1 MYELOPROLIFERATIVE SYNDROMES & LEUKEMIA Doç. Dr. Işın Doğan Ekici

2 Myeloproliferative syndromes (MPS; blast crisis)  Excess proliferation of marrow cells (myelopoiesis) with dysplasia  Progress to Leukemia  Ineffective Myelopoiesis marrow hyperplasia with pancytopenia. Primary or Secondary

3 Bone Marrow Cellularity NormalHypercellularHypocellular

4 Primary MPS  Agnogenic myeloid metaplasia  Polycythemia rubra vera  Chronic myeloid leukemia  Essential hemorrhagic thrombocythemia  Myelofibrosis

5  The following "myeloproliferative diseases" are all "tumors of the multipotent myeloid stem cell", and can transform into one another (usually from a mild one to a bad one): polycythemia rubra vera (PV) essential (hemorrhagic) thrombocythemia (ET) agnogenic myeloid metaplasia (AMM) idiopathic "aplastic anemia" (AA) chronic myeloid leukemia. (CML)

6 Myeloproliferative syndromes: Pathogenesis

7 Agnogenic (idiopathic) myeloid metaplasia Proliferation of neoplastic stem cells in the –bone marrow (becomes hypercellular) –red pulp of the spleen (enlarges greatly; splenomegaly). the cells that enter the blood are fully functional neutrophilia/neutropenia/normal neutrophil counts no tendency to over-produce red cells. Peripheral smear shows a leukoerythroblastic pattern: –red cells made in the spleen tend to be teardrop-shaped (poikilocyte), –nucleated red-cell precursors from the spleen.

8 Bone marrow  dense fibrosis (several years)  Cytopenia or transformation to acute leukemia. Differential diagnosis (if there is an unexplained myelofibrosis without splenomegaly) : –Chronic myeloid leukemia, –Polycythemia vera, –Metastatic carcinoma.

9 Polycythemia rubra vera (PV) Syn.:Osler's polycythemia; erythrocytosis. An abnormally high hemoglobin.

10 Classification Relative polycythemia –Dehydration Absolute polycythemia (increased circulating red cell mass): –Primary polycythemia Polycythemia vera rubra –Secondary polycythemia Effective renal arterial hypoxia –Emphysema –Tetralogy of Fallot –Hemoglobins with too much oxygen affinity Erythropoietin-producing tumors –Renal cell carcinoma –Hepatocellular carcinoma –Cerebellar hemangioblastoma (?!) Anabolic steroid users Sleep apnea After kidney transplant Altitude

11 Polycythemia vera is a proliferation of stem cells: –they are very erythropoietin-sensitive –mostly mature into red cells –in addition to a high red cell count, white cells and platelets are likely to be high. Older middle-age. Increased volume of hyperviscous blood. On biopsy: a very hypercellular marrow, with all cell lineages increased. In the late stages: –marrow fibrosis –replacement by blasts –transformation to acute myelogenous leukemia.

12 Complications: Congestion (widespread; red face) Venous stasis Rupture of dilated veins –hemorrhage GI bleedings Hemorrhagic stroke.

13 Myelofibrosis  The marrow is replaced by fibrous (scar) tissue.  Causes blood formation to take place in sites other than the bone marrow, such as the liver and spleen, causing enlargement of these organs. Primary  Idiopathic myeloid metaplasia Secondary  Autoimmune SLE  Polycytemia vera  Carcinoma infiltration  Leukemias  Complications: Sever anemia with low platelet & splenomegaly Hepatomegaly & Liver failure Acute myelogenous leukemia.

14 Myelofibrosis teardrop cells 

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16 (Preleukemias ; Carl Sagan's disease)  Ineffective Myelopoiesis marrow hyperplasia with pancytopenia.  Excess proliferation with dysplasia.  This is a family of disorders in which there are problems in producing red cells, granulocytes, platelets. Myelodysplastic syndromes

17 FAB classification 1. Refractory anemia (poor hemoglobinization, too few red cells): (Blasts <1%) 2. Refractory anemia with ringed sideroblasts (>15% of nucleated red cells) 3. Refractory anemia with excess blasts (5- 20% myeloblasts) 4. Refractory anemia with excess blasts in transformation (20-30% myeloblasts) 5. Chronic myelocytic leukemia.

