Leukemia

Dr Frank Kakuba
• NEOPLASTIC PROLIFERATIONS OF WHITE CELLS
• Malignant neoplasms of white cells, though less
frequent than the reactive proliferations, are the most
important from clinical point of view.
• Myeloid Neoplasms
• They form a heterogeneous group of neoplasms, which arise from early
hematopoietic progenitor cells.
• These neoplasms primarily involve the bone marrow and to a lesser
extent the secondary hematopoietic organs (the spleen, liver, and
lymph nodes).
• They usually present with symptoms related to altered hematopoiesis.
• They can be broadly categorized as:
• Acute myeloid leukemias: They are characterized by accumulation
of immature progenitor cells in the bone marrow, which suppresses the
normal hematopoiesis.
• Myelodysplastic syndromes (MDS): These syndromes are
associated with ineffective hematopoiesis which leads to
peripheral blood cytopenias.
• Myeloproliferative neoplasms (MPN): The characteristic
feature of these neoplasms is increased production of one or
more terminally differentiated myeloid elements.
• They usually produce elevated peripheral blood counts.
• Myelodysplastic/myeloproliferative neoplasms: These
neoplasms present the clinical, laboratory and morphological
features that overlap both MDS and MPN.
• Lymphoid Neoplasms
• These include a diverse group of neoplasms of B cell, T cell,
and NK cell origin. They can be sub divided into two
categories.
• Lymphocytic/lymphoid leukemias: These neoplasms
present with widespread involvement of the bone marrow and
usually (but not always) the peripheral blood.
• Lymphoma: They represent lymphoid proliferations which
present as tissue masses.
• These are categorized into two main groups namely: Non-
Hodgkin and Hodgkin lymphoma
• Histiocytic and Dendritic Cell Neoplasms
• These are uncommon proliferative lesions of macrophages and
dendritic cells.
• Langerhans cell is a special type of immature dendritic cell which
can produce a spectrum of neoplastic disorders known as
Langerhans cell histiocytosis.
• Both myeloid and lymphoid neoplasms can present as acute and
chronic leukemias.
• Though acute lymphoid and myeloid leukemias are distinct
(immunophenotypically and genotypically), they usually have
certain features in common
• ACUTE LEUKEMIA
• Leukemia is defined as a group of malignant stem cell neoplasms
characterized by:
• Diffuse replacement of bone marrow with proliferating
leukocyte precursors (blast cells)
• Abnormal numbers and forms of immature white blood cells in
circulation.
• In acute leukemia the immature, neoplastic leukemic ‘blast’
cells proliferate and accumulate, but fail to mature.
• The blasts diffusely replace the normal bone marrow and a
variable
number of these accumulate in the peripheral blood.
• Acute leukemia should be diagnosed when the blast cells
constitute more than 20% of the nucleated cells in the marrow
(normally blast cells are less than 5%).
• In some patients there may be very few /no blasts in the
peripheral blood and is termed as aleukemic/subleukemic
leukemia.
• Infiltration of the marrow by leukemic cells finally results in
bone marrow failure resulting in cytopenias.
• Most patients present with consequences of cytopenias (anemia,
neutropenia and thrombocytopenia) particularly in the acute
leukemias.
• Risk Factors
Environmental factors
• Ionizing radiation: Exposure to ionizing radiation and
X-rays are associated with increased risk of leukemias.
• The evidences for this association are:
 Survivors of atomic bomb explosions in Hiroshima and
Nagasaki, who had high incidence of acute myelogenous
leukemia (AML) and chronic myeloid leukemia (CML).
 Increased risk of AML (secondary) in patients with
malignancies/ neoplasms treated by radiation.
• Drugs: Drugs can cause secondary hematopoietic neoplasms.
 Leukemia develops in patients who have been administered
alkylating agents for neoplasms like Hodgkin lymphoma.
• The various drugs include nitrogen mustard, chlorambucil, etc.
 AML occurs in myeloma patients treated with melphalan.
 Leukemia follows chemotherapy of lung and ovarian cancer.
Some anticancer drugs induce myelodysplastic changes with
certain chromosomal abnormalities and subsequently develop
AML
• Chemicals: Benzene (used in paint industry, plastic
glues, etc) causes chromosomal abnormalities resulting
in higher incidence of acute leukemia, myelodysplastic
syndrome
and aplastic anemia.
• Genetic disorders
A few genetic disorders may be associated with acute
leukemias, e.g. Down syndrome (ALL or AML), Fanconi
anemia (AML), ataxia telangiectasia (ALL, NHL).
• Acquired Disorders
• Acquired stem cell disorders like PNH and aplastic
anemia may transform into acute leukemia.
• AML may develop de novo or secondary to
myelodysplastic syndrome (MDS).
• Classification
Depending on microscopic appearance of the involved cell and the course of leukemias,
they were initially classified as:
• Acute
• Acute myelogenous/myeloblastic/myelocytic/myeloid leukemia (AML)
• Acute lymphoblastic/lymphocytic leukemia (ALL)

