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Table of Contents
CASE REPORT
Year : 2019  |  Volume : 13  |  Issue : 2  |  Page : 141-144

Late-onset posttransplant lymphoproliferative disease in a male kidney transplant patient on minimal triple immunosuppressive therapy: Diagnosis and management


1 Department of Nephrology, Madras Medical Mission, Chennai, Tamil Nadu, India
2 Department of Pathology, Madras Medical Mission, Chennai, Tamil Nadu, India

Date of Submission17-Sep-2018
Date of Acceptance01-Mar-2019
Date of Web Publication28-Jun-2019

Correspondence Address:
Dr. Georgi Abraham
Madras Medical Mission Hospital, 4-A, Dr J J Nagar, Mogappair, Chennai, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_56_18

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  Abstract 


A 57-year-old male who had a successful live-related renal transplantation 14 years ago with stable graft function, on minimal triple immunosupression, presented with Burkholderia cepecia septicemia and graft dysfunction. He was successfully treated with parenteral imepenam. He was found to be Epstein–Barr virus Immunoglobulin G seropositive. Positron-emission tomography scan done showed metabolically active multiple cervical, mediastinal, axillary retroperitoneal, mesenteric, iliac, and inguinal lymphadenopathy. Further investigations revealed polymorphic posttransplant lymphoproliferative disease. His immunosuppressive therapy was tailored to lower cyclosporine dosage and discontinuation of azathioprine. His renal function improved. He was diagnosed to have a T-cell non-Hodgkin's lymphoma and subsequently succumbed to sepsis.

Keywords: Burkholderia cepecia septicemia, Epstein–Barr virus infection, posttransplant lymphoproliferative disease, T-cell non-Hodgkin's lymphoma


How to cite this article:
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

How to cite this URL:
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 [serial online] 2019 [cited 2019 Sep 15];13:141-4. Available from: http://www.ijtonline.in/text.asp?2019/13/2/141/261842




  Introduction Top


Posttransplant lymphoproliferative disorders (PTLDs) after kidney transplantation represent the second most common malignancy. The risk of PTLD is 3.9-fold higher than those who are in the waiting list.[1] The risk factors are age (children and those >60 years of age), Epstein-Barr virus (EBV), mismatch between donor and recipient, induction therapy with thymoglobulin and the intensity of immunosuppression.[2] PTLD is a heterogeneous group of disorders ranging from EBV-driven polyclonal proliferation to aggressive monomorphic proliferation. EBV positivity is diagnosed in 70% of patients with PTLD.[3] Although there is no consensus regarding treatment, the most important aspect is reducing immunosuppressive therapy to create an environment of antiviral and anti-tumor immunity. This strategy may lead to risk of rejection and graft loss.[4],[5] Rituximab chemotherapy and surgical resection of single lesions significantly improve patient's survival. Studies have shown the overall survival rates for patients with PTLD at 1, 5, and 10 years posttransplantation were 73%, 60%, and 55%, respectively.[6] Rejection episodes are common as graft survival is compromised by augmenting recipient's cellular immunity. In those who have undergone graft loss and graft nephrectomy, there are reports of successful retransplantation.[3]

Here, we describe PTLD in a live kidney transplant recipient 14 years after transplantation with good graft function on minimal immunosuppression, who is EBV seropositive.


