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Endocrinology, Head and Neck Surgery, Molecular Pathology, Nuclear Medicine, and Clinical Chemistry Services, Departments of Medicine, Surgery, Pathology, Radiology, and Clinical Laboratories, Memorial Hospital for Cancer and Allied Diseases, Memorial Sloan-Kettering Cancer Center, New York, New York 10021
Address all correspondence and requests for reprints to: Dr. Richard J. Robbins, Endocrine Service, Box 296, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021. E-mail: robbinsr{at}mskcc.org.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Metastases from DTC, when they occur, have a propensity for certain tissues: regional lymph nodes, lung, bone, and brain. However, distant metastases to other tissues, including pituitary, liver, kidney, skin, and spleen, have all been reported (13, 14, 15, 16). There is evidence that cancer cells can change their biological properties depending on the microenvironment of the host tissue (17). Only a few researchers have investigated the relationship between the site of metastasis and the serum Tg level (18, 19). Definition of this relationship might provide insights into the biology of thyroid cancer cells in a foreign microenvironment. Papillary thyroid cancers (PTCs) often exhibit finger-like projections in the thyroid gland and cervical lymph nodes, but in bone, the metastatic cells often take on a more follicular architecture (20). This cytoarchitectural difference may represent a response to unique extracellular matrix proteins and cytokines produced by host stromal cells. We propose that the secretory activity of metastatic thyroid cells might also change in a new microenvironment. To examine this proposal, we tested the hypothesis that the location of metastatic thyroid cancer would influence its responsiveness to TSH. For example, do DTC cells in bone have a different TSH responsiveness compared with those in cervical lymph nodes? We further hypothesized that the type and amount of thyroid cancer would also influence the responsiveness to exogenous TSH. These hypotheses were examined via a retrospective review of the changes in serum Tg after a standard acute rise in serum TSH brought about by injections of rhTSH into euthyroid patients. We chose not to analyze the rise in Tg after THW, because there is a wide degree of variation in clinical hypothyroidism and in TSH elevations, influenced by many factors, including length of withdrawal, age, and variation in the amount of functioning residual thyroid cells.
Unfortunately, many patients with metastatic thyroid cancer have lesions in more than one tissue. We therefore tried to group patients so as to minimize the influence of metastases in one tissue on another. We hoped to identify characteristic host-tissue response patterns to use the serum Tg response after rhTSH treatment to indicate which tissues would most likely be harboring the metastatic deposits.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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This study included all consecutive patients who underwent routine follow-up evaluation with rhTSH at the Memorial Sloan-Kettering Cancer Center during a 4-yr period (1998–2001). All had had a total thyroidectomy and all were taking L-T4 in sufficient dosage to suppress serum TSH to less than 0.2 µU/ml. Many of these individuals had received radioiodine to destroy thyroid remnants or to treat metastases. More than 600 rhTSH challenges were performed on 417 individuals. Twelve patients were excluded due to substances in their serum (e.g. anti-Tg antibodies) that interfered with the Tg assay. Each subject underwent a similar evaluation, which included full dosimetric analysis, measurement of suppressed (pre-rhTSH) and stimulated serum Tg (72 h after the second of two daily 0.9-mg injections of rhTSH), and a diagnostic whole body radioiodine scan (DxWBS; 72 h after a tracer dose of 131I) as previously reported (21). Patients received standard of care treatments at our medical center. We retrospectively collected all available information on these patients for analysis. Because patients were not part of a prospective study, they did not sign an informed consent document. Approval for use of this information was granted by the Office of Clinical Research at Memorial Sloan-Kettering Cancer Center. The histological diagnoses were based on direct review of surgical slides by attending pathologists at Memorial Sloan-Kettering Cancer Center in 97% of the patients. Classification of the remaining 3%, in whom slides were not available, was based on reports from other hospitals. Patients were included in the study if they had been prepared for dosimetry with rhTSH and if they had suppressed and stimulated Tg values on record. Patients were excluded if they had been prepared by THW, if Tg measurements were immeasurable due to assay interference, or if they had known anti-Tg antibodies. Only the most recent data were used for subjects who had undergone more than one rhTSH challenge during the 4-yr period. Each patient was assigned to one of three clinical groups: no evidence of disease (NED), thyroid remnant or residual disease limited to the thyroid bed (TB), or metastatic disease outside of the thyroid bed (POS). The clinical assignment was based on all clinical information, as previously reported (22). All patients with measurable Tg, either basal or stimulated, also underwent neck ultrasonography. Most with suspected metastases also had an 18F-fluoro-deoxy-glucose (FDG)-positron emission tomography scan and magnetic resonance imaging or computer tomography scanning at the discretion of the attending physician. The total number of lesions was determined by adding all unique metastatic lesions that were identified by any radiological or nuclear medicine procedure.
