Hematology 1 Leukemia

ACUTE LEUKEMIAS
HEMATOLOGY 1
INTRODUCTION TO LEUKEMIA
ACUTE VS. CHRONIC LEUKEMIA
ACUTE CHRONIC
AGE All ages, with peaks in 1st decade and Adults

after 50 years
ONSET Sudden Insidious
MEDIAN Weeks to months Months to years

SURVIVAL TIME,
UNTREATED
WBC Increased, normal or decreased Increased (may be >50,000)
DIFFERENTIAL Blast usually present More mature cells
OTHER Usually lymphoid in children and Myeloid mostly in young to

myeloid in adults middle-aged, lymphoid in older
adults. Most go into blast crisis.
ORGANIZATIONS THAT CLASSIFY LEUKEMIA

1. FRENCH AMERICAN BRITISH (FAB) CLASSIFICATION OF ACUTE LEUKEMIAS
• First system, still used by some but being replaced by WHO
• Classified acute leukemia as presence of ≥30 % blast in the peripheral
blood and bone marrow.
• Subdivide leukemia according to cellular morphology, and
cytochemical staining results.
ORGANIZATIONS THAT CLASSIFY LEUKEMIA

2. WORLD HEALTH ORGANIZATION CLASSIFICATION OF ACUTE LEUKEMIAS
• Widely used to classify leukemia. It is now the standard classification
in diagnosing leukemia
• WHO Classification is based on cellular morphology and cytochemical
stains(cytochemistry), but also utilizes information obtained from
immunophenotyping(Flow cytometry), cytogenetics abnormalities
and clinical syndrome. WHO defines acute leukemia as
• ≥ 20% peripheral blood and bone marrow blast
ACUTE LYMPHOBLASTIC LEUKEMIA
(FAB CLASSIFICATION)
ALL is divided into
■ FAB L1 (children)
■ FAB L2 (older children and adults)
■ FAB L3 (patients with leukemia secondary to Burkitt lymphoma)
The three subtypes are differentiated based on
morphology, including cell size, prominence of nucleoli,
and the amount and appearance of cytoplasm. Altered
regulation of the cell cycle and apoptosis are well-
established events in the process of neoplastic
transformation. ALL cell lines and circulating leukemic
cells from pediatric patients possess different regulatory
mechanisms.
CLINICAL SIGNS AND SYMPTOMS
The history of symptoms in ALL can vary from a few days to a few
weeks. Symptoms can include fatigue, fever, infection, headache,
nausea, and vomiting. Bone and joint pain related to the
replacement of normal hematopoietic elements is common. Pain in
the extremities, particularly the legs, is produced by an infiltration
of leukemic cells into the tissues. Physical examination may reveal
petechiae or other evidence of hemorrhage and pallor.
Gastrointestinal hemorrhage and hematuria are less common
findings.
Peripheral blood smears show a
predominance of blast cells in
about 50% of patients. In addition
to blasts, the peripheral blood is
usually composed of close to 100%
lymphoblasts, lymphocytes, and
smudge cells. The blast forms have
one or two nucleoli in the nucleus,
and Auer rods are absent from the
cytoplasm.
L1
→Lymphoblast are small and
homogenous, vary little in size
→Scanty cytoplasm and
inconspicuous nucleoli; nucleus is
round and irregular/indistinct in
shape; have high N:C ratio
→Most common CHILDHOOD ALL
with best prognosis
L2
→Lymphoblast are large and
heterogenous, variable in size
→Abundant, basophilic cytoplasm,
and the nuclei are often clefted with
nucleoli present
→Adult type ALL
L3 (BURKITT-TYPE)
→ Lymphoblasts are large,
homogenous and vacuolated
→Rarest subclass, can be found in
both children and adult
→Poor prognosis
FAB CLASSIFICATION OF ALL
The diagnosis of ALL cannot be made with complete
certainty until cytochemical staining procedures have been
performed to distinguish the lymphoblasts and
lymphocytes from positively reacting cells of AML.
(a) ALL blasts are negative for Sudan black B, peroxidase,

and naphthyl AS-D chloroacetate esterase.
(b) The acid phosphatase reaction is positive in the 20% of
patients whose ALL is of the T-lymphocyte type.
(c) Terminal deoxynucleotidly transferase (TdT) is an intracellular
DNA polymerase that is present in T and B lymphoblasts.
• TdT is weakly positive in pre-B cells.
• TdT is strongly positive in 60% to 85% of T-cell thymocytes.
• Mature peripheral T cells and mature B cells are TdT negative.
• TdT is measured with an immunofluorescence assay that uses a specific
antibody against TdT prepared in rabbits.
• This assay is used in the diagnosis of ALL, lymphoblastic lymphoma, and
the blast phase of CML. Lymphoblasts in 90% of ALL patients are TdT
positive, but blasts in only 5% of nonlymphocytic leukemias (e.g., CML)
stain positive for TdT.
There are several functional subclasses of ALL based
upon immunologic membrane surface markers.
(a) Common ALL antigen (CALLA)- which is alsoCD10, is the

most common subtype.
• Lymphocytes do not show surface features of B or T cells on blast
membranes.
• This subtype is the most common form of ALL in children and
morphologically, lymphocytes are of the FAB classification of L1.
(b) Null-cell ALL is a proliferation of lymphocytes that type

