The human body contains not only blood vessels, but also so-called “white” vessels. They were known for quite a long time, and in the mid-18th century, knowledge about the lymphatic system became more extensive. Unfortunately, they are not uncommon and can occur in any organ.

Lymphatic system

It performs quite well in human functioning important role: transport occurs thanks to the lymphatic system useful substances, excess interstitial fluid is removed. Another important ability is to provide immunity. The fluid that performs these tasks is called lymph. It has a transparent color and is predominantly composed of lymphocytes. The smallest structural unit of the system is capillaries. They pass into vessels, which are both intraorgan and extraorgan. Their structure also includes valves that prevent the reverse flow of liquid. The largest ones are called collectors. It is in them that fluid accumulates from internal organs and other large organs. Another component that the lymphatic system has (photo below) is nodes. These are round formations that have different diameters (from half a millimeter to 5 centimeters). They are located in groups along the path of blood vessels. The main function is lymph filtration. It is here that it is cleansed of harmful microorganisms.

Lymphatic organs

The following organs are also part of the human lymphatic system: tonsils, spleen, bone marrow. Lymphocytes that form in the thymus are called T cells. Their feature is continuous circulation between lymph and blood. The particles that are produced in the bone marrow are called B cells. Both types are distributed throughout the body after maturation. B cells remain in the lymphoid organs. This is where their migration stops. IN abdominal cavity Another large organ is located, which is an integral part of the lymphatic system - the spleen. It consists of two parts, one of them (white pulp) generates antibodies.

This group of diseases is based on the proliferation of lymphocytes. If changes occur in the bone marrow, the term “leukemia” is used. systems that arise in tissue outside the bone marrow are called lymphomas. According to statistics, such diseases most often occur in older patients. This diagnosis occurs more frequently in men than in women. This disease is characterized by a focus of cells that begins to grow over time. There are low, medium and high degrees, which characterize the malignancy of the process.

Possible causes

Among the causes that can cause lymphoproliferative diseases, a certain group of viruses is distinguished. The factor of heredity also plays an important role. Skin diseases that last a significant period of time (for example, psoriasis) can trigger the growth of malignant neoplasms. And, of course, it significantly affects this process radiation. Radiation, some allergens, toxic substances activate the process of cell proliferation.

Lymphomas. Diagnostics

One of the types of malignant neoplasms of the lymphatic system is lymphoma. Symptoms on initial stages may not be very pronounced.

There is an increase that is not painful. Another a clear sign- fatigue, and to a fairly large extent. The patient may complain of increased sweating at night, significant and sudden loss of body weight. Itching is also possible. Body temperature sometimes rises, especially in the evenings. You should be alert to such symptoms if they do not disappear after a few weeks. For effective treatment It is very important to determine the type of lymphoma. When diagnosing, the location, appearance of the tumor, and the type of protein that is on its surface are taken into account. The specialist prescribes a complete medical research, blood test for cancer cells, diagnostics of internal organs is carried out. For more information, a biopsy is necessary. Under a microscope, the affected cells have a specific appearance.

Lymphoma treatment

Treatment methods of this disease the following. Chemotherapy or radiotherapy (using X-rays) is used to destroy the tumor. A combination of drugs is used, they spread throughout the body and can also destroy cells that could not be diagnosed. After chemotherapy, the bone marrow is also affected, so a bone marrow transplant may be needed. It is carried out both from donor material and directly from the patient’s own bone marrow (it is first removed before the start of the procedures). Lymphoproliferative diseases are also amenable to biological therapy, but it is predominantly experimental. It is based on the use of substances that are synthesized from the patient’s cells. To achieve a good result, you must carefully follow the instructions of your doctor, take medications on time, and pay due attention to nutrition.

Leukemia. Clinical picture

The disease is characterized by a change in hematopoietic cells, in which healthy elements of the bone marrow are replaced by damaged ones. The level of lymphocytes in the blood increases significantly. Depending on which cells were degenerated, the disease is distinguished: lymphocytic leukemia (changes in lymphocytes), myeloid leukemia (myelocytes are affected). The type of disease can be determined under a microscope and by protein analysis. Lymphoproliferative disease (what it is was described above) in this case has two forms: chronic and acute. The latter is quite difficult. In this case, immediate treatment is necessary, since the cells are immature and are not able to perform their functions. Chronic form can last for many years.

Older people are often diagnosed with chronic lymphocytic leukemia. The disease progresses rather slowly, and only in the later stages are disturbances observed in the process of blood formation. Symptoms include enlarged lymph nodes and spleen, frequent infections, weight loss, and sweating. Often such lymphoproliferative diseases are discovered accidentally.

There are three stages of the disease: A, B, C. In the first, 1-2 are affected, in the second - 3 or more, but there is no anemia and thrombocytopenia. In the third, these conditions are observed. On early stages Experts do not recommend therapy, since the person maintains his usual lifestyle. It is important to follow a daily routine; your doctor can give advice on nutrition. General restorative therapy is carried out. Treatment of chronic lymphocytic leukemia should begin when signs of progression are detected. It includes chemotherapy, radiation treatment, and stem cell transplant. If the organ grows rapidly, it may be necessary to remove the spleen.

Lymphoproliferative diseases, based on the site of primary occurrence, are divided into two large groups: chronic lymphoid leukemia and malignant non-Hodgkin lymphomas, which initially have extramedullary localization (lymph nodes, spleen, skin, lymphoid tissue of the gastric mucosa, etc.), which distinguishes them from leukemia. Tumor growth may be accompanied by bone marrow infiltration and leukemia. In accordance with the criteria proposed by WHO, when verifying a diagnosis, it is mandatory to establish the linear affiliation of tumor lymphoid cells (T- or B-cells) and the degree of their differentiation (precursors or mature cells).

Diagnosis of lymphoproliferative diseases includes:
identification of the morphological substrate of the tumor:
determination of the immunophenotype of tumor cells (immunohistochemistry, flow cytometry):
establishing the extent of the tumor (stage of the disease);
identification of molecular genetic changes.

LYMPHOID TUMORS FROM PROCURECENT CELLS
B-lymphoblastic leukemia from progenitor cells/lymphoblastic lymphoma
B-lymphoblastic leukemia from progenitor cells/lymphoblastic lymphoma (B-cell acute lymphoblastic leukemia from progenitor cells) are tumors whose morphological substrate is lymphoblasts.

Diagnosis of lymphomas from progenitor cells should be carried out only taking into account immunophenotyping data. The non-tumor analogue is located in the bone marrow at an antigen-independent stage of differentiation.

The disease is relatively rare in adults (about 10%), but in children it accounts for up to 40% of all cases of non-Hodgkin's malignant lymphoma. Characteristic aggressive course involving the central nervous system, lymph nodes, liver, spleen, testicles, skin, and soft tissues. Most patients have a large tumor in the mediastinum involving the thymus. Common symptoms are arthralgia and bone pain. The bone marrow is affected in half of the initial patients and in the majority as the disease progresses.

Anemia and/or thrombocytopenia and/or neutropenia are observed in the peripheral blood. The white blood cell count may be normal, low, or high.

Diffuse in bone marrow or other tissues tumor growth. The morphology of lymphoblasts varies from microforms with scanty cytoplasm, a condensed nucleus and an indistinct nucleolus to macroforms with a dispersed distribution of chromatin, distinct nucleoli, cytoplasm of various shades of basophilia, often vacuolated. IN in rare cases it contains azurophilic granules, which can be combined with a cytogenetic abnormality - translocation t(9;22). The morphology of lymphoblasts in the form of a “hand mirror” is described. The shape of the nuclei varies from round to irregular, twisted, and folded. The number of mitoses may vary, but their number is not significant absolute sign tumor process. The morphology of B and T lymphoblasts is often similar and cannot be used to differentiate them.

Cytochemistry: lymphoblasts do not contain myeloperoxidase or lipids; PAS-positive substance is distributed in the form of small, dust-like granules along the periphery of the cytoplasm or around the nucleus, and can be localized in blocks or several large granules in a small percentage of cells.

In lymphoblasts, acid phosphatase activity of varying severity is noted.

Immunophenotype: lymphoblasts express TdT (terminal deoxynucleotidyl transferase - a marker of early progenitor cells), HLA-DR, CD19, cytoplasmic CD79a. In most cases, CD10, CD24 are present, the expression of CD20, CD22 is variable, and CD45 may be absent.

Cytogenetics: many chromosomal abnormalities have been recorded, but no molecular genetic changes pathognomonic for this disease have been identified.

T-lymphoblastic progenitor cell leukemia/lymphoblastic lymphoma
T-lymphoblastic leukemia from progenitor cells/lymphoblastic lymphoma - tumors whose morphological substrate is lymphoblasts. Non-tumor analogues are in the thymus at the antigen-independent stage of differentiation. Acute lymphoblastic leukemia accounts for 15% of all childhood acute lymphoblastic leukemias. Feature clinical picture are the frequent involvement of the mediastinum and serous membranes in the tumor process, and the appearance of effusion in the preural cavity. Other sites of tumor localization are skin, lymph nodes, liver, spleen, Waldeyer's lymphatic ring, central nervous system, testicles. Acute lymphoblastic leukemia is often accompanied by hyperleukocytosis and a large tumor mass.

