Leukemia

Leukemia is a tumor of the hematopoietic system that primarily affects the

hematopoietic cells of the bone marrow. At the same time, peripheral blood and
other tissues, especially tissues of the reticuloendothelial system, are again
involved in the process.
The incidence of malignant neoplasms in the hematopoietic and lymphatic
tissue in the population of Russia is 6.5–8.3 per 100,000 population.
Etiology. The cause of leukemia is not known. At the present stage of our
knowledge about the origin of leukemia, it is more correct (more correct) to talk
about risk factors.
Risk factors include ionizing radiation, exposure to chemicals, viral
infection, aggravated heredity.
Ionizing radiation. Several options should be distinguished: irradiation with
relatively high doses, irradiation with low doses during X-ray examination,
background irradiation.
Irradiation with relatively high doses undoubtedly causes leukemia in
humans. This is proved by the high incidence of leukemia among radiologists in
previous years, when proper precautions were not taken, in patients with
ankylosing spondylitis who received radiation therapy of the spine, in people who
survived atomic explosions (Hiroshima, Nagasaki, Chernobyl).
The leukozogenic effect of low-dose radiation during X-ray examination is
not recognized by all scientists, the research results are contradictory. For example,
some researchers see a link between the diagnosis of low-dose X-rays before the
baby is born and subsequent leukemia. In these children, in the first 10 years of
life, the number of malignant diseases is 2 times higher. On the other hand,
exposure of pregnant women or parents to pre-conception from the more massive
dosages in Hiroshima and Nagasaki did not increase the incidence of leukemia in
offspring. Thus, there is currently no consensus on the danger of low doses of
diagnostic X-ray radiation.
It is assumed that background radiation causes 1/8 of all leukemias in the
age group from 15 to 39 years.
Among the chemicals that can inhibit bone marrow hematopoiesis, we note
benzene, oil distillation products, cytostatic drugs, and other groups of drugs.
There is evidence of such side effects in butadione and chloramphenicol.
Viral infection. The viral nature of leukemia in chickens, mice, rats, cats and
other animals has been established. In relation to humans, the viral hypothesis
remains unproven.
In favor of the viral theory, cases are cited when non-blooded relatives fall ill in
families. The easiest way to explain these cases is in terms of virus infection. But
we must not forget about the influence of other mutagenic factors that could act in
the house where these people lived (radiation and chemical mutagens).
The role of heredity. It can be recognized only in a very small number of
patients. Cases when blood relatives are ill with leukemia are extremely rare.
 A somewhat different question is about those hereditary diseases that in
themselves are not related to tumor processes, but predispose to the development
of leukemia. Such diseases include, first of all, hereditary diseases associated with
ruptures, anomalies, and nondisjunction of chromosomes. These hereditary
diseases include:
• Hereditary diseases associated with ruptures, abnormalities or nondisjunction
of chromosomes: Down's disease, Blum's syndrome, Klinefelter's syndrome,
Shereshevsky-Turner syndrome, etc. Against the background of these diseases, the
incidence of leukemia increases. In Down's syndrome, for example, it increases 18
to 20 times.
• Genetic diseases with defects in immunity - Louis-Barr's disease, Viskot
Aldrig's syndrome, Bruton's disease, etc. In such cases, not the leukemias
themselves are inherited, but genetic defects of those cells from which the tumor
develops and suppression of immune control over it.
• Acquired immunity disorders also contribute to the development of leukemia.
The mechanism is inhibition of immune control over the appearance of tumor
cells.
Thus, most likely leukemia is a multifactorial disease, both external and internal
factors play a role in its occurrence, and all of them cause not leukemia itself, but
increased mutability in the tissue, from which a tumor may (but not necessarily!)
Develop in the future.

