Post-transplant lymphoproliferative disease.

immunostaining confirmed the infiltrating lymphocytes Introduction to be T cells. Her post-transplant course was complicated by Pneumocystis carinii pneumonia (without resPost-transplant lymphoproliferative disease (PTLD) is piratory failure), oesophageal and laryngeal candidiasis a group of lymphatic hyperplasias and neoplasias and Enterococcus durans urinary infection. Cyclosporin morphologically heterogeneous, with several grades of plasma trough levels were maintained around clonality, that develop after transplantation. High180 ng/ml (monoclonal RIA). grade lymphoma is considered an opportunistic neoThree months after transplantation, the patient was plasia. It is associated with Epstein–Barr virus (EBV ) readmitted because of fever of unknown origin infection and with a higher immunosuppression grade. and asthenia. Blood tests showed haematocrit 20%, PTLD is a growing problem because of the increasing leukocytes 4600/ml, platelets 219 000/ml, creatinine potency of immunosuppressive drugs in use today. 1.5 mg/dl, AST 111 U/l, ALT 89 U/l, LDH 2905 U/l The frequency of PTLD is 1–5%, causing 21% of and C-reactive protein 6.6 mg/dl. Urine and blood neoplasias in the Cincinatti Transplant Tumor Registry cultures were negative. In the abdominal CT scan [1], and being higher in non-renal than in renal transmultiple heterogeneous nodules were seen in the liver, plants (6.5 vs 0.7% respectively) [2]. The incidence of renal allograft and spleen (Figure 1). A hepatic biopsy PTLD in renal patients is 0.2% in the first postshowed an immunoblastic B-cell lymphoma. An HSV2 transplant year, and 0.04% afterwards [3]. IgM was then detected; there were no serological signs We report on two patients, EBV positive before of reactivation of EBV nor CMV. Her clinical status transplantation, who developed lymphoproliferative worsened with progressive and severe liver failure and disorder 4 months after renal transplantation, despite the absence of other known risk factors.


Introduction
to be T cells. Her post-transplant course was complicated by Pneumocystis carinii pneumonia (without res-Post-transplant lymphoproliferative disease (PTLD) is piratory failure), oesophageal and laryngeal candidiasis a group of lymphatic hyperplasias and neoplasias and Enterococcus durans urinary infection. Cyclosporin morphologically heterogeneous, with several grades of plasma trough levels were maintained around clonality, that develop after transplantation. High-180 ng/ml (monoclonal RIA). grade lymphoma is considered an opportunistic neo-Three months after transplantation, the patient was plasia. It is associated with Epstein-Barr virus ( EBV ) readmitted because of fever of unknown origin infection and with a higher immunosuppression grade. and asthenia. Blood tests showed haematocrit 20%, PTLD is a growing problem because of the increasing leukocytes 4600/ml, platelets 219 000/ml, creatinine potency of immunosuppressive drugs in use today.
1.5 mg/dl, AST 111 U/l, ALT 89 U/l, LDH 2905 U/l The frequency of PTLD is 1-5%, causing 21% of and C-reactive protein 6.6 mg/dl. Urine and blood neoplasias in the Cincinatti Transplant Tumor Registry cultures were negative. In the abdominal CT scan [1], and being higher in non-renal than in renal transmultiple heterogeneous nodules were seen in the liver, plants (6.5 vs 0.7% respectively) [2]. The incidence of renal allograft and spleen ( Figure 1). A hepatic biopsy PTLD in renal patients is 0.2% in the first postshowed an immunoblastic B-cell lymphoma. An HSV2 transplant year, and 0.04% afterwards [3].
IgM was then detected; there were no serological signs We report on two patients, EBV positive before of reactivation of EBV nor CMV. Her clinical status transplantation, who developed lymphoproliferative worsened with progressive and severe liver failure and disorder 4 months after renal transplantation, despite the absence of other known risk factors.

