Myelodysplastic Neoplasms. Myelodysplastic Neoplasms Con t

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1 Myelodysplastic Neoplasms Found primarily in patients older than 50 years Characterized by indolence, peripheral p cytopenias, hypercellular marrow, less than 20% blasts, and varying amounts and degrees of dysplasia in at least 2 cell lines Oval macrocytes, bizarre giant platelets and dysplastic myeloid cells characterize dysplasia. Thrombocythemia is often found Myelodysplastic Neoplasms Con t MDS is associated with a common mutant defective stem cell. Cytogenetic studies usually demonstrate chromosomal aberrations. The most common is -5, -7, 7q and trisomy 8 A high percentage of the MDS patients (app. 40%) will terminate in AML Treatment is infusion with blood growth factors, such as G-CSF or GM-CSF. The use of these drugs usually results in normal maturation of the malignant dysplastic clone, with relatively normal functionability. 2

2 Myelodysplastic Neoplasms Con t Treatment is infusion with G-CSF or GM-CSF. These drugs usually results in normal maturation of the dysplastic clone, with relatively normal functionability. The function of these drugs in the maturing cells is to increase chemotaxis enhance phagocytosis increase cytotoxic killing improve responsiveness to antigens Myelodysplastic Neoplasms Refractory anemia with unilineage dysplasia(ra) Refractory anemia with ringed sideroblasts (RARS) Refractory cytopenia with multilineage dysplasia Refractory anemia with multilineage dysplasia and ringed sideroblasts (RAMD-RS) Refractory Anemia with Excess of Blasts (RAEB) RAEB 1 (5-9 blasts) RAEB 2 (10-19 blasts MDS unclassified MDS associated with 5q- syndrome Childhood myelodysplastic syndrome Refractory cytopenia of childhood 3

3 Factors Indicating Poor Prognosis > 5% bone marrow blasts and circulating CD34+ cells Abnormal karyotypes and ineffective erythropoiesis with, < 20% ring sideroblasts Less than 1,000 x 103/µL granulocytes, thrombocytopenia (<140 x 103/µL) decreased monocytes hemoglobin less than 9.0g/dL Previous exposure to radiation or chemotherapy Peripheral Blood Bone Marrow Refractory Anemia (RA) Normochromic/macrocytic Normo - hypercellular Median Survival ~ 47 mo. <1% blasts Variable dyserythropoiesis decreased reticulocytes Normal granulocytes and mild anemia megakaryocytes. <5% blasts <15% ringed sideroblasts Refractory Anemia < 1% blasts Ringed sideroblasts account with Ringed Sideroblasts Dimorphic RBCs for >15% of all nucleated (RARS) Hypochromic macrocytes with marrow cells Pappenheimer bodies Dyserythropoiesis Median Survival ~ 52 mo. Mild to severe anemia < 5% blasts Refractory Cytopenias with Variable amounts of dysplasia Dysplasia in 10% of cells Multilineage dysplasia (RCMD) in 2+ lineages <5% blasts <1%blasts <15%ringedsideroblast Refractory Cytopenia with Variable amounts of dysplasia Variableamountsofdysplasia multilineage dysplasia and in 2+ lineages in 2+ lineages ringed Sideroblasts (RCMD-RS). < 1% blasts 15% ringed sideroblast Cytopenias <5% blasts Refractory Anemia Variable cytopenias. Normo hypercellular 5-9% Blasts with Excessive Blasts (RAEB 1) Severe dysplasia Uni or multilineage dysplasia Refractory Anemia with Same as above except Normo hypercellular, with Excessive Blasts (RAEB ll) 5 19% blasts granulocytic hyperplasia Uni or multilineage dysplasia 10-19% blasts Myelodysplastic Syndrome Cytopenias Unilineage dysplasia Unclassified (MDS-U) >1% blasts < 5% blasts MDS Associated with 5q - Anemia Normal to increased Normal to increased plt count dysplastic megakaryocytes <5% blasts <5% blasts Isolated 5q abnormality 4

4 Dysplastic RBCs Dysplastic platelets 5

5 Dysplastic granulocytes Hypersegmented Dysplastic PMN 6

6 Dysplastic RBCs-BONE MARROW Ringed Sideroblasts in MDS 7

7 Dysplastic Grans vs Pelger Huet Hyposegmented usual Occ. Hypersegmented Hyperchromatin Clumping except when hypersegmented Hypogranulated Lymphocytes Normal Hyposegmented Hyperchromatin Clumping Normal Granulation Lymphocyte Hyperclumped PELGER HUET ANOMALY 8

