Gastric Lymphoma

Etiology

H pylori infection of the stomach is one of the most common chronic infections, with an estimated 50% of the world’s population having been infected or previously infected by this bacteria. H pylori is detected in up to 90% of patients with gastric MALT lymphoma. Untreated H pylori infection leads to chronic inflammation and proliferation of T- and B cells in the gastric mucosa, which does not usually contain lymphoid tissue but can develop mucosal-associated lymphoid tissue in response to longstanding inflammation. This aberrant tissue can lead to malignant transformation, commonly known as gastric MALT lymphoma. In most cases, the lymphoid tissue resolves by eradicating H pylori.[2][7] 

Cases refractory to H pylori eradication are more likely to contain a genetic mutation or alteration, with the highest prevalence seen with t(11;18) (q21;q21) translocation. Rarely do these cases transform into DLBCL, which has a worse prognosis. DLBCL can result from MALT lymphoma transformation or occur de novo.[8][9] 

Several authors have described an association between other infections and MALT lymphomas, including HIV, Epstein-Barr virus (EBV), hepatitis B virus, and human T-cell lymphotropic virus-1 (HTLV-1). EBV, in particular, is rarely associated with MALT lymphoma but is implicated in about 10% of gastric DLBCL cases.[10] Other conditions implicated in the development of gastric lymphoma include celiac disease, inflammatory bowel diseases, and chronic immunosuppression.[7]

Epidemiology

Primary gastric lymphoma is rare, but its incidence has been increasing over the last 2 decades.[4][11] This disease accounts for up to 40% of extranodal lymphomas but only about 5% of gastric neoplasms. The risk of gastric lymphoma increases with advancing age, with a significant rise after age 40 and a peak incidence in the sixth decade of life. Men are 2 to 3 times more likely to develop primary gastric lymphoma than women.[4][7][11] 

Primary gastric lymphomas are more prevalent in Western countries than in their Eastern counterparts.[12] Over the years, various definitions of primary gastric lymphomas have led to some controversy in the medical literature. Most cases of gastric lymphomas are of the B-cell, non-Hodgkin subtype, with the majority classified as DLBCL of the stomach, not otherwise specified.

Pathophysiology

Gastric lymphoma arises from the formation of aberrant lymphoid tissue in the stomach. In most cases, antigen stimulation by H pylori infection recruits B- and T cells to the gastric mucosa, leading to chronic inflammation. Malignant transformation into low-grade gastric MALT lymphoma occurs in a minority of patients with chronic H pylori–associated gastritis. High-grade gastric lymphomas, also called gastric DLBCL, commonly consist of monoclonal B cells that progress independently of the presence of H pylori. Diagnosing and treating low-grade gastric MALT lymphomas is key to preventing progression to high-grade lymphomas, which have higher rates of complications, lower rates of complete remission, lower disease-free survival, and lower overall survival.[2][13][14]

In H pylori–negative gastric MALT lymphomas, various mechanisms of pathogenesis have been proposed, including the genetic alterations t(11;18), t(14;18), t(1;14), and t(3;14). In extranodal high-grade lymphomas, the oncogene Bcl-6 is present in most cases. However, Bcl-2 oncogene expression is reported to be low in gastric DLBCL.[15] 

Histopathology

Gastric lymphomas can be classified histologically as marginal zone B-cell lymphomas of MALT-type, DLBCLs, follicular lymphomas, mantle cell lymphomas, Burkitt lymphomas, T-cell lymphomas, and plasmacytomas. MALT lymphoma and DLBCL make up nearly 90% of all gastric lymphomas. The histological characteristics of MALT lymphoma include centrocyte-like cells, plasma cell infiltration, and destruction of gastric crypts, which are defined as lymphoepithelial lesions. These centrocyte-like cells express CD19, CD20, and CD79a but do not express CD5, CD10, CD23, and cyclin D1.[7] In about 2% to 8% of gastric MALT lymphoma cases, transformation to DLBCL has been reported.[16][17]

