Richter's disease what is it. Chronic lymphocytic leukemia

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Based on the clinical and laboratory picture chronic lymphocytic leukemia (HLL)there are two main clinical syndromes and three main laboratory changes in the clinical analysis of blood, available to perform in any medical institution.

Clinical syndromes are:

1) generalized lymphadenopathy: lymph nodes of soft or dense elastic consistency, painless, not welded to the surrounding tissues (except in cases of malignant transformation), can form packets, the skin over them is not changed, fistulas do not form;

2) hepato- and splenomegaly. Changes in the clinical analysis of blood: leukocytosis, absolute lymphocytosis, leukolysis cells (shadows of Botkin-Gumprecht).

Many patients long years only lymphocytosis can be noted - 40-50%, although the total number of leukocytes fluctuates around the upper limit of the norm. Lymph nodes can be almost normal in size, but they increase with various infections (for example, with angina), and after the elimination of the inflammatory process, they contract to their original size.

Lymph nodes increase gradually, usually primarily in the neck, in the armpits, then the process spreads to the mediastinum, abdominal cavity, and groin. There are nonspecific phenomena common to all leukemias: hanging fatigue, weakness, sweating. In the early stages of the disease, in most cases, there is no anemia or thrombocytopenia.

A distinctive feature of CLL is an increase in the number of peripheral blood leukocytes with a significant number of small mature lymphocytes - more than 5x10 9 / l (a reliable diagnostic sign is their number more than 10x10 9 / l), the identification of "Botkin-Gumprecht ghosts" (leukolysis cells) - destroyed during preparation smear of lymphocytes and the presence of a characteristic immunophenotype of lymphoid cells - CD5 +, CD19 +, Cd20 +, CD22 +, CD79a +, CD23 +, CD43 +, CD11c +/-, CD10-, cyclin D1-.

Lymphocytosis in the blood gradually increases: 80-90% of lymphocytes, as a rule, are observed with an almost total replacement of the bone marrow. The proliferation of lymphatic tissue in the bone marrow may not inhibit the production of normal cells for years. Even when high numbers of leukocytes in the blood reach 100,000 in 1 μl or more, there is often no anemia, the number of platelets is normal or slightly reduced.

Bone marrow puncture shows an increase in the percentage of lymphocytes in the myelogram - usually more than 30. This sign is reliable for the diagnosis of chronic lymphocytic leukemia, if the punctate is not significantly diluted with peripheral blood. In the trepanobioptate, characteristic proliferation of lymphoid cells, more often diffuse, are noted.

The morphology of lymphocytes in chronic lymphocytic leukemia does not have stable and typical signs. It can change during the course of the disease under the influence viral infections... In the blood, the majority of cells are mature B-lymphocytes, which are no different from normal ones.

Along with such cells, there can be lymphocytic elements with a more homogeneous nucleus, which do not yet have the coarse lumpiness of the chromatin of the mature lymphocyte, with a wide rim of the cytoplasm, which sometimes, as in infectious mononucleosis, has perinuclear clearing. The nuclei of cells can have a peculiar twisting of chromatin loops or be regularly round; there are also bean-shaped kernels; the cytoplasm is with broken contours, sometimes with elements of "hairiness", but without the histochemical features of hairy cell leukemia.

A characteristic sign of chronic lymphocytic leukemia is the dilapidated nuclei of lymphocytes - the shadow of Botkin-Gumprecht. Their number is not an indicator of the severity of the process. Leukolysis cells are an artifact: they are not in liquid blood, they are formed during the preparation of a smear.

At the onset of the disease, there are usually no prolymphocytes in the leukocyte formula. However, there are cases of chronic lymphocytic leukemia, which from the very beginning are accompanied by a sharp predominance of prolymphocytes in the blood - cells with homogeneous nuclear chromatin, but with a distinct nucleola. On this basis, the prolymphocytic form of chronic lymphocytic leukemia is distinguished (Vorobiev A.I. et al., 1985-2000). Sometimes such leukemia can occur with the secretion of monoclonal immunoglobulin (however, this is not very uncommon in ordinary mature cell chronic lymphocytic leukemia).

As the disease progresses, single prolymphocytes and, less often, lymphoblasts begin to occur in the blood. A large number of them appear only in the terminal stage of the disease.

initial stage

The onset of benign and progressive variants of typical CLL is almost the same. In the initial period, patients usually do not show significant complaints, the general condition is satisfactory. However, some patients, even in this period, may complain of slight weakness, sweating, and frequent colds.

As a rule, hemoblastosis is detected by chance (during preventive examinations, when contacting a doctor for any other disease). The main clinical signs CLL are at this stage enlarged lymph nodes, leukocytosis and lymphocytosis.

Most often, at this stage, there is a slight increase in lymph nodes, usually in a certain sequence. Usually, first of all, the cervical, then axillary, and much later (most often in the advanced phase of the disease) - other groups of lymph nodes increase. Enlarged lymph nodes in chronic lymphocytic leukemia of soft-elastic doughy consistency.

It should be emphasized that the density of the lymph nodes is not typical for this stage of chronic lymphocytic leukemia. The sizes of the enlarged lymph nodes are different: from a small to a very significant increase. As a rule, the lymph nodes are painless, not adhered to the skin and to each other, do not ulcerate or suppurate.

The second characteristic sign of chronic leukemia in the initial period is leukocytosis (usually 10-30x10 9 / l) and an increase in the number of lymphocytes up to 60-80%. A.I. Vorobiev et al. (2003) indicates that the number of leukocytes in the initial stage can increase up to 50x10 9 / l.

The main criteria for the initial period of chronic lymphocytic leukemia are:

Slight or moderate enlargement of several lymph nodes in one or more groups;
leukocytosis not exceeding 50x10 9 / l;
no tendency to a significant increase in leukocytosis;
satisfactory condition of the patient, absence of dysfunction of other organs and systems (state of compensation).

With a benign course of the disease, the initial period can last for several years. The increase in leukocytosis is slow (within 2-3 years). With the development of infectious and inflammatory processes, the number of leukocytes and lymphocytes in the blood can increase significantly, but after stopping the infection, leukocytosis and lymphocytosis return to their previous figures. Lymph nodes and spleen are of normal size or slightly enlarged, the consistency of the nodes is elastic, their size does not change.

With the progressive course of chronic lymphocytic leukemia, the initial stage of the disease does not last long, the number of leukocytes and lymphocytes is steadily increasing from month to month, the general condition worsens, and a significant increase in lymph nodes is noted. The cervical, supraclavicular lymph nodes usually increase first, then axillary, their consistency is dough. The spleen is not palpable at first or slightly enlarged, further its size increases significantly.

The period of pronounced clinical manifestations (advanced stage)

In this period, there is a detailed clinical picture of chronic lymphocytic leukemia. Patients complain of pronounced general weakness, decreased performance, significant sweating, especially at night, weight loss, increased body temperature, swollen lymph nodes.

On examination, attention is drawn to generalized lymphadenopathy. In this period of the disease, almost all groups of peripheral lymph nodes are usually enlarged: submandibular, posterior and anterior cervical, supraclavicular, axillary, inguinal, etc. The degree of enlargement of the lymph nodes is different - from the size of a pea to a chicken egg.

The consistency of the lymph nodes is still elastic-testate, they are not soldered between themselves and the skin. However, with a significant increase in the lymph nodes of one group, they may look like a conglomerate. Using special research methods ( ultrasound procedure (Ultrasound), CT scan (CT), X-ray), there is also an increase in intrathoracic, intra-abdominal and retroperitoneal lymph nodes, however, in the typical (classical) form of CLL, signs of compression of internal organs are not observed, in contrast to the tumor-like form. In the blood, there are varying degrees of severity of leukocytosis and absolute lymphocytosis.

Academician A.I. Vorobiev et al. (1985-2000) based on morphological and clinical signs, including the response to therapy, the following clinical and laboratory forms of CLL are distinguished:

1) Benign;
2) Progressive (classical);
3) Tumor;
4) Splenomegalic (splenic);
5) Abdominal;
6) Prolymphocytic;
7) Bone marrow.

Benign form

According to A.I. Vorobiev et al. (1985-2003), in the benign form of CLL "there is a very slow, noticeable only for years, but not months, an increase in lymphocytosis in the blood in parallel with an increase in the number of leukocytes." Leukocytosis in this form of CLL is not high, as a rule, less than 30x10 9 / l, in some cases it can reach 50x10 9 / l. The percentage of lymphocytes in the blood is 60-70.

Leukocytosis persists stably below this level for at least 3 years from the first blood test with leukocytosis. The lymph nodes are either not enlarged, or the cervical ones are very slightly enlarged (no more than 2 cm). A very slow increase in leukocytosis and lymphocytosis until a noticeable increase in lymph nodes can last for years or decades.

All this time, the patients are under dispensary supervision, they are fully able to work, they are only prohibited from increased insolation (you cannot sunbathe, but you can swim and relax in the south, except in July and August). Blood tests with counting platelets and reticulocytes are done every 1-3 months.

In the benign form, until the moment when the deterioration of the condition may require therapy, in many cases diagnostic sternal puncture, trepanobiopsy and lymph node biopsy are not done. These studies significantly traumatize the patient's psyche, who often does not need cytostatic drugs until the end of his days, but they cannot add anything to the diagnosis of this form of the disease. True, only an experienced specialist can make such decisions.

With this form, which I.A. Kassirsky called "frozen" life expectancy may not depend on the presence of chronic lymphocytic leukemia, and elderly patients die from concomitant pathology, in the absence of signs of progression of hemoblastosis.

In a benign form, the disease occurs in 20-30% of patients (Vorobiev A.I. et al., 2003). The life expectancy of such patients is the same as in the population.

Progressive (classic) form

It starts in the same way as a benign one, but the number of leukocytes increases from month to month, as does the size of the lymph nodes. The leading manifestation of this form of CLL is a significant increase in the number of leukocytes. Leukocytosis can reach 500-1000x10 9 / l and more.

At the same time, the number of lymphocytes in the leukocyte formula also increases (up to 90-99%). Mature forms predominate, but, as a rule, 5-10% of prolymphocytes are found. The content of erythrocytes, hemoglobin and platelets is initially normal, and with high leukocytosis and significant lymphocytosis, they are usually reduced due to the displacement of healthy growths by pathological lymphocytes or due to the addition of autoimmune complications.

At the same time, the size of the lymph nodes also increases. The consistency of the knots can be doughy, soft or slightly elastic. There is usually no "woody" density, and if such nodes appear, then they should be biopsied to exclude malignant transformation. In most cases, a slight increase in lymph nodes can be detected even with mild changes in the blood. Sometimes the first symptom of their increase is the reaction to infection: in acute respiratory diseases, the lymph nodes increase and then decrease in size again.

The enlargement of the spleen in such patients in most cases appears later than the enlargement of the lymph nodes and rarely reaches a significant size. Even later, the liver is usually enlarged. There is no high correlation between the degree of lymphoid infiltration of the bone marrow, the height of leukocytosis and the size of the lymph nodes, spleen and liver.

Sometimes, at the time of an acute respiratory illness, the patient has a hearing loss and a "feeling of stuffiness" in the ears. On examination, an overgrowth of lymphoid tissue is found at the mouths of the Eustachian tubes, its swelling during the period of accession of infection causes the closure of the lumen of the tubes.

In some cases of CLL, clinical manifestations of the disease (enlarged lymph nodes, spleen, liver) are absent in patients even with very high leukocytosis and lymphocytosis. In such observations, the study of bone marrow punctate usually reveals an almost total displacement of granulocytic and erythroid elements of the bone marrow by lymphocytes.

The term "classic form" means that most cases of CLL occur in this form - 45-50% (Vorobiev A.I. et al., 2003). Cytostatic therapy for these patients is usually prescribed with a noticeable increase in all manifestations of the disease, leukocytosis (usually more than 100-150x10 9 / l) and the size of the lymph nodes in the first place. The median survival rate is 96 months (Nikitin E.A., Lorie Yu.Yu., Melikyan A.L., 2003).

Tumor form

A feature of this form, which determined its name, is a significant increase and dense consistency of lymph nodes with low leukocytosis. The tonsils are enlarged, often they almost close with each other. The enlargement of the spleen is usually moderate, but it can also be significant.

In the leukocyte formula, a sufficient - 20 or more - percentage of neutrophils remains. In the bone marrow, usually no more than 20-40% of lymphocytes, although there is a total lesion. Despite the significant hyperplasia of the lymphatic tissue, intoxication is poorly expressed for a long time, in contrast to generalized lymphoma, with which this form of chronic lymphocytic leukemia is sometimes identified.

Summarizing all clinical, laboratory and instrumental data, the following features of this form of CLL can be distinguished:

Pronounced enlargement of lymph nodes, they are painless, dense elastic consistency, merge with each other, form conglomerates. First, the cervical lymph nodes increase sharply, then the axillary and inguinal lymph nodes. Lymph node enlargement can be diagnosed not only by palpation, lymph node conglomerates are clearly visualized. Often the first complaint of such patients is “the inability to fasten the collar of the shirt,” according to patients, “the neck becomes thick”, the so-called. "Wrestling neck". Along with an increase in peripheral lymph nodes, an increase in paratracheal lymph nodes with compression of the trachea and large bronchi is possible. In some patients, intra-abdominal lymph nodes are enlarged with compression of the portal vein and biliary tract, which leads to the development of portal hypertension syndrome and obstructive jaundice. Perhaps an increase in retroperitoneal lymph nodes with compression of the ureters and impaired outflow of urine.

The presence of diffuse proliferation of homogeneous lymphoid cells with light nuclei in the biptates of lymph nodes; unlike lymphoma, there are no signs of atypism and polymorphism. Mature lymphocytes and prolymphocytes are found in the prints of the lymph node;

Total diffuse lymphocytic infiltration of the bone marrow during trepanobiopsy of the iliac wing, pronounced proliferation of mature lymphocytes in the sternal punctate (about 20-40%);

Moderate leukocytosis in peripheral blood - about 20,000-50,000 in 1 μl; in the leukocyte formula there are about 60-80% of lymphocytes and moderate neutropenia (the number of neutrophils is up to 20% or more).

This form of chronic lymphocytic leukemia has a rapidly progressive course, the median survival rate is 36 months (Nikitin E.A., Lorie Yu.Yu., Melikyan A.L., 2003). Diagnosis of the tumor form of CLL is immediately the basis for the appointment of cytostatic therapy.

Splenomegalic (splenic) form

The splenomegalic form was essentially isolated already when determining the stage of chronic lymphocytic leukemia according to Rai, when it turned out that the stage of the process, which occurs only with lymphocytosis and enlargement of the spleen - stage II, is prognostically more favorable than all the others, except for zero, manifested only by lymphocytosis in the blood and bone marrow.

I. Dighiero et al. (1979) proposed to isolate the splenic form of chronic lymphocytic leukemia with a predominant increase in the spleen with a moderate increase in lymph nodes and different levels of leukocytes. The spleen in such patients can occupy most of the abdominal cavity and, with the progression of the disease, cause compression and pain syndromes.

This form differs from lymphocytoma of the spleen by diffuse growth of lymphatic elements in the bone marrow (trepanobioptat), lymph nodes, spleen. The liver is often enlarged (not very significantly). The number of leukocytes in peripheral blood may vary, but usually leukocytosis increases over the course of months. Hemolytic anemia is common.

The median survival rate of such patients is 62 months (Nikitin E.A., Lorie Yu.Yu., Melikyan A.L., 2003).

Abdominal form

If for months and years tumor growth is limited almost exclusively to the lymph nodes of the abdominal cavity, this form of CLL is called abdominal. To identify enlarged intraperitoneal lymph nodes, ultrasound and CT are used.

Prolymphocytic form

The prolymphocytic form differs, first of all, in the morphology of lymphocytes, which in smears (blood and bone marrow), prints have a large clear nucleol. Condensation of chromatin in the nucleus, as shown by electron microscopy, is expressed moderately and mainly along the periphery. In histological preparations of lymph nodes and spleen in this form of leukemia, lymphocytes also contain nucleols. Immunological characteristics reveal the B- (80%) and T-cell (20%) nature of prolymphocytic lymphocytic leukemia.

