MYELOPROLIFERATIVE DISORDERS

1
MYELOPROLIFERATIVE DISORDERS

• Masatoshi Kida, M.D.
• Dept. of Pathology
• University of Vermont

2
Hematopoietic Neoplasmsoverview

• The majority of hematopoietic neoplasms can be
  classified and characterized according to three
  characteristics
• 1. Lineage Lymphoid vs. Myelogenous
• 2. Survival Acute vs. Chronic
• 3. Blood/Bone Marrow vs. Tissue
• Virtually any combination of these
  characteristics can occur.

3
Lymphoid vs Myelogenous

• Lymphoid neoplasms
• derived from the CFU-L or one of its more
  differentiated derivatives
• can exhibit B-cell lineage or T-cell lineage
• Myelogenous neoplasms
• derived from the CFU-GEMM or one of the
  differentiated derivatives of the CFU-GEMM
• can exhibit features of multiple lineages

4
Acute vs Chronic

• Acute
• primarily of immature cells, with little of no
  differentiation
• aggressive course with survival of only weeks to
  few months if untreated
• primarily involving blood and bone marrow
• examples
• acute lymphoblastic leukemia/lymphoma (ALL)
• acute myelogenous leukemia (AML)
• various subtypes of ALL and AML exist, depending
  on the specific lineage or differentiation
  exhibited by the neoplastic cells

5
Acute vs Chronic

• Chronic
• primarily of mature cells
• tends to be indolent, with survival in years
• examples
• chronic lymphocytic leukemia (CLL)
• chronic myeloproliferative disorders
• chronic myelogenous leukemia (CML)
• polycythemia rubra vera
• essential thrombocythemia
• agnogenic myeloid metaplasia

6
Blood/BM vs Tissue

• Blood/BM ? leukemia
• Tissue ? lymphoma
• myeloid granulocytic sarcoma
• lymphoid lymphoma (non-Hodgkins)
• Hodgkins disease
• plasma cell multiple myeloma
• plasmacytoma

7
leukoproliferative disorders

• lymphoid lymphoid neoplasms acute
• chronic
• myeloid myeloid neoplasms acute
• chronic

8
leukoproliferative disorders

• lymphoid lymphoid neoplasms acute
• chronic
• myeloid myeloid neoplasms acute
• chronic

9
myeloid neoplasms

• acute myeloid leukemia gt30 blasts in BM
• (1985 FAB classification)
• trilineage morphologic
  dysplasia
• myelodysplastic syndrome
• chronic myeloproliferative disorders -

10
leukoproliferative disorders

• lymphoid lymphoid neoplasms acute
• chronic
• myeloid myeloid neoplasms acute
• chronic

11
Myeloproliferative Disorders(old classification)

• a group of disease characterized by
  overgrowth of one or more hematologic cell lines
  in BM
• 1. chronic myelogenous leukemia (CML)
• 2. polycythemia vera (PV)
• 3. essential thrombocythemia
• 4. agnogenic myeloid metaplasia/myelofibrosis

12
Chronic Myeloproliferative Disorders(new WHO
classification)

• 1. polycythemia vera
• 2. chronic idiopathic myelofibrosis
• 3. essential thrombocytosis
• 4. chronic myeloid leukemia (CML)
• 5. chronic neutrophilic leukemia
• 6. chronic eosinophilic leukemia
• 7. hypereosinophilic syndrome
• myelodysplastic/myeloproliferative diseases
• juvenile myelomonocytic leukemia
• atypical chronic myeloid leukemia (lacking
  t(922))
• chronic myelomocytic leukemia

13
Chronic Myelogenous Leukemia (CML)

• second most common leukemia
• middle aged
• excess number of mature and immature
  granulocytes
• all stages of maturation in bone marrow
• chromosomal abnormality

Philadelphia chromosome t(922)
14
Chronic Myelogenous Leukemia (CML) laboratory

• WBC gt100,000
• thrombocytosis
• numerically increased, but functionally impaired
  granulocytes

15
Chronic Myelogenous Leukemia (CML) clinical

• non-specific constitutional symptoms
• weakness
• wt. Loss
• fatigue
• excessive bleeding or bruising
• two-phase disease
• slowly progressive disease
• (chronic phase)
• terminal blast crisis
• (acute/blast phase)

16
Polycythemia Vera (PV)

• increased red blood mass
• increased blood volume and viscosity
  (hyperviscosity syndrome)
• BM hypercellular erythroid,
  megakaryocytic granulocytic hyperplasia may
  eventually become fibrotic
• Tx repeated phlebotomy

