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Golden rules in science & medicine:• Start strong stay strong ; start loose become more loose• Look for fundamentals & let the details look for themselves ( so, after study of each subject do a subject skeleton /mind map for it )
• Truly, one picture is worth ,at least, a thousand words.• Do not rush in your diagnosis.• Common is common.
Golden rules in genetics:• Each human character is controlled by
2 genes / gene clusters on 2 homologous chromosomes so, gene is the unit of inheritance. • Each specific gene encodes for a specific antigen or protein.
HEMATOLOGICAL MALIGNANCIES
Hematological Malignancies
Definition:-Group of haematological disorders characterized by
clonal expansion of
haemopoietic cells which has undergone
genetic mutation
Haemopoietic cells :in the marrow or peripheral lymphoid tissue
Clonal :derived from a single cell proliferation ( N.B. it is autonomous & uncontrolled) compare with normal haemopoiesis
Clonal evolution of malignancy
Most malignancies r the result of several sequentially acquired mutations rather than single catastrophic mutation.
Stromal cells are the major source of growth factors except for:
a. Erythropoietin, 90 % of which is synthesized in the kidney. b. Thrombopoietin, made largely in the liver.
POINTS OF INTEREST IN NORMAL HEMOPOIESIS
CDK
p53 is known as the ‘ guardian of the genome ‘
Cell cycle
The genes involved in the development of Haematological malignancies
can be broadly divided into 2 groups:
1. Oncogenes 2. anti-oncogenes / Tumour Suppressor Genes (TSG)
OncogenesOncogenes Tumour Suppressor Genes (TSG)
(anti-oncogenes)
proto-oncogenes
are often involved in
transduction ( transfer of external signals to the nucleus to activate genes )
TSG act in Cell cycle control (Checkpoint)
( G-1 S G-2 M )DNA damage cell-cycle arrest for 1 of 2
1.DNA repair & continuation of cell cycle2.Apoptosis by activating pro-apoptotic genes
Oncogenes arise because of
gain-of-function mutation in the normal cellular genes
( proto-oncogenes )
TSG may acquire
loss-of-function mutation malignant transformatione.g. p53 (at 17p13 ) & Rb (at 13q14 )
One of the striking features of haemat.malign. ( in contrast to most solid tumours ) is
high frequency of translocations ( t )
Usually point mutation or gene deletion (del.)
Examples of chromosomal translocations in haematological malignancies
will be mentioned later on
p53 the { guardian of the genome } is
The most significant TSG in human cancer
It is mutated or inactivated in > 50 % of malignant diseases including
many haematological malignancies
The aetiology of Haematological Malignancies
It is a combination of genetic background & environmental influence that determines the risk of
developing haematological malignancy
I. Inherited factors :- see next page
II. Environmental influence: #. Chemicals #. Drugs #. Radiation #. Infections
I. Inherited factorsI. Inherited factors
The incidence of leukaemia is greatly increased in some genetic diseases , particularly :
D W - F A B
D Down’s syndrome:
20-30-fold increased frequency of AL ( M-7)W Wiskott - Aldrich syndrome ( WAS ):
F Fanconi’s anaemia 10% of cases develop AML A Ataxia telangiectasia B Bloom’s syndrome Ashkenazi Jewish with TID Telangiectasia + life-threatening infections + dwarfism
