Polymorphic Post-transplant Lymphoproliferative Disorder Research Articles

Successful treatment of a classic Hodgkin lymphoma‐type post‐transplant lymphoproliferative disorder with tailored chemotherapy and Epstein–Barr virus‐specific cytotoxic T lymphocytes in a pediatric heart transplant recipient

CHL type is the least common major form of EBV-related PTLD but rarely occurs in pediatric recipients; development of CHL subsequent to other PTLD subtypes in the same transplant recipient is even more unusual. Because of its rarity, indications on the best treatment strategy are limited. Patients have been mostly treated with standard HL chemotherapy/radiotherapy, and prognosis seems more favorable than other monomorphic PTLDs. Herein, we describe a pediatric case of EBV-associated, stage IV-B, CHL arising in a heart allograft recipient eightyr after diagnosis of B-cell polymorphic PTLD. The patient was successfully treated with adjusted-dose HL chemotherapy and autologous EBV-specific CTL, without discontinuation of maintenance immunosuppression. At twoyr from therapy completion, the patient is in CR with stable organ function. With this strategy, it may be possible to reproduce the good prognostic data reported for CHL-type PTLD, with decreased risk of organ toxicity or rejection.

Posttransplant Lymphoproliferative Disorder in Pediatric Patients

Transplantation of solid organs and hematopoietic stem cells is accompanied by profound disturbance of immune function mediated by immunosuppressive drugs or delayed immune reconstitution. Disturbed T cell control of Epstein-Barr virus (EBV)-infected B cells leads to posttransplant lymphoproliferative disorder (PTLD) in up to 10% of patients. Children are at a higher risk because they are more often EBV-naïve before transplantation. Patients with PTLD often present with unspecific symptoms (pain and organ/graft dysfunction). Depending on the onset of PTLD, manifestations vary between mainly nodal (late PTLD) and extranodal sites (early PTLD). Histology, immunohistology, EBER in situ hybridization and molecular pathology are required for diagnosis and subclassification of PTLD. The three major types are early lesions (resembling reactive proliferations in immunocompetent patients), polymorphic PTLD (proliferation of B and T cells with effacement of histoarchitecture) and monomorphic PTLD (presenting as malignant lymphomas, mainly high-grade B cell lymphomas). In a subfraction of cases, including monomorphic PTLD, reduction of immunosuppressive medication alone is sufficient to induce remission. Surgical debulking of tumor mass and anti-CD20-antibody treatment with or without chemotherapy (usually at lower dosages than in immunocompetent patients) constitute the basis of additional therapy.

Colonic Perforation After Rituximab Treatment for Posttransplant Lymphoproliferative Disorder

A 3-year-old girl presented with hematochezia. Her medical history included heart transplantation for hypoplastic left heart syndrome. Investigations demonstrated an Epstein-Barr virus polymerase chain reaction of 2307 genomes. Magnetic resonance enterography of the abdomen showed changes consistent with posttransplant lymphoproliferative disorder (PTLD) (Fig. 1). Her tacrolimus target trough was decreased to 4 to 7 ng/mL. Her initial colonoscopy showed ulcerations in the sigmoid colon and biopsies confirmed polymorphic PTLD (Fig. 2). She was treated with 4 weekly doses of rituximab and she remained clinically stable. Repeat colonoscopy to assess resolution of PTLD revealed a large perforation of the sigmoid colon; the patient subsequently underwent immediate bowel resection (Fig. 3). The gross specimen (Fig. 4) revealed granulation tissue, suggesting the perforation occurred before the colonoscopy. The pathology demonstrated persistent PTLD.FIGURE 1: Magnetic resonance enterography of the abdomen showing retroperitoneal lymphadenopathy, evidence of mesenteric infiltration, focal dilatation, and bowel wall thickening in the sigmoid colon (yellow arrow) suggestive of posttransplant lymphoproliferative disorder.FIGURE 2: Histology of colonic biopsy shows nuclear positivity for Epstein-Barr virus–encoded RNA (EBER) by in situ hybridization (black arrows) (EBER in situ hybridization; original magnification × 200).FIGURE 3: Colonoscopy performed postrituximab therapy. Large perforation noted in the sigmoid colon.FIGURE 4: Gross pathology specimen showing a 1.5-cm defect in the sigmoid colonic wall.PTLD is a rare but potentially fatal complication of solid organ transplantation. Extranodal involvement is highest within the gastrointestinal (GI) tract (1). In our case, rituximab, an anti-CD20 monoclonal antibody, was used to treat PTLD; however, its use has been associated with spontaneous GI perforation from rapid chemotherapeutic lysis of the tumor (2). Rituximab should be used cautiously in GI presentations of PTLD, especially in advanced disease and patients with multiple sites of involvement (3).

