Splenic marginal zone lymphoma proposals for a revision of diagnostic, staging and therapeutic criteria

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Abstract

Since the initial description of splenic marginal zone lymphoma (SMZL) in 1992, an increasing number of publications have dealt with multiple aspects of SMZL diagnosis, molecular pathogenesis and treatment. This process has identified multiple inconsistencies in the diagnostic criteria and lack of clear guidelines for the staging and treatment. The authors of this review have held several meetings and exchanged series of cases with the objective of agreeing on the main diagnostic, staging and therapeutic guidelines for patients with this condition. Specific working groups were created for diagnostic criteria, immunophenotype, staging and treatment. As results of this work, guidelines are proposed for diagnosis, differential diagnosis, staging, prognostic factors, treatment and response criteria. The guidelines proposed here are intended to contribute to the standardization of the diagnosis and treatment of these patients, and should facilitate the future development of clinical trials that could define more precisely predictive markers for histological progression or lack of response, and evaluate new drugs or treatments.

Introduction

The term splenic marginal zone lymphoma (SMZL) was initially used by Schmid et al.1 in 1992 to describe a low-grade B-cell lymphoma with a peculiar micronodular pattern of spleen involvement, occupying the marginal zone. In the Revised European–American Classification of Lymphoid Neoplasm (REAL) classification, SMZL was considered a provisional entity, and included with marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) type and nodal marginal zone lymphoma in the category of marginal zone lymphomas.2 In the WHO (World Health Organization) classification, SMZL became a separate entity. Since the initial description, an increasing number of publications have dealt with multiple aspects of SMZL diagnosis, molecular pathogenesis and treatment. Now, after 15 years, the authors of this review have held a series of meetings and exchanged series of cases with the objective of agreeing on the main diagnostic, staging and therapeutic guidelines for patients with this condition.

Clinical features of SMZL

Splenic marginal zone lymphoma accounts for less than 2% of the lymphoid malignancies. Typically, the disease affects elderly or middle aged patients in the sixth decade without gender predominance. The main disease features are splenomegaly, lymphocytosis and cytopenias often related to hypersplenism and, less frequently to auto-antibodies or bone marrow (BM) infiltration. Lymphadenopathy and/or other organ involvement are infrequent but they may develop during the course of the disease. A subset of patients presents with an isolated lymphocytosis with lymphocyte morphology and immunophenotype consistent with SMZL. Some of these patients subsequently develop splenomegaly but others pursue a stable course and it is unclear whether they represent an indolent variant or a benign pre-lymphomatous condition. B symptoms and increase of lactate dehydrogenase (LDH) are rare at presentation, and if present during follow-up, transformation should be suspected. Under one-third of patients have a monoclonal paraprotein usually less than 20 g l−1.3 In a small number of patients, particularly those originating from Southern European countries, there is evidence of hepatitis C virus (HCV) infection;4, 5 it has been suggested that this virus may play a pathogenic role in disease development. Autoimmune phenomena are present in 20% of patients.6 The clinical course is usually chronic and the median survival is around 10 years7, 8, 9 and greater than 60% of patients are alive at 5 years.10, 11, 12 In addition, up to one-third of deaths in these patients are not related to the disease but to second neoplasms or vascular conditions.13 A proportion (10%) of cases undergo transformation to diffuse large B-cell lymphoma,14 and this should be taken into account when considering the management and treatment of these patients.

Diagnosis of SMZL

The diagnosis is based on a combination of features including lymphocyte morphology, immunophenotype, cytogenetic abnormalities, BM histology and when available spleen histology (see for details, the guidelines of this paper)3, 15 (Table 1).

Table 1 Role of specific tests in the diagnosis and choice of therapy for SMZL

Minimum diagnostic criteria for SMZL are either:

  1. 1)

    spleen histology+immunophenotype with a ‘chronic lymphocytic leukemia (CLL) score’ of 2 or less, or

  2. 2)

    typical blood and BM morphology +immunophenotype+intrasinusoidal infiltration by CD20-positive cells (if spleen histology is unavailable). Thus, in patients with clinical splenomegaly and if spleen histology is not available, typical blood and BM findings are sufficient to make the diagnosis.

Other small B-cell disorders, such as CLL, follicular lymphoma (FL), mantle-cell lymphoma (MCL) and MALT lymphoma must be excluded through the appropriate studies. Furthermore, benign B-cell lymphoproliferations, in particular persistent polyclonal B lymphocytosis whose histology mimics SMZL, must also be excluded in cases lacking clinical symptoms or showing lack of monoclonality on immunophenotyping.

