Purpose:Two tyrosine kinase inhibitors (TKIs), vandetanib and cabozantinib, have been approved for recurrent/metastatic (R/M) medullary thyroid carcinoma (MTC). To date, it is still debated when and which TKI has to be started in R/M MTC patients. This is due to 1) TKI-related toxicity burden, 2) no overall survival benefit for either TKI, and 3) progression-free survival improvement in MTC subgroups ( RETM918T and RAS mutations) treated with cabozantinib. Herein, we present a case of R/M MTC with a discordant disease behavior because of spontaneous regression of some parenchymal sites along with progression of bone metastases, putting into the question the best timing for starting TKIs in R/M MTC.Methods:We report a 46-year-old man with relapse (lymph nodes in the neck and mediastinum) after curative treatment (total thyroidectomy plus central compartment and right neck dissection) for a locally advanced MTC with only somatic RETM918T mutation. Considering the low tumor burden, absence of symptoms, as well as the potential TKI-related side effects, we decided not to start systemic therapy when metastases first appeared.Results:Some lymph nodes spontaneously regressed, while new symptomatic bone lesions appeared with need for palliative radiotherapy. In total, first-line systemic therapy (cabozantinib) was started after 2 years since first distant metastases appearance.Conclusions:Radiologic progression of disease alone seems not to be adequate for MTC patients’ selection to be treated. The progression rate, the tumor burden, and the site of disease should also be taken into account for the clinical decision process.