Waldenström's Macroglobulinaemia

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Diagnosis and reasoning

This middle aged lady has presented with an ominous collection of symptoms: upper abdominal pain, extensive weight loss, new-onset easy bruising, and constitutional symptoms, all of which developed within a period of 3 weeks. Her examination is even more alarming, revealing the presence of pallor, generalized lymphadenopathy, and hepatosplenomagaly. Note that the above collection of clinical findings is strongly suggestive of a hematological malignancy; key concerns include lymphoma, chronic leukemia, and multiple myeloma and other monoclonal gammopathies. A complete blood count and peripheral smear are essential first-line investigations; the former reveals the presence of anemia and thrombocytopenia, with a lymphocyte predominant leukocytosis; the latter shows rouleaux formation with atypical lymphocytes and plasmacytoid cells. Note that the above findings allow us to considerably narrow down the possibilities, with Non-Hodgkin's Lymphoma (NHL), chronic lymphocytic leukemia (CLL), and the monoclonal gammopathies remaining the most likely differentials. Given the possibilities listed above, serum protein electrophoresis (SPE) and a bone marrow (BM) aspiration and trephine biopsy are probably the next best steps. Note that SPE reveals the presence of an IgM spike, with immunofixation further clarifying this to be a monoclonal band fixing anti-IgM and anti-kappa; in other words, an IgM paraprotenemia is present. BM studies demonstrate a population of small atypical lymphocytes which are positive for CD19, CD20, CD79b and cytoplasmic kappa, and negative for CD5, CD10, CD38 and CD138; this immunophenotype favors a mature B-cell neoplasm, with the morphology being suggestive of a lymphoplasmacytoid lymphoma. Note that when considered together, the above picture is that of a lymphoplasmacytoid lymphoma with bone marrow involvement and IgM paraproteinemia; this fits the profile of Waldenstrom's Macroglobulinemia (WM), a rare neoplasm involving B-cells. Symptomatic WM mandates immediate treatment; the monoclonal antibody Rituximab, and cytotoxic drug cyclophosphamide are first line pharmacological agents in this regard. Allogenic stem cell transplantation is a salvage therapy used in patients who develop primary or secondary resistance to pharmacotherapy, and is not indicated immediately; plasmapheresis would have been indicated if hyperviscosity syndrome were present.


