Mucosa-Associated Lymphoid Tissue (MALT) lymphomas are a subtype of extranodal marginal zone B-cell lymphomas that arise from lymphoid tissues associated with mucosal surfaces. First described in the 1980s, these lymphomas are typically indolent and often linked to chronic antigenic stimulation, such as infection or autoimmune disease. The most common site of involvement is the stomach, where MALT lymphomas are strongly associated with Helicobacter pylori infection. However, they can also arise in other organs, including the salivary glands, thyroid, lungs, ocular adnexa, and skin.
MALT lymphomas are characterized by their slow progression and favorable prognosis, especially when detected early. Diagnosis typically involves a combination of histopathology, immunophenotyping, and molecular studies. Treatment strategies depend on the site and stage of disease but may include antibiotic therapy for H. pylori-positive gastric cases, radiotherapy, immunotherapy, or chemotherapy for more advanced or refractory disease.
Epidemiology
Non-Hodgkin lymphomas (NHLs) constitute approximately 2-3% of all malignancies, with mucosa-associated lymphoid tissue (MALT) lymphomas accounting for around 7-8% of newly diagnosed NHL cases each year. Although NHL comprises only about 4% of non-cutaneous cancers, MALT lymphomas remain a relatively uncommon subtype. Current data do not indicate a strong geographic or ethnic predisposition for MALT lymphoma, as large-scale epidemiological studies remain limited.
MALT lymphomas most frequently present in individuals in their 60s and 70s, but they have also been reported in younger populations, including children and adolescents. While there is no clear sex-based difference in the distribution of MALT, men typically possess more extensive lymphoid tissue overall. Nevertheless, some research suggests a slight female predominance in the incidence of MALT lymphomas. Similarly, although racial disparities are not well established, a marginally higher occurrence has been observed among White populations compared to Black populations in certain studies.
Anatomy
Pathophysiology
MALT lymphomas originate from post-germinal center marginal zone B-cells located in mucosal sites that typically do not contain organized lymphoid tissue under normal conditions. Their development is often linked to chronic immune stimulation, either from persistent infections or autoimmune processes, which leads to the formation of acquired MALT and promotes lymphoid proliferation.
A well-characterized example is gastric MALT lymphoma, which is commonly associated with chronic Helicobacter pylori infection. The persistent antigenic stimulus provided by H. pylori induces lymphoid tissue accumulation and ongoing B-cell activation.
The lymphoma typically features small B-cells infiltrating epithelial tissues, forming characteristic lymphoepithelial lesions.
Etiology
While the exact cause of MALT lymphomas and many other tumors remains uncertain, substantial evidence points to a strong link between autoimmune conditions and the development of MALT lymphomas. Persistent antigenic stimulation is thought to play a key role in both initiating and sustaining the disease process.
For instance, MALT lymphomas arising in the salivary glands are frequently associated with Sjögren’s syndrome, while those in the thyroid are commonly linked to Hashimoto’s thyroiditis. Additionally, conditions like Crohn’s disease and celiac disease may contribute to the development of intestinal MALT lymphomas.
Among known triggers, Helicobacter pylori infection has the most clearly established causal role, particularly in gastric MALT lymphomas. Chronic H. pylori gastritis is frequently observed in patients who go on to develop lymphoma in the stomach.
Genetics
Prognostic Factors
Site of Involvement: Gastric MALT lymphomas tend to have a better prognosis, particularly when associated with Helicobacter pylori and treated early. Non-gastric sites, such as the lungs or orbit, may show more variable outcomes.
Stage at Diagnosis: Early-stage (localized) disease has a significantly better prognosis than advanced-stage (disseminated) disease. Patients diagnosed at stage I or II generally respond well to treatment.
Genetic Abnormalities: Certain chromosomal translocations, such as t(11;18)(q21;q21), are associated with resistance to H. pylori eradication therapy and may predict a more indolent but persistent disease course.
Response to Initial Treatment: Complete remission after initial therapy, particularly in gastric MALT lymphoma following antibiotic treatment, is a strong positive prognostic sign.
Clinical History
Age group
MALT lymphomas most commonly affect older adults, with the peak incidence in the 6th to 8th decades of life (ages 60 to 80 years). However, cases have also been reported in younger individuals, including adolescents and young adults, though these are rare.
There is no strict age cutoff, but the disease is considered more typical in the elderly population. The relatively late onset is likely linked to the prolonged antigenic stimulation required for the development of MALT in mucosal tissues.
Physical Examination
Cutaneous MALT lymphoma commonly appears as skin nodules or papules.
Pulmonary involvement may lead to recurrent respiratory infections, cough, or nonspecific pulmonary symptoms.
Gastric MALT lymphoma often presents with signs resembling gastroesophageal reflux, indigestion (dyspepsia), or occult gastrointestinal bleeding.
