<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Follicular lymphoma and explain in detail? [/INST] 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-Hodgkins lymphomas, exceeded only by diffuse large B-cell lymphoma. FL accounts for 10-20% of non-Hodgkins 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. However, each year 2-3% 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. However, recent advancements in the treatment of t-FL (e.g. the addition to standard chemotherapy of agents such as rituximab) have improved overall survival times. These newer regimens may also delay the transformation of FL to t-FL. Additional advances in understanding FL may lead to further improvements in treating the disease.

Pathophysiology
Genomic alterations
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.

In situ follicular lymphoma
In situ follicular lymphoma 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 a 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 18s q arm. This translocation juxtaposes the B-cell lymphoma 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 FL 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 FL 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 FL. In all cases, the number of genetic abnormalities acquired in the B-cells of ISFL are much less than those in FL.

Follicular lymphoma
The genomic alterations found in FL 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 FL are unclear.

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. For example, laboratory studies show that: 1) follicular dendritic cells, fibroblastic reticular cells, and T helper cells provide growth and survival signals to neoplastic follicular B-cells; 2) neoplastic follicular 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 follicular cells that are embedded in this multicellular environment; and 4) bone marrow stromal cells directly support the growth of neoplastic follicular cells. Reduced levels of immune-infiltration has been shown to be strongly associated with early progression of disease.

Presentation and course
In situ follicular lymphoma
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. Similarly, individuals with >1 in 10,000 circulating lymphocytes containing the t(14:18)q32:q21) translocation are at increased but still small risk of developing FL and being diagnosed as having FL on follow up examinations.

Follicular lymphoma
FL commonly presents as an otherwise asymptomatic enlargement of lymph nodes in the neck, armpit, groin, femoral canal, 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. These enlargements may have been present for months to years and during this time waxed and waned in size. Less commonly, FL presents as extra-nodal masses in the skin, thyroid gland, salivary gland, breast, testicles. spleen, liver, and/or lung. Regardless of the type of presentation, FL is usually (~80% of cases) at an advanced stage at diagnosis as indicated by involvement of the bone marrow (50% to 70% of cases), multiple lymph nodes in different parts of the body, and/or other tissues. A minority (<33%) of FL patients present with B symptoms, i.e. recurrent unexplained fevers, recurrent night sweats, and/or weight loss ≥10% in the past 6 months. Generally, the disease has an indolent and prolonged course with a median life expectancy of 15–20 years: a large percentage of patients die from other causes than their FL disease. However, each year, including the early years after diagnosis, some 2-3% of FL cases transform to t-FL; Median survival has been ~4.5 years after the onset of this transformation.There are less common subtypes of FL that differ not only in their presentation but also in their histopathology, genetic abnormalities, and course. These subtypes, which are now (i.e. primary gastrointestinal tract FL) or may in the future (pediatric-type FL) be considered distinctive diseases, are:

Duodenal-type follicular lymphoma
Duodenal-type follicular lymphoma (DFL) was initially considered to be a type of Primary gastrointestinal tract (GI tract) follicular lymphoma (PGTFL), i.e. a follicular lymphoma in which GI tract lesions were prominent parts of the disease. 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. DFL is most often an asymptomatic disease that is diagnosed on endoscopic examination of the GI tract conducted for other reasons. Less commonly, it presents with vague abdominal symptoms. 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), with rare cases having lesions in the rectum 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.

Primary gastrointestinal tract follicular lymphoma
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,  femoral canal, and/or other areas, and/or signs and symptoms of GI tract disease due to lesions in the stomach, small intestine, large intestine or rectum may be seen. These signs and symptoms may include abdominal pain, bowel obstruction, persistent nausea and vomiting, hematochezia (i.e. passage of fresh blood usually on feces through the rectum), or melena (i.e. passage of tarry feces containing blood that has been digested in the stomach or upper intestine). 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.

Predominantly diffuse follicular lymphoma with 1p36 deletion
Predominantly diffuse follicular lymphoma with 1p36 deletion is a rare subtype of FL in which involved lymph nodes show infiltrations of centrocytes and centoblasts that generally do not form the nodular, swirling patterns characteristic of most types of FL. In addition, these cells lack the t(14:18)(q32:q21.3) translocation commonly found in other FL types but, similar to many FL cases, have a deletion in the terminal part of the short (i.e. "p") arm of chromosome 1 that encodes the TNFRSF14 gene (see pathophysiology section). Predominantly diffuse follicular lymphoma with 1p36 deletion usually presents with bulky enlargements of inguinal (i.e. groin) lymph nodes but may present with enlargements of the axillary (i.e. armpit) or cervical (i.e., neck) lymph nodes. In rare cases, there may be involvement of the bone marrow. In spite of the evidence of bulky and disseminated disease, predominantly diffuse follicular lymphoma with 1p36 deletion appears to be an indolent disorder that may require long-term observation rather than overtreatment.

