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Interest of Routine Measurement of Serum Calcitonin: Study in a Large Series of Thyroidectomized Patients

Service d’Endocrinologie (P.N., B.C.-D.) and Service de Chirurgie Endocrinienne (J-F.H.) and Laboratoire d’Anatomopathologie (C.dM.), CHU la Timone, and U-38, Faculté de Médecine (P.N.), Marseille; Service d’Endocrinologie (N.W-B., J-C.B.) et Laboratoire d’Anatomopathologie, CHU Angers (J-P.S.A.), Angers; Service d’Endocrinologie, CHU Rangueil (P.C.), Toulouse; and Service d’Endocrinologie, Hopital Avicenne (E.M.), Bobigny, France

Address all correspondence and requests for reprints to: Dr. Patricia Niccoli, Unité 38, Faculté de Médecine, boulevard Jean Moulin, 13385 Marseille Cedex 05, France.

	Abstract

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The aim of our study was to assess the ability of routine calcitonin (CT) measurement to improve the preoperative diagnosis of medullary thyroid carcinoma (MTC) in nodular thyroid diseases. We systematically determined basal CT in 1167 patients before thyroid surgery and performed a pentagastrin (Pg) CT stimulation test in 121 of these patients whose basal CT level was normal.

Sixteen MTC (1.37%) were found on histopathological examination of surgical specimens: 14 in the 34 patients (41.1%) with abnormal basal CT levels and 2 in the 1133 patients with normal basal CT levels (0.17%).

An abnormal increase in Pg-stimulated CT was observed in 7 of the 121 patients tested and was related to microscopic MTC in 2 cases.

Among 1167 thyroidectomized patients with nodular thyroid diseases, the prevalence of MTC was 1.37% and reached 41.1% when the basal CT level was abnormal (3% of the patients). CT evaluation detected MTC, whereas other procedures, such as fine needle aspiration cytology, failed, thus allowing early radical surgery.

CT measurement should thus become a routine part of the diagnostic evaluation of nodular thyroid diseases.

	Introduction

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MEDULLARY THYROID carcinoma (MTC) occurs in both familial and sporadic forms. The former may be detected by familial screening using molecular genetic studies of the gene ret (1, 2) together with basal and pentagastrin (Pg)-stimulated calcitonin (CT) measurements (3). These procedures allow early diagnosis of MTC and lead to early radical surgery, resulting in a high cure rate for the affected patients (4). On the contrary, sporadic MTC are usually diagnosed at the stage of nodal involvement, hence precluding definitive cure in most cases (5, 6, 7, 8, 9).

It is well known that serum CT is a sensitive and accurate marker of MTC and that the increase in CT after Pg injection is a specific feature of MTC (10, 11, 12, 13, 14). Serum CT measurement in nodular thyroid diseases would thus be expected to reveal sporadic MTC at a early stage.

The aim of our study was to assess the prevalence of sporadic MTC in nodular thyroid diseases and to determine the ability of routine basal CT measurement to improve the preoperative diagnosis of MTC in a large series of thyroidectomized patients. We also evaluated Pg-stimulated CT in patients with nodular thyroid diseases and normal basal CT levels.

	Subjects and Methods

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Patients

The basal serum CT level was prospectively measured in 1167 patients (215 males and 952 females), aged 9–83 yr (mean age, 47.5 yr), referred for surgical treatment of nodular thyroid diseases: multinodular euthyroid goiter (611 cases), solitary euthyroid nodule (479 cases), toxic multinodular goiter (50 cases), and autonomously functioning thyroid nodule (27 cases). CT evaluation was systematically performed as a routine procedure before surgery.

The initial evaluation included thyroid examination, thyroid ultrasonography, and measurement of serum TSH, free thyroid hormones, and thyroid autoantibodies. Fine needle aspiration cytology (FNAC) was performed in patients whose nodular formation was accessible to this procedure. We excluded from the study patients with a familial history of MTC or multiple endocrine neoplasia, patients with clinical or biological signs of multiple endocrine neoplasia, and those who underwent surgery for MTC before this referral. Informed consent was obtained for all patients included in the study.

A Pg test was prospectively performed before surgery in 121 patients exhibiting normal serum basal CT levels (i.e. <10 pg/mL with the CT assay we used). The test was performed in 29 men and 92 women, aged 22–72 yr (mean age, 42.3 yr).

Of the 1167 patients, 326 had uninodular thyroid disease and were treated by lobectomy. A total thyroidectomy was performed in 841 patients by taking account of bilateral lesions diagnosed either before surgery or during the surgical procedure. All patients with MTC were surgically treated by total thyroidectomy and central neck dissection, which was extended to bilateral neck dissection when evident lymph node involvement was revealed in one of the two sides.

