A 50-year-old man presented with a 3-week history of confusion and frequent episodes of falling. He had a past medical history of type 2 diabetes mellitus, hypertension, and depression. Left-sided weakness, ataxia, and altered mental status were detected on physical examination. Bihemispheric deep white matter lesions involving the brain stem and bilateral basal ganglia were identified on magnetic resonance imaging (Figure 1). Laboratory investigations on blood, urine, and cerebrospinal fluid, including human immunodeficiency virus testing, were noncontributory. A biopsy was performed to rule out neoplasm, infection, or transmissible spongiform encephalopathy. The biopsy yielded tan-red tissue fragments, half of which were treated according to the transmissible spongiform encephalopathy protocol, including incubation in formic acid.1 Microscopic sections consisted of cohesive to loose cell aggregates with perivascular cell aggregation and necrosis. The cells were large and demonstrated a high nuclear-cytoplasmic ratio, nuclear pleomorphism, prominent nucleoli, and frequent mitoses (Figure 2).
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Pathologic Diagnosis: Primary Central Nervous System B-Cell Lymphoma
First described by Bailey in 1929 as “perithelial sarcoma,” central nervous system (CNS) lymphomas were variably called microglioma, reticulum cell sarcoma, and adventitial sarcoma until their lymphoid lineage was defined and accepted. Primary CNS lymphomas are uncommon neoplasms and account for less than 2% of brain tumors. Primary CNS lymphomas are defined as extranodal malignant lymphomas that arise in the CNS in the absence of obvious lymphoma outside the CNS at the time of diagnosis. Their incidence appears to be increasing across a wide age range, both among immunocompetent and immunosuppressed populations, with the incidence in the latter group being several thousand-fold higher. Approximately 98% of primary CNS lymphomas are of the B-cell type (diffuse large cell being most frequent), with the remaining 2% of T-cell origin. Plasmacytoma, angiotropic lymphoma, Hodgkin disease, and mucosa-associated lymphoid tissue lymphoma of the dura have also been reported to involve the CNS. Acquired or congenital immunodeficiency predisposes to development of primary CNS lymphoma. Epstein-Barr virus–encoded nuclear antigens (EBNA 1, 2, 3a, 3b, 3c, and leader protein) and DNA of human herpesviruses (HHV-6 and HHV-8) have been identified in lymphoma cells in immunocompromised patients. No definite etiologic factors have been identified for immunocompetent patients. However, clonal abnormalities of chromosomes 1, 6, 7, and 14, as well as translocations (1; 14), (6;14), (13;18), and (14;21) have been observed.2–8
Of uncertain pathogenesis, primary CNS lymphomas arise in an organ that lacks a regular lymphatic system. It has been hypothesized that the tumor cells transform at an extracranial site and develop adhesion molecules specific for cerebral endothelia, or that lymphoma, which is systemically eradicated by an intact immune system, escapes elimination within the protective confines of the CNS. Additionally, a polyclonal intracerebral inflammatory response may precede the proliferation of monoclonal malignant lymphoid cells.
Primary CNS lymphomas arise de novo in previously healthy individuals during the sixth to the seventh decade and demonstrate a male-female ratio of 3:2. Immunocompromised patients manifest the disease at an earlier age, with a mean of 10 years for those with inherited immunodeficiency, 37 years for transplant recipients, and 39 years for patients with acquired immunodeficiency syndrome (AIDS), the majority being male. Symptoms and signs at presentation are nonspecific and display features of increased intracranial pressure and local destructive effects of the neoplasm. Common presenting symptoms include focal neurological deficits (50%–80%), neuropsychiatric symptoms (20%–30%), increased intracranial pressure (10%–30%), seizures (5%–20%), and ophthalmic symptoms (5%–20%). Angiotropic lymphoma presents as a rapidly progressive dementia with multifocal neurological deficits.3,4,7
Bilateral, symmetrical, subependymal, high-signal foci, as seen on computed tomography and magnetic resonance imaging, are suggestive of primary CNS lymphoma. This presentation differs from the ring enhancement seen in glioblastomas. By contrast, multifocal, ring-enhancing lesions with central necrosis are seen in AIDS-related primary CNS lymphoma, making it difficult to differentiate from toxoplasmosis.2–4
The macroscopic appearance of primary CNS lymphomas is variable. At times, the brain appears normal. Lesions may be single or multiple, discrete or diffusely infiltrative, and are often deep-seated and periventricular. Variegated, friable, granular, necrotic, hemorrhagic, grey to tan foci resemble glioblastoma or an infarct. A butterfly configuration, as classically associated with glioblastoma, may also be seen. Primary CNS lymphomas restricted to the dura mimic meningioma and directly invade the underlying cerebral cortex. Rarely, primary malignant lymphoma arises in the spinal extradural space or in the spinal cord.2–4
The microscopic appearance consists of dense, central cellular aggregates of atypical lymphoid cells with a sparsely infiltrated periphery and dense perivascular aggregates that are rich in reticulin. Approximately 98% of primary CNS lymphomas are of the B-cell type and are positive for the B-cell markers CD20 and CD79a, with the majority expressing monoclonal surface or cytoplasmic immunoglobulin. The cells in this case were positive for CD45 and CD20 (Figure 3). Of interest, formic acid treatment did not affect immunohistochemical reactivity.
The differential diagnosis of primary CNS lymphomas in immunocompetent adults includes glioblastoma, metastasis, demyelinating disorder, or an inflammatory lesion. Malignant gliomas have a greater degree of cellular and nuclear pleomorphism, vascular proliferation, and necrosis with pseudopalisading by tumor cells. Anaplastic carcinomas tend to be cohesive and lack angioinvasion and perivascular reticulin deposition. A macrophage-rich lesion in an elderly person poses a differential diagnosis of infarction or a demyelinating disorder. There is axonal destruction in the former and relative axonal preservation in the latter. In immunosuppressed patients, toxoplasmosis needs to be ruled out.2–4
Favorable prognostic factors for CNS lymphoma consist of single intracranial lesions, absence of periventricular and meningeal involvement, lack of immunodeficiency, age younger than 60 years, and a preoperative Karnofsky score greater than 70. Immunocompetent patients treated with radiotherapy and chemotherapy show response rates of 85%, with a median survival of 17 to 45 months and an overall survival of 40% to 75% at 2 years and 25% to 45% at 5 years. Patients with AIDS have a median survival of 2 to 6 months, or 13.5 months when given multimodality therapy.4,8
References
The authors have no relevant financial interest in the products or companies described in this article.
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