Lymphoplasmacytic Lymphoma

Etiology

The etiology of lymphoplasmacytic lymphoma is poorly understood. However, the association of the disease with hepatitis C virus and autoimmune disorders has been documented. Treatment of patients with hepatitis C and lymphoplasmacytic lymphoma with antivirals is an effective management strategy. Up to 20% of lymphoplasmacytic lymphoma cases also report familial predisposition; these patients usually present at an earlier age and show a greater degree of bone marrow involvement. Several research groups are interested in the prognostic implications of the genetic susceptibility in lymphoplasmacytic lymphoma [1][4][3].

Epidemiology

Lymphoplasmacytic lymphoma is an extremely rare neoplasm with an annual incidence of 3 to 4 cases per million people. It represents approximately two percent of all hematologic malignancies. In the United States, there are 1000 to 1500 new cases per year. Lymphoplasmacytic lymphoma is a disease of elderly individuals in the seventh and eighth decade of life, with a slight male predominance. The disease is indolent, and most patients survive 7 to 8 years post-diagnosis. In rare cases, lymphoplasmacytic lymphoma can transform into an aggressive immunoblastic variant or other high-grade lymphomas.[4][3][5][3]

Pathophysiology

The malignant cells in lymphoplasmacytic lymphoma are believed to originate from cells at a late stage of B-cell differentiation. These cells derive from a B-cell arrest after somatic hypermutation in the germinal center and before terminal differentiation to a plasma cell. The pathological findings in lymphoplasmacytic lymphoma are due to infiltration of the bone marrow with small lymphocytes and IgM monoclonal gammopathy. Visual and neurological symptoms are related to hyperviscosity and sluggishness of blood flow. Bleeding encountered in Waldenstrom macroglobulinemia is due to IgM binding to the clotting factors. Cryoglobulinemia in Waldenstrom macroglobulinemia patients leads to Raynaud phenomena and cold urticaria.[4][2]

History and Physical

The diagnosis of lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia is usually challenging due to the lack of specific morphologic, immunophenotypic, or chromosomal changes. This lack makes the differentiation of this disease entity from other small B cell lymphomas based on exclusion. Symptoms can be classified into two categories: neoplasmic organ involvement and IgM paraprotein-related symptoms. Patients may present with B-related symptoms such as fever, night sweats, weight loss. Because of the frequent involvement of bone marrow, most lymphoplasmacytic lymphoma patients present with weakness and/or fatigue related to anemia. Some patients may present with the involvement of spleen, liver, and other extranodal sites, including skin, stomach, and bowel. As a rule, the diagnosis of lymphoplasmacytic lymphoma should be considered in elderly individuals with unexplained weakness, bleeding, neurological deficits, neuropathies, and visual difficulties [6][7][1][5][8].

The 2017 World Health Organization classification of tumors of hematopoietic and lymphoid tissues have established four diagnostic criteria for Waldenstrom macroglobulinemia, including[3]:

1. Presence of IgM monoclonal gammopathy
2. Infiltration of bone marrow by small lymphocytes showing plasmacytoid or plasma cell differentiation
3. Bone marrow infiltration showing an intertrabecular pattern
4. Immunophenotype supportive of Waldenstrom macroglobulinemia that including surface IgM+, CD19+, CD20+, CD22+, CD25+, CD27+, FMC7+, CD5 variable, CD10-, CD23-, CD103-, and CD108-

Most Waldenstrom macroglobulinemia patients have monoclonal IgM. A minority can have both IgM and IgG. Waldenstrom macroglobulinemia patients can present with hyperviscosity symptoms (30%), autoimmune hemolysis (20%), coagulopathy, and/or diarrhea. Symptoms related to hyperviscosity include visual impairment, neurologic symptoms (neuropathy), bleeding, new-onset headaches, blurred vision, and cryoglobulinemia leading to Raynaud phenomena and cold urticaria. The neuropathy is sensory and affects more the feet than hands in a bilaterally symmetric pattern. The autoimmune hemolysis is due to cold agglutinins (IgM antibodies that bind at less than 37 C) [6][7][8].

Evaluation

Lymphoplasmacytic lymphoma is diagnosed by identifying small malignant lymphocytes in the bone marrow that are usually admixed with plasma cells, plasmacytoid lymphocytes, and/or mast cells. The small malignant lymphocytes can be monocytoid, centroblastic, or immunoblastic. The bone marrow infiltration in those patients can be diffuse, interstitial, paratrabecular, or focal non-paratrabecular. Lymphoplasmacytic lymphoma involvement of the lymph nodes is associated with retained overall architecture, paracortical expansion with small lymphocytes, and dilated sinuses with periodic acid Schiff positive material. Other characteristics such as Dutcher bodies (periodic acid Schiff positive intranuclear pseudoinclusions), increased mast cells, and hemosiderin deposition may be helpful in making the diagnosis. Some cases may show amyloid or other immunoglobin deposition. The presence of large prominent cells should raise the suspicion of a diagnosis other than lymphoplasmacytic lymphoma. Overall, lymphoplasmacytic lymphoma evaluation in the bone marrow and lymph node is a diagnostic challenge due to the variability of presentation and the wide differential diagnosis related to plasmacytoid differentiation. These include marginal zone lymphoma, follicular lymphoma, small lymphocytic lymphoma/chronic lymphocytic leukemia, and mantle cell lymphoma [9][10][3].

