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Myelodysplastic syndrome (MDS)
 

Myelodysplastic syndrome (MDS)

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MYELODYSPLASTIC SYNDROME

MYELODYSPLASTIC SYNDROME

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  • Dysfunction of enzymes required for detoxification, DNA mismatch repair, or differentiation
  • Degree of elevation of blast count
  • Although the FAB group classified MDS as CMML, atypical chronic myeloid leukemia, a condition characterized by equal if not more dysplasia, was characterized as a type of chronic myeloid leukemia.
  • BM trephine biopsy section, RAEB-T, showing increased numbers of blasts forming a small cluster (centre) (an abnormal localization ofimmature precursors or ALIP).
  • PB film, MDS, showing anisocytosis, poikilocytosis and two pseudo-Pelger–Huëtneutrophils, one of which is also hypogranular.
  • Refractory cytopenia with multilineage dysplasia (RCMD). Bone marrow aspirate (Wright–Giemsa stain – 100x). Erythroid precursors with nuclear irregularity and myeloid precursors with hypogranulation and hyposegmentation
  • Internuclear bridging
  • Dysrythropoietic changes- nuclear budding, karyohexxis
  • Leishman Stain (×100 magnification). Showing dyserythropoiesis. B) May–Grunwald Giemsa Stain (×100 magnification). Arrow showing binucleate erythroblast. C) Leishman Stain (×200 magnification). Showing multinucleate erythroblast and erythroid dysplasia
  • REFRACTORY CYTOPENIA WITH MULTILINEAGE DYSPLASIA: dysplastic erythroid precursor with multi-nucleation and nuclear fragments (arrow) and dysplastic myeloid precursor with both eosinophilic and basophilic granulation (arrowhead)
  • Bone marrow biopsy shows uniformly small and monolobatedmegakaryocytes (arrows).
  • BM aspirate, RA, showing a binucleatemicromegakaryocyte which is budding platelets
  • Dysplasia in myeloid precursors can be manifested by dysplastic granulation with granules of eosinophilic type and basophilic type (arrow)
  • Abnormal nuclear lobation such as seen in this myelocyte with two nuclei (long arrow), abnormal distribution of granules causing granular polarity (arrowhead), and mixed eosinophilic and basophilic granulation (top arrow)
  • Neutrophils with ring-like nuclei (ringed-neutrophil, arrow), A megaloblastoiderythroid precursor is also seen (arrowhead)
  • BM aspirate, RARS, showing numerous ring sideroblasts, several of which can be seen to have defectively haemoglobinized cytoplasm.Perls’ stain .940
  • Megakaryocytes- Megakaryocytes- Normal/increased and cytologically abnormal. They have non-lobed or bilobed nuclei but are mainly more than 30-40um in diameter.Thus they differ from the mononuclear and binuclear micromegakaryocytes associated with other forms of MDS.
  • Myelodysplastic syndrome with isolated del (5q). A, B) Bone marrow aspirate (40x and 100x). Hypolobatedmegakaryocyte seen. C, D) Bone marrow biopsy – (10x and 40x – H&E stain). Hypercellular bone marrow with myeloid proliferation associated with hypolobated or nonlobatedmegakaryocytes
  • BM trephine biopsy section from a patient with hypoplastic MDS (RAEB) showing: (a) a disorganized marrow of low cellularity;
  • BM aspirate, CMML, showing granulocytic hyperplasia
  • BM trephine biopsy section in CMML, showing neutrophilic and monocytic hyperplasia, a hypolobulatedmegakaryocyte and a megakaryocyte in mitosis.Paraffin-embedded, H&
  • PB, aCML (Ph-negative), showing a myelocyte, a bizarre macropolycyte, an abnormal monocyte, an unidentifiable cell and a lymphocyte.
