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Primary Central Nervous System Posttransplant Lymphoproliferative Disease in a Bilateral Transfemoral Lower Extremity Transplantation Recipient

2015; Elsevier BV; Volume: 15; Issue: 10 Linguagem: Inglês

10.1111/ajt.13313

1600-6143

Pedro C. Cavadas, Alessandro Thioné, Margarita Blanes, Empar Mayordomo‐Aranda,

Viral-associated cancers and disorders

American Journal of TransplantationVolume 15, Issue 10 p. 2758-2761 Case ReportFree Access Primary Central Nervous System Posttransplant Lymphoproliferative Disease in a Bilateral Transfemoral Lower Extremity Transplantation Recipient P. C. Cavadas, P. C. Cavadas Reconstructive Surgery Unit, Clinica Cavadas, Valencia, SpainSearch for more papers by this authorA. Thione, Corresponding Author A. Thione Reconstructive Surgery Unit, Clinica Cavadas, Valencia, Spain Corresponding author: Alessandro Thione, althione@gmail.comSearch for more papers by this authorM. Blanes, M. Blanes Infectious Disease Unit, Hospital La Fe, Valencia, SpainSearch for more papers by this authorE. Mayordomo-Aranda, E. Mayordomo-Aranda Anatomic Pathology Unit, Hospital La Fe, Valencia, SpainSearch for more papers by this author P. C. Cavadas, P. C. Cavadas Reconstructive Surgery Unit, Clinica Cavadas, Valencia, SpainSearch for more papers by this authorA. Thione, Corresponding Author A. Thione Reconstructive Surgery Unit, Clinica Cavadas, Valencia, Spain Corresponding author: Alessandro Thione, althione@gmail.comSearch for more papers by this authorM. Blanes, M. Blanes Infectious Disease Unit, Hospital La Fe, Valencia, SpainSearch for more papers by this authorE. Mayordomo-Aranda, E. Mayordomo-Aranda Anatomic Pathology Unit, Hospital La Fe, Valencia, SpainSearch for more papers by this author First published: 12 May 2015 https://doi.org/10.1111/ajt.13313Citations: 12AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Posttransplant lymphoproliferative disorder (PTLD) is a heterogeneous group of clinical and pathological entities characterized by malignant lymphoid cell proliferation occurring after solid organ transplantation, with frequent extranodal involvement. Central nervous system (CNS) involvement occurs in 7–15% of the cases and it is a significant negative prognostic factor. A case of primary CNS (PCNS) PTLD in the first bilateral lower limb transplant recipient is presented. Abbreviations PCNS primary central nervous system POD postoperative day POM postoperative month PTLD posttransplantation lymphoproliferative disease SOT solid organ transplantation VAL valgancyclovir Introduction Posttransplant lymphoproliferative disorder (PTLD) is a heterogeneous group of clinical and pathological entities characterized by malignant lymphoid cell proliferation occurring after solid organ transplantation, with frequent extranodal involvement 1. Central nervous system (CNS) involvement occurs in 7–15% of the cases, the majority of which are primary CNS (PCNS) lymphomas 2-4. CNS involvement is a significant negative prognostic factor 5-7. A case of PCNS PTLD in the first bilateral lower limb transplant recipient is presented. Immunosuppression was abruptly withdrawn and the transplanted extremities were urgently removed. Case Report A 22-year-old male patient with bilateral traumatic above-knee (AK) amputation received a bilateral lower limb transplant from an ABO-compatible female donor on July 2011, after proper informed consent and IRB approval. The patient was unable to walk with prostheses despite intensive rehabilitation. Cytomegalovirus (CMV) sero-status was D−/R−, Epstein–Barr Virus (EBV) was D−/R+, with complete HLA mismatch. Technical details of the surgical procedure as well as the postoperative management have already been published 8. Immunosuppression consisted of induction with alemtuzumab 30 mg IV, and maintenance with mycophenolate mophetyl (MMF) 1 g/12 h, tacrolimus (Tac) for trough levels of 10–17 ng/mL during the first month and 7–12 ng/mL thereafter, and tapering prednisone. No CMV prophylaxis was administered. CMV replication was monitored through PCR weekly. EBV PCR was performed in peripheral blood monthly. At postoperative day (POD) 90 Tac was changed for sirolimus with the intention to decrease the risk of malignancy 9. Coincidently, the patient developed CMV primary infection (CMV syndrome) and acute skin rejection (AR). IV valgancyclovir (Val) was started and IV methyl prednisolone was given for 5 days without resolution of the skin lesions. Histology showed a Banff grade I acute rejection, with positive C4d staining. Testing for donor specific antibodies (DSA) was negative. Treatment with depleting antibodies was not considered, to avoid increasing the risk of malignancy. Intravenous immunoglobulins (IVIg) were given for 7 days, and sirolimus was changed for Tac (POD 100) with rapid clinical and histological resolution of the skin AR. CMV replication in peripheral blood was negative