High-grade gastric lymphomas, or gastric DLBCL, demonstrate sheets of lymphoid cells with diffuse proliferation, resulting in invasion between gastric glands and expansion of the lamina propria. These cells are medium to large in size, with round or irregular nuclei, prominent nucleoli, and scant cytoplasm.[1] These large lymphoid cells are positive for CD20, CD79a, and PAX-5, and they exhibit an activated B-cell phenotype in immunohistochemistry. About 50% of cases are positive for Bcl-6, Bcl-2, and CD43.[18][19] DLBCL can be classified into the centroblastic type, which is more common and has a better prognosis, and the immunoblastic type, which is more aggressive.[16]

History and Physical

Presenting symptoms for gastric lymphoma vary widely. Commonly, patients present with abdominal pain, early satiety, nausea, vomiting, and indigestion. Patients can present with B symptoms such as fever, night sweats, and weight loss, but these symptoms are less common. Additionally, patients may present with gastrointestinal bleeding, ranging from occult bleeding leading to iron deficiency anemia to acute blood loss presenting as hematemesis, hematochezia, or melena. Obstruction and perforation are rare presentations of gastric lymphoma. Findings from the physical examination are often nonspecific but may include epigastric tenderness, a palpable epigastric mass, and lymphadenopathy.[4][11][20][21]

Evaluation

Gastric lymphoma most commonly occurs in the gastric antrum, and the gold standard for diagnosis is esophagogastroduodenoscopy (EGD) with biopsies, tissue analysis performed by trained pathologists, and immunohistochemistry.[22] Endoscopic findings may include irregular shallow erosions, ulcerations, enlarged rugal folds, intra-gastric nodules, or thickened gastric walls.[23]

Once diagnosed, staging of gastric lymphoma typically includes obtaining a CT scan with intravenous and oral contrast of the chest, abdomen, and pelvis. Endoscopic ultrasound is often utilized to assess the depth of invasion, perigastric lymph node involvement, and disease stage, although it is not mandatory for initial diagnosis.[24] The presence of H pylori infection helps identify gastric lymphomas, as it is detectable in up to 90% of cases, and its eradication is essential for treatment. Multiple noninvasive and invasive tests are available for H pylori, and confirmation of eradication usually requires 2 negative tests.

PET scans have been used to localize regions for biopsy in certain scenarios but are not required for diagnosis. Bone marrow biopsies are not routinely required in primary gastric non-Hodgkin lymphomas. Initial workup for gastric lymphoma typically includes a complete blood count with flow cytometry, assessment of renal and liver function, protein electrophoresis, serum lactate dehydrogenase, beta-2 microglobulin levels, viral hepatitis serologies, and HIV serology.[2][25][26]

Another essential step following the diagnosis of gastric MALT lymphoma is assessing for the t(11;18) translocation by fluorescence in situ hybridization (FISH), which should be conducted by an experienced cytogenetic or molecular pathologist. As discussed below, the presence of t(11;18) has significant implications for therapeutic decision-making.[27]

Treatment / Management

Once a gastric MALT lymphoma diagnosis is made, the patient should be treated with H pylori eradication therapy according to current guidelines, considering prior antibiotic exposure, allergies, and local antibiotic resistance patterns. Noninvasive testing should be performed to confirm eradication of H pylori using either a urea breath test or stool antigen test 6 weeks after the completion of the therapy. Notably, even if patients are confirmed H pylori–negative with 2 different forms of testing before eradication therapy, they should still undergo a 2-week course of antibiotics and proton pump inhibitors per H pylori treatment guidelines. Prior exposure to macrolide therapy imparts resistance to H pylori, potentially reducing eradication rates if reused.[28][29] Gastric MALT lymphomas have been shown to respond to H pylori eradication therapy in more than 75% of cases, regardless of bacterial presence at the time of lymphoma diagnosis. One possible theory is that infection with other unidentified bacteria may cause MALT pathology.[30](B3)

