Genomic alterations The serial progressions of in situ<unk>  to<unk>  and<unk>  to t-FL appear to involve the accumulation of increasing numbers of genomic alterations (i.e. chromosome abnormalities and gene mutations) in the formative B-cell precursors to these disorders. At least some of these alterations appear to cause the over-expression or under-expression of the products of genes that regulate these cells' susceptibility to develop further genomic alterations, to survive, to proliferate, and/or to spread to other tissues. In consequence, multiple B-cell clones that exhibit increasing genomic alterations and malignant behaviors populate the disorder. No single genomic alteration seems responsible for the development of each of the spectrum of<unk>  disorders. Rather, interactions between multiple genomic alterations appear to underlie this serial progression. In situ<unk>  In situ<unk>  is an accumulation of monoclonal B cells (i.e. cells descendent from a single ancestral cell) in the germinal centers of lymphoid tissue. These cells commonly bear an pathological genomic abnormality, i.e. a translocation between position 32 on the long (i.e. "q") arm of chromosome 14 and position 21 on chromosome 18's q arm. This translocation juxtaposes the B-cell<unk>  2 (BCL2) gene on chromosome 18 at position q21.33 near to the immunoglobulin heavy chain locus (IGH@) on chromosome 14 at position q21. In consequence, BCL2 overexpresses its product, BCL2 apoptosis regulator (i.e. Bcl2). Bcl2 functions to inhibit programmed cell death thereby prolonging cell survival. The overexpression of Bcl2 in the B-cells of ISFL is thought to be a critical factor in their pathological accumulation and subsequent malignant progression. Small numbers (e.g. 1 in 100,000) of circulating nucleated blood cells bearing this t(14:18)q32:q21) translocation are found in 50-67% of otherwise healthy individuals. The prevalence of this finding increases with age and years of tobacco smoking. Since most individuals with this translocation in their blood cells do not develop ISFL, the t(14:18)(q32:q21) translocation, while prolonging cell survival, must be just one step in the development of ISFN. This translocation is proposed to occur during the early development of immature bone marrow B-cells (i.e. pre-B-cells/pro-B-cells) after which these cells circulate freely and in rare cases accumulate and mature to centrocytes and/or centroblasts in the germinal centers of lymphoid follicles to form ISFL. The mechanism favoring this localization and further accumulation is unclear. Individuals with ISFL progress to<unk>  at a rate of 2-3%/year for at least the first 10 years following diagnosis. This progression likely involves the acquisition of genomic aberrations besides the t(14:18)q32:q21) translocation in the ISFL B-cells. Suspect mutations include those in the following genes: 1) EZH2 (encodes polycomb repressive complex 2 family protein which is involved in maintaining the transcriptional repressive state of various genes and is found in up to 27% of<unk>  cases); 2) CREBBP (encodes CREB-binding protein which contributes to the activation of various genes); 3) TNFSF14 (encodes tumor necrosis factor superfamily member 14, a member of the tumor necrosis factor superfamily which may function as a co-stimulatory factor for the activation of lymphoid cells); and 4) KMT2D (encodes histone-lysine N-methyltransferase 2D, a histone methyltransferase which regulates the expression of various genes). ISFL may also acquire numerous copy-number variations (i.e. duplications and deletions of a portion of a chromosome along with any of the genes contained therein) that may contribute to<unk> . In all cases, the number of genetic abnormalities acquired in the B-cells of ISFL are much less than those in<unk> .<unk>  The genomic alterations found in<unk>  include 1) the t(14:18)(q32:q21.3) translocation (85-90% of cases); 2) 1p36 deletions (i.e. deletions in the q arm of chromosome 1 at position 36, 60-70% of cases) that lead to lose of TNFAIP3 (encodes tumor necrosis factor, alpha-induced protein 3 which inhibits the activation of NF-κB, blocks cell death due to apoptosis, and regulates lymphocyte-based immune responses through its ubiquitin ligase activity); 3) mutations in PRDM1 (encodes the PR domain zinc finger protein which promotes the maturation and proliferation of B-cells); and 4) the same mutations seen in ISFL including KMT2D (85-90% of cases), CREEBP (40-65% of cases), BCL2 (40-65% of cases), and EZH2 (20-30% of cases) as well as other mutations such as those in the histone-modifying gene HIST1H1E (20-30% of cases), the RRAGC gene (~17% of cases) which regulates cell growth, survival, death, and proliferation, and, in ≤15% of cases several other genes including MEF2B, STAT6, EP300, ARID1A, SLC22A2, CARD11, FOXO1, GNA12, B2M (i.e. the gene for beta-2 microglobulin), and SGK1. Except for the t(14:18)(q32:q21.3) translocation and EZH2 mutations which lead to gains in the expression and function, respectively, of their products, the genetic alterations generally lead to a loss in the production or function of the cited genes products. However, the exact roles, if any, of these genomic abnormalities in promoting the progression of ISFL to<unk>  are unclear. Transformed<unk>  The transformation of<unk>  to a more aggressive state or other type of aggressive<unk>  is associated with: 1) primarily gene-activating mutations in CREEBP, KMT2D, STAT6, CARD11 (encoding a guanylate kinase which interacts with BCL10 and activates NF-κB to regulate cell survival); 2) changes in the expression of diverse genes; 3) the overproduction of various cell-activating cytokines and CD79B (encoding the Ig-beta protein component of the B-cell receptor); 4) gene-inactivating mutations in TNFAIP3, CD58 (encoding the cell adhesion molecule, lymphocyte function-associated antigen 3, that is involved in activating T-cells), CDKN2A (encoding p16INK4a and p14arf tumor suppressor proteins) or CDKN2B (encoding cyclin dependent kinase inhibitor 2B multiple tumor suppressor 2) (inactivation of either CDKN2 gene causes genome instability, i.e. increased frequency of other gene mutations), and TNFRSF4 (encoding one type of tumor necrosis factor receptor); and 5) gene-activating or -inactivating mutations in, or other causes for the under- or over-expression of, c-MYC ((encoding the c-Myc proto-oncogene transcription factor that regulates the expression of diverse genes many of which promote cell proliferation). Tumor environment The non-neoplastic immune and stromal cells as well as the extracellular matrix in tissues may enable neoplastic<unk>  cells to survive, proliferate, and avoid surveillance by the immune system. For example, laboratory studies show that: 1)<unk>  dendritic cells, fibroblastic reticular cells, and T helper cells provide growth and survival signals to neoplastic<unk>  B-cells; 2) neoplastic<unk>  B-cells recruit regulatory T cells that act to suppress immune responses to them; 3) the cytotoxic T-cells which normally kill neoplastic cells become dysfunctional in the presence of neoplastic<unk>  cells that are embedded in this multicellular environment; and 4) bone marrow stromal cells directly support the growth of neoplastic<unk>  cells. Reduced levels of immune-infiltration has been shown to be strongly associated with early progression of disease.
Follicular lymphoma
Indolent lymphoma
Gray zone lymphoma
Marginal zone B-cell lymphoma
Thymic carcinoma
Aggressive lymphoma
Nodal marginal zone B cell lymphoma
Mixed-cell lymphoma