Serum Tg assay
Serum Tg measurements were made using an immunoradiometric assay recovery assay (Dynotest TgS; Brahms, Inc., Berlin, Germany) as previously described (7). The interassay precisions at 3.0 and 60.0 ng/ml were 3.2 (coefficient of variation, 8.7%) and 62.8 (coefficient of variation, 2.3%), respectively. All assays were performed in duplicate. The functional sensitivity was 0.3 ng/ml. The Dynotest Tg-S result was calibrated to the BCR Thyroglobulin Reference Preparation, CRM457 (23), and reads 0.502 times the CRM457 standard. For example, 100 ng/ml CRM457 would be reported as 50.2 ng/ml in the Dynotest Tg-S assay. All serum Tg levels reported in this study have been standardized to CRM457 by multiplying the Dynotest Tg-S result by 2.0.
rhTSH administration
rhTSH was administered as a 0.9-mg im injection on 2 consecutive days, approximately 24 h apart. A baseline suppressed Tg measurement was determined before the first injection, and a stimulated Tg level was determined 72 h after the second injection of rhTSH, as previously reported (7).
Statistical methods
Results are presented as medians because there was an abnormal skew of the Tg data, with a small number of extremely high values. The mean ± SD are provided when the data demonstrated a normal distribution. Statistical analysis was performed using SPSS for Windows (SPSS, Inc., Chicago, IL). Mean values were compared using independent sample t test or ANOVA as appropriate. When ANOVA showed a statistically significant difference among groups, post hoc testing was used to identify which groups were significantly different from each other. Comparisons of categorical data were performed using the 
2 test (Fisher’s exact). P < 0.05 was considered significant. Multivariate analysis, including the number of lesions, the stage of disease, the location of the metastases, and the tumor histology, was performed. We employed a general linear model, including Pillai’s trace, Wilks’ 
, Hotelling’s trace, and Roy’s largest root in the SPSS program.
For the initial analysis of our raw data (see Table 2
), we assigned each patient to every group for which he/she had evidence of metastatic disease (based on such diagnostic tools as biopsy, positive DxWBS or posttherapy scan, or abnormal radiological studies). For instance, if a patient had evidence of bone, lung, and cervical metastases, he or she would appear three times: in the bone, lung, and cervical columns. The columns labeled Pure bone, Pure lung, etc., include patients who had evidence of metastatic disease only at the given location. As shown in Table 2, the median baseline Tg value is highest for individuals with bone metastases; the next highest is in patients with lung metastases, followed by mediastinal and then cervical metastases. The same trend can be observed in the median stimulated Tg values. These observations served as a rationale for our subsequent classification of patients according to a hierarchy of disease progression (Fig. 1). All subjects with bone metastases were assigned to the class 4 group; all subjects with lung metastases, except those who also had bone metastases, were assigned to class 3; all subjects with mediastinal metastases, except those who also had lung and/or bone metastases, were assigned to class 2; and all subjects with cervical metastases, except those with mediastinal, lung, and/or bone metastases, were assigned to class 1. Patients in all classes could also have had thyroid bed uptake. Patients in the pure groups did not have any thyroid bed uptake.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Four hundred and seventeen patients underwent routine follow-up evaluations with rhTSH to monitor for residual thyroid carcinoma between January 1, 1998, and December 31, 2001 (Table 1). Of these patients, 201 (48.3%) were classified as NED, 47 (11.2%) were classified as TB, and 169 (40.4%) had evidence of residual disease (POS). The mean age at diagnosis, percent female patients, American Joint Committee on Cancer disease stages at diagnosis, and cancer histology for the three groups are shown in Table 1. Classical PTC was the predominant pathological type in all three groups, comprising 63.4% of NED cases, 38.3% of TB cases, and 53.8% of POS cases. Poorly differentiated thyroid cancer was more prevalent in the POS group (7.1%) than in the NED (1.5%) and TB (2.1%) groups. Table 1 also demonstrates that the median suppressed Tg level, median stimulated Tg level, median fold increase in Tg after rhTSH stimulation, and median increment in Tg after rhTSH stimulation were all considerably higher for POS than for NED or TB patients. Serum Tg did not rise after rhTSH in 58 of the 271 patients who had measurable baseline serum Tg.
