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Myelodysplastic Syndrome.pptx
- 1. Myelodysplastic Syndrome Dr Tamil Nila Postgraduate
- 2. Definition Group of clonal hematopoietic stem cell diseases characterised by • Cytopenia (atleast 1 lineage) • Hb < 10g/dl • Platelet count < 1 lakh/cu.mm • ANC < 1800 cells/cu.mm • Monocytes < 1000/cu.mm • dysplasia in one or more of the major myeloid lineages • Ineffective hematopoiesis • Recurrent genetic abnormalities • Increased risk of AML
- 3. Hypoplastic MDS • 10% MDS • Independent favourable prognosis • DD – Aplastic Anemia • Exclude Acute marrow injury MDS with Fibrosis • 10 – 15% of MDS • Grade 2 – 3 fibrosis • Excess of Blasts • Aggressive clinical course • Bone marrow Biopsy > BMA • IHC for CD 34 • Different from Primary Myelofibrosis • No splenomegaly • No leucoerythroblastic blood picture • Intrasinusoidal hematopoiesis
- 4. Epidemiology • Older adults • Male preponderance • Annual incidence = 3 – 5 caser per 1 lakh population • At least 20 cases per 1 lakh population > 70 yrs • Median age at presentation • United Kingdom – 65 yrs • India – 45 yrs • Progression to AML – 30 – 35 %
- 5. Etiology • Hereditary • Down syndrome • Monosomy 7 • Neurofibromatosis • Congenital neutropenia • Mutagen detoxification • Family history • Fanconi Anemia • Dyskeratosis congenita • Swachman – Diamond syndrome • Diamond blackfan anemia • Acquired • Senescence • Radiation • Mutagen/genotoxic • Chemotherapy • Benzene exposure • Cigarette smoking • Agricultural solvents/chemicals • Acquired Aplastic Anemia • PNH
- 6. Clinical Features • Anemia • Most common – 85% • Lethargy • 1/3rd transfusion dependent • Leucopenia • Neutropenia – 50% • Less common • Recurrent infections • Thrombocytopenia • 25 – 30% • Bleeding manifestations • Organomegaly • 15 – 25% • Auto immune abnormalities • Cutaneous vasculitis • Monoarticular arthritis • Percarditis • Iritis • Myositis • Pleural effusion
- 7. Evaluation • History • Prior exposure to CT/RT • Recurrent infections • Bleeding/Bruising • Examination • Pallor/ bruising • organomegaly • Blood counts • Hb, TLC, Platelet count • RC • Blood film • BMA + BM Bx • IHC • CD 34 • CD 41 • CD 61 • Immunophenotyping of BM • Bone marrow cytogenetics • Biochemical tests • S. Iron • S. LDH • TSH • Red cell folate & S. B12 • Other tests • Viral markers • Autoimmune disease work up • FLAER for PNH
- 8. Exclusion of reactive causes of Dysplasia • Megaloblastic Anemia • HIV Infection • Recent cytotoxic therapy • Alcoholism • Severe intercurrent illness
- 9. Microscopy – Points to remember • >2 hrs from collection – specimen unsatisfactory • Staining is significant • Don’t diagnose MDS without detailed history • No of cells to count • PS – 200 cells • BM – 500 cells • If Cytopenic - Count from buffy coat • PS blasts can be more than BM blasts in 13% of MDS • Persistent cytopenia without dysplasia – Idiopathic cytopenia of undetermined significane • MDS associated clonal gene mutations without dysplasia – clonal hematopoiesis of indeterminate potential • If in doubt – observe patient for 6 months before diagnosis
- 10. PS Characteristics of dysplasia - RBC • Ovalocytosis • Macrocytosis • Elliptocytosis • Stomatocytes • Tear drop cells • Nucleated red cells • Basophilic stippling • Howell-Jolly bodies
- 11. PS Characteristics of Dysplasia - WBC • Hypolobation • Hyposegmentation – Pince-nez type • Hypogranulation • Ring shaped nuclei • Pseudo-Pelger Huet anomaly - marked clumping of nuclear chromatin – nuclear hypolobation • Auer rod • Irregular contour of nuclei • Blasts
- 12. PS Characteristics of dysplasia - Platelets • Giant platelets • Hypogranular platelets • Agranular platelets
- 13. Bone Marrow Aspiration – Hypercellular
