Chapter 1: CHRONIC MYELOPROLIFERATIVE DISEASE

 

A. Chronic Myelogenous Leukemia

 

General

·        Clonal

·        Abnormal pluripotent bone marrow (BM) stem cell

·        Ph and/or BCR/ABL fusion gene (all myeloid lineages and some lymphocytes)

·        Chronic phase, accelerated phase, blast phase

 

Epidemiology

·        Most common MPD

·        15-20% of all leukemia

·        1-1.5/100,000 annually world wide

·        Any age, 5th-6th decades

·        Slight male predominance

 

Site of Involvement

·        Chronic phase: limited to hematopoietic sites (primarily blood, BM, spleen, and liver)

·        Blast phase: can infiltrate extrahematopoietic sites (including LNs, skin, soft tissue, and CNS)

 

Clinical Features

·        20-40% pts asx at diagnosis, incidental findings

·        Non-specific symptoms (fatigue, wgt loss, anemia, night sweats, and splenomegaly)

·        Blast phase can be initial presentation (severe anemia, thrombocytopenia, marked splenomegaly)

 

Morphology-Chronic Phase

Peripheral blood:

·        Leukocytosis (median 170k), due mainly to neutrophils (peak in myelocytes and PMNs); no significant dysplasia; blasts <2%

·        Absolute basophilia: invariably present; eosinophilia

·        Monocytes: can be increased in absolute numbers, but usually <3%

·        Thrombocytosis common, thrombocytopenia rare

 

BM:

 

Spleen: infiltration of red pulp by granulocytic precursors

 

Morphology-Accelerated Phase

·        Blasts 10-19% in PB or BM

·        Basophils ³20% in PB

·        Plt <100k, unrelated to therapy

·        Plt >1,000k, despite therapy

·        Increasing WBC count and spleen size, unresponsive to therapy     

·        Evidence of clonal evolution

 

Morphology- Blast Phase

·        ≥20% blasts in PB or BM

·        Extramedullary proliferation of blasts

·        Large aggregates and clusters of blasts in BM bx

 

            Myeloid: 70%; lymphoid: 20-30%

 

Cytochemistry/Immunophenotype

·        Chronic phase: decreased LAP

·        Blast phase: myeloid, lymphoid (precursor B)

 

Genetics/Molecular

·        Ph: 90-95%

·        Cryptic t(9:22)-> PCR, RT-PCR, FISH

·        BCR/ABL

·        M-bcr, p210, CML (almost always)

·        m-bcr, p230, CML (rare), prominent neutrophilic maturation

·        m-bcr, p190, ALL, CML (rare)

·        p190, small amount in >90% of CML, alternative splicing

·        AP or BP, additional cytogenetic changes in 80%: extra Ph, +8, or i(17q)

 

Prognosis and Predictive Features

·        Natural history: chronic phase to AP and/or BP

·        Median survival: 5-7 yrs

·        Prognostic parameters: age, spleen, blasts, basophils, fibrosis

·        STI517 (Gleevec): tyrosine kinase inhibitor

·        Curative: BMT

 

 

B. CHRONIC NEUTROPHILIC LEUKEMIA

•      Definition

–   Sustained PB neutrophilia

–   BM hypercellularity

–   Hepatosplenomegaly

–   Should exclude

•   all causes of reactive neutrophilia

•   all other myeloproliferative diseases

 

•      Epidemiology

–   True incidence is unknown

–   <100 cases reported

–   Generally affects older adults

–   No gender predilection

 

•      Sites of involvement

–   PB and BM: always involved

–   Spleen, liver: usually show leukemic infiltrates

 

•      Clinical features

–   Most constant feature: splenomegaly

–   Hepatomegaly usually present

–   Up to 30% of cases: h/o bleeding from mucocutaneous surfaces or GI tract

–   Gout

–   Pruritis

 

•      Etiology

–   Unknown

–   a/w multiple myeloma (up to 20% of cases)

 

•      PB Morphology

–    Neutrophilia (≥25 x 109/L)

–    Mostly segs (+/- toxic granules) and bands (>80% of WBC)

–    Immature granulocytes (<10% of WBC)

–    Blasts almost never seen (<1% of WBC)

–    No dysplasia

 

•      BM morphology

–    Hypercellular (neutrophilic proliferation)

–    M:E may reach 20:1

–    No increase in myeloblasts (<5% of nucleated marrow cells) and promyelocytes

