Beyond Hypersplenism: Splenic Marginal Zone Lymphoma in an Older Adult with Hemoglobin E/Beta-Thalassemia

Abstract

With improvements in blood safety and availability, along with broad access to safe and effective iron chelation, outcomes for patients with thalassemia have greatly improved over recent decades. Previously a predominantly pediatric condition, thalassemia is now increasingly encountered in an aging population. We describe an adult man with HbE/β-thalassemia whose course was complicated by progressive splenomegaly and cytopenias, initially attributed to his underlying thalassemia. Further evaluation, however, revealed splenic marginal zone lymphoma. After the initiation of anti-B-cell therapy, he experienced rapid clinical improvement and was able to avoid surgical splenectomy. This case highlights how complications ascribed to thalassemia can overlap with other diagnoses that may become more prevalent with age, and demonstrates the importance of maintaining a broad differential when symptoms progress despite appropriate thalassemia-directed management.

Introduction

Splenomegaly is a common clinical finding in transfusion-dependent thalassemia, frequently attributed to extramedullary hematopoiesis and ineffective erythropoiesis. In older patients with thalassemia, progressive cytopenias are also often attributed to hypersplenism. However, these features are not pathognomonic and may obscure other serious etiologies, including hematologic malignancy. Here, we describe a patient with splenic marginal zone lymphoma (SMZL) diagnosed during preoperative evaluation for presumed hypersplenism in an adult with HbE/β-thalassemia, highlighting the need for diagnostic reevaluation when clinical trajectories deviate unexpectedly.

Case presentation

A 62-year-old man with transfusion-dependent HbE/β-thalassemia presented to clinic with worsening fatigue and anemia. Prior to his initial presentation to our comprehensive thalassemia center, he was not regularly transfused and was diagnosed with non-transfusion-dependent thalassemia. Since establishing care at our center in 2022, he had been maintained on a transfusion regimen targeting pre-transfusion hemoglobin levels of 9.5–10 g/dL in response to symptomatic anemia, splenomegaly, and cardiopulmonary disease. Over the preceding year, however, his pre-transfusion hemoglobin declined to 7.5–8.5 g/dL despite intensified transfusions. Although he had previously achieved excellent performance status with regular transfusions, swimming and traveling regularly, in the year prior to presentation he developed a marked decline in exercise tolerance, prompting further workup.

His medical history included iron overload with rising liver iron content (LIC: 8.5 to 12.4 mg Fe/g dry weight over one year), pulmonary hypertension, and atrial fibrillation. His medications included deferasirox 18 mg/kg daily, folic acid, levothyroxine, allopurinol, and vitamin B12. Laboratory testing revealed a white blood cell count of 15.0 K/μL (with an elevated absolute lymphocyte count of 7.5 K/μL), hemoglobin 8.2 g/dL, platelets 59 K/μL, reticulocyte count 3.7%, and ferritin 759 ng/mL. Liver and renal function were normal.

Magnetic resonance imaging (MRI) showed massive splenomegaly (27 cm craniocaudal) without discrete lesions (Figure 1A). On retrospective review, spleen size had progressively increased from a baseline of 23 cm over the past 5 years. Spine MRI demonstrated paravertebral soft tissue masses consistent with extramedullary hematopoiesis. Trials of hydroxyurea resulted in transient improvement in hemoglobin but worsened thrombocytopenia. Luspatercept was ineffective. Increasing his transfusion frequency to biweekly yielded minimal clinical benefit.

Figure 1.

Radiologic and morphologic features at presentation. (A) Abdominal MRI demonstrating massive splenomegaly. (B) Peripheral blood smear. Red arrow: a lymphocyte with atypical projections. (C) Magnified visualization of abnormal peripheral lymphocytes demonstrating irregular nuclear morphology and cytoplasmic projections (villous lymphocytes).

Given worsening cytopenias and progressive splenomegaly, splenectomy was pursued for presumed hypersplenism. However, the preoperative peripheral smear revealed atypical lymphocytes, prompting further evaluation (Figure 1B).

Diagnostic evaluation

Flow cytometry revealed a CD19⁺, CD5⁻, CD10⁻ lambda-restricted B-cell population. Bone marrow biopsy demonstrated hypercellularity (>95%) with erythroid predominance and 10% involvement by the same clonal B-cell population. There was markedly increased erythroid production with orderly maturation, with occasional cytologic atypia (irregular nuclear contours and megaloblastic changes). Myeloid elements and megakaryocytes did not show significant cytologic atypia. Immunostains performed on the biopsy for CD20, PAX5, CD3, CD5, CD34, myeloperoxidase, E-cadherin, glycophorin, and p53 confirmed the presence of scattered and small clusters of B cells accounting for <10% of marrow cellularity, without lymphoid aggregates. Molecular testing was negative for variants in the MYD88 p.L260 (p.L265) locus. Cytogenetics revealed t(9;14)(p13;q32) and gain of chromosome 3. Serum protein electrophoresis with immunofixation revealed an IgM kappa monoclonal band. PET-CT was unrevealing aside from the previously noted splenomegaly, with no FDG-avid lesions. Viral serologies, including hepatitis B and C, were negative. Workup for autoimmune etiologies was negative.

Taken together, these findings support a diagnosis of splenic marginal zone lymphoma (SMZL), a low-grade, indolent B-cell lymphoma that commonly presents with splenomegaly, with or without bone marrow and/or peripheral blood involvement [1]. Lymph node involvement is less common in SMZL but may occur as a later-stage manifestation.