8 DRUG INDUCED DYSPLASIA Dysplastic nucleus, usually round or barely indented Normal to toxic cytoplasmic granulation (depending on therapy) May be confused with a left shifted Pelger Huet Anomaly Patient history important to differentiate 9

9 Chronic Myeloproliferative Neoplasms Chronic Myelogenous Leukemia (CML) Polycythemia Vera (PV) Idiopathic Myelofibrosis Essential Thrombocythemia (ET) Chronic MPN, Unclassifiable Chronic Neutrophilic Leukemia Chronic eosinophilic leukemia NOS Mastocytosis 10

10 CML Positive Ph+ chromosomet(9;22) or BCR/C-ABL gene rearrangement characterized by a marked leukocytosis Symptomology when white counts above 50 x 109/L Increase in mature and immature cells of the granulocytic series, including both eosinophils and basophils, thrombocytosis, splenomegaly ( most likely due to extramedullary hematopoiesis) and the presence of the Ph1 chromosome t(9:22) CML con t Normocytic normochromic anemia, if present Platelets counts can rise to 800K/dL, although thrombocytopenia is not uncommon. Occasional giant forms may be seen. The higher the white count, the lower the platelets, due to "squeezing" out of marrow megakaryocytes by extremes in granulocytic hyperplasia. 11

11 Differential in CML Differential results usually approach the following figures. blasts: 1-5%; (chronic phase, PB and BM) >5 <20% (accelerated phase, PB and BM) >20% (blastic phase, PB or BM) promyelocytes: 1-10% myelocytes: 10-20% metamyelocytes: 10-30% bands: 20-40% neutrophils: 30-50% eosinophils: 2-15% ( with young forms present) basophils 2-10% normoblasts: 2-4%. CML 12

12 Prognosis of CML Blast transformation is usual course of the disease. Transformation may be of myeloid, lymphoid or megakaryocytic type. 1/3 of cases will transform into pre-b ALL. Prognosis for remission, in this case, is better, since patients often have a good response to vincristine and prednisone therapy. However, this remission is short- lived, and relapse is usually of fthe AMLtype, with ithlittle response to therapy. AML transformation is also non-responsive to conventional myeloid therapy. Prognosis of CML con t The drug having the most promising effects is Gleevac. Most efficient in early to mid stage CML. Not much promise with patients in accelerated phase or blast transformation. Hydroxyurea and plasmaphoresis used when WBC exceptionally high. The only real cure is a successful bone marrow transplant. 13

13 Signs of Impending Myeloid Blast Crisis Dysplastic changes of the myeloid line and/or Sudden decrease in the WBC or plt count and/or Increase in the blast count and/or Increasing basophils CML- Early Warning Signs of Impending Acceleration 14

14 CML EARLY ACCELLERATION WHO Criteria for CML in Accelerated Phase PB or BM blasts 10-19% 19% Persistent thrombocytopenia < 100K, not related to treatment Thrombocytosis >1 million, unresponsive to treatment Increasing WBC and spleen size 15

15 CML in Accelerated Phase con t. Evidence of clonal evolution by cytogenetic analysis +Ph, +8, iso(17q), +19 Basophilia >20% in PB Marked dysplasia in granulocytes, or prominent proliferation of dysplastic megakaryocytes associated with marked fibrosis consistent with accelerated phase 16

16 CML in AML Transition De Novo (Ph+ AML) > 20% blasts with increased basophils and/or eosinophils > 20% blasts with increase in either normal or abnormal platelets > 20% blasts with Ph+ chromosome. 17

