Medullary thyroid carcinoma (MTC) is one of many malignancies in which surgical resection remains the only curative option. Every time we come across an illness with a poor prognosis and that requires surgical intervention as the last option, scientists try to turn back the proverbial clock to see if there was any way that the patient could have been diagnosed sooner, which would afford the patient the luxury of having more than one treatment option available.
There are many aberrant signaling pathways in cancer pathophysiology that scientists can confidently pursue, knowing that all roads lead to Rome. Eckelt and colleagues wrote a study detailing the role of calcitonin and other biomarkers in the management of hereditary MTC. Their work gives us an opportunity to reflect on the role of calcitonin in being a leading MTC diagnostic biomarker in recent decades.
A Crucial Cancer Biomarker
It was only in 1961 that scientists discovered a biomarker that was released during hypercalcemia: calcitonin. It had the effect of lowering serum calcium levels and antagonizing the effects of parathormone.
Calcitonin is produced in the thyroid gland by C-cells. It has a few notable physiological functions. It increases the kidneys’ capacity to eliminate calcium, phosphate, magnesium, sodium, and potassium. In addition, it induces receptor-activator NF-κB (RANK) in bone, resulting in lower calcium and phosphate levels in the blood.
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Eckelt et al commented, “Nevertheless, calcitonin is only the third player in calcium and phosphate homeostasis behind the parathyroid hormone and calcitriol.” This is clinically significant because calcium homeostasis can remain largely unaffected even after total thyroidectomy. Another clinically significant aspect of calcitonin is that it serves as a biomarker for MTC and benign C-cell hyperplasia.
Ophsal et al wrote a paper regarding the role of calcitonin in predicting the extent of surgery needed in MTC. With regards to the use of calcitonin as a biomarker for MTC, they commented, “Calcitonin is a good tumor marker in MTC. As a rule, it is proportional to tumor load, making the hormone a good marker for pre-therapeutic staging and surgical strategy planning.”
Children can be assessed for any RET mutations through early genetic screening to detect hereditary MTC. The American Thyroid Association has three different categories of pediatric patients based on their germline RET mutation: “highest risk”, “moderate risk”, and “low risk.” Patients who are in the higher-risk categories are recommended to undergo prophylactic thyroidectomy sooner (ie, within the first to third year of life). Eckelt et al wrote, “Thyroidectomy is recommended up to the age of five years and depends on the increase of serum calcitonin concentration.”
What is prophylactic thyroidectomy? Quite simply, it is the performance of thyroidectomy on a child with a known genetic predisposition to develop MTC but before any such symptoms develop. Laboratory diagnostics such as calcitonin “represents the most sensitive and specific biomarker for MTC,” wrote Eckelt and colleagues. However, it should also be noted that there is currently no consensus on the reference range for calcitonin in childhood, and adult reference levels are often used.
In adults, calcitonin levels help surgeons make presurgical decisions. Ophsal and colleagues wrote, “preoperative calcitonin levels are significantly related to the extent of disease.” However, they also discovered through their study that there was no clear cut-off value of calcitonin levels requiring surgical intervention; instead, other factors can just as equally impact surgical decision-making, such as the size and spread of the MTC.
There is debate about how significant a role preoperative calcitonin levels should play in guiding surgical decisions.Ophsal et al wrote, “The American Thyroid Association (ATA) guidelines (2015) recommend consideration of prophylactic lymph node dissection in the lateral neck based on serum calcitonin levels in patients without distant metastases.” The authors of the study, however, did not concur with the ATA’s findings. This was because “preoperative calcitonin variation did not consistently relate to tumor stage and metastatic lymph nodes in the lateral neck,” they explained.
Calcitonin also has an important role to play post-surgery. According to current protocols, calcitonin levels should be checked routinely after thyroidectomy; by the third year, these checks should take place annually. Eckelt and colleagues wrote, “After complete thyroidectomy, patients with calcitonin levels below the detection limit are biochemically cured.”
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In addition, Eckelt et al highlighted the problem of incorrect readings of calcitonin levels. Calcitonin reading should be guided by the principle of being assay-specific. For example, higher calcitonin levels could be due to entirely nonmalignant causes, such as high normal cortisol levels due to stress, pregnancy, and smoking.
Based on the various studies on calcitonin that investigated the role of this biomarker in surgical decision-making for MTC cases, it appears that the consensus, for now, is that it has some value due to the observed increases in calcitonin levels in MTC malignancy.
However, sound decision-making must take into consideration other biomarkers and imaging scans, as well as physical examinations. Eckelt and colleagues concluded, “To treat MTC successfully, case history, DNA analysis, biomarker measurements, and guideline knowledge are necessary to develop an individual therapeutic strategy.”
Eckelt F, Pfaeffle R, Kiess W, Kratzsch J. Calcitonin and complementary biomarkers in the diagnosis of hereditary medullary thyroid carcinoma in children and adolescents. J Pediatr Endocrinol Metab. Published online September 21, 2021. doi:10.1515/jpem-2021-0163
Opsahl EM, Akslen LA, Schlichting E, et al. The role of calcitonin in predicting the extent of surgery in medullary thyroid carcinoma: a nationwide population-based study in Norway. Eur Thyroid J. Published online April 29, 2019. doi:10.1159/000499018