Mantle cell lymphoma is a mature B–cell non-Hodgkin’s lymphoma that arises from small and medium-sized cells with irregular nuclear contours. The main cause of the disease is called CCND1 gene translocation. Clinical manifestations include a slightly painful enlargement of lymph nodes, hepatosplenomegaly, nonspecific intoxication syndrome. The diagnosis of a mantle cell tumor is based on the results of cytological and immunohistochemical analysis of biopsies. Treatment of the disease involves intensive chemotherapy and immunotherapy regimens, bone marrow transplantation, and symptomatic therapy.
ICD 10
C85.7 Other specified types of non-Hodgkin’s lymphoma
General information
The diagnosis of “mantle cell lymphoma” (MCL), which is also called mantle cell lymphoma, first appeared in 1994 in the “Revised European-American Classification of Lymphoid Tumors”. It accounts for 3-10% of all non-Hodgkin’s lymphomas. The incidence of the disease varies from 0.5-0.7 cases per 100 thousand people under 65 years of age to 3.9 cases in the older age group.
Causes
In 95% of cases, the development of MCL is associated with the translocation of the CCND1 gene into the region of constitutionally overexpressed IgVH genes on B lymphocytes. The molecular genetic description of the classical transfer is (11;14) (q13;q32), variants t(2;11)(p11;q13) and t(11;22)(q13;q11) are less common. The remaining 5% of cases are caused by the rearrangement of the proto-oncogene into the genes of the light chains of immunoglobulins.
Risk factors
Provoking factors play a significant role in the development of lymphoproliferative processes. The most well-known of them are viral agents: the causative agent of hepatitis C, human immunodeficiency virus, Epstein-Barr virus. The probability of mantle cell lymphoma increases among patients with primary immunodeficiency and patients who have been receiving immunosuppressive therapy in transplant departments for a long time. The contribution of exogenous carcinogens has not yet been sufficiently studied.
Pathogenesis
The basis of the disease is a malignant transformation of normal B-lymphocytes, which occurs against the background of gene translocation and overexpression of individual variants of cyclins. Current data show that damage to the CCND1 gene is not the only oncogenic event in MCL. In 80% of cases, additional cytogenetic breakdowns and increased activity of the Cyclin D1-CDK4 complex are observed, which stimulates the transition of cells into the division phase.
The second link in the pathogenesis of mantle cell lymphoma is an increase in the synthesis of transcription factor SOX11. It regulates the division and growth of malignant cells, stimulates angiogenesis, and is a prognostically unfavorable marker. The expression of SOX11 is important for the differential diagnosis of various variants of non-Hodgkin’s lymphomas when it is not possible to determine the gene translocation typical for MCL.
Classification
The study of the molecular structure of tumors allows us to divide the MCL into classical and indolent variants. Classical lymphoma accounts for 80-90% of cases, it originates from B cells of the pregerminal stage of differentiation. The indolent type has mutations of the IGHV genes and is SOX11-negative, unlike the previous variant. In practical hematology, the modified Ann Arbor classification is widely used, in which 4 stages are distinguished:
- Stage I. It is characterized by the involvement of lymph nodes in one zone or a single lesion of extralymphatic tissue.
- Stage II. It is diagnosed with pathology of more than two groups of lymph nodes on one side of the diaphragm, or with a combined lesion of one extralymphatic organ and neighboring lymph nodes.
- Stage III. It is manifested by the involvement of lymphoid tissue on both sides of the diaphragm, including with single or multiple lesions of extranodular formations.
- Stage IV. It is established with disseminated lesions of extralymphatic organs, regardless of the involvement of lymph nodes in the process.
Of great importance for an oncologist is the assessment of the prognostic index of mantle cell lymphoma. To calculate this indicator, the age of the patient, the level of lactate dehydrogenase in the blood, the number of leukocytes and the general state of health are taken into account. The low risk of progression is established at the sum of 0-3 points, intermediate – 4-5 points, high – 6-11 points.
Mantle cell lymphoma symptoms
The main manifestation of the disease is an increase in lymph nodes in one or more areas of the body. Peripheral lymphadenopathy in the initial stages of the disease is asymptomatic. The nodes have a dense elastic consistency and remain mobile, as mantle cell lymphoma progresses, they merge into extensive conglomerates. The skin above the enlarged lymph nodes is not changed, pain syndrome is rare.
The second typical symptom of MCL is intoxication. Patients complain of an increase in body temperature, profuse sweating in the evening and at night, weakness and decreased performance. It bothers the skin itching, which leaves multiple traces of scratching on the body. The tumor process is accompanied by a sharp decrease in body weight: many patients lose 10 kg in 2-3 months. Due to the enlargement of the liver, heaviness and discomfort in the right hypochondrium are possible.
