Increased Frequency of Low-Grade Follicular Lymphoma with a High Proliferative Index: A First Step Towards Histological Transformation? a Retrospective Analysis of 25 Follicular Lymphoma Cases
Authors: Díaz Schmidt Joaquin , Triantafilo Nicolás , Spralja Biserka , Ernst Daniel 
Published: December 2023

Background:
The most common form of indolent non-Hodgkin's lymphoma (NHL) is follicular lymphoma (FL). Although the overall survival of patients is currently over 20 years, 2-3% per year will suffer from histologic transformation. Patients with low-grade (WHO 1-2) FL with high proliferative index (PI), defined as Ki-67 expression ≥30%, have a shorter time to first treatment and worse disease-specific survival. Low-grade high-proliferative index (LG-HPI) is reported to account for 20% of low-grade FL cases. A specific clinical approach for LG-HPI is still controversial. Here, we report an increased frequency of LG-HPI cases in our institution and their associated clinical characteristics.
Methods:
We retrospectively analyzed a cohort of adult patients with a confirmed diagnosis of FL. Included patients had a tissue biopsy with defined Ki-67 by immunohistochemistry (IHC) and were categorized according to the WHO classification. A high proliferative index (PI) was defined as Ki-67 ≥30%. To compare their characteristics, patients were divided into three different categories: those with low grade and high proliferative index (LG-HPI), those with low grade and low proliferative index (LG-LPI), those with high grade (HG) including 2 cases with histologic transformation. All clinical and laboratory data were retrieved from the electronic clinical database. Frequencies of categorical variables were described as percentages, while continuous variables were described as medians. Comparisons were made using ANOVA.
Results:
A total of 25 patients were evaluated. The median age at diagnosis was 66 years and 40% were female (10). 17 patients had low-grade FL (68%), six had WHO 3a high-grade FL (24%), and two had transformed high-grade FL (8%). 14 patients (56%) were diagnosed at a localized stage (I - II) and eleven at an advanced stage (44%). After diagnosis, five patients were initially observed (20%), three received radiotherapy as a single treatment (12%), and 17 received chemoimmunotherapy (68%). For actively treated patients, the median time from diagnosis to treatment was 18 days (range 2 - 392 days).
Overall, the median Ki-67 expression was 40% (range 3 - 90). Of the low grade FL patients, nine were LG-LPI (53%) and eight were LG-HPI (47%). Patients with LG-LPI had lower LDH levels and baseline SUVmax, which reached significance when compared to HG ( Figures 1 & 2). All patients initially observed at diagnosis were LG-LPI. We found no differences in hemoglobin, stage, albumin, beta-2 microglobulin, IgG and response to treatment between these groups. Data on progression or overall survival are yet immature.
Discussion:
Our data suggest that patients with LG-HPI may represent a higher proportion of FL cases than previously reported. Consistent with previous reports, LG-HPI is clinically more aggressive than LG-LPI and may represent an intermediate step toward transformation. Further improvements in quantitative Ki-67 standardization are needed to define its prognostic and clinical role.