Treatment of splenic marginal zone lymphoma
Introduction
Splenic marginal zone lymphoma (SMZL) is a distinct lymphoma entity in the WHO (World Health Organization) classification [1]. During the last years several biological and clinical features of SMZL have been clarified. SMZL is rare, accounting for less than 2% of the lymphoid malignancies. It mainly affects elderly patients without gender predilection. The disease is typically characterized by splenomegaly without lymphadenopathy besides splenic hilum [1]. Lymphocytosis is commonly present, while anaemia and thrombocytopenia are found in approximately 20% and 10%, respectively [2], [3], [4], [5], [6], [7], [8]. A serum paraprotein, mainly of the IgM type is evident in less than one third of the cases. B symptoms are rare. LDH may be moderately elevated in more than one third of the patients. A markedly raised LDH may indicate disease transformation. Autoimmune phenomena include autoimmune haemolytic anaemia (AIHA) and thrombocytopenia (ITP) as well as autoantibodies against several tissue antigens with or without clinical manifestations which may be present in ∼20% of the patients [3], [4].
Hepatitis C virus (HCV) has been implicated in the pathogenesis of a subgroup of SMZL cases, albeit with a great geographic heterogeneity [9], [10]. In African patients, a concomitant malaria infection may be present [11].
The immunoglobulin heavy variable (IGHV) genes show evidence of somatic hypermutation in the majority of the cases ranging from minimal to pronounced [12], [13], [14], [15], [16], [17], [18], [19]. However approximately 15% of cases carry truly unmutated IGHV genes. Interestingly almost one third of SMZL cases utilize the IGHV1-2*04 allele, strongly suggesting an antigen selection process [19]. Complex chromosomal aberrations are common (80% of cases display an abnormal karyotype) [20], [21], [22], [23]. The most frequent cytogenetic aberrations are gains of 3q and 12q and deletion of 7q22–36, mostly at band 7q31–32. Recently, mutations in various genes have been documented in SMZL. Among them somatic mutations clustered in NOTCH2 and KLF2 (Kruppel-like factor 2) appear to be the most common [24], [25], [26], [27], [28], [29], [30].
SMZL usually runs an indolent and chronic clinical course. The median survival is around 10 years [5], [6], [7], [8]. Interestingly more than one third of deaths are lymphoma unrelated [31], [32]. Histologic transformation to diffuse large B-cell lymphoma may occur during the course of the disease, although the exact incidence is not well documented, ranging for <5%–12% in various reports [33], [34], [35]. Several clinical and biological prognostic factors have been reported, without however reproducible results [5], [6], [7], [8], [36], [37]. Recently the Splenic Lymphoma Study Group (SLSG) proposed a risk stratification system based on the assessment of 4 variables: presence of extrahilar lymphadenopathy, elevated LDH, low haemoglobin levels and low platelet counts and separated three risk groups with significantly different lymphoma specific 5-year overall survival [38], [39]. This stratification system has been recently validated in an independent series [40]. SMZL diagnosis is based on the integration of clinical features, immunophenotype, molecular genetics and when available spleen histology, although splenic tissue is no longer necessary for the establishment of SMZL diagnosis [1], [41]. Differential diagnosis from lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM) and the provisional entities hairy cell-variant (HCLv) and splenic diffuse red pulp lymphoma (SDRLP) may be difficult and require either splenectomy or detailed molecular analysis [41], [42].
Section snippets
Management of SMZL
Due to its rarity, management of SMZL is mainly based on the experience from other low grade B-cell lymphomas as well as on data provided by relatively small retrospective series of SMZL patients. The SLSG tried to summarize the existing data on all aspects of SMZL and provided a consensus review in the form of guidelines [41]. An updated form is in process. According to the above mentioned guidelines, treatment should be considered in patients with active disease: presence of B-symptoms, bulky
Discussion
Many novel clinical and biological aspects of SMZL have been recently recognised and much knowledge has been gathered regarding treatment approaches. Due to its rarity, there are no prospective randomized studies in large series of SMZL patients. Thus, the selection of treatment is mainly based on the results derived from retrospective studies, as well as on the experience from other low grade B-cell lymphomas. Currently, the most effective treatment options include splenectomy and rituximab
Summary
SMZL treatment is not standardized due to the lack of prospective randomized studies. Based on the data gathered until now from retrospective studies as well as from the experience on other low grade lymphomas, currently the main treatment options include splenectomy and rituximab. Both of them are effective with high response rates and long duration of response. Given the toxicity profile and the fact that responses to splenectomy are not complete, splenectomy should be probably a good option
Conflict of interest
There is no conflict of interest.
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