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Departments of General, Visceral, and Vascular Surgery (A.M., H.D.) and Pathology (S.H.), Martin Luther University Halle-Wittenberg, D-06097 Halle (Saale), Germany
Address all correspondence and requests for reprints to: Andreas Machens, M.D., Department of General, Visceral, and Vascular Surgery, Martin Luther University Halle-Wittenberg, Ernst-Grube-Straβe 40, D-06097 Halle (Saale), Germany. E-mail: andreasmachens{at}aol.com.
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Abstract |
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Objective: The objective of this study was to explore the relationship between the results of the pentagastrin stimulation test and extent of disease in patients with previously untreated medullary thyroid cancer.
Design: This was a retrospective study.
Setting: The investigation took place at a tertiary referral center.
Patients: Included were 89 patients with increased basal calcitonin levels who had a pentagastrin test at this institution before initial neck surgery for medullary thyroid cancer.
Main Outcome Measure: Measurements included basal and stimulated calcitonin levels, carcinoembryonic antigen levels, primary tumor diameter, extrathyroidal extension, lymph node metastases, and distant metastases.
Results: There was a strong dose-dependent relationship between a less than 10-fold increase in preoperative calcitonin levels after iv stimulation with pentagastrin and both the frequency (41–54 vs. 4–27%; P = 0.001) and number (means of 3.0–10.8 vs. 0–1.1 positive nodes, P < 0.001) of lymph node metastases. Weaker associations were identified with the respective frequency of extrathyroidal extension (14–27 vs. 0–7%; P = 0.027), distant metastasis (9–23 vs. 0%; P = 0.017), and postoperative normalization of calcitonin (40–55 vs. 53–82%; P = 0.029). On multivariate analysis, only lymph node metastases were associated with a less than 10-fold increase in preoperative calcitonin levels.
Conclusions: Based on these clinical data and preclinical literature, reduced responsiveness to stimulation with pentagastrin may reflect early dedifferentiation. Evidence of this condition may enable early risk stratification in patients with medullary thyroid cancer.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Owing to its propensity to early miliary dissemination beyond the thyroid gland, medullary thyroid cancer is notoriously difficult to tackle. Many tumor deposits escape imaging by even the most sophisticated techniques. Absent visible tumor, clinicians traditionally have used basal calcitonin levels as an indicator of overall tumor burden, with higher levels often, but not always, reflecting advanced disease (6). Serial measurements of basal calcitonin levels, or calcitonin doubling times, have been advocated as a measure of tumor progression, but this measure may not always be useful for preoperative risk stratification because of the need for prolonged observation (7). Because both larger node-negative and smaller node-positive tumors can secrete the same quantity of calcitonin, basal calcitonin levels alone do not allow one to reliably distinguish one from the other.
Conceivably, basal serum calcitonin levels fall into two components: 1) total C cell mass multiplied by 2) the cells’ mean rates of calcitonin secretion. Between localized and advanced tumors, however, these rates of secretion may differ because of the increasing loss or dysfunction of the CCK-B/gastrin receptor during dedifferentiation. Indeed, on semiquantitative immunohistochemistry and RT-PCR analysis, CCK-B/gastrin receptor expression was higher with early tumor stages, i.e. T1 and T2 tumors confined to the thyroid gland and not exceeding 4 cm in size, than with advanced T3 and T4 tumors (8).
Theoretically, activation of the CCK-B/gastrin receptor through stimulation with pentagastrin should magnify subtle differences in basal calcitonin secretion. In occasional case reports, the absence of CCK-B/gastrin receptor expression seemed to account for negative pentagastrin stimulation tests in patients with medullary thyroid cancer (8, 9).
Among patients with medullary thyroid cancer, the relationship between the result of the pentagastrin test, which is available before the first surgical intervention, and extent of disease, the determination of which usually requires surgery and histopathological analysis, is unknown. To clarify the issue, a retrospective analysis of 89 patients from this institution who had a preoperative pentagastrin test in addition to initial neck surgery for untreated medullary thyroid cancer was set up.
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Patients and Methods |
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Between September 1995 and November 2007, 553 consecutive patients underwent operations for medullary thyroid cancer at this institution, which serves as a tertiary referral center: 273 patients (49%) had initial neck surgery for previously untreated tumors, and 280 patients (51%) had reoperations for recurrent or persistent tumors. All surgical procedures were conducted using optical magnification and bipolar coagulation, as described previously (10). Distant metastases per se were not an exclusion criterion because of the recognized longevity of patients with metastatic medullary thyroid cancers. Informed consent was obtained before each surgical procedure that represented standard practice of care in accordance with the practice guidelines of the German Society of Surgery (11).
To be included in this retrospective study, patients needed to have had before the initial neck operation both of the following: 1) an increased basal calcitonin level, measured at this institution between September 1995 until May 2004 with the ELSA-hCT solid two-site immunoradiometric calcitonin assay (CIS BioInternational, Gif-sur-Yvette, France; normal range < 10 pg/ml; or 10 ng/liter in Système International units) or after May 2004 with the Immulite 2000 calcitonin assay (Diagnostic Products Corp., Los Angeles, CA; normal range < 5 pg/ml for women and < 8.4 pg/ml for men; or < 5 ng/liter and < 8.4 ng/liter, respectively, in Système International units); and 2) a preoperative pentagastrin test with an iv bolus injection of 0.5 µg pentagastrin (Peptavlon; Laboratoires SERB, Paris, France) per kilogram body weight at this institution, allowing one to calculate the relative increase in calcitonin as the ratio of peak calcitonin level measured 2 or 5 min after stimulation divided by the respective basal calcitonin level.
