MMSC 433 Exam 3 Study Notes

MMSC 433 Exam 3 Study Notes

• Chromosomal Abnormality in CML: Philadelphia chromosome (95% of cases) - translocation of AB: proto-oncogene from band q34, chromosome 9 to BCR of band q11, chromosome 22. JAK2V617F mutation found in most cases.

• Chromosomal Abnormality in PV: Point mutation replacing guanine with thymine at exon 4, changes amino acid at position 617 from valine to phenylalanine.

• CML (Chronic Myelogenous Leukemia): Overproduction of white blood cells in the bone marrow. Caused by a genetic translocation in a pluripotential hematopoietic stem cell. Leads to clonal overproduction of myeloid cells and a predominance of immature cells (infection, bleeding, anemia, splenomegaly).

• Normal ABL Gene: Functions as a kinase involved in cell growth and proliferation. Can be active or inactive. Adds phosphate groups to other proteins.

• Normal BCR Gene: Acts as a GTPase activating protein (GAP) involved in cell signaling, active when bound to GTP.

• BCR-ABL 1 Fusion Gene: Identified with Philadelphia chromosome; present in 20% of adults and 2-5% of children.

• CML Morphology Changes in PB: Increased white blood cell count (total WBCs), neutrophils, basophils, eosinophils, myelocytes, platelets. Decreased red blood cell count (erythrocytes), low LAP score (normally 15-170). Myeloblasts increase in bone marrow, elevated basophils in blood. Spleen size increases, high leukocyte count. Characterized by more genetic lesions not linked to therapy.

• CML Accelerated Phase: Myeloblasts in bone marrow constitute >20% of the total bone marrow cellularity. Elevated basophils and spleen size increase.

• CML Treatment: Gleevec.

• PV (Polycythemia Vera): A neoplastic clonal myeloproliferative disorder characterized by overproduction of red blood cells (RBCs) in the bone marrow. Thickened blood leads to poor circulation. Increased hemoglobin, hematocrit, total white blood cells(WBCs), granulocytes, and platelets in the peripheral blood (PB).

• PV PB Morphology Changes: increased Hemoglobin, hematocrit, total WBCs, granulocytes, platelets, increase in RBC mass.

• PV Treatment: Phlebotomy, hydroxyurea.

• ET (Essential Thrombocythemia): A clonal myeloproliferative neoplasm (MPN) marked by overproduction of platelets in the bone marrow. Causes include primary thrombocytosis, idiopathic thrombocytosis, and hemorrhagic thrombocytopenia. Symptoms include vascular occlusion, hemorrhage, increased platelet count, splenomegaly, and erythromelagia.

• ET Clinical Presentation: Vascular occlusion, hemorrhage, increased platelet count, splenomegaly, and erythromelagia are symptoms.

• Common Morphology Changes in PB for ET: Decreased hemoglobin and hematocrit, increased total white blood cells (WBCs), neutrophils, and platelets.

• ET Treatment: Hydroxyurea, ruxolitinib, and/or aspirin.

• PMF (Primary Myelofibrosis): Splenomegaly, ineffective hematopoiesis, fibrosis, and increased megakaryocytes associated with areas of hypercellularity in the bone marrow. Fatigue, pruritus, bone pain, palpitations, night sweats, and splenomegaly are symptoms.

• PMF Morphology: Immature granulocytes, normoblasts, and dacrocytes.

• PMF Treatment: Hydroxyurea, ruxolitinib, and/or CYT387 and TG101348 (JAK inhibitors).

• WHO Major Criteria for PV: Increased hemoglobin (or hematocrit) above normal limits, Bone Marrow increased erythrocyte production, and presence of JAK2V617F mutation.

• WHO Minor Criteria for PV: Subnormal serum EPO level.

• WHO Criteria for Accelerated CML: Presence of neutrophils and their precursors. No or minimal absolute basophilia or monocytosis. Hypercellular bone marrow with granulocytic proliferation and dysplasia, with or without dysplasia of other lineages. No or minimal evidence of other clonal markers.