Unlike B-lymphocytes of typical chronic lymphocytic leukemia, with this form, an abundance of immunoglobulins is found on the surface of leukemic lymphocytes, more often M - or D-type; in addition, these lymphocytes form few rosettes with mouse erythrocytes. According to A.I. Vorobiev et al. (2003), "according to the characteristics of immunological markers, the prolymphocytic form is older than the usual malignant lymphocytic leukemia." Chromosomal abnormalities are very common in this form of CLL.

The main clinical and laboratory features of the prolymphocytic form are:

The age of patients in 50% of cases is over 70 years old;
severe weakness, weight loss, tendency to hemorrhages;
significant splenomegaly
not pronounced enlargement of lymph nodes;
infiltration by leukemic cells of the skin in the area of \u200b\u200bthe trunk, face, arms, the appearance of papular, non-itching rash (in approximately 1/3 of patients with T-prolymphocytic leukemia;

Changes in the analysis of peripheral blood: in 70-80% of patients, the number of lymphocytes exceeds 100,000 in 1 μl (100x10 9 / l), while 30-50% of all lymphocytes are represented by prolymphocytes; characterized by anemia and thrombocytopenia;
positive cytochemical reaction of lymphoid cells to acid phosphatase activity (in the form of granules, sometimes forming a block, is completely suppressed by tartrate); about half of the cells contain a-naphthyl esterase; in lymphoid cells, glycogen is found in the form of small granules; negative reaction to myeloperoxidase;
pronounced proliferation of prolymphocytes in the bone marrow (according to myelogram data);
rapid progression of the disease and low efficiency of cytostatic therapy.

The average life expectancy of patients with the prolymphocytic form of CLL is about 3 years.

Bone marrow form

It was first described in 1937 by Storti under the name limfadenia ossium. This form is characterized by rapidly progressive pancytopenia, total or partial replacement of the bone marrow with diffusely growing mature lymphocytes. The lymph nodes are not enlarged, the spleen, with very rare exceptions, is also not enlarged, the liver is of normal size.

Morphologically, the homogeneity of the structure of nuclear chromatin is noted, sometimes its pycnoticity, less often there are structural elements that vaguely resemble blast; cytoplasm with pronounced basophilia, narrow, often clipped. The prognosis is extremely unfavorable.

As an example, we give two cases of a typical classic course of chronic lymphocytic leukemia and a rare form of this disease.

Clinical examples

Patient A., born in 1933 The diagnosis "Chronic lymphocytic leukemia" was first exposed in 1991. The primary diagnosis was Binet stage A. Peripheral lymph nodes are no more than 2 cm in diameter. There is no hemorrhagic syndrome on the skin and visible mucous membranes. There is vesicular breathing in the lungs, no wheezing. Heart sounds are clear, the rhythm is correct. The abdomen is soft, painless on palpation. Liver along the edge of the costal arch. The spleen is not enlarged.

Clinical analysis blood: hemoglobin - 140 g / l, erythrocytes - 4.5 x 10 12 / l, leukocytes - 27x10 9 / l, platelets - 180x10 9 / l, segmented - 12%, monocytes - 2%, lymphocytes 85%.

1991 to 1996 the patient was dynamically monitored in a polyclinic. In 1996, an increase in lymph nodes up to 2 cm in diameter was noted. The lower pole of the spleen was palpable in the left hypochondrium. Primary inhibitory therapy with chlorambucil was prescribed. From 1996 to 2005, no progression of the disease was observed against the background of primary inhibitory therapy.

Since 2005, due to a significant increase in the spleen (the lower pole was palpable at the level of the pelvic bones) and liver (the lower edge was palpated 12 cm below the edge of the costal arch), generalized lymphadenopathy (lymph nodes were enlarged to 4-5 cm, dense elastic consistency, soldered in conglomerates), began to conduct course cytostatic therapy (cyclophosphamide monotherapy, polychemotherapy courses according to the SR, COP, SNOR protocols).

Since 2008, therapy has been started according to the FCR protocol, 8 courses have been conducted (2008-2009). Before starting therapy according to the FCR protocol, the sizes of peripheral lymph nodes of all groups are up to 3-4 cm, soldered into conglomerates. According to CT data, the mediastinal, intraperitoneal and retroperitoneal lymph nodes are enlarged, fused into conglomerates. Liver - the lower edge was palpated 10 cm below the costal arch edge.

The lower pole of the spleen was palpated at the level of the navel. Clinical blood test: hemoglobin - 65 g / l, erythrocytes - 2.5x10 9 / l, leukocytes - 120x10 9 / l, platelets - 80x10 9 / l, segmented - 2%, lymphocytes 98%. After 8 courses of RFC, complete remission of CLL was achieved. Lymph nodes of all groups are within normal limits. There is no hemorrhagic syndrome on the skin and visible mucous membranes. There is vesicular breathing in the lungs, no wheezing. The abdomen is soft, painless on palpation. Liver along the edge of the costal arch. The spleen was not detected by palpation.

The remission lasted from 2009 to 2014. In November 2014 - a relapse. Peripheral lymph nodes of all groups are enlarged up to 3-4 cm, soldered into conglomerates, stony density. The lower pole of the spleen is palpated at the level of the pelvic bones. According to CT data, the mediastinal, intraperitoneal and retroperitoneal lymph nodes are enlarged.

Clinical blood test: hemoglobin - 95 g / l, erythrocytes - 3.0x10 12 / l, leukocytes - 17x10 9 / l, platelets - 100x10 9 / l, segmented - 5%, lymphocytes 95%. According to the histological examination of the lymph node, transformation into large cell lymphoma (Richter's syndrome) was diagnosed.

Patient K., 32 years old, was first admitted to the hematology department of the Amur Regional Clinical Hospital in November 2010. When passing honey. examination in the hemogram revealed changes - leukocytosis, lymphocytosis, clinically - splenomegaly. The patient was referred for a consultation with a hematologist at the Amur Regional Consultative Polyclinic. The patient was admitted to the hematology department for examination and determination of further management tactics.

On admission: stable condition, complaints of slight weakness. The skin is clean, normal color, no hemorrhagic syndrome. Peripheral lymph nodes are not enlarged In the lungs, vesicular breathing, weakened in the upper left parts, single dry rales, impact frequency (BH) 18 per min. Heart sounds are rhythmic, muffled heart rate (HR) 78 rpm, arterial pressure (HELL) 120/80 mm Hg The abdomen was soft, painless, the liver along the edge of the costal arch, the spleen occupied most of the abdomen: the lower pole was palpable at the level of the pelvic bones, the right border was 10 cm from the navel to the right. Stool and urine output were normal.

In the clinical analysis of blood at the initial admission from 23.11.10: hemoglobin - 112g / l; erythrocytes - 3.54x10 12 / l; leukocytes - 156.6x10 10 / l; platelets - 90x10 9 / l; erythrocyte sedimentation rate (ESR) - 50 mm / h, prolimocytes - 77%, segmented - 3%, lymphocytes - 20%.

B / x blood test from 23.11.10: glucose - 6.1 mmol / l; bilirubin - 16.6-13.2-3.4 μmol / l; urea - 4.7 mmol / l; protein - 70g / l, AST - 64ME / l, alanine aminotransferase (ALT) - 34 IU / l, thymol test-2.0, fibrinogen-3.0 g / l, prothrombin index (PTI)- 55%.

Linked immunosorbent assay (IFA) for hepatitis from 23.11.10: negative. Blood on RW from 11/23/10: negative. Blood for HIV from 11/23/10: negative.

Myelogram from 23.11.10 No. 80: received a hypercellular bone marrow, regeneration of a megakaryocytic germ, an increase in lymphoid elements - 34.6% (18.6% prolymphocytes)

Immunophenotyping from 25.11.10: CD3-15.3%; CD3CD4 - 49.6%; CD5-27.0%; CD8 41.1%; CD4 / CD8-1.2%; CD10-33.8%; CD19-62.0%; CD20 - 69.7%; CD22 - 43.7%; CD23-4.0%; CD25-48.3%; CD38-18.9%; HLA-DR-60.9.

Ultrasound of internal organs from 27.11.10: Hepatosplenomegaly (liver - PD 160mm, LD 95 mm, portal vein - 12 mm; spleen - about 300x128 mm, splenic vein - 11 mm), gigantic spleen. Consolidation along the portal tracts of the liver. Diffuse changes in the pancreatic parenchyma.

Trepanobiopsy of the ilium from 25.11.10 No. 21421: among the bone trabeculae there are areas of the bone marrow in which the ratio of hematopoietic bone marrow and adipose tissue is 95: 5. Diffuse infiltration by mature lymphocytes. Megakaryocytes are single.

Taking into account the data of the study, the patient was diagnosed with Spleen lymphoma with leukemia.

Splenectomy was performed on December 6, 2010. Transferred satisfactorily. Histological preparations (blocks) were sent to the Blokhin Russian Oncological Research Center. Histology 1639/11 (Blokhin Russian Cancer Research Center): in histological preparations made from the provided blocks, in sections of spleen tissue, histoarchitectonics is disturbed due to a massive diffuse infiltrate of monomorphic small lymphoid cells with rounded nuclei, in which a small nucleolus is visualized.

In vessels of the capillary and sinusoidal type there are small lymphoid cells with the above-described morphology. On sections from a paraffin block, immunohistochemistry (IHC) - research using antibodies. Cells of diffuse tumor infiltrate monomorphically express CD20, Jg M. With other markers in tumor cells, the reactions are negative. Among the tumor substrate, clusters of T-cells of CD2 +, CD3 +, CD4 +, CD5 +, CD8 + (lymphoid, littorial cells) are visible. Conclusion: Taking into account the clinical and laboratory data, morphological features and immunophenotype in the spleen tissue, the substrate lesion of B-cell prolymphocytic leukemia.

According to the results of the immunohistochemical study, the patient was diagnosed with B-cell prolymphocytic leukemia. The patient received 6 courses polychemotherapy (PCT)under the FCR protocol. The last course in August 2011. A complete remission of the disease has been achieved, which remains to this day.

Currently (April 2015), the state is satisfactory. Peripheral lymph nodes of all groups are not more than 1 cm in diameter. According to CT, the lymph nodes of the mediastinum, retroperitoneal and intraperitoneal are not enlarged. There is vesicular breathing in the lungs, no wheezing. Heart sounds are clear, the rhythm is correct. The abdomen is soft, painless on palpation. The liver is not enlarged. Clinical blood test from April 2015: hemoglobin - 151 g / l; erythrocytes - 5.02x10 12; leukocytes - 8.5x10 12; platelets - 365x 10 9; ESR - 4mm / h, segmented - 43%, eosinophils - 8%, monocytes - 8%, lymphocytes - 41%.

Terminal stage

The terminal stage of CLL is characterized by a sharp progressive deterioration in the general condition of patients, exhaustion, severe intoxication, loss of appetite, high body temperature. Hyperthermia can be caused not only by CLL itself, it is often associated with the development of pulmonary tuberculosis or the addition of severe bacterial pneumonia.

The terminal stage is characterized by the development of severe complications. First of all, these are infectious and inflammatory processes with localization in various organs and systems. Severe generalized infection is often the cause of death in CLL patients.

The course of chronic lymphocytic leukemia can be complicated by pneumococcal, streptococcal pneumonia, herpes infection, etc. Possible infectious lesions not only of the lungs, but also of the urinary tract and skin. The development of infectious and inflammatory processes in CLL is facilitated by disorders of the immune system, hypogammaglobulinemia.

Herpes infection can complicate the course of CLL at any stage, but especially in the terminal phase of the disease. More often it is shingles, in many patients the herpes virus can cause generalized damage to the skin, mucous membranes of the oral cavity, gastrointestinal tract, and genitourinary system.

Severe renal failure is one of the formidable clinical signs of end-stage CLL. It is due to infiltration kidney tissue leukemic cells and is manifested by the development of oligoanuria with a significant increase in the blood content of urea, creatinine, residual nitrogen. Severe renal failure can cause death in CLL patients.

In the terminal phase of chronic lymphocytic leukemia, neuroleukemia may develop due to intensive infiltration of the meninges with young lymphocytes. The clinical picture of neuroleukemia in CLL corresponds to that in acute leukemia and is manifested by severe headaches, vomiting, the development of meningeal syndrome, cranial nerve paresis, and peripheral paralysis. Leukemic infiltration of the spinal nerve roots is accompanied by intense "radicular" pain.

In the terminal phase, due to lymphoid infiltration, severe cardiopathy may develop, leading to circulatory failure, lung damage with symptoms of severe respiratory failure, exudative pleurisy (it must be differentiated from exudative pleurisy of tuberculous genesis).

A characteristic feature the terminal stage of CLL is severe anemia. It is caused by a reduction in the red hematopoietic lineage due to lymphoid infiltration of the bone marrow, intoxication and autoimmune mechanisms. Thrombocytopenia and increased manifestations of hemorrhagic diathesis are also characteristic.

In some patients in the terminal stage, a blast crisis develops, but more often transformation into other lymphoproliferative diseases is observed. In the terminal period of CLL, there is a significant progressive enlargement of the lymph nodes and spleen. This usually indicates the transformation of CLL into malignant lymphoproliferative diseases. It is known that chronic lymphocytic leukemia can transform into Richter's syndrome, into prolymphocytic leukemia, acute lymphoblastic leukemia, plasma cell leukemia, and multiple myeloma.

Richter's syndrome

Richter's syndrome (transformation) is the transition of CLL to diffuse, aggressive large-cell immunoblastic lymphoma, consisting of large B-lymphocytes. Described in 1928, It is observed in 3-10% of patients with progressive CLL. In the development of this syndrome, the p53 gene mutation plays an important role.

The main clinical signs of Richter's syndrome are (Robertson et al., 1993; Osmanov D.Sh., 2007):

Progressive enlargement of lymph nodes, they acquire a stony density, infiltrate and squeeze adjacent tissues, including the lymphatic tract, which causes pain and swelling; many patients develop retroperitoneal lymphadenopathy;

Increased body temperature;

Decrease in body weight;

Increased degree of hepatomegaly;

Development of massive splenomegaly;

The appearance of neurological symptoms due to involvement of the central nervous system in the pathological process;

Clinical signs of severe infiltration of tumor cells of other organs - gastrointestinal tract (GIT), lungs, kidneys;

High serum levels of lactate dehydrogenase and monoclonal gammopathy (detected by protein electrophoresis).

The diagnosis of Richter's transformation is clarified by a biopsy of the lymph nodes. Characteristic is the presence of large immunoblastic cells in biopsy specimens, which have a pronounced basophilic cytoplasm and an irregularly shaped nucleus with nucleoli. The bone marrow is infiltrated with these immature cells, which can cause foci of osteolysis.

The life expectancy of patients with Richter's syndrome is about 6-12 months (Osmanov D.Sh., 2007).

Transformation to Prolymphocytic Leukemia

In approximately 15% of patients with B-cell chronic lymphocytic leukemia, in the process of tumor progression, in addition to small lymphocytes, prolymphocytes may appear in the peripheral blood, the number of which can reach from 10 to 90%. This indicates the transformation of CLL into prolymphocytic leukemia.

The clinical picture is generally consistent with the clinical picture of CLL, but the hallmark is progressive, very pronounced splenomegaly. Some patients have a t (6; 12) translocation. Patients with chronic lymphocytic leukemia with transformation into prolymphocytic leukemia respond much worse to chemotherapy, their life expectancy is reduced. According to Chani et al. (1986), after transformation, the life expectancy of patients with CLL is 9 months.

Transformation to acute leukemia

Very rarely, in about 2% of cases, the transformation of CLL into acute lymphoblastic leukemia occurs. It was found that the leukemic clone is derived from the same B-cell clone as in CLL. Blast transformation is associated with an increase in the expression of the c-MYC gene and genes responsible for the synthesis of immunoglobulins.

Leukemic blast cells express terminal deoxynucleotide transferase (TdT), high levels of surface immunoglobulin and major histocompatibility complex (HLA-DR)... Clinical manifestations of the disease correspond to those of acute lymphoblastic leukemia.

In rare cases, transformation of CLL into multiple myeloma is observed. This assumes the existence of a separate pathological clone of plasma cells in the bone marrow.

