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Etiology and pathogeny of leukoses - Practical hematology of children's age

Table of contents
Practical hematology of children's age
Embryonal hemopoiesis
Morfofunktsionalny characteristic of cells of marrow and peripheral blood
Marrow parenchyma cells
Peripheral blood of children of different age
The system of a hemostasis is normal
Etiology and pathogeny of leukoses
Acute leukoses
Acute leukoses - a preleukosis
Possibilities of a predictive assessment of a course of an acute lymphoblastoid leukosis at children
General principles of treatment of an acute leukosis
Chemotherapeutic drugs
Treatment of an acute lymphoblastoid leukosis
Treatment of myeloid forms of an acute leukosis
Infectious complications and symptomatic therapy of an acute leukosis
Consolidation and maintenance therapy of an acute leukosis
Remission and recurrence of an acute leukosis
Inborn leukosis
Macrofollicular lymphoma
Angioimmunoblastny lymphadenopathy
Leukemoid tests
Infectious lymphocytosis
Infectious mononucleosis
Leukemoid tests of different types
Dysfunctions of granulocytes
Histiocytoses - an eosinophilic granuloma
Malignant histiocytosis
Family erythrophagocytal histiocytosis
Accumulation diseases
Nimann's illness — Peak
Hemorrhagic vasculitis (Shenleyn's illness — Genokh)
Mayokki's purpura
Ataxy teleangiectasia
Entsefalotrigeminalny angiomatosis
Kortiko-meningealny diffusion angiomatosis
Cerebroretinal angiomatosis
Hypertrophic gemangiektaziya
Multiple and huge hemangiomas
Elastic fibrodisplaziya
Hereditary coagulopathies
Hemophilia And
Clinic of hemophilia
Treatment of hemophilia
Cristmas disease (Kristmas's illness)
Hereditary deficit of factors of XI, XII, XIII and I
Hereditary deficit of factors of VII, X, V and II
Deficit K-vitaminozavisimykh of factors of coagulation
Syndrome of the disseminated intravascular coagulation
Clinic and diagnosis of the IDCS
Treatment of the IDCS
Idiopathic Werlhof's disease
Clinic and diagnosis of an idiopathic Werlhof's disease
Treatment of an idiopathic Werlhof's disease
Isoimmune Werlhof's disease
Transimmune Werlhof's disease of newborns
Trombogemolitichesky Werlhof's disease (syndrome Moshkovich)
Hereditary Werlhof's diseases
The anemias connected with blood loss
Chronic posthemorrhagic anemia
Iron deficiency anemias
Clinic and diagnosis of an iron deficiency anemia
Treatment of iron deficiency anemias
Sideroakhrestichesky, sideroblastny anemias
Megaloblastny anemias
Foliyevodefitsitny anemia
Hereditary forms of megaloblastny anemias
Hereditary dizeritropoetichesky anemias
The anemias connected with oppression of proliferation of cells of marrow
Hereditary hypoplastic anemias
Hemolitic anemias
Hemolitic anemias - an ovalocytosis, a hereditary stomatocytosis
Acanthocytosis, piknotsitoz
The hereditary hemolitic anemias connected with disturbance of activity of enzymes of erythrocytes
The hereditary hemolitic anemias connected with disturbance of structure or synthesis of hemoglobin
The acquired immune hemolitic anemias
Isoimmune hemolitic anemias
Treatment of a hemolitic illness of newborns
Autoimmune hemolitic anemias
List of references

In structure of incidence of tumors of children leukoses take the leading place: about 1/3 from total number. According to different authors, the frequency of leukoses aged from 0 till 14 flyings makes 2 — 5 on 100 000 people. On statistical data, higher incidence is noted at boys. There are also certain age features of incidence of leukoses: so, at children's age the peak is noted in 3 — 4 years.