Case 1
The first patient was a 56-year-old white woman on haemodialysis for 6 years, from analgesic nephropathy, whose pretransplant study was irrelevant; she was EBV, CMV, HSV1 and HCV seropositive prior to transplantation (AST and ALT within normal values). In August 1995 she received a renal cadaver allograft, mismatched in HLA loci A and DR and matched in locus B, which had immediate function (serum creatinine 0.9 mg/dl on the third post-transplant day). Initial immunosuppression was with cyclosporin A, azathioprine, and prednisone. On the third week, acute rejection (Banff grade II ) was diagnosed and treated with methylprednisolone boluses (15 mg/kg i.v. for 3 days) with full recovery of renal function. Later, a biopsy  PTLD differs from lymphomas in the general population in the following aspects: 96% are non-Hodgkin Case 2 B-cell lymphomas (vs 65% in the control population), A 54-year-old white man on peritoneal dialysis since in 70% extralymphatic involvement is present (com-January 1996 (unknown aetiology of renal failure), pared with 24-48% in the general population) and in EBV, CMV and HSV seropositive, received a renal 20-28% central nervous system lesions are found (rare cadaver graft in October 1996. There were two misin the general population) [1]. T-cell or natural-killermatches in A, 1 in B and 1 in DR HLA loci. He was cell tumours are rare and carry a very bad prognosis treated with cyclosporin A, azathioprine, and prednis- [4]. one and on the end of the first week his serum Lymphomas have been diagnosed from 1 month to creatinine was 1.2 mg/dl. Acute rejection developed on 17 years after transplantation. Onset of symptoms has the second week (allograft biopsy was not performed ) been reported as soon as 34 days post-transplantation, and methylprednisolone boluses (13 mg/kg i.v. for 3 typically after an acute rejection episode treated with days) were given; serum creatinine came down to OKT3. previous values. A month later he had an acute febrile syndrome that lasted for 3 days and resolved without Classification of post-transplant lymphoproliferative medication.
disease Five and a half months after transplantation graft dysfunction was detected. The patient was afebrile and PTLD has been classified into several categories: physical examination was irrelevant. Serum values (i) early lesions, (ii) polymorphic post-transplant were: Hb 10.1 g/dl, leukocytes 5600/ml (N 67%, L lymphoproliferative disorders, (iii) monomorphic 23%, M 8%), platelets 228 000/ml, ESR 80, creatinine PTLD (B-and T-cell lymphomas), (iv) plasmacytoma-2.4 mg/dl; normal protein electrophoresis, except for like lesions, and (v) T-cell-rich large-B-cell lymphoma/ hypoalbuminaemia (2.6 g/dl ). IgM antibodies against Hodgkin's disease-like lesions. Monomorphic lesions EBV, CMV or HSV were not found. Graft CT scan should be classified according to the classification of showed a 5-cm solid heterogeneous hilar nodule that non-Hodgkin's lymphoma. Polymorphic lesions should was poorly vascularized and that seemed to infiltrate be carefully evaluated for clonality. This classification the upper pole and perigraft adipose tissue. There were is based on morphologic study, clonality and presence no other lesions anywhere else and enlarged ganglia of EBV infection [5]. Progression to malignant disease were not seen. Serum creatinine increased to 4.5 mg/dl occurs by steps. All lesions can be present in a single in 2 weeks. Surgical exploration of the graft was patient, and in the same host several monoclonal performed. A cyanotic tense kidney was found, with a lesions can be found. tumour that enveloped the hilum and upper pole, trapping the artery and vein. The graft and the tumour Origin were removed en bloc. Histopathological examination diagnosed a high-grade polymorphic B-cell lymphoma Usually PTLD comes from donor cells in bone marrow that involved glomeruli, tubules, and vessels with areas transplants and from receptor cells in solid-organ of serpiginous necrosis and recent vascular thrombosis. transplants [6 ]. There are, however, a few exceptions The tumour invaded the tubules as in acute rejection of PTLD arising from donor cells in solid-organ trans-( Figure 2). One year after graft nephrectomy the plants [7]. Weissmann et al. [6 ] reported that solid patient remains in complete remission. organ tumours usually arise from host lymphocytes and they admitted that due to the high antigenicity of these tumour cells, the immune system may respond more effectively to lymphomas from donor origin. Therefore it has been suggested that donor origin may imply a better prognosis. The study of five patients who received sex-mismatched allografts showed that two were of donor origin, including the one arising in the graft [7]. Alterations have been found in 44% of interferon alpha and p16 genes (on chromossome 9) in patients with PTLD vs 1.7% in lymphomas in the general population. As such, PTLD may represent a distinct subgroup of neoplasias [8]. 6.8%). This fact is probably related with total immunosuppressive dose and with a local immune response Risk factors [3,11]. Main risk factors for developing of PTLD are EBV infection and total immunosuppression dose. In Pathology immunosuppressed patients EBV-infected B cells pro-It is sometimes difficult to distinguish acute rejection liferate in an unchecked manner due to suppression of from PTLD in a renal biopsy specimen. In a series of cytotoxic T cells and elevation of B cell-promoting nine cases, diagnosis was made by needle biopsy in cytokines. Most PTLD tumour cells present an activthree cases and by nephrectomy in six patients [9]. ated B cell phenotype and an unrestricted pattern of Tubulitis and intimal arteritis, which are regarded as latent EBV gene products. EBV viral load is higher in specific for acute rejection, do not have a discriminatpatients who develop PTLD than in those who do not, ory value between PTLD and acute rejection. The independent of their pre-transplant serological state presence of an expansible lymphoid infiltrate, serpigin-[10].

Graft involvement
ous necrosis, nuclear atypia and the presence of EBV Treatment with cyclosporin seems to have brough helps to distinguish between PTLD and acute rejection, a different distribution of tumours, with more as well as infiltration of ureter, hilar adipose tissue and lymphomas and less tumours of the central nervous nerves, in nephrectomy specimens [9]. To make matters system being reported. The risk of PTLD is 1.47 higher worse, in 60% of the cases PTLD is preceded by acute in patients treated with cyclosporin vs those who rejection and the risk of rejection following reduction are not [1,11]; lymphomas constitute 25% of neoin immunosuppression is 50% [16 ]. plasias in the former group and 11% in the latter. Besides, the tumours appear earlier in cyclosporinimmunosuppressed patients (15 vs 48 months).
Treatment In a series of 14 paediatric patients with PTLD, no There is no consensus on the treatment of PTLD other patient seropositive for EBV before transplantation than reducing or stopping immunosuppression, which developed the disease and a significant association may lead to tumour regression, especially polyclonal between EBV primary infection and PTLD was evident lesions. Some patients respond to acyclovir. In non- [12]. In the University of Alberta, the incidence of renal recipients, antiviral prophylaxis for CMV (i.v. PTLD in EBV-seronegative patients was 23.1% comganciclovir followed by oral acyclovir) has been pared with 0.7% in seropositive ones. Only two EBV reported to decrease the incidence of PTLD [17]. seronegative patients received Minnesota antilympho-Interferon-a has also been reported as a successful cyte globulin (MALG)/OKT3 and both developed treatment in some cases, without loss of the graft. In PTLD [13]. In this series, three of the four patients a series in which patients were treated with anti B-cell who developed PTLD had received both MALG and antibodies, 45% of them were in remission 3 years OKT3. Besides, the incidence of PTLD in the after the diagnosis of PTLD [18]. Immunotherapy MALG/OKT3 group was 12.5%, which was significwith autologous lymphokine-activated killer cells in antly higher than in patients receiving other immuno-EBV-positive PTLD induced tumour regression, but suppressive drugs (incidence 0.7%) [13]. had no effect on EBV-negative tumours [19]. Usually, In an analysis of nearly 400 adult non-renal transradiotherapy and chemotherapy are not able to control plants, Walker determined that for EBV seronegative the tumour. Nevertheless, an aggressive chemotherapy patients the risk of PTLD was 24 times higher than protocol has been tried in heart transplant recipients for seropositive patients. Other risk factors such as with a remission rate of 75% (6 of 8 patients) at 38 therapy with OKT3 for rejection and CMV mismatch months [20]. When the tumour is localized to the (donor +ve, receptor -ve), each amplified this risk graft, graftectomy may cure the disease. four-to sixfold. Together, all risk factors increased the incidence of fatal PTLD or central nervous system Survival lymphoma by 654 [14].
PTLD occurs twice as frequently in North America The survival rate of PTLD is about 50% at 1 year, but as in Europe, which is probably related to the wider when the disease is disseminated the mortality is more use of induction protocols with anti-T-cell agents. than 80% [3]. Several cases have now been published Cummulative dosage of OKT3 is the main risk factor of retransplantation after a diagnosis of PTLD. In as administration of more than 75 mg is associated some there was no evidence of recurrence, even after with a higher risk of developing lymphoma [15]. a long follow-up (5 years) [21,22]. In contrast to B-cell lymphomas, T-cell tumours are not associated with EBV nor HTLV or HHV-8 infec-Comments on cases presented tion [4].
Lymphomas occur at a higher rate in heart than In our unit, 637 first renal cadaver transplants were performed from 1980 to 1996. Besides the two patients renal recipients and have a different distribution. Renal transplant recipients have a higher rate of kidney reported, there were only two other PTLD cases: a 6. Weissmann DJ, Ferry JA, Harris NL, Louis DN, Delmonico F, gastric lymphoma and a multiple myeloma that were