Splenic lymphomas are a diverse group of lymphoid malignancies that have clinical behavior ranging from indolent to aggressive and that have both B-cell and T-cell histologies. Several groups have focused on the description and taxonomy of these rare diseases. Splenic lymphoma with villous lymphocytes was first categorized in 1987 by Melo et al after reviewing 22 patients with disease characteristics distinct from those of hairy cell leukemia or chronic lymphocytic leukemia. Schmid et al refined the diagnosis, renaming it splenic marginal zone lymphoma (SMZL) in 1992. Since then, numerous series have been published, with each report building on earlier findings, revising diagnostic criteria, and often indicating the potential for heterogeneity among the tumors included in earlier studies. Revised most recently in 2008,[3,4] diagnostic criteria for SMZL recommend incorporating morphology, histology, immunophenotype, and cytogenetic information along with clinical data. In this issue of ONCOLOGY, Thieblemont et al point out that it can nonetheless be challenging to differentiate some cases of SMZL from other indolent small B-cell lymphomas.
In ambiguous cases, an important decision is whether or not to proceed with a diagnostic splenectomy. Although the gold standard for diagnosis is evaluation of spleen histology, splenectomy is infrequently worthwhile as a purely diagnostic procedure. Since many splenic lymphomas can mimic the histology of SMZL, examination of the spleen will seldom result in change in management of cases where morphology, immunophenotype, and cytogenetics of peripheral blood and bone marrow fail to yield a clear diagnosis. Two exceptions are (1) when the differential diagnosis includes aggressive/transformed histologies (we have found positron-emission tomography [PET] imaging to be helpful here), and (2) when the presence or absence of a malignancy remains unclear. Frequently, for the sake of practicality and quality of life, the clinician will find it necessary to manage the patient's disease, at least temporarily, without diagnostic clarity.
If diagnostic certainty often has little impact on initial management, why should the field of hematology pursue further subclassifications of these rare, mostly indolent diseases? For example, is it essential to differentiate between SMZL, extranodal mucosal-associated lymphoid tissue (MALT) lymphoma with splenic involvement, lymphoplasmacytic lymphoma (LPL), and splenic B-cell lymphoma, unclassifiable (SL-u)? The answer here seems to be "yes" more often than has previously been appreciated. The slow evolution of diagnostic criteria over the past 20 years laid the framework for a sudden burst of discoveries that became possible with key technological advances. Whole-exome sequencing of 47 patients with hairy cell leukemia revealed a V600E variant in the BRAF gene of every single case but in none of the 195 cases of other B-cell lymphomas, including 22 cases of SMZL and 16 cases of SL-u. Whole-genome sequencing of lymphoplasmacytic cells from 30 patients with Waldenström macroglobulinemia revealed a mutation in MYD88, resulting in an L265P variant in every case. With further validation, both of these findings are likely to be incorporated into diagnostic criteria in the future. More importantly, they offer the potential for development of targeted therapies. Since most splenic lymphomas involve other more readily accessible tissues, we can expect future discoveries from diagnostic material obtained elsewhere without the need for splenectomy.
It is ironic that splenectomy should be performed only rarely to make the diagnosis of SMZL but is so often considered for therapeutic purposes. As discussed by Thieblemont et al, splenectomy is commonly followed by periods of freedom-from-treatment lasting several years, despite persistent bone marrow and peripheral blood involvement. Indeed, given the historical success of the procedure, the potential benefit of surgery cannot be denied.
Increasing experience with rituximab(Drug information on rituximab) (Rituxan), however, suggests that it may be reasonable to reconsider the role of splenectomy as frontline therapy for SMZL. Ultimately, the practitioner and patient must consider which intervention is most likely to improve overall survival and which is least likely to negatively impact quality of life. Given the lack of randomized phase III trials, data demonstrating an overall survival benefit for either therapy are unlikely to become available in the near future. Of note, rituximab has demonstrated a survival benefit in virtually every other B-cell lymphoma studied, suggesting at least a potential to improve survival in SMZL.
The question of quality of life is equally challenging. Splenectomy is a one-time procedure associated with minimal morbidity and mortality. The effects of splenectomy on the immune system, however, persist indefinitely. The risk of infection requiring hospital admission may be as high as 10%. Moreover, the risk of post-splenectomy sepsis is reported to range between 0.18 to 7 per 100 person-years,[11,12] and this rate is undoubtedly higher among immunocompromised patients. Similarly, some studies suggest a potential hypercoagulable state with increased cardiovascular morbidity following splenectomy. Single-agent rituximab, on the other hand, has minimal impact on quality of life, is associated with a low risk of infection, appears to result in durable remissions in the majority of patients, and may be used successfully at the time of relapse. In spite of these advantages, rituximab maintenance cannot be routinely recommended at this time due to lack of data. Moreover, in our opinion, front-line chemoimmunotherapy seems unnecessarily aggressive in the majority of patients, although promising data with bendamustine (Treanda)-rituximab are emerging and this issue is certainly debatable.
In summary, splenic lymphomas such as SMZL commonly present diagnostic and therapeutic challenges. Fortunately, clinicians can take some comfort in the fact that most patients require minimal intervention, at least early in the course of their disease. Collaborative efforts, such as those coordinated by the Splenic B-Cell Lymphoma Group and the International Extranodal Lymphoma Study Group, have resulted in significant advances in our understanding of splenic lymphomas. We expect that contemporary studies will soon render the splenectomy an even rarer phenomenon in the routine evaluation and management of this patient population.
Financial Disclosure: Dr. Martin has served as a consultant for Cephalon and is serves on Genentech's speakers' bureau. Dr. Leonard has served as a consultant for Cephalon.