1. PATHOLOGY OF LEUKOCYTES
Professor Yu.I. Bondarenko
PP PATHOLOGY OF LEUKOCYTES LEUКЕМІА Professor Yu.I. Bondarenko Professor Yu.I. Bondarenko

2. SCHEME OF BLOODFORMING

3. QUANTITATIVE DISORDER OF LEUKOCYTES
THE TOTAL QUANTITY OF LEUKOCYTES EQUALS 4-9 G/L
QUANTITATIVE DISORDER OF LEUKOCYTES ARE REPRESENTED BY:
the total quantity of leukocytes in a liter of blood;
Changes of leukoformula indices (quantity of every form of leukocytes)
Leukocytosis - an increase in the total quantity of leukocytes;
Leukopenia a decrease in the total quantity of leukocytes

4. Leukoformula analysis
Left-Side Nuclear Shift of Neutrophils
Regenerative
Hyperregenerative
Regenerative-Degenerative
Degenerative
Right-Side Nuclear Shift of Neutrophils
- an increased propotion of mature segmented neutrophils in the leukoformula in comparison with their young precursor.

5. QUALITATIVE CHANGES IN LEUKOCYTES
anisocytosis (change in the size of leukocytes);
poikilocytosis (change in the form of leukocytes);
absence of normal granulation;
pathological inclusion in the cytoplasm (toxic granulosity, large azurophilic granules, basophilic bundes of cytoplasm);
vacuolization of the nucleus and cytoplasm;
swelling of the nucleus;
karyorrexis;
hypo- and hypersegmentation of the nucleus;
cytolysis

6. LEUKOCYTOSIS
Is an icrease in the total amount of leukocytes in peripheral blood to more than 9 G/L
TYPES
Physiological (after food intake,physical and emotional load, in pregnancy)
Pathological (in disease)
Reactive
Redistributive
Tumorous
Absolute
Relative

7. LEUKOCYTOSIS Neutrophilic; Eosinophilic; Basophilic; Lymphocytosis;
Depending on the type of leukocytes being increased
Neutrophilic;
Eosinophilic;
Basophilic;
Lymphocytosis;
Monocytosis

8. Infectious (strepto- and staphylococci and fung) Noninfectious:
NEUTROPHILIC LEUKOCYTOSIS
Etiological factors:
Infectious (strepto- and staphylococci and fung)
Noninfectious:
- produts of tissue decay and necrosis (myocardial infarction, malignant tumor decay, product of decay in chronic myeloleukemia), tissue destruction (cold, heat);
- products of erythrocyte hemolysis;
- toxic metabolites in uremia and hepatic coma

9. EOSINOPHILIC LEUKOCYTOSIS
Allergic diseases;
Helminthic invasion;
Chronic myeloleukemia;
Hypocorticism
BASOPHILIC LEUKOCYTOSIS
Ulcerative colitis;
After splenoectomy;
Myxedema

10. LYMPHOCYTIC LEUKOCYTOSIS
Tuberculosis and lues;
Viral infectious (mononucleosis, hepatitis, measles, whooping cough);
Allergic diseases;
Chronic lympholeukemia
MONOCYTOSIS
Viruses;
microorganisms (specific streptococcal endocarditis);
Protozoa;
Tuberculosis;
Syphilis

11. LEUKOPENIA
Is a decrease of the total quantity of leukocytes in the peripheral blood below 4 G/L
Types depending on the mechanisms:
1. Aquired
2. Hereditary
Types depending on the type of leukocytes being decreased:
Neutropenia;
Eosinopenia;
Lymphopenia;
Monocytopenia

12. ETIOLOGY OF LEUKOPENIA
Physical (ionizing radiation);
Chemical;
- poisons;
- medicines (aspirin, amidopyrin, cytostatics, barbiturates, glucocorticoids);
- Vitamin B12 and folic acid deficiency;
Biological;
- infectious;
- immune;
- hormonal (stress);
- genetic (mutation)

13. PATHOGENESIS OF LEUKOPENIA
Decreased leukocyte production in the hemopoietic tissue;
Increased leukocyte destruction in the blood and hemopoietic tissue;
Excessive loss of leukocytes;
Redistribution of leukocytes in the vessels;
Decelerated leukocyte release from the bone marrow

14. LEUКЕМІА
Leukemia (leucosis) is a tumour, which arises from bloodforming cells and is primary damages bone marrow.
The most characteristic signs of leucosis is the filling bone marrow by malignant cells of the local origin. It can be leucocytes and their predecessors, erythroblasts, megacaryoblasts.

