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Editorial |
Departments of Health Economics (I.B., G.D.P.) and Nuclear Medicine and Endocrine Oncology (M.S.), Institut Gustave Roussy, 94805 Villejuif Cedex, France
Address all correspondence and requests for reprints to: Martin Schlumberger, Department of Nuclear Medicine and Endocrine Oncology, Institut Gustave Roussy, 94805 Villejuif Cedex, France. E-mail: schlumbg{at}igr.fr.
By the time patients with medullary thyroid carcinoma (MTC) present with clinical disease, the condition is usually metastatic and cannot be cured by surgery (1). Plasma calcitonin is a sensitive marker of calcitonin-secreting C cell disease, and routine calcitonin determination in patients with thyroid nodules permits early diagnosis. The real aim of calcitonin testing is not just detection of smaller tumors, but rather reduced mortality, which has not been clearly demonstrated. The use of calcitonin to screen patients with nodular thyroid disease remains controversial; it has been advocated by a European consensus group, but not in the American Thyroid Association guidelines (2, 3).
In a 1997 editorial, Horvit and Gagel (4) defined key questions concerning early diagnosis of MTC and the clinical use of plasma calcitonin determination in patients with thyroid nodules. Ten years later, have we progressed in our knowledge about optimal clinical management?
What Is the Prevalence of MTC in Patients with Nodular Disease?
The prevalence of sporadic MTC in patients with thyroid nodular disease has been reported to range from 0.3 to 1.3% (5, 6, 7, 8, 9, 10, 11, 12). This variability may be explained by several factors: the incidence of thyroid nodules varies among countries, patients with the hereditary form of the disease may not have been excluded, only selected patients with elevated calcitonin levels or other suspicious abnormalities were subjected to surgery, the discovery of microscopic MTC depends on the thoroughness of histological procedures, and the criteria used to differentiate C cell hyperplasia and microscopic MTC differ. In various series, microscopic MTC has been reported to be more, the same, or less frequent than macroscopic MTC. Data regarding the prevalence of C cell hyperplasia is even more controversial, depending on the selection criteria used for surgery, its definition, and histological methods used to detect it. C cell hyperplasia has been found in up to 33% of thyroid glands at autopsy of subjects without known thyroid disorders, twice as frequently in men as women. It may be even more frequent in older patients and those with coexisting hyperparathyroidism, hypergastrinemia, and autoimmune thyroiditis, as well as in close proximity to follicular-derived thyroid tumors, especially when they are malignant (1, 13, 14, 15, 16, 17). Interestingly, the plasma calcitonin level is more frequently elevated in patients with most forms of thyroid disease, whether malignant or benign, compared with subjects without thyroid disease, even though this does not mean that MTC is more frequent in patients with all of these thyroid disorders (18).
What Is the Most Sensitive Tool that Permits the Detection of MTC?
Calcitonin measurement is the most sensitive tool for detecting C cell disease. Circulating calcitonin levels, both basally and after pentagastrin stimulation, are closely related to the mass of thyroid C cells (19). Indeed, discovery of a microscopic MTC at thyroid surgery in patients who had an undetectable preoperative basal plasma calcitonin level is infrequent (9). In all reports, there are some patients diagnosed as having MTC based on calcitonin determination or histology who were not correctly identified by fine needle aspiration cytology (5, 6, 7, 8, 9, 10, 11, 12). The incremental diagnostic value of routine calcitonin determination is most evident in patients with MTC less than 1.5 cm in diameter.
What Is the Specificity of Calcitonin Determination?
The use of a two-site immunoradiometric calcitonin assay improves its specificity by detecting only the monomeric form of circulating calcitonin (20, 21). However, the presence of heterophilic antibodies may still cause falsely elevated values (22, 23). Elevated calcitonin levels unrelated to thyroid diseases are unusual, but can be seen with impaired renal function, pseudohyperparathyroidism, or proton pump inhibitor therapy. Calcitonin-producing tumors other than MTC, particularly neuroendocrine tumors, should also be considered in the differential diagnosis (1). In fact, only 10 to 40% of patients with elevated basal calcitonin levels are ultimately diagnosed with MTC. In patients with benign cytology of their dominant nodule who were, nonetheless, submitted to surgery based on their calcitonin level, only C cell hyperplasia or microscopic MTC was found in some patients, and no C cell abnormalities whatsoever in others (5, 9, 11, 12).
