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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

Wolfram Klapper, Eva Hoster, Lars Rölver, Carsten Schrader, Dirk Janssen, Markus Tiemann, Heinz-Wolfram Bernd, Olaf Determann, Martin-Leo Hansmann, Peter Möller, Alfred Feller, Harald Stein, Hans-Heinrich Wacker, Martin Dreyling, Michael Unterhalt, Wolfgang Hiddemann, German Ott

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.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.