Introduction

Imagine being diagnosed with a type of cancer that could either hardly affect your life for years, or alternatively, could suddenly become life-threatening. This is the reality for people diagnosed with Follicular Lymphoma (FL), which is one of the most common forms of non-Hodgkin lymphoma. Some people with this disease can live almost the same as before their diagnosis, whereas others will be left fighting for their lives. Understanding the disease is crucial to allow us to predict the potential path the disease will take in an individual’s life. This article will address the mystifying nature of FL and how a prognosis can be influenced to determine what future FL will hold for each patient.

What is follicular lymphoma?

Follicular lymphoma (FL) is one of the most common types of non-Hodgkin lymphoma. It accounts for 35% of non-Hodgkin lymphomas and 70% of slow-growing lymphomas.³ It typically affects 20-35%  of individuals within Western populations, usually occurring around the age of 65. Additionally, it is slightly more common in people assigned female at birth (AFAB), as well as in those who have relatives with FL.³

The disease can be characterised as being highly heterogeneous (having multiple causes), with a low-grade malignancy and a lengthy survival period.^4,5 It is estimated that around half of patients with FL have cancer spread around the body, with the disease cycling rapidly through remissions and relapses.² Some individuals have a highly progressive form, leading to high mortality rates within a couple of years from diagnosis, whereas others can remain completely healthy and happy for years without treatment.⁴

This cancer can be largely asymptomatic (without symptoms), causing peripheral adenopathy (swollen lymph nodes) in cervical, inguinal, femoral, and axillary regions.¹ FL often goes unnoticed as it can be found within superficial lymph nodes. Bone marrow is also affected on occasion, which is seen in about 50-60% of cases.⁷ Another symptom that is much less common is presentation within the gastrointestinal (GI) tract.

Identifying which individuals are at high risk is crucial to providing appropriate treatments and enhancing overall survival.⁵ This requires a prognosis to be obtained to understand the disease severity within individual patients, where there are a variety of models that can be used to determine the prognosis of a patient.⁶

This article will discuss:

• What causes follicular lymphoma
• What the current treatments are for follicular lymphoma
• Prognosis of follicular lymphoma:
  • Biomarkers
  • Prognosis scores
  • Mutational risk
  • Limited-stage follicular lymphoma
  • Advanced-stage follicular lymphoma
  • Transformation of follicular lymphoma

What causes follicular lymphoma?

Follicular lymphoma arises from a neoplasm in the germinal centre of B cells (white blood cells).⁴ This neoplasm can mimic the secondary lymphoid follicles, which contain a mixture of small centrocytes and large centroblasts.^3,4 This disease has been commonly associated with gene mutations within B cells, particularly chromosomal translocations of t(14:18) (q32:q21) which are seen in approximately 80% of patients.⁴ These mutations (changes) can lead to effects such as the overexpression of BCL-2 (B-cell lymphoma-2 gene) which allows cells to resist death.³

What are the treatment options for follicular lymphoma?

Treatment strategies for FL have evolved significantly over the years. There was little improvement in survival rates upon developing therapeutic strategies in the 1980s and early 1990s. However, therapies, such as monoclonal antibodies, have greatly improved this.⁷ Due to this, the death hazard ratio decreased by 25% between 1983 - 1999.² This can primarily be attributed to the approval of the drug rituximab in the US in 1997, allowing it to be used for low-grade follicular lymphomas.² After the introduction of rituximab, survival rates increased to around 80%.³ The overall survival rates for 10 years have been described in the Swedish lymphoma registry between the years 2003-2010:³

• 92% in ages 18-49
•  83% in ages 50-59
• 78% in ages 60-69
• 70% in ages >70

Treatments include:

• Hematopoietic stem cell transplantation¹
• R-chemo¹
• Chemotherapy:
  • Alkylating agents²
  • Anthracyclines (antibiotic)²
  • Purine nucleoside analogues²
  • Combination chemotherapy²
• Radiation therapy²
• Unlabelled monoclonal antibodies²
• Rituximab²
• Autologous/allogenic bone marrow transplant

