– tumor diseases of the lymphatic system, represented by malignant B- and T-cell lymphomas. The primary focus can occur in the lymph nodes or other organs and subsequently metastasize through the lymphogenous or hematogenous route. The clinical picture of lymphoma is characterized by lymphadenopathy, symptoms of damage to one or another organ, and fever-intoxication syndrome. Diagnosis is based on clinical and radiological data, the results of a hemogram, biopsy of lymph nodes and bone marrow. Antitumor treatment includes courses of polychemotherapy and radiation therapy.
ICD-10
C82 C85
General information
Non-Hodgkin's lymphomas (NHL, lymphosarcoma) are malignant lymphoproliferative tumors of different morphology, clinical signs and course, different in their characteristics from Hodgkin's lymphoma (lymphogranulomatosis). Depending on the location of the primary focus, hemoblastoses are divided into leukemia (tumor lesions of the bone marrow) and lymphoma (tumors of lymphoid tissue with a primary extramarrow localization). Based on distinctive morphological features, lymphomas are in turn divided into Hodgkin and non-Hodgkin; The latter in hematology include B- and T-cell lymphomas. Non-Hodgkin's lymphomas occur in all age groups, but more than half of the cases of lymphosarcoma are diagnosed in people over 60 years of age. The average incidence rate among men is 2-7 cases, among women – 1-5 cases per 100,000 population. Over the past few years, there has been a trend toward a progressive increase in incidence.
Causes
The etiology of lymphosarcoma is not reliably known. Moreover, the causes of lymphomas of different histological types and locations vary significantly. Currently, it is more correct to talk about risk factors that increase the likelihood of developing lymphoma, which are currently well studied. The influence of some etiofactors is significant, while the contribution of others to the etiology of lymphomas is very insignificant. These types of unfavorable conditions include:
- Infections. Human immunodeficiency virus (HIV), hepatitis C, and T-lymphotropic virus type 1 have the greatest cytopathogenic effect on lymphoid cells. A connection between Epstein-Barr virus infection and the development of Burkitt's lymphoma has been proven. It is known that Helicobacter pylori infection, associated with gastric ulcer, can cause the development of lymphoma of the same localization.
- Immune defects. The risk of lymphoma increases with congenital and acquired immunodeficiencies (AIDS, Wiskott-Aldrich syndrome, Louis-Bar syndrome, X-linked lymphoproliferative syndrome, etc.). Patients receiving immunosuppressive therapy for bone marrow or organ transplantation are 30 to 50 times more likely to develop NHL.
- Accompanying illnesses. An increased risk of NHL incidence is observed among patients with rheumatoid arthritis, lupus erythematosus, which can be explained by both immune disorders and the use of immunosuppressive drugs to treat these conditions. Thyroid lymphoma usually develops against the background of autoimmune thyroiditis.
- Toxic effects. A cause-and-effect relationship is traced between lymphosarcoma and previous contact with chemical carcinogens (benzene, insecticides, herbicides), UV radiation, and radiation therapy for cancer. Cytostatic drugs used for chemotherapy have a direct cytopathic effect.
Pathogenesis
Pathological lymphogenesis is initiated by one or another oncogenic event, causing disruption of the normal cell cycle. Two mechanisms may be involved in this - activation of oncogenes or suppression of tumor suppressors (antioncogenes). The tumor clone in NHL in 90% of cases is formed from B lymphocytes, extremely rarely from T lymphocytes, NK cells or undifferentiated cells. Various types of lymphomas are characterized by certain chromosomal translocations, which lead to suppression of apoptosis, loss of control over the proliferation and differentiation of lymphocytes at any stage. This is accompanied by the appearance of a clone of blast cells in the lymphatic organs. Lymph nodes (peripheral, mediastinal, mesenteric, etc.) increase in size and can disrupt the function of nearby organs. With bone marrow infiltration, cytopenia develops. The growth and metastasis of the tumor mass is accompanied by cachexia.
Classification
Lymphosarcoma that primarily develops in the lymph nodes is called nodal, in other organs (palatine and pharyngeal tonsils, salivary glands, stomach, spleen, intestines, brain, lungs, skin, thyroid gland, etc.) - extranodal. Based on the structure of the tumor tissue, NHLs are divided into follicular (nodular) and diffuse. Based on the rate of progression, lymphomas are classified into indolent (with a slow, relatively favorable course), aggressive and highly aggressive (with rapid development and generalization). In the absence of treatment, patients with indolent lymphomas live on average 7–10 years, with aggressive ones – from several months to 1.5-2 years.
The modern classification includes over 30 different types of lymphosarcoma. Most tumors (85%) originate from B lymphocytes (B-cell lymphomas), the rest from T lymphocytes (T-cell lymphomas). Within these groups, there are different subtypes of non-Hodgkin's lymphomas. The group of B-cell tumors includes:
- diffuse large B-cell lymphoma– the most common histological type of lymphosarcoma (31%). It is characterized by aggressive growth, despite this, in almost half of the cases it can be completely cured.
- follicular lymphoma– its frequency is 22% of the NHL number. The course is indolent, but transformation into aggressive diffuse lymphoma is possible. The 5-year survival rate is 60-70%.
- small cell lymphocytic lymphoma and chronic lymphocytic leukemia– similar types of NHL, which account for 7% of their number. The course is slow, but difficult to treat. The prognosis is variable: in some cases, lymphosarcoma develops within 10 years, in others, at a certain stage it turns into a fast-growing lymphoma.
- mantle cell lymphoma– in the NHL structure it is 6%. Only 20% of patients overcome the five-year survival threshold.
- Marginal zone cell B-cell lymphomas– are divided into extranodal (can develop in the stomach, thyroid, salivary, mammary glands), nodal (develop in the lymph nodes), splenic (localized in the spleen). Characterized by slow local growth; in the early stages they are highly treatable.
- B-cell mediastinal lymphoma– is rare (in 2% of cases), but unlike other types it affects mainly young women 30-40 years old. Due to rapid growth, it causes compression of the mediastinal organs; cured in 50% of cases.
- Waldenström's macroglobulinemia(lymphoplasmacytic lymphoma) – diagnosed in 1% of patients with NHL. It is characterized by hyperproduction of IgM by tumor cells, which leads to increased blood viscosity, vascular thrombosis, and capillary ruptures. It can have both relatively benign (with survival up to 20 years) and transient development (with the death of the patient within 1-2 years).
- hairy cell leukemia is a very rare type of lymphoma that occurs in older people. The progression of the tumor is slow and does not always require treatment.
- Burkitt's lymphoma– it accounts for about 2% of the NHL. In 90% of cases, the tumor affects young men under 30 years of age. The growth of Burkitt's lymphoma is aggressive; Intensive chemotherapy allows half of the patients to be cured.
- lymphoma of the central nervous system– Primary damage to the central nervous system may affect the brain or spinal cord. More often associated with HIV infection. The five-year survival rate is 30%.
Non-Hodgkin lymphomas of T-cell origin are represented by:
- T-lymphoblastic lymphoma or progenitor cell leukemia– occurs with a frequency of 2%. The number of blast cells in the bone marrow differs: with<25% опухолевых клеток патология расценивается как лимфома, при >25% - like leukemia. It is diagnosed mainly in young people, the average age of patients is 25 years. T-lymphoblastic leukemia has the worst prognosis, the cure rate for which does not exceed 20%.
- peripheral T-cell lymphomas, including cutaneous lymphoma (Sézary syndrome, mycosis fungoides), angioimmunoblastic lymphoma, extranodal natural killer lymphoma, lymphoma with enteropathy, panniculitis-like subcutaneous lymphoma, large cell anaplastic lymphoma. The course of most T-cell lymphomas is rapid and the outcome is unfavorable.
Symptoms
The clinical manifestations of NHL vary greatly depending on the location of the primary lesion, the extent of the tumor process, the histological type of tumor, etc. All manifestations of lymphosarcoma fit into three syndromes: lymphadenopathy, fever and intoxication, extranodal lesions. In most cases, the first sign of NHL is enlargement of peripheral lymph nodes. At first they remain elastic and mobile, later they merge into vast conglomerates. The lymph nodes of one or many areas can be affected at the same time. When fistula tracts form, it is necessary to exclude actinomycosis and tuberculosis.
Nonspecific symptoms of lymphosarcoma such as fever without obvious causes, night sweats, weight loss, and asthenia in most cases indicate the generalized nature of the disease. Among extranodal lesions, non-Hodgkin lymphomas of the Pirogov-Waldeyer ring, gastrointestinal tract, and brain dominate; the mammary gland, bones, lung parenchyma, and other organs are less commonly affected. On endoscopic examination, nasopharyngeal lymphoma looks like a pale pink tumor with bumpy contours. Often the maxillary and ethmoid sinuses and orbit grow, causing difficulty in nasal breathing, rhinophony, hearing loss, and exophthalmos.
Primary testicular lymphosarcoma may have a smooth or lumpy surface, elastic or stony density. In some cases, swelling of the scrotum, ulceration of the skin over the tumor, and enlargement of the inguinal-iliac lymph nodes develop. Testicular lymphomas are prone to early dissemination with damage to the second testicle, central nervous system, etc. Breast lymphoma on palpation is defined as a clear tumor node or diffuse breast compaction; nipple retraction is uncharacteristic. When the stomach is affected, the clinical picture resembles stomach cancer, accompanied by pain, nausea, loss of appetite, and weight loss. Abdominal lymphosarcoma can manifest itself as partial or complete intestinal obstruction, peritonitis, malabsorption syndrome, abdominal pain, ascites. Lymphoma of the skin is manifested by itching, nodules and a reddish-purple induration. Primary damage to the central nervous system is more typical for patients with AIDS - the course of lymphoma of this localization is accompanied by focal or meningeal symptoms.
Complications
The presence of a significant tumor mass can cause compression of organs with the development of life-threatening conditions. When the mediastinal lymph nodes are damaged, compression of the esophagus and trachea develops, SVC compression syndrome. Enlarged intra-abdominal and retroperitoneal lymph nodes can cause intestinal obstruction, lymphostasis in the lower half of the body, obstructive jaundice, and compression of the ureter. Germination of the walls of the stomach or intestines is dangerous due to the occurrence of bleeding (in case of vascular arrosion) or peritonitis (when contents leak into the abdominal cavity). Immunosuppression makes patients susceptible to life-threatening infectious diseases. High-grade lymphomas are characterized by early lymphogenous and hematogenous metastasis to the brain and spinal cord, liver, and bones.
Diagnostics
Diagnosis of non-Hodgkin lymphomas is the responsibility of oncohematologists. Clinical criteria for lymphosarcoma are enlargement of one or more groups of lymph nodes, intoxication phenomena, and extranodal lesions. To confirm the suspected diagnosis, it is necessary to carry out morphological verification of the tumor and instrumental diagnostics:
- Study of tumor cell substrate. Diagnostic operations are performed: puncture or excisional biopsy of lymph nodes, laparoscopy, thoracoscopy, bone marrow aspiration puncture followed by immunohistochemical, cytological, cytogenetic and other studies of diagnostic material. In addition to diagnosis, establishing the structure of NHL is important for choosing treatment tactics and determining prognosis.
- Visualization methods. Enlargement of the mediastinal and intra-abdominal lymph nodes is detected using ultrasound of the mediastinum, radiography and CT scan of the chest and abdominal cavity. The examination algorithm according to indications includes ultrasound of the lymph nodes, liver, spleen, mammary glands, thyroid gland, scrotal organs, gastroscopy. To stage the tumor, an MRI of internal organs is performed; Lymphoscintigraphy and bone scintigraphy are informative in identifying metastases.
- Laboratory diagnostics. Aimed at assessing risk factors and internal organ function in lymphomas of various locations. In the risk group, the HIV antigen and anti-HCV are determined. Changes in peripheral blood (lymphocytosis) are characteristic of leukemia. In all cases, a biochemical complex is examined, including liver enzymes, LDH, uric acid, creatinine and other indicators. b2-microglobulin can serve as a unique tumor marker for NHL.
- Chemotherapy. Most often, treatment of lymphomas begins with a course of polychemotherapy. This method can be used alone or combined with radiation therapy. Combined chemoradiation therapy allows for longer remissions. Treatment continues until complete remission is achieved, after which another 2-3 consolidating courses are necessary. It is possible to include hormone therapy in treatment cycles.
- Surgical interventions. It is usually used for isolated damage to any organ, more often the gastrointestinal tract. Whenever possible, operations are radical in nature - extended and combined resections are performed. In advanced cases, when there is a threat of perforation of hollow organs, bleeding, or intestinal obstruction, cytoreductive interventions can be performed. Surgical treatment is necessarily complemented by chemotherapy.
- Radiation therapy. As a monotherapy for lymphomas, it is used only for localized forms and low-grade tumors. In addition, radiation can also be used as a palliative method if other treatment options are not possible.
- Additional treatment regimens. Of the alternative methods, immunochemotherapy using interferon and monoclonal antibodies has proven itself to be successful. To consolidate remission, transplantation of autologous or allogeneic bone marrow and the introduction of peripheral stem cells are used.
Prognosis and prevention
The prognosis for non-Hodgkin's lymphomas varies, depending mainly on the histological type of tumor and the stage of detection. With locally advanced forms, long-term survival averages 50-60%, with generalized forms - only 10-15%. Unfavorable prognostic factors include age over 60 years, stages III-IV of the oncological process, bone marrow involvement, and the presence of several extranodal lesions. At the same time, modern PCT protocols in many cases make it possible to achieve long-term remission. Prevention of lymphomas correlates with known causes: it is recommended to avoid infection with cytopathogenic viruses, toxic effects, and excessive sun exposure. If you have risk factors, you should undergo regular examination.
