Diagnosis and Staging of Marginal Zone Lymphoma

Introduction

Marginal zone lymphoma (MZL) is a rare type of cancer of the B cells (lymphocytes) which is slow-growing. Lymphomas are classified as either Hodgkin or non-Hodgkin and MZL accounts for around 8% of the non-Hodgkin lymphomas. They are called Marginal Zone due to the fact that the abnormal lymphocytes are located at the periphery of the lymphoid tissue. It is more common in people over the age of 50 and is slightly more common in women than men. Diagnosis can be challenging as MZL can look similar to other types of lymphomas and involves a combination of biopsies, scans and blood tests. After diagnosis other tests may be performed to see if the lymphoma has spread to anywhere else within the body - this is called staging and is used to plan treatment options and give a more accurate prognosis.¹ 

Types and symptoms of MZL

Types of MZL 

• Nodal marginal zone lymphoma
  • This develops in the lymph nodes
• Mucosa-Associated Lymphoid Tissue (MALT) lymphoma
  • Develops in lymphoid tissue outside the lymph nodes (extranodal)
  • Gastric or non-gastric forms
  • This is the most common form of MZL accounting for around ⅔ of cases 
• Splenic marginal zone lymphoma
  • Develops in the spleen²

Symptoms

The most common sign of lymphoma is swelling of the lymph nodes. Lymph nodes are small glands which are located all around the body where immune system cells are located. Lymph nodes can become enlarged for other reasons such as fighting an infection, so it is important if you think you may have enlarged lymph nodes to consult a doctor to determine the cause. Other symptoms may include fatigue, weight loss, severe fevers, and night sweats.¹ Additionally, around 20% of patients with splenic MZL also produce abnormal antibodies called cryoglobulins, which can result in poor circulation and a rash.³ 

Diagnosis

It is important to get an accurate diagnosis as the treatment and prognosis varies widely between different types of lymphoma. MZL is slow-growing, and patients often live for many years with this type of cancer. It develops slowly over time; however, relapse is common which necessitates treatment and further monitoring. Additionally, in around 20% of MZL cases the cells undergo a transformation into a more aggressive form which requires more intensive treatment, therefore, it is vital to monitor for this.¹ 

Initial evaluation

Firstly, a doctor will take a medical history including any close family members and do a full physical examination focusing on the locations of the lymph nodes that are clustered together (neck, armpit and groyne). Blood samples are used to assess general health including liver and kidney function as well screening for infections such as hepatitis C. This would also highlight if there is anaemia which may need treating or monitoring. The cause of MZL is unknown however, some cases have been associated with hepatitis C infection or immunosuppression, but these links are still being researched and having hepatitis C or immunosuppression does not mean you will develop MZL.

Biopsies

Samples of cells are taken from lymph nodes (or MALT) usually under local anaesthetic. If the affected area is not easily accessible (gut or lungs) samples may be taken using gastroscopy, colonoscopy,or bronchoscopy. Specially trained lymphoma pathologists then analyse the cells using the microscope to look at their features, this may indicate they are abnormal.¹ Further testing on the cells can be performed to assess the different types of proteins on the surface of the cells by using special stains. This is called immunohistochemistry and helps distinguish between different types of lymphomas. Immunohistochemistry is a very useful way of determining the type of lymphoma for certain types, however, MZL lacks specific immunohistochemistry markers making diagnosis tricky. Diagnosis is often made by the cytological appearance and the nature of the tumour (slow growing).⁴ Other techniques the lab may use to help them reach a diagnosis include fluorescence in situ hybridisation (FISH), polymerase chain reaction (PCR) and next generation sequencing (NGS). These tests may be done to rule in or rule out other types of lymphoma.⁵

FISH 

• Uses DNA markers to identify genes and chromosomes which may be altered in various disease processes including cancer 

PCR

• Amplifies a specific section of DNA to allow further analysis 

NGS

• Maps the genome to allow identification of mutations or variations in DNA sequences

Imaging

Along with blood tests and biopsies various imaging formats may be used to look for any signs of spread to other parts of the body, also known as staging. This can influence treatment options and also prognosis. This may involve some of the following: 

• X-ray
• CT scan 
• PET scan 
• MRI scan 
• Endoscopic ultrasound⁶

Staging 

Once the diagnosis has been made and imaging performed, the stage of disease can be determined. Commonly a bone marrow biopsy is also taken to assess if there is spread of cancerous cells to the bone marrow. The higher the stage the more advanced the cancer and the worse the prognosis. Generally, non-Hodgkin lymphomas are staged between I-IV and are either A or B depending on the presence of additional symptoms. 

Stage I 

• The cancer is located within one group of lymph nodes either below or above the diaphragm 

Stage II 

• Two groups of lymph nodes are affected but only one side of the diaphragm 

Stage III

• The cancer has spread to both sides of the diaphragm but still remains within lymph nodes

Stage IV

• The cancer has spread to other organs or/and the bone marrow in addition to lymph nodes

A = symptoms are restricted to enlarged lymph nodes only 

B = symptoms also involve night sweats, fever or weight loss⁷

This is based on the Lugano staging system which is commonly used for non-Hodgkin lymphoma. This has been modified from the previously used Ann-Arbor staging system to include PET-CT imaging.⁸ 

Lower-stage disease is more confined to one area and has a better prognosis than higher stages. MZL is generally slow growing and low stages may not even require treatment, just monitoring. Higher stages may need more intensive treatment possibly involving chemotherapy, radiotherapy, monoclonal antibody therapy or immunotherapy - or a combination of treatments.⁹ 

Differential diagnosis 

MZL can look like other diseases, some of which are serious, and some are more benign. This makes diagnostic testing even more important. The most common cause of enlarged lymph nodes is an active infection - bacterial or viral. This is called reactive lymphadenopathy. The body responds by accumulating lymphocytes within the local lymph nodes to help clear the infection. Other signs of infection may also include fever which can also be associated with MZL. Glandular fever is a common viral infection (Epstein-Barr virus) which results in enlarged lymph nodes, however, this is more frequently seen in younger adults and teenagers unlike MZL which is more common in older people.¹⁰ 

MZL also presents similarly to other types of lymphoma, such as follicular and mantle cell lymphoma. For example, splenic MZL shares many features with Waldenström’s macroglobulinaemia - a type of lymphoplasmacytic lymphoma which is a rare subtype of non-Hodgkin's lymphoma.³ Laboratory tests, clinical presentation and disease progression can all help distinguish between the types. 

Other infections may also complicate a diagnosis, such as Heliocobacter pylori which is a gastric bacterial infection commonly seen simultaneously with gastric MALT MZL. Similarly, skin MALT MZL can be associated with Borrelia burgdorferi and small bowel MALT MZL with Campylobacter jejuni infection (a cause of food poisoning).¹¹ 

Summary

MZL is a rare type of non-Hodgkin lymphoma which is slow-growing and often has a good long-term prognosis. Diagnosis often involves evaluation of underlying health, lymph node/mass biopsies and a series of imaging studies. Specific tests are performed on the biopsy samples at the laboratory to determine the exact type of lymphoma. From the results of the imaging the extent and spread of the disease can be determined and a stage applied. This has implications for both intensity of treatment and prognosis, therefore, it is important to get an accurate diagnosis and stage for the best outcome and avoid over or under-treating.