Primary central nervous system lymphoma pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

Overview

Primary central nervous system lymphoma may originate from a germinal center to an early postgerminal center in a secondary lymphoid organ, which may be capable of further maturation steps. EBV is almost always associated with primary CNS lymphoma in immunodeficient individuals, and latent EBV infection of B-cells leads to it's immortalization and to CNS tropism. In immunocompetent individuals, the B-cells infected with EBV are held in check by T-cells, and with the severity of immunosuppression, T cells gradually fall, leading to the B-cell proliferation and dissemination. Genes involved in the pathogenesis of primary central nervous system lymphoma include IG, BCL6, CD95, PAX5, and PIM1. Primary central nervous system lymphoma is highly associated with Epstein-Barr virus (EBV) infection (> 90%) in immunodeficient patients (such as those with AIDS and iatrogenically immunosuppressed). Primary central nervous system lymphoma presents as a solitary or multiple, well circumscribed, greater than 2 cm in diameter, well-defined or infiltrating mass lesion/s that can arise in the cortex, white matter, or deep grey matter (more common in low-grade lesions). On gross pathology, the lesions could be brownish, gray-tan, or yellow, firm, homogenous, centrally necrotic with areas of hemorrhage. On microscopic histopathological analysis, primary central nervous system lymphoma is characterized by accumulation of large atypical mononuclear cells around small calibre vascular channels with invasion of the walls of some vessels. The atypical cells have large round, oval and angulated hyperchromatic and vesicular nuclei, and a narrow rim of pale cytoplasm. An occasional mitotic figure is noted. Primary central nervous system lymphoma is demonstrated by positivity to tumor markers, including B lymphocyte markers, such as CD19, CD20, CD79a, Ki-67, GFAP, BCL-2, and BCL-6.

Pathogenesis

• Primary central nervous system lymphoma may originate from a germinal center to an early postgerminal center in a secondary lymphoid organ, which may be capable of further maturation steps.
• The understanding of the pathogenesis of primary central nervous system lymphoma is quite limited as the CNS is devoid of any B-cells.
• EBV is almost always associated with primary CNS lymphoma in immunodeficient individuals, and latent EBV infection of B-cells leads to it's immortalization and to CNS tropism. In immunocompetent individuals, the B-cells infected with EBV are held in check by T-cells, and with the severity of immunosuppression, T cells gradually fall, leading to the B-cell proliferation and dissemination.
• Rubenstein et al demonstrated that interleukin 4 and STAT6 molecules are required for the retention of peripherally derived lymphoma cells in the central nervous system as well as for the angiocentric pattern in primary CNS lymphoma. Overexpression of STAT6 is also associated with tumor progression.

Genetics

• Development of primary central nervous system lymphoma is the result of multiple genetic mutations.
• Genes involved in the pathogenesis of primary central nervous system lymphoma include:

• IG
• BCL6
• CD95
• CMYC13
• PAX5
• PIM1
• PRDM114
• TTF
• CARD11
• MALT1
• p50

Associated Conditions

• Primary central nervous system lymphoma is highly associated with Epstein-Barr virus (EBV) infection (> 90%) in immunodeficient patients (such as those with AIDS and iatrogenically immunosuppressed).

Gross Pathology

• Primary central nervous system lymphoma presents as a solitary or multiple, well circumscribed, greater than 2 cm in diameter, well-defined or infiltrating mass lesion/s that can arise in the cortex, white matter, or deep grey matter (more common in low-grade lesions).
• On gross pathology, the lesions could be brownish, gray-tan, or yellow, firm, homogenous, centrally necrotic with areas of hemorrhage.
• The lesion is mainly located at supratentorial level, usually in the periventricular regions, infiltrating the corpus callosum and the basal ganglia.
• Multiple lesions are reported in 38%–55% of non-AIDS primary CNS lymphomas. Multifocal intraparenchymal lesions, without a dural involvement, are very rare. Frontal lobe is affected in 20%–43% of primary CNS lymphoma. Other sites iclude brain stem, cerebellum, leptomeninges, spinal cord, and eyes.
• They may demonstrate areas of necrosis, especially in immunodeficient patients.
• Origin of malignant cells is not well understood as intra-axial CNS does not have lymphatic system.

Gallery

• 

  _{Gross pathological specimen primary central nervous system lymphoma in the brain parenchyma. This autopsy photograph shows involvement of cerebral hemispheres by a primary CNS lymphoma in an AIDS patient. It was a large B-cell lymphoma and the patient succumbed to it within 6 months of diagnosis.}

Microscopic Pathology

• The vast majority (>90%) of primary central nervous system lymphoma are B-cell in origin: diffuse large B-cell lymphoma and high-grade Burkitt-like B-cell lymphoma.
• Malignant cells tend to accumulate around blood vessels (angiocentric pattern).
• Low-grade tumors are more frequently T-cell in origin.
• On microscopic histopathological analysis, primary central nervous system lymphoma is characterized by accumulation of large atypical mononuclear cells around small calibre vascular channels with invasion of the walls of some vessels. The atypical cells have large round, oval and angulated hyperchromatic and vesicular nuclei, and a narrow rim of pale cytoplasm. An occasional mitotic figure is noted.

Gallery

• 

  _{Micrograph from a brain biopsy demonstrating a primary CNS lymphoma with the characteristic perivascular distribution composed of large cells with prominent nucleoli, on HPS stain.}

Immunohistochemistry

Primary central nervous system lymphoma is demonstrated by positivity to tumor markers, including B lymphocyte markers, such as:

• CD3
• CD19
• CD20
• CD22
• CD45
• CD79a
• Ki-67
• GFAP
• BCL-2
• BCL-6
• MUM1

Gallery

• 

  _{The atypical cells of primary central nervous system lymphoma demonstrating strong surface immunostaining for the B lymphocyte markers, CD20.}

References

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