Posttransplant lymphoproliferative disorders are a spectrum of lymphoproliferative disorders seen in recipients of solid-organ, bone marrow, and stem cell allografts. They include polyclonal early lesions mimicking infectious mononucleosis and monoclonal proliferations of B and T cells, indistinguishable from lymphomas occurring in immunocompetent individuals. Although most posttransplant lymphoproliferative disorders are B-cell neoplasms, T-cell posttransplant lymphoproliferative disorders are very rare. Among solid-organ transplants, renal allografts have low risk for development of posttransplant lymphopro­liferative disorders. We describe the case of an adult male who developed a T-cell posttransplant lympho­proliferative disorder involving the small intestine after renal transplant, which was diagnosed as peripheral T-cell lymphoma, not otherwise specified.

Key words : Non-Hodgkin lymphoma; transplant; kidney; Epstein-Barr virus

Introduction

Posttransplant lymphoproliferative disorders (PTLDs) are a spectrum of lymphoproliferative disorders seen in recipients of solid-organ, bone marrow, and stem cell allografts. They range from Epstein-Barr virus (EBV)-driven polyclonal early lesions mimicking infectious mononucleosis to EBV-positive or EBV-negative monoclonal proliferations of B and T cells, indistinguishable from lymphomas occurring in immunocompetent individuals. These lesions develop consequent to immunosuppression in allograft transplant recipients. The World Health Organization classifies them into 4 categories, including early lesions, polymorphic PTLDs, monomorphic PTLDs, and classical Hodgkin lymphoma type.¹ Although most PTLDs are B-cell neoplasms, T-cell PTLDs represent around 10% to 15% of all PTLDs.² Approximately one-third of PTLDs are EBV-seronegative. Epstein-Barr virus-negative PTLDs have distinct clinical and morphologic features that differentiate them from EBV-positive cases. They occur in adults at a later age, with most occurrences being of monomorphic variant and having T-cell immunophenotype.

Among solid organs, renal allografts have the lowest risk of developing PTLD (approximately 1%) as they experience lower levels of immuno­suppression, followed by hepatic and cardiac allografts. Intestinal and lung allografts have the highest rate of PTLD (≥ 5%), whereas bone marrow and stem cell grafts have lower risk.^3,4 Solid-organ transplants have allografts as the most common site of involvement, often causing confusion with rejection. Other involved sites include lymph nodes, the gastrointestinal tract, lung, liver, and the central nervous system. We describe the case of an adult male patient who developed a T-cell PTLD involving the small intestine after renal transplant.

Case Report

A 52-year-old male patient, who had received a renal allograft transplant 11 years earlier and was on a triple-drug immunosuppressive regimen of cyclo­sporine, prednisone, and azathioprine, was admitted with clinical complaints of fever. On investigation, he was found to have graft dysfunction with elevated serum creatinine levels. Enteroscopy revealed multiple deep ulcers in the small intestinal mucosa, occupying two-thirds of the circumference of proximal to midjejunum. A duodenal biopsy was performed, which showed features of nonspecific chronic duodenitis. A cytomegalovirus polymerase chain reaction performed on the duodenal biopsy was positive, and the patient was treated with ganciclovir and a reduction in immunosuppression. Serum EBV serology was positive for immuno­globulin G, but was negative for immunoglobulin M. The patient was subsequently readmitted 1 month later with clinical features suggestive of subacute intestinal obstruction. A contrast-enhanced com­puted tomography of the abdomen revealed a circumferential jejunal thickening. A laparotomy was performed, which revealed a jejunal mass measuring 8 cm × 3 cm × 2.5 cm, transmurally infiltrating the bowel wall, resulting in perforation (Figure 1). On microscopic examination (Figure 2), diffuse mucosal ulceration and acute inflammatory exudate were identified. A dense infiltrate of atypical lymphoid cells was seen dissecting through the muscularis propria, into the serosa. These atypical cells were large, with vesicular nuclei having conspicuous nucleoli, and showed brisk mitotic activity. Few eosinophils and plasma cells were admixed with the atypical lymphoid cells. Serositis was present in the vicinity of the perforation site. On immuno­histochemistry, the malignant lymphoid cells were immunopositive for CD3, CD4 (focal), and CD30, whereas they were negative for CD20, CD8, and ALK1. Epstein-Barr virus-latent membrane protein-1 was also negative in the tumor cells. The morph­ologic and immunohistochemical features were consistent with a monomorphic PTLD, that is, a peripheral T-cell lymphoma, not otherwise specified.

Discussion

The frequency of PTLDs corresponds to the allograft type, intensity of the immunosuppressive regimen, the EBV serologic status at the time of transplant, with seronegativity being an important risk factor for EBV-driven PTLD, and patient age, with higher incidence in children.^5,6 Epstein-Barr virus sero­negative patients of all ages are at 30- to 50-fold greater risk of developing PTLDs, particularly late-onset and rapidly progressive PTLDs.

Most PTLDs are of B-cell immunophenotype; T-cell PTLDs account for only approximately 14% of PTLDs in the Western literature. However, they are more frequent in Asia, where their prevalence may be as high as 40% of all transplant-related hema­tolymphoid diseases. It has been postulated that the high prevalence of T-cell PTLDs in Asia is most likely due to the endemicity of human T-cell leukemia virus infection.7 The most common type of T-cell PTLD is peripheral T-cell lymphoma, not other wise specified. Less frequent types include lymphoblastic lymph­oma, large granular lymphocytic leukemia, cutaneous T-cell lymphoma, anaplastic large-cell lymphoma, and hepatosplenic T-cell lymphoma. Most patients present with disease at extranodal sites and may be associated with lymphadenopathy on occasion. The interval between transplant and the development of T-cell PTLDs is typically longer, with a median of 15 years. Patients with T-cell PTLDs frequently have a more aggressive clinical course, and most cases carry T-cell receptor gene rear­rangements.

The reasons for PTLD development are not entirely understood. Epstein-Barr virus is believed to play a pivotal role in the pathogenesis of most PTLDs, which develop as a result of a complex interaction of multiple factors, like defective T-cell surveillance, type of immunosuppressive regimens, interleukins (IL) such as IL-4, IL-6, and IL-10, and chronic antigenic stimulation by the allograft.^8,9 Approximately 75% of T-cell PTLDs reported have been EBV-negative on serology, and a significant proportion of these EBV-negative lesions have occurred after kidney transplant, as in our case. Thus, EBV serology does not seem to have much utility as a screening tool for PTLDs in this group of patients. The low incidence of EBV infection in T-cell PTLDs may be due to the low infectivity of EBV for nonneoplastic T cells. In the case of EBV-positive PTLDs, cytotoxic T-lymphocyte responses con­trolling EBV-infected B-cells are blunted due to immunosuppression, allowing uncontrolled prolif­eration of EBV-infected lymphocytes. No single immunosuppressive drug has been identified as a causative agent. Multiple studies have shown that immunosuppressive regimen intensity seems to play a dominant role in the development of lymphoma, rather than individual agents or certain combinations.3 This theory is supported by the observation that reduction of immunosuppressive therapy promotes the regression of T-cell PTLDs in approximately one-third of cases.

To conclude, a T-cell PTLD developing in a renal allograft recipient is a rare entity, which can develop many years after transplant and at unusual extranodal sites. Definitive diagnosis requires histo­pathologic examination, including a panel of immunohistochemical markers for immunopheno­typic characterization. In cases of strong clinical suspicion, a biopsy should be performed, as monitoring of EBV serology and viral load is not always helpful, particularly in T-cell PTLDs, as most of these are EBV seronegative.

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