Leukemia 151106173804 Lva1 App6892

Leukemia
Dr. Deepak K. Gupta

Introduction
• Neoplastic proliferations of white blood cells—
leukaemias.
• Incidence is higher in men than in women
• Classified on the basis of cell types predominantly
involved – myeloid or lymphoid
• Acute: predominance of undifferentiated leucocyte
precursors or leukaemic blasts
– Acute myeloblastic leukaemia (AML) - at all ages
– Acute lymphoblastic leukaemia (ALL) – primarily a disease
of children and young adults
• Chronic: late precursor series of leucocytes
– Chronic myeloid leukaemia (CML) – middle age
– Chronic lymphocytic leukaemias (CLL) - elderly
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Introduction
Classification
Etiology
• Heredity
• Infections: Human T cell leukaemia-lymphoma
virus I (HTLV-I)
• Environmental factors
– Ionising radiation
– Chemical carcinogens
– Certain drugs.
• Association with diseases of immunity:
Immunodeficiency diseases like AIDS and
iatrogenic immunosuppression induced by
chemotherapy or radiation,
ACUTE MYELOID LEUKAEMIA
• heterogeneous disease characterised by
infiltration of malignant myeloid cells into
the blood, bone marrow and other tissues
• mainly a disease of adults (median age 50
years)
• develops due to inhibition of maturation of
myeloid stem cells due to mutations - induced
by several etiologic factors
Classification
• French-American-British (FAB) CLASSIFICATION
– Based on morphology and cytochemistry,
– It divides AML into 8 subtypes (M0 to M7)
• WHO CLASSIFICATION (2002)
– differs from revised FAB classification
– limited reliance on cytochemistry for making
the diagnosis of subtype of AML
– Based on clinical, cytogenetic and molecular
abnormalitie
FAB CLASSIFICATION
WHO CLASSIFICATION (2002)
• AML with recurrent cytogenetic abnormalities
• AML with multilineage dysplasia
• AML and MDS (Myelodysplastic Syndrome),
therapy-related
• AML, not otherwise categorised
Clinical Features
• AML and ALL share many common clinical
features - difficult to distinguish on clinical
features alone.
• 25% of patients with AML: preleukaemic
syndrome with anaemia may be present for a
few months to years prior to the development of
overt leukaemia.
• Clinical manifestations of AML are divided into 2
groups due to
– Bone marrow failure
– Organ infiltration
Clinical Features: Bone marrow failure
• Anaemia producing pallor, lethargy, dyspnoea.

