FOLLICULAR LYMPHOMAS CONTAIN A CLONALLY LINKED BUT PHENOTYPICALLY DISTINCT NEOPLASTIC B-CELL POPULATION IN THE INTERFOLLICULAR ZONE

Follicular lymphomas are thought to arise from the follicle center B c ells and are characterized by follicular structures that recapitulate many features of normal secondary lymphoid follicles. The neoplastic B cells of follicular lymphoma reside not only in follicles but also in the interfollicular zone in which they form a diffuse infiltrate. We have investigated the frequency, extent, and biological characteristic s of this interfollicular component in 30 cases of follicular lymphoma . An interfollicular B-cell infiltrate of variable extent (minimal, mo derate, or prominent) was present in all cases. Morphologically interf ollicular neoplastic B cells were small centro-cyte-like cells with lo wer grade cytology and lower proliferation fraction compared with the neoplastic follicles. The neoplastic phenotype of these cells (CD20(+) , light chain restricted) was confirmed in 18 cases. Clonal identity b etween the follicular and interfollicular components was shown in five cases using microdissection and PCR amplification of immunoglobulin h eavy chain genes. Analysis of Ig heavy chain gene sequences showed ide ntical variants of tumor subclones in both follicular and interfollicu lar compartments, indicating active tumor cell traffic between the two . In six cases in which frozen tissue was available, the immunophenoty pe of follicular and interfollicular tumor cells were compared using i mmunohistochemistry. Activation markers such as CD10, CD38, and CD95 a nd T-cell costimulatory molecules CD80 and CD86, which were expressed by neoplastic follicles, were either downregulated or absent in the in terfollicular component in most of the cases. The low-grade cytologica l features, low proliferation fraction, and downregulation of activati on markers in the interfollicular neoplastic B cells suggests that the se are resting cells analogous to memory B cells of normal lymphoid ti ssues. The presence of such a resting tumor cell subpopulation in the majority of follicular lymphomas may partly account for the remarkable resistance to therapy of this disease. (C) 1998 by The American Socie ty of Hematology.