5/28/2016 Disclosures Myelodysplastic/Myeloproliferative I have nothing to disclose Neoplasms (MDS/MPN): Diagnosis and Recent Advances Sonam Prakash, MBBS Associate Clinical Professor Laboratory Medicine, UCSF (32 nd Annual Current Issues in Anatomic Pathology, Saturday May 28 2016) What are MDS/MPN Outline of Talk • Myeloid neoplasms with clinical, laboratory and • Overview of morphologic features that overlap between myelodysplastic syndromes (cytopenias, morphologic myelodysplastic/myeloproliferative neoplasms dysplasia) and myeloproliferative neoplasms (increased peripheral counts and marrow cellularity) (MDS/MPN) • Splenomegaly: significant subset of cases (30-40%) • Diagnosing the various subtypes of • Karyotype: normal or abnormalities in common with MDS MDS/MPN: case based approach • Negative for BCR/ABL1 , PDGFRA, PDGFRB , FGFR1 or • WHO 2016 updates for MDS/MPN* PCM1-JAK2 rearrangement • Genes mutated in myeloid neoplasms present in a high proportion of cases: can be helpful for diagnosis in *Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World difficult cases Health Organization (WHO) classification of myeloid neoplasms and acute leukemia. Blood. 2016 May 19;127(20):2391-405. 1
5/28/2016 When Do We Consider a Diagnosis of Subtypes of MDS/MPN MDS/MPN • Chronic myelomonocytic leukemia (CMML) • Increased peripheral counts with associated • Atypical chronic myeloid leukemia, BCR-ABL1 – cytopenias and morphologic dysplasia negative (aCML) – Peripheral blood smear must be reviewed • Juvenile myelomonocytic leukemia (JMML) – Increased monocytes [≥1 x 10(9)/L] with or • Myelodysplastic/myeloproliferative neoplasm without increase in granulocytes: CMML, JMML with ring sideroblasts and thrombocytosis – Increased granulocytes: aCML (MDS/MPN-RS-T) – Increased platelets with anemia: MDS/MPN-RS-T • Myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U) Case 1: Peripheral Blood WBC 33.5 x10E9/L, HGB 6.9 g/dl, MCV 98 fl, PLTS 28 x10E9/L; neutrophils 25% (8.23), Case 1 lymphocytes: 16% (5.37), monocytes: 54% (18.09), immature granulocytes 5% (1.79), rare blasts. • 74 y.o. male with leukocytosis, anemia and thrombocytopenia • No splenomegaly • No history of recent infections 2
5/28/2016 Case 1: Marrow Case 1: Marrow Naphthyl butyrate esterase Increased monocytic cells Dyserythropoiesis Dysgranulopoiesis 3% blasts, G:E 8:1, no significant dysplsaia in megakaryocytes Case 1: Marrow Hypercellular marrow Granulocytic hyperplasia Additional Studies • Flow cytometry on the marrow: – 4% myeloid blasts, 30% monocytic cells • Cytogenetics – 46,XY,del(20)(q11.2q13.3)[20] – FISH negative for BCR-ABL1 3
5/28/2016 Diagnostic Criteria for Chronic Myelomonocytic Summary of Case 1 Leukemia (CMML) (WHO 2016) accounting for ≥10% of the white blood cell count ✔ • Proliferative features • Persistent PB monocytosis ≥1 X10(9)/L, WITH monocytes myelofibrosis, polycythemia vera or essential thrombocythemia ✔ – WBC 33.5, monocytosis [54%, absolute 18 x 10(9)/L] • Not meeting WHO criteria for BCR-ABL1 -positive CML, primary – Hypercellular marrow with granulocytic hyperplasia • No evidence of PDGFRA, PDGFRB or FGFR1 rearrangement or and increased monocytes Fewer than 20% blasts in the blood and bone marrow ✔ PCM1-JAK2 (should be specifically excluded in cases with • Dysplastic features Dysplasia in one or more myeloid lineages ( ✔ ). If myelodysplasia is eosinophilia) • – Anemia, thrombocytopenia • – Dysplasia in erythroid precursors and granulocytes absent or minimal, the diagnosis of CMML may still be made if the present in hematopoietic cells ✔ other requirements are met and • Other findings – an acquired clonal cytogenetic or molecular genetic abnormality is – Blasts <5% in marrow, rare blasts in peripheral blood OR – – Del(20q) the monocytosis (as previously defined) has persisted for at least 3 months and all other causes of monocytosis have been excluded Cases with monocytosis, minimal Diagnosis dysplasia, normal cytogenetics and no increase in blasts • Chronic myelomonocytic leukemia – CMML-1 by WHO 2008 criteria • Diagnosis of CMML would require: – Presence of molecular genetic abnormality in hematopoietic cells OR – Persistent monocytosis for at least 3 months and all other causes of monocytosis have been excluded 4
