Molecular and immunohistochemical characterization of B-cell lymphoma-2-negative follicular lymphomas

Aberrant expression of the annapoptotic protein BCL (B-cell lymphoma)-2 in ncoplastic germinal centers is one of the diagnostic hallmarks of follicular lymphoma. If BCL-2 cannot be detected by immunohistochemistry, the distinction between florid follicular hyperplasia and follicular lymphoma might become a diagnostic challenge. Most of those cases also lack the typical t(14;18), and the underlying pathophysiologic conditions of follicular lymphoma that lack BCL-2 protein expression arc largely unknown. Here, we collected 18 BCL-2 negative follicular lymphoma cases from 5 different institutions. After restaining, 9 cases proved to be truly BCL-2 negative (6 follicular lymphoma grade 2, 2 follicular lymphoma grade 3a, and 1 follicular lymphoma grade 3b). In 4 additional cases, BCL-2 was very faint (all grade 2). Of the 9 BCL-2 negative follicular lymphoma cases, 2 were negative for CD 10 (22%); all showed expression of BCL-6. Apoptotic level as determined by caspase 3 was the lowest in the BCL-2 positive follicular lymphoma group (15 +/- 8 m(2)), the highest in the normal/reactive group (n = 7, 60 +/- 12 mm(2)) and very similar in the BCL-2 low follicular lymphoma and BCL-2 negative follicular lymphoma groups (25 +/- 13 and 33 +/- 19 mm(2), respectively), assuming an intermediate position between reactive follicles and BCL-2 positive neoplastic follicles (P < .001 [Kruskal-Wallis]). Also noted was a difference in proliferation fractions between the BCL-2 positive follicular lymphoma (27% +/- 15%), the BCL-2 low follicular lymphoma (30% +/- 20%) and the BCL-2 negative follicular lymphoma groups (30% +/- 22%). Regarding the network of follicular dendritic cells, 8 (89%) of 9 cases from the BCL-2 negative subgroup showed disrupted, weakly developed networks, whereas all of the follicular lymphoma BCL-2 low-expression cases showed a well-defined and strongly developed follicular dendritic cell network. Among BCL-2 negative follicular lymphoma, BCL-2 and BCL-6 breaks were found in 1 case each, whereas in the follicular lymphoma BCL-2 low group, only 1 case with a BCL-6 break was recorded. No statistically significant result was achieved upon assessment of BCL-2 alpha or BCL-2 beta RNA or the ratio of alpha/beta isolated by real-time polymerase chain reaction. Taken together, BCL-2 negative follicular lymphoma did not show a BCL-2 break on the genetic level and showed both increased apoptotic and proliferation rates compared with BCL-2-positive follicular lymphoma. In our series, BCL-6 breaks were infrequent in BCL-2 negative follicular lymphoma. (C) 2012 Elsevier Inc. All rights reserved.