Μυελοδυσπλαστικά Σύνδρομα - Μορφολογία

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1 Μυελοδυσπλαστικά Σύνδρομα - Μορφολογία Κωνσταντίνος Τσαταλάς Καθηγητής Αιματολογίας Δημοκρίτειο Πανεπιστήμιο Θράκης

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3 Minimal diagnostic criteria for patients with MDS, as recommended by the International Working Conference (2007) Prerequisite criteria (both 1 and 2 required) 1. Constant cytopenia in one or more of the following cell lineages: Erythroid (hemoglobin < 11g/dL a ) Neutrophilic (absolute neutrophil count < 1.5 x 10 9 /L b ) or Megakaryocytic (platelets < 100 x 109/L) 2. Exclusion of all other hematopoietic or nonhaematopoietic disorders as the primary reason for cytopenia/dysplasia MDS-related decisive criteria (at least one required) Dysplasia in 10% of all cells in at least one of the following lineages in the BM smear: erythroid, neutrophilic, or megakaryocytic, or > 15% ringed sideroblasts (iron stain) 5% - 19% Blast cells in the BM or PB Typical chromosomal abnormality (by conventional karyotyping or fluorescence in situ hybridization [FISH]) Valent P et al. Leuk Res 2007; 31: 727

4 Minimal diagnostic criteria for patients with MDS, as recommended by the International Working Conference (2007) Co-criteria (for patients fulfilling A but not any of the B criteria above and who otherwise show typical clinical features [eg, transfusion-dependent macrocytic anemia] (at least one required) Abnormal phenotype of BM cells clearly indicative of a monoclonal population of erythroid and/or myeloid cells, determined by flow cytometry, Clear molecular signs of a monoclonal cell population on X-inactivation assay, gene chip profiling, or point mutation analysis (eg, RAS mutations), Markedly and persistently reduced colony formation (± cluster formation) of BM and/or circulating progenitor cells by colony-forming unit assay. Valent P et al. Leuk Res 2007; 31: 727

5 Summary of cytopenias ans dysplasia characteristics in MDS without an increase of marrow blasts Cytopenias Dysplasia Categories Unicytopenia Bicytopenia Unicytopenia Bicytopenia Unilineage Unilineage and 15% ring sideroblasts Refractory cytopenia with unilineage dysplasia (RCUD) Refractory anaemia (RA) Refractory neutropenia (RN) Refractory thrombocytopenia (RT) Refractory anaemia with ring sideroblasts (RARS) Pancytopenia Unilineage Myelodysplastic syndrome, unclassified (MDS-U) Unicytopenia Bicytopenia Pancytopenia Unicytopenia Bicytopenia Pancytopenia Multilineage ( 2 myeloid cells lines) Multilineage and 15% ring sideroblasts Refractory cytopenia with multilineage dysplasia (RCMD) Refractory cytopenia with multilineage dusplasia (RCMD) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Edited by SH Swerdlow et al. 4 th Edition, Lyon 2008

6 Κυτταρομορφολογική μελέτη επιχρισμάτων περ. αίματος και μυελού σε ΜΔΣ. Βασικές αρχές μεσοδιάστημα αιμοληψίας προετοιμασίας επιχρίσματος 2 ωρών (EDTA storage artefacts) υψηλής ποιότητας χρώση επιχρισμάτων (MGG, MPO, NSE) παρουσία κοκκίων στο απώτερο άκρο του μυελικού επιχρίσματος επιχρίσματα μυελού υπό μορφή smear ( στρωτό ) και squash ( σύνθλιψη ) επιστρώσεων αρίθμηση τουλάχιστον 500 κυττάρων στο μυελό και 200 στο περ. αίμα ακριβής προσδιορισμός ποσοστού κυττάρων κάθε μυελικής σειράς που εμφανίζουν στοιχεία δυσπλασίας. απαιτούνται: 10% δυσπλαστικά κύτταρα ερυθράς σειράς και κοκκιοκυτταρικής σειράς 10% δυσπλαστικά μεγακαρυοκύτταρα (μέτρηση τουλάχιστον 30 μεγα-)

7 Dysplastic changes observed in the erythroblasts of 42 subjects with adequate iron stores Abnormality No of cases in which observed Percentage of cells in which observed Binuclearity Nuclear lobulation 3 1 Detached nuclear fragments (Howell-Jolly body) Nuclear bridging Irregular nuclear membrane Cytoplasmic bridging Vacuolated, irregular or poorly haemoglobinized cytoplasm Basophilic stippling 8 1-3

