Genetic and Histologic Studies of Somatomammotropic Pituitary Tumors in Patients with the "Complex of Spotty Skin Pigmentation, Myxomas, Endocrine Overactivity and Schwannomas" (Carney Complex)

Abstract

Carney complex (CNC) is a familial multiple neoplasia and lentiginosis syndrome 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 suggested that the evolution of acromegaly in CNC resembles that of the other endocrine manifestations of CNC in its chronic, often indolent, progressive nature. However, histologic and molecular evidence has not been presented in support of this hypothesis. In this investigation, the pituitary glands of eight patients with CNC and acromegaly [age, 22.9+/-11.6 yr (mean +/- SD)] were studied histologically. Tumor DNA was used for comparative genomic hybridization (CGH) (four tumors). All tumors stained for both GH and prolactin PRL (eight of eight), and some for other hormones, including alpha-subunit. Evidence for somatomammotroph hyperplasia was present in five of the eight patients in proximity to adenoma tissue; in the remaining three only adenoma 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 were seen in the microadenomas diagnosed prospectively (3 tumors). We conclude that, in at least some patients with CNC, the pituitary gland is characterized by somatotroph hyperplasia, which precedes GH-producing tumor formation, 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 surgery, showed extensive CGH changes. We speculate that these changes represent 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 progression; and (3) suggest a model for MAS- and, perhaps, MEN 1-related GH-producing tumor formation.

Pituitary Pathology in Carney Complex Patients

“…The frequency of PRKAR1A mutations in these patients is the same as in the whole group (approximately 50%); clinical details have been described elsewhere [25]. All CNC-related GH-producing tumors stained positive for PRL and occasionally for other hormones ( Table 1).…”

“…Clinical and histopathologic analysis GH-producing tumors have been identified so far in several CNC patients (Table 1) with clinically diagnosed acromegaly at the National Institutes of Health [25]. The frequency of PRKAR1A mutations in these patients is the same as in the whole group (approximately 50%); clinical details have been described elsewhere [25].…”

Pituitary tumors in childhood: update of diagnosis, treatment and molecular genetics

“…Of note, in many of these patients, clinically significant acromegaly did not present until after surgical treatment of their Cushing syndrome (72% of these patients were diagnosed with CS due to primary pigmented nodular adrenocortical disease). This change in clinical phenotype in patients with concurrent Cushings syndrome and acromegaly is not surprising given the known relationship between cortisol and growth hormone metabolism, but as phenomenon deserves further investigation in patients affected with CNC or similar conditions, such as McCune Albright syndrome [34] For patients with CNC who have elevated GH and/or IGF-1, it is important to identify clinically significant acromegaly as defined by generally applied criteria [69]. Most CNC patients will have some abnormality of GH secretion due to the underlying pituitary hyperplasia, but almost all of them will have negative imaging studies [100,108].…”

“…GH-and/or PRL-producing are the second most frequently found functional pituitary tumors in early childhood; these tumors in children almost always occur in the familial setting or in the context of known genetic defects: GNAS, menin, PRKAR1A, AIP and p27 (CDKN1B) mutations [21,[32][33][34][35][36]; somato-and/or mammotropinomas become significantly more frequent than corticotropinomas in late childhood, adolescence and adulthood [37].…”

Acromegaly in a multiple endocrine neoplasia type 1 (MEN1) family with low penetrance of the disease

“…CNC is an inherited complex of spotty skin pigmentation, myxoma, increased endocrine activity and schwannoma. About 80% of CNC patients show paradoxical GH responses or raised IGF-I levels, whereas 10% develop active acromegaly (32,33). In a recent study, 21% of McCune -Albright syndrome patients had elevated GH levels during OGTT, and in 17%, IGF-I levels were elevated.…”