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The Ratio of FOXP3+ Regulatory T Cells to Granzyme B+ Cytotoxic T Hematopathology / FOXP3+ T CELL–GRANZYME B+ T/NK CELL RATIO The Ratio of FOXP3+ Regulatory T Cells to Granzyme B+ Cytotoxic T/NK Cells Predicts Prognosis in Classical Hodgkin Lymphoma and Is Independent of bcl-2 and MAL Expression Todd W. Kelley, MD,1 Brad Pohlman, MD,2 Paul Elson, ScD,3 and Eric D. Hsi, MD1 Key Words: FOXP3; Regulatory T-cells; Granzyme B; Cytotoxic T/NK cells; Hodgkin lymphoma; bcl-2; MAL Downloaded from https://academic.oup.com/ajcp/article/128/6/958/1765062 by guest on 30 September 2021 DOI: 10.1309/NB3947K383DJ0LQ2 Abstract Classical Hodgkin lymphoma (cHL), a neoplasm of ger- We studied the prognostic importance of tumor- minal center B-cell derivation,1 accounts for approximately infiltrating regulatory T lymphocytes (Tregs) and 10% of all lymphomas. Hodgkin–Reed-Sternberg (HRS) cells, cytotoxic T/NK lymphocytes (CTLs) in 98 diagnostic the neoplastic component of cHL, usually constitute less than biopsy specimens from patients with classical Hodgkin 1% of the cellularity of the tumor. The majority of the cells in lymphoma (cHL). Immunohistochemical analysis was the tumor are reactive and consist predominantly of T cells performed for FOXP3 to identify Tregs and for with variable numbers of other inflammatory cells, such as granzyme B (GrB) to identify activated CTLs. Failure- macrophages, neutrophils, eosinophils, and plasma cells. free survival (FFS) and overall survival (OS) were Clinically, cHL has a favorable prognosis with overall survival clinical end points. Patients with fewer than 25 of approximately 80% among all patients using modern thera- FOXP3+ cells per high-power field (HPF) had a mean py. Because of this success and the young age of most patients, ± SD 5-year FFS of 64% ± 7% vs 85% ± 5% for recent efforts have been aimed at reducing therapy to avoid late patients with 25 or more FOXP3+ cells/HPF (P = .05). complications. However, a significant minority of patients will A FOXP3/GrB ratio of 1 or less was associated with have a progressive or relapsing clinical course despite aggres- poor FFS (46% ± 10% vs 86% ± 4%; P < .001) and sive treatment and eventually die of the lymphoma. OS (67% ± 10% vs 93% ± 3%; P < .001). When prior Prognostic scoring systems such as the international prog- available MAL and bcl-2 expression data were included nostic score (IPS) have been developed. The IPS risk stratifies in a multivariate analysis of all clinical and biologic patients according to 7 high-risk features, including hypoalbu- factors, a FOXP3/GrB ratio of 1 or less and tumor cell minemia, anemia, leukocytosis, lymphopenia, stage IV, male expression of MAL and bcl-2 all independently predicted sex, and age of 45 years or older.2 Biologic markers may give poor FFS. This demonstrates the importance of evaluating additional information that results in improved patient risk strat- tumor cell markers and the tumor immune infiltrate ification, and several have recently been identified. For example, when considering biologic prognostic markers in cHL. features of the HRS cells, such as bcl-2 or MAL expression, have been shown to be independent indicators of a poor prognosis.3-5 Characteristics of the nonneoplastic immune cell infil- trate within the lymphoma tumor bed may also be prognosti- cally important. The nature of the infiltrate may be influenced by various cytokines or chemokines elaborated by the tumor cells6-8 and by latent Epstein-Barr virus (EBV) infection.9 In particular, characteristics of the background immune response have been shown to be important in follicular lymphoma.10 Indeed, gene expression profiling studies of cHL also suggest that genes related to the tumor microenvironment are important 958 Am J Clin Pathol 2007;128:958-965 © American Society for Clinical Pathology 958 DOI: 10.1309/NB3947K383DJ0LQ2 Hematopathology / ORIGINAL ARTICLE in predicting prognosis.11 Interest has grown in the role of reg- Paraffin-embedded tissue blocks, obtained at the time of the ulatory T cells (Tregs) in tumor immunity. They have been initial diagnostic procedure, were retrieved from the archives shown to be important modulators of the immune response in of the Division of Pathology and Laboratory Medicine, the setting of transplantation,12-15 autoimmune disease,16 Cleveland Clinic, Cleveland, OH. TMAs were constructed infection,17,18 and neoplasia.19 using two to four 1.0-mm cores per case. In this study, we sought to evaluate the T/NK-cell subset Immunohistochemical staining was performed using anti- composition of cHL cases from our institution. Specifically, bodies to FOXP3 (clone 22510, Abcam, Cambridge, England) we correlated the number of intratumoral Tregs (as deter- to identify regulatory T cells and GrB (clone GrB-7, Accurate mined by FOXP3 expression) and the number of activated Chemical, Westbury, NY) to identify activated CTLs. Staining granzyme B (GrB)+ cytotoxic T/NK lymphocytes (CTLs) was performed using a Ventana Discovery automated with clinical factors and outcome. Furthermore, we also eval- immunostaining system (Ventana, Tucson, AZ). Data