15. Classification of leukemia
1. Acute leukemia
2. Chronic leukemia
Acute leucosis is characterized disorder of bloodforming cells differentiation, do not go further ІV classes.
The growth up of cells, which do not mature, lead to accumulation blast cells ІІ, ІІІ and ІV classes. They more and more take part of bone marrow at the expense of volume, which should be occupied normal hemopoietic elements.

16. created by French, American and British experts.
FAB-classification
created by French, American and British experts.
It is constructed on stable morphological and cytochemical characteristics of leucosis cells. These characteristics reflect features them metabolism.
According to modern conception all acute leucosis divide on two groups – myeloblast and lymphoblast. They are represented by many nosologic forms.
Acute myeloblastic leucosis differentiate on five cytochemical signs – presence or absence in leucosis cells of the following substances: peroxidase, acid phosphatase, unspecific esterase, lipids and glycogen.

19. Reaction of myeloblastes and other cells of
Reaction of myeloblastes and other cells of neutrophilic line of peroxidase

20. Reaction of monoblastes of α-naphtylacetateesterase

21. Reaction of myeloblastes and monoblastes of acidic phosphatase

22. Reaction with black sudan of lipids

23. Acidic sulfurated mucopolysaccharides reaction

24. Classification of acute myeloblastic leucosis
M0 - acute undifferentiated leucosis
M1 - acute myeloblastic leucosis without signs of maturing (worse 3 % of promyelocytes)
M2 - acute myeloblastic leucosis with signs of maturing (over 3 % of promyelocytes)
M3 - acute promyelocytic leucosis (over 30 % of promyelocytes)
M4 - acute myelomonoblastic leucosis - over 20 % of promyelocytes
M5 - acute monoblastic leucosis
M6 - acute erythroblastic leucosis
M7 - acute megacaryoblastic leucosis

25. Acute undifferentiated leucosis - blood

26. Acute undifferentiated leucosis - blood

27. Acute undifferentiated leucosis – b. marrow

28. Acute undifferentiated leucosis– b. marrow. Аtypical cells

29. Acute myeloblastic leukemia

31. Acute myeloblastic leukemia

32. Acute myeloblastic leukemia

33. Acute promyelocytic leukemia

34. Acute myeloblastic – b. marrow. Initial stage. Granular myeloblast
Acute myeloblastic – b. marrow. Initial stage. Granular myeloblast. Aur’s stab

35. Acute megakaryoblastic leucosis – b. marrow

36. Complete hematological picture of chronic leucosis
Complete hematological picture of chronic leucosis In the blood present as the maturing cells as an abundance cells of all classes – young, transition and mature. Hiatus leukemicus is absent. In particular, in blood of chronic myelocytic leucosis will be the next cells – predecessor ІІ and ІІІ classes, myeloblasts (ІV classes), cell V classes – promyelocytes myelocytes metamyelocytes stick nucleus neutrophils and mature cells of the VІ class (neutrophils). The picture of peripheral blood of chronic lymphocytic leucosis is characterized by the following features: there are a lot of mature lymphocytes, there are prolymphocytes and lymphoblasts, and also desroyed lymphoid cells (Gumprecht’s bodies or shadows of lymphocytes).

37. Classification of acute lymphoblastic leucosis
Acute leucosis of general type ( from cells-predecessors of B lymphocytes)
2. T-lymphoblastic leucosis
3. B-lymphoblastic leucosis.

