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Originally published as JCO Early Release 10.1200/JCO.2006.10.0917 on May 29 2007 © 2007 American Society of Clinical Oncology. HLA Class II Expression by Hodgkin Reed-Sternberg Cells Is an Independent Prognostic Factor in Classical Hodgkin's Lymphoma
From the Departments of Pathology, Hematology, Genetics and Epidemiology, University Medical Center Groningen, University of Groningen; and the Comprehensive Cancer Center North Netherlands, Groningen, the Netherlands Address reprint requests to Arjan Diepstra MD, Department of Pathology and Laboratory Medicine, University Medical Center Groningen, Hanzeplein 1, PO Box 30.001, 9700 RB Groningen, the Netherlands; e-mail: a.diepstra{at}path.umcg.nl
Purpose The neoplastic Hodgkin Reed-Sternberg (HRS) cells in classical Hodgkin's lymphoma (cHL) are derived from B cells. The frequency of HLA class II downregulation and its effect on prognosis are unknown. Patients and Methods Immunohistochemistry results for HLA class II were evaluated in 292 primary cHL patients in a population-based approach. Patients were diagnosed between 1989 and 2000 in the northern part of the Netherlands. Median age at diagnosis was 38 years (range, 8 to 88 years); 63% had Ann Arbor stage I or II, 24% stage III, and 13% stage IV disease. Median follow-up was 7.1 years. For 168 patients, HLA genotype data were available. Results Lack of HLA class II cell-surface expression on HRS cells was observed in 41.4% and was more common in patients with extranodal disease, patients with Epstein-Barr virus–negative disease, and patients with HLA class I–negative HRS cells. Alleles of three microsatellite markers in the HLA class II region were associated with presence or absence of protein expression. In univariate analyses, lack of HLA class II expression coincided with adverse outcome (5-years failure free survival [FFS], 67% v 85%; P = .001; 5-years age and sex matched relative survival (RS), 80% v 90%; P = .027). This effect remained in multivariate analyses for FFS with a hazard ratio of 2.40 (95% CI, 1.45 to 3.98) and RS with a relative excess risk of death of 2.55 (95% CI, 1.22 to 5.31). Conclusion Lack of membranous HLA class II expression by HRS cells in diagnostic lymph node specimens is an independent adverse prognostic factor in cHL.
Patients with classical Hodgkin's lymphoma (cHL) can be assigned to early stage and advanced stage of disease on the basis of the Ann Arbor staging system with Cotswolds modification. Most cHL trial groups subclassify their early-stage patients in favorable and unfavorable (intermediate) groups, based on additional risk factors, such as bulky mediastinal disease, age, erythrocyte sedimentation rate, and number of involved nodal sites.1 In addition, the International Prognostic Score (IPS), which incorporates age, stage, sex, and a number of laboratory values, is of prognostic significance especially in advanced disease.2,3 With current treatment protocols adapted to cHL stage and risk group, the expected freedom from treatment failure after 5 years ranges from more than 90% for patients with early-stage favorable disease, to 55% for those with advanced-stage disease and IPS scores of 3 or higher.2 Thus, some cHL patients still experience relapse or have primary refractory disease and these patients might benefit from more intensive first-line therapy. In contrast, there is also a need to diminish treatment-related late toxic effects. Cardiovascular diseases, solid malignancies, and secondary leukemias amount to an annual rate of more than 1% of deaths due to cHL unrelated causes even 20 years after treatment.4 To further improve outcome in cHL patients, and to minimize late toxic adverse effects, improvement of risk stratification at the time of diagnosis is still needed. Biologic features of cHL may add prognostic information to the current clinical staging systems.5 The neoplastic Hodgkin Reed-Sternberg (HRS) cells of cHL are derived from germinal center B cells that express the HLA class II antigen-presenting family of glycoproteins. As has been proposed for B-cell non-Hodgkin's lymphoma, downregulation of HLA class II by HRS cells may help these cells to escape immune responses.6-11 Occurrence of cHL (and non-Hodgkin's lymphoma) has been associated with a number of HLA class II alleles and serotypes.12,13 These associations may reflect differential binding affinity of the HLA class II molecule with immunogenic antigenic peptides. The purpose of this study is to relate HLA class II expression by HRS cells with HLA class II genotypes and prognosis in a large population of cHL patients.