HODGKIN'S LYMPHOMA (LYMPHOGRANULOMATOSIS)
Hodgkin's lymphoma (Hodgkin's malignant lymphoma), a primary tumor disease of the lymphatic system.
Hodgkin's lymphoma was first described in 1832 by the English physician T. Hodgkin, who reported seven cases of the disease, which occurs with enlargement of the lymph nodes and spleen, fever, cachexia, invariably ending in the death of the patient.
In 1875 I.A. Kutarev conducted the first histological studies of a lymph node removed during the life of a patient. In 1890, Russian researcher S.Ya. Berezovsky described the histological picture of Hodgkin's lymphoma. He established the presence of giant cells pathognomonic for Hodgkin's lymphoma. In 1897-1898 Viennese pathologists I. Paltauf, S. Sternberg, D. Reed described polymorphic cell granuloma with the presence of giant multinucleated cells, later called Berezovsky-Reed-Sternberg cells.
EPIDEMIOLOGY
The importance of studying Hodgkin's lymphoma, like all malignant lymphomas, is dictated by the fact that those affected are mainly young people (the majority are from 12 to 40 years old). In the structure of cancer incidence, Hodgkin's lymphoma ranks 9-10th. The incidence rate of malignant neoplasms of lymphatic and hematopoietic tissues in the Russian Federation in 2007 was 16.0 per 100 thousand population, including Hodgkin's lymphoma - 2.2. Urban residents get sick approximately 1.5 times more often than the rural population. Hodgkin's lymphoma occurs at any age, but the first peak incidence occurs at 20-30 years of age; The 2nd peak occurs after
60 years. Men get sick somewhat more often than women. The incidence rate of the male population is 1.5-2 times higher in childhood and in the age group over 40 years.
ETIOLOGY AND PATHOGENESIS
The main argument put forward in favor of the infectious nature of Hodgkin lymphoma is based on an epidemiological analysis of the incidence rate in different regions. The high-risk group includes identical twins in case of illness in one of them, close relatives of patients and persons who have had infectious mononucleosis. Infection in early childhood can lead to immunization without showing signs of disease, and at a later date to the development of Hodgkin lymphoma. The importance of genetic factors in the etiology of the disease can be judged based on the frequency of detection of certain HLA antigens, primarily in identical twins.
Another theory is based on viral damage to T-lymphocytes. An increase in spontaneous transformation and the appearance of hyperbasophilic cells in the peripheral blood can serve as a sign of immune protection of sensitized lymphocytes from genetically foreign, virus-infected cells. The cytotoxic effect of lymphocytes obtained from patients with Hodgkin's disease on cultured Berezovsky-Reed-Sternberg cells and the similar topography of these cells and lymphocytes in the body can be explained in a similar way. Circulating immune complexes with the help of antibodies are adsorbed predominantly on these cells. Thus, the phenomenon of malignant transformation of the phagocytic system is the focus of attention of researchers, but the question of the nature of T-cell disorders remains open. The suppressor effect is attributed to malignantly transformed macrophages.
The origin of the Berezovsky-Reed-Sternberg cell has not been definitively established. Most likely, this cell comes from T and B lymphocytes. Some authors have indicated that malignant cells in lymphogranulomatosis can originate from the monocyte-histiocytic-macrophage clone. With Hodgkin's lymphoma, the structure of the lymph nodes is disrupted; connect-
calf tissue cords, growing directly from the capsule, penetrate the tissue of the lymph node, turning it into a granuloma. The cellular composition is represented by B-lymphocytes at different stages of maturation, T-lymphocytes with the T-helper and T-suppressor phenotype. In Hodgkin's lymphoma, the detection of mononuclear Hodgkin cells, which are an intermediate link in the transformation into multinucleated Berezovsky-Reed-Sternberg cells, is of particular diagnostic importance.
S. Rorrota (1992) indicates a change in karyotype in 30% of patients with lymphogranulomatosis. It was also noted that the frequency of karyotype changes is different for different histological variants of lymphogranulomatosis.
CLASSIFICATION
Histological classification of Hodgkin lymphoma
The diagnosis of Hodgkin's lymphoma can only be established on the basis of histological examination, after a biopsy of the lymphatic organ or node. Evidence of the presence of Hodgkin lymphoma is the detection of Berezovsky-Reed-Sternberg cells.
In accordance with the International Morphological Classification (Raje Classification), there are 4 classic variants of Hodgkin lymphoma:
1) nodular sclerosis (types 1 and 2);
2) the classic version, rich in lymphocytes;
3) mixed-cell variant;
4) variant of lymphoid depletion.
Classification by stages. Signs of intoxication, their prognostic significance
The prevalence of the tumor process is determined in accordance with the clinical classification adopted in 1971 at the conference on malignant lymphomas (Ann Arbor, USA).
I stage- damage to 1 lymphatic zone (I) or localized damage to 1 extralymphatic organ or tissue (IE).
II stage- damage to 2 lymphatic areas or more on one side of the diaphragm (II) or localized damage to 1 extralymphatic organ or tissue and their regional lymphatics
nodes with other (or without) lymphatic areas on the same side of the diaphragm (IIE).
III stage- damage to the lymph nodes on both sides of the diaphragm (III), which can be combined with localized damage to 1 extralymphatic organ or tissue (IIIE), with damage to the spleen (IIIS) or with their combined damage (IIIE + S).
IV stage- disseminated damage to one or more extralymphatic organs, with (or without) involvement of the lymph nodes; or isolated damage to an extralymphatic organ with involvement of distant lymph nodes.
The symbol S indicates damage to the spleen (stages IS, IIS, IIIS); symbol E - localized extranodal lesion (stages IE, IIE, IE). Symbol B indicates the presence of one or more of the following symptoms: profuse night sweats, fever above 38 °C for at least three consecutive days without signs of inflammation, loss of 10% of body weight over the past 6 months; symbol A - absence of the above symptoms.
Symptoms of intoxication are unfavorable prognostic factors in patients with Hodgkin lymphoma.
CLINICAL PICTURE. DIAGNOSTICS
The clinical course of the disease depends on the localization of the primary lesion, the degree of involvement of nearby organs in the process and the morphological variant of the disease.
The disease most often begins with an enlargement of one or more lymph nodes in the cervical-supraclavicular, axillary or inguinal region (Fig. 26.1).
With a long history, the lymph nodes can reach enormous sizes and merge into conglomerates.
If the mediastinal lymph nodes are affected, shortness of breath, cough, facial puffiness, and SVC syndrome may occur. When the process is localized in the retroperitoneum
Rice. 26.1. Hodgkin's lymphoma. Damage to the cervical and supraclavicular lymph nodes
and mesenteric lymph nodes, abdominal pain and swelling of the lower extremities may appear.
Differential diagnosis of Hodgkin lymphoma is carried out with lymphadenitis and lymphadenopathy of various etiologies. Bacterial lymphadenitis occurs in response to infection and can be observed in various diseases, such as AIDS, tuberculosis, etc. Protozoal (with toxoplasmosis) and fungal (with actinomycosis) lymphadenitis is relatively rare. The viral nature of lymphadenitis in infectious mononucleosis, influenza, and rubella is possible. Lymphadenitis can be local, most often in the area of the infection gate (with influenza, sore throat), or generalized (with sepsis). The histological structure of the lymph node in reactive lymphadenitis retains its normal elements.
In addition to the above, clinical (CS) and pathological (PS) stages are distinguished. Clinical staging is determined by a detailed clinical examination and lymph node (or tissue) biopsy. The pathological stage implies morphological confirmation of each location of the lesion, established as a result of surgical procedures: bone marrow biopsy, liver biopsy, and laparotomy with splenectomy.
To select treatment tactics for patients with Hodgkin lymphoma, a group of prognostic factors, designated as favorable and unfavorable, is used. Unfavorable prognostic factors include: the presence of massive lymph nodes with a diameter of more than 5 cm, merging into conglomerates; expansion of the mediastinal shadow on radiographs by enlarged lymph nodes by more than 1/3 of the diameter of the chest at its widest point (MTI >0.35); massive damage to the spleen, damage to three zones of lymph nodes or more; acceleration of ESR >30 mm/h - in stage B and ESR >50 mm/h in stage A. A number of researchers consider age over 40 years, extranodal lesions within the limits indicated by the symbol E, mixed-cell variant and lymphoid depletion to be unfavorable factors. The presence of one or more of the above signs serves as the basis for classifying the patient into the group with an unfavorable prognosis. The remaining patients, like all patients with pathological stage I of lymphogranulomatosis, belong to the group with a favorable prognosis.
The importance of the morphological research method. Technique
It should be noted the decisive role of morphological examination in Hodgkin lymphoma. Aspiration and open biopsy are mandatory.
The cytological picture of Hodgkin lymphoma is characterized by cellular polymorphism. Lymphocytes, prolymphocytes, eosinophils, neutrophils, plasma cells, mononuclear giant Hodgkin cells, as well as multinucleated giant Berezovsky-Reed-Sternberg cells are visible in the preparation. The final diagnosis is made only after histological examination of the biopsied lymph node.
With the lymphohistiocytic variant, proliferation of lymphocytes and histiocytes is noted. There are single Berezovsky-Reed-Sternberg cells. In the nodular sclerosis variant, collagen strands are visible dividing the lymph nodes into separate sections. In the mixed-cellular variant, the pattern of the lymph node is completely erased, and in some places lymphoid hyperplasia with lymphoblasts and lymphocytes is noted. The sinuses are destroyed, there are foci of necrosis, and there are a large number of Berezovsky-Reed-Sternberg cells in the fields of view. In the case of lymphoid depletion, a small number of lymphocytes are visible in the preparation, but they may be absent. There is diffuse sclerosis, connective tissue cords, and a large number of Berezovsky-Reed-Sternberg cells.
The method of cytological examination of punctures is based on the study of cells of the pathological focus obtained by puncture. This method consists of obtaining cellular material from lymph nodes located deep in the tissue. For this procedure, a sterile dry syringe and a dry injection needle must be prepared.
In the treatment room (dressing room), the patient is placed on the table. All rules of asepsis and antiseptics must be observed. The skin over the lymph nodes is treated with alcohol, after which the injection site is marked with a needle. The lymph nodes are fixed with the left hand, and a needle with a pre-attached syringe is inserted with the right hand. Having felt the needle enter the lymph node, they begin to pull back the piston with their right hand, and with their left hand they advance the needle either deeper or towards the surface of the tumor. Fixing the needle in the tumor, the syringe is removed in the position of the maximum retracted piston, after
why the needle is removed. Then, in a retracted position, the needle is put back on, its contents are blown onto a glass slide with a quick push of the piston, and a smear is prepared from the resulting drop of punctate.
A biopsy is understood as the intravital removal of a piece of tissue from a tumor focus for the purpose of microscopic examination. Technique biopsy depends on the depth of the lymph nodes. A knife (excisional) biopsy is performed under local anesthesia or intravenous anesthesia, depending on the depth of the lymph nodes. After processing the surgical field 3 times, an incision is made above the lymph nodes. The largest lymph node or several lymph nodes are taken for histological examination. It is better to remove the lymph node together with the capsule. If it is not possible to remove the entire lymph node, wedge resection is performed. The biopsy is completed with hemostasis and layer-by-layer sutures on the wound.
Scope of study to assess the prevalence of the tumor process. The value of diagnostic laparotomy. Splenectomy
Diagnosing Hodgkin lymphoma is not particularly difficult. A correctly collected medical history, the nature of the lymph nodes, and additional diagnostic methods with mandatory verification of the diagnosis make it possible to identify tumor pathology in the early stages of the disease.
Examination of patients with Hodgkin lymphoma includes:
1. History, clinical data (presence or absence of symptoms of intoxication), number of affected lymph nodes and areas.
2. Biopsy of the affected lymph node (cytological and morphological verification of the diagnosis with the mandatory establishment of the histological variant of Hodgkin lymphoma).
3. Immunophenotyping.
4. Complete blood count (ESR, leukocytes, leukocyte formula).
5. Biochemical blood test (liver tests, levels of alkaline phosphatase, lactate dehydrogenase (LDH), fibrinogen, haptoglobin, ceruloplasmin, and 2-globulin).
6. Trepanobiopsy of bone marrow.
7. X-ray of the chest organs (clarification of the condition of the mediastinal, hilar lymph nodes, lung tissue, pleura).
8. CT scan of the chest (if X-ray data is of little information value), establishing the size of the tumor tissue.
9. Ultrasound of the abdominal cavity and retroperitoneal region to exclude damage to the mesenteric, retroperitoneal, intrapelvic lymph nodes, liver, and spleen.
10. CT scan of the abdominal cavity (more accurate identification of affected areas and extralymphatic organs).
11. Radioisotope study of the skeletal system with 99t Tc and the lymphatic system with 67 Oa.
According to indications:
Endoscopic diagnostic methods (fibrogastroscopy, laryngoscopy, thoracoscopy, laparoscopy);
Lymphography;
Diagnostic laparotomy.
Diagnostic laparotomy is performed in patients in whom, based on clinical examination, it is not possible to accurately determine whether there is damage to the spleen or not. Laparotomy is performed with splenectomy and histological examination of the spleen. For isolated lesions of the mediastinal lymph nodes, transthoracic puncture or thoracoscopy with lymph node biopsy is indicated.
Prognosis factors
1. Massive lesion of the mediastinum (MTI >0.33).
3. Presence of a single extranodal lesion (E).
4. ESR >30 mm/h for option B and ESR >50 mm/h for option A.
5. 3 zones of affected lymph nodes or more.
Forecast groups
Favorable prognosis
Stages I and IIA, without risk factors.