Pediatric-type follicular lymphoma
Pediatric-type follicular lymphoma (PTFL) was initially reported to occur in children ages 1–17 years old (median age ~13-14) but more recently has been reported to occur in adults. The disorder was recently defined by the World Health Organization (2016) as a distinct entity that occurs mostly in males and involves swollen lymph nodes in the head (including tonsils and adenoids), neck, or, rarely, axillary, or inguinal areas, or non-lymphoid tissues. 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.The lesions in PTFL consists of infiltrates containing rapidly proliferating centrocytes and centroblasts that lack the t(14:18)(q32:q21.3) translocation but nonetheless often overexpress the BCL2 gene. These cells may show a loss of heterozygosity at 1p36 (20-50% of cases) that results in decreased expression of the TNFRSF14 gene (see Pathophysiology section) as well as mutations in the IRF8 (10-50% of cases), which contributes to the development and function of B cells, 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. PTFL has an indolent, relapsing and remitting course with a 5-year survival rate of >95%. Patients diagnosed with PTFL have been treated with chemotherapy, surgery, and combinations of these treatments. In general, these patients did well (100% survival with <5% of cases relapsing regardless of treatment modality). More recently, 36 patients have been treated with surgical resection alone followed by observation; all these patients survived with only one having a relapse. Thus, PTFL appears to be a highly indolent type of FL in which multiple studies have reported overall and progression-free survival rates of 100% and >90%, respectively, for >2 years and an estimated probability of 5-year event-free survival rate of ~96%. The therapeutic regimens versus follow-up observations that best treat this disorder in children, adolescents, and adults (adults may require different treatments than children and adolescents) requires further study.

Primary follicular lymphoma of the testis
Primary follicular lymphoma of the testis (PFLT), also termed testicular follicular lymphoma, was classified as a distinct form of FL by the World Health Organization in 2016. It is an extremely rare disease that has been recognized as occurring primarily in children and adolescents 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.

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. FL usually involves enlarged lymph nodes populated by abnormal follicles (see adjacent picture) that when examined histologically contain a mixture of centrocytes or centroblast surrounded by non-malignant cells, mostly T-cells. The centrocytes, which typically outnumber centroblasts, are small to medium-sized B-cell lymphocytes that characteristically exhibit cleaved nuclei; the centropblasts are larger B-cell lymphocytes without cleaved nuclei. Rare cases of FL may show lesions that contain tissue infiltrations dominated by B-cells with features of precursor (i.e. "blast") cells, monocytes, or malignant mantle cells such as those found in mantle cell lymphoma. Immunochemical analyses reveal that these cells generally express B-cell surface markers including the CD10 (60% of cases), CD20, CD19, CD22, and CD79 but not CD5, CD11c, or CD23 cell surface proteins; genomic analyses reveal that these cells contain t(14:18)(q32:q21.3) translocation (85-90% of cases), 1p36 deletions (60-70% of cases), and with far less frequency the other genomic abnormalities listed in the above sections on Pathophysiology and Presentation and course. None of these protein markers or genomic abnormalities are diagnostic for FL, e.g. the t(14:18)(q32:q21.3) translocation is found in 30% of diffuse large B-cell lymphoma and in a small number of reactive benign lymph nodes. Rather, the diagnosis is made by a combination of histological, immunological, and genomic abnormalities. According to World Health Organization (WHO) criteria, differences in the microscopically determined morphology of these tissues can be used to diagnose and categorized FL into the following 3 Grades with grade 3 having A and B subtypes:

Grade 1: follicles have <5 centroblasts per high-power field (hpf).
Grade 2: follicles have 6 to 15 centroblasts per hpf.
Grade 3: follicles have >15 centroblasts per hpf.
Grade 3A: Grade 3 in which the follicles contain predominantly centrocytes.
Grade 3B: Grade 3 in which the follicles consist almost entirely of centroblasts.Grades 1 and 2 are regarded as low grade FL; Grade 3A is usually also regarded as low grade FL although some studies have regarded it as high grade FL; and Grade 3B is regarded as a highly aggressive FL in the t-FL category.In addition to grade 3B disease, histologic examinations may reveal other evidence of t-FL such as histologic findings consistent with FL and diffuse large cell lymphoma in the same tissue (referred to as composite lymphomas) or in separate tissues (referred to as (discordant lymphomas) or histologic findings similar to those found in Burkitt lymphoma, 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 lymphocytic lymphoma, or histiocytic sarcoma. Other findings indicating the presence of this transformation include rapid growth in size of lymph nodes, recently acquired or new B symptoms, recent development of FL lesions in non-nodal tissue, rapid rises in serum lactate dehydrogenase levels, and the presence of high levels of serum calcium.

Differential diagnosis
FL may be confused with marginal zone B-cell lymphoma, mantle cell lymphoma, and the small lymphocytic lymphoma variant of chronic lymphocytic leukemia. The malignant cells in marginal zone B-cell lymphoma may form follicular structures but commonly proliferate in the marginal zone rather than germinal center of lymphoid tissues. These malignant cells often show features of monocytes or plasma cells. Mantle cell lymphomas show monotonous, medium-sized lymphocytes, monocytes, and atrophied germinal centers; unlike FL, the malignant lymphocytes in this disease are positive for Cyclin D1 by immunohistochemistry staining. Small lymphocytic lymphomas are composed of nodular structures with small- to medium-sized malignant cells surrounding immature lymphocytes and immunoblasts. The malignant cells in this disease, unlike FL, stain positive for CD5 and CD23.