–    Myelocytes and mature granulocytes increased

–    No dysplasia (if present, consider atypical CML)

–    Look for plasma cell dyscrasia

 

•      Cytochemistry/immunophenotype

–   Increased Leukocyte Alkaline Phosphatase (LAP)

 

•      Genetics

–   Normal in 90% of cases

–   +8, +9, del (20q), del (11q)

–   Beware of CML with P230 (PB neutrophilia)

 

•      Prognosis

–   Slowly progressive disorder

–   Variable survival (6 mo to >20 y)

–   Development of myelodysplastic features may signal transformation to acute leukemia

 

 

C. CHRONIC EOSINOPHILIC LEUKEMIA /

HYPEREOSINOPHILIC SYNDROME

(CEL / HES)

 

•             Definition

–  Persistently increased numbers of eosinophils in the blood (≥1.5 x 109/L), bone marrow, and peripheral tissues.

–  Organ damage occurs as result of leukemic infiltration or the release of cytokines, enzymes, or other proteins by the eosinophils.

 

•             To make the dx of HES

–  Exclude all causes of reactive eosinophilia

–  Exclude all neoplastic disorders in which eosinophils are part of the neoplastic clone

–  Exclude T cell population with aberrant phenotype and abnormal cytokine production

 

•      To make the dx of CEL

Same as HES, and

•   Evidence of eosinophilic clonality

•   Or > 2% but < 20% myeloblasts in PB

•   Or > 5% but < 20% myeloblasts in BM

 

•      Epidemiology

–    Rare

–    True incidence is unknown

–    HES

•    M:F = 9:1

•    Peak in 4th decade

–    CEL

•    Marked male predominance

 

•      Site of involvement

–   PB and BM always involved

–   Spleen and liver involved in 30-50% of cases

–   Heart, lungs, CNS, skin, GI tract

 

•      Clinical features

–   Asymptomatic (10%)

–   Constitutional sxs (fever, fatigue, cough, angioedema, muscle pains, pruritis, diarrhea)

–    Most serious findings are cardiac

•    Endomyocardial fibrosis with restrictive cardiomyopathy

•    Mitral/tricuspid valve scarring with regurgitation and embolization

–    Other frequent findings

•    Peripheral neuropathy, CNS dysfunction, pulmonary sxs, rheumatologic sxs

 

•      Etiology

    Unknown

 

•      PB Morphology

–   Striking eosinophilia (mainly mature eos.)

–   Possible eosinophil abnormalities

•   Sparse granulation with clear areas of cytoplasm

•   Cytoplasmic vacuolization

•   Nuclear hypersegmentation or hyposegmentation

•   Enlarged size

–   Neutrophilia

–   Monocytosis

–   If blasts >2%, consider CEL

 

•      BM Morphology

–   Hypercellular (due to proliferation of eos.)

–   Orderly eosinophilic proliferation

–   Charcot-Leyden crystals in macrophages

–   Normal erythropoiesis and megakaryopoiesis

–   If blasts 5%-19%, consider CEL

–   Possible fibrosis

 

•      Cytochemistry / immunophenotype

MPO positive (cyanide-resistant)

 

•      Genetics

–    No single abnormality identified

–    +8, i(17q) in occasional patients

–    Genetic abnormalities a/w eosinophilia

•    inv16(p13;q22)

•    t(5;12)(q33;p13)

•    8p11 translocations

–   t(8;13)(p11;q12)
–   t(8;9)(p11;q32-34)
–   t(6;8)(q27;p11)

 

•      Prognosis

–   Variable 5 yr. survival rates (up to 80%)

–   Unfavorable prognostic factors

•   Marked splenomegaly

•   Blasts in PB or BM

•   Cytogenetic abnormalities

•   Dysplasia in other myeloid lineages

 

 

D. Polycythemia Vera

General

•      Increased red cells

•      Clonal

•      Myeloid lineages also increased

•      2-13 cases per million

•      Mean age 60 years

•      Slight male predominance, M:F = 1-2:1

 

Sites of Involvement

•      Bone marrow

•      Peripheral blood

•      Liver (extramedullary hematopoiesis)

•      Spleen (extramedullary hematopoiesis)

 

WHO Criteria

•      A1: RBCs >25% above normal, or Hb >18.5g/dL in men and 16.5g/dL in women

•      A2:  No cause of secondary erythrocytosis (Hypoxia, abnormal Hb, familial conditions)

•      A3: Splenomegaly

•      A4: Clonal genetic abnormalities (but not Ph+)