negative for T-cell, B-cell, and CALLA surface antigens.
• Includes a smaller proportion of children and more adults.
• Null-cell ALL is thought to be a pre-B-cell leukemia.
(c) T-cell ALL accounts for 10% to 20% of all patients who have ALL.
• This functional subtype occurs mainly in boys.
• Patients usually show a high leukocyte count pattern and have a poor
prognosis.
• T-cell ALL is characterized by a high frequency of mediastinal tumor, skin, and
CNS involvement.
• Malignant lymphoblasts demonstrate T-cell markers such as CD2 (i.e., E
rosettes); TdT; and CD1.
(d) B-cell ALL is the rarest of subtypes, and it corresponds to

the FAB classification Burkitt’s Type L3.
• Patients who have Type L3 generally have a poor prognosis.
• L3 can be diagnosed by demonstration of B-cell typical surface Ig
receptors.
• This disorder is thought to be a memory-cell leukemia.
ACUTE MYELOID LEUKEMIA
AML is the most common leukemia subtype with an estimated
13,000 new diagnoses yearly in the United States. AML is a
genetically heterogeneous clonal disorder characterized by a
maturation block and the accumulation of acquired somatic
genetic alterations in hematopoietic progenitor cells that alter
normal mechanisms of self- renewal, proliferation, and
differentiation. AML has been recognized as a heterogeneous
disorder. Classification of AML subtypes is clinically relevant
because particular abnormalities are associated with distinct
clinical behavior—prognosis is favorable or unfavorable response to
treatment.
• Unregulated proliferation of the myeloid stem cell
• Classified using morphology, cytochemical stains, CD
markers, cytogenetics
• WHO classification standard for diagnosis
• FAB classification still widely taught
• Platelets, erythrocytes, granulocytes, and/or monocytes
can be affected.
• Found mainly in middle-aged adults; also children < 1 year
old
• Clinical symptoms: • Laboratory Findings:
− Fever − Neutropenia
− Malaise − Anemia
− Weight loss − Thrombocytopenia
− Petechiae − Variable WBC count
− Bruises − Hypercellular marrow with bone
− Mild marrow blasts >20% (WHO) or
− Hepatosplenomegaly >30% (FAB)
a. FAB MO
• Blasts exhibit myeloid markers CD13,
CD33, and CD34 but stain negatively
with the usual cytochemical stains,
myeloperoxidase.
• (MPO), and Sudan black B (SBB).
Constitutes <5% of AMLs.
b. FAB M1 (AML without maturation)

• It shows 90% or more marrow
myeloblasts; may have Auer rods
(fused primary granules)
c. FAB M2 (AML with maturation)
• It shows <90% marrow myeloblasts
• May have Auer rods; chromosome
abnormality t(8;21)
1) Both FAB M1 and FAB M2 are SBB, MPO,
and specific esterase
positive.
2) FAB M1 and FAB M2 account for 50% of
the AMLs.
3) CD13 and CD33 positive (pan myeloid
markers)
d. Acute promyelocytic leukemia (APL; FAB M3)
• Characterized by >30% marrow promyelocytes
with bundles of Auer rods (faggot cells); heavy
azurophilic granulation.
• Clinical symptoms: Severe bleeding,
hepatomegaly, and disseminated intravascular
coagulation (promyelocytes have procoagulant
activity)
• Accounts for 5% of the AMLs
• SBB, MPO, and specific esterase positive
• CD13 and CD33 positive; diagnostic chromosome
abnormality t(15;17); PML/RARA oncogene
involved
e. Acute myelomonocytic leukemia (AMML; FAB M4)
• Characterized by s=20% (WHO) or >30% (FAB)
marrow myeloblasts with >20% cells of monocytic
origin; may have Auer rods
• Proliferation of unipotential stem cell CFU-GM that
gives rise to both granulocytes and monocytes
• Accounts for 30% of the AMLs
• Increased urine/serum lysozyme
• SBB, MPO, and specific and nonspecific esterase
positive
• CD13 and CD33 positive (myeloid) and CD14 positive
(monocytes)
• M4Eo is a subclass of AMML that presents with
eosinophilia.
f. Acute monocytic leukemia (AMoL; FAB M5)
1) Characterized by £=20% (WHO) or >30% (FAB)
marrow monoblasts
2) Accounts for 10% of the AMLs
3) Nonspecific esterase positive; CD 14 positive
4) Contains two variants:
a) M5a is seen in children with >80% monoblasts
in the bone marrow.
b) M5b is seen in middle-aged adults with <80%
monoblasts in the bone marrow.
g. Acute erythroleukemia (AEL, Di Guglielmo
syndrome; FAB M6)
1) Characterized by 3=20% (WHO) or >30%
(FAB) marrow myeloblasts and >50% dysplastic
marrow normoblasts
2) Accounts for 5% of the AMLs
3) Malignant normoblasts are PAS positive. The
myeloblasts are SBB and MPO positive.
4) Malignant normoblasts are CD45 and CD71
(glycophorin A) positive. The myeloblasts are
CD13, CD15, and CD33 positive.
ACUTE MEGAKARYOCYTIC LEUKEMIA
(AMegL; FAB M7)
1) Characterized by a proliferation of
megakaryoblasts and atypical megakaryocytes in
the bone marrow; blasts may have cytoplasmic
blebs
2) Accounts for < 1 % of the AMLs
3) Marrow aspiration results in dry tap; blood shows
pancytopenia
4) Difficult to diagnose with cytochemical stains
5) CD41, CD42, and CD61 (platelet markers)
positive
ADDITIONAL INFORMATION
• Bilineage leukemias contain two cell populations. One population
expresses myeloid antigens; the other population expresses
lymphoid antigens.
• Biphenotypic leukemias occur when myeloid and lymphoid
antigens are expressed on the same cell; poor prognosis
• The WHO classification of acute myeloid leukemias has more than
20 subtypes; all have 20% marrow blasts.
FAB CLASSIFICATION OF AML
FAB CLASSIFICATION OF AML
WHO CLASSIFICATION OF AML
CHRONIC LEUKEMIAS
HEMATOLOGY 1
LYMPHOPROLIFERATIVE
DISORDERS
LYMPHOPROLIFERATIVE DISORDERS
These disorders represent a group of clonal disorders