Serum basal and Pg-stimulated CT levels were evaluated after surgery and yearly in a 2- to 4-yr follow-up. Screening for hyperparathyroidism [by measuring serum intact PTH-(1–84) and calcium levels] and pheochromocytoma (by high performance liquid chromatography measurement of urinary methoxyamine and catecholamine levels) was negative in all patients with MTC.

Methods

CT assay. Serum CT was measured by an immunometric method (Elsa-CT, Cis-Bioindustries, Gif sur Yvette, France), including monoclonal antibodies that recognize the 11–17 and 24–32 regions of the CT molecule (15). There is no cross-reaction with serum pro-CT, and this method is considered specific for the mature CT monomer. The sensitivity of the assay was 2 pg/mL. The intra- and interassay coefficients of variation were 6.7% and 7.9%, respectively, for values between 30–100 pg/mL.

CT values were considered normal according to the data of the French Medullary Study Group (GETC), in which normal subjects have a basal serum CT level of less than 10 pg/mL using the former CT assay (10, 11).

Pg stimulation CT test. The Pg stimulation CT test was performed according to the GETC-recommended procedure. Briefly, an iv injection (0.5 µg/kg) of Pg (Peptavlon, ICF Pharma, France) was conducted for 3 min. Blood samples were collected before and 3, 5, and 10 min after injection. The response is expressed as the maximum value of CT peaks 3 or 5 min after the initiation of the Pg injection. The Pg-stimulated CT value was considered normal with reference to the data from the GETC, in which 69 of 71 (97.1%) normal subjects had a peak CT value less than 30 pg/mL using the CT assay mentioned above (10, 11).

FNAC. FNAC was performed using a standard technique. Smears were examined by two pathologists of the GETC who were unaware of serum CT results.

Immunohistological examination of surgical specimens. The surgical specimens were histopathologically examined using a standard technique. Serial sections were obtained through the whole gland to detect any microscopic MTC. In patients with high basal and/or stimulated CT values, an extensive search for C cell hyperplasia (CCH) or microscopic MTC loci was conducted by immunochemistry with an anti-CT polyclonal antibody (CT-205, Immunotech, Marseille, France) at a dilution of 1:1000, stained by a peroxidase-antiperoxidase procedure.

The same immunohistological criteria were used by the pathologists of the GETC to define CCH: either a C cell density of more than 50 cells/cm² (x40) or microscopic foci containing more than 6–10 C cell micronodules/field.

	Results

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Prevalence of MTC in nodular thyroid diseases

Among 1167 thyroidectomized patients, histological examination of surgical specimens detected 16 MTC (1.37%) among the various pathologies reported in Table 1. Among these 16 patients, 10 were submitted to FNAC before surgery. FNAC suggested MTC in 3 cases and led to false diagnosis in 5 cases (2 benign adenomas, 2 anaplastic cancers, and 1 suspicion of papillary cancer). In 2 cases, the material was inadequate for the diagnosis (Table 2).

Ninety-seven percent (1133 of 1167) of the patients had normal basal CT levels of less than 10 pg/mL. Among them, histopathological examination of surgical specimens evidenced 2 microscopic MTC (cases 1 and 2 in Table 2). Three percent (34 of 1167) of the patients, 18 males and 16 females, aged 11–82 yr, had abnormal basal CT values, ranging from 11–37,000 pg/mL. Of these 34 patients, 14 (41.1%) were shown to have MTC after histopathological examination of the surgical specimens (Table 3 and cases 3–16 in Table 2). After surgery, Pg-stimulated CT level became undetectable in the 8 patients with microscopic MTC and was unchanged 2–4 yr later, whereas basal CT level remained high in patients with macroscopic MTC.

Pg-stimulated CT levels

Of the 121 patients with normal basal CT levels who underwent a Pg test prospectively, 114 (94.2%) had a Pg-stimulated CT value less than 30 pg/mL. Seven (5.8%) exhibited an abnormal CT increase (>30 pg/mL) ranging from 37 to 372 pg/mL after Pg injection (Table 4), which was related in 2 cases (patients 1 and 2 Table 2 and 4) to a microscopic MTC without nodal involvement (CT peaks of 100 and 372 pg/mL, respectively).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

In our population of 1167 patients who underwent surgery for nodular thyroid diseases, the prevalence of sporadic MTC was 1.37%, which is higher than those reported by others (17, 18) in which only patients with suspected MTC underwent surgery. We assessed the prevalence of MTC on the basis of the histopathological findings made on surgical specimens of the whole population of this large series. Furthermore, our methodology probably led us to underestimate the real prevalence of sporadic MTC, because the search for microscopic tumors was more extensive in patients with abnormal CT values (by anti-CT immunostaining procedure) than in those with normal CT values. The discovery of a microscopic MTC in 2 patients with normal basal CT supports this hypothesis.