Treatment and prognosis
FL is typically a slowly growing lymphoma with an overall median life expectancy for treated patients of 10–15 years with many cases of it waxing and waning in the size of their lesions and rare cases of it remitting spontaneously. These considerations favor the use of observation over intervention in patients whose particular form of FL has a favorable prognosis or who are intolerant to aggressive treatments. However, most cases of FL have a less favorable prognosis at some stage of their disease and will therefore require intervention. There is little consensus regarding the guidelines to be used to define the prognosis and treatment for FL at its presentation or during its course.. Currently used indicators for this include the diseases: 1) histology; 2) subtype; 3) predicted indolence and potential for transformation; and 4) extent of disease as measured by clinical examinations, bone marrow biopsy to determine bone marrow involvement, and PET/CT imaging of the chest, abdomen, pelvis, and any areas outside of these regions if physical examination suggests involvement. Some suggested guidelines using these parameters to indicate the prognosis and need for treatment in FL include:
The WHO criteria using histological grade (see previous section): Patients with Grades 1, 2, and 3A disease are predicted to have the same low risk prognosis that is seen in cases of typical FL while patients with grade 3B disease are predicted to have the high risk prognosis typical of t-FL.
The Follicular Lymphoma International Prognostic Index (FLIPI): FLIPI uses the following criteria: age ≥60 years; Ann Arbor disease stage III (i.e. lesions located both above and below the thoracic diaphragm) or IV (i.e. disseminated lesions involving one or more non-lymphatic organs); blood hemoglobin <12 gram/deciliter; serum lactose dehydrogenase level above normal; and involvement of >4 lymph nodes. Patients positive for 0–1, 2, or ≥3 of these factors are classified as in low, intermediate, and high risk group, respectively, and after treatment with regimens that include rituximab have 2 year predicted progression free survivals of 84, 72, and 65%, respectively, and overall survivals of 98, 94, and 87%, respectively.
The FLIP2 index. This modification of FLIP1 uses age ≥60; blood hemoglobin <12 gram/deciliter; serum lactose dehydrogenase level above normal; serum beta-2 microglobulin level above normal; ≥1 lymph node with a diameter >6 centimeters; and bone marrow involvement. The predicted percentage of therapy-treated patients with progression free survival at 5 years for individuals positive for 0, 1–2, and ≥3 of these factors are 80, 51, and 19%, respectively.
CT/PET imaging: This method measures total body tumor volume as detected by tissue uptake of radioactive fludeoxyglucose (F18). Progression free and overall survival at 5 years for patients with estimated tumor volumes above versus below 510 cubic centimeters are reported to be 32.7 and 84.8% versus 65.1 and 94.7%, respectively.
Lugano staging: this method classifies Stage I disease as involving a single lymphatic region or extra-lymphatic site; Stage II disease as involving ≥2 lymphatic sites or 1 lymphatic site plus 1 extralympatic site with all lesions being on the same side of the diaphragm; Stage III disease as involving ≥2 lymphatic regions that are on opposite sides of the diaphragm; and Stage IV disease as disseminated lesions that are found to be in ≥1 non-lymphatic organs.
Response-based prognosis: FL patients whose disease progresses within 24 months of initiating treatment with chemotherapy and immunotherapy versus patients whose disease does not progress within 24 months are predicted to have 5 year survival rates of 50-74% versus ~90%, respectively.The prognosis and treatment for the specific presentations of typical FL cases (see above sections for the prognoses and treatment recommendations for primary gastrointestinal tract FL, predominantly diffuse FL with 1p36 deletion, pediatric-type FL, and primary FL of the testis) that are in common use are as follows:

In situ follicular lymphoma
ISFL is a benign condition that may be reevaluated periodically to detect the rare cases of it which progress to FL; otherwise ISFL is not treated.

Localized follicular lymphoma
In 10-20% of cases, FL appears limited to single radiation field, does not involve the bone marrow, and is therefore regarded as localized early-stage FL. In these cases, which are sometimes classified as Ann Arbor stage I (i.e. disease limited to a single restricted region) or stage II (i.e. disease restricted to two sites that are on the same side of the diaphragm), radiation therapy achieves 10 year overall survival rates of 60-80% and median overall survival times of 19 years. It seems likely that many of the relapses in these cases are due to undetected disease outside of the radiation field at the time of radiation treatment. The use of PET/CT imaging is strongly recommended to insure that the FL is localized. In any case, the excellent results achieved with radiation therapy strongly support its use in localized disease. The use of an immunotherapeutic agent such as Rituximab alone or in combination with a chemotherapeutic regimen such as CVP (i.e. cyclophosphamide, vincristine, prednisone and rituximab) in cases of localized, early-stage disease may be appropriate choices for some of these early-stage patients. However, the latter approach is recommended for cases of localized disease in which the disease extends beyond a single field: 56% of patients treated in this manner had progression-free survival at 10 years while patients treated with other regimens had progression free survivals of 41%. Nonetheless, overall survival did not differ between the two groups.

Asymptomatic follicular lymphoma
Patients with asymptomatic but not localized low grade FL, gastrointestinal tract FL, and pediatric-type follicular lymphoma have been served by careful follow-up without therapeutic intervention. Even high grade, aggressive, relapsed, or transformed FL may also be served with observation in patients who are asymptomatic. Findings in asymptomatic patients who have been recommended as triggers for starting treatment include one or more of the following: tumor size ≥7 cm in diameter; involvement of ≥3 nodes in 3 distinct areas, each of which is ≥3 cm in diameter; organ compression; presence of ascites or pleural effusion (i.e. build-up of fluid in the abdominal or pleural cavities); poor performance status due to the disease; elevated levels of serum lactose dehydrogenase or beta-2 microglobulin; presence of localized bone lesions; kidney involvement; reduced levels of circulating blood platelets or any of the various types of white blood cells; onset of significant pruritus (i.e. itching sensation) or other B symptoms; and enlargement (i.e. ≥50% increase in size over a period of at least 6 months) of lymph nodes, spleen, or other follicular lymphoma-infiltrated organs or tissues.

