MINISTRY OF PUBLIC HEALTH OF UKRAINE
BUKOVINIAN STATE MEDICAL UNIVERSITY
Approval on methodological meeting
of the department of pathophisiology
Protocol №
Chief of department of the pathophysiology,
professor
Yu.Ye.Rohovyy
“___” ___________ 2008 year.
Methodological Instruction
to Practical Lesson
Мodule 2 : PATHOPHYSIOLOGY OF THE ORGANS AND SYSTEMS.
Contenting module 4. Pathophysiology of blood system.
Theme 4: Leukemia.
Chernivtsi – 2008
1.Actuality of the theme. Steady growth of number of leucosis among
the population of many countries of the world and high lethality demand
steadfast attention to the given pathology. Preventive measures have the large
significance in struggle with leucosis. Therefore it is important for the future
doctor to acquire existing submissions about etilogy of leucosis (chemical
cancerogens, ionizating radiation, virus infection). Each form of leucosis differs
by characteristic shifts of cytostructure of peripheral blood and bone marrow.
On these features differential diagnostics of leucosis is constructed. It is
necessary to mark that the therapy of leucosis mainly pathogenetic. The
deepening of our submissions about separate chains of pathogenesis will
promote perfecting of purposeful treatment.
2.Length of the employment – 2 hours.
3.Aim:
To khow: leukemia –is a disease of tumor nature, originating from blood
cells with initial affection of the bone marrow.
To be able: to analyse of the pathogenesis and blood data under acute and
chronic leukemia.
To perform practical work: to analyse of the pathogenesis of the
leukemia. Oncogenic viruses, ionizing radiation and chemical substances cause
mutation of genes or epigenomic disturbance of regulation of multiplication and
maturation of hematopoietic cells of the II-nd and III-rd levels. Leukemia viruses
can cause such chromosomal translocation that result in transmission of the
oncogenes, localized in chromosomes, to the part of genome where they can be
activated. Penetrating into cell genome, viruses can activate protooncogenes,
coding various oncoproteins,-some of them serve as growth factors (thrombocytic,
epidermal, T-cellular or interleukin-2, insulin etc.), others are receptors of growth
factor, the third ones are proteinkinases, catalyzing phosphorilation of tyrosine.
However, the ability to transform normal blood cells into tumor ones turned to be
common for all the oncoproteins. So, a clone of tumor cells appears in the bone
marrow, which is characterized by unlimited growth and low ability to
differentiation. Fast growth of leukemic cells results in spreading (metastasing) of
them in the whole blood system, including hemopoietic organs and blood.
Instability of leukemic cells genome leads to appearance of new mutations, both
spontaneous and caused by continuous effect of carcinogenic factors, that results in
appearance of the new tumor clones. Thus leukemia has two stages of it
development: monoclinic (more benign) and polyclonic (malignant, terminal).
Transition in one stage into another is the indicator of the tumor progress –
leukemic cells become very malignant. They become morphologically and
cytochemically undifferentiated, the number of blasts with degenerative changes of
the nucleus and cytoplasm increases in hemopoietic organs. Leukemic cells spread,
forming leukemic infiltrates in various organs. As a result of selection those cells
that were subject to the effect of the immune system, hormones of the organism
and cytostatic substances (chemical, hormonal and radioactive) are destroyed and
the clones of the tumor cells that are the most resistant to these effects dominate.
In leukemia first of all normal hematopoiesis is disturbed in the cells where the
tumor transformation occurred. Tumor cells push out and substitute hematopoietic
parenchyma of the bone marrow and its normal microenvironment. Besides, they
can inhibit differentiation of cells-precursors of different stems of hematopoiesis.
Inhibition of normal erythro- and thrombopoiesis leads to development of anemia
and thrombocytopenia with hemorrhage signs. Depression of normal granulo-,
monocyto- and lymphocytopoiesis promotes disturbance of the immune reaction of
the organism in leukemia, as humoral and cellular immunity reactions are inhibited
(antibody formation). It leads to secondary infection and activation of
autoinfection, weakenining of function of the immune supervision in leukemia
lymphocytes may lead to formation of forbidden clones which are able to
synthesize antibodies to their own tissues. Autoimmune processes develop.
4. Basic level.
The name of the previous disciplines
1.
histology
2.
biochemistry
3.
physiology
The receiving of the skills
Scheme of hematopoisis.
Morphological features of leucocytes.
Leucocytic formula of blood.
Function of leucocytes.
