Department of Pathology, School of Medicine, Tokai University, Tokyo, Japan.
Department of Hematology, School of Medicine, Tokai University, Tokyo, Japan.
Virchows Arch. 2024 Apr;484(4):657-676. doi: 10.1007/s00428-024-03774-z. Epub 2024 Mar 11.
BCL6-rearrangement (BCL6-R) is associated with a favorable prognosis of follicular lymphoma (FL), but the mechanism is unknown. We analyzed the clinicopathological, immune microenvironment (immune checkpoint, immuno-oncology markers), and mutational profiles of 10 BCL6-R-positive FL, and 19 BCL6-R-positive diffuse large B-cell lymphoma (DLBCL) cases (both BCL2-R and MYC-R negative). A custom-made panel included 168 genes related to aggressive B-cell lymphomas and FL. FL cases were nodal, histological grade 3A in 70%, low Ki67; and had a favorable overall and progression-free survival. DLBCL cases were extranodal in 60%, IPI high in 63%, non-GCB in 60%, EBER-negative; and had a progression-free survival comparable to that of DLBCL NOS. The microenvironment had variable infiltration of M2-like tumor-associated macrophages (TAMs) that were CD163, CSF1R, LAIR1, PD-L1, and CD85A (LILRB3) positive; but had low IL10 and PTX3 expression. In comparison to FL, DLBCL had higher TAMs, IL10, and PTX3 expression. Both lymphoma subtypes shared a common mutational profile with mutations in relevant pathogenic genes such as KMT2D, OSBPL10, CREBBP, and HLA-B (related to chromatin remodeling, metabolism, epigenetic modification, and antigen presentation). FL cases were characterized by a higher frequency of mutations of ARID1B, ATM, CD36, RHOA, PLOD2, and PRPRD (p < 0.05). DLBCL cases were characterized by mutations of BTG2, and PIM1; and mutations of HIST1H1E and MFHAS1 to disease progression (p < 0.05). Interestingly, mutations of genes usually associated with poor prognosis, such as NOTCH1/2 and CDKN2A, were infrequent in both lymphoma subtypes. Some high-confidence variant calls were likely oncogenic, loss-of-function. MYD88 L265P gain-of-function was found in 32% of DLBCL. In conclusion, both BCL6-R-positive FL and BCL6-R-positive DLBCL had a common mutational profile; but also, differences. DLBCL cases had a higher density of microenvironment markers.
BCL6 重排（BCL6-R）与滤泡性淋巴瘤（FL）的预后良好相关，但具体机制尚不清楚。我们分析了 10 例 BCL6-R 阳性滤泡性淋巴瘤和 19 例 BCL6-R 阳性弥漫性大 B 细胞淋巴瘤（DLBCL）（BCL2-R 和 MYC-R 均为阴性）的临床病理、免疫微环境（免疫检查点、免疫肿瘤标志物）和突变特征。定制面板包括 168 个与侵袭性 B 细胞淋巴瘤和 FL 相关的基因。FL 病例为结内，70%为组织学 3A 级，Ki67 低；且总生存和无进展生存良好。DLBCL 病例 60%为结外，国际预后指数（IPI）高 63%，非生发中心型（non-GCB）60%，EBER 阴性；无进展生存与 DLBCL NOS 相当。微环境中存在可变浸润的 M2 样肿瘤相关巨噬细胞（TAMs），这些巨噬细胞 CD163、CSF1R、LAIR1、PD-L1 和 CD85A（LILRB3）阳性，但 IL10 和 PTX3 表达水平低。与 FL 相比，DLBCL 有更高的 TAMs、IL10 和 PTX3 表达。两种淋巴瘤亚型均具有相同的突变特征，存在相关致病基因如 KMT2D、OSBPL10、CREBBP 和 HLA-B（与染色质重塑、代谢、表观遗传修饰和抗原呈递有关）的突变。FL 病例的 ARID1B、ATM、CD36、RHOA、PLOD2 和 PRPRD 基因突变频率更高（p<0.05）。DLBCL 病例的 BTG2 和 PIM1 基因突变以及 HIST1H1E 和 MFHAS1 基因突变与疾病进展相关（p<0.05）。有趣的是，NOTCH1/2 和 CDKN2A 等通常与预后不良相关的基因在两种淋巴瘤亚型中均不常见。一些高可信度的变异可能是致癌的，具有功能丧失作用。MYD88 L265P 获得性功能在 32%的 DLBCL 中发现。总之，BCL6-R 阳性 FL 和 BCL6-R 阳性 DLBCL 具有共同的突变特征，但也存在差异。DLBCL 病例的微环境标志物密度更高。