  • BM aspirate, aCML showing granulocytic and monocytic hyperplasia
  • PB, JMML, showing a monocyte, a basophil, dysplastic neutrophils, neutrophil precursors and thrombocytopenia
  • BM aspirate, JMML, showing granulocyte precursors and a dysplastic binucleatedmicromegakaryoc
  • Good indicates normal, 2Y,del(5q); poor, complex ($3 abnormalities), chromosome 7 anomalies; and intermediate, other abnormalities.‡ Neutropenia indicates neutrophil level less than 1800/mL; anemia, hemoglobin level less than 10 g/dL (,6.21 mmol/L); and thrombocytopenia,platelet level less than 100 000/mL.

Myelodysplastic syndrome (MDS) Myelodysplastic syndrome (MDS) Presentation Transcript

  • Myelodysplastic syndromes
  • Definition  MDSs are clonal disorders of the hematopoietic stem cell characterized by ineffective hematopoiesis leading to peripheral blood cytopenias, reflecting defects in erythroid, myeloid and megakaryocytic maturation and by frequent evolution to AML.
  • Different terminology of MDS  Refractory anemia 1938 Rhoades and Barker  Preleukemic anemia 1949 Hamilton-Paterson  Preleukemia 1953 Block et al.  Refractory anemia with ringed sideroblasts 1956 Bjorkman  Refractory normoblastic anemia 1959 Dacie et al  Smoldering acute leukemia 1963 Rheingold et al  Chronic erythremic myelosis 1969 Dameshek  Preleukemic syndrome 1973 Saarni and Linman  Subacute myelomonocytic leukemia 1974 Sexauer et al  Chronic myelomonocytic leukemia 1974 Miescher and Farguet  Hypoplastic acute myelogenous leukemia 1975 Beard et al  Refractory anemia with excess myeloblasts 1976 Dreyfus  Hematopoietic dysplasia 1978 Linman and Bagby  Subacute myeloid leukemia 1979 Cohen et al  Dysmyelopoietic syndrome 1980 Streuli et al  Myelodysplastic syndromes 1982 Bennet et al
  • Predisposing factors  Heritable predisposition  Constitutional genetic disorders  Down syndrome, Trisomy 8 mosaicism  Familial monosomy 7  Neurofibromatosis 1  Germ cell tumors (embryonal dysgenesis)  Congenital neutropenia (Kostmann syndrome or Shwachman-Diamond syndrome)  DNA repair deficiencies  Fanconi anemia, Ataxia telangiectasia, Bloom syndrome  Xeroderma pigmentosum
  • Predisposing factors…..  Acquired  Senescence  Mutagen exposure  Genotoxic therapy  Alkylators  Topoisomerase II interactive agents  ß-emitters (phosphorus-32)  Autologous bone marrow transplantation  Environmental or occupational exposure (e.g., benzene)  Tobacco •Aplastic anaemia •PNH •Polycythemia vera
  • Cytogenetic Abnormalities in Myelodysplastic Syndromes Prognosis Alteration Intermediate Trisomy 8 Favourable 5q-, 20q-, 12p- Unfavourable i(17q ) or t(17p), inv(3), translocation (3;3), complex (atleast 3 anomalies)
  • Theories of Pathophysiology involved in MDS Development Potential Targets/Componen ts Involved Overall Result of Abnormality Environmental/Aging Aging Increased BM apoptosis Decreased hematopoietic stem cell pool Environmental Exposures Smoking Radiation Benzene Viral Infections Chemotherapy Direct Toxicity to hematopoietic stem cells. Telomere Abnormalities Potential decreased telomerase and subsequent telomere shortening •Impaired ability to renew stem cell pool. •Genetic Instability
