Follicular lymphoma pathophysiology

Genes involved in the pathogenesis of follicular lymphoma include BCL-2 and BCL-6. The most common cause is reciprocal translocation t(14;18)(q32;q21). The progression to follicular lymphoma involves microRNAs (miRNAs). On microscopic histopathological analysis, centrocytes, centroblasts along with various non-neoplastic cells including T cells, follicular dendritic cells, and macrophages are the characteristic findings of follicular lymphoma.

• Follicular helper T cells (Tfh) are specialized helper T-cells that are predominantly located in germinal centers along with B-cells.^[1][2]

• Follicular lymphoma is the second most common non-Hodgkin lymphoma.^[3].
• The disease is characterized by the clonal proliferation of neoplastic lymphoid cells that share morphological, immunophenotypic and molecular genetic attributes of germinal center B-cells.
• The development of follicular lymphoma tumors in adults is dependent upon the overexpression of B-cell leukemia/lymphoma 2 (BCL-2) located on chromosome band 18q21.
• BCL-2 is an oncogene that blocks programmed cell death (apoptosis). As such, overexpression results in prolonged cell survival.
• These tumors contain a mixture of neoplastic centrocytes and centroblasts along with various non-neoplastic cells including T-cells, follicular dendritic cells, and macrophages.
• Follicular lymphoma can be designated as low grade (1 and 2) or higher grade (3A and 3B) disease, depending on the number of centroblasts per high-power field.

• The most common cause is reciprocal translocation between (14;18)(q32;q21) in 80-85% of cases.^[4]

• This somatic rearrangement is initiated within the bone marrow during B-cell lymphopoiesis and results from immunoglobulin heavy chain gene (IGH) rearrangement.
• The t(14;18) translocation leads to placement of the B cell lymphoma 2 (BCL2) gene under the influence of transcriptional enhancers associated with IGH, resulting in overexpression of anti-apoptotic BCL2 leading to increased cell survival and uncontrolled cell proliferation in germinal centers.^[5][6][7]
• BCL2, along with other anti-apoptotic proteins, inhibits apoptosis by binding and neutralizing activated pro-apoptotic proteins including the mitochondrial outer membrane permeabilizers BAX and BAK, as well as the intracellular stress sensors which activate BAX and BAK.
• Mutations in chromatin-modifying genes occur, affecting histone methyltransferases, histone acetyltransferases or histone linker proteins.
• These mutations act to promote increased proliferation of B cells.
• Genes encoding components of vacuolar H+-ATPase, or RRAGC, a guanine nucleotide binding protein, regulate the mTOR activation.
• Mutations in these genes upregulate mTOR (mammalian target of rapamycin) signaling in FL cells. These mutations are found in approximately 15 to 20 percent of cases.
• Upregulated mTOR directs many cellular processes including growth, differentiation, survival, and adhesion or cellular migration, and resulting in follicular lymphoma development.
• KMT2D, CREBBP, EZH2, EP300, HIST1H1E, KMT2C, ARID1A, and SMARCA4 are some of the other genomes which undergo mutations in very few cases.
• The tumor microenvironment comprised of T cells and dendritic cells may influence the development and progression of Follicular lymphoma.
• Communication between the tumor cells and the microenvironment involves chemokines, chemokine receptors, and adhesion molecules, the balance of which determines whether there is tumor cell growth promotion or inhibition.
• MicroRNA expression- short non-coding RNAs named microRNAs (miRNAs) have important functions in follicular lymphoma biology.^[8]
• In malignant B cells, miRNAs participate in pathways fundamental to B cell development like:
  • B cell receptor (BCR) signaling
  • B cell migration/adhesion, cell-cell interactions in immune complexes.
  • The production and class-switching of immunoglobulins.^[9]

• miRNAs influence B cell maturation, generation of pre marginal zone, follicular, B1, plasma and memory B cells.^[9]
• It is positive for the B-cell markers CD10, CD19, CD22, and usually CD20.^[10]

• A translocation between chromosome 14 and 18 results in the overexpression of the BCL-2 gene.^[11][12]
• 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.^[13]

The tumor is composed of follicles containing a mixture of the following^[14]:

• Centrocytes (small cleaved cells without nucleoli)
• Centroblasts (larger noncleaved cells with moderate cytoplasm, open chromatin, and multiple nucleoli)
• These follicles are surrounded by non-malignant cells, mostly T-cells.

Within the follicles, centrocytes typically predominate; centroblasts are usually scarce.

According to the WHO criteria, the disease is morphologically graded into:^[15]

• Grade 1 (<5 centroblasts per high-power field (hpf))
• Grade 2 (6–15 centroblasts/hpf)
• Grade 3 (>15 centroblasts/hpf)

• Grade 3A (centrocytes still present)
• Grade 3B (the follicles consist almost entirely of centroblasts)

The WHO 2008 update provided the following grading for follicular lymphoma:

• Grades 1 and 2 now as low-grade follicular lymphoma
• Grade 3A as high-grade follicular lymphoma
• Grade 3B as diffuse large B Cell lymphoma