Lymphomatosis cerebri: a rare form of primary central nervous system lymphoma. Analysis of 7 cases and systematic review of the literature

Abstract

Background: Primary central nervous system lymphomas may present as diffuse, nonenhancing infiltrative lesions. This rare variant is termed lymphomatosis cerebri (LC). We did a systematic review and analysis of the literature, adding our own cases, to better characterize LC in order to improve early diagnosis and treatment.

Methods: PubMed, ISI Web of Knowledge, and hospital databases were reviewed. Information was extracted regarding demographic, clinical, histological, cerebrospinal fluid (CSF), neuroimaging, and treatment variables. The impact of single parameters on overall survival (OS) was determined by applying univariate and multivariate analyses.

Results: Forty-two patients were included (median age: 58 y; range: 28-80 y). At consultation, 52% of patients had a poor KPS. The most common presenting symptom was cognitive decline (59.5%). Imaging studies showed supratentorial and infratentorial infiltration in 55% of patients and bilateral hemispheric involvement in 95%. CSF pleocytosis was present in 51.5% of the patients. Median time to diagnosis was 4.5 (range: 1-30) months, and the diagnosis was not established until autopsy for 33% of patients. The median OS was 2.95 (range: 0.33-56) months; however, those patients who received methotrexate had a median OS of 13.8 (range: 0.7-56) months. Analysis identified KPS ≥ 70 (HR: 0.32; 95% CI: 0.114-0.894; P = .03) and treatment with methotrexate (HR: 0.19; 95% CI: 0.041-0.886; P = .034) as independent favorable prognostic factors, whereas T-cell lymphoma was independently related with a worse outcome (HR: 6.62; 95% CI: 1.317-33.316; P = .022).

Conclusions: LC is a misdiagnosed entity associated with considerable diagnostic delay. MRI evidence of bilateral hemispheric involvement and CSF pleocytosis should be alerts for this diagnosis. Treatment with methotrexate-based chemotherapy must be considered, especially for patients with good KPS.

Keywords: diffuse infiltrative lesion; leukoencephalopathy; lymphomatosis cerebri; primary central nervous system lymphoma.

Fig. 1.

(A and B) MRI of a young male (patient 40) showing patchy contrast enhancement in the right hemisphere in axial T1 sequence (A) and diffuse hyperintense lesions in bilateral white matter on FSE-FLAIR sequence (B). (C and D) MRI of an adult female (patient 36) showing contrast in right subinsula and left thalamus (C) and diffuse bilateral abnormal hypersignal within the deep white matter in FLAIR sequence (D). (E–H) Short-TI inversion-recovery (STIR) spinal cord MRI from patient 40 showing an intramedullary hyperintense lesion (arrow) (E). Diffusion-weighted image shows elevated signal in right hemisphere (arrow) (F), and ADC map (G) shows (arrow) low signal in the lesion confirming that it is a true restricted diffusion. Perfusion-weighted image shows an elevated relative regional cerebral blood volume ratio (H).

Fig. 2.

(A) Hematoxylin and eosin (H&E) staining shows scattered atypical lymphocytes with diffuse infiltration of the parenchyma and perivascular distribution. Scale bar, 100 µm. (B) On immunohistochemical staining, atypical lymphoid cells are strongly stained with CD20. Scale bar, 50 µm. (C) H&E shows atypical lymphocytes infiltrating meninges. Scale bar, 100 µm. (D) H&E microphotograph of typical nodular primary central nervous system lymphoma with atypical lymphocytes invading brain parenchyma in compact cellular aggregates. Scale bar, 20 µm.

Fig. 3.

Kaplan-Meier curves showing overall survival of the patients with lymphomatosis cerebri stratified by age, KPS, histological subtype, and treatment options (any cytostatic treatment with methotrexate, cytostatic treatment without methotrexate, corticosteroids treatment, and no treatment).

Fig. 4.

Lymphomatosis cerebri features that would help when considering the diagnosis and a diagram performed with all patients (n = 36) whose radiological, cerebrospinal fluid, and clinical data were available.