  Case Report Top


A currently 57-year-old male live related renal allograft recipient with diabetes mellitus, coronary artery disease, and systemic hypertension came with high-grade fever for 3 days. He has a history of ascending thoracic aortic aneurysm repair 18 years ago, posttransplant diabetes mellitus for 1 year and hypertension for 3 years. Hepatitis B, anti-hepatitis C virus, and HIV serology were negative. Physical examination showed that temperature was 103 F, pulse was 120/min, regular, supine blood pressure was 100/80 mmHg and he weighed 70 kg. Examination of the abdomen showed a nontender palpable liver and mild splenomegaly, icterus, pallor, and right inguinal lymphadenopathy involving the horizontal group, which were nontender. Examination of the lungs, central nervous system, and cardiovascular system was unremarkable. Optic fundus examination was unremarkable. Serum creatinine was 2.57 mg/dL (baseline creatinine: 1.5 mg/dL). Blood culture drawn grew Burkholderia cepacia. Urine analysis showed trace albumin, sugarnil, white blood cell (WBC) 5–6/hpf, and red blood cell 3–4/hpf. Hepatitis serology for A, B, and C were negative. Other investigations for scrub typhus and leptospirosis were negative. His complete blood count revealed hemoglobin 12.3g/dl, WBC 8200/cumm, platelet count 83080/cumm, with 88% neutrophil, lymphocyte 9%, rest monocyte. He had a magnetic resonance cholangiopancreatography done outside which showed intrahepatic cholestasis. Peripheral smear showed thrombocytopenia, neutrophilia, microcytosis and hypochromia, electrolytes sodium 128 mmol/l, potassium 4 mmol/l, chloride 94 mmol/l, HCO3 17 mmol/l, Mg 1.1 mg/dl, total protein-albumin ratio was 5.7/2.8, alkaline phosphatase 104 IU/l, total bilirubin 11.2 mg/dl, direct bilirubin 8.3 mg/dl, serum glutamic oxaloacetic transaminase 109 IU/L, serum glutamic pyruvic transaminase 43 IU/L, calcium 9.4 mg/dl, phosphorus 3.1 mg/dl, and EBV Immunoglobulin G was positive. He had a cyclosporin A C0 level checked 1 year ago which was 75 ng/ml. He was treated with appropriate antibiotics and after 48 h, he became afebrile, renal function improved (serum creatinine was 1.12 mg/dl with blood urea of 66 mg/dl) and the antibiotics were continued for 3 weeks.

Imaging showed normal chest X-ray. Ultrasound sonography of the allograft was normal. His immunosuppression consisted of microemulsion cyclosporine (neoral) 75 mg BD, prednisolone 5 mg and azathioprine 100 mg/day, and anti-hypertensive drugs. His immunosupression was reduced to microemulsion cyclosporine 50 mg BD and azathioprine was discontinued. Computed tomography of the abdomen showed multiple periportal peripancreatic retroperitoneal lymph nodes, the largest in the aorto-caval region measures 18 mm × 19 mm and the left paraaortic measuring 20 mm × 16 mm. The transplant kidney noted in the right iliac fossa with maintained morphology with bilateral fat standing with a large simple cyst in the right lower pole [Figure 1]. A positron-emission tomography (PET) scan was done showing metabolically active multiple cervical mediastinal, axillary retroperitoneal mesenteric, iliac, and inguinal lymphadenopathy [Figure 2]. Biopsy of the inguinal lymph node was done which showed polymorphic PTLD [Figure 3]. The patient continued to be afebrile with the improvement of graft function. He was referred to an Oncology Center for the management of the PTLD where he received two doses of rituximab at weekly interval and the immunohistochemistry results which became available later showed T-cell non-Hodgkin's lymphoma. Eventually, he developed sepsis and died.
Figure 1: Computed tomography pelvis showing normal allograft right iliac fossa with maintained morphology with bilateral fat standing with a large simple cyst in the right lower pole

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Figure 2: Positron-emission tomography scan showing extensive lymphnode involvement

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Figure 3: (a) H and E stain (×100) - large-to-intermediate lymphoid cells with distinct nucleoli, (b) CD45 - membranous positivity in lymphoid cells, (c) CD3 - membranous positivity in small lymphoid cells, (d) CD20 -membranous positivity in large-to-intermediate cells. Diagnosis - polymorphic post-transplant lymphoproliferative disease

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  Discussion Top


This patient is unique as he developed extensive polymorphic PTLD 14 years posttransplant on minimal immunosuppressive therapy. The incidence of PTLD is bimodal. There is an increased incidence of 1-year posttransplant following which the incidence declines. It is again increased 7–10 years posttransplant. PTLD shows a high rate of association with EBV infection. Most commonly thought to be from EBV infection of recipient B cells, it may also be of donor origin in some patients. Non-Hodgkin's lymphomas are commonly of B-cell origin. In our patient, the immunohistochemistry showed T-cell non-Hodgkin's lymphoma which has a very guarded prognosis.

