen in 20–40% of cases at initial presentation, and are almost invariably observed later in the course of the disease. The densely packed cells are hyperdense on CT, isointense to hyperintense on T1-weighted MRI, and hypointense on T2-weighted MRI, and they display restricted proton diffusion (hyperintense signal on diffusion-weighted MRI [DWI], and isointense to hypointense signal on apparent diffusion coefficient map; Figure 1). There is usually strong and homogeneous contrast enhancement. Blood is seldom present, and necrotic centers characterize the disease after provision of corticosteroids. T2-weighted or fluid-attenuated inversion-recovery (FLAIR) sequences reveal nonenhancing tumor areas and vasogenic edema (Figure 1). In our experience, entirely nonenhancing PCNSL accounts for fewer than 2% of lesions. DWI reveals small-vessel ischemia accompanying intravascular and leptomeningeal lymphoma. Magnetic resonance spectroscopy identifies masses with diminished concentrations of N-acetylaspartate and elevated ratios (>3:1) of choline to creatine (Figure 1), similar to changes seen in malignant glioma. Magnetic resonance perfusion studies and PET might serve as useful additions to anatomic imaging when residual or relapsing disease is suspected.

Figure 1. Neuroimaging findings in patients with primary CNS lymphoma. (A) Head CT of a 63-year-old man with primary CNS lymphoma (PCNSL). A mass lesion isodense to gray matter is seen in the deep right frontal white matter (arrowheads) extending into the genu of the corpus callosum. (B) A 56-year-old man complained of right facial numbness and progressive imbalance. T1-weighted MRI with gadolinium revealed a homogeneously enhancing mass lesion within the right side of the pons infiltrating the trigeminal nerve. (C) T1-weighted MRI with gadolinium of a 38-year-old patient with AIDS demonstrates a large left temporal mass with faint peripheral enhancement. The tumor obstructs the temporal horn of the lateral ventricle. PCNSL was confirmed by biopsy. (D) T2-weighted MRI of a 44-year-old woman with PCNSL reveals a cellular, hypointense lesion within the inferior left frontal lobe (arrowheads) surrounded by vasogenic edema. Athough this portion of the tumor displayed homogeneous contrast enhancement on

T1-weighted images with gadolinium, the hyperintense areas within the right frontal white matter did not, probably reflecting diffusely infiltrative disease and vasogenic edema. (E,F) Diffusion-weighted MRI (E, hyperintense area relative to gray matter) and apparent diffusion coefficient map (F, hypointense area) reveal relative restriction of proton diffusion indicative of a high cytoplasmic:extracellular space ratio in the area of a left frontal PCNSL. (G) Multivoxel magnetic resonance spectroscopy of tumor (upper set of voxels) and normal-appearing white matter (lower set of voxels). Normal brain is characterized by a near 1:1 ratio of choline (1) and creatine (2) as well as presence of a dominant N-acetylaspartate peak (3), whereas the tumor displays marked increase in the choline:creatine ratio, reduction of N-acetylaspartate and presence of a lactate–lipid peak (4).

In the absence of these typical radiographic features, diagnosis of early stages of PCNSL is challenging. Early PCNSLs might appear as poorly enhancing and diffusely infiltrative processes (Figure 2). Evading histopathological diagnosis, these occurrences are under-represented in the literature.

Figure 2. The prodrome of primary CNS lymphoma. This 48-year-old woman presented with symptoms consistent with transverse myelitis. (A) Sagittal T1-weighted MRI with gadolinium; note also reversal of the cervical spine (lordosis) at the level of the myelopathy. (B) Axial T1-weighted MRI with gadolinium; a round enhancing lesion is seen on the right side of the spinal cord. Nearly complete recovery occurred after intravenous methylprednisolone treatment, but fatigue and upper back and neck pain persisted. Eight months later, the patient started experiencing mild language difficulties. (C) A T1-weighted MRI with gadolinium disclosed patchy areas of enhancement within the basal ganglia on the left side. The patient's clinical syndrome again improved with corticosteroids. She was empirically started on immunomodulatory therapy with interferon-beta1b for suspected multiple sclerosis. Her expressive dysphasia progressed relentlessly, however, and a right hemiparesis ensued 10 months after her initial neurologic symptoms. (D) T1-weighted MRI with gadolinium revealed a large left basal ganglionic mass lesion. A sterotactic brain biopsy revealed primary CNS lymphoma.

