Department of Renal Medicine, Adelaide and Meath Hospital, Dublin, Ireland
Keywords: donor malignancy; low-grade lymphoma; occult neoplasia; renal transplant; tumour transmission
Introduction
Renal transplantation is perceived to be the optimum mode of renal replacement therapy. Transplantation is not without risks and the renal transplant recipient in accepting a transplant also implicitly accepts the extra risks generated by the process of transplantation. These include an increased risk of infection and neoplasia due to the immunosuppressive agents used to prevent rejection. Development of neoplasia due to transmission of malignant cells is another recognized potential complication of transplantation. Immunosuppression facilitates proliferation of inadvertently transplanted malignant cells giving rise to local or metastatic disease. The transplant screening process is designed to minimize this risk by not accepting organs from donors with known malignancies other than specified primary CNS tumours. The current screening procedures are not infallible. Up to 40% of cases of transmitted malignancy are diagnosed retrospectively either because several recipients develop the same tumour or through the use of HLA typing and DNA analysis of donor, recipient and cancer cells of recipients who develop atypical cancers [13]. Malignancy has also been detected unexpectedly in grafts removed for therapeutic reasons [1].
Occasionally, donor malignancy is detected following successful recipient engraftment, usually as a result of donor autopsy after organ harvesting [1,4,5]. A case is presented in which a patient received a renal allograft from a cadaveric donor who was subsequently found to have a low-grade lymphoma. The unique problems relating to this case and the clinical decision making strategies that were used to resolve these problems are discussed.
Case
A 47-year-old male with end-stage renal failure due to probable IgA glomerulonephritis was referred for renal replacement therapy in September 1996. A renal biopsy was not performed, as kidney size was less than 8 cm bilaterally on ultrasound. Peritoneal dialysis was initiated immediately. On Christmas Day 1996 he received a 5 out of 6 HLA match cadaveric renal allograft at the regional transplant centre. The donor was an apparently healthy 24-year-old male. A triple immunosuppressive regimen consisting of cyclosporin A, azathioprine and prednisolone was used. Anti-lymphocyte preparations were not given at induction or subsequently. The allograft functioned immediately and the patient's serum creatinine stabilized at 170 µmol/l by day 7 post-transplant. There were no early post-transplant complications.
Two weeks post-transplant, the transplant surgeon appraised us of the possibility that a donor lymph node removed for tissue typing at the time of organ retrieval contained a low-grade follicular lymphoma. Confirmation of the precise histology took several weeks. The implications of this finding as more information became available were explained in full to the patient. Treatment options including transplant nephrectomy were discussed. The patient elected to retain his renal allograft. His immunosuppression was reduced with no adverse effect on graft function. At 36 months following transplantation, he remains clinically free of lymphoma with a well functioning transplant. The second renal allograft recipient was reluctant to retain a possibly malignant transplant and underwent elective transplant nephrectomy. Interestingly, no lymphoma was detected in the allograft following nephrectomy. The second patient was retransplanted approximately 12 months later and to our knowledge, remains well.
Discussion
Our experience in dealing with cases of this nature was limited and at the time of diagnosis there were no cases of lymphoma transmission by transplantation in the literature for comparison. In endeavouring to resolve this case the potential risk to the patient of various therapeutic options was considered. Numerous issues and questions arose while resolving this case. Was the patient truly at risk of developing neoplasia and if so, would the risk of dying from cancer with a functioning renal allograft be greater than the risk of death on dialysis? Would nephrectomy negate all risk and if not how could the patient be best monitored to detect malignancy at the earliest opportunity? Should he elect to retain the allograft how could his risk of developing malignancy be minimized? If malignancy developed, what were the treatment options? Finally, issues relating to retransplantation following nephrectomy were considered.
Opinions were sought from other nephrologists and oncologists regarding appropriate management of this patient. There was a considerable divergence of opinion regarding further care and any recommendations made were based on personal opinion rather than on similar experiences. The management of this case emphasizes how much of clinical medicine remains intuitive/anecdotal rather than evidence based. Quite simply there was no precedent in the literature for guidance.
Initial management of this case involved an estimation of risk of transmission of lymphoma from donor to recipient. Transmission of malignancy by transplantation is well described in the literature [16]. Retrospective analysis of transplant registry data estimate that 4347% of patients who receive an allograft from a donor with malignancy will subsequently demonstrate evidence of transmitted malignancy [1]. Penn's 1997 review based on Cincinnati Transplant Tumour Registry (CTTR) data identified 270 transplant recipients at risk of transmitted malignancy [1]. A total of 117 (47%) of these patients demonstrated evidence of transmitted malignancy of whom 59 (50%) are alive and cured, 8 (7%) are alive but not cured and 50 (43%) died due to the transmitted malignancy [1]. Two hundred and thirty eight of the 270 patients were renal transplant recipients of whom 41% demonstrated malignancy [1]. It should be emphasized that this data is highly selective and examines a unique group of high-risk patients. Over 50% of the at risk recipients never developed cancer suggesting that the transplanted organs were free of malignancy or that the follow-up time for these patients was too short. Penn's 1997 review also contains the only reference in the literature to lymphoma transmission by transplantation (published 9 months after our patient was transplanted). Details relating to the case are limited, lymphoma confined to the allograft was detected following nephrectomy, the indication for which was unclear and the patient survived [11].
