Aggressive differentiated thyroid cancer with multiple metastases and NRAS and TERT promoter mutations: A case report

Sorafenib, a tyrosine kinase inhibitor, is approved for the treatment of advanced differentiated thyroid carcinoma (DTC). Resistance to sorafenib may appear under treatment and may be associated with increased aggressiveness of the neoplasia. The present study reports the case of a 65-year-old male who underwent total thyroidectomy for a follicular thyroid carcinoma, Hürthle cell variant, in February 2005. Until January 2010, the patient received four consecutive ¹³¹I doses (total dose, 612 mCi) for increased serum thyroglobulin (Tg) and initial faint lung uptake (which eventually became undetectable). Subsequently, the patient developed several sequential bone (humerus, rib and skull), adrenal and lung metastases, the majority of which were surgically removed. Histological examination in all cases revealed evidence of DTC metastases that were strongly positive for Tg, as revealed by immunohistochemistry. In March 2014, sorafenib therapy was initiated, but it was discontinued 10 months later to allow an undelayable prostatectomy. Immediately upon surgery, the patient developed a large metastatic lesion in the right gluteal muscle, whose biopsy revealed undifferentiated neoplasia of epithelial origin, and the patient succumbed shortly afterwards. An extensive comparative search for biochemical and molecular markers was performed on all available tissues (primary tumor, and differentiated and undifferentiated metastases). The primary tumor and all the available metastases exhibited the same molecular oncogenic markers (namely, the RAS mutation p.Q61R and the telomerase promoter mutation C228T). In addition, the undifferentiated metastasis exhibited a p53 mutation. The present study reports a case of a sudden acceleration of DTC metastatic progression following sorafenib discontinuation, which could have been due to the emergence of sorafenib-resistant undifferentiated p53-positive tumor cell clones.