|Year : 2020 | Volume
| Issue : 3 | Page : 243-246
Isolated B cell central nervous system posttransplant lymphoproliferative disorder: Role of magnetic resonance imaging in the diagnosis and management in the absence of neurological signs - a case report
Monisha Jacob1, Milly Mathew2, Rajeevalochana Parthasarathy2, Jayanthi Arulneyam3, Siddartha Ghosh4, Jose Easow5, Sivaranjini Narayanan6, Georgi Abraham2
1 Department of Radiology, Madras Medical Mission Hospital, Chennai, Tamil Nadu, India
2 Department of Nephrology, Madras Medical Mission Hospital, Chennai, Tamil Nadu, India
3 Department of Neurology, Madras Medical Mission Hospital, Chennai, Tamil Nadu, India
4 Department of Neurosurgery, Apollo Hospital, Chennai, Tamil Nadu, India
5 Department of Oncology, Apollo Hospital, Chennai, Tamil Nadu, India
6 Department of Pathology, Medical College Baroda and SSG Hospital, Vadodara, Gujarat, India
|Date of Submission||05-May-2020|
|Date of Acceptance||15-Jul-2020|
|Date of Web Publication||30-Sep-2020|
Dr. Georgi Abraham
Madras Medical Mission Hospital, 4a, Dr. JJ Nagar, Mogappair, Chennai - 600 037, Tamil Nadu
Source of Support: None, Conflict of Interest: None
A 29-year-old female who received a kidney from her mother 9 months ago, on minimal triple immunosuppression presented with short duration vertigo. There were no focal neurological deficits. Magnetic resonance imaging of the brain revealed peripherally enhancing periventricular lesions, predominantly in the bilateral frontal lobes. Positron-emission tomography showed increased uptake in the brain lesions. A stereotactic biopsy revealed CD20+ monomorphic B cell posttransplant lymphoproliferative disorder. The donor mother and daughter were Epstein–Barr virus (EBV) immunoglobulin G (IgG+)/IgG−. The cerebrospinal fluid and brain biopsy were positive for EBV. Treatment consisted of discontinuing prednisolone and MMF and reducing tacrolimus to 0.5 mg od. Rituximab, zidovudine, ganciclovir, and dexamethasone are being used. She has stable renal function.
Keywords: Epstein–Barr virus, kidney transplantation, posttransplant lymphoproliferative disease
|How to cite this article:|
Jacob M, Mathew M, Parthasarathy R, Arulneyam J, Ghosh S, Easow J, Narayanan S, Abraham G. Isolated B cell central nervous system posttransplant lymphoproliferative disorder: Role of magnetic resonance imaging in the diagnosis and management in the absence of neurological signs - a case report. Indian J Transplant 2020;14:243-6
|How to cite this URL:|
Jacob M, Mathew M, Parthasarathy R, Arulneyam J, Ghosh S, Easow J, Narayanan S, Abraham G. Isolated B cell central nervous system posttransplant lymphoproliferative disorder: Role of magnetic resonance imaging in the diagnosis and management in the absence of neurological signs - a case report. Indian J Transplant [serial online] 2020 [cited 2021 May 18];14:243-6. Available from: https://www.ijtonline.in/text.asp?2020/14/3/243/296894
| Introduction|| |
Posttransplant lymphoproliferative disorder (PTLD) is a potentially life-threatening complication following solid organ transplantation that leads to significant morbidity and mortality. The risk factors are age (children and those >60 years of age), Epstein–Barr virus (EBV) Human leukocyte antigen (HLA) mismatch between donor and recipient, induction therapy with thymoglobulin, and the intensity of immunosuppression. The incidence is the lowest after kidney transplantation (<1%). Seventy percent of the PTLD patients are positive for EBV.
