Department of Pathology, Tokai University School of Medicine, Isehara, Japan.
Department of Hematology/Oncology, Tokai University, School of Medicine, Isehara, Japan.
Mod Pathol. 2018 Feb;31(2):313-326. doi: 10.1038/modpathol.2017.134. Epub 2017 Oct 6.
Most high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements are aggressive B-cell lymphomas. Occasional double-hit follicular lymphomas have been described but the clinicopathological features of these tumors are not well known. To clarify the characteristics of double-hit follicular lymphomas, we analyzed 10 cases of double-hit follicular lymphomas and 15 cases of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements for clinicopathological and genome-wide copy-number alterations and copy-neutral loss-of-heterozygosity profiles. For double-hit follicular lymphomas, the median age was 67.5 years (range: 48-82 years). The female/male ratio was 2.3. Eight patients presented with advanced clinical stage. The median follow-up time was 20 months (range: 1-132 months). At the end of the follow-up, 8 patients were alive, 2 patients were dead including 1 patient with diffuse large B-cell lymphoma transformation. Rearrangements of MYC/BCL2, MYC/BCL6, and MYC/BCL2/BCL6 were seen in 8, 1, and 1 cases, respectively. The partner of MYC was IGH in 6 cases. There were no cases of histological grade 1, 4 cases of grade 2, 5 cases of grade 3a, and 1 case of grade 3b. Two cases of grade 3a exhibited immunoblast-like morphology. Immunohistochemistry demonstrated 9 cases with ≥50% MYC-positive cells. There was significant difference in MYC intensity (P=0.00004) and MIB-1 positivity (P=0.001) between double-hit follicular lymphomas and high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements. The genome profile of double-hit follicular lymphomas was comparable with conventional follicular lymphomas (GSE67385, n=198) with characteristic gains of 2p25.3-p11.1, 7p22.3-q36.3, 12q11-q24.33, and loss of 18q21.32-q23 (P<0.05). In comparison with high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements, double-hit follicular lymphomas had fewer copy-number alterations and minimal common region of gain at 2p16.1 (70%), locus also significant against conventional follicular lymphomas (P=0.0001). In summary, double-hit follicular lymphomas tended to be high-grade histology, high MYC protein expression, high MYC/IGH fusion, and minimal common region of gain at 2p16.1. Double-hit follicular lymphomas seemed to be a different disease from high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements and have an indolent clinical behavior similar to follicular lymphomas without MYC rearrangement.
大多数伴有 MYC 和 BCL2 及/或 BCL6 重排的高级别 B 细胞淋巴瘤都是侵袭性 B 细胞淋巴瘤。偶尔也会描述双打击滤泡性淋巴瘤，但这些肿瘤的临床病理特征并不清楚。为了阐明双打击滤泡性淋巴瘤的特征，我们分析了 10 例双打击滤泡性淋巴瘤和 15 例伴有 MYC 和 BCL2 及/或 BCL6 重排的高级别 B 细胞淋巴瘤的临床病理和全基因组拷贝数改变及拷贝数中性杂合性缺失谱。对于双打击滤泡性淋巴瘤，中位年龄为 67.5 岁（范围：48-82 岁）。男女比例为 2.3。8 例患者表现为晚期临床分期。中位随访时间为 20 个月（范围：1-132 个月）。随访结束时，8 例患者存活，2 例患者死亡，包括 1 例发生弥漫性大 B 细胞淋巴瘤转化。8 例存在 MYC/BCL2、MYC/BCL6 和 MYC/BCL2/BCL6 重排，1 例存在 MYC/BCL6 重排。MYC 的伙伴基因 IGH 在 6 例中存在。无组织学 1 级病例，4 例为 2 级，5 例为 3a 级，1 例为 3b 级。2 例 3a 级病例表现为免疫母细胞样形态。免疫组化显示 9 例存在≥50%的 MYC 阳性细胞。双打击滤泡性淋巴瘤和伴有 MYC 和 BCL2 及/或 BCL6 重排的高级别 B 细胞淋巴瘤之间在 MYC 强度（P=0.00004）和 MIB-1 阳性率（P=0.001）方面存在显著差异。双打击滤泡性淋巴瘤的基因组谱与常规滤泡性淋巴瘤（GSE67385，n=198）相似，具有特征性的 2p25.3-p11.1、7p22.3-q36.3、12q11-q24.33 获得和 18q21.32-q23 缺失（P<0.05）。与伴有 MYC 和 BCL2 及/或 BCL6 重排的高级别 B 细胞淋巴瘤相比，双打击滤泡性淋巴瘤的拷贝数改变较少，在 2p16.1 处的最小共同增益区（70%）也显著不同，与常规滤泡性淋巴瘤相比（P=0.0001）。总之，双打击滤泡性淋巴瘤往往具有高级别组织学、高 MYC 蛋白表达、高 MYC/IGH 融合和在 2p16.1 处最小的共同增益区。双打击滤泡性淋巴瘤似乎是一种不同于伴有 MYC 和 BCL2 及/或 BCL6 重排的高级别 B 细胞淋巴瘤的疾病，其临床行为具有惰性，类似于没有 MYC 重排的滤泡性淋巴瘤。
