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Frequency and Relevance of Elevated Calcitonin Levels in Patients with Neoplastic and Nonneoplastic Thyroid Disease and in Healthy Subjects

Departments of Nuclear Medicine and Clinical Pathology, Institute for Medical and Chemical Laboratory Diagnostics, and Department of Surgery, Section of Endocrine Surgery, Division of General Surgery, University of Vienna, A-1090 Vienna, Austria

Address all correspondence and requests for reprints to: Dr. Georgios Karanikas, Department of Nuclear Medicine, University of Vienna, Waehringer Guertel 18–20, A-1090 Vienna, Austria. E-mail: georg.karanikas{at}akh-wien.ac.at.

	Abstract

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Routine measurement of serum calcitonin (CT) has been recently proposed for all patients with neoplastic thyroid disease to detect clinically occult medullary thyroid carcinoma (MTC). Data on the prevalence of elevated CT levels in nonneoplastic thyroid disease or in healthy subjects have not been reported to date. Four hundred and fourteen consecutive patients with suspected thyroid disease and 362 healthy controls underwent thyroid examination with measurement of basal serum CT. Whenever serum CT was 10 pg/ml or more, a pentagastrin (PG) stimulation test was performed. Twenty-eight of 414 patients (6.8%) showed elevated basal serum CT levels, 15 of them with nonneoplastic thyroid disease, and the remaining 13 subjects with neoplastic thyroid disease. Four patients with abnormal PG testing (stimulated CT, 100 pg/ml) were identified. Three of them had biochemical and sonographical evidence of thyroiditis. Elevated basal CT levels were significantly more frequent in patients with Hashimoto’s thyroiditis (HT; P < 0.05). One female patient with HT had a 5-mm nodule, which was classified as MTC. None of the 6 out of 362 healthy controls with elevated basal CT (1.7%) presented an abnormal PG test. Our data suggest that basal CT measurements can be of use in the detection/screening of MTC not only in subjects with neoplastic thyroid disorders, but also in patients with immunological evidence of HT. They also confirm earlier reports on the essential value of PG stimulation testing, even when basal plasma CT levels are only modestly elevated, with regard to establishing the diagnosis of MTC or its premalignant associated conditions (micro-MTC and neoplastic C cell hyperplasia).

	Introduction

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MEDULLARY THYROID CARCINOMA (MTC) occurs in both nonhereditary (sporadic) and hereditary forms. It is well known that serum calcitonin (CT) is a sensitive and accurate marker of MTC and that the increase in CT after pentagastrin (PG) injection is a specific feature of MTC (1, 2, 3). Sporadic MTC is usually diagnosed at the stage of nodal involvement, hence precluding definitive cure in most cases (4, 5, 6). Routine measurement of serum CT was recently proposed for all patients with neoplastic thyroid disease (7, 8). Particularly, patients with basal and stimulated plasma CT levels greater than 100 pg/ml should be considered for operation (9) because they probably suffer either from MTC or C cell hyperplasia (CCH), a potential precancerous condition even in the absence of germline mutations in the RET protooncogene (10, 11), which was termed neoplastic CCH (12). This strategy will increase the probability of early diagnosis of MTC, thus providing the chance of curative surgery (9, 13). However, we do not agree with the assumption that only neoplastic thyroid disease is associated with MTC. Autopsy studies revealed a high prevalence of CCH in 33–66% of specimens obtained from deceased persons without known thyroid disease, possibly reflecting an age-related effect (14, 15, 16). Despite the high prevalence of CCH, it must be emphasized that MTC is rare. It is well known that CCH may also be associated with a variety of (non) thyroidal diseases (12, 17). However, data on the prevalence of elevated CT levels in nonneoplastic thyroid disease and its presumed relationship to CCH and MTC are missing. Therefore, the aim of our study was to compare the distribution and relevance of elevated CT levels in referrals with nonneoplastic and neoplastic thyroid disease as well as in young to middle-aged subjects without a history of thyroid disease. Indeed, in this study we expand for the first time the utility of basal plasma CT measurements in the detection/screening of MTC in patients with immunological evidence of Hashimoto’s thyroiditis (HT).

