Division of Hematology, Department of Clinical and Experimental Medicine and BRMA, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
Mediterr J Hematol Infect Dis. 2009 Dec 14;1(2):e2009018. doi: 10.4084/MJHID.2009.018.
Post-transplant lymphoproliferative disorders (PTLD) are a life-threatening complication of solid organ transplantation or, more rarely, hematopoietic stem cell transplantation. The majority of PTLD is of B-cell origin and associated with Epstein-Barr virus (EBV) infection. PTLD generally display involvement of extranodal sites, aggressive histology and aggressive clinical behavior. The molecular pathogenesis of PTLD involves infection by oncogenic viruses, namely EBV, 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 cMYC, BCL6, TP53, DNA hypermethylation, and aberrant somatic hypermutation of protooncogenes. 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, MUM1 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 immunoblastic. A third group of PTLD is reminiscent of post-GC and preterminally differentiated B-cells that show the BCL6-/MUM1+/CD138+ phenotype, and are morphologically represented by either polymorphic PTLD or DLBCL immunoblastic.
移植后淋巴组织增生性疾病（PTLD）是实体器官移植或更罕见的造血干细胞移植后的一种危及生命的并发症。大多数 PTLD 起源于 B 细胞，并与 EBV 感染相关。PTLD 通常表现为结外部位受累、侵袭性组织学和侵袭性临床行为。PTLD 的分子发病机制涉及致癌病毒的感染，即 EBV，以及几个细胞基因的遗传或表观遗传改变。与在免疫功能正常的宿主中发生的淋巴瘤不同，其基因组相对稳定，一部分 PTLD 由于 DNA 错配修复机制缺陷而表现出微卫星不稳定性。除了微卫星不稳定性外，在 PTLD 中识别出的细胞基因的分子改变包括 cMYC、BCL6、TP53 的改变、DNA 高甲基化和原癌基因的异常体细胞超突变。在绝大多数 PTLD 中都存在 IGV 突变，这表明恶性转化的靶标是 EBV 阳性和 EBV 阴性病例中的生发中心（GC）B 细胞及其后代。分析 B 细胞发生的表型标志物，即 BCL6、MUM1 和 CD138，可进一步区分 PTLD 的组织发生类别。表达 BCL6+/MUM1+/-/CD138- 特征的 PTLD 反映了正在经历 GC 反应的 B 细胞，并包括弥漫性大 B 细胞淋巴瘤（DLBCL）中心母细胞和伯基特淋巴瘤。表达 BCL6-/MUM1+/CD138- 表型的 PTLD 推测源自已完成 GC 反应的 B 细胞，包括大多数多形性 PTLD 和一部分 DLBCL 免疫母细胞性。第三组 PTLD 类似于 GC 后和终末分化前的 B 细胞，表现出 BCL6-/MUM1+/CD138+ 表型，形态上表现为多形性 PTLD 或 DLBCL 免疫母细胞性。
