Monomorphic Histology Research Articles

The Changing Face of Adult Posttransplant Lymphoproliferative Disorder: Dramatic Changes in Histology between 1999-2013

INTRODUCTION: Posttransplant lymphoproliferative disorder (PTLD) typically presents with either polymorphic or monomorphic histology. While both are the end result of immunosuppressive therapies, their origins are felt to be different, resulting in two distinct malignancies with different prognoses and responsiveness to therapy. We attempted to confirm reports suggesting that the relative frequency of these two histologies is shifting over time.METHODS: 3,040 adult PTLD cases in the United Network for Organ Sharing database from 1999 to 2013 were included. We analyzed changes in PTLD histology over time and used a multivariate logistic regression model to determine factors associated with monomorphic versus polymorphic histology.RESULTS: We found that the relative proportion of polymorphic vs. monomorphic histology has changed with an increase in the proportion of monomorphic cases with time (1999-2003, 54.9% vs. 45.1%; 2004-2008, 58.3% vs. 41.7%; 2009-2013, 69.7% vs. 30.3%; p<0.001) (see figure). The change in proportion is driven by a gradual increase in the number of monomorphic PTLD cases (1999-2003, 460 cases; 2004-2008, 597 cases; 2009-2013, 821 cases), with a steady number of polymorphic PTLD cases (1999-2003, 378 cases; 2004-2008, 427 cases; 2009-2013, 357 cases), and was most prominent in recipients who were EBV serostatus positive at the time of transplant. Significant changes in the care and outcomes of solid organ transplant patients occurred during this time period, including changes from cyclosporine based immunosuppressive regimens to tacrolimus based regimens and increased survival of allografts and patients. Multivariate logistic regression revealed that tacrolimus use (p=0.034) and increased survival among transplant patients leading to later occurrence of PTLD (p<0.001) were associated with monomorphic PTLD during the time frame analyzed.CONCLUSION: As the practice of organ transplantation has evolved over time, PTLD has coevolved, shifting from predominately polymorphic to monomorphic histology. These changes in histology have important implications regarding the origin and clinical management of PTLD. [Display omitted] DisclosuresHuntington:Celgene: Consultancy, Other: Travel; Janssen: Consultancy; Pharmacyclics: Honoraria. Schuster:Genentech: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Seattle Genetics: Consultancy; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Nordic Nanovector: Consultancy; Merck: Research Funding.

The changing face of adult posttransplant lymphoproliferative disorder: Changes in histology between 1999 and 2013.

Posttransplant lymphoproliferative disorder (PTLD) typically presents with either polymorphic or monomorphic histology. While both are the end result of immunosuppressive therapies, their origins are felt to be different with different prognoses and responsiveness to therapy, resulting in 2 different malignancies. We attempted to confirm reports suggesting that the relative frequency of these 2 histologies is shifting over time. We analyzed 3040 adult PTLD cases in the UNOS OPTN database from 1999 to 2013. Changes in PTLD cases over time were analyzed for histology, time from transplant to diagnosis, and patient EBV serostatus. We found that the relative proportion of polymorphic versus monomorphic histology has changed with an increase in the proportion of monomorphic cases with time (1999-2003, 54.9% vs. 45.1%; 2004-2008, 58.3% vs. 41.7%; 2009-2013, 69.7% vs. 30.3%; P = <.001). The change is driven by a gradual increase in the number of monomorphic PTLD with a steady number of polymorphic PTLD. The change is most strongly seen in transplant recipients who were EBV serostatus positive at the time of transplant. Potential causes are changes in immunosuppressive regimens with increased tacrolimus use (P = .009) and increased survival among transplant patients leading to later occurrence of PTLD (P = .001) that have occurred during the time frame analyzed. As organ transplantation has evolved over time, PTLD has coevolved. These changes in histology have important implications regarding the origin and clinical management of PTLD.

Tratamiento de la enfermedad linfoproliferativa post-trasplante renal con Rituximab y conversión a inhibidor m-TOR.

Antecedente:La enfermedad linfoproliferativa post-trasplante es una complicación grave del trasplante de órganos cuyo tratamiento aún no se encuentra estandarizado.Objetivo:Describir la respuesta clínica, supervivencia global y del injerto en pacientes con esta complicación post trasplante renal en nuestro centro y que recibieron rituximab como parte de su tratamiento y la conversión a m-TOR.Métodos:Estudio retrospectivo que incluyó pacientes con diagnóstico de enfermedad linfoproliferativa postrasplante renal entre enero de 2011 y julio de 2014.Resultados:Se encontraron ocho casos, con presentaciones clínicas variables. La mayoría correspondieron a histología monomórfica, en 85% se asoció con virus de Epstein-Barr, 25% de los pacientes tenían compromiso tumoral del injerto renal y 12.5% linfoma primario de sistema nervioso central. Todos los pacientes se manejaron con reducción de inmunosupresión, conversión a m-TOR (excepto uno que perdió el injerto al diagnóstico) y tratamiento basado en rituximab. La tasa de respuesta global fue del 87.5% (62.5% respuesta completa, 25% respuesta parcial). La supervivencia fue del 87.5% con una mediana de seguimiento de 34 meses. Un paciente adicional perdió el injerto renal, con nefropatía crónica ya conocida. Los pacientes restantes con función renal estable.Conclusiones:No existen esquemas estandarizados de tratamiento para la enfermedad linfoproliferativa post-trasplante renal, pero estos pacientes pueden ser manejados de forma exitosa con reducción de la inmunosupresión, conversión a m-TOR y esquemas basados en rituximab.