The lack of a molecular diagnostic marker for all cases of SMZL and the fact that only a proportion of patients have spleen histology available for review make it difficult to establish the diagnosis in some cases. This has clinical implications as it is possible that data documented in some series of patients regarding response to treatment and outcome may have included cases with other B-cell malignancies. Further, the retrospective designs of all published studies, the lack of uniform response criteria and the heterogeneity in the patients characteristics hinder the interpretation of all these data.

Blood cytology

Blood involvement is common in SMZL, and may be detected morphologically and/or by flow cytometry in those cases with minimal lymphocytosis. It is characterized by the presence of circulating lymphocytes having a round nucleus with condensed chromatin and basophilic cytoplasm with short villi, which may be unevenly distributed or concentrated at one or the two poles of the cell. There is often a degree of morphological heterogeneity shown by the presence of small lymphoid cells without specific features, lymphoplasmacytoid cells, lymphocytes with nuclear clefts or medium-sized lymphoid cells with relative abundant pale cytoplasm (that is resembling monocytoid cells). Lymphoplasmacytic or plasma cells are rarely seen. The presence of nucleolated and large cells with immature chromatin usually correlates with disease progression or even transformation to a large-cell lymphoma.

An important practical issue is that storage of the specimen for a few hours in anticoagulant may result in the loss of the villi. In cases where SMZL is suspected but villi are absent, morphological examination should be repeated in freshly made blood or marrow films. The term SLVL has been widely used as an indicator of the blood manifestation of SMZL; however, in view of the possibility of technical artifact described above and the lack of agreement on the required numbers or proportion of circulating villous (VL) lymphocytes to label a case as SLVL we support the WHO recommendation to use the term SMZL+/−VL lymphocytes.

SMZL flow cytometry immunophenotype

The proportion of clonal B cells varies widely from 5 to 90%. In the large majority of patients, the monoclonal B cells express moderate to strong intensity of IgM and IgD or IgM alone; in the remaining, the cells are IgG+, IgD+ and rarely IgM/A+ or IgA+.16 In the majority of patients, the cells are CD20+, CD22+, CD24+, CD27+, FMC7+ and have strong expression of CD79b (MoAb that identifies the β chain of the B-cell receptor). The following MoAbs are expressed in a subset of cases; DBA44 (CD76) in ca. 75%, CD11c in 50%, CD23 in ca. 30%, CD103 in less than 10%, CD25 in ca. 25% and CD5 in ca. 20%. Expression of HC2 or CD10 is very infrequent. Coexpression of both CD5 and CD23 is rare (Table 2). According to the scoring system for CLL,17 most if not all SMZL+/−VL lymphocytes (SMZL+/−VL) cases have scores ranging from 0 to 2, a phenotype not seen in CLL.

Table 2 Main phenotypic features of SMZL

BM aspirate and histology

The BM aspirate shows a variable degree of lymphoid infiltration but usually this is mild; normal hemopoietic cells may be increased particularly in cases with hypersplenism. Of note, the morphology of the lymphocytes is better appreciated in peripheral blood films as BM aspiration ‘per se’ may result in the presence of artifacts (that is villi). Plasmacytic differentiation is often more frequent in the BM than in peripheral blood and cases in which this feature is prominent may raise diagnostic difficulties with lymphoplasmacytic lymphoma (LPL)/Waldenstrom macroglobulinemia.

Bone marrow aspirate is not sufficient for the diagnosis, and BM trephine histology is requested if a precise diagnosis is required. BM trephine involvement in patients with SMZL is invariably observed and is better detected after immunohistochemical staining.18 In the initial phase of the disease, BM involvement can be very subtle, less than 20% of total cellularity. The pattern of infiltration is typically intrasinusoidal and with the progression of the disease, especially after splenectomy, becomes nodular.19 In advanced cases, the combination of intrasinusoidal and nodular infiltration is highly characteristic, although not entirely specific.20 Frequently the follicles in the BM show a preserved germinal center surrounded by a rim of MZ cells. In a minority of cases, interstitial infiltration can occur admixed with intrasinusoidal and/or nodular, but never alone. In the smallest sinusoids, tumor cells are typically arranged in Indian files. The cell morphology is monomorphic. Neoplastic cells have small to medium size, round to oval nucleus with regular contour and a small rim of cytoplasm. Plasmacytoid features can be observed in a small percentage of cases. Immunohistochemical analysis shows a mature B phenotype. CD20, CD45RA, bcl2 are invariably positive, while cyclin D1, CD10 and bcl6 are negative. A minority of cases (up to 10–15%) can be positive for CD5 and/or CD43, although they are usually negative for CD23. The neoplastic B cells are light chain restricted and a light chain restricted plasma cell component is sometimes present as well. A variable number of mature T cells are admixed with tumor cells, especially in the nodules.

