Post-transplant lymphoproliferative disorder (PTLD) is a well defined, distinctive clinicopathological entity and is composed of a heterogeneous group of monoclonal or polyclonal lymphoproliferative lesions that occur exclusively in iatrogenically immunosuppressed recipients following solid organ or BMT.1 Clinically and pathologically, PTLDs represent a spectrum of diseases ranging from early Epstein Barr virus (EBV)-driven polyclonal B-cell proliferation to morphological and genetic/molecular defined malignant lymphomas.1, 2 Transplant patients have a 50–100 fold increased prevalence of B-cell lymphoma.1, 2, 3, 4 There is an overall incidence of 1–5% in solid-organ transplant recipients and of 1% in marrow transplant recipients.1, 3, 4 However, patients who receive HLA-mismatched or T-cell depleted BM and those who receive anti-CD3 MoAB therapy for GVHD after transplant are at the highest risk for development of PTLD/lymphoma.5 As such, patients typically present with widespread disease clinically and have a very poor prognosis. A higher proportion of BM transplant patients with PTLD die of their disease than do solid-organ allograft recipients.1, 3, 4, 5, 6 In a retrospective analysis of 854 allogeneic transplants over a period of 8.5 years in a single institution, an incidence of 3% EBV reactivation was noted, with a 1.3% incidence of EBV-PTLD, with a mortality rate of 82%. Over 90% of the cases occurred within the first year of transplant.6
Here we report an extremely rare, unique case of very late onset, lethal EBV-driven PTLD manifested as a typical Burkitt lymphoma/leukemia involving the BM and liver in a patient 10-year status post-allogeneic BMT for his refractory AML. The patient is a 61-year-old male with a history of primary refractory AML who underwent un-manipulated Allo-SCT from his HLA-identical brother after a myeloablative, fractionated TBI-based conditioning regimen in 1998. Post-transplant complications included extensive chronic GVHD involving the skin, oral cavity and possibly lung. The chronic GVHD was managed conservatively with tacrolimus and mycophenolate for several years, until the patient refused all immunosuppressive medication from 2005 to 2008. Approximately 1 year before the current presentation, the patient developed respiratory symptoms, which prompted an evaluation with bronchoalveolar lavage, with the isolation of both Nocardia asteroids and Aspergillus fumigatus. He was treated successfully with minocycline and voriconazole. A flare in symptoms including fatigue, weight loss and mouth discomfort, prompted a trial of re-institution of immunosuppression with low-dose prednisone and tacrolimus. After 6 weeks, the patient presented with Gram-negative bacteremia, and quickly developed pancytopenia (hemoglobin 9.3 g per 100 ml, WBC 3600/μl, plts 20 000/μl) with elevated liver enzymes, and very high serum lactate dehydrogenase level (15 041 U/l). On computed tomography scan of the chest, abdomen and pelvis, innumerable small lesions were seen throughout the liver without evidence of lymphadenopathy or splenomegaly. A BM biopsy was performed to rule out relapsed AML.
The BM core biopsy showed a diffuse and interstitial infiltrate of the marrow space by a monotonous population of blastoid immature cells with extensive necrosis, features mimicking an infiltrating pattern of acute leukemia. The immature-looking blastoid cells were uniformly intermediate in size, having scant amount of cytoplasm, round nuclear contours, fine chromatin with 1–3 small but distinct nucleoli. Numerous mitotic figures and apoptotic bodies were evident (Figure 1a). Immunohistochemical studies showed that the tumor cells were strongly positive for CD20, PAX-5 and CD10 but negative for CD3, BCL-2 or TdT, displaying characteristic morphological and immunophenotypical features of Burkitt lymphoma/leukemia based on the current World Health Organization classification (Figure 1b, CD20). Antibody against Ki-67 highlighted 100% of tumor cells, indicating an extremely high proliferation index (Figure 1c). EBV in situ hybridization showed strong nuclear positivity in all of the tumor cells (Figure 1d). Cytogenetic studies showed a t(8;14)(q24.1;q32.3), as the sole clonal aberration, in 14 of 22 mitotic cells isolated from the marrow aspirate (Figure 2, arrows). The finding was further confirmed by florescence in situ hybridization using a break-apart probe set specific for the MYC gene. At the time of diagnosis, serum q-PCR for EBV was markedly elevated (>64 × 106 viral copies/ml). Thus, this case truly represents an extremely rare, very late onset, EBV-driven PTLD with morphological, immunophenotypical and genotypical characteristics of Burkitt lymphoma/leukemia in the patient 10-year status post-Allo-SCT for his original AML. Further HLA engraftment analysis showed that the tumor cells were 100% donor-derived. A liver biopsy was performed and was confirmed involvement by PTLD/Burkitt lymphoma/leukemia with identical morphology and immunophenotype as the marrow and with strong EBV positivity in the tumor cells. After the diagnosis, immunosuppression for the patient was immediately discontinued, and weekly rituximab infusions were instituted, with prompt improvement in the pancytopenia, and decrease in the level of lactate dehydrogenase. Intrathecal MTX was administered, and all cerebrospinal fluid cytology samples were negative. The serum EBV viral load rapidly dropped to <1 × 106/ml. Cytotoxic chemotherapy was initiated, however, the patient rapidly deteriorated, with septic shock, multisystem organ failure and died ∼5 weeks after his PTLD diagnosis was made.