In 1845 P. Virchov for the first time described a leukosis at the person, and then in 2 years entered the term "leukaemia", similarly earlier used "leukemia". This name proceeded from one symptom of a disease — existence of a large number of white blood cells in peripheral blood. However further it became clear that this sign is important, but not obligatory at establishment of the diagnosis as reflects only a condition of peripheral blood, without affecting essence of pathological process. Though in foreign literature the term "leukaemia" has the broad use, in the USSR this nosological form can be designated the term "leukosis" offered V. Ellerman in 1921.
Leukosis — a malignant disease of the hemopoietic system, the tumor arising from the hemopoietic cells and affecting first of all marrow.
Leukoses can be divided on acute and chronic. Such division was for the first time offered to J. Friedreich (1857), and is later K. Slavyansky (1867) and reflected temporary distinctions of a disease. At an acute leukosis life expectancy of patients is much less, than at chronic. Now as diagnostic criteria serve pathomorphologic distinctions. At acute leukoses pathological substrate is provided by young unripe cells, at chronic — the bulk is made by mature cells. At children's age acute leukoses over chronic prevail.
Numerous works are devoted to studying of an etiology and pathogeny of acute leukoses. The last 20 years were marked by considerable achievements in this area. Accurately the tumoral essence of leukemic process appears, qualitatively new jump is made in studying of features of cellular kinetics that allowed to revise the theory dominating for many years in hematology about impetuous reproduction of the hemopoietic cells at leukoses. A number of leykozogenny factors is described. However so far are disputable and found insufficiently out an etiology of leukoses of the person what of factors are purely etiological and what — pathogenetic.
The chemicals which are formed in an organism at disbolism can be one of factors inducing a leukosis. In 1937. L. M. Shabad experimentally proved availability of blastomogenic substances in a human body. Further O. M. Raushenbakh (1956) in experiment showed that at introduction mice of low-cancer lines of extracts from bodies of the people who died of a leukosis can cause a leukosis or to promote its emergence. Intermediate products of a triptofanovy exchange, an indole, an indole indican, fatty acids possess powerful leykozogenny action. From the internal causes important in developing of leukoses, a certain part is assigned to sex hormones. However the specific mechanism of action of internal causes remains not clear.
Value of the chemicals getting into a human body from the outside as leykozogenny factors does not raise doubts. In numerous experiments thousands of substances with cancerogenic properties are tested. Polycyclic carbohydrates, an aminoazotsoyedineniya, benzene have cancerogenic effect.
The realization of leykozogenny action of carcinogenic substances is enabled by a mutation or damage of sites of chromosomes. The mutagen effect is inherent not only to one carcinogens, this property also the drugs of a cytostatic row used sometimes as immunodepressants possess. In developing of leukoses the role of the ionizing radiation is big. Sad experience of Hiroshima and Nagasaki showed that at the persons who endured explosion of an atomic bomb, the frequency of developing of a leukosis much more than at the population of other regions of Japan. And more sensitive to action of radiation were children at the age of less than 10 years among which incidence of leukoses was almost twice higher, than aged people have 19 — 60 years.
Action of the ionizing radiation is shown through a certain stage of latency. So, in Japan the peak of incidence was noted in 3 — 7 years after radiation.
There are data that radiation of an embryo leads to development of a leukosis. It is shown that among children whose mothers during pregnancy were exposed to radiation in the diagnostic purposes degree of probability of development of a leukosis makes 1,83. Also increase in cases of leukoses among the children who were exposed to radiation concerning a timomegaliya was noted.
Participation in a leykozogeneza and radioactive materials does not raise doubts. The increased incidence of leukoses at radiologists is noted. Already classical example is development of a leukosis at use with the medical purpose of radioactive phosphorus, a radioiodine and detection at the same time of specific radiation breakdowns of the chromosomal device.
According to E. Mole (1960), mechanisms of a radiation leykozogenez are diverse and they can be summed up as follows.

Radiation affects directly cells. The leukosis develops from the damaged cells owing to:

a) direct action on the genetic mechanism of a cell;
b)         the direct genetic and not genetic effect raising a susceptibility to infections or other exogenous agents.