5. The advices for students.
1. Leukemia –is a disease of tumor nature, originating from blood cells with
initial affection of the bone marrow.
2.Classification. Leukemia belongs to the group of hematopoietic tissue
tumors, called hemoblastoses. Leukemias are divided into acute and chronic types
depending on the substrate of the tumor growth and on the degree of keeping up
the ability of differentiate into mature cells. In acute leukemia the basic substrate
of the tumor is blast cells of the 2nd, 3rd and 4th levels of hemopoiesis, that lost their
ability to mature, in the chronic one maturing and mature cells, because the major
part differentiates into mature cells. According to the morphological and
cytochemical peculiarities there are myelo-, lympho-, mono- and megakaryocytic
acute leukemias, erythromyelosis and non differentiated forms (they come from the
cells of the 2nd and 3rd levels of hemopoiesis, which are not identified
morphologically). Chronic leukemia in its turn is divided into myelo-, lympho-,
mono-, megakaryocytic types and chronic eythromyelosis.
3. Etiology. The role of a number of factors was proved in causing leukemia
–oncogenic viruses, ionizing radiation, chemical carcinogenic substances and
genetic anomalies. Oncogenic viruses cause spontaneous leukemias in birds, mice,
cats, cattle, monkeys and other animals. They belong to the C-type of RNAcontaining viruses. The virus can be transmitted with feces, urine and discharge
from the nose and pharynx and from a mother to descendants (for instance in
visceral lymphomatosis in hens). Experimentally leukemia is caused by infusing
cell-free filtrates of tumor cells of sick animals to healthy ones. Virus origin of
human leukemia was proved in respect to lymphoma of Berkitt (DNA-containing
virus of Epstine-Barr) and of T-cell leukemia (of the C-HTLV type). Transmission
of the T-cell leukemia virus via blood transfusion and sexual contact (like AIDS
virus –HTLV-3) is considered possible. There is an indirect prove of the etiological
role of the RNA-containing viruses –it is presence of the reverse transcriptase
(RNA-depending DNA-polymerase). Ionizing radiation is the cause of radiation
leukemia in laboratory animals. There are data about increase of the number of
cases of leukemia in children, exposed to radiation in the uterus and in patients,
who underwent X-ray and radioactive isotope treatment. Chemical carcinogens
may cause acute leukemia in people subject to contain with certain substances
(benzene) or treatment with medicines having a mutagenous effect (cytostatic
immunodepressors, butadionum and chloramphenicol). Genetic peculiarities of
hematopoiesis also have an etiological role in causing leukemia. This is proved by
high frequency of cases in certain ethnic groups, family leukemia (there are cases
of chronic lymphoid leukemias with dominant and recessive types of inheritance),
concordance of form, clinic, and hematological signs of leukemia in 1/3 of singleegg twins. Disturbance of somatic and sexual chromosome separation, their
mutation also predisposes to the damage of hematopoietic tissue by tumor process.
So cases of leukemia are more frequent in patients with chromosome anomalies
(Down’s syndrome, syndrome of Klinefelter, Shereshevskiy-Terner’s disease),
genetic defects of the immune system. Specific chromosome mutations were found
in certain kinds of leukemia and severe as genetic markers for them. So an
abnormal Ph’ (Philadelphia) chromosome which was discovered by Nowel and
Hangerford in the city of Philadelphia, is typical of chronic myelocytic leukemia.
This chromosome appears as a result of deletion of the chromosome of the 22 nd
pair and translocation of the separated segment to the 9 th pair (in 90% of the
patients). Translocation of the 8th chromosome segment to the 14th has the same
frequency in lymphoma of Berkitt, most likely because of the influence of
Epsteine-Barr’s virus.
4. Pathogenesis. Oncogenic viruses, ionizing radiation and chemical
substances cause mutation of genes or epigenomic disturbance of regulation of
multiplication and maturation of hematopoietic cells of the II-nd and III-rd levels.
