Table of Contents
- Definition and Background
- Epidemiology of Follicular Lymphoma
- Pathogenesis of Follicular Lymphoma
- Etiology of Follicular Lymphoma
- Clinical Features of Follicular Lymphoma
- Diagnosis of Follicular Lymphoma
- Grading of Follicular Lymphoma
- Staging of Follicular Lymphoma
- Prognosis of Follicular Lymphoma
- Management of Follicular Lymphoma
- Review Questions
Definition and Background
Follicular lymphoma (FL) is a B-cell tumor and the second most common sub-type of non-Hodgkin’s lymphoma (NHL). It is characterized by slow growth (the most indolent one), and most of the patients remain asymptomatic for years before a diagnosis of FL is made.
Epidemiology of Follicular Lymphoma
The follicular lymphoma accounts for approximately 35% of all NHLs in the Unites States, with an estimated incidence of 3.18 cases per 100,000 people. The incidence increases with age and the median age is 60 years at diagnosis. It is uncommon in children and adolescents.
The incidence of FL is equal in both males and females, but it has ethnic and racial variations. The white are twice more commonly affected than the black population. The incidence of FL is low in China and Japan.
Pathogenesis of Follicular Lymphoma
The lymph nodes in follicular lymphoma have a nodular growth pattern, consisting of closely packed nodules having some variation in size and shape. With these nodules, there is a mixture of centrocytes (small to medium sized cells with elongated nuclei) and centroblasts (large cells with round or oval nuclei).
The majority of patients with FL have a chromosomal translocation, t(14;18), resulting in gene re-arrangement and an over-expression of B-cell leukemia/lymphoma 2 (BCL2) oncogene. The BCL2 oncogene blocks apoptosis (programmed cell death) leading to prolonged cell survival.
Etiology of Follicular Lymphoma
A number of risk factors have been implemented as etiologic agents for FL, but most have not been validated in independent studies. The risk factors include various immunocompromised conditions (HIV/AIDS), infections (viral, bacterial, fungal), chemical exposure (benzene, pesticides, herbicides, hair dyes, drugs, toxins), obesity and autoimmune diseases.
Clinical Features of Follicular Lymphoma
The follicular lymphoma frequently presents with chronic, painless, waxing and waning, lymphadenopathy commonly in the cervical, axillary or femoral regions. The mediastinal, hilar and abdominal lymph nodes are also often involved. Apart from enlarged lymph nodes, these patients may have the constitutional symptoms (labeled as B-symptoms), such as:
- Drenching night sweats
- Fever (>38 C)
- Unintentional weight loss (> 10% in the last six months)
The other common clinical features of FL are:
- Breathlessness, chest pain, cough
- Abdominal pain and distention
- Pain in bones
- CNS involvement
- Pallor (signs of anemia)
- Purpura, petechiae or ecchymoses (signs of thrombocytopenia)
- Palpable thyroid mass
- Abdominal mass
- Testicular mass
- Pleural effusion
- Skin lesions
Diagnosis of Follicular Lymphoma
The hallmark of the follicular lymphoma is enlarged non-tender, firm and rubbery lymph nodes. The FL is accurately diagnosed after the histopathological examination of the enlarged lymph node. About one-half of all patients have hepatosplenomegaly. The following investigations help in the diagnosis, general health status and prognosis of the patient:
- Complete blood counts (may show pancytopenia or isolated decreased blood cell lines due to bone marrow involvement)
- Quantitative analysis of immunoglobulins
- Bone marrow cytology and bone marrow histology
- LDH, β²-microglobulin
- Cytogenetics (FISH, PCR) for (14;18) in order to distinguish FL from other indolent types of NHL
- Flow cytometry: The presence of follicular dendritic cell markers (e.g., CD21, CD23) can aid in the diagnosis of FL.
- Biopsy of affected nodes; in the areas where access to the nodes is difficult, a CT needle aspiration.
