Extranodal noncutaneous lymphoid hyperplasias represent a continuous spectrum of B-cell neoplasia: demonstration by molecular genetic analysis.

We investigated 16 lymphoid proliferations occurring in the ocular adnexa, salivary glands, breast, and thyroid gland and satisfying the histopathologic and immunophenotypic criteria of benign lymphoid hyperplasia for the presence of clonal rearrangements of the antigen receptor, c-myc, bcl-1, and bcl-2 genes and Epstein-Barr virus (EBV) DNA sequences. Each of these 16 extranodal, noncutaneous lymphoid neoplasms exhibited clonal immunoglobulin heavy and/or light chain and lacked T-cell receptor (TCR) beta-chain gene rearrangements. The patterns of immunoglobulin gene rearrangements included solitary and multiple barely perceptible to faint bands, solitary clear and definite bands, and solitary high-intensity bands superimposed on a background of multiple less-intense bands. Three ocular adnexal lymphoid neoplasms exhibited bcl-1 or bcl-2 gene rearrangements. None of the 16 lymphoid neoplasms contained EBV DNA sequences. Two patients developed a histopathologically confirmed malignant lymphoma in an extranodal site. None of the remaining 14 patients developed additional lymphoid neoplasms during a mean follow-up period of 30 months, despite conservative therapy. These results demonstrate that extranodal, noncutaneous lymphoid neoplasms meeting the histopathologic and immunophenotypic criteria for benign lymphoid hyperplasia frequently contain occult monoclonal and oligoclonal B-cell populations representing a continuous and progressive spectrum of B-cell neoplasia up to and including malignant lymphoma.