The prognostic significance of the intra-follicular tumor cell proliferative rate in follicular lymphoma

Background and Objectives In follicular lymphoma histological grading is used to predict clinical behavior and to stratify patients for treatment. However, the reproducibility of histological grading is poor and the clinical significance of the difference between grade 1 and grade 2 follicular lymphoma is unclear. Data on proliferation characteristics with respect to prognosis in follicular lymphoma are inconsistent. Design and Methods We assessed the Proliferation Index in follicles, using Mib-1 immunohistochemical staining in lymph node biopsies from 51 patients with follicular lymphoma who were receiving uniform first-line treatment consisting of cyclophosphamide, vincristine, prednisone and interferon alpha 2b. Results The median Proliferation Index was 16.9 (range 3.1-49.2). In grades 1 and 2 follicular lymphoma (n=45) it was 16.1, compared to 24.2 in grade 3 (n=6; p=0.02). At a median follow-up of 71 months, patients with a Proliferation Index below the median had a significantly prolonged time to progression (median not reached vs. 15 months for those with a Proliferation Index above the median; p=0.0006) and improved overall survival (median not reached vs. 42 months, respectively; p=0.002). In multivariate analysis, the Proliferation Index retained its predictive value. Additional prognostic information was especially provided in patients with a low International Prognostic Index. Histological grade did not predict outcome. Interpretation and Conclusions The Proliferation Index is a biological marker that is strongly and independently predictive for outcome in follicular lymphoma, as shown even in this relatively small series of patients. It is easily applicable and reproducible and therefore superior to histological grading in identifying clinically aggressive follicular lymphoma, requiring other types of treatment.