EBV-negative post-transplant lymphoproliferative disorder: Clinical characteristics, response to therapy, and survival.

8578 Background: Post-transplant lymphoproliferative disorder (PTLD) is a potentially life-threatening complication of solid organ transplantation. PTLD is frequently linked with Epstein-Barr virus (EBV) and it was suggested that EBV negativity is associated with a poor prognosis and lack of response to reduction of immunosuppression (RI). We conducted a case-control study to identify the characteristics, outcome and response to therapy of EBVpos and EBVneg PTLD over a 20-year period. Methods: We reviewed data on patients diagnosed with PTLD at U. Penn. between 1982 and 2012. We determined EBV positivity on tumor samples according to WHO criteria. We compared clinical and pathologic characteristics, response to therapy, and survival of EBVpos and EBVneg patients. Results: Of 222 patients diagnosed with PTLD, we verified the EBV status of 169 patients, of whom 35% were EBVneg and 65% were EBVpos. Mean follow-up was 46.7 months. Median time from transplant to PTLD was 23.1 mo. in EBVpos vs. 59.3 mo. in EBVneg (p=0.003) with 42% of EBVpos patients being diagnosed within the first year after transplant vs. 15% in the EBVneg group (p<0.001). EBVneg PTLD was more likely to occur in non-thoracic vs. thoracic transplants (p=0.006). 28% of patients with EBVpos PTLD presented with disease originating from the graft vs. 14% in the EBVneg group (p=0.03). In terms of histology, 36% of EBVpos patients had polymorphic PTLD vs. 7% of EBVneg patients (p<0.001). Of patients who were treated with RI alone (40% of patients in both groups), the overall response rates were 50% and 48% in EBVpos and EBVneg patients respectively (p=NS). Response rates to rituximab were also similar. There was no difference in the mortality risk between groups (HR=1.04; p=0.84). The 5-year survival rates were 47% and 51% in EBVpos and EBVneg PTLD respectively (p=NS). Conclusions: In a large single-center series, EBVneg PTLD was associated with late occurrence after transplant, monomorphic histology and similar outcome in comparison with EBVpos PTLD. Importantly, the response of EBVneg PTLD to RI and rituximab was no different than EBVpos PTLD. These results have implications for the management of solid organ transplant recipients with PTLD.

Clinicopathologic spectrum and EBV status of post-transplant lymphoproliferative disorders after allogeneic hematopoietic stem cell transplantation

Post-transplant lymphoproliferative disorders (PTLDs) are serious, life-threatening complications of solid-organ transplantation (SOT) and bone marrow transplantation, and are associated with high mortality. PTLDs represent a heterogeneous group of lymphoproliferative diseases, which show a spectrum of clinical, morphologic, and molecular genetic features ranging from reactive polyclonal lesions to frank lymphomas. We describe clinicopathologic features of 17 cases of PTLD after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which were analyzed by in situ hybridization for EBV and a panel of antibodies directed against numerous antigens, including CD20, PAX5, CD3, bcl-6, CD10, MUM-1/IRF4, CD138, Kappa, Lambda, CD30, CD15, and Ki67. The cases included 13 males and 4 females with a median age of 31years (range 9-49years) and the PTLDs developed 1.5-19months post-transplant (mean 4.7months). The histological types indicated five cases of early lesions, two of plasmacytic hyperplasia and three of infectious mononucleosis-like PTLD. Eight cases were polymorphic PTLD, and four were monomorphic PTLD, including three of diffuse large B cell lymphoma, and one of plasmablastic lymphoma. Foci and sheets of necrosis were observed in five cases. The infected ratio of EBV was 88.2%. Some cases were treated by reduction of immunosuppression, antiviral therapy, donor lymphocyte infusion, or anti-CD20 monoclonal rituximab. Eight cases died. The first half year after allo-HSCT is very important for the development of PTLD. The diagnosis of PTLD relies on morphology and immunohistochemistry, and EBV plays an important role in the pathogenesis of PTLD. The prognosis of PTLD is poor, and, notably, PTLD after allo-HSCT exhibits some features different from those of PTLD after SOT.

