Non-Hodgkin's lymphoma

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

The disease usually presents with peripheral lymphadenopathy. However, in some forms there is no enlargement of the lymph nodes, but there are abnormal lymphocytes in the circulating blood. Unlike 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 lymph node or bone marrow biopsy. Treatment includes radiation and/or chemotherapy, stem cell transplantation is usually performed as salvage therapy in case of incomplete remission or relapse of the disease.

Non-Hodgkin lymphoma is more common than Hodgkin lymphoma. It is the sixth most common cancer in the United States, with approximately 56,000 new cases of non-Hodgkin lymphoma reported each year across all age groups. However, non-Hodgkin lymphoma is not a single disease but a category of lymphoproliferative malignancies. The incidence rate increases with age (median age is 50 years).

[ 1 ], [ 2 ], [ 3 ]

Causes of Non-Hodgkin's Lymphoma

Most non-Hodgkin lymphomas (80 to 85%) originate from B cells, with the remainder originating from T cells or natural killer cells. In all cases, the source is early or mature progenitor cells.

The cause of non-Hodgkin lymphomas is unknown, although, as with leukemia, there are strong indications of a viral origin (eg, human T-cell leukemia/lymphoma virus, Epstein-Barr virus, HIV). Risk factors for the development of non-Hodgkin lymphomas include immunodeficiency (secondary post-transplant immunosuppression, AIDS, primary immune diseases, dry eye syndrome, RA), Helicobacter pylori infection, exposure to certain chemicals, and previous treatment for Hodgkin lymphoma. Non-Hodgkin lymphomas are the second most common cancer in HIV-infected patients, and many primary lymphoma patients develop AIDS. The C-myc rearrangement is characteristic of some AIDS-associated lymphomas.

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

Hypogammaglobulinemia, caused by a progressive decrease 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 Lymphoma

In many patients, the disease manifests itself with asymptomatic peripheral lymphadenopathy. Enlarged lymph nodes are elastic and mobile, later they merge into conglomerates. In some patients, the disease is localized, but in most there are multiple areas of involvement. Mediastinal and retroperitoneal lymphadenopathy can cause compression symptoms in various organs. Extranodal lesions can dominate the clinical picture (for example, gastric involvement can simulate cancer; intestinal lymphoma can cause malabsorption syndrome; in patients with HIV, the central nervous system is often affected).

Skin and bone are initially involved in 15% of patients with aggressive lymphomas and in 7% with indolent lymphomas. Occasionally, patients with extensive abdominal or thoracic disease develop chylous ascites or pleural effusions due to obstruction of lymphatic ducts. Weight loss, fever, night sweats, and asthenia indicate disseminated disease. Patients may also have splenomegaly and hepatomegaly.

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

Anemia is present initially in 33% of patients and develops gradually in most patients. Anemia may be due to the following causes: bleeding from gastrointestinal lymphoma with or without thrombocytopenia; hypersplenism or Coombs-positive hemolytic anemia; bone marrow infiltration by lymphoma cells; myelosuppression caused by chemotherapy or radiation therapy.

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

Patients with anaplastic large cell lymphoma have rapidly progressive skin lesions, adenopathy, and visceral organ involvement. The disease may be mistaken for Hodgkin's lymphoma or metastasis from undifferentiated cancer.

Staging of non-Hodgkin's lymphomas

Although localized non-Hodgkin lymphomas occasionally occur, the disease is usually disseminated at diagnosis. Staging tests include chest, abdominal, and pelvic CT, PET, and bone marrow biopsy. Definitive staging of non-Hodgkin lymphomas, as with Hodgkin lymphoma, is based on clinical and histologic findings.

Classification of non-Hodgkin's lymphomas

The classification of non-Hodgkin lymphomas continues to evolve, reflecting new knowledge of the cellular nature and biological basis of these heterogeneous diseases. The most widely used is the WHO classification, which reflects the immunophenotype, genotype, and cytogenetics of the cells; other systematizations of lymphomas exist (eg, the Lyon classification). The most important new types of lymphoma included in the WHO classification are mucosa-associated lymphoid tumors; mantle cell lymphoma (formerly diffuse small cleaved cell lymphoma); and anaplastic large cell lymphoma, a heterogeneous disease of T-cell origin in 75%, B-cell origin in 15%, and unclassifiable in 10%. However, despite the diversity of lymphoma types, their treatment is often the same, except for individual types of T-cell lymphoma.