18 WHO 2008 MDS CLASSIFICATION  ● Refractory anemia (RA): 10% in one myeloid lineage ● RA with Ringed Sideroblasts (RARS): 15% or more sideroblasts, less than 5% blasts, erythroid dysplasia only ● Refractory cytopenia with multilineage dysplasia (RCMD): cytopenia, 10% of cells in two or more lineages, no Auer rods ● RA with Excess Blasts (RAEB): type 1 has 5-9% blasts in blood/marrow, peripheral cytopenia, unilineage or multilineage dysplasia, no Auer rods; type 2 has 10-19% blasts in blood/marrow, unilineage or multilineage dysplasia, Auer rods may be present, peripheral cytopenia ● MDS with isolated 5q- syndrome: anemia, <5% blasts, del(5q), no Auer rods, normal/increased hypolobated megakarycoytes ● MDS, unclassified: cytopenia(s), dysplasia in <10% of cells in one or more myeloid cell lines, accompanied by cytogenetic abnormalities with presumptive evidence of MDS, <5% blasts ● Therapy related MDS

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20 Dysplastic Erythroblasts

21 Clinical findings Most patients are older adults, often asymptomatic (detected on routine screening) in the more aggressive forms, death follows in a few years. Propensity to transform into acute myeloid leukemia.

22 LEUKEMIAS ACUTE & CHRONIC

23 WBC Neoplastic disorders  Leukemias Bone marrow, blood, blast cells Acute/Chronic & Myeloid/Lymphoid AML / ALL & CML / CLL  Lymphomas – Lymph nodes, tumor Hodgkins - Non-Hodgkins. Myeloma  Premalignant conditions: Myeloproliferative syndromes ( MPS ) Myelodysplastic syndromes ( MDS )

24 Introduction:  No Benign Neoplasms – All are considered malignant or premalignant.  Neoplastic Cells flood blood stream – Leukemia.  Commonly arise in marrow (myelo/ly) or Lymph node (lymphoid),  Spread to blood & other RES tissues rarely to other organs  Symptoms are due to deficient normal hemopoiesis. RBC, WBC & Plt.

25 Leukemia - Clinical Features  Anemia (low RBC)  Fever - Infections (low WBC)  Bleeding tendency (low PLT)  Tender bones, lymphadenopathy, spleenomegaly etc. (Leukemic infiltration)

26 Leukemia Classification  Acute Leukemias: Acute Myeloid Leukemia - AML  AML M0, M1, M2, M3, M4, M5, M6 & M7 Acute Lymphoid Leukemia - ALL  ALL - L1, L2 & L3 - maturity  Chronic Leukemias: Chronic Myeloid Leukemia- CML Chronic Lymphoid Leukemia - CLL

27 ACUTE LEUKEMIA  Genetic disorder characterized by uncontrolled clonal proliferation of expansion of hematopoietic cells that do not retain the capacity to differentiate normally to mature cells

28 Triggers of Differentiation Mishap  Not really known Virus  Clusters of leukemia Ionizing radiation  Survivors of Hiroshima and Nagasaki Genetics  Higher incidence in siblings and twins of affected pt  Higher incidence in children with fragile chromosomes and impaired DNA repair mechanisms Down syndrome, Fanconi syndrome, Bloom Syndrome Ataxia-telangiectasia, congenital hypogammaglobulinemia

29 ACUTE LEUKEMIA Systemic Findings  Cytopenias anemia, neutropenia, thrombocytopenia.  Bone pain expansion of the marrow infiltration of the periosteum.  Involvement of all other organs brain involvement is especially troublesome. T-cell leukemias often produce a mass in the anterior mediastinum.  Death hemorrhage (cerebral, GI, other), infection (neutropenia, chemotherapy), complications of bone marrow transplantation.

30 ALL-Acute Lymphocytic Leukemia  Common in Children.  FAB classification L1, L2 & L3  CD10 + and, Pre B cell type common.  Growth failure, Fever, Anemia Lymphadenopathy, bleeding.  Moderate Hepatosplenomegaly

31 The Cause  Clonal expansion of lymphoid progenitor cells is altered  Progenitor cells get stuck at a particular stage of differentiation and do not progress

32 Acute Lymphocytic Leukemia (ALL)  Acute lymphoid / lymphocytic leukemia  “ Childhood leukemia", with peak age in four year old kids.  Risk Factors: Radiation exposure Down's syndrome kids are at 15x the normal risk, Viruses (as-yet-unidentified) an unusual response to.

33 Subclassification of Acute lymphoblastic leukemia by blast morphology “FAB classification” L1 (85%): Cells <= 2x the diameter of a normal lymphocyte; smooth nuclei; common in kids. L2 (14%): Bigger cells, lots of clefts, often nucleoli; more common in adults. L3 (1%): Even bigger cells; leukemic form of Burkitt's lymphoma.

34 ALL-L1

35 ALL-L2

36 ALL-L3

37  The immunologic classification: B-cell (80%) leukemia “pre-B” cell leukemia (Burkitt's) T-cell (15%) leukemia

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39 ALL:Cervical Lymphadenopathy

40 Mediastinal Lymphadenopathy - ALL

41 AML-Acute Myeloid Leukemia  Adults common  FAB classification - M0 to M7.  Anemia, Fever, Bleeding  Hepatosplenomegaly moderate  No significant lymphadenopathy

42 Organomegaly

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44 PlateletCoagulation Petechiae, Purpura Hematoma, Joint bl.

