B-cell lymphoplasmacytic lymphoma of Waldenström

Relating to the category of malignant lymphoproliferative (immunoproliferative) diseases, lymphoplasmacytic lymphoma or Waldenström's macroglobulinemia is a cellular neoplasm of small B-lymphocytes - B-cells that provide protective functions of the lymphatic system and humoral immunity of the body. Diagnosis should be made only after all other small B-cell lymphomas have been excluded. Waldenström's macroglobulinemia was described in 1944 by Jan G. Waldenström, who reported unusual manifestations of lymphadenopathy bleeding, anemia, increased sedimentation rate, hyperviscosity, and hypergammaglobulinemia in two patients. [1], [2]

Epidemiology

This type of lymphoma is a rare, indolent hematological malignancy, and clinical statistics estimate the incidence of its detection in this group of diseases at about 2%. Moreover, there are almost twice as many male patients as female patients.

According to some reports, the frequency of annual cases of lymphoplasmacytic lymphoma in Europe is one per 102 thousand people, and in the United States - one per 260 thousand. [3] 

Causes of the lymphoplasmacytic lymphoma

To date, the etiology of most cancers remains unknown, but research into the genetic basis of some of them continues. Studying the causes of malignant  plasma cell diseases , including B-cell lymphoplasmacytic lymphoma -  Waldenström  's macroglobulinemia, researchers have found a connection between pathological proliferation (cell division) of B - lymphocytes  at a late stage of their differentiation with the presence of certain molecular gene disorders that alter basic cellular functions. 

In patients with Waldenström's macroglobulinemia, changes in some genes were revealed - somatic mutations, that is, affecting only tissues with damage to the genes of a separate clonal population of cells and forming variants of their genome, which lead to cyclic and structural disorders at the cellular level.

First of all, these are somatic mutations of the MYD88 (L265P) gene and CXCR4, which encodes a cytosolic protein that is important for the innate and adaptive immune response: as an adapter, it provides signaling of the pro-inflammatory mediator IL-1 (interleukin-1) and Toll-like cells. Receptors that activate the immune response. As a result of a somatic mutation, anomalies of the polypeptide chain of a given protein molecule, its structural basis, occur. [4]

Risk factors

In addition to general risk factors (exposure to elevated levels of radiation, carcinogenic chemicals, etc.), predictors of an increased likelihood of developing Waldenström's macroglobulinemia as a low-grade lymphoproliferative disease are:

• old age (over 65 years);
• the presence of relatives with this diagnosis, as well as with B-cell non-Hodgkin's lymphoma or chronic lymphocytic leukemia;
• chronic  hepatitis C ;
• a history of benign monoclonal gammopathy, an idiopathic hematological disease, the essence of which is the production of abnormally altered type M gamma globulins by lymphocytic plasmocytes;
• autoimmune diseases, in particular  Sjögren 's syndrome .

Pathogenesis

Upon contact with an antigen or stimulation from T-lymphocytes, a part of B-lymphocytes turns into plasma cells - lymphocytic plasmocytes, which, after certain transformations, begin to produce protective globular proteins, that is, gamma globulins (immunoglobulins or antibodies).

The pathogenesis of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia lies in the hyperproliferation of B cells, an excess of the normal level of a clone of lymphocytic plasma cells and an excess in the blood of their produced immunoglobulin M (IgM), also called monoclonal immunoglobulin or M-protein. It is a major high molecular weight, pentameric antibody produced upon initial attack by specific bacterial or viral antigens. [5]

Almost all the symptoms of this disease are associated with manifestations of the activity of the M-protein, which can disrupt the rheological properties of the blood, increase its viscosity; impregnate lymphoid and myeloid tissues of the bone marrow, accumulate in peripheral lymphoid tissues (with the formation of slowly growing neoplasias that can put pressure on surrounding organs, nerve fibers or blood vessels).

Although chronic lymphocytic leukemia, Waldenström's macroglobulinemia or lymphoplasmacytic lymphoma and  multiple myeloma  are separate diseases, they are all caused by increased proliferation of B-lymphocytes.

Symptoms of the lymphoplasmacytic lymphoma

The first signs of the disease are nonspecific and may be manifested by weakness and fatigue (due to the development of normochromic anemia), weight loss, shortness of breath, nocturnal hyperhidrosis, and recurrent low-grade fever.

In addition, at the initial stage of the disease, there is a violation of the sensitivity of the hands and feet, peripheral neuropathy occurs (numbness or tingling in the feet and legs), small focal hemorrhages of the skin capillaries (purpura), as well as cold urticaria (due to the formation and aggregation of abnormal cryoglobulin proteins in serum).

Hyperviscosity syndrome-associated symptoms include headaches and dizziness, retinal damage and blurred vision, tinnitus and hearing loss, seizures, muscle pain, high blood pressure, spontaneous nosebleeds, and bleeding gums. In women, uterine bleeding is possible.

