Next Article in Journal
A Few-Shot Learning Approach Assists in the Prognosis Prediction of Magnetic Resonance-Guided Focused Ultrasound for the Local Control of Bone Metastatic Lesions
Next Article in Special Issue
Is There a Role for [18F]FDG PET-CT in Staging MALT Lymphoma?
Previous Article in Journal
Clinical Significance of the Duality of Wnt/β-Catenin Signaling in Human Hepatocellular Carcinoma
Previous Article in Special Issue
Genetic Characterization and Clinical Features of Helicobacter pylori Negative Gastric Mucosa-Associated Lymphoid Tissue Lymphoma
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cancers
Volume 14
Issue 2
10.3390/cancers14020446
cancers-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma in the Gastrointestinal Tract in the Modern Era

by
Eri Ishikawa
1,*,
Masanao Nakamura
1,
Akira Satou
2,
Kazuyuki Shimada
3 and
Shotaro Nakamura
4
1
Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan
2
Department of Surgical Pathology, Aichi Medical University Hospital, Nagakute 480-1195, Japan
3
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan
4
Department of Gastroenterology, International University of Health and Welfare, Fukuoka 814-0001, Japan
*
Author to whom correspondence should be addressed.
Cancers 2022, 14(2), 446; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14020446
Submission received: 14 December 2021 / Revised: 8 January 2022 / Accepted: 12 January 2022 / Published: 17 January 2022
(This article belongs to the Special Issue Management of MALT Lymphoma)
Browse Figures
Review Reports Versions Notes

Abstract

:

Simple Summary

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), which is frequently linked to chronic antigenic stimulation, is clinically an indolent B-cell lymphoma. The most common site is the stomach, accounting for 35% of MALT lymphomas, with a strong association with Helicobacter pylori (H. pylori) infection. Although antibiotic eradication is first-line therapy for gastric MALT lymphoma, a recent trend showing increasing H. pylori-negative cases may require different treatment strategies. Intestinal MALT lymphoma, including immunoproliferative small intestinal disease, is relatively rare, and the pathogenesis and therapeutic approach have not been fully elucidated. In addition, the gastrointestinal tract was recently considered a preferable site of Epstein–Barr-virus-negative marginal zone lymphoma in the post-transplant setting. We review the updated clinicopathological features, treatment, and evolving concepts of MALT lymphoma of the gastrointestinal tract.

Abstract

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) typically arises from sites such as the stomach, where there is no organized lymphoid tissue. Close associations between Helicobacter pylori and gastric MALT lymphoma or Campylobacter jejuni and immunoproliferative small intestinal disease (IPSID) have been established. A subset of tumors is associated with chromosomal rearrangement and/or genetic alterations. This disease often presents as localized disease, requiring diverse treatment approaches, from antibiotic therapy to radiotherapy and immunochemotherapy. Eradication therapy for H. pylori effectively cures gastric MALT lymphoma in most patients. However, treatment strategies for H. pylori-negative gastric MALT lymphoma are still challenging. In addition, the effectiveness of antibiotic therapy has been controversial in intestinal MALT lymphoma, except for IPSID. Endoscopic treatment has been noted to usually achieve complete remission in endoscopically resectable colorectal MALT lymphoma with localized disease. MALT lymphoma has been excluded from post-transplant lymphoproliferative disorders with the exception of Epstein–Barr virus (EBV)-positive marginal zone lymphoma (MZL). We also describe the expanding spectrum of EBV-negative MZL and a close association of the disease with the gastrointestinal tract.

1. Introduction

Marginal zone B-cell lymphoma (MZL) is a group of indolent B-cell lymphomas originating from memory B cells normally present in a distinct compartment, known as the marginal zone of secondary lymphoid tissues. MZL is a heterogeneous disease with three different entities recognized in the 2017 World Health Organization (WHO) classification: nodal marginal zone lymphoma (NMZL), splenic marginal zone lymphoma (SMZL), and extranodal MZL of the mucosa-associated lymphoid tissue (MALT lymphoma).
The most common site of MALT lymphoma is the stomach (35%), followed by the ocular adnexa (13%), lungs (8.8%), salivary glands (8.3%), the colorectum (5.2%), and the small intestine (3.4%) [1]. The disease is frequently linked to immune stimulation by bacterial and/or viral agents (chronic hepatitis C virus), autoimmune diseases (Sjögren syndrome or Hashimoto thyroiditis), or IgG4-related disease. The best evidence of an etiopathogenetic link to bacterial agents is provided by the association between Helicobacter pylori and gastric MALT lymphoma [2]. Other bacterial infections have been found to be implicated in the pathogenesis of MALT lymphoma arising in the skin (Borrelia burgdorferi), the ocular adnexa (Chlamydophilia psittaci), lungs (Achromobacter xylosoxidans), and the small intestine (Campylobacter jejuni). This association is variable in different geographical areas [3,4,5]. Chronic inflammation and/or infection induces the development of oligoclonal and/or monoclonal B-cell populations. In addition, oncogenic events, such as chromosomal alterations and/or translocations, play a relevant role in lymphoma growth and progression to the point that the lymphoproliferative process may eventually become independent of antigenic stimulation.
MALT lymphomas typically have an indolent clinical course [6]. However, approximately 2% of MALT lymphomas undergo histological transformation into aggressive B-cell lymphomas, such as diffuse large B-cell lymphoma (DLBCL), resulting in a worse prognosis [6]. In the gastrointestinal (GI) tract, most gastric MALT lymphomas achieve regression and are effectively cured by the antibiotic eradication of H. pylori [7,8]. However, a recent trend showing increasing H. pylori-negative gastric MALT lymphoma cases may require different treatment strategies [9,10]. A link between C. jejuni infection and immunoproliferative small intestinal disease (IPSID) has also been established, which is classified as a variant of MALT lymphoma, with marked plasma cell differentiation and a favorable response to antibiotic therapy [11,12]. However, in the small and large intestines, only a few reported cases preclude the development of consensus guidelines for MALT lymphoma. Recently, the GI tract has been focused on as the preferable site of MALT lymphoma in the post-transplant setting [13].
In this review, we focus on the recent advances in the diagnosis and treatment of MALT lymphoma affecting the GI tract.

2. Clinicopathological Features of GI Lymphomas

In our experience of 455 patients with GI lymphomas in Kyushu University Hospital, the most common involved site was stomach (342 cases; 75%), followed by the small and large intestines (96 cases; 21%) [14]. The remaining 17 cases had lymphomas both in the stomach and intestines (4%).

2.1. Gastric Lymphomas

The most common histologic type of gastric lymphoma was MALT lymphoma (170 cases, 50%), followed by DLBCL (129 cases, 38%) [14]. Primary gastric MALT lymphoma frequently occurs in patients aged 50–60 years [7,8]. Cases newly diagnosed as gastric MALT lymphoma have decreased in the last decade, which is likely associated with a decline in the prevalence of H. pylori infection among healthy population and/or better control of H. pylori among infected people [15,16]. The association between H. pylori and gastric MALT lymphoma has decreased recently, particularly in the Western world, with instances of H. pylori-positive cases reported to be as low as 33% [17]. Patients with gastric MALT lymphoma are usually asymptomatic and found by screening esophagogastroduodenoscopy (EGD), with approximately 90% of cases having clinical stage I disease [7,8]. Bone marrow involvement is exceedingly rare (3%) [18]. There is an increasing trend of H. pylori-negative gastric MALT lymphoma cases, accounting for 6–40% of recent cases [7,8,9,19,20,21,22,23,24,25,26,27,28]. Compared to H. pylori-positive cases, H. pylori-negative gastric MALT lymphomas tend to be in an advanced clinical stage [24]. Approximately 60% of gastric MALT lymphomas can be detected by fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) or PET/computed tomography (CT) [29].
DLBCL is the second-most-common histologic type in gastric lymphomas. H. pylori infection was observed with and without the MALT lymphoma component (50–70% and 25–40%, respectively).

2.2. Intestinal Lymphomas

MALT lymphoma of the small intestine is relatively rare, with various symptoms, including abdominal pain, bloating, constipation, and diarrhea [30,31,32]. IPSID is classified as a variant of MALT lymphoma, with marked plasma-cell differentiation, and is also known as an α heavy chain disease (αHCD) [12,33]. IPSID has been reported to affect young adults (mean age 32 years) of a low socio-economic status living in poor hygienic conditions. IPSID was also recently diagnosed in renal and liver transplant recipients [34,35]. Malabsorption, intermittent diarrhea, and abdominal pain are the most frequent symptoms [33]. Serologically, roughly half of IPSID patients have elevated IgA levels, and the presence of anomalous α heavy chain protein is detected in 20% to 90% of patients [33,36].
The pathogenesis of colorectal MALT lymphoma is not well understood. Approximately 20% of patients with colorectal MALT lymphoma are H. pylori positive, and other chronic inflammation has not been documented except for a case of rectal MALT lymphoma that was possibly associated with primary biliary cirrhosis and secondary Sjögren syndrome [37,38,39]. MALT lymphoma of the large intestine affects individuals in their fifth through seventh decades, with a female predominance [38,40,41]. The ileocecum and the rectum are commonly affected [40,42]. Of the cases, 75% involved the rectum, including simultaneous involvement of the cecum in one-fifth of these patients [37,38]. Patients with colorectal MALT lymphoma sometimes present with abdominal discomfort, diarrhea, constipation, or a positive fecal occult blood test [40,43]. Approximately 90% of colorectal MALT lymphomas are localized clinical stage Lugano I-II, and bone marrow involvement is rarely seen (4–9%) [37,40,41].

3. Pathogenesis in Relation to Bacterial Infection or Chronic Antigenic Stimulation

H. pylori infection could result in the accumulation of MALT, from which gastric MALT lymphoma arises, though MALT as typified in Peyer’s patches is absent in the normal stomach. Proliferation of gastric MALT lymphoma in response to H. pylori is due to the recognition of H. pylori by tumor-infiltrating T cells [44]. This involves cognate interaction between B and T cells, and bystander T cells help the interaction via soluble ligands and cytokines, such as CD40 ligand and B-cell-activating factor (BAFF), activating the non-canonical nuclear factor (NF)-κB pathway [45].
In H. pylori-negative cases, non-H. pylori Helicobacters (NHPHs; also referred to as H. heilmannii) are occasionally associated with gastric MALT lymphoma [46]. Takigawa et al. reported that 55% of patients with H. pylori-negative gastric MALT lymphoma without a BIRC3-MALT1 chimeric transcript are infected with an NHPH [20]. NHPHs typically have a large spiral-shaped morphology and comprise H. suis, H. felis, H. bizzozeronii, H. salomonis, and Candidatus H. heilmannii, accounting for only 0.1% of cases in which gastric biopsy is performed [47,48]. A higher rate (21%) of NHPH infection was shown by a PCR of the H. pylori-negative cases with gastric disease, mainly including gastric MALT lymphoma, chronic or nodular gastritis, and gastroduodenal ulcer [49]. H. suis is the most prevalent NHPH species in human. Yang et al. indicated that IFN-γ produced by B cells plays an important role in the formation of gastric lymphoid follicles after H. suis infection [50].
Chronic antigenic stimulation with C. jejuni is known to lead to gut-mucosa-associated, IgA-producing plasma cell proliferation. IPSID shares the feature of mutant immunoglobulin heavy chain production, characterized by the deletion of the N-terminus encompassing the variable heavy chain (VH) and the constant heavy chain (CH1) domains [33]. In the absence of the CH1 domain, the mutant heavy chain cannot assemble with a light chain to produce an intact immunoglobulin. Therefore, the disease secretes a monotypic truncated immunoglobulin α heavy chain lacking an associated light chain.