45 Acute Myeloblastic Leukemia (AML) “ Poorly differentiated granulocytic leukemia", “ Acute non-lymphocytic leukemia",  This is the common acute leukemia of adults (seldom over age 40, occasionally children are affected)  Bleeding tendency: DIC Gum bleeding common

46 AML-M5 - Gum Hypertrophy:

47 Risk factors Down's syndrome Fragile chromosome syndromes Bloom's ataxia telangiectasia Fanconi's anemia Benzene exposure Ethylene oxide exposure Radiation exposure Previous cancer chemotherapy Myelodysplastic syndromes (preleukemia) Any "chronic myeloproliferative syndrome" ("blast crisis") o agnogenic myeloid metaplasia o polycythemia vera rubra o "essential" hemorrhagic thrombocythemia o chronic myelogenous leukemia o idiopathic aplastic anemia.

48 The FAB classification of AML  M0: undifferentiated myeloblasts without myeloperoxidase  M1: undifferentiated myeloblasts with myeloperoxidase  M2: some promyelocytic differentiation, maybe a few Auer rods;  M3: very granular promyelocytes, often many Auer rods, DIC (from annexin II on the surfaces which activates plasmin).  M4: myeloid and monocytic differentiation  M5: monocytic differentiation only  M6: features of red cell precursors predominate; "erythroleukemia"  M7: platelet markers; acute marrow fibrosis.

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50 Promyelocytic M3 Monocytic leukemia M5

51  M0 - AML No maturation (<3% Peroxidase +)  M1 - AML Min.Maturation(>3% Peroxidase +)  M2 - AML With full maturation  M3 - Acute Promyelocytic leukemia  M4 - Acute Myelomonocytic leukemia  M5 - Acute Monocytic L (Monocytic, Monoblastic)  M6 - Acute Erythroleukemia  M7 - Acute Megakaryocytic leukemia.

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53 AML-M0 - Undifferentiated:

54 AML-M2 - with maturation

55 AML-M3 - Auer Rods

56 AML-M4 - Myelomonocytic

57 AML-M6 : Erythroleukemia

58 AML-M7 : Megakaryocytic

59 Chronic Myeloid Leukemia  Middle age 40-60y  Philadelphia chromosome, t(9:22) BCR- ABL  Anemia, Fever & Bleeding  Marked leucocytosis – >50,000 (abnormal)  Marked splenomegaly, Hepatomegaly

60 Chronic Myeloid Leukemia:

61 Chronic Myeloid Leukemia (CML)  Syn: Chronic myelogenous leukemia, Well-differentiated granulocytic leukemia  This is cancer of the myeloid stem cells in which there is overgrowth of normally-maturing myeloid cells  Middle age  Risk Factors: radiation exposure to chemicals (notably benzene)  Marked leukocytosis  50,000 (abnormal) high counts of neutrophils and their precursors (and almost always basophils

62  Marked splenomegaly with little infarcts  White cells plugging important small vessels ("leukostatic ischemia" of the brain, etc.)  Hyperuricemia (gout, renal impairment)  After a few years, in blast crisis, (50%/50%).  The following "myeloproliferative diseases" are all "tumors of the multipotent myeloid stem cell", and can transform into one another (usually from a mild one to a bad one): polycythemia vera rubra essential hemorrhagic thrombocythemia agnogenic myeloid metaplasia idiopathic "aplastic anemia" chronic myelogenous leukemia.

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64 Chronic Lymphocytic Leukemia CLL  Elderly age  Anemia, fever & bleeding – slow over years.  Lymphocytosis & Lymphadenopathy  Spleen, & liver enlargement  Common B cell (CD5 +)

65 CLL

66 CLL – Blood Film

67 Chronic Lymphocytic Leukemia (CLL) Well-differentiated lymphocytic leukemia The liquid phase of well-differentiated lymphocytic lymphoma, A clone of B-cells which multiply slowly and do nothing useful. The lymphocytes:  do somewhat suppress the heathy plasma cells,  the patients have troubles with infections. Risk factor: ataxia-telangiectasia.  Elderly age  Anemia, fever & bleeding (slow, over years).  Lymphocytosis & Lymphadenopathy  Hepatosplenomegaly

68 Paraneoplastic syndromes are more troublesome in this disease than in most other leukemias. Autoimmune hemolytic anemia (15%)  Richter's syndrome: a few percent of patients develop a diffuse large-cell lymphoma (rapidly-fatal).  Around 1% of CLL terminates as ALL ("blast crisis of CLL").

69 Chronic Lymphocytic Leukemia (CLL)

70 Summary  Leukemias – Starts in marrow spread to blood Anemia, infections & Bleeding Enlargement of Liver, Spleen lymph nodes Acute/Chronic & Myeloid & Lymphoid.

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