Polymerase Chain Reaction Based Gene Rearrangement Studies in the Diagnosis of Follicular Lymphoma — Performance in Formaldehyde-Fixed Tissue and Application in Clinical Problem Cases
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Follicular lymphoma
Gene rearrangement
BCL6
Follicular hyperplasia
Immunoglobulin heavy chain
BCL6
Follicular lymphoma
Immunoglobulin gene
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Follicular lymphomas present with various immunohistologic patterns. The immunohistochemical markers used in the diagnosis of follicular lymphoma show variable degrees of sensitivity and specificity, and thus, additional germinal center markers are required. Smad1 has been reported to be overexpressed in follicular lymphoma, but little is known regarding the expression patterns of Smad proteins in human lymphoid tissue.In the present study, we performed immunohistochemistry for traditional germinal center markers and for Smad1 in human reactive lymphoid and follicular lymphoma tissues to investigate Smad1's usefulness in the diagnosis of follicular lymphoma.In the reactive germinal centers, most cells were positive for Smad1. Among the 27 follicular lymphoma cases, 17 of 21 (80%) were Smad1 positive, 17 of 27 (63%) were positive for CD10, and 23 of 27 (85%) were positive for Bcl6. Notably, three cases expressed CD10 only, and one only expressed Bcl6. All these cases were grade 3 tumors and showed follicular and diffuse growth patterns.These results indicate that Smad1 is a candidate as a germinal center marker. Furthermore, they suggest that the Smad signaling pathway might be involved in follicular lymphoma.
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A study was made of 80 patients whose lymph nodes were characterized by the presence of follicles throughout the lymph node. The patients were divided into two groups on the basis of the clinical follow-up information. The first group consisted of 20 patients who were alive and disease-free at the end of five years without therapy. The patients in this group were classified as having florid reactive follicular hyperplasia (FRFH). The second group of 60 patients had progressive, recurrent, clinically active disease and were classified as having follicular lymphoma (FL). Forty-six were dead of active disease, and 14 were alive with disease. Various morphologic parameters were evaluated at low and high magnification, and statistical comparisons were made between FRFH and FL. Although several criteria were helpful in distinguishing FRFH from FL, the single most valuable criterion was the type of pattern encountered. Follicles of variable size and shape lying adjacent to each other throughout the lymph node without or with very little intervening tissue are diagnostic of FL. This pattern was evident in 85% of the FL cases, but was not observed in any of the cases of FRFH.
Follicular hyperplasia
Follicular lymphoma
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Follicular lymphoma
Follicular hyperplasia
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BCL6
Follicular lymphoma
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Follicular lymphoma is one of the most frequent lymphomas. Histologically, it is characterized by a follicular (nodular) growth pattern of centrocytes and centroblasts; mixed with variable immune microenvironment cells. Clinically, it is characterized by diffuse lymphadenopathy, bone marrow involvement, and splenomegaly. It is biologically and clinically heterogeneous. In most patients it is indolent, but others have a more aggressive evolution with relapses; and transformation to diffuse large B-cell lymphoma. Tumorigenesis includes an asymptomatic preclinical phase in which premalignant B-lymphocytes with the t(14;18) chromosomal translocation acquire additional genetic alterations in the germinal centers, and clonal evolution occurs, although not all the cells progress to the tumor stage. This manuscript reviews the pathobiology and clinicopathological characteristics of follicular lymphoma. It includes a description of the physiology of the germinal center, the genetic alterations of BCL2 and BCL6, the mutational profile, the immune checkpoint, precision medicine, and highlights in the lymphoma classification. In addition, a comment and review on artificial intelligence and machine (deep) learning are made.
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Follicular lymphoma
Gene rearrangement
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To define prognostic significance of B-cell differentiation genes encoding proteins and BCL2 and BCL6 gene abnormalities in diffuse large B-cell lymphoma and follicular lymphoma grade 3 with >75% follicular growth pattern.In 53 patients with diffuse large B-cell lymphoma and 20 patients with follicular lymphoma grade 3 with >75% follicular growth pattern the following was performed: 1) determination of protein expression of BCL6, CD10, MUM1/IRF4, CD138, and BCL2 by immunohistochemistry; 2) subclassification into germinal center B-cell-like (GCB) and activated B-cell-like (ABC) groups according to the results of protein expression; 3) detection of t(14;18)(q32;q21)/IgH-BCL2 and BCL6 abnormalities by fluorescent in situ hybridization in diffuse large B-cell lymphoma and follicular lymphoma grade 3 with >75% follicular growth pattern as well as in GCB and ABC groups; and 4) assessment of the influence of the analyzed characteristics and clinical prognostic factors on overall survival.Only BCL6 expression was more frequently found in follicular lymphoma grade 3 with >75% follicular growth pattern than in diffuse large B-cell lymphoma (P=0.030). There were no differences in BCL2 and BCL6 gene abnormalities between diffuse large B-cell lymphoma and follicular lymphoma grade 3 with >75% follicular growth pattern. Diffuse large B-cell lymphoma and follicular lymphoma grade 3 with >75% follicular growth pattern patients were equally distributed in GCB and ABC groups. t(14;18)(q32;q21) was more frequently recorded in GCB group, and t(14;18)(q32;q21) with BCL2 additional signals or only BCL2 and IgH additional signals in ABC group (P=0.004). The GCB and ABC groups showed no difference in BCL6 gene abnormalities. There was no overall survival difference between the diffuse large B-cell lymphoma and follicular lymphoma grade 3 with >75% follicular growth pattern patients, however, GCB group had longer overall survival than ABC group (P=0.047). Multivariate analysis showed that BCL6, CD10, and BCL2 expression, BCL2 and BCL6 abnormalities, and International Prognostic Index were not significantly related to overall survival.Diffuse large B-cell lymphoma and follicular lymphoma grade 3 with >75% follicular growth pattern patients have very similar characteristics and their prognosis is more influenced by protein expression of B-cell differentiation stage genes than by tumor cells growth pattern, BCL2 and BCL6 abnormalities, and International Prognostic Index.
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B-cell lymphoma
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Objective To study the morphological and cytogenetic characteristics of the follicular lymphoma(FL) grade 3B and the association of disease pedigree between the follicular lymphoma grade 1-3A and the diffuse large B-cell lymphoma(DLBCL). Methods Thirty-five FL and 9 GCB-DLBCL were detected by fluorescence in situ hybridization(FISH) and immunohistochemistry. The BCL2/IGH fusion and the BCL6 separation were researched respectively by FISH. BCL2 and BCL6 proteins were detected by immunohistochemistry. All their statistical comparisons were conducted by SPSS13.0 Software. Results The prevalence of BCL2 fusion was lower in FL3B compared with FL1-3A(27% vs. 86%, P0.05). BCL2 protein expression rate was less in FL3B than that in FL1-3A(45% vs. 96%, P0.05). There was no correlation between BCL2 protein expression and BCL2/IGH fusion, as well as BCL6 separation in each group. Conclusion The follicular lymphoma grade 3B had an intermediate morphological form between the follicular lymphoma 3A and the diffuse large B-cell lymphomas.The cytogenetic change of FL3B was closed to diffuse large B-cell lymphomas. The lower BCL2/IGH fusion rate of FL3B suggested that FL3B had a different carcinogenic. pathway from FL1-3A and the diffuse large B-cell lymphomas.
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BCL6
Lymphoplasmacytic Lymphoma
Follicular lymphoma
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