Flashcards in Module 1: Heme: Plasma Cell Neoplasms + ALL + AML Deck (40):
Now to start with Plasma Cell Neoplasms: The first is Monoclonal Gammopathy of Undetermined Significance (MGUS): term applied to an asymptomatic monoclonal gammopathy. What are some features?
M proteins (IgG or IgA) are found in the serum of 1% to 3% of otherwise healthy persons older than age 50 years.
--precursor lesion with a tendency to evolve to multiple myeloma
Describe the M spike see in MGUS.
M spike (IgG or IgA) is smaller than multiple myeloma b/c less plasma cells and Igs)
What symptoms are seen in patients with MGUS?
Asymptomatic but there is a small chance of transformation to multiple myeloma
(less than 10% blasts)
The next plasma cell neoplasm is Waldenstrom. What are some features?
M spike: IgM (heaviest Ig) ---- leads to hyperviscosity syndrome (slows bloodflow --- thrombosis -----infarction ---stroke, Mi)
Platelets are used up so you get bleeding
What is the treatment for Waldenstrom?
Tx: plasmapheresis which removes IgM from serum
Next plasma cell neoplasm is Multiple Myeloma. What is the etiology for this?
Plasma cell neoplasm: malignant proliferation of B cells that retain the ability to differentiate into plasma cells and secrete antibodies and suppress the humoral immunity
What are the translocations and pathogenesis for multiple myeloma?
Malignant proliferation of a single clone of plasma cells in the bone marrow
--t11;14: overexpression of Cyclin D1 and D3
--t4;14: 15% of patients and involves fibroblast growth receptor 3 (FGFR3)
--produces large amounts of IgG (55%) and IgA (25%)
What are the favored bones in Multiple Myeloma ?
Lumbar spine, Ribs and Skull
What demographic of ppl do you see with multiple myeloma?
Older males and in people of African Origin
What is the presentation for multiple myeloma?
1. Punched out lytic lesions: due to plasma cells secreting IL-6 showing osteoclast activating factor --- results in hypercalcemia -- most common symptom is back pain --pathological fractures
2. Generalized swelling: Anasarca (Generalized edema) due to AL amyloidosis in the kidney
3. Fatigue: normochromic normocytic anemia (plasma cells take over bone marrow)
4. Neutropenia: bone marrow invasion
5. Bleeding: from thrombocytopenia (bone marrow invasion)
6. Hepatosplenomegaly: due to extramedullary hematopoiesis (liver and spleen trying to make more hematopoietic cells)
7. Restrictive cardiomyopathy: AL amyloid deposition
8. Recurrent Pyelonephritis
9. Renal Dysfunction: due to obstruction via Bence Jones Proteins
What do you see on bone marrow biopsy for patients with multiple myeloma?
Most accurate test:
greater than 10-20% plasma cells
--increased plasma cells with prominent nucleoli, perinuclear halo of clear cytoplasm.
What do you see on serum protein electrophoresis and skeletal xrays on patients with multiple myeloma?
Serum Protein Electrophoresis: M spike most frequent M protein produced by myeloma cells is IgG, followed by IgA
Skeletal Xrays: xray all bones in the body look for punched out lesions
What do you see on blood work and urine for a patient with multiple myeloma?
Hypercalcemia, elevated BUN/Creatinine, Elevated Uric Acid due to turnover of plasma cells produces uric acid --- gout
Bence Jones Proteins: Malignant plasma cells secrete both complete immunoglobins and free light chains and thus produce M proteins and Bence Jones Proteins
What are the complications of multiple myeloma?
--most common cause of death is recurrent infections
--2nd most common is renal failure
--Amyloid deposition: restrictive cardiomyopathy, carpal tunnel, and macroglossia
---CHF due to anemia
---Hyperviscosity syndrome: too many immnuoglobins in the blood leads to aggregation of platelets -- thrombosis ---bleeding
--Spinal Cord compression --paralysis
What does CRAB stand for in multiple myeloma?
Bone lytic lesions/Back Pain
The next topic we are going to discuss is Acute Lymphoblastic Leukemia. What type of people do we see this in?
Children: Especially Down's Syndrome over the age of 5
(AML is Downs syndrome patients under the age of 5)
What are the two different types of Acute Lymphoblastic Leukemia (ALL)?
B cell type (85%): childhood
---Tests, CNS (headaches, blurred vision and vomiting)
T cells (15%)- adolescent males
---mediastinal lymphadenopathy on xray (enlarged thymus)
--CD2 to CD8
What is the presentation for a patient with ALL?
1. Pancytopenia: of course recurrent infections and thrombocytopenia (stuck in lymphoblasts so they are taking over the bone marrow and causing pancytopenia)
2. Hypogammaglobulinemia (Stuck as blasts so expansion)
3. Bone pain/tenderness (due to the lymphoblasts take over)
4. Hepatosplenomegaly + Lymphadenopathy
due to extramedullary hematopoiesis
What do you see on peripheral blood smear in a patient with ALL?