17
Polycythemia Vera (PV)

• Incidence 0.5 to 3.5 per 100,000
• Age at Dx 60 y/o
• F to M ratio male dominance (11.6 to 2.2)
• Social risk factor participants in nuclear
  weapons test
• Clinical features hyperviscosity, thrombosis
• headache
• dizziness
• visual symptoms
• Median survival 12 to 13 years

18
Polycythemia Vera (PV)diagnostic criteria

• by polycythemia vera study group (1975)
• Major Criteria
• 1. increased RBC male gt 36 mL/kg
• female gt 32 mL/kg
• 2. normal arterial oxygen saturation gt 92
• 3. splenomegaly
• Minor Criteria
• 1. platelet gt 400,000/mL
• 2. leukocytes gt13,000/mL
• 3. leukocyte alkaline phosphatase gt100
• or
• vit B12 gt900 pg/mL
• or
• unbound B12 binding capacity gt2200 pg/mL

19
Essential Thrombocythemia

• Rare disorder (1.5 per 100,000)
• proliferation of megakaryocytes causing marked
  increase in circulating platelets (gt1 million)
• morphologically abnormal platelets
• splenomegaly, mucosal hemorrhage, thromboses

arrow macrothrombocyte
20
Essential Thrombocythemia

• Incidence 1.5 per 100,000
• Age at Dx 60 y/o (20 lt40 y/o)
• F to M ratio 1.6 1
• Social risk factor 1. long-term use of dark hair
  dyes
• 2. living in tuff house
• 3. electrician
• Clinical features - near normal life expectancy
• - frequent vasomotor and thrombo-
  hemorrhagic episodes
• Treatment low-dose acetylsalicylic acid

21
Myelofibrosis

• bone marrow fibrosis
• fibroblasts may be innocent bystanders
• fibrosis probably driven by neoplastic
  megakaryocytes
• middle aged adults (50-60 y/o)
• extramedullary hematopoiesis (spleen, liver)
• may occur as an extension of CML or PV
• abnormal peripheral RBCs (tear-drop nucleated
  RBCs)
• immature WBC and abnormal platelets
• infection, thrombosis and hemorrhage as a major
  complication

22
Myelofibrosis
Aniso-poikilocytosis leukemoid reaction
naked nuclear fragments
23
(No Transcript)
24
Acute Myelogenous Leukemia (AML)

• 60 of acute leukemias
• arises from myeloid stem cell line
• young to middle aged adults
• pallor petechiae may be initial presentation
• lymphadenopathy/splenomegaly may or may not be
  present
• no fever unless secondary infection

25
Acute Myelogenous Leukemia

• Incidence 3.6 per 100,000 people per year
• MF 4.43.0 (MgtF)
• incidence increases with age
• 1.7 in lt65 yrs age group
• 16.2 in gt65 yrs age group
• Etiology heredity, radiation, chemical and other
  occupational exposures and drugs have been
  implicated
• increased incidence in trisomy 21, XXY, trisomy
  13, Fanconi anemia, Bloom syndrome, ataxia
  telangiectasia, Kostmann syndrome

26
AMLclinical symptoms

• non-specific symptoms that are consequence of
• anemia
• leukocytosis
• leukopenia or leukocyte dysfunction
• thrombocytopenia
• fatigue (most common)
• anorexia and wt. loss
• fever with or without infection (10)
• bleeding, easy bruising (5)

27
AMLphysical findings

• hepatosplenomegaly, lymphadenopathy, sternal
  tenderness, evidence of infection and hemorrhage
• acute promyelocytic leukemia (APL)
• gastrointestinal bleeding
• intrapulmonary hemorrhage
• intracranial hemorrhage
• monocytic AML
• coagulopathy

28
Acute Myelogenous Leukemia (AML) peripheral blood
smear

• normocytic, normochromic anemia
• decreased reticulocyte count
• normal or depressed WBC count
• myeloblast (may be with Auer rods)
• low platelet

29
AMLhematologic findings

• anemia can be severe usually normocytic
  normochromic
• reduced reticulocyte count ? low erythropoiesis
• short erythrocyte survival ? accelerated
  destruction
• median WBC count 15,000/µL
• platelet count lt100,000/µL (75 of
  patients) lt25,000/µL (25 of patients)
• morphologic and functional platelet abnormalities

30
Acute Myelogenous Leukemia (AML) special stains

• myeloperoxidase (MP)
• Sudan black B (SBB)
• nonspecific esterase (NSE)
• chloroacetate esterase (CLE)
• periodic acid Schiff (PAS)

31
AML classification

• Until 2000, the diagnosis of AML was established
  by the presence of 30 myeloblasts in the marrow
  and further classified based on morphology and
  cytochemistry according to the French-American-Bri
  tish (FAB) schema, which includes eight major
  subtypes, M0 to M7.
• The 2001 WHO classification modified the FAB
  schema by reducing the number of blasts required
  for a diagnosis and incorporating molecular
  (including cytogenetic), morphologic
  (multilineage dysplasia), and clinical features
  (such as prior hematologic disorder) in defining
  disease entities.