When the small intestine is affected, patients may experience intermittent abdominal pain, diarrhea, or symptoms of malabsorption.
Ocular MALT lymphoma can present with eye redness, excessive tearing (epiphora), or visual disturbances, including field defects.
In cases involving the salivary glands, a unilateral or bilateral painless mass may be observed.
Age group
Associated comorbidity
Autoimmune Diseases
Sjögren’s Syndrome
Hashimoto’s Thyroiditis
Celiac Disease and Crohn’s Disease
Chronic Infections
Helicobacter pylori
Chlamydia psittaci
Campylobacter jejuni
Associated activity
Acuity of presentation
Acuity of presentation:
MALT lymphomas typically present with a chronic, indolent (slow-growing) course rather than acute symptoms. The onset is usually insidious, and many patients are asymptomatic at diagnosis, with the lymphoma discovered incidentally during evaluation for unrelated issues or chronic inflammatory conditions.
Chronic Presentation:
Most cases develop over months or even years, with gradual symptom progression.
Site-Specific Symptoms:
Gastric MALT lymphoma: Dyspepsia, bloating, nausea, or mild abdominal discomfort.
Salivary gland involvement: Painless gland enlargement, often in patients with Sjögren’s syndrome.
Thyroid MALT lymphoma: Slowly enlarging thyroid mass in the context of Hashimoto’s thyroiditis.
Pulmonary or ocular MALT lymphomas: Cough or visual disturbances may develop gradually.
Differential Diagnoses
Reactive Lesions
Reactive lymphoid hyperplasia can resemble MALT lymphoma but typically preserves normal epithelial architecture and lacks the monoclonality or lymphoepithelial lesions characteristic of MALTomas.
Diffuse Large B-Cell Lymphoma (DLBCL)
DLBCL is a high-grade B-cell neoplasm that may arise de novo or through transformation of MALT lymphoma. It shows larger tumor cells, with nuclei roughly twice the size of small lymphocytes, and is associated with more aggressive behavior and a poorer prognosis.
Follicular Lymphoma
Another B-cell neoplasm, follicular lymphoma is characterized by CD10 expression and the t(14;18) translocation involving the BCL2 gene. It typically shows a follicular growth pattern, helping differentiate it from MALToma’s diffuse infiltration.
Mantle Cell Lymphoma
Mantle cell lymphoma, while also a B-cell malignancy, is identified by CD5 expression and the t(11;14) translocation involving the CCND1 gene. These features help distinguish it from MALToma, which is usually CD5-negative.
Nodal Marginal Zone Lymphoma
This lymphoma primarily affects lymph nodes and may present with widespread nodal involvement. It is considered when extranodal non-Hodgkin lymphoma extends to the lymph nodes.
Splenic Marginal Zone Lymphoma
This diagnosis is suspected when extranodal B-cell lymphomas extend to the spleen. It shares marginal zone features but differs in clinical presentation and site of origin.
Laboratory Studies
Imaging Studies
Procedures
Histologic Findings
Staging
Treatment Paradigm
Gastric MALT Lymphoma
Treatment depends on Helicobacter pylori status and genetic factors:
pylori-positive, t(11;18)-negative: Antibiotic eradication therapy is first-line, with ~80% complete response.
t(11;18)-positive, H. pylori-negative, or antibiotic-refractory cases: Radiotherapy or systemic therapy is recommended.
Surgery is rarely used, reserved only for complications like bleeding or obstruction, due to high morbidity compared to radiation.
Non-Gastric MALT Lymphoma
Radiotherapy is typically first-line, with complete response rates >90%.
Antibiotics are used when linked to specific infections (e.g., Chlamydia psittaci in ocular adnexal MALT).
Systemic therapy is considered if radiation is contraindicated or for advanced disease:
Options include rituximab alone or rituximab plus chemotherapy (e.g., bendamustine or CVP).
Single-agent rituximab may be preferred for mildly symptomatic patients.
Combination therapy is reserved for refractory, bulky, or symptomatic disease, aiming for longer remission despite higher toxicity.
Surgical resection may be appropriate for selected cases involving the small bowel, lung, breast, or thyroid.
pylori: For gastric MALT lymphoma, eliminating H. pylori infection through antibiotic therapy is both curative and preventive in many patients.
Chlamydia psittaci: In ocular adnexal MALT, antibiotic treatment targeting this infection has shown clinical benefit.
Other bacteria (e.g., Campylobacter jejuni, Borrelia burgdorferi): Environmental or geographic exposure may be reduced with improved sanitation and vector control.
Autoimmune Disease Management
Optimizing control of conditions like Sjögren’s syndrome or Hashimoto’s thyroiditis may reduce the risk of persistent antigenic stimulation and subsequent lymphomagenesis.
Regular monitoring and early treatment of autoimmune flares may contribute to prevention.
