MALT lymphoma is a neoplasm of adults with a median age at presentation of about 60 years; a slightly higher proportion of females than males are affected. Pediatric cases are exceedingly rare. The presenting symptoms are essentially related to the primary location. Very few patients present with elevated lactate dehydrogenase (LDH) or beta-2 microglobulin levels, and constitutional B symptoms are extremely uncommon. MALT lymphoma usually remains localized for a prolonged period within the tissue of origin, but dissemination to multiple sites is not uncommon, with either synchronous or metachronous involvement of multiple mucosal sites or non-mucosal sites such as the bone marrow, the spleen, or the liver. Regional lymph nodes can also be involved. Bone marrow involvement is reported in up to 20% of cases.
The stomach is the most common site of localization, accounting for about one-third of cases. Other typical presentation sites include the salivary glands, the ocular adnexa, the thyroid, and the lung.
Advanced disease at diagnosis appears to be more common in MALT lymphomas that arise outside the gastrointestinal (GI) tract. Up to one quarter of patients with gastric lymphoma—but nearly half of those with non-GI lymphoma—present with disseminated disease.[52,53]
Within the stomach, MALT lymphoma is often multifocal, possibly explaining the reports of relapses in the gastric stump after surgical excision. Gastric MALT lymphoma can often disseminate to the small intestine
and to the splenic marginal zone. Concomitant GI and non-GI involvement can be detected in approximately 10% of cases.[52,53]
MALT lymphoma usually has a favorable outcome, with overall survival at 5 years higher than 85% in most series. Patients with lymph node or bone marrow involvement at presentation, but not those with involvement of multiple mucosal sites, may have a worse prognosis. If initially localized, the disease is generally slow to disseminate. Recurrences may involve either extranodal or nodal sites. The median time to progression has been reported to be better for GI than for non-GI lymphomas, but with no significant differences in overall survival between the two groups. In fact, non-GI MALT lymphomas, despite presenting more often as stage IV disease, usually have a quite indolent course, regardless of treatment type. Nonetheless, they are significantly more prone to relapse (most often at other mucosal sites) than primary gastric cases. Localization may have prognostic relevance because of organ-specific clinical problems that determine particular management strategies, but also because of specific local pathogenetic mechanisms, as suggested by the reports of different frequencies of different chromosomal translocations at distinct anatomic locations.
In a radiotherapy study from Toronto, gastric and thyroid MALT lymphomas had the best outcome, whereas distant failures were more common for other sites.[55,56] In a multicenter series from the International Extranodal Lymphoma Study Group (IELSG), those patients who initially presented with disease in the upper airways appeared to have a slightly poorer outcome, but their small number prevented any definitive conclusion. In general, despite frequent relapses, MALT lymphomas most often maintain an indolent course. Histological transformation to large-cell lymphoma is reported in about 10% of cases (apparently a lower rate than in other indolent lymphomas), and usually occurs late during the course of the disease and independently from dissemination.[57-59] It is unknown whether the incidence of transformation differs among sites.
Diagnosis and Management of Gastric MALT Lymphoma
The most common presenting symptoms of gastric MALT lymphoma are nonspecific upper GI complaints, often leading to endoscopy that usually reveals nonspecific gastritis or peptic ulcer, with mass lesions being unusual. Diagnosis is based on the histological evaluation of the gastric biopsy specimens.
The best staging system is still controversial. The Ann Arbor staging system, routinely used for non-Hodgkin lymphoma, was developed for Hodgkin disease and is not adequate for the specific problems posed by GI-tract lymphomas. A variety of alternative systems have therefore been proposed. We have primarily used a modification of the Blackledge system known as the ‘‘Lugano’’ staging system. However, this system was proposed before the advent of endoscopic ultrasound examination and does not accurately describe the depth of infiltration in the gastric wall, a parameter that is highly predictive of the MALT lymphoma response to anti-Helicobacter therapy. There is a general consensus that initial staging procedures should include gastro-duodenal endoscopy, with multiple biopsies from each region of the stomach, duodenum, and gastro-esophageal junction, as well as from any abnormal-appearing site. Fresh biopsy and washing material should be available for cytogenetic studies in addition to routine histology and immunohistochemistry. FISH analysis or a molecular assay for the detection of t(11;18) is recommended for identifying disease that is unlikely to respond to antibiotic therapy. The presence of active infection must be determined by histochemistry and breath test; serology studies are recommended when the results of histology are negative. Endoscopic ultrasound is recommended at the initial follow-up for evaluation of depth of infiltration and presence of perigastric lymph nodes.
