MDS 의형태학적진단 고려의대 윤수영
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1 MDS 의형태학적진단 고려의대 윤수영
2 WHO classification의기준 review (2008) Blast count Type and degree of dysplasia Ring sideroblasts Histopathology Hypoplastic MDS, MDS with myelofibrosis Childhood MDS
3 History FAB, 1982 RA/RARS/RAEB/RAEB-t/CMML IPSS, 1997 Blast/karyotype/cytopenia WHO, 1999 RA/RARS/RCMD/RCMD-RS/RAEB1/RAEB2/5q-/MDS-U Working conference on MDS, 2006 (NCCN, IWG, ELN) Minimal Dx criteria, ICUS WPSS, 2007 WHO category/karyotype/rbc transfusion requirement WHO, 2008 RCUD/RARS/RCMD/RAEB1/RAEB2/MDS-U/5q-
4 WHO classification (2008) Disease Blood findings Bone marrow findings Refratory cytopenias with unilineage dysplasia (RCUD) : RA, RN, RT Refractory anemia with ring sideroblasts (RARS) Refractory cytopenia with multilineage dysplasia (RCMD) Refractory anemia with excess blasts - 1 (RAEB-1) Refractory anemia with excess blasts - 2 (RAEB-2) Myelodysplastic syndrome unclassified (MDS-U) MDS associated with isolated del(5q) Unicytopenia or bicytopenia No or rare blasts (<1%) Anemia No blasts Cytopenia(s) No or rare blasts (<1%) No Auer rods <1X10 9 /L monocytes Cytopenia(s) <5% blasts No Auer rods <1X10 9 /L monocytes Cytopenia(s) 5-19% blasts Auer rods ± <1X10 9 /L monocytes Cytopenias 1% blasts Anemia Usually normal or increased plastelet count No or rare blasts (<1%) Unilineage dysplasia: 10% of the cells in one myeloid lineage <5% blasts <15% of erythroid precursors are ring sideroblasts 15% of erythroid precursors are ring sideroblasts Erythroid dysplasia only <5% blasts Dysplasia in 10% of the cells in two myeloid lineages (neutrophil and/or erythroid precursors and/or megakaryocytes) <5% blasts in marrow No Auer rods ±15% ring sideroblasts Unilineage or multilineage dysplasia 5-9% blasts No Auer rods Unilineage or multilineage dysplasia 10-19% blasts Auer rods ± Unequivocal dysplasia in less than 10% of cells in one or more myeloid cell lines when accompanied by a cytogenetic abnormality considered as presumptive evidence for a diagnosis of MDS <5% blasts Normal to increased megakaryocytes with hypolobated nuclei <5% blasts Isolated del (5q) cytogenetic abnormality No Auer rods
5 WHO classification (2008) Disease Blood findings Bone marrow findings Refratory cytopenias with unilineage dysplasia (RCUD) : RA, RN, RT Refractory anemia with ring sideroblasts (RARS) Refractory cytopenia with multilineage dysplasia (RCMD) Refractory anemia with excess blasts - 1 (RAEB-1) Refractory anemia with excess blasts - 2 (RAEB-2) Myelodysplastic syndrome unclassified (MDS-U) MDS associated with isolated del(5q) Unicytopenia or bicytopenia No or rare blasts (<1%) Anemia No blasts Cytopenia(s) No or rare blasts (<1%) No Auer rods <1X10 9 /L monocytes Cytopenia(s) <5% blasts No Auer rods <1X10 9 /L monocytes Cytopenia(s) 5-19% blasts Auer rods ± <1X10 9 /L monocytes Cytopenias 1% blasts Anemia Usually normal or increased plastelet count No or rare blasts (<1%) Pancytopenia Unilineage dysplasia: 10% of the cells in one myeloid lineage <5% blasts <15% of erythroid precursors are ring sideroblasts 15% of erythroid precursors are ring sideroblasts Erythroid dysplasia only <5% blasts Dysplasia in 10% of the cells in two myeloid lineages (neutrophil and/or erythroid precursors and/or megakaryocytes) <5% blasts in marrow No Auer rods ±15% ring sideroblasts Unilineage or multilineage dysplasia 5-9% blasts No Auer rods Unilineage or multilineage dysplasia 10-19% blasts Auer rods ± Unequivocal dysplasia in less than 10% of cells in one or more myeloid cell lines when accompanied by a cytogenetic abnormality considered as presumptive evidence for a diagnosis of MDS <5% blasts Normal to increased megakaryocytes with hypolobated nuclei <5% blasts Isolated del (5q) cytogenetic abnormality No Auer rods
6 WHO classification (2008) Disease Blood findings Bone marrow findings Refratory cytopenias with unilineage dysplasia (RCUD) : RA, RN, RT Refractory anemia with ring sideroblasts (RARS) Refractory cytopenia with multilineage dysplasia (RCMD) Refractory anemia with excess blasts - 1 (RAEB-1) Refractory anemia with excess blasts - 2 (RAEB-2) Myelodysplastic syndrome unclassified (MDS-U) MDS associated with isolated del(5q) Unicytopenia or bicytopenia No or rare blasts (<1%) Anemia No blasts Cytopenia(s) No or rare blasts (<1%) No Auer rods <1X10 9 /L monocytes Cytopenia(s) <5% blasts No Auer rods <1X10 9 /L monocytes Cytopenia(s) 5-19% blasts Auer rods ± <1X10 9 /L monocytes Cytopenias 1% blasts Anemia Usually