Stages Of Follicular Lymphoma

Introduction

Follicular lymphoma (FL) is the second most common type of non-Hodgkin lymphoma (NHL) after diffuse large B-cell lymphoma. It is a slow-growing B-cell lymphoproliferative disorder. About 90% of people who were affected with FL are alive after five years of diagnosis. FL is particularly found in the USA and Europe and less frequent in the rest of the world. It is diagnosed majorly in older adults of age 55 years and is less common in children and young adults; under 20 years of age.¹ 

FL accounts for around 30% of all lymphoma patients and is the most common subtype of clinically indolent (slowly growing) NHL.¹ FL is characterised by peripheral lymphadenopathy (describes the conditions under which lymph nodes transform abnormally in size, number and consistency) and involve the spleen, bone marrow as well as peripheral blood (circulating throughout the body).²

Importance of staging

Usually, symptoms associated with FL include fatigue, fever, sweating and chills at night, losing 10% of body weight without any cause within 6 months and painless swelling in the neck, armpit or groin. The common way to diagnose FL is biopsy, where a sample of cells is collected and observed. Blood cell counts are also tested to keep a check on the functioning of the kidney and liver. 

Since FL is a slow-growing disorder without significant symptoms, early detection will help in the treatment of FL at the initial stages. Staging is performed to determine the area of the body affected by lymphoma and is usually performed using a CT scan or a PET scan. Treatments for all stages of FL are available and are helpful to keep it under control for many years. The stages related to the FL will be discussed here with the possible diagnostic methods.²

Staging in lymphoma

When a patient is diagnosed with lymphoma, doctors tend to find out if it has spread, and if so, to what extent. This procedure is known as staging, which describes the part of the body affected by cancer. It helps to determine the seriousness of the lymphoma and the appropriate treatment for that. There are four stages of follicular lymphoma, which are: 

1. Stage 1: Only one group of lymph nodes has lymphoma.
2. Stage 2: Lymphoma is present in two or more groups of lymph nodes.
3. Stage 3: Lymphoma-containing lymph nodes are present on both sides of the diaphragm.
4. Stage 4: Lymphoma has spread to at least one body organ.

The first two stages are considered early stages while stage 3 and stage 4 are classified as advanced. Ann Arbor staging system is a widely accepted method for anatomic or noninvasive staging of both Hodgkin and non-Hodgkin lymphomas.³

Stages of follicular lymphoma

The Ann Arbor staging system is based on various factors such as affected lymph node regions, their location, and involvement of other organs and the main factor is the involved sites. Here, in some cases involved lymph nodes are present on one or both sides of the diaphragm and extranodal (outside lymph nodes) are involved in other cases^.4,5

The staging system for Follicular lymphoma is given below:

Stage I

• Single lymph node region or extra lymphatic site: At this stage, cancer is localised to one lymph node region or a single extra lymphatic organ like the spleen or tonsils
• Symptoms: Often asymptomatic (without symptoms) or mild symptoms such as fever, sweating and chills at night, losing 10% of body weight without any cause within 6 months and painless swelling in the neck, armpit or groin

Stage II

• Two or more lymph node regions on the same side of the diaphragm: In this stage, cancer is detected in two or more lymph node regions either above or below the diaphragm
• Extra lymphatic organ with lymph nodes: A single extra lymphatic organ with nearby lymph nodes is also involved in this
• Symptoms: Mild symptoms are present such as fatigue, fever or localized pain

Stage III

• Lymph node regions on both sides of the diaphragm: Here, cancer involves lymph nodes both above and below the diaphragm
• Involvement of the spleen: The spleen may be involved, along with lymph nodes
• Symptoms: Generalised symptoms such as night sweats, fever, or weight loss (B symptoms)

Stage IV

• Diffuse or disseminated involvement of one or more extra lymphatic organs: This stage indicates that cancer has spread to distant organs, such as the liver, bone marrow, lungs, pleura or cerebrospinal fluid
• Involvement of lymph nodes: Lymph nodes may or may not be involved
• Symptoms: More severe symptoms, including B symptoms (unexplained fever, chills and sweating at night, weight loss or fatigue) and organ-specific symptoms⁵

Importance of "B" symptoms in staging

The lymphatic system is present all over the body, due to which lymphoma reaches an advanced stage when the patient becomes symptomatic or is diagnosed with it. The extent of spread depends on the exact stage of lymphoma, based on which treatment is aimed to control or get rid of it. We have already discussed four stages of lymphoma and there are different letters used as a part of the lymphoma diagnosis.³ These letters (shown below) are followed by the stage number :

• Letter ‘A’ or ‘B’: Letter ‘A’ implies absence of any of the symptoms such as fever, sweating and chills at night, losing 10% of body weight without any cause within 6 months. While letter ‘B’ indicates the presence of one or more of these symptoms which are also called B-Symptoms. 
• Letter ‘E’: The Letter ‘E’ stands for ‘extranodal’, which means the lymphoma started in a non-lymphatic body organ like the digestive system or salivary glands
• Letter ‘S’: This indicates the spleen and thymus 

The presence of B symptoms can affect treatment and help to implement appropriate measures. 

