A systematic approach to the diagnosis of suspected central nervous system lymphoma

Abstract

Central nervous system (CNS) lymphoma can present a diagnostic challenge. Currently, there is no consensus regarding what presurgical evaluation is warranted or how to proceed when lesions are not surgically accessible. We conducted a review of the literature on CNS lymphoma diagnosis (1966 to October 2011) to determine whether a common diagnostic algorithm can be generated. We extracted data regarding the usefulness of brain and body imaging, serum and cerebrospinal fluid (CSF) studies, ophthalmologic examination, and tissue biopsy in the diagnosis of CNS lymphoma. Contrast enhancement on imaging is highly sensitive at the time of diagnosis: 98.9% in immunocompetent lymphoma and 96.1% in human immunodeficiency virus-related CNS lymphoma. The sensitivity of CSF cytology is low (2%-32%) but increases when combined with flow cytometry. Cerebrospinal fluid lactate dehydrogenase isozyme 5, β2-microglobulin, and immunoglobulin heavy chain rearrangement studies have improved sensitivity over CSF cytology (58%-85%) but have only moderate specificity (85%). New techniques of proteomics and microRNA analysis have more than 95% specificity in the diagnosis of CNS lymphoma. Positive CSF cytology, vitreous biopsy, or brain/leptomeningeal biopsy remain the current standard for diagnosis. A combined stepwise systematic approach outlined here may facilitate an expeditious, comprehensive presurgical evaluation for cases of suspected CNS lymphoma.

Figure 1

Cerebrospinal fluid (CSF) cytology in diffuse large B-cell lymphoma. Monolayer centrifuge preparation of CSF shows pleomorphic large lymphocytes with irregular nuclear contours, prominent macronucleoli, and moderate amounts of basophilic cytoplasm (May-Grünwald Giemsa stain, original magnification, ×400). Courtesy of Kirk Jones, MD.

Figure 2

Proteomics of cerebrospinal fluid (CSF) in central nervous system (CNS) lymphoma. Two-dimensional liquid chromatography/mass spectrometry identified tryptic peptides of complement factor H protein in CSF, which were upregulated in the CSF of 2 consecutive patients with CNS lymphoma compared with 2 individuals serving as controls. Courtesy of J.L.R., Chris Becker, PhD, Mimi Roy, PhD, and Howard Schulman, PhD.

Figure 3

Sensitivity and specificity data for routine and lymphoma-specific cerebrospinal fluid (CSF) and neuroimaging studies for central nervous system lymphoma. Tests are highlighted on the basis of the ability to detect parenchymal lymphoma (blue) meningeal lymphoma (yellow), or both (green). CT indicates computed tomography; EBV, Epstein-Barr virus; HIV, human immunodeficiency virus; IgH, immunoglobulin heavy chain; MRI, magnetic resonance imaging; and PCR, polymerase chain reaction.

Figure 4

Systematic evaluation for suspected central nervous system (CNS) lymphoma. *If there is a lesion with mass effect: no lumbar puncture, provide intracranial pressure management as appropriate, and proceed directly to brain biopsy. †A sample of 10.5 mL or more, hand carried to the laboratory and processed the same day. ‡If human immunodeficiency virus (HIV) positive and/or immunosuppressed (transplant, cancer, or chronic immunosuppression). §Whole-body positron emission tomography (PET) or PET/computed tomography (CT) add sensitivity and specificity in detecting systemic lymphoma when available. ||If ophthalmologic slitlamp examination reveals cells in the vitreous. CBC indicates complete blood cell count; Coags, coagulation tests; CSF, cerebrospinal fluid; EBV, Epstein-Barr virus; IgH, immunoglobulin heavy chain; LD₅, lactate dehydrogenase isozyme 5; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; and PET, positron emission tomography.