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Myelodysplastic syndrome and acute myeloid leukaemia

Leukaemia classification. FAB MIC 1987EGIL 1996REALProposed by ILSG in 1994Lymphoma classification, but principles extended to other haemic neoplasmsEncompasses all available informationConsensus approach. WHO Classification. Collaborative project of:European Association for Haematopatho

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Myelodysplastic syndrome and acute myeloid leukaemia

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    1. Myelodysplastic syndrome and acute myeloid leukaemia Dr. Edmond S. K. Ma Division of Haematology Department of Pathology The University of Hong Kong

    2. Leukaemia classification FAB MIC 1987 EGIL 1996 REAL Proposed by ILSG in 1994 Lymphoma classification, but principles extended to other haemic neoplasms Encompasses all available information Consensus approach

    3. WHO Classification Collaborative project of: European Association for Haematopathology Society for Haematopathology Started in 1995 Steering Committee Working Group Meeting in Lyon, France, November 8 – 11, 2000 Clinical Advisory Committee

    4. Myelodysplastic syndrome A group of clonal haemopoietic stem cell disorder characterized by dysplasia and ineffective haemopoiesis in one or more major myeloid cell line < 20% blasts in blood and bone marrow

    5. Myelodysplastic syndrome A disease of the elderly Incidence : 3 – 20 /100,000 Increasing number of therapy related MDS Clinical features: related to cytopenia Etiology: prior chemoradiotherapy, benzene exposure, cigarette smoking, inherited syndromal disorders (e.g. Fanconi’s anaemia)

    6. Dyserythropoiesis Nuclear budding Inter-nuclear bridging Karyorrhexis Multinuclearity Megaloblastoid maturation Ringed sideroblast Vacuolation PAS +ve

    7. Dyserythropoiesis

    8. Dyserythropoiesis

    9. Dysgranulopoiesis Small size Nuclear hypolobulation (pseudo-Pelger Heut) Hypersegmentation Hypogranularity Pseudo-Chediak Higashi granules

    10. Dysgranulopoiesis

    11. Dysgranulopoiesis

    12. Dysmegakaryocytopoiesis Hypolobulated micro-megakaryocyte Non-lobulated nuclei in megakaryocyte of all sizes Multiple, widely separated nuclei

    13. Megakaryocyte dysplasia

    14. Megakaryocyte dysplasia

    15. Abnormal localization of immature precursors Presence of 3 or more small clusters of myeloblasts and promyelocytes (5 – 8 cells) in marrow trephine biopsy in the central portion of the marrow away from the vascular structure and the endosteal surface of the bone trabeculae

    16. Abnormal localization of immature precursors

    17. Genetics 5q- syndrome del (17p), small hypolobulated or vacuolated neutrophils, p53 mutations, poor prognosis -5/5q- -7/7q- del(20q) 3q21q26 abnormality

    18. Cytogenetics and prognosis Good risk Normal, isoloted 5q-, isolated 20q-, -Y Poor risk Complex changes (> 3 abnormalities) Chromosome 7 abnormalities Intermediate risk All other changes

    19. International Prognostic Scoring System Score 0 0.5 1 1.5 % blasts <5 5-10 - 11-20 Karyotype Good Intermediate Poor Cytopenia 0-1 2-3 Cytopenia: Hb < 10 g/dL; neutrophils < 1.5 X 109/L; plt < 100 X 109/L Risk groups Low = 0; Intermediate-1 = 0.5-1; Intermediate-2 = 1.5-2; High = ?2.5

    20. Refractory anaemia PB anaemia, no or rare (<1%) blasts MB Unilineage dysplasia, restricted to erythroid lineage, < 5% blasts, < 15% ringed sideroblasts

    21. Refractory anaemia Exclusion of known secondary causes of dyserythropoiesis If no cytogenetic abnormality present, reassess after 6 months Protracted clinical course, median survival is 66 months, leukaemic transformation 6%

    22. Giant pronormoblast is parvovirus infection

    23. Refractory anaemia with ringed sideroblasts PB Anaemia No blast MB ? 15% ringed sideroblasts Erythroid dysplasia only <5% blasts

    24. Ringed sideroblast Erythroid precursor One third or more of the nucleus Encircled by 10 or more siderotic granules

    25. Refractory anaemia with ringed sideroblasts Indolent clinical course Median survival = 6 years Leukaemic transformation 1 – 2 %