Also observed: an increase in lymph nodes (lymphadenopathy); enlargement of the spleen (splenomegaly); heart failure with cardialgia and cardiac arrhythmia. Although visceral infiltration is rare, the stomach and intestines may be affected, resulting in diarrhea (often with fatty stools). [6], [7]

Forms

The 2017 World Health Organization classification of hematopoietic and lymphoid tissue tumors establishes four diagnostic criteria for Waldenström macroglobulinemia, including:

• Presence of monoclonal IgM gammopathy
• Bone marrow infiltration with small lymphocytes showing plasmacytoid or plasma cell differentiation
• Bone marrow infiltration with intertrabecular structure
• Immunophenotype supporting Waldenström's macroglobulinemia which includes surface IgM+, CD19+, CD20+, CD22+, CD25+, CD27+, FMC7+, variable CD5, CD10-, CD23-, CD103- and CD108-

Complications and consequences

Patients with lymphoplasmacytic lymphoma develop complications and consequences in the form of:

• decrease in immunity;
• insufficiency of the bone marrow with a violation of its hematopoietic functions and the development of anemia;
• deficiency of such formed blood elements as erythrocytes, leukocytes, platelets;
• damage to the structures of the gastrointestinal tract with chronic diarrhea and impaired intestinal absorption (malabsorption syndrome);
• inflammation of the walls of blood vessels (complex immune vasculitis);
• increased bone fragility (osteoporosis);
• visual and hearing impairments;
• secondary  amyloidosis  of internal organs;
• progression to paraproteinemic hemoblastosis in the form of multiple myeloma;
• transformation into a highly malignant type of lymphoma - diffuse large B-cell lymphoma.

Diagnostics of the lymphoplasmacytic lymphoma

The diagnosis of lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia is usually difficult due to the absence of specific morphological, immunophenotypic, or chromosomal changes. This deficiency makes differentiation of this disease from other small B-cell lymphomas based on exclusion. [8], 

In addition to assessing the existing symptoms, for the diagnosis of lymphoplasmacytic lymphoma, general and biochemical blood tests, a coagulogram,  immunoelectrophoresis of blood proteins  with the determination of the level of  immunoglobulin M in the blood are necessary ; general urine analysis. [9]

A bone marrow biopsy is required, for which its puncture is performed.

Instrumental diagnostics are carried out: ultrasound of the lymph nodes and spleen, x-ray of bones, CT scan of the chest and abdominal cavity, ophthalmoscopy.

Differential diagnosis

Lymphoplasmacytic lymphoma is considered a diagnosis of exclusion, therefore, differential diagnosis is carried out with B-cell chronic lymphocytic leukemia, multiple myeloma, follicular lymphoma, various subtypes of non-Hodgkin's lymphoma, plasmacytoma, reactive plasmacytosis, angiofollicular lymphoid hyperplasia (Castleman's disease), etc.

Treatment of the lymphoplasmacytic lymphoma

It should be borne in mind that Waldenström's macroglobulinemia or lymphoplasmacytic lymphoma can be asymptomatic for many years and be diagnosed with an increase in the level of M-protein in the blood.

If there is no symptom, active monitoring is carried out with regular examinations and tests.

Based on the existing symptoms and the results of laboratory tests, a decision is made to start therapy, which depends on many factors (for example, age, progression of the disease, etc.).

According to the protocol, the initial treatment of patients with this type of lymphoma is usually a combination of radiation therapy and chemotherapy with the introduction of cytostatics, for example,  Cyclophosphamide , Doxorubicin, Vincristine, as well as corticosteroids - Metprednisolone or Dexamethasone (Dexasone).

The effectiveness of chemotherapy drugs of the group of monoclonal antibodies, in particular,  Rituximab, has been proven . [10]

In cases of generalized disease, Rituximab is used in combination with antitumor nucleoside analogues (Pentostatin, Cladribine). In a slowly progressive disease with a low level of monoclonal immunoglobulin M, in addition to Rituximab, the cytostatic Chlorambucil (Leukeran) is used. [11]

To reduce blood viscosity and stabilize the level of its formed elements,  therapeutic hemapheresis is used .

With a critically low level of antibodies in the blood - to prevent concomitant re-infections - immunoglobulin replacement therapy is carried out.

According to oncohematologists, despite the fact that treatment can lead to remission of the disease, most patients experience its relapse. If it occurs earlier than 24 months, an anticancer drug such as Ibrutinib (in tablet form) can be used. With later relapses, treatment is carried out according to the original scheme. [12].  [13]. [14]

Prevention

Specialists determine the prognosis of the outcome of lymphoplasmacytic lymphoma according to the international prognostic system for assessing the main parameters: the patient's age and serum levels of hemoglobin, platelets, beta-2-microglobulin and monoclonal immunoglobulin. [15], [16]

The average survival rate for this diagnosis is about five years, but almost 40% of patients live ten years or more.