  • Genetic Alterations Cytogenetic Abnormalities Common Abnormalities: • 5q- , 20q- • Y- , Trisomy 8 • 7q-/Monosomy7, 17p Syndrome • 11q23, 3q • p53 mutations, Ras mutations • Complex Cytogenetics • Abnormalities: typically unbalanced genetic loss • Numerous theories of tumor suppressor Loss • Multi-Hit progression from low risk MDS to AML •Genetic Instability Epigenetic Modulation •Hypermethylation •Acetylation Alterations Methylation and acetylation abnormalities lead to silencing of genes important in cell cycle, differentiation, apoptosis, angiogenesis
  • Altered Bone Marrow Microenvironment Altered Bone Marrow Microenvironment Cytokines Upregulation of: TNF- , IFN-gamma, TGF-Beta, IL-1B, IL-6, Il-11 •Alteration of growth, differentiation, angiogenesis •Immune modulation Alterations in Apoptosis via Signalling •Increased TNF- levels •FAS: Increased Apoptosis •BCL-2 alterations •Increased apoptosis and proliferation in early stage MDS leading to hypercellular marrow with peripheral cytopenias • Decreased apoptosis and increased proliferation in later stage MDS leading to progression to AML Increased Angiogenesis •Increased VEG-F • Possible Increase: gFGF and EGF Angiogenin Increased Microvessel Density (MVD): role in pathogenesis not clearly elucidated but associated with progression to AML
  • Immune Dysregulation •T cell Expansion •B cell alterations •Increased T cells leading to potential attack on hematopoietic stem cells. •Etiology: Possible chronic antigenic stimulation Abnormal Differentiation •Cell Cycle Maturation arrest. •Altered Proliferation. •Transcription Factors alterations •Impaired maturation •Cytopenias • Progression to leukemia
  • FAB Classification of MDS FAB Subtype Peripheral smear Bone Marrow Refractory anemia (RA) Anaemia, blasts< 1%, monocytes <1x109 /L Blasts< 5%, ringed siderblasts < 15% of erythroblasts Refractory anemia with Ringed sideroblasts (RARS) Anaemia, blasts< 1%, monocytes <1x109 /L Blasts< 5%, ringed siderblasts> than 15% of erythroblasts Refractory anemia with excess blasts (RAEB) Anaemia, blasts>1%, monocytes <1x109 /L OR blasts <5% Blasts 5% BUT Blasts 20%
  • FAB Subtype Peripheral smear Bone Marrow Refractory anemia with excess blasts in transformation (RAEB- T) Anaemia, blasts 5% OR present Auer rods Blasts 20-29% OR present Auer rods CMML Monocytes>1x109 /L, granulocytes often increased, blasts <5%. Blasts upto 20%, promonocytes often increased.
  • Limitations of FAB classification  Prognostic differences between the refractory anaemia (RA) with and without evident myelodysplastic features in other lineages.  Same with RARS.  Prognostic differences between refractory anaemia with excess of blasts (RAEB) according to whether the bone marrow blast percentage is 5-10% or 10-20%.
  • Limitations of FAB classification…..  Patients categorized as RAEB-T on the basis of presence of Auer rods, but with BM blasts <20% were found to have better prognosis than those categorized as RAEB-T on basis of blast count in PS and BM.  Furthermore with passage of years patients with RAEB-T with more than 20% bone marrow blasts were increasingly regarded and treated as acute myeloid leukemia.  And this was also true of patients found to have t(8;21) or inv(16) even when the bone marrow blast count was less than 20%.
  • Limitations of FAB classification….. In addition there was controversy as to whether chronic myelomonocytic anaemia (CMML), particularly when the white cell count was high, was properly classified as MDS rather than as myeloproliferative disorders (MPD). Some cases were unclassifiable. Ignores presence of cytogenetic abnormalities.