Symptomatic follicular lymphoma
Symptomatic FL requires treatments directed at relieving symptoms by reducing the load of tumor cells. Various chemotherapeutic regimens have been used for this including combinations of alkylating antineoplastic agents, nucleoside analogues, and/or anthracyclines. Two commonly used chemotherapeutic regimens are CVP (see Localized FL section) and CHOP (i.e. CVP plus the anthracycline adriamycin). Newer agents used to treat FL include monoclonal antibodies such as rituximab, obinutuzumab, galiximab, inotuzumab ozogamicin, or epratuzumab and immunomodulators such as lenalidomide and interferon. The latter medications have been used in combination or alone to treat symptomatic FL. Most such regimens add rituximab (a monoclonal antibody which binds and thereby kills the CD20 cell surface protein on B cells) with CVP or CHOP regimens (termed R-CVP and R-CHOP regimens).
The R-CHOP regimen appears superior to the R-CVP regimen with, for example, one study finding 8-year progression-free survival rates of 57% versus 46% for the two respective regimens. More recently, FL patients have been treated with other regimens including: 1) rituximab combined with the chemotherapeutic alkylating agent bendamustine; 2) rituximab combined with the chemotherapeutic agent fludarabine and the inhibitor of Type II topoisomerase, mitoxantrone; and 3) rituximab combined with another immunotherapeutic agent such as galiximab, epratuzumab (monoclonal antibodies directed respectively against the CD80 or CD22 cell surface proteins on immune cells including B cells), or the immunomodulating medication, lenalidomide. While it is too soon to judge the long-term results of the latter regimens, the regimens have shown similar results when analyzed based on poor treatment responses (~10-20% poor responses). Bendamustine with rituximab may be preferable to R-CHOP or R-CVP for treating low-grade (i.e. Grades 1, 2, and possibly 3A) FL; R-CHOP may be preferred in FL that has high-risk characteristics (e.g. high levels of Beta-2 macroglobulin or bone marrow involvement). The combination of lenalidomide with rituximab has shown good potential in treating indolent cases of FL.Studies indicate that maintenance therapy with rituximab following successful induction therapy prolongs progression-free survival; for example one study found progression-free survival after 6 years of treatment was 59.2% in patients treated with rituximab maintenance and 42.7% without this maintenance; however, overall survival at 6 years was similar in the two groups, 87.4% and 88.7%, respectively. Another study found that prolonged maintenance with rituximab did not have any benefits over an eight-month maintenance period. Finally, surgery and radiation are additional therapies that can be used to relieve symptoms caused by bulky t-FL disease or to treat lesions in patients who cannot withstand other types of treatment.

Transformed follicular lymphoma
Early studies on treating t-FL with various purely chemotherapy regimens gave poor results with median overall survival times of 1–2 years. However, the addition of rituximab to the regimens such as CVP and CHOP as part of induction and maintenance therapies (i.e. R-CVP and R-CHOP) greatly improved overall 5 year survival to rates of 73%. The R-CHOP regimen is a good option for treating such cases. However, these regimens need not be started in people with FL who are asymptomatic and have low tumor burdens: the outcomes in such patients show no difference between early versus delayed treatment. Some recent studies found that the use of rituximab in combination with bendamustine (i.e. the RB regimen) provided better results than R-CHOP: progression-free survival times in one study were 69.5 months for RB and 31.2 months for R-CHOP. Similar results were obtained when RB was compared to R-CVP. These studies also found no overall survival time benefit between the RB and R-CHOP regimens. Other recently examined regimens include 1) the use of obinutuzumab instead of rituximab in the R-CHOP and R-CVP regiments to attain progression-free survival rates at 3 years of 80% for the obinutuzumab-chemotherapy regimen versus 73% for the rituximab-chemotherapy regimen and 2) the combination of rituximab with lenalidomide (no chemotherapy agent) versus various chemotherapy plus immunotherapy (principally rituximab) to achieve similar complete remission and 3 year progression-free survival rates but with rituximab plus lenalidomide causing less toxicity (i.e. severe neutropenia). Many of these studies did use rituximab maintenance therapy after induction therapy.

Prevention
Several studies, while not conclusive, suggest that the early treatment of low risk FL reduces the incidence of the disease progressing to t-FL. The treatments used in these studies include chemotherapy, radiation therapy, and immunotherapy combinations plus rituximab maintenance therapy.

Relapsed follicular lymphoma
Patients who relapse after initial therapy for FL may be followed closely without therapy if asymptomatic. When treatment is required, patients may be treated with the initial treatment regimen when such treatment led to a remission that lasted for at least one year; otherwise an alternative regimen is used. The regimens commonly used in relapsed lymphoma include R-CHOP, R-CVP, RFM (i.e. rituximab, fludarabine, and mitoxantrone), and  RB (Bendamustine plus rituximab) </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Gastrointestinal stromal tumor and explain in detail? [/INST] Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. GISTs arise in the smooth muscle pacemaker interstitial cell of Cajal, or similar cells. They are defined as tumors whose behavior is driven by mutations in the KIT gene (85%),  PDGFRA gene (10%), or BRAF kinase (rare). 95% of GISTs  stain positively for KIT (CD117).  Most (66%) occur in the stomach and gastric GISTs have a lower malignant potential than tumors found elsewhere in the GI tract.

