Molecular Pathogenesis of Primary Central Nervous System Lymphoma
Molecular Pathogenesis of Primary Central Nervous System Lymphoma
Primary central nervous system lymphoma (PCNSL) is an aggressive form of non-Hodgkin lymphoma (NHL) typically associated with a worse prognosis than other localized extranodal lymphomas with similar histological characteristics. The defining feature of PCNSL is its confinement to the central nervous system (CNS), with proclivity for growth within the leptomeningeal as well as intraocular compartments. Primary CNS lymphoma rarely disseminates outside the CNS and accounts for less than 5% of all primary brain neoplasms. At least 95% of PCNSLs are of large B-cell histology, the most common subtype of NHL. Consistent with the trend seen in systemic NHLs, the incidence of PCNSL has markedly increased over the past three decades, both in immunocompromised and immunocompetent patients. Because PCNSL is relatively rare, the identification of molecular prognostic biomarkers and the definition of a standard therapeutic strategy have been challenging. The authors discuss the current knowledge of the molecular pathogenesis of CNS lymphomas and review the recent advances in gene expression profile analysis and identification of novel prognostic biomarkers.
Primary CNS lymphoma is a rare form of NHL that occurs within the craniospinal axis and accounts for less than 5% of all primary brain tumors. It is defined as lymphoma occurring in the brain, leptomeninges, spinal cord, or eyes without evidence of lymphoma outside the CNS. The majority of PCNSL tumors are high-grade B-cell lymphomas, despite the fact that B-cells are absent from normal brain. The tumors are most often diagnosed by stereotactic brain biopsy, which is often preceded by glucocorticoid therapy, administered to reverse neurological deficits. Because the majority of PCNSLs are sensitive to glucocorticoid agents and exhibit resolution and apoptosis in response to these medications, histopathological diagnosis and classification of PCNSL cases can be difficult. More than 90% of PCNSL tumors ultimately are diagnosed as high-grade, CD20–positive, diffuse large B-cell NHLs; the remaining 10% of cases include Burkitt, Burkitt-like, and lymphoblastic B-cell lymphomas as well as T-cell lymphomas. In up to 20% of cases, the diagnosis of PCNSL may be established by the combination of cytological findings of malignancy in the CSF and the exclusion of systemic lymphoma by bone marrow biopsy and axial imaging. However, cytological analysis of CSF and specimens from intravitreal compartments is associated with extremely poor sensitivity.
Because of the relative rarity of this type of brain tumor, as well as the difficulty of obtaining intracranial samples, there is a paucity of clinical material for molecular analysis of CNS lymphomas. Nevertheless, genetic studies are beginning to elucidate features of the molecular pathogenesis of these tumors. There is now evidence that CNS lymphomas exhibit a distinct gene expression profile compared with nodal lymphomas of the same histological type. In addition, emerging data indicate that CNS lymphomas are derived from a distinct cell of origin and exhibit a unique immunophenotype. Current efforts are focused on the identification of tumor biomarkers to facilitate noninvasive diagnosis as well as prognosis. The purpose of this review is to highlight key features and recent advances in our understanding of the molecular pathogenesis of PCNSL.
Primary central nervous system lymphoma (PCNSL) is an aggressive form of non-Hodgkin lymphoma (NHL) typically associated with a worse prognosis than other localized extranodal lymphomas with similar histological characteristics. The defining feature of PCNSL is its confinement to the central nervous system (CNS), with proclivity for growth within the leptomeningeal as well as intraocular compartments. Primary CNS lymphoma rarely disseminates outside the CNS and accounts for less than 5% of all primary brain neoplasms. At least 95% of PCNSLs are of large B-cell histology, the most common subtype of NHL. Consistent with the trend seen in systemic NHLs, the incidence of PCNSL has markedly increased over the past three decades, both in immunocompromised and immunocompetent patients. Because PCNSL is relatively rare, the identification of molecular prognostic biomarkers and the definition of a standard therapeutic strategy have been challenging. The authors discuss the current knowledge of the molecular pathogenesis of CNS lymphomas and review the recent advances in gene expression profile analysis and identification of novel prognostic biomarkers.
Primary CNS lymphoma is a rare form of NHL that occurs within the craniospinal axis and accounts for less than 5% of all primary brain tumors. It is defined as lymphoma occurring in the brain, leptomeninges, spinal cord, or eyes without evidence of lymphoma outside the CNS. The majority of PCNSL tumors are high-grade B-cell lymphomas, despite the fact that B-cells are absent from normal brain. The tumors are most often diagnosed by stereotactic brain biopsy, which is often preceded by glucocorticoid therapy, administered to reverse neurological deficits. Because the majority of PCNSLs are sensitive to glucocorticoid agents and exhibit resolution and apoptosis in response to these medications, histopathological diagnosis and classification of PCNSL cases can be difficult. More than 90% of PCNSL tumors ultimately are diagnosed as high-grade, CD20–positive, diffuse large B-cell NHLs; the remaining 10% of cases include Burkitt, Burkitt-like, and lymphoblastic B-cell lymphomas as well as T-cell lymphomas. In up to 20% of cases, the diagnosis of PCNSL may be established by the combination of cytological findings of malignancy in the CSF and the exclusion of systemic lymphoma by bone marrow biopsy and axial imaging. However, cytological analysis of CSF and specimens from intravitreal compartments is associated with extremely poor sensitivity.
Because of the relative rarity of this type of brain tumor, as well as the difficulty of obtaining intracranial samples, there is a paucity of clinical material for molecular analysis of CNS lymphomas. Nevertheless, genetic studies are beginning to elucidate features of the molecular pathogenesis of these tumors. There is now evidence that CNS lymphomas exhibit a distinct gene expression profile compared with nodal lymphomas of the same histological type. In addition, emerging data indicate that CNS lymphomas are derived from a distinct cell of origin and exhibit a unique immunophenotype. Current efforts are focused on the identification of tumor biomarkers to facilitate noninvasive diagnosis as well as prognosis. The purpose of this review is to highlight key features and recent advances in our understanding of the molecular pathogenesis of PCNSL.
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