Clinical Aspects of Malt Lymphomas

LYMPHOMAS (G NOWAKOWSKI, SECTION EDITOR)

Clinical Aspects of Malt Lymphomas

Christina Kalpadakis & Gerassimos A. Pangalis & Theodoros P. Vassilakopoulos &

Stavroula Kyriakaki & Xanthi Yiakoumis & Sotirios Sachanas & Maria Moschogiannis &Pantelis Tsirkinidis & Penelope Korkolopoulou & Helen A. Papadaki &Maria K. Angelopoulou

Published online: 21 September 2014# Springer Science+Business Media New York 2014

Abstract Extranodal marginal zone lymphoma of themucosa-associated lymphoid tissue (MALT) is an indolentlymphoma arising in extranodal sites. Several infectiousagents and autoimmune disorders have been implicated in its

pathogenesis. The stomach represents the most common andbest-studied organ involved by MALT lymphoma and itsdevelopment is strongly associated with Helicobacter pylori(Hp) infection. MALT lymphomas are characterized by anindolent clinical course and excellent survival in most cases,independently of the treatment delivered. Recent progress inthe knowledge of the etiology and the cellular and molecularpathological events related to MALT lymphomas allowed usto improve our clinical understanding of this disease entityand to better define treatment strategies.

Keywords Malt lymphomas . B-cell lymphoma . Extranodalmarginal zone lymphoma

Introduction

In 1983, Isaacson and Wright introduced the concept ofmucosa-associated lymphoid tissue (MALT) lymphomas [1].MALT lymphomas are currently recognized, according to theWorld Health Organization (WHO) classification, as a distinctcategory of low-grade B-cell lymphoma with unique patho-genic, cytogenetic, histological, and clinical features [2].MALT lymphomas may arise at any anatomical site. The mostcommon and best-studied localization is the stomach [3]. Thispaper reviews the main features of MALT lymphomas andtheir current treatment approaches.

Epidemiology

MALT-lymphoma is the third most common non-Hodgkinlymphoma in the Western world, accounting for approxi-mately 8 % of all non-Hodgkin lymphomas [4]. In arecent Surveillance, Epidemiology, and End Results(SEERS) database analysis in a total of 15,908 patientswith marginal zone lymphoma (MZL), MALT lymphoma

C. Kalpadakis (*) : S. Kyriakaki :H. A. PapadakiDepartment of Haematology, Heraklion University Hospital,University of Crete, POBOX 1352, Heraklion, Crete, Greecee-mail: [email protected]

S. Kyriakakie-mail: [email protected]

H. A. Papadakie-mail: [email protected]

G. A. Pangalis :X. Yiakoumis : S. Sachanas :M. Moschogiannis :P. TsirkinidisDepartment of Haematology, Athens Medical Center, PsychiconBranch, Athens, Greece

G. A. Pangalise-mail: [email protected]

X. Yiakoumise-mail: [email protected]

S. Sachanase-mail: [email protected]

M. Moschogiannise-mail: [email protected]

P. Tsirkinidise-mail: [email protected]

P. KorkolopoulouDepartment of Pathology, University of Athens, Athens, Greecee-mail: [email protected]

T. P. Vassilakopoulos :M. K. AngelopoulouDepartment of Haematology, Laikon General Hospital, University ofAthens, Athens, Greece

T. P. Vassilakopoulose-mail: [email protected]

M. K. Angelopouloue-mail: [email protected]

Curr Hematol Malig Rep (2014) 9:262–272DOI 10.1007/s11899-014-0218-1

was the most common subtype, with an incidence rate of1.59 per 100,000 adults and constituting 5 % of all B-celllymphomas [5]. The incidence increases with age and themedian age of occurrence is around 60 years with a slightfemale predominance. MALT lymphomas may arise at anyextranodal site. The stomach is the most frequently in-volved localization, representing more than one-third ofMALT lymphoma cases [6]. Other frequently involvedsites include: salivary glands, ocular adnexa, skin, lung,and small intestine. There is a geographic variability ofthe various anatomic locations, mainly reflecting differentepidemiological risk factor distribution.

Epidemiological Associations of Various Factorsand the Development of MALT Lymphomas

Infectious Agents

Helicobacter pylori (Hp) infection has been detected in up to90 % of gastric MALT lymphomas and represents the stron-gest associat ion between a causat ive agent andlymphomatogenesis [7].

