Marginal Zone Lymphomas

Marginal Zone Lymphomas Emanuele Zucca, MD*, Francesco Bertoni, MD, Anastasios Stathis, MD, Franco Cavalli, MD, FRCP KEYWORDS  Marginal zone lymphoma  MALT lymphoma  Extranodal lymphomas

DEFINITION AND CLASSIFICATION OF MARGINAL ZONE LYMPHOMAS

In the World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues the group of marginal zone lymphomas (MZL) comprises three different entities, namely the extranodal marginal zone B-cell lymphoma of mucosaassociated lymphoid tissue (currently named ‘‘MALT lymphoma’’ and previously defined as ‘‘low grade B-cell lymphoma of MALT type’’), the nodal marginal zone B-cell lymphoma (previously known as ‘‘monocytoid lymphoma’’), and the splenic marginal zone B-cell lymphoma (with or without circulating villous lymphocytes).1 The term MZL means that extranodal MZL, nodal MZL, and splenic MZL are believed to derive from B cells normally present in the marginal zone, which is the outer part of the mantle zone of B-cell follicles. Most of the marginal zone B cells are naı¨ve B cells, with a restricted immunoglobulin repertoire. Postgerminal center memory B cells are also present in the marginal zone, as well as plasma cells, macrophages, T cells, and granulocytes. While splenic and nodal MZL are quite rare, each comprising approximately 2% of lymphomas, the extranodal MZL of MALT type is not uncommon; in a survey of more than 1,400 non-Hodgkin’s lymphomas from nine institutions in the United States, Canada, the United Kingdom, Switzerland, France, Germany, South Africa, and Hong Kong, this entity represented approximately 8% of the total number of cases, including both the most common gastrointestinal and the less usual nongastrointestinal localizations.2 This article addresses each of these entitites. EXTRANODAL MARGINAL ZONE LYMPHOMA OF MALT (MALT LYMPHOMA) General Description of Histologic Features and Etiopathogenesis

Primary gastric MALT lymphoma is the most common and best-studied MALT lymphoma, but the histologic features of extranodal B-cell MZL (MALT lymphomas) Oncology Institute of Southern Switzerland, Ospedale San Giovanni, 6500 Bellinzona, Switzerland * Corresponding author. Oncology Institute of Southern Switzerland, Ospedale San Giovanni, 6500 Bellinzona, Switzerland. E-mail address: [email protected] (E. Zucca). Hematol Oncol Clin N Am 22 (2008) 883–901 doi:10.1016/j.hoc.2008.07.011 hemonc.theclinics.com 0889-8588/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.

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are largely similar, regardless of the site of origin.3,4 The most striking feature of MALT lymphoma is the presence of a variable number of lymphoepithelial lesions defined by evident invasion and partial destruction of mucosal glands by the tumor cells. The morphology of MALT lymphoma cells is heterogeneous. Marginal-zone cells are the predominant component and are small to medium-sized cells with irregularly shaped nuclei (centrocyte-like cells). Other cell types comprise monocytoid cells and small B-lymphocytes. A variable degree of plasma cell differentiation is often present. Any of these cytologic aspects can predominate, or they can coexist within the same case. The B-cells of MALT lymphoma show the immunophenotype of the normal marginal zone B cells present in spleen, Peyer’s patches, and in lymph nodes. Therefore, the tumor B-cells express surface immunoglobulins and pan-B antigens (CD19, CD20, and CD79a), express the marginal zone-associated antigens CD35 and CD21, and lack CD5, CD10, CD23, and cyclin D1 expression. A number of non-neoplastic, reactive T cells is often present. Scattered transformed large blast cells are also usually found. Their prognostic significance is not fully understood, but only when solid or sheet-like proliferations of large cells are present should the lymphoma be considered to have transformed. The resulting tumor cannot reliably be distinguished from other diffuse large B-cell lymphomas. Therefore, current recommendation is that such cases are defined as diffuse large B-cell lymphoma, avoiding the term ‘‘highgrade’’ MALT lymphomas.3 Certain histologic features appear to indicate that the MALT lymphoma B cells might be or have been involved in an immune response: the presence of tumor lymphocytes in the germinal centers of non-neoplastic follicles (follicular colonization), the presence of scattered transformed blasts, the often prominent plasma cell differentiation, and the often rich T-cell non-neoplastic component. MALT lymphoma usually arises in mucosal sites where lymphocytes are not normally present and where a MALT is acquired in response to either chronic infectious conditions or autoimmune processes: Helicobacter pylori gastritis, Hashimoto’s thyroiditis, Sjo¨gren syndrome.5 Sequence analysis of the immunoglobulin genes expressed by the MALT lymphoma B cells shows a pattern of somatic hypermutation and intraclonal variation, suggesting that the tumor cell has undergone antigen selection in germinal centers and they continue to be at least partially driven by direct antigen stimulation.6 In the context of this continual antigenic stimulation, abnormal B cell clones acquiring successive genetic abnormalities can progressively replace the normal B cell population of the inflammatory tissue, giving rise to the lymphoma. The acquisition of MALT is induced by a series of agents that are likely different in each organs. H. pylori was identified by epidemiologic studies in the early 1990s as likely being involved in gastric MALT lymphomas pathogenesis, and this recognition was supported by the repeated demonstration of tumor regressions in 60% to 100% of patients with early-stage H. pylori-positive gastric MALT lymphoma treated with anti-helicobacter antibiotic therapy.7–16 Hence, this tumor became a popular model of the pathogenetic link between chronic inflammation and lymphoma development.5,17 Recognition of the driving sources of the antigenic stimulation in different tissues may therefore have important therapeutic implications. Indeed, other bacterial infections had later been found to be possibly implicated in the pathogenesis of marginal zone lymphomas arising in the skin (Borrelia burgdorferi),18 in the ocular adnexa (Chlamyophila psittaci),19 and in the small intestine (Campylobacter jejuni).20 Wide geographic variations have been reported in the prevalence of gastric MALT lymphoma, likely related to variations of the H. pylori incidence in the examined populations.21 Indeed, H. pylori infection can be found in 70% to 90% of patients with primary MALT lymphoma of the stomach.22,23