Can Diagnostic Performances of Calcitonin Determination Be Improved?
In this issue of the Journal, Costante et al. (5) suggest two ways to improve the specificity of calcitonin determinations for detection of MTC. One is to manage patients based on their basal calcitonin level. They argue that patients with a basal calcitonin level above 100 pg/ml should be referred for surgery because macroscopic MTC was found in all such patients in their series. At the same time, however, the patients with more extensive disease are usually not cured after surgery. The positive predictive value (PPV) of a basal calcitonin level that was greater than 20 pg/ml was only 23%. Consequently, they recommend that such patients should undergo pentagastrin stimulation, and only those with a stimulated calcitonin above 1000 pg/ml should have surgery. This approach permitted discovery of less-extensive MTC that could be surgically cured. Both basal calcitonin greater than 100 pg/ml and stimulated calcitonin greater than 1000 pg/ml had 100% PPVs for MTC, whereas stimulated plasma calcitonin concentrations between 100 and 1000 pg/ml had an 80% PPV only for C cell hyperplasia. When pentagastrin is not available, calcium infusion may be used, and will probably produce similar results (5). The alternate strategy is to perform a calcitonin determination only in selected patients, based on their nodules’ sonographic characteristics or cytology. However, this would lead to missed diagnosis of some microscopic MTC.
Does Screening for MTC Improve the Outcome of Affected Patients?
In patients with hereditary MTC, C cell hyperplasia progresses to microscopic MTC and later to clinical disease. This is the justification for prophylactic surgery in young patients with germline mutation of the proto oncogene RET. In the case of sporadic C cell disease, however, C cell hyperplasia is rarely associated with microscopic MTC, and the frequency with which microscopic MTC progresses to clinical disease is currently unknown. Indeed, the vast majority of sporadic microscopic MTC is cured by surgery alone. In fact, with introduction of routine calcitonin measurement for patients with thyroid nodules (using a basal calcitonin cutoff for surgery of 50 pg/ml), 10-yr survival improved from 44 to 87% (6). Admittedly, comparison with historical series may be biased, and tumors may have been discovered at an earlier stage in recent series due to other aspects of contemporary clinical practice (24). Furthermore, discovering C cell hyperplasia and microscopic MTC may also lead to overtreatment of a tumor that, during the patient’s lifetime, would likely have low morbidity and almost no mortality without treatment (2, 3). Indeed, if one considered discovery of microscopic MTC to be clinically relevant, a case could be made for screening the general population.
Another issue is whether preoperative diagnosis of MTC may better define the optimal surgical procedure and improve cure rates. In several studies, the completeness of initial surgery has emerged as a significant prognostic indicator (1). The diagnosis of MTC established either intraoperatively by frozen section or at final histology may both lead to completion thyroidectomy.
Is There a Medical Economic Rationale for the Early Detection of MTC?
For any screening program, among the parameters to be considered are 1) the prevalence of the target disease in the tested population, 2) the predictive value of the test, and 3) the availability of an effective treatment for patients with a positive test. Data suggest that the prevalence of sporadic MTC is low in patients with thyroid nodules. According to Costante et al. (5), with a low plasma calcitonin cutoff, a screening program would yield many false-positives and unnecessary surgeries. Furthermore, a low plasma calcitonin cutoff would detect microscopic MTC, the evolution of which to macroscopic cancers is not well established.
Based on these considerations, one can estimate the cost per life-year saved for a screening program restricted to patients with thyroid nodules. We have used the French perspective as an example and constructed a base case scenario with conservative assumptions weighted against screening, thus, representing a high estimate of cost-effectiveness. In France, the target population would be 74,000 incident thyroid nodules per year (24). If surgery is performed on the 5% of patients with a calcitonin level greater than 10 pg/ml (5), 3,587 thyroidectomies would be performed, and 280 would yield a MTC or C cell hyperplasia histologically: the true-positives. However, it must be admitted, as noted above, that the clinical benefit of detecting such lesions is uncertain. The other 3,307 patients without any C cell lesions would be false-positives who had undergone unjustified surgery.