V.V. Voitsekhovsky, T.V. Zabolotskikh, S.S. Tseluyko, Yu.S. Landyshev, A.A. Grigorenko

Chronic lymphocytic leukemia / small lymphocyte lymphoma is a disease of lymphoid tissue characterized by clonal proliferation due to constant activation of the B-cell receptor with autonomous and ligand-dependent stimulation of neoplastic committed lymphocytes (mainly CD5 + antigen-trained B cells with different levels of gene mutations in the variable region heavy chain of immunoglobulin), which leads to a steady accumulation of long-lived tumor cells in the peripheral blood, bone marrow, lymph nodes, spleen, liver, and subsequently in other organs and tissues (heart, lungs, kidneys, stomach, intestines, etc. .).

The history of the study of chronic lymphocytic leukemia begins in 1856, when R. Virkhov first linked an increase in lymph nodes and spleen with peripheral blood lymphocytosis, and subsequently, in 1903, W. Turk gave a detailed description clinical picture chronic lymphocytic leukemia.

In the 60s. XX century D.A. Galton and W. Dameshek proposed a modern concept of the pathological basis of chronic lymphocytic leukemia, based on the assumption that chronic lymphocytic leukemia is a homogeneous disease arising from long-lived, immunologically incompetent lymphocytes that accumulate in the body over time. Subsequently, on this basis, systems for the clinical staging of chronic lymphocytic leukemia were developed according to K. Rai and J. Binet. However, a continuous series of studies that began in the 1990s naturally led to questions related to the heterogeneity of the course of chronic lymphocytic leukemia, and soon an explanation of some of the biological mysteries of this disease was proposed.

EPIDEMIOLOGY
Chronic lymphocytic leukemia - the most common type of leukemia that affects the white race in the western hemisphere, accounts for 25-30% of all leukemias, while in the eastern hemisphere less than 5% suffer from it, while the median age of chronic lymphocytic leukemia at the time of diagnosis is about 70 years, however, in 10-15% of patients, the disease occurs before 50 years.

According to the National Cancer Institute's Statistical Cancer Prevalence Registry, from 2006 to 2010, 30% of all cases of chronic lymphocytic leukemia detected in the United States were diagnosed in patients aged 45-64 years.

More often men get sick than women - the incidence is 5.8 and 3.0 per 100,000 men and women, respectively.

The number of new cases of chronic lymphocytic leukemia in the United States in 2014 R. Siegel et al. estimated at 15 720 patients, and the number of deaths from chronic lymphocytic leukemia - 4600 people. The life expectancy of patients is different: despite the fact that in some patients it does not differ from the population, some patients die quickly enough. By the beginning of the 21st century, advances were made in understanding the biology, natural history and treatment of chronic lymphocytic leukemia. Survival of patients with chronic lymphocytic leukemia varies significantly depending on the stage of the disease: patients with low-risk chronic lymphocytic leukemia (Rai stage 0) had an average life expectancy of 14.5 years, compared with 2.5 years in patients with high-risk chronic lymphocytic leukemia ...

ETIOLOGY AND PATHOGENESIS
The cause of chronic lymphocytic leukemia is still unknown.

Chronic lymphocytic leukemia prevails in first-degree relatives (risk factor), occurs

At a younger age and increases in severity in each next generation - the phenomenon of anticipation, and is also associated with a greater frequency of autoimmune disorders in relatives of patients with chronic lymphocytic leukemia. The relatives of patients with chronic lymphocytic leukemia of the first degree of relationship in 13-18% of cases have "monoclonal lymphocytosis of undetermined significance", or monoclonal B-cell lymphocytosis. The term “monoclonal B-cell lymphocytosis” was proposed in 2005 and implies the detection in the blood of a monoclonal B-cell population of less than 5x109 / L without any other signs of lymphoproliferative disease. B-cell lymphocytosis is also detected in 3% of adults over 40 years old and 6% over 60 years old. The rate of progression of B-cell lymphocytosis into chronic lymphocytic leukemia, which requires treatment, is 1-4% per year.

Environmental factors such as ionizing radiation, chemical agents (benzene and solvents in the rubber industry), and drugs do not play an obvious etiological role in chronic lymphocytic leukemia.

The nature of chronic lymphocytic leukemia is most accurately reflected by biological concepts that explained the violation of biological processes in B cells based on knowledge of the mechanisms of apoptosis, the cell cycle of B lymphocytes, genetic differences in tumor B cells and chromosomal abnormalities, overexpression of CD38, ZAP-70 and other signaling molecules, as well as data on violations of the processes of functional activity of B-cells and their microenvironment in the lymph nodes and computed tomography.

Chronic lymphocytic leukemia is a model of the disease of impaired apoptosis (programmed cell death). Slowly growing cells of chronic lymphocytic leukemia accumulate in the body, mainly in the G0-phase of the cell cycle. An imbalance in the ratio of the main pro- and anti-apoptotic proteins of the bcl-2 gene family, such as BAX and BAK (inducing apoptosis), BCL-2 (anti-apoptotic), BAD, BIK and HRK (anti-apoptotic inhibitors), plays an important role in the course and in response to the treatment of chronic lymphocytic leukemia. Despite the frequent overexpression of the BCL-2 protein, no genetic translocations due to overexpression of the BCL-2 gene, such as t (14; 18), were found in patients with chronic lymphocytic leukemia. Increased overexpression of BCL-2 is associated with the deletion of the regulatory micro-RNA miRNA15a and miRNA16-1, which is detected in 70% of patients with chronic lymphocytic leukemia.

Cytokines produced and secreted by CLL cells, such as tumor necrosis factor TNF-alpha, IL-8, and IL-2, which is produced by T-lymphocytes and absorbed by CLL cells using special receptors, are involved in autocrine and paracrine regulation and cause CLL cells to survive and proliferate. An increased level of IL-8 is given great importance as a factor associated with a poor prognosis and a high risk of death in patients with chronic lymphocytic leukemia.

Expression of CD38 is an important predictor of chronic lymphocytic leukemia and should be considered to identify patients with the most likely progression of chronic lymphatic leukemia. With an increased expression of CD38, revealed by quantitative flow cytometry, the overall survival of patients was 34% over five years, in contrast to the group without an increase in the expression of CD38 (70%). The low level of expression of CD38 as a good prognostic factor was also confirmed when studying the joint expression of CD38 and CD31 on CD19 cells of chronic lymphocytic leukemia.

No specific chromosomal abnormalities were found in chronic lymphocytic leukemia. At the same time, the development of new technologies, such as fluorescence in situ hybridization (FISH), has increased the detection of multiple structural chromosomal abnormalities in almost 50% of patients with chronic lymphocytic leukemia. The most common (51%) find a 13q14 deletion (where the miRNA15a and miRNA16-1 genes are located); carriers of this anomaly have a relatively indolent course of the disease, which usually manifests itself as a stable or slowly increasing isolated lymphocytosis. An 11q22 - q23 deletion (in 17-20%) is associated with severe lymph node involvement, aggressive disease, and reduced overall survival. Trisomy 12 occurs in 15% of cases and is associated with atypical morphology and disease progression.

A 17p13 deletion is also associated with rapid progression, short remission, and decreased overall survival due to the loss of the p53 anti-oncogene suppressor function. In 8.5% of patients, the p53 mutation without a 17p deletion occurs and also leads to a poor prognosis. Despite the fact that many mutations are considered reliable prognostic markers of chronic lymphocytic leukemia, an important direction modern research is the distinction between mutations that actually cause the development of chronic lymphocytic leukemia (driver mutations), and those that are secondary and do not affect the phenotype and biology of chronic lymphocytic leukemia (passenger mutations).

In the late 1990s, the existence of two genetic variants of chronic lymphocytic leukemia was revealed, depending on the origin of one of the two types of B cells, differing in the mutational status of the genes of the variable regions of the heavy chains of immunoglobulins (Vjj-genes) in the germinal (germinal) center - the center reproduction in the secondary B-cell follicle in the cortical zone of the lymph node. A variant of chronic lymphocytic leukemia originating from naive B cells that have not passed the stage of VH gene mutations in the germinal center (homology of VH genes is ≥98% of the germline sequence), and a variant of chronic lymphocytic leukemia arising from memory B cells that have undergone somatic hypermutations of VH-genes of immunoglobulins in the germinal center (homology of VH-genes is
Thus, the median survival in patients with a variant of chronic lymphocytic leukemia without VH gene mutations and with CD38 expression was 8 years, while the presence of somatic VH gene mutations without CD38 expression determined the median survival of 25 years. Moreover, the majority of patients were in stage A. Other publications also indicate that the presence of mutations in the VH genes of B cells is often associated with the absence of CD38 expression in a group of patients with a good clinical outcome and better survival. In the work of E. Nikitin et al. it was found that the 5-year overall survival in the group of patients with chronic lymphocytic leukemia without mutations in the VH-genes of immunoglobulins was 35%, and in the group with mutations - 80% (p \u003d 0.07). At the same time, the CD38 marker was expressed on more than 50% of cells in 7 out of 14 patients with chronic lymphocytic leukemia without mutations in the VH genes of immunoglobulins and in none of 10 patients with chronic lymphocytic leukemia with mutations (p \u003d 0.007). that chronic lymphocytic leukemia cells have a characteristic gene expression profile, the product of one of which is the signaling molecule ZAP-70, which strongly correlates with the mutational status of VH genes. It is found in a subgroup of patients with chronic lymphocytic leukemia without mutations in the VH genes of B cells and is associated with a poor prognosis.

At the same time, it was shown that it is possible with a high degree of sensitivity and specificity (91 and 100%, respectively) to use the relatively simple detection of ZAP-70 + cells (using polymerase chain reaction, immunofluorescence, flow cytometry) as a substitute for a complex and expensive method for detecting VH gene mutations. ... A. Wiestner et al. in a group of 107 CLL patients showed an important role of the ZAP-70 gene for determining the mutational status of chronic lymphocytic leukemia: in patients without VH gene mutations, ZAP-70 was expressed 5.54 times more than in patients with VH gene mutations. In this study, ZAP-70 expression correctly predicted mutational status in 93% of patients.

It was also revealed that the mutation of VH genes in B cells is positively associated with telomere length: it was significantly shorter in patients with chronic lymphocytic leukemia without this gene mutation. At the same time, telomere shortening was associated with worse survival (median 59 months) compared with the group of patients with long telomeres (median overall survival was 159 months).

In patients with chronic lymphocytic leukemia with mutant VH genes of B cells, polymorphism of the P2X7 receptor gene (involved in the process of apoptosis of hematopoietic cells and chronic lymphocytic leukemia cells) contributes to significantly better survival of these patients (median - 151 months versus 98 months in patients without P2X7 polymorphism).

In addition, a German group of researchers suggested dividing patients with chronic lymphocytic leukemia by the level of serum thymidine kinase, which is significantly increased in patients with chronic lymphocytic leukemia with early progression of the disease, and when studying the ability to predict the mutational status of the s-CD23 molecule and serum thymidine kinase, it turned out that they were significantly more frequent. (p \u003d 0.03) are determined in patients without VH gene mutations and determine a poor prognosis. Another predictor of a poor prognosis in patients with chronic lymphocytic leukemia is the mutational activation of the NOTCH-1 (or NOTCH1) gene. It is detected in 8.3% of patients with chronic lymphocytic leukemia during diagnosis, significantly increases in chemoresistant patients - up to 20.8%, as well as in the progression of the disease with transformation into Richter's syndrome - in 31%. In 5-10% of patients with chronic lymphocytic leukemia, the diagnosis reveals mutations of another group of genes that contribute to the deterioration of survival - SF3B1 and BIRC3 - \u200b\u200bwith an increase to 20-25% in the group of fludarabine-resistant patients.

Recently, the hypothesis about the significant role of the microenvironment in the pathogenesis of chronic lymphocytic leukemia, at least in the initial stages, when leukemic cells receive signals for survival from the local environment using antigens, cytokines and chemokines, has been confirmed again. It has been shown that chronic lymphocytic leukemia cells without activating signals undergo rapid apoptosis in vitro, while in vivo various ways of interaction of the tumor microenvironment (bone marrow stromal cells, dendritic follicular cells, monocytic nurse cells, or nurse cells, macrophages and T -cells) with a leukemic cell by signaling through the B-cell receptor or by activating the kinase pathway.

The tumor cell recirculates between the peripheral blood and tissues (bone marrow and lymphatic organs), in which the proliferative centers or pseudofollicles are located, where the tumor clone proliferates, as shown, at a rate of 1-2% per day (from the entire clone). The key role in tumor proliferation in lymphatic tissue is played by the mechanism of signal transduction through SRS. WRC consists of antigen-specific immunoglobulin on the surface membrane (smIg) and heterodimers of immunoglobulins - Ig-a / Ig-β (CD79A, CD79B). Antigen binding to smIg induces tyrosine kinase Lyn phosphorylation of the amino acid residues ITAMs of the immunoglobulins CD79A and CD79B. This, in turn, activates SYK, BTK and PI3Kδ kinases and downstream signaling pathways including calcium mobilization, activation of gamma-2 phospholipase C, protein kinase Cβ, NF-kB, MAP kinase, and nuclear transcription.

The exact mechanism of trigger activation of SRS remains controversial. The main mechanism of stimulation of SRS is ligand-dependent interaction. In general, SRS in chronic lymphocytic leukemia cells with an unmutated genotype has a low binding affinity for a wide range of autoantigens, while affinity mature SRS of CLL cells with a mutated genotype bind to limited, more specific antigens. It was also established that WRC in patients with chronic lymphocytic leukemia can induce antigen-independent signaling associated with the region of the HCDR3 heavy chains and the internal epitope of WRC. This form of autonomous activation of SRS, along with external ligand-mediated stimulation, contributes to the growth and survival of chronic lymphocytic leukemia tumor cells. Data on the structure and function of SRS on leukemic cells of chronic lymphocytic leukemia are used to develop targeted targeted antitumor therapy.

CLINICAL PICTURE
About 40-60% of patients with chronic lymphocytic leukemia are diagnosed in the absence of symptoms associated with the disease, even with a very high number of circulating lymphocytes (\u003e 100x109 / l). Often, the presence of lymphadenopathy or an elevated white blood cell count on routine physical examination is the only reason to suggest a diagnosis of chronic lymphocytic leukemia. The remaining patients may have weakness, fatigue, prolonged (more than a month) increased night sweats, low-grade fever or fever for several weeks without signs of infection, infectious or autoimmune diseases. Physical examination usually reveals enlarged, dense, painless and mobile lymph nodes, splenomegaly (30-54% of cases) and hepatomegaly (10-20%). Metabolic abnormalities (hyperuricemia) or mechanical abnormalities (airway obstruction) associated with tumor compression may also be present.

Chronic lymphocytic leukemia cells can infiltrate any part of the body, including the skin and meningeal membranes, but such findings are rare. Manifestation of the involvement of computed tomography, especially severe anemia (hemoglobin less than 110 g / l) or thrombocytopenia (platelet count less than 100x109 / l), is noted in the diagnosis in 15% of patients with chronic lymphocytic leukemia. A positive direct antiglobulin test (Coombs' test) is found in 20% of patients at the time of diagnosis, but is usually not associated with hemolytic anemia.

The course of chronic lymphocytic leukemia is often complicated by autoimmune disorders (hemolytic anemia, thrombocytopenia), infection, and the appearance of second tumors.

The emergence of chronic lymphocytic leukemia in patients with previously diagnosed chronic myeloid leukemia with Ph "chromosome is reported by R. Salim et al. The combination of primary myelofibrosis and chronic lymphocytic leukemia is rare - 8 cases have been described in the literature by the end of 2003. In one of them, the occurrence of chronic lymphocytic leukemia through 13 years after the diagnosis of primary myelofibrosis was combined with a stable condition of the patient for 16 years of follow-up Chronic lymphocytic leukemia can occur in patients with essential thrombocythemia.

DIAGNOSTICS
With the development of possibilities for the diagnosis of chronic lymphocytic leukemia with an increasingly low number of lymphocytes, it is necessary to be confident in the correct diagnosis and to distinguish between chronic lymphocytic leukemia and B-cell lymphocytosis. Patients with lymphocytosis less than 5x109 / L and with lymphadenopathy without cytopenia may have small lymphocyte lymphoma, which should be diagnosed with a lymph node biopsy.

