Follicular lymphoma

Follicular lymphoma is the most common of the indolent non-Hodgkin's lymphomas, and the second most common form of non-Hodgkin's lymphomas overall. It is defined as a lymphoma of follicle center B-cells (centrocytes and centroblasts), which has at least a partially follicular pattern. It is positive for the B-cell markers CD10, CD19, CD20, and CD22 but almost always negative for CD5.

There are several synonymous and obsolete terms for this disease, such as CB/CC lymphoma (Centroblastic and Centrocytic lymphoma), nodular lymphoma and Brill-Symmers Disease.

Morphology
The tumor is composed of follicles containing a mixture of centrocytes (WHO nomenclature) or cleaved follicle center cells (older American nomenclature), "small cells", and centroblasts (WHO nomenclature) or large noncleaved follicle center cells (older American nomenclature), "large cells". These follicles are surrounded by non-malignant cells, mostly T-cells. In the follicles, centrocytes typically predominate; centroblasts are usually in minority.

Grading
According to the WHO criteria, the disease is morphologically graded into:
 * grade 1 (<5 centroblasts per high-power field (hpf))
 * grade 2 (6–15 centroblasts/hpf)
 * grade 3 (>15 centroblasts/hpf).

Grade 3 is further subdivided into:
 * grade 3a (centrocytes still present)
 * grade 3b (the follicles consist almost entirely of centroblasts)

The clinical relevance of this grading system is still being debated; Grades 1 and 2 are considered to be indolent or slow growth tumors while grades 3a and 3b are classified as intermediate growth. Occasional cases may show plasmacytoid differentiation or foci of marginal zone or monocytoid B-cells.

Causes
A translocation between chromosome 14 and 18 results in the overexpression of the bcl-2 gene. As the bcl-2 protein is normally involved in preventing apoptosis, cells with an overexpression of this protein are basically immortal. The bcl-2 gene is normally found on chromosome 18, and the translocation moves the gene near to the site of the immunoglobulin heavy chain enhancer element on chromosome 14.

Translocations of BCL6 at 3q27 can also be involved.

Treatment
There is no consensus regarding the best treatment protocol. Several considerations should be taken into account including age, stage and prognostic scores. Patients with advanced disease who are asymptomatic might benefit of a watch and wait approach as early treatment does not provide survival benefit. When patients are symptomatic, specific treatment is required which might include various combinations of alkylators, nucleoside analogues, anthracycline-containing regimens (e.g. CHOP) monoclonal antibodies (rituximab), radioimmunotherapy, autologous and allogeneic hematopoietic stem cell transplantation. The disease is regarded as incurable (although allogeneic stem cell transplantation may be curative, the mortality from the procedure is too high to be a first line option). The exception is localized disease, which can be cured by local irradiation.

Personalised idiotype vaccines have shown great promise, but has still to prove its efficacy in randomized clinical trials.

In 2010 Rituximab was approved by the EC for first-line maintenance treatment of follicular lymphoma.

There are a large number of recent and current clinical trials for FL.

Prognosis
Median survival is around 10 years, but the range is wide, from less than one year, to more than 20 years. Some patients may never need treatment. The overall survival rate at 5 years is 72-77%.

Epidemiology
Of all cancers involving the same class of blood cell, 22% of cases are follicular lymphomas.