Non-Hodgkin's Lymphomas

Non-Hodgkin's lymphomas are a heterogeneous group of diseases characterized by monoclonal proliferation of malignant lymphoid cells in lymphoreticicular zones, including lymph nodes, bone marrow, spleen, liver and GIT.

The disease is usually manifested by peripheral lymphadenopathy. However, in some forms there is no increase in lymph nodes, but there are abnormal lymphocytes in the circulating blood. In contrast to Hodgkin's lymphoma, the disease is characterized by dissemination of the process at the time of diagnosis. The diagnosis is based on the results of a biopsy of the lymph node or bone marrow. Treatment includes radiation and / or chemotherapy, stem cell transplantation is usually performed as salvage therapy for incomplete remission or relapse of the disease.

Non-Hodgkin's lymphoma is more common than Hodgkin's lymphoma. In terms of frequency of occurrence in the USA, it ranks 6th among other cancers, and about 56,000 new cases of non-Hodgkin's lymphomas are registered annually among all age groups. However, non-Hodgkin's lymphoma is not one disease, but a whole category of lymphoproliferative malignancies. The incidence rate increases with age (median age is 50 years).

[1], [2], [3]

Causes of non-Hodgkin's lymphomas

Most non-Hodgkin's lymphomas (80 to 85%) are derived from B cells, otherwise the tumor source is T cells or natural killers. In all cases, the source is the early or mature progenitor cells.

The cause of non-Hodgkin's lymphomas is unknown, although, like in leukemia, there are convincing signs of the viral nature of the disease (eg, T-cell leukemia / human lymphoma virus, Epstein-Barr virus, HIV). Risk factors for the development of non-Hodgkin's lymphomas are immunodeficiency (secondary posttransplantation immunosuppression, AIDS, primary immune diseases, dry eye syndrome, RA), Helicobacter pylori infection, exposure to certain chemical compounds, previous treatment of Hodgkin's lymphoma. Non-Hodgkin's lymphomas are the second most frequent oncological disease in HIV-infected patients, in many primary patients, AIDS is determined by lymphoma. Re - arranging C-tus is characteristic of some lymphomas associated with AIDS.

Leukemias and non-Hodgkin's lymphomas have many common symptoms, since both with this and other pathologies proliferation of lymphocytes or their precursors occurs. In some types of non-Hodgkin's lymphomas, a clinical picture similar to leukemia with peripheral lymphocytosis and bone marrow involvement is found in 50% of children and 20% of adults. Differential diagnosis may be difficult, but usually in patients with involvement of many lymph nodes (especially mediastinapnyh), a small number of circulating abnormal cells and blast forms in the bone marrow (<25%) is diagnosed with lymphoma. The leukemia phase usually develops with aggressive lymphomas, except for Burkitt's lymphoma and lymphoblastic lymphomas.

Hypogammaglobulinemia, caused by a progressive decline in immunoglobulin production, occurs in 15% of patients and may predispose to the development of severe bacterial infections.

[4], [5], [6], [7], [8]

Symptoms of non-Hodgkin's lymphomas

In many patients, the disease manifests asymptomatic peripheral lymphadenopathy. The enlarged lymph nodes are elastic and mobile, later they merge into conglomerates. Some patients have localized disease, but most have multiple areas of damage. Mediastinal and retroperitoneal lymphadenopathy can be the cause of compression symptoms in various organs. Extranodal lesions may dominate the clinical picture (for example, gastric lesions can simulate cancer, lymphoma of the gut can cause malabsorption syndrome, in patients with HIV the CNS is often affected).

Skin and bones were initially affected in 15% of patients with aggressive lymphomas and 7% with indolent lymphomas. Sometimes patients with a pronounced process in the abdominal or thoracic cavity develop a chylous ascites or pleural effusion caused by obstruction of the lymphatic ducts. Weight loss, fever, night sweats and asthenia indicate a disseminated disease. Patients may also have splenomegaly and hepatomegaly.

