Clinical Significance of Low Grade Follicular Lymphoma with High Proliferative Index

Introduction: Follicular lymphoma (FL) accounts for about 20% of lymphomas. The time to treatment, time to progression and overall survival are widely variable and additional prognostic factors are needed to identify patients who might benefit from upfront therapy. The association of high Ki67 proliferative index in FL with recurrence, progression, and decreased survival in unclear. Furthermore, the contribution of Ki67 proliferative index score in follicular versus interfollicular area for prognosis has not been reported.

Methods: We performed a retrospective observational analysis of newly diagnosed patients with FL evaluated at University of Minnesota, from 2003 to April 2016. All cases were graded using WHO Classification histologic grading criteria. We excluded patients with no follow-up and grade 3B. We examined medical records and performed Ki67 immunohistochemical nuclear stains. Two pathologists reviewed Ki67 staining in follicular and interfollicular area and selected areas with maximum staining. Ten consecutive follicular and interfollicular areas were scored separately for Ki67 nuclear staining. Association of Ki67 with overall survival (OS) and progression-free survival (PFS) from date of diagnosis was analyzed using Cox regression. We defined PFS as time from diagnosis to initiation of first treatment or death, whichever occurred first.

Results: We examined 69 cases, 63 were grade 1 and 2 follicular lymphoma and 6 were grade 3A. Median age at diagnosis was 59 years. Gender was distributed equally. At time of diagnosis FLIPI score was 0 in 9 patients (13%), 1 in 15 patients (21.7%), 2 in 19 patients (27.5%), 3 in 15 patients (21.7%), 4 in 3 patients (4.3%), and unknown in 8 patients (11.6%). 27.5% patients (27 cases) showed bone marrow involvement at the time of diagnosis. Median (interquartile range) Ki67 was 25% (15%, 40%) in follicular area and 5% (5%, 15%) in interfollicular area.

Median follow-up time was 4.0 years (range 0.1 to 11.7 years). 37.7% underwent upfront observation, 14.5% were treated with RCHOP as first line of therapy, 23.2% received rituximab as maintenance therapy, few (13%) cases transformed into diffuse large B-cell lymphoma, and 20% of the patients died. OS at 5-years was 86% (95% CI: 76%, 97%), and PFS at 5-years was 25% (95% CI: 16%, 40%). Median PFS was 1.6 months. In univariate analysis, follicular Ki67 was not associated with PFS (p > 0.40) or OS. Interfollicular Ki67 was highly associated with shorter PFS with hazard ratio 1.32 per 10 units of Ki67 (95% CI: 1.08, 1.63). Results were similar adjusting for FLIPI score.

Conclusions: Our data suggests that interfollicular area Ki67 score at diagnosis is prognostic to predict PFS in patients with FL. The relationship appears to be linear and doesn't change when adjusting for FLIPI score. Follicular area Ki67 has no impact on clinical outcomes. We propose that the Ki67 proliferative index should be scored in the interfollicular areas to assess the prognosis in FL.