Lifestyle and Exposure Reduction
Minimize exposure to chronic irritants, such as inhaled allergens, occupational chemicals, or chronic inflammatory agents, which may influence the development of MALT in various mucosal tissues.
Smoking cessation is recommended, especially in gastric MALT lymphoma, as smoking may worsen inflammation and delay healing.
Surveillance and Follow-Up
For patients with known risk factors or early disease, regular monitoring and timely intervention can help prevent progression or recurrence.
Effectiveness of Antineoplastics in treating Mucosa-Associated Lymphoid Tissue Lymphomas
Cyclophosphamide
Cyclophosphamide undergoes metabolic activation in the liver, where it is converted into potent alkylating compounds. These active metabolites disrupt the proliferation of rapidly dividing cancer cells by forming cross-links within their DNA, thereby inhibiting replication and triggering cell death.
Effectiveness of Antineoplastic agents in treating Mucosa-Associated Lymphoid Tissue Lymphomas
Fludarabine
Fludarabine, a nucleotide analog of vidarabine, is metabolized into 2-fluoro-ara-A, which is taken up by cells and subsequently phosphorylated to its active form, 2-fluoro-ara-ATP. This active metabolite interferes with DNA synthesis, leading to the inhibition of cell replication.
Etoposide
Etoposide targets topoisomerase II, leading to DNA strand breaks that disrupt replication. This action halts cell division, particularly during the late S phase and early G2 phase of the cell cycle.
Role of BTK Inhibitors in treating Mucosa-Associated Lymphoid Tissue Lymphomas
Ibrutinib
BTK inhibitors, such as ibrutinib, block the BCR pathway, reducing downstream survival signals and leading to apoptosis of malignant B cells.
Acalabrutinib
Acalabrutinib is a highly selective, second-generation BTK inhibitor. It blocks Bruton’s tyrosine kinase- a critical enzyme in B-cell receptor signaling thus disrupting downstream pathways like NF-κB that support malignant B-cell survival and proliferation
Surgical resection is infrequently used in the management of MALT lymphoma but may be considered for select cases involving the thyroid, lung, colon, small intestine, or breast. Although the importance of surgery has declined over time, it can still serve a dual role in diagnosis and localized treatment, particularly when less invasive modalities are not feasible or diagnostic uncertainty exists.
In gastric MALT lymphoma, randomized trials have shown no significant difference in 10-year survival between surgery and non-surgical treatments such as radiotherapy or chemotherapy, leading to a preference for non-surgical options.
For non-gastric MALT lymphomas, most of the evidence supporting surgery comes from case reports and retrospective series. One study on pulmonary MALT lymphoma reported a 97% remission rate with surgery alone. Similarly, a Japanese retrospective cohort of thyroid MALT lymphoma cases showed relapse-free survival exceeding 95% following surgical resection comparable to outcomes with localized radiotherapy.
Despite these promising findings, the limited sample sizes and lack of prospective data highlight the need for further research to determine the definitive role of surgery in non-gastric MALT lymphoma management.
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Home » CAD » Mucosa-Associated Lymphoid Tissue Lymphomas
Mucosa-Associated Lymphoid Tissue Lymphomas
Updated :
December 4, 2025
Mucosa-Associated Lymphoid Tissue (MALT) lymphomas are a subtype of extranodal marginal zone B-cell lymphomas that arise from lymphoid tissues associated with mucosal surfaces. First described in the 1980s, these lymphomas are typically indolent and often linked to chronic antigenic stimulation, such as infection or autoimmune disease. The most common site of involvement is the stomach, where MALT lymphomas are strongly associated with Helicobacter pylori infection. However, they can also arise in other organs, including the salivary glands, thyroid, lungs, ocular adnexa, and skin.
MALT lymphomas are characterized by their slow progression and favorable prognosis, especially when detected early. Diagnosis typically involves a combination of histopathology, immunophenotyping, and molecular studies. Treatment strategies depend on the site and stage of disease but may include antibiotic therapy for H. pylori-positive gastric cases, radiotherapy, immunotherapy, or chemotherapy for more advanced or refractory disease.
Non-Hodgkin lymphomas (NHLs) constitute approximately 2-3% of all malignancies, with mucosa-associated lymphoid tissue (MALT) lymphomas accounting for around 7-8% of newly diagnosed NHL cases each year. Although NHL comprises only about 4% of non-cutaneous cancers, MALT lymphomas remain a relatively uncommon subtype. Current data do not indicate a strong geographic or ethnic predisposition for MALT lymphoma, as large-scale epidemiological studies remain limited.
MALT lymphomas most frequently present in individuals in their 60s and 70s, but they have also been reported in younger populations, including children and adolescents. While there is no clear sex-based difference in the distribution of MALT, men typically possess more extensive lymphoid tissue overall. Nevertheless, some research suggests a slight female predominance in the incidence of MALT lymphomas. Similarly, although racial disparities are not well established, a marginally higher occurrence has been observed among White populations compared to Black populations in certain studies.