A distinctive feature and diagnostic criterion of chronic lymphocytic leukemia, recommended by the National Cancer Institute-sponsored Working Group (NCI-WG), is the threshold value of the number of lymphocytes in the peripheral blood, equal to at least 5x109 / l, which morphologically should be represented by mature forms. In addition, the blood is characterized by the identification of "shadows" of Humprecht (destroyed during the preparation of a smear of lymphocytes).

Lymphocyte clonality should be confirmed by flow cytometry. Chronic lymphocytic leukemia cells express CD19, CD20 and CD23 antigens as well as CD5 antigen in the absence of other pan-T cell markers; B-lymphocytes are monoclonal with respect to the expression of kappa or lambda light chains of immunoglobulins. It should be noted that 7-20% of patients with chronic lymphocytic leukemia lack CD5, the presence of which is associated with autoimmune reactions. When studying two groups of patients in a case-control study with the presence of CD5 cells of chronic lymphocytic leukemia and without CD5 cells of chronic lymphocytic leukemia (expressing CD5 less than 5% of cells), it was found that in the early stages of chronic lymphocytic leukemia, splenomegaly, lymphadenopathy and hemolytic anemia were found in CD5 + patients in a significantly larger proportion than CD5 patients. The median survival in CD5-patients was 97.2 (22-130) months, significantly exceeding that in CD5 + patients - 84.0 (19-120) months, p \u003d 0.0025. CD5 patients have a milder course of the disease and have a favorable prognosis compared to patients expressing CD5.

Although bone marrow is involved in all patients, bone marrow aspirate and biopsy are usually not necessary for the diagnosis of chronic lymphocytic leukemia, although these procedures should be performed to determine cytogenetic abnormalities and before starting myelosuppressive therapy or when cytopenias of unknown origin. In the presence of an aspirate, lymphoid cells in the smear should account for at least 30% of all nucleated cells. When studying the diagnostic value of a computed tomography aspirate study, trepanobiopsy and flow cytometry data, it was shown that flow cytometry and trepanobiopsy allow better determination of B-cell infiltration, and flow cytometry itself allows better tracking of minimal residual disease.

Computed tomography is not an obligatory method in the diagnosis and staging of chronic lymphocytic leukemia, as well as positron emission tomography, except when it is necessary to choose the most metabolically active lymph node for biopsy during transformation into Richter's syndrome.

CLASSIFICATION OF CHRONIC LYMPHOLEUKOSIS
In these systems, the detection of isolated cytopenia may not always indicate stage III or IV of the disease, since patients with chronic lymphocytic leukemia may have immune cytopenias (thrombocytopenia or anemia), which do not increase the stage of the disease. According to the J. Binet system, the presence of only lymphocytosis is not classified at all, and none of the systems includes the detection of only splenomegaly. The small number of patients, on the basis of which both staging systems are built, is also a limitation.

In this regard, A.I. Vorobiev and M.D. Brilliant, a classification of chronic lymphocytic leukemia was proposed, in which an attempt was made on the basis of morphological and clinical signs, including the response to therapy, to identify the forms of chronic lymphocytic leukemia: benign, classical (progressive), tumor, splenomegalic, bone marrow, prolymphocytic, chronic lymphocytic leukemia, complicated chronic lymphocytic leukemia, proceeding with paraproteinemia, hairy cell leukemia, T-cell chronic lymphocytic leukemia. In the revised classification of chronic lymphodeioxis, the last four forms are excluded and the abdominal form of chronic lymphocytic leukemia is added.

However, taking into account new knowledge about the nature of chronic lymphocytic leukemia, this division may not be entirely justified, since it mixes several different diseases into one group or serves as a reflection of the clinical dynamics in patients with chronic lymphocytic leukemia. Since the clinical manifestations of the natural course of chronic lymphocytic leukemia are heterogeneous, we believe that the division of chronic lymphocytic leukemia along the course can be included in the classification, since in clinical practice two variants of chronic lymphocytic leukemia that are fundamentally different in manifestations are most often encountered - slowly (many years and even decades) current chronic lymphocytic leukemia and relatively rapidly developing with steady progression. A stable course of I.A. Kassirsky described it as a "frozen" form of chronic lymphocytic leukemia. E. Montserrat et al. suggested to allocate "smoldering" or "asymptomatic" chronic lymphocytic leukemia. The term myeloblastic leukemia is also used, reflecting both a group of examined patients with monoclonal B-lymphocytosis of undetermined significance and the preclinical stage of chronic lymphocytic leukemia, often developing into chronic lymphocytic leukemia after a long period of time.

As a result of the isolation of two types of chronic lymphocytic leukemia by the mutational status of the VH-genes of immunoglobulins, which are strikingly different in terms of survival, there is reason to believe that patients with chronic lymphocytic leukemia with a stable course (frozen chronic lymphocytic leukemia) belong to the group with VH-gene mutations (and without the signal protein ZAP -70), and in patients with a progressive course of chronic lymphocytic leukemia, there are no VH gene mutations and the ZAP-70 protein is expressed.

Data on the mutational status of chronic lymphocytic leukemia even lead to a discussion of whether chronic lymphocytic leukemia is one or two diseases. It is known that the subtype of chronic lymphocytic leukemia with VH gene mutations is equally common among men and women, while chronic lymphocytic leukemia without VH gene mutations is 3 times more common in men. Although complications such as autoimmune hemolytic anemia and hypogammaglobulinemia are encountered in patients with late-stage VH gene mutations, it is believed that the two subtypes of B cells in patients with chronic lymphocytic leukemia are fundamentally different and do not transform into each other.

At the same time, even VH gene mutations are not always a reliable predictor, since among patients with somatic mutations, a new subtype of CLL cells with mutations in the VH 3-21 immunoglobulin genes has been identified, in which the survival rate of these patients corresponds to that without somatic mutations. At the same time, in patients with the VH 3-21 genotype, a shortening of the CDR3 hypervariable region was revealed, which, together with CDR1, CDR2, and CDR4, is responsible for the physical complementary antigen binding. In addition, this group has a predominant expression of the light λ-chains of immunoglobulins. One of the possible explanations for the peculiarities of the clinical course of chronic lymphocytic leukemia in patients with few or no VH gene mutations may be the more frequent presence of cytogenetic changes that portend a poor outcome (deletions 11q22-23 and 17p, trisomy12 or p53 dysfunction), while cells patients with a biologically significant number of VH gene mutations more often have a 13q14 deletion associated with a favorable clinical course.

Thus, on the basis of literature data and our observations, in 2004 we (O. Rukavitsyn, V. Pop) proposed to single out the following variants of the course of chronic lymphocytic leukemia:
1) slow-flowing chronic lymphocytic leukemia (indolent);
2) progressive chronic lymphocytic leukemia;
3) chronic lymphocytic leukemia with transformation into large cell lymphoma (Richter's syndrome) or prolymphocytic leukemia.

Slow-flowing chronic lymphocytic leukemia is characterized by a stable (chronic) course with long-term preservation of stage 0 (I) according to K. Rai or stage A according to J. Binet, the absence of infectious complications. When studying the mutational status of the VH genes of immunoglobulins, most of these patients show mutations in the VH genes and the ZAP-70 protein is absent. It has been shown that 50-70% of patients with chronic lymphocytic leukemia have signs of somatic hypermutations of the VH genes of leukemic B cells. Cytogenetic analysis often reveals a 13q14 deletion associated with a favorable clinical course.

The progressive course of chronic lymphocytic leukemia is initially characterized by a relatively rapid increase in the stages of the disease according to K. Rai or J. Binet or by the diagnosis of the disease at an advanced stage. This option is often associated with atypical morphology, high blood lymphocytosis and diffuse bone marrow infiltration. Characterized by increasing lymphadenopathy, spleno- and hepatomegaly, the appearance of general symptoms of tumor intoxication, frequent infectious complications against the background of hypogammaglobulinemia, as well as the development of autoimmune hemolytic anemia, thrombocytopenia. Most of these patients lack VH gene mutations in the study of the mutational status of immunoglobulin VH genes and express the ZAP-70 protein. It also determines the frequent presence of cytogenetic changes that portend a poor outcome (deletions 11q22-23 and 17p, trisomy 12, or p53 dysfunction). In patients with a progressive course of chronic lymphocytic leukemia, the sensitivity to therapy decreases, the effect of treatment is short-term, the disease is steadily progressing.

The transformation of chronic lymphocytic leukemia is a transition to a much more malignant condition called Richter's syndrome. In patients with chronic lymphocytic leukemia / small lymphocyte lymphoma, Richter's syndrome means the development of diffuse large B-cell lymphomas, prolymphocytic leukemia, Hodgkin's lymphoma, or acute leukemia. Richter's syndrome develops in 2-10% of patients with chronic lymphocytic leukemia in the course of their disease with a transformation rate of 0.5-1% per year. First described in 1928 by M. Richter (generalized reticular cell sarcoma), the term was proposed in 1968 WHO classification of hematological tumors defined Richter's syndrome as the transformation of chronic lymphocytic leukemia into more aggressive lymphoma. Large cells in Richter's syndrome can occur as a result of transformation of the original cells of chronic lymphocytic leukemia, and also indicate the appearance of a new malignant clone.

The transformation of chronic lymphocytic leukemia into large cell lymphoma is accompanied by clinical signs of generalization of the tumor process, but does not always indicate a terminal state, a later stage of tumor progression, and a poor prognosis. For diagnosis, a biopsy is required, but due to the fact that Richter's syndrome does not develop simultaneously in all lymph nodes, it is necessary to perform positron emission tomography to select a node for biopsy with the most pronounced metabolic activity (SUV, standardized uptake value, standardized accumulation value of at least 5 , and better - more than 7). The transformation of ordinary mature cell chronic lymphocytic leukemia into prolymphocytic leukemia (5-8% of cases) is characterized by the appearance of an aggressive course of chronic lymphocytic leukemia resistant to therapy with high lymphocytosis, represented by prolymphocytes (in the blood and bone marrow), as well as splenomegaly. B-cell prolymphocytic chronic de novo leukemia is more benign than that associated with aggressive transformation.

PREDICTIVE FACTORS
Currently, possible risk factors are being actively clarified and much attention is paid to the study of prognostic factors in patients with chronic lymphocytic leukemia. It is assumed that on the basis of this knowledge, the selection of patients for initiation of therapy and the choice (change) of the treatment strategy can be improved.

Adverse prognostic factors, regardless of clinical stage, are over 55 years of age, male, black race, poor general somatic status and clinically significant comorbidities. Very important is the mutational status of B cells (or the presence of increased expression of the ZAP-70 protein), which differentiate the two types of chronic lymphocytic leukemia.

At the same time, the expression of the ZAP-70 protein is limited in chronic lymphocytic leukemia cells with unmutated VH genes. In various laboratories, the immunofluorescence method for the identification of ZAP-70 + cells in patients with chronic lymphocytic leukemia is not fully standardized, which requires clarification of the value of ZAP-70 for routine clinical practice. When comparing the results of the ZAP-70 study and mutational status in one of the comparative studies conducted in the United States, a discrepancy in the results of 23% was found, which is higher than in the previous two European studies. The discrepancy can be explained by the fact that in the American study the number of patients was 50% more than in the two European studies, as well as the younger age of patients studied in the United States.

The question of whether the severity of bone marrow infiltration and the degree of lymphoid infiltration (blood, lymph nodes, and internal organs and tissues) are independent factors remains controversial. The predictive value of information on bcl-2, fas gene expression and multidrug resistance remains unclear.

The presence of aberrant expression of the myelomonocytic antigen CD14 was studied by V. Callea et al. as a prognostic factor in patients with chronic lymphocytic leukemia. At the same time, they showed that the median overall survival of patients with a CD14 + cell count of more than 5x109 / L was 63 months and 136 months in patients with a CD14 + cell count of less than 5x109 / L. In addition to clinical and laboratory data and genetic characteristics (17p deletion / p53 mutation), according to T. Zenz et al., Factors of poor prognosis of chronic lymphocytic leukemia (very high risk group) are considered refractoriness to fludarabine and early relapse (within 24 months) or progression after R-FC (or R-FC-like) therapy.

The course of the disease is autoimmune, in other words, the human immune system begins to work in the opposite direction, producing antibodies that do not protect the diseased organ, but affect it. Most often, young men suffer from Reiter's syndrome due to untreated chlamydia, which has passed into the chronic stage.

Causes of occurrence

In addition to contracting chlamydia from unprotected sexual contact, Reiter's syndrome can develop as a result of a person's enterocolitis caused by salmonella. The immune system fails and begins to respond inadequately to the appearance of foreign bodies. The body produces antibodies aimed at damaging its own tissues, thereby helping foreign antigens. Thus, the first to begin to suffer are the articular connective tissues, which are destroyed under the pressure of the immune system.

It is currently unknown what causes the occurrence of Reiter's syndrome in some, and the absence in others. Modern medicine calls the main reason for the susceptibility to malfunctions of the immune system at the genetic level. This partly explains why Reiter's disease is quite often a harbinger of AIDS: pathologies of immunity provoke a genitourinary or intestinal infection to involve neighboring organs in the disease.

As for Reiter's syndrome as a result of a previous sexual infection, it most of all affects the male sex at the peak of sexual activity, between the ages of 20 and 40. Women suffer from joint disease infrequently, mainly they are carriers of the pathogens of chlamydia.

But with an intestinal infection, both men and women and children fall into the same risk zone, and in 80% of cases this is the result of a genetic predisposition.

Features of the disease

Reiter's syndrome develops in stages, involving the painful process organs one by one, without affecting all at the same time.

It all starts with the above infection. Since it happens that the disease does not give visible symptoms, then no connection with inflammation is found. But for the most part, Reiter's medical history is clear enough to make the whole picture:

• Damage to the genitourinary system or intestines;
• Inflammation of the organs of vision;
• Inflammation of the joint tissues.

The first two symptoms can last a short time unnoticed. And only when the patient comes with complaints of joint pain, the doctor determines the connection in the ailments of the eyes, urogenital area and joints that have arisen in a short period of time.

Symptoms

The development of the disease takes place in two stages.

Infectious - as a result of sexual contact, chlamydia enters the genitourinary sphere, where it begins to spread (urethra, prostate in men, cervix in women). This process takes from a couple of days to a month.

Men show the following symptoms:

1. Itching and burning sensation occurs on the genitals.
2. The outlet of the urethra becomes red and swollen.
3. Discharge appears.
4. Urination becomes painful.

The disease flows into the chronic stage, and the inflammation is transferred to the appendages and the prostate gland. As a result - prostatitis and epididymitis.

Symptoms of the disease in women are as follows:

• Inflammation (cervicitis) develops in the cervix;
• There are pains in the lower abdomen;
• Mild purulent discharge appears;
• When urinating, pain appears;
• Sexual intercourse is unpleasant.

The chronic stage of chlamydia in women brings with it menstrual irregularities and bleeding from the uterus.

Reiter's syndrome due to a gut infection begins first as a common gastrointestinal disorder. As a result of the use of products of inadequate quality, symptoms such as:

Due to intoxication, the patient suffers from chills, fever, joint aches and headaches.

Immunopathological - the infection goes beyond the genitourinary sphere and begins to devour the mucous membrane and articular tissues of the body.

1. The mucous membrane of the eyelids swells.
2. Discharge as in conjunctivitis.
3. Itching appears in eyeballs, sand hit syndrome.
4. The mucous membrane turns red, the vessels expand on the sclera.

Sometimes pathological processes occur in the iris, cornea, optic nerve.

Even "neglected" joint problems can be cured at home! Just remember to smear it with it once a day.

The main symptom of Reiter's syndrome is a failure in the functioning of the musculoskeletal system.

Signs of joint disease:

1. Pain appears in the joints of the legs (knees, ankles, phalanges of the fingers).
2. The peak of pain is at night and early morning.
3. The skin in the area of \u200b\u200bthe joints turns red, reaching a purple hue on the fingers.
4. Sore joints begin to swell to a spherical state.

Reiter's disease is characterized by the fact that it affects the joints of the legs ascending from the phalanges of the fingers and rising to knee joint... In this case, the joints of the upper extremities are very rarely affected by the disease, and even then in the complete absence of treatment for the disease.

