Diagnosis and treatment of posttransplant lymphoproliferative diseases in liver transplant recipients: a single-center experience
-
摘要:
目的 总结肝移植受者移植后淋巴组织增生性疾病(PTLD)的发病情况和诊疗经验。 方法 回顾性分析734例肝移植受者的临床资料,收集肝移植受者中PTLD的发病情况、临床症状、实验室数据及影像学资料;分析PTLD受者的病理学结果与治疗方式;分析PTLD受者的预后情况。 结果 肝移植受者PTLD发生率为2.2%(16/734), 中位术后发病时间为8(3, 46)个月。PTLD的临床表现主要为发热、淋巴结肿大,部分出现贫血、肝脾肿大、肝功能异常和消化系统症状等。16例PTLD受者中,1例他克莫司血药浓度异常升高;6例转氨酶升高;14例爱泼斯坦-巴尔病毒(EBV)DNA载量升高;5例巨细胞病毒(CMV)DNA载量升高。13例受者正电子发射计算机体层显像仪(PET/CT)检查提示相关肿大淋巴结18F-氟代脱氧葡萄糖代谢增高;2例受者颈部及腹部CT检查提示相应区域多发淋巴结肿大;1例受者仅超声提示淋巴结肿大。16例PTLD受者均行病理学检查, 其中13例受者原位杂交结果提示EBV编码的小RNA(EBER)阳性。降低免疫抑制剂水平是PTLD受者的基础治疗方案,根据不同病理类型的PTLD可联合利妥昔单抗靶向治疗及化学药物治疗;针对肿大淋巴结,给予手术及放射治疗。1例受者因PTLD治疗致移植肝衰竭死亡。 结论 肝移植术后免疫抑制剂的使用可增加PTLD的患病风险,PTLD在儿童肝移植受者中发生率高于成人,尽早诊断和合理治疗可极大地改善PTLD受者的预后。 -
关键词:
- 肝移植 /
- 移植后淋巴组织增生性疾病 /
- 爱泼斯坦-巴尔病毒 /
- 免疫抑制剂 /
- 18F-氟代脱氧葡萄糖 /
- 巨细胞病毒 /
- 淋巴瘤 /
- 靶向治疗
Abstract:Objective To summarize the incidence, diagnosis and treatment experience of posttransplant lymphoproliferative diseases (PTLD) in the liver transplant recipients. Methods Clinical data of 734 liver transplant recipients were retrospectively analyzed. The incidence, clinical symptoms, laboratory and imaging data of PTLD in liver transplant recipients were collected. The pathological results and treatment methods of PTLD recipients were analyzed. The prognosis of PTLD recipients was evaluated. Results The incidence of PTLD in liver transplant recipients was 2.2% (16/734). The median time of onset after operation was 8(3, 46) months. The main clinical manifestations of PTLD were fever and lymph nodes enlargement. Some patients developed anemia, hepatosplenomegaly, abnormal liver function and digestive system symptoms, etc. Among 16 PTLD recipients, 1 case showed abnormal increase in blood concentration of tacrolimus, 6 cases of elevated transaminase levels, 14 cases of increased Epstein-Barr virus (EBV) DNA load and 5 cases of increased cytomegalovirus (CMV) DNA load. Positron emission tomography and computed tomography (PET/CT) showed hypermetabolism of 18F-flurodeoxyglucose in the enlarged lymph nodes of 13 recipients. CT scan of the neck and abdomen indicated multiple lymph node enlargement in the corresponding area of 2 recipients. Lymph nodes enlargement of 1 recipient showed on ultrasound only. All 16 PTLD recipients received pathological examination. In situ hybridization showed that EBV-encoded small RNA (EBER) was positive in 13 recipients. Reducing the immunosuppressant level was the basal treatment plan for PTLD recipients, and it can be combined with rituximab-targeted therapy and chemotherapy according to different pathological types of PTLD. Surgery and radiotherapy were used for enlarged lymph nodes. One recipient died of transplant liver failure due to PTLD treatment. Conclusions Administration of immunosuppressants after liver transplantation can increase the risk of PTLD. The incidence of PTLD is higher in pediatric liver transplant recipients than in adults. Early diagnosis and reasonable treatment can significantly improve the prognosis of PTLD recipients. -
