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Characterization and Magnetic Resonance Imaging of a Rat Model of Human B-Cell Central Nervous System Lymphoma

Authors' Affiliations: Departments of ¹ Neurology, ² Cell and Developmental Biology, ³ Medicine, ⁴ Radiation Oncology, and ⁵ Neurosurgery, Oregon Health & Science University, and ⁶ Veterans Administration Medical Center, Portland, Oregon

Requests for reprints: Edward A. Neuwelt, Blood-Brain Barrier and Neuro-Oncology Program, Department of Neurology, Oregon Health and Science University, 3181 Sam Jackson Park Road, L603, Portland, OR 97239-3098. Phone: 503-494-5626; Fax: 503-494-5627; E-mail: neuwelte{at}ohsu.edu.

Purpose: The incidence of primary central nervous system lymphoma (PCNSL) is increasing. Therapeutic approaches remain controversial. An animal model that mimics the clinical situation would be useful for evaluating PCNSL biology and treatment.

Experimental Design: Nude rats received intracerebral (caudate nucleus, n = 49) or intraventricular (n = 4) inoculation of human B-lymphoma cell line MC116. Two to five weeks after tumor inoculation, magnetic resonance imaging (MRI) was done (n = 24), and rat brains were assessed for pathology. Five rats each received whole-brain radiotherapy (WBRT, 20 Gy) or high-dose i.v. methotrexate (3 g/m²).

Results: Intracerebral tumors developed in 84% of evaluable animals with no pretreatment, 79% of rats pretreated with 4 Gy total body irradiation, and 92% of rats pretreated with cyclophosphamide (300 mg/m²). MRI showed abnormal T2 signal and gadolinium enhancement on T1-weighted images, consistent with tumor growth 19 to 24 days after inoculation. Tumor cells staining positively for B-lymphoma markers infiltrated within the inoculated hemisphere, along fiber tracks to the contralateral hemisphere, and along the subarachnoid space and ventricles. Tumors showed reactive gliosis. Intraventricular tumor cell injection resulted in periventricular parenchymal infiltration in both hemispheres. Radiation and methotrexate were effective in vitro, but only WBRT was clearly effective after 1 week in the intracerebral model.

Conclusion: This model closely mimics human PCNSL in terms of imaging, histology, and treatment sensitivity and will be useful for the development of future therapeutic strategies for PCNSL.