MALT lymphomas originate from post-germinal center marginal zone B-cells located in mucosal sites that typically do not contain organized lymphoid tissue under normal conditions. Their development is often linked to chronic immune stimulation, either from persistent infections or autoimmune processes, which leads to the formation of acquired MALT and promotes lymphoid proliferation.
A well-characterized example is gastric MALT lymphoma, which is commonly associated with chronic Helicobacter pylori infection. The persistent antigenic stimulus provided by H. pylori induces lymphoid tissue accumulation and ongoing B-cell activation.
The lymphoma typically features small B-cells infiltrating epithelial tissues, forming characteristic lymphoepithelial lesions.
While the exact cause of MALT lymphomas and many other tumors remains uncertain, substantial evidence points to a strong link between autoimmune conditions and the development of MALT lymphomas. Persistent antigenic stimulation is thought to play a key role in both initiating and sustaining the disease process.
For instance, MALT lymphomas arising in the salivary glands are frequently associated with Sjögren’s syndrome, while those in the thyroid are commonly linked to Hashimoto’s thyroiditis. Additionally, conditions like Crohn’s disease and celiac disease may contribute to the development of intestinal MALT lymphomas.
Among known triggers, Helicobacter pylori infection has the most clearly established causal role, particularly in gastric MALT lymphomas. Chronic H. pylori gastritis is frequently observed in patients who go on to develop lymphoma in the stomach.
Site of Involvement: Gastric MALT lymphomas tend to have a better prognosis, particularly when associated with Helicobacter pylori and treated early. Non-gastric sites, such as the lungs or orbit, may show more variable outcomes.
Stage at Diagnosis: Early-stage (localized) disease has a significantly better prognosis than advanced-stage (disseminated) disease. Patients diagnosed at stage I or II generally respond well to treatment.
Genetic Abnormalities: Certain chromosomal translocations, such as t(11;18)(q21;q21), are associated with resistance to H. pylori eradication therapy and may predict a more indolent but persistent disease course.
Response to Initial Treatment: Complete remission after initial therapy, particularly in gastric MALT lymphoma following antibiotic treatment, is a strong positive prognostic sign.
Age group
MALT lymphomas most commonly affect older adults, with the peak incidence in the 6th to 8th decades of life (ages 60 to 80 years). However, cases have also been reported in younger individuals, including adolescents and young adults, though these are rare.
There is no strict age cutoff, but the disease is considered more typical in the elderly population. The relatively late onset is likely linked to the prolonged antigenic stimulation required for the development of MALT in mucosal tissues.
Cutaneous MALT lymphoma commonly appears as skin nodules or papules.
Pulmonary involvement may lead to recurrent respiratory infections, cough, or nonspecific pulmonary symptoms.
Gastric MALT lymphoma often presents with signs resembling gastroesophageal reflux, indigestion (dyspepsia), or occult gastrointestinal bleeding.
When the small intestine is affected, patients may experience intermittent abdominal pain, diarrhea, or symptoms of malabsorption.
Ocular MALT lymphoma can present with eye redness, excessive tearing (epiphora), or visual disturbances, including field defects.
In cases involving the salivary glands, a unilateral or bilateral painless mass may be observed.
Autoimmune Diseases
Sjögren’s Syndrome
Hashimoto’s Thyroiditis
Celiac Disease and Crohn’s Disease
Chronic Infections
Helicobacter pylori
Chlamydia psittaci
Campylobacter jejuni
Acuity of presentation:
MALT lymphomas typically present with a chronic, indolent (slow-growing) course rather than acute symptoms. The onset is usually insidious, and many patients are asymptomatic at diagnosis, with the lymphoma discovered incidentally during evaluation for unrelated issues or chronic inflammatory conditions.
Chronic Presentation:
Most cases develop over months or even years, with gradual symptom progression.
Site-Specific Symptoms:
Gastric MALT lymphoma: Dyspepsia, bloating, nausea, or mild abdominal discomfort.
Salivary gland involvement: Painless gland enlargement, often in patients with Sjögren’s syndrome.
Thyroid MALT lymphoma: Slowly enlarging thyroid mass in the context of Hashimoto’s thyroiditis.
Pulmonary or ocular MALT lymphomas: Cough or visual disturbances may develop gradually.
Reactive Lesions
Reactive lymphoid hyperplasia can resemble MALT lymphoma but typically preserves normal epithelial architecture and lacks the monoclonality or lymphoepithelial lesions characteristic of MALTomas.
Diffuse Large B-Cell Lymphoma (DLBCL)
DLBCL is a high-grade B-cell neoplasm that may arise de novo or through transformation of MALT lymphoma. It shows larger tumor cells, with nuclei roughly twice the size of small lymphocytes, and is associated with more aggressive behavior and a poorer prognosis.