Neurological symptoms in a post-transplant patient: a cautionary tale

Primary central nervous system (CNS) post-transplant lymphoproliferative disorder (PTLD) is a rare complication of organ transplantation affecting about 1 % of transplant recipients [1, 2]. The median time from transplantation to diagnosis ranges from 12.6 months to 52 months [1, 3]. We herein describe an unusual case of Epstein barr virus (EBV) positive primary CNS PTLD, presenting after a very long delay of 12 years after renal transplant. A 50-year-old woman presented with a 12-week history of gradual onset, constant, throbbing generalised headache of moderate intensity. She also reported progressive vertigo, difficulty in walking, nausea and vomiting. She was a nonsmoker and denied use of alcohol or other illicit drugs. Twelve years previously, she had a renal transplant for endstage renal disease secondary to chronic pyelonephritis. Her routine medications included cyclosporin 50 mg twice daily, azathioprine 100 mg once daily and prednisolone 5 mg once daily. Clinical examination demonstrated broken pursuit eye movements, mild appendicular ataxia and right extensor plantar response. She walked with a slightly broadbased ataxic gait. Systemic examination was unremarkable. Laboratory studies including inflammatory markers and autoimmune screen were unremarkable. Magnetic resonance imaging (MRI) of the brain with gadolinium showed scattered nodular enhancing lesions involving bilateral cerebellar hemispheres, splenium of corpus callosum and right peritrigonal white matter (Fig. 1). Cerebrospinal fluid (CSF) analysis revealed a white cell count of 7 (100 % lymphocytes), protein 0.39 g/L and normal glucose. Stains and culture results for bacteria, mycobacteria and fungi were negative. However, CSF polymerase chain reaction for EBV was positive at 1,000 copies/ml; BK and JC virus were negative. Computed tomography scan of chest, abdomen, and pelvis was unremarkable. A biopsy of the posterior fossa lesion showed a polymorphic population of lymphoid cells, in keeping with polymorphic type PTLD (Fig. 2). Azathioprine was discontinued and cyclosporin was initially reduced to 25 mg twice daily. She was also treated with 4 cycles of methotrexate (3000 mg/m on day 1) and cytarabine (1600 mg/m every 12 h on day 2 and 3) at 3 weekly intervals, with complete clinical and radiological response. The dose of cytarabine was reduced by 20 percent from the standard dose (2000 mg/m), given the reduced baseline creatinine clearance rate of 53 mL/min/ 1.73 m. She is currently on prednisolone 5 mg daily and cyclosporin 35 mg twice daily. There has been no recurrence to date over a period of 18 months. She also retains good renal graft function. Post-transplant lymphoproliferative disorders represent a spectrum ranging from EBV-driven infectious mononucleosis type polyclonal proliferations, to EBV positive or S. K. Chhetri R. Dayanandan H. C. A. Emsley (&) Department of Neurology, Royal Preston Hospital, Preston PR2 9HT, UK e-mail: h.emsley@liv.ac.uk; hedley.emsley@manchester.ac.uk

Post-transplant lymphoproliferative disorder: a clinicopathologic study of 15 cases

To study the clinical and histopathologic features, diagnosis, pathogenesis and therapy of post-transplant lymphoproliferative disorders (PTLD). The clinical and pathologic features of 15 cases of PTLD were retrospectively analyzed by light microscopy, immunohistochemistry and in-situ hybridization, according to the updated 2008 WHO classification of tumors of hematopoietic and lymphoid tissues. Amongst the 15 cases studied, 14 cases had received allogenic hematopoietic stem cell transplantation (AHSCT) and 1 case had received renal transplantation. There were altogether 12 males and 3 females. The male-to-female ratio was 4:1. The mean age was 30.4 years and the median age was 31 years (range from 9 to 60 years). PTLD developed 1.5 to 132 months after transplantation (median 13.0 months). The mean age of the 14 patients with AHSCT was 28.3 years (range from 9 to 45 years) and PTLD developed 1.5 to 19 months after transplantation (mean 4.5 months). Major clinical presentation included fever and lymphadenopathy. Twelve cases involved mainly lymph nodes and the remaining 3 cases involved tonsils, stomach and small intestine, respectively. The histologic types in 4 cases represented early lesions, including plasmacytic hyperplasia (n = 1) and infectious mononucleosis-like PTLD (n = 3). Seven cases were polymorphic PTLD, with 4 cases containing a predominance of large cells. Graft-versus-host disease was also seen in the case of small intestinal involvement. Four cases were monomorphic PTLD, 3 of which were diffuse large B-cell lymphoma, 1 was plasmablastic lymphoma and 1 was a mixture of monomorphic and polymorphic PTLD. Foci of necrosis were seen in 5 cases. The proliferating index of Ki-67 was high. The positive rate of EBV-encoded RNA in AHSCT was 92.9%. The duration of PTLD onset was shorter in EBV-positive cases (range from 1.5 to 7 months) than EBV-negative cases (range from 19 and 132 months). Some cases were treated by reduction of immunosuppression, antiviral agents or anti-CD20 monoclonal antibody Rituximab. The duration of follow-up in 14 patients ranged from 0 to 8 months. Five of the patients died of the disease. The diagnosis of PTLD relies on morphologic examination and immunohistochemistry. Most of them are of B-cell origin. EBV plays an important role in the pathogenesis of PTLD. The duration of disease onset is shorter in EBV-positive cases. PTLD in AHSCT cases occurs in younger age group, with shorter duration of onset, as compared to solid organ transplantation. The prognosis of PTLD is poor. The modalities of treatment include reduction of immunosuppression, antiviral agents or anti-CD20 monoclonal antibody Rituximab.

