HAEMATOPATHOLOGY

HAEMATOPATHOLOGY
Development of Haemopoiesis:
Yolc sac, liver
Bone marrow
Newborn : active
marrow
in all bones
18 years :
haemopoiesis only
in central bones!
(calvarium,
sternum, ribs,
vertebrae,
prox.epiph.
femur, humerus)
HAEMOPOIESIS
normal:
fat:1
hemop:1
erythroid :1
myeloid: 3
CLASSIFICATION
CLASSIFICATION OF
OF ANAEMIA
ANAEMIA ACCORDING
ACCORDING TO
TO UNDERLYING
UNDERLYING MECHANISM
MECHANISM
I. BLOOD LOSS
A. Acute: trauma
B. Chronic: lesions of GI tract, gyn. disorders
II. INCREASED RATE OF DESTRUCTION (HEMOLYTIC ANAEMIAS)
(A. INTRINSIC ( INTRACORPUSCULAR) ABNORMALITIES OF RED CELLS
hereditary
1. Red cell membrane disorders
a. Disorders of membrane cytosceleton :
spherocytosis, elliptocytosis
b. Disorders of membrane lipid ; membrane lecithin (stomatocytosis)
2. Red cell enzime deficiencies
a. Glycolytic enzymes
b. Enzimes of hexose monophosphate shunt
3. Disorders of Hgb. synthesis
a. Deficient globin synthesis: thalassaemia syndromes
b. Structurally abnormal globin synthesis: sickle cell anaemia
Aquired:
Membrane defect:paroxysmal nocturnal haemoglobinuria
II. HAEMOLYTIC ANAEMIAS
II. B. EXTRINSIC EXTRACORPUSCULAR)
ABNORMALITIES
1. Antibody mediated
a. Isohaemagglutinins: tra. fo,
b. Autoantitbodies: idiopathic,
malignant neoplasms , mycoplasmal
2. Mechanical.trauma to red cells
a. Microangiopathic: TTP,DIC,
b. Cardiac prosthetic valves
3. Infections:
malária
4. Chemical injury: lead poisoning
5. Hypersplenism
erythroblastosis foetalis
drug-associated, SLE,
infection
mucin producing tumors
Diseases of the white blood cells
Leukocytosis - causes
Normal
homeostasis
Precursor
Storage
pool
(mature
pool
Marginating pool
Tissue pool
Circulating pool
Leukocytosis - causes
Neutrofilic~ Bact.inf., (pyogenic organisms), tissue necrosis
Eosinofilic ~ Allergic, autoimmune diseases, vasculitides,
lymphomas (Hodgkin, non-Hodgkin)
Basofilic ~
Rare, myeloproliferative diseases
Monocytosis
Autoimmune diseases, chronic infections (TBC,
rickettsiosis, malaria, bacterial endocarditis)
Lymphocytosis
Accompanies monocytosis, viral infections, whooping
cough
Lymphadenitides
Acute, non-specific
Chronic, non-specific…..
Follicular hyperplasia
Parafollicular hyperplasia
Sinus histiocytosis
Neoplastic proliferations of the
white cells
Lymphoid neoplasms
phenotypically closely resemble the particular normal stage of lymphoid
differentiation
Classification is based on this
Myeloid neoplasms
diseases of the hematopoietic cells
Acute leukaemias
Myelodysplastic syndromes
Chronic leukaemias
Histiocytoses
histiocytes, and dendritic cell diseases
Langerhans cell histiocytosis
Diseases of the white cells
- frequent chromosome aberrations
Ig gene
TCR
Congenital gene disorders
Bloom sy, Fanconi anemia, NF I, Down
Viruses
HTLV-1, KSHV/HHV8, EBV
Other infections
HP, HIV
Iatrogenic factors
Irradiation, chemotherapy
Lymphomas, leukaemias - definition
Leukaemia – bm involvement, tumor cells in the
peripheral blood
Lymphoma – lymphoid cell proliferation in the
tissues
Hodgkin – non-Hodgkin
Plasma cell neoplasias
BM
THYMUS
DN
CLP
Precursor Blymphoblastic
lymphoma / leukaemias
BLB
CLL / SLL
MyMu
Precursor T lymphoblastic
lymphoma / leukaemias
DP
NBC
CD4
PC
CD8
LYMPH NODE
Mantle zone
lymphoma
MC
FollLy
Burkitt
DLBL
PTC
GC
MZ
HL
DLBL, MZL, SLL/CLL
Peripheral T cell
lymphomas
Acute leukaemias
BM CELLS can’t maturate
Cell proliferation is not quicker than normal
Normal haemopoiesis is arrested
Normal blasts are suppressed
LEUKAEMIAS AND MYELOPROLIFERATIVE
DISORDERS
Leukaemia : neoplasms of BM stem cells
Types:
ACUTE
LYMPHOID
MYELOID
CHRONIC
LYMPHOID
MYELOID
ACUTE LEUKAEMIAS
Basis of disease:
maturation defect of BM stem cells
Cell proliferation is frequently
s lo w e r than normal!!!
