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138 Cards in this Set
- Front
- Back
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What four characteristics do Myelodysplastic syndromes (MDS) show?
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1. Ineffective hematopoiesis
2. Dysplastic morphology of cells 3. Increased apoptosis of cells 4. Peripheral blood cytopenia |
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What cytogenetic changes are commonly seen in MDS?
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1. Monosomy of 5 and 7
2. Deletion of 5q, 7q, and 20q 3. Trisomy 8 |
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What two ways may MDS typically occur?
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Either idiopathically (over age 50) or after therapy with radiation/genotoxic drugs.
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What is characteristic of MDS changes in RBCs?
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Ringed sideroblasts
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What is characteristic of granulocytes in MDS?
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Pseudo-Pelger-Huet cells
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What characteristic of Megakaryocytes is seen in MDS?
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Pawn-Ball Megakaryocytes (multiple separate nuclei)
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What is primary myelofibrosis?
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A chronic myeloproliferative disorder characterized by obliterative marrow fibrosis.
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What genetics are most commonly associated with primary myelofibrosis.
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JAK-2 point mutations (50-60%).
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What are the two stages of Primary Myelofibrosis?
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1. Cellular stage (hypercellular).
2. Fibrotic stage (dry tap). |
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What important findings would you expect for Primary Myelofibrosis?
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1. Dry tap of bone marrow
2. Pancytopenia 3. Leukoerythroblastosis 4. Extramedullary hematopoesis 5. Tear drop cells |
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What clinical findings support the diagnosis of Polycythemia vera?
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1. ↑ erythroid precursors
2. ↑ RBC number 3. ↓ EPO 4. JAK-2 mutation (>95%) |
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Broadly speaking, what genetic abnormality is associated with myeloproliferative diseases?
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Mutations which cause constitutive activation of tyrosine kinases.
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When evaluating anemias, what are the three broad categories you should consider?
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1. Blood loss
2. Increased RBC destruction 3. Decreased RBC production |
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What is aplastic anemia?
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A syndrome of chronic primary hematopoietic failure with attendant pancytopenia (anemia, neutropenia, throbocytopenia).
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Analogous to primary myelofibrosis, what is commonly seen in aplastic anemias?
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A dry tap of the bone marrow.
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If this patient presents with pancytopenia, what is a potential diagnosis?
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Aplastic Anemia
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Approximately what percentage of aplastic anemia cases are idiopathic?
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About 65% are idiopathic and the rest are spread among many different causes.
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What is the diagnosis and what is the name of the structures in the lower panel?
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Langerhans Histiocytosis. Birbeck granules.
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What types of cells are clonally expanded in Langerhans cell histiocytosis?
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Macrophages and dendritic cells.
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What phrase is pathognomonic for multiple myeloma?
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Lytic bone lesions.
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What four clinical findings are associated with multiple myeloma?
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1. Normocytic anemia
2. Pancytopenia 3. Lytic bone lesions 4. Bence Jones proteinuria |
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In multiple myeloma, what will a serum protein electrophoresis typically show?
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Instead of a broad, diffuse polyclonal IgG band, a sharp monoclonal IgG kappa band may be seen. This could also present as other antibody classes and it will only show elevated kappa or gamma chains.
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What is the key cell type that you would expect to see in multiple myeloma and what is the expected immunophenotype?
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Plasma cells (CD56, CD79a)
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What is Bence Jones protein and what is it diagnostic of?
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Immunoglobulin light chains (kappa or lamda). Found in multiple myeloma or Waldenstrom's macroblobulinemia.
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What does mantle cell lymphoma look like?
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Tumor cells which closely resemble the normal "mantle zone" cells that surround follicular centers of lymphoid tissue.
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What is the cytogenetics of mantle cell lymphoma?
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t(11:14) resulting in fusion of IgH and BCL 1
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What is the immunophenotype of mantle cell lymphoma?
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Cyclin D1, CD19, CD20, CD5
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The genotype is t(11:14) and the cells are CD 5 positive, what is the diagnosis?
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Mantle cell lymphoma.
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What is the immunophenotype of Burkitt lymphoma?
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CD 19, CD 20, CD 10, BCL 6
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What is the cytogenetics associated with Burkitt Lymphoma?
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t(8:14) c-myc/IgH
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These tumor cells have a t(8:14) genotype. What is the diagnosis?
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This is a typical starry sky pattern of dark lymphocytes and tingible body macrophages which is characteristic of Burkitt Lymphoma.
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What do cells in marginal zone lymphomas (maltomas) resemble?
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Normal marginal zone (memory) B cells.
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What is an important clinical feature of marginal zone lymphomas?