Marginal Zone Lymphomas

MALT lymphoma may occur in many different anatomic locations and the gastrointestinal (GI) tract is the most common site, encompassing half of all cases.24 Within the GI tract the disease is most frequent in the stomach, where the MALT lymphomas comprise up to 50% of all primary lymphoma.21,25 Primary intestinal involvement is typical of a special uncommon subtype of MALT lymphoma, the immunoproliferative small intestinal disease (IPSID).3 Extranodal MZLs may also arise in a variety of non-GI organs, mucosal or not, such as the salivary gland, thyroid, upper respiratory tract, lung, ocular adnexa (lachrymal gland, conjunctiva, eyelid, orbital soft tissue), skin, breast, liver, bladder, kidney, prostate, and even in the dura.26 Four recurrent chromosomal translocations have been associated with the pathogenesis of MALT lymphomas: t(11;18)(q21;q21), involving the cIAP2/MALT1 genes; t(1;14)(p22;q32), involving BCL10/IgH; t(14;18)(q32;q21), involving IgH/MALT1; and t(3;14)(p14.1;q32), involving FOXP1/IgH.27,28 These chromosomal translocations seem to be mutually exclusive and demonstrate site-specificity in terms of their incidence. Interestingly, three seemingly disparate translocations—t(11;18)(q21;q21), t(1;14)(p22;q32) and t(14;18)(q32;q21)—despite involving different genes, all appear to affect the same signaling pathway, resulting in the activation of nuclear factor kappa B (NF-kB), a transcription factor with a central role in immunity, inflammation, and apoptosis.27,28 The most common is the translocation t(11;18)(q21;q21), which results in a fusion of the cIAP2 region on chromosome 11q21 with the MALT1 gene on chromosome 18q21, and is present in more than onethird of cases. The frequency of this translocation is site-related: common in the gastrointestinal tract and lung, rare in conjunctiva and orbit, and almost absent in salivary glands, thyroid, liver, and skin. It can be speculated that there are site-specific pathogenetic pathways, however, whether the presence of different infection at different sites can lead not only to chronic B-cell proliferation but also to the specific translocations that characterize most MALT lymphomas remains to be demonstrated. Nevertheless, these translocations may have a significant clinical relevance. For instance, the t(11;18) is present in only 10% of tumors confined to the gastric wall but is common in those disseminated beyond the stomach; moreover, the presence of this translocation can predict a poor therapeutic response of gastric MALT lymphoma to H. pylori eradication29 but not necessarily to other therapeutic approaches.30,31 The pathogenetic relevance of the t(3;14)(p14.1;q32) is not completely clear; it involves the immunoglobulin heavy-chain gene on chromosome 14 and the forkhead box protein P1 (FOXP1) gene on chromosome 3.27,28,32 Nuclear FOXP1 expression has been shown in 30% of MALT lymphomas, apparently associated with poor clinical outcome, especially in cases with trisomies 3 or 18 or with increased number of scattered large activated B cells.33 Clinical Features