Interim forecast
IA and IB stages:
2. ESR >30 mm/h for option B.
3. ESR >50 mm/h for option A. Stage IIA:
1. Presence of extranodal lesion (E).
2. ESR >50 mm/h for option A.
3. Involvement of 3 zones of lymph nodes or more. Stage IIB:
1. ESR >30 mm/h for option B.
2. Involvement of 3 zones of lymph nodes or more - stage IIIA, without risk factors.
Poor prognosis
Stage IA, ? stages, stage IIA:
1. Massive lesion of the mediastinum (MTI >0.33).
2. Splenomegaly (5 or more lesions or organ enlargement with diffuse infiltration).
Stage IIB:
1. Massive lesion of the mediastinum (MTI > 0.33).
2. Splenomegaly (5 or more lesions or organ enlargement with diffuse infiltration).
3. Stage E. Stage IIIA:
1. Massive lesion of the mediastinum (MTI >0.33).
2. Splenomegaly (5 or more lesions or organ enlargement with diffuse infiltration).
3. Stage E.
4. ESR >50 mm/h.
The choice of treatment method depending on the clinical features of the disease
The main methods of treating Hodgkin lymphoma are radiation, drugs, and a combination of both.
For several decades, the only treatment for this disease was surgical removal of the affected lymph nodes. But in the second half of the 19th century, the opinion was established that as a result of surgery, the tumor process was generalized, and treatment of the disease was limited to general restoratives. In 1901, W. Pusey (Chicago, USA) performed single irradiations of the lymph nodes in 2 patients
lymphogranulomatosis. In 1902, N. Senn used x-rays in the treatment of Hodgkin's lymphoma; 4 years later this method appeared in Russia (Reshetilo D.F., 1906). It was only in the early 1940s that radiation therapy was supplemented with chemotherapy. As the first chemotherapeutic agent, L. Sooatap et al. (1946) proposed a mustargenalkylating drug from the group of chlorethylamines.
In the USSR since 1947 L.F. Larionov began to use an analogue of this drug - embiquin. Until the early 1960s, the use of chemotherapy for lymphogranulomatosis was irregular and was predominantly exploratory or palliative in nature. Radiation therapy remained the main treatment method for lymphogranulomatosis. In the early 1960s V. De Vita proposed
new course of PCT - MORR.
When using radical radiation therapy in an independent mode, the SOD is brought to 40 Gy in 4-6 weeks, and in areas of preventive radiation it is 30-60 Gy in 3-4 weeks. This treatment program is the method of choice only for patients with local (IA-IIA) pathological stages of lymphogranulomatosis and favorable prognostic factors.
In the last decade, various combined chemoradiotherapy treatment programs have become most widespread. For patients with favorable prognostic signs, treatment is carried out according to the program: 2 cycles of PCT according to any of the 1st line regimens + irradiation of only the affected areas at a dose of 36 Gy + 2 cycles of PCT according to the same regimen as before irradiation.
Combination therapy is the treatment of choice for patients with stage (and IE-PE) Hodgkin's lymphoma and poor prognosis. It is advisable to start treatment with PCT. The volume of treatment is always greater than for patients with a favorable prognosis. A program is used that includes 3 cycles of PCT according to one of the 1st line regimens + irradiation of the affected areas at a dose of 36 Gy (some authors also recommend preventive irradiation of subclinical areas) + 3 consolidating cycles of PCT.
In the treatment of patients with stage IIIA Hodgkin lymphoma, combination chemoradiotherapy has recently been increasingly used. For patients with favorable prognostic factors, the treatment program includes 4 cycles of 1st line PCT + irradiation of the affected areas at a dose of 30-40 Gy.
For patients with unfavorable prognostic factors, the treatment program includes 6-8 cycles of PCT according to the 1st line regimen + irradiation of the affected areas at a dose of 30 Gy (for patients with complete remission) and 40 Gy (for patients with residual tumor masses). For the treatment of patients with generalized stage III-IV Hodgkin lymphoma, the method of choice is cyclic PCT.
The following are the most common 1st line regimens for the treatment of Hodgkin lymphoma:
MORR: mechlorethamine (mustargen, embiquin) - 6 mg/m2 intravenously on days 1 and 8; vincristine (Oncovin) - 1.4 mg/m2 (maximum 2 mg) intravenously on days 1 and 8; procarbazine (natulan) - 100 mg/m2 daily orally from the 1st to the 14th day; prednisolone - 40 mg/m2 daily orally from the 1st to the 14th day. The break between cycles is 2 weeks. MVPP: similar to the MOPP regimen, only in it vincristine is replaced by vinblastine at a dose of 6 mg/m2 on the same days of administration. The break between cycles is 3-4 weeks. CVPP: cyclophosphamide - 600 mg/m2 intravenously on days 1 and 8; vinblastine - 6 mg/m2 intravenously on days 1 and 8; procarbazine - 100 mg/m2 daily orally from the 1st to the 14th day; prednisolone 40 mg/m2 daily orally from the 1st to the 14th day in the 1st and 4th cycles. The break between cycles is 2 weeks. SOPP: similar to the CVPP regimen, only in it vinblastine is replaced by vincristine at a dose of 1.4 mg/m2 (maximum 2 mg) on the same days of administration. The break between cycles is 2 weeks. LVPP: similar to the CVPP regimen, only in it cyclophosphamide is replaced by chlorambucil (Leukeran) at a dose of 6 mg/m2 (maximum 10 mg) from days 1 to 14 daily orally. The break between cycles is 3-4 weeks. ABVD: doxorubicin (Adriamycin) - 25 mg/m2 intravenously on days 1 and 14; bleomycin 10 mg/m2 intravenously on days 1 and 14; vinblastine - 6 mg/m2 intravenously on days 1 and 14; dacarbazine (DTIC) - 375 mg/m2 intravenously on days 1 and 14. The break between cycles is 2 weeks. When using only cyclic PCT in patients with any stage of Hodgkin's lymphoma, treatment should be carried out until complete remission is achieved, after which at least 2 more consolidating cycles must be performed. Complete remission, especially in patients with generalized stages of the disease, is rarely achieved
earlier than the 4th cycle of PCT, so the required minimum for the entire treatment program is 6 cycles.
When treating late relapses of Hodgkin lymphoma that occur after two years of complete remission, the same principles are used as in primary patients, i.e. the choice of treatment program depends on the stage of relapse, determined by the same diagnostic methods as during the initial examination. It is more difficult to treat patients with early (up to two years) relapses of Hodgkin lymphoma and patients who did not achieve complete remission during primary treatment. For patients with stages I-II and a favorable prognosis, marginal (marginal) relapses that occur during the first 5 months after radiation therapy are recommended to be additionally irradiated at the usual dose (40 Gy). The remaining patients are advised to change chemotherapy.
For the treatment of early generalized relapses after combination therapy, primary-resistant patients and patients with continuously relapsing forms of Hodgkin lymphoma, a large number of 2nd-line regimens have been proposed, and in the last decade - high-dose chemotherapy under the protection of autologous bone marrow or stem cell transplantation (3-line regimens). th line). In 2nd line regimens, drugs such as lomustine (CCNU), etoposide, teniposide are widely used, and in high-dose therapy regimens, melphalan (Alkeran), sarcolysine, cytarabine (Alexan) and platinum drugs.
2nd line regimens for the treatment of Hodgkin lymphoma: DexaBEAM: dexamethasone - 8 mg 3 times a day orally on days 1-10; carmustine - 60 mg/m2 IV on day 2 or lomustine - 80 mg/m2 IV on day 2; melphalan - 20 mg/m2 IV on the 3rd day; etoposide - 200 mg/m2 IV from days 4 to 7; cytarabine - 100 mg/m2 every 12 hours IV from days 4 to 7; CSF - from 8th to 18th days. The cycle resumes on the 28th day. After two cycles, a high-dose phase is carried out. B-CAVe: bleomycin - 5 mg/m2 intravenously on days 1, 28, 35; lomustine - 100 mg/m2 orally on day 1; doxorubicin - 60 mg/m2 intravenously on day 1; vinblastine - 6 mg/m2 intravenously on the 1st day. The course is repeated on the 42nd day. SER: lomustine - 80 mg/m2 orally on day 1; etoposide - 100 mg/m2 intravenously from days 1 to 5; prenemustine - 60 mg/m2 orally from the 1st to the 5th day. The course is repeated on the 28th day.
Modification of the SEP regimen for oral use: PESS: prednisolone - 40 mg/m2 daily orally from the 1st to the 7th day; etoposide - 200 mg/m2 daily orally from the 1st to the 3rd day; chlorambucil (leukeran) 20 mg/m2 daily orally from the 1st to the 5th day; lomustine (CCNU) 100 mg/m2 orally on day 1. The break between cycles is 3 weeks. ABVD-salvage for patients resistant to MOPP and its modifications: doxorubicin - 25 mg/m2 intravenously on days 1 and 14; bleomycin - 10 mg/m2 intravenously on days 1 and 14; vinblastine - 6 mg/m2 intravenously on days 1 and 14; dacarbazine - 175 mg/m2 daily intravenously from the 1st to the 5th day. The break between cycles is 4-6 weeks. MOPP/ABV (it is possible to use one of the modifications of the MOPP regimen in the 1st week of the cycle): mechlorethamine (Embikhin) - 6 mg/m2 intravenously on the 1st day; vincristine (Oncovin) - 1.4 mg/m2 intravenously (maximum 2 mg) on day 1; procarbazine (natulan) - 100 mg m2 daily orally from the 1st to the 7th day; prednisolone - 40 mg/m2 daily orally from days 1 to 8; doxorubicin (Adriamycin) - 35 mg/m2 intravenously on the 8th day; bleomycin - 10 mg/m2 intravenously on the 8th day; vinblastine - 6 mg/m2 intravenously on the 8th day. The break between cycles is 3 weeks. The second line also uses IGEV, ICE, IVAM schemes. 3rd line regimens (high-dose therapy + automyelotransplantation or stem cell recapture):
BEAM: carmustine (BCNU) - 300 mg/m2 intravenously on day 1; etoposide - 100-200 mg/m2 intravenously on days 2-5; cytarabine - 200-400 mg/m2 intravenously on days 2-5; melphalan - 140 mg/m2 intravenously on the 6th day; automyelotransplantation or return of stem cells on the 7th day. Currently, there is an increase in prognostically unfavorable factors and an increase in the frequency of primary forms of Hodgkin lymphoma resistant to cytostatic therapy. All this leads to a deterioration in the effect of treatment and the impossibility of carrying it out in optimal doses and modes. As a result, remission periods are reduced, the number of relapses increases, and the life expectancy of patients decreases. Recently, high-dose chemotherapy with (or without) radiation before autologous bone marrow transplantation has been widely used, high-dose chemotherapy
in combination with the introduction of recombinant human granulocyte colony-stimulating factor, high-dose chemotherapy using autologous hematopoietic precursor cells from peripheral blood.
The immediate results of treatment in patients are assessed based on the following clinical criteria.
The objective therapeutic effect is assessed using a physical examination, ultrasonographic and x-ray examination after the 3rd and 6th courses of the studied drug therapy options according to the criteria recommended by WHO (Geneva, 1979):
Complete remission - complete disappearance of all clinical and laboratory manifestations of a tumor disease for a period of at least 4 weeks; for hemoblastoses involving the bone marrow, complete normalization of the myelogram and hemogram is necessary;
Partial remission - reduction of all measurable tumors by at least 50% for a period of at least 4 weeks;
Stabilization - a decrease in tumor foci by less than 50% in the absence of new lesions or an increase in tumor foci by no more than 25%;
Progression - an increase in tumor size by 25% or more and/or the appearance of new lesions.
The dynamics of B-symptoms of tumor intoxication are assessed by their presence or absence after the 3rd and 6th courses of the studied drug therapy options.
Along with the criteria of “relapse-free survival” and “overall survival,” new criteria were introduced in the 2nd half of the 1990s to assess the effectiveness of treatment: “survival free of treatment failure” and “event-free survival.”
1. Disease-free survival(DFS - disease free survival) is calculated from the date of complete remission until the date of relapse or after the days the patient appears. Relapse-free survival characterizes only the group of patients who have achieved complete remission, and shows what proportion of these patients have the opportunity to live for the specified period without signs of recurrence of the disease.
2. Survival free from treatment failure(FFTF - freedom from treatment failure), calculated from the start of treatment until any “failure” of treatment or until the date of the patient’s last appearance. Treatment “failure” means: progression during treatment; absence of complete remission after completion of the entire treatment program
nia; relapse; complications of treatment that caused its cessation; death from any cause. This criterion characterizes the entire group of patients who started treatment and shows what part of them has the opportunity to live for the specified period without signs of the disease.
3. Disease-specific survival(DSS - disease specific survival), calculated from the date of start of treatment to the date of death from a given disease or to the date of the last appearance of the patient. This criterion characterizes the entire group of patients who began treatment and shows what part of them could have lived for the specified period if there had been no deaths from complications of treatment during the period of complete remission of the disease.
4. Overall survival(OS - overall survival) is calculated from the date of initiation of treatment until death from any cause or until the date of the last appearance of the patient. Overall survival characterizes the entire group of patients who started treatment and shows the actual survival rate for the specified period of observation.
5. Event-free survival(EFS - event free survival) is calculated from the date of start of treatment to any “negative” event or to the date of the last appearance of the patient. A “negative” event is understood as: progression, lack of complete remission after the end of the entire treatment program; complications of treatment that caused its cessation; relapse; death from any cause; the appearance of a second tumor or any other late complication of treatment that threatens the patient’s life. Event-free survival characterizes the entire group of patients who started treatment and reflects the duration and quality of life of all patients in this group.