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The arise at extranodal sites that have continuous inflammation (colonic mucosa, gastric mucosa, salivary gland).
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What are the three diseases or syndromes which predispose to extranodal marginal cell lymphomas?
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1. Hashimoto's disease
2. Sjogren's disease 3. Helicobacter gastritis |
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What is a distinguishing immunophenotype for marginal zone lymphoma?
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CD5 and CD10 are both negative
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What genotypes may be present?
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t(1;14) or t(11;18)
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What do follicular lymphoma cells resemble?
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Normal germinal center B cells.
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What are the two principal cell types seen in follicular lymphoma?
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1. Small cells with irregular or cleaved nuclei (centrocytes)
2. Centroblasts with open chromatin and several nucleoli |
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What is the immunophenotype of follicular lymphoma cells?
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CD19, CD20, CD10
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What is the genotype of follicular lymphoma cells?
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t(14;18) IgH/BCL2
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What is the most common form of adult lymphoma's?
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Follicular lymphoma
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The genotype is t(14;18) and no CD5 is expressed on the tumor cells. What is the diagnosis?
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Follicular Lymphoma
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What is seen in the bone marrow of 85% of follicular lymphoma patients?
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Para-trabecular lymphoid aggregates.
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What is the major difference between SLL and CLL?
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The degree of peripheral blood lymphocytosis. CLL, lymphocytes>4000/mm^3 in blood.
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In SLL/CLL, what typically happens to the lymphoid architecture?
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The nodal architecture becomes effaced.
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What is the immunophenotype of SLL/CLL cells?
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CD19, CD20, CD23, CD5
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What two lymphoid disorders have cells that express CD5?
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SLL/CLL and Mantle cell lymphoma
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Cells were found that were CD19, CD20, CD23, and CD5 positive. What is the important clue from this image and what is the diagnosis?
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Smudge cells indicating SLL or CLL, depending on the blood lymphocyte count.
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Is the genotype important for diagnosing SLL/CLL?
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No, not really.
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What is pathognomonic for SLL/CLL?
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Tumor with loose aggregates of prolymphocytes called proliferation centers.
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What is the diagnosis?
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Hodgkin Lymphoma (Reed-Sternberg cell)
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What is the immunophenotype for Hodgkin lymphoma?
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CD20, CD45, BCL6
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What is significant about EBV in Hodgkin lymphoma?
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EBV is present in 40% of HLs and is important for activating NF-kB which contributes to the development of HL.
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Are there any cytogenetics for diffuse large B-cell lymphoma?
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No, it is quite heterogeneous.
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What is the immunophenotype of diffuse large B-cell lymphoma?
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CD19 and CD20; CD10 and BCL6 variable (Big Robbins)
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Two subtypes of diffuse large B-cell lymphoma are associated with viral infections. What are these?
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1. Immunodeficiency associated type presenting with EBV infection.
2. Primary effusion lymphoma associated with HHV-8. |
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What cell type is oncogenic within a thymoma?
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Thymic epithelial cells.
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How are thymomas typically identified in the clinic.
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They impinge upon mediastinal structures, or they are found in myasthenia gravis patients (autoimmune connection).
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What is critical to remember about malignant thymoma relative to T-cell acute lymphoblastic lymphoma?
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The only oncogenic cells are thymic epithelial cells.
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Where does T-cell ALL appear?
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As a thymic mass in young adults.
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What mutations are associated with T-cell ALL?
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Notch1
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What is the immunophenotype of B-cell ALL?
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CD10 CD19, TdT
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What is a common immunophenotype between T-call and B-cell ALL?
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TdT
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What is the likely diagnosis based on the immunophenotype?
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B-cell ALL
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What is the critical pathogenic event in Chronic Myeloid Leukemia (CML)?
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Acquisition of the Philadelphia chromosome (BCR-ABL fusion gene).
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What is the diagnostic criterion for CML?
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Cytogenetics showing a reciprocal translocation: t(9;22) (q34;q11)
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What is LAP and why is it important?
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Leukocyte alkaline phosphatase is present in the granules of normal granulocytes, but absent in the granules of CML.
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These granulocytes are LAP negative, what is the presumptive diagnosis and what test would you like to perform next?
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Chronic Myeloid Leukemia. Cytogentic staining to look for the Philadelphia chromosome.
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What cell types are overproduced in CML?
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Granulocytes and megakaryocytes.
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What are auer rods?
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Red staining peroxidase positive azurophilic granules.
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What cells have auer rods?
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Myeloblasts.
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How can you distinguish between CML and AML on peripheral blood smears?
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Look for LAP negative leukocytes (CML) and peroxidase positive myeloblasts (AML).