- 14. BMA Characteristics of dysplasia - RBC • Megaloblastic erythropoiesis • Nuclear budding of erythroblasts • Multinucleation • Karyorrhexis • Ring sideroblasts • > 5 iron granules • Encircling > 1/3rd nucleus • Cytoplasmic vacuolation – PAS +ve • Increased Iron stores
- 15. BMA Characteristics of dysplasia - WBC • Defective granulation • Presence of Auer Rods in myeloid cells • Maturation arrest at myelocyte stage • Increase in Monocytoid cells • ALIP • Very small/large granules • Pseudo chediak higashi granules – Abnormal large granular clumping • Irregular nuclear hypersegmentation • CD 34 +ve blasts
- 16. BMA Characteristics of dysplasia - Platelets • >10% Micromegakaryocytes* • < 15 µm - Size of promyelocyte • Non/bi lobated nucleus • Eosinophilic cytoplasm • Hypogranulation of megakaryocytes • Mutliple small nuclei of megakaryocytes – Pawn ball • Nuclear Hypolobation • CD 61 & CD 41 +ve
- 17. Bone Marrow Trephine Biopsy • Cellularity of Marrow • ALIP • Reticulin Fibrosis – 20% • Megakaryocyte Dysplasia • CD 61 • CD 41 • Lymphoid aggregates • Hypoplastic MDS • Neovascularisation – transformation to AML ALIP Blasts in cell clusters located away from bone trabeculae & Vascular structures CD 34 +
- 18. IHC Immature, Blast cells CD 34 TdT CD 117 Erythroblasts Glycophorin A Megakaryoblasts CD 61 CD 41 Apoptotis Markers TNF – Alpha Bax
- 19. Immunophenotype • Flow cytometry in CD 34+ve cells • Aberrant maturation patterns in granulopoiesis can predict morphological dysplasia • Myeloblasts, monocytoid cells & maturing myeloid cells – typical expression related to lineage & stage of maturation • In MDS • Increased/ Decreased expression of normal antigens • Asynchronous maturational expression • Aberrant antigen expression • Atleast 3 aberrancies +
- 21. Genetic profile • Isolated 5q deletion alone & 5q deletion + one additional abnormality • Hypo/non – lobated megakaryocytes • Macrocytic anemia • Favourable clinical course • Loss of 17 p • pseudo pelget huer anomaly • TP 53 mutation • Therapy related • Unfavourable clinical course Conventional Karyotyping Multicolour FISH Gene sequencing SNP Array
- 22. Genetic profile • Normal Karyotype • 50% MDS • Abnormal Karyotype • 90% - t-MDS • 40 – 50% - primary MDS
- 24. Pathogenesis • Aberrations in apoptotic mechanisms – Increased Apoptosis • Increased Proliferation • Ineffective Hematopoiesis • Autocrine production of Angiogenic molecules – Expansion of leukemic clone
- 25. Classification – WHO 2016 Name Dysplasia Cytopenia RS in BM PS blasts BM Blasts MDS - SLD 1 1 – 2 < 15%SF3B1 <1% <5% MDS - MLD 2 – 3 1 – 3 MDS – RS – SLD 1 1 – 2 >15%SF3B1 MDS – RS - MLD 2 – 3 1 – 3 MDS with isolated del (5q) 1 – 3 1 – 2 None or any MDS – EB1 1 – 3 1 – 3 <5% <10% MDS – EB2 1 – 3 1 – 3 <20% <20%
- 26. MDS - U Name Dysplasia Cytopenia RS PS Blasts BM Blasts With 1% Blood blasts 1 – 3 1 – 3 None or any 1%ON 2 OCC <5% With SLD & Pancytopenia 1 3 <1% <5% Based on defining cytogenetic abnormality 0 1 – 3 <15%MDS-RS-SLD
- 27. FAB Classification Subtype Abbreviation PS –Blasts BM Refractory Anemia RA < 1% Blasts < 5% + RS < 15% RA + Ringed Sideroblasts RARS < 1% Blasts < 5% + RS > 15% RA + Excess blasts RAEB < 5% Blasts 5 – 20% RA + Excess blasts in transformation RAEB – t >5% Blasts 20 – 30 % (Auer rods) Chronic myelomonocytic leukemia CMML <5% + Monocytes > 1000/cu.mm Any of the above Acute Myeloid Leukemia AML Variable Blasts > 30 %
- 28. MDS – Single lineage dysplasia • Incidence : 7 – 20% MDS • Definition • Unexplained cytopenia/ bicytopenia • > 10% dysplastic cells in one myeloid lineage • 2008 edition – Refractory cytopenia with unilineage dysplasia • Refractory anemia • Refractory neutropenia • Refractory thrombocytopenia • Ringed sideroblasts • < 15% • <5% in cases with SF3B1 mutation No correlation between cytopenia & dysplasia
