Patients today appropriately desire individualized and personalized therapy based on the characteristics of their specific tumor. If, however, this ambitious goal of “personalized medicine” is to be achieved for patients with lymphoma, an understanding of the unique genetic and epigenetic features that underpin pathogenesis within distinct subclassifications of lymphomas is a prerequisite. The classification of non-Hodgkin lymphomas (NHLs) has significantly progressed over the past 55 years, from a system based almost exclusively on morphologic appearance to the contemporary approach of using specimens’ immunophenotype and cytogenetic and molecular properties to define and distinguish clinicopathologic entities. The extensive subclassification of NHL is a result of the complexity of the adaptive and cellular immune systems. Different lymphomas arise at different stages of B-cell differentiation, and specific recombination events result in distinct entities that correspond with a normal B-cell counterpart. The purpose of meticulous subclassification is to identify entities that do not share a prognosis and that might ultimately benefit from different therapeutic approaches.
Traverse-Glehen and colleagues nicely elucidate the myriad challenges involved in making a definite diagnosis of nodal marginal zone lymphoma (NMZL), the least common subtype of marginal zone lymphomas (MZLs). As described, MZLs as a class overlap significantly with other indolent B-cell lymphomas, with only subtle differences and no universal underlying feature. Expert review has revealed that discordant pathologic rates occur in 5% to 10% of all cases of NHL, and that rare entities such as NMZL are more likely to be misclassified. MZLs can be further subdivided, based on their clinical presentation, into nodal, extranodal, and splenic forms, but it is unclear whether these subtypes have important biologic differences. MZLs represent approximately 10% of new cases of indolent lymphomas, and NMZL is the least common of the three subtypes, making up less than 2% of new cases of NHL. Such rarity has been a significant challenge in developing a full understanding of this form of MZL.
Defining the prognosis of NMZL at the time of diagnosis is also problematic. The two international prognostic scoring systems currently used for indolent lymphomas, the Follicular Lymphoma International Prognostic Index (FLIPI) and the International Prognostic Index (IPI), remain unproven in NMZL because of the lack of prospective validation. A retrospective review of 275 patients with MZLs demonstrated that β2-microglobulin, presence of B symptoms, and gender were associated with outcomes; however, the majority of the patients had extranodal MZLs, so the applicability of these data to NMZL is not certain. As a class, MZLs clearly have distinct features with regard to morphology, settings of clinical presentation, preferred microenvironments, propensity for antigen sensitivity, and (likely) oncogenic pathway addictions.
Recently, paradigms have shifted in our understanding of the influence of factors external to the cancer cell and the effects of such factors on tumor behavior. For example, it is now appreciated that the stromal signatures of diffuse large B-cell lymphomas and the microenvironment of chronic lymphocytic leukemia contribute significantly to tumor behavior by cooperating with the ability of a cancer’s cells to form new blood vessels, escape immune surveillance, form protective niches to avoid effects of therapy rendered, and metastasize to distant sites.[6,7] Most intriguingly, it has recently been demonstrated that tumor proliferation in chronic lymphocytic leukemia occurs to a greater extent within the lymph node than in bone marrow or peripheral blood. These findings underscore the importance of a better biologic understanding of the relationship between the unique features of MZLs and their surrounding microenvironment.
Contemporary therapy of all indolent NHLs remains unable to effect cure in most instances, and specific biologically derived therapies are not available. The therapeutic strategies employed for NMZL derive largely from lessons learned in the study of follicular lymphoma, despite obvious differences between these two entities in clinical presentation, morphology, and prognosis. As a result, there is little consensus on indications for therapy, on the intensity of the regimen, or on the role of maintenance therapy. Patients are offered a wide range of therapies, from “watchful waiting” to external beam radiation therapy, to rituximab (Rituxan)-based regimens with or without concurrent chemotherapy.[10,11] These practices are not evidence-based and thus are subject to significant bias, as reflected by the fact that practices differ across different regions of the United States. More recently, impressive response rates coupled with manageable toxicity have created significant interest in the use of bendamustine with rituximab for indolent NHLs; however, the results of the study from which these data derive have not yet been published.
Another emerging strategy in the therapy of follicular lymphoma is the use of consolidative or maintenance therapy with either radioimmunotherapy or rituximab for 2 years after initial therapy.[14,15] One could make a reasonable argument that these strategies would be similarly effective in NMZL, but such an approach is in effect unstudied in the latter context. Thus, the treating clinician is left to decide which strategies are appropriate to extrapolate from the follicular lymphoma treatment paradigms and which ones are not. Importantly, other lymphomas that share many characteristics with NMZL, such as lymphoplasmacytic lymphoma, demonstrate impressive results with alternative therapies that employ agents such as the proteasome inhibitor bortezomib. Recently, it has been shown that splenic MZLs are associated with disruptions in the nuclear factor kappa B (NF-κB) pathway in up to one-third of patients. Such findings demonstrate the need to explore therapies with alternative mechanisms in the treatment of NMZL.
Delivering personalized medicine in NMZL is not currently an option, given the challenges in diagnosis, the rarity of the tumor, and the limited number of prospective trials that explore the biology and therapy of NMZL as a specific entity. Still, insights into the unique biology of NMZL are beginning to emerge, such as those stemming from the recent presentation demonstrating that the MYD88 (L265P) variant mutation might be able to distinguish between lymphoplasmacytic lymphoma and NMZL. Also, therapies can be developed that target surface proteins necessary for tumor dissemination; one example of a therapy that exploits these biologic necessities is the recently discovered anti-CD47 monoclonal antibody therapy. Until we fully engage in understanding the biologic mechanisms that separate NMZL from other indolent NHLs, however, we will continue to deliver “impersonalized medicine” that does not exploit the unique properties of the former.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this review.
Disclaimer: The views expressed in this paper are those of the authors and do not reflect the official policy of the Department of the Army, the Department of Defense, the National Institutes of Health, or the United States government.
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