abnormal blasts dominate the BM picture
normal haemopoietic elements are blocked –
this is due not only to space occupation
lymphoid leukaemias belong to
lymphoma/ leukaemia group
CLINICAL
CLINICAL APPEARANCE
APPEARANCE OF
OF ACUTE
ACUTE LEUKAEMIAS
LEUKAEMIAS
Weakness
Fever, infection
Hemorrhage
-
anaemia
granulocytopenia
thrombocytopenia
(anywhere in the body)
Bone pain, tenderness
-
Meningeal symptoms
(headache, nausea, vomit,
-
cerebral palsy,
-
subperiosteal leukaemic
infiltration
CNS involvement /
subarachnoidal
bleeding
intracerebral,
meningeal infiltration)
Symptoms, specific to certain
leukaemias
AMLM3
-
(promyelocytic)
DIC
AMLM1-2
-
soft tissue,or subperiostal
infiltration
AML4-5
-
skin, gum infiltration
LABORATORY FINDINGS
Anaemia
WBC
variable severity
50 % < 10000/mm3
20 % > 100000/mm3
Rarely : aleukaemic leukaemia
Blasts both in peripheral and BM smears,
HIATUS LEUKAEMICUS
Thrombocyte
<
100000 / mm3
Peripheral pancytopaenia : BM biopsy- RULE OUT aplastic anaemia
LABORATORY FINDINGS
CYTOCHEMISTRY
PAS
Tdt
myeloperoxidase
NON spec. esterase
ALL
+
+ (95 % )
-
AML
- (95 %)
+ (M1-3)
+ (M4-5)
PROGNOSIS , THERAPY
ALL -
2-10
5 year survival over 60 %
CHEMOTHERAPY
T cell, and adult form- grave
AML
-
BM TRANSPLANTATION
ACUTE
ACUTE MYELOID
MYELOID LEUKAEMIA
LEUKAEMIA
20
20 %of
%of childhood
childhood leukaemias,
leukaemias, occurrence
occurrence :: 15-40y
15-40y Further
Further classification
classification according
according to
to maturation
maturation arrest
arrest
stage
stage
M0 Minimally diff AML
M1 Minimally diff AML
M2 AML with slight maturation
M3 Acute promyelocytic leukaemia
2-3 %
Blasts express myeloid AB, ultrstructurally
resemble myeloblasts, but MPO neg.
20 %
2-3% of blasts MPO +. Few cytoplamic granules
(Auer rods), myeloblasts show minimal maturation.
