Patients usually present with symptoms associated with localized disease depending on the tissue of origin or site of involvement. As mentioned previously, the stomach is the most frequent site of involvement, but it can involve other parts of the gut, ocular adnexa, lung, lacrimal and salivary glands, skin, soft tissue, thyroid, breast, and synovium, etc.[11][14][24][25][26][27]

Patients present with some of the following clinical presentations, depending on the site of involvement. The typical B symptoms noted with lymphoma are rare, seen in <5 percent of patients.[28]

• Gastric: Gastroesophageal reflux disease, stomach pain or discomfort, weight loss, anorexia, gastrointestinal bleeding, nausea, vomiting.[29][30] H. pylori infection is noted in >90 percent of gastric MALT.
• Ocular adnexa: Irritation of the eye, slow-growing mass, redness of the eye, excessive eye-watering.[14]
• Skin: Papules, plaques, nodules, itching usually on the upper extremities and trunk.
• Lung: Asymptomatic with lung nodules or consolidative changes.
• Salivary gland: A slow-growing mass, sometimes bilateral involvement.[31]

EMZL usually remains localized in the tissue of origin for a prolonged period of time, but sometimes the involvement of regional lymph nodes and other mucosal surfaces is noted at diagnosis. Particularly in the non-gastric EMZLs, concomitant involvement of multiple mucosal sites is not uncommon, with 25 to 50 percent of cases having disseminated disease. Bone marrow involvement is noted in up to 5 to 25 percent of patients and more common in non-gastric EMZLs.[32]

The diagnosis of EMZL is made after a morphologic, immunophenotypic, and genetic analysis of the biopsy specimen. Clinicians should aim to obtain the largest biopsy specimen, as small biopsy specimens and fine-needle aspirates may not provide adequate tissue for diagnosis. After the diagnosis of EMZL by an experienced hematopathologist, additional evaluation should include a history and physical exam, focusing on lymph node regions, eyes, ears, nose, throat, liver, and spleen. The blood work should include a complete blood count with differential, comprehensive metabolic panel along with lactate dehydrogenase and beta-2 microglobulin. Hepatitis B and C (HBV and HCV) serology and cryoglobulins in a patient who is HCV positive. The tumor biopsy should be tested for H. pylori, especially in the gastric EMZL. Protein electrophoresis, serum, and urine immunofixation may also be sent.

Bone marrow aspirate and biopsy are highly recommended in EMZL, particularly in non-gastric lymphoma. Imaging should include computed tomography of the chest, abdomen, and pelvis; sometimes, imaging of the orbits and salivary glands are recommended depending on the primary. A positron emission tomography (PET) scan should be considered for the adequate staging of the lymphoma and also is helpful when clinical and laboratory data suggest transformation. Esophagogastroduodenoscopy (EGD) and endoscopic ultrasound (EUS) are also useful in gastric EMZL for appropriate staging. Anti-SSA/Ro and anti-SSB/La antibody evaluation should be done in patients with salivary gland involvement to rule out the association of Sjogren syndrome.

The Lugano staging system is widely used for staging. Recently, additional staging systems like the Paris staging system are also being used.[33] Also, patients should be evaluated for nutritional and Eastern Cooperative Oncology Group (ECOG) or Karnofsky performance scales for performance status.

Management of EMZL depends on the primary site of involvement. Broadly the treatment depends on if the EMZL is gastric or non-gastric EMZL.

Gastric EMZLThe majority of patients usually present as early-stage in gastric EMZL. The treatment depends on the status of H. pylori.

Patients Positive for H. pylori

The primary treatment is directed at the eradication of the H. pylori with antibiotics in early-stage gastric EMZL. The choice of therapy depends on the local antibiotic resistance of H. pylori. The antibiotic treatment resulted in the regression of lymphoma and long-term disease control in the majority of patients.[34][35] The most commonly used regimen is a combination of proton pump inhibitor (PPI) with amoxicillin and clarithromycin administered for 10 to 14 days. The majority of patients successfully eradicate H. pylori, but the remaining may need an additional course of antibiotics. The outcome of the eradication treatment should be checked by a urea breath test or a stool antigen test about 6 weeks after the eradication therapy. Gastric EMZL regression is noted in up to 75% of cases with histologic complete response.[34] The length of time necessary to obtain a remission varies significantly from a few weeks to years. Gastric EMZL, which demonstrates t(11;18), has a lower chance of responding to the antibiotic therapy and complete response.[36]

Response Evaluation

After confirming the eradication of H pylori, periodic upper gastrointestinal endoscopic evaluations are recommended at least every 3 months with multiple biopsies to evaluate for tumor response as well as for recurrence. Once the complete response is achieved on the histology, the endoscopic evaluation can be staggered to every 6 months and then yearly after the first 2 years since diagnosis.