Chlamydophyla psittaci (Cp) has been associated withthe development of MALT lymphomas in ocular adnexa[8]. Its prevalence displays marked geographic variability.Studies from Italy, Austria, Germany, and Korea havereported a high prevalence of Cp in ocular adnexal lym-phoma (OALs), ranging from 47 to 80 %, while studiesfrom the United States have not reproduced these results[8].

Borrelia burdgorferi (Bb) has been associated with thedevelopment of cutaneous MALT lymphoma. A geographicalvariation has also been reported in the prevalence of Bb incutaneous MALT lymphomas, ranging from 10 to 42 % inendemic areas such as Europe, while being absent in non-endemic areas [8].

Cambylobacter jejuni (Cj) has been implicated in the path-ogenesis of immunoproliferative small intestine disease(IPSID), a variant of MALT lymphoma [9].

Autoimmune Disorders

There is a strong association between Sjogren syndrome (SS)or lymphoepithelial sieladenitis and the development ofMALT lymphomas, mainly those affecting the salivary glands[10]. Patients with SS have a 44-fold increase in the risk ofdeveloping a MALT lymphoma.

Hashimoto’s Thyroiditis represents a common backgroundfor the development of thyroid MALT lymphoma, since in94 % of thyroid lymphomas there is evidence of underlyinglymphocytic thyroiditis [11]. Patients with Hashimoto’s thy-roiditis have a three-fold excess risk of developinglymphoma.

Pathogenesis

MALT lymphomatogenesis is a multistep process initiated bychronic antigenic stimulation, which leads to the assembly ofpolyclonal B-lymphocytes in extra nodal sites and the forma-tion of acquired MALT [12]. This chronic inflammation maybe due to either chronic infection or the autoimmune processes[13]. Sustained antigenic or auto antigenic stimulation pro-motes not only polyclonal B-cell proliferation, but also trig-gers the assembly of various microenvironmental componentsto the site of inflammation [14••] and may promote the selec-tion of auto-reactive B-cell clones. Genomic instability even-tually may lead to the prevalence of a monoclonal B-cellpopulation (Figure 1) [12, 15]. Gastric MALT lymphomasr e p r e s e n t t h e b e s t - s t u d i e d mod e l f o r MALTlymphomatogenesis. In the early 1990s, Wotherspoon et al.first described a high incidence ofHp gastritis among patientswith gastric MALT lymphoma and that the acquisition ofgastric MALT is developed in Hp-infected individuals, whichin turn facilitates the development of gastric MALT lympho-ma [7]. An inflammatory microenvironment plays an impor-tant role in the pathogenesis of these lymphomas,underscoring the notion that MALT lymphomas are highlydependent on external signals. The most important inflamma-tory components include T-lymphocytes, neutrophils, macro-phages, and endothelium [14••, 16]. T-cells act via two majormechanisms. The first one includes the CD40-CD40 ligandaxis and the expression of Th-2 type cytokines andcostimulatory molecules such as CD86, while the other in-volves the recruitment of regulatory T-cells (T-regs) (CD4+,CD25+, FOXP3+) by tumor B-cells via secretion of the T-regs-attracting chemokines (CCL17, CCL22) [17, 18]. Tumorcell proliferation is strongly enhanced by the presence ofintratumoral CD4+ T cells. The significant role of T-regs isshown by the fact that the depletion of these cells can blocktumor growth, at least in vitro [18]. Another important com-ponent of the inflammatory microenvironment is representedby neutrophils. As a part of the immune response to Hpinfection, neutrophils produce reactive oxygen species(ROS), which in turn cause DNA-damage enhancinglymphomatogenesis [19, 20]. In particular,Hp strains positiveto cytotoxin-associated gene A (CagA) generate a stronginflammatory response and ROS secretion [21]. CagA istranslocated into human B-lymphocytes and acts as anoncoprotein that contributes to lymphomatogenesis by regu-lating intracellular signaling pathways [22]. Monocytes rep-resent a reservoir for pathogens and support MALT lympho-ma progression mainly by releasing a proliferating inducingligand (APRIL) upon Hp infection [23]. Finally, in the endo-thelia, several chemokine and chemokine receptors are veryimportant compounds in the inflammatory milieu [24–29].MicroRNAs (miR) also may play a critical role in MALTl ymphoma t og en e s i s . M iR s a r e imp l i c a t e d i n

Curr Hematol Malig Rep (2014) 9:262–272 263

posttranscriptional gene regulation [30]. Various miRs havebeen shown to be either up- or downregulated in MALTlymphomas [31, 32]. Furthermore, hypermethylation of cer-tain genes such as p16, MGMT, and MINT31 may be animportant epigenetic mechanism in the development ofMALT lymphomas [33–35]. In conclusion, the developmentand progression of early-stage MALT lymphoma is based onthe cooperation of B-cell receptor-derived signals and T-helper cell signals in cooperation with other components ofthe inflammatory microenvironment in some geneticallypredisposed patients.