Follicular Lymphoma
Another B-cell neoplasm, follicular lymphoma is characterized by CD10 expression and the t(14;18) translocation involving the BCL2 gene. It typically shows a follicular growth pattern, helping differentiate it from MALToma’s diffuse infiltration.
Mantle Cell Lymphoma
Mantle cell lymphoma, while also a B-cell malignancy, is identified by CD5 expression and the t(11;14) translocation involving the CCND1 gene. These features help distinguish it from MALToma, which is usually CD5-negative.
Nodal Marginal Zone Lymphoma
This lymphoma primarily affects lymph nodes and may present with widespread nodal involvement. It is considered when extranodal non-Hodgkin lymphoma extends to the lymph nodes.
Splenic Marginal Zone Lymphoma
This diagnosis is suspected when extranodal B-cell lymphomas extend to the spleen. It shares marginal zone features but differs in clinical presentation and site of origin.
Gastric MALT Lymphoma
Treatment depends on Helicobacter pylori status and genetic factors:
pylori-positive, t(11;18)-negative: Antibiotic eradication therapy is first-line, with ~80% complete response.
t(11;18)-positive, H. pylori-negative, or antibiotic-refractory cases: Radiotherapy or systemic therapy is recommended.
Surgery is rarely used, reserved only for complications like bleeding or obstruction, due to high morbidity compared to radiation.
Non-Gastric MALT Lymphoma
Radiotherapy is typically first-line, with complete response rates >90%.
Antibiotics are used when linked to specific infections (e.g., Chlamydia psittaci in ocular adnexal MALT).
Systemic therapy is considered if radiation is contraindicated or for advanced disease:
Options include rituximab alone or rituximab plus chemotherapy (e.g., bendamustine or CVP).
Single-agent rituximab may be preferred for mildly symptomatic patients.
Combination therapy is reserved for refractory, bulky, or symptomatic disease, aiming for longer remission despite higher toxicity.
Surgical resection may be appropriate for selected cases involving the small bowel, lung, breast, or thyroid.
Hematology
Eradication of Infectious Triggers
pylori: For gastric MALT lymphoma, eliminating H. pylori infection through antibiotic therapy is both curative and preventive in many patients.
Chlamydia psittaci: In ocular adnexal MALT, antibiotic treatment targeting this infection has shown clinical benefit.
Other bacteria (e.g., Campylobacter jejuni, Borrelia burgdorferi): Environmental or geographic exposure may be reduced with improved sanitation and vector control.
Autoimmune Disease Management
Optimizing control of conditions like Sjögren’s syndrome or Hashimoto’s thyroiditis may reduce the risk of persistent antigenic stimulation and subsequent lymphomagenesis.
Regular monitoring and early treatment of autoimmune flares may contribute to prevention.
Lifestyle and Exposure Reduction
Minimize exposure to chronic irritants, such as inhaled allergens, occupational chemicals, or chronic inflammatory agents, which may influence the development of MALT in various mucosal tissues.
Smoking cessation is recommended, especially in gastric MALT lymphoma, as smoking may worsen inflammation and delay healing.
Surveillance and Follow-Up
For patients with known risk factors or early disease, regular monitoring and timely intervention can help prevent progression or recurrence.
Hematology
Cyclophosphamide
Cyclophosphamide undergoes metabolic activation in the liver, where it is converted into potent alkylating compounds. These active metabolites disrupt the proliferation of rapidly dividing cancer cells by forming cross-links within their DNA, thereby inhibiting replication and triggering cell death.
Hematology
Fludarabine
Fludarabine, a nucleotide analog of vidarabine, is metabolized into 2-fluoro-ara-A, which is taken up by cells and subsequently phosphorylated to its active form, 2-fluoro-ara-ATP. This active metabolite interferes with DNA synthesis, leading to the inhibition of cell replication.
Etoposide
Etoposide targets topoisomerase II, leading to DNA strand breaks that disrupt replication. This action halts cell division, particularly during the late S phase and early G2 phase of the cell cycle.
Hematology
Ibrutinib
BTK inhibitors, such as ibrutinib, block the BCR pathway, reducing downstream survival signals and leading to apoptosis of malignant B cells.
Acalabrutinib
Acalabrutinib is a highly selective, second-generation BTK inhibitor. It blocks Bruton’s tyrosine kinase- a critical enzyme in B-cell receptor signaling thus disrupting downstream pathways like NF-κB that support malignant B-cell survival and proliferation
Hematology
Surgical resection is infrequently used in the management of MALT lymphoma but may be considered for select cases involving the thyroid, lung, colon, small intestine, or breast. Although the importance of surgery has declined over time, it can still serve a dual role in diagnosis and localized treatment, particularly when less invasive modalities are not feasible or diagnostic uncertainty exists.
