Bcl-6 expression in reactive follicular hyperplasia, follicular lymphoma, and angioimmunoblastic T-cell lymphoma with hyperplastic germinal centers:: Heterogeneity of intrafollicular T-cells and their altered distribution in the pathogenesis of angioimmunoblastic T-cell lymphoma

Background: The Bcl-6 gene product, a nuclear phosphoprotein, is expressed independently of Bcl-6 gene rearrangement. In lymph nodes, expression of Bcl-6 protein is restricted to germinal center (GC) B-cells and 10% to 15% of CD3/CD4(+) intrafollicular T cells. Interfollicular cells are negative for Bcl-6 protein, except for rare CD3(+)/CD4(+) T cells. Recently, we reported cases of angioimmunoblastic T-cell lymphoma (AITL) with hyperplastic GCs (AITL/GC), and observed that borders of enlarged GCs were ill defined, with features suggestive of an outward migration of GC cells to surrounding interfollicular zones. This prompted a study of follicular borders with Bcl-6 staining in reactive follicular hyperplasias and follicular lymphomas to compare with AITL/GC. Materials and Methods: Formalin-fixed paraffin sections were used for immunostaining of Bcl-6. Six cases of AITL/GC, 12 nonspecific reactive follicular hyperplasia (FH), 7 HIV adenopathy, 10 follicular lymphoma (FL), and 8 typical AITL (ie, AITL without GC) were studied. Double staining for Bcl-6/CD20, Bcl-6/CD3, and Bcl-6/CD57 was performed in selected cases. Results: In FH and HIV adenopathy, staining for Bcl-6 revealed densely populated GCs with well-defined and regular GC borders, whereas Bcl-6(+) cells were rare in the interfollicular areas. An occasional GC with an ill-defined border was invariably surrounded by a broad mantle zone; those with indistinct mantle zones had well defined, regular borders. In FL, follicles were densely populated, and their borders were irregular, with some Bcl-6(+) cell in the interfollicular zones. In AITL/GC, GCs were less dense, GC borders were ill defined and irregular, and the number of interfollicular Bcl-6(+) cells was markedly increased. Double staining revealed that these interfollicular Bcl-6(+) cells in AITL/GC were Bcl-6(+)/CD3(+)/CD20(-)/CD57(-) T cells. Moreover, CD3(+) intrafollicular T cells were depleted in AITL/GC, whereas they were abundant in FH. Intrafollicular CD57(+) cells did not stain for Bcl-6, and were also depleted in AITL/GC. fn typical AITL, some neoplastic cells were positive for Bcl-6, showing variable degrees of staining Conclusions: (1) GCs of AITL/GC differed from those of other reactive follicular hyperplasias and follicular lymphomas, and staining for Bcl-6 was useful to discern them. (2) Intrafollicular CD3(+) T cells, many of which were also positive for Bcl-6, were markedly depleted in AITL/GC, with increased interfollicular Bcl-6(+)/ CD3(+) cells, suggesting an outward migration of intrafollicular T cells in this Condition. (3) Interfollicular Bcl-6(+)/CD3(+) cells in AITL/GC were too numerous to be accounted for by migration alone, suggesting local proliferation. (4) Intrafollicular CD57(+) cells were negative for Bcl-6 indicating heterogeneity of the intrafollicular T-cell. population. (5) Some neoplastic cells in AITL stained for Bcl-6, suggesting up-regulation of Bcl-6 expression in this: tumor. Copyright (C) 1999 by W.B. Saunders Company.