In the immunocompromised population, PCNSL lesions are less homogeneous and more often multifocal than in the immunocompetent population. Peripheral areas of enhancement surround zones of central necrosis, but one-third of patients have masses that do not enhance after contrast is provided. The tumors accumulate 18F-fluorodeoxyglucose during PET.

Leptomeningeal lymphoma occurs rarely, and is seen as linear areas of enhancement within the subarachnoid spaces overlying the cortex, the Virchow–Robin spaces, the walls of the ventricle and the nerve roots of the cauda equina. Lymphoma of the dura is easily confused with meningioma. Neurolymphomatosis produces notable enlargement of extradural root or plexus, which is best seen on coronal enhanced MRI images. Of 50 patients seen with ocular lymphoma, we have identified one example of an intraocular abnormality (a diffuse retinal blush on MRI), in addition to subtle infiltrates of the optic nerve and chiasm.

With therapy, restricted proton diffusion on DWI resolves within days.[39] Contrast-enhanced MRI lesions diminish in density and size and then disappear,[40] whereas FLAIR changes are reduced in volume but remain in evidence years after the tumor has seemingly been cured. Designation of 'complete response', therefore, is made difficult by the presence of small enhancing and FLAIR residua, absent symptoms, or progressive radiographic disease over many years.

Histopathology and Immunohistochemistry

More than 98% of PCNSLs are malignant NHLs of the B-cell type. The tumor contains perivascular B cells expressing pan-B-cell markers such as CD19, CD20 or CD79a. A 'reactive' T-cell infiltrate, recognized by its labeling with anti-CD3 antibodies, is always present (Figure 3). In nonimmunosuppressed patients, the majority of the tumors are categorized as DLBCL. DLBCL, Burkitt-like or atypical tumors are the most common tumor types seen in immunosuppressed individuals. Other histological subtypes, including 'low-grade' lymphomas (lymphoplasmacytic and follicular),[41] marginal zone lymphoma of the dura, or primary T-cell lymphoma of the brain, are rare.[42] Histologic diagnosis represents the standard of care, except for tumors that are inaccessible or those presumed to be present in the setting of advanced AIDS, for which pre-emptive PCNSL chemotherapy is sometimes provided. Clonal proliferates in brain tissue can be identified by immunoglobulin gene rearrangement analysis or immunohistochemistry with antibodies to IgLs (? and ?). The dense and rapidly growing tumor often has greater than 50% staining with the proliferation marker Ki-67.

Figure 3. Histopathological findings in primary CNS lymphoma. (A) Hematoxylin and eosin stain demonstrates a population of mitotically active medium-to-large-sized lymphoid cells with large vesicular nuclei and prominent nucleoli mixed with small mature lymphocytes with a distinct propensity to cluster around medium-sized vessels. (B) Immunohistochemistry using a monoclonal anti-CD20 antibody reveals clusters of highly pleomorphic B lymphocytes. (C) Immunohistochemistry using an anti-CD3 antibody highlights the dense T-cell infiltrate within B-cell PCNSL. Tumor cells are indicated by black arrows. (D) The large fraction of mitotically active cells within the tumor can be visualized by immunohistochemistry

with the Ki-67 antibody. Bars 100 microm.