8 120 δότες μυελού των οστών 46% squash preparations 10% δυσμυελοποίηση τουλάχιστον 1 σειράς 26% squash preparations 10% σε 2 σειρές 7% squash preparations 10% σε 3 σειρές

9 Haematological features that may occur in the peripheral blood in MDS τροποποιμένο από Bain BJ. Leukaemia Diagnosis. 4 th Edition, Wiley Blackwell Erythropoiesis Anaemia and red cell dysplasia Normocytic normochromic (common) Macrocytic (common) Microcytic (uncommon) Dimorphic blood film Anisocytosis, anisochromasia Poikilocytosis (± ovalocytes, elliptocytes, schistocytes, teardrop poikilocytes, stomatocytes, acanthocytes and target cells) Polychromasia (uncommon) Pappenheimer bodies, basophilic stippling Circulating nucleated red blood cells Decreased reticulocyte (usually) Increased reticulocyte count (rarely)

10 Bain BJ. Leukaemia Diagnosis. 2010; 4 th Edition, Wiley Blackwell

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12 Haematological features that may occur in the peripheral blood in MDS Granulopoiesis Neutropenia (common) Neutrophilia (uncommon) Acquired Pelger-Huët anomaly Neutrophils with hypersegmented nuclei, increased nuclear projections, ring nuclei or nuclei of bizarre shape, increased chromatin clumping, detached nuclear fragments, increased apoptotic forms Agranular and hypogranular neutrophils Hypergranular neutrophils of giant granules (uncommon) Persistence of cytoplasmic basophilia in mature neutrophils or presence of Döhle bodies Macropolycytes and binucleated neutrophils Monocytosis, abnormal monocytes Presence or promonocytes Blast cells, with or without Auer rods Eosinophilia (uncommon) Hypogranular eosinophils Basophilia (uncommon) τροποποιημένο από Bain BJ. Leukaemia Diagnosis. 2010; 4 th Edition, Wiley Blackwell IMMATURE CELLS + BLASTS CAN ALSO BE SEEN growth factor treatment active BM regeneration acute BM stress (sepsis) after ABMT

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14 Collela R et Hollensead SC. Am J Clin Pathol 2012; 137: 358

15 Collela R, Hollensead SC. Am J Clin Pathol 2012; 137: 358

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24 Haematological features that may occur in the peripheral blood in MDS Thrombopoiesis Thrombocytopenia (common) Thrombocytosis (uncommon) Giant platelets Hypogranular or agranular platelets Platelets with giant granules Micromegakaryocytes Cyclical thrombocytopenia (rare) τροποποιημένο από Bain BJ. Leukaemia Diagnosis. 2010; 4 th Edition, Wiley Blackwell

25 Morphologic manifestations of dysplasia Dyserythropoiesis Nuclear Nuclear budding Internuclear bridging Karyorrhexis Multinuclearity Nuclear hyperlobation Megaloblastic changes Hyperplasia (common) Hypoplasia (uncommon), PRCA Howell-Jolly bodies Gigantism Defective cytoplasm haemoglobinization Cytoplasmic Ring sideroblasts Vacuolization Periodic acid-schiff positivity Dysgranulopoiesis Dysmegakaryocytopoiesis Small or unusually large size Nuclear hypolobation (pseudo Pelger-Huët; pelgeroid) Irregular hypersegmentation Decreased granules; agranularity Pseudo Chediak-Higashi granules Auer rods Micromegakaryocytes Nuclear hypolobation Multinucleation (normal megakaryocytes are uninucleate with lobulated nuclei WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Edited by SH Swerdlow et al. 4 th Edition, Lyon 2008

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38 Perinuclear siderotic granules (cartoon of potential examples). Mufti G J et al. Haematologica 2008;93: by Ferrata Storti Foundation

39 Prussian blue reaction of erythroid precursors. a. Mufti G J et al. Haematologica 2008;93: by Ferrata Storti Foundation

41 Morphologic manifestations of dysplasia Dyserythropoiesis Nuclear Nuclear budding Internuclear bridging Karyorrhexis Multinuclearity Nuclear hyperlobation Megaloblastic changes Dysgranulopoiesis Cytoplasmic Ring sideroblasts Vacuolization Small or unusually large size Periodic acid-schiff positivity Nuclear hypolobation (pseudo Pelger-Huët; pelgeroid) Irregular hypersegmentation Decreased granules; agranularity Pseudo Chediak-Higashi granules Auer rods Granulocytic hyperplasia Granulocytic hypoplasia blasts Cytoplasmic vacuolation basophils, eosinophils, mast cells Dysmegakaryocytopoiesis Micromegakaryocytes Nuclear hypolobation Multinucleation (normal megakaryocytes are uninucleate with lobulated nuclei WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Edited by SH Swerdlow et al. 4 th Edition, Lyon 2008