Cytochemistry: T lymphoblasts exhibit acid phosphatase activity as a focal spot.

Immunophenotype: lymphoblasts express TdT, CDla, CD2, CD3, CD4, CD5, CD7, CD8. Co-expression of CD4 and CD8 and expression of CD10 may be observed. Depending on what stage of differentiation in the thymus the oncogenic transformation occurred, lymphoblasts may have certain antigens [at an early stage - cytoplasmic CD3, CD2, CD7, somewhat later - CDIa, CD5 (cortical thymocytes), at last stage- membrane CD3]. 

Cytogenetics: Numerous translocations affecting T-cell receptor genes are noted.

B-CELL TUMORS FROM MATURE (PERIPHERAL) B-CELLS
B-cell chronic lymphocytic leukemia/small lymphocyte lymphoma
B-cell chronic lymphocytic leukemia/small lymphocyte lymphoma - tumor lymphoid tissue, characterized by damage to the bone marrow and lymph nodes. Over the past 10 years, sufficient evidence has accumulated indicating the heterogeneity of the origin of chronic lymphoblastic leukemia. In most cases, tumor transformation occurs at the level of naive, or “virgin” (CD19+CD5+CD23+IgM+IgD+) (pregerminal) B-lymphocytes, followed by a block in their further differentiation and proliferation (reproduction) of the tumor cell clone. No less common is chronic lymphoblastic leukemia with tumor transformation of postgerminal B-lymphocytes (memory cells), as evidenced by detectable somatic hypermutations of the genes of the variable region of immunoglobulins. In accordance with the mutational status of the Ig variable region, two variants of chronic lymphoblastic leukemia have been identified: with mutations (IgVmut) and without mutations of the Ig variable region (IgVmut). The group of patients with IgVmut is characterized by an unfavorable prognosis compared to patients in the IgVmut group. The mutational status of Ig variable region genes can serve as an indicative prognostic marker.

Chronic lymphoblastic leukemia is a disease with impaired apoptosis. Most tumor B lymphocytes are quiescent. More than 99% of circulating lymphocytes are in the CO phase of the cell cycle. Cytokines secreted by tumor cells, as well as IL-2 produced by T lymphocytes, promote the proliferation and survival of chronic lymphoblastic leukemia cells.

Chronic lymphoblastic leukemia accounts for about 30% of all leukemias. The incidence is 3 per 100,000 population, age is over 55 years. The disease is detected by chance. As the tumor progresses, the most common clinical symptoms are lymphadenopathy, hepatomegaly, splenomegaly, bacterial and viral infections. The course of chronic lymphoblastic leukemia is often complicated autoimmune diseases(hemolytic anemia, thrombocytopenia), the appearance of secondary tumors.

Diagnostic criteria for chronic lymphoblastic leukemia:
absolute lymphocytosis in peripheral blood - more than 5000 in 1 μl;
prolymphocytes - less than 10%;
lymphocytosis in the bone marrow - more than 30%;
immunological phenotype - CD19+CD23+CD5+.

B-cell clonality is established by the detection of restriction of the light chains of surface immunoglobulins (K or X).

The peripheral blood picture in chronic lymphoblastic leukemia is usually normal or slightly increased amount leukocytes. Anemia and thrombocytopenia are usually absent. The main hematological indicator in chronic lymphoblastic leukemia is absolute lymphocytosis. In the leukocyte formula, morphologically mature lymphocytes make up from 45 to 95%, single prolymphocytes are found, and relative or absolute neutropenia occurs. Peripheral blood lymphocytes in chronic lymphoblastic leukemia are characterized by small sizes (7-10 μm), rounded nucleus, clumpy chromatin distribution, absence of nucleoli, narrow cytoplasm of basophilic color. Cells of cytolysis are found. In some cases of chronic lymphoblastic leukemia, cells with the morphology of atypical lymphocytes, but with the immunological phenotype characteristic of this disease, are observed.

As the tumor process progresses, leukocytosis, relative and absolute lymphocytosis, neutropenia increase, normochromic anemia and/or thrombocytopenia are observed. In the leukocyte formula, prolymphocytes make up less than 10%; when viewing the preparation, single lymphoblasts are found. Tumor progression is accompanied by an increase in the number of prolymphocytes. In chronic lymphoblastic leukemia, autoimmune hemolytic anemia may be observed, and less commonly thrombocytopenia due to the formation of autoantibodies to erythrocytes or erythrokaryocytes, platelets.

Depending on the stage of the disease, the bone marrow can be normo- or hypercellular. The number of lymphocytes in the sternal punctate exceeds 30%, the morphology of the cells is similar to peripheral blood. Tumor infiltration can be focal, diffuse, interstitial or mixed, which has prognostic significance.

Immunophenotype: tumor cells express B-cell antigens - CD19, CD20 (weak), CD22 (weak), CD79a, CD23, CD43, CD5, there is a weak expression of surface immunoglobulins of the IgM or IgM+IgD class (in some cases not detected) with restriction light chains (k or K), activation antigens CD38, CD25, CD71 are variably represented. In rare cases of chronic lymphoblastic leukemia, tumor cells have the CD19+CD5~CD23+ phenotype, or they lack the expression of immunoglobulin light chains.

CD38 expression on more than 20% of CD19+CD5+ cells is associated with poor prognosis. In recent years, the expression of a surrogate marker of the mutational status of variable regions of immunoglobulin genes - the ZAP-70 protein (70-kD Zeta-Associated Protein) - has been intensively studied. It has been shown that the expression of this protein in a variant of chronic lymphoblastic leukemia is associated with a poor prognosis.

Cytogenetics: In approximately 1/3 of cases, an additional chromosome 12 (trisomy 12) is found, which is associated with more aggressive clinical course diseases. In 25% of patients, structural abnormalities in chromosome 13 are detected. Average duration The life of patients is 7 years.

Chronic lymphocytic leukemia can transform into prolymphocytic leukemia, Richter syndrome (diffuse large cell lymphoma), acute leukemia (usually acute lymphoblastic leukemia). There is a high risk of developing secondary tumors, primarily skin and intestinal cancer.

B-cell prolymphocytic leukemia
A rare disease, accounting for about 1% of lymphatic tumors. The average age of patients is 70 years. Most often, severe splenomegaly, a slight increase in peripheral lymph nodes and a rapid increase in leukocytosis occur.

Anemia and thrombocytopenia are recorded in most patients, leukocytosis exceeds 100x109/l, prolymphocytes account for more than 55%. Prolymphocytes are medium-sized cells, 10-15 microns in diameter, with a round, less often irregularly shaped nucleus, moderately condensed chromatin, usually one nucleolus, and relatively small cytoplasm of basophilic or slightly basophilic color. In the bone marrow, diffuse lymphoid infiltration with the same cells is noted.

Immunophenotype: tumor cells express B-cell antigens - CD19, CD20, CD22, CD79a and b, FMC7; CD5 is detected in V3 observations, CD23 is absent, and there is a strong expression of surface immunoglobulins of class M+/-D.

Cytogenetics: in patients with B-prolymphocytic leukemia, the most common chromosomal abnormality is 14q+, less commonly translocation t(11;14), trisomy 12.

Hairy cell leukemia
The disease accounts for 2% of all lymphoid leukemias, occurs between the ages of 26 and 75 years, and is 4 times more common in men than in women. There are classic and variant forms of hairy cell leukemia. In the classic (indolent) form of hairy cell leukemia, the onset of the disease is imperceptible, 20% of patients do not have classical signs at the time of diagnosis, but splenomegaly and pancytopenia are most common, and hepatomegaly and lymphadenopathy are much less common.

The bone marrow is normo- or hypercellular with diffuse lymphoid infiltration, fibrosis often develops, the percentage of “hairy” cells varies significantly (8-60%). In the peripheral blood - pancytopenia or bilinear cytopenia (leukopenia, anemia and/or thrombocytopenia) or subleukemic leukocytosis. The leukogram shows absolute lymphocytosis, neutropenia (agranulocytosis), monocytopenia. Among the lymphocytes, “hairy” cells are found, the proportion of which ranges from 2 to 90% or more. These are medium-sized cells, with a round, oval, kidney-shaped nucleus, homogeneous, smoothed chromatin structure; nucleoli are usually absent or indistinct, the cytoplasm is abundant, light blue, with processes. Sometimes vacuoles can be found in the cytoplasm. Hairy cells are characterized by a diffuse granular reaction to acid phosphatase, which is not suppressed by sodium tartrate.

Immunophenotype: tumor cells express B-cell antigens - CD19, CD20, CD22, slg+ (M+/-D. G or A), CD79a, CD11c, CD25, CD103. Cells do not have CD5, CD10, CD23 on the membrane.

A variant form of hairy cell leukemia is characterized by the presence of leukocytosis in the blood (more than 50x109/l), the absence of the classical antigens CD25 and CD 103. In morphology, “hairy” cells are less mature, contain small nucleoli in the nucleus and resemble prolymphocytes, and the reaction to tartrate-resistant acid phosphatase (TRAP) ) negative. Patients respond poorly to standard therapy and have a poor prognosis.

