RET genetic screening of sporadic medullary thyroid cancer (MTC) allows the preclinical diagnosis of unsuspected gene carriers and the identification of a relevant percentage of hidden familial MTC (FMTC).

OBJECTIVE: This study was aimed to demonstrate the clinical benefits of rearranged during transfection (RET) genetic screening in patients with apparently sporadic medullary thyroid cancer (MTC) not only to identify the hereditary nature of the disease in the index case but also to discover family members harbouring the same germline mutations (i.e. gene carriers) who are unaware of their condition. CONTEXT: RET genetic screening allowed the identification of germline RET mutations in apparently sporadic MTC resulting in their re-classification as hereditary forms. PATIENTS AND MEASUREMENTS: RET genetic screening was performed in 729 apparently sporadic MTC patients by direct sequencing RET exons 5, 8, 10, 11 and 13-16. Clinical and biochemical evaluation of gene carriers was also performed. RESULTS: We discovered an unsuspected germline RET mutation in 47 of 729 (6·5%) apparently sporadic MTC who were re-classified as hereditary. We found 60 of 146 (41·1%) gene carriers, 35 of whom had biochemical or clinical evidence of MTC. Thirty gene carriers underwent total thyroidectomy and 27 of 30 (90%) were persistently cured after a mean follow-up of 6·0 years. As a further result of RET genetic screening, we observed a significantly higher prevalence of familial medullary thyroid cancer (FMTC) in our series with respect to the largest series of the International RET Consortium (P = 0·0002). CONCLUSIONS: RET genetic screening of patients with apparently sporadic MTC represents a major tool for the preclinical diagnosis and early treatment of unsuspected affected family members and allows the identification of a relevant percentage of hidden FMTC.

Recombinant human TSH (rhTSH) in 2009: new perspectives in diagnosis and therapy.

Thyrotropin stimulating hormone (TSH) exerts a physiological stimulus to growth, function and ability to take up iodine of both normal and malignant follicular cells. For this reason, the metastases deriving from well differentiated thyroid cancer (DTC) can be effectively treated with radioiodine but this procedure requires a strong TSH stimulus that can be obtained by withdrawing the L-thyroxine (LT4) therapy. However, both the social and personal life of patients while they are withdrawing the LT4 therapy are heavily affected by hypothyroidism. After more than a decade since the development of recombinant human TSH (rhTSH), this molecule has been introduced in the clinical practice (1998 in USA and 2001 in Europe) as a safe and reliable alternative to LT4 withdrawal. For several years the main clinical application of rhTSH was for diagnostic purposes (i.e. thyroglobulin stimulation) but, after the more recent demonstration of its efficacy in preparing DTC patients for radioiodine post surgical thyroid remnant ablation, also this application has been officially recognized worldwide. The validity of rhTSH has been also demonstrated in stimulating metastatic thyroid cancer cells but this employment is not yet officially approved and it can be used only in patients with contraindication to hypothyroidism (i.e. "compassionate use"). Other possible uses of rhTSH stimulation are related to its ability to enhance both 18FDG uptake during PET scan of metastatic DTC patients and the effectiveness of conventional chemotherapy. The aim of this review was to recall how the rhTSH has been developed and progressively introduced in the clinical management of DTC patients.