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Extradural Thoracic Spinal Cord Compression: Unusual Initial Presentation of Post-transplant Lymphoproliferative Disorder
Extradural Thoracic Spinal Cord Compression: Unusual Initial Presentation of Post-transplant Lymphoproliferative Disorder Nicholas. A. Bakker, MD, PhD,a J. Marc. C. van Dijk, MD, PhD,a Riemer. H. J. A. Slart, MD, PhD,b Maarten. H. Coppes, MD, PhD,a Gustaaf. W. van Imhoff, MD, PhD,c and Eric. A. M. Verschuuren, MD, PhDd Post-transplant lymphoproliferative disorder (PTLD) is a serious complication after solid-organ transplantation. We report a lung transplant recipient presenting with lower limb weakness as a result of extradural cord compression from PTLD. Diagnosis was made by laminectomy of T-3 with partial removal of the epidural mass. Further treatment consisted of chemoradiotherapy. The patient recovered completely. To our knowledge, this is the first reported case of PTLD presenting with signs and symptoms of spinal cord compression. The differential diagnosis of spinal cord compression in a patient who has had a transplant should include primary presentation of PTLD. J Heart Lung Transplant 2008;27:1165– 8. Copyright © 2008 by the International Society for Heart and Lung Transplantation.
Post-transplant lymphoproliferative disorder (PTLD) is a serious complication observed after solid-organ transplantation and affects up to 10% of lung transplant recipients. PTLD consists of a heterogeneous group of lymphoid proliferations, usually of B-cell origin and related to the Epstein–Barr virus.1 Although PTLD may present at virtually any site, early presentations are usually localized in the transplanted organ, whereas late presentations are mostly localized in the gastrointestinal tract.2,3 We describe a lung transplant recipient presenting with lower limb weakness as a result of extradural spinal cord compression from PTLD. CASE REPORT A 44-year-old man presented with lower limb weakness and sensory deficits. The patient’s history revealed a bilateral lung transplant 18 months earlier for end-stage emphysema based on ␣1-anti-trypsin deficiency. The post-operative course was uncomplicated and initial immunosuppression consisted of two doses of basiliximab and maintenance therapy with azathioprine, tacrolimus and prednisolone. The patient was Epstein– Barr virus (EBV)-seropositive prior to transplantation. Two and 4 weeks after transplantation, the patient had
From the Departments of aNeurosurgery, bNuclear Medicine and Molecular Imaging, cHaematology and dPulmonary Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. Reprint requests: N. A. Bakker, MD, Department of Neurosurgery, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. Telephone: ⫹31-50-3612837. Fax: ⫹3150-3611715. E-mail: [email protected] Copyright © 2008 by the International Society for Heart and Lung Transplantation. 1053-2498/08/$–see front matter. doi:10.1016/ j.healun.2008.06.008
acute rejection episodes for which pulse therapy with methylprednisolone was administered (3 days of 1,000 mg methylprednisolone orally), and azathioprine was converted to mycophenolate mofetil (CellCept). Three months before presentation, the patient complained of painful shoulders and sensory disturbances in both legs. During a holiday in another country, the patient experienced rapid progressive lower limb weakness. Magnetic resonance (MR) imaging in a local hospital revealed significant medullary compression at the T-3 level due to an intrapleural mass with epidural involvement, after which the patient was immediately transported to our hospital for further evaluation. On admission, sensory deficits were present from T-5 and below. In addition, progressive paresis (Medical Research Scale [MRC] ⫽ 2) of his lower extremities was present for 48 hours. Repeated MR imaging of the thoracic spine showed an intrapleural mass with epidural involvement at the T-3 level, with severe compression of the spinal cord (Figure 1a,b). Promptly, a laminectomy of T-3 was performed with partial removal of the epidural mass. On suspicion of early, EBV-positive, CD20-positive PTLD, post-operatively one dose of rituximab was already administered (375 mg/m2) and immunosuppression was reduced. However, despite decompression, the neurologic deficit initially persisted. In addition, the patient was given radiotherapy (1 ⫻ 8 Gy) at the involved level to further decrease tumor volume. Histologic study showed EBVencoded RNA (EBER)-negative, CD20-negative, plasmacytoma-like PTLD, after which rituximab was stopped. A complete work-up with bone marrow biopsy, CT scanning and 18F-fluorodeoxyglucose–positron emission tomography (FDG-PET) revealed a paravertebral FDG-PET–positive mass (Figure 2), continuous with 1165
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Figure 1. MR scan at presentation. There is a left paravertrebral lesion with involvement of the spinal canal at the T-3– 4 level and compression of the spinal cord.