originating from cells of the lymphoreticular system.
(1) When neoplastic cells involve mainly the bone marrow and blood,
the disorder is known as a leukemia.
(2) When the disease is limited mainly to lymph nodes or organs, the
disease is known as a lymphoma.
(3) Occasionally, a lymphoma develops into leukemia.
The World Health Organization (WHO) Classification of
Tumours of the Haematopoietic and Lymphoid Tissues
1. CLL/small lymphocytic lymphoma (SLL)
2. B-cell prolymphocytic leukemia
3. Hairy cell leukemia (vHCL)
4. Plasma cell neoplasms
5. Lymphoma
1. CHRONIC MYELOGENOUS LEUKEMIA
• Stem cell disorder affecting the granulocytic,
monocytic, erythrocytic , and megakaryocytic
cell lines
• In 90% of the cases of this disease one arm of
chromosome 22 is found to be translocated to
chromosome 9(Philadelphia chromosome)
• Associated with BCR/ABL1 abnormality
• Patients with this disorder who are negative for
the Philadelphia chromosome usually have a
poorer prognosis
.
Chronic lymphocytic leukemia (CLL) is a slowly progressing clonal malignancy of
lymphocytes in an arrested stage of maturation.
The patient’s clinical profile includes the following features:
• CLL is commonly seen in adults with a mean age of occurrence at 55 years.
• The disorder is twice as common in men as compared with women.
• Onset is slow, unrevealing, and is commonly discovered incidentally or only in the late
stages of the disease.
• Patients are seen with symptoms, such as weakness, fatigue, anorexia, weight loss, enlarged
lymph nodes, and abdominal discomfort caused by liver and spleen enlargement.
.
The laboratory profile of a patient who has CLL includes the following:
• Patients have a leukocytosis ranging from 10,000 to 150,000/mm3 with 80%
to 90% lymphocytes persistent over a period of weeks to months.
• Smudge cells are commonly found on blood smears.
• Lymphocytes in patients with CLL have a characteristic morphology.
− The nuclear chromatin is coarsely condensed.
− Nucleoli may be demonstrable.
− Lymphocytes show minimal size and shape variation.
− The cytoplasm is small to moderate in amount.
.
The laboratory profile of a patient who has CLL includes the following:
• Occasionally, immature lymphocytes (i.e., usually fewer than 10%) may be found
on the peripheral blood smear.
• Patients who have CLL do not usually have anemia or thrombocytopenia in early
stages. As lymphocyte proliferation replaces the marrow with leukemic cells,
production of other cell lines may suffer, and the symptoms will appear.
• AIHA develops in 10% of patients who have CLL. The patient’s blood smear
demonstrates spherocytes and reticulocytosis.
• Hypogammaglobulinemia may also be present because of qualitative defects of
the leukemic lymphocytes
.

• Ninety-five percent of CLL patients immunologically type as
having a B-cell leukemia.
• Five percent of CLL patients have a T-cell leukemia.
• Immunologic cell-marker assays for lymphocytic membrane
receptors, surface antigens, and enzymes are useful in
differentiating between lymphocytic leukemias.
.
Cluster designation markers for B lymphocytes include the following:
− CD5: positive in B-lymphocyte CLLs and some lymphomas
− CD22: positive for late B cells and hairy-cell leukemia
− CD24: positive in all stages of B-lymphocyte development (i.e., Pan-B)
.
Immunologic markers for T-cell leukemia include the following:
− CD2: E-rosette marker (i.e., sheep RBCs)
− CD3: positive for T-lymphocyte CLL, T-cell prolymphocytic
leukemia, and infectious mononucleosis
− CD8: positive for T-lymphocyte CLL
.
Treatment of CLL includes one or a combination of the following agents:
• Chemotherapy with alkylating drugs
• Glucocorticoid administration
• Radiotherapy
CLL has a variable clinical course. Clinical staging systems (Rai and Binet) for
assessing prognosis in CLL were developed in the early 1980s, based on easily
obtainable biological and clinical parameters. The staging classification is
O - Bone marrow and blood lymphocytosis
I - Lymphocytosis with enlarged nodes
II - Lymphocytosis with enlarged spleen or liver or both
III - Lymphocytosis with anemia
IV - Lymphocytosis with thrombocytopenia
2. B-CELL PROLYMPHOCYTIC LEUKEMIA

