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Blood Neoplams

March 2010

Learning issues

Understand the nature of common


blood neoplasms (AML, ALL, CML,
CLL): Clinical presentation, Pathology,
complications and prognosis
Classification of Blood neoplasms
To know the different laboratory
methods in diagnosis of blood
neoplasms

White Blood Cells:

Leucopoiesis:
1.
2.
3.
4.
5.
6.

Myeloblast
Promyelocyte
Myelocyte
Metamyelocyte
Band Neutrophil
Segmented Neutrophil.

Myeloid cells

WBC disorders:

Reactive increase in number philias


Neutrophilia Bacterial sepsis
Lymphocytosis viral, Immune
Eosinophilia Allergy & Parasites.
Decreased number penias
Neutropenia, Lymphopenia &
Eosinopenia, Pancytopenia
Drugs, viral infections, Radiation,
chemotherapy etc.

WBC Neoplastic disorders

Leukemias Bone marrow, blood, blast cells

Lymphomas Lymph nodes, tumor

Acute/Chronic & Myeloid/Lymphoid


AML / ALL & CML / CLL
Hodgkins
Non-Hodgkins

Myeloma
Premalignant conditions:

Myeloproliferative syndromes (MPS)

Myelodysplastic syndromes (MDS)

Classification

Clinically: Acute, chronic


Morphology: Myeloid, Lymphoid
Old classification followed was FAB

Using peripheral smear, bone marrow study,


cytochemistry

Latest is WHO classification of blood


neoplasms

Immunophenotyping, cytogenetics, Molecular


biology

Leukemia Classification

Acute Leukemias:

Acute Myeloid Leukemia - AML


AML M0, M1, M2, M3, M4, M5, M6 & M7
Acute Lymphoid Leukemia - ALL
ALL - L1, L2 & L3

Chronic Leukemias:

Chronic Myeloid Leukemia- CML


Chronic Lymphoid Leukemia - CLL

General Age Distribution:

ALL- Younger age population: 4-10 yrs


AML- Young Adults: 15-40 yrs
CML- Older adults: 30-60 yrs
CLL- Old age group: 50-70 yrs

Acute Leukemias:

Rapid onset & Rapid progression


High Mortality
Plenty of Blasts >20% (in PS & or BM)
Anemia, infection & bleeding
ALL-Typically presents as
Lymphadenopathy
AML- Associated with
Hepatosplenomegaly

Etiology

Radiation: Ionizing, Non ionizing.


Chemicals: Benzene, alkyalating agents.
Viruses: Leukemogenic viruses with RT
enzyme, HTLV-1.
Genetic factors: Downs, Blooms,
Fanconis, Ataxia talengiectasia.

Ac Leukemia - Clinical Features

Suppression of normal hematopoesis


Anemia (low RBC)
Fever - Infections (low WBC)
Bleeding tendency (low PLT)
Tender bones, lymphadenopathy,
spleenomegaly etc. (Leukemic
infiltration)

Clinical features of AML

Primarily in adults and in infants less


than 1 yr
15 to 20% of all leukemias
Less No. of cases after age 50 yrs.
Abrupt onset of symptoms.. Within
weeks to months.

Palor, fatigue, weakness, anaemia.


Bleeding, bruising, petichial
hemorrhages.
Infections, pneumonia, meningitis
Spleenomegaly, hepatomegaly,
lymphadenopathy.
DIC in AML-M3, skin infiltration soft
tissue masses in AML- M5 etc.

Platelet
Coagulation

Petechiae, Purpura

Hematoma, Joint bl.

AML-M5 - Gum Hypertrophy:

Organomegaly

Diagnosis of AML

High index of clinical suspicion


Family history, past history.
Simple PS examination.
PS, Bone marrow, Cytochemistry,
Immunophenotyping, Cytogenetics,
Other lab tests: Serum uric acid, LDH,
RFT, Sr.Ca, electrolytes

PS EXAMINATION IN AML

RBC are normocytic normochromic


WBC count is increased , Rarely it is
decreased or Normal.
Majority of cells are Immature cells- Blasts
PS shows > 20% Myeloblasts
Mature neutrophils are less
Morphology of AML M0- M7 type
Low platelets

BM examination in AML

Hypercellular Marrow
Blasts are > 20%
Blasts with intracytoplasmic rods- Auer
Rods
Increased M: E ratio
Less of Megakaryocytes