Fulfilling these criteria, 89 patients were included in this retrospective study. For retrospective analysis of existing data sets from routine patient care, no institutional review board approval is required under German law and applicable institutional regulations.
Extent of surgery
Total thyroidectomy had been performed on all 89 patients (100%), coupled with systematic lymph node dissection of the central neck compartment in 85 of them (96%). The central neck compartment extends vertically from the hyoid bone to the thoracic inlet and horizontally between the carotid sheaths. Among the 89 patients, the lateral neck compartments, which spread laterally from the carotid sheath to the trapezoid muscle and inferiorly from the subclavian vein to the hypoglossal nerve superiorly, had been dissected systematically in 63 patients (71%) ipsilateral to, and in 58 patients (65%) also contralateral to the largest primary thyroid tumor. Systematic lymph node dissections of the mediastinal compartment had been carried out in four of the 89 patients (5%). The mediastinal compartment comprises all nodes between the brachiocephalic vein and tracheal bifurcation within the upper anterior and posterior mediastinum.
Pathological examination and tumor staging
A total of 89 entire thyroid glands were available for histopathologic examination. After gross evaluation by the pathologist, the entire thyroid gland was divided vertically to separate the left and right lobes. The thyroid halves were then sectioned horizontally from the superior to the inferior pole, as described previously (12). After fixation in formalin, the whole thyroid gland was embedded in paraffin. Soft tissue and lymph nodes were processed separately. Conventional staining (hematoxylin and eosin) and calcitonin immunohistochemistry were performed on every surgical specimen, using the standard avidin-biotin complex peroxidase approach and a commercial polyclonal antibody (Immunotech, Marseilles, France). A diagnosis of medullary thyroid cancer was made on evidence of tumor extension beyond the basement membrane, demonstration of lymphatic or vascular invasion on histopathology, or a combination thereof. Primary tumor diameter was ascertained by direct measurements on the surgical thyroid specimens. When multiple medullary thyroid cancers were present, only the largest tumor was considered. Although a diagnosis of nodal metastasis usually required pathological confirmation, this need was waived for distant metastasis when there was such unequivocal evidence on ultrasonography, computed tomography, magnetic resonance imaging, positron emission tomography, or a combination thereof.
Statistical analysis
To control for the confounding effect of overall C cell mass on stimulated calcitonin levels, stimulated peak calcitonin levels were related to their respective basal calcitonin levels and expressed as relative (x-fold) increases in calcitonin levels. Categorical and continuous data were tested with the two-tailed Fisher exact test and one-way ANOVA, respectively. Spearman’s rank correlation was used to quantify significant correlations. Multiple testing was corrected with the Bonferroni method. Multivariate conditional logistic regression analyses were performed including variables with P 
0.10 from the univariate analysis. The level of significance was set at P < 0.05.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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). Only nominally significant were the weaker associations between the calcitonin responsiveness to stimulation with pentagastrin and the respective frequency of extrathyroidal extension (14–27 vs. 0–7%; P = 0.027), distant metastasis (9–23 vs. 0%; P = 0.017), and postoperative normalization of calcitonin levels below the upper normal range of the assay after stimulation with pentagastrin (40–55 vs. 53–82%; P = 0.029). No other significant associations were identified.
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0.10 from the univariate analysis, only lymph node metastases were significantly associated with a less than 10-fold increase to pentagastrin stimulation (Table 2). Distant metastasis was not considered because the inclusion of this variable would have destabilized the logistic regression model as a result of the absence of distant metastasis from the higher (
10-fold) calcitonin responsiveness group.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Responsiveness of calcitonin-secreting neuroendocrine tumors to pentagastrin stimulation
Expression of the CCK-B/gastrin receptor is not restricted to medullary thyroid cancer in which it revealed a 92% prevalence (22 of 24 tumors) but also occurs in small cell lung cancer (eight of 14 tumors, or 57%) and gastroenteropancreatic neuroendocrine tumors (seven of 32 tumors, or 22%) (2). All these tumors may secrete calcitonin, which can be measured peripherally. In a small pilot study (19), a 2-fold or higher relative increase in stimulated calcitonin levels was able to distinguish between eight medullary thyroid cancers, all of which responded very well to stimulation with pentagastrin, and six other neuroendocrine tumors (four small cell lung cancers, one atypical laryngeal carcinoid, and one pancreatic islet cell tumor), all of which responded poorly. Using this 2-fold cutoff rule on our 89 patients with medullary thyroid cancer, 81 patients (91%) would have been classified correctly, whereas eight patients (9%) would have been misclassified as not having medullary thyroid cancer.
Clinical implications
A less than 10-fold calcitonin responsiveness to stimulation with pentagastrin was associated with lymph node metastasis in 41–54% of our patients with medullary thyroid cancer. Loss of CCK-B/gastrin receptor expression on medullary thyroid cancer cells has been reported to abrogate the release of calcitonin by the tumor cells despite adequate stimulation with pentagastrin. These tumor cells often escaped detection by gastrin receptor scintigraphy (9, 20). Reduced responsiveness to stimulation with pentagastrin, perhaps reflecting diminished or absent expression of the CCK-B/gastrin receptor, may reflect early dedifferentiation. Loss of responsiveness to stimulation with pentagastrin can be diagnosed before the first surgical intervention, whereas ascertainment of calcitonin doubling times necessitates a lengthy phase of observation of 1 yr or more during follow-up. The opportunity of saving large amounts of observational time in an interventional research setting should kindle interest in the pentagastrin stimulation test as a means to risk stratification in patients with medullary thyroid cancer.
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Footnotes |
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First Published Online March 25, 2008
Abbreviation: CCK, Cholecystokinin.
Received December 19, 2007.
Accepted March 19, 2008.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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