Prolymphocytic leukemia (PLL) is a variation of CLL in which there is a high
number of morphologically immature larger lymphocytes, which appear as
prolymphocytes.
(a) This variation is typically seen in older men (i.e., older than 50 years).
(b) Is characterized by a lymphocytosis up to 350,000/mm3.
(c) Lymphocytes are the B-cell type.
(d) Prolymphocytes can be distinguished by their smooth nuclear chromatin
and large nucleoli
Cont..
2. B-CELL PROLYMPHOCYTIC LEUKEMIA
(e) Patients commonly have a massive splenomegaly, but
their lymph nodes are not enlarged.
(f) The prognosis is usually subacute and more resistant to
treatment than is common CLL. Patients have a mean
survival of 1 year.
(g) PLL prolymphocytes commonly type positive with the
membrane markers CD19, CD20, CD22, CD24, and strong
expression of sIg.
3. HAIRY CELL LEUKEMIA
• Hairy cell leukemia is characterized by small B lymphocytes
with abundant cytoplasm and fine (“hairy”) cytoplasmic
projections. The postulated cell of origin is the peripheral B
cell of post–germinal center stage (memory B cell).
• The cytochemical features of HCL include a strong acid
phosphatase reaction that is not inhibited by tartaric acid or
tartrate-resistant acid phosphatase (TRAP) stain.
• Hairy-cell leukemia (leukemic reticuloendotheliosis) is a rare form of CLL
found four times more in men than women. The mean age of occurrence is
50 years.
• The onset of the disease is slow and is characterized by proliferation of
abnormal lymphocytes in the secondary lymphoid organs.
• Splenomegaly is a common physical finding
• B cell malignancy (CD19, CD20 positive)
• CD25 (i.e., IL2 receptor), which is unique to patients who have hairy-cell
leukemia.
Clinical findings
− Fatigue
− Anemia
− Leukocytopenia
− Thrombocytopenia
− Splenomegaly
− Marrow fibrosis
− Pancytopenia is common.
− Bleeding and infection can be present.

A. MULTIPLE MYELOMA
• Monoclonal gammopathy causes B cell production of excessive
IgG (most common) or IgA, with decreased production of the
other immunoglobulins.
• Found in adults over 60 years old; incidence higher in males
• Multiple skeletal system tumors of plasma cells (myeloma cells)
cause lytic bone lesions and hypercalcemia.
A. MULTIPLE MYELOMA
• Identified on serum protein
electrophoresis by an "M"-spike in
the gamma-globulin region;
immunoglobulin class determined
using immunoelectrophoresis and
quantified using an immunoassay
method.

A. MULTIPLE MYELOMA
• Excessive IgG or IgA production by myeloma cells causes
increased blood viscosity.
• Abnormal immunoglobulin binds to platelets, blocking receptor
sites for coagulation factor binding; this results in prolonged
bleeding.
A. MULTIPLE MYELOMA
Laboratory:
• Bone marrow plasma cells >30%
• Marked rouleaux
• Increased erythrocyte sedimentation rate (ESR)
• Blue background to blood smear
• Plasma cells and lymphocytes on blood smear
Bence Jones proteins (free light chains—kappa or lambda) found in
the urine; toxic to tubular epithelial cells; cause kidney damage