An important symptom of Reiter's syndrome is the asymmetry of inflammatory signs. On the left foot, it can be, for example, the toes and metatarsus, and on the right foot, the heel and Achilles tendon.

In addition to inflammation of the organs of vision, ulcerative stomatitis in the mouth can be observed, ulcers appear on the head of the penis.

Feet and palms are covered with areas of keratinized, flaky skin. The nail plates break and turn yellow.

When the disease progresses to a severe stage, the most important internal organs are affected:

• Heart - expressed by myocarditis;
• Lungs - pleurisy or pneumonia develops;
• Nervous system - meningoencephalitis or polyneuropathy occurs.

Diagnosis of the disease

Collecting complete information about the development and course of the disease for the correct diagnosis is extremely important. And the main determining factor is the presence of a urogenital infection. In no case should you hide its presence out of a sense of false shame. Only a complete clinical picture will give the doctor the opportunity to make the correct diagnosis.

After the history is compiled, a number of laboratory tests are performed on samples of blood, urine, conjunctiva and mucous membranes of the urethra in men and the cervix in women. Sometimes semen is taken for analysis to determine the extent of the spread of the infection.

When Reiter's syndrome enters the stage of immunopathology and articular tissue is damaged, an analysis of synovial fluid taken by puncture is required. Such a study is extremely important if the course of the disease is aggravated by cardiac pathologies - it allows you to accurately determine the cause of arthritis, finding out whether the infection is to blame or rheumatism.

In addition to laboratory studies, X-rays of the joints are performed to determine the articular pathologies accompanying the disease.

By sowing feces, the causative agents of intestinal infections are identified. By analyzing genes, the presence of a predisposition to pathologies of a rheumatic nature is determined.

Treatment

Reiter's disease is complex in its course, and it is necessary to treat it with the involvement of specialists in various fields. Regardless of what stage the disease is at, treatment tactics are developed only after consulting the patient with a number of doctors: urologist, rheumatologist, ophthalmologist and other specialists.

This is done in order to exclude the occurrence of complications or relapse after the course of treatment.

Treatment with medicines has two main principles: anti-inflammatory and antibacterial.

To suppress the infection, use 2-3 different types antibiotics that are taken for 2 to 3 weeks:

1. Tetracycline or Doxycycline.
2. Ciprofloxacin, Lomefloxacin, Ofloxacin.
3. Erythromycin, Azithromycin, Clarithromycin.

Anti-inflammatory therapy is carried out with the aim of eliminating inflammatory currents in the articular tissues due to chlamydial lesions:

It is necessary to change the drug after two weeks of treatment for the disease in order to avoid its addiction by the body.

At the same time, complications are treated. This includes treatment with hormones, antihistamines, and other therapies.

It is imperative, in parallel with the treatment of Reiter's syndrome, to stop its concomitant diseases - cholecystitis, prostatitis, acute respiratory infections and other diseases that inhibit the effectiveness of treatment, slow down the healing process and can cause complications.

Adjunctive treatments for Reiter's syndrome

After the removal of acute inflammation in the joints, for the most effective treatment connect physiotherapy:

• Phonophoresis of joints with medicinal applicators;
• Magnetotherapy.

At the stage of the just beginning Reiter's syndrome, a complex of exercise therapy is used in order to preserve the mobility of the joints. If muscle atrophy occurs, massage and mineral baths with radon or hydrogen sulfide are used.

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CHAPTER 25 RICHTER'S SYNDROME

Richter's syndrome is a peculiar and unique in its kind clinical and morphological phenomenon, characterized by a combination of two, usually sequentially developing malignant processes - lymphocytic and large cell.

For the first time "generalized lymph node reticulosarcoma associated with lymphatic leukemia" was clearly described by M.K. Since then, due to a radical change in the concept of hemopoiesis and the widespread introduction of immunological methods of research, the lymphoid nature of a large cell tumor complicating the course of chronic lymphocytic leukemia or lymphosarcoma with lymphocytic leukemizacin has been proven and is currently not a subject of discussion. Nevertheless, for 70 years, in essence, the main pathogenetic question remains open, which logically follows from the problem of "associated" lymphoproliferative diseases - about the origin of large cell lymphosarcoma: is it the result of the transformation of lymphocytes (prolymphocytes) or is it a second tumor that is not clonally (genetically) related with lymphocytic leukemia / chronic lymphocytic leukemia?

It would seem that Richter's syndrome is a rather simple clinical situation, when a patient is consistently found two different, more often B-cell tumors - lymphocytic with lymphocytosis of the blood / bone marrow and large extra-medullary cells. However, the apparent simplicity of the phenomenon hides a clinical and morphological phenomenon that is extremely “problematic” from the point of view of interpreting its essence.

We have to admit that the current level of knowledge does not allow formulating a unified concept of the pathogenesis of "associated" lymphoproliferative diseases. The main achievement of recent years - the transition from the cellular to the molecular-genetic level of examination of patients with Richter's syndrome with the study of rearrangements / mutations of immunoglobulin genes, some oncogenes (p53, etc.) made it possible only to approach the final solution of the problem. It is most difficult to prove that diseases originate from different clones and there is no genetic (clonal) relationship between oncogenic events that led to the development of first lymphocytic and then large cell tumors. In other words, it is much easier to confirm the single-clonal origin of lymphocytic leukemia / chronic lymphocytic leukemia and large cell lymphosarcoma in Richter's syndrome than to reject it. Even the detection of various types of rearrangements of immunoglobulin genes in cells of lymphocytic and large cell tumors does not always indicate the origin of these diseases from different clones. Apparently, this is due to the very nature of immunoglobulin genes prone to somatic hypermutations, deletions, class switching with selection of the most affinity cell clones.

Most likely, the concept of "Richter's syndrome" is much broader than it seems at first glance, and includes cases of both clonal progression and the occurrence of second tumors. To a certain extent, this is confirmed by the results of morphonimmunological and in-depth molecular genetic studies, which, despite the complexity of the problem, nevertheless shed light on the clonal relationship between two malignant processes - lymphocytic and large-cell. However, the question

about whether there is one clone or two unrelated, one disease or two independent, often remains open. Essentially, Richter's syndrome has become a special and extremely complex area of \u200b\u200bimmunological and molecular genetic research.

It is known that not every erelocellular lymphatic tumor ends with the attachment of a large cell lymphosarcoma. Bo

moreover, Richter's syndrome is a rare clinical and morphological phenomenon and, according to various authors, occurs only in 3-10% of patients with chronic lymphocytic leukemia / lymphocytic lymphoma.

Judging by the literature data, the development of large cell lymphosarcoma in patients with mature cell lymphoproliferative diseases is a poor prognostic sign and, as a rule, is accompanied by deterioration of the condition, the appearance of general symptoms and generalization of the extramedullary tumor process. Life expectancy after detection of a large cell sarcoma usually does not exceed six months, despite the use of combined chemotherapy methods that are adequate for high-grade lymphomas.

An analysis of 8 our observations of Richter's syndrome indicates that the development of large cell lymphoma along the course of a chronic lymphatic tumor does not always mean a terminal state, a later stage of tumor progression, and a poor prognosis. Only in half of the patients, such a "transformation" was accompanied by a worsening of the condition and the addition of general symptoms, while the rest of the state of health remained unchanged. After the diagnosis of large cell lymphosarcoma was established, life expectancy ranged from 3.5 months to 9 years.

In Richter's syndrome, isolated extranodal localization of foci of large cell lymphosarcoma is sometimes observed. Thus, an isolated lesion of the vitreous body, skin, soft tissues with destruction of the vertebra, substance of the brain, testicles, stomach and (or) intestines, kidneys, bronchial tree with epdobronchial tumor growth is described.

It should be borne in mind that the spectrum of malignant lymphoproliferative diseases occurring with lymphocytic infiltration of the bone marrow and leukemic blood picture is not limited to chronic lymphoproliferative leukemia and its clinical variants. In all mature cell forms of lymphomas (lymphocytic, lymphoppasmocytic, centrofollicular, mantle cell, from cells of the marginal zone, including MASh ”), early involvement of the bone marrow in the tumor process with the development of a picture of chronic lymphocytic leukemia is possible. In a word, under the name "lymphocytic leukemia" can hide a wide range of mature cell lymphoproliferative tumors, in which the development of large cell lymphosarcoma is possible, which fully corresponds to the concept of Richter's syndrome.

The name “large cell lymphoma” also unites a number of lymphosarcomas with a diffuse growth pattern: centroblastic (macrolymphoblastic), immunoblastic, from cells with multilobular nuclei, as well as large cell a n and a plate

Of particular interest are those rare clinical observations in which the development of large cell lymphosarcoma is accompanied by the disappearance of blood and bone marrow lymphocytosis. Some authors describe such cases as a rare variant of Richter's syndrome with regression of chronic lymphatic leukemia. It is difficult to explain such a course of a lymphocytic tumor. It is possible that it is in these cases that speech can go

transformation (clonal progression) of one variant of malignant non-Hodgkin's lymphoma into another, more aggressive one.

However, the assumption of transformation does not find proper morphological confirmation. The fact is that in tissue infiltrates, tumor changes of two distinctly different types are most often simultaneously detected - lymphocytic and large-cell. It seems that both tumors coexist and develop simultaneously in the same tissues and organs. Our research confirms what has been said. Indeed, in histological preparations, the cellular forms transitional between small lymphocytes and large lymphoid elements were not found. However, when studying the prints in individual patients, the cytogram was mixed-cell: between the smallest cells - lymphocytes and the largest - nm-munoblasts, a rather noticeable population of medium-sized tumor elements was found, which, possibly, were at different stages of morphological differentiation and which could well be attributed to to transitional forms.

During the development of large cell (immunoblastic) lymphosarcoma in more than half of the patients, we observed spontaneous regression of lymphocytosis, i.e. the disappearance of the main symptom of a lymphocytic tumor. However, the basis of combined lymphoproliferative diseases is not so much cases with regression of lymphocytosis (there are extremely few of them), as Richter's syndrome, when both diseases - lymphocytic and large cell - coexist in parallel, often affecting the same tissues, including the bone marrow. Consequently, the disappearance of lymphocytosis during the development of a large cell tumor is by no means a regularity. On the contrary, in our observations in 2 patients, generalization of immunoblastic lymphoma was

was driven by the growth of blood and bone marrow lymphocytosis to the very high values for the entire observation period.

The immunological study of malignant lymphoma cells at the modern level involves not only the assessment of linearity, the state of activation or dormancy, but also the determination of the degree of differentiation. The detection of diffuse large cell lymphoma in a blood and bone marrow picture characteristic of a lymphocytic tumor only at first glance presents a difficult clinical situation for interpretation.In such cases, for correct diagnosis, optimal solution of tactical issues and the choice of the most adequate chemotherapy method, it is very important to number and results of nmmunologic

1. Anikin B. S. Likhachev A. A. Pekina L. N. and others. Ter. architect-1979.-№ 9, -S.118-121.

2. Arutyunov VD. Arch. US Pat. No. 1956, No. I.-С.56-59.

3. Demidova A.V. Vorobiev A.I., Datsenko S.F. et al. Probl. hematol.-1967 .-- T.! 2, No. I.-S.10-17.

4. Krtoye A.A. Ter. architect-1974.-№ 8, -S.49-51.

5. Probatova NA., Mamedov R.D., Kruglova G.V. Arch. US Pat, -1988.-T. b, No. 3.-C, 37-43.

6. Faya \\ ITain FZ, Polyanskaya AM Ter. arch.-1984.-№ 10.-С-80-83.

7. Ashog S. () 1.-1987, -YoSh, No. 12.-P.901-903.

13.Oipp R., Kii T.T .. Tgep N.G. L Roggyuz Mesh A 85-

1995. -Yo1.94, No. 1b-P.686-688.

14.W% e1 O.O., Ussigkn O.U., EipN E.E. er a1. Ateg. L CazeroenC, -! 995, -Vo1.90, No. 4.-P.635-637.

15.Eoget V., Conn / Boten R. Mtshua Mei-1984.-V01.75, N 45-46.-P.2741-2749.

16.Ezhsat K., Nut YE Sapseg -1980 .- "Yo1.4" .- RL18-134.

Reiter's disease

Reiter's disease (Reiter's syndrome) is a concomitant or simultaneous lesion of the eyes (conjunctivitis), joints (reactive mono- or oligoarthritis) and urinary organs (usually nonspecific urethroprostatitis). Reiter's disease develops when genetically predisposed people have chlamydial infection... Usually this disease develops at a young age, men get sick more often than women about twenty times. The peak incidence occurs in the age range from twenty to forty years (about 80%). There are isolated cases of morbidity in children

Reiter's disease - causes of occurrence

Most often, in the development of Reiter's disease, in addition to a genetic predisposition, various infections of the digestive and urinary systems play a role. Usually, the disease begins with urethritis, which occurs after an exacerbation of any chronic urinary tract infection or after sexual intercourse. In the presence of an unfavorable epidemic situation, which is often present in tourist and military camps, acute enterocolitis of yersiniosis, salmonella or shigellosis origin can be a catalyst for the development of Reiter's disease. In the mechanism of joint damage, the main importance is attached to hereditary predisposition and immune processes.

Reiter's disease can be caused by certain types of chlamydia, which usually affect the mucous membranes of a person, penetrating into his body through the urogenital organs and subsequently affecting other systems and organs. Due to the fact that chlamydia can be in the patient's body for a rather long time, there is a high probability of exacerbations and relapses of this disease, or the development of chronic Reiter's disease

The manifestations of conjunctivitis, arthritis and urethritis come to the fore in the clinical picture of Reyer's disease. In addition, there may be changes in the mucous membranes and parenchymal organs (central nervous system, aorta, myocardium, kidneys, liver, etc.).

The sequence of the main symptoms can be different, but most often Reiter's disease begins with the development of diseases such as cystitis, urethritis or prostatitis. With this disease, urethritis can be different in its severity - from worn out, prone to a protracted / chronic course, to acute with the presence of strong purulent discharge. Urethritis is manifested by burning, itching, scanty discharge from the vagina and urethra, hyperemia around the outlet of the urethra and unpleasant sensations when urinating. The discharge is usually slimy.

Soon after urethritis, a person experiences eye damage, which is most often manifested by conjunctivitis, less often keratitis, retrobulbar neuritis, retinitis, uveitis, iridocyclitis, iritis. Conjunctivitis in Reiter's disease is most often bilateral, mild and resolving after one or two days. Very often it goes unnoticed.

The defeat of the joints in Reiter's disease is the leading symptom and develops after one to one and a half months after the development of an acute urogenital infection. The most characteristic lesion is asymmetric arthritis, involving the joints of the lower extremities - interphalangeal, metatarsophalangeal, ankle and knee. Joint pain is usually worse in the morning and at night, the skin over them is hyperemic, there is an effusion. After several days, there is a characteristic sequential (from bottom to top) involvement of the joints. Development of calcaneal spurs, calcaneal bursitis, inflammation of the Achilles tendon is often observed. Some patients experience pain in the spine, which subsequently leads to the development of sarcoiliitis.

Relapses of arthritis are noted in 30% of patients; in 20% of patients, arthritis becomes chronic with atrophy of the adjacent muscles, as well as limitation of joint function; in 50% of patients, joint symptoms disappear completely. Due to damage to the tarsal joints, some patients may develop flat feet. The defeat of the joints of the upper extremities is extremely rare. About 50% of patients are susceptible to damage to the skin and mucous membranes. Painful ulcers appear in the area of \u200b\u200bthe glans penis and on the oral mucosa, balanoposthitis or balanitis develops, glossitis and stomatitis may develop. The defeat of the skin is characterized by the appearance of small red papules, and sometimes erythematous spots. Reiter's disease is characterized by keratoderma, which, against the background of skin hyperemia, is expressed by confluent foci of hyperkeratosis with peeling of the palms and feet. Also, often foci of hyperkeratosis are observed on the skin of the trunk and forehead.