In patients with early-stage low-grade gastric MALT lymphomas (modified Lugano stages I-IIE), an EGD should be performed 3 to 6 months after H pylori eradication. During this endoscopy, gastric mapping should be performed with a histological evaluation of each specimen using the Sydney protocol. Complete remission or histological response is determined if there is a total resolution of diffuse lymphoid infiltrates and lymphoepithelial lesions in biopsy specimens on 2 consecutive endoscopies. Notably, evidence of histological remission may take 1 to 14 months post–H pylori eradication to become apparent.[31][32] If an experienced pathologist determines complete remission, complete histological response, or probable minimal residual disease, the patient should undergo EGD with biopsies every 6 months for the first 2 years. After 2 years, the exam frequency can be extended to EGD with gastric mapping biopsies every 12 to 18 months.(B2)

Patients with H pylori–negative gastric MALT lymphoma who have limited-stage (I-II₁) disease should be managed with involved-site radiation therapy (or ISRT) or single-agent rituximab in patients with contraindications to radiotherapy.[33] When patients show evidence of incomplete eradication or residual disease of low-grade gastric MALT lymphoma after H pylori treatment, they should undergo an EGD with gastric mapping biopsies every 3 to 6 months, following an expectant observation approach. If patients show no change in low-grade gastric MALT lymphoma after H pylori eradication therapy, they can opt for EGDs every 3 to 6 months with gastric mapping biopsies for expectant observation, or they can choose treatment with localized radiation or chemotherapy, with or without rituximab.

Patients with higher-grade gastric MALT lymphoma (Lugano stages II2-IV) are generally observed expectantly with clinical surveillance alone. If any indications for treatment arise, such as gastrointestinal bleeding, constitutional symptoms, or bulky disease, chemoimmunotherapy is preferred. The most commonly utilized regimens are based on a rituximab + chemotherapy backbone, such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) or BR (bendamustine-rituximab).[33][34] Overt histological transformation to DLBCL should be treated empirically as DLBCL. Please see StatPearls' companion resource, "Diffuse Large B-cell lymphoma," for further information.(A1)

Progressive gastric MALT (non-DLBCL) lymphoma after first-line rituximab-based chemotherapy can be treated with various salvage regimens with either rituximab + lenalidomide or oral BTK or PI3K-delta inhibitors. Clinical trial enrollment should always be considered in the relapsed or refractory setting.[33] Management of salvage therapy and clinical trials should always be guided by experienced hematologists at high-volume centers.

Surgery should be reserved for patients with acute bleeding not amenable to endoscopic therapy, perforation, or obstruction. Clinicians should inform patients that remission rates with radiation are higher than with chemotherapy or immunotherapy in gastric MALT lymphoma, with some studies reporting more than 95% complete histologic remission rates. Immunotherapy with rituximab increases the risk of hepatitis B reactivation and should be discussed with patients before choosing treatment options. Screening for HIV and hepatitis B and C should be completed before starting rituximab.[2][7][23][35][36][37]

Differential Diagnosis

The differential diagnoses of gastric lymphoma include peptic ulcer disease, celiac disease, symptomatic cholelithiasis, pancreatitis, hyperemesis, gastritis, gastroparesis, inflammatory bowel disease, pancreatic cancer, gastroesophageal reflux disease, and diverticulitis.

Surgical Oncology

Surgical resection of gastric lymphoma was historically the initial first-line treatment. However, it is now reserved for complications such as perforation, obstruction, or bleeding that are not manageable with endoscopic therapy. Surgery performed by an experienced surgical oncologist may be considered for progressive gastric lymphoma despite prior treatments such as H pylori eradication, chemotherapy or immunotherapy, and radiation, especially if the patient opts against an expectant observation approach. The decision should be made through a comprehensive discussion between the patient and physician, weighing the risks (as discussed in the Complications section) and potential benefits of surgery.

