A Case of Splenic Marginal Zone Lymphoma Presenting with Hypercalcemia
Introduction/Background/Significance: Splenic marginal zone lymphoma (SMZL) is a rare subtype of non-Hodgkin lymphoma (NHL), representing < 1% of all NHLs. The annual incidence is approximately 0.13 per 100,000 individuals per year. Though it typically presents with an indolent course, approximately 5-10% of cases can transform to large B-cell lymphoma. SMZL typically presents with lymphocytosis, splenomegaly, and cytopenias; less commonly, it may present with hypercalcemia. We present a case of SMZL with hypercalcemia as the primary manifestation.
Materials and Methods/Case Presentation/Objective: An 81-year-old woman presented with progressive fatigue, weight loss, and abdominal pain. Laboratory testing revealed new-onset pancytopenia (hemoglobin 9.1 g/dL, platelets 55×109/L, WBC 2.9×109/L) and hypercalcemia (corrected calcium 12.5 mg/dL). Hypercalcemia workup demonstrated suppressed parathyroid hormone, normal parathyroid hormone-related protein, normal 25-hydroxyvitamin D, and mildly elevated 1,25-hydroxyvitamin D, suggestive of a possible paraneoplastic etiology. Serum electrophoresis showed a small IgM kappa monoclonal spike. Her hypercalcemia resolved with IV fluids, calcitonin, and zoledronic acid. An abdominal ultrasound revealed a spleen length of 18 cm, consistent with splenomegaly. Given these findings, a bone marrow biopsy was performed and demonstrated a low-grade B-cell lymphoproliferative disorder involving 70% of the marrow in an interstitial and nodular pattern, suspicious for SMZL versus lymphoplasmacytic lymphoma (LPL). Flow cytometry showed B-cells expressing CD19, CD20, CD22, CD38, and CD200 and no expression of CD5, CD10, CD23, CD11c, or CD103. B-cells had a monotypic expression of kappa light chains. Genetic testing was also negative for the MYD88 L265P alteration. These findings were consistent with stage IV SMZL. She was treated with rituximab, leading to resolution of symptoms with complete response on follow up PET imaging.
Results/Description/Main Outcome Measures: SMZL is a rare indolent B-cell lymphoma often presenting with cytopenias, lymphocytosis, and splenomegaly in older patients. In this case, hypercalcemia served as a key initial clue. Although rare, hypercalcemia may occur in SMZL due to unregulated, extrarenal synthesis of 1,25-dihydroxyvitamin D by lymphoma cells or by tumor-associated macrophages. When splenic biopsy is not feasible, SMZL can be distinguished from LPL with evaluation for the MYD88 L265P mutation, as this mutation is frequently seen in LPL but rare in SMZL. Bone marrow involvement in SMZL typically exhibits an interstitial and nodular pattern of small B-cells. The absence of lymphadenopathy further supports a diagnosis of SMZL. Rituximab monotherapy is the preferred first-line treatment and is generally well tolerated, with response rates exceeding 80%.
Conclusions: As noted in our case, while SMZL classically presents with splenomegaly, cytopenias, and lymphocytosis, it is important to recognize that metabolic abnormalities such as hypercalcemia may occasionally serve as the first sign of disease. Though typically indolent, identification is critical, as SMZL has the potential for transformation. Rituximab monotherapy remains the standard initial treatment and offers excellent outcomes in most patients.
