Regulation of proliferation and apoptosis in sporadic and hereditary medullary thyroid carcinomas and their putative precursor lesions

C-cell hyperplasia (CCH) and medullary thyroid carcinoma (MTC) in patients affected by germline mutations of the RET oncogene represent an exceptional opportunity to study the regulation of proliferation and apoptosis during tumour initiation and progression. In 56 specimens [CCH, n=1; MTC with CCH, n=26; MTC, n=20; lymph-node metastasis (LNM), n=9] from 46 patients [multi ple endocrine neoplasia type 2a (MEN2a), n=24; MEN2b, n=2; familiar MTC (FM TC), n=4; sporadic MTC, n=16] and 3 cases of non-neoplastic CCH, proliferat ion activity (MIB1), the rate of apoptosis [dUTP nick end labelling (TUNEL) ] and expression of p53, bcl-2, bcl-x and bax were investigated and compare d with clinical data. In MEN-associated CCH and small MTC, bcl-2 was strong ly expressed, bcl-x was moderately expressed and bax was only weakly expres sed. Advanced tumours and LNM did show a more heterogeneous bcl-2 staining accompanied by an increased bax expression and accelerated proliferation. T he rate of apoptosis was extremely low in all investigated tumours. P53 was detectable in three patients with rapidly growing and extensively metastas ising MTC. No somatic p53 mutations were found. Hereditary MTC with germlin e RET mutations at codon 918 (MEN2b) and codon 634 revealed a bias towards a higher proliferation activity at a younger age and are more frequently ac companied by LNM. CCH and MTC are characterised with a preponderance of bcl -2 as a factor blocking the programmed cell death. While MTC, in general, i s a slowly growing tumour, a minority of tumours do progress rapidly with h igh proliferation. The factors leading to an accelerated tumour progression do not seem to take their effect via the regulation of apoptosis. Certain alterations of RET are supposed to have a direct or indirect implication on proliferation and, because of this, an effect on the clinical course.