With Reiter's syndrome (disease), painless enlargement of the lymph nodes (often inguinal) can be observed; about 20% of patients have signs of heart damage (myocarditis, myocardial dystrophy), kidney damage (renal amyloidosis, nephritis), nervous system (polyneuritis), lungs (pleurisy, focal pneumonia) and prolonged low-grade body temperature

Diagnosis of Reiter's disease

In the presence of a triad characteristic of this disease (conjunctivitis + urethritis + arthritis), the diagnosis of Reiter's disease does not cause practically any difficulties. In case of insufficient severity of individual symptoms, or in atypical cases, an X-ray examination of the joints is indicated. Analyzing the synovial fluid will reveal signs of inflammation. A biopsy of the synovial fluid will reveal a picture of nonspecific subacute or acute inflammation. A general biochemical blood test does not reveal any abnormalities. The appearance of pus is observed in the urine

Treatment of Reiter's disease solely for joint damage, which is the most disturbing and striking manifestation of the disease, does not give the desired results and usually leads to a protracted or chronic course of the disease. Treatment with drugs of the cephalosporin and penicillin groups leads to the same result. It is necessary to treat both the patient himself and his sexual partner.

In Reiter's disease, all therapeutic measures can be conditionally subdivided into such main areas as anti-inflammatory therapy of the articular substance and antibacterial therapy of infection.

Antibacterial treatment of urethritis is primarily carried out with drugs of the tetracycline series. In the treatment of arthritis, such non-steroidal anti-inflammatory drugs as voltaren, indomethacin, aspirin, diclofenac, etc. are used. In the case of high disease activity and with pronounced systemic manifestations, the use of glucocorticoids is indicated. In the case of chronic or protracted arthritis, the use of gold salts or quinoline derivatives is indicated.

Primary prevention of Reiter's disease is based on compliance with standard sanitary and hygienic rules, timely treatment of cystitis, urethritis and other urinary infections. In the case of a chlamydial infection, treatment of both sexual partners is mandatory.

Reiter's syndrome: symptoms and treatment

Reiter's syndrome is accompanied by a triad of inflammatory lesions of the joints, eyes and genitourinary organs. In 80% of cases, it is observed in young men, less often in women, extremely rarely in children. If untreated, it can cause serious complications - up to the patient's disability.

In this article, we will introduce you to the symptoms and main methods of treatment and prevention of Reiter's syndrome. Having this information, you will be able to make a decision in time about the need to see a doctor to prevent such complications of this pathological process as chronicity of the disease, impaired mobility of the spine and the development of visual impairment (up to blindness).

For the first time, Reiter's syndrome was described as a complication of an intestinal infection, and later it became known that it can also be provoked by infectious processes in the genitourinary system. The reason for the development of this ailment is an autoimmune reaction that occurs in response to the introduction of a bacterial or viral agent.

More often it develops against the background of chlamydia, and sometimes it is not possible to identify its exact cause of development.

In addition to chlamydia, the syndrome can be provoked by ureaplasmas, salmonella, shigella and yersinia. And most experts are inclined to the theory that there is a hereditary predisposition to the occurrence of such an autoimmune reaction in response to infection.

Symptoms

Reiter's syndrome develops after 1.5-2 months after suffering a genitourinary or intestinal infection. And its course can be:

• acute - up to six months;
• protracted - up to 1 year;
• chronic - more than 1 year.

Symptoms from the genitourinary system

It is the signs of damage to the genitourinary system that often become the first signals of the onset of the development of Reiter's syndrome. They are manifested by symptoms of urethritis, cystitis, prostatitis, vaginitis, etc.

Men usually experience the following symptoms:

• discomfort during emptying the bladder: itching, burning, mucous discharge;
• increased urination;
• hyperemia of the external opening of the urethra;
• pain or discomfort during sex;
• pain in the lower abdomen.

Women usually experience the following symptoms:

• vaginal discharge;
• burning, pain and cramps when urinating;
• increased urination;
• pain during intercourse;
• discomfort or pain in the lower abdomen.

In laboratory tests - smears and urine - leukocytosis is determined.

Symptoms from the organs of vision

Within a short period after the appearance of signs of damage to the genitourinary tract, the patient develops signs of eye inflammation. Subsequently, they lead to the development of conjunctivitis, and in severe cases they cause iritis, iridocyclitis, retrobulbar neuritis, uveitis or keratitis.

With Reiter's syndrome, the patient is worried about the following symptoms of eye damage:

• pain and discomfort;
• lacrimation;
• mucous or purulent discharge;
• deterioration of vision;
• redness of the eyes;
• photophobia.

Sometimes mild manifestations of conjunctivitis are observed only during the first two days and go unnoticed.

Joint symptoms

The main manifestation of Reiter's syndrome is joint damage, which first makes itself felt 1-1.5 months after the appearance of signs of damage to the genitourinary system or their exacerbation. Usually, with this disease, inflammation of 1-2 joints occurs (mono- or oligoarthritis), but sometimes the course of the pathological process captures many joints and the patient develops polyarthritis. More often, the joints of the legs become inflamed and this process spreads according to the bottom-up principle (i.e., first, arthritis of the ankle joint develops, and then - the knee joint, etc.).

With Reiter's syndrome, the patient is worried about the following symptoms of joint damage:

• pain;
• asymmetry of joint damage;
• discoloration of the skin over the joint (from red to bluish color);
• hyperthermia and swelling of the skin in the area of \u200b\u200binflammation.

In some cases, with Reiter's syndrome, the sacroiliac joint and the joints of the spinal column are affected. In this case, the patient develops stiffness in movements in the morning and pain. And with damage to the joints of the foot, a rapid formation of flat feet can occur.

According to statistics, in half of the patients, the symptoms of arthritis disappear completely, in 30% - recurrent arthritis occurs, and in 20% - chronic arthritis, leading to limitation of the functionality of the joints and atrophy of the adjacent muscles.

Other symptoms

Sometimes with Reiter's syndrome, always accompanied by a triad of characteristic symptoms, signs of damage to other organs appear.

Red spots may appear on the skin, which rise above its surface in the form of bumps. As a rule, such changes are observed on the palms and soles. In the future, the formation of compacted zones with signs of peeling and keratinization of the skin is possible.

Sometimes with the syndrome, damage to the mucous membranes occurs. Such signs are observed on the genitals and in the mouth.

Against the background of arthritis, inflammation can occur in the area of \u200b\u200battachment of tendons and ligaments. Such processes are accompanied by the appearance of pain, redness and swelling. As a rule, such an inflammatory process is localized in the area of \u200b\u200bthe Achilles tendon.

In extremely rare cases, Reiter's syndrome leads to inflammatory processes in the kidneys, lungs or heart.

Diagnostics

A presumptive diagnosis of "Reiter's syndrome" can be made on the basis of information about a previous genitourinary or intestinal infection and the presence in the patient's complaints of data on a triad of symptoms typical for this disease. To confirm the diagnosis, the patient is assigned a number of laboratory tests:

• clinical blood test - leukocytosis, increased ESR;
• scraping from the urethra or vagina - detection of chlamydia or ureaplasma;
• analysis of joint fluid - detection of chlamydia;
• blood biochemistry - the absence of rheumatoid factor and the presence of C-reactive protein;
• scraping of the mucous membrane of the eye - identification of chlamydia;
• immunological blood test - high titer of immunoglobulins M and G;
• genetic analysis - determination of the HLA-B27 gene;
• PCR of blood - detection of DNA of chlamydia / ureaplasma.

To identify violations in the joints and adjacent tissues, the following instrumental methods can be prescribed:

Treatment

Reiter's syndrome therapy is always complex and takes from 3 to 12 months. Its main goals are aimed at eliminating the infectious agent, arresting the inflammatory process and suppressing the autoimmune response.

For the treatment of chlamydia or ureaplasmosis, several antibiotics are prescribed at maximum doses. To prevent re-infection, taking the same drugs is recommended for a sexual partner. The patient can be assigned a combination of the following funds:

• macrolides: Klacid, Zi-factor, Clarithromycin, Roxithromycin;
• fluoroquinolones: Ciprofloxacin, Sparfloxacin, Ofloxacin;
• tetracyclines: Doxycycline.

Antibiotic therapy is carried out for a long time - for 3-8 weeks - and can lead to the development of candidiasis and organ damage digestive tract... To prevent these undesirable consequences, the following drugs are used:

• hepatoprotectors: Legalon, Heptral, Karsil, Hepa-Merz, Essentiale, Hepabene, etc.;
• antimycotics: Clotrimazole, Pimafucin, Fluconazole, etc.;
• multivitamin complexes: Biovital, Alphabet, Dexavit, Vitrum, etc.

For maximum efficiency antibacterial therapy the parallel intake of proteolytic enzymes is recommended: trypsin, chymotrypsin or wobenzym.

For the treatment of inflammatory lesions of the eyes, antibacterial and anti-inflammatory drops and ointments based on tetracycline and erythromycin are used. To reduce inflammatory reactions, lotions from infusions of medicinal herbs (chamomile, calendula, etc.) allow.

• non-steroidal anti-inflammatory: Nimesulide (or Nimegesic), Arcoxia, Dicloberl, Celecoxib;
• glucocorticosteroids: Prednisolone, Polcortolone, Diprospan, Kenalog.

These drugs can help reduce inflammation, pain, swelling, and lower body temperature.

An important part of the treatment of Reiter's syndrome is the use of drugs to suppress the autoimmune reaction aimed at the destruction of connective tissue. They are used for a long time (4-12 months), and in severe cases they are prescribed to the patient for lifelong admission.

The following immunosuppressants are used to treat Reiter's syndrome:

Against the background of taking such drugs, the body's resistance to infectious diseases decreases and for their prevention, the patient is recommended to take immunomodulators:

Techniques such as ultraviolet blood irradiation and intravenous quantum therapy can be used to enhance immunity.

With an increase in temperature and intoxication, the patient is prescribed desensitizing agents (Feniramine, Loratadin, Ketotifen) and intravenous administration of rheopolyglucin or rheosorbilact solutions. Such detoxification therapy not only eases the patient's condition, but also increases the effectiveness of other drugs.

After the inflammatory process subsides, physiotherapy is prescribed:

• physiotherapy;
• amplipulse therapy;
• magnetotherapy;
• electrophoresis with novocaine solution.

Prophylaxis

There are no specific measures for the prevention of Reiter's syndrome. To prevent its development, measures are recommended to prevent and timely treatment of sexually transmitted diseases.

Which doctor to contact

The severity of Reiter's syndrome is determined by the damage to the joints, therefore the rheumatologist prescribes the main therapy. With concomitant pathology of the external genitourinary organs, it is necessary to consult a urologist, gynecologist and venereologist. Eye damage is a reason for consulting an ophthalmologist. Treatment by a physiotherapist is also necessary.

A specialist at the Moscow Doctor clinic talks about Reiter's syndrome:

Channel One, the program "Life is great!" with Elena Malysheva, in the heading "About medicine" talk about Reiter's syndrome (from 32:45):

Help children

Helpful information

Contact the specialists

Telephone appointment service for medical specialists in Moscow:

The information is provided for informational purposes only. Do not self-medicate. At the first sign of disease, consult a doctor.

Editorial office address: Moscow, 3rd Frunzenskaya st., 26

JANUARY - MARCH 2008

CLINICAL

ONCO hematology

RARE AND COMPLEX HEMATOLOGICAL SYNDROMES

Richter's syndrome with primary skin lesions in a patient with chronic lymphocytic leukemia

M. A. Volkova, M. Yu. Kichigina, D. Sh. Osmanov, A. M. Kovrigina,

N. A. Probatova, A. I. Pavlovskaya, M. A. Frenkel,

N.N. Tupitsyn, E.N. Sholokhova, A. I. Karseladze, E. A. Nikitin,

A.V. Pivnik, V.A.Tumakov, R.A.Makhmudov

ESSAY_________________________

A description of a patient who was diagnosed with chronic lymphocytic leukemia at the age of 48 is given. Periodically received various courses of chemotherapy, including alkylating drugs, purine analogs (fludarabine), anthracyclines (mitoxantrone), monoclonal antibodies (mabthera), corticosteroid hormones (dex-samethasone). In the 4th year of the disease, the patient developed tumor formations on the scalp, trunk and extremities, nasal mucosa and oropharynx. Histological and immunohistochemical studies diagnosed the development of diffuse large B-cell lymphoma - Richter's syndrome.

Keywords

chronic lymphocytic leukemia, skin, Richter's syndrome

Richter syndrome with primary cutaneous presentation in a patient with chronic lymphocytic leukemia

M.A. Volkova, M.Yu. Kitchigina, E.A. Osmanov, A.M. Kovrigina, N.A. Probatova, A.A. Pavlovskaya, M.A. Frenkel, N.N. Tupitsyn, E.N. Sholokhova, A.I. Karseladse, E.A. Nikitin, A.V. Pivnik,

V.A. Tumakov, R.A. Mahmudov

It is a case report of the patient with chronic lymphocytic leukemia (CLL) who received treatment with alkylating agents, purine analogs, anthracyclines, rituximab, glucocorticoids, and after 4 years of the disease developed Richter syndrome with primary presentation in the skin.

chronic lymphocytic leukemia, skin, Richter syndrome

N. N. Blokhin Cancer Research Center, Moscow; Research Hematology Center, Moscow; N.I. Pirogov National Medico-Surgical Center, Moscow;

Regional Hospital, Ivanovo

Contacts: [email protected]

INTRODUCTION

Specific skin lesions in chronic lymphocytic leukemia (CLL) are rare. L. Cerroni et al, 1 having, judging by the available publications, the largest number of observations, report 42 patients with CLL studied for specific skin lesions in a dermatological clinic for 25 years (from 1969 to 1994). K. Agnew et al2, among 750 patients with CLL, observed by them over a 30-year period, noted a variety of skin lesions in 40 patients, however, only three of them had skin lesions in the form of lymphoid infiltrates with a specific immunohistochemical picture for CLL.

Specific skin lesions described by different authors are diverse in appearance - these are papules, spots, nodules or rather large tumor formations. They can be localized or generalized, located on the head and neck, trunk and limbs. Some authors indicate that the most characteristic places are

the localization of specific skin lesions is the nipple, scrotum, and auricle areas.3 In old dermatology textbooks, these areas were indicated as the most typical in cases where skin lesions developed at the very beginning of CLL.4

Occasionally, specific skin lesions appear at the site of scars from herpes simplex or, more commonly, herpes zoster.1 Ulceration is uncommon for skin lesions in CLL.

In some cases, specific skin lesions appear at the very beginning of the development of CLL and are the first reason for a patient to see a doctor. Morphological and immunohistochemical studies in these cases, as a rule, reveal monomorphic infiltrative formations consisting of small CD5- and CD19-positive lymphocytes expressing immunoglobulins with light chain restriction on the surface. In all investigated cases, using the polymerase chain reaction, it was possible to confirm the belonging of lymphocytes that form skin infiltrates, and lymphocytes

GU RONTs them. N.N.Blokhin RAMS; Hematological Research Center of the Russian Academy of Medical Sciences; National

medical and surgical center. N.I. Pirogova; OGUZ Ivanovo Regional Clinical Hospital

Richter's syndrome

of this patient's bone marrow to one clone.3-5 As a rule, a small amount of T-lymphocytes is also found in the infiltrates. T-cell infiltration in these cases is polyclonal, it can be regarded as reactive, reflecting the local immune response in response to the onset of a tumor.1

Sometimes, however, in the described cases, specific skin lesions in CLL had the morphological features of large cell lymphoma. The skin could be the only localization of lymphoma or be combined with the defeat of large cell lymphoma of other organs and tissues - lymph nodes, spleen, liver.

The development of diffuse large cell lymphoma in a patient with CLL, first described by M. Richter6 in 1928 and subsequently named after him - Richter's syndrome, 7 is the outcome of CLL, according to various sources, in 2-6% of patients.8-10 The development of Richter's syndrome is usually characterized by the appearance of general symptoms - fever and weight loss, torrential sweats, weakness and a rapid increase in one or, more often, a group of lymph nodes, spleen, liver. The appearance of skin infiltrates as a manifestation of Richter's syndrome is extremely rare and, as far as we know, reports about this are limited to several publications.1,2,8,11-14 So, L. Robertson and et al, 8 published the largest number of observations of Richter's syndrome in patients CLL, skin lesions were noted in only 2 of 39 patients. L. Cerroni et al1 diagnosed Richter's syndrome in 2 of 42 CLL patients who went to a dermatological clinic for skin lesions.