In gastric MALT lymphoma, randomized trials have shown no significant difference in 10-year survival between surgery and non-surgical treatments such as radiotherapy or chemotherapy, leading to a preference for non-surgical options.
For non-gastric MALT lymphomas, most of the evidence supporting surgery comes from case reports and retrospective series. One study on pulmonary MALT lymphoma reported a 97% remission rate with surgery alone. Similarly, a Japanese retrospective cohort of thyroid MALT lymphoma cases showed relapse-free survival exceeding 95% following surgical resection comparable to outcomes with localized radiotherapy.
Despite these promising findings, the limited sample sizes and lack of prospective data highlight the need for further research to determine the definitive role of surgery in non-gastric MALT lymphoma management.
Hematology
Diagnosis and Staging
Confirm diagnosis via biopsy and immunohistochemistry.
Stage the disease with imaging (CT/PET) and bone marrow biopsy if needed.
Initial Treatment
Gastric MALT: H. pylori eradication therapy (if positive and t(11;18)-negative).
Non-gastric MALT: Site-directed radiotherapy or antibiotics (if infection-related).
Response Assessment
Monitor with endoscopy, imaging, and labs based on the site involved.
Complete response is common in localized disease.
Second-Line Therapy (if needed)
For persistent or relapsed disease: radiotherapy, immunotherapy (rituximab), or chemoimmunotherapy.
Common regimens: rituximab + bendamustine or CVP.
Long-Term Follow-Up
Regular surveillance for recurrence or transformation.
Monitor for treatment-related side effects and comorbidities.
Mucosa-Associated Lymphoid Tissue (MALT) lymphomas are a subtype of extranodal marginal zone B-cell lymphomas that arise from lymphoid tissues associated with mucosal surfaces. First described in the 1980s, these lymphomas are typically indolent and often linked to chronic antigenic stimulation, such as infection or autoimmune disease. The most common site of involvement is the stomach, where MALT lymphomas are strongly associated with Helicobacter pylori infection. However, they can also arise in other organs, including the salivary glands, thyroid, lungs, ocular adnexa, and skin.
MALT lymphomas are characterized by their slow progression and favorable prognosis, especially when detected early. Diagnosis typically involves a combination of histopathology, immunophenotyping, and molecular studies. Treatment strategies depend on the site and stage of disease but may include antibiotic therapy for H. pylori-positive gastric cases, radiotherapy, immunotherapy, or chemotherapy for more advanced or refractory disease.
Non-Hodgkin lymphomas (NHLs) constitute approximately 2-3% of all malignancies, with mucosa-associated lymphoid tissue (MALT) lymphomas accounting for around 7-8% of newly diagnosed NHL cases each year. Although NHL comprises only about 4% of non-cutaneous cancers, MALT lymphomas remain a relatively uncommon subtype. Current data do not indicate a strong geographic or ethnic predisposition for MALT lymphoma, as large-scale epidemiological studies remain limited.
MALT lymphomas most frequently present in individuals in their 60s and 70s, but they have also been reported in younger populations, including children and adolescents. While there is no clear sex-based difference in the distribution of MALT, men typically possess more extensive lymphoid tissue overall. Nevertheless, some research suggests a slight female predominance in the incidence of MALT lymphomas. Similarly, although racial disparities are not well established, a marginally higher occurrence has been observed among White populations compared to Black populations in certain studies.
MALT lymphomas originate from post-germinal center marginal zone B-cells located in mucosal sites that typically do not contain organized lymphoid tissue under normal conditions. Their development is often linked to chronic immune stimulation, either from persistent infections or autoimmune processes, which leads to the formation of acquired MALT and promotes lymphoid proliferation.
A well-characterized example is gastric MALT lymphoma, which is commonly associated with chronic Helicobacter pylori infection. The persistent antigenic stimulus provided by H. pylori induces lymphoid tissue accumulation and ongoing B-cell activation.
The lymphoma typically features small B-cells infiltrating epithelial tissues, forming characteristic lymphoepithelial lesions.
While the exact cause of MALT lymphomas and many other tumors remains uncertain, substantial evidence points to a strong link between autoimmune conditions and the development of MALT lymphomas. Persistent antigenic stimulation is thought to play a key role in both initiating and sustaining the disease process.
For instance, MALT lymphomas arising in the salivary glands are frequently associated with Sjögren’s syndrome, while those in the thyroid are commonly linked to Hashimoto’s thyroiditis. Additionally, conditions like Crohn’s disease and celiac disease may contribute to the development of intestinal MALT lymphomas.
Among known triggers, Helicobacter pylori infection has the most clearly established causal role, particularly in gastric MALT lymphomas. Chronic H. pylori gastritis is frequently observed in patients who go on to develop lymphoma in the stomach.