Classification
GIST was introduced as a diagnostic term in 1983.: 1060  Until the late 1990s, many non-epithelial tumors of the gastrointestinal tract were called "gastrointestinal stromal tumors". Histopathologists were unable to specifically distinguish among types we now know to be dissimilar molecularly. Subsequently, CD34, and later CD117 were identified as markers that could distinguish the various types. Additionally, in the absence of specific therapy, the diagnostic categorization had only a limited influence on prognosis and therapy.
The understanding of GIST biology changed significantly with identification of the molecular basis of GIST,: 1065  particularly c-KIT. Historically, literature reviews prior to the molecular definition of GIST, and for a short time thereafter, asserted that 70-80% of GISTs were benign. The identification of a molecular basis for GIST led to the exclusion of many tumors that had been considered as GIST previously, and also the incorporation of a much larger number of tumors that had been labeled as other types of sarcomas and undifferentiated carcinomas.: 1065   For example, some previous diagnoses of stomach and small bowel leiomyosarcomas (malignant tumor of smooth muscle) would be reclassified as GISTs on the basis of immunohistochemical staining. All GIST tumors are now considered to have malignant potential, and no GIST tumor can be definitively classified as "benign". Hence, all GISTs are eligible for cancer staging in the AJCC (7th edition) / UICC. Nonetheless, different GISTs have different risk assessments of their tendency to recur or to metastasize, dependent on their site of origin, size, and number of mitotic figures.
Due to the change in definition, clinical pathways of care before the year 2000 are largely uninformative in the current era.

Signs and symptoms
GISTs may present with trouble swallowing, gastrointestinal bleeding, or metastases (mainly in the liver). Intestinal obstruction is rare, due to the tumors outward pattern of growth. Often, there is a history of vague abdominal pain or discomfort, and the tumor has become rather large by time the diagnosis is made.

Pathophysiology
GISTs are tumors of connective tissue, i.e. sarcomas; unlike most gastrointestinal tumors, they are nonepithelial. About 70% occur in the stomach, 20% in the small intestine and less than 10% in the esophagus. Small tumors are generally not aggressive, especially when cell division rate is slow. GIST tumors commonly metastasize to the liver (in 28% of cases) and/or to the greater omentum, lesser omentum, or mesentery (in 30% of cases). Less common areas of metastasis include the lungs, subcutaneous tissue, lymph nodes or bones.GISTs are thought to arise from interstitial cells of Cajal (ICC), that are normally part of the autonomic nervous system of the intestine. They serve a pacemaker function in controlling motility.

Genetics
Most GISTs are sporadic. Less than 5% occur as part of hereditary familial or idiopathic multitumor syndromes. These include, in descending order of frequency, neurofibromatosis Recklinghausen (NF-1), Carneys triad (gastric GIST, pulmonary chondroma and extra-adrenal paraganglioma), germline gain-of-function mutations in c-KIT/PDGFRA, and the Carney-Stratakis syndrome. The Carney-Stratakis syndrome is a dyad of hereditary GIST and paraganglioma, that is caused by germline mutations in the mitochondrial tumor suppressor gene pathway involving the succinate dehydrogenase (SDH) subunits SDHD, SDHC and SDHB.

c-KIT mutations
Approximately 85% GISTs are associated with an abnormal c-KIT pathway. c-KIT is a gene that encodes for a transmembrane receptor for a growth factor termed stem cell factor (scf). The abnormal c-KIT pathway most commonly (85%) arises from mutation of the gene itself; a smaller subset of c-KIT-associated GISTs are associated with constitutive activity of the KIT enzymatic pathway, found by immunoblotting.: 1062   The c-KIT product/CD117 is expressed on ICCs and a large number of other cells, mainly bone marrow cells, mast cells, melanocytes and several others. In the gut, however, a mass staining positive for CD117 is likely to be a GIST, arising from ICC cells.
The c-KIT molecule comprises a long extracellular domain, a transmembrane segment, and an intracellular part. Mutations generally occur in the DNA encoding the intracellular part (exon 11), which acts as a tyrosine kinase to activate other enzymes. Mutations make c-KITfunction independent of activation by scf, leading to a high cell division rate and possibly genomic instability. Additional mutations are likely "required" for a cell with a c-KIT mutation to develop into a GIST, but the c-KIT mutation is probably the first step of this process.
Mutations in the exons 11, 9 and rarely 13 and 17 of the c-KIT gene are known to occur in GIST. The tyrosine kinase function of c-KIT is important in the medical therapy for GISTs, as described below.

KIT-D816V point mutations in c-KIT exon 17 are responsible for resistance to targeted therapy drugs like imatinib mesylate, a tyrosine kinase inhibitor.
KIT-p.D419del (exon 8) — A subset of gastrointestinal stromal tumors previously regarded as wild-type tumors carries somatic activating mutations in KIT exon 8 (p.D419del).

PDGFRA mutations
Most GIST cells with wildtype (i.e. not mutated) c-KIT instead have a mutation in another gene, PDGFR-α (platelet-derived growth factor receptor alpha), which is a related tyrosine kinase. Mutations in c-KIT and PDGFrA are mutually exclusive [4][5].

Wild-type tumors
Lesser numbers of GISTs appear to be associated with neither c-KIT nor PDGFR-α abnormalities.: 1062  About 10-15% of gastrointestinal stromal tumors (GISTs) carry wild-type sequences in all hot spots of KIT and platelet-derived growth factor receptor alpha (PDGFRA) (wt-GISTs). These tumors are currently defined by having no mutations in exons 9, 11, 13, and 17 of the KIT gene and exons 12, 14, and 18 of the PDGFRA gene.

