Introduction to Haematological Malignancies

Hematological malignancies are clonal diseases (neoplasms) that are derived from a single hematopoietic stem cell or peripheral lymphoid tissue that has undergone a genetic alteration (e.g. B cell Lymphoma)

  • Causes of hematologic malignancies **** ***In the majority of individual cases neither a genetic susceptibility nor environmental agent is apparent
    • Genetic (Inherited factors)
      • Down syndrome, have an increased frequency of Acute Leukemia. ****
      • Bloom’s syndrome,
      • Fanconi’s anemia,
      • Wiskott Aldrich Syndrome,
      • Ataxia telangiectasia and Klinefelter’s syndrome also have increased frequency for hematological malignancies. Remember acute leukemia has more immature (blast) cells, while chronic leukemia has more of mature cells
    • Environmental factors
      • Radiation (especially leukemogenic to the Bone Marrow e.g. Atomic bomb in Japan. Excludes CLL),
      • Infections
        • EBV Burkitt’s Lymphoma,
        • HTLV-1 Adult T-cell Leukemia and post-transplant lymphoproliferative disease, ****
        • HHV-8 primary effusion lymphoma,
        • HIV-1 associated High-grade B-cell lymphoma, ****
        • Helicobacter pylori MALToma,
        • Malaria in Endemic Burkitt’s lymphoma
      • Chemicals (Benzene may cause BM hypoplasia, dysplasia, Chromosomal abnormalities, myelodysplasia, AML),
      • Drugs (Alkylating agents e.g. procarbazine chlorambucil: AML especially combined with radiotherapy Etoposide antileukemic associated with secondary leukemia)
  • Genetic basis of hematologic malignancies
    • Malignancies are caused by the accummulation of genetic mutations in cellular genes.
    • Oncogenes: arise from gain-of-function mutation of proto-oncogenes through translocation (very common in hematological malignancies), inversion, or duplication.
      • Tyrosine kinase mutations underlie a large number of hematological malignancies.
        • CML t(9;22) BCR-ABL1,
        • JAK-2 point mutations in myeloproliferative disorders i.e. Polycythemia Rubra Vera**,**
      • Burkitt Lymphoma t(8;14) myc,
      • Follicular Lymphoma t(14;18) Bcl-2,
    • Duplications or amplification e.g. chronic lymphocytic leukemia in trisomy 12
    • Tumor Suppressor genes: Acquire loss of function usually by point mutation or deletions. CLL 17p deletion of p53
  • Diagnosing hematologic malignancies
    • Assessment of peripheral blood
      • Complete blood count
      • Peripheral blood film
    • Bone marrow examination: morphology, histopathology, IHC via Bone Marrow Biopsy or Aspirate. Monomorphic features e.t.c. Polymorphic features are seen in normal studies
    • Cytochemistry: PAS, MPO, Sudan Black (SB)
    • Flow cytometry: Immunophenotyping. Mainly used for lymphocytes i.e. for determining the B cell or T cell lineage. Rely on Ab made against specific cell markers.
      • Myeloid
        • AML: CD13, CD33, CD117, Glycophorin – AML-M6, Plat ag (CD41) – AML-M7, MPO – AML-MO
      • B-Lineage
        • Pre-B: CD19, CD22, CD79a, CD10, TdT
      • T-Lineage
        • T cels: TdT, CD7, CD3, CD2
    • Cytogenetics; Karyotype analysis: Cells are stimulated using PAH to induce mitosis and observed for constitutional abnormalities. ALL cytogenetics is divided into Hyperdiploid (more than 47 chromosomes with good prognosis), Pseudodiploid (46 chromosomes with structural abnormalities with poor prognosis), Diploid (46 chromosomes) and Hypodiploid (Less than 46 chromosomes)
    • FISH: Fluorescent probes label each chromosome in both metaphase and interphase cells
    • PCR: can use blood or BM to detect specific translocations (t9;12, t15;17), clonal cells of B or T cell lineage by Ig or TCR gene rearrangement analysis, relatively straightforward and extremely sensitive (detects one abnormal cell in 10^5-10^6 normal cells), Great value in the diagnosis and monitoring of minimal residual disease
    • DNA Microarray
  • What is the value of genetic markers in the management of hematological malignancies?
    • Initial diagnosis: t(11;14) translocation defines mantle cell lymphoma
    • For establishing a treatment protocol: drugs are available that target BCR-ABL fusion protein in CML and ALL that improve overall survival. Hyperdiploidy in ALL shows good prognosis
    • Monitoring response to therapy: PCR can be used to detect minimal residual disease in hematological malignancies when patients are in remission, after chemotherapy or stem cell transplant
  • Management of hematological malignancies