Genetic and histologic studies of somatomammotropic pituitary tumors in patients with the "complex of spotty skin pigmentation, myxomas, endocrine overactivity and schwannomas" (Carney complex)

Carney complex (CNC) is a familial multiple neoplasia and lentiginosis synd rome with features overlapping those of McCune-Albright syndrome (MAS) and other multiple endocrine neoplasia (MEN) syndromes, MEN type 1 (MEN 1), in particular. GH-producing pituitary tumors have been described in individual reports and in at least two large CNC patient series. It has been suggeste d that the evolution of acromegaly in CNC resembles that of the other endoc rine manifestations of CNC in its chronic, often indolent, progressive natu re. However, histologic and molecular evidence has not been presented in su pport of this hypothesis. In this investigation, the pituitary glands of ei ght patients with CNC and acromegaly [age, 22.9 +/- 11.6 yr (mean +/- SD)] were studied histologically. Tumor DNA was used for comparative genomic hyb ridization (CGH) (four tumors). All tumors stained for both GH and prolacti n PRL (eight of eight), and some for other hormones, including alpha-subuni t. Evidence for somato-mammotroph hyperplasia was present in five of the ei ght patients in proximity to adenoma tissue; in the remaining three only ad enoma tissue was available for study. CGH showed multiple changes involving losses of chromosomal regions 6q, 7q, 11p, and 11q, and gains of 1pter-p32 ,2q35-qter,9q33-qter,12q24-qter, 16, 17, 19p, 20p, 20q, 22p and 22q in the most aggressive tumor, an invasive macroadenoma; no chromosomal changes wer e seen in the microadenomas diagnosed prospectively (3 tumors). We conclude that, in at least some patients with CNC, the pituitary gland is character ized by somatotroph hyperplasia, which precedes GH-producing tumor formatio n, in a pathway similar to that suggested for MAS-related pituitary tumors. Three GH-producing microadenomas showed no genetic changes by CGH, whereas a macroadenoma in a patient, whose advanced acromegaly was not cured by su rgery, showed extensive CGH changes. We speculate that these changes repres ent secondary and tertiary genetic "hits" involved in pituitary oncogenesis . The data (1) underline the need for early investigation for acromegaly in patients with CNC; (2) provide a molecular hypothesis for its clinical pro gression; and (3) suggest a model for MAS- and, perhaps, MEN 1-related GH-p roducing tumor formation.