30-40 % Full range of myeloid maturation. Auer rods, t(8:21)
slightly better prognosis
5-10%
Majority of cells are hypergranulated promyelocytes,
(Auer rods),- DIC t(15:17), (PML-RARα)
M4 Acute myelo-monocyte leukaemia 15-20% M2, +monoblasts, (non-spec esterase+), 16Chr abn: good pr
M5aAcute monocyte leukaemia
M5bAcute monocyte leukaemia
10%
Monoblasts, monocytes in BM and periphery
Mature monocytes in peripheral blood, organomegaly,
lymphadenopathy, tissue infiltration, older age
M6 Acute erythroleukaemia
5%
Dysplastic erythroid precursors, megaloblastoid forms,
30% myeloblasts, most cases therapy induced
M7 Acute megakaryocyte leukaemia
1%
Megakaryoblasts dominate, react with GIIb/IIIa AB-s,
BM reticulin elevated
ACUTE
ACUTE MYELOID
MYELOID LEUKAEMIA
LEUKAEMIA
M0 Minimally diff AML
2-3 %
M1 Minimally diff AML
20 %
Blasts express myeloid AB, ultrstructurally
resemble myeloblasts, but MPO neg.
2-3% of blasts MPO +. Few cytoplamic granules
(Auer rods), myeloblasts show minimal maturation.
ACUTE
ACUTE MYELOID
MYELOID LEUKAEMIA
LEUKAEMIA
M0 Minimally diff AML
M1 Minimally diff AML
M2 AML with slight maturation
2-3 %
Blasts express myeloid AB, ultrstructurally
resemble myeloblasts, but MPO neg.
20 %
2-3% of blasts MPO +. Few cytoplamic granules
(Auer rods), myeloblasts show minimal maturation.
30-40 % Full range of myeloid maturation. Auer rods, t(8:21)
slightly better prognosis
ACUTE
ACUTE MYELOID
MYELOID LEUKAEMIA
LEUKAEMIA
M0 Minimally diff AML
2-3 %
M1 Minimally diff AML
20 %
M2 AML with slight maturation
30-40 %
M3 Acute promyelocytic leukaemia
5-10%
Blasts express myeloid AB, ultrstructurally
resemble myeloblasts, but MPO neg.
2-3% of blasts MPO +. Few cytoplamic granules
(Auer rods), myeloblasts show minimal maturation.
Full range of myeloid maturation. Auer rods, t(8:21)
slightly better prognosis
Majority of cells are hypergranulated promyelocytes,
(Auer rods),- DIC t(15:17), (PML-RARα)
ACUTE
ACUTE MYELOID
MYELOID LEUKAEMIA
LEUKAEMIA
M0 Minimally diff AML
M1 Minimally diff AML
M2 AML with slight maturation
M3 Acute promyelocytic leukaemia
2-3 %
Blasts express myeloid AB, ultrstructurally
resemble myeloblasts, but MPO neg.
20 %
2-3% of blasts MPO +. Few cytoplamic granules
(Auer rods), myeloblasts show minimal maturation.
30-40 % Full range of myeloid maturation. Auer rods, t(8:21)
slightly better prognosis
5-10%
Majority of cells are hypergranulated promyelocytes,
(Auer rods),- DIC t(15:17), (PML-RARα)
M4 Acute myelo-monocyte leukaemia 15-20% M2, +monoblasts, (non-spec esterase+), 16Chr abn: good pr
M5aAcute monocyte leukaemia
10%
Monoblasts, monocytes in BM and periphery
M5bAcute monocyte leukaemia
Mature monocytes in peripheral blood, organomegaly,
lymphadenopathy, tissue infiltration, older age
ACUTE
ACUTE MYELOID
MYELOID LEUKAEMIA
LEUKAEMIA
M0 Minimally diff AML
M1 Minimally diff AML
2-3 %
20 %
M2 AML with slight maturation
M3 Acute promyelocytic leukaemia
30-40 %
5-10%
M4 Acute myelo-monocyte leukaemia 15-20%
M5aAcute monocyte leukaemia
M5bAcute monocyte leukaemia
M6 Acute erythroleukaemia
Blasts express myeloid AB, ultrstructurally resemble myeloblasts, but MPO neg.
2-3% of blasts MPO +. Few cytoplamic granules (Auer rods), myeloblasts show minimal
maturation.
