Medullary thyroid carcinoma (MTC) is a relatively rare form of thyroid malignancy, accounting for only 2% to 5% of all cases. However, it is associated with a disproportionately high mortality rate. 

Around 8 in 10 cases of MTC occur sporadically, while the rest are inherited. There is remarkable international cooperation around the classification and treatment of MTC; these global efforts are intended to better predict tumor behavior and streamline grading systems. A number of parameters of interest have been highlighted, such as the Ki67 proliferative index and the mitotic index. 

Read more about MTC etiology 

Continue Reading

In most cases, patients who present with a thyroid nodule later confirmed to be MTC already have cervical lymph node involvement. The tumor metastasizes via hematogenous and lymphatic routes. 

In Biomedicines, Giusca and colleagues conducted a study to investigate if aggressive behavior in MTC can be readily predicted using a number of disease parameters. Elaborating on why this research matters, Giusca et al pointed to the fact that their hospital in Romania has an annual addressability of approximately 450 patients with thyroid pathology. This unusually high amount of thyroid cases stems from iodine deficiency and the lingering effects of the neighboring Chernobyl nuclear disaster. 

“Within this context, we analyzed the clinicopathological profile of MTC, pointing to cases with increased oncological risk,” they wrote. 

The research team conducted a retrospective study, analyzing the data of 59 consecutive cases of MTC at their local hospital. All cases of MTC were diagnosed histologically; among the 59 patients, 55 were sporadic and 4 were hereditary. The database at the hospital included key patient information such as demographic data, calcitonin values, and other clinicopathological parameters. 

The researchers then analyzed MTC cases using the international grading system — mitotic index was calculated per 2 mm2; Ki67 index was counted between 500-2000 tumor cells. In addition, the research team also analyzed the tumors according to the World Health Organization Tumor Node Metastasis staging and the American Joint Committee of Cancer criteria. Combined, these include important disease parameters, such as tumor size, lymphovascular invasion, extrathyroidal extension, metastasis, and tumor recurrence. 

Giusca and colleagues reported that a number of clinicopathological parameters correlated with disease aggression. For example, patients over 55 years of age had a more aggressive disease course compared to younger patients. Tumor size was also predictive of disease prognosis and overall survival. In addition, the research team discovered that tumor size and lymph node metastasis are closely related, and that extrathyroidal muscle invasion is an important predictor of tumor aggression. 

Resection margins are also predictive of MTC prognosis in that microscopically positive margin is generally associated with poorer outcomes. Resection margins are also important because they can dictate management—radiotherapy, for example, is only recommended after nonradical surgery with positive margins. 

According to the new proposed MTC grading system, 21 cases qualified as high-grade and 38 were considered low-grade. However, the researchers did not find a statistically significant correlation between tumor grade and tumor aggressiveness, a finding that diverges from previous studies.

“Despite these inconsistencies, we consider that the criteria included in the new proposed MTC grading system are excellent markers for the identification of the risk of aggressive behavior,” the study authors wrote. “In our opinion, the contradictory results should be explained by the relatively small number of cases in our series—an element that is an important limitation of our study.” 

Clinical Relevance 

The study by Giusca and colleagues demonstrates 2 things: first, that certain clinicopathological parameters are predictive of tumor aggression; and second, that international systems of identifying tumor grade have clinical relevance and prognostic value. 

In Endocrinology and Metabolism, Kim and Kim wrote a review article on guidelines for treating MTC according to the Korean Endocrine Society, which are mostly similar to guidelines used in the United States. A number of points appear to have universal consensus: that early diagnosis and detection is key, and that complete surgical resection of the tumor and any locoregional metastases is the only curative option for this disease. 

Read more about MTC treatment 

“However, the best management is still controversial in patients with recurrent MTC and distant metastases, because many patients with metastatic disease have indolent disease courses for a long time,” they wrote. 

Nonetheless, the most well-traveled pathway of treating this disease is to first determine whether a patient qualifies for surgery; if so, surgical resection should be carried out. Postoperatively, patients should be closely monitored to assess if structural disease or biochemistry abnormalities remain, as well as to stratify the risk of recurrence.  Physicians should monitor a patient’s serum calcitonin and carcinoembryonic antigen (CEA) levels and perform a neck ultrasound and other imaging studies. 

In the event that the tumor is not surgically resectable, Kim and Kim recommend the use of vandetanib or cabozantinib as they can stabilize disease and extend progression-free survival. They also recommend the use of selpercatinib and pralsetinib, which have shown impressive efficacy in phase 1/2 studies. A combination of medications are often prescribed, but drug resistance can occur. 

“Further studies are required to determine the mechanism of resistance to novel [tyrosine kinase inhibitors], selective RET inhibitors, and immune checkpoint inhibitors and to identify the appropriate combination regimens with various therapies,” Kim and Kim wrote. 


Kim M, Kim BH. Current guidelines for management of medullary thyroid carcinoma. Endocrinol Metab (Seoul). Published online June 22, 2021. doi:10.3803/EnM.2021.1082

Giusca SE, Andriescu EC, Caruntu ID, Ciobanu D. Clinicopathological profile of medullary thyroid carcinoma — could we predict aggressive behavior? Biomedicines. Published January 3, 2023. doi:10.3390/biomedicines11010116