4. Molecular Pathology

Chromosomal translocations associated with MALT lymphomas include t(11;18)(q21;q21), resulting in the production of a chimeric protein (BIRC3-MALT1), and t(1;14)(p22;q32), t(14;18)(q32;q21), and t(3;14)(p14.1;q32), which result in transcriptional deregulation of BCL10, MALT1, and FOXP1, respectively [51]. These different translocations are linked by the roles of BCL10 and MALT1 in the NF-κB molecular pathway in lymphocytes [45]. t(11;18)(q21;q21)/BIRC3(API2)-MALT1 translocation occurs mostly in gastric MALT lymphomas, accounting for 7% to 21% of cases, which are often H. pylori negative but positive for nuclear BCL10. However, t(11;18)/BIRC3(API2)-MALT1 translocation has been detected in 10–42% of intestinal MALT lymphoma cases [52,53].
In H. pylori-positive gastric MALT lymphomas unresponsive to eradication therapy, NF-κB pathway mutations, including TNF-receptor-associated factor 3 (TRAF3) mutations and TNF-alpha-induced protein 3 (TNFAIP3) mutations, and MALT1 translocations are enriched [54]. Furthermore, frequent TNFAIP3 inactivating mutations and translocations in MALT1/IGH have been detected in H. pylori-negative gastric MALT lymphoma, suggesting that the NF-κB pathway can be a major driver in the pathogenesis of this group [10]. In addition, a recent transcriptome analysis showed that long noncoding RNAs GHRLOS and another 44 mRNAs are aberrantly expressed in gastric MALT lymphoma [55]. Other translocations, t(1;14)(p22;q32)/IGH-BCL10 and t(3;14)(p14;q32)/IGH-FOXP1, occur infrequently in gastric and intestinal MALT lymphomas [45,56].

5. Pathological Findings

MALT lymphoma is defined as an extranodal lymphoma composed of morphologically heterogeneous small B cells, including marginal zone (centrocyte-like) cells; monocytoid cells; small lymphocytes; and scattered large cells, such as immunoblasts and centroblast-like cells. Centrocyte-like cells are small- to intermediate-sized cells with a slightly irregular nucleus [56,57]. Clear cells are regarded as a variant of centrocyte-like cells, with an abundant pale cytoplasm. A proportion of cases are accompanied by plasma cell differentiation. Lymphoma cells occasionally invade the epithelium, forming lymphoepithelial lesions (LELs), which are aggregates of three or more marginal zone cells with destruction of the glandular epithelium. The presence of LELs is suggestive of MALT lymphoma in the stomach, but this is not essential for this diagnosis because they can be also seen in other low-grade B-cell lymphomas. In immunohistochemistry, MALT lymphoma cells are CD20+, CD79a+, BCL2+, BCL6−, CD5−, CD10−, and CD23−. A distinction from follicular lymphoma (positive for CD10 and BCL6), mantle cell lymphoma (CD5, cyclin D1, and SOX11), and chronic lymphocytic leukemia (CD5, CD23, and LEF1) is needed.
In cases with IPSID, a dense lymphoplasmacytic infiltrate confined to the mucosa and/or the submucosa is seen in early stages, which may lead to villous blunting or atrophy of the small intestine [58]. The small lymphomatous cells are positive for CD19 and CD20 but negative for CD5, CD10, and CD23. The plasmacytic cell component may only express plasma cell markers, such as CD138 [56]. Both lymphocytes and plasma cells express IgA in the cytoplasm, but not kappa and lambda, immunoglobulin light chain markers [12].
Distinguishing MALT lymphoma from localized lymphoid hyperplasia (LLH) is occasionally challenging. In contrast to MALT lymphoma, LLH is usually characterized by large lymphoid follicles with active germinal centers and a narrow mantle zone and marginal zone. Most LLHs have a benign course and are resolved [59]. The distinction between MALT lymphoma and follicular lymphoma can be problematic, particularly if the biopsy is small and the MALT lymphoma shows follicular colonization associated with up-regulation of CD10 and/or BCL6 in the intrafollicular compartment. In these instances, fluorescent in situ hybridization (FISH) for the t(14;18)/BCL2 gene rearrangement may be helpful.
In gastric MALT lymphoma, diagnosis of a small biopsy specimen using Wotherspoon histological scoring is relevant to show the degree of confidence in making a diagnosis [2]. Because of the difficulty in applying the Wotherspoon system and its low reproducibility, pathologists of Groupe d’Etude des Lymphomes de l’Adulte (GELA) established a post-treatment histological grading system that classifies the morphological features into four categories: complete histological response (ChR), probable minimal residual disease (pMRD), responding/residual disease (rRD), and no change (NC) [60]. Patients with ChR or pMRD are regarded as having a clinical CR and responders, whereas the remaining categories (rRD or NC) are considered to be non-responders.

6. Endoscopic Findings

The endoscopic findings in MALT lymphoma are mainly classified as superficial type or other, which includes mass-forming, protruding, and diffuse infiltrating types [7,61]. A superficial appearance is the most common endoscopic type, accounting for approximately 70–80% of cases [7,8,24]. Therefore, gastric MALT lymphoma is often indistinguishable from gastric cancer or gastritis based on endoscopic findings alone. Nakamura et al. originally revealed that H. pylori-negative cases are more frequently located in the proximal stomach and invade the submucosa or beyond but less frequently appear as the common superficial type compared to H. pylori-positive lymphomas [62]. In addition, H. suis-associated gastric MALT lymphoma was recently documented to have a nodular gastritis-like appearance, which is distinct from the common type [63]. The endoscopic findings on narrow band imaging (NBI) magnifying endoscopy were also characterized by a tree-like appearance (TLA), which corresponded to abnormally large vessels resembling a tree trunk with long, bare branches [64]. Moreover, endocytoscopy may be useful for detecting intra-glandular aggregation of cellular components and small to moderately sized nuclei in gastric MALT lymphoma, but further studies are needed [65].
In small intestinal MALT lymphoma, single- or multiple-ulcerated lesions or polypoid lesions without villi are often identified by endoscopic examination (Figure 1) [66,67]. Some cases present with changes in the form of lesions within a short time period. Therefore, re-examination may lead to reliable diagnosis [30]. However, small intestinal MALT lymphoma, sometimes, may not form a visible tumor mass in routine practice because of complicated small intestinal obstruction [31,32]. Interestingly, a color-faded cobble-stone-like erosion in the ileum was reported in a rare case of MALT lymphoma showing histologically extensive plasma cell differentiation with prominent Russell bodies [68].
Polypoid or nodular lesions are identified in two-thirds of the patients with IPSID; the other one-third of the patients present with erythematous mucosal thickening or mucosal edema (Figure 2). The infiltrative and nodular patterns are the most sensitive and specific for a diagnosis of αHCD [58]. Kurimoto et al. reported capsule endoscopic findings of a slightly rough mucosa with swelling of the villi within the small intestine and a scar from a longitudinal ulcer extending from the superior jejunum to the middle ileum in patients with IPSID [69].
Colorectal MALT lymphoma can have varying endoscopic appearance, such as flat, elevated, polypoid, or semipedunculated lesions, the surface of which is typically smooth, granular, or nodular (Figure 3) [37,43,70,71]. In the rectum, a polypoid lesion has been reported to be 10-fold more common than an ulcerative lesion [37]. The tumors also vary in size, with the majority measuring between 15 and 30 mm [39,41,43,72]. A magnified endoscopy of the tumor surface shows a type I pit pattern with dilated tree-like microvessels on NBI [73]. Endocytoscopy could detect diffuse interglandular infiltration of small atypical cells [74].

7. Treatment and Clinical Response

7.1. Antibiotic Therapy

Eradication therapy for H. pylori is now used as the first-line therapy for gastric MALT lymphoma, regardless of stage. Antibiotic eradication of H. pylori leads to regression and an effective cure of gastric MALT lymphoma in approximately 70–80% of patients [7,20,26,27]. Triple-therapy regimens combining a proton-pump inhibitor for 4 weeks plus clarithromycin with either amoxicillin or metronidazole for 10–14 days are highly effective [75]. Most patients with minimal histologically residual gastric MALT lymphoma following H. pylori eradication exhibit CR after more than 12 months [76], some of whom achieve CR after more than 24 months [7,22,57,77]. Therefore, it is recommended to wait for at least 12 months before starting another treatment to avoid overtreatment of patients without progression [57].
Although gastric MALT lymphoma has a favorable prognosis, the remission status seems to affect progression-free survival (PFS). Kiesewetter et al. reported that responders (i.e., ChR/pMRD/rRD) to first-line treatment had a longer PFS than patients with stable disease (SD) in gastric MALT lymphoma [19].
The predictors of resistance to H. pylori eradication include the absence of H. pylori, advanced stage, proximal location, endoscopic non-superficial type, polypoid appearance, deep submucosal invasion by endoscopic ultrasonography, and the presence of t(11;18)/BIRC3(API2)-MALT1 translocation [20,75,78,79,80,81].
Although a significant decrease in the rate of gastric MALT lymphoma associated with H. pylori infection has been reported [17], the effectiveness of eradication therapy can be seen even in H. pylori-negative cases, accounting for 0–57%, though the CR rate is lower than that of H. pylori-positive patients [8,28,62,82]. A meta-analysis by Jung et al. showed that the CR rate after eradication therapy was 29% in patients with H. pylori-negative gastric MALT lymphoma [83]. Studies of patients with H. pylori-negative gastric MALT lymphoma are summarized in Table 1 [7,8,9,10,20,21,22,23,24,25,27,28]. In patients with H. pylori-negative gastric MALT lymphoma who receive eradication therapy, the median time to CR is longer than in H. pylori-positive patients [8]. Moreover, 75% of NHPH-positive cases have been reported to achieve CR [20]. In small intestinal MALT lymphoma, the ineffectiveness of H. pylori eradication has been documented in a handful of studies [30,67,84]. Although there are few cases of duodenal MALT lymphoma reported in the English literature, Na et al. reported that 46% of patients with duodenal MALT lymphoma were H. pylori positive and 50% of cases treated with eradication therapy achieved CR [85]. Antibiotic therapy for at least 6 months, including ampicillin, metronidazole, and tetracycline, alone or in combination, should be attempted in patients with IPSID [12]. Tetracycline yielded CR rates of 30% to 70%, lasting months to several years, in patients with early disease [33].
In colorectal localization, some studies have shown regressed cases of MALT lymphoma following H. pylori eradication [86,87]. A review of the English literature focused on rectal MALT lymphoma reported that 37% of cases showed H. pylori eradication with various regimens, regardless of infection status, and 37% required second-line therapy [41]. Antibiotics may eradicate other unknown organisms involved in the development of colorectal MALT lymphoma.