Failure of Initial Treatment

About 20 percent of the patients do not respond to the initial antibiotic therapy and require additional therapy. The appropriate timing for the second-line therapy is not clear as the responses from initial therapy can be slow and sometimes take up to a year. Treatment options include radiation therapy or systemic therapy with immunotherapy or chemoimmunotherapy.

Patients Negative for H. pylori

A minority of patients with gastric EMZL are negative for H. pylori at the time of diagnosis. The consensus on treatment differs slightly between the National Comprehensive Cancer Network (NCCN) and the European Society of Medical Oncologists (ESMO). While NCCN suggests the use of other modalities like radiation and systemic therapy, ESMO recommends a trial of H. pylori directed therapy as testing for H. pylori is not 100 percent sensitive where some patients can have false-negative test results. 

Advanced Gastric EMZL Patients with advanced disease who are positive for H pylori are still treated with antibiotics for eradication. In symptomatic disease, immunotherapy/chemoimmunotherapy is used as initial therapy. Those without H. pylori infections are usually treated with systemic therapy, and treatment is usually initiated when patients are symptomatic.

Non-gastric EMZL

The common sites of involvement of EMZL other than gastric are the ocular adnexa, lung, thyroid, lacrimal glands, salivary glands, breast, skin, small intestine, dura, and soft tissues as discussed above. The treatment usually depends on the stage. Patients with localized disease are usually treated with local therapy like radiation, and advanced disease is treated with systemic therapy like immunotherapy and chemoimmunotherapy, which are discussed below. 

Unlike gastric EMZL, the benefit from antibiotic use is still unclear in some of the non-gastric EMZL. Doxycycline was used in patients with ocular adnexa EMZL with evidence of C. psittaci infection, an estimated progression-free survival (PFS) at 5 years was about 55 percent.[5][37]

Radiation Therapy

Local radiation therapy results in high rates of remission in early non-gastric EMZL. The 5-year survival rates are greater than 90%.[38][39][40][41] A total dose of 25 to 30 Gy administered over three to four weeks is usually used, and recently a low dose of 24 Gy was also studied.[41] Long term complications related to radiation are rare and usually dependent on the dose of radiation as well as the site. The side effects are usually noted in patients who received ocular adnexa radiation, causing cataract, corneal ulceration, optic atrophy, and glaucoma.

Systemic Therapy

Systemic therapy is usually used in patients with advanced disease or if radiation is not feasible or if the disease progressed after local radiation.

Rituximab, a CD20 monoclonal antibody, is used with or without chemotherapy. Single-agent rituximab therapy is well tolerated, and the overall responses are in the range of 80 percent.[42][43] The use of combination therapy with chemotherapy depends on the goals of therapy. There is an increased progression-free survival, but no overall survival (OS) is noted, and the combination therapy is noted to have increased toxicity. It is usually preferred in symptomatic patients with bulky disease and patients who prefer a longer treatment-free interval.[44][45] An international phase III clinical trial with EMZL patients not responding to or not eligible for local radiation were enrolled to be treated randomly with chlorambucil with or without rituximab. A third arm was later incorporated with single-agent rituximab. The group, with combination chlorambucil with rituximab, when compared with single-agent chlorambucil, showed improved complete remission (79% vs. 63%) and a 5-year PFS (72% vs. 59%).

When compared to single-agent rituximab, the combination rituximab and chlorambucil showed improved complete response (79% vs. 56%) and a 5-year PFS (72% vs. 57%). All three treatments have a similar 5-year OS rate.[44][45] Bendamustine, in combination with rituximab (BR), is another treatment option. Two other randomized trials compared BR versus R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and R-CVP (cyclophosphamide, vincristine, and prednisone). BR resulted in equivalent efficacy with less toxicity.[46][47] It is also noted to have good activity in cases with t(11;18).