Myeloma (multiple myeloma)
Myeloma is a B-cell lymphoproliferative disease characterized by clonal proliferation in the bone marrow, less often in extramedullary foci, of plasma cells that synthesize monoclonal immunoglobulin (IgG, IgA, IgD, IgE) and/or light chains (k, X). The incidence of multiple myeloma (MD) is 3.5 per 100,000 population per year. The disease is diagnosed at the age of 40-70 years. Among the etiological factors, herpes virus type 8 is identified. In the pathogenesis of the disease, an important role is given to the activating effect of certain cytokines, in particular IL-6, which supports the proliferation of plasma cells and prevents their apoptosis. The survival and growth of tumor cells largely depend on the stromal microenvironment of the bone marrow. Adhesion of myeloma cells to the extracellular matrix of the bone marrow with the help of adhesion molecules localizes tumor cells in the bone marrow microenvironment. Syndecan-1 (CD138) regulates the growth and survival of tumor cells, and its increase in the blood correlates with poor prognosis. Adhesion of myeloma cells via syndecan-1 to collagen activates matrix metalloproteinase-1, promoting bone resorption and tumor invasion. In addition, being in close physical contact with the bone marrow stromal microenvironment, myeloma cells secrete cytokines (TNF-a, TGF-p, VEGF), which further stimulate the secretion of IL-6 by bone marrow stromal cells, promoting osteolysis.

The clinical picture is characterized by: osteodestruction of flat bones, polyneuropathy, myeloma nephropathy with the development of renal failure, less often hepatosplenomegaly, damage to the lymph nodes, bacterial and viral infections, hemorrhagic syndrome, cryoglobulinemia, amyloidosis. 

There are various clinical variants - non-secreting, dormant, indolent myeloma, plasma cell leukemia.

In the bone marrow of multiple myeloma, plasma cell infiltration of varying severity is observed, characterized by anisocytosis of both cells and their nuclei, anaplasia and varying degrees of maturity (from plasmablasts, proplasmocytes to mature plasma cells). In 10% of cases of multiple myeloma, the tumor substrate is represented by plasmablasts, and a poor prognosis of the disease is noted. In multiple myeloma, multinucleated, multilobular plasma cells are found in the bone marrow. The predominance of immature plasma cells is rarely observed in reactive plasmacytosis, which can serve as a morphological criterion of the tumor process. The cytoplasm of cells has a well-developed endoplasmic reticulum, in which immunoglobulins can condense or crystallize in the form of inclusions: grape bunch (Mott cells), Russell bodies, crystals. These inclusions are not pathognomonic only for multiple myeloma and can be found in reactive plasmacytosis. Flame-like, Gaucher-like cells (thesaurocytes) are rare. In the cytoplasm, vacuolization, the phenomenon of clasmatosis (detachment of the cytoplasm), and phagocytosis can be observed. Observations of multiple myeloma with the phenomenon of hemophagocytosis in plasma cells are described. Another important diagnostic sign of multiple myeloma is the detection of monoclonal immunoglobulin in blood serum and/or urine, detected in 99% of patients. In most patients, there is a decrease in the levels of normal immunoglobulins by more than 50%, rarely - their normal values. Monoclonal IgG occurs in 50%, IgA in approximately 20%, monoclonal light chains (Bence Jones protein) in 15%, IgD in 2%, biclonal gammopathy in 2% of patients. Bence Jones proteinuria is found in 75% of patients. Laboratory manifestations of multiple myeloma are also an increase in the erythrocyte sedimentation rate (in 70% of cases), aggregation of erythrocytes in the blood smear in the form of coin columns, cryoglobulinemia, hypercalcemia.

If the concentration of monoclonal immunoglobulin is less than 35 g/l, the proportion of plasma cells is less than 10%, there are no foci of osteolysis, anemia, hypercalcemia or renal failure, a diagnosis of benign monoclonal gammopathy is made unknown origin. Occurs in 1% of patients over 50 and 3% over 70 years of age. The most frequently registered monoclonal paraprotein is the IgG class. Approximately 25% of patients subsequently develop myeloma, Waldenström's macroglobulinemia, primary amyloidosis, or other lymphoproliferative diseases. On average, this interval is about 10 years.

Plasmacytoma
Plasmacytoma is characterized by clonal proliferation of plasma cells, which are morphologically identical to cells in multiple myeloma, but unlike the latter, the tumor is localized either in bone tissue(solitary plasmacytoma of the bone), or has an extraosseous location (extraosseous, or extraosseous, plasmacytoma). Plasmacytoma accounts for 3-5% of all cases of plasma cell tumors. Extraosseous solitary plasmacytoma occurs in all internal organs and tissues, most often in the nasopharynx, upper respiratory tract, skin, and along the gastrointestinal tract. The criteria for the diagnosis of solitary plasmacytoma are the plasma cell nature of the tumor, normal indicators blood, absence of paraprotein in the blood and urine, normal levels of immunoglobulins, absence of other bone lesions. In 15% of patients, transformation into myeloma is possible.

Acute plasmablastic (plasma cell) leukemia
Acute plasmablastic (plasma cell) leukemia can be primary, like any acute leukemia, or secondary, like a stage in the evolution of myeloma. Approximately 2% of end-stage myeloma cases transform into acute plasmablastic leukemia. Most often found in IgD and IgE myeloma. Extramedullary infiltrates are observed in 50% of patients, mainly in the liver, spleen, lymph nodes, and skin.

Osteodestructive syndrome is less common, and paraproteinemia and paraproteinuria are with the same frequency as in myeloma. Secondary immunodeficiency sharply expressed. Acute plasmablastic leukemia is characterized by diffuse damage to the bone marrow by tumor plasmablasts, which are also found in the peripheral blood (>2.0x109/l, or more than 20% of all leukocytes). In the blood there is slight leukocytosis, anemia, and possible thrombocytopenia. The life expectancy of patients with acute plasmablastic leukemia is less than a year, remissions are rare.

Waldenström's macroglobulinemia
Waldenström's macroglobulinemia is a B-cell tumor, morphologically represented by lymphocytes, mature plasma cells and transitional forms of cells secreting monoclonal IgM. Tumor transformation occurs at the level of postgerminal B lymphocytes. Waldenström's macroglobulinemia accounts for 1.5% of all cases of B-cell lymphomas. Mostly men over 60 years of age are affected. Clinical manifestations of MB are caused by the proliferation of lymphocytes in the bone marrow, liver, spleen, lymph nodes and the accumulation of monoclonal IgM in the serum (>30 g/l). Syndrome high viscosity blood, coagulopathy, cryoglobulinemia, neuropathy - the most common clinical manifestations Waldenström's macroglobulinemia. In the bone marrow, there is a proliferation of lymphocytes, sometimes with plasmatized cytoplasm, an increase in plasma cells (up to 15-20%), and mast cells. Histological examination of the bone marrow reveals diffuse, interstitial or paratrabecular proliferation of lymphocytes, plasma cells and their transitional forms, stromal fibrosis. The picture of peripheral blood is characterized by anemia, leukopenia with neutropenia is often observed, but more often the number of leukocytes is normal, monocytosis can be observed. As the disease progresses, thrombocytopenia develops. The erythrocyte sedimentation rate is always sharply increased. There is hyperproteinemia in the blood serum, and an M-gradient of the IgM class on the electropherogram, and Bence-Jones protein in the urine.

Immunophenotype: tumor cells express surface and cytoplasmic immunoglobulins, usually IgM, B-cell antigens (CD19, CD20, CD22, CD79a), CD38. Cells do not express CD23, CD5, CD10, CD43 (+/-).

Cytogenetics: in 50% of cases, the t(9;14) translocation occurs, a violation of the assembly of genes for the heavy or light chains of Ig. The life expectancy of patients with a slowly progressing process is over 5 years, with rapid progression - about 2.5 years. Transformation into diffuse large cell lymphoma is possible.

Heavy chain diseases
Heavy chain diseases are B-cell lymphatic tumors with a heterogeneous clinical and morphological picture and secretion of heavy chains (H chains) of different classes of immunoglobulins. Diagnosis of heavy chain disease is based on immunochemical analysis of serum proteins, which allows the detection of immunoglobulin heavy chains (H chains). According to the class of heavy chains synthesized by tumor cells, several variants of heavy chain disease are distinguished.

Heavy chain diseases (a variant of lymphoplasmacytic lymphoma) are more common in men under 40 years of age. Damage to the lymph nodes, bone marrow, liver, spleen, Waldeyer's pharyngeal ring, and fever are observed. Most patients have symptoms of intoxication. The blood shows signs of progressive anemia and thrombocytopenia, often of autoimmune origin, eosinophilia, and normal erythrocyte sedimentation rate. The level of pathological immunoglobulin in the serum is low, the concentration of normal immunoglobulins is reduced. The morphological substrate of the tumor is represented by lymphocytes, plasmacytoid lymphocytes, plasma cells, immunoblasts and eosinophils. Sometimes the cytological picture resembles myeloma or chronic lymphoblastic leukemia. The disease progresses rapidly, survival is 12 months. 

Heavy chain diseases are progressive lymphocytic leukemia, which differs from classical chronic lymphoblastic leukemia by pronounced hepatosplenomegaly and the absence of peripheral lymphadenopathy. In the bone marrow, lymphoid proliferation and an increase in the percentage of plasma cells with vacuolated cytoplasm are noted. Heavy chain diseases 5 with clinical and morphological manifestations of multiple myeloma were described in 1978 in Finland.