7.2. Watch-and-Wait Strategy and Re-Eradication after Eradication Therapy

In gastric MALT lymphoma, non-responders without progressive disease and recurrent patients after eradication therapy sometimes require a watch-and-wait approach without any additional treatment (Table 2). Nakamura et al. reported that the watch-and-wait approach resulted in no change in 20% of non-responders with gastric MALT lymphoma after eradication therapy [7]. In addition, more than half of recurrent cases with gastric MALT lymphoma under the watch-and-wait regimen achieved CR [7,8,24]. Recurrence of gastric MALT lymphoma was occasionally associated with reinfection with H. pylori, and more than 80% of the cases achieved CR after re-eradication treatment [8,22,24].
An interesting case with MALT lymphoma in the terminal ileum has also been reported. The case presented with multiple protruding lesions and experienced spontaneous regression in preoperative endoscopy [88]. In colorectal MALT lymphomas, Jeon et al. reported that four patients in stage I and one patient in stage IV, without any specific treatment because of their conditions and underlying diseases, experienced no disease progression during the follow-up period, which may be based on the favorable prognosis of low-grade lymphoma [40].

7.3. Radiotherapy

Non-responders to eradication therapy have been detected in 17–61% of patients with gastric MALT lymphoma (Table 2) [7,8,9,24,26,27,28]. Several studies have acknowledged the effectiveness of radiotherapy (RT) or immune-/chemotherapy as second-line treatment for non-responders with gastric MALT lymphoma [8,24,26,28]. Moderate-dose RT appears to be effective in patients with localized gastric MALT lymphoma persisting after H. pylori eradication [89]. In addition, 25 patients with localized disease receiving RT had a favorable outcome, with a 10-year recurrence-free rate of 92% [90]. The largest cohort, reported by Yahalom et al., comprised 178 H. pylori-independent gastric MALT lymphoma patients, 95% of whom exhibited a complete pathological response to RT (median dose 30 Gy), with rare acute or late toxicity [91]. Schmelz et al. revealed that a reduced RT dose of 25.2 Gy was as effective as the standard RT of 36 Gy in localized gastric MALT lymphoma [92]. The German Study Group on Gastrointestinal Lymphoma (DSGL) reported that stage-adopted reduction from extended field RT (EFRT) to involved field RT (IFRT) led to a better outcome and reduction of adverse effects in gastric MALT lymphoma [93].
Although RT is effective for MALT lymphoma limited to a focal area of the GI tract, including the rectum [43,94], precise targeting of the small intestine by RT is difficult because it is not fixed in the abdominal cavity. Reinartz et al. showed that RT adapted to stage, histology, and resection in multimodal treatment of intestinal lymphoma achieves excellent local tumor control and survival rates despite the partially decreasing field size [95]. In addition, current involved site RT (ISRT) offers the option of further reduction of normal tissue complication probability and a clinical trial of ISRT 20Gy for indolent localized gastrointestinal lymphoma is ongoing.
Recently, very-low-dose RT (4Gy) was also shown to be effective in MZLs, including those at extranodal sites, which may alternatively reduce toxicities and the duration of treatment [96].

7.4. Chemo/Immunotherapy

Rituximab as a single agent is known to exert significant antitumor activity in MALT lymphoma. Combination therapy with rituximab and alkylating agents in patients with gastric MALT lymphoma has greater efficacy than monotherapy with each, but some patients suffer from considerable toxicity [97]. Rituximab in combination with chlorambucil has also been shown to achieve CR rates of 91% and improve event-free survival (EFS) with little added toxicity in gastric MALT lymphoma patients with disease progression any time post H. pylori eradication or in gastric MALT lymphoma patients with SD and persistent lymphoma more than 1 year after H. pylori eradication (5-year EFS, 77%) [98]. Furthermore, gastric MALT lymphoma patients with unequivocally active disease after failure of H. pylori eradication or in subsequent relapse have been reported to have excellent CR rates, of 100%, and 7-year EFS of 89.5% when treated with the combination of rituximab and bendamustine, which is superior to treatment with the combination of rituximab and chlorambucil [99]. Some patients with H. pylori-negative gastric MALT lymphoma receive RT or chemotherapy as the first-line treatment, resulting in a high CR rate, of more than 80% (Table 1) [24,25,28].
For small intestinal MALT lymphoma with multiple lesions, no response to eradication, or extending throughout the entire small intestine, chemo-immunotherapy has been reported to be effective (Table 3) [30,66,67,84,100,101]. A large case analysis of colorectal MALT lymphoma reported that chemotherapy is most commonly performed for advanced disease [40]. Furthermore, IPSID patients without marked improvement after a 6-month course of antibiotics, without CR within 12 months, or with an intermediate or advanced stage of disease should also receive anthracycline-based combination chemotherapy, as this has been shown to result in a CR rate of approximately 64% in the latter group [102,103].

7.5. Endoscopic Resection

A summary of recently reported cases of colorectal MALT lymphoma is shown in Table 4. In patients with colorectal MALT lymphoma, endoscopic resection in cases with localized disease has been noted to usually achieve CR [43,70,73,106,107,108]. Approximately 40% of patients with colorectal MALT lymphoma receive endoscopic resection, 20% of whom are treated with additional RT because of positive resection margins [40]. Although one patient with transverse colon disease has been reported to have experienced recurrence at the terminal ileum, most patients treated with endoscopic mucosal resection (EMR) experience no progression. In addition, for residual tumors after EMR, endoscopic submucosal dissection (ESD) may be effective as salvage therapy [109]. In patients with colonic MALT lymphoma treated with RT, an obstructing mass could shrink and subsequently be resected by an endoscopic procedure [110].

7.6. Surgery

Surgical treatment is now restricted to gastric MALT lymphoma cases with rare complications, such as bleeding or perforation, that cannot be controlled endoscopically [57]. Patients with small intestinal MALT lymphoma causing a dilated segment, obstruction, or perforation undergo surgical resection, some of whom receive additional chemo-/immunotherapy (Table 3) [31,32,104,105]. Colonic MALT lymphoma cases of locally extended masses occasionally undergo surgical resection [43,71].

7.7. Outcome

Recurrence occurs in 3–21% of patients with gastric MALT lymphoma after eradication therapy [7,8,22,24,27,28], which may even occur 7 years after CR [22]. Patients with gastric MALT lymphoma have favorable outcomes, with 10-year disease-free survival and OS of 79–86% and 83–95%, respectively [7,22,27]. Although small intestinal MALT lymphoma has a good prognosis among patients with primary small intestinal lymphoma [111], only a small number of cases with small intestinal MALT lymphoma have been analyzed and the prognosis of the tumor remains to be elucidated. Patients with colorectal MALT lymphoma have favorable outcomes, with 5-year PFS of 92% and 5-year OS of 94% [40]. In the literature review of 73 patients with colorectal MALT lymphoma, the overall remission rate and the tumor recurrence rate were 96% and 7%, respectively [38].

8. The Risk of Developing Carcinoma and Other Malignancies

Capelle et al. reported a higher risk of synchronous and metachronous gastric cancer in patients with gastric MALT lymphoma [15]. In their study, gastric cancer was diagnosed in 2.4% of 1419 patients with gastric MALT lymphoma, the risk of which was 6-fold in comparison to the general population. In addition, many or most patients with gastric MALT lymphoma who developed gastric cancer were diagnosed with adenocarcinoma concomitantly (53%) or during later surveillance (38%). Almost all reported cases with adenocarcinoma were in early stages [26,112], though Isaka et al. reported rapid development of advanced adenocarcinoma with BIRC3(API2)-MALT1 chimeric transcript-positive gastroduodenal MALT lymphoma as a collision tumor [113]. We also reported a collision tumor of advanced gastric adenocarcinoma and MALT lymphoma detected 16 years after diagnosis of splenic MZL [114].
The development of metachronous neoplasms other than gastric adenocarcinomas, including various solid tumors and hematological neoplasms, has also been reported [7,27]. In addition, synchronous cases of adenocarcinoma and MALT lymphoma in the colorectum have been reported, but the correlation between the two diseases remains unclear [115].

9. Epstein–Barr Virus (EBV)-Negative Post-Transplant EMZL in the GI Tract

Indolent B-cell lymphoma has traditionally been excluded from the category of monomorphic post-transplant lymphoproliferative disorders (PTLDs). PTLDs are a heterogeneous group of lymphoid or plasmacytic proliferations that develop secondary to chronic immunosuppression after solid-organ or allogeneic hematopoietic stem-cell transplantation. Most PTLDs are derived from B cells and are associated with EBV infection [116]. Post-transplant MALT lymphoma is generally gastric, with a strong correlation with H. pylori infection, and responds well to eradication therapy alone, which is similar to what is seen in immunocompetent hosts [117,118,119]. Therefore, only EBV-positive MZL has been considered a form of PTLD. However, the spectrum of EBV-negative MZL in the post-transplant setting has recently been expanded.
Galera et al. reported cases with post-transplant EBV-negative MZL, all arising in solid-organ transplant recipients [13]. Five of seven patients with EMZL presented with intestinal disease, which included the colon in four cases, suggesting a difference in the preferential involvement of the intestine between post-transplant EMZL and sporadic cases. All of the patients had past histories of treatment with immunosuppressive agents and were diagnosed more than 1 year after transplant, and two had a history of ulcerative colitis. The endoscopic findings varied, including multiple polyps, erythema, ulcers, and masses. Most patients were treated with reduced immunosuppression and rituximab. Although chronic antigenic stimulation has been postulated to play a role in the pathogenesis of EMZL, the transplanted organ may fulfill this role. This issue should be investigated more in the future.

10. Conclusions

Many patients with gastric MALT lymphoma respond to H. pylori eradication, although the association between H. pylori and gastric MALT lymphoma has decreased markedly recently. Antibiotic therapy has also been shown to be effective for a subset of patients with H. pylori-negative gastric MALT lymphoma, including NHPH-associated cases. Cases with chromosomal rearrangement and/or genetic alterations should be distinguished because of a high frequency of non-responders. Gastric MALT lymphoma patients generally experience a favorable clinical course, even non-responders and recurrent cases treated with RT or immunochemotherapy. However, surveillance endoscopy is recommended after CR considering the possibility of metachronous gastric cancer. IPSID, also known as a variant of small intestinal MALT lymphoma involving C. jejuni, is uncommon, and early-stage patients may derive a benefit from antibiotic treatment. Colorectal MALT lymphoma is rare, with varying endoscopic appearance, including elevated polypoid lesions. The pathogenesis is not well known, and treatment approaches vary. The efficacy of antibiotic therapy is still controversial, but endoscopic procedures tend to be considered in endoscopically resectable colorectal MALT lymphoma with localized disease. Recently, preferential involvement of the intestine in EBV-negative MZL arising in the setting of immunosuppression was noted. Further studies of MALT lymphoma focusing on the intestines will be of interest and may lead to the development of a treatment strategy.

