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 co-deletion/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 co-mutation in dFL, as compared to 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.

中文翻译：

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CREBBP和STAT6共同突变以及16p13和1p36缺失定义了滤泡性淋巴瘤t（14; 18）阴性弥漫性变异

滤泡性淋巴瘤（dFL）的弥散变体是一种罕见的缺乏t（14; 18）的FL变体，于2009年首次描述。在这项研究中，我们使用一种综合方法通过金标准病理学定义统一的病理学和遗传学特征综述，FISH，SNP基因芯片和16例dFL的下一代测序。我们发现独特的形态学特征，包括间质硬化，微囊形成和圆形核细胞学，证实不存在t（14; 18）和反复缺失1p36，并显示出与16p13缺失/ CN-LOH的新关联（包括CREBBP），CIITA和SOCS1）。突变谱分析表明CREBBP和STAT6突变近乎均匀，具有CREBBP的克隆优势，以及生发中心B细胞淋巴瘤的典型突变。频繁的CREBBP和CIITA共删除/突变提示了逃避免疫的机制，而亚克隆STAT6激活突变并发SOCS1缺失则提示在没有BCL2重排的情况下BCL-xL / BCL2L1上调的机制。文献综述显示16p13和1p36缺失/ CN-LOH，STAT6突变以及CREBBP和STAT6显着富集与传统FL相比，dFL中的共突变。通过这种全面的方法，我们的研究证明了确诊和新颖的遗传学关联可以帮助诊断和分类这种罕见类型的淋巴瘤。