Heavy chain diseases (a variant of extranodal B-cell lymphoma marginal zone, associated with lymphoid tissue of the mucous membranes) are more often recorded in children and people under 30 years of age of both sexes. About 85% of cases were detected in the pool Mediterranean Sea; There are 2 variants of the disease: abdominal and pulmonary.

The abdominal form is characterized by diffuse infiltration of the mucous membrane small intestine and mesenteric lymph nodes with lymphoid and plasma cells, macrophages, mast cells. Damage to the entire gastrointestinal tract leads to atrophy of the villous apparatus and the development of malabsorption syndrome. The clinical picture is dominated by abdominal pain, chronic diarrhea, steatorrhea, cachexia, episodic fever. The pulmonary form occurs with bronchopulmonary lesions and mediastinal lymphadenopathy.

Follicular lymphoma
Tumor of B cells of the follicular center (centrocytes/centroblasts). Makes up 30-40% of all lymphoid tumors, middle age patients - 60 years. In follicular lymphoma, the lymph nodes, spleen, Waldeyer's pharyngeal ring, and bone marrow are predominantly involved in the tumor process (in 70% of cases). Extranodal tumor foci can be observed in the gastrointestinal tract, soft tissues, and skin. In the early stages, the disease is characterized by follicular growth. The WHO classification identifies 3 types of tumor growth: predominantly follicular (the follicular growth pattern occupies more than 75% of the visual field), follicular and diffuse (the follicular growth pattern occupies 25-75% of the visual field) and predominantly diffuse (the follicular growth pattern occupies less than 25% of the field vision). Non-neoplastic follicles are poorly defined and often lack a mantle zone.

The tumor substrate is represented by cells of the germinal center - centrocytes and centroblasts. Centrocytes are cells the size of a small lymphocyte or slightly larger, with irregular, split, folded nuclei. The nucleus contains coarse chromatin, there are no nucleoli, and the rim of cytoplasm is practically not defined. Centroblasts are larger than centrocytes, round nuclei, 1-2 nucleoli, a distinct rim of basophilic cytoplasm. The ratio of these cells varies.

The tumor has a tendency to generalize early; in only 1/3 of patients it is detected in stages I-II of the disease. In the bone marrow during the leukemia process, lymphoid infiltration is noted with the displacement of normal hematopoietic germs. In the peripheral blood, leukocytosis, anemia and/or thrombocytopenia, and absolute lymphocytosis occur. Among the lymphocytes, medium-sized cells with a high nuclear-cytoplasmic ratio, an irregularly shaped nucleus, with deep clefts and notches predominate. The cytoplasm surrounds the nucleus with a narrow rim of light blue color.

Immunophenotype: tumor cells express pan-B cell antigens (CD19, CD20, CD22, CD79a) in combination with surface immunoglobulins, often IgM, IgG; Sun12+. In most cases, CD10 expression and CD5 absence are detected. CD43 is rarely detected. Tumor cells express the nuclear protein Bc12. 

Cytogenetics: the classic anomaly is t(14;18) (q32;q21), which leads to hyperactivation of bc12 and overproduction of the bc12 gene protein - oncoprotein Bc12, a powerful inhibitor of apoptosis. It prevents the increase in Ca2+ concentration in the nucleus, which is necessary for DNA degradation and induction of apoptosis. Expression of the bc12 protein allows the differentiation of follicular lymphoma and follicular reactive lymph node hyperplasia. The progression of follicular lymphoma is accompanied by transformation into aggressive diffuse large B-cell lymphoma in 25-35% of patients.

Marginal zone lymphoma of the spleen with process lymphocytes
Makes up less than 1% of all lymphoid tumors. The average age of patients is 70-75 years. It is characterized by tumor proliferation of B-lymphocytes, which are located in the germinal centers of the white pulp of the spleen. The leading symptom is severe splenomegaly. Enlargement of peripheral lymph nodes is slight or absent. Bone marrow damage is focal. Histological examination of the spleen reveals infiltration of the white pulp with tumor cell elements. In 60% of cases, a monoclonal paraprotein of the IgM type is detected in the blood serum. Characteristic is the rapid development of leukemia process. In 50% of patients, moderate anemia, thrombocytopenia and leukocytosis are observed in the peripheral blood, rarely exceeding 25x109/l. The leukocyte formula contains absolute lymphocytosis and neutropenia. Most cells are represented by atypical lymphocytes, which have larger size than in chronic lymphocytic leukemia, a rounded nucleus, often with depressions, splits, clumpy distribution of chromatin, nucleoli are possible. The cytoplasm is scanty, moderately basophilic, has thin, short cytoplasmic projections, often localized at one of the poles of the cell. Vacuolization may be observed in the cytoplasm.

Cytochemistry: the reaction to tartrate-resistant acid phosphatase in blood and bone marrow lymphocytes is negative or weakly positive.

Immunophenotype: characterized by a clear expression of surface immunoglobulins of the class IgM, IgD, sometimes intracytoplasmic immunoglobulins are detected, expression of B-lymphocyte markers - CD19, CD20, CD22, CD79a. Unlike chronic lymphoblastic leukemia, the cells do not express CD5, CD23, CD43. Cytogenetics: in some cases, tumor cells contain trisomy 3, t(11;18) and other chromosomal abnormalities. The disease is characterized by a benign course.

Mantle cell lymphoma
Accounts for 3-10% of all malignant lymphomas. The tumor analogue is the lymphocyte of the mantle zone of the lymph node. The average age of patients is 60 years. The most characteristic clinical signs: generalized lymphadenopathy, damage to the liver, spleen, and bone marrow. Involvement of the bone marrow in the process occurs in 50-82% of cases. The most common sites of extranodal tumor localization are gastrointestinal intestinal tract and Waldeyer's pharyngeal ring. Most observations of multiple lymphomatoid polyposis (damage to the gastrointestinal tract) relate to mantle cell lymphoma. The normal pattern of the lymph node is erased, the diffuse type of lesion is much more common, and nodular is less common. There are three cytological variants: from small cells with a rounded nucleus, polymorphic (from large and medium-sized cells with a split nucleus) and blast (blastoid), reminiscent of lymphoblasts. The leukemic phase of mantle cell lymphoma is characterized by medium-sized tumor cells with an irregularly shaped nucleus, cleaved or depressed, and indistinct nucleoli. 

Immunophenotype: characterized by the expression of pan-B cell antigens (CD19, CD20, CD79a) in combination with surface IgM, often with co-expression of IgD. Expression of CD43, CD5 in the absence of CD10 and CD23 is common.

Cytogenetics: in 70-75% of cases there is a translocation t(11;14) (q13; q32), overexpression of cyclin D1 mRNA. Structural violations also found on chromosomes 7, 12 and 18.

Diffuse large B cell lymphoma
It accounts for 30-40% of all lymphosarcoma in adults, the average age of patients is 70 years. Characterized by an aggressive course. It can develop as an independent disease or as a result of transformation of mature cell lymphomas. An immunodeficiency state in patients increases the risk of developing diffuse large B-cell lymphoma. Carrier status is often detected Epstein-Barr virus. Damage to lymphoid tissue is typical, but in 40% of cases extranodal localization occurs (central nervous system, skin, gastrointestinal tract, bones, testicles, soft fabrics etc.). The WHO classification identifies several clinical variants of diffuse large B-cell lymphoma: mediastinal (thymic), intravascular, primary serous cavity lymphoma, ALC-positive large B-cell lymphoma. Non-tumor analogue - B cells of the germinal center (centroblasts) and postgerminal zone (immunoblasts). With this disease, several morphological variants have been identified: centroblastic, immunoblastic, anaplastic (characterized by the presence of large cells similar to Berezovsky-Sternberg cells). With leukemia of diffuse large B-cell lymphoma, infiltration of blast cells is observed in the bone marrow and peripheral blood.

Immunophenotype: tumor cells are characterized by the expression of pan-B cell antigens (CD19, CD20, CD22, CD79a). Surface and/or cytoplasmic immunoglobulins are detected in 50-75% of cases. They are detected in cells with morphological signs of plasmatic differentiation. Although CD30 expression is detected in most cases of anaplastic large cell lymphoma, a similar pattern may occur in non-anaplastic large cell lymphoma. Diffuse large cell B lymphoma is positive for bc16, bc12 in 30-50% of cases. The proliferating fraction of 10-67+ cells is high and amounts to 40-90%.

Cytogenetics: the most common is the t(14;18) translocation, combined with the expression of the bc12 gene, the t(3;14) translocation, and less frequently others.

Burkitt's lymphoma
Burkitt's lymphoma is an aggressive tumor, accounting for 3-5% of all malignant lymphomas. Burkitt's lymphoma is most often recorded in the first two decades of life; it rarely occurs in adults. There is an endemic type (Equatorial Africa, New Guinea), which is associated with the Epstein-Barr virus, a sporadic type (Burkitt-like lymphoma), recorded throughout the globe, and Burkitt lymphoma, associated with HIV. In Europe, the USA and Russia, the sporadic type of lymphoma is rare and accounts for 1-2% in adults. In children, Burkitt's lymphoma reaches 30-50% of all cases of lymphoma. Burkitt's lymphoma and Burkitt-like lymphomas account for up to 40% of all HIV-associated lymphomas. In some patients, the disease manifests itself in the form of acute lymphoblastic leukemia (bZ-variant).

