Risk of lymphoma after renal transplantation varies with time: an analysis of the United States Renal Data System

BACKGROUND: Characterization of the incidence of posttransplant lymphoma over time may help guide the timing and intensity of posttransplant monitoring. We analyzed the United States Renal Data System to describe the occurrence of lymphoma following renal transplantation. METHODS: All end-stage renal disease patients placed on the transplant waiting list between January 1, 1990 and December 31, 1999 were considered. Survival analysis was used to estimate lymphoma risk in renal transplant patients. RESULTS: Of 89,260 eligible patients, a total of 556 lymphoma cases were identified with 357 in transplant patients. The overall rate of posttransplant lymphoma was 33.3/10,000 person-years in transplant patients. There was variation in the duration and magnitude of increased lymphoma risk by age. The highest rates of lymphoma were among transplanted patients in the first 12 months, after which the rate of lymphoma decreased. Among Caucasian transplant recipients less than 25 years of age, the adjusted relative risk of lymphoma ranged from 13.82 [95% CI: (3.96, 48.15)] within 6 months posttransplant to 3.46 [95% CI: (0.69, 17.44)] within months 30-36 posttransplant. Only patients under 25 years had a notably increased risk beyond the first 2 posttransplant years. The risk of lymphoma differed by race, with Caucasian patients at nearly double the risk of African-Americans. Gender was not associated with lymphoma incidence. CONCLUSIONS: We found and quantified a time-varying relationship between renal transplant and lymphoma risk. This information can be used in combination with knowledge of established risk factors to guide the schedule of posttransplant monitoring.     

Primary central nervous system lymphoma in a renal transplant recipient with Bardet-Biedl syndrome

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder. End-stage renal failure has been reported as the most frequent cause of death in this disorder. There are few reports of kidney transplantation in these patients. Renal transplant patients are known to be at increased risk for the development of malignancies. Although a few patients with BBS have been described to develop malignant disease, there was no previous association with lymphoma. We report a 20-year-old patient in whom primary central nervous system lymphoma was diagnosed 20 months after renal transplantation.     

Polyclonal B cell lymphoma of renal transplant ureter induced by cyclosporine: case report

A case of a renal transplant patient who had polyclonal B cell lymphoma of the transplant ureter 3 months postoperatively while on cyclosporine therapy is reported. Removal of the ureteral segment along with acyclovir therapy and discontinuation of cyclosporine resulted in no subsequent tumor growth and stable renal function for more than 5 years.     

Pure red cell aplasia preceding malignant lymphoma in a renal transplant patient

Malignant disorders are one of the major causes of morbidity and mortality in transplant patients. We present herein a renal transplant recipient with malignant lymphoma which preceded by pure red cell aplasia (PRCA). Acquired PRCA is a rare hematologic disorder in renal transplant recipients. It has been associated with a variety of disorders of immunologic dysfunction and neoplasms, exposure to drugs and toxins, infectious diseases, pregnancy and severe nutritional deficiency. This is the first case with PRCA preceding the malign lymphoma in a renal transplant patient. Treatment of lymphoma and lymphoma-related humoral and cellular changes or other undefined effects that may be related to therapy may be responsible of the resolving of PRCA in this patient. In this regard, renal transplant patients with acquired PRCA, must be closely followed for an underlying neoplastic disorder.     

Pharmacodynamics of Rituximab in Kidney Allotransplantation

The anti-CD20 antibody rituximab has recently gained interest as a B-cell depleting agent in renal transplantation. However, little is known about the pharmacodynamics of rituximab in renal transplant recipients. We have therefore studied the effect of single-dose rituximab in combination with conventional triple immunosuppressive therapy on the B-cell population in peripheral blood as well as in tissues. A total of 49 renal transplant recipients received single-dose rituximab, as induction therapy (n = 36) or as anti-rejection therapy (n = 13). We counted B cells in peripheral blood and performed immunohistochemical staining on lymph nodes and kidney transplant tissue samples to assess the prevalence of B cells. In all but 6 patients (88%) complete depletion of B cells in peripheral blood was achieved. In adults, 15 months after treatment the CD19+ and CD20+ cell counts were still below 5 cells/muL in the majority of patients (78%). The immunohistochemical staining showed a complete elimination of B cells in kidney tissue and a reduction of B cells in lymph nodes. In conclusion, single-dose rituximab in kidney transplant recipients evokes a long-term elimination of B cells in peripheral blood as well as within the kidney transplant. The effect seems to extend beyond the expected 3-12 months observed in lymphoma patients.     