MALT lymphoma is a tumor of adults, with a median age at presentation near 60 years and a slightly higher proportion of females.2,24 The clinical features and presenting symptoms are mainly related to the primary location,5,12,26 but some general characteristics can be described.24,34,35 Few patients present with elevated lactate dehydrogenase (LDH) or beta-2-microglobulin levels. Constitutional B symptoms are extremely uncommon. MALT lymphoma usually remains localized for a prolonged period within the tissue of origin, but dissemination at multiple sites seems not uncommon, occurring in up to one-fourth of cases, with either synchronous or metachronous involvement of multiple mucosal sites or nonmucosal sites, such as spleen, bone marrow, or liver; regional lymph nodes can also be infiltrated.24,34,36

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Disseminated disease appears to be more common in non-GI MALT lymphomas.26 Bone marrow involvement is reported in up to 20% of cases.37 Within the stomach, MALT lymphoma is often multifocal, which may explain the report of relapses in the gastric stump after surgical excision.5 Gastric MALT lymphoma can disseminate to the intestine38 and to the spleen.39 A concomitant GI and non-GI involvement can be detected in approximately 10% of cases. It has been postulated that dissemination of MALT lymphoma may be because of specific expression of special homing receptors or adhesion molecules on the surface of most B-cells of MALT, either normal or transformed.40 Most patients with MALT lymphoma have a favorable outcome with prolonged overall survival (usually higher than 85% at 5 years).24,34 Patients with unfavorable international prognostic index (IPI) and those with lymph node or bone marrow involvement at presentation, but not those with involvement of multiple mucosal sites, may have a worse prognosis. If initially localized, the disease is generally slow to disseminate. Recurrences may involve either extra-nodal sites or nodal sites. The median timeto-progression is apparently better for the GI compared with the non-GI lymphomas (9 versus 5 years, respectively),35 but no significant differences in overall survival have been shown. Localization may have prognostic relevance because of organspecific clinical problems, which result in particular management strategies but, as different genetic lesions have been reported at different anatomic locations, it may also be possible that different sites have a distinct natural history. However, the frequency of involvement of any particular site, even in large multicenter series, is not high enough to clearly determine whether patients with MALT lymphomas arising at some specific sites have a significantly different survival. In a radiotherapy study from Toronto, gastric and thyroid MALT lymphomas had the best outcome, whereas distant failures were more common for other sites.41 In the multicenter series from the International Extranodal Lymphoma Study Group (IELSG), the patients with the disease initially presenting in the upper airways appeared to include a higher number of patients with advanced disease and had slightly poorer outcome (Table 1). In general, despite frequent relapses, MALT lymphomas most often maintain an indolent Table 1 Clinical features and outcome of MALT lymphomas according to the main presentation site Extranodal Site

Stage IE

Elevated LDH

Stomach

88%

1%

Intestine

56%

Lung Breast Thyroid

Bone Marrow Involvement

5-Year OS (95% CI)

7.5%

82% (67%–91%)

11%

0

100%

60%

27%

7%

100%

100%

33%

0

100%

60%

10%

0

100%

Ocular adnexaa

84%

26%

13%

94% (77%–98%)

Salivary glands

83%

17%

9%

97% (81%–100%)

Upper airways

50%

42%

33%

46% (7%–80%)

Skin

82%

9%

9%

100%

NA

26

33%

77% (43%–93%)

Multi-organb

Abbreviations: CI, confidence intervals; NA, not applicable; OS, overall survival. a Recalculated from the published34 split data on orbital and conjuntival MALT lymphomas. b Patients with multiple MALT sites with or without nodal or bone marrow (or both) involvement. Data from Pinotti G, Zucca E, Roggero E, et al. Clinical features, treatment and outcome in a series of 93 patients with low-grade gastric MALT lymphoma. Leuk Lymphoma 1997;26:529; Zucca E, Conconi A, Pedrinis E, et al. Nongastric marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue. Blood 2003;101:2490–1.

Marginal Zone Lymphomas

course. Histologic transformation to large cell lymphoma is reported in about 10% of the cases, usually as a late event and independently from dissemination.24 Recommended staging procedures