Diagnosis
CT scanning is often undertaken (see the radiology section).
The definitive diagnosis is made with a biopsy, which can be obtained endoscopically, percutaneously with CT or ultrasound guidance or at the time of surgery. A biopsy sample will be investigated under the microscope by a pathologist physician. The pathologist examines the histopathology to identify the characteristics of GISTs (spindle cells in 70-80%, epitheloid aspect in 20-30%). Smaller tumors can usually be confined to the muscularis propria layer of the intestinal wall.  Large ones grow, mainly outward, from the bowel wall until the point where they outstrip their blood supply and necrose (die) on the inside, forming a cavity that may eventually come to communicate with the bowel lumen.
When GIST is suspected—as opposed to other causes for similar tumors—the pathologist can use immunohistochemistry (specific antibodies that stain the molecule CD117 [also known as c-KIT] —see below). 95% of all GISTs are CD117-positive (other possible markers include CD34, DOG-1, desmin, and vimentin). Other cells that show CD117 positivity are mast cells.
If the CD117 stain is negative and suspicion remains that the tumor is a GIST, the newer antibody DOG-1 (Discovered On GIST-1) can be used. Also, sequencing of KIT and PDGFRA can be used to prove the diagnosis.

Imaging
The purpose of radiologic imaging is to locate the lesion, evaluate for signs of invasion and detect metastasis. Features of GIST vary depending on tumor size and organ of origin. The diameter can range from a few millimeters to more than 30 cm.  Larger tumors usually cause symptoms in contrast to those found incidentally which tend to be smaller and have better prognosis. Large tumors tend to exhibit malignant behavior but small GISTs may also demonstrate clinically aggressive behavior.

Plain radiographs are not very helpful in the evaluation of GISTs. If an abnormality is seen, it will be an indirect sign due to the tumor mass effect on adjacent organs. On abdominal x-ray, stomach GISTs may appear as a radiopaque mass altering the shape of the gastric air shadow. Intestinal GISTs may displace loops of bowel and larger tumors may obstruct the bowel and films will show an obstructive pattern. If cavitations are present, plain radiographs will show collections of air within the tumor. Calcification is an unusual feature of GIST but if present can be visible on plain films.
Barium fluoroscopic examinations and CT are commonly used to evaluate the patient with abdominal complaints. Barium swallow images show abnormalities in 80% of GIST cases. However, some GISTs may be located entirely outside the lumen of the bowel and will not be appreciated with a barium swallow. Even in cases when the barium swallow is abnormal, an MRI or CT scan must follow since it is impossible to evaluate abdominal cavities and other abdominal organs with a barium swallow alone. In a CT scan, abnormalities may be seen in 87% of patients and it should be made with both oral and intravenous contrast.  Among imaging studies, MRI has the best tissue contrast, which aids in the identification of masses within the GI tract (intramural masses). Intravenous contrast material is needed to evaluate lesion vascularity.
Preferred imaging modalities in the evaluation of GISTs are CT and MRI,: 20–21  and, in selected situations, endoscopic ultrasound. CT advantages include its ability to demonstrate evidence of nearby organ invasion, ascites, and metastases. The ability of an MRI to produce images in multiple planes is helpful in determining the bowel as the organ of origin (which is difficult when the tumor is very large), facilitating diagnosis.

Small GISTs
Since GISTs arise from the bowel layer called muscularis propria (which is deeper to the mucosa and submucosa from a luminal perspective), small GIST imaging usually suggest a submucosal process or a mass within the bowel wall. In barium swallow studies, these GISTs most commonly present with smooth borders forming right or obtuse angles with the nearby bowel wall, as seen with any other intramural mass. The mucosal surface is usually intact except for areas of ulceration, which are generally present in 50% of GISTs. Ulcerations fill with barium causing a bulls eye or target lesion appearance. In contrast-enhanced CT, small GISTs are seen as smooth, sharply defined intramural masses with homogeneous attenuation.

Large GISTs
As the tumor grows it may project outside the bowel (exophytic growth) and/or inside the bowel (intraluminal growth), but they most commonly grow exophytically such that the bulk of the tumor projects into the abdominal cavity. If the tumor outstrips its blood supply, it can necrose internally, creating a central fluid-filled cavity with bleeding and cavitations that can eventually ulcerate and communicate into the lumen of the bowel. In that case, barium swallow may show an air, air-fluid levels or oral contrast media accumulation within these areas. Mucosal ulcerations may also be present. In contrast-enhanced CT images, large GISTs appear as heterogeneous masses due to areas of living tumor cells surrounding bleeding, necrosis or cysts, which is radiographically seen as a peripheral enhancement pattern with a low attenuation center. In MRI studies, the degree of necrosis and bleeding affects the signal intensity pattern. Areas of bleeding within the tumor will vary its signal intensity depending on how long ago the bleeding occurred. The solid portions of the tumor are typically low signal intensity on T1-weighted images, are high signal intensity on T2-weighted images and enhanced after administration of gadolinium. Signal-intensity voids are present if there is gas within areas of necrotic tumor.