CD3 T-Cell Infiltrates at Diagnosis Predicts Overall Survival in Solid Organ Transplant Recipients with Post-Transplant Lymphoproliferative Disorders (PTLD)

IntroductionThe host immune status is central to both the pathogenesis and treatment of Post-Transplant Lymphoproliferative Disorders. (PTLD) The most commonly used prognostic model for PTLD, the International Prognostic Index (IPI), currently does not account for the effect of immune status on patient outcomes. We hypothesize that CD3 positive T-cell infiltrate density in the tumor microenvironment, thought to be a surrogate of the potency of the host versus tumor immune response, may be prognostic of overall survival in PTLD.MethodsA database consisting of 131 biopsy confirmed PTLD cases occurring in pediatric and adult solid organ transplant recipients after the year 2000 in Alberta, Canada was analyzed for clinical prognostic variables and overall survival. CD3 infiltrate was determined by a blinded pathologist (JZ) using a standardized integer scoring system (0 - 3) to quantify CD3-positive cells in archived, formalin-fixed paraffin embedded tissue stained by immunohistochemistry. Tissue was available and assessed on a total of 72 patients. Survival analysis was done by Cox regression, with between group differences tested by a Pearson’s chi-square test, with p < 0.05 being taken as significant.ResultsMedian age at diagnosis was 40.2 years. Histology subtypes included early (n = 7), polymorphic (n = 17), monomorphic, (n = 100) Hodgkin, (n = 8) and unavailable. (n = 2) Immune suppression regimens at diagnosis included tacrolimus + mycophenolate (n = 29), tacrolimus + azathioprine (n = 11), cyclosporine + mycophenolate (n = 14), cyclosporine + azathioprine (n = 4), single agent tacrolimus (n = 11), single agent cyclosporine (n = 2), and other immunosuppressive regimens. (n = 4)A denser CD3 T-cell infiltrate, defined as a CD3 score of 2-3, had a statistically significant protective effect by univariate Cox regression with respect to overall survival. (HR 0.352, p = 0.008) A CD3 score of 2-3 was negatively associated with a monomorphic histology (p < 0.001), but was not statistically associated with lymphocyte count, early PTLD, EBV status or bone marrow involvement. In the diffuse large B-cell type PTLD subgroup (n = 61) the association of a dense CD3 T-cell infiltrate with an improved OS was preserved. (HR 0.276, p = 0.041)Clinical factors identified as significant by univariate Cox regression with respect to overall survival included age < 18 (HR = 0.380, p = 0.010), monomorphic histology (HR = 2.287, p = 0.02), IPI 3-5 (HR = 3.697, p < 0.001), BM involvement (HR 2.437, p = 0.008), and lymphocyte count < 1.0. (HR 2.449, p = 0.001) Clinical factors deemed to not be significant with respect to overall survival by univariate Cox regression included CD20 (p = 0.730), thoracic transplant organ (p = 0.314), PTLD onset within 1 year of transplant (p = 0.763), allograft involvement (p = 0.253), albumin of < 30 (p = 0.062) and tumor EBV status. (p = 0.278)Multivariate Cox regression with respect to overall survival, including monomorphic histology, IPI 3-5, lymphocyte count < 1.0 and CD3 score of 2-3 again showed a statistically significant protective effect of a higher CD3 score. (HR 0.307, p = 0.022) No other clinical variables reached significance in the multivariate analysis.ConclusionsA dense CD3 T-cell infiltrate in the tumor microenvironment at diagnosis is protective with regards to overall survival in PTLD by both univariate and multivariate Cox regression, versus traditional clinical prognostic markers. This is reflective of the prognostic importance of the host immune response, which can be altered by changes in exogenous immunosuppression. In the future, validated histologic measures of immune status such as the CD3 score may be integrated into existing models, such as the IPI, to provide additional prognostic power in PTLD. [Display omitted] [Display omitted] [Display omitted] DisclosuresOwen:Janssen: Honoraria; Gilead: Honoraria, Research Funding; Pharmacyclics: Research Funding; Celgene: Honoraria, Research Funding; Abbvie: Honoraria; Lundbeck: Honoraria, Research Funding; Novartis: Honoraria; Roche: Honoraria, Research Funding.

Post-Transplant Diffuse Large B Cell Lymphoma with Non Germinal Center B-Cell Subtype Frequently Lacks Programmed Cell Death Ligand (PD-L1) Overexpression Which May Influence Overall Outcomes

Background : Post Transplant Lymphoproliferative disorder (PTLD) represents a distinct and rare complication following solid organ transplantation (SOT). Insight into the biology of this disorder is limited to retrospective reviews and case series. In one of the first reports for post-transplant Diffuse Large B cell Lymphoma (PT-DLBCL) cases, we demonstrated a higher incidence and improved outcomes in PT-DLBCL non-germinal center B-cell (non-GCB) subtype compared to PT-DLBCL germinal center B-cell (GCB) Subtype. Published data suggests immunocompetent DLBCL non-GCB subtypes are less common and fare worse than immunocompetent GCB DLBCL. The reason for this unexpected finding in our PT-DLBCL pts is not fully understood. Recently Kiyasu and colleagues demonstrated that PD-L1 overexpression was significantly associated with non-GCB DLBCL, EBV virus positivity and poor prognosis in immunocompetent DLBCL samples. Therefore based on this we hypothesized that PT-DLBCL non-GCB subtype may have negative PD-L1 overexpression thus possibly accounting for improved outcomes compared to their immunocompetent counterparts. Hence we sought to test PD-L1 expression in our samples with PT-DLBCL.Methods: With IRB approval, we retrospectively identified PT- DLBCL patients treated at the University of Colorado between Jan 1989 to April 2015. We retrieved formalin fixed paraffin embedded PT-DLBCL tissue specimens and determined cell of origin by the Hans Algorithm. We assessed PD-L1 expression by immunohistochemistry. PD-L1 positive PT-DLBCL was defined as 30% of more of the lymphoma cells showing distinct membranous and or cytoplasmic staining. In addition EBER-ISH was performed to assess EBV status.Results: 86 adult SOT pts with PTLD were treated at our institution. 75 of 86 pts (87%) had monomorphic histology. Among monomorphic PTLD, 64% (48 of 75) had DLBCL. The median age at transplantation was 49.5 yrs (5-74 yrs). Median time from SOT to PTLD was 37 mos (1.4-499). The most common transplanted organ included kidney (40%), liver (38%), lung (13%) and heart (9%). 31% had early PTLD (<12mos of SOT) and 69% had late PTLD (>12mos of SOT). 60% were EBV positive. 77% with early PTLD and 49% with late PTLD were EBV positive. Due to a paucity of archived tissue blocks, IHC staining was applied to 32/48 samples with DLBCL. Non-GCB subtype was identified in 75% (24/32) samples and GCB subtype in 25% (8/32) samples.Of the 48 pts with PT-DLBCL histology, PD-L1 stain was performed on 18 samples. Of the 18 PT-DLBCL samples, 77% (14/18) had non-GCB subtype and 16% (3/18) had GCB subtype. PD-L1 expression was negative in 78% (11/14) and positive in 22% (3/14) of non-GCB DLBCL samples. PD-L1 expression was negative in 100% (3/3) of GCB DLBCL samples. The sample size was too small to effectively describe the survival experience of pt subsets. Using Fisher's exact test we found no evidence to support an association between EBV Status and PDL1 expression (p-value 0.316).Conclusions: We previously reported in our consecutive series of PTLD after SOT an increased incidence and improved survival in pts with PT-DLBCL non-GCB subtype (ASH 2015) compared to PT-DLBCL GCB subtype. The reason for this is not fully understood. However, our limited series reveals that a majority of pts with PT- DLBCL non-GCB subtype was negative for PD-L1 overexpression. This might explain the improved outcomes in the PT-DLBCL non-GCB population. Despite a small sample size it is also interesting to note that 100% pts with PT-DLBCL GCB subtype were negative for PD-L1 overexpression. In the era of immunotherapy further studies in larger patient cohorts are warranted in order to understand the unique biology and outcomes of PT-DLBCL since it may have therapeutic implications. DisclosuresPollyea:Celgene: Other: advisory board, Research Funding; Ariad: Other: advisory board; Alexion: Other: advisory board; Pfizer: Other: advisory board, Research Funding; Glycomimetics: Other: DSMB member. Kamdar:Seattle Genetics: Speakers Bureau.