All 562 Hodgkin's lymphoma patients who were diagnosed from January 1989 through December 2000 and registered in the regional cancer registry of the Comprehensive Cancer Centre North Netherlands were selected. The histology of the diagnostic lymph node biopsies was reclassified according to the WHO classification by two hematopathologists and presence of Epstein-Barr virus (EBV) in HRS cells was detected by in situ hybridization for EBV-encoded small RNAs.14 Eighty-two patients were excluded because there was not enough material for reclassification. Another 39 patients were excluded because there was another malignancy at the time of diagnosis (n = 15), diagnosis was established at autopsy (n = 8), or because clinical data were lacking (n = 16). Cases of the nonclassical nodular lymphocyte predominant HL subtype (n = 23) were excluded from the analyses. Thus, 418 patients were eligible for our study. Patients were classified at initial diagnosis according to the Ann Arbor staging system with Cotswolds modification. Additional clinical data collected were age, sex, presence or absence of B symptoms, bulky disease, extranodal disease, year of diagnosis, and type and intensity of treatment. Dates of treatment failure and death were recorded until January 2005. Microsatellite marker profiles of the HLA region were available from 168 patients and first-degree relatives from a previous genotyping study.14 The study was approved by the medical ethics board of the University Medical Center Groningen.
Immunohistochemistry
Sections stained for HLA class II were only scored when the internal positive control (lymphocytes and sometimes vascular structures) showed consistent staining and when at least 50 HRS cells were present for evaluation. Membranous staining of HRS cells was scored positive if there was accentuation relative to the surrounding lymphocytes or when present in between adjacent HRS cells. Lack of membranous staining between adjacent HRS cells was denoted as negative. In cases with both negative and positive staining, the predominant staining pattern (> 50%) determined the score. Differences between HLA class II–positive and –negative patients in subgroups were analyzed using a
Genetic Associations
Survival Analysis
Patient Characteristics Clinicopathologic characteristics are summarized in Table 1. HLA class II expression could be determined in lymph node tissue of 292 (70%) of 418 patients and this group was comparable with the patients that could not be evaluated. Most patients with extranodal disease had widespread disease and were classified as Ann Arbor stage IV (38 of 43). Five patients had localized extranodal growth in contiguity with a nodal localization (IIE, n = 3; IIIE, n = 2). In the majority of patients, first-line treatment consisted of chemotherapy combined with radiotherapy or chemotherapy only (82%). A small number of patients diagnosed between 1989 and 1992 with pathologic stage I or stage II disease were treated with radiotherapy only.
HLA Class II Protein Expression Cell surface expression of HLA class II on HRS cells was lacking in 41.4% of patients (Fig 1). Lack of membranous HLA class II was more frequent in nodal biopsies in patients with extranodal disease (Ann Arbor stage IV), patients with EBV-negative cHL, and patients with HLA class I–negative HRS cells. cHL patients with the mixed cellularity subtype were most often HLA class II positive (Table 2). In the absence of HLA class II cell surface expression, the HRS cells showed cytoplasmic staining in 37.2% of patients (15.4% of all patients), varying from predominant Golgi area staining to diffuse staining of the cytoplasm.
Genotypes and HLA Class II Protein Expression Association analysis showed that alleles of three of four consecutive microsatellite markers had significantly different frequencies in patients with HRS cells that expressed HLA class II on the cell surface compared with patients with HRS cells that did not. These markers were D6S2444, D6S1666, and D6S2665, all located in the HLA class II region. Some alleles were associated with HLA class II–positive cHL, while others were associated with HLA class II–negative cHL. Sex and age adjusted odds ratios were significant for heterozygotes (P  .05), but could not be determined or were nonsignificant for homozygotes because the number of homozygotes were too small (Table 3).
FFS and RS The median follow-up time was 7.1 years. One patient did not receive treatment and was excluded from the FFS analysis. Another patient was excluded from the analyses because follow-up data were missing. Factors influencing FFS in univariate analysis were age, Ann Arbor stage, extranodal disease, and HLA class II–expression status. Year of diagnosis, sex, B symptoms, bulky disease, subtype, and EBV status were nonsignificant factors. Five-year FFS was 67% for HLA class II–negative patients compared with 85% for HLA class II–positive patients (P = .001; Table 4; Fig A1, online only). In multivariate analysis, the effect of a lack of membranous HLA class II was independent of age and extranodal (stage IV) disease with a hazard ratio of 2.40 (95% CI, 1.40 to 4.11; P = .001).
RS was defined as excess mortality over and above the mortality of the general Dutch population per calender year, accounting for age and sex. In univariate analysis, RS was influenced by extranodal disease, age, and HLA class II expression, but not stage (P < .1), sex (P < .1), year of diagnosis, B symptoms, bulky disease, subtype, or EBV status (Table 5). HLA class II–negative patients had a 5-year RS of 80%, compared with 90% in HLA class II–positive patients (P = .027). Multivariate analysis showed that HLA class II was a prognostic factor independent of age, sex, and extranodal (stage IV) disease with a relative excess risk of death of 2.55 (95% CI, 1.22 to 5.31; P = .013) for patients with HLA class II–negative HRS cells.
