Should All Patients With a Thyroid Nodule Have Routine Serum Calcitonin Measurements?

Kenneth D. Burman, MD


July 23, 2003


The current recommended approach to patients with thyroid nodule(s) is to obtain a relevant history and physical examination focusing, for example, on whether there is a history of radiation to the head or neck; a personal or family history of thyroid cancer, hyperparathyroidism, or hypertension (possibly a pheochromocytoma); and the presence of symptoms such as dysphagia, discomfort, or hoarseness. It is relevant to determine whether the nodule has been growing, if it is firm or hard and fixed to surrounding tissues, and if cervical adenopathy is present. Of course, the fine-needle aspiration yields critical information, and if it is interpreted as malignant or suspicious, then usually surgery is recommended.

An important new concept related to the initial evaluation of patients with thyroid nodules is whether serum calcitonin concentration should be measured preoperatively. This question relates to patients with a single nodule as well as those with multiple nodules. Calcitonin is a hormone found in the serum of normal subjects in concentrations lower than about 8 pg/mL. Patients with C-cell hyperplasia and medullary thyroid cancer may have elevated serum calcitonin levels. Medullary thyroid cancer may be an aggressive disease with a high recurrence and mortality rate. The survival rate, for example, in individuals diagnosed over age 50 is approximately 60% at 5 years; 41% at 10 years; and 14% at 20 years.[1] Adequate surgery represents the most effective treatment modality, and it is important to detect and treat the disease as early as possible.

Moreover, medullary thyroid cancer can occur as part of the syndrome of multiple endocrine neoplasia in conjunction with hyperparathyroidism and pheochromocytoma. Approximately 70% of cases of medullary thyroid cancer are sporadic and 30% are familial. In any given patient or family, 1 or more of these diseases can be present, and the initial clinical presentation varies. These associations make it extremely important to diagnose medullary thyroid cancer prior to surgery, if possible, since during thyroid surgery an undetected pheochromocytoma could cause serious problems. Unfortunately, even a thyroid fine-needle aspiration interpreted by an experienced cytologist may not detect or suspect medullary thyroid cancer. If it is suspected, of course, it may be helpful to stain the sample for the presence of calcitonin. Nonetheless, in the majority of cases, medullary cancer is not suspected prior to surgery, even if a thyroid fine-needle aspiration is performed.

There have been several previous studies assessing the frequency of elevated serum calcitonin in routine patients presenting with thyroid nodules. These patients, of course, have a negative relevant personal or family history. Hahm and colleagues[2] reported on 1448 patients with nodular thyroid disease; 3.9% (n = 56) had a serum calcitonin level greater than 10 pg/mL. Of these 56 patients, 10 (0.7% of the entire initial group) had medullary thyroid cancer. Two patients had their medullary thyroid cancer detected by fine-needle aspiration, and 2 had familial multiple endocrine neoplasia type 2. These authors reviewed previous reports and noted that the incidence of detecting medullary thyroid cancer in patients with nodular thyroid disease varied between about 0.20% and 2.8%.

Ozgen and colleagues[3] studied 773 patients with thyroid nodular goiter, and 4 had a serum calcitonin level greater than 150 pg/mL. All 4 of these patients had unsuspected medullary thyroid cancer, 1 of which was familial. Of these 4 patients with medullary thyroid cancer, 1 had a benign aspiration and the 3 other patients had aspirations suspicious for malignancy, but the possibility of medullary thyroid cancer was not raised specifically.

At the recent annual Endocrine Society Meeting, Vierhapper and colleagues[5] reported on 8374 patients with thyroid nodules, 82 of whom had elevated basal or stimulated calcitonin levels using routine serum calcitonin measurements. They identified 27 new cases of medullary thyroid cancer (26 sporadic, 2 familial) and an additional 29 cases of C-cell hyperplasia.

On the basis of the above studies, it does appear that it is extremely important to detect medullary thyroid cancer as early as possible, especially prior to surgery. It also appears that fine-needle aspiration is not as sensitive as a serum calcitonin level in being able to diagnose or raise suspicion for medullary thyroid cancer. Fine-needle aspiration, of course, should be routine in the assessment of patients with thyroid nodules. The question at present is whether routine determination of serum calcitonin should be performed as well.

