EBV阳性DLBCL患者表达CD30提示预后不良

瑞士卢加诺举行的国际恶性淋巴瘤年会上报告的一项研究显示，EB病毒阳性的弥漫性大B细胞淋巴瘤(即EBV+DLBCL)仅占DLBCL的一小部分，具有不同于EBV阴性DLBCL的活化B细胞型免疫表型、特异性基因表达谱以及遗传标志；另外，与EBV阴性DLBCL相比，CD30表达在EBV+DLBCL中更常见，并且预示着结局不良(Hematol. Oncol. 2013;31[(Suppl 1]:96-150[abstract 9])。

由美国德克萨斯州休斯顿MD安德森癌症中心的Ken He Young医生等人进行的这项研究，共纳入451例HIV阴性的原发性DLBCL患者，这些患者均有原发肿瘤活检标本的组织微阵列，并且统一接受利妥昔单抗+环磷酰胺、多柔比星、长春新碱及强的松龙的联合化疗方案(R-CHOP)。在这些患者中，27例(6%)EBV编码的RNA(EBER)检测结果为阳性(定义为10%以上的恶性肿瘤细胞有反应)。EBV阳性和EBV阴性患者的中位年龄相近，分别为61岁和64岁，临床特征表现也相近。不过，出现活化B细胞型标志的患者占EBV阳性患者的70%，而占EBV阴性患者的48%或49%(基于基因表达谱和免疫组化结果，采用Visco-Young算法)，存在CD30表达者占EBV阳性患者的48%，而占EBV阴性患者的15%。EBV阳性组和EBV阴性组在BCL2、MYC或这两种蛋白的表达上未见差异，但EBV阳性患者无不良的TP53突变，仅18%表现出包括BCL2、C-MYC或BCL6基因的重排。

分析结果显示，EBV阳性DLBCL患者的5年总体生存率较低，为50%，而EBV阴性DLBCL 患者为62%，即使按年龄进行分层分析后仍得出相似结果，但组间差异尚未达到统计学意义。无进展生存的情况与之相近。然而，有CD30表达的EBV阳性DLBCL患者的结局差强人意，中位总体生存率和无进展生存率分别为37%和35%，相比之下，这两项指标在CD30表达阴性的EBV阳性DLBCL患者中分别为74%和56%，差异均具有统计学意义，并且基因表达谱显示NF-kB途径活化的EBV阳性DLBCL患者存在特异性的表达标志。

研究者们在另外一篇来自国际DLBCL利妥昔单抗-CHOP联盟研究的报告中解释道，有关老年人EBV阳性DLBCL的描述最早可追溯到10年前，该病是世界卫生组织分类体系中的暂定类型，被定义为“发生于年龄在50岁以上、无已知的免疫缺陷或淋巴瘤病史的患者的EBV阳性单克隆大B细胞增殖”。他们表示，对这些肿瘤的理解加深将有助于研发出新的治疗方法，优化临床试验，改善患者结局。

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By: SHARON WORCESTER, Oncology Practice

Epstein-Barr virus-positive diffuse large B-cell lymphoma, or EBV+ DLBCL, represents only a small proportion of DLBCLs, and has an activated B-cell type immunophenotype and a unique gene expression profile and genetic signature that distinguish the neoplasm from EBV-negative DLBCL, according to a report from the International DLBCL Rituximab-CHOP Consortium Program Study.

Further, CD30 expression is more common in EBV+ DLBCL than in EBV-negative DLBCL and confers an adverse outcome, Dr. Ken He Young reported at the annual International Conference on Malignant Lymphoma in Lugano, Switzerland.

The findings are based on a study of 451 HIV-negative de novo DLBCL patients who had tissue microarrays from primary biopsy specimens available. All were uniformly treated with rituximab plus chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), said Dr. Young of the department of hematopathology at the University of Texas MD Anderson Cancer Center, Houston (Hematol. Oncol. 2013;31[(Suppl 1]:96-150[abstract 9]).

Of the 451 patients, 27 (6%) had positive EBV-encoded RNA (EBER) test results, defined as reactivity in more than 10% of malignant cells. The median age of the EBV+ and EBV- patients was similar at 61 and 64 years, respectively, as were the presenting clinical characteristics, Dr. Young noted.

However, an activated B-cell type signature occurred in 70% of EBV+ patients, compared with 48% or 49% (based on gene expression profiling and immunohistochemistry using the Visco-Young algorithm, respectively) in the EBV- patients, and CD30 expression occurred in 48% of EBV+ patients, compared with 15% of EBV- patients, he said.

No difference was seen in the expression of BCL2, MYC or both proteins between the EBV+ and EBV- groups, but the EBV+ patients had no detrimental TP53 mutation and only 18% presented rearrangements involving BCL2, C-MYC, or BCL6 genes.

Five-year overall survival appeared inferior in the EBV+ DLBCL patients at 50%, compared with 62% for the EBV- DLBCL patients, even after stratification by age, but the difference between the groups did not reach statistical significance. The same was true for progression-free survival, Dr. Young noted.

Among EBV+ DLBCL patients with CD30 expression, however, the prognosis was dismal, with median overall and progression-free survival of 37% and 35%, respectively, compared with 74% and 56%, respectively, in those with CD30 negative EBV+ DLBCL. These differences were statistically significant, Dr. Young said, adding that gene expression profiling revealed a unique expression signature in EBV+ DLBCL with NF-kB pathway activation.

In a separate report from the International DLBCL Rituximab-CHOP Consortium Program Study published online in May in Blood, Dr. Young and his colleagues explained that EBV+ DLBCL of the elderly, which was initially described 10 years ago, is a provisional entity within the World Health Organization classification system, and is defined as "an EBV-positive monoclonal large B-cell proliferation that occurs in patients greater than 50 years of age and in whom there is no known immunodeficiency or history of lymphoma," (2013;121: 2715-24 [doi:10.1182/blood-2012-10-461848]).

"It is hoped that the improved understanding of these tumors will lead to development of novel therapeutic approaches, enhance the effective clinical trials, and improve the prognosis," the investigators said.