Laboratory Diagnostics, Specimen Collection, and Biosafety Issues
CLINICAL LABORATORY DIAGNOSTICS OF HEMOBLASTOSIS Krynytska Inna Yakivna.
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Transcript of CLINICAL LABORATORY DIAGNOSTICS OF HEMOBLASTOSIS Krynytska Inna Yakivna.
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CLINICAL LABORATORY DIAGNOSTICS OF HEMOBLASTOSIS
Krynytska Inna Yakivna
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Today’s Lecture 1. Introduction to
Leukemias. 2. Acute Leukemias. 3. Chronic Leukemias
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Definition of Leukemia Leukemia is a malignant disease
characterized by unregulated proliferation of one cell type.(one clone of Immature cell) It may involve any of the cell lines or a stem
cell common to several cell lines. Leukemias are classified into 2 major groups
Chronic in which the onset is insidious, the disease is usually less aggressive, and the cells involved are usually more mature cells
Acute in which the onset is usually rapid, the disease is very aggressive, and the cells involved are usually poorly differentiated with many blasts.
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Types Both acute and chronic leukemias are further
classified according to the prominent cell line involved in the expansion:
If the prominent cell line is of the myeloid series it is a myelocytic leukemia (sometimes also called granulocytic)
If the prominent cell line is of the lymphoid series it is a lymphocytic leukemia
Therefore, there are four basic types of leukemia Acute myelocytic leukemia – AML- (includes
myeloblastic, promyelocytic, monocytic, myelomonocytic, erythrocytic, and megakaryocytic)
Acute lymphocytic leukemia – ALL- (includes T cell, B cell, and Null cell)
Chronic myelocytic leukemia – CML - (includes myelocytic and myelomonocytic)
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Acute & Chronic Types Chronic lymphocytic leukemia – CLL - (includes
plasmocytic {multiple myeloma}, Hairy cell, prolymphocytic, large granular cell lymphocytic, Sezary’s syndrome, and circulating lymphoma)
Etiology – the exact cause is frequently not known, but predisposing factors are known:
Host factors Some individuals have an inherited increased
predisposition to develop leukemia There is an increased incidence in those with an
inherited tendency for chromosome fragility or abnormality or those with increased numbers of chromosomes (such as Down’s syndrome). Many of these diseases are characterized by chromosomal translocations.
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Incidence of leukemia There is an increased incidence in those with
hereditary immunodeficiencies. There is an increased incidence in those with
chronic marrow dysfunction such as those with myeloproliferative diseases, myelodysplastic syndromes, aplastic anemia, or paroxsymal nocturnal hemoglobinuria.
Environmental factors: Exposure to ionizing radiation Exposure to mutagenic chemicals and drugs Viral infections
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Incidence of leukemia Incidence
Acute leukemias can occur in all age groups
ALL is more common in children AML is more common in adults
Chronic leukemias are usually a disease of adults
CLL is extremely rare in children and unusual before the age of 40
CML has a peak age of 30-50
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Comparison Acute Vs Chronic
Comparison of acute and chronic leukemias:
Acute ChronicAge all ages usually adultsClinical onset sudden insidiousCourse (untreated) 6 mo. or less 2-6 yearsLeukemic cells immature >30% blasts more mature cellsAnemia prominent mildThrombocytopenia prominent mildWBC count variable increasedLymphadenopathy mild present;often
prominentSplenomegaly mild present;often
prominent
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. Acute leukemia Acute leukemia –
Is a result of: Malignant transformation of a stem cell leading to
unregulated proliferation and Arrest in maturation at the primitive blast stage.
Remember that a blast is the most immature cell that can be recognized as committed to a particular cell line.
Clinical features Leukemic proliferation, accumulation, and
invasion of normal tissues, including the liver, spleen, lymph nodes, central nervous system, and skin, cause lesions ranging from rashes to tumors.
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Evaluation of leukemia Failure of the bone marrow and normal
hematopoiesis may result in pancytopenia with death from hemorrhaging and infections.
Lab evaluation The lab diagnosis is based on two things
Finding a significant increase in the number of immature cells in the bone marrow including blasts, promyelocytes, promonocytes (>30% blasts is diagnostic)
Identification of the cell lineage of the leukemic cells
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Evaluation of leukemia Peripheral blood:
Anemia (normochromic, normocytic) Decreased platlets Variable WBC count
The degree of peripheral blood involvement determines classification:
Leukemic – increased WBCs due to blasts Subleukemic – blasts without increased WBCs Aleukemic – decreased WBCs with no blasts
Classification of the immature cells involved may be done by:
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Cell Morphology in Leukemia
Morphology – an experienced morphologist can look at the size of the blast, the amount of cytoplasm, the nuclear chromatin pattern, the presence of nucleoli and the presence of auer rods (are a pink staining, splinter shaped inclusion due to a rod shaped alignment of primary granules found only in myeloproliferative processes) to identify the blast type:
AML – the myeloblast is a large blast with a moderate amount of cytoplasm, fine lacey chromatin, and prominent nucleoli. 10-40% of myeloblasts contain auer rods.