Two signs are typical for NHL and are rare in Hodgkin's lymphoma: there may be congestion and swelling of the face and neck due to compression of the superior vena cava (upper vena cava syndrome or upper mediastinal syndrome), compression of the ureter by the retroperitoneal and / or pelvic lymph nodes urine flow through the ureter and may lead to secondary renal failure.

Anemia is initially present in 33% of patients and gradually develops in most patients. Anemia can be caused by the following: bleeding with lymphoma of the digestive tract with or without thrombocytopenia; hypersplenism or Coombs-positive hemolytic anemia; infiltration of bone marrow by lymphoma cells; Myelosuppression caused by chemotherapy or radiotherapy.

T-cell lymphoma / leukemia (associated with HTLV-1) has an acute onset, a violent clinical course with skin infiltration, lymphadenopathy, hepatosplenomegaly and leukemia. Leukemia cells are malignant T cells with altered nuclei. Hypercalcemia often occurs, associated more with humoral factors than with bone damage.

Patients with anaplastic large-cell lymphoma have fast-progressive skin lesions, adenopathy and lesion of visceral organs. This disease can be mistaken for Hodgkin's lymphoma or metastasis of undifferentiated cancer.

Staging of non-Hodgkin's lymphomas

Although sometimes localized non-Hodgkin's lymphomas are found, usually at the time of diagnosis, the disease has a disseminated character. Necessary examinations for staging are CT of the chest, abdomen and pelvis, PET and bone marrow biopsy. The final staging of non-Hodgkin's lymphomas, as with Hodgkin's lymphoma, is based on clinical and histological data.

Classification of non-Hodgkin's lymphomas

The classification of non-Hodgkin's lymphomas continues to evolve, reflecting new knowledge of the cellular nature and the biological basis of these heterogeneous diseases. The most common is the WHO classification, which reflects the immunophenotype, genotype and cytogenetics of cells; there are other systematization of lymphomas (for example, the Lyons classification). The most important new types of lymphomas included in the WHO classification are lymphoid tumors associated with mucous membranes; lymphoma from cells in the mantle zone (formerly diffuse from small cleaved lymphoma cells) and anaplastic large cell lymphoma, a heterogeneous disease that occurs in 75% of cases from T cells, 15% from B cells, and 10% of cases is unclassifiable. However, despite the variety of types of lymphomas, their treatment is often not different, apart from individual types of T-cell lymphomas.

Lymphomas are usually divided into indolent and aggressive. Indolent lymphomas slowly progress and "respond" to therapy, but are incurable. Aggressive lymphomas quickly progress, but "respond" to therapy and are often curable.

In children, non-Hodgkin's lymphomas are almost always aggressive. Follicular and other indolent lymphomas are very rare. Treatment of aggressive lymphomas (Burkitt, diffuse large B-cell and lymphoblastic lymphoma) requires special approaches in connection with the involvement of such zones as the gastrointestinal tract (especially in the terminal part of the ileum); cerebral membranes and other organs (such as the brain, testicles). It is also necessary to take into account the possible development of the side effects of therapy, such as secondary malignant tumors, cardiorespiratory complications, and the need to preserve fertility. Currently, research works are aimed at addressing these issues, as well as studying the development of the tumor process at the molecular level, prognostic factors for children's lymphoma.