the thoracic cavity, and mediastinal and diaphragmal lymphadenopathy (as detected by CT scanning). Polychemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) was initiated. By 6 months after surgery, radiotherapy and chemotherapy, the neurologic deficits on his lower limbs recovered nearly completely. The strength in both his legs was maximal, whereas only mild dorsal column deficits were present. In addition, FDG-PET scanning and CT scanning
showed complete remission (Figure 3), while lung function has continued to remain stable. DISCUSSION PTLD encompasses a heterogeneous group of lymphoproliferative diseases, ranging from EBV-driven polyclonal proliferation, resembling infectious mononucleosis, to highly aggressive, monomorphic proliferations, which may be indistinguishable from aggressive types of lymphoma, such as diffuse, large B-cell lymphoma.
Figure 2. FDG-PET (left) and combined FDG-PET and CT (right). Left-sided paravertebral lesion with high focal FDG uptake at the T-3– 4 level.
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Figure 3. FDG-PET (left) and combined FDG-PET and CT (right). FDG-PET and combined FDG-PET plus CT show complete remission after 3 months of therapy.
Generally, PTLD is considered an iatrogenic complication of immunosuppression after transplantation, leading to decreased function of EBV-specific T cells, which, in turn, may lead to uncontrolled proliferation of EBV-infected B cells, ultimately leading to PTLD.4 PTLD is, however, not exclusively associated with EBV infection, as EBV-negative PTLD, with a tendency to develop late after transplantation, is also increasingly recognized.5 Although the association between EBV and PTLD is well established, the presence of EBV in tumor cells is not required for the diagnosis of PTLD. This implies that, according to the international classification, any lymphoma arising in a post-transplant patient is considered to be (a variant of) PTLD.6 The incidence of PTLD varies significantly between different types of organ transplants, with the highest incidence (5% to 20%) found after lung and small bowel transplantation. In contrast, reported incidences in kidney transplant recipients are much lower (1% to 3%). Differences in incidence most likely reflect the more aggressive immunosuppression in the first group of patients.2 The risk of PTLD development is significantly higher in the early posttransplant period (⬍1 year after transplantation), especially in heart–lung and lung transplant recipients. Primary central nervous system (CNS) localization is observed in about 5% to 15% of all PTLD cases,7 and almost invariably affects the brain. This is in contrast with patients with “conventional” non Hodgkin’s lymphoma, in which the CNS is less frequently affected.
The reasons for the observed difference in incidence between patients with and without immune deficiencies have not been elucidated.7 PTLD treatment always consists of reduced immunosuppression. Early lesions, including plasma cell hyperplasia and lesions resembling infectious mononucleosis, are usually polyclonal and often regress only after reduction of immunosuppression.8 In contrast, monomorphic PTLD, which has a clinical course more closely resembling diffuse, large B-cell lymphoma, should be treated more aggressively. Monoclonal antibody therapy (rituximab) directed against the B-cell receptor CD20 is frequently applied and is now widely regarded as first-line treatment.9,10 Polychemotherapy (mostly with cyclophosphamide, CHOP) is reserved for patients in whom other treatment options have failed or when PTLD is CD20-negative.11 Despite its early presentation, the case presented herein turned out to be CD20negative (plasmacytoma-type PTLD is almost invariably CD20-negative), after which rituximab was stopped and CHOP therapy initiated. In cases of progressive spinal cord compression by an intraspinal tumor mass, radiotherapy used to be firstline treatment for many decades. However, it seems that, in patients with progressive spinal cord compression by non-radiosensitive tumors, direct decompressive surgery should be performed before initiation of radiotherapy, because this treatment turned out to be superior to treatment with radiotherapy alone in terms of ability to walk.12 Survival among transplant recipients with PTLD ranges from 28% to 75%, and 1-year overall survival rates range
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from 44% to 73%.9,10,13,14 However, there may be subgroups of patients differing in their response to treatment. Specifically, late-onset PTLD carries a worse prognosis when compared with early-onset PTLD.15,16 This might be attributed to the higher percentage of EBV-negative PTLD in late-onset disease. Patients with CNS involvement have among the poorest prognoses.7 To the best of our knowledge, this is the first reported case of PTLD presenting with sensory and motor weakness as a result of compression of the spinal cord. Signs of spinal cord compression in a patient with a transplant in the past should therefore raise the possibility of primary PTLD. REFERENCES 1. Bakker NA, van Imhoff GW, Verschuuren EA, van Son WJ. Presentation and early detection of post-transplant lymphoproliferative disorder after solid organ transplantation. Transplant Int 2007;20:207–18. 2. Opelz G, Dohler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant 2004;4: 222–30. 3. Bakker NA, van Imhoff GW, Verschuuren EA, et al. Early onset post-transplant lymphoproliferative disease is associated with allograft localization. Clin Transplant 2005;19:327–34. 4. Tanner JE, Alfieri C. The Epstein–Barr virus and post-transplant lymphoproliferative disease: interplay of immunosuppression, EBV, and the immune system in disease pathogenesis. Transplant Infect Dis 2001;3:60 –9. 5. Nelson BP, Nalesnik MA, Bahler DW, et al. Epstein–Barr virusnegative post-transplant lymphoproliferative disorders: a distinct entity? Am J Surg Pathol 2000;24:375– 85.