General pathogenesis and cellular kinetics of leukemia

The schematic sequence of events is as follows.
1. The effect of a mutagenic factor on a hematopoietic cell. Mutagenic factors
can be one, several or all of the listed risk factors.
2. Increasing the mutability of normal hematopoietic cells
3. A specific mutation appears in one or more of them, which leads to tumor
transformation of the mutant cell.
4. A mutant cell acquires new properties, in particular the ability to unlimited
proliferation, undergoes new mutations, and gradually increases its malignancy
(tumor progression). Among the acquired new properties of a cell - a mutant
5. Maturation of the leukemic cell is suspended at the stage where the mutation
occurred, but the ability to proliferate remains
6. Due to the cessation of maturation, normal cells are not formed. Instead,
leukemia cells accumulate in the bone marrow, which replace and displace the
remaining normal cells.
7. There is a lack of formation of normal cells and leukopenia, anemia,
thrombocytopenia develop in the peripheral blood.
8. Leukemic cells acquire the ability to metastasize. They penetrate into other
organs and tissues, proliferate in them. Leukemic proliferation is especially
pronounced in the tissues of the reticuloendothelial system. Hence the enlargement
of the liver, spleen, lymph nodes (i.e. hepato- and splenomegaly and
lymphadenopathy). From the features of the pathogenesis, the general
symptomatology of leukemia occurs.
 General symptoms of leukemia
The general symptomatology of leukemia consists of several syndromes that can
be of varying severity. Among them are anemic and hemorrhagic syndromes, a
tendency to infectious diseases, hyperplastic syndrome, intoxication.
Anemic and hemorrhagic syndromes, as well as a tendency to infections, are due to
the fact that a clone of leukemic cells displaces and suppresses all hematopoietic
growths, respectively. The production of affected shoots is sharply limited. The loss of
red blood cells, hemoglobin and platelets leads to the development of anemia and
increased bleeding. A decrease in resistance to infections is induced by a deficiency of
granulocytes, monocytes and lymphocytes. Hence the loss of specific (immunity) and
nonspecific (phagocytosis) defense mechanisms. Moreover, infections can be one of
the causes of death of such patients.
Hyperplastic syndrome is associated with metastasis of leukemic cells to other
organs, reproduction and enlargement of this organ. The most susceptible are the liver
(hepatomegaly), spleen (splenomegaly), lymph nodes (lymphadenopathy), followed
by skin (skin infiltrates), meninges (neuroleukemia), kidneys, myocardium, lungs.

General concepts of leukemia

Leukemias are traditionally divided into acute and chronic. This division is
based on the degree of maturity of the cells that make up the tumor substrate.
In acute leukemia, the tumor substrate is blast cells. Acute leukemias are
subdivided into lymphoblastic (the substrate of the tumor is lymphoblasts) and
myeloblastic (the substrate of the tumor is represented by myeloblasts)
In acute leukemia, complete (total) or incomplete (subtotal) replacement of
normal hematopoietic tissue with immature blast forms is observed. The severity is
due to the absence or deficiency of mature blood cells and the loss of the functions
that these cells are supposed to perform.
In chronic leukemia, the substrate of the tumor is maturing and mature
cells. In this case, leukemic cells are characterized by a lesser degree of anaplasia.
Their maturation is suspended at later stages of development, and tumor cells in
terms of maturity are nevertheless closer to mature, normal cells. Hence their
ability to perform some of the functions of mature cells, although not fully. For
example, in chronic myeloid leukemia, neutrophils partially retain the function of
phagocytosis, and in acute myelogenous leukemia, neutrophils completely lose this
function, because there are no neurophils as such, but their early precursors are
myeloblasts.
Thus, in acute leukemia, a more significant inhibition of hematopoiesis
occurs, differentiation is suspended at the blast stage. Nevertheless, it cannot be
argued that chronic leukemia is easier, and patients without treatment live for
several months and even years, while acute leukemia without treatment leads to
death within a few weeks or months, and is more severe than chronic leukemia. In
fact, one can practically find both the rapid rapid dynamics of chronic leukemia,
and the long course of acute (especially against the background of modern
therapy). The division of leukemia into acute and chronic is based only on the
 degree of maturity of tumor cells, and not on the duration and severity of the
disease.
Acute and chronic leukemia is characterized by tumor progression. This is
a constant increase in malignant properties. Tumor progression consists, first, in
the deepening of cellular atypism - the leukemic cell acquires more and more
morphological, structural differences from its normal counterpart. Secondly, the
ability to differentiate and perform the assigned functions becomes less and less.
Thirdly, the cell is more and more autonomous, multiplies, not recognizing the
regulatory influences of the organism.
The mechanism of tumor progression is repeated multiple mutations in
leukemic cells. New clones of cells may be insensitive to drugs and the course of
leukemia becomes more severe, progresses
Is it possible to transform chronic leukemia into acute and vice versa?
Chronic leukemia can transform into acute due to the appearance of more
malignant clones that have the properties of blast cells (in accordance with the law
of tumor progression). But acute leukemia can never transform into chronic.
Leukemic, subleukemic, aleukemic variants of leukemia. If, along with an
increase in the total number of leukocytes in the blood, a large number of pathological
cells appear, then such leukemia flows according to the leukemic variant. In
subleukemic leukemia, regardless of the total number of leukocytes, the content of
abnormal cells is small and inferior to the number of normal blood cells. With
aleukemic variant, there are no abnormal cells in the blood. Leukemia with a low
number of leukocytes in 1 liter of blood, regardless of their quality, is called
leukopenic. The absence of pathological cells in the blood with the aleukemic variant
is explained by the fact that all pathological cell forms are concentrated in the bone
marrow, they do not even enter the peripheral blood, therefore the diagnosis should be
based on the study of the bone marrow.

