Introduction

Marginal zone lymphoma (MZL) is a form of B-cell cancer. Firstly, let's break down what exactly MZL refers to. 

Lymphoma refers to a type of cancer that affects the lymphatic system. The lymphatic system is a complex of tissues and organs that balances fluid levels within your body. It also plays a key role in your immune system. Lymphomas can be broadly categorised into Hodgkin and non-Hodgkin lymphomas. MZL is a non-Hodgkin lymphoma.

Lymph nodes are small pea-sized organs and are part of the lymphatic system, where they help filter and regulate fluid within your body and form a key defence against infection. These nodes contain lymphoid follicles, which can be further broken down into a marginal zone and a mantle zone. 

Next, we have B-cells, which are white blood cells that form within the lymphatic system and are part of your immune system. They fight harmful bacteria and viruses that have entered your body. Unfortunately, these cells can mutate and begin to multiply more than they should. This proliferation can occur in the marginal zone of the lymph follicles, thus causing MZL. MZL can be referred to as “indolent”, meaning the cancer is slow-growing. 

Marginal zone lymphoma subtypes

MZL can be broken down into three subtypes:

• Extranodal MZL (also known as mucosa-associated lymphoid tissue (MALT) lymphoma)
• Nodal MZL
• Splenic MZL

Extranodal marginal zone lymphoma 

Extranodal MZL (MALT lymphoma), is the most common subtype and typically originates in the mucosa-associated lymphoid tissue of the:

• Gastrointestinal tract
• Lungs
• Salivary glands
• Thyroid
• Ocular adnexa (the area directly surrounding the eye). 

Symptoms of extranodal MZL vary by origin site and depend on the organ involved.

Gastrointestinal tract

The stomach is the most common site of origin for extranodal MZL.¹ Symptoms may include:

Abdominal pain

This symptom is commonly described as a dull or aching pain, it is important to note that this can be mistaken for a peptic ulcer or gastritis.

Dyspepsia

More commonly known as indigestion, this may be accompanied by bloating and a feeling of uncomfortable fullness.¹

Nausea and vomiting

This is a less common symptom but can occur if the MZL causes gastric outlet obstruction (narrowing of the opening of the stomach into the small intestine).¹

Unintentional weight loss 

This can occur due to a loss of appetite or malabsorption. Malabsorption refers to the reduced ability of your gut to absorb digested food and nutrients. 

Lungs

If the site of extranodal MZL is within the lungs, symptoms can include:²

A persistent cough

This cough may be “productive”, more commonly known as a wet cough meaning a cough that produces phlegm or mucus.

Dyspnoea

More commonly referred to as shortness of breath, a sensation of not being able to breathe deeply or quickly enough, as if you're running out of air. This may be especially noticeable after physical exertion.

Chest pain

This symptom is rare but can occur if the pleura is affected.² The pleura are layers of membrane within your lungs.

Ocular adnexa

If extranodal MZL is around the eyes, symptoms can include:²

• Proptosis - Where your eyes may protrude or bulge out of their natural position
• Visual disturbance - Your vision may become blurred or you may see double
• Eyelid swelling - Painless swelling in the area surrounding your eye
• Conjunctival mass - The conjunctiva is a layer that is part of your eyelid. This symptom looks like a visible mass in the eye region

Nodal marginal zone lymphoma

Nodal MZL is less common than extranodal MZL and primarily involves the lymph nodes. Symptoms of nodal MZL are typically systemic (affecting the entire body), rather than presenting as symptoms associated with a specific organ. Therefore, symptoms can be more general. 

Lymphadenopathy 

Lymphadenopathy refers to enlarged or painless swelling of the lymph nodes. This commonly occurs in the neck, armpits, or groin. It can be localised, affecting a single region, or generalised, affecting multiple regions of lymph nodes.³

Systemic symptoms 

Systemic symptoms that indicate the cancer is in a more advanced stage or is aggressive include:³

• Fever
• Night sweats
• Unexplained weight loss
• Fatigue - The body's immune response to the lymphoma can be taxing, and so fatigue is a common symptom
• Hepatosplenomegaly - This refers to an enlarged or swollen liver and spleen, the symptoms manifest as tummy discomfort and fullness

Splenic marginal zone lymphoma

The splenic MZL subtype involves the bone marrow and spleen and can be identified by specific haematological and physical symptoms. Haematological symptoms concern the blood.

