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Introduction. Hodgkin's lymphoma (HL) presenting either with primary bowel involvement or with cholestasis is unusual. The combination of primary gastrointestinal HL presenting with cholestasis and ductopenia has not been previously described. Case Report. We present a case of primary gastrointestinal HL with evidence of liver involvement, but also with prominent ductopenia on liver biopsy and associated intrahepatic cholestasis. A 50-year-old man with a history of Crohn's disease presented with a bowel obstruction, for which he underwent a small bowel resection. Histology revealed HL. His course was complicated by cholestatic liver failure. A subsequent liver biopsy revealed both focal involvement by lymphoma and ductopenia, resembling vanishing bile duct syndrome (VBDS). He was treated with chemotherapy with improvement in his cholestasis, but he eventually succumbed due to further complications of his disease and treatment toxicities. Conclusion. This case of primary gastrointestinal HL associated with ductopenia does not meet classic criteria for VBDS, but the clinical presentation and pathology are suggestive of a VBDS-like paraneoplastic process. Therapies for HL in the setting of cholestatic liver failure require special consideration, but some reports of durable remissions and recovery of liver function have been reported.

The normal counterparts of mantle cell lymphoma (MCL) are naïve quiescent B-cells that have not been processed through the germinal center (GC). For this reason, while lymphomas arising from GC or post-GC B-cells often exhibit plasmacytic differentiation, MCL rarely presents with plasmacytic features. Seven cases of MCL with a monotypic plasma cell (PC) population were collected from six centers and studied by immunohistochemistry, FICTION (Fluorescence immunophenotyping and Interphase Cytogenetics as a Tool for the Investigation of Neoplasms), capillary gel electrophoresis, and restriction fragment length polymorphism of immunoglobulin heavy chain analysis (RFLP/IgH) of microdissections of each of the MCL and PC populations to assess their clonal relationship. Clinical presentation was rather unusual compared to typical MCL, with two cases arising from extranodal soft-tissues of the head. All MCL cases were morphologically and immunohistochemically typical, bearing the t(11;14)(q13;q32). In all cases PC populations were clonal. In 5 of the 7 cases, the MCL and PC clones showed identical restriction fragments, indicating a common clonal origin of the neoplastic populations. The two cases with clonal diversity denoted the coexistence of two different tumors in a composite lymphoma/plasma cell neoplasm. Our findings suggest that MCL can present with a PC component that is often clonally related to the lymphoma, representing a rare but unique biological variant of this tumor.

Abstract 670 Richter syndrome (RS) represents the transformation of chronic lymphocytic leukemia (CLL) to aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). Knowledge of the genetic lesions associated with RS is scant and represents the aim of this study. The study was based on 47 RS cases (all DLBCL). In 32 cases, paired CLL/RS samples were available (28 clonally related and 4 clonally unrelated). In 15 cases, the sole RS sample was analysed. According to CD10/BCL6/MUM1 immunohistochemistry expression pattern, 43/47 (91.5%) RS were classified as non-germinal center DLBCL. At diagnosis, 37.8% RS showed ECOG PS >1, 77.8% Binet stage B-C, 95.7% Ann Arbor stage III-IV, 44.4% B symptoms, 45.7% tumor size >5 cm, 32.6% involvement of >1 extranodal site, 66.7% LDH elevation, and 28.9% platelets Disclosures: No relevant conflicts of interest to declare.