Author Contributions

Conceptualization, E.I. and S.N.; writing—original draft preparation, E.I. and A.S.; writing—review and editing, M.N., K.S. and S.N.; supervision, S.N. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Khalil, M.O.; Morton, L.M.; Devesa, S.S.; Check, D.P.; Curtis, R.E.; Weisenburger, D.D.; Dores, G.M. Incidence of marginal zone lymphoma in the United States, 2001-2009 with a focus on primary anatomic site. Br. J. Haematol. 2014, 165, 67–77. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Wotherspoon, A.C.; Doglioni, C.; Diss, T.C.; Pan, L.X.; Moschini, A.; Deboni, M.; Isaacson, P.G. Regression of primary low-grade b-cell gastric lymphoma of mucosa-associated lymphoid-tissue type after eradication of helicobacter-pylori. Lancet 1993, 342, 575–577. [Google Scholar] [CrossRef]
  3. Chanudet, E.; Zhou, Y.; Bacon, C.M.; Wotherspoon, A.C.; Müller-Hermelink, H.K.; Adam, P.; Dong, H.Y.; de Jong, D.; Li, Y.; Wei, R.; et al. Chlamydia psittaci is variably associated with ocular adnexal MALT lymphoma in different geographical regions. J. Pathol. 2006, 209, 344–351. [Google Scholar] [CrossRef] [PubMed]
  4. Carugi, A.; Onnis, A.; Antonicelli, G.; Rossi, B.; Mannucci, S.; Luzzi, A.; Lazzi, S.; Bellan, C.; Tosi, G.M.; Sayed, S.; et al. Geographic variation and environmental conditions as cofactors in Chlamydia psittaci association with ocular adnexal lymphomas: A comparison between Italian and African samples. Hematol. Oncol. 2010, 28, 20–26. [Google Scholar]
  5. Zucca, E.; Bertoni, F. The spectrum of MALT lymphoma at different sites: Biological and therapeutic relevance. Blood 2016, 127, 2082–2092. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Teckie, S.; Qi, S.; Chelius, M.; Lovie, S.; Hsu, M.; Noy, A.; Portlock, C.; Yahalom, J. Long-term outcome of 487 patients with early-stage extra-nodal marginal zone lymphoma. Ann. Oncol. 2017, 28, 1064–1069. [Google Scholar] [CrossRef]
  7. Nakamura, S.; Sugiyama, T.; Matsumoto, T.; Iijima, K.; Ono, S.; Tajika, M.; Tari, A.; Kitadai, Y.; Matsumoto, H.; Nagaya, T.; et al. Long-term clinical outcome of gastric MALT lymphoma after eradication of Helicobacter pylori: A multicentre cohort follow-up study of 420 patients in Japan. Gut 2012, 61, 507–513. [Google Scholar] [CrossRef]
  8. Gong, E.J.; Ahn, J.Y.; Jung, H.Y.; Park, H.; Ko, Y.B.; Na, H.K.; Jung, K.W.; Kim, D.H.; Lee, J.H.; Choi, K.D.; et al. Helicobacter pylori Eradication Therapy Is Effective as the Initial Treatment for Patients with H. pylori-Negative and Disseminated Gastric Mucosa-Associated Lymphoid Tissue Lymphoma. Gut Liver 2016, 10, 706–713. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  9. Matysiak-Budnik, T.; Jamet, P.; Ruskon-Fourmestraux, A.; de Mascarel, A.; Velten, M.; Maynadi, M.; Woronoff, A.S.; Trtarre, B.; Marrer, E.; Delafosse, P.; et al. Gastric MALT lymphoma in a population-based study in France: Clinical features, treatments and survival. Aliment. Pharmacol. Ther. 2019, 50, 654–663. [Google Scholar] [CrossRef]
  10. Kiesewetter, B.; Copie-Bergman, C.; Levy, M.; Wu, F.T.; Dupuis, J.; Barau, C.; Arcaini, L.; Paulli, M.; Lucioni, M.; Bonometti, A.; et al. Genetic Characterization and Clinical Features of Helicobacter pylori Negative Gastric Mucosa-Associated Lymphoid Tissue Lymphoma. Cancers 2021, 13, 2993. [Google Scholar] [CrossRef]
  11. Lecuit, M.; Abachin, E.; Martin, A.; Poyart, C.; Pochart, P.; Suarez, F.; Bengoufa, D.; Feuillard, J.; Lavergne, A.; Gordon, J.I.; et al. Immunoproliferative small intestinal disease associated with Campylobacter jejuni. N. Engl. J. Med. 2004, 350, 239–248. [Google Scholar] [CrossRef]
  12. Bianchi, G.; Sohani, A.R. Heavy Chain Disease of the Small Bowel. Curr. Gastroenterol. Rep. 2018, 20, 3. [Google Scholar] [CrossRef] [PubMed]
  13. Galera, P.; Flavin, R.; Savage, N.M.; Saksena, A.; Gong, S.; Wang, H.Y.; Swan, N.; Xi, L.; Raffeld, M.; Pittaluga, S.; et al. Epstein-Barr Virus-negative Marginal Zone Lymphoma as an Uncommon Form of Monomorphic Posttransplant Lymphoproliferative Disorder. Am. J. Surg. Pathol. 2020, 44, 1340–1352. [Google Scholar] [CrossRef]
  14. Nakamura, S.; Matsumoto, T.; Iida, M.; Yao, T.; Tsuneyoshi, M. Primary gastrointestinal lymphoma in Japan: A clinicopathologic analysis of 455 patients with special reference to its time trends. Cancer 2003, 97, 2462–2473. [Google Scholar] [CrossRef] [PubMed]
  15. Capelle, L.G.; de Vries, A.C.; Looman, C.W.N.; Casparie, M.K.; Boot, H.; Meijer, G.A.; Kuipers, E.J. Gastric MALT lymphoma: Epidemiology and high adenocarcinoma risk in a nation-wide study. Eur. J. Cancer 2008, 44, 2470–2476. [Google Scholar] [CrossRef]
  16. Luminari, S.; Cesaretti, M.; Marcheselli, L.; Rashid, I.; Madrigali, S.; Maiorana, A.; Federico, M. Decreasing incidence of gastric MALT lymphomas in the era of anti-Helicobacter pylori interventions: Results from a population-based study on extranodal marginal zone lymphomas. Ann. Oncol. 2010, 21, 855–859. [Google Scholar] [CrossRef]
  17. Mendes LS, T.; Attygalle, A.D.; Wotherspoon, A.C. Helicobacter pylori infection in gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma: A re-evaluation. Gut 2014, 63, 1526–1527. [Google Scholar] [CrossRef]
  18. Raderer, M.; Wöhrer, S.; Streubel, B.; Troch, M.; Turetschek, K.; Jäger, U.; Skrabs, C.; Gaiger, A.; Drach, J.; Puespoek, A.; et al. Assessment of disease dissemination in gastric compared with extragastric mucosa-associated lymphoid tissue lymphoma using extensive staging: A single-center experience. J. Clin. Oncol. 2006, 24, 3136–3141. [Google Scholar] [CrossRef]
  19. Kiesewetter, B.; Simonitsch-Klupp, I.; Dolak, W.; Mayerhoefer, M.E.; Raderer, M. Depth of Remission Following First-Line Treatment Is an Independent Prognostic Marker for Progression-Free Survival in Gastric Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma. Cancers 2020, 12, 492. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  20. Takigawa, H.; Yuge, R.; Masaki, S.; Otani, R.; Kadota, H.; Naito, T.; Hayashi, R.; Urabe, Y.; Oka, S.; Tanaka, S.; et al. Involvement of non-Helicobacter pylori helicobacter infections in Helicobacter pylori-negative gastric MALT lymphoma pathogenesis and efficacy of eradication therapy. Gastric Cancer 2021, 24, 937–945. [Google Scholar] [CrossRef]
  21. Kuo, S.H.; Yeh, K.H.; Wu, M.S.; Lin, C.W.; Wei, M.F.; Liou, J.M.; Wang, H.P.; Chen, L.T.; Cheng, A.L. First-line antibiotic therapy in Helicobacter pylori-negative low-grade gastric mucosa-associated lymphoid tissue lymphoma. Sci. Rep. 2017, 7, 14333. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Moleiro, J.; Ferreira, S.; Lage, P.; Dias Pereira, A. Gastric malt lymphoma: Analysis of a series of consecutive patients over 20 years. United Eur. Gastroenterol. J. 2016, 4, 395–402. [Google Scholar] [CrossRef] [Green Version]
  23. Raderer, M.; Wöhrer, S.; Kiesewetter, B.; Dolak, W.; Lagler, H.; Wotherspoon, A.; Muellauer, L.; Chott, A. Antibiotic treatment as sole management of Helicobacter pylori-negative gastric MALT lymphoma: A single center experience with prolonged follow-up. Ann. Hematol. 2015, 94, 969–973. [Google Scholar] [CrossRef] [PubMed]
  24. Choi, Y.J.; Kim, N.; Paik, J.H.; Kim, J.M.; Lee, S.H.; Park, Y.S.; Hwang, J.H.; Kim, J.W.; Jeong, S.H.; Lee, D.H.; et al. Characteristics of Helicobacter pylori-positive and Helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphoma and their influence on clinical outcome. Helicobacter 2013, 18, 197–205. [Google Scholar] [CrossRef]
  25. Asano, N.; Iijima, K.; Terai, S.; Jin, X.; Ara, N.; Chiba, T.; Fushiya, J.; Koike, T.; Imatani, A.; Shimosegawa, T. Eradication therapy is effective for Helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphoma. Tohoku. J. Exp. Med. 2012, 228, 223–227. [Google Scholar] [CrossRef] [Green Version]
  26. Ono, S.; Kato, M.; Takagi, K.; Kodaira, J.; Kubota, K.; Matsuno, Y.; Komatsu, Y.; Asaka, M. Long-term treatment of localized gastric marginal zone B-cell mucosa associated lymphoid tissue lymphoma including incidence of metachronous gastric cancer. J. Gastroenterol. Hepatol. 2010, 25, 804–809. [Google Scholar] [CrossRef]
  27. Stathis, A.; Chini, C.; Bertoni, F.; Proserpio, I.; Capella, C.; Mazzucchelli, L.; Pedrinis, E.; Cavalli, F.; Pinotti, G.; Zucca, E. Long-term outcome following Helicobacter pylori eradication in a retrospective study of 105 patients with localized gastric marginal zone B-cell lymphoma of MALT type. Ann. Oncol. 2009, 20, 1086–1093. [Google Scholar] [CrossRef]
  28. Ishioka, M.; Hirasawa, T.; Mishima, Y. Latest trends in the incidence of Helicobacter pylori-uninfected gastric mucosa-associated lymphoid tissue lymphoma at the Cancer Institute Hospital, Japan. Int. J. Hematol. 2021, 113, 770–771. [Google Scholar] [CrossRef]