FORECAST
The 5-year overall and relapse-free survival rate of patients with local forms of Hodgkin lymphoma with supraphrenic localization of the process is about 90% with complex therapy. With stage IIIA Hodgkin's lymphoma, the 5-year overall and relapse-free survival rate is more than 80%, with stage IIIB - about 60%. The 5-year overall survival rate for stage IV patients after polychemoradiation treatment is about 45%. According to the American Cancer Society, the overall 5-year survival rate of patients with Hodgkin lymphoma in 1975-1977. was 73%, in 1984-1986. -
79%, in 1996-2002. - 86%.
Examination of disability. Social significance of rehabilitation of patients with lymphogranulomatosis
With a favorable clinical prognosis, the criteria for returning to work are:
General satisfactory condition;
Psychological “correction”;
Normalization of hematological and biochemical parameters;
Completed treatment of complications.
With effective incomplete treatment, the duration of temporary disability (TL) may be longer. If chemotherapy treatment is well tolerated and there are no complications requiring treatment between courses, patients are temporarily disabled for this period. In other cases and during chemotherapy in patients with a questionable prognosis, temporary disability should not exceed 4 months, followed by referral for a medical and social examination (MSE).
Contraindicated types and working conditions:
Heavy and moderate work;
Work in hot shops;
Work in conditions of local or general vibration. Indications for referral to ITU. The following are sent to ITU:
Radically treated patients after completion of treatment and rehabilitation if they need employment;
Patients receiving adjuvant chemotherapy and hormonal therapy;
Patients with relapse and the appearance of distant metastases;
For repeated or early examination. Examination standards for referral to ITU:
Clinical blood test;
Biochemical blood parameters;
Chest X-ray, if necessary - tomograms;
Basic hemodynamic indicators;
Ultrasound of the liver.
In the referral for MSE, it is necessary to give a complete description of the tumor and the nature of the treatment performed; if indicated, a psychologist’s opinion.
Examination of work ability allows us to assess the degree of impairment of life, social impairment and, if necessary, develop a rehabilitation program for patients with lymphogranulomatosis.
NON-HODGKIN LYMPHOMAS
In recent years, a steady upward trend in the incidence of non-Hodgkin's lymphoma (NHL) has been recorded. This is a heterogeneous group of histologically and biologically malignant neoplasms of the lymphoid system with unclear etiology.
EPIDEMIOLOGY
Around the world, approximately 4.5 million people are currently diagnosed with NHL, and 300 thousand people die from this disease every year. In developed countries, the incidence has increased by more than 50% over the past 20 years and the growth rate is 3-7% annually. A certain contribution to the increase in the incidence of NHL was made by an increase in life expectancy, an improvement in the quality of diagnosis of lymphomas, and the HIV epidemic. But this can explain only a small part of the increase. The frequency of NHL varies in different regions of the world: they are rare in Japan, India, Singapore, and very common in the USA, Canada, and Africa. There are racial differences in incidence: Caucasians get sick much more often than African Americans and especially more often than Japanese. The peak incidence of NHL in Europe was noted in the Netherlands and Scandinavian countries. Over the past 4 decades, the increase in incidence has been epidemic. The increase is mainly due to aggressive forms. The increase in the incidence of primary central nervous system (CNS) lymphomas is partly associated with their occurrence in patients with acquired immunodeficiency syndrome (AIDS), although the increase in incidence began before the AIDS epidemic and affects the HIV-uninfected population. Geographical diversity of histological subtypes of NHL has also been noted. For example, a form of Burkitt's lymphoma occurs in children in equatorial Africa; A high incidence of gastric lymphoma is observed in Northern Italy. Nasal T-cell lymphoma is widespread in China, small intestinal lymphoma is widespread in the Middle East.
East, T-cell leukemia (lymphoma) of adults - in Southern Japan and the Caribbean. Low incidence of follicular lymphoma has been reported in Asia and developing countries. Among Asian immigrants living in the United States, cases of follicular lymphoma are less common than in the general population sample. Geographic differences in the distribution of mantle zone lymphomas, certain T-cell lymphomas, and primary extranodal lymphomas have been described.
However, despite the above factors contributing to the increase in the incidence of lymphomas, most cases of NHL could not be explained by the influence of certain etiological factors. In recent years, more and more researchers have paid attention to the environmental situation in the world.
According to the Russian Cancer Research Center named after. N.N. Blokhin of the Russian Academy of Medical Sciences, in Russia NHLs account for 2.6% of all malignant tumors; 10-12 thousand new cases are detected annually. The maximum incidence of NHL occurs between 70 and 79 years of age. There is a linear relationship between age and the incidence of all forms of lymphoma. In men, a frequency close to the statistical average (8.3 per 100 thousand population) occurred in 2004 in the age group 45-49 years; in women, the indicator was observed in the age group 50-54 years. By the age of 75 years and older, the standardized incidence rate of lymphoma for men was 27.0, for women - 15.5. Lymphomas are classified as oncological forms, due to which the frequency of detection of tumor diseases at later stages has increased (Davydov M.I., 2006). The significant dispersion of statistical indicators in individual regions is associated with the lack of uniformity in the registration of various forms of lymphoproliferative diseases; NHL is often included in the statistical category of “hemoblastosis”.
ETIOLOGY AND PATHOGENESIS
The cause of most cases of NHL is unknown, but some genetic, infectious diseases, and environmental factors may play a role in the development of NHL. NHL is most common among malignant neoplasms in young people suffering from ataxia-telangiectasia or Wiskott-Aldrich syndrome, as well as in children with X-associated lymphoproliferative syndrome.
The world's scientific literature sources note a certain risk of developing NHL in people whose first-degree relatives suffered from hematological malignancies. In persons with a family history, the risk of developing NHL increased by 2-3 times. This may be due to the inheritance of the characteristics of the immune system and (or) depends on increased genetic susceptibility to the action of carcinogenic environmental factors.
The incidence of NHL is associated with various etiological factors, with HIV infection playing a special role. Immunodeficiency, including congenital and acquired conditions, may be an absolute risk factor for NHL. In HIV-infected people, the incidence of NHL is 100 times higher than in the general population. The most common types of NHL in these patients are B-cell NHL, predominantly large cell lymphomas and Burkitt lymphomas with extranodal involvement, for example, in the brain.
Infectious agents such as lymphocytic virus type I (HTLV-I), EBV, H. pylori and possibly hepatitis C virus (HCV), may increase the risk of developing NHL. In the case of Burkitt's lymphoma, Epstein-Barr virus (EBV) is one of the main risk factors. HTLV-I belongs to the group of retroviruses and has an epidemic distribution in southern Japan and the Caribbean. Infection during childhood strongly correlates with the development of T-cell leukemia and lymphoma in later life. Chronic stomach infection H. pylori associated with a 6-fold increased risk of MALT, gastric lymphoma (mucosa-associated lymphoid tissue). There is also evidence of an association of hepatitis C with some B-cell lymphomas. The results of epidemiological studies are ambiguous: studies revealing a positive correlation between hepatitis C and the type of NHL alternate with publications in which such a connection was not found.
Patients receiving immunosuppressive therapy for solid tumors (chemotherapy and radiation) or bone marrow transplantation are 30 to 50 times more likely to develop NHL. This is due to an imbalance in lymphocyte proliferation, as well as activation of latent EBV infection.
Lifestyle plays an important role in the development of lymphomas. An increased risk of NHL is associated with consumption of animal proteins,
meat, fat. On the contrary, consuming large amounts of fruits and vegetables with a high carotene content leads to its decrease. The influence of alcohol and smoking on the development of NHL is ambiguous. According to some researchers, solar radiation is associated with the development of lymphomas.
LYMPHOMOGENESIS AND MOLECULAR GENETICS
Understanding normal lymphocyte differentiation will provide insight into the morphology, immunophenotype, and clinical course of lymphomas. Lymphocytes are known to differentiate from immature stem cells in the bone marrow. At the stage of rearrangement of immunoglobulin and T-cell receptor genes, lymphoblasts (large B cells) actively proliferate until they become B lymphocytes (mature effector cells of the bone marrow). Subsequent maturation occurs in the lymph nodes and extralymphatic follicles. In the germinal center of the lymph nodes, under the influence of antigens, lymphocytes are transformed into immunoblasts or centroblasts (large proliferating cells). At this time, multiple point mutations appear in the variable regions of immunoglobulin genes, which ensures their antigenic specificity. The formation of the germinal center and the formation of plasma cells that produce IgG occur due to centrocytes (small non-proliferating lymphocytes). Some of them migrate and form marginal zones surrounding the activated follicles; there they remain as memory B cells.
Cells that differentiate into T lymphocytes are divided into 3 types of antigen-specific effector T cells: CD4 (helper and cytotoxic T cells), CD8 (suppressor and cytotoxic T cells), and memory T cells. Differentiation and maturation depend on genetic changes occurring in the cell. CD (Clusterof-differentiation antigens) are antigens of surface receptors involved in differentiation; they are detected using specific antibodies. For T- and B-lymphocytes, the antigens are different and change during the process of differentiation. CDs perform several functions in lymphocyte maturation, including recognition and adhesion to other genes and molecules. T cell CD antigens include: CD3, which interacts with T receptors and is involved in
in signal transduction, CD4, which binds to MHC class II molecules, CD5, CD8, which recognizes MHC class I molecules, and CD45. B cell CDs: include CD19 and CD20, involved in signal transduction. Lymphoblasts are characterized by the expression of terminal deoxynucleotidyl transferase and the surface antigen CD34, but they do not possess B- and T-cell antigens. Mature plasma cells lose B cell antigens and acquire CD38 antigen.
Thus, during the process of maturation, lymphocytes undergo a complex differentiation path, which ensures the performance of their inherent functions in the body’s immune system. When this course of events is disrupted, malignant neoplasms of a lymphoid nature arise.
Malignant cell transformation is based on phenomena such as disruption of the mechanisms regulating gene functioning and genome stability. A certain role in the development of NHL is played by defects in immune responses, such as an imbalance in the production of cytokines, as well as genetic disorders of the rearrangement of immunoglobulins of T-cell receptors.
Genetic damage in lymphomas can be divided into 2 large categories: activation of proto-oncogenes and inactivation of tumor suppressor genes. Disease progression is influenced by sensitivity to autocrine growth factors along with resistance to antiproliferative signals, immortalization, avoidance of apoptosis, invasion, metastasis, angiogenesis, and tumor microenvironment factors occupy a special place.
The main mechanisms of activation of proto-oncogenes in lymphatic tumors are chromosomal translocations. Often, on one of the partner chromosomes, close to the recombination site, there is a proto-oncogene, which in a typical case is not structurally changed, but the regulation of its expression is impaired. This variant of translocation can be contrasted with translocations in acute leukemia due to the fusion of two genes and the formation of a chimeric product with new oncogenic properties. Both genes involved are structurally altered. In NHL, the proto-oncogene most often moves to the region of immunoglobulin gene loci and comes under the influence of heterologous elements that regulate gene expression on the partner chromosome. This leads to constant expression of the proto-oncogene, independent of normal stimuli (whereas normally its expression occurs
only in response to these stimuli), or to a nonspecific increase in proto-oncogene expression (whereas normally its expression is very weak). Much less frequently, activation of proto-oncogenes in lymphomas occurs through other mechanisms not related to the formation of translocations. Translocations occur randomly and in most cases lead to nothing: the cells carrying the translocations simply die. A tumor arises if the translocation is “appropriate”, i.e. appears randomly in a certain subpopulation of lymphocytes at a certain stage of development.
Currently, a lot of data has been accumulated on the molecular genetic structure of certain tumors, and molecular markers that are constantly identified and characteristic of each nosological form have been established. Based on modern knowledge about the nature of multifactorial diseases, which include lymphomas, it is assumed that the set of genes responsible for predisposition to them forms a network of interconnected elements, the result of the interaction of which at the level of protein products determines the biochemical individuality of a person. Depending on this, the individual develops an inherent high or low degree of predisposition to a particular disease, which, in the case of the action of appropriate factors of the external and internal environment, leads to the development of pathology. One of the reasons for the variability of tumor progression mechanisms is the presence of genetic polymorphism. Different variants of a polymorphic locus can affect the weakening or strengthening of gene function; which, in turn, may contribute to the development of a disease in specific conditions or influence the body's susceptibility to certain forms of medications.
An analysis of the work carried out in connection with the search for genetic markers of susceptibility to lymphomas made it possible to identify several functional groups of genes based on their potential biological role (Fig. 26.2). One group includes genes that are involved in the processes of maintaining genome integrity and methylation. Polymorphic variants of these genes can alter the frequency of chromosomal aberrations, DNA repair efficiency, and DNA methylation status. Another large group is represented by genes that affect the activity and growth of B cells, including genes for pro-inflammatory and regulatory cytokines and genes responsible for
Rice. 26.2. Genes involved in the pathogenesis of NHL
involved in natural immunity, oxidative stress, maintenance of energy homeostasis and hormone production. Group 3 includes genes whose products are involved in the metabolism of xenobiotics. And these are just a few genes that are being studied in the world.
CLASSIFICATION OF LYMPHOMA.
MORPHOLOGY AND IMMUNOPHENOTYPE
In 2001, WHO published a classification of lymphomas, which was based on the European-American classification of lymphoid tumors (REAL classification), published in 1994 by the International Group for the Study of Lymphomas. The prerequisite for its creation was the diversity of morphological, immunophenotypic and molecular genetic characteristics. However, it does not reflect a genetic relationship or hierarchical dependence, but is only a list of clinical and morphological categories.
WHO classification (2001)
B cell tumors
I. Tumors from precursors IN -lymphocytes.
B-lymphoblastic leukemia/B-cell precursor lymphoma (B-cell precursor acute lymphoblastic leukemia).
