Lymphoproliferative disorders

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Lymphoproliferative disorders

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Lymphoproliferative disorders

  1. 1. Mature Lymphoproliferative disorders (1) Dr. Douaa Mohammed Sayed
  2. 2. Overview  Concepts, classification,lymphomagenesis  Epidemiology  Clinical presentation  Diagnosis  Staging
  3. 3. Concept  neoplasms of lymphoid origin, typically causing lymphadenopathy  leukemia vs lymphoma  lymphomas as clonal expansions of cells at certain developmental stages
  4. 4. Stages of Maturation/Differentiation Lineages LymphoidMyeloid • cells are defined by lineage and stage of maturation/differentiation • regulated by signaling pathways and transcription factors • role of proliferation • cell “identity” may be determined using morphology, immunophenotyping and molecular/genetic studies
  5. 5. B-Lineage Lymphopoiesis Morphology / Immunophenotyping / Molecular Studies “Blasts” “Mature” Lymphocytes
  6. 6. B-cell development stem cell lymphoid precursor progenitor-B pre-B immature B-cell mature naive B-cell germinal center B-cell memory B-cell plasma cell DLBCL, FL, BL, HL LBL, ALL CLL MCL MM MZL CLL
  7. 7. B-Lineage Lymphopoiesis Morphology / Immunophenotyping / Molecular Studies Markers are helpful in determining: 1. Lineage (ex. CD19) 2. Maturation (ex. TdT, CD34, CD10) 3. Both (ex. sIg)
  8. 8. B-Lineage Lymphopoiesis Morphology / Immunophenotyping / Molecular Studies • Status of immunglobulin genes (i.e., germline, rearranged, somatic mutations) has implications for both lineage and maturation.
  9. 9. Determining B-Cell Clonality by PCR
  10. 10. AML ALL CLL CML Lymphomas Lymphomas
  11. 11. The challenge of lymphoma classification Clinically useful classification Diseases that have distinct • clinical features • natural history • prognosis • treatment Biologically rational classification Diseases that have distinct • morphology • immunophenotype • genetic features • clinical features
  12. 12. Lymphoma classification (based on 2001 WHO)  B-cell neoplasms  Precursor B-cell neoplasms  Mature B-cell neoplasms  B-cell proliferations of uncertain malignant potential  T-cell & NK-cell neoplasms  Precursor T-cell neoplasms  Mature T-cell and NK-cell neoplasms  T-cell proliferation of uncertain malignant potential  Hodgkin lymphoma  Classical Hodgkin lymphomas  Nodular lymphocyte predominant Hodgkin lymphoma
  13. 13. A practical way to think of lymphoma Category Survival of untreated patients Curability To treat or not to treat Non- Hodgkin lymphoma Indolent Years Generally not curable Generally defer Rx if asymptomatic Aggressive Months Curable in some Treat Very aggressive Weeks Curable in some Treat Hodgkin lymphoma All types Variable – months to years Curable in most Treat
  14. 14. Lymphomas Morphology Immunophenotype
  15. 15. Lymphomas Molecular Features
  16. 16. Mechanisms of lymphomagenesis  Genetic alterations  Infection  Antigen stimulation  Immunosuppression
  17. 17. MOLECULAR PATHOGENESIS OF NON-HODGKIN’S LYMPHOMAS  Non-Hodgkin’s lymphomas (NHL) represent a heterogeneous group of diseases deriving from mature B cells 85% of cases) and, in a minority of cases, from T cells.  Among B-NHL, most histologic subtypes arise from germinal center (GC) or post-GC B cells, since they have undergone hypermutation of the immunoglobulin variable region (IgV) genes, a phenomenon restricted to GC B cells.
  18. 18. Activation of Proto-oncogenes by Chromosomal Translocation  In contrast with neoplasms of precursor lymphoid cells, chromosomal translocations associated with mature B and T-cell malignancies do not generally lead to coding fusions between two genes.  They juxtapose the proto-oncogene to heterologous regulatory sequences derived from the partner chromosome.  These sequences may derive from antigen receptor loci as well as from other loci that are expressed at sustained levels in normal cells corresponding to the differentiation stage of the lymphoma.
  19. 19.  The two exceptions to the deregulation model of NHL translocations are represented by the t(2;5) of T-cell anaplastic large cell lymphoma and the t(11;18) of MALT lymphoma, which cause gene fusions coding for chimeric proteins.
  20. 20. Inactivation of tumor suppressor loci  Disruption of tumor suppressor loci in NHL occurs through mechanisms similar to those associated with other human cancers and generally leads to biallelic inactivation, most frequently through deletion of one allele and mutation the other. The tumor suppressor genes most frequently involved in the pathogenesis of NHL are represented by p53, p16, and ATM (for ataxia telangiectasia mutated).
  21. 21.  In addition, NHL frequently carry specific chromosomal deletions, which presumably represent sites of not yet identified tumor suppressor loci. The most frequent of these deletions involve the long arm of chromosomes 6 (6q) and 13 (13q).
  22. 22. Somatic hypermutation  Recent evidence suggests that important genetic changes associated with lymphomagenesis may derive from an apparently aberrant activity of the somatic hypermutation process that normally engenders Ig diversity in germinal center B cells by mutating the IgV genes.

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