The differential diagnosis includes all other small B-cell and T-cell disorders. Immunohistochemistry is fundamental to differentiate SMZL from these conditions. A main diagnostic problem arises with lymphoplasmacytic and marginal nodal lymphomas. In these cases, a lymph node biopsy or additional cytogenetic studies can help to solve the problem. Reactive conditions, such as the benign lymphoid hyperplasia associated with HCV infection, can be confused with SMZL, but almost never have intrasinusoidal component. An important exception is persistent polyclonal B lymphocytosis,21 which may show intrasinusoidal infiltration and thus mimic SMZL.

Spleen histology

Macroscopically, the spleen shows a micronodular white milliary-like pattern that corresponds to a micronodular lymphoid infiltrate of the splenic white pulp, which is centered on pre-existing follicles. The tumor nodules are composed of an inner central zone of small lymphocytes with round or slightly irregular nuclei, replacing the mantle zone, which surrounds or replaces a reactive follicle center, and an outer zone of medium-sized cells with clear cytoplasm in the location of the marginal zone, the area where proliferation takes place in this entity, this giving a biphasic pattern. Within the outer zone there are scattered large cells with large nuclei and prominent nucleoli. The red pulp is involved in most of cases. Both cords and sinusoids are usually infiltrated.1, 22, 23, 24 Epithelioid granulomas can be found, both within the follicles or surrounding them, which may obscure the tumor infiltration.25

SMZL may show plasmacytic differentiation with serum monoclonal paraproteinemia.26 Macroscopically, the cut surface of the spleen shows the typical multimicronodular pattern. Histologically, the plasmacytic differentiation is characterized by the presence of lymphoplasmacytoid cells or plasma cells that express the same type of immunoglobulin (Ig) than the tumoral lymphocytes. Lymphoplasmacytoid cells do not have prominent Golgi bodies and their cytoplasm is less basophilic and less abundant than that of the plasma cells. These lymphoplasmacytoid or plasma cells are located in the marginal zone, in the red pulp, and characteristically occupying germinal centers, when present. This morphological feature is most easily identified by immunohistochemical analysis showing intracytoplasmic monotypic light chain expression.

A subset of cases with increased proliferation and presence of larger cells has been described,27 and it is associated with an increased frequency of progression and histological transformation to secondary DLBCL.14

SMZL immunohistochemical features

Immunohistochemistry in paraffin-embedded tissue is usually concordant with flow cytometry findings in blood or BM. The tumor cells express surface Ig (most often IgM, frequently accompanied by IgD), CD20, Pax5, BCL2 and may express DBA4410, 28 and CD38. The cells are in most cases negative for CD3, CD5, CD10, CD23 and CD43, cyclin D1, annexin-A1 and BCL6. The rate of cell proliferation determined by Ki67 staining is usually low, but Ki67 staining identifies a ring of marginal zone proliferating cells. A few cases have been reported with an atypical phenotype expressing CD5 or CD23 or CD43. But coexpression of CD5 and/or CD43 with CD23 is rare. The CD5 expression is usually weak by immunohistochemistry and sometimes restricted to a minority of tumoral cells. If plasmacytic differentiation is present, the plasma cells are light chain restricted and usually express CD38 and/or CD138 (Table 2).

The colonized follicles are identified by CD23+ follicular dendritic cell meshwork and CD10- and bcl6-negative cells, within which dispersed, residual CD10+bcl6+ follicular center cells can be observed. In striking contrast, reactive follicular centers when present are highlighted by strong expression of CD10 and bcl6. In addition, immunostaining with bcl2 highlights follicular replacement of bcl2− germinal center cells by bcl2+ tumoral cells.

