Marginal Zone Lymphoma: Symptoms, Types, Causes and Treatment

Marginal zone lymphoma (MZL) is a diverse group of slow-growing B-cell non-Hodgkin lymphomas. These cancers originate from the "marginal zone" of lymphoid tissue, a region situated around the follicles of lymph nodes, spleen, or mucosa-associated lymphoid tissue (MALT). Despite being considered indolent, MZLs present unique clinical features, causes, and treatment strategies depending on their type and location in the body. Understanding the symptoms, types, underlying causes, and therapeutic approaches is crucial for patients, caregivers, and healthcare professionals alike.

Symptoms of Marginal Zone Lymphoma

When it comes to marginal zone lymphoma, symptoms can vary widely depending on the specific subtype and the organs involved. Many people are surprised to discover that some patients have no symptoms at all, and the disease is found incidentally during imaging or routine blood tests. For others, symptoms are mild and nonspecific, making early diagnosis a challenge.

Below is a table summarizing the key symptoms associated with different MZL subtypes:

Symptom	Subtype/Location	Frequency/Notes	Source
Asymptomatic	Pulmonary MALT, SMZL	Up to 50% in pulmonary MALT	1 2 5
Swelling	Nodal, Extranodal	Enlarged lymph nodes or masses	2 4 5
Abdominal pain	Splenic, GI MALT	Due to splenomegaly or GI involvement	5 6
Autoimmune symptoms	MALT (salivary, thyroid)	Dry mouth (Sjögren), thyroid dysfunction	1 6
B-symptoms (fever, night sweats, weight loss)	Nodal MZL	Less common, more aggressive subtypes	2 5

Table 1: Key Symptoms of Marginal Zone Lymphoma

Understanding the Symptom Spectrum

Asymptomatic Presentations

• Incidental findings are common, especially in pulmonary MALT and splenic MZL. Up to half of patients with pulmonary MALT lymphoma have no symptoms at diagnosis, and the disease is detected during imaging for unrelated reasons 1 2.
• Many patients with splenic MZL also present without symptoms, and their disease is uncovered during evaluation of abnormal blood counts or splenomegaly 5.

Site-Specific Symptoms

• Swelling or masses: Nodal MZL often manifests as painless lymph node enlargement, while extranodal (MALT) lymphomas may form localized masses or nodules, for example, in the lungs or the stomach 1 2 4.
• Abdominal discomfort: Splenic involvement can lead to pain or a sensation of fullness in the left upper abdomen due to an enlarged spleen. MALT lymphoma in the gastrointestinal tract may cause abdominal pain, indigestion, or bleeding 5 6.

Autoimmune and Paraproteinemic Features

• MZLs, especially of the MALT subtype, are frequently associated with autoimmune conditions such as Sjögren’s syndrome (dry mouth, dry eyes) and Hashimoto's thyroiditis (thyroid dysfunction) 1 6.
• Some patients develop monoclonal gammopathies, leading to abnormal protein levels in the blood 1.

Systemic (B) Symptoms

• Fever, night sweats, weight loss (B-symptoms) are less common in MALT and splenic subtypes but may be seen in nodal MZL, which tends to have a more aggressive clinical course 2 5.
• These symptoms, when present, often indicate more extensive disease and warrant thorough evaluation.

Types of Marginal Zone Lymphoma

Marginal zone lymphomas are classified based on their site of origin and distinct clinicopathological features. The three main subtypes—extranodal (MALT), splenic, and nodal—exhibit different behaviors, associations, and treatment responses.

Type	Common Sites	Distinctive Features	Source
Extranodal (MALT)	Stomach, lung, orbit, salivary, thyroid, skin	Often linked to chronic inflammation or infection	2 4 6 7 8 13
Splenic (SMZL)	Spleen, bone marrow, blood	Often presents with splenomegaly, cytopenias	2 4 5 13
Nodal (NMZL)	Lymph nodes	More aggressive, often widespread at diagnosis	2 4 5 13 14

Table 2: Types of Marginal Zone Lymphoma

Extranodal Marginal Zone Lymphoma (MALT Lymphoma)

• Definition: Originates in mucosa-associated lymphoid tissue, commonly in the stomach but also seen in lungs, salivary glands, thyroid, ocular adnexa, and skin.
• Features:
  • Often results from chronic inflammation due to infection (e.g., H. pylori in the stomach) or autoimmune disease (e.g., Sjögren's syndrome in salivary glands, Hashimoto's thyroiditis in the thyroid) 6 7 8.
  • Tends to be localized and indolent, with a good prognosis 2 13.

Splenic Marginal Zone Lymphoma (SMZL)

• Definition: Originates in the spleen and often involves the bone marrow and peripheral blood.
• Features:
  • Presents with splenomegaly, sometimes cytopenias (low blood cell counts), and may have circulating villous lymphocytes 2 5 13.
  • Often indolent, with long survival even without aggressive therapy 5.

Nodal Marginal Zone Lymphoma (NMZL)

• Definition: Arises primarily in lymph nodes and is rarer than the other subtypes.
• Features:
  • Disease is usually more generalized at presentation, with multiple lymph node regions affected 2 4 5 13.
  • Tends to have a more aggressive course with shorter failure-free survival compared to other MZLs 2 5 14.
  • May rarely mimic splenic or extranodal MZLs in morphology and immunophenotype 4.

Causes of Marginal Zone Lymphoma

The exact cause of marginal zone lymphoma is complex and multifactorial, involving a combination of chronic immune stimulation, infections, autoimmune conditions, and genetic changes. Understanding these factors not only sheds light on who is at risk but also guides innovative treatment strategies.