B. WALDENSTROM’S MACROGLOBULINEMIA
• Waldenstrom’s macroglobulinemia (WM) is a hypergammaglobulinemia
variant of chronic lymphocytic leukemia, in which there is a greater
degree of maturation of the B lymphocytes into plasma cells.
• WM is characterized by a generalized proliferation of B cells and plasma
cells and an increase of monoclonal IgM in the serum that amounts to at
least 15% of the total serum protein.
Clinical symptoms of WM are primarily found in
individuals older than 40 years. Symptoms are
caused by the cellular proliferation and increased
blood viscosity caused by the increased IgM.
Patients who have WM are commonly seen with
the following symptoms:
• Neurologic abnormalities
• Renal insufficiency
• Heart failure
• Clotting abnormalities (e.g., DIC)
The laboratory profile includes the following results:
• IgM in excess of 1.0 g/dL
• Normocytic-normochromic anemia (i.e., occasionally hemolytic with a
positive direct Coombs’ test)
• Thrombocytopenia caused by IgM platelet clumping or pancytopenia
caused by marrow infiltration
• Lymphocytosis
• Marked rouleaux and increased ESR
• Bence Jones proteinuria in 10% of patients
5. Lymphoma
Lymphomas are a group of lymphoproliferative disorders in
which there is neoplastic proliferation of an arrested stage of
secondary lymphocyte maturation that usually begins in and
involves mainly the lymph nodes. As the disease progresses,
many other organs and tissues (e.g., spleen, liver, skin,
marrow) can become invaded by malignant lymph. All
lymphomas are categorized into either Hodgkin’s
lymphoma or non-Hodgkin’s lymphoma.
5. Lymphoma
The general laboratory profile of a patient who has lymphoma includes the
following results:
(a) The WBC count may vary, depending on the progression of the malignancy.
• Neutrophilia is seen only when lymph nodes are involved, but neutropenia persists when
the bone marrow is involved.
• Most frequent are WBC counts from 12,000 to 25,000/mm3 with lymphophilia and
monocytosis.
• Eosinophilia is found in 20% of patients who have lymphoma.
• Platelet count depends upon the extent of marrow involvement.
5. Lymphoma
The general laboratory profile of a patient
who has lymphoma includes the following
results:
(b) Reed-Sternberg cells, which are the
hallmark of Hodgkin’s lymphoma, may be
found in the lymph nodes and marrow of a
patient who has this disease.
• These cells can be identified as giant binucleated
or multi-nucleated cells with acidophilic nuclei.
• This cell type is thought to originate from the
monocyte-macrophage cell line.
5. Lymphoma
The general laboratory profile of a patient who has lymphoma
includes the following results:
(c) Severe Normochromic/normocytic anemia in 50% of patients.
(d) The LAP level is elevated in the active phases of the disease.
(e) Bone marrow biopsy frequently reveals granulocytic hyperplasia
with a shift to the left, slight monocytosis, and eosinophilia. Reed-
Sternberg cells may be present, depending on the clinical subtype.
5. Lymphoma
• Clinical symptom: Lymphadenopathy
• Diagnosis: Tissue biopsy, CD surface markers, cytogenetics, DNA
analysis/PCR
• World Health Organization (WHO) groups the lymphomas into
1. Hodgkin
2. T/NK cell (non-Hodgkin) neoplasms.
3. B cell
1. Hodgkin lymphoma (classical)

a.40% of lymphomas; seen in patients between 15 and 35
years of age and over 55 years of age; seen more
frequently in males; certain subtypes have an Epstein-
Barr virus (EBV) association
b.Reed-Sternberg (RS) cells found in lymph node biopsy
are large, multinucleated cells each with prominent,
large nucleoli; B cell lineage
1.Hodgkin lymphoma (classical)

Hodgkin lymphoma subtypes using WHO classification:
a) Nodular sclerosis—70% are this subtype; lowest EBV association
b) Mixed cellularity—20% are this subtype; highest EBV association
MALIGNANT LEUKOCYTE DISORDERS
c) Lymphocyte rich
d) Lymphocyte depleted—uncommon e) All subtypes are associated
with RS cells
1. Hodgkin lymphoma (classical)

Laboratory Findings:
1. Mild anemia
2. Eosinophilia
3. Monocytosis
4. Increased LAP score
5. ESR during active disease
6. Presence of Reed-Sternberg (RS) cells
2. Non-Hodgkin lymphoma
1) WHO separates B cell and T/NK cell neoplasms into
conditions with precursor cells or mature cells.
2) 60% of lymphomas; seen in patients over 50 years of
age; seen more frequently in males
3) Enlarged lymph nodes or gastrointestinal (GI) tumors
4) B cell neoplasms are more common; include Burkitt (lymphoma
phase of Burkitt leukemia), mantle cell, follicular, and other
lymphomas
5) Cells can be small and mature (e.g., small lymphocytic lymphoma) or
large and primitive (e.g., Precursor B cell lymphoblastic lymphoma).
6) Can be slow growing or very aggressive
7) Some subtypes are believed to be virally related.
• Burkitt’s lymphoma, which is associated with EBV, has a strong affinity for B
cells; this affinity causes B-cell proliferation. When the cytolytic killer T
lymphocytes’ response is deficient, an unchecked B-cell proliferation can
result in lymphoma.
• Cutaneous T-cell lymphoma (i.e., Mycosis Fungoides) is an HTLV1-promoted
helper-inducer T-cell malignancy. This lymphoma is associated with a
lymphocytosis of Sezary cells.
Mycosis fungoides (cutaneous T cell lymphoma)

1) Classified by WHO as a T/NK cell neoplasm (non-Hodgkin lymphoma)
2) Seen in patients over 50 years of age
3) Cutaneous lymphoma causes skin itching, leading to ulcerative tumors.
4) Sezary syndrome, a variant of mycosis fungoides, presents as a
disseminated disease with widespread skin involvement and circulating
lymphoma cells.
5) CD2, CDS, and CD4 positive
Mycosis fungoides is the most

common cutaneous lymphoma. It is
composed of small to medium-sized
lymphoid cells with irregular nuclear
outlines (cerebriform nuclei). Sézary
syndrome presents as a
disseminated disease with
widespread skin involvement
(erythroderma), lymphadenopathy,
and circulating lymphoma cells
(Sézary cells with characteristic
cerebriform nuclei)
Most patients who have non-Hodgkin’s lymphomas have associated
chromosome abnormalities.
1. Nodular small cleaved-cell lymphoma is associated with a translocation
between the genes of Ig heavy chains found on chromosome 14 and an
arm of chromosome 18.
2. Burkitt’s lymphoma is associated with a translocation between
chromosomes 8 and 2 or 22 and 14.
3. Small lymphocytic lymphoma and diffuse large-cell lymphoma are
associated with a translocation between chromosomes 11 and 14.
4. Cutaneous T-cell lymphoma is associated with a translocation between
chromosomes 7 and 14 or 11 and 9.
Burkitt lymphoma is characterized by

