MALToma

Etiology

The marginal zone contains post-germinal center B cells undergoing somatic hypermutation. Chronic and persistent immune stimulation, whether infectious or autoimmune in nature, leads to the development of MALTomas. The proposed pathophysiological mechanism underlying tumor development suggests that chronic inflammation triggers the accumulation of antigen-dependent B cells locally within the associated MALT. Initially monoclonal, this growth is sustained by a continuous inflammatory signal due to chronic inflammation, which predisposes B cells to accumulate mutations. Over 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.

The most commonly observed translocations in MALTomas include:

• t(14;18)(q32;q21)
• t(11;18)(q21;q21)
• t(3;14)(p13;q32)
• t(1;14)(p22;q32)

Many of these mutations lead to the activation of nuclear factor-kappa B (NF-ΚB), which increases the survival of neoplastic B cells in the marginal zone.[3][4][5]

Epidemiology

The discovery of marginal zone lymphoma occurring outside the lymph nodes is relatively rare among non-Hodgkin lymphomas, accounting for approximately 8% of all cases.[6] Usually, this tumor manifests in adults, with an average age of presentation at 66 years. The stomach is the most frequently affected extranodal site, with an incidence rate of 3.8 per 1,000,000 person-years, while the incidence of extranodal marginal zone lymphoma is 18.3 per 1,000,000 person-years. Studies indicate a lower incidence among the Black population compared to the non-Hispanic white population.[2]

Pathophysiology

Gastric MALTomas are an indolent disease, and their development is a multistep process that spans years. Gastric MALTomas are strongly associated with chronic infectious and inflammatory conditions, specifically Helicobacter pylori infections. This leads to the stimulation of local B and T cells. Chronic antigenic stimulation may lead to the accumulation of somatic mutations. Implicated in this process are several translocations, including t(1:14), t(11:18), t(14:18), and t(3:14).

These translocations lead to the constitutive activation of the NF-ΚB pathway, which stimulates the release of cytokines and enhances cell survival. Alternatively, MALTomas with t(3:14) lead to the overexpression of FOX1P, a transcriptional suppressor of caspase-dependent pro-apoptotic genes. Other chromosomal aberrations, such as trisomies 3, 12, and 18, have also been reported. Although they may not activate NF-ΚB directly, they utilize alternative pathways to resist apoptosis and promote proliferation. Moreover, somatic mutations, such as missense and frameshift mutations in cMyc and PIM1, have also been documented.

Non-gastric MALTomas have also been associated with chronic infectious or inflammatory conditions. Ocular adnexal and pulmonary MALTomas are associated with Chlamydia psittaci infections. Furthermore, deletions and mutations in genes such as PIM1, cMyc, TNFAIP3, and MyD88 have been noted. Hypermethylation of TNFAIP3 is also another alteration that may be observed in ocular adnexal, salivary, and thyroid lymphomas.[6] The pro-growth stimulatory environment created by the various cytokines and chemokines released, along with the interaction between B and T cells, contribute to increased B-cell survival. This environment can lead to the emergence of precancerous lymphoepithelial lesions, followed by monoclonal lesions.

Histopathology

Reactive follicles, similar to those found in normal MALT, are also present in MALToma. However, these follicles are infiltrated by neoplastic cells. The affected tissue usually exhibits a polymorphous infiltrate comprising small lymphocytes, plasma cells, and marginal zone B cells. Occasionally, these clones may contain large centroblast-like cells characterized by large nuclei and scant cytoplasm.

History and Physical

MALTomas present with symptoms due to localized involvement of organs, leading to variations in symptoms depending upon the site of involvement. Cutaneous MALTomas may present with nodules and papules on the skin, while pulmonary MALTomas often result in recurrent respiratory infections. Gastric MALTomas are associated with gastroesophageal reflux disease, dyspepsia, and occult gastrointestinal bleeding. MALTomas 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 unilateral or bilateral mass is found in 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 such as a complete blood count and metabolic panel can provide valuable information and are considered part of the standard workup, although they are not diagnostic independently. Additionally, hepatitis B and C titers are often obtained as part of the workup due to the risk of hepatitis B reactivation in patients undergoing chemoimmunotherapy. Hepatitis C titers should be obtained as this may be the precipitating factor in the development of splenic MALT. Echocardiography may be warranted in certain cases to establish baseline cardiac function, particularly if anthracycline-based chemotherapy is planned. Moreover, patients of childbearing age should undergo a pregnancy test, and fertility counseling should be provided as part of the comprehensive care plan.