Polymorphic lymphoid proliferations occurring in HIV-positive patients: report of a case responding to HAART

Epstein-Barr virus (EBV)-associated polymorphic lymphoid proliferations resembling polymorphic post-transplant lymphoproliferative disorders are a rare but recognised complication of the human immunodeficiency virus (HIV). These account for fewer than 5 % of HIV-associated lymphomas, and little information has been published regarding their treatment and outcome. Of the reported cases, many have presented with extranodal disease, not typical of lymphoma. We report the case of a patient presenting with lung infiltrates shown to be the result of an EBV-associated polymorphic lymphoproliferation resembling a polymorphic post-transplant lymphoproliferative disorder. The patient was simultaneously found to be HIV positive and commenced on highly active antiretroviral therapy. Without any specific anti-neoplastic treatment, the patient recovered completely and within 20 months had no symptoms or radiological evidence of a lymphoproliferative disorder. This illustrates the importance of recognising this uncommon condition in HIV-positive patients and avoiding potentially unnecessary chemotherapy.

Interim analysis of the largest prospective trial to date in adult CD20-positive post-transplant lymphoproliferative disorder (PTLD): Introducing risk-stratified sequential treatment (RSST).

8030 Background: The prospective, multicenter international phase II PTLD-1 trial of sequential treatment (ST, 4 cycles of weekly rituximab followed by 4 cycles of CHOP-21 + G-CSF) in adult CD20-positive PTLD demonstrated excellent efficacy (90% overall response rate, ORR) and safety (11% treatment-related mortality, TRM). As the response to rituximab predicted overall survival (OS), the trial was amended in 2007 introducing risk-stratified sequential treatment (RSST) according to the response to rituximab (NCT00590447). Methods: Following rituximab on days 1, 8, 15 and 22, RSST consisted of 4 3-weekly courses of rituximab monotherapy for patients (pts) in complete remission (CR, low risk) while all others (high risk) received 4 cycles of R-CHOP-21 + G-CSF. Key exclusion criteria were CNS involvement, HIV infection, severe organ dysfunction not related to PTLD, and ECOG > 2. Primary endpoint was ORR. This is an analysis of the first 91 patients treated with RSST. Results: 79/91 pts had monomorphic, 12 polymorphic PTLD. 41/91 pts were kidney, 27 liver, 12 heart, 7 lung or heart+lung, 3 heart+kidney and 1 kidney+pancreas transplant recipients. Median age at diagnosis was 60 years (range 20-82). 73/91 pts had late PTLD and 39/85 PTLDs were EBV-associated. 1 pt died before initiation of treatment; 5 pts discontinued treatment after 4 cycles rituximab. TRM of RSST was 7/90 (8%) including 5 deaths with unknown remission status. ORR was thus 74/80 (93%, 95%CI: 84-97%; CR: 62/80 [78%]). 24/90 pts (27%) achieved CR with 4 cycles of rituximab. After a median follow up of >3 years, relapse rate in low risk pts was not increased by rituximab consolidation in RSST compared to CHOP consolidation in ST (3/23 vs. 5/14, p=0.104]). In patients in PD after rituximab, R-CHOP was more effective than CHOP in achieving CR (15/23 vs. 3/11, p=0.038). OS at 3 years was higher with RSST (70%, 95% CI: 60-82%) compared to ST (61%, 95%CI 49-72%) but this difference was not significant. Conclusions: With RSST 27% of pts were classified as low risk and achieved durable tumor control without chemotherapy while R-CHOP seems more efficient than CHOP in in high risk patients.

Alterations of negative regulators of cytokine signalling in immunodeficiency‐related non‐Hodgkin lymphoma

We investigated immunodeficiency-related non-Hodgkin lymphoma for the presence of molecular alterations affecting negative regulators of the Janus family protein tyrosine kinase/signal transducer and activator of transcription pathway. Protein tyrosine phosphatase, non-receptor type 6/Src homology 2-containing tyrosine phosphatase-1 epigenetic silencing was recurrent in primary effusion lymphoma (100%), and diffuse large B-cell lymphoma (63%), with a higher prevalence in the non-germinal centre subtype, and was associated with the activation of the Janus family protein tyrosine kinase/signal transducer and activator of transcription 3 pathway. Suppressor of cytokine signalling (SOCS)1 and SOCS3 epigenetic silencing were occasionally detected, whereas SOCS1 was frequently mutated in diffuse large B-cell lymphoma and polymorphic post-transplant lymphoproliferative disorders, possibly as a cause of aberrant somatic hypermutation. However, the mutation profile of the coding region of the gene was different from that expected from the aberrant somatic hypermutation process, suggesting that, at least in some cases, SOCS1 mutations may have been selected for their functional activity.

