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Journal of Clinical Oncology, Vol 25, No 22 (August 1), 2007: pp. 3330-3336 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.10.5833 Tumor Sclerosis but Not Cell Proliferation or Malignancy Grade Is a Prognostic Marker in Advanced-Stage Follicular Lymphoma: The German Low Grade Lymphoma Study Group
From the Department of Pathology, Hematopathology Section and Lymph Node Registry; Department of Internal Medicine II, Campus Kiel, Kiel; Department of Pathology, Campus Lübeck, University Hospital Schleswig-Holstein, Lübeck; Department of Internal Medicine III, University of Munich, Munich; Department of Pathology, University of Frankfurt, Germany; Department of Pathology, University of Ulm, Ulm; Department of Pathology, University Hospital Charité, Campus Benjamin-Franklin, Berlin; and Department of Pathology, University of Würzburg, Würzburg, Germany Address reprint requests to Wolfram Klapper, MD, Department of Pathology, Hematopathology Section, Niemannsweg 11, 24105 Kiel, Germany; e-mail: wklapper{at}path.uni-kiel.de
Purpose Follicular lymphoma is an indolent lymphoma with a long median overall survival. However, a considerable number of patients die within the first 2 years after the onset of the disease. Because the treatment options vary with respect to antitumor effect and potential toxic adverse effects, the identification of high-risk patients would be helpful in directing therapeutic decisions in individual patients. Several histopathologic biomarkers for risk stratification have been suggested, but most markers have not been validated in patients treated in prospective trials. Patients and Methods We report a comprehensive approach to evaluate histopathologic biomarkers, including WHO grade, histology, and proliferation and quantitation of immune bystander cells, in 158 patients with nodal advanced-stage follicular lymphoma treated first line within a randomized trial. Results Tumor sclerosis was a significant prognostic marker of poor overall survival that was independent of the Follicular Lymphoma International Prognostic Index (FLIPI). WHO grade, proliferation, and total T-cell or macrophage content were not associated with overall survival. Conclusion The presence of sclerosis within the lymphoma is a marker of poor overall survival that is independent of the FLIPI. The quantification of macrophage or absolute T-cell content, grading, and proliferation are of no help in predicting the outcome of FL. Future studies need to identify surrogate markers for the prognostic immune signatures identified by gene expression profiling. Most importantly, new prognostic markers need to be confirmed in patients treated within prospective trials.
Follicular lymphoma (FL) is the second most frequent B-cell non-Hodgkin's lymphoma (B-NHL).1 With current treatment protocols, FL is still not curable, and most patients experience multiple relapses, with variable times to treatment failure.2-4 Although the majority of FL patients initially present with disseminated disease (stages III and IV), the clinical course is often indolent with slow progression.3 In some patients, however, the disease progresses rapidly, often with transformation into an aggressive B-cell lymphoma. Thus, although the median survival of patients with FL is 8 to 10 years, approximately 10% to 20% of patients die as a result of their disease within the first 2 years after diagnosis.3,4 Treatment strategies in FL are variable and differ in terms of their antitumor efficacy and potential toxic adverse effects. The spectrum of clinical options includes watchful waiting, chemotherapy, immunochemotherapy, and myeloablative chemo- or chemoradiotherapy with subsequent stem-cell transplantation.2 Although the introduction of immunochemotherapy using the anti-CD20 antibody rituximab substantially improved the treatment response of many B-NHLs, including FL,5,6 there is currently no obvious agreement concerning the standard treatment of FL.2 Given the heterogeneity of the clinical course, the identification of high-risk patients at the time of initial diagnosis would be helpful in the choice of treatment. Prognostic markers in FL have been defined based on clinical features,7 genetic alterations,8,9 and tumor histology.1 More recently, gene expression profiling resulted in the identification of the host immune response as an important prognostic biomarker for survival10 that is based, interestingly, on the quality of non-neoplastic bystander cells (T cells and macrophages) within the tumor. Most biomarkers, however, have not been validated within prospective trials. In the present study, we analyzed features derived from tumor histology and immunophenotype as well as from non-neoplastic bystander cells in 158 patients with advanced-stage FL enrolled in the German Low Grade Lymphoma Study Group (GLSG) prospective trial GLSG 1996 randomly comparing first-line CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and MCP (mitoxantrone, chlorambucil, and prednisolone) chemotherapy.11
Specimen Selection The samples of study patients with the diagnosis of centroblastic-centrocytic lymphoma (according to the Kiel classification) corresponding to follicular lymphoma grades 1 to 3a (according to the WHO classification) were selected by each of reference pathology centers without knowledge of the clinical data (Appendix, online only). This procedure, as well as the whole study concept, was approved by the ethic committees of the participating institutions. Hence, the study adheres to the modified Helsinki Declaration.