Management and outcome

Given the SMZL diagnosis, splenectomy was deferred in favor of medical therapy. Because his splenomegaly was felt to be attributable in part to his new lymphoma diagnosis, a trial of rituximab was pursued instead of upfront surgery, in line with contemporary guidelines. The patient began treatment with rituximab monotherapy (6 cycles). He reported marked clinical improvement, with restored energy levels. Hemoglobin improved, and platelet counts stabilized (Figure 2). Follow-up ultrasound demonstrated a significant decrease in spleen size from 27 cm to 21 cm. Maintenance rituximab therapy is planned every two months for at least two years. As of his most recent visit, he has resumed his former level of physical activity and travel, and his transfusion needs have dramatically decreased to 2 units of packed red blood cells every 3 weeks, maintaining pre-transfusion hemoglobin levels of >9.5–10 g/dL.

Figure 2.

Serial hematologic parameters prior to and following rituximab. Hemoglobin (Hgb), white blood cell count (WBC), platelet count (PLT), and absolute lymphocyte count (ALC) over the course of one year. The initiation of rituximab is demarcated with a red dashed line.

Discussion

The association between hepatocellular carcinoma and thalassemia is well established and largely driven by risk factors such as hepatitis C virus (HCV) infection and chronic iron overload, particularly in transfusion-dependent individuals [2–4]. However, historically, evidence on other forms of neoplasia in thalassemia has been less robust. In recent years, the association between thalassemia and hematologic malignancies has become increasingly recognized as patients live longer due to advances in transfusion and iron chelation therapy. A 2015 review noted that patients with thalassemia may have an elevated risk of malignancy, especially lymphomas and leukemias, with a reported 9.31-fold higher risk of hematologic malignancies among transfusion-dependent patients compared to their non-transfusion-dependent counterparts [5]. By contrast, a more recent large Italian retrospective cohort of 4,631 patients with hemoglobinopathies found the incidence of leukemias and lymphomas comparable to that of the general population [6]. Differences across studies likely reflect heterogeneity in patient populations and changes in comorbidities and survival outcomes over time, and may also reflect survivorship bias. Regardless, these data collectively suggest that while the absolute risk may not be substantially higher, malignancies do occur in this population and should not be overlooked, particularly since the number of older adults with thalassemia is rising. With age, people with thalassemia may have cancer risks that mirror those of the general population.

Since 1979, case reports have described lymphomas arising in both thalassemia major and intermedia, including diffuse large B-cell lymphoma and Hodgkin disease [7–10]. These reports typically described systemic symptoms or lymphadenopathy, in contrast to our case of isolated hypersplenism. To date, no cases of splenic marginal zone lymphoma have been reported in thalassemia. Our report is the first documented case of SMZL in a transfusion-dependent thalassemia patient and the oldest reported age at diagnosis of any indolent lymphoma among thalassemia patients. This case is significant for its close mimicry of hypersplenism, a common complication in thalassemia, and supports maintaining a broad differential diagnosis that includes lymphoproliferative disorders, especially when clinical features change or are not fully explained by thalassemia.

SMZL is a rare but indolent B-cell lymphoma that primarily involves the spleen and can also involve the bone marrow and peripheral blood, with or without lymphadenopathy. Diagnosis is supported by clinical presentation, histopathology, flow cytometry, and cytogenetic analysis [1]. Management of SMZL depends on the underlying etiology and clinical presentation. In individuals with HCV, antiviral treatment alone can lead to remission of SMZL, often eliminating the need for additional medical or surgical intervention. In HCV-negative individuals who are symptomatic or have significant cytopenias, first-line therapy typically involves rituximab monotherapy followed by maintenance, which yields excellent outcomes [11,12]. Splenectomy is typically reserved for lymphoma refractory to multiple lines of treatment. In thalassemia, where splenomegaly and cytopenias are often attributed to hypersplenism, the presentation of SMZL can be deceptively similar, complicating timely diagnosis. Although splenectomy is rarely indicated in thalassemia, it remains a last-resort treatment for refractory hypersplenism. In our case, a thorough preoperative workup led to the correct diagnosis, resulting in effective treatment with rituximab and obviating the need for surgical splenectomy, which would have posed a heightened risk given his pulmonary hypertension and atrial fibrillation.

Advances in thalassemia therapies (e.g. blood transfusions and iron chelators) and the growing availability of novel therapeutics have improved survival among the patient population. Once considered a pediatric disease, thalassemia (if well managed) now allows survival well into adulthood. As the demographics and ages of the thalassemia patient population evolve, clinicians must maintain a high index of suspicion for malignancies, particularly when symptoms or blood counts change. Timely recognition of alternative causes of clinical changes can prevent unnecessary procedures and enable targeted therapy with dramatic clinical benefit.

Conclusion

In adults with thalassemia, progressive anemia and splenomegaly should not be reflexively attributed to disease progression or hypersplenism. Malignancy, especially indolent lymphomas such as SMZL, must be considered, particularly in older patients, when the transfusion burden increases without a clear explanation or when hypersplenism does not improve with standard medical management, such as intensified transfusion therapy. Diagnostic evaluation should include a careful review of the peripheral smear, flow cytometry if leukocytosis is present, and consideration of bone marrow biopsy and/or diagnostic imaging studies. Early recognition of hematologic malignancy may redirect management and lead to improved outcomes with non-surgical approaches.