17 CML in AML Transition Lymphoblastic Transition of CML 18

18 Megakaryoblastic Transition Erythroblastic Transition of CML 19

19 WHO Criteria for Dx of Polycythemia Vera Major RBC mass >25% above mean normal predicted value, or Hgb > 18.5 g/dl in men or 16.5 g/dl in women Splenomegaly on palpation Clonal genetic abnormality other than Ph chromosome or BCR/ABL gene in marrow Endogenous erythroid colony formation in vitro Minor Thrombocytoisis i > 400,000/µL000/ WBC > 12,000/µL Panmyelosis with prominent erythroid and megakaryocytic hyperplasia on bone marrow biopsy Low serum erythropoietin levels Clinical Results of P. Vera Iron deficiency results from continual bleeding (due to hypo function of the platelets), repeated therapeutic phlebotomy, increased erythrocyte production and iron turnover, and decreased red cell survival An iron deficiency state is the desired effect, because it limits how extensively the red cell mass can expand. A greatly expanded red cell mass increases the chance of a thromboembolic episode or hemorrhage. Portal vein thrombosis is a classic presenting symptom. Most obvious change in the peripheral blood of long-term P Vera Most obvious change in the peripheral blood of long-term P Vera patients is appearance of tear drop red cells. This heralds the most common transition of P.Vera, that of increasing myelofibrosis with myeloid metaplasia. At this point, the patient is in the "spent phase" or in the "post-polycythemic myelofibrosis" (PPMF) phase of the disease. 20

20 Polycythemia Vera Post Polycythemic Myelofibrosis 21

21 PPMF s/p Splenectomy Chronic IdiopathicMyelofibrosis Associated with 13q ; t(1;13) Clonal chronic myeloproliferative disorder Found mostly in older people Found on rare occasion in children, both as a primary idiopathic disease, or secondary to acute leukemia Closely related to the other myeloproliferative diseases All of the other chronic myeloproliferative disorders can have varying amounts of fibrosis as a secondary complication. Myeloid metaplasia means there are marrow cells produced in hematopoietic sites outside the marrow. This is also referred to as extra medullary hematopoiesis. 22

22 Idiopathic Myelofibrosis con t The sites that can form hematopoietic elements are the same tissues that form blood cells in utero, such as the liver, spleen and reticuloendothelial system. Many tear drops are present, a significant ifi finding in patients t with normocytic, normochromic anemia, and should alert the technologist to search for conclusive evidence of myeloid metaplasia. Examination of the blood film usually reveals at least one other pathological finding: an occasional nucleated red blood cell, an abnormal giant agranular platelet, a rare megakaryocyte fragment, and occasional immature myeloid cell, including a rare myeloblast. Note, that although a slight reticulocytosis may be found, it is usually out of proportion to the number of nucleated red blood cells found. This is especially true as the disease progresses, indicating ineffective erythropoiesis. Idiopathic Myelofibrosis Con t Blood counts may demonstrate an increase or decrease in the number of WBCs and platelets. A mild anemia may be present, but is usually normocytic ocyt c normochromic. oc o c Occasionally, a microcytic anemia is found, usually in patients with repeated episodes of G.I. bleeding. These patients usually have abnormal coagulation studies. As diseases progresses NRBCs immature As diseases progresses, NRBCs, immature granulocytes (including myeloblasts), megakaryocytic fragments and micromegakaryocytes increase. Patients may become severely thrombocytopenic with increasing splenic sequestration, or the platelet count may become abnormally high, with giant and bizarre forms. 23

23 Idiopathic Myelofibrosis con t Splenectomy is usually palliative, and done when symptomatology dictates. Prognosis is grave, and eventually patients die from complications of total marrow failure. This failure usually results in hemorrhage, infections, or cardiac complications. Approximately 5-8% terminate in acute myeloid leukemia (M1 type) or megakaryocytic leukemia (M7 type). 3 Things Needed to Prove CIMF in Peripheral Blood Tear drop RBCs in a normocytic normochromic anemia Giant and bizarre platelets A leukoerythroblastic blood picture, preferably with at least 1 blast 24

24 Chronic Idiopathic Myelofibrosis Myelophthistic Anemia Is a non hematopoietic tumor in the marrow Associated with a leukoerythroblastic blood picture Only tumors that can cause compensatory extramedulary hematopoiesis will have tear drops. They most commonly are Breast Prostate Bladder 25

25 Essential Thrombocythemia Associated with variable chromosomal aberrations Chronic myeloproliferative disease characterized by a thrombocytosis in excess of 1 x10 12 /L. (1 million). Closely related to polycythemia vera, the major difference is that polycythemia vera is an increase in the total red cell mass; and essential thrombocythemia is an increase in the total platelet mass. Hgb must be <13 gms Most striking element is the persistence of a marked thrombocytosis, with platelet counts reaching greater than one million. On rare occasions, platelet counts reach levels of fourteen million. Essential Thrombocythemia, con t Spontaneous aggregation of platelets that have an abnormal function. Large masses of platelet aggregates seen on the blood film, with abnormal appearing giant and bizarre forms, some normal immature forms, many small forms, and an occasional megakaryocyte fragment. Gastrointestinal hemorrhage is a common risk with these patients, and is often the cause of death. Patients whose hemorrhagic tendencies have been kept under control, run the risk of an acute leukemia transformation (5-10% of cases), the most common of which is transformation to acute myelogenous leukemia. Transformation into acute lymphocytic or megakaryocytic leukemia has the same probability as the patients with CML. Treated with hydroxyurea or the newest drug, Anagrelide, which is specific for megakaryocytes. 26

