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Post-transplant plasma cell myeloma and polymorphic lymphoproliferative disorder with monoclonal serum protein occurring in solid organ transplant recipients.

Post-transplant lymphoproliferative disorders are mostly Epstein-Barr virus-related, B-cell tumors that develop as a consequence of immunosuppressive therapy in recipients of solid organ or bone marrow transplants. These disorders range from reactive, polyclonal plasmacytic hyperplasia to those that are morphologically and genotypically indistinguishable from typical non-Hodgkin's lymphomas. Plasma cell myeloma occurring after solid organ transplantation is rare. We report three plasma cell myeloma post-transplant lymphoproliferative disorder cases and one polymorphic, monoclonal post-transplant lymphoproliferative disorder case associated with a monoclonal serum protein. All three plasma cell myeloma post-transplant lymphoproliferative disorder cases had clinical, radiologic, and pathologic features of conventional plasma cell myeloma. The one polymorphic post-transplant lymphoproliferative disorder case was associated with an IgM monoclonal serum protein and was morphologically indistinguishable from a lymphoplasmacytic lymphoma. Three of the four cases, including the one polymorphic post-transplant lymphoproliferative disorder case, were positive for Epstein-Barr virus encoded small RNA by in situ hybridization. One patient died of plasma cell myeloma post-transplant lymphoproliferative disorder. The remaining three patients are alive: two are completely free of post-transplant lymphoproliferative disorder, and one has shown partial response to therapy. We compare the clinicopathologic features of these cases with those in the literature.

Aged↗

Post-transplant lymphoproliferative disorders.

Post-transplant lymphoproliferative disorder is the most common malignancy, with the exception of skin cancer, after solid organ transplantation in adults. The incidence varies according to the transplanted organ and is often associated with Epstein-Barr virus. Prognosis is variable, due in part to the heterogeneity of the disease, which ranges from reactive plasmacytic hyperplasia to aggressive monoclonal disease.

Humans↗

Post-transplant lymphoproliferative disorder.

Post-transplant lymphoproliferative disorder (PTLD) is an increasingly recognized complication of solid organ and hematopoietic stem cell transplantation. PTLD represents a spectrum of polyclonal and monoclonal lymphoproliferation, generally of B cells. Prompt diagnosis is key and requires a high index of suspicion. An increasing variety of highly effective therapies, including immune modulation via reduction in immunosuppression, monoclonal antibodies, and cellular therapy, have dramatically improved the cure rates of this once devastating disease.

Hematopoietic Stem Cell Transplantation↗

Posttransplant lymphoproliferative disorder: intrathoracic manifestations.

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication of organ transplantation and immunosuppression. Early diagnosis and treatment greatly affect prognosis. Chest radiographs (n = 13), chest computed tomographic (CT) scans (n = 2), or both (n = 20) from 35 patients with intrathoracic PTLD were retrospectively studied to define the intrathoracic manifestations of this disorder. Intrathoracic abnormalities consisted of pulmonary nodules (16 patients), patchy air-space consolidation (three patients), mediastinal and hilar adenopathy (17 patients), thymic enlargement (two patients), pericardial thickening and/or effusions (two patients), and pleural effusions (four patients). Multiple, well-circumscribed pulmonary nodules with or without mediastinal adenopathy are highly suggestive of PTLD. However, pathologic examination is usually necessary for a definitive diagnosis.

Adolescent↗

Post-transplant lymphoproliferative disorders.

Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of organ transplantation, with multiple factors being implicated in its pathogenesis. The clinical presentation of PTLD is atypical, therefore imaging and tissue biopsy are essential for diagnosis. Treatment requires drug combinations that are appropriate to the PTLD. Four patients with PTLD who had undergone orthotopic liver transplantation are documented, and their clinical characteristics and management described. These case histories identify neutropenia to be a problem and show that age does not seem to influence prognosis.

Adolescent↗

Incidence and consequences of post-transplantation lymphoproliferative disorders.

