Continuing Education Activity

The neoplastic proliferation of B cells in the marginal zone of lymphoid tissue gives rise to marginal zone B cell lymphomas. Mucosa-associated lymphoid tissue lymphoma or MALT lymphoma is the term used for extranodal marginal zone lymphoma, referred to as MALToma. This activity reviews the evaluation and treatment of MALToma and highlights the role of the interprofessional healthcare team in evaluating and treating this condition.

Objectives:

• Identify the etiology of MALToma.
• Summarize the evaluation of a patient with a diagnosis of MALToma.
• Outline the management options available for MALToma.
• Review the importance of improving care coordination among interprofessional team members to improve outcomes for patients affected by MALToma.

Introduction

The neoplastic proliferation of B cells in the marginal zone of lymphoid tissue gives rise to marginal zone B cell lymphomas.[1] B cells can also proliferate in a neoplastic manner in extranodal sites in the mucosa-associated lymphoid tissue (MALT), which is present along the mucosal linings in the human body. The stomach is the most frequently involved organ. Other commonly involved extranodal sites include other parts of the gastrointestinal tract, thyroid, salivary gland, lung, lacrimal gland, synovium, dura mater, breast, skin, and eyes.[2] MALToma occurs equally in men and women. Men usually have MALToma of the stomach, small intestine, kidney, and skin, whereas, in women, MALToma more commonly presents in the thyroid, soft tissues, and skin. Mucosa-associated lymphoid tissue (MALT) lymphoma is the term used for extranodal marginal zone lymphoma and is referred to as MALToma.

Etiology

The marginal zone contains post germinal center B cells that have undergone somatic hypermutation. Chronic and persistent immune stimulation, either of infective or autoimmune nature, leads to the development of MALTomas. The postulated pathophysiologic mechanism of tumor development is that chronic inflammation leads to the accumulation of antigen-dependent B cells locally in the associated MALT. This growth is monoclonal, but continuous growth signal due to chronic inflammation makes B cells prone to accumulating mutations. With time, the cells accumulate mutations, and the growth pattern transforms from monoclonal to polyclonal, leading to the development of neoplastic B cells in the marginal zone of the MALT. Following translocations are most commonly found in MALTomas:[3]

1. t(14;18)(q32;q21)
2. t(11;18)(q21;q21)
3. t(3;14)(p13;q32)
4. t(1;14)(p22;q32)

Many of these mutations lead to the activation of nuclear factor-kappaB (NF-kappaB), which increases the survival of neoplastic B cells in the marginal zone.[4][5]

Epidemiology

The finding of marginal zone lymphoma outside the lymph nodes is a relatively uncommon presentation for non-Hodgkin lymphoma, accounting for approximately eight percent of all non-Hodgkin lymphoma.[6] Usually, it is a tumor of adults, and the mean age at presentation is 66 years. The most commonly encountered extranodal site is the stomach, with an incidence rate of 3.8 per 1000000 person-years, while the incidence of extranodal marginal zone lymphoma is 18.3 per 1000000 person-years. In studies, the incidence has been found to be less in the Black population than the non-Hispanic white population.[2]

Histopathology

Reactive follicles present in MALToma as in a normal mucosa-associated lymphoid tissue. These follicles become colonized by neoplastic cells. The involved tissue usually has a polymorphous infiltrate of small lymphocytes, plasma cells, and marginal zone B cells. Sometimes these clones have large centroblast-like cells. These cells have large nuclei and scant cytoplasm.

History and Physical

MALTomas present with symptoms due to localized involvement of the organs, so the symptoms vary depending upon the site of involvement. Cutaneous MALTomas may present with nodules and papules on the skin. Recurrent respiratory infections in pulmonary MALTomas. Gastroesophageal reflux disease, dyspepsia, and occult gastrointestinal bleeding with gastric MALTomas. MALToma in the small intestine may cause intermittent diarrhea, abdominal pain, and malabsorption. Ocular MALTomas may present with red-eye, epiphora, or visual field defects. A finding of unilateral or bilateral mass is present in the case of salivary gland involvement. MALTomas may present nonspecific symptoms, such as low-grade fever, night sweats, malaise, abdominal pain, and weight loss in less than 5% of cases.[7]

