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Plasmablastic Posttransplant Lymphoma: Cytogenetic Aberrations and Lack of Epstein-Barr Virus Association Linked With Poor Outcome in the Prospective German Posttransplant Lymphoproliferative Disorder Registry

Zimmermann, Heiner1; Oschlies, Ilske2; Fink, Susanne3; Pott, Christiane1; Neumayer, Hans H.4; Lehmkuhl, Hans5; Hauser, Ingeborg A.6; Dreyling, Martin7; Kneba, Michael1; Gärtner, Barbara8; Anagnostopoulos, Ioannis9; Riess, Hanno3; Klapper, Wolfram2; Trappe, Ralf U.1,3,10

doi: 10.1097/TP.0b013e318242162d
Clinical and Translational Research
Free

Background. Plasmablastic posttransplant lymphoma is a rare subtype of monomorphic B-cell posttransplant lymphoproliferative disorder (PTLD). There is little published clinical data to guide treatment.

Methods. The German prospective PTLD registry D2006–2012 records baseline features, treatment, and outcome of rare PTLD subtypes in adults after solid organ transplantation. Treatment is at the discretion of the local physician. Clinical data on the patients in the registry is collected before, during, and at least 4 weeks, 6 months, 12 and 24 months after treatment.

Results. Eight cases of plasmablastic posttransplant lymphoma were reported to the registry until 2011. The majority occurred as late PTLD in male heart transplant recipients. Extranodal manifestations were common in stage I and in stage IV disease. Histological Epstein-Barr virus (EBV) association was confirmed in five of eight cases. MYC/IGH rearrangement was present in two of six patients examined. Although five of eight patients died from early disease progression, we observed that long-term survival can be achieved in localized (2/3) and in disseminated disease (1/5) by immunosuppression reduction (IR) followed by immediate systemic chemotherapy. However, all patients with cytogenetic aberrations and patients with non-EBV-associated PTLD were refractory to IR and to chemotherapy. Chemotherapy parallel to IR was associated with a high rate of infectious complications.

Conclusions. In this series, IR and local therapy were not sufficient to treat plasmablastic posttransplant lymphoma even in localized disease whereas IR and systemic chemotherapy (CHOP-21) could achieve lasting complete remissions. Cytogenetic aberrations and lack of EBV association were linked with poor outcome.

1Department of Internal Medicine II: Hematology and Oncology, University Medical Centre Schleswig-Holstein, Campus Kiel, Kiel, Germany.

2Department of Pathology, University Medical Centre Schleswig-Holstein, Campus Kiel, Kiel, Germany.

3Department of Hematology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.

4Department of Nephrology, Charité-Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.

5Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum Berlin, Berlin, Germany.

6Department of Internal Medicine III, J.W. Goethe University Hospital, Frankfurt/Main, Germany.

7Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany.

8Institute of Microbiology, University Homburg/Saar, Homburg/Saar, Germany.

9Department of Pathology, Charité-Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.

The PTLD D 2006–2012 registry is supported by grants from AMGEN, CLS Behring, Mundipharma, and Roche. The German Study Group on PTLD (DPTLDSG) is a member of the German Competence Network Malignant Lymphomas (KML).

The authors declare no conflicts of interest.

Address correspondence to: Ralf Ulrich Trappe, M.D., Department of Internal Medicine II: Hematology and Oncology, University Medical Centre Schleswig-Holstein, Arnold-Heller Strasse 3, 24015 Kiel, Germany. E-mail: ralf.trappe@uksh.de

R.U.T. is the principal investigator, coordinated the research, and takes primary responsibility for the paper. R.U.T., C.P., H.N., H.L., I.A.H., M.D., M.K., and H.R. recruited the patients. B.G. served as a reference virologist. I.O. analyzed histopathology and immunohistochemistry. W.K. performed the molecular-cytogenetic studies. I.A. and W.K. served as reference pathologists. H.Z., S.F., and R.U.T. collected and analyzed the data. H.Z. and R.U.T. wrote the manuscript.

Received 18 October 2011. Revision requested 2 November 2011.

Accepted 14 November 2011.

Posttransplant lymphoproliferative disorder (PTLD) represents a spectrum of lymphatic and plasmacytoid diseases associated with the use of potent immunosuppressive drugs after solid organ transplantation (1). PTLD is not a homogeneous entity, encompassing a wide spectrum ranging from polyclonal early lesions associated with primary Epstein-Barr virus (EBV)-infection to several types of monomorphic lymphoma as reflected in the World Health Organization (WHO) classification of PTLD (2). The majority of monomorphic PTLD lesions resemble diffuse large B-cell lymphoma (DLBCL) (3, 4). Their treatment options have recently been reviewed (5). Current treatment strategies for rare PTLD subtypes are, due to the even smaller number of cases, not based on clinical trials or case series but mostly on case reports.

