What are the diagnostic criteria for Central Nervous System (CNS) lymphoma?

From the Guidelines

Diagnosing CNS lymphoma requires a comprehensive approach involving multiple diagnostic modalities, starting with contrast-enhanced cranial MRI, followed by histopathological examination of tumor biopsy, and cerebrospinal fluid analysis via lumbar puncture, including cytology, flow cytometry, and immunoglobulin gene rearrangement studies to detect malignant cells, as recommended by the most recent guidelines 1. The diagnostic process for CNS lymphoma typically begins with neuroimaging, specifically contrast-enhanced MRI, which shows characteristic enhancing lesions that may be single or multiple.

• Key features of CNS lymphoma on MRI include:
  • Hypointensity on T1-weighted images
  • Isointensity to hypointensity on T2-weighted images
  • Reduced apparent diffusion coefficient (ADC) values
  • Variable surrounding edema
  • Homogeneous and often strong enhancement after contrast administration Following imaging, a definitive diagnosis requires tissue sampling, most commonly through stereotactic brain biopsy, as recommended by the EHA-ESMO clinical practice guideline for diagnosis, treatment, and follow-up of primary central nervous system lymphomas 1.
• The biopsy sample should be subjected to histopathological examination, including morphology and immunohistochemistry, with a minimum stain panel that includes cluster of differentiation (CD)20, CD3, CD10, B-cell lymphoma (Bcl)-6, Bcl-2, multiple myeloma 1 (MUM1), and Ki-67 antibodies. Cerebrospinal fluid analysis via lumbar puncture is also important, including cytology, flow cytometry, and immunoglobulin gene rearrangement studies to detect malignant cells.
• Additional workup should include:
  • HIV testing, as CNS lymphoma is more common in immunocompromised patients
  • Complete blood count
  • Comprehensive metabolic panel
  • Body imaging (CT chest/abdomen/pelvis) to rule out systemic lymphoma with CNS involvement
  • Bone marrow biopsy may be performed to assess for bone marrow involvement
  • Ophthalmologic evaluation with slit-lamp examination to detect vitreous or retinal involvement Corticosteroid therapy before tissue biopsy should be avoided whenever clinically possible, as it can temporarily reduce tumor size and yield false-negative results, as recommended by the EHA-ESMO guideline 1.

From the Research

Diagnostic Approaches for CNS Lymphoma

• The diagnosis of CNS lymphoma can be challenging and requires a systematic approach, including brain and body imaging, serum and cerebrospinal fluid (CSF) studies, ophthalmologic examination, and tissue biopsy 2.
• Contrast enhancement on imaging is highly sensitive at the time of diagnosis, with a sensitivity of 98.9% in immunocompetent lymphoma and 96.1% in human immunodeficiency virus-related CNS lymphoma 2.
• The sensitivity of CSF cytology is low (2%-32%), but increases when combined with flow cytometry, and other CSF studies such as lactate dehydrogenase isozyme 5, β2-microglobulin, and immunoglobulin heavy chain rearrangement have improved sensitivity (58%-85%) but moderate specificity (85%) 2.

Role of Biopsy in Diagnosis

• Brain biopsy is the preferred method of diagnosis, with a diagnostic yield of 92.3% in one study, and is considered a safe and accurate option to minimize diagnostic delay 3.
• Early brain biopsy can obviate the need for prolonged work-ups and facilitate prompt treatment, with perioperative morbidity noted in 7.6% of cases due to hemorrhages after stereotactic brain biopsy 3.

Diagnostic Markers in Blood and CSF

• Several diagnostic markers in blood and CSF have been identified, including microRNAs, CXCL13, interleukins, soluble interleukin-2-receptor, and beta-2-microglobulin, which may facilitate early diagnosis with low complication rates 4.
• CXCL-13, beta-2-microglobulin, and neopterin have the highest potential in diagnosing CNS lymphoma, but further study is needed before they can be used in clinical practice 4.

Clinical Presentation and Diagnostic Workup

• Primary CNS lymphoma is a rare, aggressive extranodal non-Hodgkin lymphoma confined to the brain, eyes, CSF, or spinal cord without systemic, non-CNS involvement, and requires a high level of suspicion for diagnosis 5.
• The optimal treatment regimen has not been defined, but methotrexate-based chemotherapy regimens are considered the standard treatment approach for induction treatment, and novel targeted agents have recently been introduced into the therapeutic arsenal 5.
• MRI of the total neuroaxis followed by CSF cytomorphology and flow cytometry are methods of choice when CNS lymphoma is suspected, and new CSF biomarkers may be of potential diagnostic value 6.