Radiation works with an indirect way, increasing probability of events, the leukosis not necessarily develops from directly irradiated cells, and owing to:
a) natural instability of processes of cellular reproduction; radiation, killing cells, changes the cellular environment, promotes instability of processes of cellular reproduction; b) radiation increases a susceptibility to infections or exogenous agents, breaking immunological reactions, mechanisms of a detoxication or other ways.


Now does not raise doubts that the ionizing radiation induces an acute lymphoblastoid leukosis at children, adults have a myelosis, an acute miyeloblastny leukosis. It has to dictate a certain constraining tactics a X-ray - and radiological inspections of children, especially preschool period.
At the present stage the virus theory of an origin of leukoses gained wide recognition. Since 50th years, the onkovirusologiya made a new quantum leap, the flow of the researches devoted to studying of leukemic viruses continuously increased. The main stages of these researches were: allocation of a virus of Gross of mice (1951), V. M. Bergolts's works (1956, 1960) about allocation from tissues of the person of the acellular leukemic agent possessing properties of a virus. More than 20 strains of viruses of leukoses of mice are allocated. Data on a virus etiology of leukoses at cats are obtained. Powerful argument was confirmation of the virus nature of leukoses at monkeys. It is established that viruses of leukoses of animals are transmitted in various ways — with milk, urine and saliva. The possibility of horizontal and vertical distribution of leukoses at animals is also proved. Several tens oncogenous viruses are described, for the majority of them existence RNA and lack of DNA is characteristic. Viruses of a leukemic complex belong to the RNA-containing S-type viruses which received the name of onkovirus. They consist of several components — proteins, lipids, nucleic acids, enzymes, among the last the special place belongs to RNA a dependent DNA polymerase, or the return transcriptase (R. P. Gale, And. V. Hoffbrand, 1986).
The proof of the virus nature of leukoses at animals nevertheless is not the proof of a virus etiology of leukoses at the person. And actually, in medical practice there is a number of the powerful facts which are not confirming contageousness (therefore, and the virus nature) leukoses of the person. The researches on studying of ways of transfer of leukoses conducted abroad showed that administration of blood and extracts of bodies of patients with a leukosis to other people did not cause development of a disease. Similar cases of a neperevivayemost of leukoses were noted also at accidental hemotransfusions from patients healthy. The fact of lack of increase of frequency of incidence of leukoses among the medical personnel working with patients is established. It is also necessary to note lack of transplacental transfer of leukoses. Children with inborn leukoses are born from healthy mothers, and, on the contrary, patients with a leukosis give birth to healthy children.
Fig. 8. The scheme of synthesis of DNA on a matrix of RNA of leukemogenic viruses (R. E. Kavetsky, 1975)

But even these facts do not allow to depart from the virus nature of leukoses at the person. So, the peculiar form of an acute leukosis which is found generally among the children's population in Africa — Berkitt's lymphoma — has obviously virus character and is shown by epidemic flashes. It should be noted that though the virus of a leukosis of the person is not allocated, in blood of patients with leukoses the virus-like elements which are seldom found at healthy people are noted and also the structural proteins similar to proteins of monkey onkovirus are found.
A specific place among enzymes of onkovirus is held by a RNA-dependent DNA polymerase, or the return transcriptase. Discovery of this enzyme allowed on new to approach a virus etiology of leukoses that found the reflection in the virusogenetichesky theory of L. A. Zilber (1968). There are several concepts of this theory. There are its basic provisions. In each cell the hereditary information DNK-provirusa similar to information of RNA-containing of the viruses which are in the slowed-down state thanks to cellular repressor is put. Influence of various factors leads to removal of repressive action, activation of oncogenes and further leukemic transformation of a cell.
Also other option when the return transcriptase implements a genome of an oncogenous virus indirectly through DNA is possible, carrying out thereby reverse transcription (fig. 8).