    26. Refractory cytopenia with multilineage dysplasia PB Bicytopenia or pancytopenia No or rare blasts No Auer rod < 1 X 109/L monocytes MB Dysplasia in ? 10% of cells in two or more myeloid cell lines < 5% blasts No Auer rod < 15% ringed sideroblasts

    27. Refractory cytopenia with multilineage dysplasia

    28. Refractory cytopenia with multilineage dysplasia

    29. Refractory cytopenia with multilineage dysplasia

    30. Refractory cytopenia with multilineage dysplasia and ringed sideroblasts PB Bicytopenia or pancytopenia No or rare blasts No Auer rod < 1 X 109/L monocytes MB Dysplasia in ? 10% of cells in two or more myeloid cell lines < 5% blasts No Auer rod ? 15% ringed sideroblasts

    31. Refractory cytopenia with multilineage dysplasia Cytogenetic abnormality seen in 50% +8 Monosomy 7 del(7q) Monosomy 5 del (5q) del (20q) Complex karyotype

    32. Refractory cytopenia with multilineage dysplasia Leukaemic transformation 11% Overall median survival 33 months RCMD and RCMD-RS are similar in clinical course Patients with complex karyotype have similar clinical course to RAEB

    33. Refractory anaemia with excess blasts-1 PB Cytopenia <5% blasts No Auer rod <1% monocytes MB Unilineage or multilineage dysplasia 5-9% blasts No Auer rod

    34. Refractory anaemia with excess blasts-2 PB Cytopenia 5-19 % blasts Auer rod ± <1% monocytes MB Unilineage or multilineage dysplasia 10-19% blasts Auer rod ±

    35. Refractory anaemia with excess blasts-2

    36. Refractory anaemia with excess blasts Blast cells show myeloid phenotype Leukaemic transformation RAEB-1 25% RAEB-2 33% Median survival RAEB-1 18 months RAEB-2 10 months

    37. Myelodysplastic syndrome, unclassifiable PB Cytopenias No or rare blasts No Auer rods MB Unilineage dysplasia, one myeloid cell line (non-erythroid) <5% blasts No Auer rod

    38. 5q- syndrome PB Anaemia Usually normal or increased platelet count <5% blasts MB Normal or increased megakaryocytes with hypolobulated nuclei <5% blasts Isolated 5q- abnormality No Auer rod

    39. 5q- syndrome

    40. Acute myeloid leukaemia Acute myeloid leukaemia with recurrent genetic abnormalities Acute myeloid leukaemia with multilineage dysplasia Acute myeloid leukaemia and myelodysplastic syndrome, therapy-related Acute myeloid leukaemia not otherwise categorized

    41. Acute myeloid leukaemia

    42. Acute myeloid leukaemia

    43. Acute myeloid leukaemia The blast % is lowered from 30% (FAB) to 20% (WHO) Median age of onset = 60 yrs Incidence 4 –10 / 100,000 Etiology

    44. Myeloblasts versus lymphoblasts

    45. Acute myeloid leukaemia

    46. Acute lymphoblastic leukaemia

    47. Acute myeloid leukaemia: cytochemistry Myeloperoxidase Sudan Black B Non-specific esterase a-naphthyl butyrate a-naphthyl acetate

    48. Cytochemistry: MPO

    49. Cytochemistry: NSE

    50. Cytochemistry

    51. Acute myeloid leukaemia: role of immunophenotyping Distinction of minimally differentiated AML from acute lymphoblastic leukaemia Recognition of AML-M7 Recognition of specific AML sub-categories (e.g CD56+ve AML) Diagnosis of biphenotypic leukaemia However, immunophenotyping is not mandatory in typical cases of AML, unlike in ALL where a phenotypic diagnosis is needed in every case

    52. Acute myeloid leukaemia: role of immunophenotyping

    53. Panel of monoclonal antibodies in classification of acute leukaemia Haemopoietic precursors: CD34, HLA-DR, Tdt, CD45 B-lineage: CD19, CD20, CD22, CD79a T-lineage: CD2, CD3, CD5, CD7 Myeloid: CD13, CD33, CD117, anti-MPO Megakaryocytic: CD41, CD61

    54. Acute myeloid leukaemia with recurrent genetic abnormalities Acute myeloid leukaemia with t(8;21)(q22;q22); AML1/ETO Acute myeloid leukaemia with abnormal bone marrow eosinophils and inv(16)(p13q22) or t(16;16)(p13;q22); CBFb/MYH11 Acute promyelocytic leukaemia (AML with t(15;17)(q22;q12); PML/RARa and variants Acute myeloid leukaemia with 11q23 (MLL) abnormalities