Effective treatment of high-grade lymphoproliferative disorder after renal transplantation using autologous lymphocyte activated killer cell therapy

Posttransplantation lymphoproliferative disorders (PTLD) is not uncommon and can occur in 2% to 5% of solid organ recipients on immunosuppression. Epstein-Barr virus (EBV) infection or reactivation and intensive anti-T lymphocyte treatment are important pathogenetic factors for a large proportion of these disorders. Nonclonal lesions with polymorphous histology have a potential for regressing when the immunosuppressants are reduced or stopped. Clonal tumors with a monomorphous histology carry a poor prognosis, and the mortality rate for monoclonal lymphoma has been reported as high as 80%. We report a renal transplant recipient who developed high-grade monoclonal lymphoma only 4 months after a live-donor transplantation. The tumor was EBV positive. Reduction of immunosuppressants resulted in minimal regression of the tumor. The patient was treated with adoptive immunotherapy using ex vivo generation of autologous lymphocyte activated killer (LAK) cells. She had leukapheresis, and autologous peripheral blood mononuclear cells were obtained and cultured in interleukin-2 (IL-2)-rich medium for 9 to 10 days. The IL-2-activated LAK cells were reinfused into the patient without any systemic administration of IL-2. The patient experienced no side effects during the infusion. There was no rejection episode, and the renal function of the patient remained stable after treatment. Computed tomography scan performed 2 months after the infusion showed marked regression of the lesions in the liver and spleen. Five months later, magnetic resonance imaging showed complete resolution of the tumor lesions. Ultrasonography 13 months after the LAK cell infusion showed no lesion. The allograft function was not affected after treatment. Adoptive immunotherapy using IL-2-activated autologous LAK cells was effective in treating this renal transplant patient with EBV-positive high-grade lymphoma. The patient's kidney allograft functioned well without any rejection.     

Primary intestinal posttransplant T-cell lymphoma

There have been only five reported cases of primary posttransplant T-cell lymphoma. We report the first case associated with the use of sirolimus (Rapamycin, Wyeth-Ayerst, Philadelphia, PA). The patient, receiving prednisone, cyclosporine, and sirolimus treatment, developed ascites, diarrhea, and weight loss 7 months after his second renal transplant. Tissue obtained at laparotomy established the diagnosis of primary T-cell lymphoma. Latent membrane protein-1 for Epstein-Barr virus was negative, but in-site hybridization test for Epstein-Barr-encoded RNA was positive. Despite aggressive chemotherapy, the patient died 8 months posttransplant. This is the sixth reported case of primary intestinal posttransplant T-cell lymphoma, but it is the first case associated with the use of sirolimus. The incidence of posttransplant lymphoproliferative disease in patients receiving sirolimus should be studied.     

A late-onset Epstein-Barr virus-related lymphoma completely remitted in a child with renal allograft

Lymphomas are frequently encountered malignancies following renal transplantations. A 17-year-old boy was found to have lymphoma 1.5 years after a the first cadaveric transplantation performed due to reflux nephropathy. Polyclonal anti-thymocyte globulin (induction) with prednisolone (PRD), azathioprine (AZT), and tacrolimus (Tac) regimen had been given after the transplantation. A hypoechoic mass (25 mm) was detected in the upper pole of the allograft by renal Doppler ultrasound performed due to graft dysfunction with a high basal serum creatinine (Cr) (2.2 mg/dL). The renal biopsy revealed a large B-cell lymphoma with CD20 staining in the medulla. The serum displayed a positive Epstein-Barr virus (EBV), immunoglobulin (Ig)G, negative IgM with negative DNA-polymerase chain reaction. However, the biopsy was positive for EBV-LMA. The viral status at the time of transplant was unknown. After withdrawing AZT and Tac therapies, a chemoimmunotherapeutic regimen consisting of PRD, cyclophosphamide, and anti-CD20 monoclonal antibody was administered twice. The patient excreted the necrosed tumor particles over a 2-month interval with hydronephrotic colic attacks. The basal Cr improved at 6 months (to 1.4 mg/dL). A low dose of Tac (0.5 mg/d) was added to PRD. The patient has remained in complete remission for 2.5 years with a well-functioning renal allograft. Although this case was a late-onset lymphoma, the patient displayed a picture like excreting stones from the allograft and remitted completely. This case illustrates that localization of a tumor may play a more important role than the elapsed time from transplant in the diagnosis in EBV-related posttransplant lymphoproliferative disease.     

