Abstract
The diffuse variant of follicular lymphoma (dFL) is a rare variant of FL lacking t(14;18) that was first described in 2009. In this study, we use a comprehensive approach to define unifying pathologic and genetic features through gold-standard pathologic review, FISH, SNP-microarray, and next-generation sequencing of 16 cases of dFL. We found unique morphologic features, including interstitial sclerosis, microfollicle formation, and rounded nuclear cytology, confirmed absence of t(14;18) and recurrent deletion of 1p36, and showed a novel association with deletion/CN-LOH of 16p13 (inclusive of CREBBP, CIITA, and SOCS1). Mutational profiling demonstrated near-uniform mutations in CREBBP and STAT6, with clonal dominance of CREBBP, among other mutations typical of germinal-center B-cell lymphomas. Frequent CREBBP and CIITA codeletion/mutation suggested a mechanism for immune evasion, while subclonal STAT6 activating mutations with concurrent SOCS1 loss suggested a mechanism of BCL-xL/BCL2L1 upregulation in the absence of BCL2 rearrangements. A review of the literature showed significant enrichment for 16p13 and 1p36 loss/CN-LOH, STAT6 mutation, and CREBBP and STAT6 comutation in dFL, as compared with conventional FL. With this comprehensive approach, our study demonstrates confirmatory and novel genetic associations that can aid in the diagnosis and subclassification of this rare type of lymphoma.
Highlights
Follicular lymphoma (FL) is the second most common nodal non-Hodgkin lymphoma accounting for ~20% of all lymphomas[1]
Frequent CREBBP and CIITA codeletion/mutation suggested a mechanism for immune evasion, while subclonal STAT6 activating mutations with concurrent SOCS1 loss suggested a mechanism of BCL-xL/BCL2L1 upregulation in the absence of BCL2 rearrangements
The proliferation of germinal center B-cells (GCB) forming abnormal follicles coupled with translocation of the antiapoptotic gene BCL2 with IGH resulting in t(14;18)(q32;q21) are diagnostic hallmarks of FL1
Summary
Follicular lymphoma (FL) is the second most common nodal non-Hodgkin lymphoma accounting for ~20% of all lymphomas[1]. The proliferation of germinal center B-cells (GCB) forming abnormal follicles coupled with translocation of the antiapoptotic gene BCL2 with IGH resulting in t(14;18)(q32;q21) are diagnostic hallmarks of FL1. There are exceptions, as ~5% of low-grade follicular lymphoma (LGFL) show a predominantly diffuse growth pattern[2,3], and ~10% of FL lack t(14;18)[1], most of which represent high-grade disease. The 2016 WHO classification recognizes several variants and related entities of FL, the latter of which is designated as conventional follicular lymphoma (cFL). The morphologically low-grade spectrum includes in-situ follicular neoplasia, duodenal-type FL, and the diffuse FL variant (dFL) with the former two entities consistently demonstrating t(14;18) BCL2/IGH rearrangements. The morphologically high-grade spectrum includes testicular FL and pediatric-type FL (pFL), neither of which carry BCL2/IGH rearrangements. The genetic abnormalities found in cFL serve as the basis against which variant subtypes can be compared
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