Clinical Review & Education
Images in Neurology
Lymphomatosis Cerebri A Diagnostic Challenge Kimmo J. Hatanpaa, MD, PhD; Franklin Fuda, DO; Prasad Koduru, PhD; Ken Young, MD; Bradley Lega, MD; Weina Chen, MD, PhD
An immunocompetent woman in her mid-60s initially presented with episodes of spasms and tremors in her right hand and forearm. She was suspected of having carpal tunnel syndrome and underwent carpal tunnel release surgery. However, the tremors recurred. She was referred to a neurologist about 7 months later. Magnetic resonance imaging (MRI) of her brain revealed either a prior stroke or demyelination, and she was treated with levetiracetam. Over the subsequent 3months,shedevelopedprogressiveright-sidedweakness,dysarthria, hand tremors, slurred speech, and gait instability. She was referred to our institution for a brain biopsy. T2-weighted fluid-attenuated inversion recovery MRI revealed hyperintensities throughout the bilateral cerebral hemispheric white matter, corpus callosum, basal ganglia, thalami, midbrain, upper pons, and middle cerebellar peduncles (Figure, A). T1-weighted fluid-attenuated inversion recovery MRI with contrast showed the absence of contrast enhancement (Figure, B). Given the multifocal distribution of the lesions and the lack of contrast enhancement, the main differential considerations were demyelinating disease, infection, and encephalitis. An open biopsy of the left frontal lesion revealed a CD5− CD10− CD19+ CD20+ BCL6+ MUM-1+ EBV/EBER− diffuse, large B-cell lymphoma (DLBCL) of a nongerminal center B-cell–like phenotype with an unusually infiltrative pattern. The majority of the cells infiltrated the brain parenchyma diffusely as single or small clustered cells rather than being limited to perivascular cuffs and sheets. These findings are diagnostic of the lymphomatosis cerebri variant of DLBCL (Figure, ARTICLE INFORMATION Author Affiliations: Department of Pathology, University of Texas Southwestern Medical Center, Dallas (Hatanpaa, Fuda, Koduru, Chen); Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston (Young); Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas (Lega).
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C and D). A cytogenetic study revealed a normal female karyotype. Fluorescence in situ hybridization studies of interphase nuclei revealed extra copies of BCL6 (3q27) and BCL2 (18q21) but no MYC abnormalities. Lymphoma cells were present in the cerebrospinal fluid but not in the bone marrow. The patient was treated with highdose methotrexate sodium, procarbazine hydrochloride, and vincristine sulfate. Her condition deteriorated rapidly. She died 11 months after the onset of symptoms.
Discussion Primary central nervous system DLBCL generally presents as single or multiple contrast-enhancing mass lesions on MRI scans. A rare pattern is the diffuse infiltration without the formation of discrete mass lesions and with little contrast enhancement, representing the lymphomatosis cerebri variant of DLBCL.1,2 The most common symptoms include a subacute onset of personality changes, ataxic gait, and cognitive deficits. Magnetic resonance imaging typically reveals diffuse white matter disease variably involving bilateral cerebral hemispheres, the periventricular region, basal ganglia, thalami, or the brainstem. This entity often presents a diagnostic challenge because the clinical presentation is subacute and because imaging findings are atypical for lymphoma. Such features more commonly raise the possibility of conditions such as demyelinating disease and encephalitis. Awareness of this rare condition is essential for an early biopsy and specific treatment.
Corresponding Author: Weina Chen, MD, PhD, Department of Pathology, University of Texas Southwestern Medical Center, BioCenter EB3.234, 2330 Inwood Rd, Dallas, TX 75390-9317 (weina [email protected]).
REFERENCES
Accepted for Publication: April 28, 2015.
2. Raz E, Tinelli E, Antonelli M, et al. MRI findings in lymphomatosis cerebri: description of a case and revision of the literature. J Neuroimaging. 2011;21 (2):e183-e186.
Published Online: July 6, 2015. doi:10.1001/jamaneurol.2015.1149. Conflict of Interest Disclosures: None reported.
1. Kitai R, Hashimoto N, Yamate K, et al. Lymphomatosis cerebri: clinical characteristics, neuroimaging, and pathological findings. Brain Tumor Pathol. 2012;29(1):47-53.
(Reprinted) JAMA Neurology Published online July 6, 2015
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Otago Library User on 07/11/2015
E1
Clinical Review & Education Images in Neurology
Figure. Extensive Nonenhancing Lesions in the Bilateral Cerebral Hemispheres Indicating Lymphomatosis Cerebri A T2-weighted FLAIR MRI scan
C
B
D Lymphoma cells expressing CD20
T1-weighted FLAIR MRI scan with contrast
Large lymphoma cells
A, Diffuse T2-weighted fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) reveals hyperintensities in the white matter and corpus callosum. The lesions extended to the basal ganglia, thalami, midbrain, pons, and middle cerebellar peduncles. B, T1-weighted FLAIR MRI with contrast
E2
reveals the absence of contrast enhancement. C, The brain parenchyma is diffusely infiltrated by large lymphoma cells (hematoxylin-eosin, original magnification ×200). D, The lymphoma cells express CD20 (immunohistochemistry, original magnification ×100).