Features of the morphology of leukemic cells

• The size is increased by 2-3 times or reduced to the size of a lymphocyte,
anisocytosis.
• The nucleus is enlarged, the contours are deformed, the chromatin is rough, its
amount is increased, vacuolization and segmentation of the nucleus.
• Nucleoles in the amount of up to 8 or more, the size is increased to 1/3 - 1/2 of
the nucleus, the larger the nucleoles, the more malignant the process.
• The cytoplasm is sharply basophilic, vacuolated, sometimes contains azurophilic
granularity and Auer's little bodies - formations in the form of rods resembling
crystals. Azurophilic granularity and Auer's little bodies are not found in all forms.
More often found in acute myeloid leukemia.

Cytochemical features of leukemic cells

Cytochemical studies are the determination of certain substances in blood cells. At
the same time, their number or their activity (if these are enzymes) is determined.
 Myeloperoxidase activity (Figure 1)

• Myeloperoxidase is present in granulocytes and monocytes. This is a kind of

marker of the myeloid series. If characteristic brown granules of myeloperoxidase
are found in the cell under study, then this cell belongs to the myeloid series
(neutrophil or monocyte). All lymphocytes give a strictly negative reaction. It is
used for the differential diagnosis of acute myeloid leukemia and acute
lymphocytic leukemia. In acute myeloid leukemia, the activity of myeloperoxidase
is high, in acute lymphocytic leukemia, the activity is absent (see Fig. 1).

Lipid content (Figure 2)

• Normally, lipid granules are found in granulocytes and in smaller amounts in

monocytes. In acute myeloid leukemia, the reaction is positive, in acute
lymphocytic leukemia, lipids are absent (see Fig. 2).
 PIC response of neutrophils (Figure 3)

PIC response of lymphocytes Figure 4

• Content of glycogen (see fig. 3 and fig. 4). It is normally found in mature
granulocytes (PIC reaction). In acute myeloid leukemia, it is absent or diffusely
diffused in the cytoplasm. Chronic myeloid leukemia gives a diffuse location of
glycogen with a halving of its amount compared to the norm. In acute and chronic
lymphocytic leukemia, the PIC reaction is positive with the location of glycogen in
the form of granules.
 Acid Phosphatase Activity (Figure 5)

• Activity of acid phosphatase (see Figure 5). It is a hydrolytic enzyme that

breaks down monophosphoric compounds in an acidic medium (pH = 2.5-5.0). It is
normally found in all leukocytes, but maximally in neutrophilic myelocytes. The
activity of acid phosphatase increases with: a) acute myeloid leukemia, especially
in the promyelocytic variant; b) acute monoblastic leukemia.

