Doc. MUDr. L. Boudová, Ph. D.
Myelodysplatic syndrome
Chronic myeloproliferative disease
Acute myeloid leukemia
Abbreviations: G-granulopoiesis, E-erythropoiesis, BM – bone marrow, PB – peripheral
blood; MDS – myelodysplastic syndrome; MPD – myeloproliferative disease; AL: acute
leukaemia; AML – acute myeloid leukaemia; ALL – acute lymphoblastic leukaemia; CML –
chronic myeloid leukaemia; PV – polycythemia vera; OMF - osteomyelofibrosis, ET –
essentail thrombycythemia
NEOPLASTIC PROLIFERATIONS OF WHITE CELLS
- myeloid, lymphoid, histiocytic
Myeloid neoplasms
from the hematopoietic stem cells that give rise to cells of myeloid lineage
-Thrombocytic
- Granulocytic
- Erythroid
Acute myelogenous (myeloid) leukaemias (AML)– immature progenitor cells accumulate in
the bone marrow
Myelodysplastic syndromes (MDS) – ineffective hematopoiesis and cytopenia in the
peripheral blood
Chronic myeloproliferative disorders (CMPD)– increased production of one or more terminal
differentiated myeloid elements – elevation of PB counts
Myelodysplastic / myeloproliferative disorders – mixed features of MDS and CMPD
Myelodysplastic synrome
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
Basic morphology:
1
Doc. MUDr. L. Boudová, Ph. D.
BM: hypercellular, increased numbers of cells in the series – but: dysplastic: pathological
forms, deranged architecture, the count of blasts may be increased – but less than 20%; which
is the threshold between AML and MDS – NEW IN THE WHO CLASSIFICATION 2001
Examples:
E: ringed sideroblasts, megaloblasts
G: lack of nuclear segmentation
M: lack of nuclear lobulation
according to morphology: 5 subcategories
possible progression to AML - various percentage according to subgroups (10 – 40%)
primary. – de novo -old people – over 60 years
secondary – therapy related – toxic exposure - worse prognosis – when it appears –
progresses more frequently and more quickly to AL
Therapy: symptomatic; some: bomne marrow transplantation
Subcategories
Refractory anemia – refractory = difficult to treat – unilineage dysplasia – affecting the E
series
RA with ringed sideroblasts – the nucleus encircled by siderotic granules (iron stained
smears)
RA with multilineage dysplasia
RA with excess blasts –more than 5%, less than 20%
MDS unclassifiable – lacks the more specefic abnormalities of other categories
MDS assoc. with isolated del (5q) chromosome abnormality – long survival
Chronic myeloproliferative disorders
2
Doc. MUDr. L. Boudová, Ph. D.
CML, PV, OMF, ET – clonal disorders, affect typically adults
Common principles:
1. stem cell genetic abnormalities, neoplastic proliferations affect one or more (all) BM
myeloid series (red, white, megakaryocytes) – the disorder of an individual series is more
pronounced ineach disease category – CML
2. neoplastic cells in the circulation – relatively normal maturation (difference when
compared to MDS – ineffective maturation with cytopenia),
3.: splenomegaly, hepatomegaly : due to. sequestration of excess blood cells, extramedullary
hematopoiesis, leukaemic infiltration - cells home to hematopoietic organs
typicallyphases of the disease - development in time:
onset is often insidious
1. proliferative phase, then: progression - -spent phase osteomyelofibrosis, or to blast phase
2. or to blast phase - all can progress to AL (CML does it
invariably) – blast phase does not have to occur in all MPD
(very rare in PV)
Chronic myelogenous leukaemia (CML)
distinctive translocation – reciprocal – t(9; 22) –long arms – Philadelphia chromosome; bcrabl gene fusion
pluripotent stem cell defect
abnormal fusion protein - increased tyrosine kinase activity
The most striking feature: proliferation of G – increased cellularity – up to 100% of BM!
maturation retained – all stages of G (no hiatus leukaemicus), hematopoiesis also
extramedullary – splenomegaly (hepatomegaly)
3
Doc. MUDr. L. Boudová, Ph. D.