Review of Histologic Features
Immunohistochemical Studies We quantified the number of tumor cells (CD20, CD10) the proliferation index (Ki-67, Repp86), the T-cell content (CD3), follicular dendritic cells (FDCs; CD23), and macrophages (Ki-M1p) in the neoplastic follicles and in the interfollicular areas separately. For CD20, CD10, CD3, Ki-67, and Repp86, the percentage of positive cells in relation to all cells in the evaluated region was estimated. Macrophages positively identified by CD68 staining were counted in three randomly chosen high-power fields (0.4-mm diameter) by one pathologist (L.R.). Table A1 shows the scoring criteria (Appendix).
Statistical Analysis To assess the prognostic impact of categoric histopathologic parameters on overall survival (OS) and time to treatment failure (TTF), Kaplan-Meier curves were calculated and group comparisons were done by means of the log-rank test. The prognostic impact of numerical parameters was assessed by univariate Cox regression and, if prognostic, adjusted for potential confounders by multiple Cox regression. Potential confounders considered were the Follicular Lymphoma International Prognostic Index (FLIPI)15 and the type of initial chemotherapy.
Clinical Characteristics We analyzed 158 of 551 patients with advanced-stage follicular lymphoma from the GLSG trial who were recruited between May 1996 and May 2000.11 One hundred six patients had been randomly assigned to receive either MCP (n = 56) or CHOP (n = 50) regimens. Four patients were not assigned (three received CHOP and one refused therapy). Forty-eight additional patients were assigned to CHOP therapy after the planned stop of initial random assignment. After initial chemotherapy, 47 responding patients underwent autologous stem-cell transplantation (ASCT), whereas 77 patients received interferon alfa (IFN  ) maintenance therapy according to the study protocol. Table 1 gives an overview of the clinical baseline characteristics of the patients. Because of trial inclusion criteria, the number of patients within the FLIPI low-risk group was relatively small. The median TTF was 33 months (median follow-up of patients without events, 75 months) and the 5-year OS was 80% (median not reached; median follow-up of patients without events, 80 months).
Cytology and Grading Results of the morphologic evaluation are depicted in Table 2. In detail, 32 (21%) of the samples, neoplastic follicles, were composed of large centrocytes.12 In these cases, a significantly higher proliferation index was ascertained, as assessed by the elevated number of Ki-67–or Repp86-positive cells in comparison with FL with small centrocytes (Ki-67: median, 30% v 20%, P = .0002; Repp86: median 10% v 5%, P = .002; both Mann-Whitney U test).
Marginal zone differentiation was detected in eight cases (5%), and a plasmacytoid/plasmacytic differentiation was recorded in five cases (3%), with one case displaying both features (Table 2). Because of the small numbers of cases in both groups, FLs displaying any kind of differentiation were lumped together for survival analysis. Neither cytologic variants nor tumor cell differentiation had any statistically significant influence on OS (log-rank P = .81 and .73, respectively). All 155 samples with appropriate tissue quality were graded according to the WHO classification as grade 1 (n = 113), grade 2 (n = 36), or grade 3 (n = 6). Only one lymphoma was graded as 3b, whereas all other grade 3 lymphomas were diagnosed as grade 3a. Tumors containing follicles with different grades (one case with grades 1 + 2, one case with grades 1 + 3a, and one case with grades 2 + 3a) were assigned to the highest grade for survival analysis. The WHO grade was assessed in the lymphoma component with follicular growth. As shown in Figure 2A, no significant difference in OS was detectable between grade 1 and 2 lymphomas. All six grade 3 lymphoma patients were alive at the time of analysis. However, because this group of grade 3 lymphomas comprised only six patients, the difference in OS was not statistically significant (Fig 2A; log-rank P = .4).
