Introduction
As a secondary lymphoid organ, the spleen is a common site of lymphoma dissemination and can be involved with any lymphoid malignancy; however, splenomegaly as the predominant presenting symptom is relatively uncommon. Several lymphoma subtypes may present with isolated splenomegaly, including diffuse large B-cell lymphoma, mantle cell lymphoma, hairy cell leukemia, splenic marginal zone lymphoma, prolymphocytic leukemia, chronic lymphocytic leukemia, and Waldenström macroglobulinemia. Establishing a correct histologic diagnosis is critical, since patient management is largely determined by histology.
Presentation and Initial Evaluation
Isolated presentation with splenomegaly is more common in indolent lymphoma than in aggressive lymphoma. Many patients seek medical attention because of progressive discomfort in the left upper quadrant and/or early satiety. When we see a patient, our initial focus is on determining urgency of diagnosis and treatment. The history, focusing on symptom duration and severity, along with a focused exam assessing for hemodynamic abnormalities, signs of marrow failure, and size of spleen/presence of symptoms of rupture, can help identify patients who may need admission for expedited evaluation.
Initial laboratory assessment should include a complete blood cell count and differential; basic metabolic panel; liver function tests; calcium, uric acid, lactate dehydrogenase, and β2 microglobulin levels; serum protein electrophoresis with immunofixation; and hepatitis B and C serology. Diagnostic-quality CT scans of the chest, abdomen, and pelvis to stage disease and assess for other areas of involvement should be performed. Fluorodeoxyglucose positron emission tomography (FDG-PET) imaging is adjunctive but optional in these cases. PET imaging is superior for detecting extranodal involvement, but most splenic lymphomas are derived from indolent lymphomas, in which FDG avidity is variable.
Many splenic lymphomas have a tropism for the bone marrow and a high likelihood of producing circulating malignant cells. Thus, evaluation of the peripheral blood with the assistance of a skilled hematopathologist may lead very rapidly to a diagnosis based on a combination of morphologic assessment and flow cytometry immunophenotyping of circulating lymphocytes. A bone marrow biopsy may be required to establish the diagnosis and will complete the staging evaluation. The marrow should be sent for immunophenotyping (if not obtained from peripheral blood), and part of the sample should be allocated for possible molecular studies (eg, chronic lymphocytic leukemia fluorescence in situ hybridization [FISH] panel).
Patients without detectable blood or bone marrow involvement but continued suspicion of splenic lymphoma represent a difficult diagnostic dilemma. Splenectomy should be discussed with the patient, as it can have the dual benefit of establishing the diagnosis while simultaneously providing therapeutic benefit. Patients should be cautioned about the infectious risks of splenectomy and should be immunized appropriately prior to proceeding with the procedure. Patients with splenomegaly due to macroscopic splenic nodules can be considered for core needle biopsy. Despite previous concerns about bleeding, a recent meta-analysis showed a major complication rate of only 1.3% when needles smaller than 18 gauge were utilized.[1-4] In cases of diffuse splenic infiltration, we prefer splenectomy over core needle biopsies, as the former is more likely to establish the diagnosis while simultaneously providing initial therapy.
Specific Diagnoses
A summary of all the entities that can present primarily as splenomegaly is beyond the scope of this piece. Therefore, we will focus on the diagnosis of the most common entities, as well as a more extensive discussion of splenic marginal zone lymphoma, hairy cell lymphoma, and hepatosplenic γδ T-cell lymphoma, which are rare entities more inclined to this particular presentation.
Two CD5+/CD10– B-cell lymphomas-chronic lymphocytic leukemia/small lymphocytic lymphoma and mantle cell lymphoma-can present with primary splenomegaly with or without lymphadenopathy and circulating cells. They can be distinguished on the basis of CD23 and cyclin D1 expression: CD23 positivity is seen in chronic lymphocytic leukemia, but not in mantle cell lymphoma, and the opposite pattern is seen for overexpression of cyclin D1. Differentiating between the two entities is crucial; although both diseases may have a minimally symptomatic period during which “watch and wait” is appropriate, mantle cell lymphoma is known to have a more aggressive course, leading us to favor more aggressive types of immunochemotherapy in these patients and early autologous transplant in those who are younger.
