Chronic Leukemias (Lymphoproliferative and Myeloproliferative Disorders)

Question 1

Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) differ only in ______ ______ involvement. If blood lymphocyte count is ______ than 5000, the cancer is classified as ______. ______ is the most common leukemia in the Western World.

Answer 1

Peripheral blood; greater; CLL; CLL

Question 2

Pathogenesis of CLL and SLL (4)

Answer 2

1. Indolent, slow growing tumor cells more focused on survival than proliferation
2. Contain high levels of BCL2, which inhibit apoptosis
3. Express signals through B cell receptor that flow through the Bruton Kinase (BTK), which contribute to expression of genes that promote survival
4. Can cause immune dysregulation, especially in B cells: the accumulation of CLL/SLL suppresses B cell function leading to hypogammaglobulinemia. This can result in autoantibodies against RBC and platelets made from non-malignant B cells due to impaired immune tolerance.

Question 3

Characteristics of CLL and SLL morphology (6)

Answer 3

1. Smudge cells: lymphocytosis of small, mature-appearing lymphs that smudge on peripheral blood smear due to fragility
2. Lymph nodes characteristic of small lymphocytes: dark, round nuclei and scant cytoplasm
3. Proliferation centers are characteristically the foci of mitotic cells
4. Bone marrow, spleen, and liver are involved in nearly all cases
5. 50% have karyotypic abnormalities: most common trisomy involvement is at chromosome 12 and most common deletions are chromosomes 11, 13, and 17
6. Chromosome translocations are rare, unlike many other B cell neoplasms

Question 4

B cell markers of CLL and SLL

Answer 4

CD20, CD5, and Ig’s

Question 5

Clinical features of CLL and SLL (9)

Answer 5

1. Initially asymptomatic
2. Most common symptoms are nonspecific, such as fatigue, weight loss, and anorexia
3. 50-60% of patients present with generalized lymphadenopathy, hepatosplenomegaly, and hypogammaglobulinemia (increased susceptibility to infection)
4. Less commonly, autoimmune hemolytic anemia and thrombocytopenia are seen
5. In SLL, WBC is increased slightly or can exceed 200,000 cells/microliter
6. The presence of TP53 is associated to a less than 30% survival rate
7. Abnormalities of chromosome 13q equates to the same survival rate as the general disease presentation
8. A small fraction of aggressive tumors (resembling DLBCL) have a median survival rate of less than 1 year
9. Cured via hematopoietic stem cell transplantation, which is reserved for young patients that failed conventional therapy

Question 6

What is HCL?

Answer 6

Hairy Cell Leukemia

Question 7

HCL is an ______ indolent B cell neoplasm characterized by the presence of ______, ______-______ cytoplasmic projections.

Answer 7

Uncommon; fine, hair-like

Question 8

All cases of HCL are associated with mutations in the ______/______ kinase, ______.

Answer 8

Serine/threonine; BRAF

Question 9

B cell markers of HCL

Answer 9

CD20, surface immunoglobin, CD11c (unique), and CD103 (unique)

Question 10

Clinical features of HCL (7)

Answer 10

1. Occurs in older males
2. Manifestations include infiltration of the bone marrow and spleen
3. Splenomegaly (most common finding), pancytopenia (marrow infiltration and splenic sequestration), leukocytosis
4. If untreated, pancytopenia and infections are the two most major problems.
5. HCL is extremely sensitive to chemotherapeutic agents, specifically purine nucleosides
6. If needed, BRAF inhibitors can become the treatment of choice
7. Excellent prognosis

Question 11

What are the 3 categories of myeloid neoplasms?

Answer 11

1. Acute myeloid leukemia (early stage maturation)
2. Myelodysplastic syndrome (terminal stage maturation)
3. Myeloproliferative neoplasms (normal maturation- increased or dysregular growth)

Question 12

______ involves synthesis of proteins for azurophilic granules (lysosomal granulates that are similar in all three times of immature granulocytes) and other specific granules for the cytoplasm (after maturation)

Answer 12

Granulopoeisis

Question 13

What are the stages of granulocyte maturation? (6)

Answer 13

1. Myeloblast (most immature)
2. Promyelocyte (contain basophilic cytoplasm and lysosomal enzymes)
3. Myelocyte (specific lineage granules appear)
4. Metamyelocyte (increasing number of granules in the cytoplasm)
5. Band cell elongation
6. Segmented granulocyte (complete maturation)

Question 14

Myeloproliferative disorders are characterized by the presence of mutated cells with activated ______ ______ or other lesions in the ______ ______ that leads to growth factor independence.