Leukemia viruses can cause such chromosomal translocation that result in
transmission of the oncogenes, localized in chromosomes, to the part of genome
where they can be activated. Penetrating into cell genome, viruses can activate
protooncogenes, coding various oncoproteins,-some of them serve as growth
factors (thrombocytic, epidermal, T-cellular or interleukin-2, insulin etc.), others
are receptors of growth factor, the third ones are proteinkinases, catalyzing
phosphorilation of tyrosine. However, the ability to transform normal blood cells
into tumor ones turned to be common for all the oncoproteins. So, a clone of tumor
cells appears in the bone marrow, which is characterized by unlimited growth and
low ability to differentiation. Fast growth of leukemic cells results in spreading
(metastasing) of them in the whole blood system, including hemopoietic organs
and blood. Instability of leukemic cells genome leads to appearance of new
mutations, both spontaneous and caused by continuous effect of carcinogenic
factors, that results in appearance of the new tumor clones. Thus leukemia has two
stages of it development: monoclinic (more benign) and polyclonic (malignant,
terminal). Transition in one stage into another is the indicator of the tumor progress
–leukemic cells become very malignant. They become morphologically and
cytochemically undifferentiated, the number of blasts with degenerative changes of
the nucleus and cytoplasm increases in hemopoietic organs. Leukemic cells spread,
forming leukemic infiltrates in various organs. As a result of selection those cells
that were subject to the effect of the immune system, hormones of the organism
and cytostatic substances (chemical, hormonal and radioactive) are destroyed and
the clones of the tumor cells that are the most resistant to these effects dominate.
In leukemia first of all normal hematopoiesis is disturbed in the cells where
the tumor transformation occurred. Tumor cells push out and substitute
hematopoietic parenchyma of the bone marrow and its normal microenvironment.
Besides, they can inhibit differentiation of cells-precursors of different stems of
hematopoiesis. Inhibition of normal erythro- and thrombopoiesis leads to
development of anemia and thrombocytopenia with hemorrhage signs.
Depression of normal granulo-, monocyto- and lymphocytopoiesis promotes
disturbance of the immune reaction of the organism in leukemia, as humoral and
cellular immunity reactions are inhibited (antibody formation). It leads to
secondary infection and activation of autoinfection, weakenining of function of the
immune supervision in leukemia lymphocytes may lead to formation of forbidden
clones which are able to synthesize antibodies to their own tissues. Autoimmune
processes develop.
5. Blood data. Total amount of leukocytes in blood depends on the stage of
leukemia (benign monoclinic or terminal polyclonic) and peculiarities of the
course of the disease. In leukemia there can be normal amount of leucocytes,
slightly increased (20-50*109/l and over) in blood or leucopenia. There is a nuclear
shift to the left of leucogram due to increase of the number of immature forms of
leucocytes. There can be various degenerative changes of leucocytes observed,
morphological and cytochemical atypicity, making identification of the cells
difficult, and also anemia and thrombocytopenia. Appearance of a large number of
blast cells in blood is typical of acute leukemia. There can be a “leukemic gap”
observed when there are no transition forms between blast cells and mature
granulocytes. This indicates serious disturbance of leucopoiesis in hematopoietic
organs –loss of the ability of tumor cells to differentiate.
Increase of the number of neutrophlic granulocytes –metamyelocytes,
“bilobe” myelocytes –with a shift to the left to myelocytes and single myeloblasts
is typical of chronic leukemia. The number of eosinophilic and basophilic
granulocytes can also be increased. Myeloid metaplasia of the lymphoid tissue is
observed. The terminal stage is characterized by blast crisis when the number of
blast cell –myeloblasts and the number of non-differentiated blasts increase in
blood sharply.
Chronic lymphoid leukemia is characterized by lymphocytosis - 80-98%.
Lymphocytes are mostly mature (B-lymphocytic kind of leukemia is more
common), but there are single prolymphocytes and lymphoblasts in blood. The
number of granulocytes, erythrocytes and platelets is decreased. This is caused by
total substitution of all hemopoietic stem by lymphocytes (lymphoid metaplasia of
myeloid tissue). Blast crisis occurs rarely in this form of leukemia (3-4%).
6. Leucocyte degeneration in blood. They are: unisocytosis vacuoles in
cytoplasm, toxigenic granules, the appearance of inclusions in cytoplasm such as
Cnyazcov-Dele’s bodies basophilically stained small bundle of cytoplasm and
others, the presence of large asurophilic granulation and absence of the normal
one, the swelling of the nucleus, its hypo- and hypersegmentation, different degree
of mutation of the nucleus and cytoplasm, cytolysis. Degenerative changes are
most frequently observed in neutrophile granulocytes and monocytes. The causes
are the disturbance in leucocyte metabolism, which to structural anomalies (in
leucosis and hereditary enzymopathy), and the damage of leucocytes in the
hemopoietic organs and blood under the influence of different pathologic factors
(bacteria, viruses and antibodies).