Growth Pattern and Sclerosis Areas with a diffuse growth pattern accounting for 25% to 100% (median, 50%) of the tumor area analyzed were present in 12 samples (8%; Table 2). Patients with these lymphomas tended to show poorer survival than did patients with lymphomas displaying an exclusively follicular growth pattern (log-rank P = .07). In addition, we assessed the presence and significance of tumor sclerosis (Fig 1). The majority of the 22 cases with sclerosis were grade 1 lymphomas (n = 18; 16%). As shown in Figure 2B, presence of tumor sclerosis identified a patient cohort with significantly worse OS compared with patients without sclerosis (log-rank P = .0034). The relative risk of patients with sclerosis was 2.8 (95% CI,1.4 to 5.9). Sclerosis was found in all FLIPI risk groups (four of 22 low risk, eight of 67 intermediate risk, and nine of 64 high risk; Fisher's exact test P = .73). Moreover, the prognostic impact of sclerosis on OS was statistically significant after adjusting for the FLIPI parameters in a Cox model with a hazard ratio for sclerosis of 2.6 (95% CI,1.2 to 5.4; P = .0141) and after adjusting for the FLIPI parameters and type of initial therapy (2.2; 95% CI, 1.0 to 4.7; P = .0431). The localizations of the lymph node specimens displaying sclerotic areas were cervical (n = 6; 27%), abdominal (n = 5; 23%), inguinal (n = 6; 27%), retroperitoneal (n = 2; 9%), or unknown (n = 3; 14%).
Dissemination of Tumor Cells in the Interfollicular Compartment
Immunophenotype and Proliferation All FLs analyzed within the frame of this study were bcl-2 positive, and only one case was CD10 negative. Tumor cells in eight cases were CD23 positive. There was no association of CD23 expression with diffuse growth or OS (log-rank P = .6). High tumor cell proliferation in FL has been linked to inferior survival.17 Proliferation, as assessed by Ki-67 or Repp86 expression18 correlated in the follicular and the interfollicular compartment (Pearson's correlation, 0.81 and 0.60, respectively) and with WHO grade (Table 5). However, we failed to find an association between proliferation index and TTF or OS (Tables 3 and 4).
Quantification of Immune Bystander Cells Gene expression profiling of FL has recently identified the quality of the host immune response to represent one of the major factors correlated with clinical outcome.10 Total T-cell content was assessed by estimating the number of CD3-positive cells, and macrophages were counted after staining with the pan-macrophage marker Ki-M1p (Tables 3 and 4). Additionally, the extent of networks of FDCs within the neoplastic follicles was evaluated using immunohistochemistry for CD23 (63 cases with reduced and 37 with expanded networks; Fig 1). We were unable to find any clinical correlation between T-cell, macrophage or FDC content, and TTF or OS (Tables 3 and 4).
The clinical course of FL in an individual patient usually is not predictable.3 Because treatment options in FL differ substantially with respect to their efficacy and particularly their adverse effects, the identification of patients with an unfavorable prognosis might facilitate a patient-tailored therapy.2 The recent development of the FLIPI may help to identify patients who are at high risk.7,15,19 In our patient cohort, we observed a clear separation of three risk groups both with respect to TTF (P = .0174) and OS (P = .0078) according to the FLIPI. Although the groups defined by the FLIPI differ in outcome, this method does not sufficiently identify patients with early treatment failure and, in addition, the FLIPI does not give information on the biology of tumors.7,15,19 Notable efforts have been made to identify characteristics of the tumor cells to define factors that might influence the clinical outcome. Genetic characteristics in FL, like the presence or absence of the translocation t(14;18) or other genetic alterations, have been reported to be of prognostic relevance.8,9,20 Histopathologic characteristics such as the growth pattern and the presence of sclerosis can easily be assessed in daily practice.1 However, most histopathologic markers have never been studied in prospective randomized trials with long follow-up. The number of centroblasts within the neoplastic follicles has been described to yield prognostic information and was, therefore, incorporated into the grading system for FL in the WHO classification.1 Grading of FL according to the rules of the WHO, however, seems to be of poor reproducibility.21 In contrast to other studies,22 we did not find any difference in TTF or OS between FL grade 1 and FL grade 2 cases. Although the number of FL grade 3 cases in our series was small, there was no indication that these lymphomas have a more aggressive clinical course.17 Comparable to findings in other published series, we found a marginal zone or plasmacytoid/plasmacytic differentiation in only 9% of our cases.13 However, in contrast to one published study,13 we were unable to detect any correlation between tumor cell differentiation and TTF or OS in our series. Reports about the prognostic value of diffuse