	Subjects and Methods

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Patients with thyroid disease

Four hundred and fourteen consecutive patients (85 males and 329 females), aged 18–88 yr (mean age, 56 yr), referred to our out-patient department for the work-up of various suspected thyroid disorders were included in the present study (Table 1). The clinical diagnosis was nonneoplastic thyroid disease in 219 (Graves’ disease, HT, nontoxic diffuse goiter, or de Quervain’s subacute thyroiditis) and neoplastic thyroid disease in 195 patients (uni- and multinodular disease; Table 1).

Serum CT was determined with a commercially available luminescence assay (Nichols Advantage, Calcitonin Chemiluminescence Assay, San Juan Capistrano, CA). Elevated CT was confirmed by an additional dilution test. In rare cases of nonconformity, the results of the diluted sample are reported (18).

Analytic sensitivity was 1 pg/ml. The intraassay coefficient of variation was 3.5–6.2%, and the day to day variation was 5.1–8.7% at average CT levels between 10–553 pg/ml. Basal serum CT was determined in each patient. Whenever serum CT was equal to or exceeded 10 pg/ml, a PG stimulation test was performed. For this purpose, blood samples for the assessment of CT were drawn through an indwelling catheter before and 2 and 5 min after an iv bolus of 0.5 µg/kg PG (Pentagastrin Injection BP, Cambridge Laboratories, Tyne & Wear, UK). Abnormal and pathological PG stimulation test results were defined by CT levels between 100–500 pg/ml and above 500 pg/ml, respectively.

Healthy controls

Three hundred and sixty-two apparently healthy controls without any history of thyroid disease or any family history of MTC were studied. Healthy subjects have been exposed to low level radiation (<20 mSv/yr) and have been obliged to pass their statutory annual check-up in our department. In addition, this check-up consists of a clinical examination, including the inspection of head and neck, a red and white blood cell count, and measurement of thyroid hormones, TSH, and thyroid autoantibodies. During the study period calcitonin was included, and subjects gave their consent. Thyroid sonography and PG stimulation testing were performed only in subjects with basal serum CT levels of 10 pg/ml or more. The mean age in these subjects was significantly lower than that in patients with thyroid disease (36 ± 10 vs. 56 ± 15 yr; P < 0.05).

The collected samples of patients and healthy controls were properly anonymized/masked for the performance of this study. Informed consent was obtained from all subjects. The study and the informed consent were part of an approved institutional review board protocol.

Sonography

Thyroid sonography was performed in all patients using a Sonoline Prima diagnostic ultrasound system (Siemens, Erlangen, Germany) or a LOGIC 400 pro series (General Electric, Fairfield, CT), using a linear 7.5-MHz transducer by experienced physicians.

Scintigraphy

Planar acquisition was performed using a one-head -camera equipped with a dedicated low energy, high resolution, parallel hole collimator (ADAC Transcam, equipped with a dedicated collimator for thyroid scintigraphy). A planar image (anterior view) of the thyroid was obtained 20 min after iv administration of 74MBq Tc^99m-pertechnetate (matrix, 128 x 128 pixels; 100 kcounts/image).

Surgery

By definition (9) patients with abnormal PG tests were candidates for surgery. Total thyroidectomy with lymph node dissection along both recurrent nerves was the treatment of choice (9).

Histology and molecular genetic analysis

Submitted thyroidectomy specimens were blocked entirely. On each block a hematoxylin and eosin stain and immunohistochemistry were performed. Immunostains were made using the avidin-biotin-peroxidase method. The CT antibody (dilution, 1:600) was obtained commercially (Chemicon, Temecula, CA). CCH was defined according to the criteria of Rosai et al. (19), when there were more than 50 C cells in a single low power field (x100 magnification) in both thyroid lobes. The search for germline mutations of the RET protooncogene should exclude hereditary types of C cell pathology in patients undergoing surgery by analyzing exons 10, 11, 13, 14, 15, and 16 of this gene on chromosome 10. DNA was obtained from peripheral blood using the DNAzol (Vienna Lab, Vienna, Austria) DNA extraction procedure. PCR amplification and DNA sequencing were performed as described previously (20).