Complete regression of cutaneous B-cell lymphoma in a renal transplant patient after conversion from cyclosporin to sirolimus

Posttransplant lymphoproliferative disease remains a serious morbidity. Herein we have reported a case of complete regression of a biopsy-proven B-cell lymphoma that occurred in the posttransplant period. A 48-year-old man received a living donor renal transplant for end-stage renal disease due to undetermined etiology. His initial immunosuppression consisted of corticosteroid, mycophenolate mofetil, and cyclosporin. The patient developed severe pneumonia within the first 2 months after transplantation due to Acineotobacter, fungus, and cytomegalovirus infections. He experienced a complete recovery and was discharged for regional follow-up. Four months after discharge, he was referred again because of presence of two nodules on his trunk. A biopsy of the nodules revealed B-cell lymphoma. Cyclosporin was stopped and he was converted to sirolimus. The lesions regressed progressively and completely within 7 weeks. The patient remains well without clinical relapses at 19 months after conversion. Renal functions remained stable. We postulated that the antincoplastic properties of sirolimus may have played an active part in the positive outcome.     

Pseudolymphoma in renal allograft recipients.

Five renal transplant recipients exhibited giant systemic lymphadenopathy shortly after transplantation. Biopsy specimens did not show Hodgkin's lymphoma. Immunosuppression was continued in all patients. In contrast to the rapidly fatal course of malignant lymphoma in transplant recipients, adenopathy in these five patients has uniformly resolved. Patients have been observed for 6 to 15 months with no evidence of residual disease. Interval biopsy specimens are not malignant. Each patient received antithymocyte globulin from a single lot for 10 to 21 days after transplantation. During administration, T cell lymphocytes were suppressed to 5% of control values. When lymphadenopathy occurred, T cell values rebounded to 371% of control values. Toxoplasmosis titers as well as viral cultures of lymph node biopsy specimens were negative. These data indicate a benign course of this histologically malignant disease and suggest a lymphoblastic rebound phenomenon to antithymocyte globulin.     

Arteriovenous fistula after biopsy of renal transplant kidney: diagnosis and treatment

An 11-year-old renal transplant recipient was noted to have a bruit over her transplant graft 26 months post transplant and 17 months following percutaneous renal biopsy during an episode of rejection. Diagnosis of an arteriovenous (AV) fistula was made by ultrasound examination with Doppler flow and was confirmed with arteriography. The AV fistula was occluded by transcatheter embolotherapy with placement of a steel coil into the fistula from the renal vein approach. This procedure allowed nonsurgical closure of the AV shunt without significant change in renal function.     

Rapid development of an immunoblastic lymphoma and death in children following cadaveric renal transplantation.

We report on three children who underwent cadaveric renal transplantation and subsequently developed an immunoblastic lymphoma, leading to death in two patients. The development of the lymphoma occurred following a multi-drug immunosuppression regimen ending with monoclonal antilymphocyte (OKT3) treatment for biopsy-proven cellular and vascular acute rejection. These patients represent three of 11 children who received OKT3 treatment for rejection in the last 18 months at this institution. Following the diagnosis of lymphoma, all three patients were treated by transplant nephrectomy, cessation of immunosuppression, and administration of intravenous acyclovir. The first two patients died at 4 days and 4 weeks, respectively, after the definitive diagnosis was made with widespread metastatic disease. The remaining child is a short-term survivor (13 months), free of demonstrable malignancy. Multidrug regimens for immunosuppression have a profound effects on T cell function. These effects, when combined with a primary infection by the Epstein-Barr virus, are implicated in the rapid development of the lymphomas and are responsible for the death of these two children.     

Mucosa-associated lymphoid tissue-type lymphomas occurring in post-transplantation patients

Post-transplantation lymphoproliferative disorders (PTLDs) are usually Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disorders that vary in their morphologic spectrum. Extranodal marginal zone lymphomas of the mucosa-associated lymphoid tissue-type (MALT-type) have not been considered to be part of this spectrum. The authors encountered five such cases recently. The clinical, histopathologic, and immunophenotypic features are reported. There were three men and two women with a mean age of 51.2 years (range, 48-63 years). Two patients were cardiac transplant recipients, two patients were liver transplant recipients, and the remaining patient was a renal transplant patient. Sites of lymphoma were the stomach in three patients and the parotid gland in two patients. Mean time to the lymphoma was 84 months after transplantation. All patients had morphologic features of low-grade extranodal marginal zone lymphomas of the MALT-type, and Helicobacter pylori was present in all three gastric cases. All patients exhibited the B-cell immunophenotype and were negative for EBV by in situ hybridization. These lymphomas were treated with a variety of modalities, including reduction of immunosuppression, antibiotics, surgical resection, radiation therapy, and chemotherapy. At last follow-up, one patient had developed signet ring adenocarcinoma at 27 months but had no evidence of PTLD, one patient relapsed at 17 months but is alive with stable disease at 24 months, and the remaining patients were alive without disease at 11, 12, and 14 months. Extranodal low-grade MALT-type lymphomas can occur in the post-transplantation setting and generally develop years after transplant. As seen in immunocompetent patients, EBV appears to play no role in the pathogenesis of these lymphomas. These lymphomas appear to have more in common with MALT-type lymphomas in nonimmunocompromised patients than conventional PTLDs, although they occur in "at-risk" patients due to their immunosuppressive therapy. These lymphomas do not appear to be clinically aggressive. Recognition of MALT-type lymphomas in the post-transplantation setting as an indolent disease avoids unnecessary treatment.     