Plasmablastic lymphoma (PBL) is associated with different forms of immunosuppression and was first described as a usually EBV-associated B-cell neoplasm with immunoblastic morphology, the immunophenotype of plasma cells and loss of mature B-cell antigens arising in the oral mucosa of HIV positive patients (6). In addition, PBL has been observed as a posttransplant lymphoproliferative disorder (PBL-PTLD) (7) and in the absence of predisposing immunodeficiency in elderly patients (8, 9). Characterized clinically by extranodal, particularly mucosal manifestations, an aggressive course and poor prognosis it is now recognized as a distinct disease entity (10). Recently, a characteristic full or partial plasmablastic immunophenotype has been described with expression of B lymphocyte-induced maturation protein 1 (BLIMP1) and nuclear x-box-binding protein 1, spliced form and negative or low PAX5 and CD20 (11). In an investigation of chromosomal alterations in 42 cases of PBL by fluorescent in situ hybridization (ISH), a MYC gene rearrangement, most commonly with the immunoglobulin light or heavy gene locus, was identified in 49% of samples, more frequently in EBV-positive than EBV-negative cases (12). In HIV-related PBL, approximately 60% of cases are positive for EBV-encoded small RNAs (EBER). The interaction of EBV and the MYC/IGH translocation in lymphomagenesis first described in Burkitt lymphoma is the subject of ongoing research (13, 14).

With regard to management and prognosis of HIV-associated PBL, case reports and case series are available. An overview of 112 published cases (15) reports treatment including active antiretroviral therapy, chemotherapy (most commonly CHOP) and radiotherapy with a median overall survival of 15 months. A response to the proteasome inhibitor bortezomib has also been documented in a single case report (16). Published data on adult solid organ recipients with PBL-PTLD is limited to a retrospective series of four adult patients with a focus on histopathological findings (7), one patient as part of a larger series (12), and two case reports of cutaneous PBL-PTLD (17, 18). Here, we present the first prospective case series including clinicopathological features, treatment, and treatment outcome of eight patients from the German PTLD registry.

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RESULTS

Baseline Characteristics

By mid-2011, 195 patients had been reported to the German PTLD registry D2006–2012. Of these, 8 (4%) had been diagnosed with PBL-PTLD. Median age at diagnosis was 47 years (range 30–67 years; Table 1) and patients were predominantly male (75%, 6/8). The transplanted solid organs were kidney (3/8) or heart/heart+lung (5/8). The underlying diseases resulting in heart transplantation were dilated cardiomyopathy (DCM) idiopathic or secondary to congenital heart defects (4/5 cases) and ischemic heart disease (1/5 cases). Median time from first transplantation to diagnosis of PBL-PTLD was 12.8 years (range, 9 months to 15.8 years) and seven of eight cases were diagnosed more than 10 years after transplantation. The one case of early PTLD occurred in the context of primary EBV infection in an adult aged 67 years. One of eight patients had single agent immunosuppression but had received cyclosporine A at relatively high doses (325 mg/day). All other patients had dual or triple immunosuppression composed of a calcineurin inhibitor±rapamycin±azathioprine±steroid. In total, two of eight patients had an immunosuppression containing rapamycin. T-cell count analyses at diagnosis of PTLD showed no severe cellular immune defect with median CD4-cell counts of 463/μL (range, 259–730, Table 1). Of note, two cases of PBL-PTLD had occurred after successful treatment of CD20-positive DLBCL-PTLD with sequential rituximab and CHOP (19) and had potentially evolved from these.

TABLE 1-a

TABLE 1-a

TABLE 1-b

TABLE 1-b

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Morphology, Immunohistochemistry, and Gene Rearrangements

PBL-PTLD lymphoma cells displayed plasmablastic cytomorphology without maturation toward plasma cells (Fig. 1). Immunohistochemistry of the plasmablast population demonstrated lambda or kappa light chain restriction in six of seven cases tested and expression of CD138 and CD38 (8/8), whereas CD20 was absent in all cases. None expressed the anaplastic lymphoma kinase. CD56 expression was found in one of eight cases and partial positivity for cyclin D1 in another one of eight. With regard to EBV status (Table 1), the one case of primary EBV infection after D+R− living donor renal transplantation had a considerably elevated EBV DNA load in peripheral blood and tumor cells expressed latent membrane protein 1 (LMP1) and Epstein-Barr nuclear antigen 2 (EBNA2) in line with EBV latency type III (20). The other seven patients had low or negative EBV DNA loads in peripheral blood. The remaining four EBER-ISH-positive cases showed no evidence of EBNA2 or LMP1 expression, consistent with latency type 0 or I (20). EBER-ISH showed no EBV association in three of eight cases.