	Results

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CT levels in referrals

As reported in Table 1, 28 of 414 patients (6.8%) showed elevated serum CT levels, 15 of them with nonneoplastic and the remaining 13 subjects with clinically occult neoplastic thyroid disease (Table 2). The ratios between males and females were 8:7 and 9:4 in patients with nonneoplastic and neoplastic thyroid disease, respectively. Patients with nonneoplastic thyroid disease were significantly younger than those with neoplastic thyroid disease. Thyroid function was not significantly different in both groups (Table 2). Basal CT and CT after PG stimulation were not different, nor was the thyroid volume (Table 3). Four of 28 patients with elevated basal CT levels revealed an increase in CT after PG stimulation above 100 pg/ml. A PG-stimulated CT between 100 and less than 500 pg/ml was found in 3 cases, whereas only 1 patient showed a CT response greater than 500 pg/ml. Table 4 details gender, age, and diagnosis of these patients. Patient 1 with HT and thyroid adenoma underwent surgery due to the pathological PG stimulation test with evidence of MTC in the final histological examination (tumor diameter, 3 mm; no lymph node metastases in 81 nodes tested). Follow-up basal and stimulated CT levels were not detectable. Patient 2 was lost for follow-up. Patient 3 suffered from de Quervain’s subacute thyroiditis until clinical remission after therapy with corticosteroids. Patient 4 refused both surgery and fine needle aspiration for personal reasons. The patient is monitored clinically at regular intervals. Over a period of 1 yr, basal and stimulated CT levels have been decreasing, although they remain elevated. Seven of 28 patients with elevated basal CT had HT (25%), whereas the prevalence of the disease was 13.3% (P < 0.05) in all 414 patients.

Six (5 males and 1 female) of 362 healthy controls (1.7%) had elevated basal CT levels, ranging from 10–12 pg/ml. Figure 1 shows the gender-related CT distribution pattern, demonstrating higher normal values in males compared with females. None of the 6 subjects had an abnormal PG stimulation test or evidence of functional or morphological thyroid abnormalities.

View larger version (17K): [in this window] [in a new window]   FIG. 1. CT levels in healthy volunteers (M, male; F, female; all, females and males together).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Only 1 of 28 referrals with an elevated basal CT had a final histological diagnosis of MTC. In the study group of referrals, the prevalence of MTC reached 0.24%, which was lower than in previously published trials, where it ranged from 0.58% (7) to 1.37% (21). Therefore, in agreement with earlier studies no rationale exists for general CT screening, because these programs should be performed for common diseases, yet this is clearly not true for MTC (22, 23). However, subjects with neoplastic or nonneoplastic thyroid disease represent a different population. In fact, the frequency of an abnormal PG test was equally high in subjects with neoplastic (2 of 195, 1%) and nonneoplastic (2 of 219, 0.9%) thyroid disease and was comparable with that in other studies (7, 8, 13, 21). At the end, 4 subjects with abnormal or pathological PG testing were identified, at least 1 of them with a final diagnosis of MTC. This patient had only 1 nonpalpable nodule, 5 mm in diameter, which might have been missed if patients were selected by clinical criteria. Importantly, this female was 1 of 3 patients with abnormal PG testing and evidence of thyroiditis (2 subjects with HT and 1 subject with de Quervain’s subacute thyroiditis). Niccoli’s study (21) revealed that 8 (50%) of 16 patients with MTC had histopathological signs of thyroiditis, whereas other groups did not comment upon the frequency of thyroiditis. An association between CCH and HT has been described (24, 25, 26, 27). Firstly, Barbot (27) reported increased serum CT levels and extensive CCH in histology after thyroidectomy in 3 of 24 patients with HT. In extended studies, Guyetant (24) reported the occurrence of CCH in 20% of HT patients. The pathophysiological link between CCH and HT may involve an immunopathological mechanism or an effect of the inflammatory mediators and cytokines secreted by infiltrating lymphocytes in the thyroid parenchyma. It is important to state that our data suggest that CT measurements should be carried out in all patients with HT.

The role of a C cell growth factor whose gene is overexpressed in hyperplastic C cells adjacent to follicular tumors is hypothesized (24). Interestingly, basal CT levels were related to stimulated CT levels in nonneoplastic, but not in neoplastic, thyroid disease, and the PG-stimulated increase in CT was lower in nonneoplastic thyroid disease. Perry et al. (12) postulated the concept of physiological and neoplastic CCH. One might hypothesize that the increase in CT reflects a cause-effect relationship in HT, a physiological response of all C cells in the thyroid gland in nonneoplastic disease, yet no biochemical markers exist for the distinction between physiological and neoplastic CCH.