Features of malignancy
Malignancy is characterized by local invasion and metastases, usually to the liver, omentum and peritoneum. However, cases of metastases to bone, pleura, lungs and retroperitoneum have been seen. In distinction to gastric adenocarcinoma or gastric/small bowel lymphoma, malignant lymphadenopathy (swollen lymph nodes) is uncommon (<10%) and thus imaging usually shows absence of lymph node enlargement. If metastases are not present, other radiologic features suggesting malignancy include: size (>5 cm), heterogeneous enhancement after contrast administration, and ulcerations. Also, overtly malignant behavior (in distinction to malignant potential of lesser degree) is less commonly seen in gastric tumors, with a ratio of behaviorally benign to overtly malignant of 3-5:1. Even if radiographic malignant features are present, these findings may also represent other tumors and definitive diagnosis must be made immunochemically.

Management
For localized, resectable adult GISTs, if  anatomically and physiologically feasible, surgery is the primary treatment of choice.: 69  Surgery can be potentially curative, but watchful waiting may be considered in small tumors in carefully selected situations. Post-surgical adjuvant treatment may be recommended. Lymph node metastases are rare, and routine removal of lymph nodes is typically not necessary. Laparoscopic surgery, a minimally invasive abdominal surgery using telescopes and specialized instruments, has been shown to be effective  for removal of these tumors without needing large incisions. The clinical issues of exact surgical indications for tumor size are controversial. The decision of appropriate laparoscopic surgery is affected by tumor size, location, and growth pattern.Radiotherapy has not historically been effective for GISTs: 1122  and GISTs do not respond to most chemotherapy medications,: 1122  with responses in less than 5%.: 1065   However, four medications have been identified for clinical benefit in GIST: imatinib, sunitinib, regorafenib, and ripretinib.
Imatinib (Glivec/Gleevec), an orally administered drug initially marketed for chronic myelogenous leukemia based on bcr-abl inhibition, also inhibits both c-KIT tyrosine kinase mutations and PDGFRA mutations other than D842V, and is useful in treating GISTs in several situations. Imatinib has been used in selected neoadjuvant settings.: 23  In the adjuvant treatment setting, the majority of GIST tumors are cured by surgery, and do not need adjuvant therapy.  An exception to this is where the anatomical position of the tumour means that surgery is technically difficult or complex. For example, rectal GIST often requires radical surgery to achieve complete resection, involving abdominoperineal resection and permanent stoma. In these situations, the use of neoadjuvant imatinib can significantly decrease both tumour size and mitotic activity, and permit less radical sphincter-preserving surgery.A substantial proportion of GIST tumors have a high risk of recurrence as estimated by a number of validated risk stratification schemes, and can be considered for adjuvant therapy. The selection criteria underpinning the decision for possible use of imatinib in these settings, including a risk assessment based on pathological factors such as tumor size, mitotic rate and location, can be used to predict the risk of recurrence in GIST patients. Tumors <2 cm with a mitotic rate of <5/50 HPF have been shown to have lower risk of recurrence than larger or more aggressive tumors. Following surgical resection of GISTs, adjuvant treatment with imatinib  reduces the risk of disease recurrence in higher risk groups. In selected higher risk adjuvant situations, imatinib is recommended for 3 years.Imatinib was approved for metastatic and unresectable GIST by the US FDA, February 1, 2002. The two-year survival of patients with advanced disease has risen to 75–80% following imatinib treatment.If resistance to imatinib is encountered, the multiple tyrosine kinase inhibitor sunitinib (marketed as Sutent) can be considered.: 26 and 31 The effectiveness of imatinib and sunitinib depend on the genotype. c-KIT- and PDGFRA-mutation negative GIST tumors are usually resistant to treatment with imatinib, as is neurofibromatosis-1-associated wild-type GIST. A specific subtype of PDGFRA mutation, D842V, is also insensitive to imatinib. Recently, in PDGFRA-mutated GIST, avapritinib has been approved by FDA.
Now there are real-world data coming for avapritinib as well (Dr Sameer Rastogi, et al.)Regorafenib (Stivarga) was FDA-approved in 2013 for advanced GISTs that cannot be surgically removed and that no longer respond to imatinib (Gleevec) and sunitinib (Sutent).

Epidemiology
GISTs occur in 10-20 per one million people. The true incidence might be higher, as novel laboratory methods are much more sensitive in diagnosing GISTs. The estimated incidence of GIST in the United States is approximately 5000 cases annually.: 1063  This makes GIST the most common form of sarcoma, which constitutes more than 70 types of cancer.
The majority of GISTs present at ages 50–70 years. Across most of the age spectrum, the incidence of GIST is similar in men and women.: 1122 Adult GISTs are rare before age 40. Pediatric GISTs are considered to be biologically distinct. Unlike GISTs at other ages, pediatric GISTs are more common in girls and young women. They appear to lack oncogenic activating tyrosine kinase mutations in both KIT and PDGFRA.  Pediatric GISTs are treated differently from adult GISTs. Although the generally accepted definition of pediatric GIST is a tumor that is diagnosed at the age of 18 years or younger, "pediatric-type" GISTs can be seen in adults, which affects risk assessment, the role of lymph node resection, and choice of therapy.

Citations
General sources
de Silva CM, Reid R (2003). "Gastrointestinal stromal tumors (GIST): c-KIT mutations, CD117 expression, differential diagnosis and targeted cancer therapy with Imatinib" (PDF). Pathol Oncol Res </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Accidental and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Overweight and explain in detail? [/INST] Being overweight or fat is having more body fat than is optimally healthy. Being overweight is especially common where food supplies are plentiful and lifestyles are sedentary.
As of 2003, excess weight reached epidemic proportions globally, with more than 1 billion adults being either overweight or obese. In 2013, this increased to more than 2 billion. Increases have been observed across all age groups.
A healthy body requires a minimum amount of fat for proper functioning of the hormonal, reproductive, and immune systems, as thermal insulation, as shock absorption for sensitive areas, and as energy for future use; however, the accumulation of too much storage fat can impair movement, flexibility, and alter the appearance of the body.

