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Journal of Clinical Oncology, Vol 24, No 34 (December 1), 2006: pp. 5350-5357 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.4766 Immunohistochemical Patterns of Reactive Microenvironment Are Associated With Clinicobiologic Behavior in Follicular Lymphoma Patients
From the Department of Pathology, Hospital Verge de la Cinta, Tortosa, Spain Address reprint requests to Tomás Álvaro-Naranjo, MD, PhD, Department of Pathology, Hospital de Tortosa Verge de la Cinta, C/Esplanetes No. 14, 43500 Tortosa, Spain; e-mail: talvaro.htvc.ics{at}gencat.net
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.
Follicular lymphoma (FL), the second most common subtype of non-Hodgkin’s lymphoma after diffuse large B-cell lymphoma, is an indolent lymphoma characterized by long median survival, even without therapy, and rare spontaneous remissions. Numerous treatment options have been proposed, including antibody therapy (rituximab), combination chemotherapy alone or with rituximab, and autologous and allogeneic transplantation. The inconsistency of the disease course makes it difficult to gain a clear consensus about the usefulness of these approaches. Currently, clinical prognostic indices, such as the International Prognostic Index and, more specifically, the Follicular Lymphoma International Prognostic Index (FLIPI), are the only principal markers of clinical course. However, it seems that the acquisition of genomic alterations such as t(14;18) translocation in tumoral cells is necessary but not sufficient for the transformation to FL and that sporadic t(14;18)-bearing B cells are associated with age, smoking history, being male, and seasonal pesticide exposure in the absence of clinical FL.1 Currently, it seems that an exclusively genetic model may not be sufficient to explain the pathogenesis of FL. Thus, other growth and progression supports, like the inflammatory/immune microenvironment response to the tumor, have been proposed. In recent studies, nonmalignant cells have been found to be important in the development and clinical behavior of FL. The majority of these studies investigated the gene expression patterns in FL in relation to the behavior of patients or the response to treatment.2-4 Their results highlight a close relationship between the presence of a higher density of predominantly nonactivated immune cells (principally T cells) and a favorable outcome or response to the treatment, whereas the presence of activated immune cells (principally macrophages or dendritic cells) seems to be related to an unfavorable outcome or no response to the treatment. Two recent immunohistochemical studies have defined CD68+ macrophages, follicular FOXP3+ regulatory T cells, and International Prognostic Index as independent predictors of overall survival (OS) in FL patients.5,6 These results imply that differences in the host immune response may underlie differences in the clinical course and outcome of FL. To provide a better definition of the reactive microenvironment in FL and to shed light on the possible impact on the outcome of these patients, we analyzed the presence and tissue distribution of T-cell subsets and inflammatory immune response in a group of 211 FL patients who were representative of all stages and grades of the disease.
Patient Characteristics This multicenter study (Spanish Hodgkin’s Lymphoma Study Group) involved 211 FL patients who were diagnosed according to the criteria in the WHO classification of hematopoietic neoplasms.7-9 Treatment modalities varied over time and were administered according to local protocols at the time of diagnosis. Treatment regimens included principally cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP; 44%); cyclophosphamide, vincristine, and prednisone (CVP; 15%); and a variety of other monotherapies, with or without adjuvant radiotherapy and/or surgery (41%). Rituximab complemented CHOP or CVP chemotherapy in only five patients.
Baseline clinicopathologic information was collected at the time of diagnosis, before treatment. The database included age, sex, Ann Arbor stage, performance status, grade, bone marrow (BM) involvement, "B" symptoms, nodal sites, lactate dehydrogenase (LDH) levels, hemoglobin levels, and FLIPI. FLIPI grouped patients according to age (
Tissue Microarrays and Immunohistochemical Analysis
T lymphocytes (CD4 and CD8), natural killer cells (CD57), regulatory T cells (FOXP3), cytotoxic cells (TIA-1), macrophages (CD68), and plasmacytoid cells (CD123) were detected in our laboratory as described previously,12,13 whereas FOXP3 was detected using the FOXP3-236A/E7 monoclonal antibody produced in the Monoclonal Antibodies Unit of the Centro Nacional de Investigaciones Oncológicas (Madrid, Spain).14,15 Immunodetection was performed by the EnVision method (Dako, Carpinteria, CA) using diaminobenzidine chromogen as substrate. The distribution of the infiltrated cells in relation to the neoplastic follicles (outside and within the follicles) was observed microscopically at x2.5 magnification under a Leica DM LB2 bright-field microscope (Leica Microsystems GmbH, Wetzlar, Germany). Two representative areas with the most abundant cellular infiltration were visualized and then scanned at x40 magnification using a Leica DFC320 Digital Camera (Leica Microsystems). The number of positively stained cells was automatically scored with the Image-Pro Plus 5.0 image analysis program (MediaCybernetics Inc, Silver Spring, MD), the process of which has been described elsewhere.12 Scoring consistency between the two areas was evaluated, and the average was calculated and defined as the interfollicular cellular infiltration. CD123 was classified as positive or negative depending on the presence or absence, respectively, of any cytoplasmic and/or nuclear staining within the representative fields of the duplicate cores.