The overall prevalence of PTLD following solid organ transplantation is 0.5%–2.5%. Isolated central nervous system (CNS) involvement is very rare comprising 5%–15% of all PTLD cases. PTLD has a bimodal presentation with the first peak during the 1st year posttransplant, but the period of greatest incidence is at approximately 5 years posttransplant for CNS PTLD. Both primary central nervous system lymphoma (PCNL) and PTLD are aggressive tumors, and differentiation is imperative. Reduction of immunosuppression is the hallmark of management along with chemotherapy/radiotherapy. Rituximab therapy is indicated in B cell PTLD for better response if they are EBV positive.
Here, we describe a case of isolated CNS PTLD in a mother to daughter kidney transplant scenario which was diagnosed on magnetic resonance imaging (MRI), 9 months later with no neurological deficit and undetectable EBV in the blood.
| Case Report|| |
A live-related kidney transplant was done from a 53-year-old mother to a 28-year-old daughter with ABO compatibility on June 27, 2019 with previous nonsensitization against class I and II antigens. The donor and the recipient were EBV immunoglobulin G (IgG+)/IgG– (EBV VCA) Viral Capsid Antigen, CMV Cytomegalovirus, IgG+/+.
She was on triple immunosuppression with prednisolone 2.5 mg and 5 mg on alternate days, tacrolimus 0.5 mg bd, and mycophenolate mofetil 500 mg tds. She also received two doses of basiliximab 20 mg to prevent graft rejection. A month following transplantation, she had a steroid-resistant acute cellular rejection which was successfully treated with one dose of thymoglobulin 50 mg on July 19, 2019. Thereafter, she underwent frequent follow-up with routine blood investigations and ultrasound to assess the graft function. She presented with complaints of central vertigo on and off for 1 week, since February 2020 with no identifiable cause. She was treated with betahistine 8 mg tds and prochlorperazine maleate 5 mg bd which provided mild symptomatic relief. On April 12, 2020, EBV by polymerase chain reaction (PCR) quantification was undetectable and Toxoplasma IgM was negative in the blood. Physical examination was unremarkable with normal blood pressure. System wise examination was normal. Repeated neurological examination by a neurologist including optic fundus examination was unremarkable. She was on thyroxine 125 mcg and was euthyroid. Baseline serum creatinine was 0.87 mg/dL. Urine analysis was unremarkable. Serology for hepatitis A, B, and C was negative. Her complete blood count revealed hemoglobin 9.1 g/dl, white blood cell 10,200/cumm, with 82% neutrophil, lymphocyte 13%, rest monocyte, and platelet count 120,000/cumm. Liver function tests and electrolytes were within the normal limits. She presented with one episode of generalized seizure.
A noncontrast computed tomography was done on April 12, 2020 which showed multiple ill-defined hypodense lesions with peripheral hyperdense rim in the periventricular region of bilateral frontal lobes. In view of history of vertigo and to further characterize these lesions, MRI of the brain with contrast [Figure 1] was done which revealed multifocal ill-defined periventricular lesions, predominantly in bilateral frontal lobes extending into the genu of the corpus callosum and the anterior one-third of the third ventricle showing ring enhancement and extensive perilesional edema. These imaging features raised the possibility of PTLD. A stereotactic biopsy of the brain lesion revealed CD20+ monomorphic B cell PTLD with the presence of EBV. A cerebrospinal fluid (CSF) analysis was done which showed EBV viral load of 44,241 copies/ml, whereas the repeat PCR on peripheral blood remained negative. A positron-emission tomography scan was done on April 24, 2020 to assess the extent of involvement, which showed increased 18F-fluorodeoxyglucose uptake in the periventricular lesions. No other foci of metabolically active disease were seen elsewhere in the whole-body survey. These findings were the probable cause for the patient's central vertigo.
|Figure 1: (a and b) Magnetic resonance imaging axial and coronal T1-weighted postcontrast image showing multifocal periventricular ring-enhancing lesions in the bilateral frontal lobes (arrows)|
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Prednisolone and mycophenolate mofetil were discontinued and the dose of tacrolimus was reduced to 0.5 mg od. She was started on a regimen consisting of rituximab 500 mg, zidovudine 300 mg 5 times a day, ganciclovir 250 mg bd, and dexamethasone 10 mg bd. Her current serum creatinine continued to remain stable at 0.8 mg/dl.