Classification
The degree to which a person is overweight is generally described by the body mass index (BMI). Overweight is defined as a BMI of 25 or more, thus it includes pre-obesity defined as a BMI between 25 and 29.9 and obesity as defined by a BMI of 30 or more. Pre-obese and overweight however are often used interchangeably, thus giving overweight a common definition of a BMI of between 25 and 29.9. There are, however, several other common ways to measure the amount of adiposity or fat present in an individuals body.

Body mass indexThe body mass index (BMI) is a measure of a persons weight taking into account their height.  It is given by the following formula: BMI equals a persons weight (mass) in kilograms divided by the square of the persons height in metres. The units therefore are kg/m2 but BMI measures are typically used and written without units.BMI provides a significantly more accurate representation of body fat content than simply measuring a persons weight. It is only moderately correlated with both body fat percentage and body fat mass (R2 of 0.68). It does not take into account certain factors such as pregnancy or bodybuilding; however, the BMI is an accurate reflection of fat percentage in the majority of the adult population.Body volume indexThe body volume index (BVI) was devised in 2000 as a computer, rather than manual, measurement of the human body for obesity and an alternative to the BMIBVI uses 3D software to create an accurate image of a person so BVI can differentiate between people with the same BMI rating, but who have a different shape and different weight distribution.
BVI measures where a persons weight and the fat are located on the body, rather than total weight or total fat content and places emphasis on the weight carried around the abdomen, commonly known as central obesity. There has been an acceptance in recent years that abdominal fat and weight around the abdomen constitute a greater health risk.Simple weighingA persons weight is measured and compared to an estimated ideal weight. This is the easiest and most common method, but by far the least accurate, as it only measures one quantity (weight) and often does not take into account many factors such as height, body type, and relative amount of muscle mass.Skinfold calipers or "pinch test"The skin at several specific points on the body is pinched and the thickness of the resulting fold is measured.  This measures the thickness of the layers of fat located under the skin, from which a general measurement of total amount of fat in the body is calculated.  This method can be reasonably accurate for many people, but it assumes particular fat distribution patterns over the body—which may not apply to all individuals, and does not account for fat deposits not directly under the skin.  Also, as the measurement and analysis generally involves a high degree of practice and interpretation, an accurate result requires that a professional perform it. It cannot generally be done by patients themselves.Bioelectrical impedance analysisA small electric current is passed through the body to measure its electrical resistance. As fat and muscle conduct electricity differently, this method can provide a direct measurement of the body fat percentage, in relation to muscle mass. In the past, this technique could only be performed reliably by trained professionals with specialized equipment, but it is now possible to buy home testing kits that let people do this themselves with a minimum of training.  Despite the improved simplicity of this process over the years, however, a number of factors can affect the results, including hydration and body temperature, so it still needs some care when taking the test to ensure that the results are accurate.Hydrostatic weighingConsidered one of the more accurate methods of measuring body fat, this technique involves complete submersion of a person in water, with special equipment to measure the persons weight while submerged. This weight is then compared with "dry weight" as recorded outside the water to determine overall body density. As fat is less dense than muscle, careful application of this technique can provide a reasonably close estimate of fat content in the body.  This technique does, however, require expensive specialized equipment and trained professionals to administer it properly.Dual-energy X-ray absorptiometry (DEXA)Originally developed to measure bone density, DEXA imaging is also used to precisely determine body fat content by using the density of various body tissues to identify which portions of the body are fat. This test is generally considered very accurate, but requires a great deal of expensive medical equipment and trained professionals to perform.The most common method for discussing this subject and the one used primarily by researchers and advisory institutions is BMI. Definitions of what is considered overweight vary by ethnicity. The current definition proposed by the US National Institutes of Health (NIH) and the World Health Organization (WHO) designates whites, Hispanics and blacks with a BMI of 25 or more as overweight. For Asians, overweight is a BMI between 23 and 29.9 and obesity for all groups is a BMI of 30 or more.
BMI, however, does not account extremes of muscle mass, some rare genetic factors, the very young, and a few other individual variations.  Thus it is possible for an individuals with a BMI of less than 25 to have excess body fat, while others may have a BMI that is significantly higher without falling into this category. Some of the above methods for determining body fat are more accurate than BMI but are less convenient to measure.
If an individual is overweight and has excess body fat it can create or lead to health risks. Reports are surfacing, however, that being mildly overweight to slightly obese – BMI being between 24 and 31.9 – may be actually beneficial and that people with a BMI between 24 and 31.9 could actually live longer than normal weight or underweight persons.

Health effects
While some negative health outcomes associated with obesity are accepted within the medical community, the health implications of the overweight category are more controversial.
A 2016 review estimated that the risk of death increases by seven percent among overweight people with a BMI of 25 to 27.5 and 20 percent among overweight people with a BMI of 27.5 to 30. Katherine Flegal et al., however, found that the mortality rate for individuals who are classified as overweight (BMI 25 to 29.9) may actually be lower than for those with an "ideal" weight (BMI 18.5 to 24.9), noting that many studies show that the lowest mortality rate is at a BMI close to 25 </s>