Jan Żeromski
Pathology
2010/2011
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Malignant proliferation of white cells of the
hematopoietic system with infestation of
blood and usually bone marrow.
Lymphoid and myeloid leukemias
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Hematopoietic stem cells differentiating to progenitor
ones, either myeloid or lymphoid lineage
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Chromosomal abnormalities, most commonly
translocations,
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Inherited genetic defects (Down syndrome, Bloom
syndrome, ataxia telangiectasia
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Some viruses: Epstein-Barr (EBV), herpesvirus -8, HTVL1 etc.
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Environmental factors: chronic infection, Helicobacter
pylori, radiation therapy, chemotherapy
Precursor leukemias
- acute lymphoblastic l.
- pro B
- pre B (common)
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Peripheral ones
- chronic lymphocytic l.
- prolymphocytic l.
- hairy cell l.
- plasma cell myeloma
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B-cell origin
Precursor leukemias
- acute lymphoblastic l.
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Peripheral ones (T and
NK)
- chronic lymphocytic l.
- large granular
lymphocytic l.
- Sezary syndrome
- NK-cell leukemia
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T-cell origin
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Definition: the set of differentiation antigens expressed
on a given cell type
Lymphoid and myeloid cell subsets in various stages of
maturation have distinct immunophenotype
Differentiation antigens are classified according to
cluster determinants (CD) system
CD classification covers more than 300 antigenic
epitopes searched by monoclonal antibodies
Each leukemia type has characteristic set of CD
markers, what constitutes nowadays current
classification hematopoietic malignancies and the basis
of diagnosis
B cell lineage antigens
differentiation
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Clonality – crucial difference between neoplastic
and normal lymphocytes
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Unique feature of lymphocytes – antigen receptor
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Antigen receptor gene rearrangement determines
antigen specificity of lymphocytes
Rearrangement precedes neoplastic transformation
Thus daughter cells from malignant cell progenitor
express the same antigen receptor (either T or B) –
form identical cell clone
Acute Lymphoblastic Leukemia
• Most cases are Tdt positive
• Most express CD10 (common ALL
antigen)
• Most are “pre-B cell” phenotype
• 15-20% T-cell lineage
• 5% B-cell phenotype
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Acute myelogenous leukemias (8 types)
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Myelodysplastic syndromes (MDS)
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Chronic myeloprolifeative disorders:
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chronic myelogenous leukemia
polycythemia vera
essential thrombocytosis
primary meylofibrosis
M0 AML – non-differentiated, incidence 2-3%
 M1 AML – almost without differentiation, 20%
 M2 AML – myeloid maturation of granuloc.30-40%
 M3 AML – hypergranular promyelocytes, 5-10%
 M4 AML – cells of both myelocytic (min.20%) and
monocytic origin (<30%), 15-20%
 M5 AML – Monoblasts (M5a) and monocytes (M5b), 10%
 M6 AML – dysplastic erythroid precursors and
myeloblasts, 5%
 M7 megakaryocytic leukemia – blasts of
megakaryoc.lineage predominate, 1%
Number of blasts in all: < 20%
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Myeloid cell lineage
antigens differentiation
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Chromosomal translocation is fairly common and may
be distinct for given subtype such as t(15;17) in M3
AML
Some leukemias do no fit to current classifications and
are described on the basis of several cytogenetic
defects such as gene fusion, deletion, insertion etc.
In lymphoid tumors antigen receptor gene
rearrangement is earlier than neoplastic transformation.
Thus, tumorous gene products (immunoglobulins or Tcell receptors) are identical in contrast to normal
lymphocytes expressing plethora of various antigen
receptors. It turned out to be of diagnostic value.
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General: symptoms are more evident in acute than in
chronic forms , but do not differ much in lymphoid vs.
myeloid leukemias,
In chronic types the onset is usually insidious: mild
anemia, weakness, easy fatigue, weight loss, anorexia
Enlargement of spleen is common in both types often
associated with left upper quadrant pain,
Acute leukemias manifest by abrupt stormy onset:
fever, infection, bleeding, bone pain,
hepatosplenomegaly, cns manifestations such a
vomiting, headache, nerve palsies.