  • WHO classification of MDS
  • Subtype Blood Bone Marrow Refractory anaemia (RA, RN, RT)/RCUD Single or bicytopenia, no blasts Unilineage dysplasia 10% of the cells in one myeloid lineage, < 5% blasts, <15% ringed sideroblasts Refractory anaemia with ring sideroblasts (RARS) Anaemia, no blasts Erythroid dysplasia only, < 5% blasts, 15% ringed sideroblasts Refractory cytopenia with multilineage dysplasia (RCMD) Cytopenia(s), no or rare blasts (<1%), no Auer rods, < 1 x 109/L monocytes Dysplasia in 10% of cells in 2 or more hematopoietic lineages, <15% ring sideroblasts, < 5% blasts, no Auer rods. RCMD and ringed sideroblasts (RCMD-RS) Cytopenias (bicytopenia or pancytopenia), No or rare blasts, No Auer rods, < 1 x 109/L monocytes Dysplasia in 10% of cells in 2 or more myeloid cell lines, < 5% blasts, 15% ringed sideroblasts, No Auer rods
  • Subtype Blood Bone Marrow Refractory anemia with excess blasts-1 (RAEB-1) Cytopenias,< 5% blasts No Auer rods, < 1 x 109/L monocytes Unilineage or multilineage dysplasia, no Auer rods, 5-9% blasts Refractory anemia with excess blasts-2 (RAEB-2) Cytopenias, 5-19% blasts, Auer rods ±, < 1 x 109/L monocytes Unilineage or multilineage dysplasia, Auer rods ±, 10- 19% blasts MDS, unclassified (MDS-U) Cytopenia(s), No or rare blasts (<1%), No Auer rods Unilineage dysplasia in granulocytes or Megakaryocytes, < 5% blasts, No Auer rods MDS associated with isolated del(5q) Anemia, < 1% blasts, platelets normal or increased Normal to increased megakaryocytes with hypolobated nuclei, < 5% blasts, No Auer rods Isolated del(5q)
  • Myelodysplastic/Myeloprolifierative Neoplasms (MDS/MPN) WHO Classification
  • Myelodysplastic/Myeloprolifierative Neoplasms (MDS/MPN) WHO Classification Subtype Blood Bone Marrow CMML-1 > 1 x 10/L monocytes, < 5% blasts 9 Dysplasia in 1 hematopoietic line, < 10% blasts CMML-2 > 1 x 10 /L monocytes, 5%- 19% blasts or Auer rods Dysplasia in 1 hematopoietic line, 10%-19% blasts, or Auer rods Atypical chronic myeloid leukemia (CML), Bcr-Abl 1 negative WBC 13 x 10 /L, neutrophil precursors > 10%, < 20% blasts Hypercellular, < 20% blasts Juvenile myelomonocytic leukemia (JMML) > 1 x 10/L monocytes, < 20% blasts > 1 x 10 /L monocytes, < 20% blasts MDS/MPN, unclassifiable ('Overlap syndrome') Dysplasia + myeloproliferative features, no prior MDS or MPN Dysplasia + myeloproliferative features
  • Changes made by WHO classification  The criteria for the diagnosis of AML was altered (20% blasts).  RAEB-T------ RAEB-II category.  Problem relating to the classification of CMML/a CML was resolved by creation of MDS/MPD category to which both were assigned together with other cases with features overlapping between MDS/MPD.
  • Changes made by WHO classification…..  Poor prognostic significance of multilineage dysplasia in RA and RARS is recognized and new categories of refractory cytopenia with multilineage dysplasia and refractory cytopenia with multilineage dysplasia and ringed sideroblasts are recognized.  The poor prognostic significance of more than 10% bone marrow blasts, in comparison with 5- 10% bone marrow blasts is recognized and RAEB is therefore separated into RAEB-I and RAEB-II.
  • Changes made by WHO classification…..  The good prognostic significance of MDS with no increase in blast cells and with an isolated deletion of long arm of chromosome 5 is recognized and assigned to a specific category.  It is recognized that there are some cases that cannot be readily classified and category for such cases is provided.  All cases of MDS/MPD in infants and children are assigned to a single category- designated juvenile myelomonocytic leukemia.
  • Drawback of WHO classification  They incorporate very little cytogenetic and molecular genetic information.  Only the 5q- syndrome is defined.