medium-sized, highly proliferating
lymphoid cells with basophilic
vacuolated cytoplasm. The WHO
classification lists three variants of this
lymphoma:
1. Endemic (occurring predominantly
in Africa)
2. Sporadic
The lymphoid proliferation is diffuse and at low 3. Immunodeficiency associated
magnification shows a prominent “starry sky” pattern
imparted by numerous tangible body macrophages.
MYELOPROLIFERATIVE DISORDERS
MYELOPROLIFERATIVE
DISORDERS
Myeloproliferative disorders are a group of closely related diseases
characterized by the spontaneous proliferation of erythroid,
granulocyte, monocyte, or megakaryocyte precursors in the
marrow. Some shared general characteristics include the following:
a. The spleen, liver, and lymph nodes may be involved.
b. All cell lines or only a single cell line may be involved.
c. Myeloproliferative disorders are clonal in origin, having arisen
from a single pluripotential hemapoietic stem cell.
d. Cytogenetic abnormalities are common to most
myeloproliferative disorders.
1. Characterized by hypercellular marrow, erythrocytosis, granulocytosis,

and thrombocytosis
a. Defect of the myeloid stem cell
b. Named for the cell line most greatly affected
c. All may terminate in acute leukemia.
2. Molecular diagnostic studies are helpful in identifying oncogenes.
a. JAK2 oncogene is implicated in polycythemia vera (80%), chronic idiopathic
myelofibrosis (50%), and essential thrombocythemia (40%).
b. The BCR/ABL oncogene is associated with chronic myelogenous leukemia.
The World Health Organization (WHO) has classified the MPNs into
four predominant disorders:
1. Chronic myelogenous leukemia (CML)
2. Polycythemia vera (PV), also known as polycythemia rubra vera
3. Essential (primary) thrombocythemia (ET)
4. Primary myelofibrosis (PMF), also known as agnogenic
myelofibrosis with myeloid metaplasia and chronic idiopathic
myelofibrosis
All of the MPNs involve dysregulation at the multipotent hematopoietic
stem cell (CD34), with one or more of the following shared features:
1. Cytogenetic abnormalities
2. Overproduction of one or more types of blood cells with dominance
of a transformed clone
3. Hypercellular marrow or marrow fibrosis
4. Thrombotic and/or hemorrhagic bleeding
5. Extramedullary hematopoiesis
6. Transformation to acute leukemia
1. CHRONIC MYELOGENOUS LEUKEMIA (CML)

CML is an MPN that originates in an abnormal
pluripotent bone marrow stem cell and is
consistently associated with the BCR-ABL 1 fusion
gene located in the Philadelphia chromosome. CML
and chronic lymphocytic leukemia (CLL) are the
other principal types of chronic leukemias.
CML occurs mainly in middle-aged adults with a slow and unrevealing onset of
symptoms.
Clinical symptoms, which are mainly caused by the body’s increased load of
myeloid cells and nutritional demands, include the following:
1. Anemia
2. Weight loss
3. Lack of energy
4. Spleen enlargement causing abdominal discomfort
5. Fever
6. Excessive bleeding or bruising (i.e., due to decreased platelet production)

A patient who has CML typically is seen with the following blood and marrow
laboratory profile:
(a) A WBC count usually >50,000/mm3 and possibly as high as 300,000/mm3.
(i) CML has a characteristic differential count showing complete maturation of
granulocyte cells from myeloblasts to segmented neutrophils and a bimodal
distribution with myelocytes and segmented neutrophils both exceeding other
types in absolute numbers. Myeloblasts are usually <10% in the blood and marrow
Cont..
(ii) Basophilia is almost always present.
(iii) An absolute eosinophilia and monocytosis are also typical.
(iv) Normocytic/normochromic anemia occurs in most cases due to
decreased RBC production.
(v) Thrombocytosis is seen in the early phases of the disease, and
thrombocytopenia occurs in later phases.
(vi) NRBCs on the blood smear are also commonly found.

(b) Bone marrow is hypercellular because of granulocyte
proliferation with all stages of maturation represented.
(i) Myeloid-erythroid ratios of 15:1 to 50:1 are common.
(ii) Eosinophil and basophil precursors are often increased.
(iii) Blasts are increased, but usually <10%.
(c) LAP is reduced or absent in more than 90% of CML
patients. In one third of CML patients who are in remission, the
LAP level returns to normal.
(d) Cytogenetic abnormalities found in CML are
highly diagnostic.
(i) Direct bone marrow preparations show that 90%
of CML patients demonstrate the “Philadelphia”
(Ph1) chromosome.
(ii) The mutation results from a translocation from
the long arm of chromosome 22 to an arm of
chromosome 9.
(iii) The 10% of CML patients who are Ph1 negative
have similar laboratory and clinical findings.
However, this group is characterized by the following:
a larger proportion of children, not as good a
response to therapy, and a shorter survival.