• Chronic
Chronic myeloid leukemia (CML)
Chronic lymphocytic leukemia (CLL)

Differentiation of two broad groups of ALL and AML from each other is important, because
of difference in the treatment, course and prognosis.
• Diagnosis of Acute Leukemia
• Presently the diagnosis of acute leukemia requires the
presence of 20% or more blasts in the bone marrow
(WHO criteria).
• The sub classification of acute leukemia is based on: (1)
morphology,(2) cytochemistry, (3) immunophenotyping,
(4) cytogenetics (e.g. karyotyping) and (5) molecular
genetics.
• Clinical Presentation of Acute Leukemia
• Though ALL and AML are distinct (immunophenotypically and
genotypically), they usually have similar clinical presentation;
• Bone marrow failure: Most often leukemic patients present
with signs and symptoms of bone marrow failure due to
replacement of normal marrow hematopoietic cells by
leukemic blast cells.
• All or any of the three cell lines are decreased, which results
in anemia, neutropenia and thrombocytopenia.
• Anemia causes fatigue, weakness and hypermetabolic
state which is directly related to the degree of anemia.
• Neutropenia results in life-threatening infections by
bacteria or opportunistic fungi, Pseudomonas and
commensals.
• The infection may develop in the oral cavity, skin, lungs,
kidneys, urinary bladder and colon.
• The common presentations include respiratory
infections (pneumonia), cellulitis or sepsis.
• Thrombocytopenia presents as bleeding manifestations
in the form of petechiae, atraumatic ecchymoses gum
bleeding, epistaxis, urinary tract and fundal
hemorrhages.
• Marrow expansion and infiltration of the
subperiosteum causes bone pain (more common in
ALL) and sternal tenderness.
• Leukostasis:
• Stasis of blood flow may develop when the blast count in the
peripheral blood is above 50 × 109 (50,000/cu mm).
• Leukostasis is more common in AML than ALL because
myeloblast is larger and expresses adhesive proteins.
• Most of the patients have leukocytosis and is responsible for
the following symptoms:
 Cerebral leukostasis may cause headache, confusion and
visual disturbances.
 Pulmonary leukostasis can cause dyspnea at rest and
tachypnea.
• Coagulopathy: Both disseminated intravascular coagulation (DIC)
and primary fibrinolysis may lead to hemorrhagic diathesis in
addition to that due to thrombocytopenia.
• Extramedullary infiltration: Leukemic blasts may infiltrate organs
like lymphnodes, spleen,gingiva, skin (leukemia cutis) and meninges.
• Hepatosplenomegaly: Splenomegaly and hepatomegaly may be
found and is more
common in AML.
 Lymphadenopathy: It is found occasionally in ALL and is rare in
AML.
• Tumor lysis syndrome (TLS): It is a group of metabolic
complications that can occur after treatment of leukemias (also in
lymphomas) and is caused by the breakdown products of
dying tumor cells.
• The killed tumor cells release intracellular ions and large amounts
metabolic byproducts (includes potassium, phosphate and nucleic
acids) into the systemic circulation.
• They result in metabolic abnormalities like hyperkalemia,
hyperphosphatemia,hyperuricemia, hyperuricosuria,
hypocalcemia, and consequent acute uric acid nephropathy and
renal failure.
• Acute Lymphoblastic Leukemia
• Acute lymphoblastic leukemia/lymphoma (ALL) is
a group of neoplasms consisting of immature,
precursor B (pre-B) or T (pre-T) lymphocytes known as
lymphoblasts.
• Morphologically it is difficult to distinguish malignant
pre-B and pre-T lymphoblasts.
• It requires immunophenotyping for subclassification of
ALL.
 Leukemia vs. Lymphoma:

• Leukemia: Proliferations of lymphoblasts in the bone

marrow and peripheral blood are termed as
lymphoblastic leukemia.