• Bleeding manifestations due to
thrombocytopenia causing spontaneous bruises,
petechiae, bleeding from gums and other
bleeding tendencies.
• Infections are quite common and include those
of mouth, throat, skin, respiratory, perianal and
other sites.
• Fever : no obvious source of infection can be
found and may occur in the absence of infection.
Clinical Features: Organ infiltration
• due to replacement of the marrow and other
tissues by leukaemic cells.
• Pain and tenderness of bones (e.g. sternal
tenderness) - bone infarcts or subperiosteal
infiltrates by leukaemic cells.
• Lymphadenopathy and enlargement of the
tonsils may occur
• Splenomegaly of moderate grade may occur –
Splenic infarction, subcapsular haemorrhages,
and rarely, splenic rupture may occur.
• Hepatomegaly
• Gum hypertrophy due to leukaemic infiltration of the
gingivae is a frequent finding.
• Chloroma or granulocytic sarcoma : localised tumour
forming mass occurring in the skin or orbit - greenish in
appearance due to the presence of myeloperoxidase.
• Meningeal involvement manifested by raised
intracranial pressure, headache, nausea and vomiting,
blurring of vision and diplopia
– Sudden death from massive intracranial haemorrhage as a
result of leucostasis may occur.
– Other organ infiltrations include testicular swelling and
mediastinal compression
Laboratory Findings
• The diagnosis of AML is made by a combination of routine
blood picture and bone marrow examination, coupled
with cytochemical stains and other special laboratory
investigations.
• BLOOD PICTURE.
– Anaemia.
– Thrombocytopenia: moderately to severely reduced (below
50,000/μl) but occasionally it may be normal.
– White blood cells: ranges from subnormal-to-markedly elevated
values
• 25% of patients – reduced to 1,000-4,000 /μl.
• More often, however, there is progressive rise in white cell count
which may exceed 100,000/μl
in more advanced disease.
• Majority of leucocytes in the peripheral blood are blasts and there is
often neutropenia
due to marrow infiltration by leukaemic cells.
Laboratory Findings
Laboratory Findings
Laboratory Findings: BONE MARROW
EXAMINATION
• Cellularity: Typically, the marrow is hypercellular but
sometimes a ‘blood tap’ or ‘dry tap’ occurs.
• Leukaemic cells
– generally tightly packed with leukaemic blast cells
– Romanowsky stains: cytochemical stains may be
employed to know the type of leukaemia. Erythropoiesis.
• Erythropoietic cells are reduced.
• Megakaryocytes. They are usually reduced or absent.
• Cytogenetics: shows karyotypic abnormalities in 75%
of cases which may have a relationship to prognosis.
• Immunophenotyping. AML cells express CD13 and
CD33 antigens. M7 shows CD41 and CD42 positivity.
Laboratory Findings: BONE MARROW
EXAMINATION
Laboratory Findings
• CYTOCHEMISTRY: Commonly employed cytochemical
stains, as an aid to classify the type of
– Myeloperoxidase: Positive in immature myeloid cells
containing granules and Auer rods
– Sudan Black
– Periodic acid-Schiff (PAS): Positive in immature lymphoid
cells and in erythroleukaemia (M6)
– Non-specific esterase (NSE): Positive in monocytic series
(M4 and M5).
– Acid phosphatase: Focal positivity in leukaemic blasts in
ALL and diffuse reaction in monocytic cells (M4 and M5).
• BIOCHEMICAL INVESTIGATIONS: may be of some help
– Serum muramidase: elevated in myelomonocytic (M4) and
monocytic (M5) leukaemias.
– Serum uric acid: frequently increased
Treatment and Complications
• TREATMENT OF ANAEMIA AND HAEMORRHAGE.
– Anaemia and haemorrhage are managed by fresh
blood transfusions and platelet concentrates.
– Patients with severe thrombocytopenia (platelet
count below 20,000/μl) require regular platelet
transfusions
• haemorrhage is an important cause of death in these cases
• TREATMENT AND PROPHYLAXIS OF INFECTION
• CYTOTOXIC DRUG THERAPY
– Aim: firstly induce remission, secondly to continue
therapy to reduce the hidden leukaemic cell
population by repeated courses of therapy.
– The most effective treatment of AML is a combination
of 3 drugs: cytosine arabinoside, anthracyclines
(daunorubicin, adriamycin) and 6-thioguanine.
– Another addition is amsacrine (m-AMSA)
administered with cytosine arabinoside, with or
without 6-thioguanine.
• BONE MARROW TRANSPLANTATION
– Bone marrow (or stem cell) transplantation from
suitable allogenic
or autologous donor
– The basic principle of marrow transplantation is to
reconstitute the patient’s haematopoietic system
after total body irradiation and intensive
chemotherapy – kill the remaining leukemic cell
– Bone marrow transplantation has resulted in cure
in about half the cases.
Prognosis
• Remission rate with AML is lower (50-70%) than in
ALL,
• Often takes longer to achieve remission, and disease-
free intervals are shorter.
• AML is most malignant of all leukaemia
• Survival with treatment is 12-18 months.
Acute Lymphocytic Leukemia (ALL)
• Most common type of leukemia in children
• 15% of acute leukemia in adults