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Myeloid maturationmyeloblast promyelocyte myelocyte metamyelocyte band neutrophil
MATURATIONMATURATION
Adapted and modified from U Va website
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Myeloblasts with auer rods
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Lymphoblasts ALL – in contrast to the myeloblast, the
lymphoblast is a small blast with scant cytoplasm, dense chromatin, indistinct nucleoli, and no auer rods
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Lymphoblast
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AML
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Auer rods in AML
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ALL
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Cytochemistry Cytochemistry – help to classify the
lineage of a leukemic cell (myeloid versus lymphoid)
Myeloperoxidase – is found in the primary granules of granulocytic cells starting at the late blast stage. Monocytes may be weakly positive.
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Sudan black Sudan black stains phospholipids, neutral fats
and sterols found in primary and secondary granules of granulocytic cells and to a lesser extent in monocytic lysosomes. Rare positives occur in lymphoid cells
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Nonspecific Esterase Nonspecific esterase – is used to identify
monocytic cells which are diffusely positive. T lymphocytes may have focal staining
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Acid phosphatase Acid phosphatase may be found in
myeloblasts and lymphoblasts. T lymphocytes have a high level of acid phosphatase and this can be used to help make a diagnosis of acute T-lymphocytic leukemia.
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Leukocyte Alkaline phosphatase
Leukocyte alkaline phosphatase – is located in the tertiary granules of segmented neutrophils, bands and metamyelocytes. The LAP score is determined by counting 100 mature neutrophils and bands. Each cell is graded from 0 to 5. The total LAP score is calculated by adding up the scores for each cell.
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Immunologic markers Immunologic markers
(immunophenotyping) – these are used mainly for lymphocytes, i.e., for determining B cell or T cell lineage. These tests rely on antibodies made against specific surface markers. (Fluorescent Antibody Tagging)
flow cytometer that will determine the number of cells that have a fluorescent tag and which are thus positive for the presence of the surface marker to which the primary antibody was made.
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Cytogenetics leukemia Cytogenetics – cytogenetics studies can now be used
for diagnosis and for prognosis of hematologic malignancies.
Many leukemias (and lymphomas) are characterized by specific chromosomal abnormalities, including specific translocations and aneuploidy. The specific type of malignancy can be identified based on the specific abnormality or translocation. These may be identified by
Looking at the karyotypes of the chromsomes from the abnormal cells
DNA based tests – these tests are very useful for following the course of the disease
A normal karyotype is usually associated with a better prognosis.
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Chromosomal translocation
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Acute leukemias FAB Classification Acute lymphoblastic leukemia –
They may be classified on the basis of the cytological features of the lymphoblasts into;
L1 - This is the most common form found in children and it has the best prognosis. The cell size is small with fine or clumped homogenous nuclear chromatin and absent or indistinct nucleoli. The nuclear shape is regular, occasionally clefting or indented. The cytoplasm is scant, with slight to moderate basophilia and variable vacuoles.
L2 – This is the most frequent ALL found in adults. The cell size is large and heterogenous with variable nuclear chromatin and prominent nucleoli. The nucleus is irregular, clefting and indented. The cytoplasm is variable and often moderate to abundant, the basophilia is variable and may be deep, and vacuoles are variable.
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ALL-L1
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ALL-L2
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Acute leukemias L3 – This is the rarest form of ALL. The
cell size is large, with fine, homogenous nuclear chromatin containing prominent nucleoli. The The nucleus is regular oval to round. The cytoplasm is moderately abundant and is deeply basophilic and vacuolated.
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ALL-L3
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Acute leukemias Incidence – ALL is primarily a disease
of young children (2-5 years), but it can also occur in adults
Clinical findings – pancytopenia with resulting fatigue, pallor, fever, weight loss, irritability, anorexia, infection, bleeding, and bone pain.
L1 occurs in children, L2 in adults, and L3 is called Burkitts leukemia
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Acute leukemias Prognosis – age, WBC count, and cell type
are the most important prognostic indicators
Patients younger then 1 and greater than 13 have a poor prognosis
If the WBC count is < 10 x 109/L at presentation, the prognosis is good; If the WBC count is > 20 x 109/L at presentation the prognosis is poor
T cell ALL (more common in males) has a poorer prognosis than any of the B cell ALLs which have a cure rate of 70%
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Acute leukemias Acute leukemias with mixed lineage –
there are occasionally acute leukemias that are biphenotypic and display phenotypes for two different lineages B lymphoid/myeloid T lymphoid/myeloid B/T lymphoid Myeloid/Natural killer A rare trilineage leukemia has also been
seen (was B/T lymphoid/myeloid!)
