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^[1] but almost always negative for CD5.^[2]

Follicular lymphoma
Specialty	Oncology

There are several synonymous and obsolete terms for this disease, such as CB/CC lymphoma (Centroblastic and Centrocytic lymphoma), nodular lymphoma^[3] and Brill-Symmers Disease.

The tumor is composed of follicles containing a mixture of centrocytes (Kiel nomenclature adopted by WHO experts) or cleaved follicle center cells (older American nomenclature), "small cells", and centroblasts (Kiel nomenclature adopted by WHO experts) 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.

According to the WHO criteria, the disease is morphologically graded into:^[4]

• 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 WHO 2008 updates is classifying grades 1 & 2 now as low grade follicular lymphoma, grade 3A as high grade follicular lymphoma, and grade 3B as Diffuse Large B Cell Lymphoma (DLBCL).

A translocation between chromosome 14 and 18 results in the overexpression of the bcl-2 gene.^[5] 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.^[6]

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 from a watch and wait approach as early treatment does not provide survival benefit.^[7][8] 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 promise, but have still to prove their efficacy in randomized clinical trials.^[9]

In 2010 Rituximab was approved by the EC for first-line maintenance treatment of follicular lymphoma.^[10] Pre-clinical evidence suggests that rituximab could be also used in combination with integrin inhibitors to overcome the resistance to rituximab mediated by stromal cells .^[11]

Trial results released in June 2012 show that bendamustine, a drug first developed in East Germany in the 1960s, more than doubled disease progression-free survival when given along with rituximab. The combination also left patients with fewer side effects than the older treatment (a combination of five drugs—rituximab, cyclophosphamide (Cytoxan), doxorubicin (Adriamycin), vincristine and prednisone, collectively called R-CHOP).^[12]

There are a large number of recent and current clinical trials for FL.^[13]

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%.^[14]

Recently, it was described that short non-coding RNAs named microRNAs (miRNAs) have important functions in lymphoma biology, including follicular lymphoma. In malignant B cells miRNAs participate in pathways fundamental to B cell development like B cell receptor (BCR) signalling, B cell migration/adhesion, cell-cell interactions in immune niches, and the production and class-switching of immunoglobulins. ^[15] MiRNAs influence B cell maturation, generation of pre-, marginal zone, follicular, B1, plasma and memory B cells. ^[16]

Of all cancers involving the same class of blood cell, 22% of cases are follicular lymphomas.^[17]

• List of hematologic conditions

• Online Resource Community for Follicular Lymphoma.
• Resource page for follicular lymphoma