The Journal of Heart and Lung Transplantation October 2008
6. Harris NL, Ferry JA, Swerdlow SH. Posttransplant lymphoproliferative disorders: summary of Society for Hematopathology workshop. Semin Diagn Pathol 1997;14:8 –14. 7. Castellano-Sanchez AA, Li S, Qian J, et al. Primary central nervous system posttransplant lymphoproliferative disorders. Am J Clin Pathol 2004;121:246 –53. 8. Nalesnik MA. The diverse pathology of post-transplant lymphoproliferative disorders: the importance of a standardized approach. Transplant Infect Dis 2001;3:88 –96. 9. Choquet S, Leblond V, Herbrecht R, et al. Efficacy and safety of rituximab in B-cell post-transplantation lymphoproliferative disorders: results of a prospective multicenter phase 2 study. Blood 2006;107:3053–7. 10. Svoboda J, Kotloff R, Tsai DE. Management of patients with post-transplant lymphoproliferative disorder: the role of rituximab. Transplant Int 2006;19:259 – 69. 11. Elstrom RL, Andreadis C, Aqui NA, et al. Treatment of PTLD with rituximab or chemotherapy. Am J Transplant 2006;6: 569 –76. 12. Patchell RA, Tibbs PA, Regine WF, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet 2005;366: 643– 8. 13. Oertel SH, Verschuuren E, Reinke P, et al. Effect of anti-CD20 antibody rituximab in patients with post-transplant lymphoproliferative disorder (PTLD). Am J Transplant 2005;5:2901– 6. 14. Raj R, Frost AE. Lung retransplantation after posttransplantation lymphoproliferative disorder (PTLD): a single-center experience and review of literature of PTLD in lung transplant recipients. J Heart Lung Transplant 2005;24:671–9. 15. Dotti G, Fiocchi R, Motta T, et al. Lymphomas occurring late after solid-organ transplantation: influence of treatment on the clinical outcome. Transplantation 2002;74:1095–102. 16. Ghobrial IM, Habermann TM, Macon WR, et al. Differences between early and late posttransplant lymphoproliferative disorders in solid organ transplant patients: are they two different diseases? Transplantation 2005;79:244 –7.
Post-transplant lymphoproliferative disorder (PTLD) is a serious complication observed after solid-organ transplantation and affects up to 10% of lung transplant recipients. PTLD consists of a heterogeneous group of lymphoid proliferations, usually of B-cell origin and related to the Epstein–Barr virus.1 Although PTLD may present at virtually any site, early presentations are usually localized in the transplanted organ, whereas late presentations are mostly localized in the gastrointestinal tract.2,3 We describe a lung transplant recipient presenting with lower limb weakness as a result of extradural spinal cord compression from PTLD. CASE REPORT A 44-year-old man presented with lower limb weakness and sensory deficits. The patient’s history revealed a bilateral lung transplant 18 months earlier for end-stage emphysema based on ␣1-anti-trypsin deficiency. The post-operative course was uncomplicated and initial immunosuppression consisted of two doses of basiliximab and maintenance therapy with azathioprine, tacrolimus and prednisolone. The patient was Epstein– Barr virus (EBV)-seropositive prior to transplantation. Two and 4 weeks after transplantation, the patient had
From the Departments of aNeurosurgery, bNuclear Medicine and Molecular Imaging, cHaematology and dPulmonary Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. Reprint requests: N. A. Bakker, MD, Department of Neurosurgery, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. Telephone: ⫹31-50-3612837. Fax: ⫹3150-3611715. E-mail: [email protected] Copyright © 2008 by the International Society for Heart and Lung Transplantation. 1053-2498/08/$–see front matter. doi:10.1016/ j.healun.2008.06.008
