MYELODYSPLASTIC SYNDROMES (MYELODYSPLASIA)=MDSSulistyo M. AgustiniDepartment of Clinical PathologyMedicine Faculty of Muhammadiyah Malang University2011

REFERENCEMcCance Huether, PATHOPHYSIOLOGY The Biologic Basic for Disease in Adults and Children, Fifth edition, Mosby-Elsevier, 2006Hoffbrand AV, Pettit JE and Moss PAH, Essential HAEMATOLOGY, fourth edition, 2003Howard MR, Hamilton PJ, HAEMATOLOGY An Illustrated Colour Text, tjird edition, 2008Kumar Hagler Schneider, Robin and Cotran PATHOLOGIC BASIC of DISEASE, 7 th edition, 2005Abeloff D et al, CLINICAL ONCOLOGY, 3 rd edition, 2004

INTRODUCTIONGroup of clonal disorder of multipotent haematopoiesis stem cell (neoplastic disorder)MDS is heterogenous group of clonal disorders of bone marrow, differentiates ineffectivellyTheir common feature is bone marrow failure ineffective haematopoiesis (reduced haematopoiesis activity)Hypercellular marrow & peripheral blood cytopeniaPredominantly a disease of the elderlyPrognosis is highly variable dependent on the subtype

CharacteristicIncreasing bone marrow failure quantitative & qualitative abnormal all three myeloid cell lineIneffective haematopoiesis (reduced haematopoiesis activity)Dysplastic morphological abnormalities form the basic for diagnosisIncreased apoptosis within the marrow is comman feature

CharacteristicIncreasing bone marrow failure quantitative & qualitative abnormal all three myeloid cell lineIneffective haematopoiesis (reduced haematopoiesis activity)Dysplastic morphological abnormalities form the basic for diagnosisIncreased apoptosis within the marrow is comman feature

Slide 3 of 50

First Previous Next Last Index Text

Myelodysplastic SyndromesClonal disorders involving bone marrow stem cells that lead to ineffective and disorderly hematopoiesisManifest as irreversible quantitative and qualitative defects of hematopoietic cells cause by abnormal division, maturation and production of erythrocytes, granulocytes/monocytes and platelet that result in blood cytopenias.

ClassificationThe French American British (FAB) & WHO

typePheripheral bloodBone marrowApproximated survival (months)Refractory anaemia (RA)Blast < 1%Blast < 5 %50RA with ring sideroblasts (RARS)Blast 5 %Blast 20-30 % or Auer rods present5Chronic myelomonocytic leukemia (CMML)As any of the above 10 x 106/l monocytesAs any of the above promonocytes11

Approach to DiagnosisLaboratory diagnosis of MDSCBC + blood smear exam for dysplasticLDHBM aspiration (Romanowsky& Iron) and BiopsyBM CytogeneticFlowcytometry (clinically indicated)Molecular (clinically indicated)Vit B12, Folate , SI-IBC,Feritin (clinically indicated)

Clinical AspectsMost common in elderly ( 60 75 ) yearsFew patients < 50 yearsMay Affect any age including childrenMen are slightly more than womenSymptoms Related to blood cytopenias

Clinical AspectsSymptoms Most frequentFatique, weakness and malaise due to anemiaLess frequentInfection due to the netropeniaHemorrhage due to thrombocytopenia.Some individual are asymptomaticCytopeniasidentified in routine blood count Small percentage (rare)Hepato- splenomegaly

Hematologic FindingHighly VariableVarious combination of CytopeniasPancytopeniaAnemia in combination with neutropenia or thrombocytopeniaIneffective hematopoiesis, dyserythropoiesis,dysgranulopoiesis and dysmegakaryopoiesisIncreased myeloblastsNormocellular or hypercellular BM

Hematologic FindingMost common example normo or hypercellular BM withineffective erythropoiesis , erythroid hyperplasiaanemia with reticulocytopenia

Dyserythropoiesis

Hematologic FindingBlood cell MeasurementsNormocytic or macrocytic anemia low or normal reticulocyteRDW elevated (anisocytosis)Leukocyte normal to markedly reducedElevated In minority of casesPlatelet count reduced or normalElevated in special type MDS isolated del (5q)

Hematologic FindingBone Marrow ExaminationHypercellular or NormocellularHypocellular (very rare)Dysplastic changesDyserythropoiesis,Dysgranulopoiesis,DysmegakaryopoiesisIncreased Myeloblast (< 20%)Iron stores often increased (RARS)

Dyserythropoiesis

RARS

Dysgranulopoiesis

PelgerHuet

RAEB

RAEB

Dysmegakaryopoiesis

Prognostic Factors in MDSClinical Therapy related MDSBloodSevere cytopeniasRaised LDH & Beta 2 microglobulinMarrowIncreased BlastTrilineage DysplasiaChromosome abnormalitiesLoss of chromosome 5 or 7Deletion of chromosome 3q,5q (excluding 5q syndrome),7q,17 pStructural abnormality of chromosome 11q 23

Prognostic Factor in MDSChromosome abnormalitiesComplex chromosome abnormalitiesKaryotypic evolutionGenetic/epigenetic abnormalitiesp53, RAS mutationOverexpression of WT1P15 hypermethylationTelomere shorteningGene expression profileImmunophenotypingCD7 positive Blast

Diagnosis MDSAt least cytopenia of one lineMorphologic evidence of dysplasiaPeripheral blood smear, bone marrow aspirate and biopsy requiredBM differential count performing 500 cells, eliminating lymphocyte and plasma cells for the countIf erythroid precursors > 50 % NEC Blast

International Prognostic Scoring System

International Prognostic Scoring SystemPatients with 20-30 % blasts may be considered as MDS or AML. Cytogenetics: Good = normal, -Y alone, del(5q) alone, del(20q) alone; Poor = complex ( 3 abnormalities) or chromosome 7 anomalies; Intermediate = other abnormalities. [This excludes karyotypes t(8;21), inv16, and t(15;17), which are considered to be AML not MDS.] Cytopenias: neutrophil count

SummaryMDS is a heterogeneous group of clonal disorder bone marrow (stem cell neoplasm) marked by cytopenia and dysplasia of minimal one lineage.Diagnosis of MDS is mainly based on CBC, peripheral blood smear, bone marrow aspirate and biopsy(depends on the presence of characteristic morfological change in the blood and marrow)Cytogenetic analysis and molecular biology is important to determine prognosis, and highly variable denpent on the subtypeSupportive care remains but growth factor and other specific therapeutic agent are increasing used. Chemotherapy and stem cell transplantation may be considered in younger patients with high-risk disease.

****