MYELOPROLIFERATIVE DISEASE Dr Mere Kende MBBS (UPNG), MMED (Path),MAACB, MACTM, MACRRM (Aus) Lecturer-SMHS UPNG
Myeloproliferative Diseases Essential to diagnosis Acquired clonal abnormalities of the hematopoietic stem cell Stem cell gives origin ----qualitative and quantitative changes are seen in all these cell lines. CML- specific characteristic chromosomal changes are seen. Morphological abnormalities to 2 or more cells lines
Normal Hemopoiesis
CLASSIFICATIONS Myeloproliferative syndromes Polycythemia vera (erythroid precursors) Myelofibrosis (fibroblast) Essential thrombocytosis (thrombocytes/megakaryocyte) Chronic myeloid leukemia (myeloid) Myelodysplastic syndromes Acute myeloid leukemia
Myeloproliferative Disease Can evolve from one for to another All Disorders can Progress to AML
Clinical Features of MPD Generalised Fatique, FUO Anemia Increased risk of Infections/Night sweats Increased thrombotic episodes Organomegaly (liver & spleen) Hyperviscosity Syndrome
Cause Idiopathic/Unknown Post-cytotoxic Chemotherapy
Polycythemia Vera Essentials of Diagnosis Increased red blood cell mass (>60%). Splenomegaly (75%). Normal arterial oxygen saturation. Usually elevated white blood count (10-20 000/mcl) and platelet count (1000000/mcl).
Polycythemia Vera
Normal Blood Film
Other Features Hyperviscocity/increased thrombosis Iron deficiency Hypercellular marrow High vitamin B12 (increased transcobalamin III) Hyperuricemia
Causes
Treatment Weekly phlebotomy (aim PCV<45%) Myelosuppressive therapy (hydroxyurea) Allopurinol (hyperuricemia)
Essential Thrombocytosis Defect in stem cells Marked proliferation of the megakaryocytes in BM Elevation of Platelet Counts Median Age: 50 60; W>M
Essential Thrombocytosis Thrombosis (abdomen) Burning sensation of tips of finger Splenomegaly (25%) BM increased megakaryocytes WBC<30,000/mcl
Essential Thrombocytosis Essentials of Diagnosis Elevated platelet count in absence of other causes >2million/mcl (reactive usu<1million/mcl) Normal red blood cell mass. Absence of Philadelphia chromosome.
Treatment Hydroxyurea Aspirin (thrombosis)
Myelofibrosis Bone Marrow fibrosis (increased PDGF/cytokines) Increased extra-medullary hemopoiesis
Other Features Age: 50 years Fatiue & Anaemia Bleeding uncommon Massive splenomegaly (common) Hepatomegaly (50%) Portal hypertension, ascites, esophageal varices,
Laboratory Features Anemia Blood Film Teardrop poikilocytosis on peripheral smear. Leukoerythroblastic blood picture; giant abnormal platelets.
Blood Film- Tear drops red cells
Bone Marrow -Fibrosis
Myelofibrosis Essentials of Diagnosis Striking splenomegaly. Teardrop poikilocytosis on peripheral smear. Leukoerythroblastic blood picture; giant abnormal platelets. Hypercellular bone marrow with reticulin or collagen fibrosis.
Treatment Medical (thalidomide/erythropoeitin) Transfusion Transplant
Chronic Myelogenous Leukemia Essentials of Diagnosis Strikingly elevated white blood count (>150,000/mcl). Markedly left-shifted myeloid series but with a low percentage of promyelocytes and blasts <5%). Presence of Philadelphia chromosome or bcr/abl gene
Philadelphia Chromosome
Other Features Median age: 55 years Fatigue, sweats, Low grade Fever Abdominal fullness/splenomegaly WBC usually >500,000/mcL. Expanding BM - sternal tenderness, bone pain, FUO
CML
CML- Increased WBC
Bone Marrow-Increased M: E ratio
CML Bone Marrow Hypercellular, increased myeloid/megakaryocyte/no fat
Treatment Medical Hydroxyurea Bulsulpan Interferon apha-b2 (expensive) -injections Allopurinol (hyepruricemia) Radiation
Summary of Laboratory Findings
Myelodysplastic Syndromes Essentials of Diagnosis Cytopenias with a hypercellular bone marrow. Morphologic abnormalities in two or more hematopoietic cell lines. Blast cells <20% (cf AML)
General Considerations Acquired clonal disorders of the hematopoietic stem cell. Characteristcis: Cytopenias, a usually hypercellular marrow, an A No. of morphologic and cytogenetic abnormalities. Cause: idopathic or post-cytotoxic chemotherapy. Transform to AML (hence termed also as preleukemia) Includes various diagnoses/syndrome Refractory Anemia without Excess Blasts Refractory anemia with excess blasts" (RAEB 5 19% blasts). Chronic myelomonocytic leukaemia (monocytosis > 1000/mcL
Clinical Findings Age: >60 years. Asymptomatic incidental abnormal FBE findings Symptomatic: fatigue, infection, or bleeding related to bone marrow failure, wasting illness with fever, weight loss, and general debility. Exam: +/-splenomegaly with pallor, bleeding, and various signs of infection.
