Abstract
Background/Aims About half of HIV+ diffuse large B-cell lymphoma (DLBCL) patients die within 2 years of diagnosis. Identification of prognostic tumor markers may assist clinical risk stratification and inform therapeutic developments. We examined if certain tumor markers in HIV+ DLBCL are associated with mortality.
Methods H&E slides from HIV+ DLBCL cases diagnosed between 1996–2007 in the Kaiser Permanente California Health Plan were reviewed to identify representative tumor blocks for tissue microarray (TMA) construction. Immunohistochemistry staining of TMA cores was used to analyze the expression of selected markers in the following categories:
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viral factor: EBV
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cell cycle regulators: Cyclin E, SKP2 and cMYC;
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B-cell activators: FOXP1, PKC-ß2, p27, and Ki-67; and
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apoptosis regulators: GAL3, p53, BCL2, surviving, and BLIMP1.
Percent of DLBCL cells with visible marker staining was scored on a scale from 0–4 (0–9%, 10–24%, 25–49%, 50–74% and =75%). Epstein Barr Virus (EBV) infection was determined by in situ hybridization of EBV RNA. Positivity for each marker was determined based on previously established cut-off values. Information on patient demographics and clinical history, DLBCL characteristics and death was collected from Kaiser Permanente’s credited cancer and HIV registries as well as electronic medical records. Each marker’s prognostic significance on 2-yr mortality was first evaluated in a univariate Cox model. Markers showing a mortality association at p<0.10 level were examined in a multivariable Cox model, adjusting for stage, presence of B symptom, Germinal Center phenotype, prior AIDS and CD4 cell count.
Results Of 194 HIV+ DLBCL cases identified; 80 had sufficient tissue for study inclusion. In the crude analyses, cMYC [hazard ratio (HR)=2.08, 95% confidence interval:0.93–4.63, p=0.07], EBV [HR=2.86 (1.45–5.63), p<0.01] and BLIMP1 [HR=2.57 (0.99–6.67), p=0.05] positivity were associated with 2-yr mortality. In the adjusted analysis, cMYC positivity remained significantly associated with a 3-fold increase in 2-yr mortality [hazard ratio=3.18 (1.15–8.80), p=0.03]. Other markers were not significantly associated with mortality.
Discussion cMYC expression may be associated with increased mortality in HIV+ DLBCL patients. Our initial findings should be confirmed in larger studies.