Although, historically, clinicians have used barium contrast studies to detect MALTomas in the gastrointestinal tract, these are not sensitive. Positron emission tomography–computed tomography (PET-CT) has emerged as a more useful tool for detecting MALTomas. In a study, PET-CT identified 42% of early MALToma cases, with sensitivity increasing to 100% for stages III and IV.[8] The accurate diagnosis of MALToma is made through a biopsy of the affected site, followed by morphological, immunophenotypic, and genetic analysis of the biopsy specimen. Biopsies for gastric MALTomas are typically obtained through endoscopy, while lung MALTomas are biopsied using bronchoscopy.

Care must be taken when obtaining a biopsy, as conventional methods may overlook the diagnosis, especially if the tumor infiltrates the submucosa without affecting the mucosal layer. Utilizing techniques such as jumbo and snare biopsies can enhance diagnostic efficiency. However, ultrasound-guided endoscopic fine-needle aspiration biopsy or endoscopic submucosal resection is the most sensitive approach.[9] Morphological features of MALTomas include diffusely infiltrative cells associated with reactive appearing follicles, which disrupt normal epithelium organization. On immunophenotyping, cells typically exhibit positivity for the B-cell markers CD19, CD20, and CD22, while being negative for CD5, CD10, and CD23. Genetic analysis may reveal trisomy 3, isochromosome 17q, 2p11 translocations, and the translocations mentioned earlier, all of which support the diagnosis of MALToma. Testing for H pylori is necessary, especially in a suspected gastric MALToma setting, as this can also significantly impact the management. This testing can be conducted during endoscopic biopsy or through non-invasive modalities such as stool antigen testing or urea breath tests.

Treatment / Management

The management of MALToma varies depending on whether the tumor is gastric or non-gastric. For gastric MALToma, the preferred treatment for t(11;18)–negative H pylori infections is eradication therapy using antibiotics. In cases where patients have positive t(11;18) status, H pylori–negative disease, or fail antibiotic therapy, radiotherapy or systemic therapy may be considered. Long-term follow-up of H pylori–positive patients with gastric MALTomas who undergo eradication therapy shows an 80% complete response rate.[10] Radiotherapy treatments typically yield higher rates of complete response and control, albeit with added long-term toxicity.[11] Surgery is rarely used in this context, given the success of less invasive approaches. Gastric resection surgery (total or partial) is reserved for those with complications such as bleeding, perforation, or obstruction, although gastrectomy carries high morbidity and recurrence rates compared to radiation therapy.

Non-gastric MALTomas are usually treated with upfront radiotherapy. However, antibiotics are utilized in patients where a chronic bacterial infection is the suspected cause (ie, Chlamydia psittaci and ocular adnexa MALT). Complete response rates exceeding 90% have been observed in patients treated with radiotherapy.[12][13][14] In instances where radiotherapy would result in unacceptable toxicity, systemic chemotherapy may be considered, although it generally yields lower response rates.[15] Advanced disease may be treated with rituximab alone or a combination of rituximab and chemotherapy. The decision to pursue combination therapy depends on the patient's values and treatment objectives.(B2)

The addition of chemotherapy has been shown to extend progression-free survival; however, it does not necessarily improve overall survival and can lead to increased toxicity. For patients with mild symptoms, single-agent rituximab may be preferred. Combination therapy can be used for refractory disease following single-agent rituximab for severely symptomatic patients with bulky disease or those who prioritize a longer treatment-free period. Common regimens used alongside rituximab include rituximab plus bendamustine or rituximab plus CVP (chlorambucil, vincristine, and prednisone). Surgical resection may be considered for MALTomas affecting the small bowel, lung, breast, and thyroid.

