Diffuse Large B-Cell Lymphoma with Overexpression of Cyclin E Substantiates Poor Standard Treatment Response and Inferior Outcome

Abstract

Purpose: Gold standard to predict survival and stratify patients for risk-adapted therapy in diffuse large B-cell lymphoma (DLBCL) is the international prognostic index, although it does not consider the molecular heterogeneity of DLBCL. Deregulation of cyclin E (CCNE) is a strong predictor of poor prognosis in some neoplastic diseases. In tumor cells, it induces chromosomal instability with an increased rate of aneuploidy/polyploidy. Experimental Design: We analyzed in this retrospective study the prognostic value of immunohistochemical CCNE expression on a validated tissue microarray containing 101de novo DLBCLs and, in 9 cases, the CCNE-induced chromosomal instability as assessed by cytometry. Results: Forty-six of 98 evaluable DLBCLs expressed CCNE in a mean proportion of 20 F 29% of tumor cells; 38 cases expressed CCNE in z20% of tumor cells. CCNE-positive samples were aneuploid compared with near tetraploidy in CCNE-negative cases. Multivariate analysis showed CCNE expression in z20% of tumor cells to be an international prognostic index^independent, Adriamycin-based treatment-independent, and BCL2-independent prognostic factor for poor disease-specific survival. CCNE expression in z80% of tumor cells was associated with dismal short-term prognosis. CCNE expression in z50% of tumor cells emerged as an independent predictive factor for standard CHOP treatment resistance. Conclusions: CCNE expression assessment is easy on paraffin-embedded tissue. The high prognostic value of CCNE expression in DLBCL may be the basis for future prospective trials. In addition, a high CCNE expression hints at the presence of a possible target for individualized cancer therapy.

Correlation of high numbers of intratumoral FOXP3+ regulatory T cells with improved survival in germinal center-like diffuse large B-cell lymphoma, follicular lymphoma and classical Hodgkin's lymphoma

“…The soundness of our analysis, the multiple previous validations of the TMA used [29][30][31][32][33][34][35] as well as the κ-values for the comparison of results from conventional lymphoma slides and TMA guarantee the reliability of the data obtained. We clearly demonstrated that the FOXP3 + cell density varies between different lymphoma types and that do lymphoma-infiltrating FOXP3 + cells may represent important lymphoma/host microenvironment-modulators, since increased amounts of these cells can positively influence survival in FL, GC-like DLBCL and cHL.…”

“…The tissue microarray (TMA) were constructed and validated as described elsewhere [29][30][31][32][33][34][35] (see Supplementary Data). In cases of FL, neoplastic GC were sampled for arraying.…”

Recurrent numerical aberrations of JAK2 and deregulation of the JAK2-STAT cascade in lymphomas

“…Treatment regimens, follow-up data and definitions of response, relapse and treatment failures are detailed in previous reports. [25][26][27] Tissue Microarray Construction…”

“…[25][26][27][28] One (peripheral T-cell lymphomas (PTCLs) and angioimmunoblastic T-cell lymphomas (AILTs)), two (DLBCLs, follicular lymphomas (FLs), small lymphocytic lymphomas/ chronic lymphocytic leukemias (SLLs/CLLs) and HLs) or three (PMBCLs) cores from every sample were arrayed. In cases of FL, neoplastic germinal centers were sampled.…”

“…When possible, DLBCLs were immunophenotypically classified as germinal center B-cell-like or nongerminal centerlike as reported previously. 25,26 Statistics Statistical analysis including data description was done using the Statistical Package of Social Sciences version 15.0 for Windows (SPSS, Chicago, IL, USA). Incomplete data were represented by empty spots in the primary SPSS table and were not excluded from the tests done.…”