A repeat MRI was done on May 29, 2020 which revealed interval regression of the periventricular lesions with no evidence of any new lesions.
| Discussion|| |
PTLDs are plasmacytic or lymphoid proliferations that develop as a consequence of immunosuppression in a recipient of solid organ or stem cell allograft. CNS-PTLD cases usually present within the 1st year with a median time to occurrence around 4–5 years. However, cases have been reported >10 years after the initial transplantation. Patients with CNS-PTLD usually have symptoms such as headache, altered sensorium, and seizures. This patient is unique having had negative test twice for EBV in the blood, with significant presence of EBV in the CSF and in the tumor. CNS PTLD is strongly associated with >90% EBV positivity by (EBER) Epstein-Barr encoding region in situ hybridization, which is much more than the association of EBV with systemic PTLD. However, only 27% were positive for detectable levels of EBV DNA in peripheral blood at the time of diagnosis. The prevalence as per the age group of EBV antibody is as follows: 6–8 years: 50%; 9–11 years: 55%; 12–14 years: 59%; 15–17 years: 69%; and 18–19 years: 89%. An Indian study revealed two genotypes of EBV with type A being detected in 32 (45.71%) and type B in blood of two (2.86%) samples. Serologic tests maybe unreliable as a diagnostic tool in immunocompromised patients due to marked delay in their humoral response to EBV antigens as in our case where the donor mother was positive and the patient received induction therapy with basiliximab 20 mg two doses to prevent intense immunosuppression. However, as she developed an acute steroid-resistant rejection, she was treated with single dose of thymoglobulin. Valganciclovir 450 mg was given every other day for 3 months as per our protocol for CMV prophylaxis.
Primary infection, through natural exposure or through transmission from an EBV-infected graft, of a previously EBV-seronegative patient during immunosuppression has been identified as a significant risk factor for the development of PTLD. It is possible that she had EBV transmission from the mother which predisposed to the development of B cell PTLD, although blood EBV testing was negative in this patient and positive in the CSF and tumor. A study by Liu et al. showed that the EBV DNA loads of CSF and tumor were higher than that of blood in patients with EBV-associated CNS diseases.
PLTD commonly appears on MRI as multifocal supratentorial lesions with a lobar distribution that are hypointense to the cortex on T1W and hyperintense on T2W with moderate diffusion restriction, probably due to high cellularity. The basal ganglia and periventricular regions are other common locations. On contrast administration, these lesions typically show complete ring enhancement. Partial ring enhancement and homogenous enhancement are less commonly seen. MR spectroscopy showed elevated choline in solid areas and elevated lipid-lactate peak in the nonenhancing/necrotic areas. In our patient, MRI was the appropriate imaging modality for the diagnosis and subsequent management, despite having paucity of neurological signs. This highlights the need for early MRI imaging in suspected patients.
The imaging features of PTLD closely resemble other conditions such as PCNL, glioblastoma, abscess, and metastasis. The stereotactic biopsy confirmed the diagnosis to enable us to initiate the appropriate treatment protocol.
Reduction/withdrawal of immunosuppression is the mainstay of treatment. Rituximab has been shown to be an integral component for the treatment of PTLD, either used alone or in combination along with methotrexate, cytarabine, and cranial radiotherapy (XRT). An international multicenter open-label phase II trial which included 70 patients with systemic PTLD supports the sequential treatment using rituximab, followed by CHOP regimen as a first-line to all patients who do not respond to a reduction/withdrawal in immunosuppressants. A study by Cavaliere et al. showed that patients who received rituximab-based regimens without concomitant cytotoxic chemotherapy or radiotherapy did very well, and six of seven patients were alive at the 20-month follow-up. The main drawback of rituximab is its inability to cross the blood–brain barrier, with a CSF concentration of only 0.1% of the systemic level. Intrathecal administration of rituximab can be considered, but further clinical trials are required to confirm its efficacy. Reconstitution of the immune system with the initiation of highly active antiviral therapy such as ganciclovir and acyclovir has been considered for EBV-driven cases at or after diagnosis to prolong survival. However, they have limited effect on tumor cells because of the absence of thymidine kinase in latently infected B-cells. Our treatment protocol consisting of rituximab, antiviral drugs, and steroids in addition to the reduction in the dose of immunosuppressant proved to be effective as suggested by the follow-up MRI in May 2020 which revealed partial regression of the periventricular lesions.