Immunogenetics

The lymphoma cells express surface rearranged, somaticallymutated immunoglobulins in the vast majority of MALTlymphomas [36–39]. However, in rare cases, mainly thosederived from primary lung localization, the IGHV genes aresomatically unmutated [40]. Approximately half of the casesshow evidence of intraclonal variation and positive and/ornegative selection [36–38, 41]. BCR immunoglobulins showa pattern of polyreactivity, displaying equally strong affinitytoward a diverse panel of foreign, but also self-antigens [42].Moreover, there is an apparently biased usage of certain IGHVgene segments by MALT lymphomas originating in specificanatomical sites [36, 43–47].

Chromosomal Abnormalities

Although antigen stimulation is important for earlylymphomatogenesis, it becomes less relevant as the diseaseprogresses, probably due to the acquisition of additional ge-netic aberrations [48]. Chromosomal rearrangements lead toconstitutive activation of the nuclear factor –κΒ (NF-κB)

signaling pathway, thus providing tumor B-cells with BCR-independent proliferation [48–51]. The most common recur-rent translocations are presented by t (11; 18), t (14; 18), t (1;14) and t (3; 14). Their frequency, biologic role, and anatom-ical distribution are presented on Table 1. The t (11;18) is themost common translocation found in MALT lymphomas,involving up to 25 % of gastric MALT lymphoma and 40–60 % of MALT lymphomas occurring in the small intestineand pulmonary location [21, 49]. It results in the production ofa chimeric oncoprotein API2-MALT1, which leads to theconstitutive activation of NF-Κβ, providing tumor cells withantigen-independent activation and survival. This is in agree-ment with the commonly seen resistance of MALT lympho-mas carrying this translocation to antibiotic therapy [52]. Thetranslocation is often associatedwith disseminated disease andsubmucosal involvement. It is more frequent in Hp-negativecases, is absent in Hp-positive gastritis, but is often found ingastric MALT lymphoma patients infected with CagA-positive Hp strains [21]. Despite the initial notion that it isinfrequently associated with diffuse, large B-cell lymphomatransformation, recent data suggests that t (11; 18) can befound at approximately equivalent frequencies in both gastricMALT lymphoma and gastric DLBCL [53]. t (11; 18) ishighly specific for MALT lymphoma and it is rarely seen withother cytogenetic abnormalities [54].

The different pattern of cytogenetic abnormalities in thevarious anatomic locations probably implies distinct processesof lymphomatogenesis [55].

Besides the aforementioned recurrent translocations, sev-eral other genetic aberrations have been described in MALTlymphomas with varying frequency. Numerical chromosomeabnormalities, mainly trisomies, are commonly detected inMALT lymphomas, but are nonspecific. Trisomy 3q27 is themost common chromosomal abnormality in gastrointestinal(GI) lymphomas, being present in about 50–60 % of cases[56]. Trisomy 18 may be seen either alone or in association

Fig. 1 Main pathogeneticpathways of gastric MALTlymphoma

264 Curr Hematol Malig Rep (2014) 9:262–272

with trisomy 3, and both of them are associated with advanceddisease stage. The pathogenic role of these two gains is stillundefined. The 6q23.3 deletion is another frequently recurrentgenetic abnormality, which occurs in approximately 15–30 %of cases [56]. It affects the TNFAIP3 (tumor necrosis factor,alpha-induced protein 3) gene, also known as A20, which isinvolved in limiting the activity of the NF-Κβ pathway. Inac-tivation of A20 also occurs by mutations, similarly to SMZL.In contrast to chromosomal translocations, unbalanced geno-mic aberrations display no preferential anatomical distribu-tion. Other less frequent genetic aberrations include: del17p, +8q, and +6p. Several other somatic genetic alterations havebeen described in the literature with varying frequencies,mainly depending on the anatomical localization as well asthe geographical locales [57].