Transformation to DLBCL, an event that can be seen in up to 10% of SMZL cases, is associated with increased expression of BCL6 and MUM1 with a high proliferation index.29

Lymph node histology

The histological appearance of the hilar lymph node is characteristic. It shows a micronodular pattern with preserved dilated sinuses. These nodules, like those in the spleen are based on pre-existing follicles. Tumoral cells are composed of small lymphoid cells with scattered larger cells. Unlike spleen morphology, marginal differentiation is generally absent in lymph node involvement.30

Additional investigations

IgVH mutational status

The first report showed that all cases of SMZL had somatic mutations, suggesting that these tumors arise from memory B cells,31, 32 without any significant pattern resulting from antigen selection. However, recent studies have indicated a molecular heterogeneity, including cases harboring germline VH genes. The sequences of more than 200 cases have been published.24, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 Somatic mutations of IgVH genes have been observed in about half of the cases. Intra-clonal heterogeneity has not been extensively studied but appears to be frequently absent (only 14 cases published). In addition, several studies have independently reported an overuse of the VH1-2 gene segment in both mutated and unmutated cases (44/184), suggesting a highly selected B-cell population. Some cases have been reported with double rearrangement (14 cases). Interestingly, four published cases displayed a common use with distinct mutation pattern of VH1-2 DH3-3 and JH4 with few or no mutation (96–100%). The alignment of the heavy chain third complementary-determining region 3 amino-acid sequences in these cases showed two similar sequences, indicating the possibility of selection by a common antigen.

Cytogenetics in SMZL

Complex chromosomal aberrations are common (80% of cases with an abnormal karyotype). The most frequent cytogenetic aberrations are gains of 3q (20–30% of cases) and 12 q (15–20% of cases), and deletion of 7q22–36, mostly at band 7q32 (30–40%). The chromosomes most frequently involved are 1, 3, 6, 7, 8, 12 and 14.41, 42, 43, 44, 45, 46, 47 The consensus deleted region on 7q is between 7q32 and 7q35. The highest incidence of genetic loss is found in band 7q32 although distinct regions of loss both centromeric and telomeric to this region have also been identified. Fluorescent in situ hybridization analysis of 14 cases with an unbalanced translocation of 3q and a variety of partner chromosomes identified a region, 3q13.q32–q29, over-represented in each case, suggesting that a gene within this region may play a pathogenic role. Using comparative genomic hybridization (CGH) experiments, two over-represented regions have been reported to 3q23–25 and 3q25–29.44

Translocations involving the Ig heavy- or light-chain loci are uncommon in SMZL. They may occur either as primary or secondary cytogenetic abnormalities; partner chromosomes include 3q27 (BCL6) 6p21 (cyclin D3), 7q21 (CDK6), 9p13 (Pax5), 11p11 and 10q24. No evidence of the t(11;18) (q21;q21), t(14;18)(q32; qq21) or t(3;14)(p14;q32) associated with MALT lymphoma has been found in SMZL. Some series revealed the presence of t(11;14)(q13;q32) in few cases, and it has been suggested that the molecular breakpoint could be different from mantle cell lymphoma cases.42 Deletion of chromosome 17p13 occur in less than 5% of SMZL cases but mono-allelic p53 loss has been found in 17% of patients in one series.43

Comparative genomic hybridization has shown chromosome gains or losses in 83% of patients with a median of four abnormalities per case. In addition to the common abnormalities detected cytogenetically, gains of chromosome 5q, 12p, 20q and 9p have been identified by CGH.44, 48

However, several of these abnormalities have been reported in other small B-cell lymphomas, including trisomy 3/3q in MCL and MALT lymphoma, trisomy 12 in CLL and MALT lymphoma, trisomy 18 in FL and MALT lymphoma and del7q in CLL, MCL and LPL. Therefore, it is important that the cytogenetic findings be correlated with the clinical, morphological and immunophenotypic features before a diagnosis of SMZL is made.

Differential diagnosis

The differential diagnosis of SMZL from other small B-cell neoplasms requires the integration of clinical, morphological, immunophenotypic and genetic data. The morphological appearance of SMZL in the spleen can be closely mimicked by a variety of primary nodal low-grade B-cell lymphomas when they involve the spleen.49 Marginal zone differentiation has been described in lymph node biopsies, and could also take place in the spleen, where a conspicuous normal marginal zone is usually present.49

Morphological variations of tumoral cells in different microenvironments are a common phenomena, which may be seen in most of small B-cell lymphomas, either in separate locations or in different areas, suggesting that tumoral cells may modulate their morphology under the influence of the local microenvironment.

Immunohistochemical studies are extremely useful in the differential diagnosis of small B-cell lymphomas in the spleen and the BM (Table 1).