Autosomal recessive characterized by :
•Defective DNA repair &•Hypersensitivity to other DNA damaging agents
X-linked recessive ( Thrombocytopenia & BLEEDING with small plt & defective plt. Aggr. + recurrent infections-due to COMBINED IMMUNE-PARESIS in infancy)
Tri-somy-21
#. Chemicals : chronic exposure to benzene may cause #. Chemicals : chronic exposure to benzene may cause BM hypoplasia , dysplasia & chromosomal BM hypoplasia , dysplasia & chromosomal
abnormalities abnormalities & is unusual cause of MDS or AML& is unusual cause of MDS or AML #. Drugs : The alkylating agent (e.g. chlorambucil ; Melphalan) #. Drugs : The alkylating agent (e.g. chlorambucil ; Melphalan)
predispose to AML,predispose to AML, especially if combined with radiotherapy especially if combined with radiotherapy or if used to treat patients with or if used to treat patients with lymphocytic or plasmacytic lymphocytic or plasmacytic
disordersdisorders
#. Radiation : Radiation ,especially to the BM, is leukaemogenic #. Radiation : Radiation ,especially to the BM, is leukaemogenic see fig.-- see fig.--
#. Infections: Pls, refer to lymphoma Fig.10-2#. Infections: Pls, refer to lymphoma Fig.10-2
II. Environmental influence II. Environmental influence
Alkylating agent express reactive alkyl group
which make covalent bond with cell molecules (particularly purine in DNA) DNA damage
The most commonSpecific abnormalityin childhood ALL is thet ( 12 ; 21 )
HAEMOPOIETICSTEM CELLS
(HSC)(CD34+ ; CD38-)
LYMPHOID STEM CELLS
MYELOID STEM CELLS
LYMPHOCYTES OTHER BLOOD CELLS
HAEMOPOIETICSTEM CELLS
(HSC)
LYMPHOID STEM CELLS
MYELOID STEM CELLS
LYMPHOCYTES RBCOTHERWBC
PLATELET
HAEMOPOIETICSTEM CELLS
LYMPHOID STEM cell
MYELOID STEM CELLS
LYMPHOCYTES
ACUTECHRONIC
OTHER BLOOD CELLS
ACUTE
CHRONIC
HSC or early progenitors
Maturing & mature cells
usually aggressive & rapidly fatal if not rapidly treated
x x
some has high cure rate e.g. ALL( L1) in children
X
HAEMOPOIETICSTEM CELLS
LYMPHOID STEM CELL
Lymphoblast
MYELOID STEM CELL
Myeloblast
LYMPHOCYTES
ACUTE
CHRONIC
MYELOID
LYMPHOID
OTHER BLOOD CELLS
Lymphoblasts
Lymphocytes Granulocytes
Myeloblasts
ALL AML
CMLCLL
LYMPHOID STEM CELLS
Pre-T
Thymocyte
Peripheral T Cells
T-Helper
T-Supp.
Pro-B
Pre-B
B- Virgin
B- Mature
LPC
PLASMACELL
ALL
CLL
MYELOIDSTEM CELLS
PRO-NORMOBLAST
RBC
MONO-BLAST
MONO-CYTE
MYELOBLAST
PRO-MYELOCYTE
MYELOCYTE
META-MYELOCYTE
BAND or STAB
GRANULOCYTES
MEGA-KARYO-BLAST
PLATELET
AMLCML
Acute Leukemia means
Maturation Arrest
Sustained SELF-RENEWALat the expense of
DIFFERENTIATION
accumulation of BLAST CELLS
Differentiation (Maturation)
Self-renewal
Maturation Arrest
Sustained self-renewal
Differentiation (Maturation)
AcuteLeukemia
Normal
ACUTE LEUKEMIASTypes&
Sub-types
INCIDENCE
Age
Clinical presentation & Lab. Data
B.M. failure Anaemiasymptoms & signs of anaemia
Neutropenia recurrent infections NB Total WBC count( High; Normal or low )
Thrombocytopenia bleeding tendency
Tissue Infiltration
Clinical presentation & Lab. Data
Anaemiasymptoms & signs of anaemia
Neutropenia recurrent infections
Thrombocytopenia bleeding tendency
Tissue Infiltration: e.g. organomegaly (hepatosplenomegaly) ; lymphadenopathy ; meningeal syndrome( headache, nausea, vomiting, blurring of vision & diplopia with blast cells in CSF) ; skin lesions ; testicular swelling -------- etc.