26 Essential Thrombocythemia CMPD - Unclassifiable Have all characteristics of a CMPD but fail to meet any specific criteria of a specific CMPD Usually have initial stages of PV, Pre fibrotic CIMF, or ET but characteristic features are missing No Philadelphia chromosome or BCR/Fusion gene No basophilia or dysplasia No signs of reactive myelopoiesis or thrombopoiesis are present It is essential to determine which specific CMPD is present, once the distinction becomes obvious, because of prognostic and therapeutic differences. 27

27 CMPD - U Chronic Neutrophilic Leukemia Rarest of the chronic myeloproliferative disease Most obvious finding is the persistence of neutrophils and bands, without t evidence of increased left shifting, and an absence of sepsis and/or fever. Toxic granulation and Döhle bodies are present Rarely, a nucleated red blood cell may be found. White blood counts may go as high as 100 x 10 9 /L, with a normal to slightly decreased platelet count, and a mild anemia. 28

28 CNL con t Hemoglobin is approximately 11 g/dl. LAP scores are extremely high, ranging from Markedly elevated B12 and B12-binding capacity is common Bone marrow shows normal maturing myeloid hyperplasia There is tissue infiltration ti with mature PMNs Hepatosplenomegaly No evidence of another myeloproliferative disorder or myelodysplastic syndrome CNL 29

29 Chronic Eosinophilic Leukemia Persistent eosinophilia 1.5 x 109/L in blood and increased in bone marrow. Hypercellular marrow <20% blasts in bone marrow, fibrosis in some cases Clonality of the eosinophils must be proved Exclude all other causes of eosinophilia: Reactive (allergy, parasites, infectious diseases, pulmonary diseases such as Loeffler s, and collagen diseases) Neoplastic disorders with secondary eosinophilia Neoplastic disorders in which eosinophils are a part of the neoplastic clone (other myeloproliferative disorders Taken from WHO Classification of Tumors - Diagnostic criteria of chronic eosinophilic leukemia Chronic Eosinophilic Leukemia 30

30 Loeffler Syndrome Also called Simple Pulmonary Eosinophilia Often caused by Ascarid infections Does well without treatment. If not can treat with anti allergens or anti parasitic drugs Marked peripheral eosinophilia, often with signs of degranulation Loeffler Endocarditis Prominent eosinophilic infiltration in tissues, such as heart, lungs, skin and CNS causing severe organ damage. 31

31 Transitions in the Chronic Myeloproliferative Disorders Myelofibrosis with Myeloid Metaplasia (Secondary) Chronic Myeloid Leukemia Polycythemia Vera 30% 20% AML (De Novo) ACUTE MYELOCYTIC LEUKEMIA Aplastic Anemia Acute Lymphocytic Leukemia Essential Thrombocythemia Paroxysmal Nocturnal Hemoglobinuria Myelodysplastic Syndromes and SML Agnogenic Myeloid Metaplasia (Primary) Frequent Infrequent Myelodysplastic/Myeloproliferative Atypical CML (acml) Juvenile CMML (jcmml) Chronic Myelomonocytic y Leukemia (CMML) Myeloproliferative/myelodysplastic neoplasm, unclassifiable 32

