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 main article: 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 follicular lymphoma replacing a lymph node; the bubble-like outgrowths are enlarged follicles. 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, follicular lymphoma can be classified morphologically by the relative amount of centroblasts. however, such classification is optional, due to poor reproducibility and little difference in prognosis and treatment, except that a lymphoma with almost only centroblasts may be diagnosed as a diffuse large b-cell lymphoma (dlbcl). the optional classification of follicular lymphoma is as follows: histologic comparison of cell types in a germinal center, h&e stain:- centrocytes are small to medium size with angulated, elongated, cleaved, or twisted nuclei.- centroblasts are larger cells containing vesicular nuclei with one to three basophilic nucleoli apposing the nuclear membrane.- follicular dendritic cells have round nuclei, centrally located nucleoli, bland and dispersed chromatin, and flattening of adjacent nuclear membrane. 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 histology of a normal lymphoid follicle. follicular lymphoma proliferate in the germinal center, whereas mantle cell and marginal cell lymphoma generally proliferate within their zones. 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