WBC disorders 2 Flashcards
Clinical features of AML
- Rapid onset of symptoms & signs of cytopenia(s):
• Anemia - fatigue
• Neutropenia – fever, sepsis
• Thrombocytopenia – spontaneous mucosal, skin, intracranial bleed - Infiltration of skin or mucosa
• AML with monocytic differentiation (M4 & M5). - Extramedullary masses (uncommon).
- Hepatomegaly, splenomegaly – mild, if present.
- Disseminated intravascular coagulation – especially with t (15;17)
Laboratory Diagnosis of AML
- Peripheral Blood: Circulating blasts cells → WBC count usually increased but may be normal or decreased
- Occasionally, no circulating blasts (“aleukemic leukemia”)
- Bone marrow aspirate & biopsy (Gold standard): ≥ 20% blasts in the bone marrow
- Flow Cytometry: expression of myeloid and blast cell surface markers.
- Cytogenetics: for diagnosis and prognosis
AML: Peripheral Blood Smear and flow cytometry
-Myeloblasts with delicate nuclear chromatin, prominent nucleoli, and fine azurophilic cytoplasmic granules
-The tumor cells are positive for the stem cell marker CD34 and the myeloid lineage specific markers CD33 and CD15 (subset).
AML Therapy/Prognosis
-Treatment with vitamin A derivative, all-trans-retinoic-acid (ATRA), induces differentiation to neutrophils→remission
-Combination chemotherapy – 60% remission, but over half relapse within 5 years.
-Bone marrow transplantation for high risk AML or relapsed AML, but AML often recurs.
Features of Myelodysplastic syndrome
-Definition: Clonal maturational defects in stem cells → ineffective hematopoiesis (abnormal differentiation) → cytopenias
-Clinical settings:
• Idiopathic/Primary MDS: >50 years of age , gradual onset
• Therapy-related MDS: about 2-8 years after chemo/radiotherapy
Morphology of MDS
Peripheral Blood Smear (PB): Macrocytic anemia, cytopenias, (blast cells may or may not be present)
Bone marrow biopsy (BM): Usually hypercellular, but ineffective disorganized hematopoiesis
• Morphologic abnormalities in RBC and/or granulocytic precursors, and/or megakaryocytes
• Ringed sideroblasts, Pseudo-Pelger Huet cells- bilobed neutrophils, Multinucleated megakaryocytes
• With severe MDS, blast cells are increased, but by definition <20% of total cells. If more- AMLp
Myeloproliferative Neoplasms (MPNs)
- ChronicMyeloidLeukemia(CML) 2. PolycythemiaVera(PV)
- EssentialThrombocytosis(ET)
- PrimaryMyelofibrosis(MF)
General Features of MPNs
• Disorders of a pluripotent progenitor cell, capable of uncontrolled proliferation with full differentiation.
• Neoplastic cells and their offspring fill BM and suppress normal hematopoiesis.
• Tumor cells circulate & home to 2o hematopoietic organs (spleen, liver)→organomegaly.
• Termination in a spent phase of progressive BM fibrosis and cytopenias (PV, ET, MF), or transformation to acute leukemia (CML)
Pathogenesis of MPNs
• Arise from a multipotent progenitor cells, capable of uncontrolled proliferation with full differentiation.
• Common pathogenic feature =
mutated, constitutively activated tyrosine kinases circumvent normal growth controls.
• Result is growth factor-independent proliferation and survival of marrow precursors.
• There is no impairment of differentiation.
Clinicopathological Features of MPNs
• Neoplastic cells and their offspring fill bone marrow and suppress normal hematopoiesis.
• Tumor cells circulate & home to secondary hematopoietic organs (spleen, liver)→organomegaly.
• Termination in transformation to acute leukemia (CML), or a “spent phase” of progressive bone marrow fibrosis and cytopenias (PCV, ET, PMF).
Chronic Myeloid Leukemia
Defect in pluripotent stem cell for myeloid and lymphoid lineages, but morphologic expression is mainly granulocytic – characterized by uncontrolled proliferation with full differentiation.
Clinical Presentation of CML
• Adult M>F, 25-60 yrs
• Gradual onset of tiredness, weakness, loss of weight and appetite (suppression of normal BM).
• Abdominal discomfort due to enlarging spleen.
Laboratory Diagnosis of CML
-Peripheral Blood Smear:
• Striking left-shifted leukocytosis, mostly neutrophils, metamyelocytes and myelocytes, also eosinophils and basophils (<10% blasts).
• Sometimes thrombocytosis.
-Bone Marrow: Nearly 100% cellular, mostly ↑ granulocytic precursors (but percentage of blast cells not ↑). Also ↑ megakaryocytes.
the Philadelphia chromosome, BCR
-Cytogenetics / Molecular genetics: Detection of hallmark translocation (t(9:22), ABL, in PB or BM specimen.
Clinical Course and Outcome CML
-Stable phase lasts median 3 years (2-5), without effective treatment.
-Accelerated phase: After 2-5 years, 50% of stable phase progress in→increasing blasts, bone marrow fibrosis, thrombocytopenia, extra cytogenetic abnormalities →
-Blast crisis: Acute leukemia (75% myeloid, 25% lymphoid) within one year.
Treatment of CML
Imatinib(Gleevec):
Inhibits BCR-ABL kinase, slows down disease, (5YSR >90%), but usually does not destroy the abnormal clone (clinical and morphological remission, but only 15% molecular remission). Does not prevent blast crisis.
Interferon-α: slows down disease. Hydroxyurea: “gentle” chemotherapy
Allogeneic bone marrow transplantation: in younger patients