Radiation Oncology

Radiation has been demonstrated to be highly effective in treating gastric lymphomas that are refractory to H pylori eradication. This therapy is particularly suitable for localized disease with manageable adverse effects. Due to the rarity of gastric lymphoma, treatment by a radiation oncologist experienced in this condition is recommended.

Staging

Staging any neoplastic disease is crucial for determining treatment options and prognosis. Gastric lymphoma lacks a uniform staging system. TNM staging system, as TNM staging has been found ineffective for lymphomas. The Ann Arbor classification system has historically been utilized for staging Hodgkin and non-Hodgkin lymphomas. However, this system also lacks specific, relevant features necessary to accurately stage extranodal gastric lymphomas.

The most commonly used staging system for gastric lymphoma is the modified Lugano staging system, which is one of the proposed modifications of the Ann Arbor classification.[38] Modified Lugano staging consists of stages I, II, IIE, and IV, with no stage III disease designated. This categorization below correlates with many experts who advocate classifying gastric lymphomas as either low- or high-grade.

• Stage I denotes lymphoma confined to the gastrointestinal tract, which may include a single primary lesion or multiple noncontiguous lesions.
• Stage II indicates lymphoma extending into the abdomen from the primary gastrointestinal site.
  • Stage II₁ indicates local nodal involvement.
  • Stage II₂ indicates distant nodal involvement.
• Stage IIE refers to lymphoma that penetrates the serosa to involve adjacent organs or tissues, requiring specification of the involved site, such as stage IIE (spleen) or IIE (pancreas).
• Stage IV denotes lymphoma with disseminated extranodal involvement or the presence of supradiaphragmatic nodal involvement.[11] 

The Paris staging system is occasionally used alongside the modified Lugano classification, emphasizing the depth of invasion into the gastrointestinal wall to provide a more precise delineation of disease stages.[5][39]

Prognosis

Gastric lymphomas are slow-growing, indolent neoplasms that typically respond well to treatment, particularly when diagnosed early in the course of the disease. Low-grade gastric MALT lymphomas involving the mucosa and submucosal layers have a favorable prognosis, with up to 90% survival at 10 years. In many cases, low-grade disease can be completely resolved with H pylori eradication therapy alone, and recurrence of the disease may be associated with reinfection with H pylori. However, deeper tissue involvement and the presence of the chromosomal translocation t(11;18) are associated with a higher risk of progressing to high-grade disease that does not resolve with H pylori eradication therapy alone.

High-grade gastric MALT lymphoma may eventually necessitate chemotherapy, immunotherapy, or surgery despite its typically slow progression over time. The MALT-IPI (International Prognostic Index) was developed to categorize patients with gastric MALT lymphoma into 3 prognostic groups—low-risk, intermediate-risk, and high-risk. Risk factors evaluated include age 60 or older, elevated serum lactate dehydrogenase levels, the Ann Arbor stage III or IV disease, and involvement of multiple mucosal sites.[40]

If no risk factors are present, the patient is considered low risk, with a 5-year event-free survival rate approaching 70% and an overall survival rate of 99%. Intermediate-risk patients with one risk factor have a 5-year event-free survival rate of 56% and an overall survival rate of 93%. High-risk patients with two or more risk factors are believed to have poor outcomes, with a 5-year event-free survival rate of 29% and an overall survival rate of 64%.[2][7][41] 

Complications

Adverse events associated with gastric MALT Lymphoma increase as the disease progresses. Complications from the lymphoma itself include gastrointestinal bleeding, perforation, and gastric outlet obstruction. Invasions into surrounding organs, such as the hepatobiliary system and pancreas, can lead to biliary obstruction, infection, and pancreatitis.

Radiation always carries a risk of complications, including adhesions, scarring, pancreatitis, and various other issues arising from inflammation and scarring. Immunotherapy with rituximab carries a risk of hepatitis B reactivation, which can lead to acute liver failure and, in rare cases, death. Therefore, hepatitis B serology should be checked before initiating rituximab. Surgical complications include bleeding, gastric outlet obstruction, anastomotic leaks, adhesions, fistulas, and infection.