The traditional Ann Arbor staging system, which is based on lymph node involvement, can be misleading in MALT lymphomas. Alternative staging systems for extranodal lymphomas had been proposed in the 1970s,42 but still a general consensus has not been achieved.43,44 The presence of asymptomatic dissemination in patients with apparently localized disease38 and the relatively common presentation with early dissemination24,34,36 appear valid reasons to suggest extensive staging procedures in all patients with MALT lymphoma.36 On the other hand, however, many patients with disseminated disease seem to have the same long-term outcome of those with localized disease. Moreover, in retrospective comparisons of different therapeutic approaches, in spite of higher complete response rate with surgery, no difference in survival was found between the treatment subsets (local treatment with surgery or radiotherapy versus systemic treatment with chemotherapy versus combined modality).12,45 Thus, outside clinical trials, it is the authors’ opinion that aggressive staging procedures should be tailored to the individual patient according to the clinical conditions (presenting localization, age, intended treatment, performance status, and symptoms). In general, the staging procedures for all locations of MALT lymphoma should comprise a complete clinical history and the physical examination with a careful evaluation of all lymph nodes regions, inspection of the upper airways and tonsils, thyroid examination, and clinical evaluation of the size of liver and spleen. Standard poster anterior and lateral chest radiographs and a computed tomography scan of thorax, abdomen, and pelvis should be performed. Bone marrow biopsy must be performed at diagnosis. Laboratory tests should include complete blood counts with cytologic examination, LDH and beta-2-microglobulin levels, evaluation of renal and liver function, serology for hepatitis C virus (HCV) and HIV infections. Utility of positron emission tomography scan is controversial.46–48 Then, according to the particular clinical presentation, the investigations may focus on specific organs. Endoscopy and endoscopic ultrasound are indicated in GI presentations, bronchoscopy with bronchoalveolar lavage may be useful in lung lesions, and mammography and MRI in cases presenting in the breast. Particular attention should finally be paid to the demonstration of certain chronic infections that may have a pathogenetic role (H. pylori, B. burgdorferi, C. psittaci, C. jejuni). Staging procedures and risk assessment in gastric MALT lymphoma

Because the stomach is the most common and best-studied site of MALT lymphoma and has peculiar therapeutic strategies, it is convenient to discuss separately the main diagnostic and clinical aspects of the gastric presentation. Non-specific upper GI complaints (dyspepsia, epigastric pain, nausea, and chronic manifestations of GI bleeding, such as anemia) are the most common presenting symptoms of gastric MALT lymphoma that often lead to an endoscopic evaluation. Gastroscopy usually reveals nonspecific gastritis or peptic ulcer, with mass lesions being unusual. Diagnosis is based on the histopathologic evaluation of the gastric biopsies.5,26 Which is the best staging system is still controversial26,43 and a variety of alternative systems have been proposed. The authors have largely used the modification of the Blackledge staging system, known as the ‘‘Lugano staging system.’’49 However, this system was proposed before the wide use of endoscopic ultrasound and does

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not accurately describe the depth of infiltration in the gastric wall, a parameter that is highly predictive for the MALT lymphoma response to anti-Helicobacter therapy. Indeed, there is a general consensus that initial staging procedures should include a gastroduodenal endoscopy, with multiple biopsies from each region of the stomach, duodenum, gastro-esophageal junction, and from any abnormal-appearing site. Fresh biopsy and washing material should be available for cytogenetic studies in addition to routine histology and immunohistochemistry. A molecular genetic or a fluorescence in situ hybridization analysis for detection of t(11;18) may be useful for identifying disease that is unlikely to respond to antibiotic therapy.50 The presence of active H. pylori infection must be determined by histochemistry (Genta stain or Warthin-Starry stain) and breath test; serology studies are recommended when the results of histology are negative. Endoscopic ultrasound is recommended in the initial follow-up for evaluation of depth of infiltration and presence of perigastric lymph nodes. Indeed, patients with deep infiltration of the gastric wall carry a higher risk of lymph node involvement, and show a lower response rate after antibiotic therapy.13–15 Although the disease remains usually localized in the stomach, systemic dissemination and bone marrow involvement should be excluded at presentation because prognosis is worse with advanced stage or adverse IPI.5 Management and Follow-up H. pylori eradication in gastric MALT lymphoma

More than 20 reported (nonrandomized) studies repeatedly confirmed that remission of the lymphoma could be obtained in the majority of patients treated with antihelicobacter therapy,17,51–53 with high probabilities of long-term disease control.54–56 Therefore, H. Pylori eradication with antibiotics is today the widely accepted initial standard treatment for stage I gastric lymphoma of MALT type.57,58 The histologic remission can usually be documented within 6 months from the H. pylori eradication but sometimes the period required is more prolonged and the therapeutic response may be delayed up to more than 1 year.5 Several effective anti-H. pylori programs are available and any of them can be employed.59 The choice should be based on the epidemiology of the infection in the different countries, taking into account the locally expected antibiotic resistance. The most commonly used regimen is triple therapy with a proton pump inhibitor (eg, omeprazole, lansoprazole, pantoprazole, or esomeprazole), in association with amoxicillin, and clarithromycin. Metronidazole can be substituted for amoxicillin in penicillin-allergic individuals. Other regimens that include bismuth, or H2-receptor antagonists (rather than proton pump inhibitors) with antibiotics are also effective. A number of molecular follow-up studies showed that postantibiotic histologic and endoscopic remission does not necessarily mean a cure; the authors and others described a frequent long-term persistence of monoclonal B-cell after histologic regression of the lymphoma.60–63 In these cases, watchful waiting is recommended.57 Indeed, most of the patients with molecular residual disease did not have a frank lymphoma relapse and the clinical relevance of the detection of monoclonality remains unclear. The need of molecular studies as a part of the routine follow-up procedures is, therefore, questionable. Transient histologic relapses have also been described, suggesting that the neoplastic clone can again temporarily expand, but without the growth stimulus from H. pylori this may usually remain a self-limiting event.64 A strict follow-up is nevertheless advisable, and histologic evaluation of repeated biopsies is the fundamental follow-up procedure.57 There is growing evidence that in case of persistent but stable residual histologic MALT lymphoma infiltrates, a ‘‘wait-andsee’’ policy may be safe.55,56,64,65