PB: leukocytosis – exceeds even 100 000/ mm3
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
AL – 70% myeloid, the rest: lymphoblasts (mostly B)
Ther. allog BMT, interferon A
PV (polycytemia vera)
increased proliferation of all three series – most striking: red cell mass increase. – in BM and
PB
hypercellular BM
PB: HTC 60%.., Hb 180 and more – symptoms: increased RC mass - hypervolemia, blood
stasis in vessels – mostly in venous circulation
frequently cyanosis – stagnation and deoxygenation of blood
hypertension, thrombotic episodes, bleeding – abnormal blood flow, abnormalities of PLT
granulopoiesis may be elevated
plt elevated + functional abnormalities
Methods of treatment – phlebotomies - being abandoned.
SPENT PHASE – myelofibrosis with myeloid metaplasia (in 20% after 10 ys)
ET (essential thrombocytemia)
the least common CMPD
PLT exceed 600 000 /mm3
BM: increased cellularity, mega: abnormal, often large
PLT: often large
4
Doc. MUDr. L. Boudová, Ph. D.
Symptoms: thrombosis and hemorrhage – abnormalities of quantity and quality of PLT
rel. indolent
Chronic idiopathic myelofibrosis
abnormal neoplastic megakaryocytes – release fibrogenic factors – PDGF and TGF
stimulate fibroblasts to proliferation
early: BM hypercellular with minimal fibrosis
progression : hypocellular , fibrotic; osteosclerosis
obliteration of BM space: extramedullary hematopoiesis - spleen; later: liver
PB: leukoerythroblastic erytrhoid and granulocytic precursors in the PB
in up to 20% - progression to AML
Acute leukaemia
Remember: all acute leukemias share some clinical similarities (namely acute course). They
are discussed separately in these notes according to their progenitor cells).
Acute leukemias: myeloid (+further subdivision according to the genetic features,
morphology, immunophenotype); affect typically adults
lymphoblastic (subdivision: B or T, +further subdivision according to the genetic features,
morphology, immunophenotype) affect typically the young (children, adolescents)
acute myeloid leukaemia (AML)
the absolutely necessary minimum is to know why AML is dangerous, what cells it may be
composed of, to know some of the categories)
Immature precursors of the myeloid series (mostly G; less commonly also erythroid series or
megakaryocytes)
Typically: adults
(only 20% of AL of children – children. typically ALL))
neoplastic cells may contain genetic alterations – acquired or inherited
BM: neoplastic cells – inhibition of terminal differentiation
-
fill the BM – suppress normal hematopoiesis – physical
replacement
5
Doc. MUDr. L. Boudová, Ph. D.
-
other mechanisms
Problems – symptoms result from:
 failure of normal hematopoiesis – anemia, neutropenia, thrombocytopenia
 infiltration of organs by neoplastic cells
BM: more than 20% of blasts
Myeloblasts: nucleus: chromatin is delicate, more cytoplasm than lymphoblasts
Azurophilic granules- peroxidase positive
Red staining Auer rods- abnormally large azurophilicgranules
Monoblasts: no Auer rods, folded nuclei
Aleukaemic leukaemia – paradoxical term – BM filled by neoplastic cells but no
neoplastic cells in the peripheral blood ("white blood without white blood")
rare
Classification – WHO 2001 – only some categories mentioned
an effort to categorize them according to the genetic features, not only according to their
appearance –such classification should be the most precise – the idea: to target the therapy at
specific sites of the cell cycle (but not all of these facts are known currently)
Categories:
 AML with recurrent gen. abnormalities – -balanced translocations, often complete
remission, favourable prognosis (translocation – fusion gene-chimeric protein); e. g.
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
FAB classification = French – American – British (older than WHO)
now used to categorise only cases which do not fall into the previous categories
M0 – without maturation – myeloblastic
6
Doc. MUDr. L. Boudová, Ph. D.
M1 – without maturation
M2 – with maturation
M3 – promyelocytic – nowadays categorised rather according to the genetic features – t(15;
17)
M4 – myelomonocytic
M5 – a – monoblastic, b- monocytic
M6 – erythroid
M7 – megakaryoblastic
Myeloid sarcoma (granulocytic s., chloroma)
solid tumour mass of AML cells - composed of myeloblasts or immature myeloid cells in an
extramedullary site or in bone
precedes or occurs concurrently with acute or chronic myeloid leukaemia (or MDS; CMPD)
chloroma – because some are green
prognosis: - when a part of AML: like AML
when completely isolated - may be cured by radiotherapy
7