Etiology

Waldenström’s primary macroglobulinemia (WM), or sim ply macroglobulinemia, is a B cell disorder characterized by the infiltration of lymphoplasmacytic cells into bone marrow and the presence of an IgM monoclonal gammopathy. WM is considered to be a lymphoplasmacytic lymphoma, as defined by the Revised European American Lymphoma (REAL) and World Health Organization (WHO) classification systems. WM is a malignant lymphocyte–plasma cell proliferative disorder that exhibits abnormally large amounts of immunoglobulin of the 19S IgM type.

The cause of WM is unknown but a possible genetic predisposition may exist. About 20% of WM patients have a familial predisposition to the disease and related B cell malignancies. A greater frequency of IgM monoclonal proteins and quantitative abnormalities have been observed in some relatives of patients with WM. In addition, research has suggested a significantly increased risk of WM after infections—hepatitis B virus, immunodeficiency virus, and rickettsiosis—and found an increased risk of WM in patients with a personal history of autoimmune disease.

Because WM is a malignant offshoot of B cell development before the myelomas, the sole gene product is IgM. Patients with WM have chromosomal rearrangements characteristic of B cell neoplasia, including t(8:14) and trisomy 12.

Epidemiology

Waldenström’s macroglobulinemia occurs about 10% as frequently as multiple myeloma. WM has an age-specific incidence; it is most often found in older individuals, with a mean age of onset of 60 to 64 years. No significant gender differences exist in the incidence of WM. Disease onset is usually insidious; the median survival is approximately 3 years after diagnosis.

Signs and Symptoms

 The signs and symptoms of WM have an indolent progression over many years. Initially, disease onset is slow and insidious, with the pace of manifestations determined by the rate of proliferation of the IgM-secreting clone. Most clinical signs and symptoms of disease stem from intravascular accumulation of high levels of IgM macroglobulin. When the IgM is precipitable at cold temperatures, as it is in 37% of cases, clinical manifestations of cold sensitivity such as Raynaud’s phenomenon, arthralgias, purpura of the extremities, renal insufficiency, and peripheral vascular occlusions may develop. Cold hypersensitivity can occur when serum IgM levels exceed 2 to 3 g/dL and the protein precipitates at temperatures exceeding 20° C (68° F).

Although the patient experiences weakness and fatigue, it is usually the onset of bleeding from the gums or nose that arouses concern. Patients undergo weight loss and the incidence of infection is twice the normal rate. As the disease progresses, about 40% of patients develop hepatomegaly, splenomegaly, and lymphadenopathy. Occasionally, the clinical manifestations may simulate those of diffuse lymphoma. Specific dysfunctions and abnormalities occur in a variety of body systems.

Skeletal Features

In contrast to multiple myeloma, bone pain is almost nonexistent in WM. Diffuse osteoporosis may be seen, but bone lesions are extremely rare.

Hematologic Abnormalities

 Patients with WM usually have chronic anemia and bleeding episodes. Bleeding problems in the form of bruising, purpura, and bleeding from the mouth, gums, nose, and gastrointestinal tract are common. The quantities of circulating platelets may be normal or decreased, but the most notable alteration is a disturbance in platelet function. Therefore, thrombocytopenia or hyperviscosity may contribute to the bleeding disorder.

In addition to anemia caused by chronic or recurrent bleeding, the decrease in red blood cells (RBCs) becomes more severe as the disease progresses because of a dilutional effect caused by increased immunoglobulin production. In addition, the presence of macroglobulin also produces an increased erythrocyte sedimentation rate (ESR). Microscopic examination of a peripheral blood smear usually reveals normocytic and frequently hypochromic RBCs with striking rouleaux (rolled coin) formation. The total blood leukocyte count is normal or slightly decreased because of moderate neutropenia. In a terminal patient, the blood may be inundated with malignant lymphoplasmacytic cells.

Renal Dysfunction

 Renal function becomes mildly or moderately impaired in about 15% of WM patients. Nephrosis is uncommon. BJ proteinuria, however, is present in about 70% of WM patients, although the quantity of light chains excreted is much less than in multiple myeloma.