Complete blood count in lymphoplasmacytic lymphoma usually shows variable degrees of cytopenias, with anemia and thrombocytopenia being common. Examination of the peripheral blood smear in lymphoplasmacytic lymphoma patients can show normochromic anemia and rouleau formation. On flow cytometry, lymphoplasmacytic lymphoma cells are surface IgM+, CD19+, CD20+, CD22+, CD25+, CD27+, FMC7+, CD5 variable, CD10-, CD23-, CD103-, and CD108-. Plasma cells are typically CD138-. Protein electrophoresis and immunofixation are usually required to assess the paraprotein in lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia serum. Assessment of serum viscosity can be helpful in making a diagnosis in some patients; levels commonly range between 4 to 8 cP [11][3].

Lymphoplasmacytic lymphoma usually shows immunoglobulin gene rearrangement and somatic hypermutation. Although no specific chromosomal abnormality has been reported in lymphoplasmacytic lymphoma, the presence of an MYD88 L265P mutation can favor diagnosis. However, this mutation is nonspecific and not necessary for the identification of the disease. This mutation has also been reported in nongerminal center subtype diffuse large B cell lymphoma (DLBCL), primary cutaneous DLBCL, leg type DLBCL, primary central nervous system DLBCL, and testicular DLBCL. Other genetic mutations that have been reported include ARID1A, TP53, CD79B, KMT2D, and MYBBP1A. The 2017 World Health Organization classification of tumors of hematopoietic and lymphoid tissues stressed that the presence of IgM paraprotein only is not diagnostic for either lymphoplasmacytic lymphoma or Waldenstrom macroglobulinemia because paraproteins may be present in other lymphoproliferative disorders and even some benign conditions [12][11][13][14].

In patients with suspected extramedullary disease (hepatosplenomegaly, lymphadenopathy), it is essential for CT scans to be with contrast. If it is confirmed, CT scans need to be used during and after treatment. [8]

Treatment / Management

Lymphoplasmacytic lymphoma management is similar to other indolent small B cell lymphomas. Asymptomatic patients are usually managed by close observation, and symptomatic patients are managed by single-agent rituximab therapy without maintenance. Treatment of Waldenstrom macroglobulinemia depends on the extent of end-organ involvement and symptoms. Asymptomatic patients are managed by close follow-up every 1 to 2 months including serial IgM measurements and assessment of serum viscosity. Symptomatic patients are managed by chemotherapy, immunotherapy, and/or an autologous bone marrow stem cell transplant. Chemotherapeutic agents that are effective in managing Waldenstrom macroglobulinemia include dexamethasone, fludarabine, bortezomib, and cyclophosphamide. A bone marrow transplant is usually reserved for younger patients with more extensive bone marrow involvement. Treatment algorithms for Waldenstrom macroglobulinemia recommend rituximab and bendamustine as a first-line treatment. In cases of failure or relapse less than 36 months, bortezomib and cyclophosphamide or ibrutinib should be considered. Third-line treatment for Waldenstrom macroglobulinemia can be either fludarabine, everolimus, or lenalidomide. Plasmapheresis is useful in managing hyperviscosity [15][16][17][4][18].

Differential Diagnosis

• Chronic lymphocytic leukemia/small lymphocytic lymphoma
• Mantle cell lymphoma
• Marginal zone lymphoma
• Plasma cell neoplasms
• Castleman disease
• Reactive plasmacytosis

Prognosis

The median survival of lymphoplasmacytic lymphoma patients is approximately five years. About 40% of patients survive for ten years or more. Typically, the cause of death is more due to advance age-associated comorbidities than WM. The International Prognostic Scoring System for WM includes five parameters, giving 1 point to each one, except for age, which receives 2 points. Parameters are: Advance age (Age >65), Hemoglobin ≤ 11.5 g/dl, Platelet count  ≤ 100 x10/L, Serum Bmicroglobulin >3 mg/L and serum monoclonal protein > 70 g/L. Score at the beginning of treatment classifies them into low risk (score ≤ 1), intermediate-risk (score 2), or high risk (score ≥ 3) with 5-year survival rates of 87,68 and 36%respectivley. Increased immunoblasts/transformed cells, deletion 6q, are considered independent adverse factors. The absence of an MYD88 L265P mutation is associated with an adverse outcome. Lymphoplasmacytic lymphoma may transform to diffuse large B-cell lymphoma (DLBCL) and is associated with poor survival.[7][16][4][19][20]