Diagnosis

Tissue Sampling and Macroscopic Findings

The diagnosis of MALT lymphomas is highly dependent onthe sampling of a representative tissue. This is especiallyimportant in gastric MALT lymphomas since they are usuallymimicking chronic gastritis.

Histopathological Findings

The establishment of diagnosis is based entirely on the histo-pathological and immunohistochemical examination. In early1980s, Isaacson and Wright observed that certain lymphomasof the GI tract recapitulated features of the MALT of Peyerpatches [58]. MALT lymphomas rarely arise in sites of nativeMALT.

Histopathology

Tumor cells infiltrate the marginal zone of reactive B-cellfollicles and spread out to form larger confluent areas andsometimes colonize germinal centers of the reactive follicles,resulting in a nodular pattern. Lymphoma cells often invadeand destroy the glandular epithelium with the formation of thelymphoepithelial lesions (LEL). These are defined as aggre-gates of more than three lymphoma cells within the glandularepithelium. Even though LEL are characteristic, they are notspecific for MALT lymphomas, since they can also be presentin reactive conditions as well as in other lymphomas. Thelymphomatous population is heterogeneous, consisting ofsmall lymphocytes, centrocyte-like cells, monocytoid, andplasmacytoid cells. In some cases plasmacytic differentiationis prominent. Large cells are scattered within the lymphoidpopulation, usually comprising less than 20 % of the totalpopulation. In rare cases in which the blast cells form solid orsheet-like proliferations, the diagnosis should be that of adiffuse, large B-cell lymphoma. Besides the tumor cells, areactive population is also recognized, consisting mainly of T-lymphocytes, neutrophils, and monocytoid cells [2].

Immunohistochemistry

Lymphoma cells typically express IgM, less often IgA or IgG,and are usually IgD-negative. Their immunophenotype reca-pitulates that of marginal zone cells. They are positive forCD20, CD79a, BCL-2, CD21, and CD35, while they arenegative for CD5, CD10, CD23, and cyclinD1. Expressionof CD11c is variable, while CD43 is expressed in approxi-mately 30–50% of cases. The demonstration of immunoglob-ulin light chain restriction helps to differentiate MALT lym-phomas from a reactive lymphoid infiltrate [2]. Recently, twonew immunohistochemical markers have been reported to becharacteristic for MALT lymphomas: immunoglobulin

Table 1 The most common recurrent chromosomal abnormalities of MALT lymphomas

TRANSLOCATION

FUSIONPROTEIN

MALTLOCATION

FREQUENCY%

CLINICALIMPACT

Mechanism ofAction

Available assay

t(11;18) (q21;p21) API2-MALT1 GI, lung 15-40 Hp independence,advanced diseasestage, alkylatingagents resistance

NF-κΒ activation FISH, PCR, BCL10IHC (nuclear)

t(14;18) (q32;q21) IGHV-MALT1 Lung, salivarygland, ocular,adnexa, skin,

liver

20 NF-κΒ activation FISH, PCR, BCL10,MALT-1 IHC(cytoplasmic)

t(1;14) (p22;q32) IGHV-BCL10 GI, lung 1-2 Hp independence NF-κΒ activation BCL10 IHC(nuclear)

t(3;14) (p13;q32) FOXP1-IGHV Thyroid, ocularadnexa, skin

<5 Adverse prognosis Unknown FISH,PCR


receptor translocation associated-1 (IRTA-1) and myeloid celldifferentiation nuclear antigen (MDNA). These molecules arealso expressed in other MZL, although IRTA-1 is notexpressed in SMZL [59, 60].

Detection of Monoclonality by PCR

In some instances it is difficult to differentiate MALT lym-phomas from reactive conditions. In such cases, the detectionof monoclonality by polymerase chain reaction (PCR) mayhelp the differential diagnosis. PCR, however, cannot replacethe histopathologic examination. Monoclonality may be de-tected in some cases of chronic inflammation, such asmyoepithelial sieladenitis, while in up to 15% of overt MALTlymphomas monoclonalty is not detected by PCR [61]. Con-sequently, PCR can be used complementary to pathologicalexamination and never alone for the establishment of MALTlymphoma diagnosis.