  • Clinical manifestations  The symptoms experienced by patients with MDS are related to the type and severity of the peripheral blood cytopenias.  Symptoms- o Fatigue, o decreased exercise tolerance, o bleeding, o easy bruisability, or recurrent bacterial infections.
  • Physical examination • Pallor • Peripheral oedema • Evidence of heart failure (severe anaemia). • Petechiae on the lower extremities or on the buccal mucosa (if severe thrombocytopenia is present). • Splenomegaly may be present, especially in patients with chronic myelomonocytic leukemia (CMML).
  • Laboratory tests  Decrease of one peripheral blood count or multiple cytopenias.  Anaemia- Microcytic/normocytic/macrocytic.  Reticulocytopenic (corrected reticulocyte count <1%).  Leukopenia due to a decrease in the absolute neutrophil count  Leukoerythroblastic picture.  An absolute monocytosis (monocytes >1000/μL) is present in CMML.  Thrombocytopenia may be present but  Thrombocytosis ( refractory anaemia (RA) and an isolated 5q− abnormality, or in some cases of RARS).
  • Bone marrow  Essential to diagnose MDS.  The BM trephine biopsy provides better assessment of marrow cellularity and is required to evaluate the existence of fibrosis. Abnormal distribution of cells is detectable.  The bone marrow biopsy usually is hypercellular for the age of the patient.  However, approx 15% of patients have a hypocellular marrow (cellularity <25%).
  • Bone marrow..…  Granulocytic precurosrs may be clustered centrally rather than showing their normal paratrabecular distribution.  This phenomenon has been designated as abnormal localization of immature precurors (ALIP).  ALIPs are diagnostically important if they are detected in since their presence confirms MDS rather than a secondary anaemia.  Use of antiglycophorin antibody highlights the presence of clusters of immature erythroid cells and helps to distinguish from ALIPs.
  • Bone marrow ..…  Abnormal megakaryocytes are readily assessed.  Megakaryocytes may be clustered or found in paratrabecular position.  Apoptosis is increased.  Nonspecific abnormalities- increased macrophages, prominent mast cells, lymphoid follicles and plasma cell aggregates.
  • Abnormal localization of immature precursors
  • Cytochemical reactions  Most important and essential- Perl’s stain for iron.  SBB and MPO- Ensure that all cases with Auer rods are recognized and classified as RAEB-T (FAB) or RAEB-2 (WHO).  In CMML- NSE is necessary to identify monocyte component in bone marrow.  PAS- Erythroblasts
  • Morphological abnormalities in MDSs
  • Erythroid  PS Bone marrow  Ovalomacrocytes Megaloblastoid erythropoiesis  Elliptocytes Nuclear budding  Acanthocytes Ringed sideroblasts  Stomatocytes Internuclear bridging  Teardrops Karyorrhexis  Nucleated erythrocytes Nuclear fragments  Basophilic stippling Cytoplasmic vacuolization  Howell-Jolly bodies Multinucleation Ring sideroblasts
  • Myeloid  PS Bone marrow  Pseudo–Pelger-Huet anomaly Defective granulation.  Auer rods Maturation arrest at myelocyte stage.  Hypogranulation Increase in monocytoid forms.  Nuclear sticks Abnormal localization of immature precursors.  Hypersegmentation  Ring-shaped nuclei  Pseudo- Chediak Higashi granules
  • Megakaryocyte  PS Bone marrow  Giant platelets Micromegakaryocytes  Hypogranular or agranular Hypogranulation platelets Multiple small nuclei
  • Refractory anaemia, RCUD, RN, RT (WHO)  10-20% of MDS.  Older adults, median age- 65-70years.  PS-  Anaemia, marked anisocytosis, poikilocytosis.  Normochromic, normocytic/macrocytic, occasional hypochromia.  Blasts are uncommon, less than 1%.