In this population-based study, we show that lack of membranous expression of HLA class II by HRS cells of cHL is common at primary diagnosis. This lack of membranous expression is associated with extranodal disease, lack of EBV in HRS cells, absence of HLA class I expression by HRS cells, and a number of specific alleles of microsatellite markers located in the HLA class II locus in patients. In our study, lack of HLA class II expression associated with adverse FFS and RS, independent of other prognostic factors. Evaluation of immunohistochemical expression of HLA class II by HRS cells is not difficult and can easily be done in a routine setting. The cells surrounding the HRS cells are usually HLA class II–negative T lymphocytes that do not obscure (lack of) membranous staining in the HRS cells and B lymphocytes in the reactive infiltrate are a useful positive control. In our study, cell surface expression of HLA class II on HRS cells was absent in 41% of cHL patients. Since HRS cells derive from germinal center B cells, lack of HLA class II expression reflects downregulation. The mechanisms involved are diverse since we observed different staining patterns including no cytoplasmic staining at all, diffuse cytoplasmic staining, and predominant Golgi area staining. Downregulation of HLA class II probably occurs as a late event in the natural course of the disease, as the proportion of HLA class II downregulated patients in our study increased with advanced (stage IV) disease. We found that expression of HLA class II by HRS cells is retained more often in EBV-associated cHL, in the mixed cellularity subtype, and in HLA class I–positive HRS cells. This is consistent with the observations that EBV-involved cHL is associated with the mixed cellularity subtype and shows expression of HLA class I in approximately 80% of patients compared with approximately 20% in EBV–negative patients (in our study 73% in EBV positive and 20% in EBV negative; manuscript in preparation).17-19 Several observations suggest that antigen presentation is involved in the pathobiology of cHL. In cHL cell lines, HRS cells stimulate T-cell proliferation in mixed lymphocyte reactions and induce cytotoxic activity in cytotoxicity assays.18,20 In situ, HRS cells have lost the majority of B-cell surface markers and transcription factors at the time of diagnosis, but they usually retain expression of molecules involved in antigen presentation, including adhesion molecules and costimulatory glycoproteins.21-25 In addition, there are many candidate cells to which antigen could be presented because HRS cells are suspended within an abundant reactive infiltrate, rich in polyclonal populations of CD4-positive T cells, and, to a lesser extent, also CD8-positive T cells.26,27 A possible explanation for the prognostic impact of HLA class II–expression status might be that HLA class II directly activates T-helper 1 (Th1) cells, thereby inducing and maintaining cytotoxic antitumor immune responses. However, there is no evidence for a predominant Th1 immune response in cHL. On the contrary, the reactive infiltrate is reported to consist mainly of anergic and T-helper 2 (Th2) –like cells,26,28 and recently at least a proportion of these cells were shown to have features of regulatory T cells (Treg).29 Both Th2 and Treg cells can inhibit Th1 responses.30 Thus, although the precise composition of different CD4–positive T cell subgroups in cHL is difficult to establish, it is likely that the reactive infiltrate contributes to inhibition of cytotoxic responses.28,31 Accordingly, we hypothesize that lack of HLA class II expression results in diminished activation of Th2 and/or Treg cells. How might diminished activation of Th2 and/or Treg cells explain adverse prognosis in patients who have downregulated HLA class II? To address this question, it is important to realize that HRS cells depend on trophic factors present in the reactive infiltrate. The constitutive activation of nuclear factor kappa B observed in HRS cells is essential for tumor cell survival and depends on activation of tumor necrosis factor receptors by ligands provided by T cells in the reactive infiltrate.28,32 However, HRS cells can also produce tumor necrosis factor–receptor ligands themselves and stimulate in an autocrine fashion.33 In addition, HRS cells do not exclusively depend on the reactive infiltrate for inhibition of cytotoxic responses as they secrete immunosuppressive cytokines interleukin-10 and transforming growth factor ß and express death-inducing Fas ligand.28,34 We speculate that HRS cells initially are highly dependent on the reactive infiltrate, but as the disease progresses this dependency may weaken because of alternative trophic and immunosuppressive strategies. Thus, downregulation of HLA class II without loss of viability of HRS cells might occur when the HRS cells have grown less dependent on the reactive infiltrate. A number of studies have indeed