Lymphomas are usually divided into indolent and aggressive. Indolent lymphomas progress slowly and respond to therapy, but are incurable. Aggressive lymphomas progress rapidly, 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's, diffuse large B-cell and lymphoblastic lymphoma) requires special approaches due to the involvement of such areas as the gastrointestinal tract (especially in the terminal ileum); meninges and other organs (such as the brain, testicles). It is also necessary to take into account the possible development of side effects of therapy, such as secondary malignancies, cardiorespiratory complications, and the need to preserve fertility. Currently, research is aimed at solving these issues, as well as studying the development of the tumor process at the molecular level, prognostic factors of childhood lymphoma.

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

B-cell tumors

T- and NK-cell tumors

From B cell precursors B-cell precursor lymphoblastic leukemia/lymphoma From mature B cells B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma. B-cell prolymphocytic leukemia. Lymphoplasmacytic lymphoma. Splenic marginal zone B-cell lymphoma. Hairy cell leukemia. Plasma cell myeloma/plasmacytoma. Extranodal marginal zone lymphoid tissue B-cell lymphoma (MALT lymphoma). Nodal marginal zone B-cell lymphoma. Follicular lymphoma. Mantle cell lymphoma. Diffuse large B-cell lymphomas (including mediastinal large B-cell lymphoma, primary exudative lymphoma). Burkitt's lymphoma

From T cell precursors T-cell precursor lymphoblastic leukemia/lymphoma. From mature T cells T-cell prolymphocytic leukemia. T-cell leukemia of large granular leukocytes. Aggressive NK cell leukemia. Adult T-cell leukemia/lymphoma (HTLV1-positive). Extranodal I-MKD cell lymphoma, nasal type. Hepatosplenic T-cell lymphoma. Subcutaneous panniculitis-like T-cell lymphoma. Mycosis fungoides/Sezary syndrome. Anaplastic large cell lymphoma of T/NK cells, primary cutaneous type. Peripheral T-cell lymphoma, non-specific. Angioimmunoblastic T-cell lymphoma

MALT - mucosa-associated lymphoid tissue.

NK - natural killers.

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

Aggressive.

Indolent.

Indolent but rapidly progressive.

[ 9 ]

Diagnosis of non-Hodgkin's lymphomas

Non-Hodgkin lymphoma is suspected in patients with painless lymphadenopathy or when mediastinal adenopathy is detected on routine chest radiography. Painless lymphadenopathy may result from infectious mononucleosis, toxoplasmosis, cytomegalovirus infection, or leukemia.

Radiographic findings may resemble lung cancer, sarcoidosis, or tuberculosis. Less commonly, the disease is detected due to lymphocytosis in the peripheral blood and nonspecific symptoms. In such cases, differential diagnosis includes leukemia, Epstein-Barr virus infection, and Duncan syndrome.

A chest X-ray is performed if not previously done, and a lymph node biopsy is performed if lymphadenopathy is confirmed by CG or PET scanning. If the mediastinal lymph nodes are enlarged, the patient should undergo a lymph node biopsy under CG or mediastinoscopy control. The following tests are routinely performed: complete blood count, alkaline phosphatase, renal and liver function tests, LDH, uric acid. Other tests are performed based on preliminary data (e.g., MRI for symptoms of spinal cord compression or CNS abnormalities).

Histologic criteria for biopsy include disruption of the normal lymph node structure and capsule invasion, as well as detection of characteristic tumor cells in adjacent adipose tissue. Immunophenotyping determines the nature of the cells, identifies specific subtypes, and helps determine the prognosis and management of the patient; these studies should also be performed on peripheral blood cells. The presence of pan-leukocyte antigen CD45 helps exclude metastatic cancer, which is often detected in the differential diagnosis of undifferentiated cancers. Determination of common leukocyte antigen and gene rearrangement (documents B- or T-cell clonality) is mandatory on fixed tissues. Cytogenetic studies and flow cytometry require fresh biopsies.

