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Original Studies |
Department of Internal Medicine and Endocrinology (M.E., T.F., A.P., R.D., S.H., T.K., J.B.), University Hospital of Mainz, 55101 Mainz, Germany; and Department of Nuclear Medicine (R.G., A.B.), University Hospital of Essen, 45122 Essen, Germany
Address correspondence and requests for reprints to: Martin Engelbach, M.D., Department of Internal Medicine and Endocrinology, 55101 Mainz, Germany. E-mail: engelbac{at}mail.uni-mainz.de
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Abstract |
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The postoperative mCT concentration was measured in 214 patients with differentiated thyroid carcinoma (MTC excepted; non-MTC patients) to determine a reference range of mCT in totally thyroidectomized patients. Monomeric CT was also determined with a two-site chemiluminescence immunoassay (Nichols) in 94 healthy subjects and in 68 MTC patients. The mCT concentrations were below the detection limit in all examined completely thyroidectomized non-MTC patients. Basal and stimulated mCT values were also below the detection limit in 32 of the 68 MTC patients. The biochemical and imaging diagnosis of the latter patients did not give any indication of tumor recurrence.
We conclude that completely thyroidectomized patients with non-MTC do not show any measurable mCT concentrations. In comparison with an unspecific CT-RIA, the more specific mCT determination by immunoluminometric assay permits a more precise differentiation between postoperative normal and pathological values and an earlier diagnosis of recurrent MTC.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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For the diagnosis of tumor recurrence in MTC patients, the postoperative CT determination is of central importance (9). CT values decreasing into the normal range are regarded as evidence of complete tumor extirpation, also called biochemical cure (3, 10, 11, 12). This reference range of the assay was established by CT measurement in healthy subjects who were not thyroidectomized (13, 14, 15). If a CT assay is used, which specifically recognizes mCT, the following question arises: What is the reference range of mCT in completely thyroidectomized patients?
In a study previously published, we examined the mCT values in a smaller group of 64 patients after total thyroidectomy (16). To exclude the remaining MTC cells as a possible source of the measured mCT values, that study included only patients totally thyroidectomized because of non-MTC (papillary, follicular, Hürthle cell, and anaplastic carcinomas). The result of the study was that there are no measurable mCT values in non-MTC patients after complete thyroidectomy. This interesting observation gives rise to the assumption that there should be no measurable mCT concentrations in MTC patients definitely cured by surgery.
The aim of the present study was to examine a larger group of non-MTC patients, with the intention of establishing a definitive mCT reference range in totally thyroidectomized patients. On the basis of this newly established reference range, the postoperative mCT concentrations in MTC patients were examined as to their validity in diagnosing tumor recurrence.
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Subjects and Methods |
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Blood samples of a total of 376 individuals were collected during the period from January 1997 to March 1999. mCT values were determined in 47 healthy women (mean age, 44.7 yr; range, 24–84 yr) and in 47 healthy men (mean age, 41.4 yr; range, 23–74 yr). To establish a reference range for totally thyroidectomized patients, the mCT concentrations after total thyroidectomy were examined in 167 female non-MTC patients and 47 male non-MTC patients (161 papillary, 37 follicular, 14 Hürthle cell, and 2 anaplastic carcinomas). Total thyroidectomy had been carried out between 1 month and 23 yr previously (mean time, 3.2 yr).
Before radioiodine therapy, the completeness of thyroidectomy in the non-MTC patients was checked by scanning the neck, with quantification of the thyroid uptake 24 h after administration of 1.4–2.4 MBq 131iodine and by measuring the thyroglobulin concentration (IRMA, SELco Tg, Medipan Diagnostica, Selchow, Germany; detection limit, 0.5 ng/mL). The scans were performed under endogenous TSH stimulation 16–27 days after thyroidectomy. In the case of 90 (42%) of a total of 214 non-MTC patients, 1 ore more radioiodine therapies had been carried out before the mCT measurements.
