Follicular Lymphoma: Development, Risk Factors, Symptoms, Causes, Morphology, Diagnosis, Treatment and Prognosis

Lymphocytes multiply and enlarge abnormally instead of dying naturally and leaving room for new cells.

The most common type of blood cancer is lymphoma, which develops from a defect in the lymphocytes of the white blood cells. It can be classified as Hodgkin’s or non-Hodgkin’s lymphoma, depending on its characteristics.

Follicular lymphoma is a type of non-Hodgkin lymphoma, which originates in B lymphocytes, or B cells, and is the most common form of the slow-growing disease.

It is defined as a B-cell lymphoma of the center of the follicle (centrocytes and centroblasts), which has at least a partially follicular pattern. It is positive for the B cell markers CD10, CD19, CD22, and usually CD20, but is almost always negative for CD5.

About 20 percent of all non-Hodgkin lymphomas are follicular lymphomas, which can develop anywhere in the body and cause symptoms such as swollen lymph nodes.

According to the American Cancer Society, the average age of people who develop the disease is 60.

Patients suffering from the disease generally do not experience solid or apparent symptoms for a long time before diagnosis due to the sluggish nature of this lymphoma.


The progression of the disease depends on many factors, but it is generally not life-threatening for patients until it is in an advanced stage, which can take years.

There are synonymous and outdated terms for this disease: CB / CC lymphoma (centroblasts and centrocytes lymphoma), nodular lymphoma, Brill-Symmes disease, and the subtype, follicular large cell lymphoma.

Development of follicular lymphoma and risk factors

Follicular lymphoma earns its name because of its appearance. The disease mainly affects the lymph nodes, like other lymphomas, and under the microscope, it shows rounded structures that resemble follicles.

Almost all patients who suffer from it have a mutation in the BCL-2 gene and a translocation between chromosomes 14 and 18, which results in abnormally high production of the BCL2 protein, responsible for apoptosis or the natural life cycle and cell death.

These mutations are not fully understood, but the disease affects men and women equally, although older patients are more likely to develop follicular lymphoma. Asians and people from Africa are less likely to create it.


Follicular lymphoma is a type of blood cancer. It is the slowest and most indolent (slow-growing) non-Hodgkin lymphoma and the second most common form of non-Hodgkin lymphoma overall.

The most common signs of lymphoma begin with painless swellings in the lymph nodes, particularly in the neck and armpits.

Most lymphomas start in lymph node tissue and can often affect other organs.

Lymphomas can affect any organ, including the skin and the gastrointestinal tract. They can cause harmful effects by invading organs and obstructing anatomical structures by a tumor mass.

For example, ureteral obstruction from enlarged lymph nodes can lead to kidney failure.

Night sweats, fever, unexplained weight loss, fatigue, and other symptoms can occur, mainly in advanced stages.

Follicular lymphoma patients are at particular risk of developing abdominal tumors that can obstruct normal digestion and urination.

Because follicular lymphoma progresses slowly, symptoms can go unnoticed for years.

Symptoms related to bone marrow dysfunction, such as anemia, leukopenia, or thrombocytopenia, are rare at presentation but can also be seen in the later stages of the disease.

Lymphocytosis, reflecting blood involvement, may also be present even though most follicular lymphomas are advanced at the time of diagnosis.

Many patients may not require treatment for long periods, and the median survival of patients with follicular lymphomas has historically been approximately 8-10 years.

The literature since the rituximab era has shown a further increase in overall survival.

Causes of follicular lymphoma

A translocation between chromosomes 14 and 18 results in the overexpression of the BCL-2 gene. As the BCL-2 protein is usually involved in preventing apoptosis, cells with overexpression of this protein are immortal.

The BCL-2 gene is usually found on chromosome 18, and the translocation moves the gene close to the site of the immunoglobulin heavy chain enhancer element on chromosome 14.

BCL6 translocations at 3q27 may also be involved.