38. Acute lymphoid leukemia

39. Acute В-lymphoblastosis – b. marrow Big vacuolized lymphoblastes

40. Acute lymphoblastic leucosis – b. marrow. Initial stage

41. Acute lymphoblastosis – b. marrow. Тоtal lymphoblastic metaplasia

43. Chronical lymphoid leukemia

44. FBA-classification acute leukemia is divided on groups L1, L2, L3.
L1 – leukemia with predominance of small lymphoid cells;
L2 – leukemia with typical lymphoblasts;
L3 – macrolymphoblastic leukemia

45. Chronic leucosis differ from acute, that the cells bone marrow mature normally (up to VІ class), but proliferate in very plenty.
1. Chronic stage
Illness represents a benign tumour and can be treatment.
2. The stage of accelerated development of illness
Illness progresses toward malignisation.
Control under dynamic of illness is lost.
The treatment becomes all less effective.
3. The stage crisis of blastic cells
Illness is exposed to radical transformation: chronic leucosis passes in acute (in 70 % - in acute myeloblastic, in 30 % - in acute lymphoblastic).
Crisis of blastic cells approaches suddenly and becomes the reason of patients death.

46. Classification of chronic myeloid leukemia
1. Chronic myeloleucosis
2. Chronic monocytic leucosis
3. Chronic erythromyelosis
4. Chronic megacaryocytic leucosis
5. Eosinophilic leucosis

48. Acute myeloblastic leukemia – bone marrow

49. Chronical myeloleucosis – blood. Stage of crisis of blastic cells

50. 1. B - cell leucosis 2. T - cell leucosis 3. Haircell leucosis
Classification of chronic lymphoid leukemia
1. B - cell leucosis
2. T - cell leucosis
3. Haircell leucosis

51. Hair-cell lymphoid leukemia

52. Hair-cell lymphoid leukemia

53. Hair-cell lymphoid leukemia

54. Etiology and pathogenesis of the leucosis
On modern conception, leucosis arise on genetic, mutational basis.
The question is about specific bloodforming cells mutation, which lead to superexpression of cell oncogenes, or protooncogenes. These genes are an integral part of cells genome and answer for proliferation of cells in norma. Cell oncogenes vitally are necessary. At the some time cell oncogenes have latent blastomogenic potentions.
To major etiological factors, which capable to transform protooncogenes in active oncogenes are the chemical agents, ionising rays and retroviruses. It is know a few mechanisms of the cell oncogenes activation.

55. Mechanisms of protooncogene activation
1. Chromosomal aberrations
2. Genic amplification
3. Point mutations
4. Viral transduction
5. Insertional mutagenesis
6. Transactivation of transcription

56. Leucosogenic action of ionising rays.
Increase of frequency leucosis took place after nuclear bombardment of Hiroshima and Nagasaki in The leucosis was fixed also in case of use ionising radiation with the medical purpose, myelomic illness, lymphogranulomatosis, autoimmune diseases, some dermatosis.
The approximately % of cells, mainly lymphocytes, after therapeutical iradiation contain chromosomal aberrations as ring chromosomes, dicentric chromosomes and acentric of fragments.
It is known leucosogenic action of radioactive isotopes. The radioactive phosphorum, which is used for treatment erythremia, caused acute leucosis in % of the patients.

57. Chromosomal aberrations.
The precise correlation between localization of oncogenes and specific translocations of chromosomes is marked. It is established, that cell oncogenes frequently placed just in those sites chromosomes, where it is easy and naturally there are their breaks with consequent translocations of deleted fragments. The translocations can be original activators protooncogenes.
To the present time in chromosomes of malignant cells more than 80 points are registered, where the breaks are observed. The analysis of distribution of these malignant spesific points and localization protooncogenes in genome of that person testify that the majority protooncogenes placed just in zones of specific breaks chromosomes.

