Anaplastic Variant of Diffuse Large B-cell Lymphoma Displays Intricate Genetic Alterations and Distinct Biological Features.

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Am J Surg Pathol. 2017 Oct;41(10):1322-1332.

Anaplastic Variant of Diffuse Large B-cell Lymphoma Displays Intricate Genetic Alterations and Distinct Biological Features.

Li M, Liu Y, Wang Y, Chen G, Chen Q, Xiao H, Liu F, Qi C, Yu Z, Li X, Fan L, Guo Y, Yan Q, Guo S, Wang Z.

*State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an †Department of Pathology, Fujian Cancer Hospital, Fuzhou ‡Department of Pathology, Hubei Cancer Hospital, Wuhan §Department of Pathology, Daping Hospital, Third Military Medical University, Chongqing ∥Department of Pathology, the First People's Hospital of Foshan, Foshan, China.

Abstract Anaplastic diffuse large B-cell lymphoma (A-DLBCL) is a rare morphologic variant characterized by the presence of polygonal, bizarre-shaped tumor cells. However, the clinicopathologic and genetic features of this variant are largely unknown. In this study, we investigated 35 cases of A-DLBCL with regard to their clinical, pathologic, and genetic characteristics. The age of the patients ranged from 23 to 89 years (median age, 62 y) with a male to female ratio of 23:12. Twenty-two of 26 (85%) patients had Ann Arbor stage III or IV disease, and 17/26 (65%) patients had a high-intermediate or high International Prognostic Index score. For the 24 patients treated with aggressive chemotherapy regimens, the median overall survival (OS) was 16 months, and the 2-year OS rate was 36%. Immunophenotypically, 30/35 (86%) cases had a non-germinal center B-cell immunophenotype. CD30 expression was present in 18/35 (51%) cases, and the p53 protein stain was positive in 28/35 (80%) cases. Fifteen of 35 (43%) cases expressed both BCL2 and MYC (double expressor). Twenty-nine of 32 (91%) cases tested positive for RELA, RELB, or c-Rel in the nucleus, indicating activation of the NFκB signaling pathway. Cytogenetically, 11/27 (41%) cases had concurrent MYC and BCL2 and/or BCL6 abnormalities (translocation or extra copy), including 5 cases with triple abnormalities. TP53 mutation was found in 17/30 (57%) cases, whereas the MYD88 L265P, CD79B, and CARD11 mutations were found in 7/35, 4/30, and 5/30 cases, respectively. We compared the A-DLBCL group with 50 patients with DLBCL without anaplastic features (common DLBCL). The OS of patients with A-DLBCL was significantly worse than that of patients with DLBCL without anaplastic features (P=0.004). Cases of A-DLBCL more often had a high International Prognostic Index score and a non-germinal center B-cell immunophenotype, more frequently expressed CD30 and p53, and more often had mutations of TP53 and concurrent abnormalities of MYC and BCL2 and/or BCL6 (P<0.05). In conclusion, A-DLBCL displays clinicopathologic features that distinguish it from ordinary DLBCL. Most patients follow an aggressive clinical course and have a poor outcome. Cases of A-DLBCL have a high frequency of TP53 mutation and genetic abnormalities of MYC, BCL2, and BCL6.

间变型弥漫大B细胞淋巴瘤表现出复杂的基因改变和明显的生物学特征

摘要：间变型弥漫大B细胞淋巴瘤（A-DLBCL）是一种罕见的形态学亚型，以多形性、奇异形肿瘤细胞为特征，但其临床病理和基因特征还不很清楚。本研究从临床、病理和基因特征方面研究了35例A-DLBCL。患者的年龄从23岁到89岁（中位年龄62岁），男女比例23:12，22/26（85％）患者Ann Arbor分期是Ⅲ或Ⅳ期，17/26（65％）患者有高分值的国际预后指数（IPI）。其中24个患者进行了激进的化疗方案，中位生存期（OS）是16个月，2年生存期是36％。免疫表型方面，30/35（86％）病例属于non-GCB表型。18/35（51％）病例表达CD30，28/35（80％）p53蛋白是阳性的，15/35（43％）病例表达BCL2和MYC（双表达），29/32（91％）病例检测出RELA，RELB或c-Rel的核阳性，表明存在NFκB信号通路的激活。细胞遗传学方面，11/27（41％）病例同时出现MYC和BCL2/BCL6异常（易位或多拷贝），其中5个病例是三个均异常。17/30（57％）病例发现TP53基因突变，而MYD88 L265P，CD79B和CARD11突变分别出现在7/35，4/30和5/30的病例中。同时将A-DLBCL和50例缺乏间变特征的DLBCL（普通DLBCL）进行比较，A-DLBCL患者明显比普通DLBCL的总生存期更差（P=0.004）， A-DLBCL的患者更常出现高分值的IPI指数和non-GCB表型，更高的CD30和p53的表达率，更易出现TP53基因突变和同时发生MYC和BCL2/BCL6异常（P＜0.05）。总之，A-DLBCL表现出的临床病理特征应当与普通DLBCL区别，大多数患者表现出侵袭性的临床进展和不良预后，A-DLBCL的病例具有更高TP53突变频率和MYC，BCL2和BCL6基因异常。(翻译 杨丽)