Differential Diagnosis

The differentials that must be considered are mentioned below when considering a diagnosis of MALToma.

• Reactive lesions: Unlike MALTomas, reactive lesions typically maintain normal epithelial organization. 

• Splenic marginal zone lymphoma: This diagnosis may be considered if 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: While also a B-cell neoplasm, mantle cell lymphoma differs from MALToma in that it expresses CD5.

• Follicular lymphoma: Another B-cell neoplasm, follicular lymphoma expresses CD10 and exhibits t(14;18) rearrangements involving the BCL2 gene.

• Diffuse large B-cell lymphoma: While both diffuse large B-cell lymphoma and MALToma are B-cell neoplasms, the former typically exhibits more rapid growth and has a poorer prognosis. This distinction can often be made based on morphology, with tumor cells in diffuse large B-cell lymphoma having larger cell size and nuclei approximately twice the size of a small lymphocyte.

Surgical Oncology

Surgical resection for MALTomas is infrequent, but it may be considered for thyroid, lung, colon, small bowel, and breast cases. Although the role of surgery in MALToma treatment is diminishing, it remains both diagnostic and therapeutic in theory. Randomized data from gastric MALToma treatment did not demonstrate any survival differences at 10 years compared to radiotherapy or chemotherapy.[16] Evidence for using surgery in non-gastric MALTomas is primarily based on case reports and case series. A retrospective analysis of patients with pulmonary MALTomas treated with resection alone showed a 97% remission rate.[17] Similarly, resected thyroid MALTomas exhibited very high rates of relapse-free survival in a Japanese retrospective cohort, exceeding 95%, which appeared similar to those treated with involved site radiation therapy.[18] However, due to the limited number of patients, further research is needed to validate these findings.

Radiation Oncology

Involved site radiotherapy is the standard treatment modality for patients with MALToma, regardless of gastric or non-gastric involvement. In this setting, radiotherapy demonstrates high complete response rates, overall survival, and relapse-free survival. The reported 10-year overall and relapse-free survival rates for MALToma are 89% and 74%, respectively. Complete response rates exceeding 90% are consistently observed in recent literature.[19][20] Notably, the majority of recurrences manifest within the initial 5 years following treatment.[21]

Dosing 

MALTomas are classified as indolent lymphomas. Recent dose de-escalation trials involving low-grade lymphomas have shown no disparities in control or disease-free survival. The standard dosing for MALTomas typically involves 24 to 30 Gy administered in 1.5 Gy per fraction.[22] However, shorter treatments, such as 4 Gy in 2 fractions, may be utilized, albeit with lower control rates.[23] Some cases, particularly ocular MALTomas, adopt a response-based approach. Initial treatment consists of 4 Gy in 2 Gy fractions, followed by a reassessment of response at 3 months. Additional radiation (up to 20 Gy) may be administered, if necessary, based on the response assessment.

Target Coverage

Target coverage in radiation therapy varies based on the organ being treated. Generally, the affected organ is considered at risk and is expected to be covered by the prescribed dose. However, exceptions to this approach may exist depending on the treatment site.

Gastric MALToma

Patients with gastric MALTomas are often presumed to have multifocal disease, necessitating the consideration of the entire stomach as at risk when the disease appears localized on imaging. Simulation instructions typically entail fasting for at least 4 hours, ingesting a small amount of oral contrast, and implementing motion management techniques such as 4-dimensional CT (4DCT), breath hold, or fluoroscopy. The gross target volume encompasses any identifiable disease. Incorporating a PET-CT fusion with the CT simulation is beneficial. The clinical target volume includes both the gross target volume and the entire stomach, spanning from the gastroesophageal junction to the duodenal bulb and including perigastric nodes. Utilizing a 4DCT enables the construction of an internal clinical target volume for the stomach. A 1- to 2-cm margin is typically added to the clinical target volume to account for stomach movement. An additional 1 cm margin is then added to construct the planning target volume.

Salivary Glands

Similar to gastric MALTomas, the entire organ is deemed at risk and should be encompassed in the treatment field. Simulation involves immobilization using a thermoplastic head mask at a minimum. Head and shoulder immobilization may be preferred to ensure shoulder clearance. The clinical target volume should include any visible disease and the entire gland.