  29. Hirose, Y.; Kaida, H.; Ishibashi, M.; Uozumi, J.; Arikawa, S.; Kurata, S.; Hayabuchi, N.; Nakahara, K.; Ohshima, K. Comparison Between Endoscopic Macroscopic Classification and F-18 FDG PET Findings in Gastric Mucosa-Associated Lymphoid Tissue Lymphoma Patients. Clin. Nucl. Med. 2012, 37, 152–157. [Google Scholar] [CrossRef]
  30. Yoneda, K.; Takahashi, H.; Abe, Y.; Inamori, M.; Kato, S.; Uchiyama, T.; Iida, H.; Mawatari, H.; Hosono, K.; Endo, H.; et al. A mucosa-associated lymphoid tissue (MALT) lymphoma of the small intestine that was difficult to diagnose endoscopically. Endoscopy 2010, 42, E175. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  31. Kinkade, Z.; Esan, O.A.; Rosado, F.G.; Craig, M.; Vos, J.A. Ileal mucosa-associated lymphoid tissue lymphoma presenting with small bowel obstruction: A case report. Diagn. Pathol. 2015, 10, 105. [Google Scholar] [CrossRef] [Green Version]
  32. Nehme, F.; Alderson, J.; Nassif, I. Small Bowel Obstruction Secondary to Ileal Mucosa-Associated Lymphoid Tissue Lymphoma. J. Gastrointest. Cancer 2018, 49, 207–210. [Google Scholar] [CrossRef] [PubMed]
  33. Al-Saleem, T.; Al-Mondhiry, H. Immunoproliferative small intestinal disease (IPSID): A model for mature B-cell neoplasms. Blood 2005, 105, 2274–2280. [Google Scholar] [CrossRef]
  34. Subbiah, A.K.; Das, P.; Bagchi, S.; Shalimar; Agarwal, S.K. Recurrent diarrhoea in a renal transplant recipient: Early immunoproliferative small intestinal disease may be missed if not considered. Nephrology 2017, 22, 265–267. [Google Scholar] [CrossRef] [PubMed]
  35. Orfanoudaki, E.; Iliadis, A.; Goulis, I.; Xylouri, E.; Voumvouraki, A.; Samonakis, D.N. Immunoproliferative Small Intestinal Disease in a Liver Transplant Recipient: A Case Report and Literature Review. Exp. Clin. Transplant. 2021, 19, 620–623. [Google Scholar] [CrossRef]
  36. Evangelista-Leite, D.; Affonso Madaloso, B.; Shouta Yamashita, B.; Enrico Aloise, F.; Polito Verdasca, L.; Lopes de Mello, M.; Murata Hayashi, R.; Zimberg Chehter, E. Treating chronic diarrhea: A systematic review on Immunoproliferative Small Intestinal Disease (IPSID). PLoS ONE. 2021, 16, e0253695. [Google Scholar] [CrossRef]
  37. Ahlawat, S.; Kanber, Y.; Charabaty-Pishvaian, A.; Ozdemirli, M.; Cohen, P.; Benjamin, S.; Haddad, N. Primary mucosa-associated lymphoid tissue (MALT) lymphoma occurring in the rectum: A case report and review of the literature. South Med. J. 2006, 99, 1378–1384. [Google Scholar] [CrossRef] [PubMed]
  38. Won, J.H.; Kim, S.M.; Kim, J.W.; Park, J.H.; Kim, J.Y. Clinical features, treatment and outcomes of colorectal mucosa-associated lymphoid tissue (MALT) lymphoma: Literature reviews published in English between 1993 and 2017. Cancer Manag. Res. 2019, 11, 8577–8587. [Google Scholar] [CrossRef] [Green Version]
  39. Kawashima, K.; Katakura, K.; Takahashi, Y.; Asama, H.; Fujiwara, T.; Kumakawa, H.; Ohira, H. Primary rectal mucosa-associated lymphoid tissue lymphoma in a patient with previously identified primary biliary cirrhosis and secondary Sjögren’s syndrome. Clin. J. Gastroenterol. 2016, 9, 124–128. [Google Scholar] [CrossRef] [PubMed]
  40. Jeon, M.K.; So, H.; Huh, J.; Hwang, H.S.; Hwang, S.W.; Park, S.H.; Yang, D.H.; Choi, K.D.; Ye, B.D.; Myung, S.J.; et al. Endoscopic features and clinical outcomes of colorectal mucosa-associated lymphoid tissue lymphoma. Gastrointest. Endosc. 2018, 87, 529–539. [Google Scholar] [CrossRef] [PubMed]
  41. Kelley, S.R. Mucosa-associated lymphoid tissue (MALT) variant of primary rectal lymphoma: A review of the English literature. Int. J. Colorectal. Dis. 2017, 32, 295–304. [Google Scholar] [CrossRef]
  42. Saito, T.; Tamaru, J.; Kishi, H.; Kayao, J.; Kuzuu, Y.; Wakita, H.; Adachi, A.; Itoyama, S.; Mikata, I. Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) arising in the small intestine with monoclonal cryoglobulinemia. Pathol. Int. 2004, 54, 712–718. [Google Scholar] [CrossRef]
  43. Akasaka, R.; Chiba, T.; Dutta, A.K.; Toya, Y.; Mizutani, T.; Shozushima, T.; Abe, K.; Kamei, M.; Kasugai, S.; Shibata, S.; et al. Colonic mucosa-associated lymphoid tissue lymphoma. Case Rep. Gastroenterol. 2012, 6, 569–575. [Google Scholar] [CrossRef]
  44. Farinha, P.; Gascoyne, R.D. Molecular pathogenesis of mucosa-associated lymphoid tissue lymphoma. J. Clin. Oncol. 2005, 23, 6370–6378. [Google Scholar] [CrossRef]
  45. Du, M.Q. MALT lymphoma: A paradigm of NF-κB dysregulation. Semin. Cancer Biol. 2016, 39, 49–60. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Morgner, A.; Lehn, N.; Andersen, L.P.; Thiede, C.; Bennedsen, M.; Trebesius, K.; Neubauer, B.; Neubauer, A.; Stolte, M.; Bayerdorffer, E. Helicobacter heilmannii-associated primary gastric low-grade MALT lymphoma: Complete remission after curing the infection. Gastroenterology 2000, 118, 821–828. [Google Scholar] [CrossRef]
  47. Okiyama, Y.; Matsuzawa, K.; Hidaka, E.; Sano, K.; Akamatsu, T.; Ota, H. Helicobacter heilmannii infection: Clinical, endoscopic and histopathological features in Japanese patients. Pathol. Int. 2005, 55, 398–404. [Google Scholar] [CrossRef]
  48. Heilmann, K.L.; Borchard, F. Gastritis due to spiral shaped bacteria other than helicobacter-pylori-clinical, histological, and ultrastructural findings. Gut 1991, 32, 137–140. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  49. Nakamura, M.; Overby, A.; Michimae, H.; Matsui, H.; Takahashi, S.; Mabe, K.; Shimoyama, T.; Sasaki, M.; Terao, S.; Kamada, T.; et al. PCR analysis and specific immunohistochemistry revealing a high prevalence of non-Helicobacter pyloriHelicobacters inHelicobacter pylori-negative gastric disease patients in Japan: High susceptibility to an Hp eradication regimen. Helicobacter 2020, 25, e12700. [Google Scholar] [CrossRef]
  50. Yang, L.; Yamamoto, K.; Nishiumi, S.; Nakamura, M.; Matsui, H.; Takahashi, S.; Dohi, T.; Okada, T.; Kakimoto, K.; Hoshi, N.; et al. Interferon-γ-producing B cells induce the formation of gastric lymphoid follicles after Helicobacter suis infection. Mucosa Immunol. 2015, 8, 279–295. [Google Scholar] [CrossRef] [Green Version]
  51. Streubel, B.; Simonitsch-Klupp, I.; Mullauer, L.; Lamprecht, A.; Huber, D.; Siebert, R.; Stolte, M.; Trautinger, F.; Lukas, J.; Puspok, A.; et al. Variable frequencies of MALT lymphoma-associated genetic aberrations in MALT lymphomas of different sites. Leukemia 2004, 18, 1722–1726. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Remstein, E.D.; Dogan, A.; Einerson, R.R.; Paternoster, S.F.; Fink, S.R.; Law, M.; Dewald, G.W.; Kurtin, P.J. The incidence and anatomic site specificity of chromosomal translocations in primary extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) in North America. Am. J. Surg. Pathol. 2006, 30, 1546–1553. [Google Scholar] [CrossRef] [PubMed]
  53. Sakugawa, S.T.; Yoshino, T.; Nakamura, S.; Inagaki, H.; Sadahira, Y.; Nakamine, H.; Okabe, M.; Ichimura, K.; Tanimoto, M.; Akagi, T. API2-MALT1 fusion gene in colorectal lymphoma. Mod. Pathol. 2003, 16, 1232–1241. [Google Scholar] [CrossRef] [PubMed]
  54. Hyeon, J.; Lee, B.; Shin, S.H.; Yoo, H.Y.; Kim, S.J.; Kim, W.S.; Park, W.Y.; Ko, Y.H. Targeted deep sequencing of gastric marginal zone lymphoma identified alterations of TRAF3 and TNFAIP3 that were mutually exclusive for MALT1 rearrangement. Mod. Pathol. 2018, 31, 1418–1428. [Google Scholar] [CrossRef] [PubMed]
  55. Zhang, J.; Wei, J.M.; Wang, Z.X.; Feng, Y.; Wei, Z.W.; Hou, X.; Xu, J.B.; He, Y.L.; Yang, D.J. Transcriptome hallmarks in Helicobacter pylori infection influence gastric cancer and MALT lymphoma. Epigenomics 2020, 12, 661–671. [Google Scholar] [CrossRef]
  56. Nakamura, S.; Ponzoni, M. Marginal zone B-cell lymphoma: Lessons from Western and Eastern diagnostic approaches. Pathology 2020, 52, 15–29. [Google Scholar] [CrossRef] [Green Version]
  57. Zucca, E.; Arcaini, L.; Buske, C.; Johnson, P.W.; Ponzoni, M.; Raderer, M.; Ricardi, U.; Salar, A.; Stamatopoulos, K.; Thieblemont, C.; et al. Marginal zone lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2020, 31, 17–29. [Google Scholar] [CrossRef] [Green Version]
  58. Pervez, S.; Mumtaz, K.; Ullah, S.S.; Akhtar, N.; Ali, N.; Aaqil, H. Immunoproliferative small intestinal disease (IPSID). J. Coll. Physicians Surg. Pak. 2011, 21, 57–58. [Google Scholar]
  59. Hong, J.T.; Kim, E.R.; Park, S.W.; Kim, J.W.; Hong, S.N.; Chang, D.K.; Kim, Y.H.; Cho, J.H. Long-term Prognosis of Localized Lymphoid Hyperplasia of the Rectum. Gut Liver 2021, 15, 77–84. [Google Scholar] [CrossRef] [Green Version]
