Review article
Primary CNS lymphoma: clinical presentation, pathological classification, molecular pathogenesis and treatment

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Abstract

Primary CNS lymphomas (PCNSL) represent malignant non-Hodgkin’s B cell lymphomas, which are confined to the central nervous system. They show a dramatic increase in frequency in the immunocompromised as well as in the immunocompetent population. Recent studies have identified germinal center B cells as the cellular origin of PCNSL; however, the details of their molecular pathogenesis still remain to be elucidated. Treatment recommendations are not clearly established. Radiotherapy (RT) is efficient in terms of tumor response, but not curative. Median survival after RT alone is about 1 year. According to the results of uncontrolled studies the combination of RT and chemotherapy based on high-dose methotrexate (HD-MTX) is most efficient in terms of survival rates. However, long-term neurotoxicity overshadows treatment efficacy, especially in patients over 60 years of age. The authors favor the systematic evaluation of chemotherapy alone with protocols including HD MTX, because unicenter results are promising in terms of both survival as well as quality of life in long term survivors.

Introduction

Primary CNS lymphomas (PCNSL) are defined as extranodal lymphomas which arise in the CNS in the absence of systemic disease and which are confined to the CNS [1]. This definition excludes cerebral metastasis of systemic lymphomas to the CNS and angiotropic lymphoma, which is characterized by the growth of lymphoma cells in blood vessel lumina [2], [3]. Within the last two decades, the incidence of PCNSL has increased dramatically in immunocompromised as well as in immunocompetent individuals [4], [5], [6], [7]. PCNSL has become the most frequent brain tumor in AIDS patients with an overall frequency of 2–6% of patients showing clinical symptoms during the course of the disease [8], [9], [10], [11] and a frequency of 12% at autopsy [4], [5], [12]. Some investigators have even suggested that PCNSL will become the most frequent primary brain tumor in immunocompetent patients in this decade, which according to recent epidemiological data probably will not be the case [13]. The issue of how to treat PCNSL adequately is still a matter of debate. It has also been questioned whether lymphoma classifications established for extracerebral lymphomas can be applied to PCNSL, since PCNSL differ from other lymphoma entities in several important aspects as outlined below. Current intense scientific efforts aim at the characterization of the molecular origin of this tumor. The present review will focus on clinical and neuroradiological features, pathological classification of PCNSL, recent progress in understanding of its molecular pathogenesis as well as on novel therapeutic protocols.

Section snippets

Clinical and radiological presentation

PCNSL may affect all age groups with a peak incidence in the fifth to seventh decade in non-AIDS patients [11]. Tumor manifestation is often diffuse and multifocal and most frequently affects the supratentorial brain parenchyma [14]. While older series have reported histological subtypes to be associated with a poor prognosis [15], [16], more recent data could not confirm such a correlation [17], [18], [19]. An occult systemic lymphoma is found in less than 5% of patients by systemic staging if

Diagnosis

There is broad consensus that if PCNSL is suspected, stereotactic biopsy is the diagnostic procedure of choice [14], [22]. Open neurosurgical intervention is not superior to stereotactic biopsy and partial resection is even associated with worse survival [23]. If possible, steroids should be withheld and raised intracranial pressure should be treated with osmotic therapy, since tumor cells may disappear completely macroscopically and microscopically after application of cortisone which may even

Pathological classification

PCNSL present either as single or multiple tumors, often located deeply in the cerebral hemispheres with a predilection for the periventricular brain tissue. Macroscopically, the tumors are brownish, gray or yellow masses with mostly poorly defined margins. Primary or exclusive meningeal location is rare [31], however, meningeal seeding of tumor cells frequently complicates the course of the disease and may be responsible for relapse in successfully treated patients [32]. Microscopically, PCNSL

Molecular pathogenesis

In order to elucidate the obscure pathogenesis of PCNSL, it was obligatory to analyze the immunological and cytogenetic phenotype of the tumor cells and to characterize their molecular abnormalities. In the past, such studies have largely been hampered by the very limited tissue obtained by stereotactic biopsy. With the recent progress in molecular genetics, sensitive methods have been developed which require only small amounts of tumor tissue and provide us with the opportunity to approach the

Treatment

Symptomatic therapy alone results in a median survival of 2–3 months [16], which may be prolonged by the administration of steroids to a median of 4–5 months. A dramatic shrinkage of tumor volume after short term steroid treatment is present in 15–25% of cases [71], which is transient and lasts only a few weeks in the vast majority of patients. Only a small minority experiences a complete remission for several months up to years [14], [72], [73]. Every attempt of tumor resection is

Conclusions and future perspectives

The diagnosis of PCNSL in an elderly person with psycho-organic syndrome, focal neurological signs, no steroid pretreatment and characteristic imaging results is straightforward by means of stereotactic biopsy. However, diagnosis may be difficult in rare cases with primary leptomeningeal manifestation with pleocytosis but lack of cytological evidence of tumor cells, in cases of atypical histological results with abundance of ‘reactive’ T-lymphocytes, in the infrequent cases of ‘low-grade’ CNS

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