It is probable that reports by Penn and others overestimate the risk of transmission of malignant disease to allograft recipients [1,7]. One potential reason for overestimation of that risk relates to undetected donor occult neoplasia, defined as clinically unsuspected malignancy in the donor. Published autopsy series demonstrate incidences of occult neoplasia of between 11% and 42% depending on the age profile of the population studied [810]. Autopsy studies following organ harvesting also demonstrate occult neoplasia not detected macroscopically during organ retrieval [11,12]. As donor autopsy following organ procurement is not mandatory at present the true incidence of donor neoplasia is not known yet it is likely, based on the results of autopsy series to be as high as 510% [810]. Rising donor age due to ongoing organ shortages may further contribute to a high rate of undetected malignancy amongst donors.
The risk of neoplastic transmission is in part related to tumour type, histological grade, metastatic potential and extent of disease in the donor [1,2,4,5]. Tumours at high risk for transmission include choriocarcinoma and malignant melanoma [15]. Penn's analysis of CTTR data documents the development of choriocarcinoma in 13 out of 14 (93%) recipients at risk and malignant melanoma in 21 out of 28 (75%) recipients at risk [1].
The final histological diagnosis in our case was of low-grade follicular and diffuse pattern B-cell malignant lymphoma with extracapsular extension. As the diagnosis of malignancy was delayed for several weeks following transplantation, full donor autopsy for staging was not possible. Based on available findings we concluded that the donor had early stage low-grade lymphoma.
Early allograft removal has been advocated in cases where donor malignancy is discovered following transplantation [1]. Whilst there is no certainty that the malignancy has remained confined to the allograft, concomitant cessation of immunosuppressive therapy at the time of organ removal restores recipient immunity allowing selective killing of malignant cells which are recognized as non-self by the now intact donor immune system. If allograft removal is contemplated, a replacement organ is obligatory except in the case of renal transplant recipients who can return to an alternative form of renal replacement therapy [1,4,5]. In situations where organ removal is not possible, reduction of immunosuppressive therapy may suffice to cause tumour regression but this has to be managed with great care in transplant recipients for whom no artificial form of organ replacement is available should organ rejection occur [1,4,5]. Transplant nephrectomy was not performed because the patient was considered to be at low risk of developing cancer. The subsequent absence of lymphoma in the other donor kidney was reassuring in this regard. Likewise, removal of the graft after several weeks (late removal) could not guarantee complete cure for the patient, as any lymphomatous elements may have already metastasized.
The feasibility of early retransplantation following transplant nephrectomy was also considered and was discussed in detail with the patient. Re-transplantation could be more difficult due to sensitization from the previous graft. Current guidelines recommend that a 5-year disease-free period elapse prior to transplanting patients with a history of malignancy. The consensus was that early retransplantation would be feasible if there was no evidence of lymphoma in the nephrectomized graft. Penn and others have indicated that safe retransplantation is possible following tumour regression in patients treated for transmitted malignancy [1,5]. They recommend a minimum 1-year recurrence-free period prior to retransplantation [1,55].
Whilst the risk of developing transmitted malignancy was considered low, it could not be completely excluded. To minimize the risk, immunosuppression was reduced without compromising graft function. Trough cyclosporin A levels were maintained at 200 ng/ml for the first 6 months post-transplant and thereafter at 150 ng/ml. Azathioprine dose was reduced from 2 mg/kg to 1 mg/kg. Graft function remained stable and there were no episodes of acute rejection. Haematological parameters were within the normal range at all times.
The issue of how best to monitor the patient so as to detect developing lymphoma at the earliest opportunity was also addressed. Blood film examination has been used to detect circulating lymphoma cells particularly in patients with low-grade non-Hodgkin lymphoma. Circulating lymphoma cells appear earlier in the course of the disease than either clinical signs or lymphocytosis and could therefore aid earlier disease recognition [13]. In the case of B-cell lymphomas, a diagnosis suspected on the basis of an abnormal blood film may be confirmed using flow cytometric techniques [13]. In practice, very few lymphoma cells are likely to be in circulation at any time; therefore, this technique was considered unlikely to be useful in the early detection of lymphoma in our patient. The role of serial 6 monthly computerized tomographic (CT) examinations to detect lymphadenopathy was also addressed. Despite the availability of spiral CT scanning (associated with lower radiation exposure), there were concerns about the risk to the patient of repeated radiation exposure, which might accelerate any ongoing malignant process. Currently, careful regular physical examination and a high degree of suspicion regarding atypical symptoms seem to be the best available form of follow-up.
Having carefully considered all therapeutic options and calculated the risk to the patient inherent in each of these, we concluded that the best option for our patient was to retain the allograft but to minimize immunosuppressive therapy. Factors influencing our decision included the limited disease load and favourable histology of the donor lymphoma and the infrequent reporting of cases of transmitted malignancy in the literature despite high reported incidences of occult neoplasia in autopsy series. The patient's desire not to return to dialysis was also a significant factor. There was no absolute certainty that the recipient would not develop transmitted malignancy, but after 36 months of follow-up, it seems unlikely. In view of this experience, one would have to question current guidelines regarding organ donation and suggest that full donor autopsy should be routinely performed on all transplant donors. Only through careful donor selection can similar situations be avoided in the future.
Notes
Correspondence and offprint requests to: Dr G. Mellotte, Department of Renal Medicine, The Adelaide and Meath Hospital, Tallaght, Dublin 24, Ireland.
References