表 1 16例肝移植术后PTLD受者的临床资料
Table 1. Clinical data of 16 cases of PTLD recipients after liver transplantation
例序 性别 年龄 术后发病时间(月) 术前血清学状态 病理学结果 治疗 预后 EBV CMV EBER①原位杂交 组织学分型 1 男 19个月 8 D②+/R③+ D+/R+ 阳性 PTLD,早期病变 RIS④;利妥昔单抗靶向治疗2周期 部分缓解 2 男 29个月 6 D-/R- D-/R- 阳性 PTLD,早期病变 RIS;利妥昔单抗靶向治疗2周期 部分缓解 3 女 8个月 16 D- D- 阳性 颈部淋巴结:淋巴组织反应性增生伴EBV感染;肝脏穿刺组织:单形性,EBV阳性T细胞淋巴组织增生性疾病 RIS 疾病稳定 4 女 6个月 9 R- D-/R- 阳性 多形性PTLD RIS;RIS后转氨酶升高,甲泼尼龙冲击治疗3 d;利妥昔单抗靶向治疗1周期 部分缓解 5 女 27个月 46 -⑤ - 阴性 淋巴组织反应性增生 RIS 疾病稳定 6 女 7个月 11 D-/R- D-/R- 阳性 PTLD,传染性单核细胞增生性早期病变 RIS;利妥昔单抗靶向治疗2周期 疾病稳定 7 女 13个月 7 D+/R- D+/R+ 阳性 PTLD,单形性,非霍奇金弥漫大B细胞淋巴瘤 RIS;手术切除坏死肠管;R-CHOP⑥方案化疗⑦1周期 部分缓解 8 男 9个月 7 D-/R- D-/R- 阴性 淋巴组织反应性增生伴慢性炎症 RIS;阿昔洛韦抗病毒治疗 疾病稳定 9 男 6个月 9 D- D- 阳性 淋巴结非破坏性PTLD(传染性单核细胞增生性早期病变)伴皮病性淋巴结炎 RIS 疾病稳定 10 男 5个月 10 R- D-/R- 阳性 淋巴结滤泡为主的反应性增生,伴EBV感染 RIS 疾病稳定 11 男 13个月 5 - - 阳性 PTLD,早期病变;形态符合卡波西肉瘤 RIS;利妥昔单抗靶向治疗1周期 PTLD复发 12 女 32个月 36 D- D- 阳性 淋巴组织反应性增生 RIS 疾病稳定 13 男 8个月 4 D-/R- D-/R- 阳性 淋巴组织反应性增生 RIS 疾病稳定 14 男 46岁 7 - - 阳性 多形性PTLD RIS;利妥昔单抗靶向治疗4周期;肝门部病灶放射治疗 疾病稳定 15 男 46岁 11 D+ D- 阴性 PTLD,单形性,呈非霍奇金弥漫大B细胞淋巴瘤改变 RIS;R-COP⑧化疗1周期,R-CHOP化疗2周期,利妥昔单抗靶向治疗1周期;病灶部位放射治疗 PTLD部分缓解,移植肝衰竭死亡 16 女 53岁 3 - - 阳性 多形性PTLD RIS,后因排斥反应恢复用药;停吗替麦考酚酯;利妥昔单抗靶向治疗1周期,R-COP化疗1周期,VP16⑨联合CHOP⑩化疗1周期,后患者拒绝化疗 部分缓解 注:①EBER为EBV编码的小RNA。
② D为供者。
③ R为受者。
④ RIS为降低免疫抑制剂水平,包括减量或停用他克莫司、伴或不伴有同时口服糖皮质激素。
⑤-为未检测。
⑥ R-CHOP为利妥昔单抗+环磷酰胺+多柔比星+长春新碱+地塞米松。
⑦化疗为化学药物治疗。
⑧ R-COP为利妥昔单抗+环磷酰胺+长春新碱+地塞米松。
⑨ VP16为依托泊苷。
⑩ CHOP为环磷酰胺+多柔比星+长春新碱+地塞米松。 -
[1] DIERICKX D, HABERMANN TM. Post-transplantation lymphoproliferative disorders in adults[J]. N Engl J Med, 2018, 378(6):549-562. DOI: 10.1056/NEJMra1702693. [2] SWERDLOW SH, CAMPO E, PILERI SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms[J]. Blood, 2016, 127(20):2375-2390. DOI: 10.1182/blood-2016-01-643569. [3] QIN T, GU XQ, JEONG SS, et al. Impact of EBV infection and immune function assay for lymphoproliferative disorder in pediatric patients after liver transplantation: a single-center experience[J]. Hepatobiliary Pancreat Dis Int, 2020, 19(1):3-11. DOI: 10.1016/j.hbpd.2019.12.005. [4] KEMPF C, TINGUELY M, RUSHING EJ. Posttransplant lymphoproliferative disorder of the central nervous system[J]. Pathobiology, 2013, 80(6):310-318. DOI:10. 