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Table of Contents
Year : 2019  |  Volume : 13  |  Issue : 4  |  Page : 282-285

Isolated gastrointestinal posttransplant lymphoproliferative disorder in a child

1 Department of Nephrology, Aster Medcity, Kochi, Kerala, India
2 Department of Pathology, Aster Medcity, Kochi, Kerala, India
3 Department of Gastroenterology, Aster Medcity, Kochi, Kerala, India

Date of Submission05-Aug-2019
Date of Acceptance26-Nov-2019
Date of Web Publication31-Dec-2019

Correspondence Address:
Dr. K Vinod Kumar
Department of Nephrology, Aster Medcity, Cheranalloor, Kochi - 682 027, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijot.ijot_30_19

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We report a 12-year-old male renal allograft recipient, 10 months following the transplant surgery, who presented with diffuse abdominal pain, constipation, vomiting, and weight loss of 5 kg in 2 months. He was on standard maintenance immunosuppression (tacrolimus/mycophenolate mofetil/prednisolone) and had not received induction agents. Upper gastrointestinal (GI) endoscopy showed nodularity in the body of the stomach, and colonoscopy showed deep ulcers in the sigmoid colon and descending colon. Biopsy from the lesions showed dense infiltration of atypical lymphoid cells (B-cell markers, CD20, CD30, and BCL2 being positive), with immunohistochemistry showing strong positivity for Epstein–Barr virus (EBV). EBV DNA polymerase chain reaction in the blood was strongly positive (2200 copies/mL), confirming EBV-positive posttransplant lymphoproliferative disorder (PTLD). Positron emission tomography–computed tomography and bone marrow biopsy confirmed that the disease was confined to the GI tract. It is a rare complication seen after solid organ transplantation occurring usually in the 1st year after transplant. The most important risk factor is a higher degree of immunosuppression; tacrolimus levels remained high in spite of repeated revisions of the drug dose in our case. The patient was treated with injection rituximab (dose: 375 mg/m2), weekly injections of four doses, and his immunosuppressive medications were reduced by 50%. He had a good symptomatic relief. PTLD confined to GI tract is rare; constipation as a presenting manifestation is very rare. A high index of suspicion is essential to make an early diagnosis.

Keywords: Epstein–Barr virus, lymphoma, tacrolimus

How to cite this article:
Kumar K V, Unni V N, Kachare N, Siyad I, Pullockara J, Prasannan B. Isolated gastrointestinal posttransplant lymphoproliferative disorder in a child. Indian J Transplant 2019;13:282-5

How to cite this URL:
Kumar K V, Unni V N, Kachare N, Siyad I, Pullockara J, Prasannan B. Isolated gastrointestinal posttransplant lymphoproliferative disorder in a child. Indian J Transplant [serial online] 2019 [cited 2020 Apr 8];13:282-5. Available from: http://www.ijtonline.in/text.asp?2019/13/4/282/274606

  Introduction Top

Although there is a dramatic improvement in patients' survival with the advent of modern immunosuppressive therapy in the field of solid organ transplantation, it is not devoid of adverse effects. Gastrointestinal (GI) manifestations are the most frequent side effects with immunosuppressive medications and occur in 40% of the recipients.[1] Drug-related acute gastritis is the most common adverse effect seen; however, with the decrease in immunity, opportunistic infections and neoplasms are frequently encountered. GI posttransplant lymphoproliferative disorder (PTLD) is a rare manifestation, seen in solid organ recipients, and can pose significant diagnostic challenges, as they present with vague symptoms, resulting in delay in diagnosis. We report a case of renal allograft recipient presenting with features of GI PTLD manifesting as chronic abdominal pain and constipation.