JAMA Neurology Published online July 6, 2015 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Otago Library User on 07/11/2015
jamaneurology.com
Images in Neurology
Lymphomatosis Cerebri A Diagnostic Challenge Kimmo J. Hatanpaa, MD, PhD; Franklin Fuda, DO; Prasad Koduru, PhD; Ken Young, MD; Bradley Lega, MD; Weina Chen, MD, PhD
An immunocompetent woman in her mid-60s initially presented with episodes of spasms and tremors in her right hand and forearm. She was suspected of having carpal tunnel syndrome and underwent carpal tunnel release surgery. However, the tremors recurred. She was referred to a neurologist about 7 months later. Magnetic resonance imaging (MRI) of her brain revealed either a prior stroke or demyelination, and she was treated with levetiracetam. Over the subsequent 3months,shedevelopedprogressiveright-sidedweakness,dysarthria, hand tremors, slurred speech, and gait instability. She was referred to our institution for a brain biopsy. T2-weighted fluid-attenuated inversion recovery MRI revealed hyperintensities throughout the bilateral cerebral hemispheric white matter, corpus callosum, basal ganglia, thalami, midbrain, upper pons, and middle cerebellar peduncles (Figure, A). T1-weighted fluid-attenuated inversion recovery MRI with contrast showed the absence of contrast enhancement (Figure, B). Given the multifocal distribution of the lesions and the lack of contrast enhancement, the main differential considerations were demyelinating disease, infection, and encephalitis. An open biopsy of the left frontal lesion revealed a CD5− CD10− CD19+ CD20+ BCL6+ MUM-1+ EBV/EBER− diffuse, large B-cell lymphoma (DLBCL) of a nongerminal center B-cell–like phenotype with an unusually infiltrative pattern. The majority of the cells infiltrated the brain parenchyma diffusely as single or small clustered cells rather than being limited to perivascular cuffs and sheets. These findings are diagnostic of the lymphomatosis cerebri variant of DLBCL (Figure, ARTICLE INFORMATION Author Affiliations: Department of Pathology, University of Texas Southwestern Medical Center, Dallas (Hatanpaa, Fuda, Koduru, Chen); Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston (Young); Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas (Lega).
jamaneurology.com
C and D). A cytogenetic study revealed a normal female karyotype. Fluorescence in situ hybridization studies of interphase nuclei revealed extra copies of BCL6 (3q27) and BCL2 (18q21) but no MYC abnormalities. Lymphoma cells were present in the cerebrospinal fluid but not in the bone marrow. The patient was treated with highdose methotrexate sodium, procarbazine hydrochloride, and vincristine sulfate. Her condition deteriorated rapidly. She died 11 months after the onset of symptoms.
Discussion Primary central nervous system DLBCL generally presents as single or multiple contrast-enhancing mass lesions on MRI scans. A rare pattern is the diffuse infiltration without the formation of discrete mass lesions and with little contrast enhancement, representing the lymphomatosis cerebri variant of DLBCL.1,2 The most common symptoms include a subacute onset of personality changes, ataxic gait, and cognitive deficits. Magnetic resonance imaging typically reveals diffuse white matter disease variably involving bilateral cerebral hemispheres, the periventricular region, basal ganglia, thalami, or the brainstem. This entity often presents a diagnostic challenge because the clinical presentation is subacute and because imaging findings are atypical for lymphoma. Such features more commonly raise the possibility of conditions such as demyelinating disease and encephalitis. Awareness of this rare condition is essential for an early biopsy and specific treatment.
Corresponding Author: Weina Chen, MD, PhD, Department of Pathology, University of Texas Southwestern Medical Center, BioCenter EB3.234, 2330 Inwood Rd, Dallas, TX 75390-9317 (weina [email protected]).
REFERENCES
Accepted for Publication: April 28, 2015.
2. Raz E, Tinelli E, Antonelli M, et al. MRI findings in lymphomatosis cerebri: description of a case and revision of the literature. J Neuroimaging. 2011;21 (2):e183-e186.
Published Online: July 6, 2015. doi:10.1001/jamaneurol.2015.1149. Conflict of Interest Disclosures: None reported.
1. Kitai R, Hashimoto N, Yamate K, et al. Lymphomatosis cerebri: clinical characteristics, neuroimaging, and pathological findings. Brain Tumor Pathol. 2012;29(1):47-53.
(Reprinted) JAMA Neurology Published online July 6, 2015
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Otago Library User on 07/11/2015
E1
Clinical Review & Education Images in Neurology
Figure. Extensive Nonenhancing Lesions in the Bilateral Cerebral Hemispheres Indicating Lymphomatosis Cerebri A T2-weighted FLAIR MRI scan
C
B
D Lymphoma cells expressing CD20
T1-weighted FLAIR MRI scan with contrast
Large lymphoma cells
A, Diffuse T2-weighted fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) reveals hyperintensities in the white matter and corpus callosum. The lesions extended to the basal ganglia, thalami, midbrain, pons, and middle cerebellar peduncles. B, T1-weighted FLAIR MRI with contrast
E2
reveals the absence of contrast enhancement. C, The brain parenchyma is diffusely infiltrated by large lymphoma cells (hematoxylin-eosin, original magnification ×200). D, The lymphoma cells express CD20 (immunohistochemistry, original magnification ×100).
JAMA Neurology Published online July 6, 2015 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Otago Library User on 07/11/2015
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