Nonspecific esterase activity (Figure 6)

• Activity of nonspecific esterase (see Fig. 6). It is a hydrolytic enzyme that
breaks down the short chain carbohydrate esters of carbolic acids. Normally, the
activity of nonspecific esterases was detected in all leukocytes. Activity increases
in acute monoblastic leukemia and, to a lesser extent, in acute myeloid leukemia
(especially sharply in the promyelocytic variant).
• Activity of alkaline phosphatase. Alkaline phosphatase hydrolyzes phosphoric
esters in an alkaline environment. Normally contained in granulocytes. The activity
of the enzyme first appears at the stage of metamyelocyte, then, as differentiation
progresses, it increases. The maximum activity is noted in segmented neutrophils,
it decreases with aging of the cell. Decreased alkaline phosphatase activity is
characteristic of chronic myeloid leukemia. Enzyme hyperactivity is observed
under conditions of erythremia, leukemoid reactions, suppurative processes. An
increase in the activity of alkaline phosphatase in acute lymphocytic leukemia is a
favorable sign, because these patients are more likely to be in remission.

Cytogenetic data with various forms of leukemia

The karyotype of a healthy person contains somatic chromosomes (autosomes -
44A) and sex (gonosomes - X and Y). Thus, the genotype formula for men is 44A
+ XY, for women 44A + XX.
In chronic myeloid leukemia, chromosome number 21 or number 22 is smaller
due to the loss of almost half of the long arm. This altered chromosome is called
"Philadelphia" and is designated Ph '. In chronic myeloid leukemia, Ph 'is always
found and is its marker (see Fig. 7).

Cell karyotype of a patient with chronic myeloid leukemia Figure 7

In acute lymphocytic leukemia, aneuploidy, polyploidy and changes in the

structure of chromosomes are observed. Aneuploidy is a change in the number of
chromosomes that is not a multiple of the basic number. For example: 41 to 65.
 Acute leukemia
Acute leukemias (AL) are quite stereotyped from the standpoint of clinical
picture and morphology.
The morphological substrate of the tumor is made up of blast cells, the
proliferation of which is formed in the bone marrow. Subsequently, leukemic blast
cells with their large light nuclei metastasize to lymph nodes, spleen, liver tissue
and other organs and tissues.
The classification is based on the cytochemical characteristics and appearance of
pathological cells, as well as their immunophenotype and genetic characteristics.
Includes the following nosological units of acute leukemia:
• Lymphoblastic - ALL.
• Myeloblastic - AML.
• Monoblastic - АMnL.
• Myelomonoblastic - АMMnL.
• Promyelocytic
• Erythromyelosis - AEM.
• Nondifferentiable - ANL.
There is another, more detailed classification. This classification was proposed
by hematologists in France, England and America and therefore has the name
FAB. The FAB classification is based on the same morphological and
cytochemical criteria, but it has more variations.
In practical terms, it is not the option that is more important, but the cytological
form of acute leukemia. Based on the characteristics of cytostatic therapy, for
practical purposes, hematologists divide all acute leukemias into lymphoblastic and
non-lymphoblastic (all other forms of acute leukemia). With lymphoblastic acute
leukemia, a more sparing cytostatic therapy is performed, and the number of
recovered from leukemia (especially children) reaches 85–90%. In non-
lymphoblastic acute leukemia, more intensive polychemotherapy with repeated
courses is used and, despite this, recovery is achieved only in 50–55% of cases.
Blood and bone marrow picture in acute leukemia.
• Red blood cells are reduced to 1.00-1.50x1012 / l as a result of displacement of
the erythroid germ by leukemic cells. The concentration of hemoglobin decreases
to 20-60 g / l due to suppression of the erythroid germ, non-assimilation of vitamin
B12 and folic acid and hemolysis of erythrocytes. Anemia is normo- or
hyperchromic, less often - hypochromic.
• Thrombocytopenia due to suppression and displacement of the megakaryocytic
lineage by leukemic cells.
• Total blood leukocytes range from 1.00 - 2.00 - 3.00x109 / l to 100.00 - 200.00 -
300.00x109 / l. Moreover, leukopenic forms account for up to 50% of cases.
• Leukocyte formula - in typical cases, blast cells appear in the blood up to 95-
99% and only 1-5% are in mature cells (this is the production of preserved foci of
normal hematopoiesis). The phenomenon is called "leukemic gap" - there are no
maturing forms between blast cells and mature cells.
• Blast cells predominate in the bone marrow more than 5% to total blastosis,
erythroid and megakaryocytic sprouts are sharply narrowed.
 • Cytochemical blood test is used for differential diagnosis of individual forms of
acute leukemia.
• Immunofluorescent examination of blood and bone marrow is carried out in
addition to cytochemical in order to distinguish between individual forms of acute
leukemia.
• Cytogenetic research is assigned for the same purpose.