  • Refractory anaemia (WHO)…….  Unilineage dysplasia must be present in 10% of cells of one myeloid lineage.  Bone marrow is usually hypercellular but can be normocellular or hypocellular.  Ring sideroblasts are less than 15% of erythroblasts and blasts are less than 5%.  Low or intermediate IPSS scores.  Progression to AML in 2%.
  • Refractory anaemia with ring sideroblasts (WHO)  3-11% cases of MDS.  PS-  Anaemia, normocytic normochromic, often macrocytic, microcytic hypochromic, giving dimorphic picture.  Pappenheimer bodies may be present.  Platelet counts increased, but not more than 450x109/L
  • Refractory anaemia with ring sideroblasts (WHO)………  Bone marrow shows erythroid hyperplasia.  Myeloblasts are <5% of BM nucleated cells.  15% or more of red cell precursors are ring sideroblasts.  Iron laden macrophages may be prominent.  Very low rate of evolution to AML.
  • Refractory cytopenia with multilineage dysplasia (WHO)  Comprises about 30% of cases of MDS.  Mostly elderly patients.  PS-  Cytopenias (Hb<10g/dl, absolute neutrophil count <1.8x 109 /L and platelet count <100x 109 /L)  <1% blasts,  Auer rods not present and  monocytes are less than 1x 109 /L.
  • Refractory cytopenia with multilineage dysplasia…..  Bone marrow-  Hypercellular  Dysplasia in 10% of the cells in at least two myeloid lineages (neutrophils and/or erythroid precursors and/or megakaryocytes).  <5% blasts, no Auer rods.  >15% ring sideroblasts.  Intermediate scores according to IPSS.  Frequency of leukemic transformation at the end of two years in approximately 10%.
  • Refractory anaemia with excess of blasts-1  Comprises around 40% of cases (RAEB-1 & RAEB-2).  PS-  Cytopenia.  Anisopoikilocytosis, large/giant/hypogranular platelets, abnormal cytoplasmic granularity and nuclear segmentation of neutrophils, Auer rods absent.  <5% blasts.  Monocyte count 1X109 /L
  • Refractory anaemia with excess of blasts-1…..  Bone marrow-  Dysplasia in at least 10% of cells of one or more myeloid lineages.  Hypercellular, unilineage/multilineage dysplasia, 5-9% blasts and no Auer rods.  Abnormalities in three myeloid cell lines (trilineage dysplasia).  Biopsy- both erythropoiesis and megakaryopiesis dislocated towards paratrabecular areas that are predominantly occupied by granulopoietic cells.  Median survival is around 18 months.
  • Refractory anaemia with excess of blasts-2  It is categorized as RAEB-2 if bone marrow blasts are 10-19%, if the peripheral blood blasts are 5- 19% (regardless of bone marrow blast count) or if Auer rods are present.  Dysplasia in at least 10% of cells of one or more myeloid lineages.  More than a third patient suffered transformation to AML.  Median survival poor than RAEB-1.
  • MDS associated with isolated 5q deletion syndrome  This is MDS associated with isolated 5q- .  Etiology- loss of tumour suppressor gene in the deleted region.  In the FAB classification patients with 5q- anomaly fell into RA, RARS or RAEB categories.  Patients are mainly women, usually middle aged or elderly.  PS- Cytopenias, 1% blasts,
  • MDS associated with isolated 5q deletion syndrome…..  Bone marrow-  Hypercellular/normocellular.  Erythroid hyperplasia.  Megakaryocytes are increased in number and are normal to decreased in size with hypolobated nuclei.  <5% blasts.  The rate of leukemic transformation is 3%.
  • MDS unclassifiable  It is a subtype of MDS which initially lacks findings appropriate for classification into any other MDS category.  Diagnostic criteria- 1. Pancytopenia in a patient who would otherwise fit the criteria for RCUD OR 2. PS blasts <1% on two occasions in a patient who would otherwise meet the criteria for RCUD and RCMD OR
  • MDS- U 4. Unequivocal dysplasia in not present in10% of the cells in any lineages but a clonal cytogenetic abnormality giving presumptive evidence of MDS is present AND 5. PS blasts are not greater than 1%. 6. Bone marrow blasts <5%.
