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Year : 2013  |  Volume : 9  |  Issue : 3  |  Page : 534-536

Isolated cerebral post-transplant lymphoproliferative disorder in a lymphoma recipient

1 Division of Hematology-Oncology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
2 Department of Pathology, Chang Gung Memorial Hospital, Taoyuan, Taiwan

Date of Web Publication8-Oct-2013

Correspondence Address:
Hung Chang
No. 5, Fu-Shin Street, Kweishan, Taoyuan
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.119373

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 > Abstract 

Post-transplant lymphoproliferative disorder (PTLD) can occur after solid organ transplantation (SOT) or hematopoietic stem cell transplantation (HSCT). The majority of PTLDs are related to the reactivation of Epstein-Barr virus (EBV) in the lymphoid organs. PLTDs in HSCT recipients tend to present with systemic involvement, and isolated PTLD in these patients is rare. Only 14 isolated cerebral PTLDs have been reported in HSCT recipients, and none have been reported in lymphoma patients. When diagnosing PTLD in a lymphoma patient, it is challenging to discriminate between a PTLD that originated from previous disease and a newly developed clone and to distinguish between donor and recipient origin. In this report, we present the first case of a B-cell lymphoma patient who developed isolated PTLD in the CNS, and we confirmed that the PTLD originated in a distinct clone and from a different origin. Furthermore, the role of EBV-DNA monitoring in such patients is discussed.

Keywords: Central nervous system, Epstein-Barr virus, Post-transplant lymphoproliferative disorders

How to cite this article:
Tang TC, Chuang WY, Chang H. Isolated cerebral post-transplant lymphoproliferative disorder in a lymphoma recipient. J Can Res Ther 2013;9:534-6

How to cite this URL:
Tang TC, Chuang WY, Chang H. Isolated cerebral post-transplant lymphoproliferative disorder in a lymphoma recipient. J Can Res Ther [serial online] 2013 [cited 2022 Dec 4];9:534-6. Available from: https://www.cancerjournal.net/text.asp?2013/9/3/534/119373

 > Introduction Top

Immunosuppressive therapy is used to treat or prevent rejection and graft-versus-host disease (GvHD) after transplantation. This therapy may lead to the reactivation of the Epstein-Barr virus (EBV) in B lymphocytes, followed by the induction of clonal proliferation of the lymphoid organ, resulting in post-transplant lymphoproliferative disorder (PTLD). PTLDs, a rare and heterogeneous subset of lymphoproliferative disorders (LPDs), can originate from cells of donor or recipient origin. A limited number of studies have demonstrated that PTLDs in HSCT recipients predominantly originate from the donor. [1] However, it is unclear whether PTLDs of different origins impact patient prognosis and outcome.

PTLDs are more likely to manifest with systemic involvement in HSCT recipients than in solid organ transplant (SOT) recipients. Conversely, isolated PTLDs in HSCT recipients are notably rare, especially those occurring in the central nervous system (CNS). Till date, only 14 cases have been reported in the literature, and none occurred in lymphoma patients. [2],[3] In this paper, we report the first case of a B-cell lymphoma presenting with an isolated PTLD in the CNS after HSCT.

 > Case Report Top

A 59-year-old male presented to the clinic with generalized peripheral lymphadenopathies. Complete blood and differential counts revealed a white blood cell count of 668.9 × 10 9 /L, 95% of which were abnormal lymphoid cells. The computed tomography scan demonstrated disseminated, enlarged lymph nodes in the cervical, axillary, inguinal, mediastinal, retroperitoneal and para-aortic regions. A trephine bone marrow biopsy showed lymphoma cell infiltration. The pathology of the inguinal lymph node showed follicular infiltrates composed of a mixture of centrocytes and centroblasts, and more than 15 centroblasts per high-power field were observed [Figure 1]a. Immunohistochemical (IHC) analyses showed that these cells were positive for CD20 [Figure 1]b, CD10 [Figure 1]c and BCL-2 [Figure 1]d expression and negative for CD5 expression. Reverse transcription polymerase chain reaction (PCR) analysis to detect the t (14;18)/BCL-2 fusion transcript was negative. Based on these data, the patient was diagnosed with grade 3A follicular lymphoma (FL).
Figure 1: Pathological analysis of the lymph node showed follicular infiltrates of centrocytes and centroblasts (a). magnification 400 X. IHC staining showed positive expression of CD20 (b). CD10 (c). and BCL-2 (d) magnification 400 X