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

Treatment of non-Hodgkin's lymphomas

Treatment of non-Hodgkin's lymphoma varies significantly depending on the cell type of lymphoma, and there are many treatment programs, which does not allow us to consider them in detail. Approaches to the treatment of localized and disseminated stages of lymphoma, as well as aggressive and indolent lymphomas, are fundamentally different.

Localized non-Hodgkin's lymphoma (stages I and II)

Indolent lymphoma is rarely diagnosed at the localized stage, but when localized disease is present, regional radiation therapy can result in long-term remission. However, the disease may recur more than 10 years after radiation therapy.

About half of patients with aggressive lymphomas are diagnosed at the localized stage, in which case polychemotherapy with or without regional radiation therapy is usually effective. Patients with lymphoblastic lymphomas or Burkitt lymphoma, even with localized disease, should be treated with intensive polychemotherapy regimens with CNS prophylaxis. Maintenance therapy may be required (for lymphoblastic lymphoma), but complete recovery is possible.

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

There are various approaches to the treatment of indolent lymphomas. A watch-and-wait approach, therapy with a single alkylating agent, or a combination of 2 or 3 chemotherapy agents may be used. The choice of treatment strategy is based on a number of criteria, including age, performance status, extent of disease, tumor size, histologic variant, and expected response to treatment. Rituximab (anti-CD20 antibody to B cells) and other biologic agents are effective, used in combination with chemotherapy or as monotherapy. Recent reports of antibodies conjugated to radioisotopes are promising. Although survival may be measured in years, the long-term prognosis is poor due to the occurrence of late relapses.

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

The use of autologous transplantation in first-line therapy is being studied. According to the IPT, high-risk patients may be selected for dose-intensified regimens. Whether this treatment strategy improves the chances of cure is currently being studied. Selected patients with mantle cell lymphoma may also be candidates for this type of therapy.

Relapse of aggressive lymphoma

The first relapse after first-line therapy is almost always treated with autologous hematopoietic stem cell transplantation. Patients must be younger than 70 years, have a good performance status, respond to standard chemotherapy, and have the required number of CD34+ stem cells collected (from peripheral blood or bone marrow). Consolidation myeloablative therapy includes chemotherapy with or without radiotherapy. The use of immunotherapy (eg, rituximab, vaccination, IL-2) after completion of chemotherapy is under study.

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

Recovery is expected in 30-50% of patients with aggressive lymphomas treated with myeloablative therapy. In indolent lymphomas, recovery after autologous transplantation is questionable, although remission may be achieved more often than with palliative therapy alone. Patient mortality after the use of a myeloablative regimen ranges from 2 to 5% after autologous transplantation, and about 15% after allogeneic transplantation.

The consequences of standard and high-dose chemotherapy are secondary tumors, myelodysplasia, and acute myeloid leukemia. Chemotherapy in combination with radiation therapy increases this risk, although the incidence of these complications does not exceed 3%.

Prognosis of non-Hodgkin lymphomas

The prognosis for patients with T-cell lymphoma is generally worse than for patients with B-cell lymphomas, although newer intensive treatment programs are improving the prognosis.

Survival also depends on many factors. The International Prognostic Index (IPI) is often used for aggressive lymphomas. It is based on 5 risk factors: age over 60 years, poor performance status [according to ECOG (Eastern Cooperative Oncology Group)], elevated LDH, extranodal disease, stage III or IV. The effectiveness of treatment worsens with an increase in the number of risk factors; the actual survival also depends on the cell type of the tumor, for example, in large cell lymphoma, the 5-year survival in patients with 0 or 1 risk factor is 76%, while in patients with 4 or 5 risk factors it is only 26%. Typically, patients with > 2 risk factors should undergo more aggressive or experimental treatment. For indolent lymphomas, a modified Follicular Lymphoma International Prognostic Index (FLIPI) is used.