1159/000347225. [5] SINGAVI AK, HARRINGTON AM, FENSKE TS. Posttransplant lymphoproliferative disorders[J]. Cancer Treat Res, 2015, 165:305-327. DOI:10.1007/978-3-319-13150- 4_13. [6] L'HUILLIER AG, DIPCHAND AI, NG VL, et al. Posttransplant lymphoproliferative disorder in pediatric patients: characteristics of disease in EBV-seropositive recipients[J]. Transplantation, 2019, 103(11):e369-e374. DOI: 10.1097/TP.0000000000002898. [7] HSU CT, CHANG MH, HO MC, et al. Post-transplantation lymphoproliferative disease in pediatric liver recipients in Taiwan[J]. J Formos Med Assoc, 2019, 118(11):1537- 1545. DOI: 10.1016/j.jfma.2018.12.023. [8] SEO E, KIM J, OH SH, et al. Epstein-Barr viral load monitoring for diagnosing post-transplant lymphoproliferative disorder in pediatric liver transplant recipients[J]. Pediatr Transplant, 2020, 24(4):e13666. DOI: 10.1111/petr.13666. [9] NARKEWICZ MR, GREEN M, DUNN S, et al. Decreasing incidence of symptomatic Epstein-Barr virus disease and posttransplant lymphoproliferative disorder in pediatric liver transplant recipients: report of the studies of pediatric liver transplantation experience[J]. Liver Transpl, 2013, 19(7):730-740. DOI: 10.1002/lt.23659. [10] ØSTENSEN AB, SANENGEN T, HOLTER E, et al. No effect of treatment with intravenous ganciclovir on Epstein-Barr virus viremia demonstrated after pediatric liver transplantation[J]. Pediatr Transplant, 2017, 21(6):e13010. DOI: 10.1111/petr.13010. [11] ALDABBAGH MA, GITMAN MR, KUMAR D, et al. The role of antiviral prophylaxis for the prevention of Epstein-Barr virus-associated posttransplant lymphoproliferative disease in solid organ transplant recipients: a systematic review[J]. Am J Transplant, 2017, 17(3):770-781. DOI: 10.1111/ajt.14020. [12] ALLEN UD, PREIKSAITIS JK, AST Infectious Diseases Community of Practice. Epstein-Barr virus and posttransplant lymphoproliferative disorder in solid organ transplantation[J]. Am J Transplant, 2013, 13 (Suppl 4): 107-120. DOI: 10.1111/ajt.12104. [13] SILVA JT, FERNÁNDEZ-RUIZ M, AGUADO JM. Prevention and therapy of viral infections in patients with solid organ transplantation[J]. Enferm Infecc Microbiol Clin, 2020, DOI: 10.1016/j.eimc.2020.01.021[Epub ahead of print]. [14] GEORGE TI, JENG M, BERQUIST W, et al. EpsteinBarr virus-associated peripheral T-cell lymphoma and hemophagocytic syndrome arising after liver transplantation: case report and review of the literature[J]. Pediatr Blood Cancer, 2005, 44(3):270-276. DOI:10.1002/ pbc.20231. [15] MUMTAZ K, FAISAL N, MARQUEZ M, et al. Posttransplant lymphoproliferative disorder in liver recipients: characteristics, management, and outcome from a singlecentre experience with >1 000 liver transplantations[J]. Can J Gastroenterol Hepatol, 2015, 29(8):417-422. DOI: 10.1155/2015/517359. [16] BISHNOI R, MINISH J, FRANKE AJ, et al. Singleinstitution retrospective analysis of prognostic factors influencing very late-onset post-transplant lymphoproliferative disorder[J]. Cureus, 