normal or increased plastelet count No or rare blasts (<1%) Unilineage dysplasia: 10% of the cells in one myeloid lineage <5% blasts <15% of erythroid precursors are ring sideroblasts 15% of erythroid precursors are ring sideroblasts Erythroid dysplasia only <5% blasts 1 5 Dysplasia in 10% of the cells in two myeloid lineages (neutrophil and/or erythroid precursors and/or megakaryocytes) <5% blasts in marrow No Auer rods ±15% ring sideroblasts Unilineage or multilineage dysplasia 5-9% blasts No Auer rods Unilineage or multilineage dysplasia 10-19% blasts Auer rods ± Unequivocal dysplasia in less than 10% of cells in one or more myeloid cell lines when accompanied by a cytogenetic abnormality considered as presumptive evidence for a diagnosis of MDS <5% blasts Normal to increased megakaryocytes with hypolobated nuclei <5% blasts Isolated del (5q) cytogenetic abnormality No Auer rods
7 WHO classification (2008) Disease Blood findings Bone marrow findings Refratory cytopenias with unilineage dysplasia (RCUD) : RA, RN, RT Refractory anemia with ring sideroblasts (RARS) Refractory cytopenia with multilineage dysplasia (RCMD) Refractory anemia with excess blasts - 1 (RAEB-1) Refractory anemia with excess blasts - 2 (RAEB-2) Myelodysplastic syndrome unclassified (MDS-U) MDS associated with isolated del(5q) Unicytopenia or bicytopenia No or rare blasts (<1%) Anemia No blasts Cytopenia(s) No or rare blasts (<1%) No Auer rods <1X10 9 /L monocytes Cytopenia(s) <5% blasts No Auer rods <1X10 9 /L monocytes Cytopenia(s) 5-19% blasts Auer rods ± <1X10 9 /L monocytes Cytopenias 1% blasts Anemia Usually normal or increased plastelet count No or rare blasts (<1%) Unilineage dysplasia: 10% of the cells in one myeloid lineage <5% blasts <15% of erythroid precursors are ring sideroblasts 15% of erythroid precursors are ring sideroblasts Erythroid dysplasia only <5% blasts Dysplasia in 10% of the cells in two myeloid lineages (neutrophil and/or erythroid precursors and/or megakaryocytes) <5% blasts in marrow No Auer rods ±15% ring sideroblasts Unilineage or multilineage dysplasia 5-9% blasts No Auer rods Unilineage or multilineage dysplasia 10-19% blasts Auer rods ± Unequivocal dysplasia in less than 10% of cells in one or more myeloid cell lines when accompanied by a cytogenetic abnormality considered as presumptive evidence for a diagnosis of MDS <5% blasts Normal to increased megakaryocytes with hypolobated nuclei <5% blasts Isolated del (5q) cytogenetic abnormality No Auer rods
8 Morphological classification of MDS Percent of blasts in the BM/PB Type and degree of dysplasia Presence of ring sideroblasts
9 Characteristic of the dysplasia Distinguishing between various types of MDS Predicting biology Cytogenetic abnormalities association Isolated del(5q) - Hypolobated and nonlobated megakaryocyte nuclei Del (17p) - hypolobated neutrophil nuclei
10 Specimen preparation Critical importance of recognition of dysplasia in MDS Dx High quality slide Freshly obtained >2 hr exposed to anticoagulantsunsatisfactory
11 No MDS dx should be made without clinical or drug history No MDS should be reclassified during growth factor tx Cytopenia without dysplasia should not be interpreted as an MDS If genetic abnormalities presumptive MDS Persistent cytopenia without dysplasia without specific cytogenetic abnormality -> ICUS (idiopathic cytopenia with undetermined significance)
12 WHO classification의기준 review (2008) Blast count Type and degree of dysplasia Ring sideroblasts Histopathology Hypoplastic MDS, MDS with myelofibrosis Childhood MDS
13 Blast percentage BM 500 d/c of all nucleated cells In smear or trephine imprint M:E ratio 1:1이상인경우 NEC 500 d/c % of blasts - based on the NEC PB 200 leukocyte d/c
14 FAB blast Type I - agranular Type II scanty granules Type III more than 20 fine azurophilic granules but otherwise with the characteristics of a blast
15 IWGM-MDS International working group on morphology of MDS Mufti, G. J. et al. Haematologica 2008;93: Figure 1. Blasts, promyelocytes, abnormal promyelocytes Copyright 2008 Ferrata Storti Foundation
16 WHO classification의기준 review (2008) Blast count Type and degree of dysplasia Ring sideroblasts Histopathology Hypoplastic MDS, MDS with myelofibrosis Childhood MDS
17 Type and degree of dysplasia
18 dyserythropoiesis Nuclear Nuclear budding Internuclear bridging Karyorrhexis Multinuclearity Nuclear hyperlobation Megaloblastic changes* Cytoplasmic Ring sideroblasts Valcuolization Periodic acid-shiff positivity