MALT lymphoma

Occasionally, the differential diagnosis with MALT-type marginal zone lymphoma is necessary due to the existence of cases of MALT lymphomas infiltrating the spleen with a micronodular pattern. In these cases, the spleen shows widening of the marginal zone external to a preserved mantle, with small cluster of similar cells in the red pulp.50 Two useful features to distinguish these two conditions are the absence of t(11;18)(q21;q21) in SMZL cases,51 and the frequent IgD expression in SMZL that is only rarely observed in MALT lymphomas.50

Follicular lymphoma

Macroscopically, unlike SMZL, the splenic nodules in FL are usually of variable size. The tumoral follicles accumulate principally in the white pulp and the cytological features of these nodules show that they are composed entirely of a mixture of centrocytes and centroblasts.52 Frequently, FL in the spleen shows a peripheral zone without an intervening mantle, in which the tumor cells contain more abundant cytoplasm, resembling marginal zone cells.49 In some cases, there is true marginal zone differentiation; usually with a preserved mantle.49 Expression of CD10 and bcl6 is useful for FL diagnosis.

However, there are some splenic FLs with absence of bcl2 expression; in such cases, the differential diagnosis with SMZL is especially difficult. Morphological features of tumoral cells, MIB1-staining pattern, residual mantle cell, IgD staining of tumoral cells, in addition to histological findings in the BM and/or hilar lymph nodes' histological findings help to establish the diagnosis.

Mantle cell lymphoma

Splenic involvement by MCL shows white pulp nodules and a variable intensity of diffuse red pulp infiltration.53 Although marginal zone differentiation may be found in MCL, the monomorphous morphology of the lymphoma cells without the presence of nucleolated large cells and the cyclin D1 expression by tumor cells in MCL are the features that will help to distinguish MCL from SMZL.

Chronic lymphocytic leukemia

Splenic involvement in CLL is characterized by a red and white pulp infiltration with effacement of follicles. The cytological composition of these cases shows a predominance of small lymphocytes, with scattered prolymphocytes and paraimmunoblasts with or without proliferation centers. Cases in which splenic involvement shows a micronodular infiltrate with marginal zone differentiation may be problematic, and may require attention to the hilar lymph nodes or to the peripheral blood or BM findings. The immunophenotype CD23+, CD43+, CD5+, IgD+ and low proliferation fraction (without annular pattern of staining) are in favour of CLL diagnosis.49 Blood and BM morphology, together with flow cytometry data may be necessary for the differential diagnosis.

Lymphoplasmacytic lymphoma

Differential diagnosis from LPL can be difficult since SMZL may show plasmacytic differentiation with serum monoclonal band.26 Currently, LPL is a diagnosis of exclusion, with marginal zone lymphoma being the most frequently overlapping entity. The presence of a mixed pattern of white and red pulp involvement by periarteriolar aggregates of plasmacytoid cells, small lymphocytes, plasma cells and a variable number of immunoblasts, with absence of marginal zone differentiation are all findings pointing toward a diagnosis of LPL.54 Although early reports suggested the presence of t(9;14)(p13;q32) and other PAX5 translocations in a small number of B-cell lymphomas with plasmacytic differentiation, more recent reports have been unable to reproduce these findings.55 Deletions of 7q, gains of 3q and intrasinusoidal infiltration are in favor of SMZL, while del6q is more in favor of LPL. Isolated del(6q) is more suggestive of LPL/Waldenstrom macroglobulinemia.56 BM on LPL usually lacks the intrasinusoidal involvement that is seen on SMZL.

Splenic diffuse red pulp small B-cell lymphoma

In contrast to classical SMZL, the splenic cut surface is homogeneously brown-red, without tumor nodules. Microscopically, there is diffuse obliteration of the normal splenic architecture by neoplastic cells. There is extensive red pulp involvement with infiltration of both the cords and sinuses and effacement of the white pulp. Only occasional atrophic residual white pulp nodules are present. Tumoral cytology is quite monomorphous with scattered large cells. Neither follicular replacement nor marginal zone differentiation nor biphasic cytology is detected.57 A variable proportion of cases have been reported to express IgG, but not IgD.24, 58

The massive red pulp pattern of infiltration is similar to that observed in hairy cell leukemia (HCL), but the blood cell lakes are inconstant and less extensive. Furthermore, the morphology and immunophenotype, including absence of annexin-1 expression, are inconsistent with HCL.