Splenic (spleen) symptoms

Symptoms of splenic MZL may include:

Splenomegaly

This symptom involves the enlargement of the spleen, resulting in stomach pain and discomfort. This is typically the most noticeable symptom of splenic MZL.

Hypersplenism

This refers to the spleen becoming overactive, giving rise to multiple other conditions such as cytopenias (having a reduced level of red or white blood cells, or platelets).

Bone marrow-related symptoms

Bone marrow is a soft, spongy substance inside our bones where our blood cells are made. Blood marrow-related symptoms generally involve an underproduction of blood cells. Symptoms may include:

Anaemia

Anaemia is a condition where you produce less blood cells than you should. Symptoms include fatigue, pallor, and general weakness.

Leukopenia

Leukopenia refers to an underproduction of white blood cells, white blood cells are part of your immune response and so a reduced level of them makes you more susceptible to infection. 

Thrombocytopenia

This condition involves the underproduction of platelets. Platelets are a type of blood cell that form clots at the site of wounds to prevent blood loss. Symptoms may include bruising easily, bleeding gums, excessive bleeding, and petechiae (small red spots or blemishes on the skin).

Diagnoses and clinical presentations

Diagnosis of MZL typically requires a combination of clinical evaluation, imaging studies, and examination of biopsy tissue. These are further detailed below.

Histopathological biopsy 

This is crucial for a definitive diagnosis. A histopathological biopsy involves removing a sample of tissue or cells from your body for further analysis in a laboratory. The term histopathological simply refers to the study of diseased tissue. This examination can confirm whether you have MZL and which subtype.⁴

Imaging studies 

Imaging studies include:

• CT scans
• PET scans
• Ultrasounds 

These scans are non-invasive procedures that can produce detailed images of the inside of your body.⁴

Blood tests 

Blood tests are used to determine:⁴

• Complete blood count
• Lactate dehydrogenase (LDH) levels
• Liver function
• Organ health
• Overall health

A complete blood count is a general blood test and can be useful in assessing overall health. LDH is an important enzyme and measuring it can also be useful when assessing overall health.

Differential diagnosis

When seeking a diagnosis, it is important for your healthcare provider to consider whether your symptoms indicate MZL or a different condition entirely, as indicators of MZL often overlap with other conditions. This is known as a differential diagnosis and is crucial for confirming your official diagnosis. Other conditions to consider include:

Other lymphomas 

Other lymphomas such as diffuse large B-cell lymphoma or follicular lymphoma have similar symptoms.⁵

Autoimmune disorders

Autoimmune disorders are conditions where your immune system attacks your healthy cells, mistaking them for harmful foreign substances or microbes. Disorders such as Sjögren’s syndrome can have similar symptoms.² 

Infectious disease

It is important to identify whether the symptoms are a result of infection, rather than, or in conjunction with the cancer.  For example, infection by Heliobacter pylori is linked to gastrointestinal extranodal MZL.¹

Management 

Treatment of MZL can be multifaceted and depends on the subtype, how far the disease has progressed, and the overall health of the patient. Typical treatments may include:

Radiotherapy

Radiotherapy uses radiation such as X-rays to treat cancer. It is most often effective for a localised disease. 

Chemotherapy

Chemotherapy is used if the condition reaches a more advanced stage, or is systemic. Chemotherapy is a medicine that kills cancer cells, it can be administered orally or intravenously. 

Immunotherapy

This type of treatment involves the use of medicines that work with your immune system, helping it target and attack cancer cells. The drug Rituximab is often used in conjunction with chemotherapy.

Prognosis

The prognosis for MZL is often favourable, with high rates of survival 5 years after diagnosis. However, it is worth noting that survival rates are an average based on data collected over time, and don't always reflect individual experiences. The progression of the disease can vary by individual and subtype, and in some cases can transform into more aggressive lymphomas. 

Summary

Marginal zone lymphoma encompasses 3 distinct subtypes: extranodal MZL, nodal MZL, and splenic MZL. Each has its own array of symptoms which can vary significantly, from systemic to organ-specific. Recognising these symptoms is essential for an early diagnosis, subsequent management, and a good prognosis. Diagnosis, treatment, and management are multifaceted and dependent on the subtype and your overall health. If you suspect that you are unwell, it is important to consult a healthcare professional as soon as possible.