- 29. MDS – Multi lineage dysplasia • 1 or >1 cytopenia • 2 or >2 dysplasia in the myeloid lineages (> 10%) • 200 erythroid, 200 Neutrophil precursors & 30 megakaryocytes (30 – 40%) to be examined in the BMA or BM Bx • Blasts • Peripheral smear - < 1% • Bone marrow - <5% • Auer rods – Absent • Monocyte count - < 1000 cells/cu.mm • Marrow fibrosis – 16% Incidence 30% of all cases 48% of cases without excess blasts 65% along with MDS – RS – MLD
- 30. MDS with Ringed sideroblasts • Incidence: 3 – 11 % • >15% ringed sideroblasts in the bone marrow • >5% in case of SF3B1 mutation • Other subtypes to be excluded • MDS – RS – SLD – Usually anemia + Erythroid Dysplasia (9982/3) • MDS – RS – MLD – any number of cytopenias / dysplasias (9993/3)
- 31. MDS with Excess Blasts • < 20% in both Bone Marrow (5 – 19%) & Blood ( 2 – 19%) • Incidence – 40% • Hypercellular marrow • 30 – 50% have clonal genetic abnormalities EB 1 EB 2 PS Blasts 2 – 4 % 5 – 19% BM Blasts 5 – 9 % 10 – 19 % Auer rods Absent Present Progression to AML 25% 33% Median Survival 16 months 9 months
- 32. Variants MDS EB & Erythroid Predominance • Maturing Erythroblasts > 50% of marrow cells • Myeloblasts > 20% of non erythroid nucleated cells MDS EB & Fibrosis • 15% show significant degree of fibrosis • Therapy related MDS • Presence of excess blasts confirmed by IHC – CD 34 • Increased dysplastic megakaryocytes • FCM – CD 34 & C-KIT +ve
- 33. MDS with isolated del 5q • Anemia + other cytopenia + Thrombocytosis • Thrombocytosis in 1/3rd – ½ of cases • Loss of tumour suppressor genes in the minimally deleted region (q31 – q33) • Erythroid hypoplasia • Dysplastic Megakaryocytic hyperplasia • Del 5q demonstrated by FISH analysis • Cases with addl monosomy 7/ Del 7q is included in this category • Subsets show JAK2 V617F mutation & SF3B1 mutation • Median survival – 66 – 145 months • AML transformation < 10 %
- 34. MDS - Unclassifiable • Diagnosed by Exclusion • Incidence : 6.3% of cases with <5% blasts • 1% blasts in the blood on 2 separate occasions • Persistent cytopenia • < 2% Blasts in blood • < 5% blast in BM • < 10% Dysplasia • Prognosis in cases with 1% blasts • Median survival – 30 months • AML Progression – 14%
- 35. Childhood MDS • < 5% of all hematopoietic neoplasms in less than 14 yrs • Subtypes • Refractory Cytopenia of childhood (Blasts <5% in BM & <2% in PS) • Conventional MDS • MDS – EB • MDS – RS • T - MDS • GATA2 germline mutation is present in 7% primary MDS • Criteria for diagnosis - MDS (atleast 2) • Sustained unexplained cytopenia • Bilineage morphologic dysplasia • Acquired clonal cytogenetic morphology • Increased blasts (>5%)
- 36. Therapy related MDS • Late complication of Chemotherapy/ radiotherapy administered for prior neoplastic or non neoplastic disorder • Incidence: 10 – 20% of all cases of AML, MDS & MDS/MPN • Prior history • 70% for solid tumours (Breast Cancer) • 30% Hematopoietic neoplasms (Non Hodgkin’s lymphoma) • Poor Prognosis
- 37. Risk factors for t-MDS
- 40. Very low Low Intermediate High Very High Patients % 19% 38% 20% 13% 10% Survival 8.8 5.3 3.0 1.6 0.8 AML transformation Not reported 10.8 3.2 1.4 0.7
- 41. Differential Diagnosis • Vitamin B12 and Folic Acid Deficiency • Essential element deficiency (Copper) • Exposure to heavy metals (lead, arsenic & zinc) • Drugs • Isoniazole • Cotrimoxazole • Tacrolimus • Mycophenolate mofetil • Hereditary AD Pelger-huet anomaly • Congenital Dyserythropoietic anemia • Parvovirus B19 infection • Chemotherapy • GCSF therapy • Hypothyroidism • PNH • Autoimmune disorders • Lymphoma Spillover
- 42. References • Atlas & textbook of hematology, Tejinder Singh • WHO Classification of Tumours of Hematopoietic & Lymphoid tissues • American Association of Pathology Atlas of Bone Marrow Pathology • Wintrobe’s Clinical Hematology • Williams Hematology Malignant Lymphoid Diseases