  60. Copie-Bergman, C.; Gaulard, P.; Lavergne-Slove, A.; Brousse, N.; Flejou, J.F.; Dordonne, K.; de Mascarel, A.; Wotherspoon, A.C.; GELA. Proposal for a new histological grading system for post-treatment evaluation of gastric MALT lymphoma. Gut 2003, 52, 1656. [Google Scholar] [CrossRef] [Green Version]
  61. Nakamura, S.; Yao, T.; Aoyagi, K.; Iida, M.; Fujishima, M.; Tsuneyoshi, M. Helicobacter pylori and primary gastric lymphoma. A histopathologic and immunohistochemical analysis of 237 patients. Cancer 1997, 79, 3–11. [Google Scholar] [CrossRef]
  62. Nakamura, S.; Matsumoto, T.; Ye, H.T.; Nakamura, S.; Suekane, H.; Matsumoto, H.; Yao, T.; Tsuneyoshi, M.; Du, M.Q.; Iida, M. Helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphoma—A clinicopathologic and molecular study with reference to antibiotic treatment. Cancer 2006, 107, 2770–2778. [Google Scholar] [CrossRef]
  63. Takigawa, H.; Masaki, S.; Naito, T.; Yuge, R.; Urabe, Y.; Tanaka, S.; Sentani, K.; Matsuo, T.; Matsuo, K.; Chayama, K.; et al. Helicobacter suis infection is associated with nodular gastritis-like appearance of gastric mucosa-associated lymphoid tissue lymphoma. Cancer Med. 2019, 8, 4370–4379. [Google Scholar] [CrossRef] [Green Version]
  64. Nonaka, K.; Ishikawa, K.; Shimizu, M.; Sakurai, T.; Nakai, Y.; Nakao, M.; Yoshino, K.; Arai, S.; Kita, H. Gastrointestinal: Gastric mucosa-associated lymphoma presented with unique vascular features on magnified endoscopy combined with narrow-band imaging. J. Gastroenterol. Hepatol. 2009, 24, 1697. [Google Scholar]
  65. Isomoto, H.; Matsushima, K.; Hayashi, T.; Imaizumi, Y.; Shiota, J.; Ishii, H.; Minami, H.; Ohnita, K.; Takeshima, F.; Shikuwa, S.; et al. Endocytoscopic findings of lymphomas of the stomach. BMC Gastroenterol. 2013, 13, 174. [Google Scholar] [CrossRef] [Green Version]
  66. Terada, T. Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) of the ileum in a 35-year-old Japanese woman. Int. J. Clin. Exp. Pathol. 2013, 6, 951–956. [Google Scholar]
  67. Ohashi, S.; Yazumi, S.; Watanabe, N.; Matsumoto, S.; Fukui, T.; Nishio, A.; Chiba, T. Education and imaging. Gastrointestinal: MALT lymphoma of the terminal ileum. J. Gastroenterol. Hepatol. 2006, 21, 1495. [Google Scholar] [CrossRef] [PubMed]
  68. Kai, K.; Miyahara, M.; Tokuda, Y.; Kido, S.; Masuda, M.; Takase, Y.; Tokunaga, O. A case of mucosa-associated lymphoid tissue lymphoma of the gastrointestinal tract showing extensive plasma cell differentiation with prominent Russell bodies. World J. Clin. Cases 2013, 1, 176–180. [Google Scholar] [CrossRef]
  69. Kurimoto, M.; Sonoki, T.; Nakamura, Y.; Yamamoto, Y.; Maeda, Y.; Kuriyama, K.; Mushino, T.; Hosoi, H.; Murata, S.; Shimanuki, M.; et al. Severe enteropathy caused by α-heavy chain disease lacking detectable M-proteins. Intern. Med. 2014, 53, 581–585. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  70. Kim, M.H.; Jung, J.T.; Kim, E.J.; Kim, T.W.; Kim, S.Y.; Kwon, J.G.; Kim, E.Y.; Sung, W.J. A case of mucosa-associated lymphoid tissue lymphoma of the sigmoid colon presenting as a semipedunculated polyp. Clin. Endosc. 2014, 47, 192–196. [Google Scholar] [CrossRef]
  71. Seo, S.W.; Lee, S.H.; Lee, D.J.; Kim, K.M.; Kang, J.K.; Kim, D.W.; Lee, J.H. Colonic mucosa-associated lymphoid tissue lymphoma identified by chromoendoscopy. World J. Gastroenterol. 2014, 20, 18487–18494. [Google Scholar] [CrossRef] [PubMed]
  72. Chahil, N.; Bloom, P.; Tyson, J.; Jazwari, S.; Robilotti, J.; Gaultieri, N. Novel approach to treatment of rectal mucosa-associated lymphoid tissue lymphoma. BMJ Case Rep. 2011, 2011, 2969. [Google Scholar] [CrossRef] [Green Version]
  73. Hasegawa, D.; Yoshida, N.; Ishii, M.; Takamasu, M.; Kishimoto, M.; Yagi, N.; Naitou, Y.; Yanagisawa, A. A case of colonic mucosa-associated lymphoid tissue lymphoma observed under endoscopy with narrow-band imaging. Nihon Shokakibyo Gakkai Zasshi 2013, 110, 2100–2106. [Google Scholar] [PubMed]
  74. Satoh, T.; Hotta, K.; Imai, K. Endocytoscopy for the diagnosis of marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type in the rectum: Report of two cases. Dig. Endosc. 2020, 32, E54–E56. [Google Scholar] [CrossRef]
  75. Zullo, A.; Hassan, C.; Cristofari, F.; Andriani, A.; De Francesco, V.; Ierardi, E.; Tomao, S.; Stolte, M.; Morini, S.; Vaira, D. Effects of Helicobacter pylori Eradication on Early Stage Gastric Mucosa-Associated Lymphoid Tissue Lymphoma. Clin. Gastroenterol. Hepatol. 2010, 8, 105–110. [Google Scholar] [CrossRef]
  76. Fischbach, W.; Goebeler, M.E.; Ruskone-Fourmestraux, A.; Wundisch, T.; Neubauer, A.; Raderer, M.; Savio, A.; Grp, E. Most patients with minimal histological residuals of gastric MALT lymphoma after successful eradication of Helicobacter pylori can be managed safely by a watch and wait strategy: Experience from a large international series. Gut 2007, 56, 1685–1687. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Ruskoné-Fourmestraux, A.; Fischbach, W.; Aleman, B.M.; Boot, H.; Du, M.Q.; Megraud, F.; Montalban, C.; Raderer, M.; Savio, A.; Wotherspoon, A. EGILS consensus report. Gastric extranodal marginal zone B-cell lymphoma of MALT. Gut 2011, 60, 747–758. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  78. Nakamura, S.; Matsumoto, T.; Suekane, H.; Nakamura, S.; Matsumoto, H.; Esaki, M.; Yao, T.; Iida, M. Long-term clinical outcome of Helicobacter pylori eradication for gastric mucosa-associated lymphoid tissue lymphoma with a reference to second-line treatment. Cancer 2005, 104, 532–540. [Google Scholar] [CrossRef]
  79. Nakamura, S.; Ye, H.T.; Bacon, C.M.; Goatly, A.; Liu, H.X.; Banham, A.H.; Ventura, R.; Matsumoto, T.; Iida, M.; Ohji, Y.; et al. Clinical impact of genetic aberrations in gastric MALT lymphoma: A comprehensive analysis using interphase fluorescence in situ hybridisation. Gut 2007, 56, 1358–1363. [Google Scholar] [CrossRef] [Green Version]
  80. Yokoi, T.; Nakamura, T.; Kasugai, K.; Yatabe, Y.; Fujita, M.; Kuroda, M.; Akaza, K.; Nomura, C.; Hamajima, E.; Suchi, T.; et al. Primary low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma with polypoid appearance. Polypoid gastric MALT lymphoma: A clinicopathologic study of eight cases. Pathol. Int. 1999, 49, 702–709. [Google Scholar]
  81. Nakamura, T.; Seto, M.; Tajika, M.; Kawai, H.; Yokoi, T.; Yatabe, Y.; Nakamura, S. Clinical features and prognosis of gastric MALT lymphoma with special reference to responsiveness to H-Pylori eradication and API2-MALT1 status. Am. J. Gastroenterol. 2008, 103, 62–70. [Google Scholar] [CrossRef]
  82. Raderer, M.; Streubel, B.; Wohrer, S.; Hafner, M.; Chott, A. Successful antibiotic treatment of Helicobacter pylori negative gastric mucosa associated lymphoid tissue lymphomas. Gut 2006, 55, 616–618. [Google Scholar] [CrossRef] [Green Version]
  83. Jung, K.; Kim, D.H.; Seo, H.I.; Gong, E.J.; Bang, C.S. Efficacy of eradication therapy in Helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphoma: A meta-analysis. Helicobacter 2021, 26, e12774. [Google Scholar] [CrossRef]
  84. Hirata, N.; Tominaga, K.; Ohta, K.; Kadouchi, K.; Okazaki, H.; Tanigawa, T.; Shiba, M.; Watanabe, T.; Fujiwara, Y.; Nakamura, S.; et al. A case of mucosa-associated lymphoid tissue lymphoma forming multiple lymphomatous polyposis in the small intestine. World J. Gastroenterol. 2007, 13, 1453–1457. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Na, H.K.; Won, S.H.; Ahn, J.Y.; Kim, G.H.; Jung, K.W.; Lee, J.H.; Kim, D.H.; Choi, K.D.; Song, H.J.; Lee, G.H.; et al. Clinical course of duodenal mucosa-associated lymphoid tissue lymphoma: Comparison with gastric mucosa-associated lymphoid tissue lymphoma. J. Gastroenterol. Hepatol. 2021, 36, 406–412. [Google Scholar] [CrossRef] [PubMed]
  86. Matsumoto, T.; Iida, M.; Shimizu, M. Regression of mucosa-associated lymphoid-tissue lymphoma of rectum after eradication of Helicobacter pylori. Lancet 1997, 350, 115–116. [Google Scholar] [CrossRef]
  87. Nomura, E.; Uchimi, K.; Abue, M.; Kon, H.; Noguchi, T.; Suzuki, S.; Suzuki, M.; Onodera, H.; Tateno, H.; Ota, Y. Regression of MALT lymphoma of the rectum after Helicobacter pylori eradication therapy in a patient negative for Helicobacter pylori. Nihon Shokakibyo Gakkai Zasshi 2010, 107, 1466–1473. [Google Scholar]
  88. Makino, Y.; Suzuki, H.; Nishizawa, T.; Kameyama, K.; Hisamatsu, T.; Imaeda, H.; Mukai, M.; Hibi, T. Ileal Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma with a Large-Cell Component That Regressed Spontaneously. Gut Liver 2010, 4, 117–121. [Google Scholar] [CrossRef]