AML-M2 - with maturation

AML-M3 Promyelocytic

Special investigations

Difficult to distinguish blasts among other cells


Cytochemistry

Blast cells show reaction to cytochemical stains. This


property is used to identify & differentiate cells
Myeloblasts are +ve for Sudan black B &
Myeloperoxidase (MPO)
Lymphoblasts are +ve for Periodic acid schiff (PAS)
AML M4 & M5 blasts are +ve for Non- specific esterase
(NSE)

Immunophenotyping

Identifying cells by surface markers using antibodies

NSE positive in AML-M5

Cytogenetics in AML

To detect genetic abnormality in


leukemias
Confirms the diagnosis
Prognostication of patients
t(15;17) in AML M3
t(8;21) in AML M2
inv16 in AML M4

ALL-Acute Lymphoblastic Leukemia

Common in Children.
FAB classification L1, L2 & L3
Neoplastic cells are CD10 +ve & most are
Pre B cell type.
2% of child ALL & 20-30% of adult onset
ALL has t(9;22)
Growth failure, Fever, Anemia
Lymphadenopathy, bleeding.
Mild to Moderate Hepatosplenomegaly

ALL:Cervical Lymphadenopathy

Mediastinal Lymphadenopathy - ALL

ALL-L2

Diagnosis of ALL

High clinical suspicion


PS & BM study (aspiration/ biopsy)

Morphological diagnosis

Lymphnode aspiration & biopsy


Immunophenotyping, cytogenetics
Imaging (USG scan, CT)

Chronic leukemias

Also divided as Myeloid and lymphoid


(FAB)
Have indolent course.
More mature forms are seen in the PS
like lymphocyte and neutrophil
Blasts in PS or BM is less than 20% (510%)
WBC counts are very high

Chronic Myeloproliferative
syndrome
1. Chronic myeloid leukemia (CML)
2. Polycythaemia vera
3. Essential thrombocytosis
4. Myelofibrosis.
Marrow fibrosis Cytopenias

Acute leukemia

Chronic Myeloid Leukemia

Middle age 40-60y, insidious onset


Philadelphia chromosome, t(9:22)
Anemia, Fever & Bleeding
Marked leucocytosis >1,00,000/ cumm
Marked splenomegaly, Hepatomegaly,
weight loss
Sometimes, discovered accidentally
Three phases: Chronic, Accelerated, Blast
crisis

PATHOPHYSIOLOGY

Clonal stem cell disorder. Targeted at


PSC.
All hemopoetic cells are involved in the
neoplasm.
Acquired chromosomal abnormality
Ph (Philadelphia) chromosome is found
in all neoplastic blood cells

PHILADELPHIA CHROMOSOME

Reciprocal translocation b/w Chr 9 & 22


t (9;22)
Movement of ABL (Abelson) gene on
Chr 9 to BCR (Break point cluster) gene
on Chr 22.
The translocation produces abnormal
protein called p210.
Additional Chr abnormalities: Tri 8, Loss
of Y, additional Ph.

PHILADELPHIA CHROMOSOME

Expressed in all blood cells except in T


lymphocytes & few B cells.
2-5% of child ALL, 25% of adult ALL &
some AML are also Ph Positive.
The abnormal protein may by p210 or
p190.

BLOOD PICTURE in CML

Moderate anemia: 8 to 11 gm/dl


Markedly elevated WBC count with full
spectrum. Counts up to 500 X 109 /L
Myeloblasts up to 10%.
PLT count may be normal, decreased or
increased.

Increased in early CML (Chronic)


Late CML Thrombocytopenia

BLOOD PICTURE

Segmented neutrophils & myelocytes


constitute majority of cells
Monocytes, Basophils, eosinophils are also
increased
Basophilia & eosinophilia > 20%
Aggressive course
Decreased LAP score (Increased in
Leukaemoid reaction)

LAP = Leukocyte alkaline phosphatase

COURSE OF CML

Chronic phase may last 30 40


months.
Accelerated phase: Increasing
spleen, severe prostration, raising
WBC count, worsening of anaemia,
Thrombocytopenia, blasts 10-19%,
increasing Basophils, eosinophils.
Blast crisis: 1/3rd may develop blast
crisis.= AML.

BLAST CRISIS

Now classified as AML.


