Chronic Lymphocytic Leukemia (CLL) and Others Flashcards Preview

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Flashcards in Chronic Lymphocytic Leukemia (CLL) and Others Deck (32):

What are some distinctions and overlapping features of CLL and other lymphomas?

  • —Clonal leukemic proliferations of either B- or T-cell lymphocytes that have a “mature” phenotype
  • —Involve blood and bone marrow – may also infiltrate other organs such as lymph node and spleen
  • —Diseases of older adults
  • —Survivals months or years without therapy - usually considered incurable
  • —Leukemias initially manifest in bone marrow and blood while lymphomas present in lymph nodes, spleen, etc.
  • —Leukemias may involve lymph nodes
  • —Lymphomas may infiltrate blood and marrow
  • —Designation as leukemia or lymphoma may be arbitrary


What are the major classifications of CLL?

  • —B-Cell
    • —Chronic lymphocytic leukemia
    • —Hairy cell leukemia
    • —Prolymphocytic leukemia
  • —T-Cell
    • —Large granular lymphocyte leukemia
    • —Adult T-cell leukemia/lymphoma 
    • —Sézary syndrome
    • —Prolymphocytic leukemia


What is the epidiomology and etiology of CLL?

  • CLL most common leukemia in Western countries (rare in some Eastern countries such as Japan)
  • —Middle age to elderly
  • — M>F
  • —Etiology unknown
    • —Probable genetic predisposition


What are the features of small lymphocytic lymphoma (SLL)? How is it differentiated from CLL?

  • —No leukemia but lymph node or other tissue morphology and immunophenotype identical to CLL
  • —Much rarer than CLL
  • —CLL and SLL considered to be same diseases with different manifestations
  • —Designation CLL/SLL often used to include both diseases


What are some of the common peripheral blood findings at diagnosis for CLL?

  • —Elevated leukocyte count
    • —Clonal B lymphocytosis (>5000/uL) - small lymphocytes with condensed chromatin
    • —May be neutropenia
  • —Hb/Hct normal or decreased
  • —Platelet count normal or decreased
  • **Note: If there are <5000 clonal B cells, call it monoclonal B lymphocytosis.


What is monoclonal B cell lymphocytosis?

  • —6-7% of individuals >60 yr have monoclonal B-lymphocytosis (MBL) detected in PB (usually CLL-type immunophenotype)
  • —< 5000 clonal B cells in peripheral blood (arbitrary cutoff)
  • —No cytopenias, organomegaly, etc.
  • —Precursor lesion - ~1%/yr progress to CLL—


What are the clinical findings of CLL?

  • —Patients often asymptomatic
  • —Weakness, fatigue, weight loss
  • —Lymphadenopathy and/or splenomegaly may be present
  • —Infections – common complication, especially in later stages of disease
    • —Bacterial most common, especially with encapsulated organisms (i.e. Streptococcus or Staphylooccus) – often pneumonia
    • —Viral and fungal infections also occur  


What are some common histological findings of CLL?

  • White count elevated with anemia and thrombocytopenia
  • Large “smudge” cell on left common in CLL
  • All of the lymphocytes look alike – cookie cutter cells, same mold
  • Chromatin patterns are very condensed, no nucleoli, scant cytoplasm, textbook picture


What is the immunophenotype of CLL?

  • —Disease of activated, antigen experienced B cells
  • —Expresses B-cell antigens: CD19, CD20 (weak)
  • —Monotypic: low density surface Ig: IgM+/- IgD with kappa or lambda light chains
  • —Positive for CD5, a T-cell associated antigen
  • —Expresses CD23, an activation antigen


What is the importance of proliferation centers in CLL?

  • Can see a diffuse proliferation of lymphocytes, often will see a proliferation center
  • Some of the cells in the cells in these centers are bigger with nucleoli
  • Centers of mitosis, which keeps the disease going


What are the immune complications of CLL?

  • —Hypogammaglobulinemia - ~6-%
  • —Inability to make specific antibody
  • —Autoimmune disorders
    • —Autoimmune hemolytic anemia- ~10-25%
    • —Autoimmune thrombocytopenia- ~2%
  • —T cells also abnormal


What is the clinical course of CLL?

  • —Slowly progressive disease
  • —Survivals variable
    • —overall survival 10-15 years
    • —1/3 of patients: >25 years (never need therapy)
    • —1/3 of patients: more aggressive disease (med. survival – 8 yrs) – need therapy


Describe the clinical staging of CLL.

  • Stage 0 – lymphocytosis in blood and marrow
  • Stage 1 – lymphocytosis plus lymphadenopathy
  • Stage 2 – lymphocytosis with hepatomegaly   and/or splenomegaly
  • Stage 3 – lymphocytosis with anemia
  • Stage 4 – lymphocytosis with thrombocytopenia


Describe the genetics of CLL.

  • —High incidence (~ 80%) of clonal abnormalities but none specific for CLL
    • —Deletion 13q14 – most common (50%)
    • —trisomy 12 (20%)
    • —Deletions of 11q (site of ATM gene), 17p (TP53) less common
  • —Prognostic information
    • 13q sole abnormality – good prognosis
    • 11q,17p – poorer prognosis
  • About 50% of CLL’s exhibit somatic mutation of IgVH - good prognosis of survival
    • —Mutated CLL is associated with better survivals than unmutated CLL 


How often does CLL transform into a high grade  lymphoma?