Despite extensive material about a virus etiology of leukoses, this theory needs further development and allocation of more accurate interconnecting links.
In developing of leukoses genetic factors are important. The role of heredity is traced at a chronic lymphoid leukosis of which the big frequency of family cases and high percent (43%) of compliance of a form of a disease at relatives of the first degree is the share. It is known that at children's age the chronic lymphoid leukosis almost does not meet. However the role of hereditary factors is especially important in pediatric practice and not only in cases of an assessment of incidence of leukoses. The retrospective assessment showed that big body weight at the birth is characteristic of the children who got sick with a leukosis, more advanced age of mothers.
The typical example which is found in many managements and confirming value of genetic factors in developing of leukoses are descriptions of leukoses at monozygotic twins. It is possible to provide also data that the probability of development of an acute leukosis in one of monozygotic twins in the presence of an illness at another increases in inverse proportion to age and on the first year approaches 100% (L. Degos> of 1973). Many cases of a "family" leukosis at brothers, sisters and at one of their parents are described. Families in which the leukosis was noted in several generations are known. In the same number of proofs of a role of hereditary factors there are cases of the inborn leukoses developing in the first months, and sometimes and in the first days after the child's birth.
Children have a high risk of developing of leukoses with chromosomal diseases. Most often in this group the Down syndrome meets. As it appeared, such children are surprised a leukosis 20 times more often, in comparison with healthy. And it is noted that at children with a Down syndrome the acute leukosis develops at earlier age,
and, besides, at them the percent of inborn leukoses is high. A certain connection of leukoses with other hereditary diseases of which chromosomal disturbances are characteristic is established: syndromes Cline - a felter, Shereshevsky — Turner, Blum, Fankoni's anemia and others.
Considering a genetic linkage of a Down syndrome and leukosis, searches of other chromosomal disturbances at patients with leukoses were undertaken.
The only form of a leukosis at which the chromosomal device is damaged is the myelosis. In 1960 the changed small chromosome which received the name Philadelphian (Ph' - a chromosome) was found in patients with a myelosis, according to the name of the city where it is found. For a Philadelphian chromosome characteristic disturbance is deletion (loss) of a long shoulder of one of chromosomes of group G. Now it is proved that the Philadelphian chromosome belongs to the 22nd couple of chromosomes, but not to the 21st as was considered for a row of years.
As a result of the cytogenetic researches conducted at patients with an acute leukosis various chromosomal abberation which are in most cases not specific are revealed. The most characteristic change of the chromosomal device is the aneuploidy. As a rule, numerical and structural disturbances are continuous at each specific patient, that is carry clonal type. But chances of change of cellular clones that to some extent contradicts an etiological role of chromosomal disturbances in developing of leukoses. It is necessary to emphasize that the percent of chromosomal disturbances at an acute leukosis is much higher at children, than at adults. Does not raise doubts that chromosomal anomalies exert a certain impact on the course of leynozny process, but their role as leykozogenny factor is doubtful.
Returning to a role of hereditary factors in development of leukoses, it is necessary to consider an immune responsiveness of an organism which is one of important conditions of life activity of an organism, its resistance to various diseases. At the present stage it is allocated several links of immunity participating in protection of an organism, including antineoplastic. Distinguish cellular factors of immunity which carriers is T lymphocytes, and humoral, for which V-cells are responsible. It is established that at hereditary immunodeficiency incidence of leukoses is much higher, than at healthy people. Bruton's illness, an agammaglobulinemia — a state, the protection which are characterized by hereditary insufficiency of humoral mechanisms, on this background the frequency of leukoses increases by 10 000 times. At other hereditary immunodeficiency — Louis's syndromes — Bara, Viskotta — Aldrich, Chediak — Higasi — incidence of leukoses also high. And more lymphoma, in smaller — acute lymphoblastoid leukoses.