A non-tumor analogue is blast cells of early germinal centers (follicular B-blast). Most often, the tumor has extranodal localization (organs of the gastrointestinal tract, bones of the facial part of the skull, mediastinum, kidneys, mammary gland, central nervous system) with a diffuse growth pattern. Leukemia of the tumor process is characterized by infiltration of the bone marrow and peripheral blood by monomorphic lymphoid elements of medium size with intense basophilia and vacuolization of the cytoplasm containing a significant amount of lipids. The nuclei contain 2-3 small nucleoli, the size of the cells varies. There are many macrophages containing cellular fragments - apoptotic bodies, which creates a picture of a “starry sky”. Rarely, large cells predominate and may be mistaken for large B-cell lymphoma cells. Many mitotic figures are observed. The proliferating fraction of Cl-67+ cells is high and ranges from 80 to 100%.

Immunophenotype: tumor cells express surface immunoglobulins IgM and pan-B cell antigens (CD19, CD20, CD22), CD10, Bc1b, often CD21 (Epstein-Barr virus receptor).

Cytogenetics: characteristic is the translocation t(8;14) (q24; q32) with activation of the proto-oncogene c-tyc. Translocations t(2;8) and t(8;22) can be detected. Overexpression of the c-myc gene leads to dysregulation cell growth and is a key event in the pathogenesis of Burkitt lymphoma.

T-CELL TUMORS FROM MATURE (PERIPHERAL) T-CELLS
This is a heterogeneous group of tumors represented by T lymphocytes with a mature postthymic immunological phenotype. About 15% of malignant lymphomas are of T-cell origin. A connection between these diseases and certain geographical areas has been noted. Thus, in Japan and other Asian countries, T-cell lymphomas associated with the HTLV-I virus (human T-lymphotropic virus type 1) predominate.

T-cell prolymphocytic leukemia
A rare disease, registered over the age of 70 years, has an aggressive course. The clinical picture includes generalized lymphadenopathy, skin lesions in the form of erythematous, papular rashes, and hepatosplenomegaly. In the bone marrow, diffuse lymphoid infiltration with a predominance of prolymphocytes is noted. In the peripheral blood - anemia, hyperleukocytosis with an increased number of prolymphocytes - medium-sized cells, a round, oval or irregularly shaped nucleus, 1-2 nucleoli and varying degrees of basophilia in the cytoplasm. Sometimes the cells are small and the nucleoli in the nucleus are indistinguishable (small cell variant). In some cases of the T-cell variant of prolymphocytic leukemia, polymorphism of the prolymphocyte nuclei occurs (crimped, twisted, split, brain-shaped).

Immunophenotype: tumor cells express CD2+CD3+CD5+CD7+ CD4+CD8-/+.

Cytogenetics: in T-prolymphocytic leukemia, abnormalities of chromosome 14, translocation t(14;14), are observed. The average life expectancy of patients is about 7 months.

T-cell leukemia of large granular lymphocytes
The disease is characterized by prolonged lymphocytosis (>6 months) without a clearly established cause due to large granular lymphocytes. T-cell leukemia of large granular lymphocytes accounts for 2-3% of all cases of chronic lymphoblastic leukemia. It is characterized by a benign course of the process. The clinical picture of the disease is characterized by recurrent bacterial infections, symptoms rheumatoid arthritis, enlarged spleen, polyclonal hypergammaglobulinemia, cytopenia (neutropenia, anemia), absolute lymphocytosis. Large granular lymphocytes have a diameter of 12-15 µm, the nucleus is round or slightly oval, located somewhat eccentrically, the chromatin is condensed, the nucleoli are not visualized. The cytoplasm is wide, light or slightly basophilic, with delicate or dense azurophilic granules different sizes and quantity. Immunophenotype: in 80% of cases CD3+, CD4-, CD8\ TCRaP+ occurs.

Rare options:
CD3+, TCRaP+, CD4+, CD8-; CD3+, TCRap+, CD4\CD8+;
expression of CD3+, TCRy5\ CD4 and CD8 is unclear;
the expression of CD11b, CD56, CD57 varies significantly.

Aggressive NK cell leukemia
Leukemia from natural killer T cells characterized by clonal proliferation of NK cells and an aggressive clinical course. The disease is registered more often in Asian countries in young people. Fever, hepatosplenomegaly, gastrointestinal tract damage, and lymphadenopathy develop. The disease can be complicated by coagulopathies, hemophagocytic syndrome, and multiple organ failure. The Epstein-Barr virus plays a role in the pathogenesis of leukemia from natural killer T cells. In the bone marrow, massive infiltration of tumor NK cells with the morphology of large granular lymphocytes is observed. Reactive histiocytes with the phenomenon of hemophagocytosis may occur. In the peripheral blood - anemia, leukocytosis with absolute lymphocytosis due to large granular lymphocytes.

Immunophenotype: tumor cells express CD2+CD16+CD56\ lack CD3.

Mycosis fungoides/Sézary syndrome (primary T-cell cutaneous lymphoma)
Accounts for 2-3% of all malignant lymphomas. The non-tumor counterpart is peripheral epidermotropic T-lymphocytes. The disease develops slowly. Characteristic skin lesions are papules and erythema, which gradually ulcerate and are accompanied by itching. Alopecia develops as a consequence of involvement of the scalp in the process. Another manifestation of the disease is erythroderma with intense itching and cold intolerance. The progression of mycosis fungoides is accompanied by lymphadenopathy, damage to the liver, lungs, and central nervous system.

Sézary syndrome is considered a leukemic variant of the disease, which is characterized by lymphadenopathy, erythroderma and the presence of tumor T cells in the bone marrow and peripheral blood. In the bone marrow and peripheral blood, atypical lymphocytes with medullary nuclei are found, among which large cells (classical Sezary cells) and small ones are distinguished. Nuclei occupy most of the cell; they are usually round or oval in shape, with a brain-like, convoluted chromatin structure, often without nucleoli. The cytoplasm is basophilic, located around the nucleus in the form of a rim, and does not contain granules. Small cells are detected more often than large ones, have the size of small lymphocytes, an indented chromatin structure (which corresponds to its brain-like structure under electron microscopy) and a narrow rim of cytoplasm. The extent of bone marrow infiltration by Sézary cells varies significantly.

Immunophenotype: tumor cells have the phenotype of mature T lymphocytes (CD2, CD3, CD5, CD4). Observations of Sézary syndrome with reduced expression of CD2, CD3 are described. CD8, CD7, CD30 are not expressed.

(section written jointly with V.M. Sotnikov and A.M. Bershanskaya)

The incidence of malignant tumors of lymphatic and hematopoietic tissue is steadily increasing. In 1995, 9547 primary patients with malignant lymphomas were identified in Russia (2.3% of all oncological diseases).

During 1985-1995, the incidence of hematological malignancies in Russia increased by 17.5% in men and by 21.3% in women [Dvoirin V.V. et al., 1996].

Most likely, these figures are not complete enough, since, for example, in the United States, about 43,000 cases of malignant lymphoma are diagnosed annually.

Gelder C.M., Hetzel M.R. (1993) according to the collected statistics, lymphoma was noted in 321 cases of malignant neoplasms of the trachea in 4 (1.2%).

The source of the development of diverse lymphoproliferative processes in the tracheal wall, both hyperplastic and tumor, are accumulations of lymphoid cells scattered in the submucosal layer. The so-called bronchi-associated lymphoid tissue (BALT) - component department of lymphoid tissue associated with mucous membranes (mucosa-associated lymphoid tissue - MALT).

S.G. Borzhima first became interested in the distribution of lymphoid elements in the wall of the trachea in 1930, after the famous otolaryngologist M.I. Zaevloshin removed a tracheal tumor (at the level of the 4th ring) from the lymphoid tissue. Similar lesions were previously described by Watanabe in Japan.

S.G. Borzhima examined pieces of trachea from 101 corpses. In 51.8% of cases, accumulations of lymphoid elements were found in the form of islands or diffuse accumulations - either directly under the epithelium or deep among the mucous glands. In some cases, the clusters formed germinal centers. In most observations, it was possible to trace the moments of the eviction of lymphoid elements: some of them were located between epithelial cells, others on the surface of the mucous membrane. In the upper third of the trachea, lymphoid tissue was found in 44.5% of cases, in the middle - in 53.7%, in the lower - in 57.1%. Most often - at the age of 20-50 years. The maximum concentration of lymphoid tissue was noted in the area of ​​the tracheal bifurcation. In bronchi, especially small ones, it was less common.

The spectrum of tracheal lymphoproliferative processes extends from multifocal proliferation in the thickness of the tracheal wall (BALT follicular hyperplasia) to more pronounced forms of proliferation with the formation of solitary masses or nodules (nodular lymphoid hyperplasia or “pseudolymphoma”), or diffuse or diffuse nodular BALT lymphoid hyperplasia (lymphoid interstitial pneumonitis). Hyperplasia of tracheal lymphoid tissue is based on the physiological proliferation of B lymphocytes in the presence of activated antigen-dependent T lymphocytes, including those associated with viral infection (Epstein-Barr virus, HIV).