• CML is treated with chemotherapeutic agents such as
busulfan, which is an alkylating agent, or hydroxyurea,
which is a folic acid antagonist.
(a) Alkylating agents are thought to combine with guanine in
DNA to inhibit rapidly growing cells.
(b) Toxic effects of chemotherapy occur, such as bone marrow
depression and bleeding.
2. POLYCYTHEMIA VERA
• Malignant hyperplasia of the multipotential myeloid stem
cell causes increase in all cell lines (polycythemia);
erythrocytes most greatly increased despite decreased
erythropoietin (EPO); inappropriate erythropoiesis
• High blood viscosity can cause high blood pressure, stroke,
and heart attack.
• Found in adults 50 years of age and older
Laboratory Findings:
• Increased RBC (7-10 X 1012/L)
• Hemoglobin (>20 g/dl)
• Hematocrit (>60%)
• Increased leukocytes and platelets indicate polycythemia
• RBC mass is increased with a normal plasma volume
• Patients who have PV have decreased levels of serum and urine
EPO. This can be a diagnostic characteristic, because all secondary
polycythemias are the result of an increased level of EPO
• Blood smear RBC morphology shows some macrocytes,
polychromatic cells, and normoblasts.
• RBC production is increased, and RBC survival is normal, but RBC
survival is reduced if the spleen is enlarged.
• Treatment of PV is with one or a combination of the following
methods:
1. Therapeutic phlebotomy
2. Splenectomy
3. Chemotherapy
4. Radioisotope phosphorus 32
• PV is a chronic disease with a life expectancy after diagnosis of up to
20 years.
Must differentiate from other forms of polycythemia
a. Secondary polycythemia
• Increase in RBC mass is an appropriate response to increased EPO or
tissue hypoxia. Plasma volume, leukocyte count, and platelet count
are normal.
• Can be caused by smoking, emphysema, or high altitude
Must differentiate from other forms of polycythemia
b. Relative (pseudo-) polycythemia
• Decreased plasma volume with a normal RBC mass caused by
dehydration (diarrhea, diuretics, or burns)
• Increased hemoglobin, normal leukocyte and platelet count,
normal EPO
3. ESSENTIAL THROMBOCYTHEMIA
• Essential thrombocythemia is a clonal malignancy most
closely related to PV. It is characterized by a predominance
of megakaryocytic proliferation in the marrow.
• Clinically, patients are often seen with reoccurring,
spontaneous hemorrhages (i.e., mostly GI in origin).
• Found mainly in adults 60 years of age and older
3. ESSENTIAL THROMBOCYTHEMIA
• A patient who has thrombocythemia typically demonstrates the following blood
and bone marrow laboratory profile:
(a) The peripheral blood shows a marked increase in platelets (between
900,000/mm3 and 1,400,000/mm3) with abnormal giant forms and fragments of
megakaryocytes.
(i) Patients have a leukocytosis.
(ii) The LAP level is normal.
(iii) Many patients demonstrate a hypochromic-microcytic anemia due to chronic blood loss.
(iv) Platelet function defects can be present, and platelets may show a decreased aggregation in
response to epinephrine.
4. PRIMARY MYELOFIBROSIS
• Myeloid stem cell disorder characterized by proliferation of
erythroid, granulocytic, and megakaryocytic precursors in marrow
with dyspoiesis.
• Progressive marrow fibrosis
• Found in adults 50 years of age and older
• Patients demonstrate a massive splenomegaly caused by
extramedullary hematopoiesis
• A patient with MMM typically demonstrates the following blood and
bone marrow laboratory profile:
(a) The peripheral blood shows a moderate normocytic-normochromic
anemia with some basophilic stippling.
(i) RBC morphology shows moderate anisocytosis and
poikilocytosis (e.g., fragmented forms); dacryocytes; elliptocytes;
and NRBCs.
(ii) Reticulocytosis is common.
Cont…
(iii) The leukocyte count is normal or slightly increased, and
the differential shows a few immature granulocytes.
(iv) The LAP level is increased.
(v) Platelet counts can be normal or decreased with the
presence of abnormal platelets.
• The usual course of MMM is progressive anemia, enlargement of
the spleen, and opportunistic infections.
Myelodysplastic
Syndromes (MDSs)
MYELODYSPLASTIC SYNDROMES
• Myelodysplastic syndrome (MDS) is a family of marrow

disorders found mainly in persons older than 50 years.
MDS is characterized by ineffective cellular production.
• MDS is believed to be caused by a defect in a member of
the marrow stem cell pool, which results in increased
proliferation and inadequate maturation or an imbalance
in one or more cell lines
• This group of disorders has been termed preleukemias

because most patients progress to have acute leukemias.
• Between 40% and 90% of MDS patients have
demonstrated chromosome abnormalities. Mutations
have been commonly found on chromosome 5, but also
have been noted on chromosomes 7, 8, 12, and 20.
Dyspoiesis affects erythroid, myeloid, and megakaryocytic cell lines.
Hematologic evidence of dyspoiesis:
1) Erythroid: Variable anemia; erythrocytes can be macrocytic (with
oval macrocytes) or microcytic and hypochromic; dimorphic
erythrocytes, poikilocytosis, Howell-Jolly bodies, basophilic stippling,
Cabot rings, nucleated RBCs
2) Myeloid: Neutropenia, hypogranulation, hyposegmentation of
neutrophils, shift to the left
3) Thrombocytes: Variable platelet count, giant platelets,
hypogranulation, micromegakaryocytes
MDS is classified into five subtypes, as defined by the French-

