Introduction 

Lymphoma is a term used for blood cancers caused by the out-of-control growth of white blood cells called lymphocytes within the lymphatic system. The lymphatic system is involved in the filtration of blood and lymph (additional fluid). The lymphocytes are crucial cells within this system and play a key role in fighting infections.

There are two types of lymphocytes, B and T cell lymphocytes, and there are also two main groups of lymphomas, Hodgkin and non-Hodgkin lymphoma.

Non-Hodgkin lymphoma (NHL) arises from B cells, and follicular lymphoma is the second most common type of NHL, with around 2,300 people being diagnosed with the cancer every year. It usually affects elderly populations with a mean age of 55 years.¹ 

Follicular lymphoma is typically a slow-growing cancer with variable symptoms. The overall diagnosis of follicular lymphoma is based on the clinical history and presentation of symptoms, histopathological, immunohistochemical, and molecular genetic testing. Other tests, like blood tests and imaging scans, may also be useful in staging and grading the cancer.^2,7

Why is early diagnosis important? 

Early diagnosis is important with follicular lymphoma because it is a ‘low-grade’ and slow-growing cancer. This means that it grows gradually, and early stages are either asymptomatic or associated with only a few symptoms, reflecting longer survival rates.⁵ 

Diagnosis is important at the early stage, as over time, the cancer can transform into a more aggressive and rapidly growing cancer called diffuse large B-cell lymphoma. This type of cancer is associated with more severe symptoms and may spread widely to organs outside of the lymphatic system and the bone marrow.

Physical examination 

One of the initial steps of diagnosing follicular lymphoma is through physical examination and patient history to identify characteristic symptoms of this cancer.

Physical examination may include palpation of lymph nodes and certain other organs of the lymphatic system, like the spleen, to detect if there is any swelling present. A doctor will check if the patient has any symptoms usually found with follicular lymphoma, and these can include:

• Palpable lymph nodes, usually in the neck, groin, or armpit, which are hard and painless 
• An enlarged spleen 
• Low levels of white, red and platelet cells 
• Anaemia, due to low red blood cells, is a disease that presents with symptoms like pale skin colour, tiredness, weakness, breathing difficulties, and headaches
• Increased risk of infection due to low white blood cell count 
• Increased bleeding and bruising due to low platelets

Non-specific symptoms of follicular lymphoma include: 

• Persistent fever 
• Abnormal weight loss
• Excessive sweating, especially at night 

The presence of these symptoms may cause a doctor to carry out further clinical tests to establish a diagnosis.

Blood tests

Usually, after a patient presents with these symptoms, the next step in diagnosis will be a complete blood count test, which is used to detect the white, red, and platelet cells in the body. 

This test is not diagnostic but may indicate a problem that warrants further investigation. For example, with follicular lymphoma, there is a higher number of abnormal circulating white blood cells than normal mature white blood cells.³

Other components measured in a blood test:

• Proteins like beta-2 microglobulin: High amounts indicate advanced lymphoma 
• Enzymes like lactate dehydrogenase: It is normal in slow-growing follicular lymphoma and raised in high-grade lymphoma

Histopathological examination

This is the gold standard method for diagnosing follicular lymphoma. A lymph node or bone marrow biopsy is undertaken to see the microscopic changes in the cells. Two types of lymph node biopsies may be used. It includes the excisional biopsy, where most of the enlarged lymph node is removed and analysed. This is the recommended method for such a type of cancer, or the core needle biopsy, which is less invasive (only a small amount of the lymph node is removed for analysis), can be used. The lymph nodes can also be examined externally, which is known as a gross examination, and they are often described as a bulging section with a nodular pattern.²

Under a microscope, lymph nodes have various-sized cells and have more closely packed follicles. They may have small and cleaved or large and non-cleaved B cell lymphocytes. They may contain some apoptotic cells with multiple or no nucleoli. There is usually infiltration into the capsules, and the mantle zones of the lymph nodes are usually absent. More aggressive forms of follicular lymphoma may contain a greater number of larger cells.¹

A bone marrow biopsy can detect whether the lymphoma is present in the bone marrow. It is a more invasive diagnostic test and involves taking a sample of bone marrow, usually from the back of the hip. Both these biopsy types are important in staging and grading the follicular lymphoma.

Immunohistochemistry 

Immunohistochemistry is a technique used to diagnose and differentiate follicular lymphomas from other types of lymphomas and is also important in the grading of this cancer. 

It detects and uses antibodies which bind to the specific B cell markers that are expressed on the cell surface. Markers that will be positive for follicular lymphoma are CD10, CD19, CD20, CD79a, BCL2, and BCL6.^4,6 It also helps to distinguish follicular lymphoma from diffuse large B-cell lymphoma (DLBCL), which needs a different treatment pathway.¹ 

Genetic and molecular testing

Other than histopathology and immunohistochemistry as diagnostic tests, genetic and molecular testing can also be useful. Doctors can use a technique called FISH, which stands for fluorescent in situ hybridisation, that involves attaching marked coloured or fluorescent probes to portions of the chromosome that are responsible for causing follicular lymphoma. 

The exchange of genetic material between chromosomes 14 and 18 (translocation) is responsible for causing the overexpression of the BCL2 gene, which is implicated in the cause of this condition and can be detected using FISH.¹ PCR is another molecular technique used for diagnosis. It is less reliable than the FISH technique, but it works by amplifying and making copies of specific segments of DNA to identify the translocations.

Other tests 

CT scan

A CT scan can be used to visualise and locate the lymphoma and is especially useful in lymphomas that can not be palpated. It is a non-invasive procedure that involves lying flat on a specialised table and allowing a scanner to take several images of the body.

PET scan 

PET scans are used for patients with asymptomatic follicular lymphoma. It detects more active cancer cells in comparison with normal cells using a dye known as a radiotracer that is injected into the body and highlights areas of cancer. Often, these two scans are performed together and are especially useful in determining if there are any transformations of follicular lymphoma. Any changes to the size of the cancer and the response to treatment can also be analysed using this.

Differential diagnosis

Several other conditions may be mistaken for and diagnosed as follicular lymphoma. Consequently, they need to be differentiated from and considered during diagnosis: 

• Reactive follicular hyperplasia
• Mantle cell lymphoma
• Nodular lymphocyte-predominant Hodgkin lymphoma
• Lymphocyte-rich classic Hodgkin lymphoma
• Nodal marginal zone lymphoma
• Castleman disease
• Progressive transformation of germinal centres⁴

However, follicular lymphoma occurs with fewer symptoms or can be asymptomatic and requires timely diagnosis for early treatment and to save lives. Different diagnostic methods can be used to detect the stage of cancer and enhance a patient’s chances of survival.

Summary 

The diagnosis of follicular lymphoma involves different steps and tests. It is largely reliant on both the clinical presentation of the patient and the gold-standard histopathological examinations. Patients with this condition may have symptoms such as swollen lymph nodes, anaemia, abnormal blood test values, persistent fever, abnormal weight loss, and excessive night sweats. 

These symptoms may be followed up with blood tests, lymph nodes and bone marrow biopsies, genetic and molecular tests, and even scans to visualise non-palpable lymphomas. Early diagnosis is especially important as it is more easily treated in its initial stages and reduces the risk of transforming into a more aggressive type of cancer.