Diagnostic tools for staging

Follicular lymphoma is commonly characterised by slow progressive growth. The majority of patients do not have clinical symptoms, particularly in the early stages of FL. The characteristic symptoms often include painless swollen lymph nodes, present on the neck, armpit, groin and abdomen.⁶  

Some patients undergo losses in performance (38%) and around 34% have fatigue. B-symptoms are experienced by 25% of patients, whereas night sweats are the most common B-symptoms.⁷ The swollen lymph nodes last for several weeks or more and require a histological investigation. A possibly large tissue sample is harvested, and complete removal of lymph nodes is preferred by experts to perform a biopsy. 

A cytological aspirate is not sufficient for the diagnosis of lymphoma, so histology is complemented by immunohistochemistry (a kind of antigen-antibody test). It helps to confirm the B-cell nature of the FL, the germinal centre phenotype and the criteria of malignancy (malignancy implies abnormal growth of cells and invasion to the nearby tissues). Such a type of histopathological diagnosis should be executed by an experienced pathologist. This confirms follicular lymphoma, and the stage or therapeutic requirements are determined by using appropriate investigations.⁴

Since most of the patients remain asymptomatic (without symptoms), immediate therapy followed  by certain examinations within 4–6 weeks should be performed which include:

• Medical history
• Physical examination: It involves checking whether superficial (near the surface of the skin) lymph nodes, spleen or liver are enlarged or not.
• Laboratory tests:
  • Blood count – including differential blood count
  • Lactate dehydrogenase level.
  • Liver function and kidney function tests.
  • Beta-2 Microglobulin test
• MRI or CT scan: Neck, thorax and abdomen.
• Bone marrow biopsy 
• PET scan: If the above procedures do not provide any indications about stages III and IV, then it is performed to determine the spread of FL and to assess the area to be irradiated.⁷

Prognostic factors and implications of staging

The prognosis of the FL is diverse and many treatments may be proposed after the diagnosis of follicular lymphoma. To determine the FL prognosis, the Follicular Lymphoma International Prognostic Index (FLIPI) standard is present and a validated prognostic index (PI) is helpful in implementing significant treatments.¹

The FL International Prognosis Index (FLIPI) standard used to predict FL prognosis is FLIPI-1. In recent years, IDEC-C2B8 (rituximab), a monoclonal antibody ( a type of protein used to enhance the immune system) for treating FL, has been commonly used. Due to this a new clinical prognostic scoring system called FLIPI-2 is introduced as an improved version of FLIPI-1.⁸ The FLIP-2 associated factors include:

• Beta-2 microglobulin greater than the maximum limit of normal.
• Bone marrow involved.
• Hemoglobin less than 120 g/L.
• The diameter of the largest lymph node involved is greater than 6 cm.
• Age above 60 years.

Based on the above factors, a 5-year progression-free survival (PFS) classification consisting of risk factors is provided as listed below: 

• Low risk (0-1 risk factors): 80%
• Intermediate risk (2 risk factors): 51%
• High risk (3 or more risk factors): 19%

The management of FL is based on the stage of the disease and the available treatment methods for FL are:

• Radiotherapy (RT): Of the patients with FL, less than 10% have stage-1 or 2 disease. Radiation therapy (RT) is the common treatment of choice for limited or initial-stage FL. It results in 10-year overall survival rates of 60%–80%.
• Immunochemotherapy (rituximab with chemotherapy)
• Bendamustine with immunotherapy
• Rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulphate and prednisone (R-CHOP)
• Immunochemotherapy plus RT
• Cyclophosphamide, vincristine, and prednisolone (CVP)
• Single-agent rituximab
• Observation until progression

The treatment considerations depend on the disease stage and preference of the physician as well as the patient. In stage-1 and stage-2 FL, RT is preferred, but in patients with grade 3B FL is treated with aggressive treatments such as R-CHOP (used for other aggressive lymphomas). At stage 3 and stage 4, therapy including chemotherapy, immunotherapy, and stem cell transplant are applied. The treatment of FL stage-2, 3 and 4 focuses on improving quality of life, mitigating symptoms, and reversing cytopenias. Asymptomatic patients are closely monitored without any intervention. 

Now, anti-CD20 antibodies (obinutuzumab, rituximab) integrated with chemotherapy regimens are used to treat symptomatic advanced FLs.⁹  Autologous hematopoietic stem cell transplantation is preferred for the management of relapsed patients or patients who have faced a transformation to high-grade lymphoma. Patients affected with advanced, relapsed, or refractory disease are encouraged to take part in clinical trials related to new therapies like CAR (chimeric antigen receptor) T-cell therapy).

Summary

Follicular lymphoma is a slow-growing cancer that may appear with symptoms or asymptomatic in lymph nodes, bone marrow and other organs. Symptoms such as fever, night sweats, and weight loss are common in FL. The incidence rate of FL is more in Caucasians than in Asians and African Americans. A patient diagnosed with lymphoma is investigated to find out areas affected by FL. This is performed through staging, where 4 different stages describe the part of the body affected with or without symptoms. The diagnostic method involves physical or medical examinations, medical tests and other imaging methods. The Follicular Lymphoma International Prognostic Index (FLIPI) based on various factors assesses the possible risks before initiating an appropriate treatment. FL can be a serious and challenging illness if not diagnosed at an early stage because it affects your emotional well-being long before it affects your physical well-being.