We present our own observation of the development of Richter's syndrome with skin lesions in a patient with CLL. It is the only one in our practice among hundreds of patients observed for CLL.

CLINICAL CASE

Patient P., 52 years old, applied to the N.N. NN Blokhin in November 2005 about the appearance of lumpy formations on the scalp, trunk and limbs and a rapid increase in their size and number.

From the anamnesis it is known that in July 2001, when visiting a doctor at the place of residence for an acute respiratory illness, the patient was diagnosed with CLL. The number of leukocytes at that time was 19x 109 / l, of which lymphocytes - 67%. In the myelogram, lymphocytes accounted for 68.2%. Since the hemoglobin level, the number of erythrocytes and platelets were normal, the patient was not prescribed treatment. In February 2002, the number of leukocytes in the blood reached 49 x 109 / L, of which 86% were lymphocytes. The hemoglobin content, the number of erythrocytes and platelets remained normal, the size of the lymph nodes was only slightly increased. Received no treatment.

In May 2002, the number of leukocytes in the blood increased to 62 x 109 / l, of which 92% were lymphocytes. The patient was consulted at the Hematological Scientific Center of the Russian Academy of Medical Sciences. Treatment with COP was recommended, followed by maintenance therapy with cyclophosphamide or chlorobutin. The patient received 6 courses of COP, after which he received cyclophosphamide 300 mg 1-2 times a week. The condition remained satisfactory until February 2003, but there was a gradual increase in the size of the lymph nodes in the cervical-subclavian, axillary and groin areas, and the spleen began to be palpable. Immunophenotyping of blood cells and bone marrow punctate (RCRC RAMS, 02/20/03) confirmed the diagnosis of CLL (CD19 + CD5 + lymphocytes in the blood were 61.9%, CD19 + Cd23 + ------ 47%, CD38 + ---- 15.1%, in bone marrow

vom punctate CD19 + CD19 + CD5 + lymphocytes accounted for 79.8%, CD19 + CD23 + - 45.3%, CD38 + - 15.3%).

In February 2003, the patient was again consulted at the Hematological Research Center of the Russian Academy of Medical Sciences, where he was recommended to receive treatment according to the R-MFCD scheme: rituximab (mabthera), mitoxantrone, fludarabin, cyclophosphamide, dexamethasone. During the year received only 6 cycles of therapy with the indicated drugs: 3 with MabThera and 3 without

Fig. 1. Picture of scalp lesions before treatment

Fig. 2. The same area of \u200b\u200bthe scalp after treatment

mabthera. After that, from December 2004 to May 2005, he received only cyclophosphamide treatment. In May 2005, due to a new increase in the number of leukocytes and lymphocytes in the blood, treatment with fludarabine in combination with mabthera was started. In total, he received 3 courses of such therapy, the last one in September 2005.

In June 2005, the patient for the first time noted the appearance on the mucous membrane of the mouth and on the skin throughout the body of formations of various shapes, sizes and colors. Some of them had the character of spots without clear boundaries, but more often they were dense, bumpy, reddish-cyanotic tumor-like formations of different sizes. They somewhat decreased in size during the course of therapy, but a few days after the end of treatment they acquired the same or even more significant sizes. In September, a tumor-like formation appeared in the nasal cavity, which impedes nasal breathing.

The patient turned to the Russian Cancer Research Center and on November 17, 05 was hospitalized in the department of chemotherapy for hemoblastosis.

Upon admission, the general condition is satisfactory, active. The voice is changed due to the almost complete absence of nasal breathing. On the scalp, trunk and extremities there are multiple convex, rounded reddish-cyanotic tumor formations ranging in size from a pea to a large walnut (Fig. 1), some have indistinct edges and a diameter of up to 7 - 8 cm. On the oral mucosa and in the corners of the eyes there are small formations of the same type. On the anterolateral surface of the right lower leg under the skin, a dense formation measuring 12 x 7 cm is palpable. The skin above it is not changed, the skin temperature is not increased.

There is an increase in peripheral lymph nodes - occipital, submandibular, cervical, chin, their sizes from 2 x 1.5 to 2x3 cm. Inguinal lymph nodes enlarged significantly and form conglomerates - on the right 8 x 10 cm, on the left 4 x 5 cm, dense consistency. The liver is not palpable, the edge of the spleen is palpable in the position on the right side.

X-ray and computed tomography of the chest organs revealed multiple enlarged lymph nodes in the root zones of both lungs. Ultrasound examination confirmed an increase in peripheral

M.A. Volkova et al.

lymph nodes and spleen, which measures 16.3 X 9.2 cm, enlarged lymph nodes were found in the abdominal cavity along the mesenteric vessels with a diameter of up to 2 X 3 cm.

With ultrasound examination of soft tissues

of the right lower leg, a formation of reduced echogenicity was found, extending practically from the knee to the ankle joints. There are signs of soft tissue edema around the ankle. With Doppler ultrasound, an intense blood flow is determined in the detected formation.

Blood test from 18.11.05: hemoglobin - 127 g / l, er. - 4.64 X 1012 / l, l. - 8.12 X 109 / l, tr. - 111 X 109 / l, pal. - 6%, segm. - 42%, eos. - 3%, limf. - 39%, mon. - ten%.

In the biochemical analysis of blood, a slight increase in glucose content was constantly noted - 6.6-6.7 mmol / l (the norm is up to 6.1), total bilirubin - 23-25 \u200b\u200bμmol / l (the norm is up to 20), a decrease in the level of total protein - 61 -62 g / l (norm 66-87) and constantly increased level of lactate dehydrogenase (LDH) - from 625 to 734 units / l (norm up to 450).

Myelogram from 11/18/05. Moderate-cell bone marrow, granulocytic and erythroid sprouts are narrowed (the amount of granulocytes is 53.6%, the amount of erythroid cells is 12.6%), lymphocytes, mainly mature forms, are

31.4%. The immunophenotype is characteristic for B-CLL: CD19 + CD23 + -

45.6%, CD19 + CD5 + - 49%. Attention was drawn to the high content of lymphocytes expressing the CD38 antigen - 62.9%.

A cytogenetic study (FISH method) revealed an 11q deletion in 52% of cells, a deletion in 23% of cells

When determining the mutational status of the genes of the variable region of the heavy chains of immunoglobulins, a clonal rearrangement of the VH genes of the third family was revealed. The variable region is encoded by genes VH3-64, D3-3, JH6. When comparing the patient's and the germinal sequence of the VH3-64 gene, the degree of homology was 96.9%. This indicates the presence of somatic mutations in the VH genes (in the absence of such mutations, the degree of homology between the studied and germline genes is 99-100%).

Trepanobiopsy of the ilium revealed hypercellular bone marrow due to interstitial proliferation of lymphoid cells such as small lymphocytes and numerous prolymphocytes.

An immunocytological study of the skin bioptat revealed a pronounced polymorphic-cellular lymphoid infiltrate. Small lymphoid cells are represented by T-lymphocytes, among which CD8-positive cells are predominantly found. The tumor infiltrate is represented by B cells with the immunophenotype CD19 + CD20 + CD21- CD5 + CD10-CD23-. Compared to bone marrow cells, tumor infiltrate cells in the skin are large in size and lack the CD23 and CD21 antigens. Expression of the CD38 marker is retained in most cells. B-cell immunophenotype of tumor cells, weak expression of the CD20 antigen typical for CLL, expression of the CD5 antigen in combination with the loss of CD23 antigen made it possible to regard changes in the dermis as a manifestation of the development of large B-cell lymphoma in a patient with CLL.

A histological examination of a biopsy of the skin in all parts of the dermis and hypodermis revealed a massive infiltrate of lymphoid cells such as small lymphocytes and prolymphocytes, an increased number of paraimmunoblasts located discretely. An immunohistochemical study revealed the expression by lymphoid cells of the infiltrate of antigens CD45, CD20, IgM, Bcl2, focal expression of CD23, weak expression of CD21. Ki 67 is expressed by 20-25% of cells. The indicated morphological and immunohistochemical data also made it possible to interpret the detected changes as the initial manifestations of the development of Richter's syndrome - large cell lymphoma.

The patient was treated according to DHAP regimens (cisplatin 200 mg, high doses of cytarabine - 8000 mg, dexamethasone 80 mg) EMVP (methotrexate 2000 mg, etoposide, vincristine, prednisolone), MINE (mesna, ifosfomide, mitoxantrone, etoposide), high doses of methotrexate mono mode. The use of each of these schemes gave only a short-term effect (no more than 2-3 days) in reducing the size of tumor formations (Fig. 2).

When re-examining the myelogram on 03/09/06, a small number of lymphoid elements were detected

(6%) large monstrous cells of irregular shape. The shape of the nuclei of these cells is folded, the chromatin structure is delicate. In the nuclei, one large nucleole is determined. The color of the cytoplasm of these cells is moderately or strongly basophilic, in some of the cells there is vacuolization. Granularity is not detected. These cells have been regarded as large cell lymphoma cells.

Despite the constant treatment, the patient's condition gradually worsened, increased temperature, torrential sweats, and increased weakness. The patient was discharged from the clinic in March 2006 and soon died at the hospital at his place of residence at the time of bleeding from one of the tumor formations. An autopsy was not carried out at the request of the relatives.

DISCUSSION

The presented observation concerns a patient who, at the age of 48 years, was diagnosed with CLL, for which he received multiple courses of therapy, including alkylating drugs, purine analogs, anthracyclines and monoclonal antibodies. After 4 years, the patient developed Richter's syndrome with skin lesions. The treatment was ineffective.

As you know, the average age of patients with CLL, according to different authors, is 65-69 years. With the general rarity of Richter's syndrome, some authors note its more frequent development in young patients.

So, in a study that included 1011 patients with CLL, the overall frequency of Richter's syndrome was 2.2%, while in patients under 55 years of age it occurred 5 times more often than in patients of older age groups: 5.9 and 1.2% respectively (p< 0,00001).15

A large number of prolymphocytes was found in our patient in a bone marrow trepanate upon admission to the chemotherapy department of hemoblastosis of the Russian Cancer Center (4 years after the onset of the disease), which is usually not found in patients with a favorable course of CLL and is a poor prognostic sign. Since the patient had not undergone trepanobiopsy of the bone marrow before admission to the RCRC, it is not known whether the prolymphocytes were in the trepanate at the beginning of the disease or appeared at a later stage as a sign of a change in the nature of the disease.

The role of an increase in the number of prolymphocytes in the prognosis of CLL is shown in the work of Y. Ma et al.16 Periodically examining bone marrow punctures of patients with CLL, the authors noted that in a number of patients, over time, among a large number of typical lymphocytes, separate large cells with nucleoli exceeding the usual size lymphocyte by 2 times, and sometimes the size of the prolymphocytes found in CLL. The analysis showed that in those cases when there were more than 7% of such cells, the life expectancy of patients was significantly shorter than that of the rest. After analyzing the significance of various signs for the prognosis of CLL on a large number of observations, the authors noted that the life expectancy of 78 patients in whom the number of large cells exceeded 7% was the same as the life expectancy of 29 patients with Richter's syndrome in the study group.

Our patient had chromosomal aberrations associated with a poor prognosis: an 11q deletion and a 17p deletion, leading to a partial loss of the Tr53 gene, which ensures the stability of the cell genome.

Of the chromosomal aberrations inherent in CLL, the most significant for the development of Richter's syndrome are, in all likelihood, the trisomy of chromosome 12 (+12) and the deletion of the long arm of chromosome 11 (11q-). E. Matutes et al, 17 having examined 544 patients with CLL, found trisomy 12 in 53% of patients with large cells in the bone marrow and only in 9.7% (p< 0,001) без таких клеток. У нашего больного

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Richter's syndrome

there was no trisomy 12, but there was an 11q- deletion in 52% of the cells examined. The significance of the 11q23 deletion in CLL is well known. Patients with this chromosomal aberration are often regarded as patients with "tumor form of CLL", since they are characterized by a significant increase in lymph nodes, especially in the abdominal cavity and mediastinal, and, according to our observations, also in the submandibular and cervical regions. Y. Zhu et al, 18 examined 161 patients with various lymphoproliferative diseases, diagnosed Richter's syndrome in three patients with CLL, and all had an 11q23 deletion.

Some authors note that the 11q23 deletion occurs almost exclusively in patients with CLL, in whom the IgVH genes do not show signs of somatic hypermutations, 19 but in our patient, a study of the mutational status of these genes revealed the presence of such mutations.

It should be emphasized that our patient had two unfavorable chromosomal abnormalities - an 11q deletion and a 17p deletion. As you know, at the same time, various karyotype disorders in Richter's syndrome occur much more often than in CLL.16,20 The value of combined karyotype disorders for the development of Richter's syndrome is confirmed by the work of E. Matutes et al, 17 who found that in the group of patients with trisomy 12 and at the same time others chromosomal aberrations, large cells with atypical morphology were found in 70% of patients, while in patients with trisomy 12 as the only chromosomal aberration - only in 40%.

As already mentioned, before the development of Richter's syndrome from May 2002 to June 2005, our patient repeatedly received treatment with a combination of various drugs: 6 cycles of CPP, followed by maintenance therapy with cyclophosphan for 6-7 months, then 3 cycles, including mabthera, mitoxantrone, fludarabine, cyclophosphamide, dex-samethasone, and 3 cycles of the same therapy without mabthera, then maintenance therapy with cyclophosphane for 2-3 months, followed by 3 courses of treatment with a combination of mabthera and fludarabine. Skin changes first appeared in the patient during the first course of treatment with MabThera and Fludarabine.

In some cases, there is an increase in the frequency of Richter's syndrome with an increase in the intensity, number of courses and the number of different chemotherapy regimens. So, in the MD Anderson Cancer Center from 1972 to 1992, 1374 patients with CLL were observed. Richter's syndrome developed in 39 of them, which amounted to 2.8% .8 In the next 10 years, from 1992 to 2002, 2147 patients with CLL were observed in the same center, Richter's syndrome developed in 105 of them, which amounted to 4.9 %. The incidence of Richter's syndrome was significantly higher in patients who received more than two different chemotherapy regimens for CLL.15 Of course, when assessing the role of previous treatment in the development of Richter's syndrome, one should take into account that 2-3 or more different regimens of therapy are received by patients with progressive and poor treatable CLL, in which the development of Richter's syndrome is generally more common.

Some researchers in recent years have noted a more frequent development of Richter's syndrome in patients who received purine analogues for the treatment of CLL. Thus, in the publication by S. Tabuteau et al20 it is reported that Richter's syndrome was observed in 6% (37 out of 620) of patients receiving fludarabin, which was significantly higher than the incidence of this syndrome in the group of patients treated with combinations of drugs that did not contain fludarabine. An even higher incidence of Richter's syndrome in patients treated with fludarabine was noted by P Thornton et al: 21 over 10 years, from 1990 to 2000, treatment with fludarabine or fludarabine in combination

101 patients were treated with other drugs (most often with cyclophosphamide and mitoxantrone). Richter's syndrome developed in 12 (12%) of them. This is one of the highest rates of development of Richter's syndrome in CLL known to us from publications. None of the 12 patients had skin lesions. It should be noted that only one of these patients received fludarabine as the first therapeutic agent, the rest - as the second or third line of therapy after treatment with chlorambucil, prednisolone, anthracyclins. In 6 of 12 patients, Richter's syndrome developed within four months after the end of treatment with Fludar Bin. The same rapid development of Richter's syndrome after treatment of patients with CLL and follicular lymphoma with a combination of fludarabine, cyclophosphamide and mabthera was observed

Y. Cohen et al. 22

Nevertheless, the role of purine analogs and monoclonal antibodies in the development of Richter's syndrome cannot be recognized as proven on the basis of the above studies, since there are also opposite data. Thus, L. Robertson et al8 reported on the development of Richter's syndrome in 22 (3.4%) of 649 CLL patients who received purine analogs, and in 17 (2.3%) of 725 patients treated with alkylating drugs alone, which is not statistically significant difference. There was no difference in the interval from the start of treatment to the development of Richter's syndrome with different treatment programs. Leporrier et al23, as a result of a large randomized trial, also did not note a difference in the incidence of Richter syndrome in CLL patients treated with and untreated with purine analogues. T. Robak et al, 24 having analyzed the frequency of second tumors and Richter's syndrome in 1487 patients with CLL, of which 251 patients received only cladribine, 913 - alkylating drugs, and 323 - both, did not note a significant difference in the frequency of both second tumors and Richter's syndrome in these groups: Richter's syndrome developed in 1% of patients treated with cladribine, in 0.9% of patients receiving alkylating drugs, and in 0.6% of patients receiving both regimens of therapy. The same results were obtained by B. Cheson et al, 25 who analyzed the incidence of second tumors and Richter's syndrome in 2014 patients with CLL.

