Genotypic monoclonality in immunophenotypically polyclonal orbital lymphoid tumors. A model of tumor progression in the lymphoid system. The 1986 Wendell Hughes lecture.

Molecular genetic (genotypic) analysis elucidates gene rearrangements within lymphocytes that are responsible for either immunoglobulin production in B-lymphocytes or the expression of cell-surface antigen recognition receptors in T-lymphocytes. Molecular genetic analysis is far more sensitive than immunophenotypic methods for the detection of small clones of lymphocytes because as few as 2 to 5% of cells in an infiltrate can be discovered to possess the same rearranged DNA sequences with genetic probes. In truly polyclonal proliferations, each lymphocyte reorganizes its immunoglobulin or T-antigen receptor genes in a unique manner, resulting in an almost infinite number of combinations of genetic rearrangement and the absence of any new hybridizing bands upon Southern blotting. In monoclonal proliferations, a new, homogeneous, nongermline band is identified on Southern blotting because a sufficiently large number of lymphocytes exhibit an identical genetic rearrangement. In a group of five orbital lymphoid tumors that appeared to be benign reactive hyperplasias by light microscopy and that were polyclonal by immunophenotypic methods, three were found by molecular genetic analysis to harbor small clones of B-lymphocytes with new rearrangement bands on Southern blotting. No clonal abnormalities of T-lymphocytes were found in these five lesions, despite the fact that they were the preponderant cells in the tumors. These observations suggest that "reactive lymphoid hyperplasia" of the orbit may be an unstable lesion, owing to a T-cell immunoregulatory imbalance, with the potential for developing clonal expansions of B-lymphocytes that nonetheless usually remain localized to the orbit.