Evaluation

Laboratory tests are not diagnostic but can provide valuable information about the organ affected. Historically clinicians used barium contrast studies to detect MALTomas of the gastrointestinal tract, but these are not sensitive. Positron emission tomography-computed tomography (PET-CT) is more useful for the detection of MALTomas. In one study, PET-CT identified 42% of cases of early MALTomas, but sensitivity increases to 100% for stage III-IV disease.[8] The accurate diagnosis of MALToma is made through the biopsy of the affected site and doing a morphologic, immunophenotypic, and genetic analysis of the biopsy specimen. For gastric MALTomas, the biopsy is through endoscopy, as for lung MALToma through bronchoscopy. Care is necessary while taking a biopsy, as conventional biopsies may miss the diagnosis because sometimes the tumor can infiltrate the submucosa without affecting the mucosal layer. Jumbo biopsies and snare biopsies can lead to a diagnosis more efficiently. The most sensitive of all is ultrasound-guided endoscopic fine-needle aspiration biopsy or endoscopic submucosal resection.[9] Morphologic features include diffusely infiltrative cells associated with reactive appearing follicles that disrupt normal epithelium organization. On immunophenotype, one would find cells to be positive for the B cell markers CD19, CD20, and CD22, and negative for CD5, CD10, and CD23. On genetic analysis, trisomy 3, isochromosome 17q, and 2p11 translocations, and the translocations mentioned above can be present, but these findings support the diagnosis of MALToma. 

Treatment / Management

Management of MALToma depends on whether the tumor is gastric or nongastric.

For gastric MALToma, the treatment of choice is Helicobacter pylori eradication if the patient tests positive for H. pylori. Four weeks after the completion of H. pylori eradication therapy, testing is necessary to confirm the elimination of infection. After eradication, patients must be monitored with serial endoscopies to evaluate the response to treatment, recurrence, and the development of gastric adenocarcinoma. Guidelines suggest performing endoscopy with biopsy every three months until achieving a complete histologic response, and then endoscopy every six months for at least the first two years, and then endoscopy every 18 months. Surveillance endoscopies can stop in asymptomatic patients once two sequential endoscopies show no abnormalities on biopsy. Proton pump inhibitors and antibiotics are very effective in eradicating H. pylori infection. Studies show that approximately 20 to 30 percent of patients do not respond to H. pylori eradication therapy and require a second course of H. pylori-directed therapy to achieve eradication. If there is no response to H. pylori eradication therapy or the gastric MALToma does not correlate with H. pylori. These cases are treated with localized radiation therapy if the involved site can be encompassed in a single radiation field. Radiation therapy is more effective in achieving a complete histologic response and has lower relapse rates but has the potential for more complications. If MALToma persists after radiation therapy or the involved site is not amenable to radiation therapy, systemic therapy with pharmacologic agents is recommended. These agents are described below with treatment for nongastric MALTomas. These systemic therapies are not curative but may control symptoms and prolong survival. Gastric resection surgery (total or partial) is reserved for those with complications such as bleeding, perforation, or obstruction, but gastrectomy is associated with high morbidity and higher recurrence rates than seen with radiation therapy.

Treatment of nongastric MALTomas depends on the site and stage of the disease. For Stage I-II disease at a radiation conducive site, the tumor is treated with locoregional radiation therapy. Rituximab is the alternative for the early-stage disease at a radiation non-conducive site. Surgery, which is typically used for diagnostic purposes only, can play a role in the treatment of tumors in areas not amenable to radiation therapy (e.g., lung). The addition of adjuvant chemotherapy has not demonstrated improved survival rates in early-stage non-gastric MALToma. The late-stage (III and IV) disease is either treated by rituximab alone or a combination of rituximab and chemotherapy. The decision to use combination therapy depends on patient values and the goals of treatment. The addition of chemotherapy results in prolonged progression-free survival but does not improve overall survival and has associated problem of increased toxicity. Patients with mild symptoms may prefer single-agent rituximab. Combination therapy can be used for refractory disease following single-agent rituximab or for severely symptomatic patients with bulky disease, or those who place a high value on a longer treatment-free period. The regimen most commonly used with rituximab is either rituximab plus bendamustine or rituximab plus CVP (chlorambucil, vincristine, prednisone).

Differential Diagnosis

While considering a diagnosis of MALToma, the following differentials must be kept in mind.

• Reactive lesions: Reactive lesions do not destroy the normal epithelial organization, while MALTomas do. 
• Splenic marginal zone lymphoma: This diagnosis is a possibility when non-Hodgkin tumors arising from an extranodal site extend to involve the spleen.
• Nodal marginal zone lymphoma: This is a potential diagnosis when non-Hodgkin tumors arising from an extranodal site extend to involve nodes in a widespread fashion.
• Mantle cell lymphoma: Mantle cell lymphoma is also a B cell neoplasm, but in contrast to MALToma, it expresses CD5.
• Follicular lymphoma: Another B cell neoplasm that expresses CD 10 and exhibits t(14;18) rearrangements that involve the BCL2 gene.
• Diffuse large B cell lymphoma: Both diffuse large B cell lymphoma and MALToma are B cell neoplasms, but the former has more rapid growth with a poor prognosis. This differential is possible on morphology only with tumor cells of diffuse large B cell lymphoma having large cell size and nuclei as big as twice the size of a small lymphocyte.