From the study of Elisei et al. (6), we estimated that routine measurement of plasma calcitonin in thyroid nodule patients would yield an additional 2.2 life-years per positive patient.
The unit cost of plasma calcitonin measurement in France is 
24. Thus, routine screening for all thyroid nodule patients would cost 1.8 million. At a unit cost of hospitalization for thyroidectomy of 3,440, the total cost of unnecessary surgeries would be 11.4 million, and the estimated cost of sick leave for active patients was estimated to be 8.1 million. Consequently, total cost for screening would be approximately 21.3 million. In the base case, the incremental cost-effectiveness ratio (representing the incremental cost per year of life gained per patient screened) was estimated to be approximately 35,000. In sensitivity analysis, the most cost-effective strategy was to perform surgery in patients with a plasma calcitonin greater than 50 pg/ml, which yielded a cost per life-year saved of approximately 6,000. If pentagastrin stimulation testing was employed to improve the sensitivity of MTC screening for patients with basal calcitonin between 20 and 100 pg/ml, its costs were estimated to be more than offset by savings from fewer surgeries and their related sick leave. Overall, based on our assumptions, plasma calcitonin determination in the assessment of thyroid nodule patients would appear to be highly favorable compared with a number of other accepted health interventions (25). At the same time, further studies are obviously needed to confirm the benefits of routine calcitonin screening on life expectancy and, conversely, on unnecessary treatment. These studies should be prospective, randomized, and based on a large number of patients who are followed for a protracted period of time. Until such studies are done, uncertainties will remain, and physicians will do what they feel is best, based on imperfect information.
Footnotes
Abbreviations: MTC, Medullary thyroid carcinoma; PPV, positive predictive value.
Received December 11, 2006.
Accepted December 15, 2006.
References
This article has been cited by other articles:
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  H Gharib, E Papini, and R Paschke Thyroid nodules: a review of current guidelines, practices, and prospects Eur. J. Endocrinol., November 1, 2008; 159(5): 493 - 505. [Abstract] [Full Text] [PDF]
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 K. Cheung, S. A. Roman, T. S. Wang, H. D. Walker, and J. A. Sosa Calcitonin Measurement in the Evaluation of Thyroid Nodules in the United States: A Cost-Effectiveness and Decision Analysis J. Clin. Endocrinol. Metab., June 1, 2008; 93(6): 2173 - 2180. [Abstract] [Full Text] [PDF]
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L Foppiani, F Forzano, I Ceccherini, W Bruno, P Ghiorzo, F Caroli, P Quilici, R Bandelloni, A Arlandini, G Sartini, et al. Uncommon association of germline mutations of RET proto-oncogene and CDKN2A gene Eur. J. Endocrinol., March 1, 2008; 158(3): 417 - 422. [Abstract] [Full Text] [PDF]
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M. d'Herbomez, P. Caron, C. Bauters, C. Do Cao, J.-L. Schlienger, R. Sapin, L. Baldet, B. Carnaille, J.-L. Wemeau, and the French Group GTE (Groupe des Tumeurs Endocrine Reference range of serum calcitonin levels in humans: influence of calcitonin assays, sex, age, and cigarette smoking Eur. J. Endocrinol., December 1, 2007; 157(6): 749 - 755. [Abstract] [Full Text] [PDF]
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F. Boi, I. Maurelli, G. Pinna, F. Atzeni, M. Piga, M. L. Lai, and S. Mariotti Calcitonin Measurement in Wash-Out Fluid from Fine Needle Aspiration of Neck Masses in Patients with Primary and Metastatic Medullary Thyroid Carcinoma J. Clin. Endocrinol. Metab., June 1, 2007; 92(6): 2115 - 2118. [Abstract] [Full Text] [PDF]
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