B.M. failure caused byaccumulation of
BLAST cells
ALL AML
TYPES & AGE mainly children
~ 4 yr
mainly adults
ALL the most common malignancy of childhood
( 25-30 % )
a second rise
after the age of 40 yr
AML incidence increase with age
LAB DIAGNOSIS OF ACUTE LEUKAEMIA
• Complete Blood Count (CBC) & smear
• BM aspiration & trephine BiopsyBM aspiration & trephine Biopsy
• Special (cyto-chemical) StainsSpecial (cyto-chemical) Stains
• Immunological markers Immunological markers (Immuno-pheno-type “ IPT”) by (Immuno-pheno-type “ IPT”) by Flow cyto metry “FCM”Flow cyto metry “FCM”
• Chromosomal studiesChromosomal studies
• Cyto-genetic analysisCyto-genetic analysis• Molecular genetic analysis including FISHMolecular genetic analysis including FISH
• Storage of BM smears wrapped in aluminum foil at -20˚CStorage of BM smears wrapped in aluminum foil at -20˚C
• Others: microbiological ; Biochemical .........etc. Others: microbiological ; Biochemical .........etc.
CBC ;Smear & BM aspiration
Acute Leukaemia (AL) is defined as the presence of over 20 % of blast cells in the peripheral blood or bone marrowat clinical presentation
Q: Could we diagnose AL with less than 20 % blasts ?A: YES , if specific leukaemia-associated cytogenetic or molecular genetics abnormalities are present
AML
FAB SUB-TYPES OF AL
M0
M1
M2
M3M4
M5
M6
M7L1
L2
L3
ALL
Morphological classification of AL
Burkitt’s Lymphoma is the Lymphomatous correlate of L- 3 ALL
LYMPHOBLASTS IN ALL FAB SUBTYPES
L1 L2 L3small & monomorphic
é large N/C ratio
Larger& heterogeneousé more abundant Cy.
& more prominent Ni.
large & homogeneous
é marked Cy. basophilia &
Cy. vacuoles
ACUTE LEUKEMIAS SPECIAL STAINS
M1-M4
M5
L2 LYMPHOBLAST
MYELOBLAST
MONOBLAST
PASPeriodic acid- Schiff
*Sudan Black-B’SBB’*Myeloperoxidase’MPO’
*Specific Esterase
Non-Specific Esterase
IPT of AL
Pro-B common Pre-B
CD 10 ( CALLA )
- ++
±
often infant
Commonly child
cIg +ve
malepredominance &Mediastinalmass
B-ALL
sIg +v e
CD14&CD15: M4 & M5Glycophorin -A : M6CD41a(GpIIb/IIIa) : M7
CD 14 & !% in M4& M5Glycophorin A in M6CD41a in(
Myeloperoxidae in M0CD14 &CD15 in M4 & M5Glycophorin-A in M6CD41a in M7
TdT ; Terminal deoxynucleotidyl transferase
~12%
L1 or L2
~ 3%
L3
~85%
L1 or L2
Prognostic factors in ALLPrognostic factors in ALL
Good PoorAge Child Adult ( or infant < 2
yr )
Sex Girls boys (?) testes is a common site for relapse
CNS disease at presentation
( - ) ( + )
WBC count Low High (> 50.000 /µL)
IPT CALLA T-ALL ( in children )
Cytogenetics Normal or Hyperdiploid
Ph + ve , or Pseudo-diploid
Time to clear blasts from blood
< 1 week > 1 week
Time to remission
< 4 week > 4 week
Minimal residual disease (MRD)
(- ve) at 1-3 months
( still + ve) at 3 - 6 months
MyeloblastM0-M1
MonoblastM5
Pro-normoblast
Megakaryo -blast
M7
Promyelocyte
M3
AMLFAB-sub-types M0 - M7
M2
M4
M6
N.B. odd No.:- single cell even No.:- double cell
Auer rods
M5a(monoblastic)
M5b(monocytic)
Pro-normoblast
M7Megakaryo -
blastic
M3 Ac. Promyelocytic L.