Renal dysplasia/hypoplasia, Williams Syndrome phenotype and non-Hodgkin lymphoma in the same patient: only a coincidence?

Congenital renal anomalies, Williams Syndrome and non-Hodgkin lymphoma all occur separately at low incidence, so their simultaneous presence in the same patient is exceptional. We present a young patient manifesting all three conditions. This child is a boy with a Williams Syndrome phenotype who was diagnosed with severe chronic kidney disease secondary to bilateral renal dysplasia/hypoplasia. Due to his small size, he received treatment with growth hormone. He progressed to end stage kidney disease and, after 8 months, a renal transplant was performed. A number of suspicious abdominal adenopathies were removed during the surgery and, thereafter, immunosupressive treatment with prednisone, azathioprine and cyclosporine was initiated. Examination of the biopsy tissue confirmed the presence of a T-cell lymphoblastic lymphoma. Appropriate chemotherapy was given, and the immunosupressive regimen was eventually reduced to prednisone alone. Now, 8 years since the initial diagnosis of T-cell lymphoblastic lymphoma and 6 years after the completion of the chemotherapy, the patient is still in complete remission with a functional donor kidney. We discuss some possible explanations of this association. Chemotherapy has not appeared to have affected the viability of the grafted kidney and, in fact, it may even have induced immunotolerance.     

Low incidence of malignancies following renal transplantation in India

Summary: Renal transplant recipients have an increased incidence of certain malignancies. the nature of these malignancies varies with the geographic location and the nature of immunosuppressive therapy. There are no reports on the incidence and spectrum of cancers in renal transplant recipients from India. In a retrospective analysis of 294 patients followed up for more than 6 months after transplantation at our centre, we noted six malignancies in four patients, giving an incidence of 2%. Among 157 of those who were followed up for more than 2 years, the incidence was 3.8%. the mean duration of follow up was 5.8 years (range 6 months to 18.5 years). Cyclosporine was given for the first year after transplantation in 168 patients and 126 patients received only azathioprine and steroids. the interval between transplantation and development of malignancies varied from 24 to 169 months. the tumours included extranodal non-Hodgkin's lymphoma (NHL) involving the central nervous system and small bowel and carcinoma of the tongue in one case each. the fourth patient, who survived for 14 years after transplantation, developed three squamous cell malignancies during this period: carcinoma of the cervix, perianal region and nasopharynx. Both patients with NHL died despite surgical excision of the tumour. None of the patients developed a cutaneous malignancy. In conclusion, renal transplant recipients living in a tropical environment have alow incidence of malignancies compared to those in temperate zones. This discrepancy can be explained by an absence of malignant tumours of the exposed skin in our patients. the absence of any tumours within the first 2 years is also unusual.     

Lymphoma masquerading as a recurrent brachial artery aneurysm.

Malignant lymphoma infiltrating the brachial artery in a renal transplant patient has not been documented previously. We report an angiodestructive B-cell lymphoma in a 64-year-old post-renal transplant recipient. Improved longevity post-transplantation has been associated with an increased incidence of cancer which means that we will be seeing such patients more frequently in the future.     

A matched case-control study on the prognosis of native kidney neoplasia in renal transplant recipients

A matched case-control study was performed to compare the prognosis of six renal transplant recipients with a control group of non-transplant patients, both groups presenting with native kidney tumors. Patients were matched for age, gender, neoplasm histology, and TNM classification. The follow-up ranged from 8 to 131 months (median 32 months) after nephrectomy or nephroureterectomy of the native kidney. Five out of six recipients retained good graft function. No evidence of recurrent local disease or distant metastasis of kidney neoplasms was observed in either group. In the transplant group, two patients developed basal cell carcinoma, and one, lung cancer and a disseminated lymphoma. Among control group patients, prostate and bladder cancer were noted. Prognosis of early-stage kidney malignancy in the transplant and non-transplant group was comparable despite immunosuppression; however, recovery from the primary kidney malignancy did not exclude the risk of developing a new type of neoplasm in either group.     