At that time, the TSH values were between 10.2 and 233.8 mU/L (median, 51.1 mU/L). The normal range of the assay is between 0.3 and 4.0 mU/L (DYNOtest TSH 1, Brahms Diagnostica, Berlin, Germany). In the non-MTC patients who had undergone radioiodine therapy, the completeness of thyroablation was checked by a visual evaluation of the therapeutic or diagnostic radioiodine whole-body scintigram (performed with 1000–7400 MBq 131iodine, administered orally under endogenous TSH stimulation, 4 weeks after levothyroxine withdrawal) and thyroglobulin measurements.
The results of the completeness of thyroidectomy in the examined non-MTC patients depend on the therapeutic treatment. The scintigram of the majority of patients in the group of non-MTC patients without radioiodine therapy (n = 124) showed only minimal residual thyroid tissue (131I uptake: not detectable, 23%; median, 6.4%). In this group of 124 patients, sonographic proof of residual thyroid tissue was found only in those with higher 131I uptake values (>14%). The thyroglobulin values in the 124 non-MTC patients without radioiodine therapies were just above the lower detection limit (range, <0.5 to 13.6; median, 0.9 ng/mL). The whole-body scintigram of non-MTC patients with one or more radioiodine therapies showed minimal residual tissue only in a minority of cases. Most (92%) of the non-MTC patients had a thyroglobulin value below the detection limit (range, < 0.5 to 3.77 ng/mL). The higher thyroglobulin values in non-MTC patients with scintigraphic proof of metastases were not considered, as far as the completeness of thyroidectomy is concerned.
The thyroglobulin values in the MTC patients were in the range between <0.5 and 15.1 ng/mL (median, 0.9 ng/mL). The thyroid scintigrams of 12 MTC patients, for the purpose of this study, showed only minimal residual thyroid tissue, comparable with the scintigraphic findings in non-MTC patients without radioiodine therapy. At the time of the thyroglobulin determination and the scintigrams, the TSH values ranged from 3.2–12.6 mU/L.
The mCT values of 19 patients with a hereditary MTC (11 women, 8 men; mean age at the time of mCT determination, 36.0 yr; range, 6–62 yr) and of 49 patients with a sporadic MTC (24 women, 25 men; mean age at the time of mCT determination, 55.6 yr; range, 30–81 yr) were measured. The median follow-up period was 82 months for patients with the hereditary form of MTC (range, 13–154 months) and 60.8 months for those with the sporadic form (range, 16–166 months). All probands and patients taking part in this investigation gave their informed consent.
Pentagastrin test
Stimulation tests were carried out by using an iv bolus injection of 0.5 µg pentagastrin/kg BW (Cambridge Laboratories, Newcastle, UK), and mCT values were determined before and 2, 5, and 10 min after the injection. Basal and stimulated blood samples were taken from 20 healthy individuals and 10 out of the 214 thyroidectomized non-MTC patients.
Calcitonin assay
mCT in the serum of the patients was measured with a commercially available chemiluminescence immunoassay (immunoluminometric assay, Nichols Institute Diagnostics, Nijmegen, The Netherlands) (14, 16). The ILMA mainly recognizes the mature monomeric form of CT (calibration to WHO 2nd IS 89/620). The specificity of the ILMA was checked by means of gel filtration analysis (product information from the manufacturer). The lower detection limit was 0.5 pg/mL. The intraassay variation was 18.5% for 2.6 pg/mL and 5.4% for 14.8 pg/mL. The interassay variation was 25.0% for 3.2 pg/mL and 11.1% for 94.4 pg/mL.
For comparison, the serum samples of 24 non-MTC patients were also measured with a commercially available RIA (Nichols Institute Diagnostics) (17). The lower detection limit in this assay was 0.9 pg/mL. The upper limit of the reference range for women was 17; and for men, 26 pg/mL.