Abstract 967 Mutations of the TP53 tumor suppressor gene are associated with a poor clinical outcome in DLBCL patients treated with CHOP. The impact of TP53 mutations on clinical outcome of DLBCL patients treated with Rituxan-CHOP has not been comprehensively analyzed. The purpose of this study was to analyze the frequency and type of TP53 mutations in Rituxan-CHOP treated DLBCL patients from twenty-two medical centers, and to correlate these with clinical outcome. TP53 mutations were identified in 138/604 (22.7%) Rituxan-CHOP treated DLBCL cases and included missense (n=133), nonsense (n=16), splice site (n=9) and frameshift (n=1) mutations. The presence of any TP53 mutation correlated with poor overall survival (OS) with a median OS of 50 months in the TP53 mutation group versus 69 months in the wild-type group (wt-TP53, P=0.0042). Seventy-three of 138 cases (53%) had mutations in the DNA binding domains of the TP53 gene, which were found to be the most important predictor of poor OS (P=0.0044). In contrast, mutations in the non-DNA binding domains did not correlate with poor OS (P=0.157). Overexpression of p53 protein significantly correlated with only TP53 missense mutations (P=0.002), but not with other types of TP53 mutations, while TP53 deletion did not correlate with mutation or OS. In comparison to our previous series of patients treated only with CHOP, Rituxan-CHOP regimen improved OS in both wt-TP53 and TP53 mutated groups. The 5-year survival rate was 42% in patients with any TP53 mutation (median survival=50 months) and 41% in patients with the DNA-binding domain mutations (median survival=49 months) compared to 52% for those with wt-TP53 (median survival=69 months). The complete remission rate was 51% in patients with any TP53 mutation and 44% in patients with the DNA-binding domain mutations, compared to 77% for those with wt-TP53. However, the clinical outcome and treatment response to the Rituxan-CHOP varied in patients with mutations in different regions of the DNA-binding domains. Patients with mutations in the DNA minor binding groove motif (Loop L3, 17% of all mutations) had significantly decreased median OS (17 months) when compared to patients with Loop L2 (16% of all mutations) or loop-sheet-helix motifs (Loop L1-S10-H2, 20% of all mutations) with median OS of 49 and 50 months, respectively. In contrast to our previous CHOP series study, median survival was significantly improved for Rituxan-CHOP treated DLBCL patients with mutations in the loop-sheet-helix motifs (43 months). Multivariate analysis confirmed that TP53 mutations and activated B-cell-like (ABC)/germinal center B-cell-like (GCB) subtype classification were independent predictors of OS with a hazard ratio of 0.69 (GCB vs ABC, 95% CI 0.49-0.98) and 1.60 (TP53 vs wt-TP53, 95% CI 1.10-2.31), respectively. Similar to our previous CHOP study, the TP53 mutation profile, regardless of location, was found to stratify GCB-DLBCL, but not ABC-DLBCL, into molecularly distinct subsets with different clinical outcomes in Rituxan-CHOP treated DLBCL patients. This study demonstrates the importance of TP53 mutational profile for predicting clinical outcome. Elucidation of the roles of specific TP53 domain mutations, as documented in our study, will help in refining prognostic models for DLBCL patients treated with either the CHOP or Rituxan-CHOP regimen. These findings also provide the rationale and strategies for p53 targeted therapeutic intervention in DLBCL patients. Disclosures: Kahl: Milllennium: Consultancy, Research Funding; Cephalon: Consultancy, Research Funding.

The p53 pathway is known to play a role in pathogenesis and prognosis of human malignancies including diffuse large B-cell lymphoma (DLBCL). The MDM2 protein has been shown to regulate p53 function and stability via a multi-factorial negative feedback loop. MDM2 is involved in transport of p53 out of the nucleus and its subsequent degradation. Additionally, MDM2 binds p53 protein and inhibits its function as a transcription factor. As an integral part of the regulation of the p53 pathway, we hypothesize MDM2 expression contributes to the pathogenesis of DLBCL and affects survival. The purpose of this study is to investigate the potential role of the MDM2 protein in DLBCL by correlating expression of MDM2 with p53 expression, TP53 mutation status and clinical outcome. Immunostains for MDM2 and TP53 gene-product proteins were performed in 133 cases from 6 medical centers. A positive immunostain was defined as nuclear staining in 10% or more of the tumor cells. The TP53 gene was analyzed for mutations with PCR-based and sequencing methods. Patients were treated with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or CHOP-like regimen. The Kaplan-Meier method was used for survival analysis. MDM2 immunostains were positive in 64 of 133 cases of DLBCL (48%). There was a trend toward poor overall survival (OS) with MDM2 expression in the entire group of patient with DLBCL (p=0.32). Twelve of 24 cases (50%) with TP53 mutations demonstrated MDM2 expression. Within this TP53 mutated group, no significant difference in OS was observed between MDM2-positive and MDM2-negative cases (p=0.32). Of patients with wild-type (WT) TP53, 51 of 107 cases (48%) expressed MDM2. In this subset of patients, the MDM2-positive phenotype predicted for poor 5-year OS (38% vs 67%, p=0.002), and a significantly shorter median disease-free survival (2.3 years vs. >5.0 years; p=0.013). The complete remission rate was 57% in MDM2-positive cases compared to 73% in MDM2-negative cases in the WT-TP53 group (p=0.08). Multivariate analysis confirmed that MDM2 expression was an independent predictor of poor OS in patient with DLBCL with a WT-TP53 gene (HR 2.0, 95% CI 1.15–3.56; p=0.015). This study demonstrates the negative survival impact of MDM2 expression in patients with wild-type TP53, suggesting that MDM2 provides an alternative mechanism of p53 pathway inactivation in DLBCL cases with a WT-TP53 gene.