Laboratory Findings Anemia (MCV normal or may be increased ) Macro-ovalocytes WBC count usually normal or reduced, Neutropenia is common +/-morphologic abnormalities,) Left-shifted myeloid series (promyelocytes or blasts) Platelets normal or reduced, and hypogranular platelets may be present
PERIPHERAL BLOOD 50 x.) PMN cellshyposegmentation (socalled Pelger-Huet anomaly) as well as hypogranularity. While not present in all patients with myelodysplastic syndrome, these findings would be very suggestive of this diagnosis as the underlying disorder. (Courtesy of L Damon.)
BONE MARROW Hypercellular / Erythroid hyperplasia is common, Signs of abnormal erythropoies (megaloblastic features, nuclear budding, or multinucleated erythroid precursors (see micrograph). The Prussian blue stain may demonstrate ringed sideroblasts. Left-shifted myeloid series Dwarf megakaryocytes with unilobed nucleus Variety of cytogenetic abnormalties (chrmosomal deletions)
Bone Marrow Myelodysplastic syndrome. (Bone marrow aspirate, 100 x.) Increased erythroid cells with basophilic cytoplasm. Abnormal looking RBC precursors & megaloblastic picture, dysmorphic granulocyte maturation or megakaryocyte maturation (Courtesy of L Damon.)
Treatment Traditionally no effective therapy Supportive: RBC transfusions. Recently, Erythropoietin (epoetin alfa), Lenalidomide (70% response rate, expensive Azacitidine (5-azacytidine)-primary choice Immuno-suppresive therapy Stem cell transplants
Course & Prognosis Fatal if untreated Transplant 30-60% cure Risk of transformation AML with higher blasts cells Poor prognosis with cytogenic abnormalities
Acute Myeloid Leukaemia Myelogenous/myeloid leukaemia Abnormality in myeloid line of cells (granulocytes, monocytes, erythroids, megakaryocytes) Proliferation of abnormal myeloid cells and failure to differentiate to normal mature cells Suppressed normal myeloid cell line (granulocytes, monocytes, platelets, red cells) RESULTS: malignant blast cells--anemia, risk of infections, bleeding tendencies
Epidemiology AML is seen 80% of time in adults; only <10% in children (<10 yrs) Median age: 65; 2x common in males
Association/Risk factors Chemical exposure Radiation Tobacco Chemotherapy Trisomy 21 (Down s syndrome) Fanconi Anaemia Aplastic anaemia Myeloid dysplasia Myeloproliferative diseases (CML; ET; MF;PV)
Clinical Presentation Non-specific symptoms: wt loss, fatigue Anemia (pallor; tachycardia) Bleeding (gingival; epistaxis; ecchymoses, menorrhagia)----thrombocytopenia Infections (mild-severe) Onset weeks-months Promonomyelocytic CNS symptoms; gum hypertrophy) Lymphadenopath----less common Splenomegaly/hepatomegaly-----if transformed from MPD/CML
Tumour lysis Syndrome Hyperphosphatemia Hypocalcemia Hyperuricemia Hyper/hypokalemia Lactic acidosis Hypoxaemia
Laboratory tests FBE: low Hb (normochromic, normocytic) Thrombocytopenia <100,000 x/mcl (75%) Low reticulocytes (retics) Leukocytosis >100,000 /mcl (20%); <5,000 (20-40%); median 15,000 BLAST CELLS (>20% diagnostic) if less examine BM
Myeloblasts Immature; large nucleus; prominent nucleoli Pale-blue cytoplasm AUER RODS Myeloperoxidase +ve Flow cytometry-characteristic antigen panel
Myeloblasts Immature; large nucleus; prominent nucleoli Pale-blue cytoplasm Myeloperoxidase +ve AUER RODS
Flow cytometrycharacteristic antigen panel
Bone Marrow biopsy/aspirate Key to diagnosis of AML Hypercellular BLAST cells (>20%) Decreased normal cells Small percents may have hypocellular BM
Prognostic/Choice of treatment Flow cytometry Cytogenetics infromation molecular studies (latest)
Differential Diagnosis ALL No auer rods Negative myeloperoxidase Negative sudan black stain Flow cytometry ( different antigen panels) Cytogenics (t (1,22)- with AML
Treatment Supportive Adults >65yrs-poor prognosis Chemotherapy on selected cases Overall only <20% live more than 5 years
References Current Medical Diagnosis and Treatment 2008 LG. Gomella, SA. Haist; Clinicians Pocket Reference 11 th Edition 2007 Harrison s Text of Medicine 17 th Edition