An appropriate analysis of cost-effectiveness needs to be published and should consider, as well, the frequency of false-positive calcitonin levels that lead to additional studies that determine that significant pathology is not present. Hahm and colleagues, as noted above, had false elevations (apparently) in 46 of 56 patients who had calcitonin elevations. It can only be known with certainty that a calcitonin elevation is spurious if a patient has a thyroidectomy. The degree of calcitonin elevation also should be taken into account, although the exact cutoff value needs to be studied further. In general, the higher the serum calcitonin concentration the more likely it is that the patient has authentic calcitonin being measured. This concept is not always correct, however, and sometimes cross-reactive substances can cause significant calcitonin elevations.

Uwaifo and colleagues[6] recently reviewed the causes of calcitonin elevations other than medullary thyroid cancer. These factors were multiple and resulted in an elevated calcitonin either because there was C-cell hyperplasia that was not related to medullary thyroid cancer (eg, pernicious anemia with elevated gastrin that stimulates C-cells), because of calcitonin production (eg, carcinoid tumors, small cell lung cancer, pancreatic neuroendocrine tumors), or there was spurious elevation. Calcitonin assays vary in their ability to measure only serum calcitonin and not calcitonin precursors. It seems that the optimal assay is a double sandwich assay in which 2 different anticalcitonin monoclonal antibodies are used to capture calcitonin and then a sensitive detection system is used. In such an assay, the likelihood of detecting calcitonin precursors is lessened but not eliminated.

Engelbach and colleagues[7] utilized such an assay to assess serum calcitonin levels in normal subjects and in patients who had a thyroidectomy. The normal range is less than about 4 pg/mL for women and less than about 8 pg/mL for men. Three of 124 patients who had a total thyroidectomy had detectable levels in the 3 to 8 pg/mL range. Further, 1 of the 90 patients who had a thyroidectomy with subsequent 131-I therapy (for differentiated thyroid cancer) had an inappropriate calcitonin level of about 30 pg/mL. It is always possible, of course, that the pathologic interpretation was in error or was incomplete, or that these patients had significant residual thyroid tissue remaining. Nonetheless, the most plausible explanation is that the serum calcitonin assay is being interfered with, resulting in spurious calcitonin readings. It is realized that calcitonin precursors are secreted disproportionately in patients with systemic illness, burns, trauma, or infections. These precursors are believed to be a part of the systemic inflammatory response, but its physiologic purpose is unknown. Different patients may actually have spurious elevations due to cross-reactive substances such as calcitonin antibodies.

In summary, on the one hand, it is extremely important to detect medullary thyroid cancer as soon as possible, and routine determination of serum calcitonin in patients with thyroid nodular disease may be very helpful. On the other hand, the incidence of medullary cancer in routine patients with thyroid nodular disease is about 0.5% to 2%. There are many instances of calcitonin elevations not representing medullary thyroid cancer, and a subsequent evaluation would be costly and time intensive.

We certainly need additional studies, especially studies that define a cutoff value for calcitonin above which it is more likely that a patient has medullary thyroid cancer rather than a false-positive result. Analyses of cost-effectiveness are also needed. In the meantime, is there enough evidence to recommend the routine determination of calcitonin in all patients with nodular thyroid disease? My personal view is that I am impressed with the studies that have been performed suggesting that calcitonin levels may be even more sensitive than a fine-needle aspiration, and it is important to utilize these 2 techniques together. In a larger sense, how can we put a price tag on the importance of detecting medullary thyroid cancer in a patient or his/her family? The clinical implications of medullary thyroid cancer are enormous, and it is possible that preoperative detection would help guide the surgical approach, and, in rare instances, would help prevent significant problems with an undetected pheochromocytoma. Furthermore, if a patient had a benign (or even suspicious) fine-needle aspiration and thyroidectomy was not planned, the definitive diagnosis of medullary thyroid cancer would be delayed in the patient, perhaps resulting in significant morbidity and even mortality. If the diagnosis is delayed in the patient, then, of course, it is also delayed in the patient's family (when familial in nature), and this can have serious consequences itself. However, perhaps 5% to10% of the US population have thyroid nodules, with the prevalence being higher in women and increasing with age in both genders. Is it really reasonable to recommend routine serum calcitonin measurements in all of these patients? Clinical examination and history must play a role. It is known as well, for example, that familial medullary cancer typically (but certainly not always) may present as bilateral nodules located at the junction of the upper third and lower two thirds of the thyroid gland.

At this point, pending additional studies, I have come to the conclusion that whether to measure serum calcitonin routinely in patients with nodular thyroid disease is an individual decision for each physician based on his or her interpretation of the literature and the desires and characteristics of the patients served. To be certain, clinicians must constantly bear in mind the possibility of medullary thyroid cancer in the patients they see.