Surgery
The standard surgical therapy for patients with hereditary MTC was total thyroidectomy with compartment-oriented lymphadenectomy (11, 12). In the context of prophylactic thyroidectomy, lymphadenectomy was limited to the central compartments. In the case of patients with sporadic or known hereditary MTC, the additional dissection of both lateral compartments was carried out. The histological examination of the thyroid tissue removed from all MTC patients showed C-cell hyperplasia and an MTC.
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Results |
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The upper limit of the normal range (defined as the 95th percentile) was 8.8 pg/mL for men and 5.8 pg/mL for women. Serum CT was found in 83% of the healthy males (median, 3.0; range, <0.5 to 11.5 pg/mL) and in 46% of the healthy females (median, 0.5; range, <0.5 to 7.6 pg/mL). According to the 95th percentile, the upper limit of the reference range of mCT after pentagastrin application was established at 30 pg/mL (data not shown).
Calcitonin concentration in totally thyroidectomized non-MTC patients
In the group of thyroidectomized non-MTC patients without
postoperative radioiodine therapy, the mCT value was below the
detection limit in 121 of 124 (97.0%) persons (Fig. 1
). The mCT value was also below the
detection limit in 89 of 90 (98.9%) examined thyroidectomized non-MTC
patients who had undergone a radioiodine therapy. After pentagastrin
application, the mCT value was likewise undetectable in 10 examined
non-MTC patients (data not shown). Measured with the CT-RIA, the CT
concentrations of 24 thyroidectomized non-MTC patients were within the
normal range of nonthyroidectomized healthy persons (Fig. 2).
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The examined MTC patients can be subdivided into 5 different
groups, according to their basal and stimulated mCT values (Table 1). The pentagastrin test was not applied
to patients who already showed a clearly increased basal mCT value
(>30 pg/mL). Indications of tumor recurrence or of remaining MTC cells
were increasing mCT values in the case of the follow-up or the
identification of recurrence by diagnostic imaging procedures
[sonography, CT, or magnetic resonance imaging (MRI); occasional
octreotide-scintigraphy; or positron emission tomography], with
additional detection of tumor cells by optional excisional biopsy.
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In the course of follow-up, lymph node metastasis was found to be the
cause of postoperatively measurable mCT values in 1 female patient of
the remaining 14 MTC patients (Fig. 3).
The basal and the stimulated mCT values of another female patient in
the group of 14 increased during follow-up, so that tumor recurrence
can be suspected in this case too. At the present time, there is no
definite indication of tumor recurrence in the remaining 12 patients of
this group.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Among the 124 totally thyroidectomized non-MTC patients without radioiodine therapy examined by us, 121 (97.6%) showed no detectable mCT values. A minimal residual thyroid tissue can be suspected in some of these patients because of a thyroglobulin value still within the measurable range and a low thyroid radioiodine uptake in the scintigram. Residual tissue was not detectable by means of sonography or CT in the majority of cases. It should be emphasized that in most of the patients there was no measurable mCT, in spite of the suspected only-near-total thyroidectomy. Only in 3 patients could the mCT concentrations be traced to an only-near-complete thyroidectomy (24 h after administration of 2 MBq 131I; uptake, 4, 10, and 23%). Because 1 of these 3 patients suffered from anaplastic thyroid carcinoma, no postoperative radioiodine therapy was applied. After radioiodine therapy, the mCT value of the other 2 patients decreased below the detection limit of the ILMA. The pathologically increased mCT concentration in 1 of the 90 examined non-MTC patients with radioiodine therapy was caused by paraneoplastic CT secretion related to squamous cell carcinoma (16). The resulting consequence for differential diagnosis is that increased mCT values can be caused by a non-MTC tumor with paraneoplastic CT secretion.