089 Delayed primary CNS post-transplant lymphoproliferative disorder (PTLD)

Primary central nervous system (PCNS) PTLD is a very rare complication that occurs as a result of immunosuppression in the setting of solid organ transplantation. The median time from transplantation...

Post-Transplantation Lymphoproliferative Disorders (PTLD) Management in Solid Organ Transplantation (SOT) Recipients

Abstract 4941 Introduction:PTLD are lymphoid proliferations that develop as a consequence of immunosuppression in 1% of SOT recipients. The majority of PTLD are associated with Epstein-Barr virus (EBV) infection, as therapeutic immunosuppression causes decreased T-cell surveillance, increasing the proliferative potential of EBV in latently infected B-cells. PTLD may manifest as early lesions including polyclonal plasmacytic hyperplasia and infectious mononucleosis-like PTLD as well as monoclonal polymorphic PTLD. Patients who develop polymorphic PTLD, universally associated with EBV and occurring early after transplant, usually have good prognosis and respond well to reduction of immunosuppression and antiviral therapy. Monomorphic PTLD is indistinguishable from a subset of B-cell and much less frequently T-cell lymphomas that occur in immunocompetent individuals. Monomorphic PTLD in SOT patients frequently involve extranodal sites as well as the allograft and causes significant morbidity and mortality in this group of patients. There is no universally accepted treatment strategy for monomorphic PTLD as randomized trials are lacking with most of the data coming from prospective and retrospective cohort trials evaluating heterogeneous populations of patients. Standard therapy consists of a stepwise treatment approach, aimed at partially restoring cellular immunity by reduction of immunosuppression (RI) sometimes in combination with or followed by rituximab. If there is no response chemotherapy is initiated. However, this strategy is vague as there are no clear rules for how much and for how long immunosuppression is reduced and may be associated with both graft loss and disease progression. We believe that aggressive monomorphic PTLD patients can be successfully treated by employing aggressive chemo-immunotherapy and withdrawal of standard immunosuppressive agents. We prefer to use “dose dense” administration schedule to 1) provide intensive therapy and 2) provide strong enough immunosuppression to prevent rejection. This retrospective study was designed to assess the outcome of such a strategy in monomorphic PTLD patients treated at the Yale Cancer Center (YCC) over a 15 year period. Patients and Methods:We identified patients with the PTLD after SOT by searching Yale Tumor Registry. Patients were eligible for selection if they were diagnosed with PTLD after SOT between January 1st of 1995 and December 31st of 2009 provided they were 18 years of age or older at the time of diagnosis (diagnosis criteria). We planned to analyze the outcomes among patients treated with combined approach (treatment criteria). Sixteen patients met inclusion criteria. Results:Out of 16 identified patients 11 received kidney, 1 kidney and pancreas, 3 heart and 1 liver transplants. Thirteen patients (81%) were diagnosed with diffuse large B cell lymphoma (DLBCL), 3 with Burkitt or Burkitt-like lymphoma (19%). All patients were treated with a combined approach with most of the patients (n=11, 69%) receiving CHOP-R every 2 weeks (“dose dense”). 10 out of the 16 patients had EBV positive lymphoma (62%). Only one patient had early PTLD (< 1 year after SOT) which was EBV positive. 6 out of 15 patients with late PTLD had EBV negative tumors. 9 (56%) patients had an advanced stage disease and 13 (81%) had extranodal involvement. One patient who developed PTLD after kidney transplantation had graft involvement with PTLD. Complete response (CR) was seen in all but one patient (94%). Median overall survival and median progression free survival were 5.39 years. Only 3 patients died due to PTLD and median cause specific survival time has not been reached. Out of the 16 patients, 4 had graft rejection and graft loss due to PTLD. Both the PTLD related-graft-rejection rate and graft loss rate were 25% with 95% CI (0.07-0.52). Conclusion:Combined therapy approach utilized at the YCC yields excellent results for patients with monomorphic PTLD after SOT. High CR rate, low number of PTLD-related deaths and low graft rejection /graft loss rate make this strategy an appealing option in the treatment armamentarium for this disease. Disclosures:No relevant conflicts of interest to declare.