Waldenström macroglobulinemia typically presents with anemia and fatigue and is usually suspected based on serology showing an immunoglobulin M monoclonal gammopathy. Still, occasionally splenomegaly will be the sentinel symptom leading to diagnosis. Immunophenotype, although not typically pathognomonic, includes positivity for CD19, CD20, and surface immunoglobulin. CD5, CD10, and CD23 are typically negative, but CD5 expression is seen in a significant minority (5% to 20%).[5]
B-cell prolymphocytic leukemia is another rare lymphoma that can cause an aggressive presentation with predominant splenomegaly, although most cases will also feature large numbers of circulating lymphocytes. T-cell prolymphocytic leukemia, on the other hand, essentially always features lymphocytosis. Typically, cells express B-cell antigens such as CD20 and CD22 strongly, as well as expressing surface immunoglobulin, with the strength of CD20 being markedly more intense than in chronic lymphocytic leukemia. FMC7 and CD11c are typically positive; CD5 is only positive in 30% of cases.[6] The disease is clinically, and likely genetically, heterogeneous, with more extensive immunophenotype, revealing some cases clustering with mantle cell lymphoma, and others closer to chronic lymphocytic leukemia. A benign initial presentation may occur, similar to that seen in chronic lymphocytic leukemia, but once the disease becomes symptomatic in the older population, where it is prevalent, average survival is 3 to 5 years even with therapy.[6] In rare circumstances when we see younger, fit patients with the disorder, we favor chronic lymphocytic leukemia–like regimens such as FCR (fludarabine, cyclophosphamide, rituximab) or bendamustine-rituximab, and we consider referral for allogeneic transplantation. In older patients who cannot tolerate systemic therapy, splenic irradiation or splenectomy can provide palliation.[6]
Hairy cell leukemia is an indolent B-cell lymphoma that typically presents in older men, with splenomegaly, monocytopenia, and circulating cells; the disease has a distinctive immunophenotype, showing CD11c, CD103, CD123, CD25, and bright CD20.[8] Pentostatin and cladribine have both been used as therapy for hairy cell leukemia, with excellent results. We typically favor the 7-day continuous infusion therapy at 0.1 mg/kg/day over the intermittent 5-day dosing schedule, although both show excellent efficacy and tolerability.[9-10] Relapses are typically managed by repeating the original regimen with or without rituximab, given the greater than 50% durable response rate at relapse, and the fact that most second remissions are durable.[9]
Key Points in the Management of Splenic Lymphomas Presenting as Splenomegaly
- Multiple subtypes of lymphoma can present as isolated splenomegaly, but treatment remains specific to histology.
- Analysis of peripheral blood and marrow should be undertaken to establish the diagnosis.
- In cases where tissue diagnosis must be made from the spleen, we favor splenectomy, given the simultaneous benefit of establishing the diagnosis and providing effective therapy.
- Single-agent rituximab is uniquely active in splenic marginal zone lymphoma and can be used in lieu of splenectomy in some cases, particularly in patients who are poor surgical candidates or patients with significant disease burden outside the spleen.
Splenic marginal zone lymphoma is an indolent B-cell lymphoproliferative disorder, typically involving the circulating blood, spleen, and bone marrow, which represents about 20% of marginal zone lymphoma cases.[11] Like other marginal zone lymphomas, this malignancy is CD5–/CD10–, with CD20 expression and few distinctive immunophenotypic markers, leading to a need for bone marrow biopsy and FISH for clear diagnosis. Patients typically present with cytopenias and splenomegaly with circulating villous lymphocytes.[12] Splenic marginal zone lymphoma can be associated with hepatitis C infection, and regression of splenic marginal zone lymphoma after successful hepatitis C treatment has been reported.[13,14] For the majority of splenic marginal zone lymphoma patients who are not hepatitis C–positive, single-agent rituximab and splenectomy both have excellent rates of disease control, with a median progression-free survival of more than 5 years and an overall survival of greater than 75% at 5 years.[11,15,16] Choosing between splenectomy and rituximab can be difficult, however. Certainly, patients with substantial disease burden outside the spleen are best served with systemic therapy, but for patients with disease mostly confined to the spleen, we tend to favor splenectomy as initial therapy in younger patients (preserving rituximab for later in the disease course) and favor rituximab for elderly patients who may not tolerate surgery as well.
Hepatosplenic γδ T-cell lymphoma is a very rare histology, accounting for only 3% of newly diagnosed T-cell lymphomas. Notably, even though hepatosplenic γδ T-cell lymphoma frequently has circulating malignant cells, these may be missed on immunophenotype, as they are CD4–/CD8– T cells, which may lack the αβ T-cell receptor. Cells typically express T-cell markers CD2 and CD3, and CD38, while CD5 is only positive in a minority of cases.[17] The condition is associated with inflammatory bowel disease and most commonly occurs in men in their 30s. Generally, patients present with significant symptoms, including hepatosplenomegaly, cytopenias, and fever.[17,18] Primary chemoresistance is common, and median overall survival in this entity is dismal. We tend to follow the Memorial Sloan Kettering Cancer Center protocol with ifosfamide-based induction followed by autologous transplant consolidation, which is the only reported regimen to yield long-term survival in more than 50% of patients.[19] Given the rarity and mortality of hepatosplenic γδ T-cell lymphoma, for patients who are fit and willing to travel, referral to a center with experience in treating this entity and trial options is advisable.
Financial Disclosure:Dr. Kahl consults for Genentech/Roche. Dr. Hall has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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