Examination of Cerebrospinal Fluid and Vitreous Samples

Estimates of the rate of PCNSL involvement of meninges vary between 5% (our experience) and 50%. This wide range reflects variability between observers of cytologic materials. Cytopathological examination of cerebrospinal and vitreous fluid remains the primary mode of diagnosis. Automated sorting of fluorescently tagged cells is highly specific, but obligates cell numbers in excess of 40,000 cells. Diagnoses made on the basis of polymerase chain reaction (PCR) analysis of rearrangements of immunoglobulin or T-cell-receptor genes are increasingly being accepted for the evaluation of small cell numbers (Figure 4), although the application of these techniques to the evaluation of cerebrospinal fluid or vitreous fluid still requires validation.[43,44,45] Spinal fluid analysis with PCR using primers specific for EBV genes has proved to be useful in the diagnosis of PCNSL in immunosuppressed patients, but the positive predictive value is low.[46,47]

Figure 4. Analysis of paucicellular specimens. (A) Cytopathological specimen of a patient with post-transplantation lymphoma. The cerebrospinal fluid sediment is composed of inconspicuous small lymphocytes (black arrow) admixed with a population of atypical larger lymphoid cells, some of which display nuclear clefts and prominent nucleoli (bar 20 µm; image courtesy of Dr Serguei Bannykh). (B) Flow cytometry of a vitreous biopsy specimen retrieved from a patient with ocular lymphoma. A small monoclonal CD19+ B-cell population with restricted immunoglobulin ? light chain expression is identified in the right upper quadrant of this scatter plot. Immunoglobulin-?-light-chain-positive, CD19+ cells were not present (not shown). (C) Immunoglobulin heavy chain gene rearrangement analysis of a stereotactic brain biopsy specimen obtained from a patient with primary CNS lymphoma. Polymerase chain reaction using DNA isolated from tissue and degenerate primers for the immunoglobulin heavy chain gene yielded a single product of 267 base pairs in length. This result was reproducible in duplicate assays, and was indicative of a clonal B-cell population (capillary electropherogram: blue curve, primer labeled with the fluorophore 6-FAM; red curve: primer labeled with the fluorophore HEX. Upper graph: 'polyclonal control' using DNA isolated from a human tonsil as a template and framework 3 primers; lower graph: patient's specimen using framework 2 primers). Courtesy of Dr Pei Hui. Abbreviation: PCR, polymerase chain reaction.

Treatment

Therapy at Initial Diagnosis

Surgery for PCNSL is limited to CT-based or MRI-based stereotactic or incisional biopsy. Partial resection

is associated with poorer survival.[48] The diagnostic accuracy is increased by avoidance of the 'routine' provision of glucocorticoids in favor of osmotic edema therapy with parenteral mannitol. Recommendations for staging evaluations are listed in Box 1 .

Box 1. Staging evaluations in patients with primary CNS lymphoma. Tests listed in parentheses might increase diagnostic sensitivity.

Methotrexate, at doses exceeding 3.5 g/m2, is an essential component of any treatment regimen for PCNSL. In early studies, we used methotrexate, before irradiation, at 3.5 g/m2 and later at 8 g/m2 at 10–14-day intervals until complete radiographic remission was achieved.[49] This therapy was followed by monthly consolidation treatments for at least 1 year. The same protocol was used in a recently completed prospective multicenter trial.[50] The drug is well tolerated by older patients. Although the area under the concentration–time curve correlates positively with outcome, the data do not explain the inability to achieve complete responses in up to 40% of patients. Infusion rate, a determinant of the area under the curve, should exceed 800 mg/m2/h.[51]

Various regimens have combined high-dose methotrexate with other chemotherapeutic agents. These approaches share quite similar rates of response and survival. Complete responses are achieved in 50–60% of patients, with progression-free survival approximating 3 years and overall survival 5 years ( Table 1 ).

