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Endocrine Care |
Endocrinology, Clinical Chemistry, and Nuclear Medicine Services, Departments of Medicine, Clinical Laboratories, and Radiology, 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: Richard J. Robbins, M.D., Endocrinology Service, Box 296, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021. E-mail: . robbinsr{at}mskcc.org
Abstract
The serum thyroglobulin (Tg) response to elevated TSH is one of the most sensitive indexes of residual thyroid carcinoma. We have explored the possibility that this test alone would be sufficient to detect residual thyroid carcinoma in thyroid cancer patients after total thyroidectomy and radioiodine remnant ablation. We used recombinant human TSH (rhTSH) to elevate serum TSH, rather than withdraw the patients from thyroid hormone. Routine evaluations, including diagnostic radioiodine whole body scans (DxWBS) and serum Tg, were performed on 366 patients after preparation by rhTSH, over a 2-yr interval. A retrospective analysis of the data from these patients revealed that 76% of those whose stimulated Tg rose to more than 2 µg/liter had evidence for residual thyroid carcinoma, whereas the same was true for only 13% of those whose stimulated Tg was 2 µg/liter or less. Using risk group stratification, we analyzed outcomes in a low risk subset (which excluded patients with elevated Tg levels on suppression, known metastatic disease, and clinical or histological evidence of aggressive disease). In this low risk group, we found that a stimulated Tg of 2 µg/liter or less had a 91.7% negative predictive value. No low risk patient who had had a prior negative DxWBS and a stimulated Tg of 2 µg/liter or less had any evidence of residual thyroid carcinoma. We conclude that the stimulated Tg alone is not sufficient by itself to screen unselected patients, but that it may be sufficient in low risk patients, especially those who have had a prior negative DxWBS.
DIFFERENTIATED THYROID carcinoma is increasing in the United States, especially in women (1, 2). The causes of this trend are unclear. Timely and complete surgical removal of the primary tumor accounts for much of the high cure rate that is seen in this disease (3). However, differentiated thyroid carcinoma cells may spread to local and distant sites. Fortunately, excellent surveillance tools are available for clinicians to monitor for residual disease (4).
The risk of local recurrence is increased in patients who have less than near-total thyroidectomy (5), positive lymph nodes, extrathyroidal extension, and certain variants of papillary thyroid carcinoma (6). Patients who undergo radioiodine remnant ablation after near-total thyroidectomy are reported to have fewer local recurrences and improved overall survival (6).
The National Comprehensive Cancer Network advises that after total thyroidectomy for cancers larger than 1 cm, thyroid remnant ablation and TSH suppression are indicated (7). Furthermore, regular physical exams should be supplemented by serum thyroglobulin (Tg) measurements, and periodic diagnostic whole body radioiodine scans (DxWBS). Scanning should be continued until one or two consecutive DxWBS are negative. Recombinant human TSH (rhTSH) now enables the performance of DxWBS and measurement of stimulated Tg without the need to induce hypothyroidism by withdrawal of thyroid hormone (8, 9, 10).
Several experienced investigators have raised the question of whether the serum Tg response to rhTSH might be sufficient by itself to detect occult residual thyroid cancer without the need for whole body scans (6). Our recent analysis of the sensitivity of the DxWBS after rhTSH found that it was slightly, but not significantly, less sensitive than preparation by thyroid hormone withdrawal (10), in agreement with the report of Haugen et al. (9). Conversely, we found that the stimulated serum Tg level had a higher sensitivity and negative predictive value after rhTSH than after thyroid hormone withdrawal (10).
In an attempt to streamline the surveillance of thyroid cancer survivors, we tested the hypothesis that the serum Tg response to rhTSH alone was a sufficiently sensitive means to detect residual thyroid cancer in all thyroid cancer survivors. We tested this hypothesis in a cohort of thyroid cancer patients undergoing routine surveillance, including rhTSH-assisted follow-up examinations during a 2-yr interval. In addition, we analyzed a low risk subset of this cohort. Low risk patients make up the majority of those under surveillance and if this test alone is sufficient, then additional tests in that group, such as DxWBS, might be unnecessary.
Subjects and Methods
During a 2-yr period (1999–2000) at the Memorial Sloan-Kettering Cancer Center (MSKCC), 377 patients underwent routine follow-up evaluations after receiving 2 consecutive daily doses of 0.9 mg rhTSH (Thyrogen, Genzyme Transgenics Corp., Cambridge, MA). Routine evaluations include full dosimetric analysis, measurement of suppressed and stimulated serum Tg (72 h after the final dose of rhTSH), and DxWBS (72 h after a tracer dose of 131I) as previously reported (10). We retrospectively collected all information on these patients for analysis.