Of clinical significance is that malignant tracheal lymphomas grow rapidly. There is a lot of controversy in this difficult field of oncology. In particular, there is no uniform terminology and morphological classification of non-Hodgkin lymphomas. Several classifications are used and compete with each other: WHO, Rappoport, Kiel, Working Formulation, clinical value which are almost the same.

Development of increasingly sophisticated laboratory techniques such as genetic analysis, immunophenotyping, has led to a significant increase in the number of types of lymphomas. The recently proposed REAL classification distinguishes 43 types of malignant lymphomas. At the same time, due to the wide range of biological behavior and significant differences in treatment tactics and prognosis, the most accurate diagnosis of the morphological type of lymphoma is necessary. Additional diagnostic difficulties arise when different morphological types of lymphoma are combined in one tumor (composite lymphoma), in different foci in the same patient (discordant lymphoma), transformation of one morphological type into another, with the corresponding dynamics of the clinical picture of the disease.

Traditionally, malignant lymphomas have been considered systemic diseases, primarily affecting lymphoid organs. However, about 20% of malignant lymphomas occur isolated in individual bodies, including in the lungs and trachea.

The etiology of malignant lymphomas of the respiratory tract differs from the etiology lung cancer. Epidemiological studies have shown that smoking does not increase the risk of developing malignant lymphomas of the respiratory tract. In recent years it has been proven viral nature some types of lymphoma. At least some cases of malignant lymphomas are associated with carriage of the Epstein-Barr virus. Chronic antigenic stimulation and chemical factors of environmental pollution, including herbicides, contribute to the development of malignant lymphomas. Often a tumor occurs against the background of immunological changes, including in AIDS and in patients who have undergone organ transplantation.

Late 80s special attention noted an increase in the frequency of lymphoproliferative disorders after organ allotransplantation against the background of severe immunosuppression. This complication (from polyclonal conglomerates to lymphosarcoma) most often occurred in long term after transplantation of the cardiopulmonary complex. At long-term follow-up on average, 7.9% of recipients developed lymphoproliferative disorders.

Typically, the tumor in the recipient arises from B lymphocytes. Immunophenotyping can often detect DNA or RNA of the Epstein-Barr virus. The original cells in most cases come from the recipient: although this issue has not yet been completely resolved.

The WHO International Histological and Cytological Classification of Tumors of Hematopoietic and Lymphatic Tissue has been officially adopted in Russia. This classification distinguishes nodular and diffuse types of tumor structure (Table 18). In accordance with the cytological characteristics of tumor cells, lymphocytic, lymphoplasmacytic, prolymphocytic (with a prolymphocytic-lymphoblastic subvariant), lymphoblastic (with a twisted and untwisted nucleus), immunoblastic, and Burkitt-type variants are presented. Phenotypic heterogeneity within the specified morphological variants is indicated. Nuclear dissection is proposed as one of the morphological markers of the B-cell type; nuclear torsion is proposed for the T-cell type.

The WHO classification includes mycosis fungoides, reticulosarcoma (this group also includes the histiocytic variant), plasmacytoma, unclassified malignant lymphomas, and Hodgkin's disease.

Table 18. TUMORS OF HEMATOPOIETIC AND LYMPHOID TISSUE (WHO classification)

A. LYMPHOSARCOMA

1. Lymphosarcoma nodular

2. Diffuse lymphosarcoma

a) lymphocytic

b) lymphoplasmacytic

c) prolymphocytic

d) lymphoblastic

e) immunoblastic

e) Burkitt's tumor

B. MYCOSIS FUNGOIDS

B. PLASMOCITOMA

D. RETICULOSARCOMA

E. UNCLASSIFIED MALIGNANT LYMPHOMAS

E. HODGKIN'S DISEASE (LYMPHOGRANULOMATOSIS)

1. With a predominance of lymphocytes

2. With nodular sclerosis

3. Mixed cell variant

4. With depletion of lymphoid tissue

G. OTHER

1.Eosinophilic granuloma

2.Mastocytoma

The WHO classification is not the only one. The Kiel classification (revised 1992) and the recently proposed REAL classification are also widely used and allow the identification of new types of malignant lymphomas. Comparative characteristics of these classifications are presented in Table 19.

Table 19. Main classifications of lymphoproliferative diseases

Most significant achievement recent years is to identify a class of MALT lymphomas that arise extranodal in the mucous membranes of any organ, including the trachea and upper respiratory tract. TO characteristic features MALT lymphomas include:

1. Low degree of malignancy.

2. The tumor may remain local for many years.

3. Unlike other non-Hodgkin lymphomas, the bone marrow is rarely affected, in no more than 5% of cases.

4. Often develops against the background of chronic organ infections and autoimmune diseases.

5.Good prognosis with local treatment.

6.Transformation into high-grade lymphoma

(probability of transformation is unknown).

7. Damage to the mucous membranes of other organs

Summarizing the literature data, we can propose the following working classification of malignant tracheal lymphomas:

I. Primary non-Hodgkin's lymphoma of the trachea.

1. B-cell: MALT lymphomas (low and high grade) Mantle lymphoma (lymphoid polyposis) Other types equivalent to nodal lymphomas

2. T-cell.

II. Hodgkin's disease (lymphogranulomatosis).

III. Plasmacytoma.

IV. Secondary lesions of the trachea in malignant lymphomas of other locations.

The invention relates to medicine, namely to oncology, and can be used for the treatment of non-Hodgkin lymphomas and granulomatosis. It is proposed to carry out plasmapheresis on the 1st and 8th days of treatment, collect autoplasma in an amount of 200-250 ml, conduct a course of chemotherapy: vincristine - 1 mg, doxorubicin - 40-50 mg, cyclophosphamide - 600-800 mg on the 1st and the 8th day, cytostatics are mixed with autoplasma, incubated at 37 o C for 1 hour and reinfused to the patient, treatment is carried out while using prednisolone 40 mg/day from days 1 to 14 orally and intramuscularly. The method allows to increase the effectiveness of treatment.