Recurrent NTRK1 Gene Fusions Define a Novel Subset of Locally Aggressive Lipofibromatosis-like Neural Tumors

The family of pediatric fibroblastic and myofibroblastic proliferations encompasses a wide spectrum of pathologic entities with overlapping morphologies and ill-defined genetic abnormalities. Among the superficial lesions, lipofibromatosis (LPF), composed of an admixture of adipose tissue and fibroblastic elements, in the past has been variously classified as infantile fibromatosis or fibrous hamartoma of infancy. In this regard, we have encountered a group of superficial soft tissue tumors occurring in children and young adults, with a notably infiltrative growth pattern reminiscent of LPF, variable cytologic atypia, and a distinct immunoprofile of S100 protein and CD34 reactivity, suggestive of neural differentiation. SOX10 and melanocytic markers were negative in all cases tested. In contrast, a control group of classic LPF displayed bland, monomorphic histology and lacked S100 protein immunoreactivity. To define the pathogenetic abnormalities in these seemingly distinctive groups, we performed RNA sequencing for fusion gene discovery in 2 cases each, followed by screening for any novel alterations identified in a larger cohort representing both entities. The 2 index LPF-like neural tumors (LPF-NT) showed TPR-NTRK1 and TPM3-NTRK1 gene fusions, which were further validated by fluorescence in situ hybridization (FISH) and reverse transcription polymerase chain reaction. Subsequent FISH screening of 14 LPF-NT identified recurrent NTRK1 gene rearrangements in 10 (71%) cases. Of the NTRK1-negative LPF-NT cases, 1 case each showed ROS1 and ALK gene rearrangements. In contrast, none of the 25 classic LPFs showed NTRK1 gene rearrangements, although regional abnormalities were noted in the 1q21-22 region by FISH in a majority of cases. Furthermore, NTRK1 immunostaining was positive only in NTRK1-rearranged S100-positive LPF-NT but negative in classic LPF. These results suggest that NTRK1 oncogenic activation through gene fusion defines a novel and distinct subset of soft tissue tumors resembling LPF, but displaying cytologic atypia and a neural immunophenotype, provisionally named LPF-like neural tumors.

IHC Analysis and Prognostic Factors in Post Transplant Lymphoproliferative Disorders after Solid Organ Transplantation: A Single Center Experience