Glomerular lesions are the predominant form of renal injury. IgM collects on the endothelial side of the basement membrane of the kidney; sometimes these macroglobulin accumulations obstruct glomerular capillaries.

Ocular Manifestations

Blurred vision is a frequent abnormality of WM. Rouleaux induced by elevations of IgM causes distention of veins and capillaries; retinal oxygenation diminishes as rouleaux-inducing IgM rises. As a result of increased IgM levels, retinal hemorrhage, exudate formation, and varicosities develop, which can lead to more permanent retinal damage unless IgM levels are lowered by therapy.

Neuropsychiatric Problems

 The most common serious neurologic consequence of the slowed cerebral perfusion caused by macroglobulinemia is acute cerebral malfunction, beginning with headache, fluctuating confusion, forgetfulness, and slowed mentation. This can progress to somnolence, stupor, and coma–diffuse brain syndrome, sometimes termed coma paraproteinaemicum. Neurologic abnormalities can be improved by a reduction of plasma viscosity.

Polyneuropathy affects 5% to 10% of patients with WM. This condition is associated with an increase in spinal fluid protein and deposits of monoclonal IgM on myelin sheaths. Monoclonal IgM found in the plasma and attached to dam aged nerves has been shown in some cases to share idiotypic determinants. This suggests that the polyneuropathy of WM may be an autoimmune process caused by monoclonal IgM possessing antibody activity for a component of nerve tissue.

Cardiopulmonary Abnormalities

 Congestive heart failure becomes a serious problem in patients with chronic uncontrolled WM. About 90% of IgM remains trapped in the circulating plasma and exerts an unbalanced transendothelial osmotic effect sufficient to cause marked expansion of the plasma volume. This in turn creates a dilutional anemia and augments cardiac filling and cardiac output. As a result, increased cardiac output and blood viscosity over work the myocardium.

About 10% of patients develop pulmonary lesions. Pulmonary tumors, diffuse infiltrates, and pleural involvement are all about equally represented. The signs and symptoms of pulmonary dysfunction include coughing and dyspnea.

Cutaneous Manifestations

Cold sensitivity is a frequent manifestation of WM; however, skin lesions are uncommon. A small number of patients develop flat, violaceous, macular skin lesions resulting from dense infiltration by lymphoplasmacytoid cells. Pink, pearly-looking papules caused by dense deposits of IgM may be seen.

Immunologic Manifestations

 The basic abnormality in this macroglobulinemia is uncontrolled proliferation of B lymphocytes and plasma cells. As a result, there is a heavy accumulation of monoclonal IgM in the circulating plasma and plasmacytoid lymphocytes in the bone marrow.

In many cases, WM is associated with mixed cryoglobulinemia, which reflects the binding of IgG or IgA antiidiotypic antibody to the mutant IgM. In a small number of patients, dysplastic tumor cells secrete 7S IgM monomers, µ chains, or other monoclonal immunoglobulins or fragments. Therefore, the major IgM production indicates that the immunoglobulin (gene) lesion sometimes degenerates and codes for more than one M component.

Diagnostic Evaluation

 Hematologic Assessment

 Microscopic examination of a bone marrow aspirate reveals that the lymphoplasmacytic cells vary morphologically from small lymphocytes to obvious plasma cells. Frequently, the cellular cytoplasm is ragged and may contain material staining positive with periodic acid–Schiff (PAS) stain, probably identical to the circulating macroglobulin.

The total peripheral blood leukocyte count is usually nor mal, with an absolute lymphocytosis. Moderate to severe degrees of anemia are frequently observed on peripheral blood smears, as well as rouleaux formation. The patient’s plasma volume may be greatly increased and the ESR is also increased.