Chronic leukemia
Chronic leukemias are divided into myeloproliferative and lymphoproliferative
tumors.

Myeloproliferative tumors
This collective name refers to a group of chronic leukemias that arise at the level
of early precursors of myelopoiesis.
The offspring of myelopoiesis includes granulocytes, monocytes,
erythrokaryocytes, and megakaryocytes. All these offspring may belong to a tumor
clone. But in most cases, unlimited proliferation concerns mainly one or two shoots. If
there is a 3-fold damage to proliferation, then they speak of panmyelosis.
The main diseases of this group are chronic myeloid leukemia, erythremia,
chronic monocytic leukemia, and subleukemic leukemia.

Chronic myeloid leukemia

In chronic myeloid leukemia, inhibition of differentiation is established at the
level of maturing granulocytes. Therefore, the tumor substrate is represented by
mature neutrophils, metamyelocytes, myelocytes, promyelocytes, myeloblasts (in
small numbers).
Blood and bone marrow picture.
• Red blood. Its changes are not typical. Often at the onset of the disease, red
blood retains a normal composition, only later anemia appears (with the
progression of the process) due to a decrease in the amount of hemoglobin and
erythrocytes. Moreover, many authors believe that the decrease in hemoglobin and
erythrocytes occurs due to the displacement of the erythroid germ by the tumor,
spleen hyperactivity and hemolysis as a result of shortening the life of
erythrocytes.
• Platelets. The amount in 1 liter of blood is within the normal range or increased.
Thrombocytopenia can be in the terminal stage or as a result of chemotherapy
treatment.
• Total blood leukocytes. As a rule, they are increased to 200.00 - 400.00 x 10 9 / l,
sometimes up to 800.00 - 1000, - x 109 / l .
• Leukocyte formula. There is a degenerative left shift due to the appearance of
promyelocytes, myelocytes and metamyelocytes, as well as eosinophilic-basophilic
association, i.e. eosiniphilia and basophilia are absolute and relative.
• In the bone marrow, the number of myelokaryocytes is increased due to an
increase in the percentage of promyelocytes, myelocytes and metamyelocytes. In
addition, the megakaryocytic lineage expands.
• Cytochemical studies. Increased myeloperoxidase activity and lipid content. The
glycogen level is halved from the norm, the activity of alkaline phosphatase is
reduced.
• Cytogenetic studies. The Ph ‘- chromosome is revealed. It is a marker of
leukemic cells in chronic myeloid leukemia.
Terminal stage of chronic myeloid leukemia. The terminal stage of chronic
myeloid leukemia is clinically manifested by a change in the whole picture of the
disease: the spleen grows rapidly (a high percentage of blast cells is found during
puncture), the temperature rises for no reason, severe bone pains appear, dense foci
of sarcoma growth in the skin and lymph nodes. New manifestations of the disease
are associated with the emergence of new mutant subclones within the main tumor
clone. These new subclones supersede the original clone. Sometimes the disease
debuts from the terminal stage.
Blood picture.
• Red blood. Deepening of anemia is characteristic.
• Platelets gradually decrease until thrombocytopenia occurs.
• Total leukocytes in some cases decrease to profound leukopenia (but not
always).
• Leukocyte formula - options are possible: a) "blast crisis" - an increase in the
content of blast cells in the bone marrow and in the blood. The picture resembles
acute leukemia with the phenomenon of "leukemic failure"; b) a decrease in the
percentage of rod and segmented neutrophils, but an increase in the percentage of
myeloblasts, promyelocytes and myelocytes. The absolute and relative content of
basophils sharply increases.