In literature the huge actual material reflecting different aspects of developing of leukoses at the person is saved up. However so far there is no causal treatment of leukoses. Undoubtedly, internal causes, chemical mutagens, the ionizing radiation, heredity, viruses play a large role in developing of leukoses at the person. However thin mechanisms of interaction, relationships of cause and effect of these factors still demand further studying.
Now the clonal nature of tumors at some types of a leukosis is proved. These proofs are constructed on a number of the facts. As it was already specified, at acute leukoses at each specific patient chromosomal anomalies are constant, that is have clonal character. It also belongs to a myelosis for which a specific marker is the Philadelphian chromosome. At research of surface markers of V-lymphocytes at chronic lymphoid leukoses uniformity of immunoglobulins in each case is found. All this allows to assume that these leukoses not initially multiple tumors, but the new growths coming from one pathological cell that is have a clonal origin. Along with it the leukemic tumors which are closely connected with system of a hemopoiesis quickly metastasize. It causes systemic lesion of internals.
Many patterns of leukemic process, clinical manifestations, features of a current, sensitivity to therapy follow from the theory of a tumoral progression. The first provisions of a tumoral progression were formulated by L. Foulds (1949) on the basis of studying of a tumor of mammary glands at mice. The concept of a tumoral progression allowed to create the harmonous system explaining many parties of a pathogeny of leukemic process. A big merit in it A. I. Vorobyov (1979) who formulated the basic rules of a tumoral progression of leukoses. We give them below.

  1. The most important feature of a progression of leukoses is oppression of normal sprouts of a hemopoiesis, sometimes everything, is sometimes selective — either granulotsitarny, or platelet, or erythrocyte, but first of all from what the leukosis developed.
  2. The integral property of a progression of leukoses is change of the differentiated cells making a tumor, imperious. All leukoses with this or that frequency pass two stages: monoclonal (high-quality) and polyclonal (malignant).
  3. The general property of blast cells at acute leukoses and imperious crises is spasmodic or gradual loss of fermental specificity: cells become morphologically and tsitokhimichesk nondifferentiable on belonging to this or that number of a hemopoiesis.
  4. Natural stage of development of acute leukoses is change of a form of a kernel and cytoplasm of blast cells: krugloyaderny blasts with narrow cytoplasm replace blasts of irregular shape with increase in the area of a kernel and cytoplasm; often these changes are connected with a palindromia.
  5. In process of a progression leukemic cells find ability to grow out of bodies of a haemo cytopoiesis: proliferata from tumor cells appear in skin, kidneys, a meninx, etc. At long current acute leukoses and blast crises this phenomenon becomes almost obligatory and leads to disturbance of normal functions of an organism. Innidiation in fabrics and bodies represents a new stage of a progression and happens independently from each other. So, the infiltration of a meninx at an acute lymphoblastoid leukosis represents earlier stage, than an infiltration of testicles, and the last — earlier stage, than an infiltration of skin or kidneys.
  6. In the conditions of modern cytostatic therapy the progression is reflected by spasmodic or gradual leaving of a tumor from under control of cytostatic influence (specific complexes: chemical, beam, hormonal).
  7. Increase of process is characterized by an exit of blast elements in blood (quite often they are absent when diagnosing a leukosis or before recurrence), transition from an aleukemic picture of blood to leukemic.

The knowledge of the main patterns of a tumoral progression of leukoses gives valuable information to the doctor and helps to be guided with features of disease at each child. Each stage of a progression is the qualitatively new step of pathological process demanding first of all change of therapeutic tactics. Cases of small efficiency of therapy at the acute leukosis which is followed by a hyperleukocytosis are clear: this hematologic sign testifies to a final stage of a progression. Emergence of symptoms of a neuroleukosis or infiltrates on skin at positive dynamics of the main klinikogematologichesky symptoms, is not an occasion to the pessimistic forecast and change of cytostatic drugs. The changed picture demonstrates only emergence of the new isolated centers in a meninx or skin, each of which demands the treatment against already carried out therapy.