•      A5:  Endogenous erythroid colony formation in vitro

 

•      B1: Thrombocytosis >400 x 109/L

•      B2:  WBCs >12 x 109/L

•      B3:  BM Bx with panmyelosis, erythroid and megakaryocytic hyperplasia

•      B4:  Low serum erythropoietin levels

 

Diagnosis of Polycythemia Vera

•      A1 + A2 and any other category A, or

•      A1 + A2 and any two of category B

 

Clinical Features

•      Thrombosis (25%)

•      Hemorrhage

•      Stroke

•      Plethora (70%)

•      Splenomegaly (70%)

•      Hepatomegaly (40%)

•      Leukocyte Alkaline Phosphatase (LAP): normal

 

Polycythemic Stage

•      Erythroid proliferation in BM

•      Normochromic, normocytic RBCs in PB

•      If bleeding, RBCs hypochromic and microcytic

•      Neutrophilia

•      Basophilia

•      Thrombocytosis (>50%)

•      BM cellularity 35-100% (median 80%)

•      Panmyelosis (Erythroid, granulocytic, and megakaryocytic proliferation)

•      Blasts not increased

•      Megakaryocytes: increased, clustered (parasinusoidal and paratrabecular); sinusoids dilated, pleomorphic, nuclear hyperlobulation, but not dysplastic

•      No stainable iron in 95% of cases

•      Only 30% with fibrosis (reticulin increased)

•      Spleen and liver congested

•      Extramedullary hematopoiesis: minimal

•      10-50% progress to fibrotic stage

 

“Spent” Phase - Post-Polycythemic Myelofibrosis and Myeloid Metaplasia

•      Red cell mass decreases

•      BM cellularity decreases

•      BM fibrosis (reticulin and collagen increased)

•      Splenomegaly - Extramedullary hematopoiesis

•      Leukoerythroblastic blood smear: RBC poikilocytosis with tear-drop cells, NRBCs, immature granulocytes

•      Megakaryocytes still prominent and clustered

 

Genetics

•      Specific defects in only 20%

•      +8, +9, del (20q), del (13q), del (1p)

•      No Philadelphia chromosome or BCR/ABL fusion gene

•      Genetic defects increase during progression to MDS or AML

 

Prognosis

•      Without therapy: survival few months

•      With therapy: survival >10 years

•      Death due to thrombosis or hemorrhage

•      MDS or AML in only 2% treated without cytotoxic agents

•      MDS or AML in 10-20% treated with cytotoxic agents

 

 

 

E. Chronic Idiopathic Myelofibrosis (CIMF)

General

•      Megakaryocytic proliferation

•      Granulocytic proliferation

•      Bone marrow fibrosis

•      Extramedullary hematopoiesis

•      Initial prefibrotic stage - hypercellular bone marrow

•      Fibrotic stage with leukoerythroblastic peripheral blood

•      Hepato- and splenomegaly with extramedullary hematopoiesis

 

Epidemiology

•      0.5-1.5 per 100,000 per year

•      Seventh decade

•      Men and women equally

 

Anatomic Sites

•      Blood and bone marrow

•      Spleen and liver with extramedullay hematopoiesis

•      Lymph nodes (and other sites)

 

Clinical Features

•      30% asymptomatic, discovered by chance

•      Splenomegaly (90%) (fibrotic stage)

•      Hepatomegaly (20%) (fibrotic stage)

•      Mild anemia

•      Leukocytosis

•      Thrombocytosis

 

Prefibrotic (Cellular) Stage

•      20-30% detected in this stage

•      Peripheral blood with leukocytosis, thrombocytosis, anemia

•      Bone marrow hypercellular

•      Granulocytic hyperplasia

•      Megakaryocytic hyperplasia with naked megakaryocytic nuclei

•      Erythroid lineage variable

•      Megakaryocytes large and bizarre form

•      “Cloud-like” or “balloon-like” lobulation of megakaryocytic nuclei

•      Reticulin minimal or variable

•      Blasts not increased

 

Fibrotic Stage

•      Most diagnosed in this stage (70-80%)

•      Splenomegaly and hepatomegaly

•      Extramedullary hematopoiesis

•      Leukoerythroblastic peripheral blood smear with “tear-drop”  RBCs (dacrocytes) and nucleated RBCs

•      Leukocytosis, leucopenia, or normal

•      Bone marrow fibrosis (reticulin increased)