Clinical Features

Patients usually are asymptomatic or present with symptomsrelated to the primary organ involvement, e.g., for gastricMALT lymphomas the most common presenting symptomsare dyspepsia, nausea, and epigastric pain. Usually there is noimpairment of patient performance status. B-symptoms areextremely rare, and adverse biological prognostic factors suchas high lactate dehydrogenase (LDH) or β2-microglobulinlevels are infrequently elevated [62, 63]. Despite the initialnotion thatMALT lymphomas have a tendency to be localizedat presentation, recent data suggest the opposite, since morethan one-third of the cases display involvement of multipleextranodal sites [62–67]. There is a higher tendency for mul-tiple MALT involvement in extragastric MALT lymphomascompared to gastric ones. Dissemination at presentation hasbeen reported with varying frequencies, probably relating tothe extensiveness of the staging procedures [64, 66]. Bonemarrow is not usually infiltrated (2–15 %). Generalizedlymphadenopathy is also rare (<10 %). The frequency ofparaproteinemia varies depending mainly on the primaryMALT localization.

Prognosis

MALT lymphomas usually run an indolent clinical coursewith long survival. In a retrospective study by the Internation-al Extranodal Lymphoma Study Group (IELSG) of a largeseries of patients with non-gastric MALT lymphoma, the five-year overall survival (OS) was 90 %, despite the fact that one-quarter of cases presented with advanced disease stage and

regardless of treatment type [62]. A recent study evaluatedthe clinical characteristics and survival of patients with MZLsubtypes in the unselected population included in the SEERdatabase [52]. The median OS was 12.6 years with a signifi-cant improvement in the probability of lymphoma-relateddeath for patients with MALT lymphoma that were diagnosedafter 2000, while further improvement was observed after2005. There is no prognostic index specific for MALT lym-phomas. The International Prognostic Index (IPI) has beencorrelated with time to relapse in some studies, while theutility of Follicular Lymphoma IPI (FLIPI) is controversial[68]. The tendency of MALT lymphomas to involve multipleMALT sites at presentation is not associated with inferioroutcome, as it has been shown by various studies [62–67].On the contrary, bone marrow and nodal involvement ad-versely affected overall survival, at least in some series [62].In contrast to extragastric, gastric MALT lymphomas arepresented as localized disease in the majority of cases(~90 %) [63]. The median time to progression is apparentlybetter for the gastric comparedwith the nongastric lymphomas(9 vs. 5 years, respectively), but no significant differences inOS have been shown [66]. Despite frequent relapses, MALTlymphomas most often maintain an indolent clinical course.Primary disease localization may have an impact on outcome[52, 62, 66]. Histologic transformation to large-cell lymphomaoccurs less often than in follicular lymphomas (<10 %) as alate event [64, 67].

Staging Procedures

Gastric MALT Lymphomas

The staging procedures at diagnosis should include anesophagogastroduodenoscopy (EGD), with multiple biopsiesnot only from sites with abnormal appearance but also fromevery region of the stomach, duodenum, and gastroesophagealjunction [69•]. In addition to routine histology, fresh biopsyshould be available for cytogenetic studies, particularly for thedetection of t (11; 18) translocation. The presence of Hpinfection must be determined either by histology or serologystudies. Endoscopic ultrasound is recommended to evaluatethe depth of gastric wall infiltration and regional lymph nodeinvolvement. Other studies should include the typical proce-dures followed for staging any lymphoma (e.g., CBC, bio-chemical studies, whole-body CT scan, bone marrow biopsy).Bone marrow involvement has been reported in up to 15 % ofcases. The value of a positron emission tomography is con-troversial and currently is not recommended in the routinework-up of MALT lymphomas patients [69•]. The best stag-ing system is still not known. The “Paris staging” can ade-quately record the tumor extension and depth of infiltration[70].


Non-Gastric MALT Lymphomas

Since extragastric MALT lymphomas usually present withmultiple MALT involvement, it is important to assess allMALT sites at presentation. Besides the typical staging pro-cedures, further investigation should be guided by the clinicalpresentation. However, the extent of staging procedures is stillcontroversial. Our strategy is to perform upper endoscopy inall extragastric MALT lymphoma cases in addition to theaforementioned investigation, since the stomach representedthe most commonly seen secondary MALT site of involve-ment in our series [66]. Extensive staging is very important,especially when local treatment approaches are going to beused. Moreover, it is highly recommended to search for thedetection of certain chronic infections that may have a patho-genic role. The Ann Arbor staging system has limited value instaging MALT lymphomas [62]. However, there is no alter-native staging system for extragastric MALT lymphomas.