Staging

There have been many proposed staging systems, but the most widely accepted staging system is the Lugano staging system. The Lugano staging system was developed to incorporate measures of distant nodal involvement.

• Stage I: Involvement of a single lymph node region or lymphoid structure such as the spleen, thymus, or Waldeyer's ring.
• Stage II: Involvement of two or more lymph node regions or lymph node structures on the same side of the diaphragm.
• Stage III: Involvement of lymph node regions or lymphoid structures on both sides of the diaphragm.
• Stage IV: Lymphoma has spread to several organs (for example, the lungs, liver, bone marrow, or solid bones), with or without lymph node involvement.

Prognosis

Prognosis depends on the involved organ system and the stage of the disease. Patients with MALToma usually have a good prognosis with a median survival of more than ten years. A prognostic score, called the "MALT-IPI," is used to predict the risk of progression of the disease. It has three prognostic factors, including age greater than or equal to 70 years, serum lactate dehydrogenase level over the upper limit of normal, and stage III or IV disease.[10] Overall survival decrease as the number of these risk factors increases in a single patient. Having no risk factor constitutes low risk with overall survival of approximately 99 percent, one risk factor makes MALToma intermediate risk with overall survival of about 93 percent, and two or more risk factors make it high risk with overall survival of approximately 64 percent. The patient's age and performance status also determine the prognosis.

Progression occurs in the form of histologic transformation to high-grade lymphoma. Histologic transformation is more likely in those with more than four nodal sites involved, elevated LDH, and failure to achieve a complete remission after initial treatment. Patients with histologic transformation have a worse prognosis and lower five-year survival rates. The prognosis also depends on the grade of the tumor, with long-term survival possible for patients with low-grade tumors. However, the cure is more difficult in patients with MALTomas in advanced stages. Disease-free survival for MALToma is estimated to be approximately 77 to 80 percent. From studies involving patients with marginal zone lymphomas, we have found that a five-year survival rate for stage I is around 80 percent, stage II about 75 percent, stage III approximated to be more than 50 percent, and stage IV approximately 65 percent. These figures show that more people with stage IV disease survive for five years or more compared to people with stage III disease. This difference could be because several other factors (not just stage) play a part in a person’s outcome. For example, the treatments people have and specific features of their lymphoma also influence survival.

Complications

Complications are usually site-specific depending on the organ involved. About 30% of patients with gastric MALToma and 50% of patients with extraintestinal MALToma may have lymphomatous involvement within another organ, which can lead to the recurrence of disease following local treatment.[11] Certain MALTomas can transform into aggressive diffuse large B-cell lymphoma, with resultant poor prognosis and survival.[12]

Deterrence and Patient Education

MALToma is a cancer of one of the blood cell types, but it can involve any organ, and hence, symptoms depend on the location where it forms. The presenting symptoms can be non-specific at times, so patients must seek advice from healthcare professionals. MALTomas formed in the stomach are mostly related to the stomach infection due to H. pylori bacteria and fortunately can be treated with antibiotics. If being managed for MALTomas, the patient must adhere to regular follow-ups as MALTomas increase the likelihood of other types of cancers even after successful treatment. Regular follow-ups may include talking to a doctor and having exams. Also, patients must keep an eye on the recurrence of the symptoms. For the MALTomas formed inside the stomach, there are follow-up tests to confirm that the H. pylori infection has gone away. These include breath tests, checking a stool sample, and upper endoscopy.

Enhancing Healthcare Team Outcomes

MALToma frequently poses a diagnostic dilemma due to its varied presentation involving almost any organ system. These patients may present with non-specific signs and symptoms. History and physical exam very rarely suggest the presence of a MALToma; hence it is difficult to make a diagnosis without proper diagnostic studies. While the oncologist is almost always involved in the care of patients with a MALToma, it is best managed by an interprofessional team that includes specialists, pharmacists, and nurses. Care is necessary while taking a biopsy, as conventional biopsies may miss the diagnosis because sometimes the tumor can infiltrate the submucosa without affecting the mucosal layer. Proper technique with jumbo biopsies and snare biopsies can lead to a diagnosis more efficiently. The most sensitive of all is ultrasound-guided endoscopic fine-needle aspiration biopsy or endoscopic submucosal resection.

The pharmacist should have involvement in the medical management, working with the clinician on agent selection, appropriate dosing, and checking for interactions. Nurses monitor the patient on follow-up visits, with an eye for adverse drug reactions, assessing patient compliance, and answering patient questions, while keeping the other clinicians informed of their findings.

The outcomes of MALToma depend on the organ system involved and the stage of the disease. However, to improve outcomes and obtain an early diagnosis, the involvement of an interprofessional group of specialists is the optimal approach. [Level 5]