Chronic Leukemia
• Often discovered because of an
abnormal lab or an abnormal physical
examination
• Severe cytopenias characteristic of
acute leukemia are seldom present at
time of diagnosis
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Fairly good in precursor B-cell leukemias in childhood
In chronic B-cell leukemias life expectancy may be
comparable to normal one, provided that there is no cns
involvement
Acute myeloid leukemias have usually unfavourable
prognosis (15-30% remain free of disease for 5 years),
In chronic myelogenous leukemia supplementation of
blood and proper chemotherapy allow fro 4-5 years
survival, but the end is almost always fatal.
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Clinical – pancytopenia, normal lymph nodes and
splenomegaly
Incidence –mostly middle age males (2% of
lymphomas)
Origin – mature B cells but with peculiar
projections best seen in phase-contrast
microscope. They are pan B, CD5-, CD25+,
CD11c+, CD103+
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Infiltration of spleen, bone marrow and liver
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Accompanying infections common often with
M0 AML – non-differentiated, incidence 2-3%
 M1 AML – almost without differentiation, 20%
 M2 AML – myeloid maturation of granuloc.30-40%
 M3 AML – hypergranular promyelocytes, 5-10%
 M4 AML – cells of both myelocytic (min.20%) and
monocytic origin (<30%), 15-20%
 M5 AML – Monoblasts (M5a) and monocytes (M5b), 10%
 M6 AML – dysplastic erythroid precursors and
myeloblasts, 5%
 M7 megakaryocytic leukemia – blasts of
megakaryoc.lineage predominate, 1%
Number of blasts in all: < 20%
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Incidence: middle age, older adults and
children
Bone marrow: normal cells are replaced but
undifferentiated blasts with some myeloid
features. They have blocked maturation,
increased survival and the replication rate
lower than normal myeloid progenitors,
Genetic: several chromosomal rearrangements
disrupting genes encoding transcription factors
needed for normal myeloid maturation,
Lab findings: anemia, neutropenia,
thrombocytopenia
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Flow cytometry: due to poor cell granularity
blasts have very low site scatter. They usually
show myeloid-specific surface markers (CD13,
CD33) and markers of progenitor cells (CD34,
CD117), but various departures from the above
are common,
Clinical: fatigue, spontaneous bleedings,
infections, often caused by opportunistic
pathogens such as fungi or Pseudomonas.
Organomegaly of liver, spleen, infiltration of
skin, gingiva by normal monocytes is often
seen.
Petechiae, Purpura
Hematoma, Joint bl.
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Disease of adults (25 – 60 yrs), more common in
women,
Bone marrow – highly cellular, mainly maturing
granulocyte precursors, increased numbers of
megakaryocytes
Molecular – translocation of BCR gene (chromosome 9)
to ABL gene (on chromosome 22) The resultant BCRABL fusion gene encodes protein with tyrosine kinase
activity. So-called Philadelphia chromosome seen in
karyotyping studies is the reflection of (9;22)
translocation
Clinical – slow progression up to 5 years, afterwards
some 50% of patients enter „accelerated phase” with
appearance of blasts, resembling acute leukemia.
BCR-ABL translocation
Chronic Myelogenous Leukemia
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Cell origin: multipotent myeloid stem cell
Bone marrow: increased production of erythroid,
granulocytic and megakaryocytic maturing cell types
Blood: erythrocytosis, granulocytosis, thrombocytosis,
increased hematocrit and red cell mass
Clinical: insidious onset in late middle age (above 60
yrs). Patients suffer from headache, dizziness,
hypertension, gastrointestinal abnormalities, gout due
to high cell turnover. Thrombosis episodes are
common.
Final fate: either „spent phase” leading to marrow
myelofibrosis with extramedullary hematopoesis or
terminal AML
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Definition: clonal cell disorders marked by maturation
defects, ineffective hematopoiesis and increased risk of AML
(10-40%)
Two distinct types:
idiopatic (primary) MDS in older people with insidious
course. Often discovered incidentally on routine testing.
therapy-related MDS, due to previous chemo-or radiation
therapy, usually 2 to 8 years after,
Bone marrow: several distorted cells of myeloid lineage
showing various abnormalities. Myeloblasts may be
increased, but below 20%. If higher – it is already leukemia,
Survival: primary MDS-9-29 mo, therapy-related – 4 to 8 mo.