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The patient was treated with 8 courses of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone chemotherapy. The FL relapsed after 4 months of complete remission. Partial remission was reached after treatment with 4 courses of salvage chemotherapy, and sibling-matched HSCT was subsequently performed. Complete donor chimerism was documented in short tandem repeat (STR) analyses after HSCT. The patient was treated with cyclosporine (CsA) and prednisone to manage GvHD. Three months after the HSCT, the patient experienced episodes of convulsion. Magnetic resonance imaging of the brain showed a rim-enhanced lesion in the frontal area [Figure 2]a. An open biopsy was performed, and the pathology indicated monomorphic PTLD. In contrast to the previous FL cells, the lymphoid cells in the brain presented with necrotic feature sand infiltrated into the perivascular areas [Figure 2]b. IHC indicated positive staining for CD20 [Figure 2]c, CD30 and latent membrane protein 1 (LMP-1) and negative staining for CD10, which confirmed the diagnosis of EBV-associated, diffuse large B-cell lymphoma (DLBCL) of PTLD. We performed in situ hybridization for EBV-encoded RNA (EBER) in pre-HSCT (lymph node) and post-HSCT (brain) specimens. The results were negative in the pre-HSCT sample [Figure 2]d and positive in the post-HSCT sample [Figure 2]e. The re-staging work-up showed that the PTLD was confined to the CNS. To determine whether the CNS tumor was relapsed or transformed disease from the previous FL or new PTLD from a new clone, we performed immunoglobulin heavy chain (IgH) gene rearrangement, which demonstrated that the clonalities of the lymphoma from the bone marrow (pre-HSCT) and CNS (post-HSCT) of the patient were distinct [Figure 3]a. STR analysis of the tumor in the CNS was identical to that of the donor type [Figure 3]b. EBV-DNA was undetectable (<200 copies/mL) in the serum and cerebrospinal fluid (CSF) at the time of PTLD diagnosis and at the time of progression.
Figure 2: MRI showed a rim-enhanced lesion in the frontal area (a). Pathological analysis of the CNS lesion showed lymphoma cells infiltrated in the perivascular areas with obvious necrotic features (b). and IHC revealed positive staining for CD20 (c). magnification 400 X. In situ hybridization of EBER was negative in the lymph node (d). and positive in the CNS lesion (e). magnification 400 X

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Figure 3: IgH gene rearrangement analyses demonstrated that the clonalities of the lymphoma from the bone marrow and CNS were distinct (a). STR analysis revealed that the tumor in the CNS had the same markers as the donor tissue (b)

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CsA and prednisone were immediately discontinued after the diagnosis was established. Although the patient was promptly treated with intrathecal (IT) chemotherapy followed by whole brain radiotherapy, the patient still succumbed to rapid PTLD progression.

 > Discussion Top

Compared to SOT recipients, HSCT recipients develop PTLD at earlier time points after transplant and frequently exhibit systemic involvement. The optimal treatment of PTLD in HSCT recipients remain sun determined, but reducing the immunosuppressant dose is regarded as the first step of treatment to reconstitute host immunity and eliminate PTLD. However, this treatment may lead to overwhelming GvHD. Other treatment modalities, such as chemotherapy, immunotherapy, target therapy and HSCT have been studied, but the results of these studies were inconclusive. [4],[5] For patients presenting with CD20-positive cells, using rituximab to treat PTLD is a mainstay. However, rituximab is less effective for patient's with CD20 (+) PTLD in the CNS because the concentration of rituximab in the CSF is low. As such, using intravenous, high-dose orIT rituximab has been reported to treat some patients successfully. [6],[7]

Because EBV is strongly correlated with the development of PTLD, periodically monitoring the serum EBV-DNA concentration can predict the occurrence of PTLD, and pre-emptive therapy can be administered to patients with a high viral load of EBV. [8] However, for patients presenting with isolated cerebral PTLD, it is unclear whether the EBVDNA concentration in the CSF can be used as an indicator of PTLD. [3],[9] In the presented case, although EBER in situ hybridization and LMP-1 staining in the brain biopsy were positive, the EBVDNA concentration indicated that the viral load in the serum and CSF was normal at the time of PTLD diagnosis and progression. We were unable to determine whether it is useful to examine the EBVDNA concentration in patients with isolated cerebral PTLD. However, clinicians should remain cautious when a transplant recipient manifests with CNS lesions in the absence of EBVDNA in the serum or CSF, and tissue confirmation is necessary.