(APL)
AMLFAB-sub-types
M2
with
gran
ulo
cytic
matu
ration
M4 with granulocytic & monocytic
maturation
M6 ( Erythroleukaemia)
N.B. odd No.:- single cell even No.:- double cell
M0undifferentiated
M1 without maturation
M5Megakaryo-
blast
M7
Promyelocyte
M3 & M-3v
AMLSpecific clinical. features
M4 tissue infiltration
Acute MF(no splenomegaly BM MK—blasts)
DD:- MMMMyelofibrosis éMyeloid Metaplasia DIC
00
ACUTE LEUKEMIAS SPECIAL STAINS
M4
M5
MYELOBLAST
MONOBLAST
*Sudan Black-B’SBB’*Myeloperoxidase’MPO’
*Specific Esterase
Non-Specific Esterase
DE
M2-SBB+ve Auer rod M2-SBB+ve CG
M2-MPO+ve CG
M4-SBB+ve My
Mo-ve
AML é.out
Maturation M1 M2 AML égranulocytic Maturation
Myeloblast
Promyelocyte
C: Heavy azurophilic granulation
(hypergranular) & Auer rods (rod-shaped granules) strongly positive for MPO
Faggot cells : cells with bundles of Auer rods
N: with nucleoli (Ni)
APL M3Classical
APL APL M3
Faggot cell
APLAPL(M-3v) micro-granular (M-3v) micro-granular variantvariant
Characterized by: paucity of myeloid granules & dumb-bell nucleus
M-3v
AML (AMML)
M4 AML with granulocytic & monocytic maturation
Monoblast Myeloblast+
M5
Myeloblast
Pro-normoblast
> 50% of the nucleated marrow cells r
erythroid &Myeloblasts < 30% BM NEC
M6AMLErythroleukemia
M6
Myeloblast
Megakaryo-blast
Large and small megakaryoblasts with high N/C ratio
C: is pale & agranular with blebs
EM Platelets Peroxidase +ve
AML
M7
Megakaryoblastic L.
IPT of AL
Pro-B common Pre-B
CD 10 ( CALLA )
- ++
±
often infant
Commonly child
cIg +ve
malepredominance &Mediastinalmass B-ALL
sIg +v e
CD14&CD15: M4 & M5Glycophorin -A : M6CD41a(GpIIb/IIIa) : M7
CD 14 & !% in M4& M5Glycophorin A in M6CD41a in(
Myeloperoxidae in M0CD14 &CD15 in M4 & M5Glycophorin-A in M6CD41a in M7
TdT; Terminal deoxynucleotidyl transferase
~12%
L1 or L2
~ 3%
L3
~85%
L1 or L2
M5t ( 9 ; 11 )
t ( 11 ; 19 )del (11q)
M3 t ( 15 ; 17 )
AML Translocations (t) & other chromosomal changes
M2
t ( 8 ; 21 )
M4-Eo inv ( 16 ) del ( 16q )
11q23 abnormalities
detected in 85 % of secondary AML
Prognostic factors in AMLPrognostic factors in AML Good Poor
Age Aged 40-60 yr induction remission 80%
Adult ( >60 yr ) or (infant < 2 yr )
Previous MDS / MPD / Chemotherapy
( - ) i.e. denovo ( + )
CML-BC lymphoid myeloidCNS or extra med. Disease at presentation
( - ) ( + )
WBC count Low High (> 50.000 µL)
Trilineage Dysplasia ( - ) ( + )
IPT ( CD-34 ; HLA-DR & TdT ) ( - ve ) ( + ve )
Translocations t(8,21) ; t(15,17) & inv(16)
del ( 5 or7 ) ; ( 11q23 )
Complete remission
after 1 course ?
Yes No
Multi-drug resistance
(MDR) ( - ) ( + )
Hybrid Acute Leukaemia (Hybrid Hybrid Acute Leukaemia (Hybrid AL)AL)
AL with blast cells showingAL with blast cells showing
features of both ALL & AMLfeatures of both ALL & AML
Bi-phenotypic
Bi-lineal
Blasts
with features of ALL
Blasts with features of both ALL & AML on
the same cell
Blasts
with features of AML
2 separate cell populations
Up to 1993,the reported
cases are 160
The 1st reported case in Arab countries
AML is the type often found inCong. Leukaemiaparticularly M5&M7
Prognosis is extremely poor
The Practitioner.Vol.10,No12,Dec.1999
Clinical presentation & Lab. Data
Anaemiasymptoms & signs of anaemia
Neutropenia recurrent infections
Thrombocytopenia bleeding tendency
Tissue Infiltration: e.g. organomegaly (hepatosplenomegaly) ; lymphadenopathy ; meningeal syndrome( headache, nausea, vomiting, blurring of vision & diplopia with blast cells in CSF) ; skin lesions ; testicular swelling -------- etc.