• Lymphoma: Primary involvement of lymphnodes or

extranodal sites by lymphoblasts is referred to as
lymphoblastic lymphoma
• About 85% of ALLs are tumors of precursor B cells
which are primarily seen in childhood and present as
acute leukemias.
• Remaining 15% of ALLs are derived from precursor T
cells and present in adolescent males as lymphomas,
often with involvement of mediastinum (thymus).
• Clinical Features
Age and Sex: ALL is the most common hematological
malignancy of children.
• Most commonly found between 1 to 5 years of age and
second peak in adults is found between 30 to 40 years.
• There is a slight male preponderance.
• Onset: Abrupt.
Symptoms: They are related to depressed marrow
function due to infiltration by blasts.
• This includes symptoms due to anemia, neutropenia
and thrombocytopenia.
• Testicular enlargement.
• ALL may present with:
• Lymphadenopathy: It is present in 75% of patients.
• Hepatosplenomegaly: Splenomegaly is more common
than hepatomegaly.
• Mediastinal mass: Mediastinal thymic mass may
compress blood vessels and airways in the mediastinum.
• This is more common in T-ALL.
• Central nervous system involvement: It may spread
into the meninges and is more common in ALL (pre-B).
• Laboratory Findings
Peripheral Blood
• Total WBC count: Total white cell count is markedly raised ranging
from 20 × 109/L to 200 × 109/L. In few cases count may be normal or
even reduced.
 Subleukemic leukemia: It is characterized by a total white cell
count lower than 4 × 109/L and peripheral blood shows very few blasts.
 Aleukemic leukemia: The term aleukemic leukemia is used when
total white cell count is low (< 4 × 109/L) with no blasts in the
peripheral blood.
• The diagnosis in such cases requires bone marrow examination to
demonstrate 20% or more blast cells.
• Hemoglobin: Hemoglobin progressively decreases
and may be reduced even to 3 gm/dL.
• Peripheral smear:
 RBCs: They show normocytic normochromic type of
anemia.
 WBCs: Total count is usually markedly increased.
Few may present with pancytopenia.
Blasts may replace normal myeloid series and can
cause neutropenia.
• Lymphoblasts: The minimum requirement for
diagnosis by WHO criteria is 20% blasts or more.
• The morphologic distinctions between B and T require
lymphocyte-specific markers.
• Platelets: Thrombocytopenia is common and is
responsible for bleeding from skin and mucosa.
• Cytochemistry of lymphoblasts
• Periodic Acid Schiff (PAS) positive.
• Myeloperoxidase negative.
• Sudan Black B negative.
• Bone Marrow
• Cellularity: Bone marrow is markedly hypercellular
due to proliferation of blasts which replace normal
hematopoietic cells.
• Erythropoiesis and myelopoiesis: Reduced.
• Megakaryopoiesis: Megakaryocytes gradually
decrease

Blasts
• They constitute 20–100% of the marrow cells.
• Biochemical Findings (Refer tumor lysis syndrome)
• Hyperuricemia (increased serum uric acid)
• Hyperkalemia (increased serum potassium)
• Hyperphosphatemia (increased serum phosphate)
• Hypocalcemia (decreased serum calcium) due to
hyperphosphatemia
• LDH is increased due to increased turnover of
leukemic cells.
• Prognosis
About 95% of children undergo complete remission and
75 to 85% are cured with currently available
chemotherapy.
 ACUTE MYELOGENOUS LEUKEMIA

Definition
• Acute myelogenous leukemia (AML) is a neoplasm of
hematopoietic progenitors due to acquired mutations
which hinder its differentiation, resulting in
accumulation of immature myeloblasts in the
marrow.
It is also called as myeloid/myeloblastic/myelocytic
leukemia.
• Aberrant tyrosine kinase activation is a common feature
of AML.Thus mutated tyrosine kinase along with transcription
factor aberrations result in development of AML.
• Clinical Features
Age: AML may develop at any age, but is more common in
adults.
Symptoms: They are related to depressed marrow function
due to infiltration by neoplastic blast cells.
• This includes symptoms due to anemia, neutropenia and
thrombocytopenia
• Laboratory Findings
Peripheral Blood
• The characteristic feature is the presence of blasts in
blood and bone marrow with reduction of normal
hematopoietic cells.
• Total WBC Count: It is markedly raised ranging from
20 × 109/L to 100 × 109/L. In few cases count may be
normal or even reduced.
• Hemoglobin: It is decreased and ranges from 5 to 9
gm/dL.
• Total WBC count is usually markedly increased.
Leukemic blast cells may replace normal myeloid series
in the marrow and can cause neutropenia.
•
• Shows more than 20% myeloid blasts.
• Auer rods: They are distinctive azurophilic needle-like structures of
varying length and width. They represent an abnormal alignment and
crystallization of azurophilic granules
and are peroxidase-positive.
• Presence of Auer rods is definitive evidence of myeloid
differentiation
• Platelets: They are variably decreased. There is moderate to severe
thrombocytopenia and is responsible for bleeding from skin and mucosa.
• Myeloblasts stain positively with myeloperoxidase (MPO)
and Sudan black B.
Bone Marrow
• Cellularity: Bone marrow is markedly hypercellular due to
proliferation of blasts which replace normal hematopoietic cells.
• Erythropoiesis: Markedly suppressed.
• Myelopoiesis: It shows suppression of myeloid maturation
and myeloblasts constitute more than 20% of marrow cells.
• Megakaryopoiesis: Megakaryocytes are gradually
decreased.
• Prognosis
• It has a fulminant course and has worse prognosis than
ALL. Cytogenetic markers are major determinants of
prognosis.

E N D