Treatment

Gastric MALT Lymphomas

First-line therapy for gastric MALT lymphoma associatedwith Hp infection is well documented, and includes the erad-ication of Hp with antibiotics and a proton pump inhibitor(PPI) [7]. Several effective antihelicobacter regimens areavailable [71]. The most commonly used regimen includes acombination of PPI plus clarithromycin-based therapy witheither amoxicillin or metronidazole for 10-14 days. In caseswith persistentHp infection a second-line treatment should beused with alternative triple- or quadruble-therapy regimens ofPPI plus antibiotics. Successful eradication ofHp is associatedwith histologic regression of the gastric MALT lymphoma inapproximately 75 % of patients with localized disease [72,73••].

Main factors predicting adverse response to eradicationinclude:

1. Absence of Hp infection, although eradication therapymay also be successful in a small proportion of Hp-neg-ative patients (~15 %) [74].

2. Infiltration beyond the mucosa layers and regional lymphnode involvement. Complete endoscopic and histopatho-logic remission is higher in stage I than in stage II disease,and when lymphoma is confined to the submucosa, ascompared to a deeper invasion [73••].

3. Translocations t (11; 18) and t (1;14) are associated withresistance to Hp eradication therapy, although completelymphoma regression can still be obtained in about 20 %of t (11; 18)-positive cases after Hp eradication [73••].

4. Proximal location has been associated with inferior re-sponse rather than localization in the distal stomach[73••].

5. Patient ethnicity. Asian patients respond better thanWest-ern patients [74].

In addition, increased numbers of Tregs in gastric lympho-ma may be associated with a better response toHp eradicationtherapy [75•]. Furthermore, the over-expression of either miR-142-5p or miR-155 in MALT lymphoma was associated witha lower probability of response to Hp therapy [76].

According to the currently published ESMO guidelines,Hp eradication therapy should be given to all gastric MALTlymphomas, independently of stage and even in Hp-negativecases [69•].

Follow-up of Patients After Eradication Therapy

Lymphoma may take more than 12 months to regress afterHperadication, indicating that refractoriness should not be as-sumed prematurely, even in cases with residual lymphoma atthe histological level [69•]. Eradication of Hp should bechecked for at least six weeks after the end of therapy. Lym-phoma regression should be checked by EGD by 3–6 monthsafter eradication therapy. Patients who have achieved at least aclinical and endoscopic remission should be followed closelywith EGD every 3–6 months, since disease may regress orremain stable in the majority of patients. Detection ofmonoclonality by PCR has no clinical relevance, since it hasbeen shown by several studies that the persistence of mono-clonal B cells is found in almost half of patients with histo-logic regression of MALT lymphoma [61, 77]. The interpre-tation of post-treatment gastric biopsies may be difficultsince there are no uniform reproducible criteria for thedefinition of histologic remission. The recently proposedGELA system may help to solve this problem, although itsreproducibility requires further confirmation [78]. Patients incomplete remission require regular long-term follow-up en-doscopies, not only due to the risk of lymphoma recurrence,but also due to the risk of development of gastric adenocar-cinoma [79]. Endoscopic check-up should be performedevery six months for the first two years and every 12–18months thereafter.

Outcome

Complete remissions achieved after Hp eradication therapyare usually prolonged. Relapses are in the range of 5–17 % inreported series, may occur either with or without Hp infectionrecurrence, and essentially involve the stomach [73••]. In ananalysis of 994 patients, lymphoma relapse occurred in 7.2 %after 3,253 patient-years of follow up, with a yearly recurrencerate of 2.2 % [73••]. Several trials showed that the five-year


OS and disease-free survival (DFS) rates in patients with earlydisease stage were 90 % and 75 %, respectively [80]. The riskof transformation into aggressive lymphoma is lower than inother indolent lymphomas, although it has not yet been clearlydetermined.

Treatment of Patients With Gastric MALT Lymphoma whoFail Antibiotics Treatment as Well as Those With non-GastricMALT

There is no standard treatment approach for the managementof these patients. Primary MALT localization is an importantfactor due to organ-specific problems requiring particulartreatment strategies.

Local Therapies Surgery is an option in some cases, such asin thyroid MALT lymphoma, with excellent long-term,progression-free survival. For gastric MALT lymphoma sys-temic therapies or radiotherapy is suggested as first-line treat-ment, while gastrectomy is not superior to organ preservationstrategies and is no longer considered as a first-line treatmentoption [69•].

