There are growing evidences suggesting the existence of intra-tumor heterogeneity within the same patient, leading to a different genetic pattern between primary tumour and metastases.
We report a paradigmatic example of genetic heterogeneity in thyroid cancer (TC). A 42 years old female patient was submitted, for a follicular TC, to total thyroidectomy and lymphadenectomy followed by radioiodine residue ablation in late 1999. In 2000 and 2001 diagnostic total body scans (TBS) were negative, thyroglobulin (Tg) and anti-thyroglobulin antibodies (TgAb) under TSH stimulation were negative, and patient was considered cured until April 2005 when Tg levels began to progressively increase. Between July 2006 and February 2008 the patient was submitted to four additional radioiodine treatments for lung metastases (total dose 27 750 MBq), with Tg levels ranging 3040 ng/ml and negative TgAb neg. Since then, Tg and TgAb levels continued to increase and in November 2014 the patient was submitted to the surgical removal of a vertebral metastasis. At the molecular analysis, this bone metastasis was shown to harbour a C228T TERT mutation, while both the primary tumor and the lymph-node metastases were negative for the mutation. Possible explanation to this interesting finding are: 1) TERT mutation could have been acquired as a secondary event and transmitted to a subset of tumor cells at the primary site (sub-clonal distribution), 2) TERT mutation could have been acquired at the metastatic site, 3) the primary tumor could have been polyclonal. The present case clearly demonstrate that thyroid cancer can be genetically heterogeneous. This finding is highly relevant because clinicians must consider that the genetic pattern found in the primary tumor, that in some cases have oriented the clinical and therapeutic decisions, may evolve during tumor progression, in particular in the regional or distant metastases, also due to the selection pressure of treatment.