Discussion

Waldenstrom's Macroglobulinaemia (WM) is a chronic, indolent, lymphoproliferative disorder characterized by the presence of high concentrations of Immunoglobulin M (IgM), elevated serum viscosity, and a lymphoplasmacytic infiltrate in the bone marrow. The condition can be considered a type of non-Hodgkin lymphoma (NHL); it is also classified as a malignant monoclonal gammopathy. Note that the World Health Organization (WHO) classification and Revised European American Lymphoma Classification (REAL) specifically define WM as a lymphoplasmacytic lymphoma due to clonal disease of B-lymphocytes. WM is relatively rare, with only 1500 cases diagnosed each year in United States; it accounts for approximately 2% of all hematological malignancies. The disease mainly affects the elderly, with a median age of diagnosis of 65 years, and a slight male predominance. No definite etiological agent has been identified; however, environmental, genetic and viral factors are known to be associated with the condition. Note also that IgM monoclonal gammopathies of undetermined significance (MGUS) are considered to be precursors of WM, with a reported 20% of such individuals developing non-Hodgkin lymphoma or multiple myeloma within a period of 20 years. The clinical manifestations of WM result from 2 important factors: secretion of IgM paraprotein, and neoplastic lymphoplasmacytic cell infiltration. The IgM paraprotenima gives rise to hyperviscosity syndrome, type 1 and type 2 cryoglobulinemia, coagulation abnormalities, sensorimotor peripheral neuropathy, cold agglutinin disease, primary amyloidosis, anemia, and deposition of amorphous IgM in the skin, gastrointestinal tract and other organs. The neoplastic cells infiltrate the bone marrow, spleen, lymph nodes, and less commonly, the liver, lungs, gastrointestinal tract, kidneys, skin, eyes and central nervous system, giving rise to numerous clinical signs and symptoms. As the onset of WM is insidious, most patients are detected incidentally, while still asymptomatic; in those who present with symptoms, lethargy, anorexia and weight loss are most frequently seen. Fever, peripheral neuropathy and Raynaud phenomenon due to cryoglobulinemia are less common findings; individuals who develop hyperviscosity syndrome may demonstrate bleeding, dizziness, headache, blurred vision, and visual or hearing problems. Mental state changes such as lethargy, stupor and even coma may also be observed, while central nervous system infiltration by the malignant clone may result in a syndrome of confusion, memory loss, disorientation and motor abnormalities; this is termed Bing-Neel syndrome. Note also that WM is typically associated with a slowly progressive, distal, symmetrical, sensory-motor neuropathy; however, chronic ataxic neuropathy, and POEMS syndrome (Polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes) are also reported to occur in association with the disease. The characteristic examination findings of WM are due to tissue infiltration by the malignant clonal cells, hyperviscosity caused by antigen-antibody reactions, and homeostatic derangement by the paraprotein. Hepatosplenomegaly and lymphadenopathy are commonly present, while hemorrhages are not uncommon. Ophthalmological signs include papilledema, distended veins and hemorrhages. Dermatological manifestations include purpura, papules on the extremities, cutaneous plaques and nodules, bullous skin disease, chronic urticaria, Raynaud phenomenon, livedo reticularis, and acrocyanosis. Pulmonary involvement is rare (occurring in only 3% to 5% of patients), while congestive heart failure is unusual. The diagnosis of WM is based on identification of malignant cells in bone marrow aspirate and biopsy, and demonstration of a significant monoclonal IgM spike. A complete blood count and peripheral smear are essential first line investigations; these typically reveal normochromic normocytic anemia, leukopenia, thrombocytosis, plasmacytoid lymphocytes, and rouleaux formation. Urine immunoelectrophoresis may demonstrate light chains of the kappa type in approximately 40% of patients; at times this may exceed 1g/day. Serum electrophoresis will reveal a monoclonal spike, but cannot confirm this to be IgM in nature; however, immunoelectrophoresis and immunofixation are capable of identifying and quantifying the monoclonal paraprotein. Bone marrow aspiration and biopsy are key for confirmation of the diagnosis; these will demonstrate infiltration of the bone marrow by lymphocytes showing plasmacytic differentiation which is either diffuse or interstitial; periodic acid-Schiff (PAS) staining will also be positive, due to extravasation of IgM light chains. Flow cytometry should also be performed on plasma cells in either the bone marrow or peripheral blood. This will reveal surface expression of IgM and B-cell differentiation markers such as the IgM+ CD5-, CD10-, CD19+, CD20+, or CD23- immunophenotypes. Note also that in patients presenting with neuropathy, nerve conduction studies and antimyelin-associated glycoprotein serology is often recommended. Asymptomatic individuals with WM do not require specific treatment; careful observation with periodic monitoring of immunoglobulin M components, and serum viscosity is adequate. Indications for active management include clinical evidence of adverse effects of the paraprotein, late stage disease, or development of constitutional symptoms. In such individuals, the two key goals of management are treatment of the disease itself, and treatment of complications of the paraproteinemia. Most current treatment regimens combine the monoclonal antibody rituximab with chemotherapeutic drugs such as cyclophosphamide, chlorambucil, vincristine or thalidomide; corticosteroids such as prednisone are an alternative to the latter. Other novel agents which show promising results for targeted therapy of WM include bortezomib, perifosine, atacicept, oblimersen sodium, and tositumomab. In patients who develop primary or secondary resistance to treatment, salvage therapy, including allogenic stem cell transplantation should be considered. Individuals with hyperviscosity syndrome should be treated with plasmapheresis, which removes the paraproteins; note that this does not treat the underlying disease. Across all ages, the 5 year survival rate of WM is approximately 70%; factors associated with a worse prognosis include age >65 years, hemoglobin levels <10 g/dL, albumin levels <4.0 g/dl, and elevated beta-2 micro globulin levels. Note also that patients with a nodular type of bone marrow involvement show a better prognosis as compared to those with diffuse involvement.


Take home messages

  1. Waldenstrom's Macroglobulinemia (WM) is a lymphoplasmacytic lymphoma secondary to clonal disease of B-lymphocytes.2. WM has an indolent presentation; many patients are diagnosed incidentally, while still asymptomatic.
  2. The diagnosis of WM requires identification of malignant plasma cells in the bone marrow aspirate and biopsy, and demonstration of a significant monoclonal IgM spike.4. The management of WM depends on whether the patient is symptomatic or asymptomatic; the latter only require periodic monitoring, while the former should receive chemotherapy..

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