growth in FL are inconsistent.23-26 We found no significant association between diffuse growth and TTF or OS in our series of FL, although there was a tendency toward shorter OS in cases with a diffuse component. The only histopathologic feature established in our series to have a statistically significant association with survival was the presence of tumor sclerosis. Tumor sclerosis is frequently observed in retroperitoneal biopsy specimens.27 A considerable number of lymph nodes with sclerosis in our series were from localizations other than retroperitoneal. The negative effect of tumor sclerosis on OS was still significant after adjusting for the FLIPI and the type of initial chemotherapy in a Cox model. We conclude that tumor sclerosis is a relevant histopathologic prognostic marker that can be easily assessed in daily diagnostic settings. However, sclerosis was observed in only 14% of the samples analyzed in our series and does not precisely distinguish between patients with long and short OS. Moreover, we analyzed lymph node specimens only. Therefore, it is unclear whether sclerosis in specimens in extranodal sites can also be used as a prognostic marker in FL. Within the interfollicular compartment, lymphoma cells can be detected by their positivity for CD10, but the biologic significance of this feature is uncertain.16 The distribution of CD20- or CD10-positive interfollicular cells in our series was highly variable. However, the extent of interfollicular lymphoma cells is not associated with clinical outcome. Increased tumor cell proliferation has been reported to be associated with shorter survival in FL.17 We applied two different proliferation markers to our series of lymphomas.18,28-30 Comparable to published reports,17,31 the proliferative index in our series increased with the number of centroblasts and higher WHO grade. However, no association between proliferation and TTF or OS was found in our series. Of note, a cytologic variant of FL with large centrocytes displayed increased proliferation, although these lymphomas usually contained only few centroblasts. The distinction between FL with large centrocytes from FL grade 3 may thus pose a diagnostic challenge. Knowledge derived from gene expression profiling has greatly improved our understanding of the pathogenesis of B-cell lymphomas. In contrast to other lymphoma entities,32-36 many of the genes whose expression was found to be prognostically important in FL were not expressed by the tumor cells, but rather in bystander cells within the tumor.10,37 A follow-up study, testing the role of immune cells in paraffin embedded material revealed that a high content of macrophages was associated with poor clinical outcome.38 Although both studies differ in patient characteristics, our data as well as those of others39,40 do not support the value of the macrophage content as a predictor of clinical outcome. Comparable to results of other published studies,38,41 we found no association between T-cell content and TTF or OS. It should be take into consideration, however, that the results of gene expression studies strongly suggest that the presence of certain T-cell subsets within the tumor represent the prognostic marker in FL rather than the total number of T-cells.10,37 In line with this concept, recently the quantification of FOXP3-positive regulatory T cells, or CD8-, CD4-positive T cells, were reported to correlate with clinical outcome in FL.39-43 However, because the published data are contradictory to some extent, the prognostic role of all T-cell subsets has to be confirmed in patient cohorts from prospective randomized trials to solve this issue. The high proportion of FLIPI high-risk patients in our patient cohort resulted from the trial inclusion criteria. Thus, our results can be interpreted only within the scope of the inclusion criteria of the trial. Nevertheless, we would not expect to detect a prognostic relevance of the histopathologic parameter assessed if limited-stage patients or patients without need of therapy had been included. This would be the case only if in those patients the parameters would have an extremely high impact.
For the many parameters without prognostic relevance for OS or TTF, we did not adjust for different therapies administered. Exploratory analyses, however, revealed no change of the results in the subgroup of MCP- or CHOP-treated patients. For sclerosis, the only prognostic factor identified, the prognostic value could be confirmed after adjustment for initial chemotherapy regimen. In addition, patients were randomly assigned to ASCT or IFN In summary, in our comprehensive approach to study histopathologic markers in FL to predict outcome, neither grading of FL nor the assessment of the proliferative index appears to be of clinical relevance. The presence of sclerosis within the lymphoma is a marker of poor prognosis independent of the FLIPI. Most importantly, new prognostic markers need to be confirmed in patients treated within prospective randomized trials.
The author(s) indicated no potential conflicts of interest.