| Conclusion|| |
A high index of suspicion and early evaluation with MR imaging and appropriate histopathological correlation is highly essential for the early detection of CNS-PTLD in posttransplant patients in the absence of neurological signs.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Anupama SH, Mathew M, Bandolo V, Koshy P, Abraham G. Late-onset posttransplant lymphoproliferative disease in a male kidney transplant patient on minimal triple immunosuppressive therapy: Diagnosis and management. Indian J Transplant 2019;13:141-4. [Full text]
Hansen, P. B., & Nielsen, S. L. (2012). Successful Treatment of Posttransplant EBV-Associated Lymphoma and Plasmacytoma Solely Localized to the CNS. Case reports in hematology, 2012, 497614.
Caillard S, Cellot E, Dantal J, Thaunat O, Provot F, Janbon B, et al
. A French cohort study of kidney retransplantation after post-transplant lymphoproliferative disorders. Clin J Am Soc Nephrol 2017;12:1663-70.
Book by Anne G. Osborn, Garry L. Hedlund, and Karen L. Salzman. Osborn's Textbook Brain Imaging, pathology and Anatomy. 2nd
Castellano-Sanchez AA, Li S, Qian J, Lagoo A, Weir E, Brat DJ. Primary central nervous system posttransplant lymphoproliferative disorders. Am J Clin Pathol 2004;121:246-53.
White ML, Moore DW, Zhang Y, Mark KD, Greiner TC, Bierman PJ. Primary central nervous system post-transplant lymphoproliferative disorders: The spectrum of imaging appearances and differential. Insights Imaging 2019;10:46.
Sundin A, Grzywacz BJ, Yohe S, Linden MA, Courville EL. B-cell posttransplant lymphoproliferative disorder isolated to the central nervous system is Epstein-Barr virus positive and lacks p53 and Myc expression by immunohistochemistry. Hum Pathol 2017;61:140-7.
Balfour HH Jr, Sifakis F, Sliman JA, Knight JA, Schmeling DO, Thomas W. Age-specific prevalence of Epstein-Barr virus infection among individuals aged 6-19 years in the United States and factors affecting its acquisition. J Infect Dis. 2013;208:1286-93.
Janani MK. A clinico-molecular biological and genotypic study on Epstein-Barr virus in Chennai population. Birla Institute of Technology and Science.2015.
Liu QF, Ling YW, Fan ZP, Jiang QL, Sun J, Wu XL, et al
. Epstein-Barr virus (EBV) load in cerebrospinal fluid and peripheral blood of patients with EBV-associated central nervous system diseases after allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis 2013;15:379-92.
Trappe R, Oertel S, Leblond V, Mollee P, Sender M, Reinke P, et al
., and German PTLD Study Group, and European PTLD Network. 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. Lancet Oncol 2012;13:196-206.
Cavaliere R, Petroni G, Lopes MB, Schiff D. Primary central nervous system post-transplantation lymphoproliferative disorder. Cancer 2010;116:863-70.
Twombley K, Pokala H, Ardura MI, Harker-Murray P, Johnson-Welch SF, Weinberg A, et al
. Intraventricular rituximab and systemic chemotherapy for treatment of central nervous system post-transplant lymphoproliferative disorder after kidney transplantation. Pediatr Transplant 2012;16:E201-9.