- CT scan of the neck/thorax/abdomen/pelvis
- Positron emission tomography (PET) in higher grades of the malignant process
Grading of Follicular Lymphoma
The follicular lymphoma is composed of closely packed nodules having a mixture of centrocytes (small to medium sized cells) and centroblasts (large cells). The centroblasts are often in a smaller number. The World Health Organization (WHO) has classified FL into different grades on the basis of the number of centroblasts.
|1||0 – 5 centroblasts per hpf|
|2||6 – 15 centroblasts per hpf|
|3||>15 centroblasts per hpf|
Staging of Follicular Lymphoma
The follicular lymphoma is staged, like other non-Hodgkin lymphomas, by the Ann-Arbor classification.
|Involvement of a single lymph node region (I/N), or of a single or localized extra nodal site (I/E)|
|Involvement of two or more lymph node regions on the same side of the diaphragm (II/N), or involvement of an extranodal site or organ (II/E) and one or more lymph node regions on the same side of the diaphragm (II/N/E)|
|Involvement of two or more lymph node regions on both sides of the diaphragm (III/N), or involvement of localized extranodal foci and affected lymph nodes on both sides of the diaphragm (III/E or III/N/E)|
|Diffuse or disseminated involvement of one or more extralymphatic organs, with or without lymph node involvement|
Prognosis of Follicular Lymphoma
The follicular lymphoma international prognostic index is used to predict the prognosis of patients with FL. It consists of the following five risk factors:
- > 4 affected lymph node regions
- Lactate dehydrogenase > normal
- Age > 60 years
- Ann-Arbor stage III or IV
- Hemoglobin <12g/dl
The 10-year survival rate depends upon the presence of a number of these risk factors, which is given:
|Number of Risk Factors||Risk of Relapse||10-Year Survival Rate in %|
|0 – 1||Low||62 – 71|
|2||Intermediate||48 – 51|
|3 – 5||High||34 – 36|
Management of Follicular Lymphoma
Early stages I and II of FL are successfully treated with administration of radiotherapy and the patients do not require hospitalization. Rituximab as a monotherapy is another option in low-grade FL (mediate target-cell lysis).
The frontline immunochemotherapy for FL consists of:
- Alkylating agents (inhibits cell grows and proliferation)
- Antimetabolites (block the pathway required for the targeted cells)
- Anthracyclines (inhibits DNA synthesis)
- Vinca alkaloids (interferes with mitotic cycle)
- Corticosteroids (induces lymphocytic effect and alter a body`s immune reaction to the abnormal stimuli).
Bone marrow transplantation is efficient in non-advanced stages of the disease.
The correct answers can be found below the references.
1. A 67-year-old woman complains of enlarged lymph nodes in her neck and underarms. Her body temperature is 39°C, she is drowsy and sweaty and there is pallor and dryness of the skin. The patient is breathless and complains of dizziness and chest pain. The CBC reveals anemia and decreased platelets. The biopsy of the neck node indicates >15 centroblasts per HPF. Follicular lymphoma is a primary diagnosis. What stage of FL can be diagnosed in this patient according to the result of a histological examination?
- Grade 1
- Grade 2
- Grade 3
- Grade 3A
- Grade 3B
2. The highest risk of relapse of FL is in the presence of…
- 0 – 1 risk factors
- 1 – 2 risk factors
- 3 – 4 risk factors
- 5 risk factors
3. A 59-year-old white farmer was diagnosed with follicular lymphoma stage 2 a week ago. There were 13 centroblasts per HPF in the histological study of biomaterial obtained from the cervical lymph node and a CT revealed two affected nodes above the diaphragm. What is the treatment strategy for this stage of FL?
- Radiotherapy, watch and wait strategy.
- Monotherapy with Rituximab, watch and wait strategy.
- Bone marrow transplantation, watch and wait.
- Radiotherapy and further bone transplantation.
- None of the above.