Our results lead to the conclusion that measurable basal mCT concentrations are no longer detectable after total thyroidectomy. The pentagastrin test carried out in 10 non-MTC patients did not show any detectable mCT values after stimulation either. With the reservation that the number of cases was small, it can be assumed that the stimulated mCT values in totally thyroidectomized patients are also below the detection limit. The absence of mCT in these patients can most likely be traced to the fact that measurable mCT secretion in humans is caused by the C cells of the thyroid gland. In contrast, the RIA measures detectable CT values in totally thyroidectomized non-MTC patients. Because of its low specificity, the measurements include not only mCT and the dimeric form of CT but also CT precursors. It can be supposed that detectable CT values in totally thyroidectomized non-MTC patients, based on RIA measurement, may result from the ectopic secretion of CT precursors from other neuroendocrine cells (8).
Our study did not give any indication of tumor recurrence in 32 MTC patients with basal and stimulated undetectable mCT values. The extent to which these findings are an indication of curative treatment cannot be estimated at present because of the limited length of the observation time. The aftercare data available, so far, lead to the assumption that these patients have the best prognosis of all MTC patients. Fugazzola et al. (18) arrived at a similar result regarding patients with postoperatively undetectable CT values. In this study, however, only 7 MTC patients were reexamined over a period of 9 months.
A recurrent tumor could be diagnosed by imaging procedures in 11 of 22 MTC patients with already pathologically increased basal values. Tumor recurrence in the remaining 11 patients is most likely because of the steadily rising mCT values. An already increased basal mCT value can consequently be regarded as an indication of a recurrent tumor.
The correct interpretation of measurable low mCT values in the
remaining 14 MTC patients is difficult. The postoperative examination
of a female patient who had undergone surgery at an out-of-town
hospital showed a measurable basal mCT value within the normal range of
healthy, nonthyroidectomized persons (Fig. 3
). According to our
results, this mCT concentration in the thyroidectomized patient made us
suspect a recurrent tumor. On the other hand, RIA measurements of the
basal CT values and CEA values between 4/97 and 8/98 were within the
normal range. Because of pentagastrin intolerance, this patient could
not take the stimulation test. Diagnostic procedure revealed a
suspicious lymph node in the left cervicolateral compartment. In the
subsequent operation, a lymph node metastasis of the MTC was extirpated
(size, 0.8 cm). After this operation, the mCT value dropped below the
detection limit. It should be emphasized that the patient did not
receive adequate initial surgery.
The outcome of the reexamination of the prophylactically thyroidectomized patients with hereditary MTC and still measurable low mCT concentrations will be a matter of special interest. The data concerning the completeness of thyroidectomy show that thyroidectomy in MTC patients is so radical that they can be compared with non-MTC patients without radioiodine therapy. Measurable mCT values in 3 of 124 non-MTC patients could be traced to postoperative residual thyroid tissue. It can be supposed that, after prophylactic thyroidectomy, multiple endocrine neoplasia type II (MEN II) patients have measurable mCT values of similar frequency. This can be traced to remaining residual thyroid tissue after an incomplete thyroidectomy, rather than to a persistent tumor. This hypothesis can be verified by a postoperative thyroid scintigram. In principle, it can be said that in MEN II patients with residual thyroid tissue, the remaining C cells also create a predisposition for the development of hereditary MTC. At present, the importance of radiotherapy in the treatment of MTC is controversial (19, 20). Possibly, radiotherapy can prevent the development of a recurrent tumor in hereditary MTC patients with postoperative measurable mCT values. To clarify this problem, a long follow-up interval will be necessary.
In our group of patients, there was none with a verified tumor recurrence in which the MTC did not secrete mCT as well. The conclusion is that all MTCs can be biochemically detected and controlled in their further development also by using specific CT ILMAs.
In conclusion, our data demonstrate that 1) all completely thyroidectomized non-MTC patients were without detectable mCT concentrations if no extrathyroidal mCT source was present; 2) undetectable postoperative mCT values in totally thyroidectomized MTC patients suggest complete tumor extirpation; and 3) in comparison with RIA or unspecific IRMA, the new specific two-site assays for mCT allow, in some cases, the early identification of patients with recurrent MTC.
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Acknowledgments |
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Footnotes |
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Received September 29, 1999.
Revised January 24, 2000.
Accepted February 2, 2000.
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