The tumor is composed of follicles that contain a mixture of centrocytes (Kiel nomenclature adopted by experts from the World Health Organization) or cells of the center of the strand segmented (older American terminology) “small cells.”

And centroblasts (Kiel nomenclature adopted by experts from the World Health Organization) or large cells in the center of the follicle not broken (older American terminology), “large cells.”

These follicles are surrounded by non-malignant cells, mostly T cells. In follicles, centrocytes generally predominate; Centroblasts are usually in the minority. The peripheral smear will also reveal buttock cells.

Diagnosis of follicular lymphoma

As silent cancer with subtle symptoms, the diagnosis is more complex and is often made in later stages of the disease.

When a doctor suspects that a patient has lymphoma, the first step is to perform a complete physical exam and request a medical history.

All lymph nodes and the reticuloendothelial system areas should be examined during the physical evaluation. The nodes involved are generally non-resistant, firm, and rubbery inconsistency.

In addition, the throat should be examined for the involvement of the oropharyngeal lymphoid tissue (i.e., Waldeyer’s ring), and special attention should be paid to the abdominal examination (such as liver and spleen).

Splenomegaly is present in approximately 50% of patients at presentation, and hepatosplenomegaly may occur.

The most common diagnostic method is a biopsy, but other tests may be needed to assess the type, extent, and stage of the disease, including:

Routine laboratory tests

A complete blood cell count (CBC) and differential should be obtained, along with an examination of the peripheral blood smear if the differential is abnormal. Abnormal lymphocytes can often be identified in the blood smear, reflecting blood involvement.

Blood chemistries should be evaluated, including lactate dehydrogenase (LDH) levels, uric acid levels, liver function tests, and creatinine measurements. Lactate dehydrogenase indicates tumor burden, and a high level is an adverse prognostic factor.

Hyperuricemia can be observed at presentation or during treatment. Allopurinol should be considered in patients with hyperuricemia and before treatment to prevent uric acid nephropathy.

Increased creatinine levels can be seen in patients with renal obstruction caused by lymphadenopathy. High measurements of alkaline phosphatase and bilirubin can be observed in patients with biliary obstruction due to lymphadenopathy or liver involvement.

If rituximab treatment is being considered, serology should be obtained for hepatitis B (i.e., hepatitis B surface antigen, core antibody, and surface antibody) and hepatitis C.

Computed tomography and positron emission tomography

CT scans of the chest, abdomen, and pelvis should determine if adenopathy is present. CT scans allow visualization of the kidneys, ureters, and the hepatobiliary system.

A CT scan of the chest, abdomen, and pelvis can determine if there is abdominal or pelvic adenopathy. Positron emission tomography scanning may also be helpful in specific clinical settings, such as localized diseases or when the transformed disease is suspected.

In some cases, these organs are affected by obstruction due to lymphadenopathy or by the involvement of the parenchyma with lymphoma.

Positron emission tomography complements standard radiological tests, but only a minority of patients will be diagnosed with a more advanced stage of the disease.

After therapy, this imaging modality can distinguish between viable tumors and fibrosis in patients with residual lymphadenopathy. Still, because most cases of follicular lymphoma are not curable, such a finding may not change treatment.

This is in contrast to Hodgkin’s lymphoma and intermediate-grade lymphoma. A positive positron emission tomography scan can lead to salvage chemotherapy or radiation because the goal of treatment in these diseases is the cure.


The surgeon’s role is to obtain an adequate excisional biopsy to establish the diagnosis.

The surgeon must be instructed on the proper handling of the specimen and the special tests required. Discussing these problems with the pathologist before the biopsy is often helpful.

Pathological diagnosis from a biopsy sample

A biopsy is essential to establish a diagnosis of lymphoma. Obtain an excisional biopsy of an involved node. Note that needle aspiration is not suitable for the initial diagnosis of lymphoma.

If the disease is extranodal, a surgical biopsy sample of the affected organ should be obtained. A core biopsy may be acceptable if an excisional or incisional biopsy cannot be accepted due to location.