Table 1. Selected Chemotherapy and Multimodality Treatment Protocols for Primary CNS Lymphoma

General physical examination including evaluation of lymph nodes and testicles

Opthalmologic evaluation including a slit lamp examination of the eye Cerebrospinal fluid evaluation: cytopathology, flow cytometry (immunoglobulin heavy chain gene

rearrangement analysis) Computed tomography of chest, abdomen and pelvis (18F-fluorodeoxyglucose PET scan) Bone marrow biopsy—only in patients in whom systemic lymphoma is suspected; generally

recommended by others[85] HIV testing Serum lactate dehydrogenase

Reference Systemic chemotherapy regimen Intrathecal

chemotherapy WBXRT

(Gy) CRa (%)

PRa (%)

OSa (months)

PFSa (months)

Abrey et al. (2000)[83]

Methotrexate, procarbazine, vincristine; cytarabine after WBXRT

Methotrexate 45 56 33 60 35+

Batchelor et al. (2003)[50]

Methotrexate No No 52 22 22.8+ 12.8

DeAngelis et al. (2002)[53]

Methotrexate, procarbazine, vincristine, dexamethasone; cytarabine

Methotrexate 45 58 36 36.9 24

McAllister et al. (2000)[84]

Intra-arterial methotrexate after blood–brainbarrier disruption with mannitol; intravenous cyclophosphamide, etoposide

No No 65 19 40 Not available

Pels et al. (2003)[85]

Six chemotherapy cycles: A1, B1, C1, A2, B2 and C2. Cycle A: methotrexate,

Prednisolone, methotrexate,

No 61 10 50 21b

aResponse and survival data are not based on the intention-to-treat principle in all studies reported.bTime to treatment failure. Abbreviations: +, not reached; CR, complete remission; OS, overall survival; PFS, progression-free survival; PR, partial remission; WBXRT, whole-brain radiation therapy.

Methotrexate coadministered with mannitol-induced blood–brain-barrier disruption followed by intravenous cyclophosphamide and etoposide achieves uniquely high response rates.[52] Similar results have, however, been achieved with less-complicated treatments that avoid monthly intracranial angiography and procedure-related complications.

Methotrexate-based chemotherapy has been administered along with external beam irradiation.[53,54] This combination prolonged progression-free survival, but with the disadvantage of neurocognitive decline, and without overall survival advantage.

The addition of methotrexate chemotherapy altered the historical reliance on whole-brain external beam radiotherapy (WBXRT).[55] The latter produced average survival of less than 1 year (overall survivorship at 1 year 48%), and was associated with brain recurrence in 61% of patients, and neurocognitive sequelae in a large number of survivors. In most cases, WBXRT is limited to treatment of patients in whom multiple levels of chemotherapy have failed, or to provision of lower dose brain irradiation in clinical trials. Neurolymphomatosis often requires local irradiation for bulky disease in addition to systemic chemotherapy.

Therapy for meningeal disease has emphasized treatment with high-dose methotrexate-based parenteral regimens, often interspersed with intrathecal formulations of cytosine arabinoside. The systemic use of high-dose methotrexate and cytarabine leads to therapeutic drug concentrations in the cerebrospinal fluid.[56] Less convincing is the role of prophylaxis of the spinal fluid. Therapies that exclude intrathecal chemotherapy have achieved sustained remission rates comparable to those that include these therapies ( Table 1 ).

Salvage Therapy for Relapsed Lymphoma

At relapse, PCNSL remains treatment-sensitive, often to previously used therapies. Methotrexate produces responses in over half of patients,[57] whereas topotecan is less effective and more toxic. Small case series have demonstrated efficacy for PCV (procarbazine, lomustine and vincristine), VIA (etoposide, ifosfamide and cytarabine), or temozolomide. The experience with systemic or intrathecal rituximab with temozolomide gives cause for cautious optimism, and is surprising in view of the large size of the rituximab molecule and its dependence on complement for function.[58] The role of WBXRT in the treatment of chemoresistant disease isundisputed.[59]