• Immature lymphocytes proliferate in the bone
marrow
• Signs and symptoms may appear abruptly
– Fever, bleeding
• Insidious with progressive
– Weakness, fatigue
• Central nervous system manifestations
Chronic Myeloid Leukemia (CML)
Introduction
• Excessive development of mature neoplastic
granulocytes in the bone marrow
– Move into the peripheral blood in massive numbers
– Ultimately infiltrate the liver and spleen
• Philadelphia chromosome
– The chromosome abnormality that causes chronic
myeloid leukemia (CML) (9 &22)
– Genetic marker
• Chronic, stable phase followed by acute,
aggressive (blastic) phase
Clinical Features
• 20% of all leukaemias
• Peak incidence is seen in 3rd and 4th decades of
life.
• A distinctive variant seen in children is called
juvenile CML.
• Both sexes are affected equally.
• Some of the common presenting manifestations
are as under
– Anemia
– Hypermetabolism such as weight loss, lassitude,
anorexia, night sweats.
Clinical Features
• Splenomegaly is almost always present and is
frequently massive.
• Bleeding tendencies such as easy bruising, epistaxis,
menorrhagia and haematomas may occur.
• Less common features include gout, visual disturbance,
neurologic manifestations.
• Juvenile CML
– often associated with lymph node enlargement than
splenomegaly.
– Other features are frequent infections, haemorrhagic
manifestations and facial rash.
Laboratory Findings
• The diagnosis of CML is generally possible on
blood picture alone. However, bone marrow,
cytochemical stains and other investigations
are also useful
• BLOOD PICTURE
– Anaemia. Anaemia is usually of moderate degree
and is normocytic normochromic in type.
Laboratory Findings
– White blood cells. Characteristically, there is marked
leucocytosis (approximately 200,000/μl or more at the time of
presentation). The natural history of CML consists of 3
phases—chronic, accelerated, and blastic.
• Chronic phase: begins as a myeloproliferative disorder and consists of
excessive proliferation of myeloid cells of intermediate grade (i.e.
myelocytes and metamyelocytes) and mature segmented neutrophils.
• Accelerated phase: increasing degree of anaemia, blast count in blood
or marrow between 10-20%, marrow basophils 20% or more, and
platelet count falling below 1,00,000/μl.
• Blastic phase or blast crisis: blood or marrow blasts >20%. Myeloid
blast crisis in CML is more common and resembles AML.
– Auer rods are not seen in myeloblasts of CML in blast crisis.
– Platelets. Platelet count may be normal but is raised in about
half the cases.
Laboratory Findings
Laboratory Findings
• BONE MARROW EXAMINATION
• Cellularity: hypercellularity with total or partial replacement of
fat spaces by proliferating myeloid cells.
• Myeloid cells: predominate in the bone marrow with increased
myeloid-erythroid ratio. The differential counts of myeloid cells
in the marrow show similar findings as seen in the peripheral
blood with predominance of myelocytes.
• Erythropoiesis: normoblastic but there is reduction in
erythropoietic cells.
• Megakaryocytes: are conspicuous but lare usually smaller in
size than normal.
• Cytogenetics: the characteristic chromosomal abnormality
called Philadelphia (Ph) chromosome (90-95%)
Philadelphia (Ph) chromosome
Laboratory Findings
• CYTOCHEMISTRY
• The only significant finding on cytochemical stains is
reduced scores of neutrophil alkaline phosphatase (NAP)
• These helps to distinguish CML from myeloid leukaemoid
reaction in which case NAP scores are elevated
• OTHER INVESTIGATIONS
• Elevated serum vitamin B 12 and vitamin B12 binding
capacity.
• Elevated serum uric acid (hyperuricaemia).
Treatment
• Knowledge of molecular mechanism of CML has brought
about major changes in its therapy.
• The approach of modern therapy in CML is targetted at
removal of all malignant clones of cells bearing BCR/ABL
fusion protein,
• So that patient reverts back to prolonged non-clonal
haematopoiesis.
• This is achievable by the following approaches
– Imatinib oral therapy
– Allogenic bone marrow (stem cell) transplantation.
– Interferon-α.
– Chemotherapy
– Others: splenic irradiation, splenectomy and leucopheresis.
• The most common cause of death (in 80% cases) in CML is
disease acceleration and blastic transformation
Chronic Lymphocytic Leukemia (CLL)
• Production and accumulation of functionally
inactive but long-lived, mature-appearing
lymphocytes
• B cell involvement
• Lymph node enlargement is noticeable
throughout the body
– ↑ incidence of infection
• Complications from early-stage CLL is rare
– May develop as the disease advances
– Pain, paralysis from enlarged lymph nodes causing
pressure
References
• Robbinson's basic pathology 8 ed
• Harsh Mohan - Textbook of Pathology 6th Ed.
• Color atlas of pathology
THANKS……
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Leukemia

Dr. Deepak K. Gupta

• Anaemia producing pallor, lethargy, dyspnoea.

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