Full range of myeloid maturation. Auer rods, t(8:21) slightly better prognosis
Majority of cells are hypergranulated promyelocytes,
(Auer rods),- DIC t(15:17), (PML-RARα)
M2, +monoblasts, (non-spec esterase+), 16Chr abn: good pr
10%
Monoblasts, monocytes in BM and periphery
Mature monocytes in peripheral blood, organomegaly,
lymphadenopathy, tissue infiltration, older age
5%
Dysplastic erythroid precursors, megaloblastoid forms,
30% myeloblasts, most cases therapy induced
ACUTE
ACUTE MYELOID
MYELOID LEUKAEMIA
LEUKAEMIA
M0 Minimally diff AML
2-3 %
Blasts express myeloid AB, ultrstructurally
resemble myeloblasts, but MPO neg.
M1
Minimally diff AML
20 %
2-3% of blasts MPO +. Few cytoplamic granules
(Auer rods), myeloblasts show minimal maturation.
M2 AML with slight maturation
30-40 %
Full range of myeloid maturation. Auer rods, t(8:21)
slightly better prognosis
M3 Acute promyelocytic leukaemia
5-10%
Majority of cells are hypergranulated promyelocytes,
(Auer rods),- DIC t(15:17), (PML-RARα)
M4
Acute myelo-monocyte leukaemia
15-20%
M2, +monoblasts, (non-spec esterase+), 16Chr abn: good pr
M5aAcute monocyte leukaemia10%
Monoblasts, monocytes in BM and periphery
M5bAcute monocyte leukaemia
Mature monocytes in peripheral blood, organomegaly,
lymphadenopathy, tissue infiltration, older age
M6 Acute erythroleukaemia
5%
Dysplastic erythroid precursors, megaloblastoid forms,
30% myeloblasts, most cases therapy induced
M7 Acute megakaryocyte leukaemia
1%
Megakaryoblasts dominate, react with GIIb/IIIa AB-s,
BM reticulin elevated
V.S. Female, 75
1979 (20 years before) examination for headache,
dizziness
1982 surgical ,then combined chemo/radioth for
breast cancer
1999 febr.: cough, dyspnoe at rest for 3 weeks .
Symptoms ameliorated after AB administration
Labor.: pancytopenia, ESR ,
dizziness
OVSZ: peripheral blastosis,
Trephine biopsy:
MYELODYSPLASTIC
MYELODYSPLASTIC SYNDROMES
SYNDROMES
Myeloid stem cells can mature, but the cells are defective
(ineffectiv haemopoiesis)
Diseased sten cell is genetically instable, with worsening capacity
of differenciation, end stage: AML in 30%
Pancytopenia at periphery (clin signs are equal with those of acute
leukaemia)
BM hypercellular, (ring sideroblasts, megaloblastoid maturation,
polypoid blasts, agranular granulocytes, hypolobulated
megakaryocytes),
blasts less than 20%-!
Morphological subtypes : according to cells in the BM and periphery
Some cases de novo, (MDS), most patients after therapy with
alkilating agents, radiotherapy (tMDS)
Chromosome aberrations: 5, 7 monosomy, 5q, 7q , 20q del., 8
trisomy
CHRONIC MYELOPROLIFERATIVE
DISEASES
CML
POLYCYTHAEMIA VERA
MYELOID METAPLASIA WITH
MYELOFIBROSIS
ESSENTIAL THROMBOCYTAEMIA
CML
15-20 % - leukaemias
Philadelphia chromosome
t(9;22)bcr-c-abl fusion gene
gene product has tyrosin kinase aktivity
(erythroid, megakaryocyte precursors)
Disease of the pluripotent or multipotent stem cell
granulocyte precursor dominates
NO MATURATION ARREST, CELL PROLIFERATION
IS SLOWER THAN PHYSIOLOGICAL
BM: number of cells of granulocyte line are 20 fold
higher than the normal!