Post Transplant Lymphoproliferative Disorder (PTLD) represents one of the most fatal complications following solid organ transplants (SOT). A multicenter analysis in 2010 reported a 3yr overall survival (OS) of 62%. In 2014 a single institutional study reported an improved median OS of 8 years in the rituximab era. Clinical studies have attempted to subdivide post transplant diffuse large B cell lymphomas (PT-DLBCL) into immunophenotypic subgroups with most reviews demonstrating a higher incidence of activated B-cell (ABC) subtype. Because of the rarity of PTLD, insight into disease development and progression is currently limited. We examined the clinical features and outcomes based on immunohistochemical (IHC) analysis in consecutive PTLD pts treated at the University of Colorado over a 25-year period.Methods: This retrospective analysis focused on 52 adult SOT pts who were treated for PTLD at our institution between Jan 1989 to April 2015.Results: 52 pts were analyzed. The median age at transplantation was 47.5 years (5-73yrs) and the median time from SOT to PTLD was 52.5 months (2.6 to 251). The most common transplanted organ included liver (46%), kidney (40%), heart (10%), lung (2%) and [kidney pancreas] (2 %). The grafted organ was involved in 10 pts (19%)Males comprised 67%, 63% were Stage III-IV, 69% were EBV positive, 23% had extranodal involvement, 19% had bone marrow involvement and 21% had CNS involvement. Of the 52 patients, 46 (88 %) had monomorphic histology. Amongst monomorphic PTLD 31 pts (60%) had DLBCL, 6 pts (14%) had Burkitt Lymphoma, 4 pts (9%) had CNS lymphoma, 1 pt (2%) had plasmablastic lymphoma, 1 pt (2%) had NK/T cell lymphoma and 1 pt (2%) had aggressive B cell lymphoma unclassifiable. Of the analyzed pts 85% were CD20 positive, 77 % had elevated LDH and 49% had an International Prognostic Index (IPI) > 1. Thirty Eight pts (73%) were on >1 immunosuppressive agent with a median immunosuppressive treatment duration of 36 months (range 0.25 to 23 yrs).All pts (100%) diagnosed within 12 months of SOT were EBV positive. Similarly all pts (100%) diagnosed 12 months after were EBV negative.Initial treatments included reduction in immunosuppression in 63% pts, rituximab monotherapy in 28% pts and chemotherapy in 53% pts. 67% of pts received rituximab either alone or in combination with chemotherapy. 48 of 52 pts were assessable for response; 4 pts were lost to follow up. 64% achieved a complete remission after first line therapy while 12% were refractory to front line therapy. 7 of 48 pts (14%) pts relapsed with a median time of 60 months (2yrs-15yrs). IHC staining utilizing the Hans Algorithm was applied on 20/31 pt samples with DLBCL. ABC subtype was identified in 70% (14/20) and GC (germinal center B-cell) subtype in 30% (6/20) samples.Median overall survival was 69 months (Figure 1).On univariate analysis CNS disease (HR 2.82, 95% CI 1.25- 6.3, p= 0.01), pts who received chemotherapy (HR 6.65, 95% CI 1.63-27.04, p= 0.008), graft involvement with PTLD (HR 2.63, 95% CI 1.01-6.86, p=0.04) and IPI > 1 (HR: 3.55; 95% CI: 1.47 - 8.57, p= 0.005) were associated with poor survival whereas EBV positivity (HR .25, 95% CI 0.10-0 .64, p= 0.005) was associated with improved survival. Advanced stage (Stage III-IV), high LDH, monomorphic histology, ABC DLBCL subtype, more than 1 immunosuppressive agents and rituximab treatment were not statistically significant parameters for survival.In multivariate analysis, EBV positivity was predictive of improved survival (p=0.006) while graft organ involvement (p=0.02) and chemotherapy administration (0.013) was associated with poor overall survival.Conclusion:In this consecutive series of PTLD after SOT from a single institution over a 25 year period, EBV positivity was associated with improved survival whereas graft organ involvement and chemotherapy was associated with poor outcomes. Similar to previously published data, in PT-DLBCL cases we were not able to demonstrate a definite association between histogenetic phenotype and prognosis. However we found 70% of PT-DLBCL samples to have an ABC subtype (Figure 2). The reason for this increased predilection is not fully understood. ABC subtype is known to have an inferior overall survival compared to GCB DLBCL which could explain the relatively poor outcomes in PT-DLBCL patients. This merits further studies in larger patient cohorts due to potential therapeutic implications. [Display omitted] [Display omitted] DisclosuresPollyea:Ariad: Consultancy; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlycoMimetics: Other: Member of data safety monitoring board; Karyopharm: Consultancy; Pfizer: Consultancy.

The Impact of EBV Status on Characteristics and Outcomes of Posttransplantation Lymphoproliferative Disorder

We examined the associations of Epstein-Barr virus (EBV) status with characteristics and outcomes of posttransplantation lymphoproliferative disorder (PTLD) by studying 176 adult solid organ transplant recipients diagnosed with PTLD between 1990 and 2013 (58 [33%] EBV-negative; 118 [67%] EBV-positive). The proportion of EBV-negative cases increased over time from 10% (1990-1995) to 48% (2008-2013) (p < 0.001). EBV-negative PTLD had distinct characteristics (monomorphic histology, longer latency) though high-risk features (advanced stage, older age, high lactate dehydrogenase, central nervous system involvement) were not more common compared to EBV-positive PTLD. In multivariable analysis, EBV negativity was not significantly associated with worse response to initial therapy (adjusted odds ratio, 0.84; p = 0.75). The likelihood of achieving a complete remission (CR) was not significantly different for EBV-negative versus EBV-positive PTLD including when therapy was reduction of immunosuppression alone (35% vs. 43%, respectively, p = 0.60) or rituximab (43% vs. 47%, p = 1.0). EBV negativity was also not associated with worse overall survival (adjusted hazard ratio, 0.91; p = 0.71). Our findings indicate that EBV status is not prognostic or predictive of treatment response in adults with PTLD. The high proportion of EBV-negative disease diagnosed in recent years highlights the need for new strategies for prevention and management of EBV-negative PTLD.

Epstein-Barr virus-positive diffuse large B-cell lymphoma in children: a disease reminiscent of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly.

Pediatric Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (EBV+ DLBCL) is a rare disease in nonimmunocompromised hosts. In a review of 231 cases of malignant lymphoma (87 Hodgkin lymphoma and 144 non-Hodgkin lymphoma) occurring in Iraqi children, 7 cases (5% of NHLs) were classified as EBV+ DLBCL. Six children presented with nodal disease, and 1 presented with extranodal localization (bone). In all cases, the disease was at an advanced clinical stage (III/IV). Evidence of immunodeficiency (Evans syndrome and selective IgA deficiency) was observed in a single case. Two cases were "monomorphic" with immunoblastic histology, and 5 cases were "polymorphic" with histologic aspects reminiscent of nodular lymphocyte-predominant Hodgkin lymphoma (2 cases) and of CD30+ classical Hodgkin lymphoma (3 cases). In all cases, tumor cells were EBV infected (EBER+/LMP-1+), were medium-large B-cells (CD20+/CD79a+/PAX-5+/BOB-1+/OCT-2+) of non-germinal center (non-GC) origin (CD10-/MUM-1+), and had high proliferative activity (50%-70%). Chromosomal translocations involving BCL2, MYC, and IGH genes were not observed. IGH monoclonality could be demonstrated in 3 of 3 investigated cases. Six cases of EBV-negative DLBCL (4% of NHL) were present in the same series. All had monomorphic histology with centroblastic/immunoblastic morphology; 3 cases were of GC type and 3 of non-GC type. Our findings indicate that in Iraq, DLBCLs are 9% of NHLs. Moreover, 2 different types of the disease do exist; the EBV-positive cases, with strong histologic and immunohistochemical resemblance with EBV+ DLBCL of the elderly, and the EBV-negative cases, which are similar to the pediatric DLBCL usually observed in Western populations.

