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

SCHEME OF BLOODFORMING

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

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.

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

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

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

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

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

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

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

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)

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

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.

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.

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.

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

Reaction of monoblastes of α-naphtylacetateesterase

Reaction of myeloblastes and monoblastes of acidic phosphatase

Reaction with black sudan of lipids

Acidic sulfurated mucopolysaccharides reaction

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

Acute undifferentiated leucosis - blood

Acute undifferentiated leucosis - blood

Acute undifferentiated leucosis – b. marrow

Acute undifferentiated leucosis– b. marrow. Аtypical cells

Acute myeloblastic leukemia

Acute myeloblastic leukemia

Acute myeloblastic leukemia

Acute promyelocytic leukemia

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

Acute megakaryoblastic leucosis – b. marrow

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).

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

Acute lymphoid leukemia

Acute В-lymphoblastosis – b. marrow Big vacuolized lymphoblastes

Acute lymphoblastic leucosis – b. marrow. Initial stage

Acute lymphoblastosis – b. marrow. Тоtal lymphoblastic metaplasia

Chronical lymphoid leukemia

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

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.

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

Acute myeloblastic leukemia – bone marrow

Chronical myeloleucosis – blood. Stage of crisis of blastic cells

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

Hair-cell lymphoid leukemia

Hair-cell lymphoid leukemia

Hair-cell lymphoid leukemia

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.

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

Leucosogenic action of ionising rays. Increase of frequency leucosis took place after nuclear bombardment of Hiroshima and Nagasaki in 1945. The leucosis was fixed also in case of use ionising radiation with the medical purpose, myelomic illness, lymphogranulomatosis, autoimmune diseases, some dermatosis. The approximately 25-35 % 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 15-18 % of the patients.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

LEUKEMIC INFILTRATION OF HEART

THANK YOU !!!