CML-Clinical signs :
-slow progression
-splenomegaly - frequently the first sign
-weakness
-loss of weight anorexia
- leukocyte count
> 100000 / mm3, many segments,
full range of myeloid elements
-thrombocytosis at the beginning in 50% of cases
LACK OF GRANULOCYTE ALKALINE PHOSPHATASE
diff. dg- (leukaemoid reaction)
After variable period, in half of the cases
a c c e l e r a t e d phase:
-failure of response to treatment
- increasing anaemia, thrombocytopenia
BLAST CRISIS
70 % AML
30 % ALL
(in half of the cases, blast crisis occurs without
accelerated phase )
CHEMOTHERAPY
not sufficient
in chronic phase:
BONE MARROW TRANSPLANTATION
POLYCYTHAEMIA
POLYCYTHAEMIA VERA
VERA
Both (erythroid, megakaryoid, myeloid) cell lines involved, but
ERYTHROID CELLS DOMINATE
RBC count high, ( erythropoietin unmeasurable)
Morphological changes:
Blood volume and viscosity - extremely high
Plethora and congestion in all organs!
Hepatosplenomegaly, myeloid metaplasia
Leading symptoms:
THROMBOSIS, INFARCTION!
Haemorrhage in 30% due to blood vessel distension, abnormal
thrombocyte function
BM:
- hypercellular, with full range of cells of all three cell lines
deposition of reticulin , than fibrosis, increased blasts
Laboratory findings:
- RBC: 6-10 mill. / mm3
- WBC: 80000 / mm3 (granulocyte alk.phosph.
-diff.dg.CML!)
- thr.: > 500000 /mm3 (funct. morph.
abnormalities)
Clinical:
- dizziness, headaches
- GI bleedings , + ulcers ( basophilia, histamin
level )
- pruritus ( basophilia, histamine level )
- abdominal pain, splenic, renal infarctions!
- hyperuricaemia , gout
Death: thrombotic sequales
Therapy: PHLEBOTOMY
(chemotherapy, BM irradiation-sequales!)
Sequales
- myelofibrosis with myeloid metaplasia
AML ( 2 %, with phlebotomy only)
AML (15%, after chemo, radiotherapy!)
MYELOID
MYELOID METAPLASIA
METAPLASIA WITH
WITH MYELOFIBROSIS
MYELOFIBROSIS
BM: fibroblasts, fibrosis,
Spleen: neoplastic stem cells proliferate
- sometimes burnt out polycythaemia vera, or CML
-more frequently primary (agnogenic , idiopathic )
BM FIBROBLASTS DON’T BELONG TO THE NEOPLASTIC CLONE
(neoplastic thrombocytes, megakaryocytes produce PDGF, TGFb)
Tumor cells first proliferate in BM, than „move” to spleen, liver
Morphology:
-splenomegaly , extramedullary hemopoiesis, with all three cell lines
- hepatomegaly – due to hemopoiesis
-lymph nodes – hemopoiesis might occur
- BM- hypercellular first , (clinically inapparent)
fibrosis in central bones, hemopoiesis in small bones of the limbs
Laboratory findings:
- anaemia (normochromic, normocytic, teardrop-shape,
numerous
normoblasts)
-WBC count: high or low full range of maturation, basophilia
- platelet count: high, many abnormal forms
Signs:
haemorrhage, thrombosis, infarction, infection
Diff.dg:
- CML
( alk. phosph., Philadelphia chr. )
- myelophtisis-anamnestic data
Therapy
transfusion
Prognosis: relatively good
5-10 % - AML
Essential thrombocytaemia
Diagnosis of exclusion!
Platelet count at periphery 600.000!
BM: mild hypercellularity, many atypical
megakaryoblasts, other blasts appear norm.
NO marked fibrosis
Perif: atypical, large megakaryocytes, mild
leukocytosis
Clin: haemorrhage, thrombosis, overall survival:
12-15 y
REAL
REAL classification
classification of
of Lymphoid
Lymphoid neoplasms
neoplasms
(Revised
(Revised European-American
European-American Classification
Classification of
of Lymphoid
Lymphoid
Neoplasms)
Neoplasms)
I.
Precursor B- cell lymphoma group
( Precursor B lymphoblastic leukaemia/ lymphoma )
III.