Marginal Zone Lymphomas

Anti-Helicobacter therapy in diffuse large B-cell lymphoma of the stomach

Gastric lymphoma with diffuse large cell infiltration should be treated according to the recommendations for diffuse large cell lymphomas. Nevertheless, the efficacy of antiHelicobacter therapy has been reported in some localized cases of diffuse large B-cell lymphoma of the stomach, suggesting that high-grade transformation is not necessarily associated with the loss of H. pylori dependence.66 At present, however, this approach has not yet been validated by prospective studies and the sole antibiotic therapy for gastric large cell lymphoma cannot be advised outside clinical trials. Posttreatment histologic evaluation

The interpretation of residual lymphoid infiltrate in gastric biopsies after antibiotic treatment can be very difficult and there are no uniform criteria for the definition of histologic remission. The histologic score proposed by Wotherspoon in 1993.7 is very useful to express the degree of confidence in the MALT lymphoma diagnosis, but it is often difficult to use in the evaluation of the response to therapy on small gastric biopsies and other criteria have also been proposed (Table 2).11,67 This lack of standard reproducible criteria can affect the comparison of the results of the different clinical trials and may explain the relatively wide range of complete responses in the literature reports. Factors predicting the lymphoma response to H. pylori eradication

The large majority of gastric MALT lymphomas can be cured by H. pylori eradication; nevertheless, it would be very useful to identify, at the time of diagnosis, the cases that will not respond to H pylori eradication. In general, lymphomas at stage II or above do not respond to H pylori eradication because a response to antibiotic therapy is unlikely in the cases with documented nodal involvement.14,15,68 However, the majority of gastric MALT lymphomas at diagnosis are at stage IE and the prognostic value of staging in these cases is limited. In this setting, endoscopic ultrasound can be useful to predict the lymphoma response to H. pylori eradication. Several studies showed that there is a significant difference between the response rates of lymphomas restricted to the gastric mucosa and those with less superficial lesions.13,16 The response rate is highest for the mucosa-confined lymphomas (approximately 70%–90%) and then decreases markedly and progressively for the tumors infiltrating the submucosa, the muscularis propria, and the serosa. Liu and colleagues50,69 have shown that the t(11;18) was present in only 10% of tumors confined to the gastric wall but in 78% of those disseminated beyond the stomach. As stated before, the presence of the t(11;18) translocation can predict the therapeutic response of gastric MALT lymphoma to H. pylori eradication but not necessarily to other therapeutic approaches.30,31 H. pylori-independent status is often associated with nuclear translocation of BCL10 and gastric MALT lymphomas with strong BCL10 nuclear expression or t(1;14) are also usually resistant to H. pylori eradication.70 Indeed, the frequencies of t(11;18)(q21;q21) and BCL10 nuclear expression are significantly higher in the H. pylori-negative than in the H. pylori-positive cases.71 Management of H. pylori-negative or antibiotic-resistant cases

No definite guidelines exist for the management of the subset of H. pylori-negative cases and for the patients who fail antibiotic therapy.57 In two retrospective series of patients with gastric low-grade MALT lymphoma, no statistically significant difference was apparent in survival between patients who received different initial treatments (including chemotherapy alone, surgery alone, surgery with additional chemotherapy or radiation therapy or antibiotics against H. pylori).12,45 Patients with a negative H. pylori status and those with persistant gastric lymphoma infiltrates

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Table 2 Different reported criteria to define histologic lymphoma remission in gastric MALT lymphoma endoscopic biopsies after anti-Helicobacter treatment Response

Definition

Histologic Features

Wotherspoon’s score7 Score 0

Complete histologic remission

Normal gastric mucosa with scattered plasma cells in LP.