Survival 1-2 months.
Blasts in PS & or BM >20%.
Need aggressive treatment.
Counts may decrease in PS.
Few patients go in for
Myelofibrosis.

NOW..CML what Next??

Chronic course
Spontaneous remission
Accelerated phase
Blast crisis

LEUKEMOID REACTION

Leukocytosis exceeding 50,000 WBC/mm3


Increase in band cells, myelocytes,
metamyelocytes, promyelocytes
Generally benign and are not dangerous
Response to a chronic bacterial disease state
Blood picture is similar to CML
Blast cells in BM aspirate are < 2%
Increase in Leukocyte alkaline phosphatase (LAP
score)
No Basophilia
No Ph cromosome
Counts return to normal following Antibiotics

Leukemoid Reaction:

Differences between CML & Leukemoid Rn

CML
Malignancy
Hepatosplenomegaly
Large spleen
Slow course
Total count Increased
Thrombocytosis
LAP decreased
Ph chromosome
Basophilia

Leukemoid reaction
Inflammatory lesion
Hepatomegaly
Mild spleen if present
Short duration
Increased but not much
Platelets- Normal
LAP increased
No Ph chromosome
Antibiotics

CLL:

Most common in Older age (60-70yr).


May be asymptomatic.
Present with Lymphadenopathy
Indolent course.
No need of aggressive therapy.

Morphology in CLL

PS: Total count increased, Majority are Mature


lymphocytes, Smudge cells, (Smear cells, Basket
cells), Less of neutrophils
Some prolymphocytes +
Identical tumor of Lymphnode SLL (small
lymphocytic lymphoma)
Autoimmune HA, Autoimmune Thrombocytopenia
is common (10% of cases)
May progress to aggressive types

Prolymphocytic leukemia
Diffuse large B cell lymphoma (Richter syndrome)

CLL:

Myeloproliferative Syndromes:

Neoplasms, Slow, Chronic, Proliferation


Increased, Functionally abnormal cells.
Extramedullary hemopoiesis - Organomegaly
Progress to Leukemia end stage.

Classification:

Polycythemia rubra vera (PV)


Chronic Myeloid Leukemia (CML)
Essential Thrombocythemia (ET)
Myelofibrosis (MF)

MPS: Classification

POLYCYTHEMIA VERA

Increase in cellular blood elements


Unregulated proliferation of erythroid
elements in BM.
Affects the pluripotent stem cells
granulocytes & platelets are also
affected.

CLASSIFICATION OF POLYCYTHEMIA

Polycythemia Vera (Primary)


Secondary Polycythemia:
High altitude, COPD, Obesity, Tumors,
CRF,
Relative Polycythemia:
Giasbocks syndrome, dehydration.

PATHOPHYSIOLOGY OF PV

Clonal stem cell defect


EPO independent unregulated
erythrocyte hyperplasia.
Hypersensitivity of erythroid stem cells
to EPO, GF & abnormal GF.

CLINICAL FEATURES

Ages of 40-60 yrs.


Asymptomatic for several years
Increased red cell massheadache,
weakness, pruritis, Wt. loss.
Thrombotic episodes.
Splenomegaly, hepatomegaly.
Hypertension, plethora, congestion of eyes

BLOOD & BM

Hb: >18gm%, PCV > 52% in males.


ESR < 4 mm/hr
Leukocytosis: 12-20K, shift to left.
LAP is > 100.
Plt > 4,00,000., giant forms, abnormal
aggregation.
Hypercellular marrow, M:E ratio is normal,
increase in Megakaryocytes

COURSE & PROGNOSIS

No known cure.
Phlebotomy, Myelosuppression
Progression to Myelofibrosis or rarely
acute leukemia.

Summary:

Leukemias Starts in marrow spread to blood

Lymphomas Tumors of lymphnodes.

Anemia, infections & Bleeding


Enlargement of Liver, Spleen lymphnodes
Acute/Chronic & Myeloid & Lymphoid.
Fever & lymphadenopathy
Types - Hodgkins & non- hodgkins, special types.

Premalignant conditions

MDS: Myelodysplastic syn Less & Dysplastic


MPS: Myeloproliferative dis -Excess & abnormal

Learning issues

Understand the nature of common


blood neoplasms (AML, ALL, CML,
CLL): Clinical presentation, Pathology,
complications and prognosis
Classification of Blood neoplasms
To know the different laboratory
methods in diagnosis of blood
neoplasms