acute rejection episodes for which pulse therapy with methylprednisolone was administered (3 days of 1,000 mg methylprednisolone orally), and azathioprine was converted to mycophenolate mofetil (CellCept). Three months before presentation, the patient complained of painful shoulders and sensory disturbances in both legs. During a holiday in another country, the patient experienced rapid progressive lower limb weakness. Magnetic resonance (MR) imaging in a local hospital revealed significant medullary compression at the T-3 level due to an intrapleural mass with epidural involvement, after which the patient was immediately transported to our hospital for further evaluation. On admission, sensory deficits were present from T-5 and below. In addition, progressive paresis (Medical Research Scale [MRC] ⫽ 2) of his lower extremities was present for 48 hours. Repeated MR imaging of the thoracic spine showed an intrapleural mass with epidural involvement at the T-3 level, with severe compression of the spinal cord (Figure 1a,b). Promptly, a laminectomy of T-3 was performed with partial removal of the epidural mass. On suspicion of early, EBV-positive, CD20-positive PTLD, post-operatively one dose of rituximab was already administered (375 mg/m2) and immunosuppression was reduced. However, despite decompression, the neurologic deficit initially persisted. In addition, the patient was given radiotherapy (1 ⫻ 8 Gy) at the involved level to further decrease tumor volume. Histologic study showed EBVencoded RNA (EBER)-negative, CD20-negative, plasmacytoma-like PTLD, after which rituximab was stopped. A complete work-up with bone marrow biopsy, CT scanning and 18F-fluorodeoxyglucose–positron emission tomography (FDG-PET) revealed a paravertebral FDG-PET–positive mass (Figure 2), continuous with 1165
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Figure 1. MR scan at presentation. There is a left paravertrebral lesion with involvement of the spinal canal at the T-3– 4 level and compression of the spinal cord.
the thoracic cavity, and mediastinal and diaphragmal lymphadenopathy (as detected by CT scanning). Polychemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) was initiated. By 6 months after surgery, radiotherapy and chemotherapy, the neurologic deficits on his lower limbs recovered nearly completely. The strength in both his legs was maximal, whereas only mild dorsal column deficits were present. In addition, FDG-PET scanning and CT scanning
showed complete remission (Figure 3), while lung function has continued to remain stable. DISCUSSION PTLD encompasses a heterogeneous group of lymphoproliferative diseases, ranging from EBV-driven polyclonal proliferation, resembling infectious mononucleosis, to highly aggressive, monomorphic proliferations, which may be indistinguishable from aggressive types of lymphoma, such as diffuse, large B-cell lymphoma.
Figure 2. FDG-PET (left) and combined FDG-PET and CT (right). Left-sided paravertebral lesion with high focal FDG uptake at the T-3– 4 level.
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Figure 3. FDG-PET (left) and combined FDG-PET and CT (right). FDG-PET and combined FDG-PET plus CT show complete remission after 3 months of therapy.
Generally, PTLD is considered an iatrogenic complication of immunosuppression after transplantation, leading to decreased function of EBV-specific T cells, which, in turn, may lead to uncontrolled proliferation of EBV-infected B cells, ultimately leading to PTLD.4 PTLD is, however, not exclusively associated with EBV infection, as EBV-negative PTLD, with a tendency to develop late after transplantation, is also increasingly recognized.5 Although the association between EBV and PTLD is well established, the presence of EBV in tumor cells is not required for the diagnosis of PTLD. This implies that, according to the international classification, any lymphoma arising in a post-transplant patient is considered to be (a variant of) PTLD.6 The incidence of PTLD varies significantly between different types of organ transplants, with the highest incidence (5% to 20%) found after lung and small bowel transplantation. In contrast, reported incidences in kidney transplant recipients are much lower (1% to 3%). Differences in incidence most likely reflect the more aggressive immunosuppression in the first group of patients.2 The risk of PTLD development is significantly higher in the early posttransplant period (⬍1 year after transplantation), especially in heart–lung and lung transplant recipients. Primary central nervous system (CNS) localization is observed in about 5% to 15% of all PTLD cases,7 and almost invariably affects the brain. This is in contrast with patients with “conventional” non Hodgkin’s lymphoma, in which the CNS is less frequently affected.