32
Acute Myelogenous Leukemia (AML) WHO
classification (2001)

• I. AML with rucurrent genetic abnormalities
• AML with t(821)(q22q22)AML1(CBFa)/ETO
• AML with abnormal bone marrow eosinophils
  inv(16)(p13q22) or t(1616)(p13q22)CBFß/MYH11
• Acute promyelocytic leukemia AML with
  t(1517)(q22q12) (PML/RARa and variants
• AML with 11q23 (MLL) abnormalities
• II. AML with multilineage dysplasia
• Following a myelodysplastic syndrome or
  myelodysplastic syndrome/myeloproliferative
  disorder
• Without antecedent myelodysplastic syndrome

• III. AML and myelodysplastic syndromes,
  therapy-related
• Alkylating agent-related
• Topoisomerase type II inhibitor-related
• Other types
• IV. AML not otherwise categorized
• AML minimally differentiated
• AML without maturation
• AML with maturation
• Acute myelomonocytic leukemia
• Acute monoblastic and monocytic leukemia
• Acute erythroid leukemia
• Acute megakaryoblastic leukemia
• Acute basophilic leukemia
• Acute panmyelosis with myelofibrosis
• Myeloid sarcoma

20 myeloblasts in blood and/or bone marrow AML
positive myeloperoxidase reaction in gt3 of
blasts AML (? ALL)
33
Acute Myelogenous Leukemia (AML) FAB
classification (1985)

• M0 minimally differentiated acute myeloblastic
  leukemia
• M1 acute myeloblastic leukemia without
  maturation
• M2 acute myeloblastic leukemia with maturation
• M3 acute promyelocytic leukemia
• M4 acute myelomonocytic leukemia
• M5 acute monocytic leukemia
• M6 erythroleukemia
• M7 acute megakaryoblastic leukemia

34
M0 Minimally Differentiated Acute Myelogenous
Leukemia

• no conclusive morphologic evidence of cellular
  differentiation

35
M1 Acute Myeloblastic Leukemia without
Maturation

• MP (), SBB (), NSE (neg), CLE ()
• 90 or more of BM non-erythroid cells are blasts

36
M2 Acute Myeloblastic Leukemia with Maturation

• MP (), SBB (), NSE (neg), CLE (neg)
• blasts in 30-9 of BM non-erythroid cells
• t(821) --- seen in 40-50 of case favorable
  prognosis

37
M3 Acute Promyelocytic Leukemia

• MP (), SBB (), NSE (neg), CLE ()
• abnormal promyelocytes
• heavy primary granulation
• frequently associated with DIC
• t(1517) --- favorable prognosis

38
M4 Acute Myelomonocytic Leukemia

• MP (), SBB (), NSE (), CLE ()
• monocytic lineage cells in 20-80 of BM
  non-erythroid cells
• abnormal 11q

39
M5 Acute Monocytic Leukemia

• MP (), SBB (), NSE (), CLE (neg)
• monocytic lineage cells in 80 or more of BM
  non-erythroid cells
• erythrophagocytosis may be present
• hypertrophied gum, oral and anorectal ulcers
• chloroma (green tumor)
• lymphadenopathy and splenomegaly
• t(911) --- unfavorable prognosis

40
M6 Erythroleukemia

• gt50 of all nucleated cells in BM are
  erythroblasts
• gt30 of non-erythroid cells are blasts
• dyserythropoiesis
• unfavorable prognosis

41
M7 Acute Megakaryoblastic Leukemia

• MP (neg), SBB (neg)
• associated with trisomy 21
• unfavorable prognosis

42
Acute Myelogenous Leukemia (AML) prognostic
factors

• good bad
• age lt40 y/o gt60 y/o
• WBC lt10,000 gt100,000
• DIC absent present
• LDH normal high
• type M3, M4Eo M0, M5, M6, M7
• cytogenetics t(1517) complex karyotype
• t(821) -7
• inv(16) inv(3)
• molecular markers PTD of MLL
• ITD of FLT3
• history primary lesion post-therapy

43
(No Transcript)
44
(No Transcript)
45
(No Transcript)
46
(No Transcript)
47
(No Transcript)
48
(No Transcript)
49
(No Transcript)