Bilateral posterior iliac crest bone marrow aspiration and biopsies

Although a diagnosis of follicular lymphoma can be established based on histological findings of the lymph nodes and bone marrow involvement, it can be diagnosed by morphological criteria.

Cytogenetic analysis of bone marrow cells should be performed because the t (14; 18) translocation is found in most patients with follicular lymphoma and can help establish the diagnosis.

Fluorescent in situ hybridization (FISH) testing for a t (14; 18) chromosome translocation may also be helpful.

Acquired non-random chromosomal translocations

The most common non-random chromosomal translocation in patients with follicular lymphomas is the t (14; 18) translocation, which is found in more than 80% of cases.

This chromosomal translocation brings the BCL-2 proto-oncogene under the transcriptional influence of the immunoglobulin heavy chain gene, leading to overexpression of a functionally normal BCL-2 protein.

Overexpression of the BCL-2 protein, a mitochondrial membrane protein, confers a survival advantage on cancer cells by inhibiting programmed cell death (apoptosis).

Although the exact mechanism of action of BCL-2 is unclear, its interaction with other homologs is believed to determine the likelihood that a cell will undergo apoptosis.

Detection of the t (14; 18) product by polymerase chain reaction is frequently used to diagnose and follow up patients with follicular lymphomas. However, this translocation has been detected in healthy patients and patients with other types of tumors.

Staging and classification

Most patients with follicular lymphoma are in an advanced stage, and most patients have bone marrow involvement at the time of diagnosis. Staging is as follows:

  • Phase I: one involved lymph node or lymph node area.
  • Stage II: Two or more affected lymph nodes or lymph node areas on the same side of the diaphragm.
  • Stage III: lymph nodes or affected lymph node areas on both sides of the diaphragm.
  • Stage IV: disseminated disease, such as the involvement of the bone marrow, liver, or central nervous system.

Follicular lymphoma is graded by the number of centroblasts per high-power field (HPF), as follows:

  • Grade 1 – 0-5 centroblasts for hpf.
  • Grade 2 – 6-15 centroblasts per HPF.
  • Grade 3 -> 15 centroblasts per HPF.

Grade 3 disease is subdivided into grade 3A, in which centrocytes are present, and grade 3B, follicles composed of centrocytes are present.

The 2008 World Health Organization update classifies grades 1 and 2 as low-grade follicular lymphoma, grade 3A as high-grade follicular lymphoma, and grade 3B as diffuse large B-cell lymphoma (DLBCL). ).


There is no consensus regarding the best treatment protocol. Treatment of follicular lymphoma differs depending on the stage of the disease, among other factors.

Since it grows so slowly, watchful waiting may be recommended in the early stages. Radiation therapy and chemotherapy are the most common options for treating the disease, helping to control the lymphoma rather than cure it.

Most cases of follicular lymphoma are incurable, but the average survival in the advanced stages of follicular lymphoma is about 20 years.

Several considerations must be considered, including age, stage, and prognostic scores.

Patients with advanced diseases who are asymptomatic could benefit from a watch-and-wait approach, as early treatment does not provide a survival benefit.

When patients are symptomatic, specific treatment is required, which may include various combinations of alkylating agents, nucleoside analogs, and chemotherapy regimens containing:

Anthracycline (such as CHOP, the acronym for a chemotherapy regimen), monoclonal antibodies (such as Rituximab), radioimmunotherapy, autologous (self), and allogeneic (donor) hematopoietic stem cell transplantation.

Follicular lymphoma is considered incurable unless the disease is localized, in which case it can be cured by local radiation.

However, follicular lymphoma that is CD20 negative will not benefit from Rituximab, which targets CD20.

The study ‘ Follicular lymphoma – treatment and prognostic factors ‘, published in 2012, revealed that the treatment of follicular lymphoma has improved dramatically in recent years due to the use of highly effective immunochemotherapy regimens’.