Erythremia
Erythremia is chronic myeloid leukemia with damage to 4 germs: granulocytic,
monocytic, erythroid, megakaryocytic. The defeat of the sprouts is of the type of
hyperplasia. The most damaged erythroid sprout.
Synonyms: a) polycythemia vera; b) Vakez disease
Blood picture: pancytosis, i.e. a simultaneous increase in the cellularity of red and
white blood - erythrocytosis, reticulocytosis, thrombocytosis and leukocytosis.
• Red blood - hemoglobin increased to 180-220 g / l, erythrocytes up to 6.00 -
8.00x1012 / l, increased hematocrit, blood viscosity. ESR sharply decreases.
• Platelets - an increase over 1000.00x109 / l. Simultaneously vascular
complications.
• Total leukocytes - increased to 9.00 - 15.00x109 / l. Sometimes up to 50.00x109 /
l.
• Leukoformula - a) absolute and relative neutrophilia; b) An increase in the
percentage of stab neutrophils; c) relative eosinophilia.
• Bone marrow - punctate is highly diluted with blood. There is a decrease in the
leukoerythroblastic ratio due to hyperplasia of the erythroid series, an increase in
absolute megakaryocytes (when counted in the chamber).
• Bone trepanobiopsy - a decrease in the volume of adipose tissue, panmyelosis
(hyperplasia of all three sprouts), an increase in the size of megakaryocytes, an
increase in the process of lacing of platelets.

Chronic monocytic leukemia

Chronic monocytic leukemia is a tumor process with a significant increase in the
content of monocytic cells in the blood and in the bone marrow with normal or
high leukocytosis.
The course is long-term, benign.
Manifestations: persistent absolute and relative (over 30-40%) monocytosis in the
blood, an increased percentage of monocytes in the bone marrow (over 30-40%),
leukocytosis up to 15.00 - 20.00x10 9 / l, the appearance of lysozyme (muromidase)
in blood and urine.
In the terminal stage, a blast crisis develops as an acute monocytic leukemia.

Lymphoproliferative tumors
Lymphoproliferative tumors are a group of tumors that originate from maturing
and mature T and B lymphocytes.
The main nosological forms:
• Chronic lymphocytic leukemia (CLL).
• Paraproteinemic hemoblastosis: a) multiple myeloma; b) heavy chain disease; c)
Waldenstrom's disease.
• Extra bone marrow lymphocytic neoplasms.
• Cutaneous lymphocytic tumors.
Chronic lymphocytic leukemia
Chronic lymphocytic leukemia is a tumor of the hematopoietic system, the
substrate of which is mainly morphologically mature lymphocytes. In addition,
maturing prolymphocytes and lymphocytes may be present in the tumor.
Features of leukemic lymphocytes.
• Morphological (external) similarity with the lymphocytes of a healthy person. It
is almost impossible to distinguish normal lymphocytes from leukemic ones by
external signs.
• Functional inferiority of leukemic lymphocytes. It manifests itself in the
following: a) inability to produce antibodies; b) the formation of antibodies
(immunoglobulins) with perverse properties. The consequences are frequent
microbial complications and immunological conflicts. Example: autoimmune
hemolytic anemia that can accompany chronic lymphatic leukemia.
• The inability of leukemic lymphocytes to react with blast transformation, whereas
in a healthy person, lymphocytes have this property. Normally, the blast
transformation reaction translates B-lymphocytes into plasma cells, which form
immunoglobulins and form a humoral immune response. In chronic lymphocytic
leukemia, plasma cells are not formed at all and the humoral link of the immune
defense falls out.
• Leukemic cells are “long-lived,” while healthy lymphocytes have a limited
lifespan.
Progression and severity of chronic lymphocytic leukemia. Determined by clinical
and hematological criteria.
The clinical criteria include, first of all, the proliferation of lymph nodes and their
spread, the infiltration of lymphoid elements of various organs, primarily the
spleen and liver. Hence hepato- and splenomegaly. In addition, there are various
complications associated with impaired antibody formation and perverted
properties of immunoglobulins. These are various microbial complications and
immunological conflicts.
Hematological criteria (picture of blood and bone marrow).
• Red blood. At the beginning of the disease, little changes, in the future
anemia develops. The mechanism of anemia: a) suppression and displacement of
the erythroid germ; b) the formation of antibodies AT against own erythrocytes.
• Platelets - a tendency to decrease. Thrombocytopenia does not appear
immediately, but in some cases it can occur very early. The mechanism of
thrombocytopenia: a) suppression and displacement of the megakaryocytic germ;
b) autoimmune destruction of platelets and megakaryocytes.
• Total leukocytes - more often increase to 30.0-200.0x109 / l. In more rare cases,
leukopenia develops up to 1.5-3.0x109 / l.
• Leukocyte formula - absolute and relative lymphocytosis is traced. Relative
lymphocytosis up to 80-99%. Among lymphocytes, there may be prolymphocytes
(from a few to 5-10%) and lymphoblasts. The appearance or increase of
prolymphocytes and lymphoblasts indicates a heavier process. Leukemic
lymphocytes are quite fragile and are often destroyed during smear preparation.
Such destroyed cells are called Botkin-Gumprecht shadows. The appearance of
Botkin-Gumprecht shadows in the smear is a characteristic hematological sign of
chronic lymphocytic leukemia.
• Blood cytochemistry - an increase in the level of glycogen in leukemic
lymphocytes (granules).
• Bone marrow - a) an increase in the volume of the lymphocytic lineage. In the
myelogram, their percentage exceeds 30%, in severe cases - over 50 - 60 - 95%; b)
narrowing of germs: granulocytic, erythroid, monocytic, megakaryocytic.