The most commonly used pathologic classification of PTLD is the World Health Organization classification, which divides PTLD into three categories as follows: early lesions, polymorphic PTLD, and monomorphic PTLD. We have not checked EBV status either in the donor or the recipient pretransplant. The treatment of PTLD includes reduction and tailoring off immunosuppressive therapy as we did rituximab 375 mg/m2 once a week for 1 month. As there was no uptake by the allograft on the PET scan, there was no indication to do a graft nephrectomy. Acyclovir and ganciclovir are capable of inhibiting EBV DNA replication. The intensity of immunosuppression rather than the use of specific agents is the main determinant of PTLD. For this reason, reduction (withdrawal) of immunosuppression is the mainstay of therapy.[7] The recovery of the host immune system will elicit the development of a cytotoxic T-lymphocyte against EBV, regaining control on the EBV-driven B-cell proliferation [Flowchart 1]. Mycophenolate mofetil use does not seem to increase the risk of PTLD.[8] Human studies have failed to confirm that mammalian target of rapamycin inhibitors inhibit the development of PTLD. The mortality rate is much greater with PTLD than with lymphomas in the general population. In our patient, who developed PTLD 14 years after successful allografting without prolonged or repeated administration of lymphocyte depleting antibody preparation is intriguing. CMV infection may serendipitously reduce EBV replication and the incidence of PTLD. PTLD may respond to withdrawal or drastic reduction of immunosuppressive therapy. Standard chemotherapy may often be required. Extra-nodal involvement, although common, was not present in our patient. Our patient did not present with severe graft dysfunction and the disease was not localized to the allograft.




  Conclusion Top


A male patient with polymorphic PTLD, 14 years after successful kidney transplantation who presented with Burkholderia cepacia septicemia and past EBV infection, was initially treated with appropriate antibiotic therapy and tailored immunosuppressive agents. The immunohistochemistry showed T-cell non-Hodgkin's lymphoma which has a guarded prognosis. The patient died with the recurrence of septicemia.

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

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Kasiske BL, Snyder JJ, Gilbertson DT, Wang C. Cancer after kidney transplantation in the United States. Am J Transplant 2004;4:905-13.  Back to cited text no. 1
    
2.
Sampaio MS, Cho YW, Shah T, Bunnapradist S, Hutchinson IV. Association of immunosuppressive maintenance regimens with posttransplant lymphoproliferative disorder in kidney transplant recipients. Transplantation 2012;93:73-81.  Back to cited text no. 2
    
3.
Caillard S, Cellot E, Dantal J, Thaunat O, Provot F, Janbon B, et al. AFrench cohort study of kidney retransplantation after post-transplant lymphoproliferative disorders. Clin J Am Soc Nephrol 2017;12:1663-70.  Back to cited text no. 3
    
4.
Reshef R, Vardhanabhuti S, Luskin MR, Heitjan DF, Hadjiliadis D, Goral S, et al. Reduction of immunosuppression as initial therapy for posttransplantation lymphoproliferative disorder. Am J Transplant 2011;11:336-47.  Back to cited text no. 4
    
5.
Serre JE, Michonneau D, Bachy E, Noël LH, Dubois V, Suberbielle C, et al. Maintaining calcineurin inhibition after the diagnosis of post-transplant lymphoproliferative disorder improves renal graft survival. Kidney Int 2014;85:182-90.  Back to cited text no. 5
    
6.
Caillard S, Lamy FX, Quelen C, Dantal J, Lebranchu Y, Lang P, et al. Epidemiology of posttransplant lymphoproliferative disorders in adult kidney and kidney pancreas recipients: Report of the French registry and analysis of subgroups of lymphomas. Am J Transplant 2012;12:682-93.  Back to cited text no. 6
    
7.
Tsai DE, Hardy CL, Tomaszewski JE, Kotloff RM, Oltoff KM, Somer BG, et al. Reduction in immunosuppression as initial therapy for posttransplant lymphoproliferative disorder: Analysis of prognostic variables and long-term follow-up of 42 adult patients. Transplantation 2001;71:1076-88.  Back to cited text no. 7
    
8.
Robson R, Cecka JM, Opelz G, Budde M, Sacks S. Prospective registry-based observational cohort study of the long-term risk of malignancies in renal transplant patients treated with mycophenolate mofetil. Am J Transplant 2005;5:2954-60.  Back to cited text no. 8
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]



 

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