Researchers reported a rare case of calcitonin-negative medullary thyroid carcinoma (MTC) with brain metastasis in a 64-year-old man and found that although serum calcitonin and carcinoembryonic antigen (CEA) concentrations typically serve as biomarkers for MTC diagnosis, both were normal in this case.

“We describe a case of metastatic MTC that, despite tumor positivity for calcitonin, showed normal preoperative serum levels of calcitonin and CEA,” they wrote in a study published in Annales d’Endocrinologie.

“Some authors hypothesize a ‘hook effect’ whereby falsely low analyte levels in the immunoassay actually result from very high serum levels of calcitonin saturating the binding capacity of the antibody; however they recognize that this is less likely with the most recent assays.”

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There are various additional hypotheses to explain the normal calcitonin levels, such as the production of specific types of calcitonin that are not recognized in current immunoassays, genetic interference with the calcitonin gene, or a loss of the ability to produce calcitonin due to tumor characteristics. However, no study has been able to clearly identify the underlying mechanisms involved.

The authors note that alternative biomarkers can be used to monitor disease progression in cases of MTC with normal calcitonin levels, such as procalcitonin and calcitonin gene-related peptide (CGRP). However, the lack of current assays to measure CGRP limits its usefulness.

In this case, at relapse, the patient had maintained normal calcitonin levels and had pulmonary metastatic MTC without brain lesions. The mean survival of patients with brain metastases in the literature is 17.4 months, but the present case was at the 40th month of follow-up at the time of writing, which is the longest reported to date. In cases of normal calcitonin levels in MTC, the authors recommend close serial imaging including neck ultrasound and computed tomography.


Ferreira Baptista P, Martines Fonseca CM, Couto de Carvalho AF, et al. Brain metastasis from calcitonin-negative medullary thyroid carcinoma. Ann Endocrinol (Paris). Published online May 7, 2022. doi:10.1016/j.ando.2022.04.015