Posttransplant Lymphoproliferative Disorder in Kidney Transplant Patients: A Report of 68 Cases

Abstract 2662Posttransplant Lymphoproliferative Disorder (PTLD) is a rare complication of kidney transplantation that often arises due to reactivation of the Epstein-Bar Virus (EBV). Given the rarity of this disease, a full understanding of its presentation and optimal therapies has yet to be determined. Out of the 3160 patients who received a kidney transplant at the Hospital of the University of Pennsylvania between October 1987 and December 2010, we provide a retrospective analysis of 68 patients who developed PTLD. These patients were 82% Caucasian, 62% male, and 9% combined kidney and pancreas transplant patients. The most common underlying diseases leading to transplantation were glomerulonephritis (26%) and diabetes mellitus (17%). Most patients received a kidney from an unrelated donor (74%) and experienced one or more rejection episodes prior to PTLD diagnosis (59%). The median age at PTLD diagnosis was 48 yrs (range 17–76 yrs), and the median time from transplantation to diagnosis was 3 yrs (range 6 days– 25 yrs). PTLD histology consisted of 48% monomorphic, 37% polymorphic, 7% plasmacytoma, 4% T cell, and 3% Hodgkin lymphoma. At diagnosis, patients were taking steroids (96%), cyclosporine (53%), tacrolimus (35%), azathioprine (52%), and/or mycophenolate mofetil (28%). Common initial PTLD symptoms include fever (48%), pain (42%), weight loss (33%), fatigue (33%), and mass (24%). The disease commonly presented in lymph nodes (38%), kidney allograft (29%), and/or GI tract (18%). Most PTLD cases were diagnosed at stage 1 (43%) or stage 4 (31%). Laboratory analyses reveal that 62% of patient tumors tested positive for EBV and 61% of patients had elevated LDH levels. Common PTLD therapies included reduction of immunosuppression (88%), treatment with rituximab (31%), surgery (29%), and/or radiation therapy (9%). Reduction of immunosuppression alone led to CR (50%), PR (8%), SD (4%), and PD (38%). Of the 68 patients, 21 (31%) ultimately died a PTLD related death.Interestingly, PTLD patients under age 40 were more likely to have allograft involvement (p=0.007) and a polymorphic histology (p=0.007). Furthermore, allograft involvement tended to occur sooner after transplant (p=0.0001) and those with allograft involvement were more likely to present with allograft failure (p= 0.0001). Compared to monomorphic PTLD, polymorphic PTLD was more likely to be EBV positive (82% vs 51%, p=0.03) and have a lower chance of PTLD-related death (15% vs 40%, p=0.03). Finally, patients with allograft PTLD were more likely to have a polymorphic histology (80%, p<0.001). In summary, PTLD occurs in about 2% of kidney recipients and is typically EBV-associated. EBV positive PTLD is more common in younger recipients, frequently presenting with polymorphic histology in the allograft and appears to have a better prognosis. Disclosures:No relevant conflicts of interest to declare.

Usefulness of F-18 FDG PET/CT in the Evaluation of Neck Swelling in Polymorphic Posttransplant Lymphoproliferative Disorder After Renal Transplantation

A 38-year-old man with a history of renal transplantation presented with a 3-month history of bilateral neck swelling. Ultrasonography of the neck showed multiple enlarged lymph nodes at the bilateral neck. Histologic examination of a specimen from an excisional biopsy at right level II cervical lymph node revealed polymorphic posttransplant lymphoproliferative disorder. F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography scan was performed for further evaluation. The scan revealed marked enlargement and intense hypermetabolism of the lymph nodes along the bilateral cervical lymph node chains (Fig. 1). Several reports have described that diverse infectious or inflammatory disorders and malignant diseases show various degree of FDG uptake of cervical lymph nodes. This case illustrates that the possibility of posttransplant lymphoproliferative disorder should be considered in renal transplant patients with increased FDG uptake of cervical lymph nodes on F-18 FDG positron emission tomography/computed tomography scan.

Gammaherpesvirus and lymphoproliferative disorders in immunocompromised patients

Two lymphotropic human gamma herpesviruses can cause lymphoproliferative disorders: Epstein Barr virus (EBV, formally designated as human herpesvirus 4) and Kaposi sarcoma herpesvirus (KSHV, also called human herpesvirus 8). Individuals with inherited or acquired immunodeficiency have a greatly increased risk of developing a malignancy caused by one of these two viruses. Specific types of lymphoproliferations, including malignant lymphomas, occur in individuals with HIV infection, transplant recipients and children with primary immunodeficiency. Some of these diseases, such as Hodgkin’s and nonHodgkin lymphoma resemble those occurring in immunocompetent patients, but the proportion of tumors in which EBV is present is increased. Others, like primary effusion lymphoma and polymorphic post-transplant lymphoproliferative disorder are rarely seen outside the context of a specific immunodeficient state. Understanding the specific viral associations in selected lymphoproliferative disorders, and the insights into the molecular mechanisms of viral oncogenesis, will lead to better treatments for these frequently devastating diseases.