Post-transplant lymphoproliferative disorder (PTLD) is a recognized severe complication arising in allograft recipients treated with immunosuppressive drugs. Although not common, PTLD is one of the most frequent tumours among graft recipients, comprising 15-25% of neoplasms, compared with 5% in the general population. The introduction of cyclosporin A (CyA) in the early 1980's and the very potent new immunosuppressants such as anti-CD3 monoclonal OKT3 and FK506 have been associated with a significant rise in the incidence of PTLD and with their earlier presentation. The incidence of this malignancy varies with the organ transplanted (1-2% of renal transplant recipients) and with the nature and severity of the accompanying immunosuppressive regimen. While the precise etiology of PTLD is still unclear, significant advances have been made recently in the understanding of its pathogenesis. Most PTLD tumour cells present an activated B-cell phenotype and an unrestricted pattern of latent EBV gene products. It is generally accepted that Epstein-Barr virus (EBV) infection or reactivation and intensive anti-T lymphocyte regimens play a major role in the genesis of PTLD. They include a spectrum of EBV-related disorders ranging from lymphoid hyperplasia to frank malignant non-Hodgkin's lymphoma. Although different therapeutic attempts have been proposed, optimal treatment remains elusive. The mortality rate for monoclonal lymphomas was reported to be as high as 80%. Infusion of anti-B monoclonal antibodies seems to be a promising modality. Different preventive approaches have been proposed, including EBV sero-negative donor/recipient matching and careful monitoring of EBV infection. Cautious use of anti-rejection treatment in combination with prophylactic antiviral therapy is recommended.

Humans↗

Limitations of EBV-PCR monitoring to detect EBV associated post-transplant lymphoproliferative disorder.

Post-transplant lymphoproliferative disorder (PTLD) represents a significant threat to the survival of pediatric transplant recipients. Epstein-Barr (EBV) viral load monitoring using polymerase chain reaction (PCR) has been reported to have a variable sensitively with relatively higher specificity as in an indicator of the development of PTLD. We report two cases of pathologically confirmed PTLD in children who failed to develop sustained increases in their EBV-PCR determined viral loads. We suggest that clinicians should be aware of the potential for false-negative results of EBV-PCR in pediatric transplant recipients.

Child↗

Mini-BEAM and autologous hematopoietic stem-cell transplant for treatment of post-transplant lymphoproliferative disorders.

Post-transplant lymphoproliferative disorder (PTLD) represents a spectrum of lymphoid proliferative diseases seen as result of immunosuppression in recipients of solid organ or hematopoietic stem-cell transplantation. Options of treatment include reduction or discontinuation of immunosuppressive agents, antiviral drugs, rituximab, chemotherapy, and radiation. We report two unique cases of PTLD (CNS and plasmacytoma-like) treated successfully with salvage chemotherapy, mini-BEAM chemotherapy, and autologous stem-cell transplant. In both cases, patients were also treated with sirolimus and prednisone as immunosuppression, and neither patient rejected their solid organ transplants. With over 30 months of follow-up, both patients remain in complete remission with excellent allograft function.

Adult↗

[Identification of prognostic factors in post-transplantation lymphoproliferative disorders].

Post-transplantation lymphoproliferative disorders (PTLD) represent a severe complication of organ transplantation, so the determination of prognostic factors for the response and the survival is of major interest. Studies on PTLD are hindered by the small number of cases, explaining the conflicting published results. In order to identify, prognostic factors in this kind of disease, 61 patients have been analyzed in a retrospective multicenter study. A new index is proposed to assess the survival probability, it is composed of two factors: the performance status (PS < or = 1 versus 2-3) and the number of involved sites (1 versus > 1). This index seems to be more accurate in PTLD than the IPI, the reference in immunocompetent patients with non Hodgkin lymphomas. However, a similar analysis in a more homogeneous population remains necessary.

Adolescent↗

Post-transplant lymphoproliferative disorders.

Post-transplant lymphoproliferative disorder (PTLD) is a life-threatening complication after hematopoietic stem cell or solid organ transplantation. The majority of PTLD is of B-cell origin and associated with Epstein-Barr virus (EBV). During the past decade progress has been made in better understanding the pathogenesis of PTLD, and early detection strategies, such as serial measurement of EBV-DNA load in peripheral blood samples, have assisted in the identification of high-risk patients. In addition, novel immunotherapies have been developed, including the use of monoclonal antibodies and adoptive transfer of EBV-specific T cells. Despite these advances, it remains a major challenge to define indications for preemptive therapies for PTLD and to integrate novel therapeutic approaches with conventional therapies.