  Case Report Top

A 12-year-old male renal allograft recipient presented 10 months after renal transplant surgery, with diffuse abdominal pain of 2-month duration, associated with constipation and few episodes of diarrhea. Pain abdomen was intermittent, colicky in nature and associated with vomiting for 10 days; the child had no fever, hematochezia, or hematemesis. He had a weight loss of 5 kg in 2 months. He was on follow-up elsewhere and was receiving standard maintenance immunosuppression (tacrolimus/mycophenolate mofetil/prednisolone). He was not given induction immunosuppression (mother was the donor). He was started on tacrolimus at a dose of 0.1 mg/kg/day, and the drug levels were periodically monitored. Tacrolimus drug levels persistently remained high (>10 ng/mL), requiring frequent reduction in the dose of the drug. Complete blood count, renal function tests, and liver function tests were normal and are shown in [Table 1]. Stool routine examination and stool cultures were normal. The whole-blood tacrolimus trough level was 8.8 ng/mL. X-ray and ultrasonogram abdomen were normal. There was no relief of symptoms with proton-pump inhibitors and antiemetics. Computed tomography (CT) scan of the abdomen with intravenous contrast showed circumferential thickening with enhancement in the entire colon, duodenum, and terminal ileum alongside multiple subcentimetric mesenteric, para-aortic lymph nodes. In view of worsening symptoms, upper GI endoscopy was done which showed nodularity in the body of the stomach, and colonoscopy showed deep ulcers in the sigmoid colon, transverse colon, and descending colon [Figure 1]a and [Figure 1]b. Multiple biopsies from the lesions in the gastric antrum, transverse colon, and sigmoid colon showed surface ulcerations and diffuse and dense infiltration with atypical lymphoid cells with hyperchromatic nuclei in the lamina propria and submucosa [Figure 2]a. The immunohistochemistry panel for lymphoma was performed, and immunohistochemistry showed immunoexpression of B-cell markers for CD20, PAX5, CD30, BCL2, BCL6, C-myc, and MUM1 [Figure 2]b, [Figure 2]c, [Figure 2]d, [Figure 2]e, [Figure 2]f, [Figure 2]g, [Figure 2]h. The Ki-67 proliferation index of 60% was seen. The morphology and immunoprofile indicated PTLD of monomorphic type consistent with diffuse large B-cell lymphoma. The immunohistochemistry and Cytomegalovirus (CMV) DNA polymerase chain reaction (PCR) were negative for CMV. The in situ hybridization study for Epstein–Barr virus (EBV) mRNA showed strong positivity for EBV. EBV DNA PCR in the blood was strongly positive (2200 copies/mL), confirming EBV-positive PTLD. EBV serology before the transplant was positive for IgG in both the recipient and the donor indicating past infection. Bone marrow smear and biopsy were normal. Positron emission tomography-CT showed an increased fluorodeoxyglucose (FDG) uptake in the stomach and colon; there was no FDG uptake in the visceral or peripheral lymph nodes, indicating isolated GI-PTLD. The patient was treated with rituximab (dose: 375 mg/m2), weekly injections for four doses, and his immunosuppressive medications (both tacrolimus and mycophenolate mofetil) were reduced by 50%. He had good symptomatic relief and did not require the use of additional chemotherapy.
Table 1: Laboratory parameters of the patient

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Figure 1: (a) Upper gastrointestinal endoscopy showing nodularity with surrounding edema and erosions in the gastric body (arrow).(b) Colonoscopy showing deep ulcer in the transverse colon with surrounding erythema and slough (arrow)

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Figure 2: Diffuse infiltrate of atypical lymphoid cells in gastric mucosa (a, H and E, ×40) and colon mucosa (e, H and E, ×40) with strong immunoexpression of CD20 (b, f), CD30 (c, g) positive B-cells with high Ki-67 proliferation index (d, h)

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  Discussion Top

GI manifestations are the most frequent drug-related side effects seen in solid organ transplantation. GI CMV infection is the most common viral infection in renal allograft recipients, which can have varied manifestations and can affect any part of the GI tract. Although there was an initial suspicion of CMV infection in our case, it was ruled out histologically and by blood tests.

PTLD is one of the most common malignancies in transplant patients, comprising 20% of all posttransplant malignancies.[2] The incidence of PTLD in kidney transplant recipients is between 1% and 3%.[3] The majority (>80%) occurs in the 1st year posttransplant, as seen in our patient also. Rates of PTLD-associated lymphoma are higher in children than adults, owing to the relatively low rates of EBV seropositivity in pediatric population.[4]

The most common manifestations of PTLD are fever and lymphadenopathy. However, extranodal PTLD is seen in two-third of the cases.[5] Isolated GI PTLD is an uncommon presentation and predominantly presents with anemia, failure to thrive, abdominal pain, and vomiting. Constipation is an uncommon manifestation, as seen in our case, posing diagnostic challenge. The colon and stomach were the most common sites involved, with rubbery, raised, and ulcerated lesions seen on endoscopy.[6] Similar findings were seen on endoscopy in our case. Approximately 85% of PTLD is of B-cell origin, and more than 80% of these are associated with EBV.[7]

EBV seroconversion is an important risk factor for developing PTLD. EBV-negative recipients who receive an organ from an EBV-positive donor are at a particularly high risk for PTLD; however, in our case, both the donor and the recipient had evidence of past EBV infection. Other risk factors for PTLD include the degree and duration of immunosuppressive therapy, use of antilymphocyte therapy, CMV disease, and HLA mismatch. The degree of T-cell immunosuppression is more important than the overall immunosuppression. EBV-infected B-cells are held “in check” by cytotoxic T-cells, and impairment of T-cell function promotes the development of PTLD, particularly in children.[8] In our case, the degree of immunosuppression was persistently high as the tacrolimus levels remained high in spite of repeated revisions of the drug dose. Among maintenance immunosuppressive agents, tacrolimus has the highest risk for PTLD when compared to mycophenolate mofetil and steroids.[9],[10] Our patient had not received antilymphocyte therapy.