5.1. Content of the theme. What is leukemia ? Classification of the
leukemia.Etiology of the leukemia. The pathogenesis of leukemia. Blood picture
under the leukemia. Leucocyte degeneration in blood.
5.2. Control questions of the theme:
1.
2.
3.
4.
5.
6.
What is leukemia ?
Classification of the leukemia.
Etiology of the leukemia.
The pathogenesis of leukemia.
Blood picture under the leukemia.
Leucocyte degeneration in blood.
5.3. Practice Examination.
Task 1.
In a patient with leucosis parameters of white blood are the following:
amount of leucocytes – 100∙109/l, from them basophiles – 1 %,
eosinophiles – 2 %, stab neutrophils – 4 %, segmental leucocytes – 7 %,
lymphoblasts – 2 %, lymphocytes – 80 %, monocytes – 4 %. In blood there
are a lot of desroyed lymphocytes (Gymprehkt bodies). These parameters
are characterized for
A. Acute myeloblastic leucosis B. Chronic mielocytic leucosis
C. Chronic lymphocytic leucosis D. Acute plasmoblastic leucosis
E. Chronic monocytic leucosis
Task 2.
Leucogram of a patient with leucosis looks as follows: an amount of
leucocytes – 250∙109/l, basophiles – 3 %, eosinophiles – 5 %, myeloblasts
– 11 %, promyelocytes – 10 %, myelocytes – 14 %, metamyelocytes – 16
%, stab neutrophiles – 14 %, segmental neutrophiles – 13 %, lymphocytes
– 12 %, monocytes – 2 %. These data allow to diagnose :
A. Acute lymphoblastic leucosis B. Acute monoblastic leucosis
C. Chronic myelocytic leucosis D. Chronic lymphocytic leucosis
E. Chronic eosinophilic leucosis
Task 3. The diagnosis of leucosis is established to the patient. Parameters of blood
: an amount of leucocytes – 30∙109/l, basophiles – 1 %, eosinophiles – 1 %,
myeloblasts – 81 %, stab neutrophiles – 3 %, segmental neutrophiles – 3
%, lymphocytes - 9 %, monocytes – 2 %. These data testify of availability
of:
A. Acute myelocytic leucosis B. Chronic lymphocytic leucosis
C. Chronic monocytic leucosis D. Acute promyelocytic leucosis
E. Acute myeloblastic leucosis
Real-life situations to be solved:
Task 1
Total
amount of
leucocytes
100,0.109/л
Baso- Eosinophiles philes
1%
Neutrophiles
Stab
MetamyeloSegmental
cytes
2%
-
4%
Lymphoblasts
Lymphocytes
Monocytes
2%
80 %
4%
7%
1. Indicate, what parameters mentioned deviate from norm. What the essence of
this deviation - decrease, increase, appearance of the unusual forms ?
2. What form of leucosis this leucogram is characterized for?
Task 2
Total
Basoamount of philes
leucocytes
75,0.109/л
1%
EosiNeutrophiles
nophi- Myelo- Promie- Myelo- Metablasts locytes cytes myeloles
1%
78 %
2%
-
cytes
-
Stab
Segmental
3%
3%
Lym- Monopho- cytes
cytes
10 %
2%
1. Indicate, what from above mentioned parameters deviate from norm. In what
the essence of this deviation - decrease, increase, appearance of the unusual forms
consists?
2. What form of leucosis this leucogram is characterized for?
Task 3
Total
amount of
leucocytes
Basophiles
Eosinophiles
250,0.109/л
3%
5%
Neutrophiles
MyeProMye- Metalomye- locytes myeblasts locytes
locytes
11 %
10 %
14 %
16 %
Stab
Segmental
Lymphocytes
14 %
13 %
12 %
Monocytes
2%
1. Indicate, what from above mentioned parameters deviate from norm. In what the
essence of this deviation decrease, increase, appearance of the unusual forms
consists?
2. What form of leukosis this leukogram is characterized for?
Literature:
1. Gozhenko A.I., Makulkin R.F., Gurcalova I.P. at al. General and clinical
pathophysiology/ Workbook for medical students and practitioners.-Odessa, 2001.
2. Gozhenko A.I., Gurcalova I.P. General and clinical pathophysiology/ Study
guide for medical students and practitioners.-Odessa, 2003.
3. Robbins Pathologic basis of disease.-6th ed./Ramzi S.Cotnar, Vinay Kumar,
Tucker Collins.-Philadelphia, London, Toronto, Montreal, Sydney, Tokyo.-1999.