58. Chromosomal role aberrations in activation of protooncogenes represent chromosomal and genes of illness, which are characterized by increased instability of chromosomes.
Dawn’s illness;
Fankony’s anemia;
Blum’s syndrome;
Louis-Bar’s syndrome and etc.
It is established, that among patients with Down’s illness the frequency leucosis in 20 times is higher, than among persones without Down’s illness. Fankony’s anemia the diverse deviations karyotype from norm are found: chromatide breaks, acentric fragmentation, dicentric chromosomes, chromatide exchanges. In children with the Blum’s syndrome large percent of breaks chromosomes, as Fankony’s anemia is observed.

59. Every type of leucosis are characterized
Every type of leucosis are characterized specific chromosomal aberrations.
The most better is investigated translocation 9/22, characterized for chronic myelocytic leucosis. This anomaly the first time was described in 1960 in Philadelphia (USA). Changed chromosome named philadelphian. That chromosome derivated in result reciprocal translocation between 9-th and 22-nd chromosome. Long shoulder of 9-th chromosome contains protooncogene abl (Abelson’s), which in mice causes leucosis, and long shoulder of 22-nd chromosome contains protooncogene sis, which causes sarcoma in haired monkeys.

60. Expression of Abelson’s oncogene in bone marrow to a cell stipulate appearance in it special oncoprotein with molecular weight 210 kD and by thyrosine activity. This oncoproteine is coded simultaneously Abelson’s oncogene from 9-th chromosome and site 22-nd chromosome, which adjoins to the point of break.
The data about a role of chromosome aberrations in leucosis etiology can be generalized as follows.
The anomalies karyotype only when can cause leucosis, if they seize chromosome locuses, where are located protooncogenes.
The activation stipulates these protooncogenes pathological proliferation and leucosis. Each chromosome has so-called fragile sites, which can be identified by means of differential colouring. Just here there are deletion, inversions and translocation, which become by the initiators of activation protooncogenes more often.

61. Virus transduction.
On leucosogenic properties retroviruses divide on two groups – fast-transformed (viruses acute leucosis) and slow- transformed (viruses of chronic leucosis).
Retroviruses of the acute leucosis differ by that their gene has an additional gene. It represents cells oncogene, which was snatched out from genome of cell and is built in virus RNA. It is uncellular and virus oncogene.
This additional gene consider as the specific factor, which causes malignant transformation of a cell, and the process of massage cells oncogene through a virus is named virus transduction.

62. After repeated introduce in a cell virus (form cells) oncogene shows high propensity to expression.
The first reason – it is seized by virus without surrounding regulatoring repressors genes.
The second reason – DNA-copy retrovirus is not absolutely exactly reading out return transcriptase.
When the again created virus particles are introduced into the following cell, their DNA-copies with an additional gene (virus oncogene) are built in cell by the gene and easily expression or because mutational virus oncogene becomes inaccessible repressoring gene to environment, or because this environment in general is absent.

63. Insertion of provirus.
Most of viruses leucosis belongs not to fast transformational, and to slow transformational retroviruses.
They do not contain oncogenes and induce experimental leucosis in an animal less effectively, than fast transformational.
Slow transformational retroviruses cause transformation of cells because their DNA-copies are inserted in cells by a gene near to cells oncogene.
The presence of another's DNA sometime activates cells oncogene up to very high level expression.

64. Genes amplification.
This increase of copies of separate genes in reply to change of the external environment.
In leucosis cells are detected amplificated of copy some protooncogenes.
In itself amplification of oncogene does not concern to initiating events in leucogenesis.
It is connected to a progression already of initiated cells. But in any case amplification of gene results in increase of level expressed RNA.

65. Major chain of pathogenesis leucosis is oppression by leucosis cells normal hemopoiesis.
1. Leucosis cells are capable produced in redundant amount colonialstimulation factor – stimulator of myelopoiesis.
2. This factor acts on leucosis cells stronger, than on the normal predecessors hemopoiesis.

66. Clinical signs of leukemia
1. Metaplastic anemia
2. Thrombocytopenia and hemorrhagic syndrome
3. Inhibition of immune
4. Decrease of resistance to infectious agent

67. LEUKEMIC INFILTRATION OF HEART

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