Although the disease usually remains localized to the stomach, systemic dissemination and bone marrow involvement should be excluded at presentation. Staging should include complete blood cell counts; basic biochemical studies; CT of the chest, abdomen and pelvis; and a bone marrow biopsy.[61,62]
H pylori Eradication in Gastric MALT Lymphoma
A major change in the management of gastric MALT lymphoma occurred following the identification of H pylori as its etiologic agent. Surgical resection, often followed by postoperative radiotherapy or chemotherapy, was standard up to the early 1990s. After the initial report by Wotherspoon et al in 1993, several groups have now confirmed the achievement of durable lymphoma remissions in 60% to 100% of patients with localized (ie, confined to the gastric wall) H pylori–positive gastric MALT lymphoma treated with antibiotics. Differences in the response criteria used in individual studies to evaluate the lymphoma eradication after antibiotic therapy may explain the wide range of reported remission rates. Unfortunately, the interpretation of residual lymphoid infiltrate in post-treatment gastric biopsy specimens can be very difficult, and there are no uniform criteria in the literature defining histological remission.[63,64] Copie-Bergmann et al have proposed a new histological grading system with the aim of providing information that is useful to clinicians.[64,65] This system, summarized in Table 2, may become a useful tool if its reproducibility can be confirmed in larger series. Histological remission can usually be documented within 6 months following H pylori eradication, but sometimes the period required is more prolonged and the therapeutic response may be delayed for more than a year.
Several effective programs are available for the treatment of H pylori infection.[66-68] The choice should be based on the epidemiology of the infection in the patient’s country of residence, taking into account the locally expected antibiotic resistance. The most commonly used regimen is triple therapy: a proton pump inhibitor (eg, omeprazole(Drug information on omeprazole), lansoprazole(Drug information on lansoprazole) [Prevacid], pantoprazole [Protonix], or esomeprazole(Drug information on esomeprazole) [Nexium]) in association with amoxicillin and clarithromycin(Drug information on clarithromycin). Metronidazole(Drug information on metronidazole) can be substituted for amoxicillin(Drug information on amoxicillin) in penicillin-allergic individuals. Other regimens that use bismuth or H2-receptor antagonists with antibiotics are also effective.
The role of additional chemotherapy after antibiotics was investigated in a randomized study (whose power, however, was limited due to its not having reached the planned accrual). In this study, chlorambucil(Drug information on chlorambucil) (Leukeran) conferred no benefit, with progression-free survival and overall survival rates similar for observed-only and chlorambucil-treated patients.
Anti-Helicobacter Therapy in Gastric Diffuse Large B-Cell Lymphoma
Antibiotic therapy may also be of benefit in some cases of gastric DLBCL, since in the subset of cases that may have been derived from a lymphoma of the MALT type, antibiotics may eliminate the persistent antigen stimulation that could be responsible for tumor recurrence. Cases of regression of gastric DLBCL after anti-Helicobacter therapy have been reported. However, relying solely on antibiotic therapy for gastric large-cell lymphomas cannot be advised outside clinical trials until large-scale prospective studies have validated its use as first-line therapy, and at present we recommend treating gastric large-cell lymphomas as localized DLBCL.
Factors That Predict Response to H pylori Eradication
Endoscopic ultrasound can be useful for predicting a lymphoma's response to H pylori eradication. There is a significant difference between the response rates of lymphomas restricted to the gastric mucosa and rates in less superficial lesions. The response rate is highest for mucosa-confined lymphomas (approximately 70% to 90%) and then decreases markedly and progressively for tumors infiltrating the submucosa, the muscularis propria, and the serosa.[71-75] In cases with documented nodal involvement, response is highly unlikely.[73-75] Almost no gastric lymphomas with the t(11;18) translocation will respond to H pylori eradication therapy. A French study indicates that the t(11;18) translocation can also—to some extent—predict the therapeutic response of gastric MALT lymphoma to chlorambucil, but this is not necessarily true for responses to other therapeutic approaches, such as chemotherapy or immunotherapy.[77,78] Moreover, the cases that carry this translocation rarely undergo high-grade transformation and have been reported to have a significantly longer relapse-free survival irrespective of treatment modality.