Subtypes of non-Hodgkin's lymphoma (WHO classification)

B-cell tumors

T- and NK-cell tumors

From the precursors of B cells B-lymphoblastic leukemia / lymphoma from B-cell progenitors Of mature B cells B-cell chronic lymphocytic leukemia / small cell lymphocytic lymphoma. B-cell prolymphocytic leukemia. Lymphoplasmocytic lymphoma. B-cell lymphoma from the cells of the marginal zone of the spleen. Hairy cell leukemia. Plasma cell myeloma / plasmacytoma. Extranodal B-cell lymphoma of the marginal zone of lymphoid tissue (MALT-lymphoma). Nodal B-cell lymphoma from cells in the marginal zone. Follicular lymphoma. Lymphoma from the cells of the mantle zone. Diffuse large B-cell lymphomas. (including mediastinal large-cell B-cell lymphoma, primarily exudative lymphoma). Burkitt's lymphoma

From T-cell progenitors T-lymphoblastic leukemia / lymphoma from T-cell progenitors. Of mature T cells T-cell prolymphocytic leukemia. T-cell leukemia from large granular white blood cells. Aggressive NK cell leukemia. T-cell leukemia / adult lymphoma (HTLV1-positive). Extranodal 1MKD-cell lymphoma, nasal type. Hepatosplenic T-cell lymphoma. Subcutaneous panniculitis-like T-cell lymphoma. Mushroom mycosis / Cesary syndrome. Anaplastic large cell lymphoma from T / NK cells, primary cutaneous type. Peripheral T-cell lymphoma, nonspecific. Angioimmunoblastic T-cell lymphoma

MALT - lymphoid tissue associated with mucous membranes.

NK is a natural killer.

HTLV 1 (human T-cell leukemia virus 1) is a human T-cell leukemia virus 1.

Aggressive.

Indolent.

Indolent, but rapidly progressive.

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Diagnosis of non-Hodgkin's lymphomas

Non-Hodgkin's lymphoma is suspected in patients with painless lymphadenopathy or when mediastinal adenopathy is detected during routine chest X-ray. Painless lymphadenopathy can result from infectious mononucleosis, toxoplasmosis, cytomegalovirus infection, or leukemia.

X-ray data may be similar to lung cancer, sarcoidosis or tuberculosis. Less often the disease is detected in connection with lymphocytosis in the peripheral blood and the presence of nonspecific symptoms. In such cases, a differential diagnosis is made with leukemia, an infection caused by the Epstein-Barr virus and Duncan syndrome.

Chest radiography is performed if it has not been performed beforehand, as well as biopsy of the lymph node, if the lymphadenopathy is confirmed on a CG or PET scan. If there are enlarged mediastinal lymph nodes, the patient should undergo a biopsy of the lymph node under the control of CG or mediastinoscopy. The following tests are routinely performed: general blood test, alkaline phosphatase, renal and hepatic functional tests, LDH, uric acid. Other examinations are performed based on preliminary data (eg, MRI with symptoms of spinal cord compression or CNS abnormalities).

Histological criteria for biopsy are the violation of the normal structure of the lymph node and the invasion of the capsule, as well as the detection of characteristic tumor cells in the adjacent fatty tissue. Immunophenotyping determines the nature of cells, identifies specific subtypes and helps to determine the prognosis and tactics of patient management; these studies should also be performed on peripheral blood cells. The presence of panellocytic antigen CD45 helps to exclude metastatic cancer, which is often found in differential diagnosis of undifferentiated types of cancer. Determination of total leukocyte antigen and gene rearrangement (documents B-or T-cell clonality) is necessarily performed on fixed tissues. Cytogenetic studies and flow cytometry require fresh biopsy specimens.

[10], [11], [12], [13], [14]

Treatment of non-Hodgkin's lymphomas

Treatment of non-Hodgkin's lymphoma varies considerably depending on the cellular type of lymphoma, and there are many treatment programs that do not allow us to dwell on their detailed treatment. Fundamentally different approaches to the therapy of localized and disseminated stages of lymphoma, as well as aggressive and indolent lymphomas.

The localized form of non-Hodgkin's lymphoma (stages I and II)

The diagnosis of indolent lymphoma is rarely established at the stage of localized lesion, but in the presence of such a lesion, regional radiation therapy can lead to long-term remission. Nevertheless, more than 10 years after radiation therapy, the disease can recur.

