Follicular lymphoma (FL) is an indolent, B-cell, non-Hodgkin’s lymphoma with varying cytological appearance and clinical behavior. The genetic hallmark of FL is the t(14;18) translocation, and as a germinal center derived entity it is also characterized by somatic hypermutation of the immunoglobulin heavy chain (IgH) gene. In an attempt to correlate this molecular signature with the cytological grading of FL, we have analyzed the IgH variable (IgV_H), regions in all cytological grades of FL. Four FL cases showing t(14;18) translocation were classified into grade I-III categories according to the current WHO guidelines. The IgV_H gene segments were PCR-amplified, sequenced, and compared to their respective germline IgV_H sequences. The neoplastic cells of grade I and II FLs revealed clonally related, but highly divergent IgV_H gene sequences indicating the ongoing nature of somatic hypermutation. Grade III FL also showed extensive presence of somatic hypermutation, but these mutations were not associated with intraclonal divergence. Thus, these results suggest that grade I-II and grade III FL may represent different biological entities. The presence of ongoing somatic hypermutation of IgV_H sequences in grade I and II FLs is compatible with direct follicular origin of these tumor cells, contrasting the homogenous, stable clones of grade III FL resembling a post-follicular stage of B-cell development. Our findings demonstrate that contrary to the three tiered cytological grading, molecular features of IgH genes classify FL into two distinct subcategories. These studies also suggest that with progression FL gains post-follicular–like molecular features and becomes independent of the germinal center microenvironment.

滤泡性淋巴瘤 (FL) 是一种惰性的 B 细胞非霍奇金淋巴瘤，具有不同的细胞学表现和临床行为。FL 的遗传标志是 t(14;18) 易位，作为生发中心衍生的实体，它的特征还在于免疫球蛋白重链 (IgH) 基因的体细胞超突变。为了将这种分子特征与 FL 的细胞学分级相关联，我们分析了 IgH 变量 (IgV _H )，即 FL 的所有细胞学分级中的区域。根据当前的 WHO 指南，显示 t(14;18) 易位的 4 例 FL 病例被分类为 I-III 级。对 IgV _H基因片段进行 PCR 扩增、测序，并与它们各自的种系 IgV _{H进行比较}序列。I 级和 II 级 FL 的肿瘤细胞显示出克隆相关但高度不同的 IgV _H基因序列，表明体细胞超突变的持续性质。III 级 FL 也显示出广泛存在的体细胞超突变，但这些突变与克隆内分化无关。因此，这些结果表明 I-II 级和 III 级 FL 可能代表不同的生物实体。存在正在进行的 IgV _{H体细胞超突变}I 级和 II 级 FL 中的序列与这些肿瘤细胞的直接滤泡起源相容，与类似于 B 细胞发育的滤泡后阶段的 III 级 FL 的同质、稳定克隆形成对比。我们的研究结果表明，与三层细胞学分级相反，IgH 基因的分子特征将 FL 分为两个不同的子类别。这些研究还表明，随着进展，FL 获得后滤泡样分子特征并且变得独立于生发中心微环境。