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22 Dysgranulopoiesis Small or unusually large size Nuclear hypolobation (psuedo Pelger-Huet; pelgeroid) Irregular hypersegmentation Decreased granules; agranularity Pseudo Chediak-Higashi granules Auer rods
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26 Dysmegakaryocytopoiesis Micromegakaryocytes Nuclear hypolobation Multinucleation
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30 Degree of dysplasia WHO, 2008 Unilineage or multilineage Significant dysplasia > 10% in erythroid precursors and granulocytes >10% dysplastic megakaryocytes based on evaluation of at least 30 MK
31 Degree of dysplasia Matsuda A, 1998 In RA 3% Pseudo-Pelger-Heut anomalie 10% micromegakaryocytes Tassin F, 2000 Megaloblastosis Neutrophil agranularity Hypogranularity Pelger-Heut anomaly
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33 Degree of dysplasia Matsuda M, 2007 FAB-RA 중 RCMD 로분류하는기준제안 DysG >10%, dysmgk >40%, or mmgk+ Verburgh E, 2007 Nuclear dysplasia PLUS cytoplasmic dysplasia in 10% of erythoid Nuclear dysplasia in 10% of myeloid OR cytoplasmic dysplasia 10% of myeloid Micro MK, monolobar MK, dispersed N in 10% of MK
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35 WHO classification의기준 review (2008) Blast count Type and degree of dysplasia Ring sideroblasts Histopathology Hypoplastic MDS, MDS with myelofibrosis Childhood MDS
36 Ring sideroblasts Type 1 sidroblasts: fewer than 5 siderotic granules in the cytoplasm Type 2: 5 or more siderotic gs, not in a perinuclear distribution Type 3: 5 or more gs in a perinuclear position, surrounding the nucleus or encompassing at least one third of the nuclear circumference All stages of erythoid precursors, >100
37 Copyright 2008 Ferrata Storti Foundation Figure 3. Perinuclear siderotic granules (cartoon of potential examples) Mufti, G. J. et al. Haematologica 2008;93:
38 Copyright 2008 Ferrata Storti Foundation Figure 4. Prussian blue reaction of erythroid precursors. a. Upper panel (left to right): no siderotic granules; type 1 sideroblast (1 granule); type 3 sideroblast (numerous granules). b. Lower panel (left to right): type 1 sideroblast (upper cell), type 2 sideroblast (lower cell); type 3 sideroblasts (lower right); hematoxylin counter stain Mufti, G. J. et al. Haematologica 2008;93:
39 WHO classification의기준 review (2008) Blast count Type and degree of dysplasia Ring sideroblasts Histopathology Hypoplastic MDS, MDS with myelofibrosis Childhood MDS
40 Histopathology Cellularity Stromal change : myelofibrosis ALIP - Presence of aggregates(3-5) or clusters(>5) of blasts localized in the central portion of the BM away from the v and endosteal surfaces of the bone trabeculae CD 34 IHC Occult BM lesion
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42 Hypoplastic MDS RCUD>RCMD>RAEB BM biopsy Abnormal LIP IHC for CD34
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44 MDS with myelofibrosis Fibrosis degree 에대한 consensus 아직없다 Working definition : diffuse coarse reticulin fibrosis with or without collagenization, associated with dysplasia in at least two cell lineages RAEB-F presence of excess blasts usually be demonstrated using IHC for CD34 Morphologically overlap acute panmyelosis with myelofibrosis
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46 WHO classification의기준 review (2008) Blast count Type and degree of dysplasia Ring sideroblasts Histopathology Hypoplastic MDS, MDS with myelofibrosis Childhood MDS
47 Childhood MDS RA, RARS, 5q- syndrome rare RAEB, RAEB-t more stable Refractory cytopenia of childhood (RCC) Provisional entity Persistent cytopenia <5% blast in the BM <2% blast in the PB In 75% of RCC - hypocellularity
48 Minimal diagnostic criteria for refractory cytopenia of childhood Erythropoiesis Granulopoiesis Megakaryopoiesis Bone marrow aspirate Bone marrow biopsy Peripheral blood Dysplastic changes And/or megaloblastoid changes in at least 10% of erythroid precursors A few clusters of at least 20 erythroid precursors. Stop in maturation with increased numbers of proerythroblasts. Increased numbers of mitoses Dysplastic changes in at least 10% of granulocytic presursors and neutrophils; <5% blasts No minimal diagnostic criteria Unequivocal micromegakaryocyt es, other dysplastic changes in variable numbers Unequivocal micromegkaryocyte s; immunohistochemi stry is obligatory(cd61, CD41) other dysplastic changes in variable numbers Dysplastic changes in at least 10% of neutrophils; <2% blasts
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