Double Pathology: Malignant Epithelial Ovarian Tumor and Germ Cell Tumor (Choriocarcinoma), a Rare Coexistence

Surface epithelial stromal tumors account for approximately 60% of all ovarian tumors and approximately 90% of all ovarian malignancies. Sex cord stromal tumors account for 7% of all malignant ovarian tumors. Germ cell tumors make up only 3-7% of malignant ovarian tumors. A combination of serous carcinoma of the ovary and choriocarcinoma is rare. Until today such combination has been documented only in six cases in the English literature. Here, we describe a case of ovarian serous carcinoma, where histopathology revealed a combination of serous carcinoma with adjacent choriocarcinoma component in the extraovarian peritoneal deposits. A 64-year-old post-menopausal female was diagnosed to have stage IV ovarian cancer. She received six cycles chemotherapy. Subsequently she underwent optimal cytoreductive surgery. Microscopically, monomorphic histology (serous carcinoma) was noted in both the ovaries and dimorphic histologies (serous carcinoma and choriocarcinoma) in the sigmoid mesocolon nodule, omentum and left subdiaphragmatic nodules. Metronomic chemotherapy continued and patient is on regular follow-up for the past 1 year with stable disease. Recognition of choriocarcinomatous components in ovarian carcinomas is important because of its association with aggressive behavior. In spite of the aggressive histology, the patient is surviving for the past 1 year. Different chemotherapeutic regimens have been used in cases of mixed choriocarcinoma and carcinoma, but established chemotherapeutic regimens have not been described. Chemotherapeutic regimens that target both components have been advocated and used. The absence of choriocarcinoma in ovarian primary and its presence in the extraovarian peritoneal deposits have not been described in the English literature so far. This case is being presented for its rarity.

Post Transplant Lymphoproliferative Disorders (PTLD) after Solid Organ Transplant: Cleveland Clinic Experience

Background: Post transplant lymphoproliferative disorders (PTLD) are rare pathologically and clinically heterogeneous diseases arising in the setting of immunosuppression following hematopoietic stem cell and solid organ transplants (SOT). Our understanding of PTLD is restricted by its low incidence and heterogeneous treatment approaches, resulting in paucity of data. We sought to further describe characteristics and outcomes in PTLD patients who underwent treatment at our institution.Methods and Patients: We performed a retrospective study to describe our institutional experience in a relatively large cohort of PTLD patients after SOT. Patient and disease characteristics were examined and prognostic factors for survival were determined using univariate and multivariate Cox analysis.Results: Between May 1987 to January 2014, 98 patients with a confirmed diagnosis of PTLD underwent treatment at our institution. Median time from SOT to PTLD diagnosis was 60 months with median follow of 68 months from PTLD diagnosis. Baseline characteristics include male gender 77%, ECOG performance status (PS) 0-1 in 61%, and stage III-IV 69% with a median age at diagnosis of 47 years. Most common transplanted organ included heart 30%, lung 24%, kidney 20% and liver 19% and median time from SOT to PTLD diagnosis was 60 months. Most cases had monomorphic histology (81%) and were EBV+ (82%). Graft involvement and rejection were observed in 32% and 43% respectively. Of the 84% with extranodal (EN) involvement, gastrointestinal tract (37%) and lung (27%) were the common sites, while 3.2% had bone marrow (BM) involvement. Central nervous system (CNS) was involved in 11% of the cases. Only 58% received rituximab as part of the initial therapy, as significant part of our cohort was treated prior to rituximab era. Reduction in immunosuppression (73%), chemotherapy (40%), radiation (11%) and surgery (8%) were utilized either as single modality or in combination for treatment. Of the 66 patients with response data, 59% had complete response (CR) and 14% had progressive disease (PD). Relapse occurred in 23% of cases. Median overall survival (OS) from diagnosis of PTLD was 6 years (Figure 1), but in rituximab treated patients it was 8 years. On univariate analysis, higher age at diagnosis (HR 1.19, 95% CI 1.01-1.40, p=0.033), lung transplant (HR 2.42, 95% CI 1.36-4.33, p=0.003), higher IPI (HR 1.83, 95% CI 1.40-2.39, p=<0.001), decreased PS (HR 2.43, 95% CI 1.70-3.48, p=<0.001), and platelet count <200,000 (HR 2.84, 95% CI 1.27-6.33, p=0.011) were associated with lower OS, whereas liver transplant (HR 0.24, 95% CI 0.09-0.68, p=0.007) and GI involvement (HR 0.47, 95% CI 0.24-0.95, p=0.036) predicted better OS. Rituximab treatment (Figure 2) and achieving CR were associated with better OS. Histology, EN involvement, and EBV status were not significant predictors for survival. On multivariate analysis only lung transplant, IPI, and PS were predictive for OS. Lung transplant patients had a higher risk of mortality compared to other SOT (HR 2.63, 95% CI 1.39-4.95, p=0.003). Both higher IPI (HR 1.66, 95% CI 1.18-2.32, p=0.003) and poor PS (HR 1.94, 95% CI 1.27-2.96, p=0.002) were associated with inferior OS.Conclusions: In this large cohort of PTLD patients after SOT, lung transplants, higher IPI and poor PS were identified as poor prognostic factors for OS on both univariate and multivariate analysis. Rituximab treatment was a favorable prognostic factor for OS that resulted in prolonged survival observed in this cohort. [Display omitted] [Display omitted] DisclosuresHill:Millenium: Research Funding; Novartis: Research Funding.

Outcomes With Rituximab Monotherapy Versus R-CHOP In Post-Transplant Lymphoproliferative Disease Arising After Solid Organ Transplant: A Multicentre UK Study

