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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 5 1589-1593
Copyright © 1997 by The Endocrine Society

Clinical Studies

Routine Measurement of Plasma Calcitonin in Nodular Thyroid Diseases

H. Vierhapper, W. Raber, C. Bieglmayer, K. Kaserer, A. Weinhäusl and B. Niederle

Division of Endocrinology and Metabolism, Department of Internal Medicine III, Institute for Medical and Chemical Laboratory Diagnostics, Institute of Pathology, and the Department of Surgery, Division of General Surgery, University of Vienna, and St. Anna Kinderspital, Vienna, Austria A-1090

Address all correspondence and requests for reprints to: H. Vierhapper, M.D., Division of Endocrinology and Metabolism, University Clinic for Internal Medicine III, University of Vienna, Wahringer Gurtel 18–20, A-1090 Wien, Austria.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
In a prospective study, plasma concentrations of human calcitonin (hCT) were determined in 1062 consecutive patients with thyroid nodular disease. Basal plasma hCT was above the normal range (>6 pg/mL) in 55 patients and was elevated up to more than 100 pg/mL (range, 127-5459) in 3 of these 55 patients. A pentagastrin-induced rise in hCT up to more than 100 pg/mL was observed in only 1 of 38 patients with a basal concentration of hCT between 5–10 pg/mL, but was found in 10 of 31 patients with basal hCT ranging from 10–100 pg/mL. Histologically, 7 of the 14 patients with either basal or stimulated plasma concentrations of hCT above 100 pg/mL presented C cell hyperplasia, which in one case showed histological transition into a small (diameter, 3 mm) medullary thyroid carcinoma (MTC). Including this patient, MTC was found in 6 of the 12 patients. We conclude that the routine determination of hCT in all patients with thyroid nodular disease should be supplemented by pentagastrin-stimulation when the basal hCT concentration exceeds 10 pg/mL. Patients with basal and/or stimulated plasma CT concentrations of more than 100 pg/mL should be operated on because they run a substantial risk to suffer either MTC or C cell hyperplasia, a potentially precancerous condition. This will increase the chance of a timely diagnosis of MTC and provide the chance of curative surgery.


   Introduction
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 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
APPROXIMATELY 25–50% of autopsied patients have either single or multiple thyroid nodules (1, 2). Even in countries with adequate iodine supply, palpable thyroid nodules are found in 4–7% of adults (3, 4). Less than 5% (4) of these lesions are malignant. Elevated plasma concentrations of human calcitonin (hCT) identify patients with medullary thyroid carcinoma (MTC) (5). Unfortunately, MTC is believed to account for less than 10% of all thyroid cancers (6), and routine measurement of serum hCT, as recently proposed for all patients with nodular thyroid disease (7, 8), could, therefore, be prohibitively expensive in an area with high goiter prevalence, such as Austria. This report summarizes our experience with the first 1000 patients with nodular thyroid disease referred to our institution after the introduction of a systematic screening program for hCT.


   Subjects and Methods
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 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients

From August 1, 1994, through September 30, 1995, 3240 patients were referred to our out-patient department due to various suspected thyroid disorders. Patients with previously established sporadic (n = 1) or familiar (n = 2) MTC and 1 patient referred because of hypercalcitonemia (n = 1) were not considered to be part of this investigation. Thyroid nodules were found by palpation and/or sonography in 1062 (33%) of the remaining 3236 patients. Autonomous thyroid adenomas were seen in 124 patients, whereas in 340 patients the nodules were considered to be scintigraphically cold. At present, 9 differentiated thyroid carcinomas (7 papillary and 2 follicular) have been identified. Serum CT concentrations were determined in each of these 1062 patients. Whenever plasma CT exceeded 5 pg/mL, a pentagastrin stimulation test was performed. To this end blood samples for the determination of hCT were drawn through an indwelling catheter before and 2, 5, and 10 min after an iv bolus of 0.5 µg/kg pentagastrin (Peptavlon, Zeneca, Vienna, Austria).

Plasma CT was determined by a commercially available RIA (Cis-Biointernational, Gif-sur-Yvette, France). Intraassay precisions were 19% (4.4 pg/mL), 5% (18 pg/mL), and 6% (82 pg/mL). The analytic sensitivity of the modified assay was about 1 pg/mL (free + 2 SD).

