One of the most frequent presentations of medullary thyroid carcinoma (MTC) and other forms of thyroid cancer is the presence of a thyroid nodule. A simple definition of a thyroid nodule is a lesion on the thyroid region that is radiographically distinct from the tissue surrounding the lesion. So how should physicians evaluate a thyroid nodule upon presentation to ensure that diagnoses such as MTC are not missed? 

First, a detailed history of the nodule should be obtained, including accompanying signs and symptoms. Clinical features such as dysphagia and neck pain are commonly reported. Physicians should also ask questions pertaining to hypothyroidism and hyperthyroidism. 

In addition, physicians should perform an ultrasonographic assessment of the thyroid nodule, since certain sonographic patterns raise the risk of malignancy and thus guide decision-making on whether a fine needle aspiration (FNA) is needed. 

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High-suspicion nodules tend to be hypoechoic, have irregular borders and microcalcifications, increased vascularity, and possess taller-than-wide morphology. Extrathyroidal extensions are also often observed. If a thyroid nodule ticks these boxes, then the risk of it being a malignancy is 70% to 90%. 

Read more about MTC diagnosis

If there is a sound chance that a thyroid nodule could turn out to be a malignancy, an FNA should be performed. The usefulness of FNA as a diagnostic method for malignancy is hotly debated in the medical literature. While some studies suggest it can be used to diagnose MTC in nearly 90% of cases, others estimate that only half are detected via cytology. 

Another excellent tool for the diagnosis of MTC is to measure calcitonin levels in the aspirate specimen. The success rate of diagnosing MTC via measuring calcitonin is significantly high; some studies give it a nearly 100% record of correctly identifying MTC. This is particularly true if the threshold for FNA calcitonin is set at 39.6 pg/mL. 

“Secretion of calcitonin and [carcinoembryonic antigen] by MTC occurs in direct proportion to the C cell mass,” Thomas and colleagues wrote in Current Oncology. “Elevated serum calcitonin might help to identify thyroid nodules that have benign features on ultrasound and yet harbor MTC.”

However, a limitation of measuring serum calcitonin for the purpose of diagnosing MTC is that a wide variation exists within the population. Studies estimate that around 3% to 10% of normal subjects have serum calcitonin levels above 10 pg/mL, which is the typical reference range. In addition, a number of factors can result in a higher calcitonin baseline, such as an increased BMI, smoking, and chronic kidney disease. 

Molecular Imaging 

In the Recent Developments of Nuclear Medicine in Cancer Diagnosis and Theranostics, Giovanella and colleagues wrote, “The main limitations of thyroid FNA, however, are ‘indeterminate’ nodules. The rate of malignancy ranges from 10[%] to 30% in such cases, with histological examination a necessity to achieve the final diagnosis.” 

In these instances, molecular imaging methods can better help physicians arrive at a diagnosis of MTC. 

For example, thyroid scintigraphy is the only method available that can detect autonomously functioning thyroid nodules. In addition, it can exclude malignancy even when TSH levels are low-normal, having a 96% to 99% negative predictive value. In addition, molecular imaging can be used to help differentiate between benign and malignant indeterminate nodules. 

The [99mTc]Tc-MIBI can cross the cell membrane, reversibly penetrating the cytoplasm and then irreversibly moving through the mitochondrial membrane. Tumor cells can be differentiated from normal cells because they demonstrate a characteristically higher negative inner membrane electric potential. Hence, the  [99mTc]Tc-MIBI can be highly useful to characterize cytologically indeterminate nodules. 

In addition, [18F]FDG positron emission tomography can also be useful as a diagnostic tool for MTC. Giovanella and colleagues wrote, “A visually [18F]FDG-negative indeterminate thyroid nodule has a negligible risk of malignancy, making [18F]FDG PET/CT a suitable ruling-out test (as robustly demonstrated by meta-analyses).” Preliminary radiomics analyses reveal that it has high specificity and a high positive predictive value. 

Pathological Diagnosis 

The diagnosis of MTC is often made after the resection of the lobe of the thyroid concerned. MTC has certain characteristic morphology: the tumor is usually poorly delineated and infiltrative, consisting of solid nests of discohesive cells contained within a fibrous stroma, which might also contain amyloid. The diagnosis of MTC can be missed when the tumor is oncocytic, has a follicular architecture, or contains pseudopapillary patterns. 

Read more about MTC etiology 

Ki-67 is often used for the grading of neuroendocrine tumors, but the applicability of that modality for MTC remains a matter of debate. However, the hyperplasia of C cells in the contralateral lobe should be assessed, given that it has a strong likelihood of indicating germline RET mutations and inherited disease. 

In summary, Thomas and colleagues wrote, “After a diagnosis of MTC on FNA, next steps should be measurement of serum calcitonin and [carcinoembryonic antigen], analysis for a RET germline mutation, the appropriate workup for pheochromocytoma and hyperparathyroidism as indicated based on RET mutation status, and assessment for metastatic disease.”


Giovanella L, Deandreis D, Vrachimis A, Campenni A, Petranovic Ovcaricek P. Molecular imaging and theragnostics of thyroid cancersCancers (Basel). 2022;14(5):1272. doi:10.3390/cancers14051272

Thomas CM, Asa SL, Ezzat S, Sawka AM, Goldstein D. Diagnosis and pathologic characteristics of medullary thyroid carcinoma-review of current guidelinesCurr Oncol. 2019;26(5):338-344. doi:10.3747/co.26.5539

Leimbach RD, Hoang TD, Shakir MKM. Diagnostic challenges of medullary thyroid carcinomaOncology. 2021;99(7):422-432. doi:10.1159/000515373