Expanded and highly active proliferation centers identify a histological subtype of chronic lymphocytic leukemia ("accelerated" chronic lymphocytic leukemia) with aggressive clinical behavior

Abstract

Background: The concept of "accelerated" chronic lymphocytic leukemia is frequently used by both pathologists and clinicians. However, neither histological criteria to define this form of chronic lymphocytic leukemia nor its clinical correlates and prognostic impact have been formally defined in large series of patients.

Design and methods: Tissue biopsies from 100 patients with chronic lymphocytic leukemia were analyzed for the size of proliferation centers and their proliferation rate as assessed by mitosis count and Ki-67 immunostaining. Histological patterns were correlated with main clinico-biological features and outcome.

Results: A suspicion of disease transformation was the main reason for carrying out tissue biopsy, which was performed at a median time of 14 months (range, 0 to 204 months) after the diagnosis of chronic lymphocytic leukemia. The biopsy showed histological transformation to diffuse large B-cell lymphoma in 22 cases. In the remaining 78 patients, the presence of expanded proliferation centers (broader than a 20x field) and high proliferation rate (either >2.4 mitoses/proliferation center or Ki-67 >40%/proliferation center) predicted a poor outcome and were selected to define a highly proliferative group. Thus, 23 patients with either expanded proliferation centers or high proliferation rate were considered as having "accelerated" chronic lymphocytic leukemia. These patients displayed particular features, including higher serum lactate dehydrogenase levels and more frequently elevated ZAP-70 than "non-accelerated" cases. The median survival from biopsy of patients with "non-accelerated" chronic lymphocytic leukemia, "accelerated" chronic lymphocytic leukemia and transformation to diffuse large B-cell leukemia was 76, 34, and 4.3 months, respectively (P<0.001).

Conclusions: The presence of expanded and/or highly active proliferation centers identifies a group of patients with "accelerated" chronic lymphocytic leukemia characterized by an aggressive clinical behavior.

Figure 1.

Survival from the time of tissue biopsy of patients with non-transformed CLL according to the characteristics of proliferation centers (PC): (A) presence of expanded PC broader than a 20x field (17 versus 75 months, PC broader than a 20x field versus PC not broader than a 20x field, respectively; P=0.001); (B) >2.4 mitoses per PC (34 versus 75 months, >2.4 mitoses/PC versus ≤2.4 mitoses/PC, respectively; P=0.016); (C) >40% Ki-67 positivity per PC (11 versus 68 months, >40%/PC versus ≤40%/PC, respectively; P=0.014).

Figure 2.

(A-D-G-J). A representative case of lymph node involvement by chronic lymphocytic leukemia. (A) At low magnification the tumor shows the typical biphasic growth pattern with dark areas representing the small lymphocytic component and the clear areas corresponding to small proliferation centers (PC) (hematoxylin-eosin stain, Olympus DP70, X10). (D) The PC are small (lesser than 20x) and contain some large prolymphocytic cells. Scattered mitoses may also be seen (hematoxylin-eosin stain, Olympus DP70, X20). PC are highlighted by negative staining with p27 (G), and low Ki-67 labeling index (J). (B-E-H-K): A representative CLL case with expanded proliferation centers (B, E) wider than a 20x field. PC are highlighted by negative staining with p27 (H). The mitotic count as well as the Ki-67 index (K) is high. (C-F-I-L): Representative sections of DLBCL transformation of a CLL case. (C) Partial involvement of the lymph node by a diffuse proliferation (bottom) of large immunoblastic cells (F). p27 is negative in the tumor cells (I) that shows a very high proliferative rate (L).

Figure 3.

Survival from biopsy according to the histological patterns of “non-accelerated” CLL, “accelerated” CLL and DLBCL transformation: median survival 76 months, 34 months and 4.3 months, respectively (P<0.001).