Posttransplant lymphoproliferative disorder is a serious, life-threatening complication in organ transplant patients receiving immunosuppressive therapy. Isolated posttransplant lymphoproliferative disorder of the gastrointestinal tract is rare. Posttransplant lymphoproliferative disorder encompasses a spectrum of clinical manifestations, in addition to a wide range of histopathological findings, from B-cell hyperplasia to lymphoma. Renal transplant patients with small intestinal posttransplant lymphoproliferative disorder are more likely to be of younger age, but less frequently represent Hodgkin and Hodgkin-like lesions. They also have better patient survival compared with transplant recipients with posttransplant lymphoproliferative disorder in other locations. We report on the treatment of a kidney transplant recipient with confirmed isolated posttransplant lymphoproliferative disorder in the small intestine. The patient presented with acute abdomen and small intestine perforation, 17 years after kidney transplant, despite being without calcineurin inhibitor in immunosuppressive therapy, to mitigate previous ductal breast carcinoma. Pathological examinations revealed isolated Epstein-Barr virus-positive diffuse large B-cell non-Hodgkin lymphoma of small intestine, clinical stage IV A E. The patient was treated with reduction of immunosuppression, rituximab, and the CHOP regimen (ie, cyclophosphamide, doxorubicin, vincristine, and prednisone). A complete remission was achieved. Kidney allograft function was stable throughout the follow-up period. Physicians should consider isolated gastrointestinal posttransplant lymphoproliferative disorder as a possible etiology in posttransplant, immunocompromised patients who present with different gastrointestinal symptoms. Given good clinical response to treatment, early identification of posttransplant lymphoproliferative disorder has a key role in monitoring and treatment.
Key words : Kidney transplant complications, Rituximab
Posttransplant lymphoproliferative disorder (PTLD) is a serious, life-threatening complication in organ transplant patients receiving immunosuppressive therapy.1 Posttransplant lymphoproliferative disorder represents a major challenging diagnostic and therapeutic problem characterized by irregular proliferation of B cells or T cells in the lymphoid tissue.2 Penn and colleagues3 were the first investigators to publish a report on PTLD in a patient who had undergone living related kidney transplant in 1969. Investigators have suggested that the incidence, time interval, prognosis, and presentation of PTLD vary depending on the age of the patients, presence of viral infections (Epstein-Barr virus), intensity of immunosuppression, and the organ transplanted.4 Walker and colleagues reported PTLD in 5.2% of patients after kidney and pancreas transplant.5 Posttransplant lymphoproliferative disorder encompasses a spectrum of clinical manifestations, in addition to a wide range of histopathological findings, from B-cell hyperplasia to lymphoma.6 According to a study by Khedmat and colleagues, renal transplant patients with small intestinal PTLD are more likely to be of younger age, but less frequently represent Hodgkin and Hodgkin-like lesions. Such patients also have better patient survival compared with transplant recipients with PTLD in other locations.7 Here, we describe a kidney transplant recipient with confirmed PTLD isolated in small intestine and treatment.
A 50-year-old woman who was diagnosed with type 1 diabetes at 3 years of age had since then been treated with insulin therapy. She developed end-stage renal disease at the age of 33 years and in a short time period was treated with chronic hemodialysis. She had successful kidney transplant from a living related donor (mother) 17 years ago. At the beginning, the immunosuppressive regimen consisted of cyclosporin A, mycophenolate mofetil, and steroid. She had high serum concentrations of cyclosporine, despite the small dosage, and many side effects. Therefore, tacrolimus was introduced in therapy, but soon after its introduction, she developed the same side effects and high serum concentrations. Immunosuppressive therapy in the next period consisted of mycophenolate mofetil and steroid, with good graft function, despite absence of calcineurin inhibitor, without episodes of graft rejections or other complications. Eight years after kidney transplant she was diagnosed with breast carcinoma, ductal carcinoma in situ and treated with total left mastectomy, additional radiation therapy, and the selective estrogen receptor modulator tamoxifen. Three years after mastectomy, she was treated with prophylactic bilateral oophorectomy. After the diagnosis of ductal carcinoma in situ, her immunosuppressive regimen was changed to everolimus and steroid. Graft function was regular in the next 9 years of follow-up.
Seventeen years after kidney transplant, the patient developed a clinical presentation of acute abdomen perforation of the small intestine, verified by computed tomography. Resection of a 21-cm length of terminal ileum had been performed with an ileo-ascending colon anastomosis.