Statistical Methods
Clinicopathologic Characteristics, Treatment, and Effect on FL Patient Survival Baseline clinical and tumoral data of the patients, some of whom had been included in a previous study, are listed in Table 2. The median OS time was 13.25 years (median follow-up, 6 years), and the median PFS time was 3.40 years (median follow-up time, 7 years). The univariate analysis (log-rank test, Table 2) indicated that factors unfavorably influencing OS in our group of FL patients were male, age older than 60 years, presence of BM involvement, performance status more than 1, and advanced stage of disease. Clinical factors unfavorably influencing PFS were presence of BM involvement, performance status more than 1, and advanced stage of disease. Patients in intermediate- or high-risk groups for FLIPI showed significantly less favorable survival.
The possible effect of therapy on treatment outcome was evaluated by dividing our cohort of patients into the following three distinct groups: patients receiving CHOP (n = 64), patients receiving CVP (n = 22), and patients receiving various and different treatments (n = 61). The baseline clinicobiologic characteristics exhibiting statistical differences between at least two treatment groups were the stage of disease (  2 test, P = .018), the presence or absence of B symptoms (2 test, P < .001), and the involvement or noninvolvement of BM (2 test, P = .014). However, there were no significant differences in the OS (Fig 1A) and PFS (Fig 1B) between the three treatment groups.
Immunophenotype of Reactive Microenvironment Components, Mutual Correlation, and Effect on Patient Survival The principal pattern of distribution of the different immune cell markers is shown in Figure 2. The analysis of the distribution of the cells indicates that 98.4% of CD4+ and 96.7% of CD8+ T cells were present outside the neoplastic follicles, whereas the CD57+ cells were observed within the follicle in 50% of patients. There were also significantly more TIA-1+ cytolytic cells, FOXP3+ regulatory T cells, CD68+ macrophages, and CD123+ plasmacytoid cells outside than within the neoplastic follicles.
For the automated quantitative results of the biomarkers, the mean numbers of infiltrated cells were as follows: 108.9 ± 46.0 CD4+ T lymphocytes/field (range, 0 to 479 lymphocytes/field), 108.2 ± 86.0 CD8+ T lymphocytes/field (range, 1 to 431 lymphocytes/field), 183.8 ± 66.7 CD57+ cells/field (range, 18 to 368 cells/field), 11.8 ± 12.7 TIA-1+ cytotoxic cells/field (range, 0 to 74 cells/field), 54.6 ± 45.1 CD68+ macrophages/field (range, 2 to 219 macrophages/field), and 69.5 ± 57.3 FOXP3+ regulatory T cells/field (range, 0 to 293 cells/field); 52.6% of the available patients stained positive for CD123+ plasmacytoid cells.
The mean values of infiltrated immune cells were chosen as the best cutoff point that allowed groups with low and high levels of cell infiltration to be distinguished. Under these conditions, only a greater number of infiltrated CD8+ T cells was significantly associated with favorable patient survival, whereas the univariate analysis showed that the rest of the cells present in the reactive microenvironment had no impact on patient outcome. The median OS time of patients with more than 108 cells/field was 181 months compared with only 154 months in patients with
To determine whether there was any relationship between the different cellular components of the immune system, the Spearman correlation was estimated. A positive relationship was found between most of the cell types present in the reactive microenvironment. The level of CD4+ T lymphocytes was correlated with the level of CD8+ T lymphocytes (rho = 0.335; P < .00001), FOXP3+ regulatory T cells (rho = 0.195; P = .013), and CD57+ cells (rho = 0.331; P < .00001). The number of infiltrated CD8+ T lymphocytes was correlated with the number of CD57+ cells (rho = 0.322; P < .00001), CD68+ macrophages (rho = 0.350; P < .00001), and CD123+ plasmacytoid cells (Mann-Whitney U test, P = .001). Finally, the quantity of TIA-1+ cells was correlated with the principal infiltrated cells with cytotoxic activity, such as the CD8+ T lymphocytes (rho = 0.290; P < .00001), CD68+ macrophages (rho = 0.483; P < .00001), and CD123+ plasmacytoid cells (Mann-Whitney U test, P = .010). A schematic diagram representing these significant relationships is presented in Figure 4.
