Institute of Pathology, University Hospital Basel, University of Basel, 4031 Basel, Switzerland.
Hum Pathol. 2012 Mar;43(3):405-12. doi: 10.1016/j.humpath.2011.05.018. Epub 2011 Aug 19.
Aberrant expression of the antiapoptotic protein BCL (B-cell lymphoma)-2 in neoplastic germinal centers is one of the diagnostic hallmarks of follicular lymphoma. If BCL-2 cannot be detected by immunohistochemistry, the distinction between florid follicular hyperplasia and follicular lymphoma might become a diagnostic challenge. Most of those cases also lack the typical t(14;18), and the underlying pathophysiologic conditions of follicular lymphoma that lack BCL-2 protein expression are largely unknown. Here, we collected 18 BCL-2-negative follicular lymphoma cases from 5 different institutions. After restaining, 9 cases proved to be truly BCL-2 negative (6 follicular lymphoma grade 2, 2 follicular lymphoma grade 3a, and 1 follicular lymphoma grade 3b). In 4 additional cases, BCL-2 was very faint (all grade 2). Of the 9 BCL-2-negative follicular lymphoma cases, 2 were negative for CD10 (22%); all showed expression of BCL-6. Apoptotic level as determined by caspase 3 was the lowest in the BCL-2-positive follicular lymphoma group (15 ± 8 mm(2)), the highest in the normal/reactive group (n = 7, 60 ± 12 mm(2)) and very similar in the BCL-2 low follicular lymphoma and BCL-2-negative follicular lymphoma groups (25 ± 13 and 33 ± 19 mm(2), respectively), assuming an intermediate position between reactive follicles and BCL-2-positive neoplastic follicles (P < .001 [Kruskal-Wallis]). Also noted was a difference in proliferation fractions between the BCL-2-positive follicular lymphoma (27% ± 15%), the BCL-2 low follicular lymphoma (30% ± 20%) and the BCL-2-negative follicular lymphoma groups (30% ± 22%). Regarding the network of follicular dendritic cells, 8 (89%) of 9 cases from the BCL-2-negative subgroup showed disrupted, weakly developed networks, whereas all of the follicular lymphoma BCL-2 low-expression cases showed a well-defined and strongly developed follicular dendritic cell network. Among BCL-2-negative follicular lymphoma, BCL-2 and BCL-6 breaks were found in 1 case each, whereas in the follicular lymphoma BCL-2 low group, only 1 case with a BCL-6 break was recorded. No statistically significant result was achieved upon assessment of BCL-2α or BCL-2β RNA or the ratio of α/β isolated by real-time-polymerase chain reaction. Taken together, BCL-2-negative follicular lymphoma did not show a BCL-2 break on the genetic level and showed both increased apoptotic and proliferation rates compared with BCL-2-positive follicular lymphoma. In our series, BCL-6 breaks were infrequent in BCL-2-negative follicular lymphoma.
抗凋亡蛋白 BCL（B 细胞淋巴瘤）-2 在肿瘤生发中心的异常表达是滤泡性淋巴瘤的诊断标志之一。如果免疫组织化学不能检测到 BCL-2，则可能成为滤泡性增生和滤泡性淋巴瘤之间的诊断挑战。这些病例大多缺乏典型的 t（14；18），缺乏 BCL-2 蛋白表达的滤泡性淋巴瘤的潜在病理生理状况在很大程度上是未知的。在这里，我们从 5 个不同的机构收集了 18 例 BCL-2 阴性滤泡性淋巴瘤病例。重新染色后，有 9 例被证实为真正的 BCL-2 阴性（6 例滤泡性淋巴瘤 2 级，2 例滤泡性淋巴瘤 3a 级，1 例滤泡性淋巴瘤 3b 级）。在另外 4 例中，BCL-2 非常微弱（均为 2 级）。在 9 例 BCL-2 阴性滤泡性淋巴瘤中，有 2 例 CD10 阴性（22%）；所有病例均表达 BCL-6。通过 caspase 3 测定的凋亡水平在 BCL-2 阳性滤泡性淋巴瘤组最低（15 ± 8mm2），在正常/反应组最高（n=7，60 ± 12mm2），在 BCL-2 低表达滤泡性淋巴瘤和 BCL-2 阴性滤泡性淋巴瘤组非常相似（分别为 25 ± 13 和 33 ± 19mm2），介于反应性滤泡和 BCL-2 阳性肿瘤滤泡之间（P <.001 [Kruskal-Wallis]）。还注意到 BCL-2 阳性滤泡性淋巴瘤（27% ± 15%）、BCL-2 低表达滤泡性淋巴瘤（30% ± 20%）和 BCL-2 阴性滤泡性淋巴瘤组之间的增殖分数存在差异（30% ± 22%）。关于滤泡树突状细胞网络，9 例 BCL-2 阴性亚组中的 8 例（89%）显示网络中断，发育不良，而所有 BCL-2 低表达滤泡性淋巴瘤病例均显示出定义明确且发育良好的滤泡树突状细胞网络。在 BCL-2 阴性滤泡性淋巴瘤中，1 例发现 BCL-2 和 BCL-6 断裂，而在 BCL-2 低表达滤泡性淋巴瘤组中，仅记录到 1 例 BCL-6 断裂。通过实时聚合酶链反应评估 BCL-2α 或 BCL-2β RNA 或其比值并未获得统计学显著结果。总的来说，BCL-2 阴性滤泡性淋巴瘤在遗传水平上没有 BCL-2 断裂，并且与 BCL-2 阳性滤泡性淋巴瘤相比，凋亡和增殖率均增加。在我们的系列中，BCL-6 断裂在 BCL-2 阴性滤泡性淋巴瘤中很少见。