  • —Diffuse large B-cell lymphoma
  • —Develops in 2-8% of CLL
  • —Majority (not all) clonally related to original CLL
  • —Survival  <1 year


What is the treatment for CLL?

  • —Traditionally “watch and wait” for early stage CLL
    • —Chlorambucil has been standard therapy
    • —CLL incurable
  • —Now more effective therapies
    • —Purine analogues, MoAb, transplantation
    • —Targeted therapy


What is Hariy Cell Leukemia?

  • —Rare clonal disorder of B lymphocytes
  • —Affects adults (median age ~55 years)
  • —Males >> females
  • —Etiology unknown


What are the clinical features of Hairy Cell Leukemia?

  • —Pancytopenia (50%) or cytopenias (100%)
    • —Leukocyte count usually low (neutropenia, monocytopenia)
    • —Hairy cells usually present but may be rare
    • —Anemia and/or thrombocytopenia frequent
  • —Peripheral lymphadenopathy usually absent
  • —Splenomegaly (80%)


What are the presenting signs and symptoms of hairy cell leukemia?

  • —Fatigue, weakness, weight loss
  • —Abdominal discomfort
  • —Infections
  • —Bleeding


What are the histologic and immunohistologic findings of hairy cell leukemia?

  • Histology
    • Hairy cells - membrane projections
    • Mone marrow core shows, cells wide apart (fried eggs)
  • Immunophenotype
    • —Express B-cell surface antigens (CD19,CD20)
    • —Monoclonal surface immunoglobulin
      • —Kappa or lambda
    • —Negative for CD5
    • —Positive for CD11c, CD25, CD103


What are the genetics of hairy cell leukemia?

  • —Gene sequencing identified BRAF mutation in majority/all HCL
  • —Mutation lies in activation loop of the kinase domain of BRAF – explains the activation of the Raf-MEK-ERK pathway in HCL
  • —BRAF mutation is key driver of HCL and a rational therapeutic target


What is the clinical course of hairy cell leukemia?

  • —Indolent, slowly progressive disease
  • —Complications include infection, bleeding
  • —Effective medical therapies
    • —>90% respond to purine analogue therapy
  • —Survival - years


What is large granular lymphocyte leukemia and what are the clinical characteristics?

  • —Rare disorder
    • —Most common in older adults (45-75 yrs)
  • —In most cases lymphocytes exhibit mature T cytotoxic phenotype (CD3+, CD8+, CD4-, CD56-/+, CD57+, CD16+, )
    • —Clonal T-cell receptor gene rearrangement
  • —STAT3 mutations in many LGLLs – involvement of JAK/STAT in pathogenesis 
  • Clinical Presentation
    • —Peripheral blood increase in LGL’s – no underlying cause
    • —Neutropenia (recurrent infections) most common, other lineages can be decreased
    • —Polyclonal hypergammaglobulinia
    • —Splenomegaly
    • —Subset have rheumatoid arthritis


What are the histologic findings and immunohistological characteristics of large granular lymphocyte leukemia?

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What is the clinical course of large granular lymphocyte leukemia?

  • —Clinical course variable
    • —Usually indolent
  • —No specific therapy
    • —Chemotherapy
    • —Steroids


What is adult T-cell Laukdemia/Lymphoma (ATLL)?

  • Aggressive malignancy of T-lymphocytes
  • First described in SW Japan; also occurs in Africa, Caribbean basin, northern areas of South America, and SW United States
  • Caused by HTLV-1 retrovirus - must be infected!
    • HTLV-1 integrated into DNA of T-lymphocytes
    • —Virus transmitted by:
      • blood transfusions
      • needle exchange
      • sexual contact
      • breast feeding
      • transplacentally
  • —Initial stage is carrier stage
  • —Disease expression occurs in adult (in small subset of carriers)


What are the histological and immunohistochemical findings of ATLL?

  • —Leukocyte counts variable; often >100,000/uL
  • —Lymphadenopathy, splenomegaly, skin lesions common
  • —May have hypercalcemia, bone lesions
  • —Abnormal lymphocytes have “flower-like” nuclei
  • —Lymphocytes are CD3+, CD7-, CD4+, CD8-, CD25+


What ist he clinical course of ATLL?

  • —Usually acute course with median survival 4-5 months
  • —Often unresponsive to chemotherapy
  • —More chronic forms also occur


What is Sezary Syndrome?

  • —Leukemic form of cutaneous T-cell lymphoma
  • —Generalized erythroderma
  • —Hyperkeratosis of palms and soles
  • —Pruritis
  • —Lymphadenopathy


What are the immunohistochemical and histological findings of Sezary Sydrome?

  • —Lymphoma cells with cerebriform nuclei
  • —Circulate in the blood (leukemic)
  • —Mature T- helper phenotype (CD3+, CD4+, CD8-)
  • —Cells express adhesion molecules that contribute to “homing” to skin—


What is the therapy of Sezary Syndrome?

  • —Primarily directed toward the erythroderma
  • —Topical or systemic
  • —Median survival – about 5 years—


What are the prominent features of T cell prolymphocytic leukemia?

  • —Rare leukemia of adults, 
  • —Hepatosplenomegaly and lymphadenopathy
  • —Lymphocyte count often >100x109/L
  • —Usually aggressive
  • —Most CD4+, subset CD4+/CD8+
  • —Most frequent genetic abnormality is inv(14) involving TCL1 → constitutive activation of TCL-1
    • —May respond well to Campath (monoclonal antibody to CD52)