Lymphoproliferative Disorders After Solid Organ Transplantation—Classification, Incidence, Risk Factors, Early Detection and Treatment Options

Posttransplant lymphoproliferative disorder (PTLD) is a heterogeneous disease group of benign and malignant entities. The new World Health Organisation classification introduced in 2008 distinguishes early lesions, polymorphic, monomorphic and classical Hodgkin lymphoma-type PTLD. Based on the time of appearance, early and late forms can be identified.PTLDs are the second most frequent posttransplantation tumors in adulthood, and the most frequent ones in childhood. The incidence varies with the transplanted organ-from 1%-2% following kidney transplantation to as high as 10% following thoracic organ transplantation-due to different intensities in immunosuppression. Immunocompromised state and Epstein-Barr virus (EBV) infection are the two major risk factors.In Europe and the US approximately 85% of PTLDs are of B-cell origin, and the majority are EBV-associated. Symptoms are often unspecific; extranodal, organ manifestations and central nervous system involvement is common. Early lesions respond well to a decrease in immunosuppression. Malignant entities are treated with rituximab, chemotherapy, radiotherapy and surgical therapy. Adoptive T-cell transfer represents a promising therapeutic approach. The prognosis is favorable in early PTLD, and poor in late PTLD. Five-year survival is 30% for high-grade lymphomas. The prognosis of EBV-negative lymphomas is worse.Lowering the risk of PTLD may be achieved by low dose maintenance immunosuppression, immunosuppressive drugs inhibiting cell proliferation, and special immunotherapy (e.g. interleukin-2 inhibitors). Early detection is especially important for high risk-e.g. EBV-negative-patients, where the appearance of EBV-DNA and the increase in its titer may help.

The Effect of Tacrolimus on Time to Development of Post-Transplant Lymphoproliferative Disorder (PTLD).

AbstractAbstract 4500 Background:Post Transplant Lymphoproliferative Disorder (PTLD) is a rare but potentially fatal complication occurring after solid organ transplant. PTLD is divided pathologically into three subgroups: early lesions, polymorphic PTLD, and monomorphic PTLD. The severity of these complications ranges from reactive lymphoid hyperplasia to aggressive non-Hodgkin lymphoma and Hodgkin-like lymphoma. Most PTLD are of B cell lineage associated with infection or reactivation of Epstein Barr virus (EBV). Post-transplant patients on immunosuppressive therapy may lack sufficient cytotoxic T cells to clear EBV-infected B cells, allowing unchecked polyclonal B cell proliferation and infection of other cells with EBV. Immunosuppression with cyclosporine and tacrolimus has been associated with a higher risk for development of PTLD. This study examines the relationship between tacrolimus and PTLD among solid-organ transplant patients. Methods:Differences in time to PTLD between patients with and without exposure to tacrolimus were assessed using a retrospective, case-control design. University of Virginia Health System registry records were searched to identify all patients in the post- solid organ transplant population diagnosed with malignancy in the years 1998–2009. Bone marrow transplant patients were excluded. Following IRB approval, data was collected on the type of transplant, immunosuppressive regimen, time from transplant to development of PTLD, and lymphoma treatment; from electronic charts and pathology reports were reviewed. Results:A total of 2841 patients with solid organ transplants were identified, including1486 patients who received tacrolimus for immunosuppression. There were 26 cases of PTLD: 19 with exposure to tacrolimus (1.3%), and 8 without exposure (0.6%). The mean time to PTLD was 2.52 years (SD = 0.65) in the tacrolimus group, and was 6.75 years (SD = 1.80) among those not exposed. This difference in time to event was stat istically significant (Log-Rank = 5.347, p = .0208). Conclusion:In our population of post solid organ transplant patients with PTLD, exposure to tacrolimus was associated with significantly shorter time to development. Prospective studies are needed to better elucidate the relationship between type of immunosuppression and development of PTLD. These results suggest that immunosuppressive regimens using tacrolimus may be associated with increased risk of developing PTLD. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Post-Transplantation Lymphoproliferative Disorders: Diagnosis, Prognosis, and Current Approaches to Therapy

Post-transplantation lymphoproliferative disorders (PTLD) are a heterogenous group of abnormal lymphoid proliferations that occur after solid organ transplant (SOT) or hematopoietic transplantation. PTLDs consist of a disease spectrum ranging from hyperplasia to aggressive lymphomas with 60-70% being Epstein-Barr virus positive. The majority of cases are B-cell, although 10-15% are of T-cell origin or rarely Hodgkin lymphoma. Recent SOT series suggest PTLD occurs at a median of 36-40 months after transplant. Clinically, extra-nodal disease is common (up to 75-85%) including CNS involvement, which is seen in 10-15% of all cases. Since the first report over 40 years ago, PTLD has remained one of the most morbid complications associated with SOT. However, recent data suggests improved survival in the modern era, especially with the integration of early rituximab-based therapy. These studies utilized first line rituximab (+/- chemotherapy) together with reduced immune suppression (RI) for monomorphic and polymorphic PTLD. It will be critical in future studies to determine which PTLDs are most amenable to initial therapy with RI alone, versus RI/rituximab, versus RI/rituximab/chemotherapy. Additionally, novel therapeutics, such as adoptive immunotherapy, should continue to be explored.