Rituximab, in combination with lenalidomide, has shown promising activity in a phase II trial.[48] Anthracycline containing regimens are usually not required unless there is a transformation to a large cell lymphoma. Ibrutinib is another medication studied in MZL in a phase II trial, where responses are seen in about 48 percent of patients after progressing on the previous CD20 directed therapy.[49] Idelalisib also has been studied in relapsed and refractory MZL and has a modest response.[50] Autologous stem cell transplantation is considered in some fit patients who have clinically aggressive disease relapse.[51]

Surgery is not recommended in patients with EMZL, as it may impair quality of life, especially with local treatments having a significantly high overall survival even at 10 years. 

Transformation

Indolent lymphomas, including EMZL, can transform into more aggressive high-grade large cell lymphoma. It should be suspected in patients who develop B symptoms (fever, weight loss, drenching night sweats), a significant elevation in LDH, or rapid growth of a lymph node. A concern for large cell transformation should be further evaluated by a biopsy and PET scan for appropriate staging and treatment considerations. PET scan also can help select the appropriate site to do the biopsy.

Differential diagnosis to consider are: 

• Reactive lesions
• Nodal and splenic marginal zone lymphoma
• Diffuse large B cell lymphoma
• Small cell lymphoma
• Mantle cell lymphoma
• Follicular lymphoma

Lugano staging system for the gastrointestinal tract lymphoma:

• Stage I: Confined to the GI tract (single primary or multiple, non-contiguous)
• Stage II: Extending into the abdomen     II1: Local nodal involvement     II2: Distant nodal involvement
• Stage IIE: Penetration of serosa to involve adjacent organs or tissues
• Stage IV: Disseminated extra-nodal involvement or concomitant supra-diaphragmatic nodal involvement

EMZL has a relatively good prognosis with median survival greater than 10 years. However, some patients with high-risk disease are more likely to progress. MALT-IPI is a prognostic score that may be able to identify high-risk patients.[52]

The independent prognostic factors were identified:

• Age > 70 years
• Stage III or IV disease
• Serum lactate dehydrogenase greater than the upper limit of normal

The patients are divided into three risk groups depending on the number of prognostic factors.

• Low risk – zero risk factors
• Intermediate risk – one risk factor
• High risk – two or more risk factors

The prognosis of the patients depends on what group they fall into, and the 5 -year progression-free survival (PFS) and overall survival (OS) are as follows.

• Low risk – PFS 76%, OS 99%
• Intermediate risk – PFS 63%, OS 93%
• High risk – PFS 33%, OS 64%

Also, the prognosis depends on the histological transformation to a high-grade lymphoma, where patients had lower five-year survival rates.[53]

Complications of MALT-lymphoma usually are related to the local organ involvement as well as associated with therapy. Some of the common complications noted include the following:

• Gastric bleeding 
• Iron deficiency anemia 
• Gastric perforation 
• Obstruction
• Cachexia
• Therapy-related complications like a life-threatening infection, hospitalization, decreased blood counts, secondary cancers, etc.

Patients should receive education regarding the diagnosis, prognosis, and available treatment options. Patients should be educated on the possible adverse side effects associated with the treatment. Education on lifestyle modifications, smoking cessation, diet, and exercise should be provided. Patients should be alerted to monitor the common symptoms of the disease like fever, drenching night sweats, swollen lymph nodes, unintentional weight loss. Cancer survivorship education, as well as education on long-term complications, should be provided.

The management of MALT lymphoma is complex and needs an interprofessional team approach. Hematologists and oncologists are always involved in the care of these patients, but other interprofessional team members, including radiation oncologists, pathologists, gastroenterologists, and radiologists, are also pivotal. It is recommended that these complex patients are discussed in a multidisciplinary tumor board for a consensus treatment plan. This approach will facilitate optimal patient care, individualized treatment decisions, and also improve enrollment in the clinical trials.

Other allied health professionals, including the pharmacists, nurses, social workers, dieticians, physical therapists, also are involved in the care of these patients. Constant interaction and discussion between these health professionals improve the outcomes of these patients. Having oncology trained psychologists as part of the team also plays a significant role in addressing psycho-social issues pertaining to the diagnosis and management of lymphomas. Family and friends are also involved in the care of the patient, and every effort should be made to communicate with them and educate them regarding the disease. [Level 5]