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Describe the bone marrow appearance and sites of hematopoesis in CML.
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Bone marrow is hypercellular (~100%) and most of the erythropoeisis is extramedullary.
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What stain is used for monoblasts?
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non-specific esterase.
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What staining procedure would you use to establish a diagnosis for this disease?
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Tartrate resistant acid phosphatase (TRAP). If positive, then probably hairy cell leukemia.
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What is a major difference between Waldenstrom's macroglobulinemia and multiple myeloma in terms of antibody production.
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In MM, light chains are over-produced leading to Bence-Jones proteinuria, where as in WM, the production is balanced and renal failure/amyloidosis are rare.
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What may cause immune hemolytic anemia with cold agglutinins?
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Waldenstrom's macroglobulinemia because it causes overproduction of IgE which may cause autoimmune destruction of RBCs.
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Apart from the ABO antigens, what are four additional antigens which may cause sensitization if present on transfused RBCs?
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1. D (Rh)
2. Kell 3. Duffy 4. Kidd |
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What may cause hereditary spherocytosis?
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Mutations effecting RBC membrane integrity including: ankyrin, spectrin, band 3 or band 4.
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What happens to RBCs in hereditary spherocytosis?
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They age much quicker, giving off small membrane fragments and are then trapped in the spleen and eaten by macrophages.
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How may hereditary spherocytosis be treated?
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Splenectomy.
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What is the critical role of G-6-P dehydrogenase in RBCs?
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By oxidizing glucose, it provides reducing equivalents to glutathione which can protect against oxidative damage.
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What is the average lifetime of an RBC?
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120 days
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What food should people suffering from G-6-PD deficiency not eat and why is this significant?
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Fava beans. This food is endemic to the middle east which is where a large number of G-6-PD variants occur.
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This is a blood smear stained with H&E or crystal violet from a patient with G6PD deficiency. Identify two abnormalities and how they arise.
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1. Heinz bodies are precipitated globulins.
2. Bite cells result from macrophages plucking out these inclusions. |
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Why is the penetrance of G6PD and sickle cell alleles so high in Africa?
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Because of the heterozygote advantage against falciparum malaria.
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What is the change in sickle cell disease?
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Point mutation of glutamate to valine.
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What is vaso-occlusive crisis in sickle cell disease?
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When sickled RBCs block capilaries and lead to painful infarcts which may include organs.
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What is autosplenectomy?
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Over time, sickle cell patients will autoinfarct their spleen due to continuous vaso-occlusive crises.
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Infection by what virus may lead to aplastic crisis in sickle cell patients?
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Parvovirus B19
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List viruses which may cause tumors and the associated tumors.
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1. EBV: Diffuse large B-cell lymphoma (Immunodeficiency type)
2. HHV8: Diffuse large B-cell lymphoma (Body cavity tumor) 3. Adenovirus: ALL 4. HTLV-1: Adult T-cell leukemia/lymphoma |
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What are the morphological classifications of anemias?
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1. Microcytic anemias (MCV < 80 fL)
2. Normocytic anemias (80 < MCV < 100 fL) 3. Macrocytic anemias (MCV > 100 fL) |
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List the four microcytic anemias.
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1. Iron deficiency
2. Anemia of chronic disease 3. Thalassemia 4. Sideroblastic anemias |
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What are macrocytic, megaloblastic anemias typically associated with?
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Vitamin B12 and/or folate deficiency
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How is iron abosrption regulated?
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Important key players:
DMT1, Ferroportin, Transferrin, Ferritin, Hepcidin |
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How many copies of α- and β-globin genes are there?
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α-globin: 2 copies
β-globin: 1 copy |
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What are the defective alleles associated with β-thalassemias?
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β+ : splicing or promoter mutations leading to decreased β-globin synthesis
β0 : chain terminator mutations completely blocking β-globin synthesis |
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What are the genotypes for β-thalassemia major?
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β+/β+ or β+/β0 or β0/β0
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What is the clinical outcome for patients with β-thalassemia major?
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Severe tranfusion-dependent anemia.
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What are the genotypes for β-thalassemia trait (minor)?
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β+/β or β0/β
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What are some major laboratory features of β-thalassemia major?
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anisocytosis, poikilocytosis, microcytosis and hypochromia. Target cells, basophillic stippling, and fragmented RBCs are seen.
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What is a major X-ray finding of patients with β-thalassemia major?
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"Crew Cut" appearance due to extramedullary hematopoiesis
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Are patients with β-thalassemia trait usually symptomatic?
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No, but they may have mild anemia and some red cell abnormalities.
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What is another word for β-thalassemia trait?
