Leukocytes 4-10 000/mm3 Differential count: neutrophils 60- 70%, eosinophils 2-4% basophils - up to 1% ly: 20 – 30%, mono 3-8%

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Leukocytes 4-10 000/mm3Differential
countneutrophils 60- 70, eosinophils
2-4basophils - up to 1ly 20 30, mono 3-8

• ? Leukopenias
• most often neutropenia
• lymphopenia less common congenital ID
• diseases, corticosteroid therapy
• ? Proliferations reactive infections,
  other conditions
• neoplastic

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• NEOPLASTIC PROLIFERATIONS
• OF WHITE CELLS
• myeloid
• from the hematopoietic stem cells giving rise to
  cells of myeloid lineage thrombocytic,
  granulocytic, erythroid
• Acute myelogenous (myeloid) leukaemias
• Myelodysplastic syndromes
• Chronic myeloproliferative disorders
• B. lymphoid - tumors of lymphocytes, lymphomas
  and leukaemia
• Hodgkin lymphoma versus non-Hodgkin lymphomas
• B- versus T- cell lymphomas
• precursor cells (B or T or NK) lymphoblastic
• versus mature cells B or T (or NK)
• C. histiocytic proliferative lesions of
  histiocytes
• Langerhans histiocytosis

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Myelodysplastic syndrome

• Bone marrow(BM)
• Hyper /normocellular
• Dysplastic architecture, cytology
• Ineffective bone marrow failure
• Peripheral blood (PB) - pancytopenia
• Blood cells few and pathological
• (size, shape, function)

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Myelodysplastic syndrome

• clonal disorders of stem cells
• defects of maturation in the BM - ineffective
  hematopoiesis (progressive failure of BM
  function)
• cells in the PB decreased numbers
  pancytopenia defective in function,
  pathological shapes

• BM hypercellular,
• but dysplastic pathological forms, architecture
• blasts may be increased
• (but less than 20, threshold AML versus MDS)

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Myelodysplastic syndrome

• Clinical symptoms and complications ???

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Myelodysplastic syndrome

• Clinical symptoms and complications
• Anemia
• Thrombocytopenia - bleeding
• Leukopenia infection
• (Splenomegaly -)
• Asymptomatic one half

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Myelodysplastic syndrome

• primary de novo - old people over 60
• secondary therapy related toxic exposure -
  worse prognosis, more prone to AML

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Myelodysplastic syndrome

• Subcategories
• Refractory anemia unilineage dysplasia
• RA with ringed sideroblasts the nucleus
  encircled by siderotic granules
• RA with multilineage dysplasia
• RA with excess blasts more than 5, less than
  20
• MDS unclassifiable
• MDS assoc. with isolated del. (5q) chromosome

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Chronic myeloproliferative diseases
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Chronic myeloproliferative diseases

• Clonal disorders
• Adults
• 1. Chronic myeloid leukemia
• 2. Polycythemia vera
• 3. Essential thrombocytemia
• 4. Chronic osteomyelofibrosis

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Chronic myeloproliferative diseases

• Common principles
• 1. Bone marrow stem cell genetic abnormalities,
• neoplastic proliferation of one or more (all) BM
  myeloid series (red, white, megakaryocytes)
• disorder of an individual series more pronounced
  in each of the categories
• 2. Peripheral blood increased numbers of cells
  relatively normal maturation
• 3. Splenomegaly, hepatomegaly
• sequestration of excess blood cells,
  extramedullary hematopoiesis, leukaemic
  infiltration

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Chronic myeloproliferative diseasescommon
features

• phases of the disease in time
• 1. onset insidious
• proliferative phase,
• 2. progression - spent phase -
  osteomyelofibrosis
• - blast phase
• all can (do not have to) progress to AL CML does
  it invariably)

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Chronic myelogenous leukaemia (CML)

• t(9 22) Philadelphia chromosome, bcr-abl gene
  pluripotent stem cell defect
• abnormal fusion protein - increased tyrosine
  kinase activity
• most striking proliferation of G
• increased cellularity
• maturation retained (no hiatus leukaemicus)
• hematopoiesis also extramedullary splenomegaly
  (hepatomegaly)
• PB leukocytosis exceeds even 100 000/ mm3

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CML
PB no hiatus leukaemicus mature neutrophils,
some metamyelocytes, and a myelocyte.
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Chronic myelogenous leukaemia (CML)

• Phases
• 1. chronic aver. 3 ys
• 2. accelerated gradual failure of response to
  treatment, increasing anemia and
  thrombocytopenia, basophilia
• 3. blast crisis after accelerated phase or
  without the acceler. phase
• Blast crisis acute leukaemia - 70 myeloid,
  30 lymphoblastic

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Chronic myeloid leukaemia
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Chronic myeloid leukaemia
uric acid deposition
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JAK2 mutation

• In one half
• of
• Polycythemia vera
• Essential thrombocythemia
• Chronic myelofibrosis

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Polycythaemia veramorbus Vaquez

• increased proliferation of all three series
• most striking red cells
• hypercellular BM
• PB HTC 60, Hb over 180g/l
• For the diagnosis exclude secondary polycythemia

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Polycythaemia vera

• increased RC mass - symptoms
• hypervolemia, blood stasis (mostly venous),
  cyanosis stagnation and deoxygenation of blood
• hypertension, thromboses, bleeding abnormal
  blood flow, abnormalities of PLT
• granulopoiesis may be elevated
• plt elevated functional abnormalities
• SPENT PHASE myelofibrosis
• (20/10 ys)

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Polycythemia vera. Plethora.
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Polycythemia vera. Plethora.
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Polycythemia vera distension of retinal vessels
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Polycythemia vera Gout - right great toe
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Gouty tophi
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Polycythemia vera, spent phase, advanced marrow
myelofibrosis. Massive splenomegaly (3020 gm
normal 150 to 200 gm) largely owing to
extramedullary hematopoiesis
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Essential thrombocythaemia