The researchers also believe that improvements in the field will continue to occur, leading to newer and more effective monoclonal antibodies, the identification of safer chemotherapy regimens, and new maintenance therapies.

Results from trials published in June 2012 show that bendamustine, a drug first developed in East Germany in the 1960s, more than doubled progression-free survival when co-administered with Rituximab.

This combination therapy also left patients with fewer side effects than the previous treatment (a combination of five drugs: Rituximab, cyclophosphamide (Cytoxan), and doxorubicin (Adriamycin), vincristine, and prednisone, collectively called R-CHOP).

There are many recent and current clinical trials for follicular lymphoma.

Post-treatment follow-up

Patients should be monitored periodically to facilitate early treatment of complications of the disease and those involving obstruction (such as biliary, ureteral, bronchial) due to increased adenopathy.


The overall 5-year survival rate is 72-77%. Recent advances and the addition of Rituximab improved median survival. Recent reports for 1986 and 2012 estimate the median survival of more than 20 years.

The overall survival rate of patients with follicular lymphoma is 72-77% at five years. The median survival was approximately 8-10 years, but it has increased further since the advent of the rituximab era.

The Follicular Lymphoma International Prognostic Index (FLIPI) is predictive of survival in patients with follicular lymphomas.

Patients who have four or more of the following adverse prognostic factors have a 10-year survival rate of approximately 36% (compared to 71% for those with one or none of these variables):

  • Age 60 years or older.
  • Ann Arbor Stage III or IV.
  • Lactate dehydrogenase (LDH) level is above the upper limit of normal at the time of diagnosis.
  • Hemoglobin less than 12g/dL.
  • Presence of more than four nodal sites of disease.


Of all cancers that involve the same class of blood cells (lymphoproliferative disorders), 22% of cases are follicular lymphomas.

Non-Hodgkin lymphoma (NHL) is the fifth most frequently diagnosed malignancy in the United States. The American Cancer Society estimates that 72,240 cases of non-Hodgkin lymphoma will be diagnosed in 2017.

Follicular lymphomas constitute approximately 20% of non-Hodgkin lymphomas. Sexual preponderance is not seen.

Age-adjusted non-Hodgkin lymphoma incidence rates are higher in more developed countries.

The incidence of follicular lymphomas increases with age; These conditions are infrequent in children, although the World Health Organization has outlined a pediatric variant.

The median age at diagnosis is 60-65 years. The age-adjusted incidence rates of non-Hodgkin lymphoma ranged from 3.7-14 cases per 100,000 person-years from 1983 to 1987 in different countries.

Variations in racial incidence are found throughout the world. The incidence of follicular lymphomas is low in China and Japan, but people of Ashkenazi Jewish descent have a higher incidence of lymphoma.

In the United States, the incidence is 2-3 times higher in white individuals than black people.

Etiology and pathophysiology

Viruses and chemicals

Viruses have been implicated as etiological factors for lymphomas, including Epstein-Barr virus (EBV), human T-cell lymphotropic virus (HTLV) type I, and herpesvirus associated with Kaposi’s sarcoma (i.e., Kaposi’s sarcoma virus). Human herpes [HHV] -8).

Hepatitis B and C viruses are also associated with lymphoma risk. However, these viruses have been mainly associated with diffuse or high-grade lymphomas.

Chemicals such as defoliants (such as Agent Orange) and hair dyes have been associated with lymphoma.

Immunodeficiency states

Congenital immunodeficiencies have been associated with lymphoma. Acquired immunodeficiencies can include infection with the human immunodeficiency virus (HIV).

Most HIV-associated lymphomas are intermediate-grade or high-grade lymphomas.

Patients who have been taking immunosuppressive medications after organ transplantation can develop lymphoma. Most of these lymphomas are diffuse or high-grade lymphomas.

Autoimmune diseases and treatments for them (such as Methotrexate) that can enable lymphomagenesis are associated with an increased risk of lymphoma.