Department of Medicine, University of Texas Health Science Center, San Antonio, Texas, USA
Sir,
It is well established that prolonged use of immunosuppression in renal transplant patients is complicated by the development of an unusual assortment of malignancies [1]. Among these, lymphoproliferative disorders (PTLD) account for nearly 17% of post-transplant malignancies. Non-Hodgkin's lymphomas (NHL) comprise 93% of the PTLDs compared to 65% of all lymphomas in the general population. Among transplant-associated NHLs, 86% originate in the B-cell, 14% are T-cell derived, and less than 1% are of null-cell origin [1]. T-cell PTLDs are relatively rare and tend to be of clonal origin, including T-cell large granular lymphocyte (LGL) leukaemia [2]. To our knowledge, however, a case of true non-clonal large granular cell lymphocytosis in a post-transplant patient has not been reported to date. We report a novel case of non-clonal LGL lymphocytosis in a renal transplant recipient.
Case.
A 27-year-old Hispanic woman was on peritoneal dialysis for 7 years for management of end-stage renal disease of unknown aetiology. Pre-transplant screening revealed that she was previously exposed to EpsteinBarr virus (EBV) although there was no antibody evidence of exposure to cytomegalovirus (CMV), human immunodeficiency, herpes simplex, human T-cell leukaemia viruses types 1 and 2 and hepatitis viruses. Her pre-transplant blood tests showed haemoglobin 10.4 gm/dl; haematocrit 30; platelet count 176 000/mm3 white blood cell count 6400/mm3 with 28.5% lymphocytes and calculated total lymphocyte count of 1824/mm3. She received a cadaveric renal transplant in October 1996. Serologic tests showed that the donor had exposure to CMV and EBV but not to hepatitis B and C viruses. As the donor was CMV positive, the patient received CMV hyperimmune globulin and gancyclovir prophylaxis in the post-operative period. Her initial immunosuppressive regimen included mycophenolate mofetil, tacrolimus and prednisone. Mycophenolate was stopped in December 1997 as per routine practice in our institution; tacrolimus and prednisone were continued. Her tacrolimus dose was adjusted to maintain a trough level of 1012 ng/ml. She also received long acting nifedipine 120 mg once a day, metoprolol 150 mg twice a day, and pravastatin 20 mg once a day. She had no episodes of acute rejection. An allograft biopsy performed in April 1997 for transient elevation of serum creatinine did not reveal acute rejection. She developed recurrent episodes of urinary tract infections from vesico-ureteral reflux through her implanted ureter and was placed on prophylactic antibiotics. Lymphocytosis was noted during routine blood testing in February 1998, about 16 months into the post-transplant period. On physical examination, enlargement of lymph nodes, liver or spleen was not evident. Blood count revealed haemoglobin 13.3 gm/dl; haematocrit 38.2%, platelets 157 000/mm3, and white blood cell count 11 000/mm3, with 54.8% lymphocytes. The absolute lymphocyte count was 6000/mm3. Immunophenotype analysis indicated a mature T-cell phenotype (CD2, 3, 5, 7, 8 positive), with a subset co-expressing CD57, CD16, CD56 and CD11c. These characteristics are consistent with a T-LGL proliferative disorder. Bone marrow examination did not show increased numbers of lymphocytes. However, by immunophenotype analysis, a majority of the lymphoid cells present had characteristics of LGL. CMV cultures of the bone marrow were negative. Clonality studies performed on her peripheral blood cells did not show evidence for gene rearrangements of the ß or the chain of T-cell receptor. A CT scan of chest and abdomen showed enlarged thymus but no detectable lymphadenopathy. As she did not have evidence of clonal proliferation and lymph node enlargement no attempt was made to decrease the immunosuppressive dose. In June 1999, physical examination revealed enlargement of a cervical lymph node that disappeared in a week. A CT scan of the chest and abdomen did not show enlargement of lymph nodes, liver or spleen. White blood cell count was 19 600/mm3, with 55% lymphocytes. The absolute lymphocyte count was 10 900/mm3. There has been no anaemia, neutropenia or thrombocytopenia during her entire course. Plasma creatinine concentration has remained 0.91.1 mg/dl from post-transplant day 7.
Comment.
To our knowledge this is the first report of a non-clonal T-LGL lymphocytosis in a patient with solid organ transplant. PTLDs are a clinically, morphologically, immunophenotypically, and genetically heterogeneous group of lymphoproliferative disorders in solid organ and bone marrow transplant recipients. Most PTLDs are of B-cell lineage associated with EBV infection, and in the setting of solid organ transplant they are of host cell origin. Occasional cases of T-cell PTLDs have been reported including LGL leukaemia [24]. Analysis of T-cell receptor gene rearrangement has shown that LGL leukaemic cells are derived from a single clone [2]. We tested for gene rearrangements for both ß and chains of the T-cell receptor as it has been reported previously that T-cell PTLDs can rearrange genes of
/
chain alone or of both
/ß and
/
chains [4]. Results showed that the T-LGL lymphocytosis was non-clonal in our patient.
Aggressive immunosuppression and viral infections have been identified as possible aetiologic factors in PTLD [1]. Long-term studies on renal transplant recipients have shown conflicting evidence on frequency of PTLD in patients receiving mycophenolate mofetil [5,6]. Although aetiology of T-cell PTLD is unknown, association with EBV, hepatitis-B and hepatitis-C viruses, and human T-cell leukaemia/lymphoma viruses I and II have been reported [1,2]. However, in a series of 32 PTLD cases, four tumours expressed T-cell surface markers and only one had EBV DNA sequences [3]. Thus, no definitive viral association has emerged either in non-transplant or in transplant patients with T-cell PTLDs. Our patient did not have any episodes of graft rejection and had no evidence of CMV infection.
The clinical course in post-transplant T-cell leukaemias is variably described as being indolent to being very aggressive [2,3]. Most of the aggressive T-cell PTLD have tissue invasion with involvement of bone marrow and cytopenias and phenotypically they express CD3, CD8, and CD56, but lack CD57 [2]. In our patient, the peripheral lymphocytes expressed each of these markers and, in addition, they were CD57 positive. CD57 expression is a defining characteristic of granular lymphocytes. Its presence in our case serves to differentiate this disease from the more aggressive forms of T-cell PTLD. The time interval from the transplant to appearance of T-cell PTLD varied from 37 years in different series, longer than a B-cell PTLD. However, in our patient the T-cell PTLD was evident within 16 months of transplant. Decrease of immunosuppression has been reported to result in remission in some cases of PTLD; however, in others no response was observed, the disease becoming fatal. In our patient, the disease has taken a benign course during a follow-up for nearly a year without changes in immunosuppression.
In summary, we describe a case of non-clonal LGL lymphocytosis in a renal transplant recipient in the absence of aggressive immunosuppression or infections with commonly encountered viruses. Observation for nearly 1 year following diagnosis has not revealed either leukaemic transformation or an aggressive course of the disease. This observation extends the spectrum of PTLD encountered in renal transplantation.
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