Dose-Response Relationship, Drug↗

Use of serum protein electrophoresis to monitor patients with post-transplant lymphoproliferative disorder.

Post-transplant lymphoproliferative disorder (PTLD) is a potentially life-threatening complication of solid organ transplantation. Reduction in immunosuppression is usually the first line of therapy and is often curative. While undergoing treatment, imaging studies including MRI and CT scans are commonly used to follow the disease course. Laboratory studies such as lactate dehydrogenase and Epstein-Barr virus PCR can also be used to monitoring disease status. We report here a case of PTLD developing 48 months post renal transplant. A monoclonal protein (M protein) was demonstrated at diagnosis with a corresponding antibody expressed on the malignant lymphocytes. The patient was followed with serial serum protein electrophoreses (SPEP) to monitor his response to therapy. The amount of M protein paralleled the disease course, decreasing as the clinical symptoms improved. This case illustrates the utility of using SPEP to monitor patients with PTLD.

Adult↗

Bcl6/Laz3 rearrangements in post-transplant lymphoproliferative disorders.

Post-transplant lymphoproliferative disorders (PTLD) are well-known complications of iatrogenic immune deficiency and are thought to result from the proliferation of B cells infected by the Epstein-Barr virus (EBV). Some large cell lymphomas occurring in the general population carry a rearrangement of the Bcl6/Laz3 zinc-finger-encoding gene. 15 EBV-associated PTLD were tested for the presence of Bcl6/Laz3 rearrangements by Southern blot analysis using two specific probes (F370, F372). One out of 15 cases displayed a rearranged band independent of the germline one. In contrast, 10 lymphoblastoid cell lines and one lymphoblastoid cell line passaged in an SCID mouse carried only germline alleles of Bcl6/Laz3 after Southern blot hybridization. This indicates that genetic abnormalities may also play an important role in the development of some PTLD.

Animals↗

Relative adrenal insufficiency in post-transplant lymphoproliferative disorder.

Post-transplant lymphoproliferative disorder is treated with rapid decrement of immunosuppressive therapy. This cannot be achieved with ease in patients on long-term glucocorticoid therapy, as chronically suppressed adrenal glands may not be capable of mounting adequate response to stress. A 52-year-old Caucasian male presented with fever, orthostatic hypotension, lymphadenopathy and hyponatraemia. Serum cortisol levels were within normal levels with a sub optimal response to stimulation by ACTH. Hyponatraemia and orthostasis responded poorly to fluid restriction, saline and salt repletion but corrected after increasing the steroid dose. The normal baseline cortisol levels represented a stimulated adrenal gland, however, the ACTH stimulation had inadequate response. This sub optimal stimulation and a good response to increased steroids suggest the presence of relative or occult adrenal insufficiency. Relative adrenal insufficiency must be considered in patients who have received prolonged glucocorticoid therapy and have symptoms such as hypotension and/or hyponatraemia.

Adrenal Insufficiency↗

Interferon-alpha affects the immune response in post-transplant lymphoproliferative disorder.

Post-transplant lymphoproliferative disorder (PTLD) is associated with Epstein-Barr virus (EBV) and characterized by fever, lymphadenopathy, and graft dysfunction. We describe the clinical course of an EBV seronegative 11-yr-old boy who underwent double lung transplantation and subsequently developed PTLD in the graft. A reduction in immunosuppression and the addition of acyclovir did not result in improvement. Treatment with interferon-alpha (IFN-alpha), however, led to dramatic clinical, radiographic, and histologic improvement. Semiquantitative measurements of cytokine mRNA in his bronchoalveolar lavage cells prior to therapy with IFN-alpha revealed high levels of IL-4 and IL-10 mRNA, which decreased significantly with treatment. We speculate that the beneficial effect of IFN-alpha in the treatment of PTLD is directly related to the inhibition of type 2 helper (Th2-like) T-cells.