Bone marrow typically shows a massive intrasinusoidal involvement, while peripheral blood cells are characterized by the villous cytology.

Although this entity has findings that overlap with those corresponding to classical SMZL, other cardinal features such as IgD expression, micronodular pattern or follicular replacement are lacking in most cases. Further series and molecular studies are required to more clearly define whether this is a different disorder, with characteristic molecular pathogenesis and requiring appropriate treatment.

Hairy cell leukemia and hairy cell leukemia variant

The immunophenotypic profile of the lymphoma cells is different from that of HCL.

Some degree of overlapping can be, nevertheless, established with the denominated HCL-variant (HCL-v),59, 60 this differential requiring further case collection and comparative study. The term HCL-v describes cases of B-chronic lymphoproliferative disorders that look like classic HCL but shows variant cytological features (that is leukocytosis, presence of monocytes, cells with prominent nucleoli, cells with blastic or convoluted nuclei and/or absence of hairy silhouette contours), variant immunophenotype (that is absence of CD25, CD123––anti-interleukin-3 receptor, annexin-1 or TRAP), and resistance to conventional HCL therapy.61, 62, 63

Cases of HCL-v with spleen, BM or peripheral blood features overlapping those of SMZL have been reported,64, 65 and more in particular with the entity denominated as splenic diffuse red pulp small B-cell lymphoma. Still in HCL-v, the cells are often CD103+ (two-thirds of the cases), while they are negative with CD25 and, usually CD24 negative.66 This is an area that requires further study.

Management of SMZL

There are no published/agreed criteria for initiating treatment in SMZL+/−VL. The level of evidence supporting these recommendations is unfortunately weak due to the absence of prospective clinical trials; nevertheless, they summarize the clinical evidence gathered in a series of clinical centers with a significant experience on the management of SMZL. As in other low-grade B-cell malignancies such as CLL, therapeutic intervention should be considered in patients with active disease, whereas in asymptomatic patients without evidence of disease progression a policy of watch and wait is reasonable.

In symptomatic patients, therapeutic intervention and modalities to be used in SMZL+/−VL remain a challenge to the clinician. Considering the indolent natural history of this lymphoma, the patient's age and comorbidities, treatment should usually aim to achieve control of the disease and symptoms rather than eradication of the lymphoma.

There are several therapeutic options that have proved effective in these patients. These include

  1. 1

    Splenectomy in patients fit for surgery. Responses to splenectomy are seen in the majority of the patients and up to half of them may not require further therapy.7, 12, 67

  2. 2

    Chemotherapy

    1. a)

      alkylating agents appear to be of marginal benefit in SMZL+/−VL as two-thirds of the patients treated with chlorambucil as first-line therapy do not respond. Those that do respond frequently relapse quickly and require further treatment.3, 10, 12

    2. b)

      purine analogs, in particular fludarabine (F) in combination or not with rituximab and rituximab alone have demonstrated in different studies a greater efficacy than alkylating agents in terms of quality of response and longer progression-free survival.4, 68, 69, 70, 71, 72, 73, 74, 75, 76 Thus, although the total number of patients treated with purine analogs and/or rituximab is relatively small, these drugs seem to be very effective and warrant consideration as first-line therapy in patients who are not fit for surgery or have progressed following splenectomy.

In the small proportion of patients with concomitant HCV infection, interferon-α 2b (IFN), ribavirin or a combination of both these agents has demonstrated a significant activity with clearance of HCV RNA in the blood;8, 77, 78 therefore, these agents should be considered in the therapeutic scenario as a first line in this small cohort of patients.

A minority of patients (ca. 8–10%) of SMZL+/−VL transform into a high-grade B-cell lymphoma12, 14 and a few have TP53 abnormalities43 and a worse clinical course. Patients with features of transformation should be managed with different schedules as those used in high-grade B-cell lymphomas or transformed from CLL or FL.

Prospective randomized trials would be desirable in SMZL+/−VL to ascertain the independent prognostic factors and the biological features of this lymphoma that predict for disease progression and drug resistance. However, at present, randomized trials have not been set up and thus, information is lacking. Therefore, this review is aimed to provide diagnostic and staging guidelines for the workup of SMZL+/−VL and outline the current treatment options based on the evidence of retrospective studies.