Correlation and Prognosis Analysis of Microenvironment Components With Clinicopathologic Features As shown in Table 3, higher infiltration of CD4+ and CD8+ T lymphocytes was detected more frequently in patients without B symptoms and with a low performance status, whereas more FOXP3+ regulatory T cells were detected in patients who did not exhibit B symptoms and who were in the low-risk FLIPI group. Higher infiltration of CD68+ macrophages was identified more frequently in patients lacking BM involvement and with a low Ann Arbor stage (I or II), whereas lower infiltration of CD57+ cells was detected more persistently in patients with fewer than four nodal sites and without BM involvement and also in patients who were included in the low-risk FLIPI group. No significant differences in the number of infiltrated immune cells or LDH and hemoglobin levels were observed between the different age and sex groups of FL patients. The number of infiltrated TIA-1+ cytotoxic cells and CD123+ plasmacytoid cells did not differ significantly between the different groups of patients.
Examination of the relationship between the histologic grade of FL patients (low grade, 1 to 2 v high grade, 3) and the immune cells present in the microenvironment revealed fewer infiltrated CD68+ macrophages (mean, 52.0 ± 44.3 v 71.5 ± 44.7 macrophages, respectively; P = .002) and more CD57+ cells (mean, 192.9 ± 65.5 v 161.1 ± 64.8 cells, respectively; P = .006) in low-grade patients. Although the histologic grade was not significantly associated with survival of FL patients, a low grade (1 or 2) seemed to be significantly associated with the presence of B symptoms ( 2 test, P = .006) and BM involvement (2 test, P < .00001). The multivariate analyses, which were performed to assess the prognostic significance of immune infiltration and clinical and tumoral features for OS, indicated that only a high FLIPI value was associated with a shorter OS time (Cox hazard regression model; relative risk = 7.761; 95% CI, 1.913 to 31.477; P = .004). CD8+ T lymphocytes and histologic grade were not prognostic factors for the survival of FL patients.
Recent gene profiling studies have provided evidence of the decisive role of the reactive microenvironment in the clinical outcome of FL patients.2-4,16 The aggressiveness of the disease seems to be conditioned by the presence of T lymphocytes and accessory cells such as dendritic cells and macrophages.17-19 Indeed, the presence of the latter type has been shown to predict survival.5 However, gene expression studies do not allow us to distinguish the immune cells within the follicles from those outside the follicles, and contradictory results have been reported in separate studies related to T-cell rich and T-cell poor FL patients.20-26 In our cohort of patients, the immunohistochemical localization of reactive components showed that there were frequently more infiltrated T lymphocytes and macrophages, but fewer infiltrated CD57+ cells, in the group of FL patients with indolent clinical behavior. The correlation study showed a positive relationship between the representative elements of the specific immunity (CD4+ and CD8+ T lymphocytes) and the predominant constituent of the nonspecific immunity (CD57+ cells and CD68+ macrophages). The number of FOXP3+ regulatory T cells, with a capacity to migrate to follicles and suppress germinal center CD4+ T-helper (Th) cells,27 correlated with the presence of CD4+ T lymphocytes. CD57+CD4+ T cells are known to be the main Th-cell subset for germinal center B cells that drive B-cell production of immunoglobulin.28 The number of CD8+ T lymphocytes was also associated with the quantity of CD57+ cells and CD68+, CD123+ cells, representative of macrophage-, dendritic cell–, and plasmacytoid cell–mediated nonspecific immunity, respectively. These cells were associated with the cytotoxic expression of TIA-1+ cells. These results imply that there is a balance between specific and nonspecific immunity. Probably this is related to the diverse cytokines and interleukins present in the medium and arises by direct contact with tumoral cells, especially for cells of nonspecific immunity. Significant differences were observed in the host immune response between patients with indolent clinicobiologic behavior and aggressive clinicobiologic behavior. There was a clear disparity in the number of T lymphocytes, regulatory T cells, and macrophages with respect to the type of host response to the tumor and also in relation to the characteristics reflecting the invasive potential of the tumor. Patients with an immunosurveillance pattern, restrictive tumoral cell migration, and low aggressive potential, showed significantly greater infiltration of tumoral T lymphocytes and macrophages. These results are consistent with the greater infiltration of T lymphocytes observed in low-grade FL with spontaneous regression,29 the relatively low absolute number of T cells observed on transformation,4,30,31 and the role of naïve and memory T cells in downregulating tumor proliferation rate.20 Previous studies have demonstrated that a lower abundance of macrophages and the presence of regulatory T cells are related to a better outcome in FL.5,6 The discrepancy with our results could be a result of the restrictive criteria used for patient inclusion in the previous study (younger than 61 years of age and advanced-stage FL). Moreover, the location of immune cells in the tumor and the method used to quantify the positive cells could explain the different results obtained in our study. Although there is no conclusive evidence regarding the association between our immunohistochemical results and the clinicobiologic features of FL patients, the schematic representation of the two possible ways of specific and nonspecific host response shown in Figure 5 could be used as a guide in the search for experimental evidence.