Bronchoalveolar Lavage Fluid↗

Identifying the patient at risk for post-transplant lymphoproliferative disorder.

Post-transplant lymphoproliferative disorders (PTLD) are a recognized complication of the immunosuppression required to prevent allograft rejection, occurring in 1-20% of recipients of solid organ transplants. Several factors greatly increase the risk of developing PTLD early post-transplant in any individual recipient. Epstein-Barr virus (EBV) infection is critical in the pathogenesis of the majority of these cases. Pre-transplant EBV seronegativity increases the incidence of PTLD 10- to 75-fold over that of EBV-seropositive recipients. Other risk factors include very young recipient age, cytomegalovirus infection or mismatching (donor positive-recipient negative), aggressive immunosuppression with conventional biologic agents, and the type of organ transplanted. In contrast, the risk of developing PTLD late in the post-transplant course does not appear to be influenced by the type of immunosuppressive agents employed, but rather by the duration of any immunosuppression. The role of EBV in late PTLD is also less certain, as a greater proportion of lesions are not associated with evidence of EBV infection. As the understanding of these risk factors has expanded, opportunities exist to target those populations at highest risk for the development of PTLD for aggressive monitoring and pre-emptive or prophylactic therapy. It is hoped that implementation of such strategies will render early PTLD a preventable complication of transplantation.

Humans↗

Cytologic features of post-transplant lymphoproliferative disorder.

Post-transplant lymphoproliferative disorders (PTLD) are Epstein-Barr virus (EBV)-associated lymphoid proliferations which affect approximately 2% of organ allograft recipients. Although the histologic features of PTLD are well described, they have been described only rarely in cytologic specimens. The cytomorphologic features of PTLD in body fluid specimens, needle aspirations, and a gastric brushing specimen from seven patients with histologically confirmed PTLD were therefore reviewed. In the cytologic specimens, PTLD was characterized by a mostly polymorphous population of lymphoid cells containing many large transformed lymphocytes, occasional immunoblast-like atypical lymphocytes, necrosis, and, frequently, obvious plasmacytoid differentiation. The presence of EBV was documented in five of the seven cases in the corresponding tissue biopsies. The four patients with PTLD in a body fluid specimen all died within 3 months of detection of the PTLD in the body fluid. The three remaining patients are alive with resolution of PTLD (follow-up of 7, 8, and 14 months). The diagnosis of PTLD should be suggested when cytologic specimens from organ allograft recipients show a polymorphous atypical lymphoid proliferation, frequently with plasmacytoid differentiation and necrosis. Cytologic samples may provide the initial diagnosis of this potentially fatal disease and allow appropriate intervention. The presence of PTLD in a body fluid specimen is a poor prognostic indicator.

Adult↗

Serum protein electrophoresis abnormalities in adult solid organ transplant patients with post-transplant lymphoproliferative disorder.

Post-transplant lymphoproliferative disorder (PTLD) is an Epstein-Barr virus (EBV) associated malignancy that occurs in the setting of pharmacologic immunosuppression used after organ transplantation. The presence of monoclonal gammopathy (MG) after organ transplantation is a risk factor for the development of PTLD. We retrospectively explored the characteristics of serum protein electrophoresis (SPEP) in 38 adult solid organ transplant patients with biopsy proven PTLD and SPEP. Twenty-three (61%) had MG with nine (24%) showing multiple MG. Background gammaglobulin levels were abnormal in 13 (34%) patients with five (13%) and eight (21%) having polyclonal hypergammaglobulinemia or hypogammaglobulinemia, respectively. Hypogammaglobulinemia was correlated with the presence of MG (p = 0.01) and polymorphic B-cell hyperplasia histology (p = 0.01). No correlation between SPEP findings and overall survival were noted. With median follow-up of 116 wk (range 2-261 wk), 21 (55%) patients are alive with 20 (53%) in complete remission. Response to reduction in immunosuppression was correlated with improved overall survival (262 wk vs. 68 wk, p = 0.003). Persistence of MG after complete response of the PTLD did not predict relapse. There is a high incidence of MG and gammaglobulin abnormalities in patients with PTLD.

Adult↗