The invention relates to medicine, namely to oncology, and can be used for the treatment of lymphogranulomatosis, non-Hodgkin lymphomas with various stages of the process, resistant forms and relapses, as well as in the presence of concomitant diseases. There is a known method of treating hematosarcomas (see "Chemotherapy tumor diseases under. ed. Perevodchikova N.I. M., 2000, p.259), chosen as an analogue by combination antitumor drugs CHOP, including cyclophosphamide 750 mg/m2, adriablastine 50 mg/m2, vincristine 1.4 mg/m2 intravenously on day 1 of treatment, prednisolone 60 mg/m2 orally on days 1-5 of treatment, the course is repeated every 3 weeks . The disadvantages of the known method of treatment include pronounced side effects of cytostatics, requiring a significant reduction in standard single and course doses of drugs, immunosuppressive effects, which does not allow compliance with the planned regimens and ultimately negatively affects the effectiveness of treatment of lymphoproliferative diseases. There is a known method of treating locally advanced breast cancer (Author's abstract of thesis ... Ph.D. Vladimirova L.Yu. "Neoadjuvant chemotherapy for natural environments organism using the pineal gland peptide epithalamin in the complex treatment of locally advanced breast cancer" Rostov-on-Don, 2000, p. 10), chosen by us as a prototype, which consists in the fact that a single dose of chemotherapy is mixed with 100-150 ml chemotherapy drugs, incubated at 37 o C for 1 hour and administered intravenously 3 times a week. This method of treatment improved the effectiveness of treatment of patients with breast cancer, used the properties of autoplasma as a modifier of the action of chemotherapy drugs, but had pronounced toxicity associated with the effect on rapidly proliferating drugs. blood cells and mucous membranes, and did not allow the collection of autoplasma of more than 100-150 ml. The use of autoplasma chemotherapy in various cases is unknown. malignant diseases, in particular in the treatment of lymphoproliferative malignant processes of varying degrees of prevalence, with relapses of diseases. Particular clinical difficulties arise in cases with concomitant pathology, which forces the dose of cytostatics to be reduced and negatively affects the effect of chemotherapy. The purpose of the invention is to improve the immediate and long-term results of treatment of patients with lymphoproliferative diseases. The goal is achieved by the fact that on the 1st and 8th days of treatment, plasmapheresis is carried out, autoplasma is collected in an amount of 200-250 ml, a course of chemotherapy is carried out: vincristine - 1 mg, doxorubicin - 40-50 mg, cyclophosphamide - 600-800 mg on days 1 and 8, cytostatics are mixed with autoplasma, incubated at 37 o C for 1 hour, and reinfused to the patient, treatment is carried out while using prednisolone 40 mg/day from days 1 to 14 orally or intramuscularly. The invention is new, since it is not known from the level of medicine in the field drug therapy in oncohematology. The novelty of the invention lies in the fact that to carry out a course of chemotherapy on the 1st and 8th days of treatment, plasmapheresis is carried out, discrete or continuous (hardware filtration or centrifugal), autoplasma is collected, which is incubated with single doses of chemotherapy at 37 o C in for 1 hour and reinfused. The introduction of chemotherapy drugs on autoplasma leads to the acquisition of new properties by the chemotherapy drug-protein complex, which ensure its high tropism towards tumor tissues, thereby ensuring the high efficiency of the method. Exfusion of autoplasma also has immunocorrective, detoxifying and reocorrective properties, which additionally increases the effectiveness of treatment due to nonspecific influences. Using the body's own environment completely eliminates transfusion and allergic reactions . This method increases the therapeutic capabilities of the method and allows for the treatment of patients with lymphogranulomatosis, non-Hodgkin's lymphoma, including relapses and resistant forms. The particular clinical value of this method is in the successful treatment of patients with concomitant pathologies, since it allows not to reduce doses, which has a positive effect on the effect of treatment. The invention has an inventive step, since for a specialist oncologist-chemotherapist it does not clearly follow from the level of modern medicine in this field of treatment of lymphoproliferative diseases. The invention is not obvious, new, not following the level of modern medicine, and is not known either in the world or in the domestic literature. The invention is industrially applied, as it can be used in healthcare, medical institutions involved in the treatment of cancer, oncology research institutes, and cancer clinics. The method for treating lymphoproliferative diseases is performed as follows. A patient with malignant lymphoma undergoes plasmapheresis once a week by any of the methods - discrete or continuous machine centrifugal or filtration, autoplasma is collected in an amount of 200-250 ml, chemotherapy drugs are dissolved in 10 ml of saline. solution, injected into a bottle with autoplasma, incubated at 37 o C for 60 minutes and reinfused intravenously. The combination of antitumor drugs we use is designed for 2 weeks and is administered in doses: vincristine 1 mg, doxorubicin 40-50 mg, cyclophosphamide 600-800 mg intravenously on days 1 and 8; prednisolone 40 mg/day orally from days 1 to 14 of treatment. Before and after plasmapheresis, the indicators of red blood cells, hemoglobin, hematocrit, leukocyte formula, platelets, PTI, and total protein are monitored. Observe the general condition of patients. In addition, a general blood and urine test is monitored at least 2 times a week, and an ECG is monitored before and after a course of chemotherapy. In the case of plasmapheresis, a discrete method is used to collect 250-300 ml of autologous blood, which is centrifuged at 1500 rpm for 40 minutes, the resulting supernatant plasma is separated and used for administering chemotherapy, and the cell sediment is reinfused. When performing hardware plasmapheresis, an ADM/ABM 08 monitor, a PlS filter, and standard pipeline systems were used. Vascular access - by catheterization of central or peripheral veins. Combined heparinization after preoperative hemocorrection with crystalloid solutions, autoplasma is collected. Examples of specific applications of the method for treating lymphoproliferative diseases. Example 1. Patient D., 47 years old, and. b. 10959/e, was treated at the RNIOI from September 26, 1997 with a diagnosis of Lymphoblastic lymphosarcoma with damage to the parotid, submandibular, cervical lymph nodes on both sides, mediastinal, st. MB. The diagnosis was confirmed morphologically (histological examination 491658 - 660 dated September 26, 1997). Concomitant diseases: hypertrophic cardiomyopathy, stage I heart failure, chronic bronchitis, chronic pyelonephritis, secondary anemia. From December 2, 1997 to December 12, 1997, a course of chemotherapy was carried out on autoplasma, obtained by discrete plasmapheresis. Course doses were: doxorubicin 80 mg, vincristine 2.5 mg, cyclophosphamide 1200 mg, prednisolone 40 mg/day orally from days 1 to 14 of treatment. Complications: alopecia II degree, leukopenia I degree. As a result of treatment, complete regression was noted after 2 weeks peripheral lymph nodes(parotid, submandibular, cervical), which before treatment were represented by a single, dense, immobile conglomerate of 75 cm, the fluorogram showed regression of the mediastinal lymph nodes of more than 80%, signs of intoxication disappeared (temperature normalized, sweating disappeared), ESR decreased from 47 before treatment to 15 mm/h, cough disappeared, general condition improved. The patient then underwent DHT on the lesions at a dose of 36 Gy. So, instead of the standard 6 courses of chemotherapy and DHT, the patient received 1 course of chemotherapy and DHT. The patient has been under observation at the RNIOI for 3.5 years without signs of disease progression. Example 2. Patient L., 30 years old, i.b. 4063/n. He has been under treatment at the RNIOI since March 20, 2001 with a diagnosis of lymphogranulomatosis (lymphoid depletion) with damage to the lymph nodes of the mediastinum and the roots of the lungs and spleen. Art. III B. The patient received 4 courses of chemotherapy using autoplasma, which was obtained by continuous filtration apparatus plasmapheresis. Course doses were: doxorubicin 100 mg, cyclophosphamide 1200 mg, vincristine 3 mg, prednisolone 40 mg/day orally from days 1 to 14. Complications: alopecia of the second degree, nausea of ​​the first degree during the 2nd and 3rd courses. After the first course, it was noted: complete regression of lesions in the spleen and a decrease in its size to normal, lymph nodes of the mediastinum and roots of the lungs decreased by 70%, temperature normalized, ESR decreased from 50 to 4 mm/h, hemoglobin level increased from 98 to 120 g/l . Currently, the patient is undergoing a course of DHT according to a radical program. Thus, the examples demonstrate the possibility of collecting plasma using two different methods of plasmapheresis both in patients with lymphogranulomatosis and in patients with non-Hodgkin's lymphomas. The first example shows that in a patient with concomitant pathology, such a course is an adequate chemotherapeutic effect and allows achieving high efficiency treatment based on both immediate and 3-year survival outcomes. The second example shows a high immediate effect, the ability to speed up the timing of radical treatment in a patient with lymphogranulomatosis, who has an unfavorable morphological variant of the disease - lymphoid depletion. The technical and economic efficiency of the method for treating lymphoproliferative diseases lies in increasing the effectiveness of treatment due to the use of the modifying properties of autoplasma, and not by increasing the doses of antitumor chemotherapy drugs. Positive side This approach is determined not only by a reduction in the toxic effects of chemotherapy on the patient’s body, but also by a reduction in drug costs. Autoplasma chemotherapy has immunomodulatory properties and allows you to achieve a pronounced clinical effect in short terms, which makes its use economically profitable and allows you to bring the deadlines closer radiation therapy, as well as improve long-term treatment results and increase survival rates.

Formula of invention

A method of treating lymphoproliferative diseases, including polychemotherapy and intravenous drip administration of chemotherapy drugs, characterized in that on the 1st and 8th days of treatment, plasmapheresis is performed, autoplasma is collected in an amount of 200-250 ml, a course of chemotherapy is administered: vincristine - 1 mg, doxorubicin - 40-50 mg, cyclophosphamide - 600-800 mg on days 1 and 8, cytostatics are mixed with autoplasma, incubated at 37 o C for 1 hour and reinfused to the patient, treatment is carried out while using prednisolone 40 mg / day with 1 1st to 14th days orally and intramuscularly.

Similar patents:

The invention relates to new ortho-sulfonamidobicyclic heteroaryl hydroxamic acids of the formula where W and X are both carbon, T is nitrogen, U is CR1, where R1 is hydrogen, or alkyl containing 1-8 carbon atoms, P is -N( CH2R5)-SO2-Z, Q represents -(C=O)-NHOH, and is a benzene ring or is a heteroaryl ring with 5-6 atoms in the ring, which may contain 0-2 heteroatoms selected from nitrogen, oxygen and sulfur, in addition to a nitrogen heteroatom designated as W; wherein the benzene or heteroaryl ring may optionally contain one or two R1 substituents where appropriate; Z is phenyl, which is optionally substituted with phenyl, alkyl of 1-8 carbon atoms, or an OR2 group; R1 represents halogen, alkyl with 1-8 carbon atoms, alkenyl with 2-6 carbon atoms, perfluoroalkyl with 1-4 carbon atoms, phenyl, optionally substituted with 1-2 -OR2 groups, -NO2 group, -(CH2)nZ group , where Z is phenyl and n=1-6, thienyl and the group -OR2, where R2 represents alkyl with 1-8 carbon atoms; R2 represents an alkyl of 1-8 carbon atoms, phenyl, optionally substituted with halogen, or a heteroaryl radical containing 5-6 ring atoms, including 1-2 heteroatoms selected from nitrogen, oxygen and sulfur; R5 is hydrogen, alkyl with 1-8 carbon atoms, phenyl, or heteroaryl containing 5-6 ring atoms, including 1-2 heteroatoms selected from nitrogen, oxygen and sulfur; or pharmaceutically acceptable salts thereof

Malignant lymphomas. Lymphoproliferative processes. Hodgkin's lymphoma.

Neoplasms arising from elements of a lymph node or extranodal lymphoid tissue are called LYMPHOMAS. Lymphomas are classified as diseases of the hematopoietic tissue - hemoblastoses, among which leukemia (2/3) and sarcomas (hematosarcomas) account for 1/3. Leukemia is characterized by primary damage to the bone marrow; Hemoblastoses are characterized by the presence, even at stage 1, of the development of focal tumor growths from elements of hematopoietic tissue without damage to the bone marrow (lymph node). There are common criteria between them: leukemia can be accompanied by damage to the lymph nodes, neural membranes, pleura, and so on. Hemoblastoses can, during dissemination, involve the bone marrow (leukolization) or generalize (hematosarcomatosis). In the histological classification of hematosarcomas, there are:

A. LYMPHOSARCOMA (nodular, diffuse), synonym – Non-Hodgkin lymphoma:

Lymphocytic,

Lymphoplasmacytic,

Prolymphocytic,

Lymphoblastic,

Immunoblastic,

Burkitt's tumor (lymphoma).