after 37 days of treatment. Val was stopped on day 307 after verification of cellular CMV immunity through QuantiFERON-CMV. Function of the lower extremities was steadily improving, with active knee extension, strong foot plantar flexion and incipient foot dorsiflexion, and the patient was able to walk on parallel bars 8 at postoperative month (POM) 15. Clinically the patient was stable with negative CMV and EBV replication in peripheral blood. The patient developed diplopia and strabismus of the left eye with hipertropia. Trough levels of Tac were 7 ng/mL. Brain MRI showed a 25-mm mass in the brainstem (Figures 1 and 2). Positron emission tomography (PET) showed no other metabolically significant locations. Toxoplasma and fungal antigens were negative. EBV PCR was positive in cerebrospinal fluid (CSF). Stereotaxic biopsy confirmed the diagnosis of PTLD, with large pleomorphic lymphoid cells CD20+, CD79a+, CD10−, BCL2−, BCL6−, TdT−, and MUM1−. EBV PCR was negative in these cells, although EBV protein LMP1 was positive. CMV and JC virus PCR were also negative. Figure 1Open in figure viewerPowerPoint Brain MRI showed a 25-mm mass in the brainstem: Sagittal view (red arrow). Figure 2Open in figure viewerPowerPoint Brain MRI showed a 25-mm mass in the brainstem: Coronal view (red arrow). After discussion with the patient and his family, the immunosuppressive therapy was abruptly interrupted and the legs removed. The patient was treated with high dose of methotrexate and stereotaxic radiotherapy with complete remission. The hipertropia of the left eye remained and was treated surgically. At the time of this writing the patient is asymptomatic and continues in complete remission 23 months after the diagnosis of PCNS PTLD (Figures 3 and 4). Figure 3Open in figure viewerPowerPoint Twenty-three months post-VCA amputation. Brain MRI showing no visible mass in the brainstem: Sagittal view. Figure 4Open in figure viewerPowerPoint Twenty-three months post-VCA amputation. Brain MRI showing no visible mass in the brainstem: Coronal view. Discussion Despite improvements in immunosuppressive therapy, PTLD continues to be a significant risk in transplanted patients. Extranodal involvement is frequent 1. CNS involvement, usually primary CNS lymphoma, occurs in 7–15% of all PTLD 2-4. PTLD has been extensively studied in solid organ transplantation (SOT) and less so in vascularized composite allotransplantation (VCA), probably due to the smaller number of patients and shorter follow-up in VCA recipients. At least two other cases of PTLD have been reported in a face transplant recipient and a hand recipient. There was no CNS involvement and both resulted in chronic rejection after drastic immunosuppressive reduction (International Registry of Hand and Composite Tissue Allotransplantation: www.handregistry.com). In SOT, PCNS PTLD tends to occur late, 4–5 years after transplantation 4, 10. EBV mismatch (D+/R−), pediatric age and use of lymphodepleting antibodies are significant risk factors. In the case presented here PTLD occurred in a low-risk adult patient, EBV D−/R+ mismatched, not having received repeated doses of lymphodepleting antibodies, and at earlier posttransplant evolution. EBV replication monitoring in peripheral blood was consistently negative. Discordance between EBV replication in blood and CSF is nevertheless frequent in PCNS PTLD 11-13 and the predictive value of EBV monitoring in early PTLD diagnosis has been questioned 14, 15. The prognosis of PCNS PTLD is poor, with overall survival ranging from 0% to 43% 7, 10, 16, the most important prognostic factor being a response to the first-line therapy 11. PCNS PTLD has a somewhat better overall survival compared to PTLD with secondary CNS involvement 3. Reduction or cessation of immunosuppression, with the obvious risk of allograft rejection and loss, and various combinations of chemotherapy and radiation therapy are the mainstay of the treatment of PCNS PTLD 11, 16-19. Rituximab does not cross the blood–brain barrier and thus has a smaller role in the treatment of PCNS PTLD compared to non-CNS PTLD 16. Intraventricular rituximab is not recommended for deep brain PTLD lesions, as the one presented herein. The incidence of PTLD relates to the type of transplanted organ, being highest in small intestine transplants and lowest in heart recipients 20. In VCA, due to the relatively small number of cases, the incidence of PTLD has not yet been established. The occurrence of PTLD in the case reported herein does not seem to be related to the particular tissue composition of the transplanted part. Among VCA, hand and upper extremity transplantation is now a well-accepted procedure, with a favorable risk-benefit ratio especially in bilateral cases 21. The risk benefit of lower limb transplantation in trans-femoral bilateral amputees has not yet been determined, and it is a subject of debate 8, 22. 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