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Patients in whom we could find no evidence for residual disease (NED) based on physical exam, radioiodine scanning, or radiological procedures had a median baseline Tg level of 0.6 ng/ml, but it ranged as high as 7.6 ng/ml. After rhTSH, the median stimulated Tg for NED patients was 1.2 ng/ml, with a high in one patient of 26 ng/ml. For patients who only had minimal uptake in the thyroid bed (TB) the median baseline Tg was 0.6 ng/ml, with the highest being 66 ng/ml. After rhTSH, the median stimulated Tg in TB patients was 1.2 ng/ml, but it ranged as high as 250 ng/ml. The median rise in serum Tg in TB patients was 0.6 ng/ml.
Serum Tg values and sites of metastases
In Table 2
, the 169 patients classified as POS are subdivided into groups based on location of metastatic disease. As described above (see Statistical methods), each of the 169 POS patients was assigned to every group for which he or she had evidence of metastatic disease. Of the 38 patients listed in the All bone group, for example, 31 patients also had metastases in other regions and are cross-listed under those groups as well. In contrast, the data in the columns labeled Pure bone, Pure lung, etc., were obtained from patients who only had detectable metastases in one tissue, so there was no cross-listing among the pure groups. The median values in the pure groups are suggestive of the extent to which each type of metastatic lesion alone affects serum Tg levels in the absence of influence from other metastases. However, there were not enough subjects within each pure group to render this data statistically significant. Considering the data in the All categories, the patients with bone metastases had the highest median suppressed and stimulated Tg values, followed by lung, mediastinal, and cervical metastases. The fold increases in serum Tg after TSH stimulation in the All groups is fairly constant across the different sites of metastases, ranging between 3.2 and 3.3, with the exception of bone metastases, which had a lower median fold increase of 2.5.
Because patients with thyroid cancer metastases often have lesions in multiple tissues, we also examined the Tg levels based on a step-down method in which each patient can only be a member of one group or class. Based on the data in Table 2, we developed a hierarchy of Tg production to eliminate the effect of patient cross-listing in multiple metastatic groups (as in Table 2). Patients with bone metastases were the highest Tg producers, followed by those with lung, mediastinal, and cervical metastases (see above). All patients with bone metastases were assigned to class 4; all lung cancer patients who were not in class 4 were assigned to class 3. All patients with mediastinal metastases not in class 3 or 4 made up class 2. Lastly, all patients with cervical metastases who were not already in a higher class made up the class 1 group. Once we had assigned each of the 169 POS patients to the appropriate class, we analyzed serum Tg levels in terms of site of metastases. The data points are represented on a scatter diagram (Fig. 1). Patients with bone metastases (class 4; n = 38) had the highest serum Tg values (both pre- and post-rhTSH stimulation), followed by patients with lung (class 3; n = 68), mediastinal (class 2; n = 22), and cervical (class 1; n = 35) metastases. The wide range of values in each tissue emphasizes that even mild elevations of Tg can be associated with distant metastases in lung or bone.
Patients with residual disease limited to cervical nodes had a median suppressed Tg of 2 ng/ml with a rise to a median of 8 ng/ml after rhTSH treatment. Patients with mediastinal disease (with or without cervical node disease) had a median suppressed Tg of 5 ng/ml with a rise to 18 after rhTSH treatment. Patients with lung metastases (with or without loco-regional metastases) had a median suppressed Tg of 15 ng/ml with a rise to 160 ng/ml after rhTSH treatment. Finally, patients with bone metastases (with or without any other metastatic deposits) had a median suppressed Tg of 687 ng/ml, which rose to 2030 ng/ml after rhTSH treatment.
Influence of the number of metastatic lesions (Fig. 2)
We hypothesized that the volume of tumor would affect the serum Tg response to rhTSH. Because we could not accurately determine the true volume of disease, we employed a surrogate, the number of metastatic lesions. We subdivided the 169 POS patients according to the number of metastatic lesions that were radiologically identified in each patient. Thyroid bed uptake on the DxWBS was not considered to be evidence of metastasis, because it is rare for local recurrence to develop in these patients (none of the 47 TB patients developed a local recurrence 3 yr after the end of enrollment). Consequently, a patient who had a single lung metastasis as well as thyroid bed uptake would be counted as having only one metastatic lesion. We were unable to locate the metastases in seven of 169 POS who had DxWBS, postradioiodine therapy scans, and other imaging studies, yet were classified as POS due to very high suppressed Tg levels (all >10 ng/ml). These seven patients were not included in this analysis. Of the remaining 162 patients, 65 had one metastatic lesion, 55 had two lesions, 27 had three, 12 had four, and 3 had more than four lesions. Diffuse radioiodine lung uptake without discrete lesions was counted as one lesion. Only 28% of those with lung metastases and 32% of those with bone metastases had a single discrete lesion. The median suppressed serum Tg values (with ranges) for one, two, three, four, and more than four lesions were 4 ng/ml (range, 0.6–1,160), 14 ng/ml (0.6–64,000), 360 ng/ml (0.6–62,000), 380 ng/ml (8–65, 400), and 2600 ng/ml (780–7, 800), respectively (Fig. 2A). There was a positive correlation between the number of lesions and the suppressed Tg level (by ANOVA, P = 0.013). The suppressed Tg level was significantly lower for one lesion than for three (P = 0.004) or four (P = 0.009) lesions. The suppressed Tg level was also significantly lower for two lesions than for either three (P = 0.045) or four (P = 0.047) lesions. There was no significant difference between one and two lesions. The number of patients with five or more lesions was too small for meaningful comparisons.