American British (FAB) Cooperative Pathology Group.
1. Refractory anemia (RA)
2. Refractory anemia with ring sideroblasts (RARS)
3. Refractory anemia with excess blasts (RAEB)
4. Chronic Myelomonocytic leukemia (CMML)
5. RAEB in transformation (RAEBIT)
1. Refractory anemia (RA) has the following identifying

characteristics:
• Anemia with a decreased reticulocyte count
• Abnormal erythrocytes (e.g., ovalocytes)
• Blasts <1% in peripheral blood
• Approximately 10% of RA patients progress to AML
2. Refractory anemia with ring sideroblasts (RARS) has the

following identifying characteristics:
• Greater than 15% ring sideroblasts in the marrow (i.e., any nucleated
erythroid precursor cell that contains stainable iron granules)
• Ring sideroblasts have a “necklace” of iron granules around the
nucleus
• Approximately 10% of RARS patients progress to AML
3. Refractory anemia with excess blasts (RAEB) has the

• A cytopenia in two of the three cell lines
• Greater than 1%, but <5% circulating blasts
• Between 5% and 20% blasts in the marrow
4. Chronic Myelomonocytic leukemia (CMML) has the

• Chronic monocytosis >1,000/mm3
• Frequent granulocytosis
• Less than 5% circulating blasts
• Greater percent of promonocytes seen in marrow
Diagnosis of CMML, according to the FAB classification criteria,

distinguishes between two forms, CMML-1 and CMML-2. One
shows only an increase of mature monocytes, and it has no
relationship to the type that transforms into AML. It is considered a
reactive monocytosis. The other form, in addition to an increase of
mature monocytes, shows an increase of a few monoblasts and
promonocytes. This is considered to be a true CMML and usually
quickly develops into the M4 or M5 forms of leukemia (AML). The
clinical symptoms closely resemble those of subacute
myelogenous leukemia
5. RAEB in transformation (RAEBIT) has the following

identifying characteristics:
• Greater than 5% circulating blasts
• Between 20% and 30% blasts in the marrow
• Presence of Auer bodies in blasts
• Approximately 60% of patients with RAEBIT transform into
AML
• Additional information
1. WHO classification of MDS has
additional groups (e.g., refractory
cytopenia with multilineage
dysplasia, 5q deletion syndrome).
2. WHO created the new category of
myelodysplastic/myeloproliferati
ve disease, which includes the
FAB's CMML.
ADDITIONAL INFORMATION
• Treatment of MDS depends on the prognosis. If the prognosis is favorable,
patients may receive only supportive therapy.
• Other treatments that have met with limited success include
chemotherapeutic agents and epigenetic modifiers.
• Currently, the only cure for MDS is bone marrow or hematopoietic stem cell
transplantation.
• Future treatment possibilities include the use of apoptosis controlling drugs.

Hematology 1 Leukemia

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Hematology 1 Leukemia

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ACUTE LEUKEMIAS

AGE All ages, with peaks in 1st decade and Adults

MEDIAN Weeks to months Months to years

DIFFERENTIAL Blast usually present More mature cells

OTHER Usually lymphoid in children and Myeloid mostly in young to

ORGANIZATIONS THAT CLASSIFY LEUKEMIA

ORGANIZATIONS THAT CLASSIFY LEUKEMIA

(a) ALL blasts are negative for Sudan black B, peroxidase,

(a) Common ALL antigen (CALLA)- which is alsoCD10, is the

(b) Null-cell ALL is a proliferation of lymphocytes that type

(d) B-cell ALL is the rarest of subtypes, and it corresponds to

b. FAB M1 (AML without maturation)

These disorders represent a group of clonal disorders

1. CHRONIC MYELOGENOUS LEUKEMIA

2. B-CELL PROLYMPHOCYTIC LEUKEMIA

4. Plasma cell neoplasms

4. Plasma cell neoplasms

4. Plasma cell neoplasms

1. Hodgkin lymphoma (classical)

1.Hodgkin lymphoma (classical)

1. Hodgkin lymphoma (classical)

Mycosis fungoides (cutaneous T cell lymphoma)

Mycosis fungoides is the most

Burkitt lymphoma is characterized by

1. Characterized by hypercellular marrow, erythrocytosis, granulocytosis,

1. CHRONIC MYELOGENOUS LEUKEMIA (CML)

1. CHRONIC MYELOGENOUS LEUKEMIA (CML)

1. CHRONIC MYELOGENOUS LEUKEMIA (CML)

1. CHRONIC MYELOGENOUS LEUKEMIA (CML)

• Myelodysplastic syndrome (MDS) is a family of marrow

• This group of disorders has been termed preleukemias

MDS is classified into five subtypes, as defined by the French-

1. Refractory anemia (RA) has the following identifying

2. Refractory anemia with ring sideroblasts (RARS) has the

3. Refractory anemia with excess blasts (RAEB) has the

4. Chronic Myelomonocytic leukemia (CMML) has the

Diagnosis of CMML, according to the FAB classification criteria,

5. RAEB in transformation (RAEBIT) has the following

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