32 MDS/CMPD Peripheral Blood Bone Marrow Chronic Myelomonocytic Persistent monocytosis of Increase in dysplastic monos Leukemia (CMML) >1x109/L for 3 or more months <20% blasts Variable dysgranulopoiesis. Variable dysgranulopoiesis <5% blasts More aggressive forms may Monos appear mature but have Auer rods in marrow Median Survival dysplastic myeloblasts highly variable CMML - 1 = <5% blasts <10% in bone marrow CMML - 2 = 5-19% blasts 10-19% in bone marrow Atypical CML (acml) Granulocytic Leukocytosis Neg for Ph+ and BCR/ABL Marked dysplasia in granulocytes Dysplastic granulocytic No monocytosis hyperplasia No Basophilia Variable dysplasia in erythroid or megakaryocytic line. < 20% blasts Juvenile CMML (jcmml) Monocytosis of >1x109/L Blasts < 20% (includes Blasts < 20% (includes promonocytes) promonocytes) Neg for Ph+ and BCR/ABL Increase in immature grans Common for monosomy 7 WHO Criteria for CMML Persistent blood monocytosis >1000/µL Negative Philadelphia chromosome and BCR/ABL fusion gene. <20% *blasts in blood or bone marrow Usually have multilineage dysplasia; if not then other requirements are necessary Acquired cytogenetic abnormality in bone marrow cells or Monocytosis persistent for at least 3 months and All other causes of monocytosis has been eliminated. *Blasts include myeloblasts, promonoytes and monoblasts. 33

33 WHO Criteria for jmml Abnormal granulocytes and monocytes (promonocytes are equivalent to blasts Monocytes >1000/µL, with blasts and promonocytes < 20% in blood and marrow Philadelphia chromosome and BCR/ABL fusion gene negative Plus 2 or more of the following Hgb F increased for age Immature granulocytes in blood WBC > 10,000/µL. 000/µL Clonal chromosomal abnormality often monosomy 7 GM-CSF hypersensitivity of myeloidprogenitors in vitro Taken from WHO Classification of Tumors - Diagnostic criteria of juvenile myelomonocytic leukemia. CMML 34

34 Atypical CML (acml) Leukemic disorder that has both myelodysplastic and myeloproliferative features Leukocytosis with mature and immature granulocytes Dysplastic features often seen in all 3 lines Basophilia is absent Philadelphia l chromosome and/or BCR/ABL fusion gene absent Found in older people median age is 7 th to 8 th decade Hepatosplenomegaly is common acml 35

35 Acute Myeloid Leukemia (NOS AML (M0) with minimal differentiation AML (M1) no maturation AML (M2) with maturation AML (M4) myelomonocytic AML (M5) monocytic AML (M6) erythrocytic AML (M7) megakaryocytic Acute Basophilic Leukemia Acute Panmyelosis with Myelofibrosis Myeloid Sarcoma Acute Leukemia of Ambiguous Lineage Undifferentiated acute leukemia Biclonal acute leukemia Biphenotypic acute leukemia 36

36 Acute Myeloid Leukemia with Recurrent Cytogenetic AML with maturation t(8;21) AML with abnormal BM eosinophils (inv)16 Acute promyelocytic leukemia AML with 11q23 (MLL) abnormalities t(15;17) AML with inversion 3 (inv 3) AML with multilineage dysplasia AML and MDS syndromes, therapy related Factors predicting a poor prognosis >than 5% bone marrow blasts Abnormal karyotypes Less than 1,000 x 103/µL granulocytes Thrombocytopenia (<140 x 103/µL) Decreased monocytes 37

37 Factors predicting a poor prognosis (con t) Ineffective erythropoiesis Hemoglobin less than 9.0g/dL Previous exposure to radiation or chemotherapy Less than 20% ring sideroblasts in bone marrow Circulating blasts and circulating CD34+ cells. AML Minimally Differentiated No evidence of myeloid differentiation by morphology or microscopic cytochemistry Diagnosed by immunophenotyping with positivity for CD34, CD38 and DR. Also express pan-myeloid antigens of CD13, CD33 and CD117. Very poor prognosis 38

38 Minimally Differentiated AML AML (M1) Blasts >90% of non erythroid cells in the marrow with no maturation. Several of the Blasts may be type l or ll blasts Auer rods may be seen Special stains = MPO + NSE - 39

39 AML (M1) AML with Maturation (M2) >20% marrow blasts with maturation seen in blood or bone marrow Auer rods may be present Type ll and lll blasts are common. Promyelocytes, myelocytes, and mature neutrophils make up >10% of marrow cells Dysplasia in the myeloid line may be seen. Special stains = MPO + NSE - 40

40 AML with Maturation (M2) Acute Myelomonocytic Leukemia (M4) Both myeloblasts and monoblasts present, with some maturation in both lines. Special stains = MPO + NSE + in bone marrow and blood Maturation appears dysplastic Bone marrow morphologically, tends to appear more myeloid than monocytic; monocytic element and their precursors + neutrophils and their precursors exceeds 20% of nucleated cells in marrow. Cytogenetics = abnormalities involving chromosome 11. Inv(3) seen with normal to increased plts. 41