FIGURE 1

FIGURE 1

The analysis of gene rearrangements involving the MYC, IGH, BCL2, and BCL6 loci identified MCY/IGH rearrangements in two of six patients. One of these was associated with a gain of the BCL6 locus (three copies) and an aberrant karyotype. In one more patient, an IGH rearrangement with an unknown partner was identified (Table 1). In two patients, only a reduced set of cytogenetic breakpoints could be analyzed due to a shortage of tumor tissue.

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Clinical Features

Clinically (Table 2), PBL-PTLD was localized in two of eight and disseminated in six of eight cases. Oral/mucosal involvement occurred in two of eight patients. Seven of eight cases presented with both extranodal and nodal manifestations, whereas bone marrow involvement was present in only two of seven patients. Osteolytic lesions were rare and associated with infiltrating soft tissue manifestations in all cases. A paraprotein was identified in two of three patients analyzed and correlated with light chain restriction. One of three patients also exhibited some degree of increased plasma immunoglobulin levels. Lactate dehydrogenase levels were elevated only in disseminated disease.

TABLE 2

TABLE 2

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Treatment and Response

Because of the aggressive nature of the disease, most patients received immunosuppression reduction (IR) combined with systemic chemotherapy as initial treatment (Table 3). Only one patient had IR+irradiation for localized disease. However, when new lesions occurred early after irradiation, systemic chemotherapy was commenced. Even though five of eight patients died from early disease progression, complete remission (CR) was achieved and maintained in PBL-PTLD in localized (2/3) and in disseminated disease (1/5). CR was reached in all three patients with IR followed by CHOP-21-based systemic chemotherapy. The International Prognostic Index (Table 2) of the three survivors ranged from 0 to 4 (median 0), whereas the five patients with early PTLD progression had an International Prognostic Index from 3 to 5. Notably, none of the patients who achieved long-term survival had cytogenetic rearrangements involving the IGH locus and all were EBV-positive by EBER without LMP1 or EBNA2 expression. All patients with gene rearrangements (3/8) and patients with non-EBV-associated PTLD (2/8) were refractory to chemotherapy despite the use of aggressive treatment protocols (escalated BEACOPP, DexaBEAM, CHOP-14; Table 3) and a trial of the proteasome inhibitor bortezomib. Supportive treatment including granulocyte-colony stimulating factor administration notwithstanding, immediate initiation of chemotherapy parallel to reduction of immunosuppression was associated with a high rate of severe infections (5/7) as a consequence of prolonged °III/°IV neutropenia (7/7) in combination with already reduced immune competence.

TABLE 3

TABLE 3

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DISCUSSION

In the largest case series so far, IR and local therapy were not sufficient to treat PBL-PTLD even in localized disease whereas IR and systemic chemotherapy (CHOP-21) could achieve lasting CRs and may allow a cure even in disseminated disease. In our experience, successful treatment was only possible in lymphomas both EBV-associated and negative for the translocations examined here, MYC/IGH in particular. However, the small numbers of subjects and the observational character of this study make it impossible to draw definitive conclusions regarding the best therapy approach.

Our clinical observation that PBL-PTLD had a poor prognosis if any gene (particularly MYC) rearrangements were present or EBER-ISH (EBV-association) was negative is compatible with findings from other PTLD subtypes, PBL in the nontransplant setting, DLBCL and with cell culture models: MYC translocations have been associated with poor prognosis in DLBCL (21) and a nonsignificant trend toward poorer survival has been noted before in PBL (12, 22). As an explanation, it has been discussed (12), that cytogenetic rearrangements of MYC/IGH might help to overcome the repressor effect of BLIMP1 on proliferation in terminally differentiated plasmablasts as apoptosis induced by ectopic BLIMP1 expression in cell culture models can be partially overcome by ectopic MYC expression (23).

The absence of histological EBV association has long been associated with failure to achieve CR and lower survival in PTLD (24). A recent series of cell culture experiments using a conditionally expressed dominant negative derivative of EBNA1 to evict EBV DNA from Burkitt lymphoma and PTLD cell lines has shown that the degree to which the different malignant cell lines depend on EBV for survival (evasion of apoptosis, permission, and promotion of proliferation) varies correlating to the number of viral genes expressed within them. This was interpreted as evidence for a model of EBV lymphomagenesis whereby proto-tumor cells—rather than expressing defined sets of latency programs—silence or lose viral genes under selective pressure of the immune response as they acquire complementary cellular oncogenic mutations (14). In keeping with this idea and previous observations in PTLD (25), only our one case of early PBL-PTLD (after primary EBV infection) showed expression of EBNA2 and LMP1. The seven late PBL-PTLDs, on the other hand, expressed neither EBNA2 nor LMP1. This and the fact that all three EBV negative cases of PBL-PTLD described here were refractory to chemotherapy can be interpreted in support of the aforementioned hypothesis.