▪Post-transplant lymphoproliferative disease (PTLD) remains an important complication of solid organ transplantation. For B-cell PTLD, current first line therapies are Rituximab monotherapy (R-Mono) or R-CHOP. However, optimal selection of initial treatment is challenging due to concerns about the relative efficacy and toxicity of these modalities, and because of uncertainty about the prognostic value of baseline factors.This retrospective study identified 72 biopsy-proven cases of PTLD, diagnosed between 2000 and 2012, from 4 UK centres. These included 34 liver, 32 renal and 6 cardiothoracic transplant recipients. The median age at histological diagnosis was 47 years (range 16 - 72 years) and 68% were male. The median time from transplant to diagnosis of PTLD was 93 months (range 2 – 302 months), with 83% of cases occurring after 1 year. Tumour histology included 14 polymorphic and 49 monomorphic lesions (including 34 diffuse large B-cell, 5 plasmablastic, 4 Hodgkin and 1 T-cell lymphomas) whilst in 9 cases the PTLD subtype was unspecified. EBV-association was noted in 39/72 (54%) and this was significantly related to disease presenting within a year of transplant (X2 p=0.004).Initial therapy was R-Mono in 16/72 (22%) and R-CHOP in 34/72 (47%). Selection of R-CHOP versus R-Mono was significantly associated with stage ≥3 disease (odds ratio [OR] 6.7, p=0.01), onset more than 1 year after transplant (OR 7.3, p=0.03), lack of EBV association (OR 0.1, p=0.002) and monomorphic versus polymorphic histology (OR 14.0, p=0.004). In a multivariate logistic model, advanced stage (OR 11.0, p=0.06) and monomorphic histology (OR 8.5, p=0.03) retained significance.Of patients who received R-Mono, 15/16 (94%) completed at least 4 infusions, with no treatment-related deaths. Of these, 4 patients subsequently received R-CHOP for consolidation of response (2 patients) or for relapsed / refractory disease (2 patients). Of those who received R-CHOP as initial therapy, 23/34 (68%) completed at least 6 cycles, with 4 treatment-related deaths.The overall response rate to R-Mono was 81% (10 CR [complete remission], 3 PR [partial remission] and 3 NR [no remission]), similar to that of R-CHOP at 74% (19 CR, 6 PR, 5 NR and 4 undetermined; X2 p=0.67). With a median follow-up of 38 months, survival outcomes for R-Mono and R-CHOP were 2 year Event-Free Survival of 62% and 54% (p=0.77), 2 year Progression-Free Survival of 67% and 58% (p=0.48) and 2 year Overall Survival (OS) of 74% and 59% (p=0.52; Figure 1A) respectively.Amongst all study patients, significant baseline predictors of (inferior) OS were age ≥50 years (HR 2.9, p=0.006), stage ≥2 disease (HR 4.9, p=0.003), ECOG performance status ≥2 (HR 2.1, p=0.05), and elevated LDH (HR 2.2, p=0.08 borderline significance). Extra-nodal disease, histology, EBV-association and time from transplant were not predictive. In multivariate analysis, age>50 (HR 3.2, p=0.01) and advanced stage (HR 4.0, p=0.02) retained significance. Importantly, amongst those treated with R-Mono or R-CHOP, response to initial therapy was highly predictive of OS (overall response, HR 0.2, p<0.0001; complete response, HR 0.1, p<0.0001).Applying a 4 point modified prognostic index comprised of age>50, stage ≥2 disease, ECOG performance status ≥2 and elevated LDH, patients treated with R-Mono or R-CHOP with low risk disease (<2 points) had significantly improved survival compared to those with high risk disease (≥2 points), with 2 year OS of 90% versus 43% (p=0.001, Figure 1B). Notably, comparison of outcomes for R-Mono versus R-CHOP within high risk or low risk groups revealed no significant differences in survival. However, there was a trend towards inferior response amongst patients with high risk disease treated with R-Mono compared to R-CHOP (CR rate 1/6 [17%] versus 9/16 [56%]; X2 p=0.16), which was not observed for low risk disease.We report outcomes for R-Mono versus R-CHOP as initial therapy for PTLD arising after adult solid organ transplantation. Whilst R-CHOP is associated with greater toxicity, R-Mono may deliver inferior response rates in patients with high risk disease. Survival outcomes were not significantly different between therapies. Importantly, using a modified prognostic index we identify a subset of patients with high risk disease who exhibit very poor outcome, irrespective of initial treatment, for whom novel therapeutic strategies are urgently required. [Display omitted] Disclosures:Chaganti:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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&lt;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&lt;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.

Lymphopenia and EBER-Negativity Predict Poor Survival in Patients with Post-Transplant Lymphoproliferative Disorder (PTLD) Treated in the Rituximab Era

Abstract 1645Post-transplant lymphoproliferative disorders (PTLD) are an important complication of solid organ transplant (SOT) with a high mortality rate. PTLD represents a spectrum of disease thought to be driven by Epstein Barr virus (EBV) and ranges from indolent polyclonal lymphoproliferation to aggressive lymphoma. Therapeutic options include reduction of immunosuppression (RIS), antiviral therapy, anti-CD20 monoclonal antibody rituximab, and combination chemotherapy, but no previous studies have reliably determined a risk-stratified approach. Several prognostic factors have been reported previously but are not well-defined in patients treated with rituximab. The objective of this study was to analyze a cohort of patients diagnosed with PTLD in the rituximab era to determine clinical and laboratory prognostic factors and survival outcomes.We retrospectively reviewed outcomes of all adult patients who developed PTLD after 1998 following SOT at the University of Alberta (n=52). Prognostic factors for overall survival (OS) were analyzed using the Kaplan-Meier method and the logrank test.The median age at PTLD diagnosis was 52 years (range 19–74) and the median time from SOT to PTLD diagnosis was 4.7 years (109 days-20.9 years). Other patient characteristics are listed in Table 1. The majority of patients had PTLD over 1 year post-SOT (75%), monomorphic histology (69%) and were CD20 positive (63%). All patients were treated with RIS and antivirals if EBV viremia was detected by PCR. The majority of patients (n=34, 65%) received first-line rituximab at 375 mg/m2 IV with 4 weekly doses planned; 6 of these patients (12%) required further chemoimmunotherapy progressed or died before completing 4 doses, and 13 patients (38%) progressed and required further therapy after completing 4 doses. Sixteen patients (47%) achieved at least a partial response (PR) to rituximab monotherapy. Of the 18 patients who did not receive rituximab monotherapy, 3 received first-line chemoimmunotherapy, 5 received chemotherapy alone, and 10 had an unknown history of therapy. All patients who did not receive rituximab were CD20 negative.Table 1Patient characteristicsn=52Patient characteristicsn=52Organ transplantedPTLD ≤ 1 yr post-SOT13Kidney19EBV serology mismatch12Lung17CMV serology mismatch12Liver9EBV viremia (at dx)10Heart5EBER+28Pancreas1CD20+33>1 SOT pre-PTLD12Monomorphic histology36Tumour histologyIPI score 3–520Diffuse large B cell lymphoma23Age >6015B cell lymphoma4ECOG >216Primary CNS lymphoma1>1 extranodal site21Intravascular B cell lymphoma1LDH elevated18Burkitt lymphoma1Hemoglobin <120 g/L29Hodgkin lymphoma4Lymphs <1.2x109/L26T cell lymphomas6Allograft involvement9Polymorphic PTLD4CNS involvement6Unknown8BM involvement6The median OS of the whole cohort was 1.99 years (range 3 days to 12 years), with 44% of patients remaining alive at 5 years. Thirty patients have died, and 17 deaths were attributed to PTLD. The median follow up of the surviving patients was 4.7 years. The patient characteristics listed in Table 1, as well as rituximab monotherapy, were tested in univariate analyses for their potential to predict OS. The factors significantly associated with worse prognosis were EBER negativity (p=0.017, HR=2.76 [1.10 to 6.90]), no EBV serology mismatch at SOT (p=0.0499, HR=2.44 [1.12 to 5.26]), IPI 3–5 (p=0.009, HR=2.78 [1.15 to 6.72]), ECOG >2 (p=0.047, HR=2.26 [0.91 to 5.58]), lymphocyte count < 1.2 × 109/L (p=0.012, HR=5.05 [2.03 to 12.59]), and no front-line rituximab monotherapy (p=0.001, HR=3.33 [1.16 to 9.52]). In the cohort that received front-line rituximab monotherapy (n=34), EBER negativity (p=0.002, HR=4.61 [1.33 to 15.87]) and less than PR to rituximab monotherapy (p=0.006, HR=4.37 [1.47 to 12.99]) were significantly associated with worse survival.In conclusion, even in the rituximab era, the 5 year median OS for patients with PTLD was poor at 44%, indicating the need for improved therapeutic strategies. However, patients who received front-line rituximab and those who responded had significantly improved outcomes. We showed that EBER negativity and lack of EBV serostatus mismatch at the time of transplant as well as poor performance status predicted a worse prognosis. Finally, we demonstrated that lymphopenia, a novel prognostic marker, has a strong negative impact on survival in PTLD. Disclosures:No relevant conflicts of interest to declare.

