Elsevier

Blood Reviews

Volume 19, Issue 1, January 2005, Pages 39-51
Blood Reviews

REVIEW
Splenic marginal zone lymphoma

https://doi.org/10.1016/j.blre.2004.03.002Get rights and content

Abstract

Splenic marginal zone lymphoma (SMZL) is an indolent B cell malignancy usually involving spleen, bone marrow and blood. The disease presents as an incidental finding or with symptoms of splenic enlargement or anaemia. Diagnosis is based on a combination of lymphocyte morphology, immunophenotype and marrow and /or splenic histology. There is no genetic abnormality specific for SMZL, but deletions of chromosome 7q are the commonest abnormality and are found in 30-50% of cases. SMZL cells may have either mutated or unmutated immunoglobulin variable region genes and probably arise from different subsets of splenic marginal zone B cells. Prognostic factors are poorly defined and only loss or mutation of the p53 gene is consistently associated with a poor outcome. Therapeutic options include splenectomy, splenic irradiation, alkylating agents, purine analogues or anti CD20 antibody. The median survival is 10–13 years and most disease-related deaths are associated with transformation to diffuse large cell lymphoma.

Introduction

The existence of an indolent B cell disorder characterised by splenomegaly and circulating lymphocytes with an irregular cytoplasmic border, distinct from hairy cell leukaemia, was first reported in 1979.1 In 1987 Melo et al.2 introduced the term splenic lymphoma with villous lymphocytes (SLVL) to describe this condition, which was incorporated as a distinct entity in the French-American-British proposal for the classification of chronic B cell leukaemias in 1989.3 Schmid et al.4 first used the term splenic marginal zone lymphoma (SMZL) to describe the splenic histology in four patients who presented with splenomegaly and a lymphoid infiltrate in the marrow. In 19945 the same group confirmed that the splenic histology of patients diagnosed as SLVL who subsequently underwent splenectomy was typical of SMZL. SMZL was included as a provisional entity in the Revised European-American Classification of Lymphoid Neoplasms in 1994,6 and as a separate entity, distinct from marginal zone lymphomas originating in mucosa associated lymphoid tissue or lymph nodes, in the World Health Organisation classification published in 2001.7

It is now possible to predict that patients presenting with SLVL and splenomegaly have SMZL without the need for splenectomy, based on careful morphological and immunophenotypic examination of the blood and bone marrow, supplemented in difficult cases by cytogenetic and/or molecular genetic studies. This is analogous to the relationship between chronic lymphocytic leukaemia and small lymphocytic lymphoma. In this review we will use the term SMZL to encompass both SMZL and SLVL unless referring to articles which use the term SLVL. However it is important to note that not all cases of SLVL present with or develop palpable splenomegaly and the circulating neoplastic lymphocytes in SMZL do not always have cytoplasmic villi.

Section snippets

Clinical features

SMZL is a disease of the elderly; the median age at presentation is approximately 65 years while virtually all patients are aged greater than 50 years. The reported incidence is 1–2% of non-Hodgkin lymphomas,[8], [9] but these figures do not include the more benign cases which do not undergo splenectomy or require any form of treatment. It is a disorder, which characteristically involves the spleen, bone marrow and peripheral blood. A typical patient will present with symptoms of fatigue and/or

Blood and marrow morphology

Approximately 75% of patients with SMZL will have a peripheral blood lymphocytosis although peripheral blood involvement can be documented in most patients if multiparameter flow cytometry is utilised.[1], [11], [12], [13] One of the most characteristic features of SMZL is the presence of so-called villous lymphocytes on peripheral blood smears. These are small to intermediate sized lymphocytes with clumped nuclear chromatin, indistinct nucleoli and short cytoplasmic projections, which may

Pathogenesis

Based on the distribution of disease within the spleen and the existence of cases in which the disease appears to be confined to the spleen, it is currently assumed that SMZL originates in the marginal zone of the spleen. In health the splenic marginal zone contains many types of cells. These include both unmutated B cells, which are thought to respond to T-independent antigens and participate in the early immune response to blood borne polysaccharide bacterial antigens, and mutated memory B

Differential diagnosis

It has been argued by many haematopathologists that SMZL can only be confidently diagnosed by histological (and immunohistochemical) examination of the spleen. However with the routine use of multiparameter flow cytometry and immunohistochemistry on trephine biopsy sections it is possible to make a diagnosis of SMZL in most patients without recourse to splenectomy.21 Difficulties can arise but it is usually possible to distinguish SMZL from other B-cell lymphoproliferative disorders by

Prognostic factors

A number of investigators have evaluated prognostic factors in SMZL and SLVL but there is little consensus between studies. Parry-Jones et al12 demonstrated that age >70 years, haemoglobin <11g/dl, lymphocytes >16 × 109/l, and platelets <100 × 109/l all had an adverse effect on overall and cause specific survival. Thieblemont et al19 showed that the International Prognostic Index lacked prognostic significance in SMZL but found that a lymphocytosis of >9 × 109/l, raised β2 microglobulin and the

Treatment

Many patients with SMZL are asymptomatic at diagnosis. Between a quarter and a half of patients in the largest reported series of SMZL received no initial treatment (Table 2). Reliable information on the rate of progression to treatment is scarce. Twenty-eight percentage of a group of 50 SLVL patients who required no initial therapy did not progress to treatment over follow-up periods of 1–6 years, although four patients died of unrelated causes,65 while the median time to progression in 20

Practice points

  • Lymphocyte morphology may vary between cases; not all have circulating villous lymphocytes.

  • Although the immunophenotype is usually that of a post germinal centre B cell, approximately 20% of patients have circulating lymphoma cells which are weakly CD5 positive.

  • Intrasinusoidal lymphoma cells in trephine biopsy sections are a characteristic feature of SMZL and most easily detected using CD20 immunostaining.

  • Lympadenopathy, other than enlarged splenic hilar nodes, is rare in SMZL and suggests

Research agenda

  • Gene expression profiling may provide insight into the pathogenesis of SMZL, its relationship to other marginal zone lymphomas and yield new diagnostic markers.

  • Multicentre and multinational trials are required to evaluate new treatments such as purine analogues and anti CD20, alone and in combination.

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