Primary central nervous system lymphoma with diffuse subcortical white matter diffusion restriction

Dear Editor,

We read with great interest the article “Diffuse subcortical white matter restriction: An uncommon finding on metronidazole toxicity,” written by Salari al., ¹ in which the authors reported a patient with metronidazole toxicity, who presented with neurologic disturbances, and subcortical white matter restricted diffusion on brain magnetic resonance imaging (MRI), and discussed the differential diagnosis of restricted diffusion on diverse anatomical locations, and their specific patterns. In addition, we would like to add a discussion about cerebral lymphomatosis, a rare cause of subcortical restricted diffusion, not mentioned by the authors in the differential diagnosis, which may present with no mass effect, no increased perfusion, and no gadolinium-enhancement, leading to a diagnosis delay, if not considered.

A previously healthy 45-year-old man presented with a progressive cognitive deficit, associated with visual blurring. Brain MRI demonstrated an infiltrative lesion with hyperintense signal on T2-weighted imaging and fluid-attenuated inversion recovery (FLAIR) in the bilateral frontoparietal subcortical white matter, internal capsule, corpus callosum, and brainstem, with restricted diffusion, but no evidence of gadolinium-enhancement or hyperperfusion, with a pattern of leukoencephalopathy (Figure 1). Exogenous intoxication, infection, and autoimmune encephalitis were considered, but discarded, since the patient did not show clinical signs of intoxication, and the cerebrospinal fluid (CSF) analysis and complete blood count were normal. The search for autoantibodies was negative. CSF analysis was negative for toxoplasmosis, influenza, herpes simplex virus, varicella zoster virus, cytomegalovirus, dengue, John Cunningham virus, and syphilis. The patient serology for human immunodeficiency virus was negative. Chest and abdominal computed tomography, and testicular ultrasonography were normal. The lesion was biopsied and the histopathological analysis revealed a hypercellular neoplasm with poorly differentiated large atypical cells. Immunohistochemical staining showed positivity for CD20 and negativity for CD3. The proliferation index was high through Ki-67. The final diagnosis was high-grade diffuse large B-cell lymphoma (Figure 2).

Figure 1.

45-year-old man with brain lymphomatosis presented with progressive cognitive deficit, associated with visual blurring. (a) Brain MRI demonstrated an infiltrative lesion with hyperintense signal on FLAIR affecting the subcortical frontoparietal white matter, corpus callosum, and internal capsule (arrows), with a pattern of leukoencephalopathy. (b) Gadolinium-enhanced T1-weighted imaging showed no contrast-enhancement. (c) Diffusion-weighted imaging showed restricted diffusion (arrows). (d) Perfusion-weighted imaging showed no signs of hyperperfusion.

Figure 2.

45-year-old man with brain lymphomatosis presented with progressive cognitive deficit, associated with visual blurring. (a) Histological section stained with hematoxylin and eosin revealed a lymphoma, characterized by a hypercellular neoplasm with poorly differentiated large atypical cells (original magnification, ×200). The immunohistochemical analysis showed positivity for CD20 (b; original magnification, ×100) and negativity for CD3 (c; original magnification, ×100). (d) The proliferation index was high through Ki-67 analysis (original magnification, ×50). The final diagnosis was high-grade diffuse large B-cell lymphoma.

Cerebral lymphomatosis (CL) is a rare variant of primary CNS lymphoma that progresses with non-mass or architectural distortion by the lymphocyte cells, often diagnosed as nonspecific diffuse leukoencephalopathy.^2,3 Clinical manifestations range from weakness, gait disturbance, personality changes, cognitive decline (most common manifestation), anorexia, orthostatic hypotension, and weight loss. ²

The typical appearance of CL on MRI is characterized by hyperintense signal on T2-weighted imaging and FLAIR, intermediate to hypointense signal on T1-weighted imaging, without gadolinium-enhancement, and with restricted diffusion. ³ Usually, the affected area is the white matter of at least three brain lobes or anatomical regions of the CNS, most often the subcortical, deep and periventricular white matter, including corpus callosum, pons, medulla, U-shaped fibers, and cerebellum, as well as basal ganglia, thalamus, dentate nuclei, and cerebral and cerebellar cortices. Spectroscopy can suggest a neoplasia, through elevated levels of choline (Cho/NAA >1.9). However, the final diagnosis is only possible with histopathological study. ²

Differential diagnosis of this pattern of leukoencephalopathy comprise exogenous intoxication, inherited metabolic diseases, chemotherapy, infectious leukoencephalopathy caused by viruses such as dengue, and influenza, among others, autoimmune encephalitis, and other inflammatory diseases, such as sarcoidosis. ⁴

Therefore, it is important to keep in mind the possibility of lymphoma, in patients with a leukoencephalopathy pattern with restricted diffusion on imaging, but no signs of exogenous intoxication, metabolic disease, or infection, in order to guide a brain biopsy.