Unlike T cells and macrophages, the higher infiltration of CD57+ cells seems to be related to unfavorable clinicobiologic factors in FL. In addition to FOXP3+ regulatory T cells, the CD57+ cells have been described as representing another subset of CD4+ Th cells that differ from the classic Th cells because they do not enhance B-cell proliferation and differentiation without the addition of exogenous interleukin-232 and they produce few cytokines in vitro compared with the CD4+CD57– subset.33,34 Nevertheless, unlike FOXP3+ regulatory T cells, CD4+CD57+ T cells reside only within germinal centers, and functional results have shown that these cells are able to regulate the duration and/or the magnitude of CD4+ T-cell responses by giving instructions for Th2 differentiation or by furnishing T-cell unresponsiveness.35,36 The grading of FL has poor reproducibility even when carried out by experienced hematopathologists and pathologists.4,37 Most reports about prolonged survival in grade 3 FL indicate that differences in survival are a result of other prognostic factors, especially limited-stage disease and FLIPI.38,39 Nevertheless, our results indicate that patients with grade 1 or 2 disease show a significantly higher percentage of B symptoms and BM involvement than patients with grade 3 FL. These results are consistent with the fact that normal germinal centers are rather closed compartments that allow for independent clonal evolution of the included B cells, whereas the neoplastic follicles seem to permit interfollicular tumor cell trafficking, particularly in low-grade patients.40-42 In this study, the heterogeneity of therapy did not have a significant impact on treatment outcome and does not require us to revise our conclusions regarding the associations between the immune features and the clinicobiologic data. These observations are in line with our statement regarding the existence of specific immune patterns directly associated with the clinicobiologic features of FL and not with clinical outcome. In summary, the host response in FL could be represented, in one way, by the nonspecific inflammatory infiltrate that seems to be mainly involved in the control of growth and expansion of tumoral cells and, in another way, by the specific immune infiltrate that seems to be principally involved in the host immune response against the tumor and the main clinical features. Both systems seem to emerge directly associated with the capacity to disseminate tumoral cells, BM involvement, and the presence of B symptoms. Further experimental studies will be necessary to corroborate the biologic basis of these findings, especially in homogenous clinical series of rituximab-treated FL patients. These data are of interest given our increasing appreciation of the importance of the immune response and its cellular components in the biology of FL.
The authors indicated no potential conflicts of interest.
We thank FI Camacho for sharing the tissue microarrays and patients’ medical data; all members of the Spanish Lymphoma Study Group; and Maria del Mar Barberà, Rosa Risa, Bàrbara Tomàs, Vanesa Gestí, Ana Suñé, and Marc Iniesta for their technical assistance.
Supported by Grants No. G03/179 and FIS 05/0474 from the Ministerio de Ciencia y Tecnología, Spain. Some results were presented at XXII Jornades Mèdiques i Ciències de la Salut de les Terres de L’Ebre, February 24–25, 2006, Tortosa, Spain. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
60 v > 60 years), Ann Arbor stage (I and II v III and IV), hemoglobin level (
), whereas single-headed arrows (
) show a positive mutual correlation. Statistics are reported in the text.