Surgery

In all patients undergoing surgery due to elevated basal and/or pentagastrin-stimulated plasma concentrations of hCT, total thyroidectomy was performed. Routinely, both recurrent nerves were dissected carefully, and a systematic microdissection of the central lymph node compartments along both nerves from the upper thoracic outlet up to the larynx was performed. If central or lateral lymph nodes were suspicious or proven to be metastatic, a systematic microdissection of the lateral lymph node compartment was added. Transsternal systematic lymphadenectomy of the upper mediastinum was performed in one patient (no. 13). In patient 14 with biochemically proven primary hyperparathyroidism, a single enlarged parathyroid gland, histologically classified as an adenoma, was removed. No permanent paralysis of the recurrent nerves or a permanent hypoparathyroidism was observed. A local hematoma was seen postoperatively in one patient, but no reoperation was necessary.

Molecular genetic analysis

Germ-line mutations of the ret protooncogene were excluded (9) in all 14 patients undergoing surgery by analyzing exons 10, 11, 13, 14, and 16 of this gene on chromosome 10.

Histology

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). C Cell hyperplasia was diagnosed according to the criteria of Rosai et al. (10), when there were more than 50 C cells in a single low power field (x100 magnification) in the right and left lobes.


   Results
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 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Basal plasma CT concentrations exceeded 100 pg/mL in 3 patients (Table 1Go). Furthermore, in 11 of 75 patients with basal plasma hCT levels more than 5 pg/mL and less than 100 pg/mL, pentagastrin induced a rise in hCT to more than 100 pg/mL. Basal plasma concentrations of hCT were between 10–20 pg/mL in 4 and >20 pg in 6 patients of these 11 patients. Only 1 patient of this group had a basal hCT level less than 10 pg/mL, and this patient was later shown to be histologically free of MTC. In 1 patient (no. 14), later shown to suffer from MTC, subsequent workup discovered the concomitant presence of primary hyperparathyroidism. Surgery was recommended to all patients with a basal and/or pentagastrin-stimulated hCT concentration greater than 100 pg/mL (11). One patients (maximum hCT after stimulation by pentagastrin; 100 picograms per mL) declined surgery. Of the remaining 12 patients, the histological diagnosis was MTC in six and C cell hyperplasia in six patients, respectively. A state of incipient MTC emerging from C cell hyperplasia was documented in one patient (Fig. 1Go). Table 2BGo shows the size of the MTC and tumor staging in the six patients with histologically proven MTC.


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  		Table 1. Distribution of basal and pentagastrin-stimulated plasma concentrations of hCT in 1062 patients with nodular thyroid disease

 


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  		Figure 1. Transition of C cell hyperplasia into MTC (patient 9). A, Immunohistochemical staining for CT (100 x) of a diffuse and nodular C cell hyperplasia. The darkly staining C cells completely surround the follicular circumference or obliterate the lumen of some of the follicles. B, Hematoxylin and eosin staining of an early invasive MTC in C cell hyperplasia (magnification, x200). The arrow points to a single layered strand of invasive C cells surrounded by desmoplastic stroma.

 

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  		Table 2B. Tumor staging (IUCC) in six patients with proven medullary thyroid carcinoma

 
Postoperatively, three (of five) patients with C cell hyperplasia and three (of six) patients with MTC presented basal concentrations less than 1 pg/mL, and all but one patient with MTC had a normal postoperative response to pentagastrin stimulation. This patient (no. 10) although improved, regrettably still shows a rise from basal, 7.4 pg/mL, up to 511 pg hCT/mL (preoperatively, 5,459 and 75,680 pg hCT/mL, respectively). Subsequent regional venous sampling suggested the presence of metastatic disease rather than incomplete surgical removal of the tumor.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
MTC (12) is believed to account for less than 10% of thyroid malignancies (13). Within families known to harbor a ret protooncogene mutation, case identification is best accomplished by genetic screening. The index case, however, must be identified by biochemical means, like must cases with sporadic MTC (7, 8). Having instituted the routine determination of hCT in patients with nodular thyroid diseases, we have, during a period of 13 months, identified 14 patients with basal and/or pentagastrin-stimulated plasma concentrations of hCT above 100 pg/mL. In retrospect, as only 1 of 38 patients with basal hCT levels below 10 pg/mL responded to iv pentagastrin with a rise slightly above the chosen cut-off value of 100 pg/mL (11), it appears sufficient to perform pentagastrin stimulation tests in patients with basal hCT concentrations exceeding 10, rather than 5 pg/mL. Among our patients this would have reduced the frequency of this subjectively unpleasant procedure by more than 50%.