Ocular Adnexa

Extraocular MALTomas are generally localized to the conjunctiva, lacrimal gland, eyelid, or retrobulbar soft tissues. When the lacrimal gland, eyelid, or retrobulbar soft tissues are involved, the treatment objective is to cover the entire orbit. Consequently, the clinical target volume, in this case, is the whole bony orbit. The treatment technique includes a superior-inferior wedge pair to spare the contralateral orbit. In cases of conjunctival involvement, the clinical target volume should include the conjunctival sac, reflections, and fornices. Electron therapy is used to reduce unnecessary doses to the deep structures. Bolus allows for more superficial dose deposition.

Complications

Acute toxicity: Acute toxicity varies depending on the treated organ. Gastritis, nausea, and vomiting are prominent side effects of radiation therapy for gastric MALTomas. Patients are advised to take antiemetics during radiation treatment to alleviate these symptoms. Additionally, H2 blockers or proton pump inhibitors can be used preventively to reduce the risk of gastritis, nausea, and vomiting. When administering radiotherapy to the orbit, patients often experience common acute adverse effects such as conjunctival irritation and dermatitis. Xerostomia, or dry mouth, may also arise as a result of treatment targeting the salivary glands.

Late toxicity: Late complications are a significant concern with radiation treatment, affecting up to 50% of patients undergoing radiation to the orbit. Xerophthalmia occurs in 20% to 40% of cases, while cataracts are reported in 30% to 50% of patients. Doses exceeding 36 Gy are associated with retinopathy, neovascular glaucoma, and corneal ulceration.[24] However, recent data on dose de-escalation in this setting has led to a decline in such incidences. Abdominal radiation may lead to complications such as bowel obstruction, perforation, gastric outlet obstruction, ulceration, fistula formation, radiation-induced liver disease, and radiation-induced chronic kidney disease.

Medical Oncology

Gastric MALToma

Systemic therapy is considered the first-line approach for t(11:18)-negative H pylori–positive gastric MALTomas. Common regimens include triple and quadruple therapies. Triple therapy comprises a 14-day regimen of clarithromycin, amoxicillin, or metronidazole, along with a proton pump inhibitor. Response to treatment is not immediate and may require several months. According to the National Comprehensive Cancer Network (NCCN) guidelines, restaging with endoscopic biopsies is recommended at least 3 months post-initial antibiotic therapy. If initial therapy fails, second-line treatment may be considered for patients still presenting evidence of H pylori.

Second-line therapies include quadruple therapy, which consists of tetracycline, metronidazole, bismuth, and a proton pump inhibitor. Additional options include rifabutin or levofloxacin-based triple therapy. Treatment selection should be tailored to the patient's needs, considering factors such as local antibiotic resistance, antibiotic hypersensitivity, patient compliance, potential side effects, and drug interactions. In a significantly large meta-analysis, eradication rates were comparable between triple and quadruple therapy (68.9% versus 77.6%). However, clarithromycin resistance significantly affected the efficacy of triple therapy.[25] Complete response rates with antibiotic therapy range from 60% to 80% and a 5-year survival of 90%.[10][26][27]

Single-agent rituximab (anti-CD20 antibody) may be used in patients with t(11:18) or those who are H pylori–negative and unsuitable candidates for radiotherapy. Although this therapy is typically well tolerated, it carries the risk of hepatitis B reactivation, necessitating hepatitis B titers before administration. However, response rates are generally lower compared to those seen with radiotherapy or antibiotic therapy, with an objective response rate ranging from 73% to 77% and complete response rates of 46%.[28] The addition of chemotherapy to rituximab did not show significant improvements in outcomes. In cases where patients exhibit threatened end-organ dysfunction, B-symptoms, cytopenias, or rapid disease progression, more advanced disease may necessitate treatment with chemo-immunotherapy, such as R-CHOP or R-Bendamustine.