About half of patients with aggressive lymphomas are detected in the stage of localized lesions, in which polychemotherapy in combination with regional radiation therapy or without it is usually effective. Patients with lymphoblastic lymphomas or Burkitt's lymphoma, even with localized lesions, should be treated with intensive polychemotherapy regimens with prevention of CNS involvement. Supportive therapy may be required (with lymphoblastic lymphoma), but nevertheless complete recovery is possible.

The common form of non-Hodgkin's lymphoma (III and IV stages)

There are different approaches to the therapy of indolent lymphomas. A "watch and wait" approach can be applied, therapy with one alkylating drug or a combination of 2 or 3 chemotherapy drugs. The choice of treatment tactics is based on a number of criteria, including age, general status, prevalence of the disease, tumor size, histological variant and the expected efficacy of treatment. Effective rituximab (anti-CD20 antibodies to B cells) and other biological agents that are used in combination with chemotherapy or as monotherapy. Promising are recent reports of the use of antibodies conjugated with radioisotopes. Although the survival of patients can be estimated in years, the long-term prognosis is unfavorable because of the occurrence of late relapses.

For patients with aggressive B-cell lymphomas (eg, diffuse large-cell B-cell lymphoma), the standard combination is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone). Complete regression of the disease occurs in more than 70% of patients and depends on the risk category (defined by MPI). More than 70% of patients with a full response to treatment recover, relapses 2 years after completion of treatment are rare.

The effectiveness of autologous transplantation in the first line of therapy is being studied. In accordance with the MPI, patients with high risk can be selected for treatment with regimens with dose intensification. At the present time, it is being studied whether such a therapeutic tactic increases the chances of a cure. Individual patients with lymphoma from cells in the mantle zone may also be candidates for this type of therapy.

Relapse of aggressive lymphoma

The first relapse after the first line of therapy is almost always treated using autologous stem cell transplantation. Patients should be under 70 years of age with a satisfactory general status, respond to standard chemotherapy and have the required number of collected CD34 + stem cells (the fence is made from peripheral blood or bone marrow). Consolidation myeloablative therapy includes chemotherapy with or without radiotherapy. The feasibility of using immunotherapy (for example, rituximab, vaccination, IL-2) after the completion of chemotherapy is being studied.

With allogeneic transplantation, stem cells are collected from a compatible donor (brother, sister or compatible unrelated donor). Allogeneic transplantation provides a dual effect: the restoration of normal hematopoiesis and the "graft versus disease" effect.

Recovery is expected in 30-50% of patients with aggressive lymphomas subjected to myeloablative therapy. With indolent lymphomas, recovery after autologous transplantation is doubtful, although remission can be achieved more often than with palliative therapy alone. The mortality of patients after the application of the myeloablative regimen is 2 to 5% after autologous transplantation, and about 15% after allogeneic.

Consequences of standard and high-dose chemotherapy are secondary tumors, myelodysplasia and acute myeloblastic leukemia. Chemotherapy combined with radiotherapy increases this risk, although the incidence of these complications does not exceed 3%.

Prognosis of non-Hodgkin's lymphomas

The prognosis for patients with T-cell lymphoma is usually worse than for patients with B-cell lymphomas, although the use of new intensive treatment programs improves prognosis.

Survival also depends on many factors. The International Prognostic Index (IPI) is often used in aggressive lymphomas. It is based on 5 risk factors: age over 60 years, poor overall status [according to ECOG (Eastern Cooperative Oncology Group)], increased LDH, extranodal lesions, stage III or IV. The effectiveness of treatment deteriorates with increasing number of risk factors; real survival also depends on the cell type of the tumor, for example, in large-cell lymphoma, 5-year survival in patients with 0 or 1 risk factor is 76%, while in patients with 4 or 5 risk factors, only 26%. Usually patients who have> 2 risk factors should undergo more aggressive or experimental treatment. In indolent lymphomas, a modified international prognostic index for follicular lymphoma (FLIPI) is used.