Posttransplant lymphoproliferative disorders (PTLD) develop in organ allograft recipients because of the immunodeficient state induced by immunosuppressive drugs used to prevent graft rejection. In B-cell PTLD, Epstein-Barr virus (EBV) plays an important etiologic role, as unchecked EBV replication in infected B cells ultimately leads to neoplastic transformation. In T-cell PTLD, however, EBV is often not involved, so that it remains unclear what the pathogenetic mechanism(s) may be.
A 30-year-old man received a cadaveric renal allograft for chronic glomerulonephritis. Five years later, he presented with a generalized seizure. A computered tomography showed a 4-cm frontal lobe lesion (arrow, Fig. 1A). Biopsy showed monotonous sheets of malignant large lymphoid cells, expressing CD20 and EBV-encoded small RNA, consistent with monomorphic B-cell PTLD. Further staging investigations, including computed tomography of thorax and abdomen and bilateral marrow biopsies, were negative. Furthermore, circulating EBV DNA as a surrogate biomarker (1) was negative, showing that there was no extracranial involvement. Cyclosporine was stopped. Local radiotherapy (30 Gy) and intrathecal anti-CD20 antibody rituximab (2) (30 mg twice weekly×eight doses) produced a complete remission. However, graft rejection ensued, requiring hemodialysis and erythropoietin (EPO: 4000 IU weekly) treatment. Six months later, a blood count showed hemoglobin (Hb): 4.0 g/dL, undetectable reticulocytes, white cell count: 3×109/L, 15% large granular lymphocytes (LGLs) (Fig. 1B), and platelet count: 108×109/L. A marrow biopsy showed pure red cell aplasia (PRCA) with virtually absent erythropoiesis (Fig. 1C). Serologic tests for parvovirus B19 and antierythropoietin antibody were negative.
The abnormal LGLs were CD3+ve, CD4−ve, CD8+ve, and EBV-encoded small RNA-negative. To confirm the clonal nature of the T-LGLs, polymerase chain reaction (PCR) for T-cell receptor gamma (TCRγ) gene was performed as previously described (3). Clonally rearranged TCRγ gene was demonstrated, confirming the presence of T-LGL leukemia (Fig. 1D). Therefore, the overall diagnosis was T-LGL leukemia with PRCA, a well-defined clinical syndrome (4). To delineate the time when the T-LGL leukemia first developed, the clonal TCRγ PCR product was sequenced, and a clonal-specific primer was designed (Fig. 1D). With clonal specific PCR, the neoplastic T-LGL leukemia clone was in fact already present at the time of diagnosis of the B-cell PTLD (Fig. 1D).
Treatment with the anti-CD52 antibody alemtuzumab (30 mg×three doses) resulted in a rapid normalization of the Hb. PCR also showed that a molecular remission was attained. At the latest follow-up 28 months postalemtuzumab, his blood counts showed Hb: 14.2 g/dL, white cell count: 3.9×109/L, and platelet count: 128×109/L.
EBV-positive B-cell lymphoproliferative diseases are the prototype of PTLD, developing usually early posttransplantation. However, the pathogenesis of EBV-negative lymphoid malignancies posttransplantation remains obscure. While some can be coincidental lymphomas, many EBV-negative PTLD respond to reduction of immunosuppression, implying that the pathogenesis may be similar to EBV-positive PTLD (5). T-LGL leukemia has been described as a T-cell PTLD (6–8). As these cases including ours were all EBV-negative, their relationship with the organ allograft and the immunosuppression remains undefined. De novo T-LGL leukemia is thought to develop because of prolonged antigen stimulation (9). In our case, the renal allograft was an obvious source of chronic antigen stimulation. Interestingly, T-LGL proliferation has also been described in patients with an underlying B-cell lymphoid malignancy, indicating that the neoplastic B cells may also be a source of antigenic stimulation (10).
Our case was instructive in several ways. The concomitant presence of a B-cell PTLD and the T-LGL leukemic clone suggested that the latter might have arisen because of chronic antigenic stimulation, possibly from the B-cell lymphoma. On withdrawal of cyclosporine, the T-LGL leukemia did not regress, showing further that the leukemia was unrelated to immunosuppression. In fact, cyclosporine is a very effective treatment for T-LGL leukemia, (4) and its withdrawal might have been the reason why the T-LGL leukemia became clinically manifest later. Hence, the pathogenetic mechanisms of the B-cell and T-cell neoplasms were disparate in our case. Finally, PRCA is the most common manifestation of T-LGL leukemia in our population (4). Effective treatment of T-LGL leukemia with alemtuzumab led to complete recovery of the PRCA.
Rock Y. Y. Leung2
1Department of Medicine
Queen Mary Hospital, Hong Kong
2Department of Pathology
Queen Elizabeth Hospital, Hong Kong
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