Autologous Bone Marrow Transplantation

Given the virtual four-fold event-free survival benefit of marrow transplantation for systemic lymphoma, it is not surprising that PCNSL has been treated with high-dose chemotherapy supported by autologous stem cell transplantation. In 20 patients with relapsing and refractory disease, 3-year probability of overall survival after intensive therapy was 60%.[60] Results from a clinical trial for newly diagnosed PCNSL, however, were disappointing: 14 patients who had achieved a complete response to high-dose methotrexate and cytarabine achieved an overall median event-free survival of 9.3 months after further stem-cell-supported high-dose chemotherapy.[61]

vincristine, ifosfamide and dexamethasone; cycle B: methotrexate, vincristine, cyclophosphamide and dexamethasone; cycle C: cytarabine, vindesine and dexamethasone

cytarabine

AIDS-related Disease

WBXRT, the standard treatment for immunocompromised patients, has produced responses lasting less than 6 months in patients with AIDS. Patients without comorbidities or with preserved CD4+ cell counts tolerate methotrexate or PCV therapy.[62] HAART has markedly reduced the incidence of PCNSL, and has increased eligibility for chemotherapy and survival after chemotherapy.[63] At least two ongoing trials are exploring the role of methotrexate and HAART in this patient population ( Table 2 ).

Table 2. Ongoing Clinical Trials for Primary CNS Lymphoma

Abbreviations: CR = complete remission; HAART = highly active antiretroviral therapy; NA = not applicable; PD = progressive disease; PR = partial response; SD = stable disease; In = indium; WBXRT = whole-brain radiation therapy; Y = yttrium.

Primary CNS Lymphoma in Transplant Patients

PTLD carries a poor prognosis even after chemotherapy and radiation therapy. Reduction of

Study group or lead institution Systemic chemotherapy regimen WBXRT (Gy) Study type

Neurooncological Working Group, Oncology Working Group of the German Cancer Society[71,72]

Methotrexate; cytarabine for PR, SD, PD 45 Phase IV

University of California at San Francisco[73]

Methotrexate, temozolomide, rituximab; cytarabine plus etoposide for CR

No Phase II

Radiation Therapy Oncology Group[74] Rituximab, methotrexate, temozolomide (before and after radiation)

38 Phase I/II

Memorial Sloan–Kettering Cancer Center, New York; University of Virginia[75]

Methotrexate, procarbazine, vincristine, rituximab

For CR —

Memorial Sloan–Kettering Cancer Center, New York[76]

Rituximab, methotrexate, procarbazine, vincristine, then high-dose chemotherapy and stem-cell rescue

NA Phase II

Oregon Health & Science University[77] Intra-arterial methotrexate with blood–brain-barrier disruption, rituximab, carboplatin for newly diagnosed disease

NA Phase II

Eastern Cooperative Oncology Group-E1F05[78]

Rituximab; methotrexate, vincristine, procarbazine, dexamethasone, cytarabine

NA —

International Extranodal Lymphoma Study Group[79]

Methotrexate with or without cytarabine Tailored to response and age

Phase II

Memorial Sloan–Kettering Cancer Center, New York[76]

Rituximab; In 111-ibritumomab tiuxetan scans. If scan positive then 90Yibritumomab tiuxetan

NA 'Pilot study'

Northwestern University, Chicago[75] Pemetrexed disodium NA Phase II

National Cancer Institute (NCI-06-C-0051)[80]

Methotrexate, leucovorin, rituximab, and HAART for AIDS-related disease

NA Phase II

immunosuppression might lead to tumor regression, but many patients lose their donor organ as a result of this approach. Rituximab has been successfully used in systemic PTLD, and case reports exist of successful rituximab-based multidrug use in brain PTLD, but this has not been systematically studied and many tumors do not express the CD20 epitopes that are recognized by this antibody. The anecdotal benefits of zidovudine and ganciclovir in CNS PTLD are similarly unstudied. In the majority of patients treated with these drugs, immunosuppression was simultaneously reduced or discontinued.[64]

Ocular Lymphoma

Although a 'localized' disease, primary IOL mandates systemic chemotherapy to prevent CNS relapse. Patients with eye and brain involvement are also treated with systemic chemotherapy. Micromolar therapeutic concentrations of methotrexate are achieved in vitreous fluid after systemic administration.[65] Vitreal injections performed before orbital irradiation have included methotrexate.[66] Trials of local rituximab approaches are commencing.