• PrePMF (WHO Criteria): Anemia not linked to a comorbid condition, Leukocytosis >11 x10^9/L, Palpable Splenomegaly, elevated LDH to values exceeding normal limits, and Leukoerythroblastosis.

• Overt PMF (WHO Criteria): Megakaryocytic proliferation accompanied by reticulin and/or collagen fibrosis grades 2 or 3. Does NOT meet criteria for ET, PV, BCR-ABL1+CML, MDS, or other myeloid neoplasms, and lacks evidence of a reactice myelofibrosis. Presence of JAK2, CALR, or MPL mutation.

• ET WHO Criteria Major: Platelet count > 450 x 10^9/L; Bone marrow biopsy showing increased megakaryocytic proliferation predominantly with enlarged, mature megakaryocytes and hyperlobulated nuclei. No significant erythro/myeloid increase. No evidence of other hematological malignancies. Identification of JAK2, CALR, or MPL mutation.

• **ET WHO Criteria Minor:**Presence of a clonal marker and absent evidence of reactive thrombocytosis.

• MDS Treatment: Supportive care, lenalidomide, azacitidine, decitabine (these are FDA approved). Growth factors (EPO, TPO, G-CSF), Immunosuppressive Therapy and/or Hematopoietic stem cell transplantation.

• MDS Etiology: Radiation or chemical insult. Pathological clone of progenitor cells that interferes with normal hematopoiesis. "Crowding out"/dyspoiesis.

• Therapy Related MDS: Patients receiving chemotherapy or radiotherapy treatment. 4-7 years post treatment. MDS is often more aggressive than de novo MDS; tends to transition into AML.

• MDS with Isolated del(5q) Lab Findings: Dysplastic lineages, cytopenias, thrombocytosis can be present.

• MDS Morphology (PB): Oval macrocytes, hypochromic microcytes, dimorphic red blood cell population, poikilocytosis, basophilic stippling, Howell-Jolly bodies, and Pappenheimer bodies.

• MDS Morphology (BM): RBC precursors with >1 nucleus, abnormal nuclear shapes, nuclear lobes/buds, nuclear fragments, nuclear bridging, ringed sideroblasts, and megaloblastoid cellular development.

• Common Childhood Leukemia: Acute lymphoblastic leukemia (ALL)

• Myeloperoxidase: ALL negative, AML positive, AMML positive, AMOL negative, and Megakaryocytic leukemia negative.

• Sudan Black B: ALL negative, AML positive.

• WHO Classification of Acute Leukemias: Acute megakaryocytic leukemia, AML with recurrent genetic abnormalities.

• Normal Lymph Node Function: Filter substances in lymphatic fluid. Contains lymphocytes which combat infection.

• Cells found in Lymph Nodes: Lymphocytes, B cells, T cells, dendritic cells, macrophages, and plasma cells.

• Preferred Workup for Lymphoproliferative Disorders: Touch imprint of nodes, Lymph node biopsy.

• Diagnostic Workup for Lymphoproliferative Disorders: Touch imprint of nodes, lymph node biopsy.

• TRAP (Tartrate-resistant Acid Phosphatase): A stain used to identify hairy cells. Red color persists in hairy cells. Dissipates in other cells.

• Classic Cell that defines B cell neoplasm: Popcorn cells.

• Hodgkin's Lymphoma: Normal lymph node architecture replaced by nodular proliferation of neoplastic cells with "popcorn" cells.

• Multiple Myeloma Etiology: IL-6 stimulates osteoclast formation, breaking down bone. RANKL binds to RANK leading to osteoclast proliferation. DKK1 blocks osteoblast formation and accelerates osteoclast formation. MIP-osteoclast recruitment.

• Multiple Myeloma Sxs: Lytic bone lesions (skull), bone pain, pathologic fractures, infections. Increased susceptibility to infections, renal insufficiency.

• Multiple Myeloma Lab Findings: N/N anemia, rouleaux formation, increased ESR, elevated serum calcium, Increased plasma cells (1-90% BM), proteinuria, "flame cells" (IgA)., Russell bodies, hyper viscosity.