II. Mature IN -cell tumors (B-cell tumors with a mature lymphocyte phenotype).
1. Chronic lymphocytic leukemia/small lymphocyte lymphoma.
2. B-cell prolymphocytic leukemia.
3. Lymphoplasmacytic lymphoma.
4. Splenic marginal zone lymphoma.
5. Hairy cell leukemia.
6. Plasmacytic myeloma.
7. Monoclonal gammopathy of uncertain potential.
8. Solitary plasmacytoma of bones.
9. Extraosseous plasmacytoma.
10. Primary amyloidosis.
11. Heavy chain disease.
12. Extranodal marginal zone B-cell lymphoma (mucosa-associated lymphoid tissue lymphoma; MALT lymphoma).
13. Nodal marginal zone B-cell lymphoma.
14. Follicular lymphoma.
15. Lymphoma from cells of the mantle zone.
16. Diffuse large B-cell lymphoma.
17. Mediastinal large B-cell lymphoma.
18. Intravascular large B-cell lymphoma.
19. Primary lymphoma of serous cavities.
20. Burkitt's lymphoma/leukemia.
III. B-cell lymphoproliferative processes with uncertain tumor potential.
1. Lymphomatoid granulomatosis.
2. Post-transplant lymphoproliferative disease, polymorphic cell.
T cell tumors
I. Tumors from T-lymphocyte precursors.
T-lymphoblastic leukemia/T-cell precursor lymphoma (T-cell precursor acute lymphoblastic leukemia).
II. T- and NK-cell tumors with a mature lymphocyte phenotype.
Leukemias and primary disseminated lymphomas:
1. T-cell prolymphocytic leukemia.
2. T-cell leukemia of large granular lymphocytes.
3. Aggressive NK-cell leukemia.
4. Adult T-cell leukemia/lymphoma. Cutaneous lymphomas
1. Mycosis fungoides.
2. Sezary syndrome.
3. Primary cutaneous large cell anaplastic lymphoma.
4. Lymphomatoid papulosis.
III. Other extranodal lymphomas.
1. Extranodal NK/T-cell lymphoma, nasal type.
2. T-cell lymphoma enteropathy type.
3. Hepatolienal T-cell lymphoma.
4. Panniculitis-like T-cell lymphoma of the subcutaneous tissue.
IV. Lymphomas of the lymph nodes.
1. Angioimmunoblastic T-cell lymphoma.
2. Lymphoma from cells with the immunophenotype of peripheral T-lymphocytes, unspecified.
3. Anaplastic large cell lymphoma.
V. Tumor of uncertain differentiation. Blast NK cell lymphoma.
Morphological characteristics, uniting lymphomas into groups of similar histological structure:
1) proliferation of blast cells;
2) diffuse proliferation of small cells;
3) diffuse proliferation of large cells;
4) follicular growth of lymphoid tissue;
5) nodular growth pattern of tumor tissue;
6) anaplastic morphology of lymphoid cells;
7) diffuse polymorphic cell lymphoid proliferation;
8) lymphogranulomatosis-like structure of the tumor. Lymphoblastic lymphomas from B-lymphocyte precursor cells,
lymphoblastic lymphomas from T-lymphocyte precursor cells and a blastoid variant of lymphoma from mantle zone cells. Diffuse proliferation of lymphoid cells with blast morphology is characterized by the replacement of lymph node tissue with a rather uniform proliferation of medium-sized cells (1.5-2 times larger than the nucleus of a small lymphocyte). The nuclei of these cells are round, regular in shape or with uneven, sometimes jagged contours. The cytoplasm can be distinguished as a narrow grayish rim. Many mitotic figures. The key feature that determines the blast morphology of tumor cells is the structure of the nucleus. Heterochromatin in the nuclei has a homogeneous dusty, granular or finely lumpy structure. In some cases, the mesh and delicately looped structure of chromatin, which looks like thin filaments, is clearly visible. Heterochromatin is evenly distributed throughout the entire volume of the nucleus. The nuclei contain 1-3 small polymorphic nucleoli. In some cases, blasts may contain rather coarse chromatin in the nuclei in the form of small clumps, slightly different in size; Chromatin may be distributed with increasing amounts near the nuclear membrane. Histological examination does not allow differentiation of lymphoblastic lymphomas, which differ in their belonging to the B- or T-cell line.
Lymphoplasmacytic, lymphocytic, follicular lymphomas and B-cell marginal zone lymphomas. With diffuse proliferation of small lymphoid cells, voluminous tumor masses of a monotonous structure are usually found, replacing organized lymphoid tissue. Characterized by infiltrative growth beyond the capsule of the lymph node into the perinodal adipose tissue, a monomorphic cellular composition and more or less pronounced signs of cellular atypia. Diagnostic problems arise when examining small or highly deformed biopsies, when it is difficult to assess tissue structure and cell structure.
Follicular lymphomas. Follicular growth of lymphoid tissue means the B-cell nature of the tumor or hyperplastic process, therefore there is no need for an immunohistochemical study with antibodies to B-linear antigens.
Tumor follicles in follicular lymphomas are found in all anatomical zones of the lymph node. Follicles are often of a uniform shape and approximately the same size, which makes them different from reactive follicles during hyperplastic processes in the lymph nodes. Tumor follicles can be located so closely that they deform each other and acquire a partially polygonal shape. Nevertheless, between the follicles in follicular lymphoma it is almost always possible to distinguish a more or less pronounced T-zone, which contains small lymphocytes and post-capillary venules.
A thorough examination under high magnification of the interfollicular spaces in follicular lymphomas always reveals centrocytes - small angular cells that are normally not found outside lymphoid follicles, and large lymphoid cells with signs of atypia in the form of nuclei with deep depressions and irregular nuclear contours.
Tumor follicles are not surrounded by a layer of small lymphocytes called the mantle zone. Clear concentric layers of small lymphoid cells are a sign characteristic of the hyperplastic process.
Centrocytes and centroblasts form a fairly homogeneous mixture; For tumor follicles, structural polarization is uncharacteristic. The mitotic and proliferative (Ki-67) activity of follicular lymphoma cells is usually low, almost always less than in reactive follicles. Macrophages in the tissue of follicular lymphoma almost do not phagocytose, while in the reactive light centers of follicle reproduction it is easy to detect phagocytosis of fragments of nuclear substance. Extracellular protein eosinophilic deposits are also rarely found in tumor follicles, which distinguishes lymphoma from reactive changes.
Angioimmunoblastic T-cell lymphoma and lymphoma of cells with the immunophenotype of peripheral T-lymphocytes, unspecified, extranodal NK-/T-cell lymphoma of the nasal type, subcutaneous panniculitis-like T-cell lymphoma and T-cell lymphoma of the enteropathy type. For a preliminary histological diagnosis, the following morphological signs should be considered as confirmation that NHL of the polymorphic cellular structure belongs to the T-cell type: 1) the diffuse nature of the growth of lymphoma with damage to the paracortical zone in the initial stages of tumor development; 2) appearance
a large number of postcapillary venules with swollen endothelium; 3) nested type of arrangement (compartmentalization) of tumor cells with the formation of groups separated by thin bundles of collagen fibers; 4) wide variations in the size and shape of nuclei, the absence of cells with split nuclei; 5) with light cytoplasm and a clear membrane, sometimes they form a “cobblestone street” pattern; 6) the presence of polymorphic cells, including those similar to Berezovsky-Reed-Sternberg cells; 7) an admixture of histiocytes, epithelioid cells, eosinophilic leukocytes, plasma cells.
The structure of angioimmunoblastic T-cell lymphoma is distinguished by the presence of residual follicles in the affected lymph node; quite often these follicles have the appearance of “burnt out”, i.e. those that are small in size with few activated cells in their composition against the background of fibrosis and hyalinosis. Another feature is the focal proliferation of follicular dendritic cells, especially intense near postcapillary venules with swollen endothelium. The T-cell nature of the tumor is confirmed by the expression of T-linear antigens by lymphoid cells of small, medium and large sizes. Large activated B cells are often found, which, together with small B lymphocytes, plasma cells, histiocytes and eosinophilic granulocytes, belong to the reactive component.
Lymphomas from cells with the immunophenotype of peripheral T-lymphocytes, unspecified, can differ significantly in patients in tissue organization and cellular composition. This makes it possible to distinguish histological (cytological) variants in a tumor with the immunophenotype of peripheral T cells: pleomorphic cell, lymphoepithelioid cell, T-zone. But the differential features are low-specific and do not have a clear connection with the clinical course of the tumor, therefore, in practical work, the identification of histological variants is not necessary.
The histological structure and cytological composition of extranodal T- and NK-cell lymphomas without any significant features that could have a differential diagnostic value. Extranodal NK-/T-cell lymphoma of the nasal type is characterized by angiocentric and angiodestructive tumor growth, which causes extensive circulatory necrosis, but these features can also be found in other tumors. The cytotoxic properties of tumor cells become another
the cause of necrosis in the tumor, as well as programmed cell death - apoptosis.
Immunological diagnosis of lymphomas consists of a detailed study of the membrane and cytoplasm antigens of tumor cells in order to determine the origin of the lymphoma (B- or T-cell) and the stage at which their normal development is stopped. A comparison is being made immunophenotype(i.e., a set of markers) of tumor cells with the immunophenotype of a normal cellular counterpart. During the formation of lymphoma, tumor lymphoid cells acquire unusual (normally practically absent) immunological characteristics and partially lose typical antigens.
B- and T-cell lymphomas are divided into 2 broad groups: progenitor cell lymphomas and peripheral lymphomas. This takes into account the monoclonality or monotypic nature of the lymphoid tumor proliferation and its differences from normal cells of the lymph node. The most common feature of B-cell lymphomas is the monoclonality of malignant B cells according to the type of light polypeptide chains of immunoglobulins (κ or λ).
NHLs are often of B cell origin, expressing pan-B cell antigens (>90%): CD19, CD20, CD22, usually in combination with HLA/DR and surface immunoglobulin molecules. The presence of other B-cell antigens (CD5, CD10, CD38, CD23, etc.) allows us to most reliably establish the B-cell subvariant of NHL, which underlies the choice of adequate treatment tactics (>90%).
T-cell tumors are characterized by the presence of CD4, CD7, CD8. Additional immunophenotypic characteristics contribute to the differential diagnosis of different variants of NHL.
DIAGNOSTICS AND CLINICAL PICTURE
The diagnosis of a lymphoid tissue tumor should be based on histological and immunohistochemical examination of the biopsy specimen, medical history, objective status, and laboratory data in order to determine the stage and further treatment planning.
The patient's medical history and objective status are fundamental factors for assessing his condition and prescribing the necessary studies. When interviewing, you should focus on the duration and rate of the disease
(sudden reduction of previously enlarged lymph nodes, which is often observed with follicular lymphoma). The presence of certain signs will characterize the prognosis of the disease and the response to treatment. These include fever, evening sweats and unexplained weight loss. The primary tumor focus can be localized in the lymph nodes (nodal lesion) or in other organs and tissues (extranodal lesion).
Spread occurs by lymphogenous and hematogenous metastasis. Clinical manifestations are determined by the location of tumor foci. Most often, the first manifestation of the disease is damage to the lymph nodes (45-50% of cases); in this case, peripheral lymph nodes are involved in the process much more often (35-38%) than mediastinal, retroperitoneal and intra-abdominal ones. Lymph nodes can reach large sizes (Fig. 26.3), merge into conglomerates - the so-called “target lesion” or “bulky”, when the size of one of the lymph nodes/conglomerates exceeds 7 cm and (or) a tumor in the mediastinum is visible on an x-ray direct projection. Damage to the mediastinal lymph nodes can manifest as shortness of breath, cough, facial puffiness, and SVC syndrome. When processes are localized in the retroperitoneal and mesenteric lymph nodes, abdominal pain and swelling of the lower extremities may be observed. Extranodal lesions often occur in the gastrointestinal tract, Pirogov-Waldeyer lymphoid ring, skin, central nervous system, and less commonly in the pleura, lungs, bones, soft tissues, etc. According to complaints made by patients
A b
Rice. 26.3. NHL. Conglomerate of lymph nodes on the neck on the right: a - front view; b - side view
Thus, you can approximately determine the level of damage (pain in the chest, abdomen or bones). For example, signs of CNS lymphoma include headache, lethargy, central neurological signs, parasthesias, or paralysis.
Physical research methods (inspection, palpation, auscultation) with the study of all groups of peripheral lymph nodes make it possible to assess the involvement in the process of the pharyngeal ring, thyroid gland, pleural cavity (pleurisy), abdominal cavity (hepatomegaly, splenomegaly, ascites), skin (Fig. 26.4 , 26.5).
Laboratory research methods should include a general blood test and its biochemical analysis, and to assess the function of the kidneys and liver - determination of serum glucose, calcium content, albumin, LDH and P 2 -microglobulin levels. The purpose of these studies is to help determine prognosis (eg, LDH, P2-microglobulin, albumin) and to identify abnormalities in other organ function that might complicate therapy (eg, renal or hepatic failure).
The diagnosis should be made on the basis of histological and immunohistochemical examination of the biopsy specimen (Fig. 26.6, 26.7). Material for morphological examination of a lymph node can be obtained using biopsy - aspiration (cell suspension), puncture (tissue column), open incisional (lymph node fragment) and open excisional
Rice. 26.4. NHL. Lesion of the axillary lymph nodes on the left, specific skin lesions
Rice. 26.5. NHL. Orbital damage, germination and deformation of the left eyeball
Rice. 26.6. Biopsy in a patient with NHL
Rice. 26.7. Sternal puncture in a patient with NHL
(the entire lymph node or a conglomerate of lymph nodes). The histological examination of lymph node biopsies, like all other organs and tissues, is based on a detailed study of the tissue structure (architectonics) and cellular composition of the biopsy. Cytological examination is highly informative and should be widely performed on an outpatient basis. The importance of this method has recently increased, as effective methods for immunophenotyping on cytological preparations have been developed. However, histological examination of a tumor tissue biopsy with immunophenotyping should be considered definitive. Cytological verification is allowed only in cases where taking material for histological examination is associated with a high risk to life.