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). There was no significant correlation between the number of sites and the fold increase in Tg after rhTSH treatment (by ANOVA, P = 0.967).
Effects of the histological type of thyroid cancer (Table 3)
The median suppressed Tg values (with ranges) for PTC, PTC (follicular variant), FTC, Hurthle cell, and poorly DTC were 9.4 ng/ml (0.6–12,000; n = 91), 8 ng/ml (0.6–64,000; n = 29), 1,050 ng/ml (5.4–65,400; n = 18), 52 ng/ml (0.6–55,000; n = 9), and 37 ng/ml (1–21,600; n = 12), respectively (Table 3). There was a significant relationship between the suppressed Tg and the histology of the primary tumor (by ANOVA, P = 0.036). The only significant differences were that the suppressed Tg levels were significantly higher in patients with FTC (P = 0.035) and Hurthle cell (P = 0.025) histologies compared with patients with PTC.
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Influence of radioiodine concentrating ability
DxWBS were negative in 277 patients, had thyroid bed uptake only in 56, and had uptake in cervical nodes (n = 43), mediastinum (n = 16), lung (n = 31), or bone (n = 20) in the remainder. Many had uptake in more than one tissue. Those with metastatic lesions (POS) that concentrated radioiodine on the DxWBS had a mean ± SD fold increase of 4.2 ± 2.5 (n = 91), which was significantly lower (P = 0.01, by unpaired t test) than that of patients with metastatic lesions that did not concentrate radioiodine (mean fold increase, 6.6 ± 7.0; n = 76).
Multivariate analysis
Because many individual factors influenced the basal Tg levels and/or the fold increase in Tg after rhTSH, we used a multivariate approach to determine the relative strengths of various competing influences on these outcomes. Multivariate analysis revealed multiple significant interactions between the site of metastasis, the histology, and the number of lesions. For example, metastatic FTC was most often found in class 3 and class 4 patients, as expected based on the biological propensity of FTC to spread to bone. Furthermore, class 4 patients had the highest number of metastatic lesions, as is common with bony metastases (24). In the final analyses, no individual clinical factor maintained a significant independent influence on either basal Tg or fold increase when a multivariate analysis was applied.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Our control groups consisted of patients in whom we could find no anatomical evidence of disease on radioiodine scanning, neck ultrasonography, physical exam, and additional radiological procedures, as indicated. We named this group NED, although we do not imply that they are cured. Some investigators argue that any rise in serum Tg after total thyroidectomy and remnant ablation proves that there is residual cancer. This convention is not well substantiated, and rather than speculating whether they do or do not have cancer we simply describe them as NED. For instance, it is likely that remnants of thyroid tissue after radioiodine ablation may produce low levels of Tg that slowly disappear over years without additional therapy (29, 30). Patients in the TB group after total thyroidectomy all had radioiodine uptake only in the thyroid bed on DxWBS. Such patients typically had a 2-fold increase in serum Tg after rhTSH.
The records of 169 patients with loco-regional or distant metastases were then studied. We found that the baseline suppressed Tg level correlated with the number of lesions, a finding that fits with the conventional wisdom that serum Tg correlates with the volume of disease. This is in agreement with the recent publication of Bachelot et al. (31). Possibly due to the small number of patients in each group, we did not find a correlation between the histological type of cancer and the baseline Tg, although the highest levels were present in patients with FTC. Our results are in agreement with those of Dralle et al. (32), who found that the production of Tg by FTCs was higher than that by comparably sized PTCs. Shah et al. (33) also found that metastases from FTCs tended to be associated with the highest levels of Tg.
