Abstract：
OBJECTIVE: It is unknown whether Epstein-Barr virus (EBV) infection can occur in high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, also known as double-hit or triple-hit lymphoma (DHL/THL).
RESULTS: Here we report 16 cases of EBV+ DHL/THL from screening 846 cases of DHL/THL and obtaining additional EBV+ cases through multi-institutional collaboration: 8 MYC/BCL2 DHL, 6 MYC/BCL6 DHL, and 2 THL. There were 8 men and 8 women with a median age of 65 years (range, 32-86). Two patients had a history of follicular lymphoma and one had AIDS. Nine of 14 patients had an International Prognostic Index of ≥3. Half of the cases showed high-grade/Burkitt-like morphology and the other half diffuse large B-cell lymphoma morphology. By immunohistochemistry, the lymphoma cells were positive for MYC (n=14/16), BCL2 (n=12/16), BCL6 (n=14/16), CD10 (n=13/16), and MUM1 (n=6/14). By Hans algorithm, 13 cases were classified as GCB and 3 as non-GCB. The lymphomas frequently showed an EBV latency type I with a median EBV-encoded small RNAs of 80% positive cells (range, 20-100%). After a median follow-up of 36.3 months (range, 2.0-41.6), 7 patients died with a median survival of 15.4 months (range, 3.4-47.3) after diagnosis of EBV+ DHL/THL. Five of 6 patients with MYC/BCL6 DHL were alive including 4 in complete remission. In contrast, only 4/10 patients with MYC/BCL2 DHL or THL were alive including 2 in complete remission. The median survival in patients with MYC/BCL6 DHL was unreached and was 21.6 months in patients with MYC/BCL2 DHL or THL.
CONCLUSIONS: EBV infection in DHL/THL is rare (~1.5%). Cases of EBV+ DHL/THL are largely similar to their EBV-negative counterparts clinicopathologically. Our findings expand the spectrum of EBV+ B-cell lymphomas currently recognized in the WHO classification and suggest differences between EBV+ MYC/BCL2 and MYC/BCL6 DHL that may have therapeutic implications.
RESULTS: Here we report 16 cases of EBV+ DHL/THL from screening 846 cases of DHL/THL and obtaining additional EBV+ cases through multi-institutional collaboration: 8 MYC/BCL2 DHL, 6 MYC/BCL6 DHL, and 2 THL. There were 8 men and 8 women with a median age of 65 years (range, 32-86). Two patients had a history of follicular lymphoma and one had AIDS. Nine of 14 patients had an International Prognostic Index of ≥3. Half of the cases showed high-grade/Burkitt-like morphology and the other half diffuse large B-cell lymphoma morphology. By immunohistochemistry, the lymphoma cells were positive for MYC (n=14/16), BCL2 (n=12/16), BCL6 (n=14/16), CD10 (n=13/16), and MUM1 (n=6/14). By Hans algorithm, 13 cases were classified as GCB and 3 as non-GCB. The lymphomas frequently showed an EBV latency type I with a median EBV-encoded small RNAs of 80% positive cells (range, 20-100%). After a median follow-up of 36.3 months (range, 2.0-41.6), 7 patients died with a median survival of 15.4 months (range, 3.4-47.3) after diagnosis of EBV+ DHL/THL. Five of 6 patients with MYC/BCL6 DHL were alive including 4 in complete remission. In contrast, only 4/10 patients with MYC/BCL2 DHL or THL were alive including 2 in complete remission. The median survival in patients with MYC/BCL6 DHL was unreached and was 21.6 months in patients with MYC/BCL2 DHL or THL.
CONCLUSIONS: EBV infection in DHL/THL is rare (~1.5%). Cases of EBV+ DHL/THL are largely similar to their EBV-negative counterparts clinicopathologically. Our findings expand the spectrum of EBV+ B-cell lymphomas currently recognized in the WHO classification and suggest differences between EBV+ MYC/BCL2 and MYC/BCL6 DHL that may have therapeutic implications.