  89. Ruskone-Fourmestraux, A.; Matysiak-Budnik, T.; Fabiani, B.; Cervera, P.; Brixi, H.; Le Malicot, K.; Nion-Larmurier, I.; Flejou, J.F.; Hennequin, C.; Quero, L.; et al. Exclusive moderate-dose radiotherapy in gastric marginal zone B-cell MALT lymphoma: Results of a prospective study with a long term follow-up. Radiother. Oncol. 2015, 117, 178–182. [Google Scholar] [CrossRef] [PubMed]
  90. Goda, J.S.; Gospodarowicz, M.; Pintilie, M.; Wells, W.; Hodgson, D.C.; Sun, A.; Crump, M.; Tsang, R.W. Long-Term Outcome in Localized Extranodal Mucosa-Associated Lymphoid Tissue Lymphomas Treated with Radiotherapy. Cancer 2010, 116, 3815–3824. [Google Scholar] [CrossRef]
  91. Yahalom, J.; Xu, A.J.; Noy, A.; Lobaugh, S.; Chelius, M.; Chau, K.; Portlock, C.; Hajj, C.; Imber, B.S.; Straus, D.J.; et al. Involved-site radiotherapy for Helicobacter pylori-independent gastric MALT lymphoma: 26 years of experience with 178 patients. Blood Adv. 2021, 5, 1830–1836. [Google Scholar] [CrossRef] [PubMed]
  92. Schmelz, R.; Miehlke, S.; Thiede, C.; Brueckner, S.; Dawel, M.; Kuhn, M.; Ruskoné-Formestraux, A.; Stolte, M.; Jentsch, C.; Hampe, J.; et al. Sequential H. pylori eradication and radiation therapy with reduced dose compared to standard dose for gastric MALT lymphoma stages IE & II1E: A prospective randomized trial. J. Gastroenterol. 2019, 54, 388–395. [Google Scholar]
  93. Reinartz, G.; Pyra, R.P.; Lenz, G.; Liersch, R.; Stüben, G.; Micke, O.; Willborn, K.; Hess, C.F.; Probst, A.; Fietkau, R.; et al. Favorable radiation field decrease in gastric marginal zone lymphoma: Experience of the German Study Group on Gastrointestinal Lymphoma (DSGL). Strahlenther. Onkol. 2019, 195, 544–557. [Google Scholar] [CrossRef]
  94. Okamura, T.; Suga, T.; Iwaya, Y.; Ito, T.; Yokosawa, S.; Arakura, N.; Ota, H.; Tanaka, E. Helicobacter pylori-Negative Primary Rectal MALT Lymphoma: Complete Remission after Radiotherapy. Case Rep. Gastroenterol. 2012, 6, 319–327. [Google Scholar] [CrossRef]
  95. Reinartz, G.; Molavi Tabrizi, C.; Liersch, R.; Ullerich, H.; Hering, D.; Willborn, K.; Schultze, J.; Micke, O.; Ruebe, C.; Fischbach, W.; et al. Renaissance of Radiotherapy in Intestinal Lymphoma? 10-Year Efficacy and Tolerance in Multimodal Treatment of 134 Patients: Follow-up of Two German Multicenter Consecutive Prospective Phase II Trials. Oncologist 2020, 25, e816–e832. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Imber, B.S.; Chau, K.W.; Lee, J.; Lee, J.; Casey, D.L.; Yang, J.C.; Wijentunga, N.A.; Shepherd, A.; Hajj, C.; Qi, S.; et al. Excellent response to very-low-dose radiation (4 Gy) for indolent B-cell lymphomas: Is 4 Gy suitable for curable patients? Blood Adv. 2021, 5, 4185–4197. [Google Scholar] [CrossRef]
  97. Amiot, A.; Levy, M.; Copie-Bergman, C.; Dupuis, J.; Szablewski, V.; Le Baleur, Y.; Baia, M.; Belhadj, K.; Sobhani, I.; Leroy, K.; et al. Rituximab, alkylating agents or combination therapy for gastric mucosa-associated lymphoid tissue lymphoma: A monocentric non-randomised observational study. Aliment. Pharmacol. Ther. 2014, 39, 619–628. [Google Scholar] [CrossRef]
  98. Zucca, E.; Conconi, A.; Martinelli, G.; Bouabdallah, R.; Tucci, A.; Vitolo, U.; Martelli, M.; Pettengell, R.; Salles, G.; Sebban, C.; et al. Final Results of the IELSG-19 Randomized Trial of Mucosa-Associated Lymphoid Tissue Lymphoma: Improved Event-Free and Progression-Free Survival with Rituximab Plus Chlorambucil Versus Either Chlorambucil or Rituximab Monotherapy. J. Clin. Oncol. 2017, 35, 1905–1912. [Google Scholar] [CrossRef]
  99. Salar, A.; Domingo-Domenech, E.; Panizo, C.; Nicolas, C.; Bargay, J.; Muntanola, A.; Canales, M.; Bello, J.L.; Sancho, J.M.; Tomas, J.F.; et al. Long-term results of a phase 2 study of rituximab and bendamustine for mucosa-associated lymphoid tissue lymphoma. Blood 2017, 130, 1772–1774. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  100. Tsukamoto, A.; Nakamura, F.; Nannya, Y.; Kobayashi, Y.; Shibahara, J.; Ichikawa, M.; Fukayama, M.; Koike, K.; Kurokawa, M. MALT lymphoma of the small bowel with protein-losing enteropathy. Int. J. Hematol. 2014, 99, 198–201. [Google Scholar] [CrossRef]
  101. Marks, D.J.; Prodromou, A.; Silvanto, A.; Cox, A.; Pakzad, F.; Train, M.; Mitchell, I.C. Ileal MALT lymphoma causing massive gastrointestinal haemorrhage revealed on computed tomography angiography. Postgrad. Med. J. 2009, 85, 163–165. [Google Scholar] [CrossRef]
  102. Akbulut, H.; Soykan, I.; Yakaryilmaz, F.; Icii, F.; Aksoy, F.; Haznedaroglu, S.; Yildirim, S. Five-year results of the treatment of 23 patients with immunoproliferative small intestinal disease: A Turkish experience. Cancer 1997, 80, 8–14. [Google Scholar] [CrossRef] [Green Version]
  103. Bianchi, G.; Anderson, K.C.; Harris, N.L.; Sohani, A.R. The Heavy Chain Diseases: Clinical and Pathologic Features. Oncology 2014, 28, 45–53. [Google Scholar]
  104. Nadatani, Y.; Tanigawa, T.; Fukunaga, S.; Kinoshita, Y.; Ominami, M.; Obayashi, T.; Morimoto, K.; Sogawa, M.; Yamagami, H.; Shiba, M.; et al. Primary small intestinal mucosa-associated lymphoid tissue lymphoma diagnosed by balloon-assisted enteroscopy. Intern. Med. 2014, 53, 2671–2674. [Google Scholar] [CrossRef] [Green Version]
  105. Dhull, A.K.; Kaushal, V.; Singh, S.; Pal, M.; Lathwal, A. A journey into insidious world of MALT lymphoma of the ileum: From the beginning to the end. J. Gastrointest. Oncol. 2014, 5, E125–E127. [Google Scholar] [PubMed]
  106. Lin, P.C.; Chen, J.S.; Deng, P.; Wang, C.W.; Huang, C.H.; Tang, R.; Chiang, J.M.; Yeh, C.Y.; Hsieh, P.S.; Tsai, W.S.; et al. Concurrent colonic mucosa-associated lymphoid tissue lymphoma and adenoma diagnosed after a positive fecal occult blood test: A case report. J. Med. Case Rep. 2016, 10, 24. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  107. Chen, P.H.; Lin, Y.M.; Yen, H.H. Primary mucosa-associated lymphoid tissue lymphoma of the colon. Clin. Gastroenterol. Hepatol. 2011, 9, e74–e75. [Google Scholar] [CrossRef] [PubMed]
  108. Han, J.; Zhu, Z.; Zhang, C.; Xie, H.P. Successful Endoscopic Resection of Primary Rectal Mucosa-Associated Lymphoid Tissue Lymphoma by Endoscopic Submucosal Dissection: A Case Report. Front. Med. 2021, 8, 715256. [Google Scholar] [CrossRef] [PubMed]
  109. Choi, J. Successful Endoscopic Resection of Residual Colonic Mucosa-Associated Lymphoid Tissue Lymphoma after Polypectomy. Clin. Endosc. 2021, 54, 759–762. [Google Scholar] [CrossRef] [PubMed]
  110. Piotrowski, R.; Kramer, R.; Kamal, A. Image of the month. Extranodal marginal zone B-cell (mucosa-associated lymphoid tissue) lymphoma of the colon presenting as an obstructing mass. Clin. Gastroenterol. Hepatol. 2008, 6, e18–e19. [Google Scholar] [CrossRef]
  111. Nakamura, S.; Matsumoto, T.; Takeshita, M.; Kurahara, K.; Yao, T.; Tsuneyoshi, M.; Iida, M.; Fujishima, M. A clinicopathologic study of primary small intestine lymphoma: Prognostic significance of mucosa-associated lymphoid tissue-derived lymphoma. Cancer 2000, 88, 286–294. [Google Scholar] [CrossRef]
  112. Nakamura, S.; Aoyagi, K.; Iwanaga, S.; Yao, T.; Tsuneyoshi, M.; Fujishima, M. Synchronous and metachronous primary gastric lymphoma and adenocarcinoma—A clinicopathologic study of 12 patients. Cancer 1997, 79, 1077–1085. [Google Scholar] [CrossRef]
  113. Isaka, T.; Nakamura, T.; Tajika, M.; Kawai, H.; Imaoka, H.; Okamoto, Y.; Aoki, M.; Inoue, H.; Takahashi, K.; Mizuno, N.; et al. API2-MALT1 chimeric transcript-positive gastroduodenal MALT lymphoma with subsequent development of adenocarcinoma as a collision tumour over a clinical course of 7 years. Histopathology 2007, 51, 119–123. [Google Scholar] [CrossRef]
  114. Kobayashi, K.; Furukawa, K.; Ishikawa, E.; Mitsuma, A.; Funasaka, K.; Kakushima, N.; Furune, S.; Ito, N.; Wada, H.; Hirose, T.; et al. Collision Tumors of Gastric Adenocarcinoma and Mucosa-associated Lymphoid Tissue Lymphoma. Intern. Med. 2021, 60, 2419–2424. [Google Scholar] [CrossRef]
  115. Devi, P.; Pattanayak, L.; Samantaray, S. Synchronous adenocarcinoma and mucosa-associated lymphoid tissue lymphoma of the colon. Saudi J. Gastroenterol. 2011, 17, 69–71. [Google Scholar] [PubMed]
  116. Dierickx, D.; Habermann, T.M. Post-Transplantation Lymphoproliferative Disorders in Adults. N. Engl. J. Med. 2018, 378, 549–562. [Google Scholar] [CrossRef] [PubMed]
  117. Le Meur, Y.; Pontoizeau-Potelune, N.; Jaccard, A.; Paraf, F.; Leroux-Robert, C. Regression of a gastric lymphoma of mucosa-associated lymphoid tissue after eradication of Helicobacter pylori in a kidney graft recipient. Am. J. Med. 1999, 107, 530. [Google Scholar]
  118. Shehab, T.M.; Hsi, E.D.; Poterucha, J.J.; Gunaratnam, N.T.; Fontana, R.J. Helicobacter pylori-associated gastric MALT lymphoma in liver transplant recipients. Transplantation 2001, 71, 1172–1175. [Google Scholar] [CrossRef] [Green Version]