B.M. failure caused byaccumulation of
BLAST cells
PallorPallor
InfectionInfectionss
Pneumonia
Bleeding Tendenc
y
Extensive BruisingMucosal Bleeding
Purpura
Bleeding TendencyBleeding Tendency
Retina
Cerebral
Lymphadenopathy
Gum Hypertrophy
Leukemic Skin Infiltrate
Testicular Leukemia
Leukemic Infiltrate
Mediastinal InvolvementMediastinal Involvement
Therapy of ALTherapy of AL
Supportive: for BM failureSupportive: for BM failure
Specific: Chemotherapy Specific: Chemotherapy ± Radiotherapy± Radiotherapy
*. Induction of remission*. Induction of remission
*. Intensification (consolidation)*. Intensification (consolidation)
*. Cranial prophylaxis*. Cranial prophylaxis
*. Maintenance therapy*. Maintenance therapy
Stem Cell Transplantation: allogeneic SCTStem Cell Transplantation: allogeneic SCT
Myelodysplasia of
Haemopoietic cells
Ineffective Haemopoiesis
Anaemiasymptoms & signs of anaemia
Neutropenia recurrent infections
Thrombocytopenia bleeding tendency
Myelodysplastic Syndrome Myelodysplastic Syndrome (MDS)(MDS)
ANT in various combinations : RA : Refractory anaemia RN : Refractory Neutropenia RT : Refractory Thrombocytopenia R Bicytopenia : ( e.g. A + N ; A + T ; N + T etc.---------------)
M D SM D SPB BM
Refractory anaemia ( RA )
Blasts < 1 % Blasts < 5 %
RA withring sideroblast( RARS )
Blasts < 1 %
Blasts < 5 %Ring sideroblasts
> 15 % of total erythroblasts
RA with excess blasts( RAEB )
Blasts < 5 % Blasts 5 - 20 %
RAEB in transformation( RAEB-t )
Blasts >5 % Blasts over 20 %or Auer rods present
Chronic myelo-monocytic leuk.
( CMML ) 20% of MDSTissue infiltr.( gum hypertrophy; splenomeg.; skin rash & LAP)
As any of the above with
Persistent monocytosis
> 1.0 X 10 3/ µL
Any of the above with
Promonocytes
LOW
RISK
HIGH
RISK
ChronicLymphocyticLeukaemia
(CLL)
Chronic Myeloid
Leukaemia(CML)
TYPES & AGE
Peak incidence
70 ± 10 yr Male : female 2 : 1
Any age but most frequently at the age of
50 ± 10 yr Male : female 1.4 : 1
Only 15 %before the age of 50 yr
Chronic
Myeloid
Leukaemia
(CML)
Anaemiasymptoms & signs of anaemia
High total WBC count : 50 – 500 X 10 3 / µLHyper-Leucocytosis
*..In up to 50 % of casesDx. is made incidentally from the routine CBC
bleeding tendencyinspite thrombocytosis(?)Plt.dysfunction
Clinical Presentation of CML
Huge spleenDiscomfort& Indigestion (small meals)
Hyper-metabolism: #.weight loss #. Lassitude #.night sweat #.anorexia (?) mimic hyper-thyroidism
Gout &Renal impairment
Visual disturbances & Priapism 2ry to hyperleucocytosis & leuco-stasis with impaired microcirculation
Urticaria
AnaemiaNormocyticNormochromic
High total WBC count e.g. 50 - 500X10 3 / µLHyper-Leucocytosis
Smear: complete spectrumof myeloid cells (myeloblast in the chronic phase: less than 5 %)with eosinophilia & basophilia
#. Most frequent thrombocytosis but, may be normal or low#. Plt.dysfunction
Laboratory features of CML
• Ph’ pos.: over 95 % NB: Ph’ neg. BCR-ABL pos. CML behaves clinically like Ph’ pos. CML
• Hyperuricaemia• High B12& B12 binding capacity (due to increased TC-1 from neutrophil)• False hyperkalaemia