Only 14 isolated cerebral PTLDs in HSCT patients have been reported in the literature, and these included cases of leukemia, myelodysplastic syndromes, a plastic anemia, multiple myeloma and congenital metabolic disorder. We have reported the first case of a B-cell lymphomapatient who developed an isolated PTLD in the CNS. There is a diagnostic dilemma when a lymphoma patient presents with an LPD in the CNS after HSCT. Because the immunophenotypes of the cells before and after HSCT were of B-cell origin, it must be determined whether the LPD in the CNS represents relapsed disease (or a transformation of a previous FL) or a newly formed LPD from a different clone. Previous studies have demonstrated that PTLD can be derived from the donor or the recipient, but most PTLDs in HSCT recipients are of donor origin. Donor-derived PTLDs usually occur in EBV-seronegative recipients and do not confer significantly different overall survival compared with recipient-derived PTLDs. [10] Although the IgH gene rearrangement revealed separate clonality in the bone marrow (pre-HSCT) and the brain (post-HSCT), we were unable to conclude that they were derived from two different origins. It is possible that the lymphoma cells presented as a clonal evolution from FL to DLBCL. Therefore, we performed STR analysis and found that the STR from the brain tissue was identical to that of the donor, supporting the hypothesis that the PTLD was a newly developed disorder.

In conclusion, isolated cerebral PTLD in HSCT recipients is exceedingly rare. The EBVDNA concentration in the serum and CSF is insufficient to provide definitive evidence to determine the diagnosis and appropriate therapeutic response or to indicate a relapse. Tissue confirmation is necessary when there is a suspicion of PTLD in the CNS. Clonality and STR analyses are useful to further determine the cell origin.

 > Acknowledgement Top

We thank Professor Lee-Yung Shih (Division of Hematology-Oncology. Chang Gung Memorial Hospital) and Miss Mei-Chia Wang (Department of Laboratory Medicine. Chang Gung Memorial Hospital) for the molecular and clonality analyses.

 > References Top

1.Zutter MM, Martin PJ, Sale GE, Shulman HM, Fisher L, Thomas ED, et al. Eps. tein-Barr virus lymphoproliferation after bone marrow transplantation. Blood 1988;72:520-9.  Back to cited text no. 1
2.Lieberman F, Yazbeck V, Raptis A, Felgar R, Boyiadzis M. Primary central nervous system post-transplant lymphoproliferative disorders following allogeneic hematopoietic stem cell transplantation. J Neurooncol 2012;107:225-32.  Back to cited text no. 2
3.Shimizu H, Saitoh T, Koya H, Yuzuriha A, Hoshino T, Hatsumi N, et al. Discrepancy in EBV-DNA load between peripheral blood and cerebrospinal fluid in a patient with isolated CNS post-transplant lymphoproliferative disorder. Int J Hematol 2011;94:495-8.  Back to cited text no. 3
4.Parker A, Bowles K, Bradley JA, Emery V, Featherstone C, Gupte G, et al. Management of post-transplant lymphoproliferative disorder in adult solid organ transplant recipients - BCSH and BTS guidelines. Br J Haematol 2010;149:693-705.  Back to cited text no. 4
5.Nourse JP, Jones K, Gandhi MK. Epstein-Barr virus-related post-transplant lymphoproliferative disorders: Pathogenetic insights for targeted therapy. Am J Transplant 2011;11:888-95.  Back to cited text no. 5
6.Patrick A, Wee A, Hedderman A, Wilson D, Weiss J, Govani M. High-dose intravenous rituximab for multifocal, monomorphic primary central nervous system post transplant lymphoproliferative disorder. J Neurooncol 2010;103:739-43.  Back to cited text no. 6
7.Bonney DK, Htwe EE, Turner A, Kelsey A, Shabani A, Hughes S, et al. Sustained response to intrathecal rituximab in EBV associated post-transplant lymphoproliferative disease confined to the central nervous system following haematopoietic stem cell transplant. Pediatr Blood Cancer 2012;58:459-61.  Back to cited text no. 7
8.Worth A, Conyers R, Cohen J, Jagani M, Chiesa R, Rao K, et al. Pre-emptive rituximab based on viraemia and T cell reconstitution: A highly effective strategy for the prevention of Epstein-Barr virus-associated lymphoproliferative disease following stem cell transplantation. Br J Haematol 2011;155:377-85.  Back to cited text no. 8
9.Hamadani M, Martin LK, Benson DM, Copelan EA, Devine SM, Hofmeister CC. Central nervous system post-transplant lymphoproliferative disorder despite negative serum and spinal fluid Epstein-Barr virus DNA PCR. Bone Marrow Transplant 2007;39:249-51.  Back to cited text no. 9
10.Olagne J, Caillard S, Gaub MP, Chenard MP, Moulin B. Post-transplant lymphoproliferative disorders: Determination of donor/recipient origin in a large cohort of kidney recipients. Am J Transplant 2011;11:1260-9.  Back to cited text no. 10


  [Figure 1], [Figure 2], [Figure 3]


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