C CLL | Anatomy2Medicine
Chronic Lymphocytic Leukemia

C CLL

    • Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
      • Diagnostic requirement for CLL – absolute lymphocyte count >4000 per mm3 (MCQ)
      • most common leukemia of adults (MCQ)
      • The median age at diagnosis is 60 years(MCQ)
      • 2 : 1 male predominance
  • Morphology
        • Lymph nodes are diffusely effaced by an infiltrate of predominantly small lymphocytes
  • 6 to 12 μm in diameter
  • round to slightly irregular nuclei
  • condensed chromatin,
  • cant cytoplasm
  • Proliferation centers – pathognomonic FINDING
  • Admixed are variable numbers of larger activated lymphocytes that often gather in loose aggregates referred to as proliferation centers
          • contain mitotically active cells.
  • When present, proliferation centers are pathognomonic for CLL/SLL. (MCQ)
  • Blood picture
          • large numbers of small round lymphocytes with scant cytoplasm
  • Some of these cells are usually disrupted in the process of making smears, producing so-called smudge cells. (MCQ)
  • Bone marrow is almost always involved by interstitial infiltrates or aggregates of tumor cells.
  • Infiltrates are also virtually always seen in the splenic white and red pulp and the hepatic portal tracts
  • Immunophenotype.
      • tumor cells express
        • pan-B cell markers CD19 and CD20, (MCQ)
  • CD23 and CD5(MCQ)
      • Low-level expression of surface Ig (usually IgM or IgM and IgD) is also typical. (MCQ)
  • Molecular Pathogenesis.
        • Unlike most other lymphoid malignancies, chromosomal translocations are rare in CLL/SLL.
        • The most common findings are (MCQ)
          • deletions of 13q14.3, 11q, and 17p
          • trisomy 12q.
  • Proliferation centers are breeding ground for cancer
          • The growth of CLL/SLL cells is largely confined to proliferation centers, where tumor cells must receive critical cues from the microenvironment.
          • Stromal cells in proliferation centers seem to express a variety of factors that stimulate the activity of the transcription factor NF-κB, which promotes cell growth and survival.
  • Clinical Features
        • Patients are often asymptomatic at diagnosis.
        • nonspecific symptoms include easy fatigability, weight loss, and anorexia.
        • Generalized lymphadenopathy and hepatosplenomegaly are present in 50% to 60% of symptomatic patients.
  • Luekocyte count
          • leukopenia can be seen in individuals with SLL and marrow involvement, (MCQ)
          • counts in excess of 200,000 per mm3 are sometimes seen in CLL patients with heavy tumor burdens. (MCQ)
          • Some asymptomatic patients that have in their peripheral blood monoclonal CD5+ B cells in numbers that are too few to merit the diagnosis of CLL.
  • CLL/SLL disrupts normal immune function
          • Hypogammaglobulinemia is common and contributes to an increased susceptibility to infections, particularly those caused by bacteria.
          • Autoimmune hemolytic anemia or thrombocytopenia due to autoa ntibodies made by non-neoplastic B cells. (MCQ)
      • Course and prognosis
      • Overall median survival is 4 to 6 years
      • variables that correlate with a worse outcome include(MCQ)
  • the presence of deletions of 11q and 17p,
        • a lack of somatic hypermutation,
  • the expression of ZAP-70, a protein that augments signals produced by the Ig receptor
  • Bone marrow transplantation is being offered to the relatively young.
      • Patient survival depends on the tendency of CLL/SLL to transform to more aggressive tumors.
        • prolymphocytic transformation is most common
  • Richter syndrome(MCQ)
        • transformation to diffuse large B-cell lymphoma,
      • Prolymphocytic transformation is marked by
        • worsening cytopenias
        • increasing splenomegaly,
        • appearance of increased numbers of “prolymphocytes” (large cells with a single prominent, centrally placed nucleolus) in the peripheral blood.
      • Transformation to diffuse large B-cell lymphoma is often heralded by development of a rapidly enlarging mass within a lymph node or the spleen.

Topic – 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).