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51 Morphologic manifestations of dysplasia Dyserythropoiesis Nuclear Nuclear budding Internuclear bridging Karyorrhexis Multinuclearity Nuclear hyperlobation Megaloblastic changes Cytoplasmic Ring sideroblasts Vacuolization Periodic acid-schiff positivity Dysgranulopoiesis Dysmegakaryocytopoiesis Small or unusually large size Nuclear hypolobation (pseudo Pelger-Huët; pelgeroid) Irregular hypersegmentation Decreased granules; agranularity Pseudo Chediak-Higashi granules Auer rods Micromegakaryocytes Nuclear hypolobation Multinucleation (normal megakaryocytes are uninucleate with lobulated nuclei Mega normal Mega Mega WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Edited by SH Swerdlow et al. 4 th Edition, Lyon 2008

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62 Germing U. Leuk Res 2012; 36: 727

63 Germing U. Leuk Res 2012; 36: 727

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65 Germing U. Leuk Res 2012; 36:727

66 Evaluation of dysplasia through detailed cytomorphology in 3156 patients from the Düsseldorf Registry on myelodysplastic syndromes μεμονωμένη δυσπλαστική διαταραχή ή συνδυασμός διαταραχών δεν αποτελούν παθογνωμονικό εύρημα για τη διάγνωση ΜΔΣ ερυθροποίηση μεγαλοβλαστοειδείς αλλοιώσεις πολυπύρηνες μορφές κοκκιοποίηση ψευδο-pelger Hüet κύτταρα υποκοκκίωση θρομβοποίηση μικρομεγακαρυοκύτταρα μονοπύρηνα μεγακαρυοκύτταρα συχνότερες δυσπλαστικές διαταραχές ο αριθμός δυσπλαστικών διαταραχών/ασθενή είναι σχετικά μικρός (~6) επιβάλλεται αναζήτηση όλων των πιθανών διαταραχών δυσπλασίας στο περ. αίμα και μυελό Germing U et al. Leuk Res 2012; 36: 727

67 Evaluation of dysplasia through detailed cytomorphology in 3156 patients from the Düsseldorf Registry on myelodysplastic syndromes δακτυλιοειδείς σιδηροβλάστες ανισομετρία αιμοπεταλίων αριστερή στροφή κοκκιοποίησης Συχνά ανευρίσκονται σ όλους τους τύπους ΜΔΣ del (5q): συνοδεύεται με υπολοβιωμένα μεγα-, ερυθροκυτταρική υποπλασία και λεμφοκυττάρων RARS: συνοδεύεται με εκσεσημασμένη δυσερυθροποίηση ο δυσπλαστικός φαινότυπος έχει κυρίως διαγνωστική αξία και λιγότερο προγνωστική Germing U et al. Leuk Res 2012; 36: 727

68 Δευτεροπαθής παροδική δυσπλασία έλλειψη αιματινικών παραγόντων-διατροφικών παραγόντων Β 12 φυλλικό οξύ χαλκός σελήνιο σύνθετη έλλειψη σε νευρογενή ανορεξία δυσερυθροποίηση μετά από μυελικό stress αιμόλυση αναγέννηση μυελού μετά από ABMT ή χημειοθεραπεία τοξίνες αλκοόλ αρσενικό βαρειά μέταλλα φάρμακα μεθοτρεξάτη, αζαθειοπρίνη, adalimumab, etanercept, ifliximub, ciplatin, σουλρομεθοξαζόλη, μυκοφαινολικό οξύ, γκανσικλοβίρη αυξητικοί παράγοντες λοιμώξεις HIV ελονοσία babesiosis λοιπά συμπληρώματα διατροφής, προϊόντα ebay, γιατρικά βότανα

69 Νοσήματα με συνοδές δυσπλαστικές αλλοιώσεις μυελού αυτοανοσία συστηματικός ερυθηματώδης λύκος 1a,b ρευματοειδής αρθρίτιδα χρόνια ιδιοπαθής ουδετεροπενία 2 πολλαπλούν μυέλωμα 3 παρανεοπλασματική δυσπλασία 4,5 λεμφώματα συμπαγείς όγκοι: Ca παχέος, πνευμόνων, νεφρών, προστάτου, στομάχου συγγενείς δυσερυθροποιητικές αναιμίες αιμοσφαιρινοπάθειες ετερόζυγη β-μεσογειακή αναιμία απλαστική αναιμία παροξυντική νυκτερινή αιμοσφαιρινουρία 1a. Voulgarelis M et al. Am J Hem 2006; 590 1b. Giannoulis S et al. 2006; 65: Palmblad J, Papadaki H. Curr Opin Hematol 2008; Matarraz S et al. Haematologica 2012; Sans-Sabrafen et al. Am J Hematol 1992; 41:4 5. Castelo A et al. Haematologica 1992; 77:392