The main defect at all types of a leukosis is disturbance of cellular differentiation (maturing) and proliferation (reproduction). Studying of cellular kinetics at leukoses became possible by means of an autoradiografiya method. Use of radioactive nuclides — 3H-thymidine, the predecessor of DNA and 8H-uridine joining mainly in RNA — helped to solve a number of questions of a cytopathogeny of leukoses. For many years in hematology the thought of impetuous reproduction of unripe pathological cells dominated. Now this theory is revised.
It is proved that at acute leukoses tumoral cellular weight is heterogeneous on the proliferative potentialities. Leukemic population is divided into two subpopulations: the pool of tumor cells proliferating and not proliferating at present. The proliferating pool, that is cells which are in a mitotic cycle and capable to division makes insignificant part of leukemic population — 6 — 10%. The main weight is provided by the leukemic cells which are out of a mitotic cycle in a phase of "rest" Go and not capable to division. Therefore, impetuous reproduction of cells at an acute leukosis does not happen. Important feature of the based tumor cells are considerable lengthening of their life, in comparison with normal cells, and a possibility of an uncontrollable exit from a phase of "rest" in a mitotic cycle that is a factor of maintenance of pathological process (M. Andreeff, 1986). Speaking about the general decrease in proliferative potential of all leukemic population, there is a question: what to explain the systemic lesion of fabrics which is the leading clinical sign of an acute leukosis with? Mathematical calculations showed that one sharing pathological cell of which within 3 — 4 months through 40 consecutive divisions the tumor weighing about 1 kg (1012 cells) is formed suffices, in general it gives a clinical picture of the developed stage of an acute leukosis (Page G. Craddok, 1962).
In modern literature on the basis of kinetic researches the theory of pathogenetic mechanisms of development of an acute leukosis is hypothetically formulated (G. I. Kozinets, 1973; L. G. Kovalyova, 1975; A. I. Vorobyov, 1975; E. B. Vladimirskaya, 1975). Etiological leukemic factors lead to formation of the tumor cell which lost ability to differentiation, but kept ability to proliferation. In an initial stage of a disease there is a reproduction of a leukemic clone and accumulation of pathological cells, it finally demonstrates a clinical picture. Formation of considerable mass of tumor cells causes decrease in their proliferation. At the same time there is a braking of a normal haemo cytopoiesis. In this case it is noted as simple replacement of healthy haemocytes by a leukemic tumor, and oppression by their humoral inhibitors. Increase of mass of leukemic cells even more strengthens braking of a normal haemo cytopoiesis by the principle of feedback.
Clinical trials at a myelosis showed that proliferative activity of cells is not identical and fluctuates depending on a disease stage. In a quiet stage of disturbances of proliferation it is not observed, it proceeds with the same intensity, as is normal. During blast crisis of a myelosis proliferative activity decreases, reminding that at an acute leukosis.
Autoradiografichesky researches of synthesis and transport of RNA at leukoses also revealed a number of features. It is known that all RNA main types are synthesized in a cellular kernel in the form of high-molecular predecessors. Then in the course of maturing the most part of a molecule is chipped off and only the informative part of molecule RNA is transferred to cytoplasm. Thus, at transport of RNA transfer of hereditary information from DNA matrix from a kernel in cytoplasm of cells to places of synthesis of protein is carried out. By means of this mechanism control over implementation of the hereditary program of a cell, that is over proliferation and differentiation is exercised. Now it is proved that at acute and chronic leukoses RNA transport from a kernel in cytoplasm is suppressed. Perhaps, this braking is one of the mechanisms causing disturbance of maturing of tumor cells. And these disturbances in cells are expressed more at an acute leukosis, than at a myelosis and a chronic lymphoid leukosis.
We do not provide the developed classification of leukoses as at children's age from all types of chronic leukoses only the myeloleukemia meets in this section. Classification of acute leukoses will be given in appropriate section.

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