Site of Involvement: Gastric MALT lymphomas tend to have a better prognosis, particularly when associated with Helicobacter pylori and treated early. Non-gastric sites, such as the lungs or orbit, may show more variable outcomes.
Stage at Diagnosis: Early-stage (localized) disease has a significantly better prognosis than advanced-stage (disseminated) disease. Patients diagnosed at stage I or II generally respond well to treatment.
Genetic Abnormalities: Certain chromosomal translocations, such as t(11;18)(q21;q21), are associated with resistance to H. pylori eradication therapy and may predict a more indolent but persistent disease course.
Response to Initial Treatment: Complete remission after initial therapy, particularly in gastric MALT lymphoma following antibiotic treatment, is a strong positive prognostic sign.
Age group
MALT lymphomas most commonly affect older adults, with the peak incidence in the 6th to 8th decades of life (ages 60 to 80 years). However, cases have also been reported in younger individuals, including adolescents and young adults, though these are rare.
There is no strict age cutoff, but the disease is considered more typical in the elderly population. The relatively late onset is likely linked to the prolonged antigenic stimulation required for the development of MALT in mucosal tissues.
Cutaneous MALT lymphoma commonly appears as skin nodules or papules.
Pulmonary involvement may lead to recurrent respiratory infections, cough, or nonspecific pulmonary symptoms.
Gastric MALT lymphoma often presents with signs resembling gastroesophageal reflux, indigestion (dyspepsia), or occult gastrointestinal bleeding.
When the small intestine is affected, patients may experience intermittent abdominal pain, diarrhea, or symptoms of malabsorption.
Ocular MALT lymphoma can present with eye redness, excessive tearing (epiphora), or visual disturbances, including field defects.
In cases involving the salivary glands, a unilateral or bilateral painless mass may be observed.
Autoimmune Diseases
Sjögren’s Syndrome
Hashimoto’s Thyroiditis
Celiac Disease and Crohn’s Disease
Chronic Infections
Helicobacter pylori
Chlamydia psittaci
Campylobacter jejuni
Acuity of presentation:
MALT lymphomas typically present with a chronic, indolent (slow-growing) course rather than acute symptoms. The onset is usually insidious, and many patients are asymptomatic at diagnosis, with the lymphoma discovered incidentally during evaluation for unrelated issues or chronic inflammatory conditions.
Chronic Presentation:
Most cases develop over months or even years, with gradual symptom progression.
Site-Specific Symptoms:
Gastric MALT lymphoma: Dyspepsia, bloating, nausea, or mild abdominal discomfort.
Salivary gland involvement: Painless gland enlargement, often in patients with Sjögren’s syndrome.
Thyroid MALT lymphoma: Slowly enlarging thyroid mass in the context of Hashimoto’s thyroiditis.
Pulmonary or ocular MALT lymphomas: Cough or visual disturbances may develop gradually.
Reactive Lesions
Reactive lymphoid hyperplasia can resemble MALT lymphoma but typically preserves normal epithelial architecture and lacks the monoclonality or lymphoepithelial lesions characteristic of MALTomas.
Diffuse Large B-Cell Lymphoma (DLBCL)
DLBCL is a high-grade B-cell neoplasm that may arise de novo or through transformation of MALT lymphoma. It shows larger tumor cells, with nuclei roughly twice the size of small lymphocytes, and is associated with more aggressive behavior and a poorer prognosis.
Follicular Lymphoma
Another B-cell neoplasm, follicular lymphoma is characterized by CD10 expression and the t(14;18) translocation involving the BCL2 gene. It typically shows a follicular growth pattern, helping differentiate it from MALToma’s diffuse infiltration.
Mantle Cell Lymphoma
Mantle cell lymphoma, while also a B-cell malignancy, is identified by CD5 expression and the t(11;14) translocation involving the CCND1 gene. These features help distinguish it from MALToma, which is usually CD5-negative.
Nodal Marginal Zone Lymphoma
This lymphoma primarily affects lymph nodes and may present with widespread nodal involvement. It is considered when extranodal non-Hodgkin lymphoma extends to the lymph nodes.
Splenic Marginal Zone Lymphoma
This diagnosis is suspected when extranodal B-cell lymphomas extend to the spleen. It shares marginal zone features but differs in clinical presentation and site of origin.
Gastric MALT Lymphoma
Treatment depends on Helicobacter pylori status and genetic factors:
pylori-positive, t(11;18)-negative: Antibiotic eradication therapy is first-line, with ~80% complete response.
t(11;18)-positive, H. pylori-negative, or antibiotic-refractory cases: Radiotherapy or systemic therapy is recommended.
Surgery is rarely used, reserved only for complications like bleeding or obstruction, due to high morbidity compared to radiation.
Non-Gastric MALT Lymphoma
Radiotherapy is typically first-line, with complete response rates >90%.
