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Zucca E, Arcaini L, Buske C, et al; ESMO Guidelines Committee. Marginal zone lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020 Jan;31(1):17-29. doi: 10.1016/j.annonc.2019.10.010. PMID: 31912792.
Rohatiner A, d'Amore F, Coiffier B, et al. Report on a workshop convened to discuss the pathological and staging classifications of gastrointestinal tract lymphoma. Ann Oncol. 1994 May;5(5):397-400. PMID: 8075046.
Definition, Etiology, PathogenesisTop
Low-grade B-cell lymphoma or extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) is a non-Hodgkin lymphoma presumably originating from the post–germinal center memory B cells. There are common chromosomal translocations associated with this type of lymphoma, the most frequent ones being t(11;18)(q21;q21) and t(14;18)(q32;q21).
Stomach is the most common site of gastrointestinal (GI) extranodal lymphomas, accounting for two-thirds of cases. MALT lymphoma and diffuse large B-cell lymphoma (DLBCL) are the two most common types found in the stomach. MALT lymphoma is more frequent in middle-aged patients and accounts for a half of all cases of gastric lymphoma. The overall incidence is estimated to be ~4 in 1,000,000 and involves both men and women equally.
1. Helicobacter pylori (the most common risk factor).
2. Autoimmune disorders (most commonly Sjögren syndrome and systemic lupus erythematosus).
3. Immune deficiency or immunosuppressive therapy.
4. Celiac disease.
5. Inflammatory bowel disease.
6. Nodular lymphoid hyperplasia.
Clinical FeaturesTop
In most people MALT lymphoma is an incidental finding. The symptoms are very nonspecific and include epigastric pain, weight loss, anorexia, nausea and vomiting, early satiety, or GI bleeding. Occasionally anemia or elevated erythrocyte sedimentation rate may be detected.
DiagnosisTop
1. Upper endoscopy: Endoscopic assessment with biopsy is the most important diagnostic tool. Macroscopic findings may include erythema, mass, ulcer, nodularity, and thickened gastric folds. The key histologic feature of MALT lymphoma is the presence of lymphoepithelial lesions that are due to unequivocal invasion and partial destruction of gastric glands or crypts by a tumor cell aggregate. Biopsies should be taken from any abnormal-appearing mucosa as well as the duodenum, gastric antrum, gastric body, and gastroesophageal junction. Endoscopic ultrasonography (EUS) can also play a role in determining the depth of invasion and can be used to obtain core specimens from surrounding enlarged lymph nodes.
The need for confirmation or exclusion of H pylori infection dictates the use of the most sensitive diagnostic strategy. Apart from having a diagnostic value for MALT lymphoma itself, biopsies should be obtained from the normal stomach and examined for the presence of H pylori.
2. Alternative tests, such as the urea breath test, should be used if biopsies are negative for H pylori (effectively performing 2 tests, each with high sensitivity). Genetic testing for t(11;18) identifies tumors that are less likely to transform to high-grade lymphoma or less likely to respond to H pylori eradication therapy. It is important to obtain chest, abdominal, and pelvic computed tomography (CT) scans to exclude distant metastasis.
DLBCL is the second most common type of lymphoma in the stomach and, given its prognosis, it should always be excluded. The less common types include mantle cell lymphoma, follicular lymphoma, and peripheral T-cell lymphoma.
Lugano and Paris systems are the 2 most commonly used staging systems in patients with MALT lymphoma. The Lugano system is based on relative extension from the GI tract and the Paris system relies on the TNM classification.
At this time there are no defined strategies recommended to screen the general population for MALT lymphoma.
TreatmentTop
Treatment depends on the stage of MALT lymphoma. In nonadvanced disease (stage I or II), which is the most common clinical scenario, eradication of H pylori is the mainstay of treatment, with complete response in >50% of patients. Local guidelines should be applied in choosing the best therapeutic regimen to treat H pylori. It is essential to confirm eradication of H pylori at least 4 weeks after completion of an eradication regimen. It is also key to avoid proton pump inhibitors for ≥1 week (or 2 weeks if well tolerated by the patient) before the confirmation test to prevent false-negative results, as the use of PPIs decreases test sensitivity (sensitivity difference of 3%-4% between 1 and 2 weeks of PPI abstinence).Evidence 1Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Laine L, Estrada R, Trujillo M, Knigge K, Fennerty MB. Effect of proton-pump inhibitor therapy on diagnostic testing for Helicobacter pylori. Ann Intern Med. 1998 Oct 1;129(7):547-50. PMID: 9758575. It is not uncommon for H pylori to require a second or third line of treatment to achieve eradication. The preferred test for confirming eradication is the urea breath test or endoscopic biopsy. Serology should not be used for this purpose. Also see Peptic Ulcer Disease.
If eradication is confirmed, surveillance endoscopies are required to monitor tumor response. It is crucial to exclude more advanced lymphomas, such as DLBCL. If the disease persists despite H pylori eradication or in patients without H pylori infection, localized radiotherapy is the next universally accepted therapeutic option. In those with stage III or IV MALT lymphoma, the disease is less defined and may require rituximab or chemotherapy.
A follow-up endoscopy is recommended 1 year and 2 years after successful treatment to monitor for recurrence.
PrognosisTop
Prognosis is generally good, with the 5-year survival rate >90%. Lack of response to first-line treatment carries much worse prognosis, with ~50% 1-year mortality.