Our case shows two unique clinical and pathological characteristics that may challenge the clinical and pathological diagnosis and need to be recognized and managed in a timely manner. First, the patient presented with an exceptionally late onset of the disease (10 years). Although the clinical features of PTLD at presentation are variable and are directly correlated with the types of transplantation, immunosuppression, and to some extent with morphologically defined categories, the majority of PTLD in BM allograft recipients develop within the first 5 months after transplantation. EBV-positive PTLD cases tend to occur earlier (median interval 6–10 months) than EBV-negative cases (median interval 4–5 years), which are also more likely to be of monomorphic type or frank lymphoma.1, 3, 4, 5, 6 Our patient had an initial diagnosis of AML and underwent a fully myeloablative and un-manipulated (that is, T-cell replete) fully HLA-matched Allo-SCT exactly 10 years before onset of his PTLD. The morphological and immunophenotypical features of the strong EBV-driven lymphoid proliferation, which developed in the BM and the liver, in our patient clearly fit the rare category of late onset, EBV-positive PTLD rather than relapse of AML. PTLDs have been well known to be closely associated with EBV infection/reactivation in a setting of decreased host T-cell immune surveillance, particularly the CTLs, leading to an unchecked EBV-infected B-lymphocyte proliferation, acquisition of somatic mutation and eventual malignant lymphoma.1, 3, 4, 5, 6, 7, 8, 9 This model agrees with the general observation that more than 80% of PTLDs are closely associated with EBV infection/reactivation and they truly represent an EBV-induced monoclonal or less often polyclonal B-cell or rarely T-cell proliferation.1 In general, EBV+ cases tend to occur earlier than EBV− cases because more potent immunosuppression is often given immediately after the transplantation. Despite a very late onset of disease in this patient, extremely high EBV viral copies in our patient's blood and strong expression of viral RNA in the tumor cells indicate that EBV driven B-cell proliferation may occur any time during the course of immunosuppression.1, 2, 3, 4, 5, 6, 7, 8, 9, 10 Although the exact mechanism of this sudden onset of PTLD so late in the post-transplant course is not clear, persistent chronic GVHD in our patient with recently elevated immunosuppression may have played a critical role in triggering such profound EBV reactivation and eventually lead to the lethal PTLD.10, 11 Furthermore, as in the majority of PTLDs after allogeneic hematopoietic stem cell transplant, all lymphoma cells of the current case were of donor origin.1 Thus, it is very likely that EBV status in donor before the transplantation may be a contributing factor to the vulnerability for later acute EBV infection/reactivation as shown in this case.
Second, the current case presented as an extremely rare, aggressive Burkitt lymphoma/leukemia as a PTLD. Although the majority of monomorphic PTLDs fall into the category of diffuse large B-cell lymphoma according to the current World Health Organization classification, other types of lymphoma may also occur.1, 6, 12, 13 These include low-grade B-cell lymphoma, plasma cell myeloma, Hodgkin lymphoma or HD-like PTLD as well as various T-cell lymphomas with or without EBV infection. PTLD cases present as a typical Burkitt lymphoma/leukemia are extremely rare.1 Our case showed morphological and immunophenotypical characteristics of Burkitt lymphoma/leukemia, which was further confirmed by the detection of the typical t(8;14)(q24.1;q32.3) involving rearrangement of MYC gene locus, as a sole chromosomal abnormality. Burkitt lymphoma/leukemia is a unique, high-grade B-lymphoid neoplasm, which was once considered to be L3-type acute lymphoblastic leukemia/lymphoblastic lymphoma by the old FAB.13 It is the only genotypically distinct subtype that can be identified by the morphological and immunophenotypical characteristics of the tumor cells.12, 13 The neoplastic cells usually consist of intermediate to large cells with variable, intense basophilic cytoplasm with prominent vacuoles, round nuclei with fine to slightly clumped chromatin and several indistinct nucleoli. Immunologically, the immature-looking tumor cells display mature B-cell phenotype expressing CD19, CD20, CD79a, CD22 and CD10 but are negative for BCL-1, BCL-2, CD5 or CD23. Typically, they show absence of CD34 or TdT expression but presence of bright slg with light chain restriction.12, 13 Owing to the high proliferation index of Burkitt cells and extremely aggressive clinical course of Burkitt lymphoma/leukemia, early recognition of those features is required for both pathologists and hematologists for prompt and accurate diagnosis with timely and appropriate management of such patients.
Conflict of interest
The authors declare no conflict of interest.
About this article
Very late relapse of PTLD 10 yr after allogeneic HSCT and nine yr after stopping immunosuppressive therapy
Pediatric Transplantation (2014)