2020, 12(2):e6912.DOI: 10.7759/cureus.6912. [17] PETERS AC, AKINWUMI MS, CERVERA C, et al. The changing epidemiology of posttransplant lymphoproliferative disorder in adult solid organ transplant recipients over 30 years: a single-center experience[J]. Transplantation, 2018, 102(9):1553-1562. DOI:10.1097/ TP.0000000000002146. [18] ABSALON MJ, KHOURY RA, PHILLIPS CL. Posttransplant lymphoproliferative disorder after solid-organ transplant in children[J]. Semin Pediatr Surg, 2017, 26(4):257-266. DOI: 10.1053/j.sempedsurg.2017.07.002. [19] CAMACHO JC, MORENO CC, HARRI PA, et al. Posttransplantation lymphoproliferative disease: proposed imaging classification[J]. Radiographics, 2014, 34(7):2025- 2038. DOI: 10.1148/rg.347130130. [20] XU YF, YANG JG. Roles of F-18-fluoro-2-deoxy-glucose PET/computed tomography scans in the management of post-transplant lymphoproliferative disease in pediatric patient[J]. PET Clin, 2020, 15(3):309-319. DOI:10.1016/ j.cpet.2020.03.006. [21] EVENS AM, ROY R, STERRENBERG D, et al. Posttransplantation lymphoproliferative disorders: diagnosis, prognosis, and current approaches to therapy[J]. Curr Oncol Rep, 2010, 12(6):383-394. DOI:10.1007/s11912- 010-0132-1. [22] GROSS TG, ORJUELA MA, PERKINS SL, et al. Lowdose chemotherapy and rituximab for posttransplant lymphoproliferative disease (PTLD): a children's oncology group report[J]. Am J Transplant, 2012, 12(11):3069- 3075. DOI: 10.1111/j.1600-6143.2012.04206.x. [23] TRAPPE R, OERTEL S, LEBLOND V, et al. Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial[J]. Lancet Oncol, 2012, 13(2):196-206. DOI: 10.1016/S1470-2045(11)70300-X. [24] IGNACAK E, SUŁOWICZ J, GIZA A, et al. Posttransplant lymphoproliferative disorder in a patient after kidney transplant, 5-year follow-up: a case report[J]. Transplant Proc, 2020, 52(8):2517-2519. DOI:10.1016/ j.transproceed.2020.02.083. [25] VAN BESIEN K, BACHIER-RODRIGUEZ L, SATLIN M, et al. Prophylactic rituximab prevents EBV PTLD in haplo-cord transplant recipients at high risk[J]. Leuk Lymphoma, 2019, 60(7):1693-1696. DOI:10.1080/10428 194.2018.1543877. [26] ROSSIGNOL J, TERRIOU L, ROBU D, et al. Radioimmunotherapy ((90) y-ibritumomab tiuxetan) for posttransplant lymphoproliferative disorders after prior exposure to rituximab[J]. Am J Transplant, 2015, 15(7):1976-1981. DOI: 10.1111/ajt.13244. [27] CHIOU FK, BEATH SV, WILKIE GM, et al. Cytotoxic T-lymphocyte therapy for post-transplant lymphoproliferative disorder after solid organ transplantation in children[J]. Pediatr Transplant, 2018, 22(2). DOI: 10.1111/petr.13133. [28] BUNCHORNTAVAKUL C, REDDY KR. Epstein-Barr virus and cytomegalovirus infections of the liver[J]. Gastroenterol Clin North Am, 2020, 49(2):331-346. DOI: 10.1016/j.gtc.2020.01.008.