• the least common CMPD
• PLT exceed 600 000 /mm3
• BM increased cellularity,
• megakaryocytes abnormal,
• often large
• PB PLT often large
• Symptoms
• thrombosis and hemorrhage abnormalities of
  quantity and quality of PLT
• rel. indolent

Giant platelets
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Essential thrombocythaemia
haemorrhages
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Essential thrombocythaemia
thrombosis, gangrene
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Chronic idiopathic myelofibrosis

• Myelofibrosis with myeloid metaplasia
• Agnogenic myeloid metaplasia

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Chronic idiopathic myelofibrosis

• abnormal neoplastic megakaryocytes release
  fibrogenic factors PDGF and TGFa
• stimulate fibroblasts to proliferation
• early BM hypercellular, minimal fibrosis
• progression BM hypocellular, fibrotic
  osteosclerosis
• obliteration of BM space extramedullary
  hematopoiesis - spleen later liver
• PB leukoerythroblasticerytroid and granulocytic
  precursors
• 20 - progression to AML

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Primary myelofibrosis (peripheral blood smear).
Two nucleated erythroid precursors and several
teardrop-shaped red cells (dacryocytes). Immature
myeloid cells present in other fields. An
identical picture - in other diseases producing
marrow distortion and fibrosis.
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Leukaemia

• Acute myeloid lymphoblastic - B, T
• Chronic myeloid, lymphocytic B, T

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Acute leukaemia (AL)

• Common acute course
• untreated death in weeks, months
• Problems symptoms result from
• A. failure of normal hematopoiesis anemia,
  neutropenia, thrombocytopenia
• B. infiltration of organs by neoplastic cells
• 1. Myeloid (adults)
• 2. Lymphoblastic (young B or T)
• further subdivision
• genetics, morphology, immunophenotype

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Acute leukaemia
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Acute myeloid leukaemia

• Categories
• AML with recurrent gen. abnormalities balanced
  translocations, often complete remission,
  favourable prognosis (fusion gene - chimeric
  protein)
• t(1517) AML M3 promyelocytic treatment
  with transretinoic acid
• t(8 21) or inversion of chromosome 16
• AML therapy related
• AML with multilineage dysplasia
• AML NOS- minim.differentiated
• Without maturation
• With maturation

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Acute myeloid leukaemia

• FAB classification French American British
  
• M0 without maturation myeloblastic
• M1 without maturation
• M2 with maturation
• M3 promyelocytic now categorised rather
  according to the genetics t(15 17)
• M4 myelomonocytic
• M5 a monoblastic, b- monocytic
• M6 erythroid
• M7 megakaryoblastic

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Myeloid sarcoma

• Tumour mass of immature myeloid cells
• Extramedullary (bone)
• Association - before or concurrently
• 1. AML (or as a relapse)
• 2. Chronic myelogenous leukaemia
• other myeloproliferative disorders
• 3. MDS

Extramedullary myeloid tumour, granulocytic
sarcoma, chloroma
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Myeloid sarcoma

• Localization
• 1. Bones subperiosteal
• (skull, paranasal sinuses, sternum, ribs,
  vertebrae, pelvis)
• 2. Lymph nodes
• Skin
• Histological types
• A. Granulocytic
• B. Monoblastic
• C. Trilineage haematopoiesis

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Myeloid sarcoma - poorly differentiated

• a high index of suspicion...
• Stains CHAE, MPO, lysozyme CD15, CD68,
  CD117, CD43 (CD43 only!)
• Differential diagnosis
• 1. Lymphoblastoma
• 2. Burkitt lymphoma
• 3. Large cell lymphoma
• 4. Small round cell tumours
• (neurobl., Ewing/PNET,
• medullobl.)

Lymphoblastoma
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Myeloid sarcoma

• Prognosis
• If MPD, MDS as a blast transformation
• If AML as this AML
• If isolated curative radiotherapy
• prolonged survival

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Precursor (lymphoblastic)B-cell neoplasmsB-acute
lymphoblastic leukaemia/lymphoblastic lymphoma

• 1. Leukaemia (more common) involves the bone
  marrow and PB
• 2. occasionally solid primary nodal or extranodal
  mass /B-lymphopblastic lymphoma/ without PB and
  BM involevement
• - leukaemization possible. biologic unity of
  B-ALL and B-LBL, division arbitrary

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Precursor (lymphoblastic)B-cell neoplasms

• Small to medium sized cells
• scant cytoplasm, dispersed chromatin, and
  inconspicuous nucleoli

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Acute lymphoblastic leukemia/lymphoma.
Lymphoblasts condensed nuclear chromatin, small
nucleoli, and scant agranular cytoplasm
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Lymphoblastic leukaemia

• More common B
• B-ALL children, but also adults relatively
  frequent, good prognosis
• Children 95 complete remission, 80 cured
  /adults worse/
• Lymphoblastoma (LBL)
• More common T
• B-LBL rare
• T-LBL- rapidly growing mass in mediastinum,
  adolescent male

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Acute B-cell lymphoblastic leukaemia

• B-ALL children, but also adults relatively
  frequent
• B-LBL - much less common - skin, bone, soft
  tissues, LN
• Symptoms BM failure
• Enlarged LN, liver, spleen
• Antigenic profileTdT, CD10 (CALLA) various
  degree of differentiation, B-antigens (CD79a,
  CD20)
• Genetic abnormalities prognostically important
• Good hyperdiploidy t (12, 21)
• Poor t(9, 22), hypodiploidy
• In general a good prognosis leukaemia
• Children 95 complete remission, 80 cured
  /adults worse/