Cause Type	Examples/Details	Role in Lymphoma Development	Source
Chronic infection	H. pylori, C. psittaci, B. burgdorferi, HCV	Drives chronic immune stimulation	6 7 8 10
Autoimmune disease	Sjögren’s syndrome, Hashimoto’s thyroiditis	Creates pro-inflammatory environment	1 6 8
Genetic alterations	t(11;18), t(1;14), trisomy 3, BCL6 gene	Promote cell survival, transformation	3 9
Chronic inflammation	Long-term antigenic stimulation	Sustains lymphoid proliferation	6 7 8

Table 3: Causes and Risk Factors for Marginal Zone Lymphoma

Chronic Infections

• Helicobacter pylori: Strongly linked to gastric MALT lymphoma; its eradication can lead to lymphoma regression 6 7 8 10 13.
• Other pathogens: Chlamydophila psittaci (ocular adnexal MALT), Borrelia burgdorferi (cutaneous MALT), Campylobacter jejuni (small intestine), and hepatitis C virus (splenic MZL) have also been connected to MZL pathogenesis 7 8 10.

Autoimmune Disorders

• Autoimmune diseases such as Sjögren’s syndrome (salivary gland MALT) and Hashimoto’s thyroiditis (thyroid MALT) are risk factors due to their role in creating a chronically inflamed microenvironment 1 6 8.
• Chronic inflammation from these conditions can trigger abnormal B-cell proliferation, setting the stage for lymphoma development.

Genetic and Molecular Factors

• Chromosomal translocations: The t(11;18)(q21;q21) translocation is the most common genetic aberration in MALT lymphoma, resulting in abnormal activation of pathways that prevent cell death 3 9.
• Other changes involve genes like BCL10, BCL6, and alterations affecting apoptosis (e.g., FAS gene mutations) 3 9.
• These genetic abnormalities can drive the transformation from low-grade to higher-grade lymphoma in some patients 3.

Chronic Antigenic and Inflammatory Stimulation

• Persistent immune stimulation—whether from infection or autoimmunity—leads to the accumulation of lymphoid tissue and eventually to the emergence of malignant clones 6 7 8.
• Unlike some other lymphomas, the inciting agent does not directly transform lymphoid cells but acts indirectly by maintaining a protracted immune response 7.

Treatment of Marginal Zone Lymphoma

Treatment strategies for marginal zone lymphoma are as diverse as the disease itself, reflecting differences in subtype, site, extent, and underlying causes. Fortunately, many patients benefit from less aggressive approaches, and therapies targeting the root cause—such as infection—are possible in select cases.

Treatment Approach	Indication/Subtype	Outcome/Notes	Source
Antibiotics	Gastric MALT (H. pylori+)	High remission rates if infection-driven	6 8 10 13
Radiotherapy	Localized MALT (orbit, lung, etc.)	Excellent local control, high CR rates	15 13
Chemotherapy	Advanced or refractory MZL	Effective, but risk of toxicity	11 12 13 14
Immunotherapy (Rituximab)	Advanced MALT, other MZL	Moderate activity, good disease control	11 12 13
Surgery	Splenic MZL (splenectomy)	Useful for symptom control	13
Observation	Indolent, asymptomatic cases	Safe in select patients	2 5 13

Table 4: Treatment Approaches for Marginal Zone Lymphoma

Antibiotic Therapy

• Gastric MALT lymphoma: If associated with H. pylori infection, eradication with antibiotics can induce complete remission in a majority of cases 6 8 10 13.
• Careful long-term follow-up is necessary, as malignant clones may persist even after apparent remission 13.

Radiotherapy

• Localized MALT lymphoma: Moderate-dose radiotherapy is highly effective for early-stage disease in sites such as the orbit or lung, with high complete remission rates and low recurrence 15 13.
• Side effects are generally mild, but site-specific complications (e.g., cataracts after orbital irradiation) can occur 15.

Immunotherapy and Chemotherapy

• Rituximab (anti-CD20 monoclonal antibody): Used alone or in combination with chemotherapy for advanced, disseminated, or refractory MZL. Has moderate efficacy and can provide durable disease control 11 12 13.
• Chemoimmunotherapy (e.g., fludarabine plus rituximab, CHOP regimens): Highly effective but may carry significant hematologic and infectious toxicity, necessitating careful patient selection and monitoring 11 14.
• The optimal regimen for non-gastric MZL is still under investigation, and treatment is individualized 13 14.

Surgery

• Splenectomy: Often used for splenic MZL to control symptoms related to massive splenomegaly or cytopenias 13.
• May not be curative but can provide significant clinical benefit.

Watchful Waiting

• For indolent, asymptomatic cases—especially in splenic or leukemic subtypes—observation without immediate therapy can be appropriate, as these lymphomas may progress very slowly 2 5 13.

Conclusion

Marginal zone lymphoma is a complex, heterogeneous group of indolent lymphomas with distinct subtypes, risk factors, and therapeutic options. Early recognition and tailored management are essential for optimizing patient outcomes.

Key Takeaways:

• Symptoms can be absent, mild, or site-specific; nodal MZL may be more aggressive.
• Types include extranodal (MALT), splenic, and nodal MZL, each with distinctive features and associations.
• Causes involve chronic infections, autoimmune diseases, and genetic changes. Treating the underlying infection or inflammation can sometimes reverse the lymphoma.
• Treatment is highly individualized, ranging from antibiotics and observation to advanced chemoimmunotherapy and radiotherapy, depending on subtype, location, and disease extent.

Marginal zone lymphoma exemplifies how understanding the interplay between chronic inflammation, genetics, and immunity can lead to more targeted and effective therapies for lymphoma patients.