PAS (lymphoblasts contain glycogen) and TdT positive lymphoblasts (marker for pre-T and pre-B cells)
What do you see on flow cytometry in a patient will ALL?
B cell: CD10,19,20
T cell: CD2-8
--this is how you differentiate the two
What do you see on bone marrow aspirate of patient with ALL?
Bone marrow aspirate:
greater than 20-25% lymphoblasts
What are the complications for a patient with ALL?
Recurrent infections: most common cause of death (due to the neutropenia and hypogammaglobinemia because lymphoblasts dont make immunoglobins)
B cell: CNS infiltration (meningitis, encephalitis) , testes infiltration (balls and brains) --this is not good because treatment doesnt typically cross the barriers
Give methotrexate treatment , response is good
What are indicators a good prognosis for a patient with ALL?
Age: 2-10 years old
WBC count: high because the lymphoblasts count as WBC even though there is high WBC there is still pancytopenia (due to the neutropenia)
Immunophenotype: B cell
Cytogentics: Hyperploidy t(12;21)
The next Leukemia to be discussed is Acute Myeloblastic Leukemia (AML). What population is affected?
More common in older adults (over 50)
There are 8 different types of AML, however, two types are important. AML- Acute promyelocytic leukemia (M3) is the first type to be discussed, what is the pathogenesis for this?
AML M3: t(15,17); deletions have worse prognosis
--translocation of the RAR
--fusion of Vit A receptor
How do patients with M3 present?
1. Pancytopenia from bone marrow invasion of promyelocytes
2. Heptaosplenomegaly due to organ infiltration by the promyelocytes and lymphadenopathy
3. Recurrent Infections
What tests can be done for AML M3?
FISH most accurate diagnostic test
Bone marrow aspirate: greater than 20-25% blasts (immature myeloblasts)
Bone marrow biopsy hypercellular
Peripheral Blood Smear: lots of myeloblasts with Auer Rods --needle shaped in the cytoplasm , used MPO stain and cytoplasm appears black .
What are the complications for AML M3?
1. Recurrent Infections most common cause of death
2. Heart Failure: Anemia
3. Do not give chem
4. Auer rods are thrombogenic --- DIC
5. Waterhouse Friderichsen Syndrome: DIC + septic shock + bilateral adrenal hemorrhages
6. Destruction of renal cortex can lead to Addison's Disease
7. Schistocytes on blood smear: also see them with HUS and TPP
What is the treatment for AML M3?
ATRA (All trans retinoic acid)
--patients tend to have a favorable response to this
The next type of AML is -- Acute Monocytic Leukemia (M5), what is the main symptom associated with this type of AML?
Usually detected first by dentists and dermatologists
Finally for any AML what do you see on blood work?
Increased bleeding time
Increased PT and PTT
What diseases can transform to AML?
Myeloproliferative disorders (blast crisis)
--CML (most common)
PNH- can also transform to MDS
Moving on to Myelodysplastic syndromes, what are some common features?
The bone marrow is partly or wholly replaced by the clonal progeny of a transformed multipotent stem cell that retains the capacity to differentiate into red cells, granulocytes, and platelets , but in a manner that is ineffective and disordered.
--marrow is hypercellular or normocellular
--Peripheral blood smear: one or more cytopenias
What are the two types of Myelodysplastic Syndromes (MDS)?
1. Idiopathic/primary MDS: greater than 50, gradual onset
2. Therapy-related MDS with suppression of myeloid precursor cells --- neutropenia: 2-8 years post chemotherapy (ex: low stage Hodgkin's lymphoma o radiotherapy for 8 years; dysgermination, seminoma or medullary carcinoma of the breast)
--can also get papillary carcinoma of the thyroid post ionizing radiation
What is the outcome of myelodysplastic syndrome?
Transformation to AML or death related to complications of cytopenias
What are the karyotypic abnormalities for MDS?
Monosomy 5 or 7; deletions of 5q,7q,20q
What is the treatment for MDS?
Allo-BMT in younger patients
Supportive therapy in older patients
Next we are going to focus on the chronic myeloproliferative neoplasms. What is the common pathogenic feature?
Mutated, constitutively activated TKs circumvent normal growth controls
---proliferation of mature cells of myeloid lineage (high WBC with hypercellular bone marrow)
--seen in late adulthood (over 50)
What are the four major entities (neoplasms) associated with chronic myeloproliferative neoplasms?
1. Chronic Myeloid Leukemia: mutation in t(9;22) Philadelphia, BCR-ABL, fusion gene; with a 100% frequency, result = constitutive ABL kinase activation
2. Polycythemia Vera: JAK2 point mutation with over 95% frequency, result = constitutive JAK2 kinase activation
3. Essential Thrombocythemia: JAK2 point mutations, MPL point mutations with 50-60% frequency. Result = constitutive kinase activations
4. Primary Myelofibrosis: JAK2 point mutations, MPL point mutations with 50-60% frequency. Result= constitutive kinase activation