TNF-α Expression in Tumor Cells as a Novel Prognostic Marker for Diffuse Large B-cell Lymphoma, Not Otherwise Specified

Abstract

Several cytokines promote malignant cell growth and are therefore believed to contribute to disease aggressiveness. The cytokine tumor necrosis factor-α (TNF-α) acts as a tumor-promoting factor and has been linked to all tumorigenic stages in many cancers. Here, we evaluated 62 lymphoma tissue specimens from patients having diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) by immunostaining with anti-TNF-α antibody. Cytoplasmic TNF-α reactivity in ≥20% of the tumor cells was considered positive. Our results demonstrated that tumor specimens from DLBCL, NOS patients could be divided into 2 types-TNF-α positive (38 cases, 61%) and TNF-α negative (24 cases, 39%)--and that TNF-α positivity in DLBCL, NOS was correlated with poorer overall survival (OS; P=0.0005, log rank test) and progression-free survival (PFS; P=0.0330, log rank test) compared with TNF-α negativity. Cox regression analysis showed that TNF-α expression was a significant prognostic factor for OS (P<0.0001) and PFS (P=0.0323). Regarding OS and PFS, multivariate analysis showed that TNF-α expression in tumor cells was an independent prognostic factor for the International Prognostic Index (IPI). Therefore, TNF-α-positive DLBCL, NOS may constitute a unique subtype of DLBCL, NOS with an aggressive clinical course. The addition of TNF-α expression to the IPI may significantly improve the predictive prognostic value. The therapeutic strategy of DLBCL, NOS patients should be based on correct prognosis; therefore, patients with poor prognoses could be more accurately detected by evaluating both TNF-α expression levels and the IPI.

Biomarkers of HIV-associated Cancer

“…A marked increase in B-cell activation is commonly seen in HIV infection, which is driven by the overproduction of B-cell stimulatory cytokines, such as IL-6 and IL-10, as well as by stimulation of B-cells by HIV and other microbial antigens 94. In addition, HIV itself induces the production of inflammatory cytokines that cause B-cell stimulation, proliferation, and activation, and the cell lines derived from HIV-NHL have been found to express cytokines including interleukin 6, 10, and tumor necrosis factor-α 95–98. B-cell activation is characterized by lymphocyte proliferation, class switch recombination (CSR), and somatic hypermutation, all of which are prone to resultant errors in DNA that may lead to lymphomagenesis.…”

Infiltration of effector regulatory T cells predicts poor prognosis of diffuse large B-cell lymphoma, not otherwise specified

“…There have been some reports showing a relationship between biological markers on the tumor cells (eg, bcl2, CD44, and tumor necrosis factor-a expression), as well as the Ki67 labeling index and patients' prognosis. 4,5 In particular, an immunophenotypic analysis revealed that the germinal center B-cell-like (GCB) phenotype has a better prognosis than non-germinal center B-cell-like (non-GCB) phenotype, which is an independent predictor of IPI. 6 The tumor microenvironment is important for the development and progression of tumors, and influences the patients' prognosis 7 ; thus, it is essential for the development of novel treatment strategies.…”

Practical Applications in Immunohistochemistry: Evaluation of Diffuse Large B-Cell Lymphoma and Related Large B-Cell Lymphomas

“…A wide range of individual markers may be associated with prognosis in DLBCL and related lymphomas, supporting the idea that this is a complex and heterogeneous group of neoplasms, and each year additional markers are put forward for evaluation [5][6][7][8][9][10][11][12][13][14][15][16][17][18] (Table 5). While a plethora of unique aspects of DLBCL is prognostic, only those markers that have been vetted by extensive clinical study and can be routinely applied are the primary focus of this report.…”