were Downloaded from https://academic.oup.com/ajcp/article/128/6/958/1765062 by guest on 30 September 2021 uated the ratio of tumor infiltrating FOXP3+ cells to GrB+ obtained by counting 5 separate 1,000× high-power fields cells (FOXP3/GrB ratio) in predicting survival. (HPFs) and calculating the mean number of positively stain- ing cells per HPF. Counts were performed using an Olympus CX31 microscope (Olympus America, Center Valley, PA). Materials and Methods Hypocellular, fibrous bands associated with the nodular scle- rosis subtype were avoided. Appropriate positive and negative Case Selection control stains were generated and evaluated. We identified 98 consecutive cases with paraffin-embedded For quality control purposes and to evaluate interobserv- archival tissue from the initial diagnostic procedure and adequate er reproducibility, 11 (11%) of 98 cases were recounted by a clinical follow-up for inclusion in this study. HIV+ cases were second observer. A comparison of the 2 data sets showed excluded. All patients were initially treated with curative intent excellent reproducibility (FOXP3, Spearman correlation coef- according to the standard of care at the time of diagnosis. ficient, 0.93; P < .001; GrB, Spearman correlation coefficient, However, owing to the long study period (between January 1988 0.94; P < .001). The FOXP3/GrB ratio change did not change and December 2002), standards of care changed, and, conse- significantly in any of the recounted cases. TMAs were qual- quently, the study patients did not receive uniform treatment. The itatively evaluated (positive or negative) for MAL and bcl-2 general treatment regimens were as follows: patients with early- immunoreactivity in HRS cells as described previously.3,5 stage disease received radiation therapy (RT) alone or combina- tion chemotherapy that may have also included RT. Patients with Statistical Analysis advanced-stage disease received combination chemotherapy with OS was defined as the period from initial diagnosis to or without RT. Patients in whom treatment failed after primary death of any cause. FFS was defined as time from initial diag- RT received combination chemotherapy. Patients who experi- nosis to progression of cHL or death of any cause. OS and enced treatment failure after initial chemotherapy received sal- FFS were summarized by using the method of Kaplan and vage chemotherapy and may have also received high-dose thera- Meier. The Wilcoxon rank sum test was used to evaluate asso- py with autologous stem-cell transplantation. These cases have ciations between intratumoral FOXP3+ cells or GrB+ cells been reported in earlier unrelated studies.3 and clinical factors (ie, sex, age, stage, IPS, presence of bulky The medical records were reviewed for clinical character- disease, and histologic subtype). The generalized Wilcoxon istics, including sex, age, stage, IPS, presence of bulky disease, rank sum was used to evaluate outcome. The Cox proportion- presence of B symptoms, number of involved sites, disease al hazards model, with stepwise variable selection, was used progression, and survival. Histologic features were reviewed; to simultaneously assess multiple factors. Significance was set all cases were diagnosed as classical Hodgkin lymphoma at a P value of .05 or less for univariate and multivariate analy- according to the World Health Organization classification ses. The association between the number of intratumoral scheme.20 Histologic subtype (nodular sclerosis, mixed cellu- FOXP3+ cells and GrB+ cells was evaluated using the larity, lymphocyte-rich, lymphocyte-depleted) was noted. Spearman rank correlation coefficient. For convenience, the Survival analysis was performed using failure-free survival numbers of intratumoral FOXP3+ cells and GrB+ cells were (FFS) and overall survival (OS) as clinical end points. dichotomized in the OS and FFS analyses using cut points derived from a recursive partitioning algorithm that identified Immunohistochemical Analysis an optimal FOXP3 cut point of 25 positive cells per HPF. The Tissue microarrays (TMAs) have been shown to be a power- optimal GrB cut point was 7.5 positive cells per HPF. In addi- ful tool for the evaluation of large numbers of samples under iden- tion to evaluating the impact of the absolute number of tical immunohistochemical staining conditions with excellent cor- FOXP3+ and GrB+ cells present, the impact of their relative relation with whole tissue sections, including in lymphoma.21 presence was also assessed. Again using recursive partitioning, © American Society for Clinical Pathology Am J Clin Pathol 2007;128:958-965 959 959 DOI: 10.1309/NB3947K383DJ0LQ2 959 Kelley et al / FOXP3+ T CELL–GRANZYME B+ T/NK CELL RATIO a FOXP3/GrB ratio of 0.85 was identified as an optimal cut to be 76% ± 4% and 86% ± 4%, respectively. Of 98 patients, point; however, for convenience, this was rounded to 1.0. 70 (71%) remained alive and free of progression at a median of 8.6 years (range, 11 months to 19.9 years). A shorter FFS was associated with an age of 45 years or older (P = .05) and an IPS Results of more than 2 (P = .05).
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