Purpose: Recent studies of Hodgkin's lymphoma (HL) have suggested that the presence of regulatory T cells in the reactive background may explain the inhibition of the antitumoral host immune response observed in these patients. This study aimed to assess the relevance of regulatory T cells and CTLs present in the background of HL samples in the prognosis of a series of classic HL (cHL) patients. Experimental Design: Expression of granzyme B and TIA-1 (markers for CTL) and FOXP3 (a marker for regulatory T cells) were evaluated independently by immunohistochemistry in tissue microarrays of 257 cHL patients and correlated with patient outcome. Results: The combined influence of the presence of FOXP3⁺ and TIA-1⁺ cells distinguished three risk groups of patients with 5-year overall survival of 100%, 88%, and 73%. The presence of a small number of FOXP3⁺ cells and a high proportion of TIA-1⁺ cells in the infiltrate represent an independent prognostic factor that negatively influenced event-free survival and disease-free survival in cHL. Compared with the features at diagnosis, relapsed samples tended to have more TIA-1⁺ cells and a lower proportion of FOXP3⁺ cells in the reactive background. Conclusions: These data suggest that low infiltration of FOXP3⁺ cells in conjunction with high infiltration of TIA-1⁺ cells in cHL may represent biological markers predicting an unfavorable outcome. Moreover, the variation of these markers over the course of the disease implies a possible role for them in the progression of HL cases.

Increasing evidence points towards a role of hepatitis C virus (HCV) infection in causing malignant lymphomas. We pooled case-control study data to provide robust estimates of the risk of non-Hodgkin's lymphoma (NHL) subtypes after HCV infection. The analysis included 7 member studies from the International Lymphoma Epidemiology Consortium (InterLymph) based in Europe, North America, and Australia. Adult cases of NHL (n = 4784) were diagnosed between 1988 and 2004 and controls (n = 6269) were matched by age, sex, and study center. All studies used third-generation enzyme-linked immunosorbent assays to test for antibodies against HCV in serum samples. Participants who were human immunodeficiency virus positive or were organ-transplant recipients were excluded. HCV infection was detected in 172 NHL cases (3.60%) and in 169 (2.70%) controls (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.40-2.25). In subtype-specific analyses, HCV prevalence was associated with marginal zone lymphoma (OR, 2.47; 95% CI, 1.44-4.23), diffuse large B-cell lymphoma (OR, 2.24; 95% CI, 1.68-2.99), and lymphoplasmacytic lymphoma (OR, 2.57; 95% CI, 1.14-5.79). Notably, risk estimates were not increased for follicular lymphoma (OR, 1.02; 95% CI, 0.65-1.60). These results confirm the association between HCV infection and NHL and specific B-NHL subtypes (diffuse large B-cell lymphoma, marginal zone lymphoma, and lymphoplasmacytic lymphoma).

Purpose: Recent molecular data have suggested that non-neoplastic cells are powerful modulators that may confer a selective advantage or disadvantage on the outcome of follicular lymphoma (FL) patients.Patients and Methods: The prevalence of the principal inflammatory and immune-infiltrated cells was measured immunohistochemically in the tissue of 211 FL patients, and associations were sought with their traditional clinicobiologic characteristics.Results: Our results confirmed the presence of a large number of T lymphocytes (CD4⁺and CD8⁺) and CD57⁺cells and, at a moderate level, the presence of TIA-1⁺cytotoxic cells, CD68⁺macrophages, CD123⁺plasmacytoid cells, and FOXP3⁺regulatory T cells among the pool of non-neoplastic cells. In addition to the conventional clinical variables, univariate analysis identified a low level of infiltrated CD8⁺T lymphocytes as a significantly negative prognostic factor of overall survival. The following significant differences in the abundance of cells of specific and nonspecific immunity were observed in relation to the clinicobiologic features of FL: (1) a reactive microenvironment mainly made up of T lymphocytes and macrophages was significantly associated with a favorable clinical behavior of FL patients; and (2) a reactive microenvironment infiltrated predominantly by CD57⁺T cells was associated with a significantly higher frequency of adverse clinicobiologic manifestations such as “B” symptoms and bone marrow involvement.Conclusion: Our results demonstrate the existence of two specific patterns in the reactive microenvironment of FL, an immunosurveillance pattern (T lymphocytes and macrophages) and an immune-escape pattern (CD57⁺T cells), that were directly associated with the clinicobiologic features of these patients.

The present study aimed to describe the general tissular composition of the immune infiltrate observed in Hodgkin's lymphoma (HL) and its possible relationship with clinical and survival prognostic factors. In this retrospective study of 267 HL patients, the relative proportions of infiltrating T lymphocytes (CD4 + , CD8 + ), natural killer cells (CD56 + , CD57 + ), cytotoxic cells (Granzyme B + , TIA-1 + ) and dendritic cells (CD21 + , S-100 + ) were quantified immunohistochemically with tissue microarray technology. Our results confirm the predominance of CD4 + T lymphocytes in the background of tumoral cells, in addition to a high number of cytotoxic lymphocytes (CD8, CD57 and TIA-1). Patients with low numbers of infiltrating CD8, CD56, CD57 + cells and high numbers of Granzyme B and TIA-1 + cells presented a significantly unfavourable clinical course (presence of leukocytosis, B symptoms, advanced clinical stage (III/IV), non-responding patients). A reduced infiltration of CD4 + T lymphocytes was related with the presence of Epstein – Barr virus. Significantly longer survival times were observed in patients with a high level of infiltrating CD57, as well as a low level of Granzyme B and TIA-1 + cells (log-rank test). When evaluated in a multivariate model, high levels of infiltrating TIA-1 and Granzyme B + cells were shown to be independent prognostic factors that negatively influenced overall survival. The presence of TIA-1 + cells was found to be the only unfavorable prognostic factor of event-free survival and disease-free survival. The overall detection of tumor-infiltrating cells in HL confirms the importance of cytotoxic T lymphocyte infiltration (Granzyme B and TIA-1 + cells) in these patients. Independently of the classical clinical and pathological features, these cells appear to be an unfavourable prognostic factor in HL and, more particularly, the presence of cytotoxic TIA-1 + cells.