  • Childhood MDS  Uncommon in children, accounts for less than 5% of all haematopoietic neoplasms in patients less than 14 years of age.  Refractory cytopenia of childhood (RCC) is a myelodysplastic syndrome characterized by persistent cytopenia with <5% blasts in the bone marrow and <2% blasts in the peripheral blood.  Monosomy 7 is the most common cytogenetic abnormality (significantly higher probability of progression).
  • RCC…..  Dysplastic changes in at least 10% of cells of at least two myeloid lineages.  Erythroid island with at least 20 cells maturation arrest with excess proerythroblasts, increased mitosis in erythroid cells.  The detection of micromegakaryocytes is a strong indicator of RCC.  About 75% of children with RCC show considerable hypocellularity of the bone marrow.
  • Disorders which may present with morphological features indistinguishable from refractory cytopenia of childhood  Infections (CMV, Herpes, parvovirus B19, Leishmaniasis).  Vitamin def (B12, Folate, Vit E).  Metabolic disorders (mevalonate kinase def).  Rheumatic ds.  Autoimmune lymphoproliferative disorder (FAS def).  Inherited BM failure disorders (Facnconi anaemia, dyskeratosis congenita, Shwachmann-Diamond syndrome).  PNH.  Acquired aplastic anaemia during haematological recovery.
  • Other categories or features of MDSs  Hypocellular MDS-  FAB group initially described MDS having a hypercellular or normocellular bone marrow.  Subsequently it became apparent that some cases, approximately 15% in all had a hypocellular bone marrow.  Their prognosis does not differ from MDS in general.  D/Ds- Hypocellular AML and aplastic anaemia.
  • MDS with myelofibrosis  Some patients with MDS have considerable reticulin deposition.  It is important to distinguish these cases from M7 AML with myelofibrosis.  M7 AML has more than 20% blasts whereas MDS with myelofibrosis has fewer.  They have high incidence of complex chromosomal abnormalities and poor prognosis.
  • Therapy related MDS  Distinctive haematological and cytogenetic features.  Eosinophilia and basophilia are more common.  Marked trilineage dysplasia, hypocellularity and reticular fibrosis are common.  Cytogenetic abnormalities are more often present than in de novo MDS.  Very poor prognosis.
  • Chronic Myelomonocytic Leukemia (CMML)  Clonal haematopoietic malignancy that is characterized by features of both MPD and MDS.  Absence of Philadelphia and BCR/ABL fusion gene.  Persistent Monocytosis >1x109/L in PS.  No rearrangement of PDGFRA/PDGFRB.  <20% blasts (PS & BM), including myeloblasts, monoblasts and promonocytes  Dysplasia in 1 or more BM lineages or clonal cytogenetic abnormality or monocytosis persisting for atleast 3 months.
  • CMML….. • CMML-1 blasts+promonocytes<5% PS and <10% BM • CMML-2 blasts+promonocytes 5-19% PS and 10-19% BM or Auer rods+. • CMML needs to be distinguished from aCML with which it shares some features. It has been recommended that cases in which more than 15% of circulating white cells are granulocyte precursors should be categorized as aCML and cases with fewer as CMML.
  • Atypical chronic myeloid leukaemia  aCML is a rare Ph-negative, BCR-ABL1 negative condition.  Higher median age and worse prognosis than CGL.  C/F- Anaemia and spleenomegaly.