Treatment includes the reduction of immunosuppressive therapy and addition of anti-CD20 monoclonal antibody. In addition, chemotherapy, radiotherapy, or combination of these can be considered based on the site of the lesion.[11] Often, a reduction of 25%–50% of immunosuppression is recommended. In our case, the dose of both tacrolimus and mycophenolate mofetil was reduced by 50%, and a small dose of steroids was continued. There is no consensus on dosing recommendations for rituximab in PTLD patients. Rituximab 375 mg/m2/week for 4 weeks was employed in a prospective trial involving 43 patients and had overall response rates of 44%.[12] Our patient was also treated with the same regimen, and the child had a good symptomatic relief. Chemoimmunotherapy can be tried in patients with high-grade lymphoma or in those who failed to respond with rituximab alone. Rituximab in combination with chemotherapy has shown an overall response rate of 65%.[13] Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone is the commonly suggested regimen in such cases. Chemotherapy was not used in our case, as he had a good response with rituximab alone.

PTLD confined to GI tract is rare; constipation as a presenting manifestation is very rare. A high index of suspicion is essential to make an early diagnosis.

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.

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Conflicts of interest

There are nao conflicts of interest.

  References Top

Ponticelli C, Passerini P. Gastrointestinal complications in renal transplant recipients. Transpl Int 2005;18:643-50.  Back to cited text no. 1
Penn I. Cancers complicating organ transplantation. N Engl J Med 1990;323:1767-9.  Back to cited text no. 2
LaCasce AS. Post-transplant lymphoproliferative disorders. Oncologist 2006;11:674-80.  Back to cited text no. 3
Opelz G, Döhler B. Lymphomas after solid organ transplantation: A collaborative transplant study report. Am J Transplant 2004;4:222-30.  Back to cited text no. 4
Al-Mansour Z, Nelson BP, Evens AM. Post-transplant lymphoproliferative disease (PTLD): Risk factors, diagnosis, and current treatment strategies. Curr Hematol Malig Rep 2013;8:173-83.  Back to cited text no. 5
O'Connor JA, Cogley C, Burton M, Lancaster-Weiss K, Cordle RA. Posttransplantation lymphoproliferative disorder: Endoscopic findings. J Pediatr Gastroenterol Nutr 2000;31:458-61.  Back to cited text no. 6
Allen U, Alfieri C, Preiksaitis J, Humar A, Moore D, Tapiero B, et al. Epstein-Barr virus infection in transplant recipients: Summary of a workshop on surveillance, prevention and treatment. Can J Infect Dis 2002;13:89-99.  Back to cited text no. 7
Lucas KG, Small TN, Heller G, Dupont B, O'Reilly RJ. The development of cellular immunity to Epstein-Barr virus after allogeneic bone marrow transplantation. Blood 1996;87:2594-603.  Back to cited text no. 8
Bustami RT, Ojo AO, Wolfe RA, Merion RM, Bennett WM, McDiarmid SV, et al. Immunosuppression and the risk of post-transplant malignancy among cadaveric first kidney transplant recipients. Am J Transplant 2004;4:87-93.  Back to cited text no. 9
Funch DP, Ko HH, Travasso J, Brady J, Kew CE 2nd, Nalesnik MA, et al. Posttransplant lymphoproliferative disorder among renal transplant patients in relation to the use of mycophenolate mofetil. Transplantation 2005;80:1174-80.  Back to cited text no. 10
Kamdar KY, Rooney CM, Heslop HE. Posttransplant lymphoproliferative disease following liver transplantation. Curr Opin Organ Transplant 2011;16:274-80.  Back to cited text no. 11
Choquet S, Leblond V, Herbrecht R, Socié G, Stoppa AM, Vandenberghe P, 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.  Back to cited text no. 12
Trappe R, Oertel S, Leblond V, Mollee P, Sender M, Reinke P, et al. 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.  Back to cited text no. 13


  [Figure 1], [Figure 2]

  [Table 1]

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1 Mycophenolate mofetil/prednisolone/tacrolimus
Reactions Weekly. 2020; 1790(1): 166
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