移植后淋巴组织增生性疾病的临床病理观察

Post-transplant lymphoproliferative disorder： a clinicopathologic study of 15 cases

目的探讨移植后淋巴组织增生性疾病（PTLD）的临床病理学特征、诊断、发病机制及治疗。方法按2008年WHO造血与淋巴组织肿瘤分类，应用光镜观察、免疫组织化学EnVision法、原位杂交方法，结合文献，对北京大学人民医院2008年5月至2011年10月诊断的15例PTLD进行临床病理学分析。结果15例PTLD中，14例为异基因造血干细胞移植（AHSCT），1例为肾移植。男12例，女3例，男女之比为4：1。从移植到诊断PTLD的时间为1．5～132个月，平均13．0个月。14例AHSCT年龄范围9～45岁，平均年龄28．3岁，从移植到诊断PTLD的时间为1．5～19个月，平均为4．5个月。临床表现主要为发热、淋巴结肿大。淋巴结活检12例，扁桃体、胃、肠黏膜活检各1例。组织学类型：早期病变4例，其中1例为浆细胞增生，3例为传染性单核细胞增多症样；多形性PTLD7例，其中4例CD20阳性大细胞数目较多，肠黏膜活检病例伴有移植物抗宿主病；单一形PTLD4例，3例为弥漫性大B细胞淋巴瘤，1例为浆母细胞性淋巴瘤，其中1例为单一形与多形性PTLD混合。5例可见灶片状坏死，Ki-67阳性指数高，AHSCT者EB病毒编码的小分子RNA（EBER）阳性比例13／14，肾移植者为阴性。EB病毒阳性者移植后发生PTLD的时间（1．5—7个月）比EB病毒阴性者短（19、132个月）。诊断PTLD后部分病例采用免疫抑制剂减量、抗病毒或利妥昔单抗治疗。随访时间0～8个月，5例死亡。结论形态学和免疫组织化学对于PTLD的诊断尤为重要。EB病毒阳性者移植后发生PTLD的时间比EB病毒阴性者短。AHSCT发生PTLD多见于年轻人，发生PTLD的时间比实体器官移植短。PTLD预后差，应用免疫抑制剂减量、抗EB病毒或利妥昔单抗治疗对于PTLD有效。

Objective To study the clinical and histopathologic features, diagnosis, pathogenesis and therapy of post-transplant lymphoproliferative disorders （PTLD）. Methods The clinical and pathologic features of 15 cases of PTLD were retrospectively analyzed by light microscopy, immunohistochemistry and in-situ hybridization, according to the updated 2008 WHO classification of tumors of hematopoietic and lymphoid tissues. Results Amongst the 15 cases studied, 14 cases had received allogenic hematopoietic stem cell transplantation （AHSCT） and 1 case had received renal transplantation. There were altogether 12 males and 3 females. The male-to-female ratio was 4： 1. The mean age was 30. 4 years and the median age was 31 years （range from 9 to 60 years）. PTLD developed 1.5 to 132 months after transplantation （median 13.0 months）. The mean age of the 14 patients with AHSCT was 28.3 years （ range from 9 to 45 years） and PTLD developed 1.5 to 19 months after transplantation （ mean 4. 5 months）. Major clinical presentation included fever and lymphadenopathy. Twelve cases involved mainly lymph nodes and the remaining 3 cases involved tonsils, stomach and small intestine, respectively. The histologic types in 4 cases represented early lesions, including plasmacytic hyperplasia （ n = 1 ） and infectious mononucleosis-like PTLD （ n = 3 ）. Seven cases were polymorphic PTLD, with 4 cases containing a predominance of large cells. Graft-versus-host disease was also seen in the case of small intestinal involvement. Four cases were monomorphic PTLD, 3 of which were diffuse large B-cell lymphoma, 1 was plasmablastic lymphoma and 1 was a mixture of monomorphic and polymorphic PTLD. Foci of necrosis were seen in 5 cases. The proliferating index of Ki-67 was high. The positive rate of EBV-encoded RNA in AHSCT was 92. 9%. The duration of PTLD onset was shorter in EBV-positive cases （range from 1.5 to 7 months） than EBV-negative cases （range from 19 and 132 months）. Some cases were treated by reduction of immunosuppression, antiviral agents or anti-CD20 monoclonal antibody Rituximab. The duration of follow-up in lg patients ranged from 0 to 8 months. Five of the patients died of the disease. Conclusions The diagnosis of PTLD relies on morphologic examination and immunohistochemistry. Most of them are of B-cell origin. EBV plays an important role in the pathogenesis of PTLD. The duration of disease onset is shorter in EBV-positive cases. PTLD in AHSCT cases occurs in younger age group, with shorter duration of onset, as compared to solid organ transplantation. The prognosis of PTLD is poor. The modalities of treatment include reduction of immunosuppression, antiviral agents or anti-CD20 monoclonal antibody Rituximab.