The reasons for the observed difference in incidence between patients with and without immune deficiencies have not been elucidated.7 PTLD treatment always consists of reduced immunosuppression. Early lesions, including plasma cell hyperplasia and lesions resembling infectious mononucleosis, are usually polyclonal and often regress only after reduction of immunosuppression.8 In contrast, monomorphic PTLD, which has a clinical course more closely resembling diffuse, large B-cell lymphoma, should be treated more aggressively. Monoclonal antibody therapy (rituximab) directed against the B-cell receptor CD20 is frequently applied and is now widely regarded as first-line treatment.9,10 Polychemotherapy (mostly with cyclophosphamide, CHOP) is reserved for patients in whom other treatment options have failed or when PTLD is CD20-negative.11 Despite its early presentation, the case presented herein turned out to be CD20negative (plasmacytoma-type PTLD is almost invariably CD20-negative), after which rituximab was stopped and CHOP therapy initiated. In cases of progressive spinal cord compression by an intraspinal tumor mass, radiotherapy used to be firstline treatment for many decades. However, it seems that, in patients with progressive spinal cord compression by non-radiosensitive tumors, direct decompressive surgery should be performed before initiation of radiotherapy, because this treatment turned out to be superior to treatment with radiotherapy alone in terms of ability to walk.12 Survival among transplant recipients with PTLD ranges from 28% to 75%, and 1-year overall survival rates range
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from 44% to 73%.9,10,13,14 However, there may be subgroups of patients differing in their response to treatment. Specifically, late-onset PTLD carries a worse prognosis when compared with early-onset PTLD.15,16 This might be attributed to the higher percentage of EBV-negative PTLD in late-onset disease. Patients with CNS involvement have among the poorest prognoses.7 To the best of our knowledge, this is the first reported case of PTLD presenting with sensory and motor weakness as a result of compression of the spinal cord. Signs of spinal cord compression in a patient with a transplant in the past should therefore raise the possibility of primary PTLD. REFERENCES 1. Bakker NA, van Imhoff GW, Verschuuren EA, van Son WJ. Presentation and early detection of post-transplant lymphoproliferative disorder after solid organ transplantation. Transplant Int 2007;20:207–18. 2. Opelz G, Dohler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant 2004;4: 222–30. 3. Bakker NA, van Imhoff GW, Verschuuren EA, et al. Early onset post-transplant lymphoproliferative disease is associated with allograft localization. Clin Transplant 2005;19:327–34. 4. Tanner JE, Alfieri C. The Epstein–Barr virus and post-transplant lymphoproliferative disease: interplay of immunosuppression, EBV, and the immune system in disease pathogenesis. Transplant Infect Dis 2001;3:60 –9. 5. Nelson BP, Nalesnik MA, Bahler DW, et al. Epstein–Barr virusnegative post-transplant lymphoproliferative disorders: a distinct entity? Am J Surg Pathol 2000;24:375– 85.
The Journal of Heart and Lung Transplantation October 2008
6. Harris NL, Ferry JA, Swerdlow SH. Posttransplant lymphoproliferative disorders: summary of Society for Hematopathology workshop. Semin Diagn Pathol 1997;14:8 –14. 7. Castellano-Sanchez AA, Li S, Qian J, et al. Primary central nervous system posttransplant lymphoproliferative disorders. Am J Clin Pathol 2004;121:246 –53. 8. Nalesnik MA. The diverse pathology of post-transplant lymphoproliferative disorders: the importance of a standardized approach. Transplant Infect Dis 2001;3:88 –96. 9. Choquet S, Leblond V, Herbrecht R, et al. Efficacy and safety of rituximab in B-cell post-transplantation lymphoproliferative disorders: results of a prospective multicenter phase 2 study. Blood 2006;107:3053–7. 10. Svoboda J, Kotloff R, Tsai DE. Management of patients with post-transplant lymphoproliferative disorder: the role of rituximab. Transplant Int 2006;19:259 – 69. 11. Elstrom RL, Andreadis C, Aqui NA, et al. Treatment of PTLD with rituximab or chemotherapy. Am J Transplant 2006;6: 569 –76. 12. Patchell RA, Tibbs PA, Regine WF, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet 2005;366: 643– 8. 13. Oertel SH, Verschuuren E, Reinke P, et al. Effect of anti-CD20 antibody rituximab in patients with post-transplant lymphoproliferative disorder (PTLD). Am J Transplant 2005;5:2901– 6. 14. Raj R, Frost AE. Lung retransplantation after posttransplantation lymphoproliferative disorder (PTLD): a single-center experience and review of literature of PTLD in lung transplant recipients. J Heart Lung Transplant 2005;24:671–9. 15. Dotti G, Fiocchi R, Motta T, et al. Lymphomas occurring late after solid-organ transplantation: influence of treatment on the clinical outcome. Transplantation 2002;74:1095–102. 16. Ghobrial IM, Habermann TM, Macon WR, et al. Differences between early and late posttransplant lymphoproliferative disorders in solid organ transplant patients: are they two different diseases? Transplantation 2005;79:244 –7.