  119. Aull, M.J.; Buell, J.F.; Peddi, V.R.; Trofe, J.; Beebe, T.M.; Hanaway, M.J.; Roy-Chaudhury, P.; Alloway, R.R.; First, M.R.; Woodle, E.S. MALToma: A Helicobacter pylori-associated malignancy in transplant patients: A report from the Israel Penn International Transplant Tumor Registry with a review of published literature. Transplantation 2003, 75, 225–228. [Google Scholar] [CrossRef] [PubMed]
Cancers 14 00446 g001 550
Figure 1. Endoscopic images of small intestinal MALT lymphoma. (A) Irregularity of the duodenal mucosa. (B) A shallow ulcer with diffuse mucosal edema in the jejunum. (C,D) Multiple ulcerated lesions in the ileum.
Figure 1. Endoscopic images of small intestinal MALT lymphoma. (A) Irregularity of the duodenal mucosa. (B) A shallow ulcer with diffuse mucosal edema in the jejunum. (C,D) Multiple ulcerated lesions in the ileum.
Cancers 14 00446 g001
Cancers 14 00446 g002 550
Figure 2. Immunoproliferative small intestinal disease (IPSID). (A,B) Double-balloon endoscopy showing villous edema in the ileum. (C) A biopsy specimen revealing blunting of the villi. (D,E) A dense lymphoplasmacytic infiltrate detected. (F,G) The tumor cells are positive for CD138 (F) and IgA (G). Original magnification: ×25 (C), ×100 (D), and ×400 (E–G).
Figure 2. Immunoproliferative small intestinal disease (IPSID). (A,B) Double-balloon endoscopy showing villous edema in the ileum. (C) A biopsy specimen revealing blunting of the villi. (D,E) A dense lymphoplasmacytic infiltrate detected. (F,G) The tumor cells are positive for CD138 (F) and IgA (G). Original magnification: ×25 (C), ×100 (D), and ×400 (E–G).
Cancers 14 00446 g002
Cancers 14 00446 g003 550
Figure 3. Rectal-mucosa-associated lymphoid tissue (MALT) lymphoma. (A,B) Endoscopic images showing a 10 mm solitary elevated lesion with erosion on the surface. (C) Narrow band imaging showing enlarged vessels on the surface of the lesion. (D) Specimen from endoscopic mucosal resection. (E,F) Monotonous proliferation of small- to intermediate-sized centrocyte-like cells observed. (G–I) The tumor cells are positive for CD20 (G) and negative for CD5 (H) and CD10 (I). Original magnification: ×100 (E) and ×400 (F–I).
Figure 3. Rectal-mucosa-associated lymphoid tissue (MALT) lymphoma. (A,B) Endoscopic images showing a 10 mm solitary elevated lesion with erosion on the surface. (C) Narrow band imaging showing enlarged vessels on the surface of the lesion. (D) Specimen from endoscopic mucosal resection. (E,F) Monotonous proliferation of small- to intermediate-sized centrocyte-like cells observed. (G–I) The tumor cells are positive for CD20 (G) and negative for CD5 (H) and CD10 (I). Original magnification: ×100 (E) and ×400 (F–I).
Cancers 14 00446 g003
Table
Table 1. H. pylori-negative patients with gastric MALT lymphoma.
Table 1. H. pylori-negative patients with gastric MALT lymphoma.
nStageBIRC3-MALT11st-Tx 2nd-Tx after EradiationRef.
EradicationOther Tx
nCR RatenCR RatenCR Rate *
14I, II1NE1433% [27]
18I, II17 (64%)1729%1 (RT)100%12 (WW 7, RT 5)100%[25]
44I–IVNE4414% [7]
13I, II15 (56%)540%5 (RT)80%3 (WW 1, RT 1, CTx 1)100%[24]
24I, II3 (23%)1338% 8 (CTx ± IM 8)100%[23]
28I–IVNE2857% 12 (WW 5, RT 6, CTx 1)71%[8]
30I, IINE1833% [22]
25I, II17 (28%)2536% 14 (RT 3, CTx ± IM 11)86%[21]
131I–IVNE6317%68 (RT or CTx ± IM or S)72% [9]
57I–IV22 (39%) †90%48 (WW 2, RT 1, CTx 44, other 1)33% [10]
34NENE3444% 19 (RT 19)100%[20]
37I–IV11 (30%)1811%19 (RT 16, CTx 3)89% ‡16 (WW 3, RT 12, CTx 1)92%[28]
CR: complete remission; CTx: chemotherapy; IM: immunotherapy; NE: no evaluation; RT: radiotherapy; S: surgery; Tx: treatment; WW: watch and wait. * CR rate in the treated patients except for the cases under the watch-and-wait strategy; † MALT1 rearrangement; ‡ 100% in RT, 33% in CTx.
Table
Table 2. Second-line treatment in non-responders to eradication therapy in gastric MALT lymphoma.
Table 2. Second-line treatment in non-responders to eradication therapy in gastric MALT lymphoma.
nStageHP (−)Non-CR,
n (%)		2nd-Tx 2nd-Tx *Ref.
WWRTOther Tx
nCR
Rate		nCR
Rate		nCR
Rate		nCR Rate
105I, II113%24(24%)10NE 14 (CTx ± IM 12, CTx + S 1, S 1)27% [27]
60I, II112%10(17%)10% (SD 1)7100%2 (RT + CTx 1, ER 1)100% [26]
420I–IV10%97(23%)150% (NC 15) 82 †94%[7]
66I, II120%16(29%)250%989%1 (CTx)0% [24]
345I–IV8%61(18%)42NE1788%1 (CTx)100% [8]
339I–IV40%157(61%)57NE 100 ‡79%[9]
96I–IV39%44(60%)3NE3391%5 (CTx)63% [28]
CR: complete remission; CTx: chemotherapy; ER: endoscopic resection; HP: Helicobacter pylori; IM: immunotherapy; NC: no change; NE: no evaluation; R: rituximab; RT: radiotherapy; S: surgery; SD: stable disease; Tx: treatment; WW: watch and wait. * CR rate of each treatment was unavailable. † RT 47, CTx 22, RT + CTx 5, S 5, ER 1, R 1, and third-line antibiotic therapy 1; ‡ RT, CTx ± IM, and Sur were performed but detailed information was unavailable.
Table
Table 3. Summary of recently reported cases of small intestinal MALT lymphoma.
Table 3. Summary of recently reported cases of small intestinal MALT lymphoma.
AgeSexSiteMacroscopic
Findings		Stage1st-TxResponseFU Time, yearsRef.
75MJejunumStricture, shallow ulcerNAE, R-CTxPRNA[30]
78FJejunumMultiple ulcerative lesionsII1S (perforation)CRNA[104]
67FIleumLong raised mucosal surfaceII2S (obstruction)CR0.5[32]
58MIleum8 cm saccular dilationIIIES + RPR0.5[31]
55MIleumNANAS + CTx (dilated segment)CR1[105]
56FIleumNANAR-CTxCRNA[101]
73FIleumCobble-stone-like erosionNANone (progression to T-prolymphocytic leukemia)NA0.6 (DD)[68]
35FIleumMultiple tumors and ulcersLoCTxCRNA[66]
38MTIMultiple protruding lesionsLoNone *CR2[88]
61FTIMultiple polypoid lesionsIIA, CTxNANA[67]
73FEntireNodular mucosal lesionsIR-CTxCRNA[100]
50FEntireMultiple polypoid lesionsIIA, R-CTxCR5[84]
A: antibiotics; CR: complete remission; CTx: chemotherapy; DD: died of disease; E: eradication; F: female; FU: follow-up; I: ileum; J: jejunum; Lo: localized; M: male; NA: not available; PR: partial response; R: rituximab; S: surgery; TI: terminal ileum; Tx: treatment. * Spontaneous regression in 2 months.
Table
Table 4. Summary of recently reported cases of colorectal MALT lymphoma.
Table 4. Summary of recently reported cases of colorectal MALT lymphoma.
AgeSexSiteNumberSize, mmStage1st-TxResponseFU Time, yearsRef.
n = 51 Re, C, IC, Mul *Sin:Mul 27:16 I–VER 17, RT 12, S 8, CTx 4, ER + RT 4, S + RT 1, WW 5Rec 2, DOC 23.8 ‡[40]
n = 8 Re/C, Mul †Sin:Mul 4:4 I–IIER 2, S 4, CTx 1, S + CTx 1CR9 ‡[42]
64FCSinNALoEMRCR6[43]
80FC + AMulNALoE (HP+)PR→PD0.5[86]
61MASin5LoEMRCRNA[107]
79MTSin20IESD + E (HP+)CR1[73]
64MTSinNAIIESCR1[71]
59MSigSin20LoEMRCR3[106]
54MSigSin20IEEMRCR0.8[70]
50FSigSin18LoSNANA[43]
83FAV25cmSinNAIERT→ERCRNA[110]
57FReSinNALoESDNANA[43]
58FReSin5LoESDCR0.8[108]
54FReSin30IEEMR→ESD for residual tumorCR4[109]
57FReSin>30LoRTCR0.8[43]
65MReSin10IRTCR5.4[94]
83FReSin30II2RCR0.3[39]
78FReSin30NAENC3[72]
53FReSin20IE (HP−)CR0.3[87]
56FReMul10, 25IEMR + RTCR6.3[94]
62FReMul6, 20IRTCR1.1[94]
A: ascending colon; AV: anal verge; C: cecum; CR: complete remission; CTx: chemotherapy; DOC: died of other cause; E: eradication; EMR: endoscopic mucosal resection; ER: endoscopic resection; ESD: endoscopic submucosal dissection; F: female; FU: follow-up; He: hepatic flexure; HP: Helicobacter pylori; I: ileum; IC: ileocecum; Lo: localized; M: male; Mul: multiple; NA: not available; NC: no change; PD: progressive disease; PR: partial response; R: rituximab; Re: rectum; Rec: recurrence; RT: radiotherapy; S: surgery; Sig: sigmoid colon; Sin: single; T: transverse colon; Tx: treatment; WW: watch and wait. * Re 20, C 12, IC 15, Mul 4. † Re/C 7, Mul 1. ‡ Median follow-up time.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Ishikawa, E.; Nakamura, M.; Satou, A.; Shimada, K.; Nakamura, S. Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma in the Gastrointestinal Tract in the Modern Era. Cancers 2022, 14, 446. https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14020446

AMA Style

Ishikawa E, Nakamura M, Satou A, Shimada K, Nakamura S. Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma in the Gastrointestinal Tract in the Modern Era. Cancers. 2022; 14(2):446. https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14020446

Chicago/Turabian Style

Ishikawa, Eri, Masanao Nakamura, Akira Satou, Kazuyuki Shimada, and Shotaro Nakamura. 2022. "Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma in the Gastrointestinal Tract in the Modern Era" Cancers 14, no. 2: 446. https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14020446

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop