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Incidence and clinical characteristics of posttransplant lymphoproliferative disorders: report from a single center

In the period 1973–1998, among 2 139 allograft recipients treated with standard immunosuppression, posttransplant lymphoproliferative disorders (PTLD) developed in 19 patients (0.9 %): one plasmacytic hyperplasia, two polymorphic PTLD, one myeloma, and 15 lymphomas. PTLD developed 1 year after transplantation (tx) in 14 patients. Five patients were diagnosed at autopsy, 2 were lost to follow up, 3 died before therapy could be instituted, and 1 patient has just started chemotherapy. Of the 8 evaluable patients, 2 received acyclovir and are alive in complete remission (CR) and 6 received chemotherapy ± surgery. Of these 6, 4 died of lymphoma and/or infection, 1 died of unrelated causes in CR, and 1 is alive in CR. PTLD is a severe complication of tx, usually running an aggressive course which may preclude prompt diagnosis and treatment. Nevertheless, therapy is feasible and must be tailored on the histologic subtype. Seventy-four percent of patients were diagnosed with late-onset PTLD stressing the need for long-term follow up.

Abstract In the period 1973±1998, among 2 139 allograft recipients treated with standard immunosuppression, posttransplant lymphoproliferative disorders (PTLD) developed in 19 patients (0.9 %): one plasmacytic hyperplasia, two polymorphic PTLD, one myeloma, and 15 lymphomas. PTLD developed 1 year after transplantation (tx) in 14 patients. Five patients were diagnosed at autopsy, 2 were lost to follow up, 3 died before therapy could be instituted, and 1 patient has just started chemotherapy. Of the 8 evaluable patients, 2 received acyclovir and are alive in complete remission (CR) and 6 received chemotherapy surgery. Of these 6, 4 died of lymphoma and/or infection, 1 died of unrelated causes in CR, and 1 is alive in CR. PTLD is a severe complication of tx, usually running an aggressive course which may preclude prompt diagnosis and treatment. Nevertheless, therapy is feasible and must be tailored on the histologic subtype. Seventy-four percent of patients were diagnosed with late-onset PTLD stressing the need for long-term follow up.
verse clinical features ranging from the indolent and often responsive to treatment behavior of PH to the aggressive and frequently fatal course of ML/MM. Clinical characteristics and response to treatment in a group of PTLD patients diagnosed at our hospital are presented.

Patient population
In the time period 1973±1998, 2139 transplants (1,058 kidney, 483 heart, 412 liver, 137 bone marrow, and 49 lung) were performed at our hospital on adult patients. Solid organ transplant recipients received induction immunosuppression with anti-thymocyte globulin (OKT3 monoclonal antibody was never used) followed by a triple drug regimen consisting of oral cyclosporine A, azathioprine, and prednisone. Conditioning for bone marrow transplant consisted of high-dose chemotherapy regimens total body radiotherapy followed by a short course of metotrexate followed by cyclosporine A in allogeneic bone marrow recipients.
Patients diagnosed either at autopsy or in vita with PTLD constitute our study population. Staging was done according to the Ann Arbor criteria for lymphomas and the Durie and Salamon classification for multiple myeloma. Patients diagnosed in vita underwent routine blood chemistry tests, total body CT scans (including CNS when clinically indicated), and bone marrow biopsy and aspirate.

Pathology
A single pathologist (P. L. O.) reviewed all diagnostic biopsy and autopsy material. Morphologic classification of malignant lymphomas was made according to the criteria exposed by the Revised European American Lymphoma classification [6]. The diagnosis of PTLD and its division into three recognized histologic subtypes, PH, PLD, and ML/MM, were based upon criteria established by Harris and Chadburn [3,7].

PTLD incidence and patient characteristics
Among the 2 139 transplants performed, PTLD developed in 19 patients (0.9 %): nine heart, six kidney, threeliver, and 1 lung recipients. In 5 patients (26 %) earlyonset ( < 12 months from transplantation) PTLD was diagnosed after a median time interval of 5 months, range 1±10 months. In the remaining 14 patients (74 %) late onset ( > 12 months from transplantation) PTLD was diagnosed after a median time interval of 53 months (range 17±174 months). Incidence and onset of PTLD varies according to the organ transplanted; none of the bone marrow recipients developed PTLD. Data are presented in Table 1. Patient clinical profiles are reported in Table 2. In 2 patients PTLD confined to the graft was present; in 3 patients the graft was involved in the setting of widespread disease. Extranodal disease was common, with gastrointestinal tract, liver, and lung being, the most frequently affected sites. CNS involvement was demonstrated only in 1 of the 2 patients with Burkitt ML.

Clinical course and treatment
Reduction of immunosuppression was the first step in the management of patients diagnosed in vita; azathioprine was discontinued and cyclosporine A was reduced. However, this failed to prevent disease progression in all patients (Table 3). Plasmacytic hyperplasia (1 patient) Patient number 13 was diagnosed with PH after resection of a single skin nodule which was surgically removed with disease resolution. In the following months, he developed chronic EBV disease with recurrent mononucleosis-like episodes characterized by fever and node enlargement. The first episode resolved after acyclovir administration; the second one proved to be unresponsive to acyclovir but responded to ganciclovir; the third one, ensuing only after a month from the preceding one, did not respond to either antiviral. Node biopsy showed histologic progression to polyclonal B-cell PLD and therefore, cytoxan 200 mg/m 2 per day for 5 consecutive days every 4 weeks associated with highdose immunoglobulins (HDIg) every 21 days and i. v. ganciclovir twice a week were started. The patient is currently still receiving chemotherapy; he is well, with no signs of disease at 820 days from diagnosis of PTLD and 150 days from histologic progression to PLD.

Polymorphic lymphoproliferative disorder (2 patients)
Patient number 8 proved unresponsive to i. v. acyclovir; he received a single course of cytoxan (1 g i. v.) and died at 40 days from diagnosis of PTLD of acute respiratory distress syndrome. Patient number 15 received i. v. acyclovir 30 mg/kg per day associated with HDIg every 21 days and disease control was achieved. Acyclovir was tapered after 3 months and discontinued at 1 year. The patient is currently in complete remission at 790 days from diagnosis of PTLD.

Malignant lymphoma/multiple myeloma (16 patients)
In this group only nine patients are evaluable since there were five autopsy diagnoses and two patients, one with ML and the one with MM, were lost to follow up shortly after diagnosis. Patients number 7 and 16 died of multiorgan failure and disease progression at 10 days from diagnosis of PTLD; no therapy other than reduced immunosuppression could be instituted because of deteriorated clinical status at diagnosis of PTLD. Patient number 14 underwent palliation surgery because of intestinal obstruction secondary to enlarged abdominal nodes; no further therapy was feasible and the patient died of sepsis at 60 days from diagnosis of PTLD.
Six patients received chemotherapy. Three patients, numbers 9 and 11 treated with VACOP-B regimen and number 10 treated with CHOP, did not complete chemotherapy and died of infection at 120, 47, and 18 days from diagnosis of PTLD, respectively. Patient number 19 (Burkitt ML with CNS involvement) received polychemotherapy comprising cytoxan, high-dose cytosine arabinoside, and metotrexate plus intrathecal chemo-S 384  PTLD occurred more frequently in the 1st year after transplantation, however, early-onset PTLD represents only a minority of cases, 26 % in our study population, while the majority of patients are diagnosed more than 12 months after transplantation. This is especially the case in kidney recipients among whom PTLD may be diagnosed as late as 174 months from transplantation. This peculiar behavior implies that continuous, longterm follow up is mandatory for timely diagnosis of this condition. A more favorable outcome for early-onset vs late-onset PTLD is reported in the literature [1]. In our study population outcome does not differ in these two groups of patients: mortality is 80 % in the former and 75 % in the latter group, respectively.
EBV-negative PTLD represent 28 % of patients tested (5/18) and are uniformely distributed among earlyand late-onset PTLD, 20 % and 30 %, respectively. Similarly to reported data [9], EBV-negative PTLD bear a worse prognosis compared to EBV-positive PTLD: in our study population mortality was 100 % for the former and 67 % for the latter. However, it should be noted that among our patients and those reported by Leblond, all EBV-negative PTLD belong to the ML category.
A correlation between histology, clinical presentation, and outcome similar to that reported by Chadburn et al. could also be found in our study population [3]. Patients with PH and PLD were in stage I and II at diagnosis while 75 % of patients with ML/MM were in stage III and IV. Moreover, mortality secondary to disease progression or to treatment-related toxicity was 0 % in PH patients, 50 % in PLD patients, and 85 % in ML/MM patients.
Optimal therapeutic approach to PTLD patients is yet to be defined, and many aspects of patient manage-ment are still open to discussion. Data from the literature and our own experience seem to indicate that more favorable histologic forms of PTLD, namely, PH and PLD, may respond to a combination of antivirals and HDIg in a setting of reduced immunosuppression. On the contrary, for ML and MM with widespread disease, prompt administration of chemotherapy is mandatory, since response to antivirals alone is unlikely in these forms which display a rapidly progressive and aggressive clinical course as indicated by the high number of autopsy diagnoses, 31 % in our series. Chemotherapy should be started even though its toxicity is prominent, requiring intensive supportive measures, and adequate timing is not always possible due to intercurrent infectious or toxic episodes. Choice of a chemotherapy regimen should also take into account special problems which specifically apply to this category of patients. Antracycline toxicity is especially prominent among heart recipients [12]. Renal failure secondary to tumor lysis and drug toxicy is more frequent and severe possibly due to chronic administration of cyclosporine A.
However, our experience, and that of others, demonstrates that treatment of PTLD and achievement of complete responses are possible. The immunosuppressive regimen more suitable for patients who respond to treatment remains a matter of debate. Withdrawal for a short period of time or reduction of immunosuppressants while chemotherapy is being administered are feasible; however, once complete remission is achieved, intensity of immunosuppression should take into account both the risk of graft rejection and the risk of recurrence of PTLD. S 386