摘要：
目的：尚不清楚EB病毒（EBV）感染是否可发生在伴有MYC和BCL2和/或BCL6重排的高级别B细胞淋巴瘤中，也称为双重打击或三重打击淋巴瘤（DHL/THL）。
结果：在这里，我们报告了16例EBV+DHL/THL，从846例DHL/THL的筛查和通过多机构合作获得额外的EBV+病例：8MYC/BCL2DHL，6MYC/BCL6DHL,2THL有8名男性和8名女性，中位年龄为65岁(范围，32-86).两名患者有滤泡性淋巴瘤病史，一名患有AIDS。14例患者中有9例的国际预后指数≥3。一半病例表现为高级别/Burkitt样形态，另一半为弥漫性大B细胞淋巴瘤形态。通过免疫组织化学，淋巴瘤细胞MYC阳性（n=14/16），BCL2（n=12/16），BCL6（n=14/16），CD10（n=13/16），和MUM1(n=6/14)。根据汉斯算法，13例分为GCB，3例为非GCB。淋巴瘤经常显示EBV潜伏期I型，EBV编码的小RNA中位数为80％阳性细胞（范围，20-100%）。经过36.3个月的中位随访（范围，2.0-41.6),7例患者死亡，中位生存期为15.4个月(范围，3.4-47.3）诊断为EBVDHL/THL后。6例MYC/BCL6DHL患者中有5例存活，其中4例完全缓解。相比之下,只有4/10的MYC/BCL2DHL或THL患者存活，其中2例完全缓解。MYC/BCL6DHL患者的中位生存期未达到，MYC/BCL2DHL或THL患者的中位生存期为21.6个月。
结论：EBV感染在DHL/THL中是罕见的(~1.5%)。EBVDHL/THL病例在临床病理上与EBV阴性的病例在很大程度上相似。我们的发现扩大了目前在WHO分类中认可的EBVB细胞淋巴瘤的范围，并表明EBVMYC/BCL2和MYC/BCL6DHL之间的差异可能具有治疗意义。
结果：在这里，我们报告了16例EBV+DHL/THL，从846例DHL/THL的筛查和通过多机构合作获得额外的EBV+病例：8MYC/BCL2DHL，6MYC/BCL6DHL,2THL有8名男性和8名女性，中位年龄为65岁(范围，32-86).两名患者有滤泡性淋巴瘤病史，一名患有AIDS。14例患者中有9例的国际预后指数≥3。一半病例表现为高级别/Burkitt样形态，另一半为弥漫性大B细胞淋巴瘤形态。通过免疫组织化学，淋巴瘤细胞MYC阳性（n=14/16），BCL2（n=12/16），BCL6（n=14/16），CD10（n=13/16），和MUM1(n=6/14)。根据汉斯算法，13例分为GCB，3例为非GCB。淋巴瘤经常显示EBV潜伏期I型，EBV编码的小RNA中位数为80％阳性细胞（范围，20-100%）。经过36.3个月的中位随访（范围，2.0-41.6),7例患者死亡，中位生存期为15.4个月(范围，3.4-47.3）诊断为EBVDHL/THL后。6例MYC/BCL6DHL患者中有5例存活，其中4例完全缓解。相比之下,只有4/10的MYC/BCL2DHL或THL患者存活，其中2例完全缓解。MYC/BCL6DHL患者的中位生存期未达到，MYC/BCL2DHL或THL患者的中位生存期为21.6个月。
结论：EBV感染在DHL/THL中是罕见的(~1.5%)。EBVDHL/THL病例在临床病理上与EBV阴性的病例在很大程度上相似。我们的发现扩大了目前在WHO分类中认可的EBVB细胞淋巴瘤的范围，并表明EBVMYC/BCL2和MYC/BCL6DHL之间的差异可能具有治疗意义。
