Metachronous <scp>B</scp>‐cell and <scp>T</scp>‐cell post‐transplant lymphoproliferative disorders with features of chronic active <scp>E</scp>pstein–<scp>B</scp>arr virus infection
Authors: Isaac Desheng liu, Poh‐Lin Tan, Christelle Xian‐Ting Tan, Mas Suhaila Isa, Perry Yew‐Weng Lau, Wee‐Song Yeo, Swasti Chaturvedi, Mariflor Sarmiento Villegas, Kar‐Hui Ng, Hui‐Kim Yap, Siok‐Bian Ng
Journal: American Journal of Hematology (2015)

To The Editor: We report an unusual case of metachronous T-cell post-transplant lymphoproliferative disease (PTLD) with clinicopathologic manifestations resembling chronic active Epstein–Barr virus (CAEBV) infection of T/NK subtype and hemophagocytic lymphohistiocytosis (HLH), more than 4 years following the occurrence of B-cell PTLD. A 15 year-old Chinese girl, in end-stage renal failure since 13 years of age from chronic glomerulonephritis, received a cadaveric donor Epstein–Barr virus (EBV)-unknown to recipient-seronegative renal transplant. She received EBV prophylaxis with oral valganciclovir. Five months post-transplant, she developed exudative tonsillitis and underwent tonsillectomy. Histology of the tonsils revealed a diffuse, destructive, and polymorphous lymphoid infiltrate composed of lymphoid cells showing a full range of B-cell maturation. The lymphoid cells were positive for CD20, CD79A, and showed kappa light chain restriction (Supporting Information Fig. 1). In situ hybridization for Epstein–Barr virus-encoded small ribonucleic acid (EBER) was positive in B-cells but not T-cells. Features were consistent with EBV-positive PTLD, polymorphic type. Positron emission tomography-computed tomography (PET-CT) scan showed an intensely fluorodeoxyglucose (FDG)-avid soft tissue mass lesion in the nasopharynx and posterior nasal cavity associated with retropharyngeal and cervical adenopathy. Plasma EBV DNA by polymerase chain reaction (PCR) was 134 copies per μg DNA (reference <100 copies per μg DNA). Throat swab EBV DNA was 1,225 copies per μg DNA. She was treated with intravenous rituximab and immunoglobulin with continued antiviral therapy. Immunosuppression was reduced with tacrolimus weaned to minimal levels. Repeat PET-CT scan following tonsillectomy showed resolution of the FDG-avid lesions. In the ensuing period from 2 to 3 years post-transplant, the patient experienced recurrent episodes of pancytopenia which required treatment with granulocyte-colony stimulating factor. Throughout this period, her EBV viral load remained high (1,500–2,500 copies per μg DNA) while surveillance PET-CT scans were negative for metabolically active lesions. The cause of the pancytopenia was attributed to persistent EBV viremia with marrow suppression. Four years and 6 months post-transplant, the patient was treated for acute cellular rejection with intravenous pulse methylprednisolone. A month later, she developed high fevers, epistaxis, and spontaneous bruising. Physical examination revealed hepatosplenomegaly, cervical lymphadenopathy, and lower limb ecchymoses. Investigations showed pancytopenia with haemoglobin 7.1 g/dL, total white cell count 2.72 × 109/L (absolute neutrophil count 0.44 × 109/L), and platelet count 38 × 109/L. Serum ferritin was 6,355 ng/mL (reference 10–120 ng/mL), triglycerides were 3.31 mmol/L (reference <1.7 mmol/L), and plasma EBV titers were 879 copies per μg DNA. A bone marrow biopsy revealed hemophagocytosis and an interstitial infiltrate of large monomorphous T-lymphoid cells with irregular nuclei and prominent nucleoli. The T-lymphocytes expressed CD3, granzyme B, TIA1, TCRBeta, and EBER (Supporting Information Fig. 2A–C). Having fulfilled the criteria for HLH, patient was treated with the HLH-2004 protocol (Supporting Information Data Reference S1) including dexamethasone, cyclosporine, and etoposide. Two months later, she again presented with massive hematochezia and ileum resection showed multiple ulcers associated with a dense, polymorphous lymphoid population comprising mainly T-cells which were positive for CD3, CD8, TIA1, granzyme B, and EBER (Supporting Information Fig. 2D–F). No abnormal B-cell proliferation was present. A monoclonal TCRG gene rearrangement was identified in