The pathogenesis of Richter's syndrome is not entirely clear to date. Epstein-Barr virus (EBV) is given a certain importance in its development. It is a lymphotropic virus that infects more than 90% of the world's population.26 EBV has been shown to cause proliferation of B-lymphocytes in vitro, blocking the pathways of apoptosis of these cells by increasing the expression of the BCL-2.27 protein. immune factors and therefore can survive longer.28 Patients with Richter's syndrome infected with EBV have a particularly rapid course and resistance to therapy.29 Increased proliferation of EBV-infected cells contributes to the occurrence of genomic aberrations in them.

It is known that diffuse large cell lymphoma in Richter syndrome develops from the same clone as CLL in 2/3 of patients.19 In other cases of Richter syndrome, different clones of CLL and diffuse large cell lymphoma are found. Recent studies30 have confirmed the previously established fact: 31 true transformation of CLL into diffuse large cell lymphoma, i.e., the development of lymphoma from lymphocytes of the same clone that makes up the CLL substrate, was found in patients in whom IgVH genes did not undergo somatic mutations. In the same cases when the development of large cell lymphoma occurs in patients with mutated IgVH

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M.A. Volkova et al.

genes, as was the case in our patient, lymphoma develops from a different cell lineage than CLL. In these cases, the appearance of large cell lymphoma should be regarded as the development of a second tumor in a patient with a defect in the immune system. There is no doubt that intensive treatment, especially those containing purine analogs, which cause long-term suppression of the T-cell link of immunity, can contribute to the development of second tumors, especially in patients with chromosomal aberrations reflecting the instability of the cellular genome.

If cutaneous lesions develop as the first manifestation of CLL, they usually respond well to the drugs used to treat CLL and low-grade lymphomas. E. Robak et al11 described a patient whose reason for seeking medical attention was the appearance of dense infiltrates on the skin. Examination of the patient showed that he had CLL, and morphological and immunological studies established the specific nature of skin infiltrates and the belonging of lymphocytes from infiltrates and lymphocytes of the patient's bone marrow to the same clone. Cladribine treatment led to the normalization of the blood picture and the disappearance of skin infiltrates. The successful use of local ultraviolet irradiation for the treatment of specific skin lesions in CLL has been described.32

Rarely described skin T-cell tumors (fungal mycosis, Sesari syndrome) that develop in patients with CLL, as a rule, proceed and respond to treatment in the same way as in patients without CLL. 33-35

At the same time, treatment of Richter's syndrome remains a difficult problem, regardless of the location of the developed large cell lymphoma. As a rule, remission is rarely obtained, and the life expectancy of patients from the time of development of Richter's syndrome is estimated at five to eight months. L. Robertson et al, 8 using intensive regimens of therapy (CHOP-BLEO, MACOP-B, AHAP, PFA) for the treatment of 39 patients with Richter's syndrome, obtained an effect in 16 (42%) patients, and in 10 patients complete remissions were achieved ... However, the median life expectancy since the onset of Richter's syndrome was only 5 months. Only three patients survived for more than 1 year, and in all of them Richter's syndrome was diagnosed as the first manifestation of the disease, and they had not received any treatment before. In the observations of T. Han et al36, one in three patients with Richter's syndrome lived for more than three years. His Richter's syndrome was also the first reason for seeking medical attention and had never received any treatment for CLL in the past. In the observations of L. Robertson et al8, the longest life expectancy in Richter's syndrome was achieved in patients treated with fludara-bin: 17 months on average, while in patients treated without fludarabine - 5 months. With this in mind, MD Anderson Cancer Center has developed a treatment regimen containing fludarabine, cytosine-arabinoside, cyclophos-fan, cisplatin, and granulocyte-macrophage colonies.

stimulating factor (GM-CSF). However, this treatment regimen turned out to be not only toxic, but also ineffective: complete remission was achieved in only one out of 16 patients.37 Somewhat better results were obtained when using the regimen developed at MD Anderson Cancer Center, which the authors called hyper-CVAD: high doses of cyclophosphane , vincristine, liposomal daunorubicin, dexamethasone, mabthera and GM-CSF. Remissions were achieved in 43% of patients, including 27% (8 out of 30) - complete. The average duration of remission was 8.5 months, 9 patients survived for 12 months, but 18% of patients died from complications associated with treatment.

The experience of hematopoietic stem cell (HSC) transplantation in Richter's syndrome is still small. J. Rodriguez et al40 published data on eight patients with Richter's syndrome who underwent allogeneic HSC transplantation, including two patients from an unrelated donor. The mean duration of CLL prior to the development of Richter's syndrome was 48 months. All patients with CLL, and then in connection with the development of Richter's syndrome, received 2-5 different treatment courses, including those containing fludarabine. During the first 30 days after transplantation, 5 out of 8 patients died from infectious complications. By the time of publication, 3 patients, including 2 who received transplant from an unrelated donor, were in complete remission for 14, 47 and 67 months. In a very interesting observation by I. Espanol et al, 41 a patient with CLL underwent allogeneic SCC transplantation. After 4 months, he developed a relapse of CLL and was simultaneously diagnosed with diffuse large cell lymphoma. After the complete cessation of immunosuppressive therapy and several infusions of donor lymphocytes, complete remission of both CLL and lymphoma was achieved, which by the time of publication had lasted 18 months.

CONCLUSION

Thus, Richter's syndrome remains a disease, the pathogenesis of which has not been fully elucidated, and therapy has not been developed.

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18.02.2017

Chronic lymphocytic leukemia is a common cancer in Western countries.

This oncological disease is characterized by a high content of mature abnormal B-leukocytes in the liver and blood. The spleen and bone marrow are also affected. A characteristic sign of the disease is the rapid inflammation of the lymph nodes.

At the initial stage, lymphocytic leukemia manifests itself as an increase in internal organs (liver, spleen), anemia, hemorrhage, increased bleeding.

Also, there is a sharp decrease in immunity, the occurrence of frequent infectious diseases. The final diagnosis can be established only after carrying out a whole range of laboratory tests. After this, therapy is prescribed.

The reasons for the development of chronic lymphocytic leukemia

Chronic lymphocytic leukemia belongs to the group of oncological diseases of non-Hodgkin's lymphomas. It is chronic lymphocytic leukemia that accounts for 1/3 of all types and forms of leukemia. It should be noted that the disease is diagnosed more often in men than in women. And the age peak of chronic lymphocytic leukemia is considered to be 50-65 years old.

At a younger age, the symptoms of a chronic form are very rare. So, chronic lymphocytic leukemia at the age of 40 is diagnosed and manifests itself only in 10% of all patients with leukemia. Over the past few years, experts have been talking about some "rejuvenation" of the disease. Therefore, there is always a risk of developing the disease.

As for the course of chronic lymphocytic leukemia, it can be different. There is both a long-term remission without progression, and a rapid development with a lethal end within the first two years after the detection of the disease. To date, the underlying causes of CLL are not yet known.

This is the only type of leukemia that does not have a direct connection between the onset of the disease and unfavorable environmental conditions (carcinogens, radiation). Doctors have identified one major factor in the rapid development of chronic lymphocytic leukemia. This is a factor of heredity and genetic predisposition. Also, it has been confirmed that chromosome mutations occur in the body.

Chronic lymphocytic leukemia can also be autoimmune. In the patient's body, antibodies to hematopoietic cells begin to form rapidly. Also, these antibodies have a pathogenic effect on maturing bone marrow cells, mature blood cells and bone marrow. So, there is a complete destruction of red blood cells. The autoimmune type of CLL is proven by a Coombs test.

Chronic lymphocytic leukemia and its classification

Considering all morphological signs, symptoms, rapidity of development, response to treatment, chronic lymphocytic leukemia is classified into several types. Thus, one type is benign CLL.

In this case, the patient's well-being remains good. The level of leukocytes in the blood increases at a slow rate. From the time of establishment and confirmation of this diagnosis to a noticeable enlargement of the lymph nodes, as a rule, it takes a long time (decades).

The patient in this case fully retains his active labor activity, the rhythm and way of life is not disturbed.

Also, the following types of chronic lymphocytic leukemia can be noted:

• Progression form. Leukocytosis develops rapidly, over the course of 2-4 months. In parallel, there is an increase in the patient's lymph nodes.
• tumor form. In this case, a pronounced increase in the size of the lymph nodes can be observed, but leukocytosis is poorly expressed.
• bone marrow form. Rapid cytopenia is observed. The lymph nodes are not enlarged. Spleen and liver remain normal in size.
• chronic lymphocytic leukemia with paraproteinemia. Monoclonal M or G-gammopathy is added to all the symptoms of this disease.
• prelimophytic form. This form differs in that lymphocytes contain nucleoles. They are detected during the analysis of smears of bone marrow, blood, examination of the tissues of the spleen and liver.
• hairy cell leukemia. Inflammation of the lymph nodes is not observed. But, the study reveals splenomegaly, cytopenia. Diagnostics of the blood shows the presence of lymphocytes with uneven, ragged cytoplasm, with sprouts resembling villi.
• T-cell form. It is quite rare (5% of all patients). It is characterized by infiltration of the (leukemic) dermis. It develops very quickly and rapidly.

Quite often in practice, chronic lymphocytic leukemia occurs, which is accompanied by an increase in the spleen. The lymph nodes are not inflamed. Experts note only three degrees of the symptomatic course of this disease: initial, stage of expanded signs, thermal.

Chronic lymphocytic leukemia: symptoms

This cancer is very insidious. At the initial stage, it proceeds without any symptoms. It can take a very long time before the first symptoms appear. And the defeat of the body will occur systematically. In this case, CLL can only be detected by a blood test.

In the presence of an initial stage of the development of the disease, lymphocytosis is determined in the patient. And the level of lymphocytes in the blood is as close as possible to the boundary level of the permissible norm. The lymph nodes are not enlarged. An increase can only occur in the presence of an infectious or viral disease. After complete recovery, they return to their normal size.

The constant increase in lymph nodes, for no apparent reason, may indicate the rapid development of this oncological disease. This symptom is often associated with hepatomegaly. Rapid inflammation of an organ such as the spleen can also be observed.

Chronic lymphocytic leukemia begins with enlargement of the lymph nodes in the neck and armpits. Then the nodes of the peritoneum and mediastinum are damaged. Last but not least, the lymph nodes of the groin area become inflamed. During the study, palpation is determined by mobile, dense neoplasms that are not associated with tissues and skin.

In the case of chronic lymphocytic leukemia, the size of the nodes can reach up to 5 centimeters, or even more. Large peripheral nodes burst, resulting in a noticeable cosmetic defect. If, with this disease, the patient has an increase and inflammation of the spleen, liver, the work of other internal organs is disrupted. Since there is strong compression of adjacent organs.

Patients with this chronic ailment often complain of such general symptoms:

• increased fatigue;
• fatigue;
• decreased ability to work;
• dizziness;
• insomnia.

When conducting a blood test in patients, there is a significant increase in lymphocytosis (up to 90%). Platelet and red blood cell counts are usually normal. In a small number of patients, thrombocytopenia is observed in parallel.

The neglected form of this chronic ailment is marked by significant sweating at night, an increase in body temperature, and a decrease in body weight. During this period, various disorders of the immune system begin. After this, the patient begins to very often get sick with cystitis, urethritis, colds and viral diseases.

Ulcers appear in the subcutaneous fatty tissue, and even the most harmless wounds are suppurating. If we talk about the lethal end in lymphocytic leukemia, this is due to frequent infectious and viral diseases. So, inflammation of the lungs is often determined, which leads to a decrease in lung tissue, impaired ventilation. Also, you can observe a disease such as exudative pleurisy. A complication of this disease is rupture of the lymphatic duct in chest... Very often, patients with lymphocytic leukemia develop chickenpox, herpes, and shingles.

Some other complications include hearing impairment, tinnitus, and infiltration of the lining of the brain and nerve roots. Sometimes CLL develops into Richter's syndrome (diffuse lymphoma). In this case, a rapid growth of lymph nodes occurs, and the foci spread far beyond the boundaries of the lymphatic system. Up to this stage of lymphocytic leukemia, no more than 5-6% of all patients survive. Death, as a rule, occurs from internal bleeding, complications from infections, anemia. Renal failure may occur.

Diagnostics of the chronic lymphocytic leukemia

In 50% of cases, this disease is detected by chance, during a routine medical examination, or with complaints about other health problems. The diagnosis is made after a general examination, examination of the patient, clarification of the manifestations of the first symptoms, the results of blood tests. The main criterion that indicates chronic lymphocytic leukemia is an increase in the level of leukocytes in the blood. At the same time, there are certain violations of the immunophenotype of these new lymphocytes.

Microscopic diagnostics of blood for this disease shows the following deviations:

• small B-lymphocytes;
• large lymphocytes;
• shadows of Gumprecht;
• atypical lymphocytes.

The stage of chronic lymphocytic leukemia is determined against the background of the clinical picture of the disease, the results of the diagnosis of lymph nodes. To draw up a plan and principle of treatment of the disease, to assess the prognosis, it is necessary to carry out cytogenetic diagnostics. If lymphoma is suspected, a biopsy is required. Without fail, to determine the main cause of this chronic oncological pathology, puncture of the bone marrow, microscopic examination of the material taken are performed.

Chronic lymphocytic leukemia: treatment

Treatment of different stages of the disease is carried out using different methods. So, for the initial stage of this chronic ailment, doctors choose the tactics of waiting. The patient needs to undergo examinations every three months. If during this period there is no development of the disease, progression, treatment is not prescribed. Just regular examinations are enough.

Therapy is prescribed in cases where the number of leukocytes is at least doubled for just six months. The main treatment for this disease is, of course, chemotherapy. As the practice of doctors shows, a combination of the following drugs is highly effective:

• rituximab;
• fludarabine;
• cyclophosphamide.

If the progression of chronic lymphocytic leukemia does not stop, the doctor prescribes a large number of hormonal drugs. Further, it is important to perform a bone marrow transplant in a timely manner. In old age, chemotherapy and surgery can be dangerous and difficult to tolerate. In such cases, specialists decide on monoclonal antibody therapy (monotherapy). In this case, a drug such as chlorambucil is used. It is sometimes combined with rituximab. Prednisolone may be prescribed in case of autoimmune cytopenia.

Such treatment lasts until a noticeable improvement in the patient's condition occurs. On average, the course of this therapy is 7-12 months. Once the improvement has stabilized, therapy is discontinued. During the entire time after the end of treatment, the patient is regularly diagnosed. If there are deviations in the analyzes or in the patient's well-being, this indicates the re-active development of chronic lymphocytic leukemia. The therapy is resumed again without fail.

To alleviate the patient's condition for a short time, they resort to radiation therapy. The impact occurs on the area of \u200b\u200bthe spleen, lymph nodes, liver. In some cases, the entire body is highly effective, only in small doses.

In general, chronic lymphocytic leukemia is classified as an incurable oncological disease, which has a long duration. With timely treatment and constant examination by a doctor, the disease has a relatively favorable prognosis. Only in 15% of all cases of chronic lymphocytic leukemia, rapid progression occurs, an increase in leukocytosis, and the development of all symptoms. In this case, death can occur one year after the diagnosis. For all other cases, the sluggish progression of the disease is characteristic. In this case, the patient can live up to 10 years after the detection of this pathology.

If a benign course of chronic lymphocytic leukemia is determined, the patient lives for decades. With timely treatment, the patient's well-being improves in 70% of cases. This is a very large percentage for cancer. But, full-fledged, stable remissions are rare.