Answer 14

Tyrosine kinase; signaling pathway

Question 15

What is CML?

Answer 15

Chronic Myeloid Leukemia

Question 16

Characteristics of CML morphology? (4)

Answer 16

1. Circulating cells are predominately neutrophils, metamyelocytes, myelocytes, and a greater number of platelets
2. Basophils and eosinophils are also prominent
3. Bone marrow is hypercellular due to high numbers of maturing granulocytes and megakaryocytes
4. During blast crisis, 30% of cases resemble precursor B cells, and the remaining resemble AML (acute myeloid leukemia)

Question 17

Pathogenesis of CML (3)

Answer 17

1. Presence of BCR-ABL gene: BCR from chromosome 22 and ABL (tyrosine kinase component) from chromosome 9. In 95% of cases, this is due to a t(9;22) translocation - Philadelphia Chromosome
2. The BCR-ABL presents in granulocytes, erythroid precursors, megakaryotic precursors, and B cell precursors. T cell precursors too in some cases. Tyrosine kinase from ABL contributes to fast replication of transformed hematopoietic stem cells.
3. Growth factors of CML progenitors are decreased by signals that are generated by BCR-ABL, which mimic the effects of growth factor receptor activation. BCR-ABL does not inhibit differentiation, therefore, it produces granulocytes and platelets in excess.

Question 18

Clinical features of CML (10)

Answer 18

1. Adults 25-60 years of age
2. 4,500 new cases per year
3. Elevated leukocyte count over 100,000 cells/microliter
4. Spleen in enlarged due to extensive extramedullary hematopoiesis, which can lead to splenic infarcts
5. Presents with nonspecific symptoms: fatigue, weakness, weight loss
6. “Dragging” sensation in the abdomen may be due to splenomegaly
7. Diagnosed by BCR-ABL fusion gene karyotype, FISH, and PCR
8. 3 year survival rate without treatment
9. Half CML cases can enter an accelerated phase marked by increasing anemia, thrombocytopenia, additional cytogenic abnormalities, and transformation into a disease resembling acute leukemia (blast crisis)
10. Treatment with tyrosine kinase inhibitors (imatinib) early on can prevent progression to blast crisis

Question 19

Characteristics of Polycthemia Vera (PV) morphology (6)

Answer 19

1. Increase in blood volume and viscosity due to large red cell mass increases chances of thromboses, and infarctions of the heart, spleen, and kidneys.
2. Liver is enlarged and contains foci that show extramedullary hematopoiesis
3. Spleen appears enlarged likely due to splenic congestion
4. Bone marrow appears hypercellular due to erythroid, myeloid, and megakaryocytic forms.
5. Some bone marrow fibrosis may be present
6. In some patients, progression to the spent phase, where marrow is replaced by fibroblasts and collagen, occurs

Question 20

Pathogenesis of PV (4)

Answer 20

1. Activating point mutation in the tyrosine kinase JAK2 lowers the dependence of hematopoietic cells on growth factors for growth and survival
2. Increased proliferation of erythroid, granulocytic, and megakaryocytic cells. Can also increase red cell mass.
3. Low levels of erythropoietin is consistent with growth factor independence
4. JAK2 usually acts in the signaling pathway to promote growth factors on erythropoietic cells

Question 21

Clinical features of PV (8)

Answer 21

1. Insidious, more common in late-middle age
2. Patients appear plethoric (overload of blood) and cyanotic (decreased oxygen)
3. Other complaints include thrombotic and hemorrhagic HTN (30% of patients), headache, dizziness, GI symptoms, hematemesis, and melena.
4. Life-threatening hemorrhage occurs in 5-10% of patients
5. Diagnosed via increased RBC range from 6-10 million with hematocrit greater than 60%. Granulocytes can be as high as 50,000 and platelet count of 400,000. Basophilia is common. Platelets and megakaryocytes can be seen on blood smear.
6. Without treatment, death from vascular complications typically occur
7. With treatment, survival rate increases to 10 years by lowering RBC count with phlebotomy
8. Prolonged survival spent phase resembles primary myelofibrosis; JAK2 inhibitors have been approved for treatment in these cases

Question 22

Characteristics of Primary Myelofibrosis (PMF) morphology (2)

Answer 22

1. Development of obliterative marrow fibrosis reduces bone marrow hematopoiesis and leads to cytopenia and/or extramedullary hematopoiesis
2. Blood smear is abnormal with poikilocytes, teardrop cells, and abnormally large platelets. Nucleated precursors along with immature white cells manifest as leukoerythroblastosis.