Anti-Tumor Necrosis Factor Therapy for Inflammatory Bowel Disease Management in Liver Transplant Recipients

Purpose: Ulcerative colitis (UC) or Crohn's disease can be difficult to manage following orthotopic liver transplantation (OLT) despite conventional immunosuppressive therapy. We sought to evaluate the efficacy and safety of antitumor necrosis factor (anti-TNF) agents for the management of inflammatory bowel disease (IBD) following OLT. Methods: All patients with an established diagnosis of UC or Crohn's disease who underwent OLT at the Mayo Clinic between January 1, 1985 and December 30, 2009 were identified. Patients were included if they had received anti-TNF therapy post-OLT. Medical records were reviewed to obtain patient demographic, clinical, and outcomes data. Response was defined as a clinician's assessment of improvement after 12 weeks of usage and mucosal healing was defined as the absence of ulcerations on follow-up endoscopy. Results: Of the 8 patients identified, median age was 42 years and 38% were females. All patients had an IBD diagnosis prior to OLT, 3 with UC and 5 with Crohn's disease. Median IBD disease duration was 17 years (range, 5-48 years). All patients underwent OLT for primary sclerosing cholangitis (PSC), 3 also had cholangiocarcinoma. Three patients had received anti-TNF therapy before OLT, but no anti-TNF agents were continued at the time of OLT. Median time from OLT to anti-TNF usage was 3.5 years (range, 1-14 years). Agents administered included infliximab (n=4), infliximab followed by adalimumab (n=2), and adalimumab (n=2). Reasons for changing from infliximab to adalimumab included infusion reaction (n=1) and loss of response (n=1). The most common indications for anti-TNF agents were diarrhea (n=6), diarrhea with penetrating disease (n=1), and diarrhea with extra-intestinal disease manifestations (n=1). Clinical response was demonstrated in 7 of 8 patients with initial therapy. Of the two patients changed to adalimumab, only one demonstrated a clinical response (patient with infliximab allergy). Mucosal healing was demonstrated in 3 of 7 patients. Five patients were tapered off prednisone. Four infections in 3 patients were reported while on anti-TNF therapy, including oral candidiasis, Clostridium difficile colitis, pneumonia, and cryptosporidiosis. One individual developed an Epstein-Barr virus-positive polymorphic post-transplant lympho-proliferative disorder in the absence of depleting antilymphocyte therapy. No organ rejection was reported while on anti-TNF therapy. One death occurred due to complications from recurrent PSC. Conclusion: Initiation of anti-TNF therapy post-OLT appears to be an effective option for IBD management. Further studies are needed to adequately assess potential risks. Disclosure: Dr Bruining: Centocor-past research support.

Multiple Clinical Presentations of Lymphoproliferative Disorders in Pediatric Liver Transplant Recipients: A Single-Center Experience

Posttransplantation lymphoproliferative disorder (PTLD) is a serious complication following solid organ transplantation that has been linked to Epstein-Barr virus (EBV) infection. The aim of this article was to describe a single-center experience with the multiplicity of clinical presentations of PTLD. Among 350 liver transplantations performed in 303 children, 13 survivor children displayed a histological diagnosis of PTLD (13/242 survivors; 5.4%). The age at diagnosis ranged from 12 to 258 months (median, 47), and the time from transplantation ranged from 1 to 84 months (median, 13). Ten of these children (76.9%) were EBV-naïve prior to transplantation. Fever was present in all cases. The clinical signs at presentation were anemia (92.3%), diarrhea and vomiting (69.2%), recurrent upper airway infections (38.4%), Waldeyer ring lymphoid tissue hypertrophy (23.0%), abdominal mass lesions (30.7%), massive cervical and mediastinal adenopathy (15.3%), or gastrointestinal and respiratory symptoms (30.7%). One child developed fulminant hepatic allograft failure secondary to graft involvement by PTLD. Polymorphic PTLD was diagnosed in 6 patients; 7 had the diagnosis of lymphoma. Treatment consisted of stopping immunosuppression as well as starting intravenous gancyclovir and anti-CD20 monoclonal antibody therapy. The mortality rate was 53.8%. The clinical presentation of PTLD varied from fever of unknown origin to fulminant hepatic failure. The other symptoms that may be linked to the diagnosis of PTLD are pancytopenia, tonsil and adenoid hypertrophy, cervical or mediastinal lymph node enlargement, as well as abdominal masses. Despite numerous advances, the optimal treatment approach for PTLD is not completely known and the mortality rate is still high.