All but one patient followed the advice to undergo thyroid surgery (11). In one case, the only patient of this group with a basal plasma hCT level less than 10 pg/mL and an only marginally elevated pentagastrin-stimulated hCT level, histology was negative. The remaining 12 patients included 6 patients with sporadic MTC and 6 patients with C cell hyperplasia. In 1 patient, a transition of C cell hyperplasia to MTC was seen on the histological specimen. Although C cell hyperplasia has also been observed in association with other conditions, such as hypercalcemia, hypergastrinemia, estrogen or cimetidine therapy, and follicular cell tumors (14), this finding confirms the importance of C cell hyperplasia as a potential precancerosis (15) and renders additional justification to the surgical approach in the other 6 patients with this disorder.

Although 213 of our 3240 patients have undergone thyroid surgery for various reasons, MTC was found only in patients preoperatively identified by hCT screening. This high specificity (>90%) in the recognition of sporadic MTC and C cell hyperplasia suggests the validity of the diagnostic criteria used (11). However, to determine either the sensitivity of our screening program or to assess the true relative frequency of MTC and/or C cell hyperplasia among patients with nodular thyroid disease would mean performing surgery on every single patient with nodular thyroid disease. Obviously this cannot be done. Therefore, any cut-off value chosen as a criterium to recommend surgery remains arbitrary, and it appears prudent to carefully follow-up patients who present pentagastrin-stimulated concentrations of hCT of more than 50 pg/mL, especially as even a conscientious case history does not exclude the possibility of familial MTC where different criteria apply (11).

It might be argued that precise clinical evaluation and/or fine needle aspiration biopsy (FNAB) would have been sufficient in the workup of all of our patients. As clinical criteria, i.e. the assessment of a nodule’s growth pattern and its consistency, were documented in our patients before the determination of hCT, it is safe to say that based on clinical grounds alone, surgery would have been recommended to only four of them (Table 2AGo). As surgery was recommended to our patients based on the plasma CT concentrations alone, FNAB was not performed in all of them. However, in one of the three patients with MTC (no. 12), the diagnosis was not made cytologically even though the markedly elevated concentration of hCT was known to the pathologist. Furthermore, it is questionable (7, 8) whether a reliable result of FNAB might have been expected in two patients with only sonographically apparent nodules (no. 13 and 14). Finally, fine needle aspiration would clearly have been of no help in patient 9, who presented an incipient MTC of only 3 mm in diameter.


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  		Table 2A. Patients with basal and/or pentagastrin-stimulated plasma concentrations of hCT greater than 100 pg/mL

 
The relative share of sporadic MTC among all cases of thyroid cancer identified during the period of this study was 40% (6 of 15), larger than expected based on previously documented evidence (6) and also substantially larger than the frequency predicted by our institution’s past experience. As in previous years the referred number of patients with nodular thyroid disease referred to our department and that of identified differentiated carcinomas was comparable to the respective figures of the 13-month study period, it follows that a number of cases of sporadic MTC may/must have previously remained undiagnosed. The 10-yr survival rate of sporadic MTC is believed to be only about 60%. It is, of course, quite possible that the enforced screening for MTC establishes this diagnosis in patients with very benign forms of the disease who would have been unharmed by their disorder for years to come. If so, the currently accepted data for the life expectancy of MTC may eventually prove to be inaccurate. However, as long as this point remains to be clarified there is no other choice but to proceed on the basis of currently available figures, which clearly call for early surgical ingression (16). Preoperative establishment of the diagnosis helps to plan the extent of surgery and facilitates the diagnosis of related endocrine disorders, such as primary hyperparathyroidism and pheochromocytoma.