• Immunoglobulins in Multiple Myeloma: 25% light chains (Bence Jones proteins), hypogammaglobulinemia.

• Multiple Myeloma Treatment: Lenalidomide, Dexamethasone.

• Waldenstrom Macroglobulinemia Etiology: Abnormal IgM immunoglobulin production from pathological plasma cells. Mutations in MYD88 (chromosome 3) and 6q

• Waldenstrom Clinical Features: Hyperviscosity, amyloidosis, cryoglobulinemic purpura, anemia, prolonged PT/PTT/BT, and Raynaud’s phenomenon.

• Waldenstrom Lab Findings: N/N anemia, thrombocytopenia, lymphocytosis, Dutcher bodies, rouleaux formations, increased ESR, and bence jones proteins.

• Waldenstrom Treatment: Chemotherapy, plasmapheresis.

• Plasma Cell Leukemia: Increased plasma cells in blood (> 20%) in peripheral blood smear. Fatigue, kidney damage, hepatosplenomegaly, hypercalcemia.

• Plasma Cell Leukemia Tx: chemo. Bortezomib, Lenalidomide.

• Burkitt Lymphoma Etiology: EBV. Chromosomal translocations (t(8;14), t(8;22), t(2;8)).

• Burkitt Lymphoma Sxs: Abdominal mass, occurs in GI tract, gonads, breast tissue, and organ transplant.

• Burkitt Lymphoma Tx: chemotherapy. Cyclophosphamide, cytarabine, doxorubicin, methotrexate.

• Burkitt Lymphoma Lab Findings: Low magnification "starry sky" appearance. Macrophages phagocytize apoptotic debris.

• Burkitt Cell Lymphoma Morphology: Diffuse proliferation of lymphoid cells; medium size with round nuclei, and fine chromatin; small nucleoli; cytoplasm is vacuolated.

• Most Common Burkitt Lymphoma Translocation: t(8;14)

• Immunophenotype of Burkitt Lymphoma: CD19+, CD20+, CD10+.

• Non-Hodgkin's Lymphoma (NHL): A malignant neoplasm of lymphoid tissue. Cancer cells originate in tissue such as the thymus, lymph nodes, bone marrow, or spleen.

• Symptoms of NHL: Swollen lymph nodes, unexplained fever, weight loss, drenching night sweats, cough, breathlessness, fatigue.

• Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT): A subtype of lymphoma occurring in extranodal locations.

• Follicular Lymphoma Morphology: Predominantly diffuse nodular or mantle zone pattern. Medium to large-sized lymphocytes with irregular nuclei, CD20+, CD19+, CD5+, and FMC7+. t(14;18).

• Mantle Cell Lymphoma Morphology: Diffuse, nodular, or mantle zone pattern. Medium-sized lymphocytes with irregular nuclei. CD20+, CD19+, CD5+, FMC7+. t(11;14).

• Types of Plasma Cell Myeloma: B-CLL with hypoidy, B-CLL with hyperploidy.

• CLL Lymphocytes Morphology: Sheets / large aggregates of plasma cells; "soccer ball" appearance in PB.

• B-CLL With Hypo- or Hyperploidy: B-CLL with hypo or hyperploidy are related to the number of chromosomes of B-lymphocytes. B-CLL with hypoidy has fewer than 46 chromosomes, blasts contain <46 chromosmes; poor prognosis. Neoplasm of B cell lineage, immunophenotyping: CD10+, CD19+. B-CLL with hyperploidy has more than 46 chromosomes, blasts contain >50 chromosomes without translocations. Favorable prognosis. Affects 25-35% of children aged 3-5, immunophenotyping: CD19+, CD10+, CD34+, CD45 negative.

• Plasma cell myeloma Morphology: Sheets/large aggregates of plasma cells, "soccer ball" appearance in peripheral blood (PB)

Prepare for your MMSC 433 Exam 3 with these detailed study notes on chromosomal abnormalities in CML and PV. Understand the genetic mutations involved, the role of ABL and BCR genes, and the implications of these findings in leukemias. This quiz covers critical concepts essential for mastering the subject.