shown that a decrease in Treg cells and an increase in activated cytotoxic T cells are associated with adverse prognosis in cHL.35-38 We found that three microsatellite markers mapping in the HLA class II locus were associated with the HLA class II–expression status. Although genetic fine-screening is needed to pinpoint the precise polymorphism(s), it can be anticipated that these markers associate with one or more HLA class II gene(s). We speculate that some HLA class II alleles may be less efficient in inducing T-cell responses that aid HRS cell survival. This would provide a stronger selection pressure on HRS cells to develop alternative trophic and immunosuppressive strategies. These HLA class II alleles would then be associated with early independency, HLA class II downregulation, and adverse prognosis. Interestingly, Voo et al39 have shown that certain HLA class II allotypes that present EBV-derived EBNA-1 antigenic peptides, preferentially activate Treg cells instead of Th cells. In agreement with our hypothesis, this may explain why expression of HLA class II by HRS cells is retained more often in EBV-associated cHL. Because genotyping was done on blood samples from patients who were alive, it was not possible to study the effect of risk haplotypes on survival. We did not find an effect of risk haplotypes on FFS (n = 122), but the number of events (12%) was too low to draw a firm conclusion (results not shown). We expect that HLA class II alleles may modify the chance of HLA class II being downregulated, but are less strong predictors of adverse prognosis than HLA class II protein expression. The components of the Ann Arbor staging system with Cotswolds modification and the IPS reflect crude measures of tumor burden, tumor activity, and patient factors.40 Most of these factors were incorporated in the FFS and RS analyses in this study, but unfortunately, we did not have sufficient data for determining the IPS (serum albumin, hemoglobin, WBC count, and lymphocyte count) in all patients. However, it is unlikely that these factors are related to expression of HLA class II by HRS cells and vice versa. Stage and IPS provide prognostic information at the time of diagnosis in cHL. In addition, [18F]fluorodeoxyglucose positron emission tomography scanning is very useful in detecting viable tumor and has been shown to have prognostic impact during and after therapy.41-43 Combined, these important tools determine current treatment strategies. In addition, a number of tumor biologic markers have been studied to predict treatment outcome in cHL. Serum levels of soluble CD30 and the chemokine TARC, both highly expressed by HRS cells, reflect tumor burden or presence of residual disease.44-47 High expression of activated caspase 3, a central component of the apoptosis pathway in HRS cells, is associated with chemosensitivity and improved outcome.48 Expression of the antiapoptotic protein bcl-2 by HRS cells is reported to have adverse prognostic value.49,50 Unfortunately, these factors have not yet been validated in prospective studies. We have addressed the significance of antigen presentation in cHL and have shown that membranous expression of HLA class II by HRS cells is an independent prognostic factor. HLA class II–expression status may be a promising addition to current prognostic scores in cHL and merits validation in a large prospective study.
The author(s) indicated no potential conflicts of interest.
Conception and design: Arjan Diepstra, Gustaaf W. van Imhoff, Anke van den Berg, Gerard J. te Meerman, Edo Vellenga, Sibrand Poppema Administrative support: Arjan Diepstra, Henrike E. Karim-Kos Provision of study materials or patients: Gustaaf W. van Imhoff, Edo Vellenga Collection and assembly of data: Arjan Diepstra, Henrike E. Karim-Kos, Marijke Niens Data analysis and interpretation: Arjan Diepstra, Gustaaf W. van Imhoff, Henrike E. Karim-Kos, Gerard J. te Meerman, Ilja M. Nolte, Esther Bastiaannet, Michael Schaapveld, Sibrand Poppema Manuscript writing: Arjan Diepstra, Gustaaf W. van Imhoff Final approval of manuscript: Arjan Diepstra, Gustaaf W. van Imhoff, Henrike E. Karim-Kos, Anke van den Berg, Gerard J. te Meerman, Marijke Niens, Ilja M. Nolte, Esther Bastiaannet, Michael Schaapveld, Edo Vellenga, Sibrand Poppema
We thank Marcel Boot, Inge Platteel, Tineke van der Sluis, Tjasso Blokzijl, and Geert Harms from the Department of Pathology and Laboratory Medicine, University Medical Center Groningen, Groningen, the Netherlands, for performing immunohistochemical analyses.
published online ahead of print at www.jco.org on May 29, 2007. Supported by the Dutch Cancer Society (KWF Grant No. RUG 2000-2315) and the Dutch Organization of Scientific Research (NWO-MW Grant No. 920-03-136). Presented at the 47th Annual Meeting of the American Society of Hematology, Atlanta, GA, December 10-13, 2005. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test or Fisher's exact test when appropriate. 