Non-Gastric MALToma

Non-gastric MALTomas include the ocular adnexa, lung, lacrimal glands, thyroid, salivary gland, breast, and small intestine. Patients with early-stage disease are typically treated with local therapies such as radiotherapy or surgery. However, single-agent rituximab may also be considered, yielding a complete response rate of 43% and an overall response rate of 73%.[15] Unlike gastric MALTomas, the use of antibiotic therapy in non-gastric cases remains controversial. However, an association between MALT in the ocular adnexa and Chlamydia psittaci has been observed. Treatment with doxycycline has demonstrated response rates ranging from 27% to 50%, with a 5-year progression-free survival rate of 55% to 61%.[29][30]

Staging

Given the inadequacies of the Ann Arbor Staging System, several staging systems have emerged for MALToma. A comprehensive staging system is important for accurate prognostication and to guide treatment decisions. In gastric MALTomas, staging systems include the Lugano Staging System, which considers the extent of the primary tumor invasion and local or distal nodal involvement. Additionally, a TNM system has been devised, where the T stage is determined by the depth of invasion through the gastric wall (T1-T3) and the involvement of adjacent structures (T4). Nodal involvement (N) is assessed based on the proximity of nodes to the primary tumor. 

Perigastric nodes are classified as N1, while more distant nodes, such as pancreaticoduodenal, pyloric, and hepatic, are categorized as N2. Nodes located above the diaphragm are designated as N3 disease. Involvement of the bone marrow or additional extranodal sites is denoted as M1. The Lugano modification of the Ann Arbor Staging System, which includes stages I and II with an E designation to indicate extranodal involvement, is also commonly used.[31] Disseminated disease is classified as stage IV in these staging systems, with no stage III designation.

Nongastric MALTomas are staged using the Lugano Classification System. Limited disease with 1 or 2 involved nodal groups with or without contiguous extranodal involvement is considered stage I or II. As with gastric staging, the E designator indicates extranodal involvement but is only relevant in limited disease and is not applicable for advanced disease (stages III-IV). Bulky disease (≥7 cm in size) may also be noted, but the X designator has since been removed.[32] More advanced diseases have nodal involvement on either side of the diaphragm (stage III) or additional noncontagious lymphatic involvement.

Prognosis

Patients diagnosed with MALToma typically exhibit a favorable prognosis, often exceeding 10 years in median survival. A relatively recent addition, the MALT-IPI, aids in predicting disease progression risk by considering 3 key prognostic factors—patient's age equal to or exceeding 70, serum lactate dehydrogenase levels surpassing the upper limit of normal, and stage III or IV disease.[33] Overall survival decreases as these risk factors increase in a single patient. Notably, no single risk factor indicates low risk, with a 5-year overall survival rate of approximately 99%. A single risk factor elevates MALToma to intermediate risk, with an overall survival of around 93%, while the presence of 2 or more risk factors designates the condition as high risk, with an overall survival of approximately 64%. The 5-year event-free survival, cancer-specific survival, and progression-free survival align with these trends. The patient's age and performance status also contribute significantly to prognosis determination.

Progression in MALToma often manifests as histological transformation into high-grade lymphoma. Factors associated with a higher likelihood of histologic transformation include involvement of more than 4 nodal sites, elevated lactate dehydrogenase levels, and failure to achieve complete remission after initial treatment. Patients experiencing histological transformation typically face a worse prognosis, with lower 5-year survival rates. Additionally, prognosis varies based on the tumor grade, with long-term survival feasible for those with low-grade tumors. However, achieving a cure becomes more challenging for patients with advanced-stage MALTomas. Disease-free survival for MALToma is estimated to be approximately 77% to 80%. Studies involving patients with marginal zone lymphomas suggest a 5-year survival rate of around 80% for stage I, about 75% for stage II, more than 50% for stage III, and approximately 65% for stage IV.  

Complications

Complications associated with MALToma are typically organ-specific. Approximately 30% of patients with gastric MALToma and 50% of those with extraintestinal MALToma may exhibit lymphomatous involvement in another organ, which can lead to the recurrence of disease following local treatment.[34] In some cases, MALTomas may transform into aggressive diffuse large B-cell lymphoma, leading to a poorer prognosis and reduced survival rates.[35]