Lymphomas are usually described as incurable with chemotherapy. However, more intensive therapies, such as high doses of chemotherapy alongside stem cell transplants, have been suggested to be curative.⁵ In some cases, a combination of antibodies and chemotherapies can even achieve molecular remission.⁵

Prognosis of follicular lymphoma

Prognosis can be determined through a variety of factors including age, performance, and overall health.¹

Ann arbor staging

This system can assess prognosis directly including factors such as:¹

• Tumour burden
• Bone marrow involvement
• Bulky disease

Clinical and laboratory

This takes into account more specific clinical traits such as:¹

• Presence/extent of bone marrow involvement
• Tumor diameter
• Nodal/extranodal sites of disease number
• Presence of B-symptoms (fever, night sweats and weight loss)
• Lactic dehydrogenase (LDH)
• B2-microglobulin (B2M) values
• Elevated erythrocyte sedimentation rate (ESR)
• Low haemoglobin levels

Mutational risk

This can potentially include mutational status alongside a prognostic score, such as the deletions of TP53 and CREBBP (both are types of protein) that have been associated with shortened survival.³

Prognostic scores

The Italian Lymphoma Intergroup (ILI), the International Follicular Lymphoma Prognostic Factor Project (IFLPFP) and progression-free survival are all different ways to obtain a prognostic score for a patient.¹

The italian lymphoma intergroup (ILI)

The ILI score is determined by:¹

• Age
• Gender
• B symptoms
• Number of extranodal sites
• EDR and LDH

From these factors, 3 risk groups can be determined, where each risk group has a different survival rate over 10 years which include:⁴

• 65%
• 54%
• 11%

The International Follicular Lymphoma Prognostic Factor Project (IFLPFP)

The IFLPFP is determined by the five risk factors:¹

• Ann Arbor stage
• Haemoglobin level
• Areas of serum LDH level
• Number of nodal sites involved

This classifies individuals into 3 categories with different survival rates, including:⁴

• 71%
• 51%
• 36%

Progression-free survival

Progression-free survival (a modified version of FLIPI also called FLIPI2) is determined using:³

• Age
• Bone marrow involvement
• Haemoglobin level
• Longest diameter of the largest lymph node
• B2 microglobulin value

Stages of follicular lymphoma

Limited-stage follicular lymphoma (early stages)

Patients within the early stages can often be treated successfully with radiotherapy. Sometimes, a combination of chemotherapy and rituximab is used to achieve high remission rates, whilst also having reduced toxicity.⁴

Advanced follicular lymphoma

Treatment is required for advanced-stage FL, which is typically not curable.⁴ However, it can be managed with therapies such as sequential systemic chemotherapy.² Even with treatment, advanced FL remains a chronic condition.

Transformation of follicular lymphoma

FL can transform into a more aggressive form called diffuse large B cell lymphoma (DLBCL), which can rapidly progress, with little to no response to therapy.³ This transformation occurs in 3% of cases every year and is considered the primary cause of death from FL.³ While there are no specific biomarkers definitively linked to an increased risk of transformation, a higher FLIPI score may indicate a higher likelihood.⁴

Summary

Follicular Lymphoma is a complex and heterogeneous disease with a wide range of outcomes. While some individuals are able to live with minimal intervention, others can face a more aggressive course that demands a more intensive treatment. Advances in therapy, such as rituximab, have significantly improved survival rates, yet FL is still incurable, especially within its advanced stages. Currently, FLIPI is the main indicator for prognosis and how medical professionals should proceed with treatments. However, there is still a pressing need for more precise biomarkers to aid in treatment decisions. Ongoing research into genetic markers may provide new insights into personalised treatment approaches, particularly for patients who are resistant to standard therapies.