Pathological examinations of resected terminal ileum showed lymphoid tumor infiltration that penetrated all parts of the intestinal wall. The infiltrate was composed of lymphoid cells, which morphologically correspond to centroblasts, with a smaller number of immunoblasts and a larger number of CD68-positive histiocytes. Immunohistochemically, tumor cells were clearly positive for PAX5, CD20 (high membrane positivity), CD30, multiple myeloma oncogene MUM1, and B-cell lymphoma BCL2. Expression of Epstein-Barr virus latent membrane protein LMP1 was found in 40% of cells. Proliferative activity (Ki67 positive) was observed in 60% of tumor cells. The presence of the Epstein-Barr encoding region in the nuclei of all tumor cells was proved by the in situ hybridization method. The morphological characteristics and immunophenotype of the tumor tissue corresponded to Epstein-Barr virus-positive diffuse large B-cell non-Hodgkin lymphoma. Immunohistochemical characteristics suggested origin outside the germinal center (non-germinal center B cell).
Positron emission tomography-computed tomography examination did not reveal disease activity in other body parts. Clinical stage IV A E, according to the Ann Arbor classification, was determined.
In the hematology department, the patient was treated with combined immunopolychemotherapy, according to the R-CHOP regimen (ie, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) 4 times every 3 weeks, in doses adjusted to graft function, followed by maintenance treatment with rituximab (375 mg/m2; 3 doses every 3 weeks). A complete remission was achieved, confirmed with computed tomography scan and colonoscopy.
The existing immunosuppressive treatment was not modified, with continued administration of everolimus (concentrations from 5.4 to 10.2 ng/mL) and methylprednisolone.
The patient was followed by hematologists and a nephrologist. Kidney allograft function was stable throughout the follow-up period, with creatinine values not exceeding 90 μmol/L, without significant proteinuria.
An increased risk of PTLD development occurs mainly in the first year after transplant. Opelz and Dohler evaluated more than 50 000 patients after heart or kidney transplant and found a significantly higher incidence of B-cell PTLD in the first year after transplant, whereas T-cell PTLD should be expected 5 years after transplant.8 The pathogenesis of PTLD is not completely understood. Epstein-Barr virus, known to provoke malignant transformation of B cells, is a major risk factor for the development of PTLD, accounting for more than 70% of cases.9
Our patient, despite reduced immunosuppression (most likely due to slow metabolism of calcineurin inhibitors and their toxicity, as well as previously diagnosed breast cancer), developed PTLD 17 years after kidney transplant. It was B-cell non-Hodgkin lymphoma, not T-cell non-Hodgkin lymphoma, although it appeared many years after the kidney transplant.
Studies have demonstrated that up to one-half of patients with PTLD have evidence of disease in the small bowel, colon, or mesenteric lymph nodes. However, isolated PTLD of the gastrointestinal tract is rare.10 Gastrointestinal involvement of PTLD can cause life-threatening ulcers and perforations, as seen in our case.
The goal of treatment for patients with PTLD is to achieve a balance between tumor treatment and maintenance of graft function. Therefore, reduction of immunosuppressive therapy and administration of rituximab as monotherapy, or rituximab in combination with the CHOP protocol, are required in patients at higher risk of developing more severe forms of the disease and complications.11,12 Outcomes in PTLD treated with immunosuppression reduction and chemotherapy are promising, with response rates of 82% to 90%.13 The combination of rituximab and CHOP was effective therapy in our patient, with success in preserving renal allograft function.
Physicians should consider isolated gastrointestinal PTLD as a possible etiology in posttransplant immunocompromised patients who present with different gastrointestinal symptoms.14 Treatment should be chosen according to all individual patient characteristics, with consideration for the years after transplant, immunosuppressive protocol, present comorbidities, and the risk assessment of complications and progression of PTLD, as well as molecular phenotypic characteristics of the tumor.
Given good clinical response to treatment, early identification of PTLD has a key role in monitoring and treatment of patients with solid-organ transplant. With the increased number of solid-organ transplants, it is important to consider PTLD as a potential complication in this specific population of patients.15
Volume : 19
Issue : 1
Pages : 77 - 79
DOI : 10.6002/ect.2020.0437
From the 1Clinical Center of Montenegro, Clinic for Nephrology, Podgorica,
Montenegro; the 2Clinical Center of Montenegro, Hematology Department,
Podgorica, Montenegro; and the 3Clinical Hospital Center Zagreb, Nephrology,
Arterial Hypertension, Dialysis and Transplantation Division, Zagreb, Croatia
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential interest.
Corresponding author: Danilo Radunovic, Clinic for Nephrology, Clinical Center of Montenegro, Ljubljanska bb, 81000 Podgorica, Montenegro
Phone: +38 220412476