Immunohistochemical examination of tumors of lymphoid tissue is the method of choice if differential diagnosis of tumors with a pronounced similarity in histological structure is necessary. In addition to diagnostic biopsy, all patients should undergo bone marrow biopsy. Bone marrow involvement in the malignant process depends on the subtype of lymphoma. Thus, 70% of patients with lymphoplasmacytic lymphoma and mantle zone lymphoma have bone marrow involvement, 50% with follicular lymphoma, and approximately 15% of patients with diffuse large B-cell lymphoma.
In certain situations, a cytological examination of the cerebrospinal fluid is indicated. These include paranasal sinus, testicular, epidural lymphoma and possibly
Bone marrow involvement in large cell lymphoma. With such types of lesions, the likelihood of the process spreading to the meninges is quite high, and therefore a diagnostic lumbar puncture is justified. In addition, the latter is often recommended for patients with highly aggressive histology and HIV-infected patients. If damage to the central nervous system or peripheral nervous system is suspected, consultation with a neurologist is necessary.
Reliable confirmation of a tumor lesion of the lymphatic system of Waldeyer's ring is the data of fibrolaryngoscopy with a biopsy of the affected areas. X-ray examination (preferably CT) of the chest allows one to clarify the condition of the mediastinal lymph nodes (mediastinal lymphadenopathy is observed on average in 15-25% of patients, with the exception of primary mediastinal NHL or lymphoblastic lymphoma from progenitor cells, in which this is the first or main manifestation of the disease ) and identify parenchymal lung damage, observed in 3-6% of cases. The development of specific pleurisy is observed infrequently (8-10%), mainly in aggressive and highly aggressive NHL, or is the only clinical symptom in primary B-cell NHL of the serous membranes (primary effusion lymphoma). Proof of the tumor nature of pleurisy is a cytological examination of the exudate.
Data on the high incidence of gastrointestinal involvement (15-25%) make it imperative to perform an X-ray examination of the stomach or (preferably) gastroscopy with multiple biopsies of suspicious areas of the mucous membrane. When identifying a specific lesion of the stomach, an X-ray examination of all parts of the intestine is mandatory, since in 4% of patients in this case, combined involvement of several parts of the DCT is possible. All patients, regardless of the clinical manifestations of the disease determined at the time of diagnosis, undergo an ultrasound scan of the abdominal cavity and pelvis.
A necessary step in the examination is a contrast-enhanced CT scan and (or) MRI of the neck, mediastinum, abdominal cavity and pelvis. These methods allow not only to more fully determine the volume of the lesion, but also to give an objective assessment of the effectiveness of the therapy. MRI is also
the method of choice in case of damage to the central nervous system and (to a lesser extent) bone marrow, while trepanobiopsy is not excluded.
Scintigraphy is prescribed for suspected damage to the bones, spleen, and also to differentiate fibrosis and residual active (residual) tumor after treatment. To diagnose lymphomas, 67 Ga is used, which binds to transferrin receptors in tumor cells. PET is an imaging technique based on glycolytic activity, which is increased in tumor tissues, including lymphomas. PET allows you to study the whole body with a lower dose load than CT. The method has high specificity and makes it possible to differentiate non-tumor processes from a specific lesion with a greater degree of probability.
Differential diagnosis NHL is performed with lymphadenopathy of various etiologies, lymphogranulomatosis, cancer metastases, acute leukemia, chronic lymphocytic leukemia. Bacterial lymphadenitis can be observed in various diseases - such as AIDS, tuberculosis, etc. Protozoal (with toxoplasmosis) and fungal (with actinomycosis) lymphadenitis is relatively rare. The viral nature of lymphadenitis in infectious mononucleosis, influenza, and rubella is possible. Lymphadenitis can be local, in the area of the infection gate (flu, tonsillitis), or generalized (sepsis). The differential diagnosis is based on immunomorphological examination of the lymph node.
Determination of prevalence (staging). International Prognostic Index
Staging of NHL uses the Ann Arbor clinical classification, originally developed for Hodgkin lymphoma. The TNM classification is not used for lymphomas, since lymphoma is a systemic disease, more often initially having a generalized manifestation (stages III and IV) than a local one (stages I and II). Determination of the prevalence of the process is based on data from the anamnesis, clinical examination, imaging methods and biopsy (Table 26.1).
In isolated lesions, the spleen is considered a lymphoid region.
Table 26.1. Distribution of NHL by stages (according to Ann Arbor, 1971)
The presence or absence of symptoms of intoxication caused by a lymphatic tumor has prognostic significance and is indicated in the stage:
category B- unexplained loss of more than 10% of body weight over 6 months. Unexplained fever with an increase in temperature to 38 ° C or higher. Night sweats (“with wet pillow”). Itching (usually generalized), the severity of which varies depending on the activity of the disease.
In addition to the indicated clinical staging (cS), pathological and anatomical staging (pS) is distinguished. Classification is used in cases where there is histological examination data for it, i.e. morphological confirmation of each lesion localization established as a result of surgical procedures.
Taking into account the variability of the clinical course within the histological type, during a special international project, an international prognostic index (IPI) was developed, which was based on 5 parameters with approximately equal and independent effects on survival (Table 26.2). This system is important in predicting and planning treatment for each individual patient.
Table 26.2. International Prognostic Index (IPI)
If the value is unfavorable, each of these parameters is assigned 1 point. MPI is equal to the number of unfavorable risk factors: 0-1 - low risk group; 2 - intermediate/low; 3 - intermediate/high; 4 or 5 - high.
MPI remains one of the main indicators used to prescribe modern therapeutic regimens, including chemoimmunotherapy.
TREATMENT
For general treatment algorithms for NHL in each specific case, the determining factor for the choice of treatment principles is the division of NHL into immunophenotypes (B-cell and T-cell NHL) and within them, according to the nature of the course, into indolent, aggressive and highly aggressive.
The relationship between the histological variant of lymphoma and survival is presented in Table. 26.3.
Table 26.3. Histological variants of NHL and survival
All types of antitumor therapy are used to treat NHL.
Currently, indications for surgical intervention in stage I NHL, the gastrointestinal tract is only a life-threatening complication (perforation, bleeding, intestinal obstruction). In the future, surgical treatment must be supplemented with chemotherapy.
Radiation therapy for lymphomas, it is used as an independent method in exceptional cases. Indications for the use of radiation therapy:
Combination with chemotherapy;
Impossibility/futility of chemotherapy (palliative radiation).
For all histological variants, localizations and stages of NHL, the main method of treatment is chemotherapy.
The standard treatment for most B-cell aggressive lymphomas can be considered combination chemotherapy according to the well-known CHOP program (ACOP) in the form of 6-8 cycles - with two cycles after achieving complete remission at 3-week intervals (CHOP-21). Reducing the interval between cycles
clearly increases efficiency: the advantages of the CHOP-14 scheme compared to CHOP-21 are documented.
Currently, patients under the age of 60 years are recommended to be prescribed the CHOEP regimen in the 1st line of chemotherapy. The addition of etoposide has a positive effect on overall survival. In the case of a favorable prognosis, the scheme CHOEP-21 is used, and if the prognosis is unfavorable, CHOEP-14 or CHOP-14 is used. Patients over 60 years of age are not prescribed the CHOEP regimen because etoposide is highly toxic. Also, in the treatment of elderly and older patients, it is permissible to replace doxorubicin (with severe cardiotoxicity) with other antitumor antibiotics: idarubicin at a dose of 10 mg/m2 (COP regimen), epirubicin (farmorubicin) at a dose of 70-80 mg/m2 (FCOP regimen ), mitoxantrone (novantrone) at a dose of 10-12 mg/m2 (CNOP regimen).
Over the past 5 years, the results of treatment of primary patients with aggressive lymphomas have significantly improved. In patients with B-cell lymphomas containing the CD20 antigen (detected in the tumor by immunohistochemical method), it is advisable to use monoclonal antibodies (MAbs) - rituximab (mabthera) in combination with the CHOP regimen - R-CHOP regimen: on day 1 rituximab at a dose of 375 mg/m2 as a long-term intravenous infusion, day 2 - standard CHOP regimen.
For a number of patients in whom the use of CHOP is unacceptable for some reason, other combinations of chemotherapy drugs are used. For patients with hypertension or diabetes mellitus, it is necessary to select regimens without corticosteroid hormones - CytaBEP, MEV, VAMA, "3+7", with heart failure - exclude anthracyclines and prescribe SOPP, MOPP, POMP, COAP, COP-intensive, COP-Bleo , MEV, VAMP, with functional disorders of the liver, kidneys, pancreas - replace drugs toxic to parenchymal organs (usually cyclophosphamide) with sarcolysine or melphalan.
CHOP: 25 mg/m2 instead of 750 mg/m2 cyclophosphamide.
SOP (5-day): 10 mg/m> instead of 400 mg/m2 cyclophosphamide.
SOPP: 20 mg/m2 instead of 650 mg/m2 cyclophosphamide.
The treatment algorithm for indolent lymphomas differs from the treatment method for aggressive forms. Its main feature is that it is intended for the treatment of B-cell variants, mainly follicular lymphomas of grades I and II. However, when
their transformation into diffuse large B-cell (observed in 20-30% of cases) requires treatment according to the principle for aggressive forms, which also include grade III follicular NHL.
Radiation therapy in stages I and II (30-50 Gy per lesion) provides from 54 to 88% 10-year relapse-free survival. The attitude towards wait-and-see tactics (i.e. until symptoms of intoxication or progression appear) is ambiguous. According to ESMO clinical guidelines (2003), watchful waiting is appropriate only after initial treatment. In domestic practice, especially with fairly large tumor masses in stages III-IV, it is customary to begin treatment with chemotherapy - mono- (alkylating agents, vinca alkaloids) or combined (LOPP, COP). It should be kept in mind that combination chemotherapy increases the response rate and disease-free period, but does not affect overall survival, the median of which is 8-10 years. However, with high-dose chemotherapy with stem cell transplantation, contradictory results have been noted in this regard, even when molecular remissions are achieved.
An absolute achievement in the treatment of indolent (follicular grades I-II) lymphomas is the use of the drug rituximab (mabthera) in stages III-IV, which induces up to 73% response in monoimmunotherapy, with a median time to progression of 552 days, and in primary refractory forms and relapses - at least 50% of long-term remissions. Significant support for prolonging the achieved remission in follicular NHL degrees I and II is provided by the use of recombinant IFN-α, which significantly increases the duration of remission and survival with long-term (12-18 months) use of this cytokine.
1st line regimens for NHL treatment:
SNOR-21:
prednisolone orally 60 mg/m2 on days 1 and 5. SNOER-21: cyclophosphamide intravenously 750 mg/m2 on day 1;
doxorubicin intravenously 50 mg/m2 on day 1;
vincristine intravenously 1.4 mg/m2 on day 1;
etoposide 100 mg/m2 on days 3-5;
prednisolone orally 60 mg/m2 on days 1-5.
SOR: cyclophosphamide intravenously, intramuscularly
750 mg/m2 on day 1;
vincristine intravenously 1.4 mg/m2 on day 1; prednisolone orally 60 mg/m2 on days 1-5. COP-BLEO: cyclophosphamide intravenously, intramuscularly 125 mg/m2 on days 1-14;
vincristine intravenously 1.4 mg/m2 on days 1 and 8; prednisolone orally 60 mg/m2 on days 1-5; bleomycin intravenously 10 mg/m2 on days 1 and 8. SORR: cyclophosphamide intravenously 650 mg/m2 on days 1 and 8;
vincristine intravenously 1.4 mg/m2 on days 1 and 8;
prednisolone orally 60 mg/m2 on days 1-14. SU T R: cyclophosphamide intravenously 650 mg/m2 on days 1, 8;
vinblastine intravenously 6 mg/m2 on days 1, 8;
procarbazine orally 100 mg/m2 on days 1-14;
prednisolone orally 60 mg/m2 on days 1-14. Treatment of relapsed aggressive lymphomas depends on the duration of remission. If relapses occur after a complete remission that lasted at least 6 months, i.e. at a later date, repeat the previous treatment. If relapses develop against the background of partial remission or in the early stages after the end of treatment, the treatment regimen must be revised, replacing it with more intensive ones.
2nd line PCT regimens include various combinations of drugs that are still rarely used in the first stages of treatment: lomustine (BAEM, LABO), carmustine (BVCPP), cytarabine IHAP), cypla-
tin (CEMP, REV), ifosfamide (MINE, ICE, IVE), methyl gag (MIME),
etoposide and mitoxantrone (CEPP [B], OPEN, VEMP, BACOD-E). In others, the same drugs are used in high and increased doses (IAP, ESAP, DHAP).
In case of primary resistance, drugs and their combinations that were not used during the initial treatment can be used in normal and increased doses. For this purpose it is advisable to use the so-called Salvage therapy(MINE, E5HAP, DHAP, Dexa-BEAM).
If bone marrow is involved in the tumor process with blastic leukemia, treatment is necessary in accordance with the type of leukemia that has developed. With blastic transformation of the bone marrow,
lymphoblastic, large cell tumors, testicular and Burkitt's lymphoma, especially with damage to the mediastinum and skin, prevention of central nervous system damage is carried out as in acute leukemia. Methotrexate (12.5 mg/m2), cytarabine (20 mg/m2) and dexamethasone (4 mg/m2) or prednisolone (25-30 mg/m2) are injected into the spinal canal. The drugs are administered on the 1st day of each treatment cycle.