(K+ released from leucocytes) &false hypoglycemia ( glucose consumed by leucocytes)
• Low NAP score ( N :20-100 ) (neutrophil alkaline phosphatase)
BM: Hypercellular with granulocytic predominance
RaisedRaised LowLow
PPolymorphnuclear Leucocytosis olymorphnuclear Leucocytosis
( Myeloid Leukaemoid ( Myeloid Leukaemoid Reaction ;Reaction ;
Neutrophilia ;Neutrophilia ;
Neutrophil leucocytosis)Neutrophil leucocytosis)
MyeloMyelopproliferative Disorders roliferative Disorders (MPD)(MPD) - - Polycythaemia (rubra) vera - PRVPolycythaemia (rubra) vera - PRV
- Myelofibrosis ( MF )- Myelofibrosis ( MF )
PPregnancyregnancy
NAP score
CML
The Philadelphia ( Ph’ ) chromosome: reciprocal translocation
BCR-ABL oncoprotein :
210 KDa in CML & some Ph’+ve ALL due to M-BCR: Major-BCR 190 KDa in other Ph’+ve ALL due to m-BCR: minor-BCR
BCR-ABL = Breakpoint Cluster Region- Abelson Leukaemia
Chronic Myeloid Leukaemias (CML)Chronic Myeloid Leukaemias (CML)
CML , Ph + ( CGL- CML , Ph + ( CGL- Chronic Granulocytic LeukaemiaChronic Granulocytic Leukaemia)) CML , Ph – ( atypical ) CML , Ph – ( atypical ) <5% poor prognosis<5% poor prognosis Juvenile myelomonocytic leukaemiaJuvenile myelomonocytic leukaemia (Juvenile (Juvenile
CML)CML)
Chronic neutrophilic leukaemiaChronic neutrophilic leukaemia Eosinophilic leukaemiaEosinophilic leukaemia Chronic myelomonocytic leukaemia (CMMLChronic myelomonocytic leukaemia (CMML))
refer to refer to Myelodysplastic Syndrome Myelodysplastic Syndrome
(MDS)(MDS)
ChronicPhase
AcceleratedPhase
CML
BlastCrisis
( 70 % of CML )
BLAST CELLSBLAST CELLS
less than less than
5 %5 % more than more than
20 %20 %inbetween
Glivec is the first line drug in the management of CML-chronic phaseComplete haematological response in virtually all patients ,
but the aim of treatment is Complete cytogenetic response { (-) Ph’ chromosome in BM in cytogenetic analysis }
Juvenile CMLJuvenile CML
Young Children (1st 4 yr of life) boys: girls (2:1) Tissue infiltrations ( Skin rash ; HSM & LAP ) Blasts & promonocytes < 20% in PB & BM Monocytosis >1X103/µL hence, the name JMML No BCR-ABL fusion gene Hb-F high for age (a useful diagnostic feature) Poor prognosis (if untreated BC& death usually occur within 4 yr)
Treatment of choice is SCT
Juvenile myelo-monocytic leukaemia (JMML)
Chronic LymphocyticLeukaemia(s)
*. B-Chronic Lymphocytic Leukaemia ( CLL ) The most common of Chronic Lymphoid Leukaemias
ChronicLymphocyticLeukaemia
(CLL)
Chronic Myeloid
Leukaemia(CML)
TYPES & AGE
Peak incidence
70 ± 10 yr
Any age but most frequently at the age of
50 ± 10 yr only 15 %before the age of 50 yr
Male : female 2 : 1
Male : female 1.4 : 1
Chronic Lymphocytic Leukaemia (CLL)Chronic Lymphocytic Leukaemia (CLL)
Etiology : Etiology : UnUnknownknown No higher incidence after chemo-therapy or radio-No higher incidence after chemo-therapy or radio-
therapytherapy ( in contrast to( in contrast to CML: CML: incresed incidence in survivors of atom bomb in Japan)incresed incidence in survivors of atom bomb in Japan)
