Don't Miss the Dx: A Patient With Weight Loss, Fatigue, Splenomegaly, and Anemia

Maurie Markman, MD


September 19, 2023

An otherwise healthy, 66-year-old White man reports being fatigued and weak for several weeks. Although he is slightly overweight, he states that he has been losing weight but hasn't changed his diet. He reports that he has lost about 10 lb in the past 3 months. He has also been noticing that his bedsheets have been soaked with sweat most mornings over the past month or so.

Physical examination reveals splenomegaly and pallor. Laboratory results indicate that the patient is anemic (hemoglobin, 11.3 g/dL), but his absolute neutrophil count (3000 cells/µL) and platelet count (157,000 cells/µL) are normal. His lactate dehydrogenase level is 313 U/mL; serum albumin is 3.4 g/dL; and beta-2 microglobulin is 3.36 mg/dL. Viral serology is negative for hepatitis B and C and HIV.

Further Evaluation

Peripheral blood smear shows normochromic anemia and rouleau formation. Flow cytometry identifies lymphoplasmacytic lymphoma cells that are surface IgM+, CD19+, CD20+, CD22+, CD25+, CD27+, FMC7+, CD5 variable, CD10-, CD23-, CD103-, and CD108-. A bone marrow biopsy shows infiltration by clonal lymphoplasmacytic cells, and immunofixation electrophoresis detects monoclonal IgM.

Differential Diagnoses

Several potential diagnoses should be considered. For example, iron deficiency should be investigated as a possible cause of anemia. The presentation is nonspecific; thus, consideration should be given to lymphomas and myeloma.

Multiple myeloma is a cancer of plasma cells resulting in monoclonal plasma cell proliferation in the bone marrow and an overabundance of monoclonal paraprotein (M protein), bone destruction, and displacement of other hematopoietic cell lines. Bone pain with lytic lesions, weakness, anemia, infection, hypercalcemia, spinal cord compression and renal failure are presenting signs and symptoms. Diagnostic criteria include clonal bone marrow plasma cells ≥ 10% or biopsy-proven bony or extramedullary plasmacytoma and one or more myeloma-defining events.

Mantle cell lymphoma is a lymphoproliferative disorder of the naive pregerminal center cells in the primary follicles or in the mantle region of secondary follicles. B symptoms, generalized lymphadenopathy, abdominal distention from hepatosplenomegaly, and fatigue from anemia or bulky disease are presenting signs and symptoms. Diagnosis is based on immunophenotyping monoclonal B cells that express surface Ig, IgM, or IgD; these cells are CD5+ and pan B-cell antigen positive but lack CD10 and CD23 expression, and cyclin D1 is overexpressed.

Follicular lymphoma is a type of non-Hodgkin lymphoma presenting most commonly as a painless, slowly progressive adenopathy. Fever, drenching night sweats, or weight loss in excess of 10% of ideal body weight or asthenia are systemic symptoms that arise during the later stages of cancer. Symptoms related to bone marrow dysfunction are rare at presentation.

Chronic lymphocytic leukemia /small lymphocytic lymphoma is an indolent monoclonal cancer that is characterized by progressive proliferation of mature yet functionally incompetent lymphocytes. Enlarged lymph nodes, liver, or spleen; recurrent infections; loss of appetite or early satiety; abnormal bruising; fatigue; and night sweats are presenting signs and symptoms. Diagnosis is based on higher-than-normal B lymphocyte count (> 5000 monoclonal lymphocytes/µL) for at least 3 months.

Waldenström macroglobulinemia should be considered when an older patient presents with unexplained weakness, bleeding, neurologic deficits, neuropathies, and visual difficulties. Waldenström macroglobulinemia is an indolent, malignant monoclonal gammopathy, characterized by a high IgM level, elevated serum viscosity, and the presence of lymphoplasmacytic infiltrate of the bone marrow.


As a slow-growing variant of lymphoplasmacytic lymphoma, Waldenström macroglobulinemia is usually diagnosed on the basis of exclusion of all other small B-cell lymphomas. The patient presented with B-related symptoms, including night sweats and weight loss, and also with fatigue and weakness due to anemia. Histopathologic confirmation of bone marrow infiltration by clonal lymphoplasmacytic cells and immunofixation electrophoresis to detect monoclonal IgM are required. Organomegaly is common in Waldenström macroglobulinemia but uncommon in multiple myeloma, whereas lytic bony disease and renal disease are uncommon in Waldenström macroglobulinemia but common in multiple myeloma.

Specifically, the World Health Organization diagnostic criteria require:

  • Neoplasm of small B lymphocytes, plasmacytoid lymphocytes, and plasma cells

  • Usually involving bone marrow and sometimes lymph nodes and spleen

  • Does not fulfill criteria of any other small B-cell lymphoid neoplasm that may also have plasmocytic differentiation

  • Lymphoplasmacytic lymphoma with bone marrow involvement and IgM monoclonal gammopathy of any concentration


Treatment for Waldenström macroglobulinemia should be initiated if patients are symptomatic, including hyperviscosity, neuropathy, symptomatic adenopathy or organomegaly, amyloidosis, cryoglobulinemia, cold agglutinin disease, anemia, and cytopenia. A high IgM level is not necessarily an indication for the initiation of therapy in the absence of other symptoms, and exclusion of other causes for these symptoms is necessary.

The National Comprehensive Cancer Network recommends ibrutinib with or without rituximab, zanubrutinib, or bendamustine plus rituximab as primary treatment. If the patient has symptomatic hyperviscosity, plasmapheresis is recommended prior to systemic therapy.


Patients with Waldenström macroglobulinemia have a median survival of approximately 78 months, which is dependent on the patient's risk assessment. The factors in Table 1 are included in that assessment.

Table 1. Prognostic Scoring System in Waldenström Macroglobulinemia
Parameter Points
≤ 65 y 0
66-75 y 1
≥ 76 y 2
Beta-2 microglobulin > 4 mg/L 1
Lactate dehydrogenase ≥ 250 IU/L (ULN < 225 IU/L) 1
Serum albumin < 3.5 g/dL 1
ULN = upper limit of normal

Risk groups are defined on the basis of the sum of the points (Table 2).

Table 2. Disease Stage and Death Rates Based on Prognostic Score
Total Score Stage 3-Year Death Rate (%)
0 Very low 0
1 Low 10
2 Intermediate 14
3 High 38
4-5 Very high 48

Clinical Takeaway

  • For patients who present with unexplained fatigue and weakness, neurologic symptoms, unexplained bleeding, visual blurring, and neuropathies, reaching a timely diagnosis of Waldenström macroglobulinemia is important so that symptomatic patients can be monitored for hyperviscosity syndrome, which can be life threatening.

  • Evolving therapeutics and guidance for patients with Waldenström macroglobulinemia focus on providing symptom relief and reduce the risk for organ damage, so timely diagnosis and treatment are important.


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