5/28/2016 Somatic Mutations in CMML WHO 2016 Updates in CMML • Most commonly mutated genes: SRSF2, TET2, • Subtypes of CMML (prognostic and/or ASXL1 (>80% of cases) significance) • Other mutations: SETBP1, NRAS/KRAS, – Based on blast percentage: RUNX1, CBL, and EZH2 • CMML-0 : <2% blasts in PB and <5% blasts in BM • In the proper clinical context, can be used to • CMML-1 : 2 to 4% blasts in PB and/or 5 to 9% support a diagnosis of CMML – Many of these mutations can be age-related, must blasts in BM • CMML-2 : 5 to 19% blasts in PB, 10 to 19% in BM, be interpreted cautiously • ASXL1 and NPM1: Poor prognosis in CMML and/or presence of Auer rods Prognosis in CMML Prognosis in CMML n=386 CMML-0=101 CMML-1=204 CMML-2=81 1 tttttttttttttt 1 ttttttt CMML-0 CMML-1 CMML-2 p < 0.0001 p < 0.0001 Kaplan–Meier curve of survival of CMML 0 versus CMML I versus CMML II. Kaplan–Meier curves of cumulative AML evolution of CMML 0, I and II E. Schuler, M. Schroeder, J. Neukirchen, C. Strupp, B. Xicoy, A. Kündgen, B. Hildebrandt, R. Haas, N. Gattermann, U. Germing. Refined medullary blast and white blood cell count based classification of chronic myelomonocytic leukemias. Leukemia E. Schuler, M. Schroeder, J. Neukirchen, C. Strupp, B. Xicoy, A. Kündgen, B. Hildebrandt, R. Haas, N. Gattermann, U. Germing. Research, Volume 38, Issue 12, 2014, 1413–1419 Refined medullary blast and white blood cell count based classification of chronic myelomonocytic leukemias . Leukemia Research, Volume 38, Issue 12, 2014, 1413–1419 5
5/28/2016 Prognosis in CMML WHO 2016 Updates in CMML • Subtypes of CMML (prognostic significance) Kaplan–Meier curve of survival of CMML Kaplan–Meier curve of survival of CMML I dysplastic vs CMML I proliferative. 0 dysplastic vs CMML 0 proliferative. – Based on WBC count • Proliferative type : WBC ≥13 x 10(9)/L • Dysplastic type : WBC <13 x 10(9)/L Kaplan–Meier curve of survival of CMML II dysplastic vs. CMML II proliferative. E. Schuler, et al. Refined medullary blast and white blood cell count based classification of chronic myelomonocytic leukemias. Leukemia Research, Volume 38, Issue 12, 2014, 1413–1419 Promonocytes vs Abnormal Monocytes Other Things to Remember in CMML Abnormal monocytes Promonocytes • Rare cases of MPN with associated monocytosis may simulate CMML. – A previous documented history of MPN excludes CMML – The presence of classical MPN features in the bone marrow and/or of MPN associated mutations (JAK2, CALR or MPL) tend to support MPN with monocytosis rather than CMML. • Important to distinguish blast equivalents (myeloblasts, monoblasts and promonocytes) from abnormal monocytes 6
5/28/2016 Differential Diagnosis of CMML Case 2 • Reactive monocytosis: more common than CMML • 60 y.o. man who was found to have anemia and • Acute myeloid leukemia vs CMML-2 thrombocytopenia on a CBC prior to cataract – Important to distinguish abnormal monocytes from blast surgery. Within a few weeks he developed equivalents • Chronic myelogenous leukemia, particularly CML with marked leukocytosis and was referred to UCSF • Presence of night sweats, diarrhea and elevated p190 fusion protein: BCR/ABL must be evaluated • Lymphoid/myeloid neoplasms with PDGFRA , PDGFRB and LFTs FGFR1 rearrangements vs. CMML with eosinophilia • Also found to have hepatosplenomegaly and • Myelodysplastic syndrome vs. low count CMML: lymphadenopathy – Monocytosis ≥1 X10(9)/L, with monocytes accounting for ≥10% • No reactive etiology for leukocytosis identified of the white blood cell count : CMML Case 2: Peripheral Blood Case 2: Marrow (dry tap) WBC 79.5 x10E9/L, HGB 8.3 g/dl, MCV 89 fl, PLTS 30 x10E9/L; neutrophils 64% (50.88), lymphocytes: 13% (10.33) , monocyte 7% (6.16) , immature granulocytes 14% (11.13), blasts: 2% (1.59), basophils 0. Hypercellular marrow Marked granulocytic hyperplasia Decreased megakaryocytes Virtually absent erythropoiesis No increase in blasts by CD34 and CD117 7
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