In summary, the determination of CT in a series of 1065 patients with nodular thyroid diseases resulted in 13 newly diagnosed cases of either MTC or C cell hyperplasia, 12 of which are, at present, biochemically cured. As the laboratory costs for the determination of CT in our institution are approximately $35, it follows that about $3000 were spent for each newly diagnosed case (or $6000 if only cases of MTC are considered). Although CT reagents are apparently more expensive elsewhere, even the costs calculated by others are not prohibitive when balanced against savings for a potential reoperation (6) or, indeed, a missed diagnosis. Therefore, plasma CT should be determined in all patients with nodular thyroid diseases.

Received September 26, 1996.

Revised January 14, 1997.

Accepted February 4, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Mortensen JD, Woolner LJ, Bennet WA. 1955 Gross and microscopic findings in clinically normal thyroid glands. J Clin Endocrinol Metab. 15:1270–1280.
  2. Oertel JE, Klick GH. 1965 Structural changes in the thyroid glands of healthy young men. Med Ann District Columbia. 34:75–77.
  3. Ridgway EC. 1992 Clinician’s evaluation of a solitary thyroid nodule. J Clin Endocrinol Metab. 74:231–235.[CrossRef][Medline]
  4. Mazzaferri EL. 1992 Thyroid cancer in thyroid nodules: finding a needle in the haystack. Am J Med. 93:359–362.[CrossRef][Medline]
  5. Melvin KEW, Miller HH, Tashjian Jr AH. 1973 Early diagnosis of medullary carcinoma of the thyroid by means of calcitonin assay. N Engl J Med. 285:1115–1120.
  6. Sheppard MC. 1995 Should serum calcitonin be measured routinely in all patients with nodular thyroid disease? Clin Endocrinol (Oxf). 42:451–452.[Medline]
  7. Pacini F, Fontanelli M, Fugazzola L, et al. 1994 Routine measurement of serum calcitonin in nodular thyroid diseases allows the preoperative diagnosis of unsuspected sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab. 78:826–829.[Abstract]
  8. Rieu M, Lame C-C, Richard A, et al. 1995 Prevalence of sporadic medullary thyroid carcinoma: the importance of routine measurement of serum calcitonin in the diagnostic evaluation of thyroid nodules. Clin Endocrinol (Oxf). 42:453–460.[Medline]
  9. Fink M, Weinhäusel A, Niederle B, Haas OA. 1996 Distinction between sporadic and hereditary medullary thyroid carcinoma (MTC) by mutation analysis of the ret proto-oncogene. Int J Cancer. 69:312–316.[CrossRef][Medline]
  10. Rosai J, Caracangiu ML, DeLellis RA. 1992 Atlas of tumor pathology: tumors of the thyroid gland, 3rd series. Washington DC: Armed Forcees Institute of Pathology; 247–258.
  11. Barbot N, Calmettes C, Schuffenecker I, et al. 1994 Pentagastrin stimulation test and early diagnosis of medullary thyroid carcinoma using an immunoradiometric assay of calcitonin: comparison with genetic screening in hereditary medullary thyroid carcinoma. J Clin Endocrinol Metab. 78:114–120.[Abstract]
  12. Hedinger C, Williams ED, Sobin LH. 1988 Histological typing of thyroid tumors. In: World Health Organization international histological classification of tumors, 2nd ed. Berlin: Springer-Verlag.
  13. Papotti M, Sambataro D, Pecchioni C, Bussolati G. 1996 The pathology of medullary carcinoma of the thyroid: review of the literature and personal experience on 62 cases. Endocr Pathol. 7:1–20.[Medline]
  14. Albores-Saavedra J, Monforte H, Nadji M, Morales AR. 1988 C-Cell hyperplasia in thyroid tissue adjacent to follicular cell tumors. Hum Pathol. 19:795–799.[CrossRef][Medline]
  15. Wolfe HJ, Melvin KEW, Cervi-Skinner SJ, et al. 1973 C-cell hyperplasia preceding medullary thyroid carcinoma. N Engl J Med. 289:437–441.
  16. Längle F, Soliman T, Neuhold N, et al. 1974 CD15(LeuM1) immunoreactivity: prognostic factor for sporadic and hereditary medullary thyroid cancer? World J Surg. 18:583–587.



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