Complications
The main problem of mantle cell lymphoma is its recurrence, which is not always possible to prevent even intensive pharmacotherapy regimens. Enlargement of deep lymph nodes is fraught with compression of the trachea, esophagus, intestines and ureters. Compression of organs causes respiratory failure, intestinal obstruction, urinary retention. Immunosuppression increases the risk of bacterial, viral and fungal infections.
Diagnostics
Patients with symptoms of lymphoproliferative diseases are examined by an oncogematologist. During the initial examination, attention is paid to the number and size of enlarged lymph nodes, the presence of hepatosplenomegaly, anthropometric indicators and external signs of protein-energy deficiency. The following research methods are prescribed for diagnosis:
- Ultrasound of the lymph nodes. Sonography is used to detect an increase in peripheral and intra-abdominal lymph nodes, a change in their structure. Additionally, ultrasound imaging of the liver and spleen is performed to determine the linear dimensions and structure of the parenchyma of the organs.
- Lymph node biopsy. Invasive diagnosis is indicated for all patients with suspected MCL before the appointment of antitumor treatment. A tissue sample of an enlarged lymphoid formation or an affected extralymphatic organ is required for the study.
- Computed tomography. Examination of the neck, thoracic and abdominal cavities is recommended to assess the size and extent of lymphadenopathy. According to the indications, MRI, PET-CT, radioisotope scanning with gallium is performed.
- Histological examination. In the mantle cell type of lymphoma, a mature cell tumor with nodular, diffuse or mixed growth pattern is determined. When viewed under a microscope, the cells have irregularly shaped nuclei and a rim of pale cytoplasm.
- Immunohistochemical analysis. MCL cells are characterized by fixation of surface immunoglobulins M and D, which are positive for CD20, CD79a, CD5, CD43. Positive staining for nuclear cyclin D1 is observed. According to the results of immunohistochemistry, the morphological form of the tumor is verified.
- Blood test. The hemogram determines an increase in ESR, a decrease in the number of erythrocytes and hemoglobin, moderate thrombocytosis. In the biochemical analysis of blood, special attention is paid to the indicators of LDH, total protein, electrolytes in order to identify the syndrome of tumor lysis and concomitant lesions of internal organs. The growth of the D-dimer is observed in the coagulogram.
Differential diagnosis
Mantle cell lymphoma is differentiated from the more common causes of lymphadenopathy:
- lymphogranulomatosis;
- infectious mononucleosis;
- specific infectious lymphadenitis in brucellosis, syphilis, tuberculosis.
When the tumor is localized in the mediastinal region, it is necessary to exclude thymoma. As part of the immunohistochemical study, differential diagnosis of different types of non-Hodgkin’s lymphomas is carried out.
Treatment
Conservative therapy
The basis of the treatment of the disease is an intensive immunochemotherapy regimen with subsequent consolidation. The choice of a therapeutic program depends on the molecular genetic characteristics of the tumor, the age and somatic status of the patient, and the severity of concomitant diseases. Given the aggressive course of classical MCL, it is recommended to start therapy as early as possible. With an indolent form, a wait-and-see tactic is possible.
High-dose chemotherapy, which is carried out according to generally accepted protocols, is recognized as the best option. It includes one or more antitumor drugs with different mechanisms of action. In patients under 65 years of age without significant comorbid conditions, pharmacotherapy is supplemented with autologous hematopoietic stem cell transplantation. HSCT is preceded by conditioning, which requires a combination of radiation therapy and chemotherapy.
To alleviate the condition of patients during the course of immunochemotherapy, symptomatic treatment is prescribed. Be sure to use analgesic therapy, including the use of opioid analgesics. Prevention of nausea and vomiting with centrally acting drugs plays an important role. Correction of the level of shaped blood elements is carried out, manifestations of nutritional deficiency are eliminated.
Experimental treatment
Particular attention is paid to the treatment of patients over 65 years of age, when it is necessary to find a balance between the antitumor effect of drugs and permissible side effects. Of great interest are the “chemo-free” regimens, which include an induction stage and supportive therapy. The duration of the protocols does not exceed 3 years. In clinical trials, the chemo-free scheme shows an overall 5-year survival rate of 77%.
Standard chemotherapy regimens are supplemented with new immunotherapeutic drugs. Inhibitors of proteasome 26S, which interacts with the Cyclin D1–CDK4 complex, have good prospects. In complex treatment, B-cell receptor inhibitors are used, which inhibit the proliferation of tumor cells. For the treatment of recurrent MCL, drugs from the group of mTOR kinase inhibitors are used.
Prognosis and prevention
The appearance of new drugs allows to remove the “seal of fatality” from mantle cell lymphoma. However, the overall 5-year survival rate is no more than 71%, the progression–free survival rate is 45%. A more favorable prognosis for patients with an indolent variant of pathology, which is characterized by a low tumor load and low proliferative activity (the level of the Ki67 nuclear protein is less than 10%). Measures for the prevention of MCL have not yet been developed.