Expanded Proliferation Centers (PCs) Identify a Histological Subtype of Chronic Lymphocytic Leukemia (“Accelerated” CLL) with Adverse Clinical Outcome.

Abstract 2335

Poster Board II-312

The proliferation compartment in lymphoid tissues involved by CLL is essentially represented by large-cells that form proliferation centers (PCs) whose biological and clinical significance is a matter of investigation. For this, tissue biopsies consecutively obtained from 100 patients diagnosed with CLL were analyzed. Histological review was independently performed by three investigators (EC, AM and DM) in a BX51 Olympus microscope. Each biopsy was analyzed for the presence and size of proliferation centers (PCs), delineated by p27 negative immunostains, and for the proliferation rate inside the PCs assessed by means of mitosis count and Ki-67 immunostain. Histological characteristics were correlated with the main clinical characteristics and survival from the time of biopsy. To define the best cut-offs for histological variables in predicting survival, the Maximally Selected Rank Statistics was applied. CLL/SLL diagnosis was established in 78 cases, whereas DLBCL transformation was observed in 22 cases. Upon variables selection by the Maximally Selected Rank Statistics, CLL cases with enlarged and confluent PCs (broader than 20x field) (p=0.001), >2.4 mitosis per PCs (p=0.019), or >30% Ki-67 per PCs (p=0.024) were considered as having “accelerated” CLL (n= 23). Positive p53 immunostaining was observed in 24% “accelerated” CLLs compared to 5% CLLs without adverse features in the biopsy (p=0.02). The presence of p53 positivity was also frequently observed in DLBCL transformed cases (67%). “Accelerated” CLL cases were detected early in the course of the disease (median time from diagnosis: 16 months; 39% of cases at diagnosis), as opposite to DLBCL transformed cases (median time form diagnosis: 45 months; 14% at diagnosis). Tissue biopsy was performed in 73% of cases to rule out a transformation into an aggressive lymphoma. “Accelerated” CLL/SLL displayed high beta-2-microglobulin levels, elevated ZAP-70 expression and unmutated IgVH status more frequently than CLL/SLL without adverse features in the biopsy (p< 0.05). Median survival of “accelerated” CLLs from the time of biopsy was 34 months, whereas it was of 75 months (HR 2.2, 95%CI HR 1.21-3.86; p=0.008) for cases without adverse features in the tissue biopsy. Patients diagnosed with DLBCL transformation (n=22) had a median survival of 4 months. Notably, only one patient with an “accelerated” CLL pattern transformed into DLBCL after a median follow-up of 5 years. In conclusion, in lymph node biopsies from CLL/SLL patients, enlarged and confluent PCs and/or an increased proliferation activity in the PCs without DLBCL criteria identifies a new histological subtype of CLL/SLL (“accelerated CLL) with adverse biological features and inferior survival. Whether these patients require specific therapeutic approaches warrants investigation.