We found that 97% of the 1167 patients exhibited basal CT values less than 10 pg/mL. The prevalence of sporadic MTC in such patients was very low (0.17%); 2 microscopic MTC were found in these 1133 patients. When the basal CT level was more than 10 pg/mL (3% of the 1167 patients), the prevalence of MTC reached 41.1%. If we consider only the 841 patients who underwent total thyroidectomy with histopathological analysis of the whole surgical specimen removed, the sensitivity of basal CT measurement for MTC diagnosis was 69.9%, and the specificity was 97.6%.

Routine CT measurement allowed us to detect MTC at an early stage; 8 of 14 MTC were microscopic tumors with no nodal metastases. The radical surgical procedure used allowed us to normalize CT levels in these patients, and it is thus expected to improve the prognosis and survival of sporadic MTC (8, 9, 17, 18).

The benefit of CT measurement in nodular thyroid diseases is underlined by the inferior performance of other procedures for detecting MTC. Indeed, most of the researchers have reported that FNAC may fail to detect MTC (17, 18). In our series, FNAC failed in 7 of 10 cases. As expected, FNAC missed microscopic MTC in 5 cases, although basal CT measurement could detect it. In 2 cases, FNAC led to the false diagnosis of anaplastic thyroid carcinoma, and CT evaluation allowed us to correct the diagnosis and to perform the surgical treatment required. Indeed, the diagnosis of MTC was difficult, as CT immunostaining of cytological samples is not usually performed unless specifically requested, and FNAC is limited by the position and size of the nodule studied. Our results show that CT measurement detected MTC in patients who would have escaped attention. CT measurement thus appears to be an important criterion for surgery in nodular thyroid diseases. For solitary adenoma, CT may indicate total thyroidectomy for patients in whom clinical evaluation or FNAC would have indicated only unilateral surgery. In bilateral disease, only CT determination may reveal MTC and lead to the first radical surgery requested.

Our results showed that 9 of 34 patients had mild hypercalcitoninemia related to CCH, which is known to cause increased CT levels as reported in differentiated thyroid neoplasms or lymphocytic thyroiditis (19, 20, 21, 22, 23). We found that both benign nodular diseases and multinodular colloid goiters may also be responsible for basal hypercalcitoninemia. The absence of CCH in the 11 other patients exhibiting mild hypercalcitoninemia may be explained by our definition of CCH, which may be too restrictive. An accurate definition of CCH has not yet been agreed upon (24, 25, 26); thus, CCH may be underestimated.

The performance of basal CT evaluation and the strategy in screening MTC have to be considered with reference to the CT value itself. In our series, a high CT level clearly revealed 12 of 16 MTC (basal CT ranging between 70–37,000 pg/mL), whereas FNAC suggested MTC in only 3 cases. The preoperative diagnosis of MTC allowed radical surgical treatment to be performed early. Thus, for patients with nodular thyroid diseases, high basal CT values (>35 pg/mL, as we did not observe false positive diagnosis of MTC at CT levels over such a value in our series) in routine evaluation (which may be confirmed by a positive Pg test) strongly suggest MTC and must, whatever the FNAC results, lead to radical surgery. On the contrary, it appears difficult to propose such action when mild hypercalcitoninemia (<35 pg/mL) is observed. In such a circumstance, as FNAC is not contributive, we suggest monitoring basal CT levels again and performing a Pg test before considering radical surgery. A Pg-stimulated CT value over 100 pg/mL may be considered to be strongly related to MTC, although mild CT peaks may be found in healthy subjects (12, 27) and also in patients with various nodular thyroid diseases, as we showed in this study.

In conclusion, our study confirms that screening the population of patients with nodular thyroid diseases by CT measurement allows unsuspected MTC to be diagnosed, often at an early stage when they can be surgically cured. The Pg-stimulated CT test remains a reliable means of evaluation to accurately diagnose MTC when the basal CT level is slightly abnormal. As the prevalence of sporadic MTC is not negligible, basal serum CT measurement should become a routine aspect of the diagnostic evaluation of nodular thyroid diseases.

Received December 12, 1995.

Revised April 3, 1996.

Revised July 11, 1996.

Accepted September 28, 1996.

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