Radiotherapy with moderate doses of irradiation (24–30 Gy) has extensively been used and is associated with highresponse rates (>90 %) and long response duration [81, 82].Intralesional rituximab in primary cutaneous MZL proved tobe highly effective, leading to favorable outcome of the dis-ease without the need of systemic treatment or local radiother-apy [83].

Systemic Therapies Systemic therapies including monothera-py or combination chemotherapy and immunotherapy, areeffective in patients with gastric or non-gastric MALT lym-phomas. There is no definitive data to support the choice ofone chemotherapy regimen over the other. Single-agentalkylators, mainly chlorambucil, have shown clinical activitywith acceptable toxicity, although t (11;18) has been associat-ed with refractoriness to alkylating agents [84]. Nucleosideanalogues, mainly cladribine, have been used in phase IIstudies demonstrating significant activity with more than80 % complete responses, albeit with significant toxicity[85]. Combination chemotherapy with chlorambucil plusmitoxantrone and prednisone, as well as fludarabine in com-bination with mitoxantrone and the classic CVP are active andwell-tolerated regimens [86, 87]. Rituximab monotherapy isalso effective in gastric MALT lymphomas regardless oft(11;18) with an overall response rate of 77 %, however,complete responses have been observed in about only half ofthe cases [88]. Levy et al. showed a significantly greaterresponse to rituximab-chlorambucil than to rituximab alonein patients carrying the t(11;18) [89]. A recent randomizedstudy by the IELSG found that the addition of rituximab tochlorambucil was significantly better than chlorambucil alonein terms of event-free survival, with no OS benefit [90•].Aggressive anthracycline-containing regimens are to be re-served for cases with transformation or bulky masses [91].Antibiotic treatment with doxycycline appears to be a reason-able first-line therapy for patients with OAL [92]. Antibiotics,however, remain experimental for the time being in patientswith other non-GI MALT lymphomas [93].

Fig. 2 Suggested MALTlymphoma treatment algorithm


Overall, the results of these studies suggest that bothradiotherapy as well as systemic therapies are effective.For practical reasons, we suggest a treatment algorithmof MALT lymphomas based on the available data(Figure 2).

Novel Agents

Bendamustine alone or in combination with rituximab hasshown significant activity in indolent lymphomas, includingMALT lymphomas [94]. A phase II study demonstrated sig-nificant antitumor activity of lenalidomide [95]. Furthermore,the combination of lenalidomide with rituximab resulted in a90 % response rate [96]. Besides rituximab, other anti-CD20moAbs such as ofatumumab and obinutuzumab (GA101)have been recently tested in several clinical trials in patientswith relapsed/refractory indolent lymphomas with promisingresults [97, 98]. Novel therapies such as BTK-inhibitors,vorinostat, and PI3-K inhibitors are in clinical trials for pa-tients with relapsed or refractory MZL [99, 100]. Everolimusdisplayed moderate activity in a phase II clinical trial includ-ing patients with relapsed/refractory MZL [101]. Bortezomibwas also associated with moderate activity and significanttoxicity in a phase II study [102].

Conclusions

Extraordinary progress has been made regarding the un-derstanding of pathogenesis and clinical behavior ofMALT lymphomas. Chronic inflammation is usually thenecessary background for the development of a MALTlymphoma, while the tissue microenvironment has a sig-nificant role in the establishment of the neoplastic process.Patients with MALT lymphoma have a favorable outcomewithout significant difference between GI or non-GI lym-phoma or between localized and disseminated disease.With the exception of Hp-positive gastric MALT lympho-ma, there are no treatment guidelines for the managementof patients with MALT lymphoma. Therefore, controlledclinical trials are needed in order this goal to be achieved.International study groups are significantly contributing tothis effort.

Compliance with Ethics Guidelines

Conflict of Interest Dr. Christina Kalpadakis, Dr. Gerassimos A.Pangalis, Dr. Theodoros P. Vassilakopoulos, Dr. Stavroula Kyriakaki,Dr. Xanthi Yiakoumis, Dr. Sotirios Sachanas, Dr. Maria Moschogiannis,Dr. Pantelis Tsirkinidis, Dr. Penelope Korkolopoulou, Dr. Helen A.Papadaki, and Dr. Maria K. Angelopoulou each declare no potentialconflicts of interest.

Human and Animal Rights and Informed Consent This article doesnot contain any studies with human or animal subjects performed by anyof the authors.

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Clinical Aspects of Malt Lymphomas