B. LYMPHOGRANULOMATOSIS (disease, Hodgkin's lymphoma)

C. MYCOSIS FUNGOIDES

D. RETICULOSARCOMA

E. PLASMOCITOMA

F. UNCLASSIFIED LYMPHOMAS

G. OTHER (MASTOCYTOMA, EOSINOPHILIC GRANULOMA).

Hodgkin's lymphoma, Lymphogranulomatosis is a malignant tumor of the lymph nodes and lymphatic system with subsequent possible involvement of other organs; The pathomorphological substrate of the tumor is large multinucleated Berezovsky-Sternberg and Pirogov-Reed cells. The disease was first described in 1832 by Thomas Hodgkin, and this nosology was formed in 1865. In 1904, at the VII Congress of German Pathologists, the term LYMPHOGRANULOMATOSIS was introduced, and in 2001, in the most recent WHO recommendation, the term Hodgkin's LYMPHOMA was proposed to designate this disease. To date, etiological factors have not been fully established. There are several theories of the occurrence of Hodgkin lymphoma:

Infectious - in families with patients with LGM, the incidence is almost 3 times higher. A case of simultaneous illness of several classmates with Hodgkin's lymphoma is described. According to a few scientists, tuberculosis, diphtherobacilli, fungi, staphylococci, and E. coli can provoke the occurrence of this pathology.

Viral –

Immunodeficiency - decreased immune reactivity, resulting in a tendency to viral infections, herpes, development of solid tumors, high level prostaglandins, monocytosis (a sign of suppression of T-B lymphocytes).

Tumor – obeys the laws of tumor progression, unicentricity, metastasis, spread of atypical cells by hematogenous and lymphogenous routes.

Dysfunction of cellular immunity is expressed by a decrease in the response to mitogens in culture and a decrease in the delayed hypersensitivity reaction upon intradermal administration of tuberculin and T-dependent antigens. In addition, with LGM there is a disruption in the interaction of T and B lymphocytes. Impaired suppressor function of T-lymphocytes in the manifestation of hypergammaglobulinemia. Clinically, a tendency to viral infections, a tendency to autoimmune cytopenias, decreased resistance to bacterial infections. Most scientists adhere to the unicentric origin of Hodgkin lymphoma.

Prevalence and epidemiology

In Russia, the incidence of Hodgkin's lymphoma was 2.3 per 100 thousand population, in the USA - 2.8 per 100 thousand. Men get sick several times more often than women. The incidence occurs at any age, but the curve has two peaks - 15-35 years, and the second after 50. Recently, the presence of a second peak has been questioned. Women predominate among young patients, and men predominate among older age groups. Among young patients, women predominate. Among the patients in the older groups are men.

Etiological factors of lymphoproliferative processes.

Numerous studies have noted a relationship between infection with the Epstein-Barr virus and the incidence of lymphoma. Moreover, in infected patients the risk of developing Hodgkin lymphoma is 3 times higher than in the uninfected population. There is also a high risk of Hodgkin lymphoma in patients with infectious mononucleosis. However, the pathogenesis of Hodgkin lymphoma remains not entirely clear. Currently, among the numerous theories of the origin of Berezovsky-Sternberg cells, the hypothesis of German scientists is distinguished: large mononuclear cells (Hodgkin) and Berezovsky-Reed-Sternberg are the result of monoclonal proliferation of mature B cells originating from the germinal center of the follicle of the lymph node. These cells, having avoided apoptosis, were able to proliferate uncontrollably. In this case, the main link in the pathogenesis of this pathology is the block of apoptosis. Immunological markers of differential diagnostic significance are the CD15 and CD30 antigens, usually in the absence of CD45 and rare expression of CD 20 by Berezovsky-Reed-Sterntberg cells. Hodgkin's lymphoma is accompanied by suppression of T-cell immunity. Patients are susceptible to various viral infections, primarily herpes (H. Zoster). Less commonly, Hodgkin's lymphoma is combined with tuberculosis.

Pathomorphological characteristics.

The diagnosis of Hodgkin's lymphoma is established exclusively histologically and is considered reliable only if specific binuclear or multinucleated Berezovsky-Reed-Sternberg cells are found. A cytological examination is mandatory at the first stage of diagnosis to develop an examination plan. However, this method is not always possible to establish the variant of Hodgkin's lymphoma and make a differential diagnosis with various types of large cell non-Hodgkin's lymphomas. For an adequate histological examination, the lymph node must be removed entirely, since a full diagnosis is possible only by examining the structure of the entire node. This is due to the fact that there are often situations when only part of the removed lymph node is affected by the tumor. In difficult differential diagnostic situations, it is necessary to conduct an immunomorphological study of tumor tissue.

According to the modern international morphological classification, there are 4 histological variants of classical Hodgkin lymphoma:

1) with nodular (nodular) sclerosis

2) mixed-cellular;

3) lymphocyte-rich classical Hodgkin's Lymphoma;

4) with lymphoid depletion (or suppression) of the diffuse fibrosis type or the so-called reticular type.

Lymphohistiocytic. Pronounced lymphoid proliferation of histiocytes. Diffuse focal and uneven accumulation of eosinophils and plasma cells. There are few characteristic Berezovsky-Reed-Sternberg cells. There are no foci of necrosis.

Mixed cell version. Motley cellular composition lymph node with a large number of Berezovsky-Reed-Sternberg cells with foci of necrosis. Most often the entire node is affected, but focal damage to the node is possible.

Nodular sclerosis. The development of coarse fibrous layers of connective tissue dividing the lymph node into separate nodes, in which there are typical Berezovsky-Reed-Sternberg cells, foci of necrosis against the background of accumulation of neutrophils and histiocytes.

Lymphoid depletion. Disorderly development of connective tissue, a significant decrease in the number of cells, proliferation of atypical histiocytes and Berezovsky-Reed-Sternberg cells.

The uniqueness of classical Hodgkin lymphoma is determined by its morphological substrate: the presence of a polymorphic cell granuloma formed by lymphocytes, neutrophils, eosinophils, histiocytes, plasma cells, among which large mononuclear Hodgkin cells and giant bi- or multinucleated Berezovsky-Reed-Sternberg cells are rarely located. The phenomena of fibrosis can be expressed to varying degrees, and foci of necrosis occur. The normal pattern of structure in the affected lymph node is gradually erased. Of the variety of granuloma elements, only Hodgkin and Berezovsky-Reed-Sternberg cells are tumor cells (their aneuploidy and clonality have been proven). All other cellular elements - lymphocytes, histiocytes, plasma cells, eosinophils, etc. - constitute a reactive component and are not tumor; it is believed that they reflect the reaction of lymphoid tissue to the proliferation of Berezovsky-Reed-Sternberg cells.

The variant with nodular sclerosis is more common in young patients, among whom women predominate. With this option, there are more early stages with damage to the lymph nodes only above the diaphragm. The originality of the architectonics of tumor tissue is due to the presence of collagen strands dividing the node into round-shaped areas - nodules.

The mixed-cell variant occurs mainly in patients of the older age group. This variant has a classic morphological picture, when the structure of the lymph node is erased, and Hodgkin cells and Berezovsky-Reed-Sternberg tumor cells are rarely scattered among lymphocytes, eosinophils, histiocytes, etc.

Lymphocyte-rich classic Hodgkin lymphoma is rare. During histological examination in the lymph node, small lymphocytes predominate among reactive cells, and Hodgkin and Berezovsky-Reed-Sternberg cells are few in number. This variant of Hodgkin lymphoma has the most favorable course - the 15-year survival rate of patients reaches 90%.

The variant with lymphoid depletion is very rare. Among diffuse fibrosis, small accumulations of various cellular elements are found; Berezovsky-Reed-Sternberg tumor cells predominate. The variant is characterized by a poor prognosis.

The most common and approximately equal proportions are the variants with nodular sclerosis and mixed-cellular (30-45% each) and equally rare (up to 10%) - rich in lymphocytes and with lymphoid depletion.

Differential diagnosis of Hodgkin lymphoma is carried out with large cell lymphomas, both B- and T cell nature: also with nonspecific lymphadenitis. Cells resembling Hodgkin cells and Pirogov-Langhans type (large, multinucleated cellular elements) can occur in tuberculosis and actinomycosis and cause diagnostic difficulties. However, the absence of multinucleated Berezovsky-Reed-Sternberg cells allows, as a rule, to make a differential diagnosis even at the level of light microscopy.

Clinical picture.

There are 3 forms of flow.

Acute – characterized fast start, high body temperature, adynamia, heavy sweats, damage to the liver, lungs, etc.

Subacute – there is an uncontrollable progression of the process, anemia, exhaustion.

It is impossible to clarify the primary localization in these forms.

Chronic – (92% of cases) the average duration of diagnosis is about 3 months from the moment of clinical manifestations (tuberculosis, rheumatism, lymphadenitis, mononucleosis, infections, syphilis).

General symptoms are manifested by an increase in body temperature to subfebrile, febrile levels, lasting up to 2-3 days with good tolerance, remitting nature, weakness. Increased sweating (usually at night), skin itching - limited or generalized. Weight loss – 10% or more of body weight, pain in joints, muscles, headaches.

Examination of patients with.

Treatment of patients with.

Treatment results and five-year survival