HEMATOLOGIC NEOPLASMS

• Peripheral blood film


  Examination of a blood smear under the microscope
• The peripheral blood film from the patient in the case study showed inclusions at the arrows
• Hematologic neoplasms


  Abnormal growth of cells of the hematopoietic system
• Hematologic neoplasms are acquired genetic diseases, not inherited
• Hematologic neoplasms


  • The first human cancers in which a consistent genetic defect was identified
  • They initiate in a hematopoietic cell as a result of acquisition of one or more mutations in key genes that regulate cell growth, survival, differentiation, or maturation
  • Most are not localized but rather are systemic at initiation of the malignant process
• Leukemias


  Originate in bone marrow and readily pass into peripheral blood, can also infiltrate lymphoid tissues and other organs
• Lymphomas


  Solid tumors of lymphoid cells that usually originate in the lymphatic system and proliferate in lymph nodes and other lymphoid organs and tissues
• Most treatments for hematologic neoplasms given with curative intent are systemic, not localized like radiation or surgery
• Types of leukemias


  • Lymphoid
  • Myeloid
  • Acute (precursor cell)
  • Chronic (mature cell)
• Acute leukemias


  • Onset is sudden, progression is rapid, outcome is fatal in weeks or months if left untreated
  • White blood cell count is variable, excess accumulation of precursor cells or blasts due to maturation arrest
• Chronic leukemias


  • Onset is insidious, progression is slower, longer survival compared to acute
  • White blood cell count is usually elevated, proliferation and accumulation of mature and maturing cells
• In untreated leukemias, most normal hematopoietic cells in bone marrow are eventually replaced by leukemia cells, affecting normal bone marrow function
• Symptoms of acute leukemia at presentation include fever, mucocutaneous bleeding, and fatigue
• Symptoms of chronic leukemia at presentation are generally nonspecific and variable, some patients may be asymptomatic
• Laboratory methods used to diagnose and monitor hematologic neoplasms include complete blood cell count, peripheral blood film examination, bone marrow examination, immunophenotyping by flow cytometry, molecular diagnostics, and cytogenetics
• The National Cancer Institute estimated 60,300 new cases of leukemia, 74,680 cases of non-Hodgkin lymphoma, and 8500 cases of Hodgkin lymphoma in the US for 2018
• Certain types of leukemia are more prevalent in particular age groups
• Causes of hematologic neoplasms

  • Environmental toxins like radiation and organic solvents
  • Chemotherapy used to treat other cancers
  • Viruses like HTLV-1 and Epstein-Barr virus
  • Hereditary cancer predisposition syndromes
• The WHO classification of hematologic neoplasms considers clinical features, morphology, immunophenotyping, cytogenetics, and molecular genetics
• Cellular processes perturbed in hematologic neoplasms

  • Uncontrolled proliferation
  • Loss of DNA repair and cell cycle control
  • Block in differentiation
  • Continued cell survival and inhibition of apoptosis
• Epigenetic mechanisms


  Control how genes are expressed and silenced, aberrant epigenetic changes can initiate and maintain hematologic neoplasms
• Oncogenes


  Derived from normal cellular protooncogenes, mutation can convert them to have leukemogenic potential
• t(8;21) translocation


  Fusion of the core-binding transcription factor gene, RUNX1, with the RUNX1T1 gene in acute myeloid leukemia
• t(15;17) translocation


  Fusion of the retinoic acid receptor gene, RARA, with the PML gene in acute promyelocytic leukemia
• Hypermethylation


  Common method of silencing tumor suppressor genes
• Oncogenes


  Originally identified in tumor-forming retroviruses but derived from normal human cellular homologues called protooncogenes
• Protooncogenes


  • DNA sequence is highly conserved and the protein products they encode are essential for normal cellular function
  • Important in signaling pathways, cell proliferation, cell differentiation, and apoptosis
  • Mutation can convert to an oncogene with leukemogenic potential
• Dominant disorders


  Only one mutated copy of the oncogene is required to contribute to leukemogenesis
• Gain-of-function mutations


  Cause constitutive (continuous) and unregulated activation of the oncogene
• Types of protooncogenes usually involved in hematologic neoplasms

  • Signal transducers (such as tyrosine kinases)
  • Growth factor receptors
  • Transcription factors
• Qualitative mutations


  Involve a structural change to the protooncogene and production of an abnormal protein product
• Qualitative mutations


  • Translocation resulting in a chimeric fusion gene (e.g. t(9;22) translocation forming the BCR-ABL1 fusion gene)
  • Point mutations (e.g. JAK2 p. Val617Phe mutation in polycythemia vera)
  • Internal tandem duplication (e.g. FLT3-ITD mutation in acute myeloid leukemia)
• Quantitative mutations


  Overexpression of a normal protooncogene in a hematopoietic cell
• Quantitative mutations


  • Translocation of a protooncogene next to the promoter of the immunoglobulin heavy chain (IGH) locus (e.g. t(14;18) translocation in follicular lymphoma with overexpression of BCL2, t(11;14) translocation in mantle cell lymphoma with overexpression of CCND1)
  • Gene amplification
• Tumor suppressor genes


  Code for proteins that protect cells from malignant transformation by slowing down cell division or promoting apoptosis
• Loss-of-function mutations


  Both alleles of a tumor suppressor gene need to be deleted or inactivated for malignant transformation
• Tumor suppressor genes


  • TP53 in Li-Fraumeni syndrome
  • RB1 in familial retinoblastoma
  • WT1 in Wilms tumor
• DNA repair genes


  Mutations cause genetic instability and increased mutation rates, leading to an increased risk of malignant transformation
• DNA repair genes


  • Fanconi anemia gene, FA
• Oncogene activation or the loss of tumor suppressor or DNA repair genes have adverse molecular effects on proliferation, differentiation, maturation, survival, apoptosis, cell cycle control, and/or DNA repair mechanisms in hematopoietic cells, and an increased risk of malignant transformation