Clinicopathologic Analysis of Primary Gastrointestinal T-Cell Lymphoma with a Special Reference to Intestinal and Gastric Type in Japan.

Primary gastrointestinal T-cell lymphomas (PGITL) are very rare and heterogeneous diseases with poor prognosis. Their incidence and pathogenesis may vary with geographical locations. In this study, we aimed to define clinicopathologic and prognostic features of PGITL in Japan, non endemic area for celiac disease, with compared to those in Western countries. 79 patients with PGITL (41 gastric and 38 intestinal lymphoma cases) were enrolled. Epstein-Barr virus associated NK-/T-cell lymphoma and human T-cell leukemia virus type 1 associated adult T-cell leukemia/lymphoma cases were excluded from this study. Our intestinal cases (63%) were histopathologically characterized by monomorphic small-to medium-sized tumor cells, which appeared to be contrasted with higher incidence of pleomorphic appearance among Western patients, and by frequent expression of CD8, CD56, and cytotoxic molecules (CM) of those cells, which is consistent with immunohistochemical features of Western cases. Our gastric cases were unique in showing a wide range of histologic and immunophenotypical characteristics with a significantly higher inclusion of non-cytotoxic lymphoma than intestinal cases (33% vs. 9%, P=.0299). Approximately 62% of patients also showed pleomorphic appearance most frequently with CD4+CD8− and CD4–CD8-phenotype. In comparison with gastric patients, intestinal ones were significantly associated with several clinical factors to indicate poor prognosis such as poorer performance status (P=.0232), lower total protein level (P=.0018), and lower serum albumin level (P=.0303). Overall survival of intestinal cases were significantly inferior to that of gastric patients (P = 0.026), while no statistically significant differences were found in survival between CM-positive PGITL cases and –negative ones (P = 0.6). In univariate analysis, the factors that turned out to correlate significantly with survival were total protein level (<6.0g/dL) (HR, 3.696; 95% CI, 1.671 to 8.171; P=.0012), platelet level (<10.0 /μl) (HR, 10.706; 95% CI, 2.713 to 42.244; P=.0007), a higher than normal serum lactate dehydrogenase (LDH) level (HR, 2.574; 95% CI, 1.266 to5.231; P=.009), direct invasion or gastrointestinal perforation (HR, 2.079; 95% CI, 1.013 to 4.267; P=.046), bone marrow involvement of the disease (HR, 3.134; 95% CI, 1.136 to 8.651; P=.0274), performance status equal to or more than 2 (HR, 3.988; 95% CI, 1.763 to 8.882; P=.0007), the International Prognostic Index (IPI) more than low-intermediate (HR, 3.317; 95% CI, 1.304 to 8.441; P=.0119), Prognostic Index for T-cell lymphoma (PIT) scores more than 2 (HR, 8.166; 95% CI, 2.574 to25.904; P=.004), CD8 positivity (HR, 2.041; 95% CI, 1.032 to 4.037; P=.0404), and intestinal case (HR, 2.955; 95% CI, 1.493 to 5.849; P=.0019). Multivariate analysis with individual factors confirmed that PIT scores was a significant (HR, 6.622; 95% CI, 1.108 to 39.566; P=.0382) and platelet level (<10.0 /μl) was a marginally significant (HR, 5.343; 95% CI, .837 to 34.116; P=.0765) prognostic factors independent from other clinical factors. In conclusion, Japanese intestinal lymphoma patients were in keeping with characteristics of Enteropathy type T-cell lymphoma other than an association with celiac disease and monomorphic histology. However, gastric T-cell lymphomas were distinct from intestinal ones, and were separately considered.

BCL6 Expression Correlates With Monomorphic Histology in Children With Posttransplantation Lymphoproliferative Disease

Posttransplantation lymphoproliferative disease (PTLD) is a complication of organ transplantation with high mortality. Predicting response to first-line therapy, reduction of immune suppression, is difficult because of the heterogeneity of lesions and disease behavior. We sought to determine if BCL6 protein expression in PTLD cells is associated with poor outcome. In a cohort of 25 children with PTLD, 9 of the patients' tumor specimens were positive for BCL6 protein expression. Eight of 13 monomorphic lesions were BCL6 positive, compared with 1 of 11 evaluable polymorphic lesions (P=0.01). Only 1 of the patients with BCL6 expression responded to reduced immune suppression (P=0.19). Recipients of heart transplants who developed PTLD had reduced overall survival rates compared with recipients of other organ transplants who developed PTLD (P=0.04).