Antibiotics are used when linked to specific infections (e.g., Chlamydia psittaci in ocular adnexal MALT).
Systemic therapy is considered if radiation is contraindicated or for advanced disease:
Options include rituximab alone or rituximab plus chemotherapy (e.g., bendamustine or CVP).
Single-agent rituximab may be preferred for mildly symptomatic patients.
Combination therapy is reserved for refractory, bulky, or symptomatic disease, aiming for longer remission despite higher toxicity.
Surgical resection may be appropriate for selected cases involving the small bowel, lung, breast, or thyroid.
Hematology
Eradication of Infectious Triggers
pylori: For gastric MALT lymphoma, eliminating H. pylori infection through antibiotic therapy is both curative and preventive in many patients.
Chlamydia psittaci: In ocular adnexal MALT, antibiotic treatment targeting this infection has shown clinical benefit.
Other bacteria (e.g., Campylobacter jejuni, Borrelia burgdorferi): Environmental or geographic exposure may be reduced with improved sanitation and vector control.
Autoimmune Disease Management
Optimizing control of conditions like Sjögren’s syndrome or Hashimoto’s thyroiditis may reduce the risk of persistent antigenic stimulation and subsequent lymphomagenesis.
Regular monitoring and early treatment of autoimmune flares may contribute to prevention.
Lifestyle and Exposure Reduction
Minimize exposure to chronic irritants, such as inhaled allergens, occupational chemicals, or chronic inflammatory agents, which may influence the development of MALT in various mucosal tissues.
Smoking cessation is recommended, especially in gastric MALT lymphoma, as smoking may worsen inflammation and delay healing.
Surveillance and Follow-Up
For patients with known risk factors or early disease, regular monitoring and timely intervention can help prevent progression or recurrence.
Hematology
Cyclophosphamide
Cyclophosphamide undergoes metabolic activation in the liver, where it is converted into potent alkylating compounds. These active metabolites disrupt the proliferation of rapidly dividing cancer cells by forming cross-links within their DNA, thereby inhibiting replication and triggering cell death.
Hematology
Fludarabine
Fludarabine, a nucleotide analog of vidarabine, is metabolized into 2-fluoro-ara-A, which is taken up by cells and subsequently phosphorylated to its active form, 2-fluoro-ara-ATP. This active metabolite interferes with DNA synthesis, leading to the inhibition of cell replication.
Etoposide
Etoposide targets topoisomerase II, leading to DNA strand breaks that disrupt replication. This action halts cell division, particularly during the late S phase and early G2 phase of the cell cycle.
Hematology
Ibrutinib
BTK inhibitors, such as ibrutinib, block the BCR pathway, reducing downstream survival signals and leading to apoptosis of malignant B cells.
Acalabrutinib
Acalabrutinib is a highly selective, second-generation BTK inhibitor. It blocks Bruton’s tyrosine kinase- a critical enzyme in B-cell receptor signaling thus disrupting downstream pathways like NF-κB that support malignant B-cell survival and proliferation
Hematology
Surgical resection is infrequently used in the management of MALT lymphoma but may be considered for select cases involving the thyroid, lung, colon, small intestine, or breast. Although the importance of surgery has declined over time, it can still serve a dual role in diagnosis and localized treatment, particularly when less invasive modalities are not feasible or diagnostic uncertainty exists.
In gastric MALT lymphoma, randomized trials have shown no significant difference in 10-year survival between surgery and non-surgical treatments such as radiotherapy or chemotherapy, leading to a preference for non-surgical options.
For non-gastric MALT lymphomas, most of the evidence supporting surgery comes from case reports and retrospective series. One study on pulmonary MALT lymphoma reported a 97% remission rate with surgery alone. Similarly, a Japanese retrospective cohort of thyroid MALT lymphoma cases showed relapse-free survival exceeding 95% following surgical resection comparable to outcomes with localized radiotherapy.
Despite these promising findings, the limited sample sizes and lack of prospective data highlight the need for further research to determine the definitive role of surgery in non-gastric MALT lymphoma management.
Hematology
Diagnosis and Staging
Confirm diagnosis via biopsy and immunohistochemistry.
Stage the disease with imaging (CT/PET) and bone marrow biopsy if needed.
Initial Treatment
Gastric MALT: H. pylori eradication therapy (if positive and t(11;18)-negative).
Non-gastric MALT: Site-directed radiotherapy or antibiotics (if infection-related).
Response Assessment
Monitor with endoscopy, imaging, and labs based on the site involved.
Complete response is common in localized disease.
Second-Line Therapy (if needed)
For persistent or relapsed disease: radiotherapy, immunotherapy (rituximab), or chemoimmunotherapy.
Common regimens: rituximab + bendamustine or CVP.
Long-Term Follow-Up
Regular surveillance for recurrence or transformation.
Monitor for treatment-related side effects and comorbidities.
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