Prognostic factors

The Integruppo Italiano Linfomi carried out a study to assess the outcomes of SMZL to identify prognostic factors in 309 patients. Using three variables, hemoglobin level less than 12 g dl−1, LDH level greater than normal and albumin level less than 3.5 g dl−1, they grouped patients into three prognostic categories: low-risk group (41%) with no adverse factors, intermediate-risk group (34%) with one adverse factor and high-risk group (25%) with two or three adverse factors. The 5-year CSS rate was 88% for the low-risk group, 73% for the intermediate-risk group and 50% for the high-risk group.8

The development of lymphadenopathy, high lymphocyte count or infiltration of non-hematopoietic sites has been also found to be associated with progression and shorter overall survival and progression-free survival.9, 10 Progression may be associated with histological transformation to large-cell lymphoma, as described in 13% of a series of SMZL.14

Other biological markers have been found to correlate with progression—high-growth fraction and more frequent 7q deletion79 or unfavorable outcome, such as the expression of NF-κB signature genes.80 In different studies, the presence of p53 mutations, although a rare event, has been found to be associated with shorter survival.9, 43

Further studies, in the setting of clinical trials, are required to define more precisely predictive markers for histological progression or lack of response.

Diagnostic and staging workup

  1. 1)

    Full blood count (FBC) with differential counts, reticulocytes, Coomb's test and autoimmune screen (ANA, anti-DNA, AMA, anti-thyroid, rheumatoid factor)

  2. 2)

    Renal and liver biochemistry including calcium levels and LDH

  3. 3)

    Serum and urine Igs and B-2 microglobulin

  4. 4)

    Serology for hepatitis C (if positive, reverse transcriptase-PCR for HCV RNA in the blood) and virus genotyping, when possible

  5. 5)

    HIV serology should be investigated, with the limitations due to specific countries policies

  6. 6)

    Review of blood morphology and flow cytometry (if circulating lymphoma cells)

  7. 7)

    BM aspirate with morphology and flow cytometry and trephine biopsy with immunohistochemistry (IHC). BM aspirate in the absence of trephine biopsy and immunohistochemistry may have a low diagnostic value.

  8. 8)

    Computerized tomography scan of the abdomen and chest

Optional

  1. 1)

    Helicobacter pylori (if the patient has gastric symptoms) and full viral screen, including hepatitis B virus, Epstein Barr Virus (EBV) and cytomegalovirus (CMV) by PCR

  2. 2)

    Thyroid function if anti-thyroid antibodies have been detected

  3. 3)

    Fluorescent in situ hybridization/cytogenetic analysis in the relevant sample involved (to exclude the diagnosis of other B-cell lymphomas in cases with uncertain diagnosis, particularly CLL or MCL in CD5+ cases and FL)

  4. 4)

    Cryoglobulins if HCV positive

  5. 5)

    On the basis of these investigations and once the diagnosis of SMZL+/−VL has been established, the patients can be stratified into

    1. a)

      Early/asymptomatic SMZL+/−VL. These comprise patients with no B-symptoms, absent or mild cytopenias, non-bulky splenomegaly, no significant (<2 cm) lymphadenopathy and no evidence of symptomatic or active hemolysis. BM infiltration may be present but with a good hemopoietic reserve

    2. b)

      Advanced/symptomatic SMZL+/−VL comprises patients with symptomatic cytopenias, progressive splenomegaly, rapidly raising lymphocyte counts and/or development of lymphadenopathy or involvement of extranodal sites.

Treatment options

(a) Early/asymptomatic disease. A policy of watch and wait is recommended with follow-ups every 3–6 months with physical examination and blood counts and biochemistry. If there is evidence of disease progression, re-staging is indicated as in above. Treatment can be initiated as per advanced/symptomatic patients.

(b) Advanced/symptomatic SMZL.

HCV+. IFN alone at a dose of 3 million IU three times a week for 6–12 months or in combination with ribavirin 1000–1200 mg/p.o./day in patients with HCV serology. According to local policies, IF or peg-IF could be used. The precise antiviral regimens should depend on the infecting HCV genotype.81

Splenectomy. This should be the first option in patients with bulky spleens and/or hypersplenism, fit for surgery, without significant lymphadenopathy and no evidence of HCV infection.