Paraproteinemic hemoblastosis
Paraproteinemic hemoblastoses are tumors of the hematopoietic system, the
substrate of which is malignant B lymphocytes and plasma cells.
Plasma cells are normally derived from B lymphocytes, formed from B
lymphocytes as a result of the blast transformation reaction. In the process of
maturation, the stages of plasmablast, proplasmacyte and plasmacyte pass. Plasma
cells are responsible for antibody production of immunocompetent
immunoglobulins and the formation of a humoral response. The role of plasma
cells in the synthesis of immunoglobulins is enormous. They are compared to the
"unicellular gland". An increase in the concentration of gamma globulins in the
blood serum always goes hand in hand with an increase in the proliferation of
plasma cells. Normally, the number of plasma cells in the bone marrow (in
myelogram) is 0.1 - 3.0%. An increase in their content is observed in chronic
infections (syphilis, tuberculosis), tumors, liver cirrhosis, collagenoses, etc.
Normally, an immunoglobulin molecule consists of two (2) heavy polypeptide
chains (H-chains) with a molecular weight of ≈ 50,000 D; b) two (2) light
polypeptide chains (L-chains) with a molecular weight of ≈ 20,000 D. These
chains are interconnected by disulfide bonds. H-chains can be: μ γ α ε δ. Hence the
types of immunoglobulins - Ig: M G A E D. L-chains can be only 2 (two) classes: χ
and λ. Normally, the entire set of human plasma cells is heterogeneous and is
divided into many clones. A clone is the offspring of one cell - the ancestor of the
clone. All plasmocytes-members of one (first) clone synthesize a strictly defined
immunoglobulin with a strictly defined set of H and L chains. Plasma cells of
another (second) clone synthesize another immunoglobulin with their own set of H
and L chains. Plasmacytes of the third clone form the 3rd (third) immunoglobulin
with only its characteristic composition in H- and L-chains. Thus, in a healthy
organism, various clones of plasma cells simultaneously synthesize up to 10,000
types of immunoglobulins, which are characterized by their own combinations of
heavy H and light L chains. But each individual clone synthesizes a strictly defined
type of immunoglobulins, i.e. a completely identical monoclonal product. In
paraproteinemic hemoblastosis, one of the clones of plasma cells grows and
displaces the remaining clones, the production of which is sharply suppressed. The
cells-members of the expanded clone continue to synthesize their own
immunoglobulin (the so-called monoclonal immunoglobulin, i.e. characteristic of
this clone). Thus, all serum immunoglobulins of a patient are represented by a
single variant of immunoglobulin molecules, for example Ig G with light chains.
Monoclonal immunoglobulin, which is produced in paraproteismic hematological
malignancies, is called paraprotein.
There are several options for paraproteins. In a number of patients, paraproteins
do not bear gross structural defects and correspond to normal immunoglobulins of
one clone. In such patients, the pathology consists in the fact that plasma cells
synthesize one variant of immunoglobulins instead of the conventional 10,000, as
is the case in the norm. In other cases, truly abnormal paraproteins with various
structural defects are formed: a) only free light L-chains without H-chains are
synthesized (such paraproteins are called the Bens-Jones protein); b) only half of
the molecule is formed, consisting of one L-chain and one H-chain without
disulfide bonds; c) the formation and secretion of only fragments of H-chains of
various classes of immunoglobulins.
Classification of paraproteinemic hemoblastoses.
• Multiple myeloma (multiple myeloma). The tumor substrate consists of plasma
cells. The tumor produces several types of paraproteins, depending on this,
multiple myeloma is subdivided into several immunochemical variants.
• Waldstrom's macroglobulinemia. The tumor substrate is represented by
lymphocytes, plasma cells and their maturing forms. Tumor cells synthesize
immunoglobulins M.
• Heavy chain disease. The tumor consists of lymphocytes and plasma cells of
varying degrees of maturity with a significant admixture of eosinophils and
reticular cells of the bone marrow stroma. Tumor cells form fragments of H-chains
of various classes of immunoglobulins. Depending on this, 4 types of heavy chain
disease are distinguished: γ (G), α (A), μ (M), δ (D) - by the name of the H-chains
of the corresponding class of immunoglobulins.
• Benign paraproteinemia. In these cases, paraprotein is found in the blood of
practically healthy people.