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74 An MDS Differential Diagnosis diagnoses who were referred to rule out MDS, or with a suspected MDS diagnosis Other neoplasms MDS/MPN overlap syndromes e.g., CMML MPN, BCR/ABL-negative CML AML Hairy cell leukemia Congenital syndromes Fanconia anemia Dyskeratosis congenita Congenital dyserythropoietic anemia Congenital sideroblastic anemia (ALAS2 mutant and others) Congenital or cyclic neutropenia (ELANE mutation, CSF3R mutation) Gray platelet syndrome GATA1 mutant macrothrombocytopenia MYH9 mutant macrothrombocytopenia Bloom syndrome Erythropoietic protoporphyria Iron-refractory iron deficiency (TMPRSS6 mutation) African-American neutropenia variant Other undefined Steensma DP. Curr Hematol Malig Rep 2012; 7:310

75 An MDS Differential Diagnosis diagnoses who were referred to rule out MDS, or with a suspected MDS diagnosis Immune disorders Aplastic anemia Paroxysmal nocturnal hemoglobinuria Pure red cell aplasia T cell-lgl, with or without thymoma NK cell-lgl Autoimmune hemolytic anemia Immune thrombocytopenia WHIM syndrome (warts, hypogammaglobulinemia, immunodeficiency, myelokathexis) Rheumatoid arthritis Systemic lupus Chronic benign neutropenia Steensma DP. Curr Hematol Malig Rep 2012; 7:310

76 An MDS Differential Diagnosis diagnoses who were referred to rule out MDS, or with a suspected MDS diagnosis Nutritional deficiencies B 12 Folate Copper Selenium Multiple (anorexia nervosa or other) Reactive conditions or infections HIV infection Alcohol abuse Malaria Babesiosis Drug effect Methotrexate, azathioprine, adalimumab, etanercept, infliximab, cisplatin Due to herbal preparation obtained on ebay with unknown compounds Steensma DP. Curr Hematol Malig Rep 2012; 7:310

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79 Peripheral blood and bone marrow findings in myelodysplastic syndromes (MDS) Disease Blood findings Bone marrow findings Refractory cytopenias with unilineage dysplasia (RCUD); Refractory anaemia (RA); Refractory neutropenia (RN); Refractory thrombocytopenia (RT) Unicytopenia or bicytopenia No or rare blasts (<1%) Unilineage dysplasia: 10% of the cells in one myeloid lineage < 5% blasts < 15% of erythroid precursors are ring sideroblasts Refractory anaemia with ring sideroblasts (RARS) Anaemia No blasts 15% of erythroid precursors are ring sideroblasts Erythroid dysplasia only < 5% blasts Refractory cytopenia with multilineage dysplasia (RCMD) Refractory anaemia with excess blasts-1 (RAEB-1) Refractory anaemia with excess blasts-2 (RAEB-2) Myelodysplastic syndrome unclassified (MDS-U) MDS associated with isolated del(5q) 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 Anaemia Usually normal or increased platelet count No or rare blasts (<1%) 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 WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Edited by SH Swerdlow et al. 4 th Edition, Lyon 2008

85 Wang SA, Hematol Oncol Clin N Am 2011; 25: 1085

86 Morphologic manifestations of dysplasia Dyserythropoiesis Nuclear Nuclear budding Internuclear brinding Karyorrhexis Multinuclearity Nuclear hyperlobation Megaloblastic changes Cytoplasmic Ring sideroblasts Vacuolization Periodic acid-schiff positivity Dysgranulopoiesis Small or unusually large size Nuclear hypolobation (pseudo Pelger-Huët; pelgeroid) Irregular hypersegmentation Decreased granules; agranularity Pseudo Chediak-Higashi granules Auer rods Dysmegakaryocytopoiesis Micromegakaryocytes Nuclear hypolobation Multinucleation (normal megakaryocytes are uninucleate with lobulated nuclei) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Edited by SH Swerdlow et al. 4 th Edition, Lyon 2008

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89 Like son, like father

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92 Atlas of Clinical Hematology. Löffler H et al. 6 th Edition

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97 Bain BJ, Br J of Haematol 1996; 94: 206