41 Acute Myelomonocytic Leukemia (M4) Acute Monocytic Leukemia >80% of marrow cells are monoblasts, promonocytes, and some monocytes. WHO separates the monoblastic leukemias and monocytic leukemias listed under one heading, similar to FAB. In monoblastic leukemias, the majority of the monocytic cells are monoblasts (>80%).This is the FAB M5A. In the acute monocytic leukemias, the majority of monocytic cells are promonocytes. This is the FAB M5B. Monoblasts very large with abundant cytoplasm, sometimes with pseudopod formation. May have few azurophilic granules and vacuoles. They have a round nucleus with delicate lacey chromatin. Large nucleoli. Convolutions are not seen Promonocytes more irregular than the blast, with delicate convolutions. Nucleoli may be seen. Vacuoles and azurophilic granules are more obvious. Smaller nucleoli than in blast. 42

42 Acute Monoblastic Leukemia Acute Monocytic Leukemia 43

43 Acute Erythroid Leukemia Greater than 50% erythroblasts and 20% myeloblasts in the marrow. Anemia is often severe Peripheral blood may have blood picture identical to MDS patients with more extreme RBC changes. Patient is often pancytopenic. This actually is a three stage disease, starting out as an erythroid leukemia, slowly transforming to an intermediate stage with an increase in myeloblasts, and finally terminating into a phase indistinguishable from acute myeloid leukemia (M1). This is probably not an acute leukemia de novo, but a rapid transformation from a myelodysplastic syndrome. Acute Erythroid Leukemia 44

44 Pure Erythroblastic Leukemia Referred to in the past as erythemic myelosis This is a pure erythroblastic leukemia. Leukopenia, marked anemia and thrombocytopenia are the classic signs, with either increased or decreased numbers of proerythroblasts in the peripheral blood. The bone marrow is hypercellular, with a marked increase in promegaloblastoid cells. There is a marked decrease in both myeloid and megakaryocytic elements. This is the rarest of the myeloid leukemias, with a life expectancy of approximately 5-8 weeks. Pure Erythroblastic Leukemia 45

45 Acute Megakaryocytic Leukemia Acute myelosclerosis is similar to M7, however it does not have the trilineage dysplasia. Megakaryoblasts have basophilic cytoplasm, some of which show cytoplasmic blebbing and vacuoles Bizarre platelets may be present with exact morphology as the megakaryoblast cytoplasm. Micromegakaryocytes may be present Bone marrow is often fibrotic Acute Megakaryocytic Leukemia con t If associated with abnormal chromosome 3, patient often appears normal shortly before the acute phase The acute leukemia presents with normal to increased numbers of giant and bizarre platelets Appears to have a poorer prognosis than the other myeloid leukemias CD61 positive. Should be proven with slide immunophenotyping 46

46 Acute Megakaryocytic Leukemia Transient Megakaryocytic Leukemia of Downs Syndrome (TMPD) Children born with Downs Syndrome Severe granulocytopenia and thrombocytopenia Megakaryoblastic leukemia in blood and bone marrow Disappears at approximately 3 months of age. Stands a high probability of returning as AML at 3-5 years of age. 47

47 ACUTE BASOPHILIC LEUKEMIA < 1% of all AML cases Could be de novo or transition from other BCR/ABL + CML All other features of AML are present May show signs of some lytic lesions, cutaneous involvement, organomegaly, g and symptoms usually related to hyperhystaminemia Positive for toluidine blue positive.\ 48

48 Acute Leukemia of Ambiguous Lineage Undifferentiated acute leukemia Biclonal acute leukemia Biphenotypic acute leukemia 49

49 AML NOS Biphenotypic AML/T-Cell ALL 50

50 Acute Myeloid Leukemia with Recurrent Cytogenetic Abnormalities AML with maturation t(8;21) AML with abnormal BM eosinophils (inv)16 Acute promyelocytic leukemia AML with 11q23 (MLL) abnormalities AML with inv (3) AML with multilineage dysplasia t(15;17) AML and MDS syndromes, therapy related AML t(8;21) This is the most common translocations in AML Associated with good response to chemotherapy and with high complete remission and long term disease free survival The presence of CD56 expression and other karyotypic abnormalities affect survival The only acute myeloid leukemia that can have blasts below 20% and still be considered an acute leukemia, as long as t(8;21) is present 51