The most common leukaemia in the western worldThe most common leukaemia in the western world ( ( ?? due to increased routine medical check-up ) due to increased routine medical check-up ) 77 fold increased risk of CLL in fold increased risk of CLL in the close relativesthe close relatives of the patient of the patient
CLLCLL is characterized by proliferation and accumulation of is characterized by proliferation and accumulation of
mature-lookingmature-looking but but bbiologically immature iologically immature B lymphocytesB lymphocytes ( ( weak surface expression of Ig-M & Ig-Dweak surface expression of Ig-M & Ig-D ). ). #. Accumulation ; where & why ?#. Accumulation ; where & why ? PB ; BM ; LN ; liver & spleenPB ; BM ; LN ; liver & spleen as a result of impaired apoptosis i.e. elderly lymphocytesas a result of impaired apoptosis i.e. elderly lymphocytes
Early:
Bacterial infections
Advanced Disease:
viral & fungal infections
Immunosuppression is significant Due to:
1. Hypo- gamma- globulin- aemia
2. Cellular immune dys- function
Anaemia: Hb < 10 g/dL
Thrombocytopenia: Plt < 100 x10 3 / µL
Lymphadenopathy Symmetrical ; discrete & not tender (cervical ; axillary or inguinal) The most frequent clinical sign
Hepatosplenomegaly
Absolute Lymphocytosis ( > 5x103/µL & sustained ) most cases Dx in routine CBC
Stage III : As stage 0 + Anaemia (Hb < 10 g/dL)
± Adenopathy ± Organomegaly
Stage IV: As stage 0 + Thrombocytopenia (Plt < 100 x 10 3 / µL) ± Adenopathy ± Organomegaly
Stage I : As stage 0 + Adeno-pathy
Stage II:
Stage 0: Absolute Lymphocytosis
As stage 0
+ Organomegaly ( Enlarged liver & / or spleen)
± Adeno-pathy
Rai classification of CLL
Early:
Bacterial infections
Advanced Disease: viral & fungal infections reduced S. Ig conc.
Anaemia Hb < 10 g/dL normocytic &normochromic
Thrombocytopenia: Plt < 100 x10 3 / µL
Lymphocytosis (5-300 x103/µL)
Smear: 70-99% small mature-looking lymphocytes with smudge (smear) cells
BM aspiration : Lymphocytic replacement of normal marrow elements Lymphocytes comprise 60 ± 35 %
Lab. Dx
Causes of anemia in CLLCauses of anemia in CLL
Primary( Marrow Infiltration )
Hyper-splenism Immune
Chemotherapy
FolateDeficiency
Elderly NutritionalDeficiency
SECONDARY
Causes of thrombocytopenia in Causes of thrombocytopenia in CLLCLL
Primary( Marrow Infiltration )
Hyper-splenism Immune
Chemotherapy
SECONDARY
The most common The most common Chromosomal Abnormalities in CLLChromosomal Abnormalities in CLL
Deletion 11q23Trisomy 12
Deletion 17pinvolving the p53
deletion 13q14 good prognosis
Bad prognosis
Bilateral inguinal lymphadenopathy
Gross enlargement of the lymph nodes inboth axillary regions in a 70-year-old female
C L L
Richter’s Syndrome (Large cell transformation)
(Immuno- blastic transformation)
5 % of CLL with fever & weight loss
Large blast cell (previously termed Immuno-
blast) spillover to the blood with monoclonal protein in
serum & free light chain in urine
BM & LN examination reveals the same cells
( Large cell lymphoma)
PBS showing large blast cells (immunoblasts)