•      Dilated marrow sinuses with intrasinusoidal hematopoiesis

•      Marrow cellularity decreases

•      Osteosclerosis

•      Blasts <10%; if more, then accelerated phase

•      If blasts >20%, then acute leukemia (DDX with acute panmyelosis with myelofibrosis if organomegaly is not prominent)

•      Extramedullary hematopoiesis in splenic red pulp and hepatic sinusoids

•      Fibrosis and cirrhosis

 

Genetics

•      Cytogenetic abnormalities in 60%

•      None specific for CIMF

•      No Philadelphia chromosome or BCR/ABL fusion gene

•      Del 13q, del(20q), partial trisomy 1q most common

 

Prognosis

•      Survival range: months to decades

•      Median survival: 3 to 5 years from Dx

•      Adverse factors: >70 years, Hb <10g/dL, platelets <100 x 106/L, granulocytic immaturity, abnormal karyotype

•      Morbidity and mortality: bone marrow failure, infection, thromboembolic events, portal hypertension, cardiac failure, and acute leukemia

•      Acute leukemia: 5-30%

•      Some, but not all, may be cytotoxic therapy related

 

 

F. Essential Thrombocythemia

General

•      Incidence 1-2.5 per 100,000 annually

•      50-60 years of age, equally in men and women

•      Minor peak at 30 years, mostly women

•      Rarely in children

 

Sites of involvement

Bone marrow

Peripheral blood

Spleen (platelet sequestration site - minimal extramedullary hematopoiesis)

 

Clinical Features

•      More than one-half asymptomatic - discovered fortuitously

•      The rest with thrombosis or hemorrhage

•      Modest splenomegaly in 50%

•      Significant hepatomegaly in 15-20%

 

Diagnostic criteria

Positive criteria

•      Platelets >600 x 109/L

•      BM Bx proliferation of enlarged, mature megakaryocytes

 

Exclusion criteria

1. No evidence of Polycythemia vera

·        Hb <18.5 g/dL in men and <16.5 g/dL in women

·        Stainable iron in BM

·        Normal ferritin levels

2. No CML (Ph negative)

3. No chronic idiopathic myelofibrosis

4. No MDS

5. No reactive thrombocytosis (tumor, infection, splenectomy)

 

Peripheral Blood Morphology

•      Thrombocytosis

•      Anisocytosis - platelets small to giant

•      WBCs normal

•      Basophilia absent

•      RBCs normal

 

Bone Marrow Morphology

•      Normocellular or mildly hypercellular

•      Giant megakaryocytes:  clustered or scattered, abundant mature cytoplasm, hyperlobulated nuclei

•      Reticulin not increased

 

Genetics

•      Only 5-10% with abnormal karyotype

•      del (13q22), +8, +9

 

Prognosis and Predictive Factors

•      10-15 year survival common

•      Splenectomy worsens survival (elimination of sequestration reservoir increases PLTs)

•      Transformation to MDS and AML in <5% and usually therapy-related

•      Fibrosis may increase (DDX: CIMF)

 

 

G. Chronic Myeloproliferative Disease, Unclassifiable (CMPD, U)


General

•      Fail to meet criteria of any one disease

•      Overlap with several specific diseases

•      No Philadelphia chromosome or BCR/ABL fusion gene

•      Initial stages of polycythemia vera, essential thrombocythemia, chronic idiopathic myelofibrosis

•      Late stages of above diseases after myelosclerosis, osteosclerosis, or acute transformation

•      Term used after exclusion of specific diseases

•      Must exclude other non-CMPD diseases

•      Proper sampling must be performed with adequate follow-up

•      Rule out non-myeloproliferative processes: infection, chemotherapy, toxins, growth factors, immunosuppressive agents, lymphomas and metastatic tumors

•      CMPDs do have overlapping characteristics

•      Variations occur

•      10-20% of all CMPDs

•      Clinical and morphologic features similar to other CMPDs, but without clear-cut categorization

•      Many cases in early stages are categorized after adequate follow-up

•      If blasts between 10-19%, then accelerated stage of CMPD, U

•      If blasts >20%, then AML suggestive of transformation of previous CMPD, U

•      If dysplasia present, then MDS/CMPD, U

 

Genetics and Immunophenotype

•      Similar to other CMPDs

•      Philadelphia chromosome or BCR/ABL fusion product gene must be excluded

 

Prognosis

•      Patients with marrow fibrosis have advanced disease and poor outcome

•      Patients in early stages have outcome similar to those of the group into which their disease evolves

 

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