51 AML t(8;21) con t Contain large blasts and promyelocytes with abundant granules. Dysplasia in the maturing granulocytes often seen in the blood Promyelocytes have a distinct Golgi Single Auer Rods often found that are long and sharp with tapered ends The single feature that distinguishes a t(8;21) is blasts containing very large salmon colored granules. Often find increased numbers of normal eosinophils AML t(8;21) 52

52 AMML Eo inv(16) AML with features of myeloid and monocytic differentiation Good prognosis, with high rates of complete remission when treated with cytarabine in the consolidation phase Increased numbers of eosinophils in all stages. Immature eosinophils contain not only large eosinophilic granules, but also varying numbers of large purple to black granules. Granules of some eosinophils sometimes so dense, the morphology of nucleus is obscured ASD chloracetate esterase, usually negative in normal eosinophils is characteristically faintly positive in these eosinophils. AML EOS (inv 16) 53

53 Acute Promyelocytic Leukemia t(15;17) AML with a predominence of abnormal microgranular, hypogranular, or rarely hypergranular promyelocytes Distinct nuclear shapes, with bi-nucleate and butterfly forms Variable numbers of azurophilic granules in the microgranule variant to sub microscopic granules in the hypogranular variant Bundles of Auer rods (faggot cells) often present Gene Rearrangement Findings Associated with t(15;17). There is a breakpoint on chromosome 17 in the region of the retinoic acid receptoralpha (RAR-a) Present chemotherapy - this receptor, (RAR-a), has been shown to be involved with growth and differentiation of myeloid cells in vitro, and treatment with All Transretinoic Acid (ATRA) induces complete remission Response to this therapy shows: maturation of leukemic cells during initial induction and remission achieved with low morbidity Complications of DIC are possibly related to release of granules during treatment Patients with the occ. T(11;17) do not respond to ATRA therapy 54

54 A new therapy now in clinical trials is Is called Tamibarotene It s a synthetic retinoid It is approximately ten times more potent than ATRA in inducing cell differentiation and apoptosis in vitro Acute Promyelocytic Leukemia t(15;17) 55

55 M1 with Inversion 3 Characterized with giant and bizarre platelets l t in blood. No other dysplasia present Bone marrow shows increased uninuclear and binuclear megakaryocytes 56

56 AML with Myelodysplastic Changes Non Malignant and Toxic Conditions May Hegglin Anomaly Muccopolysacharide Disorders Chediak-Higashi Disorder Parvo virus B19 Infection Bacterial, Fungal, Parasitic Infections Histoplasmosis 57

57 May Hegglin Anomaly Transmitted as autosomal dominant. Giant Döhle-like bodies (crescent shaped) found in PMNs, eos, basos, monos, and rarely lymphs. These Döhle - like bodies probably represent alterations in RNA. Moderate thrombocytopenia, with giant bizarre platelets, having abnormal thromboplastic function. It is important to recognize the bizarreness of the platelets. Sometimes they are agranular, but often have abnormal granules centrally located in an adentritic platelet. l t Patients rarely have spontaneous bleeding tendencies, but have excess bleeding even after minor trauma. May Hegglin Anomaly 58

58 Muccopolysacharidosis Chediak Higashi Syndrome 59

59 PARVOVIRUS B19 INFECTION Parvovirus B19 is the only known human pathogenic parvovirus asymptomatic in the non immunocompromised in patients infected during hemolytic crisis episode, a marked, but transient, erythroid aplasia can occur due to failure of erythroid line to mature beyond proerythroblast stage. In patients infected during a hemolytic crisis episode, a marked, but transient, erythroid aplasia can occur due to failure of the erythroid line to mature beyond the proerythroblast stage. This viral cytopathology is only evident in the erythroid line PARVOVIRUS B19 con t Infection creates an inability of the pronormoblast to mature beyond the pronormoblastic stage Studies demonstrate that it s essential for RBCs to have a specific cellular receptor before viral infection can occur. It is proposed that the receptor for infection with parvovirus B19 is the erythrocyte P antigen Marrow pronormoblasts have a giant appearance, with smooth chromatin pattern with intense cytoplasmic RNA staining. There are characteristic large pink to lilac intranuclear inclusions present 60

60 PARVOVIRUS B19 INFECTION Bacterial, Fungal and Parasitic Infections E. Coli Candida Yeast Hyphae Erlichiosis 61

61 Histoplasmosis Spirochetes Babesia Malaria 62

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