In repeatedly treated patients, complete remission can be achieved with fludarabine and cladribine alone. Fludarabine is administered at a rate of 25 mg/m2 intravenously for 5 consecutive days every 4 weeks or 4 consecutive days every 3 weeks. Cladribine is used at a dose of 0.1 mg/kg daily for 7 days every 4-5 weeks. Carry out 6-8 cycles. However, an advantage is obtained when using combinations of fludarabine with or without mitoxantrone or cyclophosphamide and corticosteroids (FMP, FC): remissions occur faster and much more often.
When transforming mature cell lymphomas into blasts (Richter's syndrome), it is recommended to carry out the same regimens as for high-grade lymphomas.
2nd line treatment regimens for NHL:
ESHAP: etoposide intravenously 1-hour infusion of 60 mg/m2 on days 1-4;
methylprednisolone orally 500 mg/m2 on days 1-4; cytarabine intravenously 2-hour infusion of 2000 mg/m2 on days 1-4;
cisplatin intravenously 25 mg/m2 on the 1st day.
Frequency - 28 days. FC: fludarabine intravenously 25 mg/m2 on days 1-3;
cyclophosphamide intravenously 400 mg/m2 on days 1-3.
Frequency - 21 days. LABO: lomustine orally 1000 mg/m2 on day 1;
doxorubicin intravenously 35 mg/m2 on days 1 and 8;
bleomycin intramuscularly 15 mg/m2 on days 1 and 8;
vincristine intravenously 1.4 mg/m2 on days 1 and 8.
Frequency - 21-28 days. OPEN: vincristine intravenously 1.4 mg/m2 on day 1;
prednisolone orally 60 mg/m2 on days 1-5;
etoposide intravenously 100 mg/m2 on days 1-3;
mitoxantrone intravenously 10 mg/m2 on the 1st day.
Frequency - 28 days.
An obligatory part of the treatment of NHL is the criteria for objective assessment of its effectiveness, without which it is impossible not only to compare the results obtained, but also the approach itself to determining primary or acquired resistance, completeness and degree of response, relapses and other clinical situations requiring strategic and tactical decisions on the issue of refusal or continuation of therapy.
6 categories of effectiveness response to treatment in NHL have been identified, while the size of lymph nodes is measured only by the largest transverse diameter, the size of the spleen and liver, and their dynamics are taken into account - in all cases using CT and NMR. The evaluation criteria also included the results of the study (trephine biopsy or aspirate) of the bone marrow.
Complete remission (CR - complete remission) - complete disappearance of all tumor manifestations of the disease, confirmed by the same research methods by which these changes were detected, and, if necessary, additional research methods. Complete remission is stated after the end of treatment, and only if it persists for at least 4 months after the end of the program.
Uncertain complete remission, “unconfirmed/doubtful complete remission” (CR[u] - unconfirmed/uncertain complete remission) is stated in patients with residual nodes no larger than 1.5 cm in size, which cannot be verified histologically. Like complete remission, uncertain complete remission is confirmed if it persists for at least 4 months after the end of treatment.
If tumor growth resumes earlier than after 4 months, remission is not stated, and the result of treatment is assessed as progression.
Partial remission (PR - partial remission) - reduction in the size of tumor manifestations by more than 50% of the original size.
Stabilization (SD) - a decrease in the size of tumor manifestations by more than 25%, but less than 50% of the original size.
No effect - reduction or increase in the size of tumor manifestations by less than 25% of the original size.
Progression (Pr) - an increase in the size of tumor manifestations by more than 25% of their minimum size achieved during treatment, or the appearance of at least one new lesion
lesions, as well as the return of the disease after remission was established during the first 4 months after the end of the treatment program.
In addition to the listed categories, it is proposed to use several more indicators that are mandatory for the final assessment of the effectiveness of treatment in groups of NHL patients compared in clinical trials. Of these, 3 are paramount: 1) overall survival among all patients, which is calculated from the moment of inclusion in the study until death from any cause; 2) “event-free” survival(for patients with CR, CRu and PR - from the same moment until progression, relapse or death from any cause (time to treatment failure - TTF) and 3) progression-free survival(for all patients - from the time of inclusion in the study or the start of treatment until progression or death from NHL). “Secondary” (second end points) are considered 4 more indicators, applicable in each individual case: 1) duration of disease-free survival- time from the 1st response assessment to relapse (only for patients with CR, CRu); 2) response duration for patients with CR, CRu and PR - from the same moment until relapse or progression; 3) mortality, directly related to NHL (cause-specific death) - among all patients and 4) time until next treatment(all patients - from the start of treatment to the start of another).
According to the American Cancer Society, the overall 5-year survival rate of patients with NHL in 1975-1977. was 48%, in 1984-1986. - 53%, in 1996-2002. - 63%.
Questions for self-control
1. Define malignant lymphomas, what groups of diseases does this nosological group unite?
2. What is lymphogranulomatosis, who first described this disease?
3. In what age groups can lymphogranulomatosis occur?
4. Which groups of lymph nodes are most often affected by lymphogranulomatosis?
5. What does the definition of “symptoms of intoxication” include?
6. How does a needle biopsy differ from an open biopsy?
7. What histological variants of lymphogranulomatosis do you know?
8. What is the name of the diagnostic cell for lymphogranulomatosis?
9. What can be seen on an x-ray in patients with lymphogranulomatosis with damage to the mediastinal lymph nodes?
10. What radioisotope preparation is used to diagnose the extent of lesions in patients with lymphogranulomatosis?
11. How many stages of lymphogranulomatosis do you know?
12. What treatment methods are used in patients with lymphogranulomatosis?
13. What polychemotherapy regimens (first line) are most often used in patients with lymphogranulomatosis?
14. What factors are prognostically unfavorable in patients with lymphogranulomatosis?
15. How and in what doses is radiation therapy performed in patients with lymphogranulomatosis?
16. How are the results of treatment of patients with lymphogranulomatosis assessed?
17. What are the long-term results of treatment of patients with lymphogranulomatosis?
18. Describe the incidence of non-Hodgkin lymphomas.
19. What are the etiopathogenetic features of NHL?
20. Describe the concepts of lymphomagenesis and molecular genetics of NHL.
21. Give the classification of non-Hodgkin lymphomas according to morphology and immunophenotypes.
This is a heterogeneous group of oncological diseases of the lymphatic tissue, characterized by enlarged lymph nodes and/or damage to various internal organs, in which there is an uncontrolled accumulation of “tumor” lymphocytes.
Typically, the first symptom of lymphoma is a significant increase in the size of the lymph nodes in the neck, armpits, or groin area.
Moreover, unlike infectious diseases, enlarged lymph nodes are painless, their size does not decrease over time and when treated with antibiotics.
Sometimes, due to pressure from the enlarged liver, spleen and lymph nodes, there is a feeling of fullness in the abdomen, difficulty breathing, bursting pain in the lower back, a feeling of pressure in the face or neck.
Other symptoms encountered with lymphoma are:
Weakness,
increase in body temperature,
sweating,
weight loss,
digestive disorders.
The term non-Hodgkin's lymphoma refers to a fairly large group of lymphomas that are not Hodgkin's disease (lymphogranulomatosis). The decision whether a lymphoma belongs to the group of non-Hodgkin's lymphomas or to Hodgkin's disease is made after a histological examination of a sample of biopsied tissue.
If, during microscopic examination, Berezovsky-Sternberg-Reed cells specific for Hodgkin's disease are found, then a diagnosis of Hodgkin's disease is made. If these specific cells are not found, then the lymphoma is classified as non-Hodgkin's.
Non-Hodgkin's lymphomas have many variants, which differ in histological appearance, clinical manifestations and approaches to their treatment. Some types of lymphomas have a slow and favorable course, and sometimes do not require special treatment for a long time. Such lymphomas are called indolent. A number of other lymphomas, on the contrary, are characterized by rapid progression, a large number of symptoms and require immediate treatment.
Such lymphomas are called aggressive. There are lymphomas with intermediate characteristics. Most often, abnormal growth of lymphocytes begins in the lymph nodes, and the classic version of lymphoma develops, accompanied by enlarged lymph nodes. However, there are lymphomas in which the lymph nodes do not enlarge, because the disease primarily occurs not in the lymph node, but in various organs: spleen, stomach, intestines, lungs, brain. Such lymphomas are called extranodal.
For a long time, in many countries there were different classifications, including different names and terms for the same type of non-Hodgkin lymphoma, which created great difficulties for both doctors and patients. In 2001, the international community developed unified approaches to the classification of lymphomas, and a single, so-called classification was adopted World Health Organization (WHO), which is used today in most countries of the world. In the future, this classification is constantly updated.
Classification of non-Hodgkin's lymphomas
World Health Organization classification of non-Hodgkin's lymphomas B-cell tumors from B-lymphocyte precursors:B-lymphoblastic lymphoma/progenitor cell leukemia (B-cell acute lymphoblastic leukemia from progenitor cells).
B-cell tumors from peripheral (mature) B-lymphocytes:
Chronic lymphocytic leukemia/small lymphocyte lymphoma (lymphocytic lymphoma)
B-cell prolymphocytic leukemia
Lymphoplasmacytic lymphoma
Splenic marginal zone lymphoma (+/- villous lymphocytes)
Hairy cell leukemia
Diffuse B-cell lymphoma from small lymphocytes of the red pulp of the spleen
Lymphoplasmacytic lymphoma
Heavy chain diseases
Plasma cell myeloma/plasmacytoma
Extranodal marginal zone B-cell lymphoma MALT type
Nodal marginal zone B-cell lymphoma (+/- monocytoid B cells)
Follicular lymphoma
Mantle cell lymphoma
Diffuse large B cell lymphoma
Mediastinal diffuse large B-cell lymphoma
Primary exudative lymphoma
Burkitt's lymphoma/leukemia
T- and NK-cell tumors from T-lymphocyte precursors:
T-lymphoblastic lymphoma/progenitor cell leukemia (T-cell acute lymphoblastic leukemia from progenitor cells)
T-cell lymphomas from peripheral (mature) T-lymphocytes:
T-cell prolymphocytic leukemia
T-cell leukemia of large granular lymphocytes
Aggressive NK cell leukemia
Adult T-cell lymphoma/leukemia (HTLV1+)
Extranodal NK/T-cell lymphoma, nasal type
T-cell lymphoma associated with enteropathy
Hepatolienal T-cell lymphoma
T-cell panniculitis-like lymphoma of subcutaneous tissue
Mycosis fungoides/Sézary syndrome
Anaplastic large cell lymphoma, T/0 cell, with primary skin involvement
Peripheral T-cell lymphoma, unspecified
Angioimmunoblastic T-cell lymphoma
Anaplastic large cell lymphoma, T/0 cell, with primary systemic involvement
Stages of lymphomas
Determining the stage of lymphoma helps to understand the extent of the disease. This is important information for making the right decision regarding your treatment program. Approaches to the treatment of initial (local) stages and advanced stages of lymphomas usually differ.When choosing a treatment program, not only the stage is taken into account, but also many other factors: the type of lymphoma, the results of additional studies (cytogenetic, immunological, molecular, etc.), the patient’s condition, his age, concomitant diseases, etc. However, information about the stage of the disease is extremely important for developing an effective treatment program.
In accordance with the generally accepted international classification (it is called the Ann Arbor classification (after the name of the city in the USA where it was adopted), 4 stages of the disease are distinguished: I, II, III and IV. The letters A or B are usually added to the stage number. Using These letters indicate the presence or absence of 3 important symptoms that can occur in patients with lymphoma: fever, severe night sweats and weight loss.If the letter A is used, this means that the above symptoms are absent, if the letter B is used, this indicates the patient has the above symptoms.
Table 29.
The classification identifies four stages of the disease, which can be conditionally designated as local (local, limited) - stages I and II and widespread - stages III and IV:
Stage I - involvement of one area of lymph nodes in the lymphoma process is allowed
Stage II - involvement of two or more areas of lymph nodes on one side of the diaphragm is allowed.
Stage III - damage to the lymph nodes on both sides of the diaphragm is allowed.
Stage IV - the disease spreads in addition to the lymph nodes to the internal organs: heart, liver, kidneys, intestines, bone marrow, etc.
Follicular lymphoma
Follicular lymphoma (FL)- one of the most common types non-Hodgkin's lymphoma(NHL). According to the WHO classification, three types (gradations) of FL are distinguished based on the histological picture. With follicular lymphoma of the 1st type, 0-5 centroblasts are found in the field of view, with FL of the 2nd type - 6-15 centroblasts, with follicular lymphoma of the 3rd type - more than 15 cetroblasts. FL types 1 and 2 are indolent lymphomas, follicular lymphoma type 3 is aggressive.FL is the second histological group of NHL (after Burkitt lymphoma), in which an association has been established with a certain cytogenetic disorder t(14;18)(q32;q21), which leads to activation of the BCL-2 oncogene, the protein of which blocks programmed cell death (apoptosis ) B-lymphocytes of the follicular centers of the lymph node and increases the life expectancy of cells with this translocation.
Less common in follicular lymphoma are other quantitative (trisomy of chromosomes X, 2, 5, 7, 8, 9, 12, 17, 18, 20, 21; loss of sex chromosomes) and structural changes: deletion of 6q; isochromosomes i(17) (q10) and i(18) (q10).
Characteristic immunophenotype: CD19+, CD20+, CD22+, CD79a+, CD10+, CD5-
The disease occurs more often in older people (median age 55 years). Clinically, FL most often manifests as lymphadenopathy and splenomegaly. Localized stages (I and II) are rare, more often at the onset of the disease there is already a generalization of the process, including damage to the bone marrow, and then the picture of the peripheral blood resembles CLL.