  • Criteria for diagnosis of atypical chronic myeloid leukemia
  • Leucocytosis with dysplastic neutrophils and precursors; precursors (promyelocytes to metamyelocytes) at least 10% of leucocytes, basophils usually less than 2% Fewer than 10% monocytes in the blood Fewer than 20% blasts in blood and bone marrow Hypercellular bone marrow with dysplasia at least in granulocyte lineage No Ph chromosome, BCR-ABL1 fusion gene or rearrangement of PDGFRA or PDGFRB Diagnosis of atypical chronic myeloid lekemia
  • Juvenile myelomonocytic leukemia (JMML)  It is a Ph-negative condition which occurs mainly in children less than 5 years of age.  Encompasses previously designated juvenile chronic myeloid leukaemia, the infantile monosomy 7 syndrome and other MDS/MPD of childhood.  There is an increased incidence in children with neurofibromatosis and in Down’s syndrome.  Clinical features often include anaemia, hepatomegaly, splenomegaly, lymphadenopathy and rash.
  • Criteria for diagnosis of JMML
  • Monocytes >1X109/L Fewer than 20% blast cells (plus promonocytes) in the blood and bone marrow No Ph chromosome or BCR-ABL1 fusion gene Two or more of the following criteria: •Hb F increased for age. •Immature granulocytes in PS. •WBC>10X109/L •Clonal chromosomal abnormality (monosomy 7 not excluded). •Myeloid progenitors hypersensitive to GM-CSF in vitro Diagnosis of juvenile myelomonocytic lekemia
  • Myelodysplastic/myeloproliferative neoplasms, unclassifiable
  • Meets criteria for one of the categories of MDS Prominent myeloproliferative features. No preceding history of MDS or MPN and cannot be assigned to a more specific category of MDS/MPN No BCR-ABL1 or rearrangement of PDGFRA, PDGFRB or FGFR1. No isolated del (5q), t(3;3) or inv(3) Diagnosis of myelodysplastic/myeloproliferative neoplasm, unclassifiable And
  • Evolution of MDS  Patients with MDS may die of marrow failure as a direct consequence of MDS or may die following transformation to acute leukemia.  Myelodysplastic syndromes may evolve into other MDS.  Change is usually into a worse prognostic category and very rarely into favorable.  Thus RA and RARS may evolve into either CMML.
  • Evolution of MDS…..  Variation in number of monocytes can alter classification, mainly between CMML and RAEB and rarely ring sideroblasts disappear so that RARS converts to RA.  When acute leukemia supervenes it may develop within a brief period or there may be stepwise evolution over weeks and months.  Acute leukemia that occurs in MDS is always AML, but rare cases of ALL and bilineage/biphenotypic leukemia have been reported.
  • Algorithm of MDS diagnosis
  • Has there been exposure to cytotoxic drugs or radiation No Are there 5-19% blast cells in the blood or 10-19% blast cells in the bone marrow or Auer rods Are there no more than 5% blasts cells in the blood and 5-9% in the bone marrow No No Is there an isloated 5q- No Is there multilineage dysplasia No RA or RARS Yes Therapy related MDS Yes RAEB-II Yes RAEB-I Yes 5q- syndrome Yes RCMD
  • References 1. Barabara Bain. The WHO classification of Myelodysplastic syndromes. Exp Oncol 2004, 26 (3):166-69. 2. Barbara Bain, David Clark and Bridget Wilkins. Bone marrow pathology, 4th edition, 2008. 3. Who classification of tumours of haematopoietic and lymphoid tissue. 4th edition, 2008. 4. Ha Thanh Nishino, MD; Chung-Che Chang. Myelodysplastic Syndromes. Clinicopathologic Features, Pathobiology, and Molecular Pathogenesis. Arch Pathol Lab Med—Vol 129, October 2005. 5. Raphael Itzykson, Lionel Ades, and Pierre Fenaux. Biology and Prognostic Factors of Myelodysplastic Syndrome. American Society of Clinical Oncology 2011. 6. E.D. Warlick and B.D. Smith. Myelodysplastic Syndromes: Review of Pathophysiology and Current Novel Treatment Approaches. Current Cancer Drug Targets 2007, 7:541-558