Capello Daniela, Rossi Davide, Gaidano Gianluca
Division of Hematology, Department of Medical Sciences and IRCAD, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
Hematol Oncol. 2005 Jun;23(2):61-7. doi: 10.1002/hon.751.
Post-transplant lymphoproliferative disorders (PTLD) represent a serious complication of solid organ and allogeneic bone marrow transplantation. PTLD generally display B-cell lineage derivation, involvement of extranodal sites, aggressive histology and clinical behaviour, and frequent association with EBV infection. The occurrence of IgV mutations in the overwhelming majority of PTLD documents that malignant transformation targets germinal centre (GC) B-cells and their descendants both in EBV-positive and EBV-negative cases. Analysis of phenotypic markers of B-cell histogenesis, namely BCL6, MUM-1 and CD138, allows further distinction of PTLD histogenetic categories. PTLD expressing the BCL6(+)/MUM1(+/-)/CD138(-) profile reflect B-cells actively experiencing the GC reaction and comprise diffuse large B-cell lymphoma (DLBCL) centroblastic and Burkitt lymphoma. PTLD expressing the BCL6(-)/MUM1(+)/CD138(-) phenotype putatively derive from B-cells that have concluded the GC reaction and comprise the majority of polymorphic PTLD and a fraction of DLBCL. A third group of PTLD is reminiscent of post-GC and pre- terminally differentiated B-cells that show the BCL6(-)/MUM1(+)/CD138(+) phenotype and are morphologically represented by either polymorphic PTLD or DLBCL immunoblastic. The molecular pathogenesis of PTLD involves infection by oncogenic viruses, namely Epstein-Barr virus, as well as genetic or epigenetic alterations of several cellular genes. At variance with lymphoma arising in immunocompetent hosts, whose genome is relatively stable, a fraction of PTLD are characterized by microsatellite instability as a consequence of defects in the DNA mismatch repair mechanism. Apart from microsatellite instability, molecular alterations of cellular genes recognized in PTLD include alterations of c-MYC, BCL-6, p53, DNA hypermethylation, and aberrant somatic hypermutation of proto-oncogenes.
移植后淋巴细胞增生性疾病（PTLD）是实体器官和异基因骨髓移植的一种严重并发症。PTLD通常表现为B细胞系起源、结外部位受累、侵袭性组织学和临床行为，且常与EB病毒感染相关。绝大多数PTLD中IgV突变的出现表明，在EB病毒阳性和阴性病例中，恶性转化均靶向生发中心（GC）B细胞及其后代。对B细胞组织发生的表型标志物，即BCL6、MUM-1和CD138进行分析，有助于进一步区分PTLD的组织发生类别。表达BCL6(+)/MUM1(+/-)/CD138(-)特征的PTLD反映了正在积极经历GC反应的B细胞，包括弥漫性大B细胞淋巴瘤（DLBCL）中心母细胞型和伯基特淋巴瘤。表达BCL6(-)/MUM1(+)/CD138(-)表型的PTLD可能源自已完成GC反应的B细胞，包括大多数多形性PTLD和一部分DLBCL。第三组PTLD让人联想到GC后和终末分化前的B细胞，它们表现出BCL6(-)/MUM1(+)/CD138(+)表型，在形态上表现为多形性PTLD或DLBCL免疫母细胞型。PTLD的分子发病机制涉及致癌病毒感染，即爱泼斯坦-巴尔病毒，以及多个细胞基因的遗传或表观遗传改变。与免疫功能正常宿主中发生的淋巴瘤不同，后者的基因组相对稳定，一部分PTLD因DNA错配修复机制缺陷而具有微卫星不稳定性。除微卫星不稳定性外，PTLD中识别出的细胞基因分子改变还包括c-MYC、BCL-6、p53的改变、DNA高甲基化以及原癌基因的异常体细胞超突变。