Multiple myeloma
Multiple myeloma is a tumor of hematopoietic tissue, the substrate of
which is plasma cells.
The entire mass of plasma cells in multiple myeloma is the offspring of only
one cell - the precursor, which underwent tumor transformation, but retained the
ability to multiply and produce paraprotein (or paraimmunoglobulin G).
Immunochemical variants are variants of multiple myeloma, depending on
the class and type of secreted paraimmunoglobulins. Most often (approximately 1:
1000) only L-chains without H-chains are formed. This immunochemical variant is
called Bence Jones myeloma or light chain disease.
Blood and bone marrow picture.
• Red blood. At the onset of the disease, changes in red blood may be absent,
but with the generalization of the process, normochromic anemia develops and
progresses. Sometimes this symptom is the initial and basic one in the clinical
picture of the disease.
• Platelets. Their content in the peripheral blood decreases only in the later stages
of the disease.
• The total number of leukocytes. Leukopenia with a nuclear shift to the left,
much less often leukocytosis up to 10, -30.0x109 / l.
• Leukocyte formula. Rejuvenation of white blood is sometimes observed in
combination with the simultaneous presence of plasma cells.
• Bone marrow. Light microscopy of the bone marrow is a mandatory (but
not the main) examination for suspected multiple myeloma. In the bone marrow,
tumor myeloma cells are determined in an amount of more than 15% of all
punctate cells. These cells repeat the morphological characteristics of plasma cells
and resemble proplasmacytes. The diagnosis of multiple myeloma is reliable with a
significant number of myeloma cells, the appearance of atypical multinucleated
plasma cells, the detection of plasmablasts and multicellular colonies.
A biochemical blood test reveals hyperproteinemia up to 10-12-30 g / l.
An electrophoretic study of blood plasma proteins is performed on a serum
electrophoretogram. A narrow band appears in the zone of migration of γ- and α2-
globulins. In this case, the concentration of the γ-fraction decreases. This band is
called the M-gradient and is formed due to the migration of paraprotein G. In an
electrophoretic study, the immunochemical variant of the disease is also
determined.
Determination of Bens-Jones protein in urine. Bens-Jones protein is found in
urine when myeloma cells are able to synthesize and secrete only light polypeptide
L-chains. This immunochemical variant of multiple myeloma (the most common)
is called Bens-Jones myeloma or light chain disease.
Bens-Jones protein has a low molecular weight, therefore it easily passes through
an intact kidney filter into urine and can be determined there using a precipitation
reaction: 10.0 urine + 3-4 drops of 10% CH3 COOH + 2.0 NaCl. Heat in a water
bath with a constant increase in temperature. If there is Bens-Jones protein in the
urine, then at a temperature of 45-600C, a diffuse clouding appears or a dense
white precipitate forms. When heated to boiling, the precipitate dissolves, and
when cooled, it reappears.