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β-thalassemia minor.
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Where are β-thalassemias most common?
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Mediterranean countries, parts of Africa, and Southeast Asia.
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What is the genotype for Hemoglobin H disease?
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Deletion of three α-globin chains
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What is hemoglobin H (HbH)?
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A tetramer of β-globins which form due to low levels of α-globin.
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Anemia in patients with a decreased TIBC, decreased serum iron, and decreased iron saturation?
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Anemia of chronic disease
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Anemia presenting with increased TIBC, decreased ferritin, decreased serum iron.
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Mycrocytic, Hypochromic, usually secondary to iron deficiency. Also seen with Thalassemia, lead poisoning
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Anemia in patients with an increased TIBC, decreased serum iron, and normal iron saturation?
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Iron-deficiency anemia.
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How is the diagnosis of immunohemolytic anemia made?
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On the basis of a dirct Coombs antiglobulin test (patient's RBCs + anti-IgG antibodies → agglutination)
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What are the obvious clinical signs of paroxysmal nocturnal hemoglobinuria, and how does this happen?
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Dark urine in the morning due to increased complement activation during sleep when the CO2 level ↑ and thus pH ↓.
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What are the two prinicple types of immune hemolytic anemia?
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1. Warm autoantibodies (IgG)
2. Cold autoantibodies (IgE) |
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What very important autoimmune disease may cause immune hemolytic anemia?
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Systemic Lupus Erythematosus
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What are the two major mechanisms of hemolysis?
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Extravascular (immune mediated in spleen) and intravascular (mechanical) hemolysis.
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What are some laboratory and clinical findings that distinguish between intravascular and extravascular hemolysis?
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Intravascular: hemoglobinuria, dark urine, and urine hemosiderin.
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What is disseminated intravascular coagulation (DIC)?
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Activation of coagulation cascade and widespread deposition of fibrin throughout microcirculation. Often called consumption coagulopathy.
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What is commonly seen in DIC?
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Increased D-dimers and other fibrin split products.
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What is thrombotic thrombocytopenic purpura (TTP)?
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Defect in ADAMTS13 (cleaves vWF) leads to ↑ plasma vWF and widespread formation of platelet throbmi in microcirculation.
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What is hemolytic uremic syndrome (HUS)?
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E. coli 0157:H7 shiga-like toxin binds to endothelial cells in kidney and microvasculature, initiating platelet activation.
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What major clinical findings differentiate TTP and HUS?
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TTP: transient neurological defects
HUS: acute renal failure |
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What does the prothrombin time (PT) measure?
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Extrinsic and common coagulation pathways.
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What does the partial thromboplastin time (PTT) measure?
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Intrinsic and common coagulation pathways.
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How can TTP and HUS be distinguished from DIC?
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PT and PTT should be normal in TTP and HUS because coagulation cascade is not important in the mechanism.
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What is immune thrombocytopenic purpura (ITP)?
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Autoantibodies to gp IIb-IIa or Ib-IX obsonize platelets → phagocytosed in spleen.
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What will you expect to see in the bone marrow in ITP?
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Increase in the size and number of megakaryocytes in response to platelet destruction.
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How is chronic ITP treated?
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splenectomy.
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List several important disorders that are associated with schistocytes (helmet cells).
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Mechanical heart valves, DIC, TTP, HUS, SLE.
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What is reactive lymphadenitis?
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Enlargement of the lymph nodes in response to acute or chronic infections.
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What is infectious mononucleosis usually caused by?
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Epstein Barr Virus (EBV)
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What are two major pathological changes associated with infectious mononucleosis?
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1. Reactive lymphadenitis
2. Atypical lymphocytes (Downey Cells) |
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What is the most common inherited bleeding disorder?
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Von Willebrand Disease
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What is the major clinical feature of Von Willebrand Disease?
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Prolonged bleeding time despite normal platelet count. May see ↑ PTT due to ↓ Factor VIII
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What is the pathophysiology behind Hemophilia A and Hemophilia B?
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Hemophilia A: Factor VIII deficiency
Hemophilia B: Factor IX deficiency |
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Why are Hemophilia A and B clinically indistinguishable?
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Because Factor VIII and Factor IX interact to activate Factor X. Thus deficiency in either VIII or IX will have the same outcome.
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What are the clinical features of Hemophilia A and B?
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Recurrent severe hemarthroses, easy bruising, massive hemorrhage after trauma, prolonged PTT.
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How is Von Willebrand Disease differentiated from hemophilias?
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Hemarthroses are uncommon in Von Willebrand disease.
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What does bleeding time test?
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The platelet response. Prolonged times indicate low platelet numbers and/or defective platelets.
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