CT measurement contains numerous methodological aspects. Mature CT is formed by posttranslational proteolytic processing of a large precursor molecule, and various split products of prepro-CT may also exist in the circulation (28). Conceivably, for MTC screening only tests free of cross-reactions with immature CT should be used (29). There are several reports in the literature on rarely assay-dependent CT elevations, which may be partly explained by the presence of heterophilic antibodies within the sample matrix (18, 30, 31). To block such interference, most noncompetitive immunoassays, including the test used in this study, contain an excess of nonimmune-competent immunoglobulin G of the same animal species. Despite this, we observed that several lots of the assay used were still susceptible to immunological interference, making either dilution testing or addition of an external blocking agent necessary to obtain correct results (18). Our findings are in agreement with reported data, and the assay used throughout this study has been demonstrated to be a reliable and sensitive assay (32).

Identification of subjects at risk for MTC relies on an appropriate cut-off value for basal and stimulated CT. From experience in our institution a cut-off of 100 pg/ml was appropriate to identify CCH (9). To stimulate CT secretion we routinely use pentagastrin and have established criteria for test interpretation, which have been clinically validated (9).

In our study a cut-off value of 10 pg/ml was set up for performing PG tests regardless of gender. Vierhapper et al. (13) used a cut-off of 5 pg/ml, and 72 of 1062 patients exceeded this value, yet in only 11 of 34 patients with greater than 10 pg/ml was CCH or MTCfound. In Pacini’s study all subjects with MTC had a basal CT level greater than 55 pg/ml (7). Niccoli noted that 2 (0.17%) of 16 patients with MTC had a basal CT ranging between 5–10 pg/ml using of a less sensitive CT assay (21). According to our data, any higher CT cut-off point would substantially decrease the sensitivity of basal CT measurements for the detection of (neoplastic) CCH.

However, less is known about the physiological variation in CT levels. They might be related to the subject’s nutritional status (fasting/nonfasting) or influenced by blood sample collection. In our institution, as in many others, basal CT was measured first during thyroid work-up in a nonfasting state with the patient seated. This is in contrast to the standardized conditions during PG stimulation testing. These differences might account for the variation in basal CT levels observed in our patients. Eighteen of 28 patients had basal CT values of 10 pg/ml or less at the time of PG stimulation. It is noteworthy that in our study basal CT levels were only moderately elevated in subjects with either abnormal or pathological PG testing. As reported recently (9), patients with abnormal PG testing should undergo operation. This strategy is supported by findings that metastatic MTC might occur even in patients with microcarcinoma (11).

Patient 3, suffering from de Quervain’s subacute thyroiditis, is an example of the need to obtain clinical information for interpretation of CT levels. Even after a follow-up period of 2 yr in clinical remission, this patient still showed evidence of elevated basal and stimulated CT, with a trendwise decrease over time. For that reason, interpretation of CT and PG test results should be made cautiously and with respect to the underlying condition. Nevertheless, this patient is still a candidate for surgery to exclude definitely micro-MTC.

Clinical conclusion

In accordance with previous studies and recommendations (13), CT measurements should be performed in all subjects with neoplastic thyroid disease as evidenced by sonography. Our data suggest that the number of basal CT measurements should be increased by extending them to all HT patients. This might change the cost-effectiveness of basal CT screening. PG testing is essential even when basal CT levels are only moderately elevated to diagnose MTC or its premalignant conditions. However, by accumulating evidence for the impact of CT measurement for early diagnosis of nonhereditary MTC, further studies are necessary to define how often CT levels should be assessed in patients with neoplastic thyroid disease, because this information implies substantial consequences in terms of cost effectiveness. Furthermore, the effects of various forms of thyroiditis on CT levels and its potential impact on the outcome of CT measurements need to be investigated.

	Footnotes

 
Abbreviations: CCH, C Cell hyperplasia; CT, calcitonin; HT, Hashimoto’s thyroiditis; MTC, medullary thyroid carcinoma; PG, pentagastrin.

Received April 21, 2003.

Accepted September 25, 2003.

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