Blood Neoplams

March 2010

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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. Myeloblast2. Promyelocyte3. Myelocyte4. Metamyelocyte5. Band Neutrophil6. 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 Acute/Chronic & Myeloid/Lymphoid AML / ALL & CML / CLL

Lymphomas Lymph nodes, tumor 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.

PlateletCoagulation

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% (5-

10%) WBC counts are very high

Chronic Myeloproliferative syndrome

1. Chronic myeloid leukemia (CML)2. Polycythaemia vera3. Essential thrombocytosis4. 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:

CMLMalignancyHepatosplenomegalyLarge spleenSlow courseTotal count IncreasedThrombocytosisLAP decreasedPh chromosomeBasophilia

Leukemoid reactionInflammatory lesionHepatomegalyMild spleen if presentShort durationIncreased but not muchPlatelets- NormalLAP increasedNo Ph chromosomeAntibiotics

Differences between CML & Leukemoid Rn

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

Anemia, infections & Bleeding Enlargement of Liver, Spleen lymphnodes Acute/Chronic & Myeloid & Lymphoid.

Lymphomas Tumors of lymphnodes. 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