Leukocytes 4-10 000/mm3
Differential count:
neutrophils 60- 70%, eosinophils 2-4%
basophils - up to 1%
ly: 20 – 30%, mono 3-8%
↓ Leukopenias
most often: neutropenia
lymphopenia: less common – congenital ID
diseases, corticosteroid therapy
↑ Proliferations : reactive – infections,
other conditions
neoplastic
NEOPLASTIC PROLIFERATIONS
OF WHITE CELLS
A. 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
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)
Myelodysplastic syndrome
• clonal disorders of stem cells
• defects of maturation in the BM - ineffective
hematopoiesis (progressive failure of BM
function)
• BM:
hypercellular,
but dysplastic: pathological forms, architecture
blasts may be increased
(but less than 20%, threshold AML versus MDS)
• cells in the PB : decreased numbers –
pancytopenia + defective in function, pathological
shapes
Myelodysplastic syndrome
Clinical symptoms and complications ???
Myelodysplastic syndrome
Clinical symptoms and complications
• Anemia
• Thrombocytopenia - bleeding
• Leukopenia – infection
• (Splenomegaly +-)
Asymptomatic – one half
Myelodysplastic syndrome
• primary – de novo - old people – over 60
• secondary – therapy related – toxic exposure worse prognosis, more prone to AML
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
Chronic
myeloproliferative
diseases
Chronic myeloproliferative diseases
Clonal disorders
Adults
1. Chronic myeloid leukemia
2. Polycythemia vera
3. Essential thrombocytemia
4. Chronic osteomyelofibrosis
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
Chronic myeloproliferative diseases
common 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)
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
CML
PB: no hiatus leukaemicus;
mature neutrophils, some metamyelocytes, and a myelocyte.
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
Chronic myeloid leukaemia
Chronic myeloid leukaemia
uric acid deposition
JAK2 mutation
• In one half
• of
• Polycythemia vera
• Essential thrombocythemia
• Chronic myelofibrosis
Polycythaemia vera
morbus 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
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)
Polycythemia vera. Plethora.
Polycythemia vera. Plethora.
Polycythemia vera
distension of retinal vessels
Polycythemia vera
Gout - right great toe
Gouty tophi
Polycythemia vera, spent phase, advanced marrow myelofibrosis.
Massive splenomegaly (3020 gm; normal: 150 to 200 gm)
largely owing to extramedullary hematopoiesis
Essential thrombocythaemia
• the least common CMPD
• PLT exceed 600 000 /mm3
• BM: increased cellularity,
megakaryocytes: abnormal,
often large
• PB: PLT: often large
Giant platelets
• Symptoms:
• thrombosis and hemorrhage – abnormalities of
quantity and quality of PLT
• rel. indolent
Essential thrombocythaemia
haemorrhages
Essential thrombocythaemia
thrombosis, gangrene
Chronic idiopathic myelofibrosis
• Myelofibrosis with myeloid metaplasia
• Agnogenic myeloid metaplasia
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: leukoerythroblastic=erytroid and
granulocytic precursors
• 20% - progression to AML
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.
Leukaemia
• Acute – myeloid; lymphoblastic - B, T
• Chronic – myeloid, lymphocytic – B, T
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
Acute leukaemia
Acute myeloid leukaemia
• Categories:
• AML with recurrent gen. abnormalities –balanced
translocations, often complete remission, favourable
prognosis (fusion gene - chimeric protein);
– t(15;17) – 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
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
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
Myeloid sarcoma
1.
2.
3.
A.
B.
C.
Localization
Bones – subperiosteal
(skull, paranasal sinuses, sternum, ribs,
vertebrae, pelvis)
Lymph nodes
Skin
Histological types
Granulocytic
Monoblastic
Trilineage haematopoiesis
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
Myeloid sarcoma
Prognosis
If + MPD, MDS = as a blast transformation
If + AML – as this AML
If isolated:
curative radiotherapy
prolonged survival
Precursor (lymphoblastic)B-cell neoplasms
B-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 BALL and B-LBL, division arbitrary
Precursor (lymphoblastic)B-cell neoplasms
• Small to medium sized cells
• scant cytoplasm, dispersed chromatin,
and inconspicuous nucleoli
Acute lymphoblastic leukemia/lymphoma.
Lymphoblasts: condensed nuclear chromatin, small nucleoli,
and scant agranular cytoplasm
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
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 profile:TdT, 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/