Score 1

Complete histologic remission

Chronic active gastritis with small clusters of lymphocytes in LP, no lymphoid follicles; no LEL

Score 2

Complete histologic remission

Chronic active gastritis with prominent lymphoid follicles with surrounding mantle zone and plasma cells; no LEL

Score 3

Partial histologic remission

Suspicious lymphoid infiltrate, probably reactive with lymphoid follicles surrounded by small lymphocytes that infiltrate diffusely in LP and occasionally into epithelium

Score 4

No change (persistent lymphoma)

Suspicious lymphoid infiltrate, probably lymphoma with lymphoid follicles surrounded by centrocyte-like cells that infiltrate diffusely in LP and into epithelium in small groups

Score 5

No change (persistent lymphoma)

MALT lymphoma with dense diffuse infiltrate of centrocyte-like cells in LP and prominent LEL

German system9,11 CR

Complete histologic regression

No remnant lymphoma cells detectable in the post-treatment biopsy specimens and ‘‘empty’’ LP with small basal clusters of lymphocytes and scattered plasma cells

PR

Partial histologic regression

Only partial depletion of atypical lymphoid cells from the LP or focal LEL

NC

No change (low-grade gastric MALT lymphoma)

Unequivocal evidence of LEL and replacement of the gastric glands by uniform centrocyte-like cells

Groupe d’Etudes des Lymphomes de L’Adulte grading system67 CR

Complete histologic remission

Normal or empty LP or fibrosis with absent or scattered plasma cells and small lymphoid cells in the LP, no LEL

pMRD

Probable minimal residual disease

Empty LP or fibrosis with aggregates of lymphoid cells or lymphoid nodules in the LP/MM or SM, no LEL

rRD

Responding residual disease

Focal empty LP or fibrosis with dense, diffuse or nodular lymphoid infiltrate, extending around glands in the LP, focal LEL or absent

NC

No change

Dense, diffuse or nodular lymphoid infiltrate, LEL usually present

Abbreviations: LEL, lymphoepithelial lesions; LP, lamina propria; MM, muscolaris mucosa; SM, submucosa. Data from Refs.7,11,67

Marginal Zone Lymphomas

following effective anti-Helicobacter treatment are usually referred for oncologic treatments (irradiation, surgery, chemotherapy, immunotherapy or a combination of these).72 However, these patients do not necessarily need prompt aggressive lymphoma therapy. Indeed, response to antibiotic treatment can sometimes be observed also in H. pylori-negative patients, especially if they are not carrying t(11;18)(q21;q21).71 Moreover, most patients with persistent but stable minimal histologic residuals of gastric MALT lymphoma after successful eradication of H. pylori appear to have a favorable disease course without oncologic treatment.56,65 Thus, a ‘‘wait-and-see’’ strategy with regular endoscopies and biopsies appears to be safe and should be considered in this situation. There are no published randomized studies to help the treatment choice when treatment is needed. Surgery has been widely and successfully used in the past, but the precise role for surgical resection should be redefined in view of the promising results of the conservative approach.5 Excellent disease control using radiation therapy has been reported by several institutions, supporting the approach that involved-field radiotherapy (30–36 Gy given in 4 weeks of radiation to the stomach and perigastric nodes) is the treatment of choice for patients with stage I-II MALT lymphoma of the stomach without evidence of H. pylori infection or with persistent lymphoma after antibiotics.41,73,74 Patients with systemic disease should be considered for systemic treatment with chemotherapy or immunotherapy with anti CD20 monoclonal antibodies.17,75 In the presence of disseminated or advanced disease, chemotherapy is an obvious choice, but only few compounds and regimens have been tested specifically in MALT lymphomas. Oral alkylatyng agents (either cyclophosphamide or chlorambucil, with median treatment duration of 1 year) can result in a high rate of disease control.68,76 More recent phase II studies demonstrated the antitumor activity of the purine analogs fludarabine77 and cladribine (2-CDA),78 which might however be associated with an increased risk of secondary myelodysplasic syndrome,79 and of a combination regimen of chlorambucil/mitoxantrone/prednisone.80 Aggressive anthracyclinecontaining chemotherapy should be reserved for patients with high tumor burden (bulky masses, high IPI score).81 The activity of rituximab has been shown in a phase II studies (with response rate of about 70%) and may represent an additional option.30,82,83 The efficacy of the combination of rituximab with chemotherapy is being explored in a phase III study of the IELSG. Management of nongastric localizations