the ileum resection (Supporting Information Data for additional clonality results). Graft nephrectomy was performed 5 years post-transplant due to graft failure and immunosuppressive therapy was withdrawn. The graft showed chronic active T-cell mediated rejection and involvement by EBV-positive T-PTLD with a similar phenotype (Supporting Information Fig. 2G,H) as those in the bone marrow and ileum. Her plasma EBV DNA titers remained high in the ensuing 2 years with further episodes of hematochezia due to involvement of the colon by EBV-positive T-PTLD. Immunohistochemistry for cyclinE2/CD3 was performed in the bone marrow biopsy, graft nephrectomy, and colon biopsy specimen. Positive cyclinE2 expression was detected in a minor population of T-cells: 5–10% in the bone marrow biopsy and less than 1% in the graft nephrectomy (Supporting Information Fig. 2I) and colon biopsy. This is an unusual case of T-PTLD with features of CAEBV infection and HLH. The T-cell lymphoid proliferation was EBV-positive, monoclonal, and predominantly polymorphous in morphology with involvement of multiple extranodal sites including bone marrow, graft kidney, small and large intestines. The unexpected occurrence of a second PTLD accounts for the perplexing and persistent elevation of EBV viral load. Removal of the graft kidney and cessation of immunosuppression failed to eliminate the EBV-infected T-cell proliferation which remained periodically symptomatic in this patient. Monoclonal T-cell populations in patients with B-cell PTLD have been described but most of these T-cell clones are not associated with morphologic features of a co-existent T-cell malignancy 1. On the other hand, co-existing T-cell and B-cell malignancies in post-transplant patients are rare and only five cases of synchronous and metachronous T-cell and B-cell PTLD, including the current case, have been reported so far 2-5 (Table 1). It remains unclear whether the emergence of T-cell clones is a host reaction triggered by monoclonal B-cell proliferation (EBV-infected or otherwise) or is secondary to failure of immune surveillance. It is likely that our patient contracted primary EBV infection as an initial event and developed B-PTLD due to an immunosuppressed cytotoxic T-cell response. In addition, EBV also infected the T-lymphocytes leading to a persistent state of active EBV infection and subsequent T-PTLD years later. Specific genetic defects in lymphocyte regulation and function are known associations of CAEBV and familial HLH (Supporting Information Data Reference S2). Our patient had normal levels of perforin in NK-cells with normal NK- and T-cell degranulation and hence was unlikely to harbor a familial defect. In our previous study on systemic EBV-positive T/NK lymphoproliferative disease, including CAEBV, in non-immunocompromised children, we demonstrated a statistically significant worse outcome in patients with high cyclinE2 expression (defined as >15%) and monomorphic morphology compared to patients with low cyclinE2 and polymorphic infiltrate 6. In this patient, the T-cell proliferation was predominantly polymorphic and cyclinE2 expression was low. This correlates well with her prolonged survival without aggressive chemotherapy and the patient remained alive 5 years after the onset of T-PTLD symptoms. In contrast, the overall survival for T/NK-cell PTLD is only about 6 months (Supporting Information Data Reference S3). This suggests that morphology and cyclinE2 expression may be of prognostic utility in CAEBV occurring in the post-transplant setting. Isaac Desheng liu1, Poh-Lin Tan1, Christelle Xian-Ting Tan1, Mas Suhaila Isa1, Perry Yew-Weng Lau1, Wee-Song Yeo1, Swasti Chaturvedi1, Mariflor Sarmiento Villegas1, Kar-Hui Ng1,2 Hui-Kim Yap1,2Siok-Bian Ng3* 1Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore; 2Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 3Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore Additional Supporting Information may be found in the online version of this article. Supporting Information Supporting Information Supporting Information Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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