D Cml | Anatomy2Medicine
D Cml

D Cml

 

  • Myeloproliferative Disorders
  • Pathophysiology – tyrosine kinases
  • The common pathogenic feature of the myeloproliferative disorders is the presence of mutated, constitutively activated tyrosine kinases (MCQ)

 

        • Hematopoietic growth factors act on normal progenitors by binding to surface receptors and activating tyrosine kinases, which turn on pathways that promote growth and survival.
        • The mutated tyrosine kinases found in the myeloproliferative disorders circumvent normal controls and lead to the growth factor–independent proliferation and survival of marrow progenitors.
        • The tyrosine kinase mutations do not impair differentiation, the most common consequence is an increase in the production of one or more mature blood elements.
      • The common features of myeloproliferative disorders include
      • Increased proliferative drive in the bone marrow

 

  • extramedullary hematopoiesis (MCQ)

 

      • marrow fibrosis and peripheral blood cytopenias

 

  • Variable transformation to acute leukemia

 

 

    • Chronic Myeloid Leukemia

 

  • distinguished from other myeloproliferative disorders by the presence of a chimeric BCR-ABL gene derived from portions of the BCR gene on chromosome 22 and the ABL gene on chromosome 9. (MCQ)
  • BCR-ABL

 

        • directs the synthesis of a constitutively active BCR-ABL tyrosine kinase
        • in CML tyrosine kinase is usually 210 kDa in size.

 

  • BCR-ABL is created by a reciprocal (9;22)(q34;q11) translocation (the so-called Philadelphia chromosome [Ph]) (MCQ)

 

        • BCR-ABL preferentially drives the proliferation of granulocytic and megakaryocytic progenitors
        • BCR-ABL causes the abnormal release of immature granulocytic forms from the marrow into the blood.

 

  • Morphology
  • Bone marrow
  • markedly hypercellular (MCQ)

 

          • massively increased numbers of maturing granulocytic precursors, which usually include an elevated proportion of eosinophils and basophils. Megakaryocytes are also increased and usually include small, dysplastic forms.
          • Erythroid progenitors are present in normal or mildly decreased numbers

 

  • Sea-blue histiocytes(MCQ)

 

            • A characteristic finding is the presence of scattered macrophages with abundant wrinkled, green-blue cytoplasm so-called sea-blue histiocytes.
          • Increased deposition of reticulin is typical, but overt marrow fibrosis is rare early in the course.

 

  • Blood pcture
  • leukocytosis, often exceeding 100,000 cells/mm3

 

          • consists predominantly of neutrophils, band forms, metamyelocytes, myelocytes, eosinophils, and basophils. (MCQ)
          • Blasts usually make up less than 10% of the circulating cells.
          • Platelets are also usually increased,
      • Extramedullary hematopoiesis causes(MCQ)
        • spleen is often greatly enlarged
        • mild hepatomegaly

 

  • lymphadenopathy
  • Clinical Features.

 

        • peak incidence is in the fifth to sixth decades of life
        • The onset is insidious.
        • fatigability, weakness, weight loss, and anorexia due to
          • Mild-to-moderate anemia
          • hypermetabolism due to increased cell turnover
        • dragging sensation in the abdomen caused by splenomegaly
        • acute onset of left upper quadrant pain due to splenic infarction.

 

  • CML is best differentiated from other myeloproliferative disorders by detection of the BCR-ABL fusion gene through either chromosomal analysis or PCR-based tests. (MCQ)

 

      • Natural history

 

  • Stable 3 years

 

          • slow progression

 

  • even without treatment, the median survival is about 3 years
  • “accelerated phase”

 

          • occur after 3 years
          • about 50% of patients enter this
          • marked by increasing anemia and thrombocytopenia, sometimes accompanied by a rise in the number of basophils in the blood
          • Additional clonal cytogenetic abnormalities that appear (MCQ)

 

  • trisomy 8
  • isochromosome 17q
  • duplication of the Ph chromosome
  • Blast crisis phase

 

          • Occur within 6 to 12 months

 

  • accelerated phase terminates in a picture resembling acute leukemia

 

          • In 70% of crises, the blasts are of myeloid origin (myeloid blast crisis)

 

  • in 30% of cases ,the blasts are of pre–B cell origin (lymphoid blast crisis).