A new prognosticator for post‐transplant lymphoproliferative disorders after renal transplantation

A new prognosticator for post‐transplant lymphoproliferative disorders after renal transplantation

Salvage Chemotherapy for Refractory and Relapsed Posttransplant Lymphoproliferative Disorders (PTLD) After Treatment With Single-Agent Rituximab

Single-agent rituximab has demonstrated encouraging efficacy and tolerability in posttransplant lymphoproliferative disorders (PTLDs) failing to respond to immunosuppression reduction (IR). This retrospective analysis was undertaken to determine the efficacy and safety of salvage therapy in recipients of solid organ transplants with progression of PTLD after rituximab first-line therapy. Eleven patients who had received IR and single-agent rituximab were analyzed. Of these, 10 had received CHOP salvage chemotherapy. One patient with limited disease received tumor irradiation and further IR. Most patients (73%) had late PTLD (median onset of disease 145 months posttransplant), and most (83%) had monomorphic histology; 36% had EBV-association. IR and irradiation therapy re-induced complete remission (CR) and allowed long-term disease control in a patient with polymorphic PTLD relapse. CHOP therapy achieved CR in five (50%) and partial remission (PR) in two (20%) patients. Four of five (80%) patients achieving CR remained in CR at a median follow-up of 44.2 months. Of the patients achieving PR, one is currently alive, and the second died from transplant rejection after converting to CR after consolidative chemotherapy. Patients with stable disease (two) and progressive disease (one) have died from PTLD. There was one possible CHOP-associated death (acute cardiac event) and two patients had to be switched to less-toxic monotherapies. Median overall survival was 46.5 months (95% confidence interval: 23.6-49.1 months). CHOP salvage therapy achieved a favorable overall response rate of 70% in this setting, indicating that PTLD generally remains chemotherapy-sensitive after progression following first-line rituximab.

Posttransplant Lymphoproliferative Disorder After Umbilical Cord Blood Transplantation in Children

Reported are 7 cases of posttransplant lymphoproliferative disorder (PTLD) arising in children who received umbilical cord blood transplantation (UCBT). There were 4 females and 3 males with a median age of 3 years (range, 1-16 years). All 7 patients received UCBT, including 1 patient who received multiple units and 1 transplanted under nonmyeloablative condition. The time interval from UCBT to PTLD averaged 4 months (range, 2 weeks to 9 months). Patients typically presented with high-stage disease with visceral organ involvement. Histology of the PTLDs showed monomorphic morphology in 5 cases and polymorphic morphology in the remaining 2 cases. Bone marrow biopsies were performed in 3 cases and were negative for PTLD. Epstein-Barr virus (EBV) was detected in the PTLD in all 7 patients by in situ hybridization. Evidence of past EBV infection was found in the recipients, but the EBV genome was not detected in the donor cord blood samples, suggesting that donor cord blood was not the source of EBV infection. The origin of the PTLD was investigated in 5 cases. PTLD was of host origin in 2 patients who failed engraftment and of donor origin in the remaining 3 patients who had complete engraftment. Four of 5 patients with monomorphic PTLD failed to demonstrate significant responses to rituximab and/or reduction of immunosuppression and died within 1 month after diagnosis. The remaining 2 patients with polymorphic PTLD showed complete response to therapy. One patient was alive 35 months after transplant, and the other patient died of infection 6 months after transplant. It is concluded that PTLD arising after UCBT in children occurs early after transplant and represents a serious EBV-related complication. PTLD may be of donor or recipient origin depending on engraftment status. Both monomorphic and polymorphic histology may be seen, and monomorphic histology appears to predict an unfavorable prognosis.

BCL-6 Overexpression Predicts Poor Response to Reduced Immune Suppression Therapy in Children with Post-Transplantation Lymphoproliferative Disease (PTLD).

Background: PTLD is a well known complication of organ transplantation. While the understanding of this disease is increasing, the diagnosis and treatment remain challenging. The clinical, morphological, and molecular findings in PTLD vary widely. Reduction of immune suppression is the treatment of choice, but is effective in only 20–50% of patients. Mutations in the BCL6 gene have been demonstrated in some lymphomas and PTLD and may have prognostic implications. A single study, in which most subjects were adults, has suggested that BCL6 mutation in PTLD predicts a lack of response to reduced immunosuppression (IS).Objectives: To determine if BCL-6 overexpression predicts poor response to reduced IS or decreased survival in children with PTLD.Methods: Clinical data of patients identified with PTLD at The Children's Hospital (TCH) from 1992–2002 were obtained, including age, type of organ transplanted, subtype of PTLD, treatment received, response to treatment, relapse free survival (RFS), and overall survival (OS). Archived specimens of lesions obtained at the time of diagnosis of PTLD were evaluated for the presence of BCL-6 expression by immunohistochemistry.Results: Between 1992 and 2002, 486 organ transplants (211 heart, 107 hematopoietic stem cell (HSC), 86 liver, 82 kidney) were performed at TCH. During that same period, 20 children were diagnosed with 21 cases of PTLD. Eleven patients had liver transplants (12.7% of transplants), 5 had heart transplants (2.4%), 3 had HSC transplants (2.8%), and 1 had a kidney transplant (1.2%). Histologic classifications of PTLD included 1 follicular hyperplasia, 9 polymorphic PTLD, and 11 lymphomas. Only 5 of 20 patients responded to reduced IS. Overall mortality was 45% (9/20). BCL-6 was overexpressed in 7 of 18 evaluable specimens from 20 patients. None of the patients with BCL-6 overexpression responded to reduced IS (p=0.05). BCL-6 overexpression was associated with monomorphic histology (p=0.02), but did not predict RFS or OS.Conclusions: BCL-6 expression is associated with monomorphic histology and non-response to reduced IS in children with PTLD. Larger, prospective studies of BCL-6 mutation and expression are needed to verify the clinical significance of these findings.