Question 23

Pathogenesis of PMF

Answer 23

Underlying JAK-STAT mechanism causes inappropriate release of fibrogenic factors from neoplastic megakaryocytes, leading to fibrosis

Question 24

Clinical features of PMF (6)

Answer 24

1. Occurs in individuals 60+ years old
2. Initial symptoms include fatigue, weight loss, night sweats
3. Can cause progressive anemia and splenomegaly
4. The anemia is normochromic and normocytic with leukoerythroblastosis
5. Median survival rate is 4-5 years
6. More difficult to treat than PV or CML

Question 25

Characteristics of Essential Thrombocytosis (ET) morphology (2)

Answer 25

1. Hyperproliferation of platelet progenitors | 2. Blood smear shows abnormally large platelets with mild leukocytosis

Question 26

Pathogenesis of ET (2)

Answer 26

1. Activated point mutation in JAK2 (50% of cases) and MPL (5-10%) 2. Mutations lead to hyperproliferation of thrombopoietin-independent progenitors

Question 27

Clinical features of ET (5)

Answer 27

1. Indolent with asymptomatic periods followed by thrombotic and hemorrhagic crises 2. Median survival rate is 12-15 years 3. Occurs in individuals 60+, but also young adults (1-3/100,000) 4. Diagnosed via elevated platelet count in the absence of polycythemia and marrow fibrosis 5. Treated with gentle chemotherapeutic agents that suppress thrombopoiesis

Question 28

Neoplastic plasma cells secrete ______ ______ or fragments that can be used as ______ ______; these often have pathological consequences.

Answer 28

Monoclonal immunoglobin; tumor markers

Question 29

M proteins are restricted to ______ and ______ ______. They are excluded from urine in the absence of glomerular damage. Some light chains cause amyloidosis (build up of amyloid proteins in the heart and kidneys).

Answer 29

Plasma; extracellular fluid

Question 30

Neoplastic plasma cells make excess ______ ______ _____ along with complete immunoglobulins.

Answer 30

Immunoglobin light chains

Question 31

Terms for abnormal immunoglobulins include monoclonal gammopathy, ______, and paraproteinemia.

Answer 31

Dysproteinemia

Question 32

Neoplastic plasma cells account for ______% of deaths by lymphoid neoplasms.

Answer 32

15

Question 33

Characteristics of Multiple Myeloma (MM) morphology? (3)

Answer 33

1. Increased number of plasma cells (greater than 30% of normal) with abnormal features such as prominent nucleoli, and cytoplasmic inclusions containing IG 2. The plasma cells can advance to viscera and soft tissues in advanced stages 3. Bone marrow sample shows normocytic, normochromic anemia with moderate leukopenia and thrombocytopenia

Question 34

Pathogenesis of MM (6)

Answer 34

1. IgH locus on chromosome 14 fuses with oncogenes D1 and D3 causing dysregulation of D cyclins and an increase in cell proliferation 2. Factors produced by neoplastic cells cause bone destruction in the vertebrae, ribs, skull, pelvis, femurs, clavicle, and scapula 3. Lytic bone lesions arise in medullary cavities that appear as “punched out holes”, leading to increased cancellous bone and destruction of the bone cortex; increases fracture risk 4. Hypercalcemia occurs, which can cause neurological manifestations: confusion, weakness, lethargy 5. Can also cause defects in humoral immunity and increased risk for bacterial infections 6. Renal dysfunction can occur alone or in combination with other symptoms; present in 50% of patients and associated with Bence Jones proteinuria.

Question 35

Clinical features of MM (9)

Answer 35

1. Most common lymphoid malignancy (20,000 cases/year) 2. Median age of 70 3. Males more affected that females 4. Greater dominance in individuals of African origin 5. Most frequent M protein is IgG (60%), IgA (20-25%) - rarely seen in IgM, IgD, or IgE 6. In the remaining cases, kappa and gamma light chains change: become smaller in size, are excreted in urine, and are termed Bence Jones proteins 7. Malignant cases consist of M proteins and Bence Jones proteins (seen together in 60-70% of cases); in 20% of cases, only free light chains are present 8. Labs show increased IG levels in blood and Bence Jones proteins in urine 9. Prognosis is relative: 6-12 months if untreated; median survival rate is 4-7 years.