    55. Acute myeloid leukaemia with t(8;21)(q22;q22); AML1/ETO t(8;21) is the commonest translocation in AML Associated with AML-M2 morphology Tumour masses (granulocytic sarcoma)

    56. Acute myeloid leukaemia with t(8;21)(q22;q22); AML1/ETO Morphology Large blasts, heavily granulated Frequent Auer rods Variable dysplasia in granulocytic series Rare cases with blast count < 20% Immunophenotype CD13+ CD33+ anti-MPO+ CD19+ CD34+ CD56±

    57. Acute myeloid leukaemia with t(8;21)(q22;q22); AML1/ETO

    58. Acute myeloid leukaemia with t(8;21)(q22;q22); AML1/ETO

    59. Acute myeloid leukaemia with t(8;21)(q22;q22); AML1/ETO

    60. Acute myeloid leukaemia with t(8;21)(q22;q22); AML1/ETO

    61. Detection of fusion genes by FISH

    62. Detection of fusion genes by FISH

    63. Acute myeloid leukaemia with t(8;21)(q22;q22); AML1/ETO Prognosis Good response to chemotherapy and high complete response rate Long term disease free survival Adverse factors additional chromosomal changes e.g. 9q- CD56 +ve

    64. Acute myeloid leukaemia with inv(16)(p13q22) or t(16;16)(p13;q22); CBFb/MYH11 Granuolocytic and monocytic features AML-M4 (acute myelomonocytic leukaemia) morphology Abnormal eosinophils with coarse basophilic granules

    65. Acute myeloid leukaemia with inv(16)(p13q22) or t(16;16)(p13;q22); CBFb/MYH11

    66. Acute myeloid leukaemia with inv(16)(p13q22) or t(16;16)(p13;q22); CBFb/MYH11 Cytochemistry Abnormal eosinophils are CAE +ve Immunophenotype Granulocytic and monocytic markers Co-expression of CD2 in blast population Prognosis Favourable

    67. Acute myeloid leukaemia with inv(16)(p13q22) or t(16;16)(p13;q22); CBFb/MYH11

    68. Acute promyelocytic leukaemia AML with t(15;17)(q22;q12); PML/RARa and variants Characteristic morphology Associated with disseminated intravascular coagulation

    69. Acute promyelocytic leukaemia

    70. Acute promyelocytic leukaemia

    71. Acute promyelocytic leukaemia Immunophenotype CD33+ CD13+ HLA-DR and CD34 negative Co-expression of CD2 and CD9 Genetics t(15;17)(q22;q12) Variants: t(11;17)(q23;q12) PLZF/RARa; t(5;17)(q32;q12) NPM/RARa; t(11;17)(q13;q12) NuMA/RARa

    72. Acute promyelocytic leukaemia

    73. Acute promyelocytic leukaemia Treatment All-trans retinoic acid (ATRA) Arsenic for relapse cases RARa variants: resistant to ATRA Prognosis Favourable when treated optimally with ATRA followed by anthracyclines

    74. Acute myeloid leukaemia with 11q23 abnormalities Infant leukaemia Therapy related AML after exposure to DNA topoisomerase II inhibitors Acute monocytic and myelomonocytic leukaemia Associated with MLL rearrangement

    75. Acute myeloid leukaemia with multilineage dysplasia Following MDS or MDS/MPD Without antecedent MDS Dysplasia in ? 50% of cells in at least 2 lines Poor prognosis

    76. AML and MDS, therapy related Alkylating agent related Topoisomerase type II inhibitor related

    77. Acute myeloid leukaemia not otherwise categorized Equivalent to FAB classification AML minimally differentiated AML without maturation AML with maturation Acute myelomonocytic leukaemia Acute monoblastic and monocytic leukaemia Acute erythroid leukaemia Acute megakaryoblastic leukaemia Acute basophilic leukaemia Acute panmyelosis with myelofibrosis Myeloid sarcoma

    78. AML without maturation

    79. Acute myeloid leukaemia with maturation

    80. Acute monocytic leukaemia

    81. Erythroleukaemia

    82. Acute leukaemia of ambiguous lineage Mixed myeloid and lymphoid characteristics Biclonal (two clones) Biphenotypic (two characteristics on same blast cell)

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