The disease is characterized by relatively slow progression. Often, follicular lymphoma transforms into aggressive lymphoma (diffuse large B-cell lymphoma), which is accompanied by a clear clinical picture (rapid enlargement of lymph nodes with a change in their density, the appearance of symptoms of tumor intoxication and additional genetic damage). Extranodal FL is rare.
Diffuse large B cell lymphoma
Diffuse large B-cell lymphoma (DLBCL)- the most common form of aggressive NHL. DLBCL accounts for about 40% of all B-cell lymphomas. The tumor probably originates from peripheral B cells, although its exact origin is unclear. Morphologically, DLBCL is quite heterogeneous and is represented mainly by large cells resembling centroblasts or immunoblasts.In a cytogenetic study, t(14;18) is detected in the karyotype of 25% of patients. Some of these tumors develop from a preexisting follicular lymphoma, but t(14;18) or its molecular equivalent (BCL-2) is also found in de novo DLBCL. Most t(14;18)-positive DLBCL have additional changes in the karyotype. Characteristic is t(3;14) (q27;q32), in which the BCL-6/LAZ-3 oncogene, located at 3q27, is activated by moving to the Ig heavy chain gene.
The immunophenotype of tumor cells is characterized by the expression of CD19, CD20, CD22, CD45; in some cases, surface Ig, CD5 and CD10 may be expressed.
Genetic analysis has shown that DLBCL can be divided into two groups that differ in clinical course and prognosis: DLBCL with a germ cell genotype and DLBCL with an activated cell genotype. There is a correlation between the genetic pattern and immunohistochemical data: DLBCL from germ cells (with a better prognosis) are characterized by a different phenotype (CD10+,BCL-6+,MUM1-) than DLBCL from activated cells (CD10-,BCL-6-, MUM1+).
In recent years, there has been a clear increase in the incidence of DLBCL. The disease can occur at any age, but is more common in older people. Clinically, DLBCL is characterized by the rapid growth of affected lymph nodes, which can reach gigantic sizes.
The bone marrow is affected in 10-20% of cases. Primary extranodal DLBCL with lesions are often found central nervous system (CNS), stomach, intestines, skin, mammary glands, testicles, bones, thyroid gland. The most common and prognostically unfavorable primary extranodal variants include primary DLBCL with central nervous system involvement.
Extranodal marginal zone B-cell lymphoma MALT type
A feature of this type of NHL is its histological similarity to mucosa-associated lymphoid tissue (MALT). The term marginal zone B-cell lymphoma emphasizes the genetic similarity to the marginal zone B cells of the lymph node follicle.Extranodal MALT lymphomas occur in various organs: stomach, intestines, salivary glands, respiratory tract, thyroid gland, thymus gland, genitourinary tract, skin, etc. Most often, the tumor occurs in the stomach. A characteristic feature of MALT lymphomas of this localization is their antigenic dependence on infection of the gastric mucosa Helicobacter pylori (HP).
The persistence of HP in the layer of gastric mucus leads to the appearance of organized lymphoid tissue in the gastric mucosa, and subsequently to the formation of a tumor, which allows us to consider HP as an etiological factor in gastric MALT lymphomas.
Early cytogenetic changes in the development of MALT lymphomas include t(11;18)(q21;q21) and trisomy 3 - genetic damage resulting from genetic instability, which is denoted by the English abbreviation “replication error repair (RER)”, as well as p53 mutations and c-myc. At this stage of the disease, the growth of lymphoma tissue is directly dependent on the interaction of tumor B cells with H. Pylori-specific T lymphocytes present in the tumor substrate.
In this regard, eradication of the microbe can lead to regression of lymphoma. As a result, t(11;18)(q21;21) juxtaposition of the API2 gene (MALT lymphoma-associated translocation gene) occurs on the 18th chromosome. This is one of the most common chromosomal damage in MALT lymphoma (seen in 25-50% of cases).
Later, t(1;14)(p22;q32) may occur, which is associated with the ability of the tumor to grow autonomously, loss of sensitivity to NR, and cell dissemination outside the stomach or intestine. This is due to the movement of the bcl-10 suppressor gene, located in the 1p22 region, to the Ig heavy chain gene. Impaired tumor suppression contributes to the progression of lymphoma.
Transformation of MALT lymphoma into high-grade tumors can also be associated with inactivation of the p53 gene, deletion of p16 and t(8;14).
The immunophenotype of MALT lymphomas is characterized by the expression of pan-B cell antigens (CD19, 20 and 79a), surface immunoglobulins, as well as CD21 and CD35, characteristic of marginal zone B cells.
MALT lymphoma of the stomach most often occurs in people of mature age (median age - 50 years). There are no differences in incidence between men and women. The clinical picture depends on the stage of the disease. In the early stages, MALT lymphoma is characterized by the absence of symptoms or minimal manifestations of dyspeptic and pain syndrome and differs little from other chronic diseases of the stomach.
As it progresses, severe dyspeptic syndrome occurs (heartburn, belching of air or food), aching pain in the epigastric region, often not associated with food intake. The pain syndrome is more reminiscent of chronic gastritis than a peptic ulcer. Features that distinguish the clinical picture of MALT lymphoma of the stomach from other diseases of this organ (with the exception of cancer) include: 1) stability of symptoms; 2) frequent (more than 3 per year) exacerbations of the disease with a gradual increase in clinical manifestations of gastric damage.
Further development of gastric MALT lymphoma is accompanied by the appearance of symptoms characteristic of malignant tumors - loss of appetite, weight loss, lymphadenopathy, fever and other signs of tumor progression.
Mantle cell lymphoma
Mantle cell lymphoma (MCL)- a separate type of lymphoma, the exact identification of which is possible by comparing histological data with the immunophenotype and molecular genetics of the tumor.There are two main cytological variants of LCM: typical (classical) and blastoid, characterized by a more aggressive course. In this regard, the classic variant is classified as indolent lymphoma, while the blastoid variant is classified as aggressive.
In general, LCM as a nosological form occupies an intermediate position between indolent and aggressive lymphomas and combines the worst features of these diseases: on the one hand, it is incurable with standard chemotherapy, on the other hand, it is characterized by a more aggressive course and a lower median survival of patients than indolent lymphoma.
The most common karyotype disorder is t(11;14)(q13;q32), which at the molecular level is characterized by juxtaposition of the bcl-1 locus on chromosome 11 with the Ig heavy chain gene sequence on chromosome 14. This leads to dysregulation and increased expression the cyclin D1 gene, which controls the cell cycle.
Characteristic immunophenotype: IgM+/IgD+, CD5+, CD10-, CD23-. In addition, the expression of pan-B cell antigens (CD19, CD20, CD22) is determined.
LCM usually occurs in older patients (median age 62 years). Men get sick more often. In most patients, at the onset the late stages of the disease are determined. The lymph nodes, spleen, bone marrow, Waldeyer's ring, and often the gastrointestinal tract are most often affected.
Anaplastic large cell lymphoma
Anaplastic large cell lymphoma (ALCL)- morphophysiologically, immunologically and clinically isolated group of NHL. The disease is characterized by a binodal distribution with a predominance of young patients. Infiltration of the skin by large pleomorphic lymphoma cells is often detected; in the lymph nodes, such cells are located mainly in the sinuses and paracortical areas. Bone marrow involvement is relatively rare, and the prognosis of the disease is better than with other B-cell NHL.The development of ALCL correlates with a specific translocation t(2;5)(p23;q35). As a result of the interaction of the ALK gene (anaplastic lymphoma kinase gene), located in 2p23, and the NPM gene (nucleophosmin gene), localized in 5q35, the hybrid protein NPM-ALK (p80) is expressed, which can lead to tumor transformation. On the other hand, t( 2;5) and its molecular equivalent is not always detected, and ALK-negative ASCI has a worse prognosis compared to ALK-positive.
The immunophenotype of ALCL is characterized by the expression of CD3, which indicates the T-cell origin of the tumor. Expression of CD30, EMA, and ALK protein is also characteristic. CD20 and CD15 are not expressed.
Burkitt's lymphoma
Burkitt's lymphoma is an aggressive disease with extranodal manifestations, most often found in children. There are two forms of the disease: endemic and non-endemic. The endemic form is found in equatorial Africa and is almost always associated with infection Ebstein-Barr virus (EBV); in the non-endemic form, EBV is detected in only 20% of cases.In both forms, a very high frequency of t(8;14)(q24;q32) with MYC gene rearrangement is detected. Breakpoints at t(8;14) in endemic and nonendemic forms of Burkitt lymphoma differ at the molecular level, but are not identified by cytogenetic testing.
The immunophenotype is characterized by the expression of CD19, CD20, CD22, CD79a, CD10 and CD43, while surface IgM, CD5, CD23 and BLC-2 are absent. Proliferative indices are approaching 100%.
Clinically, Burkitt's lymphoma is characterized by a very rapid course (the doubling of the tumor mass occurs within 24-48 hours) and requires immediate treatment. The endemic form is characterized by damage to the lower jaw in the form of large solid formations, less commonly the abdominal organs and testicles. In the sporadic form, the abdominal organs are affected, and ascites quickly increases.
Lymphoblastic lymphoma
Lymphoblastic lymphomas are biologically and morphologically indistinguishable from acute lymphoblastic leukemia (ALL), and therefore in the WHO classification these previously separate nosological forms are combined into one.
Previously, the disease was regarded as ALL with primary damage to the bone marrow and peripheral blood and as lymphoblastic NHL with primary damage to the lymph nodes or extranodal organs. Currently, the same approaches to diagnosis and treatment are adopted for lymphoblastic lymphoma as for ALL.
V.V. Voitsekhovsky, T.V. Zabolotskikh, S.S. Tseluiko, Yu.S. Landyshev, A.A. Grigorenko
Malignant lymphomas- tumors, the initial cellular substrate of which is predominantly B- and T-lymphoid cells of varying degrees of maturity. Lymphomas are characterized by local tumor growth, while at the beginning of the disease, and sometimes for a long time, the bone marrow is not affected.
Histological and cytological classification of neoplastic diseases of hematopoietic and lymphoid tissues (WHO, 1976)
1. Modular lymphosarcoma:
a) prolymphocytic;
b) prolymphocytic-lymphoblastic.
2. Diffuse lymphosarcoma:
a) lymphocytic;
b) lymphoplasmacytic;
c) prolymphocytic;
d) lymphoblastic;
e) immunoblastic;
f) Burkitt's tumor.
3. Plasmacytoma.
4. Mycosis fungoides.
5. Reticulosarcoma.
6. Unclassified malignant lymphomas.
Clinic.
The most characteristic and early symptom of malignant lymphoma is enlarged lymph nodes. More often, at the onset of the disease, the lymph nodes of one or two groups are enlarged, although there may be generalized adenopathy. Lymph nodes become dense early, form conglomerates, and grow into neighboring tissues and organs.
Primary lesions of organs where there is lymphoid tissue may occur.
Clinical symptoms of malignant lymphoma depend on the location of the process.
Thus, when the mediastinum is damaged, shortness of breath, cyanosis and swelling of the face and neck develop; with an increase in the mesenteric and retroperitoneal nodes, the function of the intestines and urinary organs is disrupted, intestinal obstruction and ascites occur; when the common bile duct is compressed at the porta hepatis, jaundice is observed, etc.
Symptoms of intoxication appear early: weakness, fever, sweating, weight loss, cachexia; various organs and tissues are involved in the process (liver, spleen, stomach, pleura, lungs, skin, bone marrow, etc.). The blood picture is characterized by hypochromic anemia, moderate neutrophilic leukocytosis, and elevated ESR.
Bone marrow damage is observed during leukemia process, more often with prolymphocytic lymphosarcoma, and proceeds as acute prolymphocytic leukemia or chronic lymphocytic leukemia.
The clinical and hematological picture of malignant lymphoma has features depending on its morphological variant.
The T-cell variant of lymphocytic lymphoma is characterized by splenomegaly, high lymphocytosis, and skin lesions. With Burkitt's lymphoma, damage to the bones, kidneys, ovaries, retroperitoneal lymph nodes, lungs, and parotid glands is observed. Mycosis fungoides is characterized by skin lesions.
According to the prevalence of the process, there are 5 stages of malignant lymphoma (G. Mathe, 1976):
I-damage to one lymph node;
II - damage to several lymph nodes on one side of the diaphragm;
III - damage to several lymph nodes on both sides of the diaphragm;
IV - generalization of the lesion to all nodes and organs (skin, liver, spleen, etc.);
V - leukemic damage to the bone marrow, possible leukemia of the blood.
At each stage of the disease, a distinction is made between form A (absence of intoxication) and B (presence of intoxication - fever, excessive sweating, emaciation).
Diagnostics.
The diagnosis is made only after a biopsy and examination of the removed tumor or part of it using cytological, histological and histochemical methods. A trepanobiopsy and bone marrow puncture and determination of immunoglobulins are required.
Differential diagnosis is carried out with chronic lymphocytic leukemia, lymphogranulomatosis, metastases of cancer and sarcoma to the lymph nodes.
Treatment
includes radiation therapy and chemotherapy, surgical treatment methods. In recent years, a combination of radiation with chemotherapy or chemotherapy alone has been recommended already in stage I of the disease.
Only for early-stage low-grade lymphomas is radiation the treatment of choice.
For generalized forms of malignant lymphoma, polychemotherapy is recommended: COP (cyclophosphamide-fvincristine + prednisolone), MOPP (mustargen + oncovin-f procarbazine + prednisolone), C+MOPP (cyclophosphamide + MOPP).
To treat high-grade lymphomas, polychemotherapy is used, the same as in the treatment of acute leukemia.
The prognosis of the disease is determined by the stage of the process and the cytomorphological variant.
The average life expectancy of patients is about 2 years. Patients with malignant lymphomas are treated and monitored by an oncologist or hematologist and a primary care physician.
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