Conception and design: Wolfram Klapper, Martin Dreyling, German Ott Administrative support: Martin Dreyling Provision of study materials or patients: Wolfgang Hiddemann Collection and assembly of data: Wolfram Klapper, Lars Rölver, Dirk Janssen, Markus Tiemann, Heinz-Wolfram Bernd, Olaf Determann, Martin-Leo Hansmann, Peter Möller, Alfred Feller, Harald Stein, Hans-Heinrich Wacker, Martin Dreyling, Wolfgang Hiddemann Data analysis and interpretation: Wolfram Klapper, Eva Hoster, Carsten Schrader, Martin Dreyling, Michael Unterhalt, German Ott Manuscript writing: Wolfram Klapper, Eva Hoster, Martin Dreyling, Wolfgang Hiddemann, German Ott Final approval of manuscript: Wolfram Klapper
Specimen Selection The samples were selected by each of reference pathology center without knowledge of the clinical data by the following criteria: nodal biopsy, size of at least 1 cm2, and good histomorphology. Because of the nature of the morphologic review process, with at least two specialists evaluating the cases together, the stringent selection criteria, especially in respect of the morphologic assessability, not all FLs in the trial were analyzed. The GLSG1996 trial included patients with Ann Arbor stage III or IV centroblastic-centrocytic lymphoma (according to the Kiel classification [Feller A, Diebold J. Berlin, Germany, Springer-Verlag, 2003]) corresponding to follicular lymphoma, grades 1 to 3a (according to the WHO classification [Jaffe E, Harris N, Stein H, et al. Lyon, France, IARC Press, 2001]), who were in need of treatment. Patients were randomly assigned to initial chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and MCP (mitroxantrone, chlorambucil, and prednisolone) and patients younger than 60 years were randomly assigned between autologous stem-cell transplantation and interferon alfa maintenance therapy. Patients aged 60 years or older and responding to initial therapy received interferon alfa maintenance (Nickenig C, Dreyling M, Hoster E, et al. Cancer 107:1014-1022, 2006).
Immunohistochemical Studies
We thank Christiane Stange and Michael Weiss for excellent technical assistance and F. Leithäuser for support of the pathology panel meeting. This work is dedicated to Reza Parwaresch, who died during the project.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Jaffe E, Harris N, Stein H, et al: Pathology and Genetics of Tumours of Haematopoetic and Lymphoid Tissues. Lyon, France, IARC Press, 2001 2. Hiddemann W, Buske C, Dreyling M, et al: Treatment strategies in follicular lymphomas: Current status and future perspectives. J Clin Oncol 23:6394-6399, 2005 3. Horning SJ: Natural history of and therapy for the indolent non-Hodgkin's lymphomas. Semin Oncol 20:75-88, 1993[Medline] 4. Horning SJ: Follicular lymphoma: Have we made any progress? Ann Oncol 11:23-27, 2000 (suppl) 5. Hiddemann W, Kneba M, Dreyling M, et al: Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: Results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 106:3725-3732, 2005 6. 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Farinha P, Masoudi H, Skinnider BF, et al: Analysis of multiple biomarkers shows that lymphoma-associated macrophage (LAM) content is an independent predictor of survival in follicular lymphoma (FL). Blood 106:2169-2174, 2005 39. Alvaro T, Lejeune M, Salvado MT, et al: Immunohistochemical patterns of reactive microenvironment are associated with clinicobiologic behavior in follicular lymphoma patients. J Clin Oncol 24:5350-5357, 2006 40. Glas AM, Knoops L, Delahaye L, et al: Gene-expression and immunohistochemical study of specific T-cell subsets and accessory cell types in the transformation and prognosis of follicular lymphoma. J Clin Oncol 25:390-398, 2007 41. Carreras J, Lopez-Guillermo A, Fox BC, et al: High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma. Blood 108:2957-2964, 2006 42. Wahlin BE, Sander B, Christensson B, et al: CD8+ T-cell content in diagnostic lymph nodes measured by flow cytometry is a predictor of survival in follicular lymphoma. Clin Cancer Res 13:388-397, 2007 43. Lee AM, Clear AJ, Calaminici M, et al: Number of CD4+ cells and location of forkhead box protein P3-positive cells in diagnostic follicular lymphoma tissue microarrays correlates with outcome. J Clin Oncol 24:5052-5059, 2006 Submitted December 28, 2006; accepted May 3, 2007.
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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