Platelet counts are usually normal. Faulty platelet aggregation and release of platelet factor 3 are caused by the nonspecific coating of platelets by IgM. The most common coagulation defect is a prolonged thrombin time, resulting from the binding of M component to fibrin monomers and consequent gel clotting of IgM-coated fibrin. Bleeding abnormalities can be demonstrated by the following:

 • Faulty platelet adhesiveness

 • Defective platelet aggregation

• Abnormal release of platelet factor 3

• Impaired clot retraction

• Prolonged bleeding time

• Positive tourniquet test

 • Prolonged thrombin-prothrombin time test

• Decreased levels of factor VIII

Immunologic Assessment

Serum electrophoresis usually demonstrates the overproduction of IgM (19S) antibodies. Diagnosis is made by the demonstration of a homogeneous M component composed of monoclonal IgM. Quantitation of immunoglobulins reveals IgM levels ranging from 1 to 12 g/dL (usually, >3 g/dL), accounting for 20% to 70% of total protein. Characteristically, blood samples are described as having hyperviscosity.

In addition, cryoglobulins can be detected in the patient’s serum. Cryoglobulins are proteins that precipitate or gel when cooled to 0° C (32° F) and dissolve when heated. In most cases, monoclonal cryoglobulins are IgM or IgG. Occasionally, the macroglobulin is cryoprecipitable and capable of cold-induced, anti-I–mediated agglutination of RBCs. IgM may also occasionally be a pyroglobulin, which precipitates on heating to 50° C to 60° C (122° F to 140° F) but does not redissolve on cooling or intensified heating, as do typical BJ pyroglobulins. Many cryoglobulins have the ability to fix complement and initiate an inflammatory reaction similar to that of antigen antibody complexes. Cryoglobulins have been classified into the following three types:

• Type I is composed of a single class. IgM and IgG classes are most common; IgA or light-chain, single cryoglobulins are seen less frequently. Type I constitutes about 25% of cryoglobulins and is generally associated with multiple myeloma, macroglobulinemia, and other, rarer neoplastic proliferations of plasma cells and lymphocytes.

 • Type II cryoglobulins consist of two forms. The monoclonal form always has rheumatoid factor activity and usually is an IgM with κ light chains. The second form is polyclonal IgG, which reacts with the monoclonal IgM rheumatoid factor.

• Type III is a mixed cryoglobulin in which both constituent immunoglobulins are polyclonal. More than 90% of type III cryoglobulins contain IgM rheumatoid factor and IgG. Type III cryoglobulins are seen in a variety of autoimmune, systemic rheumatic diseases and persistent infections with immune complexes (e.g., bacterial endocarditis).

Treatment

Current treatment of WM includes single-agent alkylator, nucleoside analogue, or standard-dose rituximab therapy. Newer studies have suggested that extended-dose rituximab and other treatment options are likely to yield as good or even better results than currently recommended therapy. These include therapy with nucleoside analogues or alkylator agents, rituximab in combination with nucleoside analogues, nucleoside analogues plus alkylator agents, and combination chemotherapy (e.g., cyclophosphamide, doxorubicin, vincristine, prednisone [CHOP]) or cyclophosphamide and dexamethasone.

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العتبة العباسية المقدسة تنظّم محاضرة توعوية لطالبات كلية الأسوة للبنات في باكستان

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المزيد

الآخبار الصحية

اختراع صيني.. لاصق يصلح كسور العظام خلال دقائق

اكتشاف حلقات عملاقة من الحمض النووي.. تقلل خطر السرطان

آباء أميركيون يطالبون بتنظيم روبوتات الدردشة لحماية الأطفال ؟

4 إشارات من القلب لا يجب تجاهلها أبدا

المزيد

الآخبار التكنلوجية

"تحليل المحادثات" يكشف كيف يستخدم الناس تشات جي بي تي

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المزيد

مواضيع ذات صلة

Diagnostic Evaluation of Multiple myeloma

Signs and Symptoms of Multiple myeloma

Pathophysiology of Multiple myeloma

CANCER

العوامل البيئية المسببة للسرطان

الأورام الصماوية للبنكرياس

متلازمة الأورام الغدية الصماوية المتعددة Multiple Endocrine Neoplasia (MEN) Syndrome

خصائص الخلايا السرطانية

Testicular germ cell tumours

Prostate carcinoma

Renal cell carcinoma

المسببات الكيميائية للسرطان chemical causes of cancer