Activating thyrotropin receptor mutations are present in nonadenomatous hyperfunctioning nodules of toxic or autonomous multinodular goiter

Toxic multinodular goiter, a heterogeneous disease producing hyperthyroidis m, is frequently found in iodine-deficient areas. The pathogenesis of this common clinical entity is still unclear. The aim of the present study was t o search for activating TSH receptor (TSHr) or Gs alpha mutations in areas of toxic or functionally autonomous multinodular goiters that appeared hype rfunctioning at thyroid scintiscan but did not clearly correspond to defini te nodules at physical or ultrasonographic examination. Surgical tissue spe cimens from nine patients were carefully dissected, matching thyroid scinti scan and thyroid ultrasonography, to isolate hyperfunctioning and nonfuncti oning areas even if they did not correspond to well-defined nodules. TSHr and Gs alpha mutations were searched for by direct sequencing after PC R amplification of genomic DNA. Only 2 adenomas were identified at microsco pic examination, whereas the remaining 18 hyperfunctioning areas correspond ed to hyperplastic nodules containing multiple aggregates of micromacrofoll icules not surrounded by a capsule. Activating TSHr mutations were detected in 14 of these 20 hyperfunctioning areas, whereas no mutation was identifi ed in nonfunctioning nodules or areas contained in the same gland. No Gs al pha mutation was found. In conclusion, activating TSHr mutations are present in the majority of non adenomatous hyperfunctioning nodules scattered throughout the gland in pati ents with toxic or functionally autonomous multinodular goiter.