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A 44-year-old man with total thyroidectomy for papillary thyroid carcinoma (PTC) performed at the age of 38 years was referred for mediastinal metastases demonstrated on chest radiograph and high serum thyroglobulin (Tg 328 ng/ml). Computed tomography revealed mediastinal lymph node enlargement with left bronchial compression and reduction of bronchial diameter, as well as two metastases in the left lung. Bronchoscopic biopsy findings showed a poorly-differentiated PTC, while a whole body scan after 131-Iodine therapy demonstrated uptake in the right subclavicular region. External beam radiotherapy and chemotherapy yielded no benefit; the neoplasm was aggressive, diffuse and experienced fast growth, leading to the formation of metastases also at unusual sites, such as the skin and thigh muscle. The patient died from a brain metastasis. We report a rare case of PTC metastasis with a poorly-differentiated component in a young patient. Rapid and diffuse metastases also to unusual sites led to death eight years after the initial diagnosis and treatment.

Background: A novel Cys-Ser Ret germline point mutation in a 58-year-old woman with bilateral medullary thyroid carcinoma (MTC) prompted us to perform genetic analysis of the family and evaluate the biological consequences of such a mutation., Methods: Ret analysis by direct sequencing was performed in five family members. The biological activity and biochemical properties of the Ret- Cys515Ser mutant were analyzed in NIH-3T3 cells., Results: The proband's son, age 35, had the Ret- Cys515Ser mutation and the L769 CTT/CTG exon 13 polymorphic variant, which was also found in his father. Clinical evaluation of the son also revealed bilateral multifocal microscopic MTC and papillary thyroid carcinoma (PTC). In vitro and in vivo analysis indicated ligand-independent activation of the Ret-Cys515Ser mutant due to aberrant disulfide homodimerization, increased mitogenic activity, and ability to induce anchorage-independent growth in NIH-3T3 cells in comparison to wild-type Ret, suggesting a possible role of Cys515Ser in tumor development., Conclusions: The Cys515Ser mutation adds to cysteine substitution groups that have been described in association with MTC. Our data also highlight the importance of performing a complete genetic analysis in patients who present with MTC.