Chemotherapy and/or antibody therapy

  1. 1

    Indicated in patients not fit for surgery or without bulky splenomegaly and in those with generalized lymphadenopathy, cytopenias due to BM infiltration and/or raising lymphocyte counts and/or extranodal involvement. Modalities to be used are (1) F as a single agent or in combination with cyclophosphamide (FC) either oral or i.v. at the standard doses used in CLL; (2) rituximab as a single agent given weekly at a dose of 375 mg m−1 for 4–8 weeks or (3) combination of F or FC plus rituximab. Rituximab as single agent will be preferable than F or FC in elderly patients (>75 years) or those with impaired renal function. Some unpublished observations suggest that when the response is insufficient, splenectomy may provide better additional response and better tolerance for chemotherapy.

  2. 2

    For patients that transform to high-grade lymphoma, cyclophosphamide, doxorubicin, vincristin, prednisone and rituximab (CHOP-R) (14 or 21) as used in de novo large-cell lymphoma or in low-grade lymphomas transformed to high grade is indicated

Caution: Patients with autoimmune hemolytic anemia (AHA) or idiopathic thrombocytopenic purpura (ITP) should receive conventional treatments for these disorders prior to specific therapy for SMZL, if indicated.

Adjuvant therapy

Patients undergoing splenectomy should receive vaccinations for Pneumococcus and Haemophilus; vaccination for Meningococcus and antibiotic prophylaxis should be given following local policies.

Patients receiving F or FC, rituximab or combinations should be on sulfamethoxazole+trimethoprim 800/160 mg/p.o./o.d. or other alternatives for PCP prophylaxis if they are allergic to sulfonamides (that is, pentamidine nebulization).

Aciclovir prophylaxis (that is 200 mg/p.o./t.i.d) if previous history of herpes simplex or zoster

Fluconazole 50–100 mg/p.o./o.d. prophylaxis

Response criteria

Splenectomy: response will be considered when there is at least 50% improvement on the blood counts, non-progressive lymphocytosis and no change or improvement in the degree of BM infiltration.

Chemotherapy, antibody therapy and IFN plus or not ribavirin:

Partial response: 50% or greater improvement in the disease manifestations. This should include resolution or decrease in spleen size, improvement on cytopenias and resolution or decrease in lymphadenopathy if present. BM should show a decrease in the level of lymphoid infiltration and improvement of the hemopoietic reserve.

Complete response: Resolution of organomegaly, normalization of the blood counts (Hb>12 g dl−1; platelets>100 × 10 l−1; neutrophils >1.5 × 10 l−1 and no evidence of circulating clonal B cells). No evidence or minor BM infiltration detected by immunohistochemistry.

No response and progressive disease: Less than 10% improvement on the disease manifestations or deterioration of the above, respectively.

Monitoring

  1. 1

    Asymptomatic (off therapy patients): physical examination, peripheral blood counts and biochemistry every 4–6 months; A computerized tomography scan or BM will not be indicated unless signs of disease progression by the above parameters

  2. 2

    Splenectomized patients: every 4–6 weeks with blood counts and biochemistry during the first 3 months and thereafter every 6 months. A complete reassessment with computerized tomography scan and BM biopsy should be performed if there are signs indicative of progressive disease

  3. 3

    Patients receiving F, FC with or without rituximab should be monitored during therapy every 2 weeks with blood counts and biochemistry. If neutropenic, they should be given granulocyte-colony-stimulating factor and/or ciprofloxacin prophylaxis. Assessment of the response to FC or F+/− rituximab with computerized tomography scan and BM should be carried after four courses to evaluate response and whether patients should go for a further two courses (total of six courses)

  4. 4

    Patients on rituximab should be assessed after six infusions to see the degree of response and proceed with two further infusions if indicated as above

  5. 5

    Patients on IFN, ribavirin or combination of both should be monitored for HVC load in the blood by PCR in addition to disease manifestations. Of note that it may take up to 12 months to achieve a complete response/partial response

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Acknowledgements

Other active participants in the preparatory meetings for this manuscript, and members of the Splenic Marginal Zone Lymphoma group, were Lucile Baseggio, Martine French, Jose A Martínez-Climent, Jesus M Hernandez-Rivas, Dolores Caballero, Zadie Davies, Alison Morilla, David Gonzalez, Marta Salido, Wolfram Klapper and Reiner Siebert. Preparatory work has been partially funded by grants from the Ministerio de Sanidad y Consumo (G03/179, PI051623, PI052800), the Ministerio de Ciencia y Tecnología (SAF2005-00221, SAF2004-04286) and Fundacion la Caixa, Spain.

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Correspondence to M A Piris.

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Keywords

  • splenic marginal zone lymphoma
  • guidelines
  • lymphoma

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