Nongastric MALT lymphomas have been difficult to characterize because these tumors are widely distributed throughout the body and it is difficult to assemble adequate series of any single site. At least one-fourth of non-GI MALT lymphomas has been reported to present with involvement of multiple mucosal sites with or without the participation of nonmucosal sites, such as bone marrow and lymph nodes.24,34,36 Non-GI MALT lymphomas, despite presenting with stage IV disease more often than the gastric variant, usually have a quite indolent course. In a multicenter retrospective survey of 180 nongastric cases observed over a long period, subjects were treated according to the current policy of each institution at the time of diagnosis. This study showed no evidence of a clear advantage for any type of therapy and, despite the high proportion of cases with disseminated disease, which should require a systemic approach, no clear advantage was associated with a chemotherapy program.34 In general, the consideration previously done regarding the treatment of H. pylorinegative cases can be applied to nongastric MALT lymphoma. Radiation therapy is the best studied approach and is considered the treatment of choice for localized

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lesions.74 The finding that C. psittaci is associated with MALT lymphoma of the ocular adnexa may provide the rationale for the antibiotic treatment of localized lesions. Preliminary encouraging results have been reported but need to be confirmed by additional prospective studies and at present this approach should be considered investigational.84 In general, the optimal management of disseminated MALT lymphomas is less clearly defined and should take into account the site, the stage, and the clinical characteristics of the individual patient. Immunoproliferative small intestinal disease

IPSID, also known as Mediterranean lymphoma or alpha-heavy-chain disease, is today considered a special variant of MALT lymphoma.3,85 It is characterized by a diffuse lymphoplasmacytic/plasmacytic infiltrate in the proximal small intestine.86 The distinguishing feature of IPSID is the synthesis of alpha-heavy chain. Most of the cases have been described in the Middle East, especially in the Mediterranean area where the disease is endemic, affecting young adults of both sexes but predominantly the males. A few cases have been reported from industrialized Western countries, usually among immigrants from the endemic area.85 The IPSID natural course is usually prolonged, often over many years, including a potentially reversible early phase, with the disease usually confined to the abdomen. It was already known in the 1970s that in the early phases of IPSID, durable remissions can be obtained with sustained treatment with antibiotics, but only in 2004 Lecuit and colleagues20 demonstrated the presence of a specific pathogen, linking this lymphoma to C. jejuni. In early-stage disease antibiotic treatment directed against C. jejuni may lead to lymphoma regression.20 However, there is no clear evidence that antibiotics alone are of benefit in the advanced phases. Surgery has a diagnostic but no therapeutic role because intestinal involvement is generally diffuse. Although the early studies reported that aggressive chemotherapy is not well tolerated by patients with advanced disease and severe malabsorption who then have poor survival rates, more recent data suggest that anthracycline-containing regimens, combined with nutritional support plus antibiotics to control diarrhea and malabsorption, may offer the best chance of cure.85,86 PRIMARY SPLENIC MARGINAL ZONE LYMPHOMA (WITH OR WITHOUT CIRCULATING VILLOUS LYMPHOCYTES)

Splenic MZL (SMZL) is a very rare disorder, comprising less than 2% of all lymphoid malignancies.87 The term SMZL was first used in 1992 to describe a primary splenic indolent lymphoma with the morphology and immunophenotype of splenic marginal zone lymphocytes and a micronodular pattern of spleen involvement.88 Up to twothirds of the patients with SMZL present circulating villous lymphocytes with characteristic fine cytoplasm polar projections. When these are more than 20% of the lymphocyte count, the term ‘‘splenic lymphoma with villous lymphocytes’’ is commonly used. In the WHO classification, SMZL with or without villous lymphocytes is considered as a separate entity.89 cDNA microarray expression profiling and tissue microarray immunohistochemical studies showed a largely homogenous signature of SMZLs, suggesting the existence of a single molecular entity.90,91 Revised guidelines for its diagnosis, staging, and treatment was proposed by a panel of experts in 2007.87 In series from southern Europe, HCV seems to be involved in lymphomagenesis, but there are relevant geographic variations.92–99 Very interesting is the observation that some patients with splenic lymphoma with villous lymphocyes and HCV infection obtained a complete remission after treatment with interferon alfa.100 Interferon treatment had no antitumor effect on HCV-negative SMZL. These data,