Treatment of oropharyngeal cancer in renal transplant recipients without cessation of immunosuppressive therapy

INTRODUCTION: Renal transplantation and immunosuppression are associated with an increased incidence of malignancy. Reduction or cessation of immunosuppressive therapy has been advocated in these cases to prevent tumor progression and recurrence. We evaluated the outcome of treatment of oropharyngeal cancer (OC) after renal transplantation without cessation of immunosuppressive therapy. METHODS: The database of patients with OC after renal transplantation was analyzed with respect to age, sex, type of immunosuppression, interval between transplantation and diagnosis of cancer, as well as method of treatment and survival. RESULTS: Thirty one (2.06%) renal transplant recipients developed malignancy including 6 (20%) with OC. Lingual cancer was seen in three, and one each showed an isolated tonsillar lymphoma, a parotid carcinoma, or a carcinoma of the larynx with only the last having had two other malignancies in the past. Three subjects were on immunosuppression with azathioprine and prednisolone, and the others were prescribed cyclosporine and prednisolone. Average time from transplantation to diagnosis of OC was 106 months. The interval was the shortest (2 years) for tonsillar lymphoma in an 18-year-old patient who received cyclosporine and showed features of left follicular tonsillitis. The patient with advanced carcinoma of the larynx did not receive any treatment and succumbed within 3 months. The dose of cyclosporine was reduced in the lymphoma case but immunosuppression was not altered in the other patients. All subjects were treated with a standard protocol. During a mean follow-up of 33 months, one had local recurrence of parotid carcinoma and the others showed well functioning renal grafts. CONCLUSION: Comprehensive treatment of OC after renal transplantation without withdrawing the immunosuppression prolonged the life of these patients with functioning grafts.     

Valsartan-induced hematocrit changes in renal transplant patients

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor type 1 blockers (ARB) are frequently prescribed for renal transplant patients. The main reasons for their use are that their antihypertensive and antifibrogenic effects may prevent chronic renal allograft dysfunction, potentially improving transplant survival. Furthermore, ACE and ARB have been used to reduce the hematocrit in patients with posttransplant erythrocytosis. We evaluated the effects of the ARB valsartan on the evolution of hematocrit in stable renal transplant patients treated with cyclosporine (CsA), azathioprine (Aza), and prednisone. PATIENTS AND METHODS: Twenty-six stable renal transplant patients treated with valsartan 80 mg/d orally were followed for 6 months. Evaluations were performed prior to as well as at 3 and 6 months following the initiation of valsartan. RESULTS: The hematocrit levels decreased significantly at 3 months (46.1 +/- 7.3 vs 39.9 +/- 5.8 ; P < .0001) in patients with a normal hematocrit, namely a level over 38%, with no further reduction at 6 months. In recipients with an hematocrit less than 38%, there was no significant reduction, either at 3 or 6 months follow-up. Valsartan was well tolerated without significant side effects. CONCLUSION: We postulate that inhibition of the proerythropoietic effects of angiotensin II and/or the reduction in hypoxia within the renal tubulointerstitium as well as the vasodilator effects on the efferent arterioles, represent possible mechanisms for the reduction and stabilization of the hematocrit in stable renal transplant patients.     

Lymphomas After Solid Organ Transplantation: A Collaborative Transplant Study Report

We used the Collaborative Transplant Study database to analyze the incidence, risk, and impact of malignant lymphomas in approximately 200,000 organ transplant recipients. Over a 10-year period, the risk in renal transplant recipients was 11.8-fold higher than that in a matched nontransplanted population (p<0.0001). The majority of lymphomas were diagnosed after the first post-transplant year. Heart-lung transplants showed the highest relative risk (RR 239.5) among different types of organ transplants. In kidney recipients, immunosuppression with cyclosporine did not confer added risk compared with azathioprine/steroid treatment, whereas treatment with FK506 increased the risk approximately twofold. Induction therapy with OKT3 or ATG, but not with anti-IL2 receptor antibodies, increased the risk of lymphoma during the first year. Antirejection therapy with OKT3 or ATG also increased the risk. First-year mortality in renal and heart transplant patients with lymphoma was approximately 40% and 50%, respectively, and showed no improvement in recent years. A pattern of preferential localization to the vicinity of the transplant was noted, and the prognosis of the patient was related to localization. This study highlights the continuing risk for lymphoma with time post-transplantation, the contribution of immunosuppression to increased risk, and continuing poor outcomes in patients with post-transplant lymphoma.