Peripheral B cell lymphomas
Chronic lymphoid leukaemia, / Small lymphocytic lymphoma
Lymphoplasmocytic lymphoma
Mantle cell lymphoma
Follicular lymphoma Cyt. Grade I.,II.III
Marginal zone lymphoma
Hairy cell leukaemia
Plasmocytoma, / plasma cell myeloma
Diffuse large B cell lymphoma
Burkitt lymphoma
REAL classification of Lymphoid neoplasms
(Revised European-American Classification of Lymphoid Neoplasms)
II.
Precursor T- cell lymphoma group
( Precursor T lymphoblastic leukaemia/ lymphoma )
IV.
Peripherial Tcelllymphomas
T cell chronic leukaemia
Large, granular cell lymphoid leukaemia
Mycosis fungoides-Sézary syndrome
Periferal T cell lymphoma
Angioimmunoblastic T cell lymphoma
Intestinal T cell lymphoma
Adult T cell leukaemia / lymphoma
Large cell, anaplastic lymphoma
ACUTE LYMPHOID LEUKAEMIA
I. Precursor B- cell lymphoma group
( Precursor B lymphoblastic leukaemia/ lymphoma )
I. Precursor T- cell lymphoma group
( Precursor T lymphoblastic leukaemia/ lymphoma
Most frequent childhood leukaemia
Classification:based on morphological,
surface immunglobulins (flow cytometry)
Maturation, prognosis correlates with spec.
chromosomal aberrations
Hyperdiploidy, (t12:21),
(-early precursor, - age: 2-10,-good prognosis
Pseudodiploidy (t9;22)(t4;11)-early B-worse
prognosis
Special
characteristics:
hepato-splenomegaly,
lymph node
enlargement,
BM failure,
testicular,
CNS involvement!
T
T cell
cell ALL
ALL -- Precursor
Precursor TT- cell
cell lymphoma
lymphoma group
group
(( Precursor
Precursor T
T lymphoblastic
lymphoblastic leukaemia/
leukaemia/ lymphoma
lymphoma ))
-- thymus enlargement, liver, spleen , BM
-
involvement
mikr. „starry sky”
adolescents, young adults
CLL, small lymphocytic lymphoma
„Mildest ” leukaemia
5.6.decade
males: 2
females:1
95% B cell , equal with chronic lymphoid leukaemia
Neoplastic B cells:
- surface immunglobulins (IgM, IgD)
monoclonal
- Tdt , CD10 negative
- CD5, CD19, CD20 positive
- long life time, no diff to plasma cell,
- few proliferating cells
lymphoid infiltrate BM, blood, lymph nodes
Chromosomal
Chromosomal abnormalities:
abnormalities:
12
12 trisomy,
trisomy, 14.
14. or
or 11
11 chr.
chr. abnormalities,
abnormalities, needs
needs treatment
treatment worse
worse
progn.
progn.
Other:
Other: hypogammaglobulinaemia,
hypogammaglobulinaemia, but
but AUTOANTIBODIES
AUTOANTIBODIES ,,
HAEMOLYSIS!
HAEMOLYSIS!
No
No blastic
blastic crisis,
crisis, but
but
Richter
Richter syndrome
syndrome can
can occur!
occur!
Stage
A
B
C
Characteristics
less, then 3
lymphoid regions involved,
lymphocytosis, anaemia,
thrombocytopenia, more,
than 3 regions involved
anaemia, thr.cytopenia,
any regions can be involved
Overall survival
10 years
5 years
2 years
Aplastic anaemia
Aquired
Idiopathic
Primary stem cell defect
Immune mediated
Chemical egents
Dose related
Alkilating agents
Antimetabolites
Benzene
Chloramphenicol
Inorganic arsenicals
Idiosyncratic
Chloramphenicol
Phenylbutazone
Organic arsenicals
Idiosyncrratic contd.
Methylphenylethylhydantoin
Streptomycin
Chlorpromazine
Insecticides
Physical agents (irradiation)
Viral infections
Viral hepatitis
CMV
Epstein-Barr
Herpes-Varicella-Zooster
Miscellaneous
Other drugs and chemicals
Inherited
Fanconi anaemia
Aplastic anaemia
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