From the perspective of posttransplant epidemiology, patients receiving heart transplants (5/8) for DCM (4/8) are overrepresented among PBL-PTLD. Heart transplants usually account for only 10% to 30% of PTLD (2628) and DCM in turn accounts for only approximately 30% of heart transplants (29). One potential explanation is that the combination of prolonged survival of these young patients with few cardiovascular risk factors and the long interval from transplantation to diagnosis of PBL-PTLD (more than 10 years in 7/8 cases in this series) leads to selection bias. However, no association with heart transplantation has been described in plasmacytoma-like PTLD, which occurs similarly late (median time to PTLD 8.3 years (30). Another causative factor could be the relatively high level of immunosuppression after heart transplantation. In contrast to HIV-associated PBL (31), however, CD4 T-cell counts were not significantly reduced, suggesting that potent long-term iatrogenic immunosuppression causes a functional inhibition of the immune system similar to massive T-cell depletion.

It has been suggested in the past that immunosuppression with the mammalian target of rapamycin-inhibitor rapamycin might prevent EBV-induced B-cell PTLD development on the basis of in vitro data showing inhibition of LMP1-induced IL-10 production (32). Seven of eight PBL did not express LMP1 and we have previously shown that serum IL-10 levels in PTLD, whereas elevated at diagnosis, do not correlate with treatment response (33). In our case series, long-term rapamycin did not prevent PBL-PTLD development.

Finally, several aspects of PBL-PTLD lend themselves to comparison with PBL overall—in particular with the 42 case cohort by Valera et al. (12) including predominately HIV-associated cases. Epidemiologically, median age and sex at diagnosis of PBL-PTLD were remarkably similar (47 years, 75% male for PBL-PTLD vs. 48 years, 81% male for PBL). The rate of EBV-association (EBER) was also nearly identical at 63% (5/8) vs. 59%. With the exception of one case associated with primary EBV infection, the pattern of EBV latency type was identical (EBNA2 negative throughout and LMP1 0% vs. 6%). MYC rearrangements were found in a slightly lower percentage (2/6, 33%) of cases in our series versus 49% in the series of Valera et al. (12).

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MATERIALS AND METHODS

To assess the clinical features, treatment options and outcome of rare PTLD subtypes, a prospective PTLD registry has been initiated in Germany in 2006. Here, we present our data on solid organ transplant recipients diagnosed with PBL-PTLD from 2006 to 2011. Treatment was at the discretion of the local physician. Clinical data on the patients in the registry are collected before, during and at least 4 weeks, 6 months, 12 and 24 months after treatment. The responsible local ethics committee approved the registry, and all patients gave written informed consent according to the Declaration of Helsinki. Follow-up data were reviewed for all patients up to November 2011. Tumor response to treatment was defined according to the WHO criteria. Disease-free survival (DFS) was defined from first evidence of CR to disease progression or to death from PTLD, whereas overall survival was defined from diagnosis of PTLD to death from any cause.

The diagnosis of PTLD was based on the examination of histological material, obtained by open biopsy or core needle biopsy. Diagnostic tissue samples were reviewed independently by two expert pathologists (I.A. and W.K.) and classified morphologically according to the WHO classification. Histological EBV association was confirmed by ISH for EBER; latency type was assessed by immunohistochemical staining for LMP1 and EBNA2. The extent of existing disease was determined through a complete patient history; physical examination; laboratory investigations (including full blood count, lactate dehydrogenase [upper limit, 240 U/L]; renal and liver function tests and determination of the EBV DNA load in peripheral blood); bone marrow biopsy; and computed tomography scans of the chest, abdomen, and pelvis.

Immunohistochemistry was performed using standard commercially available antibodies for the Bond-autostainer (CD20, CD38, CD138, CD56, cyclin D1, Alk1, kappa, lambda, EBNA2, LMP1). ISH for EBV-encoded mRNAs was performed using a commercially available probe (Menarini, Bond, Leica). Staining for EBER-ISH, cyclin D1 and Ki-67 was assessed in percent of positive tumor cells. CD38 and CD138 were scored positive when more than 25% of the tumor cells reacted positive. Interphase fluorescence ISH for the detection of breakpoints affecting the IGH, BCL2, BCL6, and MYC loci or fusions of MYC and IGH was carried out on paraffin sections of tumor tissues using commercially available probes (Abbott/Vysis, Downers Grove, IL) and a recently published protocol (34).

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Keywords:

Plasmablastic lymphoma; Posttransplant lymphoproliferative disorder (PTLD); DLBCL; CD138; MYC.

© 2012 Lippincott Williams & Wilkins, Inc.