Apoptosis and the BCL-2 gene family - Patterns of expression and prognostic value in stage I and II follicular center lymphoma

Purpose: The prognostic significance of spontaneous levels of apoptosis and Bcl-2, Bar, and Bcl-x protein expression in follicular center lymphoma (FC L) is unknown. The objectives of this retrospective study were (1) to inves tigate the relationship between pretreatment apoptosis levels and long-term treatment outcome in patients with Stage I and II FCL; (2) to define the i ncidence and patterns of Bar and Bcl-x protein expression in human FC; and (3) to determine the relationship of Bcl-2, Pax, and Bcl-x expression with spontaneous apoptosis levels and clinical outcome in localized FCL. Methods and Materials: Between 1974 and 1988, 144 patients with Stage I or II FCL were treated. Hematoxylin and eosin (H & E) stained tissue sections of pretreatment specimens were retrieved for 96 patients. Treatment consist ed of regional radiation therapy (XRT) for 25 patients, combined modality t herapy (CMT) consisting of combination chemotherapy and XRT for 57 patients , and other treatments for 14 patients. Median follow-up for living patient s was nearly 12 years. The apoptotic index (AI) was calculated by dividing the number of apoptotic cells by the total number of cells counted and mult iplying by 100. Expression of Bcl-2, Bar, and Bcl-x proteins was assessed u sing immunohistochemistry. Results: The mean and median AI values for the entire group were 0.53 and 0 .4, respectively (range: 0-5.2). The AI strongly correlated with cytologic grade, with mean AI values of 0.25 for grade 1, 0.56 for grade 2, and 0.84 for grade 3 (p < 0.0005; Kendall correlation). A positive correlation was p resent between grouped AI and grouped mitotic index (MI) (p = 0.014). For p atients treated with CMT, an AI < 0.4 correlated with improved freedom from relapse (FFR) (p = 0.0145) and overall survival (OS) (p = 0.0081). An AI < 0.4 did not correlate with clinical outcome for the entire cohort or for p atients receiving XRT only. Staining of tumor follicles for the Bcl-2 prote in was positive, variable, and negative in 73%, 15%, and 12% of cases, resp ectively. Positive staining of tumor follicles was observed in 96% of cases for both the Bar and Bcl-x proteins. Expression of Bcl-2, Bar, or Bcl-x di d not correlate with AI or clinical outcome. Conclusion: The level of spontaneous apoptosis in pretreatment specimens co rrelates with cytologic grade of FCL and is a significant predictor of FFR and OS for patients with localized FCL receiving CMT. (C) 1999 Elsevier Sci ence Inc.