Marginal Zone Lymphomas

confirmed also by other groups,99 suggest a pathogenetic relationship between HCV and some cases of SMZL. Most patients with primary SMZL are over 60, with a similar incidence in males and females.87 The disease usually presents with massive splenomegay, which produces abdominal discomfort and pain. Diagnosis is often made at splenectomy performed to establish the cause of unexplained spleen enlargement. According to the WHO classification, the peripheral lymph node involvement is typically absent,101 but some reports refer to SMZL even with some evidence of peripheral nodal or extranodal involvement.102 Patients with disseminated marginal zone lymphomas can be observed in advanced stages of either SMZL or nodal MZL or extranodal MZL,103 and a precise diagnosis can be very difficult in cases presenting with concomitant splenic, extranodal, and nodal involvement. In a retrospective French series of 124 patients with non-MALT type MZL,104 four clinical subtypes were observed: splenic (48% of cases), nodal (30%), disseminated (splenic and nodal, 16%), and leukemic (not splenic nor nodal, 6%). Even when the disease is restricted to the cases presenting with splenomegaly, nearly all patients have bone marrow involvement, often accompanied by involvement of peripheral blood (defined as the present of absolute lymphocytosis of more than 5%),102 Because of the high frequency of bone marrow or liver involvement, about 95% of cases are classified as Ann Arbor stage IV. The clinical course is most usually indolent, with 5-year overall survival ranging from 65% to 80%. Histologic transformation is rare, often associated with B-symptoms, disease dissemination and poorer outcome.81 Most patients can be initially managed with a ‘‘wait-and-see’’ policy, and they did not seem to have a worst outcome.87,102–106 All the cases should be tested for HCV infection and antiviral therapy should be considered in the positive cases before any decision about more aggressive therapeutic approaches. Interferon-alpha (or pegylated interferon) alone or in combination with Ribavirine could be used according to the HCV genotype.87 When treatment is needed, this is usually because of large symptomatic splenomegaly or cytopenias. Splenectomy appears to be the treatment of choice in patients with bulky spleen or hypersplenism and no evidence of HCV infection;87 it allows a reduction or disappearance of circulating tumor lymphocytes and recover of the lymphoma-associated cytopenia.103,105–107 The benefit of splenectomy often persists for several years and time to next treatment can be longer than 5 years. Adjuvant chemotherapy after splenectomy may result in higher rate of complete responses; however, there is no evidence of a survival benefit.103 Chemotherapy alone may be considered for patients who require treatment but have contraindication to splenectomy and for the patient with clinical progression after spleen removal. Alkylating agents (chlorambucil or cyclophosphamide) have been reported to be active and can be used as single agent or in combination (as in the cyclophosphamide, vincristine, prednisone or CVP and cyclophosphamide-hydroxydaunomycin oncovin prednisone or CHOP regimens). Among the purine analogs, Fludarabine has been shown to be effective108 and can be used alone or in combination with cyclophosphamide.87 Rituximab, alone or in combination with chemotherapy is very active109–111 and rituximab alone can be the treatment of choice in elderly patients and in those with impaired renal function.87 NODAL MARGINAL ZONE LYMPHOMA (MONOCYTOID LYMPHOMA)

Nodal MZL is very rare and accounts for less than 1% of all lymphomas.2,81 It also has been associated with HCV infection in some epidemiologic studies.98,99 This type of

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lymphoma is a disease of older people, with the median age at presentation in the sixth decade, and affects both sexes, with a slight female predominance. In contrast with mucosa-based extranodal MALT lymphoma, nodal marginal zone (nodal MZL) lymphoma typically affects the lymph-nodes.112 A common presenting feature is a localized adenopathy, most often in the neck. Concurrent extranodal involvement, most often of the salivary gland, is not rare, and some patients have a history of Sjo¨gren’s syndrome or other autoimmune diseases, suggesting a possible overlap with extranodal MALT lymphomas. Many patients present with generalized adenopathy. Bone marrow is involved at presentation in less than half of the cases. Transformation to high-grade lymphoma has been described in some cases. There is at present no consensus about the best treatment, individual cases being managed differently according to site and stage. In the above-mentioned French series of non-MALT marginal zone B-cell lymphomas,104 the nodal cases comprised 30% of patients and showed a more aggressive behavior. Nodal and disseminated subtypes had shorter median time-to-progression (about 1 year) in comparison with the splenic and leukemic subtypes (median time to progression longer than 5 years). The cases with disseminated disease more often presented with poor prognosis parameters (high LDH and beta 2 microglobulin, poor performance status, bulky disease) and might represent the end-stage of the other subtypes.103,104 However, in all subsets, even if the median time-to-progression was short, a prolonged overall survival was observed (splenic, 9 years; nodal, 5.5 years; disseminated 15 years; leukemic 7 years). The retrospective nature of the published studies precludes any conclusion on the therapeutic aspects and treatment decision should be based on the histologic and clinical features of the individual patient.98,113 Conservative treatments seem recommended for leukemic and splenic subtypes, while in nodal and disseminated subtypes front-line chemotherapy may be considered. Treatment options may include single agent chlorambucil or fludarabine or combination chemotherapy regimens (such as the CVP or CHOP). Rituximab may also have some efficacy114 and can be combined with chemotherapy;81 anti-HCV treatment may induce lymphoma regression in some HCV-infected patients.115 Autologous transplantation has been used in younger patients with adverse prognostic factors or increased large cell number.104 REFERENCES

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