Cognitive Outcome of Primary CNS Lymphoma and its Treatment

With PCNSL survival now exceeding 5 years, the focus has shifted to quality of life and neurocognitive outcome of therapy. Quality-of-life measures (including Functional Assessment of Cancer Therapy-Brain [FACT-BR], SF-36® [Medical Outcomes Trust, Waltham, MA] and other neuropsychologic test batteries) are often applied to treated patients. Although methotrexate therapy achieves clearance of contrast -enhancing lesions, FLAIR changes persist in white matter, and there is evidence from retrospective cohorts that this leukoencephalopathy remains clinically silent for years.[67] WBXRT, particularly when followed by intrathecal or intravenous methotrexate therapy, gives rise to a progressive neurodegenerative process involving both gray and white matter, which is associated with increased morbidity and mortality in one-third of patients (42 of 129 individuals).[68] Few studies are available that have prospectively assessed the effects of chemotherapy and radiation in concert.[69,70] Prospective studies of neurocognitive deterioration after combined chemotherapy and WBXRT report post-treatment declines of performance in attention, memory, psychomotor function and language tests. Patients who received chemotherapy alone had significantly higher scores than did patients treated with WBXRT with or without chemotherapy on the memory domain.[69] There is a consensus that future trials should include serial neurocognitive testing.

Ongoing Trials

Ongoing trials in PCNSL ( Table 2 ) are investigating four major themes.[71,72,73,74,75,76,77,78,79,80] First, the role of CD20 antibodies in combination with methotrexate-based drug combinations is being studied. Early-phase trials are exploring radiolabeled B-cell antibodies (yttrium-90-labeled ibritumomab tiuxetan and iodine-131-labeled tositumomab). Second, the role of methotrexate-based combination chemotherapy for newly diagnosed and recurrent PCNSL is being explored in comparison with historic controls. Several studies include modified doses of WBXRT administered to complete responders to drug therapies. Third, the role of blood–brain-barrier disruption during methotrexate-based chemotherapy is being explored with and without CD20-targeted agents. Last, the role of the methotrexate analog pemetrexed is being explored for recurrent PCNSL.

In general, these trials include provision of intrathecal drugs for meningeal involvement and ocular therapy for vitreal or retinal involvement. At present, the utility of prolonged 'maintenance' chemotherapy has not been subjected to formal evaluation. Many ongoing trials end therapy after 1 year.

Conclusions

Therapy for PCNSL is offering high-functioning long-term survival in a growing number of patients. Specialized multidisciplinary centers provide methotrexate alone (8 g/m2) or methotrexate-based combinations. Two-thirds of immunocompetent PCNSL patients achieve complete response but experience

relapse within 2–5 years, and survive for shorter lengths of time than do those with systemic DLBCL. Population-based statistical analyses have failed to reveal improvement in survival despite the therapeutic advances,[81] a finding that should encourage molecular and imaging investigations for earlier diagnosis. Clearly, insights from systemic lymphoma will facilitate molecular studies of PCNSL in support of an expanded role for CD20-targeted and antimetabolite therapies. Extrapolating from systemic DLBCL, future progress will depend on the development of transgenic or explanted animal models bearing brain lymphoma, the development of therapies aimed at causative viruses, identification of immunosuppressive risk factors, and creation of sensitive techniques by which to identify minimal residual disease, as well as adhesion molecules responsible for brain homing. With increasing life expectancy, long-term treatments must include measures of neurocognitive function and white-matter toxicity.

Key Points

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Addendum

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