Фолликулярлық лимфома: себептері, белгілері және дамуы

Follicular lymphoma (FL) is a cancer that involves certain types of white blood cells known as lymphocytes. The cancer originates from the uncontrolled division of specific types of B cells known as centrocytes and centroblasts. These cells normally occupy the follicles (nodular swirls of various types of lymphocytes) in the germinal centers of lymphoid tissues such as lymph nodes. The cancerous cells in FL typically form follicular or follicle like structures (see adjacent Figure) in the tissues they invade. These structures are usually the dominant histological feature of this cancer. There are several synonymous and obsolete terms for FL such as CB/CC lymphoma (centroblastic and centrocytic lymphoma), nodular lymphoma, Brill Symmers Disease, and the subtype designation, follicular large cell lymphoma. In the US and Europe, this disease is the second most common form of non Hodgkin's lymphomas, exceeded only by diffuse large B cell lymphoma. FL accounts for 10–20% of non Hodgkin's lymphomas with ~15,000 new cases of it being newly diagnosed each year in the US and Europe. Recent studies indicate that FL is similarly prevalent in Japan. FL is a broad and extremely complex clinical entity with a wide range of manifestations which have not yet been fully systematized. It is commonly preceded by a benign precancerous disorder in which abnormal centrocytes and/or centroblasts accumulate in lymphoid tissue. They may then circulate in the blood to cause an asymptomatic condition termed in situ lymphoid neoplasia of the follicular lymphoma type (i. e. ISFL). A small percentage of these cases progress to FL. Most commonly, however, FL presents as a swelling of lymph nodes in the neck, armpits, and/or groin. Less often, it presents as a gastrointestinal tract cancer, a cancer in children involving lymphoid tissues of the head and neck area (e. g. tonsils), or one or more masses in non lymphoid tissues such as the testes. FL typically has a slow disease course which persists essentially unchanged for years. of FL cases progress to a highly aggressive form often termed stage 3B FL, to an aggressive diffuse large B cell lymphoma, or to another type of aggressive B cell cancer. These transformed follicular lymphomas (t FL) are essentially incurable.

The serial progressions of in situ FL to FL and FL 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 FL disorders. Rather, interactions between multiple genomic alterations appear to underlie this serial progression. 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. Individuals with ISFL progress to FL at a rate of 2–3%/year for at least the first 10 years following diagnosis. and is found in up to 27% of FL cases);); 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 FL. In all cases, the number of genetic abnormalities acquired in the B cells of ISFL are much less than those in FL. ); 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 FL are unclear.

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).

FL is commonly preceded by but uncommonly progresses to ISFL, an asymptomatic disorder that usually is discovered in tissues which are biopsied for other reasons. FL lymphoma may be diagnosed in the uncommon cases in which individuals with ISFL are found to have FL on follow up examinations. or other sites in individuals (median age 65) without a known history of ISFL or abnormal numbers of circulating t(14:18)q32:q21 conatianing lymphocytes. However, a subset of PGTFL cases had lesions that were localized to the duodenum and other parts of the small intestine usually without involving other parts of the GI tract or tissues outside of the GI tract. This contrasts with the other cases of PGTFL which were systemic diseases involving a wide range of GI tract and non GI tract tissues. Consequently, the World Health Organization (2017) removed the localized disease from the primary gastrointestinal tract follicular lymphoma category, reclassified it as a distinct disease entity, and termed it duodenal type follicular lymphoma. In one review of former studies, the lesions in 85% of primary duodenal follicular lymphoma were located not only in the duodenum but also other sites in the intestine (i. e. jejunum and/or ileum), or cecum PDF is an indolent disease that may spontaneously remit and relapse but only rarely progresses to a more aggressive form. A watch and wait strategy has been a generally recommended method for the initial treatment of the disease.

PGTFL is a follicular lymphoma (which as currently defined excludes cases of duodenal type follicular lymphoma) that has a prominent component of GI tract involvement. The disease may present with signs and symptoms typical of the common type of follicular lymphoma. For example, enlargement of lymph nodes in the neck, armpit, groin, PGTFL is generally treated like cases of common follicular lymphoma: depending on the severity of the disease and its symptoms, patients are treated with watchful waiting, surgery, chemotherapy, radiation, immunotherapy plus radiotherapy, or combinations of these modalities. The disorder was recently defined by the World Health Organization (2016) as a distinct entity that occurs mostly in males Currently, however, patients who had exhibited or are exhibiting involvement of areas or tissues outside of the head, neck, armpit, or groin areas are now regarded as far more likely to have a newly and provisionally defined disease, large B cell lymphoma with IRF4 rearrangement. and the MAP2K1 gene (10–40% of cases), which regulates activation of the ERK cell signaling pathway. More than 2 dozen other genes have been reported to be mutated in rare cases of PTFL but in general the genetic abnormalities found in this disorder are fewer and less complex than those in other types of FL. but also has been reported in 5 adults. PFLT differs from cases of typical follicular lymphoma that involve the testis in that it more often occurs in children and adolescents; involves malignant B cells that do have the t(14:18)q32:q21) translocation; and presents with disease that is strictly limited to the testis. While similar to pediatric type follicular lymphoma in not involving cells that bear the t(14:18)q32:q21) translocation, PFLT differs from the former disease in that it is limited to the testis and involves malignant cells that do not express Bcl2. PFTL is an extremely indolent disease which is manifested by lesions that exhibit a typical FL histology or, more commonly, a mixed FL diffuse large cell lymphoma histology. It usually involves a 2–4 centimeter lesion in a single testicle. Patients have been treated with removal of the involved testes followed by various standard anti lymphoma chemotherapy regimens to attain excellent results, i. e. 100% completed remissions with no recurrence of disease in 15 child and adolescent patients observed for 4–96 months. No cases of primary follicular lymphoma of the testis have been reported to progress to t FL. Surgery followed by less strenuous or even no chemotherapy may prove to be the optimal treatment for this disease.