Transformed follicular lymphoma
The transformation of FL to a more aggressive state or other type of aggressive lymphoma 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 follicular cells to survive, proliferate, and avoid surveillance by the immune system.
Transformed follicular lymphoma
FL progresses at a rate of 2-3% per year for at least the first 10 years after diagnosis to a more aggressive form, principally diffuse large B-cell lymphoma (~93% of cases) or Burkitt-like lymphoma (~7% of cases) or in rare cases exhibit the histology resembling precursor B-cell lymphoblastic leukemia, plasmablastic lymphoma, the high grade subtype of B-cell lymphoma, Hodgkin lymphoma of the B-cell type, chronic lymphocytic leukemia/small cell lymphcytic lymphoma, or histiocytic sarcoma. t-FL is almost always diagnosed in patients being followed for FL. These FL patients present with the: fast growth of lymph nodes; formation of extra-nodal lesions in extra-nodal sites such as the central nervous system, liver or bone; the onset of B-symptoms (i.e. fever, night sweats, weight loss); development of hypercalcemia (i.e. high serum levels of calcium); and/or sudden rises in serum levels of the enzyme lactate dehydrogenase. A minority of t-FL patients present without a history of FL. These patients generally present with advanced, bulky disease that may be accompanied by extra-nodal lesions and B-symptoms. Typically, all the various forms of t-FL are aggressive, rapidly progressive diseases with overall media survival times in treated patients of ~4.5 years. The transformation of FL to DLBCL is in over 70% of cases associated with the gain of MYC activity by genetic or non-genetic mechanisms. Diagnosis
The diagnosis of FL depends on examining involved tissues for histological, immunological, and chromosomal abnormalities that are indicative of the disease.