We hypothesized that the site of the lesion would influence its responsiveness to acute exposure to TSH. We were unable to substantiate this hypothesis. The percent rise (or fold increase) in serum Tg after rhTSH was similar regardless of the anatomical site(s) of the lesions. This was true whether we examined patients with multiple sites or a single site. We did, however, find a clear relationship between the baseline Tg levels and the site of metastases, with bone being highest, followed by lung metastases, mediastinal metastases, and cervical metastases, in that order. This could be due to the generally larger size of bone metastases compared, for instance, with cervical lymph nodes. Unfortunately, the ability to accurately determine the volume of metastases in bone and bone marrow is difficult. Shah et al. (33) also found that Tg levels were highest in patients with bone metastases. Schlumberger et al. (3) studied the relationship between the site of metastasis and the serum Tg level. They found, during T4 therapy, that the mean Tg level in patients with bone metastases was 219 ng/ml, and it rose to 2355 ng/ml when the patients were made hypothyroid. Patients with lung metastases had much lower mean Tg levels (range, 2.5–800) during T4 treatment and after thyroid hormone withdrawal (range, 10–7000). The mean serum Tg level for lung cancer metastases was not provided in that publication. They found no correlation between histology and serum Tg levels. In a subsequent analysis of similar patients, Schlumberger et al. (34) confirmed that patients with bone metastases had higher serum Tg levels than those with lung metastases. Bednar et al. (35) reported that Tg levels could be normal in patients with metastases, especially poorly differentiated cancers and in patients who only had disease in cervical lymph nodes. They also reported that the highest Tg levels were in patients with lung and bone metastases. Our findings are in agreement with Giovanni et al. (36), who found that the stimulated Tg levels after rhTSH treatment are highest in patients with lung and bone metastases, next highest in loco-regional metastases, and lowest in those with only thyroid bed remnants.
Our third hypothesis was that the histological type of thyroid cancer would influence the serum Tg response to an acute rise in serum TSH. Our results confirmed that the histological type did have a significant influence on the fold increase in Tg after rhTSH stimulation. The poorly differentiated and Hurthle cell cancer patients had the smallest Tg changes, whereas the PTC patients had the greatest increases. The possibility that the Tg secretory response reflects the biological characteristic of the tumor was also supported by the finding that the volume of disease alone did not influence the fold increase.
An important fact that could influence the Tg response to rhTSH is whether the patients had received previous treatments with radioiodine. In theory, this could deplete the metastatic lesion of the cells with good iodine avidity and leave only the less differentiated cells. Surprisingly, we found that the fold increase in Tg was significantly higher in patients whose metastases did not take up radioiodine than in those with positive iodine uptake on a DxWBS. This would argue that there is not a simple relationship between the ability of metastases to concentrate radioiodine and their ability to produce Tg in response to TSH. This conclusion is supported by the data of Lazar et al. (37), who noted the persistence of the TSH receptor in thyroid cancers that often have little or no sodium iodide symporter expression.
Can the serum Tg levels provide the clinician with any clues about the possible location of residual metastatic disease? Patients with only cervical node metastases seldom have a suppressed Tg greater than 10 ng/ml, and rhTSH stimulated levels are seldom more than 100 ng/ml. Patients with loco-regional metastases, including the mediastinum, have slightly higher suppressed Tg levels, but they rarely rise to more than 200 ng/ml after rhTSH treatment. Tg levels in patients with lung metastases are the most variable, because they can be very low or very high. Patients with lung metastasis tend to have the highest fold increases in Tg, although they overlap with patients who have disease at other sites so much that the fold increase is not discriminatory. Suppressed Tg levels greater than 100 ng/ml and stimulated levels greater than 300 ng/ml increase the possibility of lung and/or bone metastases. Suppressed Tg levels greater than 1000 ng/ml are most likely to be associated with bone metastases. Although it is important to note that many patients with bone metastases had suppressed levels less than 100 ng/ml. Finally, suppressed Tg levels greater than 300 ng/ml are more likely to be associated with FTC and to be present in patients who have three or more metastatic deposits.
In summary, the site of metastasis and the volume of disease correlate with the suppressed Tg level, being highest when metastases are present in bone and/or lung. The responsiveness of the metastatic lesions to TSH, as judged by the percent change in the serum Tg after rhTSH, does not appear to be influenced by the site of the metastatic deposit or the volume of disease, but is influenced by the histological type of thyroid carcinoma. The serum Tg level in DTC survivors who have had a total thyroidectomy and a remnant ablation may provide clues to the presence and location of residual disease. If the suppressed Tg level is over 5 ng/ml, it is very likely that residual thyroid cancer is present (7, 12). If the suppressed Tg is greater than 50 ng/ml, it is likely that there are distant metastases in lung or bone. If the suppressed Tg is greater than 300 ng/ml, the presence of bone metastases should be carefully ruled out.
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Footnotes |
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Received September 8, 2003.
Accepted August 27, 2004.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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