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Acute leukemias Acute myeloid leukemia (also called acute
granulocytic leukemia) – classification depends upon Bone marrow blast morphology Degree of cell maturation Cytochemical stains Immunophenotyping AML is divided into 7 different classifications:
M1 – myeloblastic without maturation The bone marrow shows 90% blasts and < 10%
promyelocytes The disease occurs in older adults
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AML – M1 Note the myeloblasts and the auer
rod:
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Acute leukemias M2 – myeloblastic with maturation
The bone marrow shows 30-89% blasts and > 10% promyelocytes;
This is characterized by an 8,21 chromosomal translocation
This occurs in older adults M3 – hypergranular promyelocytic
This form of AML has a bone marrow with >30% blasts Is more virulent than other forms Occurs with a medium age of 39 The WBC count is decreased Treatment causes a release of the granules and may
send the patient into disseminated intravascular coagulation and subsequent bleeding
It is characterized by a 15,17 chromosomal translocation
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AML – M2 Note myeloblasts and
hypogranulated PMNs:
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AML – M3 Note hypergranular
promyelocytes:
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Acute leukemias M3m – hypogranular promyelocytic –
The bone marrow has > 30% blasts The WBC count is increased. Like the M3 type, treatment causes a release of the
granules and may send the patient into disseminated intravascular coagulation and subsequent bleeding and
It is characterized by a 15,17 translocation M4 – acute myelomonoblastic leukemia
Both myeloblasts and monoblasts are seen in the bone marrow and peripheral blood
Infiltration of extramedullary sites is more common than with the pure granulocytic variants
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AML – M3m Note hypogranular promyelocytes:
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AML – M4 Note monoblasts and
promonocytes:
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Acute leukemias M5 – acute monoblastic leukemia
>80% of the nonerythroid cells in the bone marrow are monocytic
There is extensive infiltration of the gums, CNS, lymph nodes and extramedullary sites
This form is further divided into M5A - Poorly differentiated (>80% monoblasts) M5B - Well differentiated (<80% monoblasts)
M6 – erythroleukemia This is rare and is characterized by a bone marrow having a
predominance of erythroblasts It has 3 sequentially morphologically defined phases;
Preponderance of abnormal erythroblasts Erythroleukemia – there is an increase in both erythroblasts
and myeloblasts Myeloblastic leukemia – M1, M2, or M4
Anemia is common
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AML – M5A Note monoblasts:
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AML-M5B Note monoblasts, promonocytes,
and monocytes:
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AML – M6 Note M1 type monoblasts
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Acute leukemias M7 - Acute megkaryoblastic leukemia
This is a rare disorder characterized by extensive proliferation of megakaryoblasts, atypical megakaryocytes and thrombocytopenia
Treatment of leukemias – There are 2 goals:
Eradicate the leukemic cell mass Give supportive care
Except for ALL in children, cures are not common but complete remission (absence of any leukemia related signs and symptoms and return of bone marrow and peripheral blood values to within normal values) is
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Acute leukemias There are four general types of
therapy Chemotherapy – usually a combination of
drugs is used Bone marrow transplant Radiotherapy Immunotherapy – stimulate the patients
own immune system to mount a response against the malignant cells
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Chronic Lymphocytic leukemia
Commonest leukemia in the western world
Clonal proliferation of the B-Lymphocytes
Disease of the elderly Younger patients now seen M:F ratio, 2:1 CLL is highly variable disorder 75% cases, diagnosis by chance on a
routine blood test
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Aetiology
Cause unknown
Not associated with radiation or exposure to occupational hazards
Among the leukemias, CLL has the strongest tendency for familial incidence
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Clinical Findings Asymptomatic: incidental finding Anaemia & thrombocytopenia Infections Weight loss, Night sweats, Fever (B
Symptoms) Lymphadenopathy Splenomegaly AIHA (Auto immune haemolytic anaemia)
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Prognosis
Late stage patients have usually progressive disease
Highly Variable for early stage patients
Significant subset of early stage eventually progress Refractory to treatment Infectious Complications Autoimmune complications
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Chronic Myeloid Leukaemia Malignancy of the haemopoietic system Transformation of the pluripotent stem cell 9;22 translocation giving rise to the
Philadelphia (Ph’) chromosome Creation of a leukaemia specific mRNA
(BCR-ABL) Resistance to apoptosis, abnormal
signalling and adhesion Molecular diagnostics Molecular and cellular therapeutics
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Cytogenetic Abnormality of CML:The Ph Chromosome
1 2 3 4 5
6 7 8 10 119 12
13 14 15 16 17 18
19 20 21 22 x Y
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Molecular Methods the Ph Chromosome Fluorescence in situ hybridisation (FISH)
Interphase Metaphase
Courtesy of Charles Sawyers, UCLA.