Inclusion and exclusion criteria for the low risk group
From this total group (n = 377) we eliminated all patients who had a high probability of thyroid remnant, previously documented metastatic thyroid cancer, or features that might predict increased likelihood of tumor relapse to establish a low risk group. The exclusion criteria were inability to measure Tg due to autoantibodies (n = 11); serum Tg above 2 µg/liter while serum TSH was suppressed (n = 132); known distant metastases, American Joint Commission on Cancer (AJCC) stage III or IV, and poorly differentiated or anaplastic histology (n = 80); and first postoperative evaluation for possible ablation (n = 26). When the same patient had more than 1 evaluation during the 2-yr period, only 1 was chosen at random to be included, which eliminated 19 evaluations. The inclusion criteria for the low risk group were total thyroidectomy with differentiated thyroid carcinoma confirmed by a MSKCC attending pathologist, age at current evaluation 18 yr or older, radioactive iodine ablation of thyroid remnant or postoperative radioiodine scan showing no residual thyroid bed uptake, no abnormal masses or lymphadenopathy on exam, completion of whole body scan, and Tg level obtained 72 h after the second dose of rhTSH. Only 109 of the 377 patients met these criteria and were designated the low risk group.
Other evaluations
As routine part of clinical care, MSKCC attending physicians performed additional studies when clinically indicated to localize possible residual thyroid carcinoma. As this is a retrospective study, there was no prospective set of additional studies performed on all patients. We categorized the final status of each patient as: no evidence of disease (NED), thyroid bed uptake only (TB), or positive evidence of metastatic thyroid carcinoma (POS). It is important to point out that NED does not imply cure, but only negative radiological imaging results. The POS category required uptake of 131I in foci outside the thyroid bed or elevated serum Tg (on T4 suppression) associated with abnormal radiological (e.g. magnetic resonance imaging, computed tomography, and ultrasonography) or nuclear medicine studies [e.g. positron emission tomography (PET) and bone scan] strongly suggestive of metastases or biopsy-proven metastatic thyroid carcinoma. A stimulated Tg above 10 µg/liter, associated with negative imaging studies, was also taken as evidence for residual thyroid carcinoma (n = 6).
Clinical chemistry
Serum Tg was measured with an immunoradiometric assay using two antigen-specific antibodies, each reacting with different epitopes on the Tg molecule (Dynotest-TgS, Brahms, Inc., Berlin, Germany). One antibody (rabbit polyclonal) is immobilized on the inside of a plastic test tube, and the second antibody (mouse monoclonal) is 125I labeled and acts as a tracer. A recovery assay spiked with 50 ng human Tg is simultaneously performed with each Tg assay to monitor potential interference by factors such as Tg autoantibodies. The interassay precisions for the Tg assay at 3.0 and 60.0 µg/liter were 3.2 (coefficient of variation, 8.7%) and 62.8 (coefficient of variation, 2.3%) µg/liter, respectively. The functional sensitivity was 0.3 µg/liter. Tg concentrations less than 0.3 µg/liter were reported as less than 0.3 ng/ml. Recovery assay precision was considered acceptable if the spiked sample read between 42 and 60 ng higher than the unspiked sample. Tg recovery levels beyond these limits indicate recovery disturbance or a high dose (>2000 µg/liter) hook effect, and results were considered unreliable. Eleven patients had abnormal recovery results and were eliminated from further analysis in this report. The Dynotest Tg-S was calibrated against the BCR Thyroglobulin Reference Preparation, CRM457, and reads 0.5 times the CRM457 standard. For example, 100 ng/ml CRM457 would be reported as 50 ng/ml in the Dynotest Tg-S assay. TSH was determined by a heterogeneous sandwich immunoassay on an Immuno 1 System (Bayer Corp., Tarrytown, NY). This assay allows the determination of TSH with a third generation sensitivity and precision as defined by the American Thyroid Association. The assay exhibits a functional sensitivity of 0.014 mIU/liter.
rhTSH administration
rhTSH was administered as a 0.9-mg im injection on 2 consecutive d, 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.
Nuclear medicine and radiology studies
DxWBS was performed as previously described (11). The mean ± SD scanning activity administered was 4.32 ± 1.5 mCi. Two MSKCC attending nuclear medicine staff physicians read the scans separately as part of routine care. The nuclear medicine physicians were not blinded to the clinical status of the patients before reading the films, although they were unaware of any plans to use their readings in a formal analysis. Posttherapy scans were performed as previously reported (10). Neck ultrasonography was performed when clinically indicated using Power Doppler technology with fine needle aspiration of suspicious lymph nodes or masses. [18F]Fluoro-2-deoxyglucose-PET was generally performed in patients with elevated Tg levels and negative DxWBS as previously reported (11).
Statistical methods
All data are presented as the mean ± SD, with medians when appropriate. 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. Comparisons of categorical data were performed using the 
2 test (Fisher’s exact). P < 0.05 was considered significant. As no single test is sufficiently accurate enough to serve as the gold standard, we considered any proof of metastatic disease (e.g. biopsy, positive DxWBS, or abnormal radiological studies) as the gold standard. Conversely, patients in whom all tests were negative were judged to be NED, which does not imply cure, only the inability to detect residual disease. We constructed a 2 x 2 analysis of POS or NED and compared it to either elevated or nonelevated Tg levels. Stimulated Tg accuracy testing was based on true positive (TP), true negative (TN), false positive (FP), and false negative (FN) results. Sensitivity was defined as TP/TP + FN, specificity was TN/FP + TN, the positive predictive value was TP/TP + FP, and the negative predictive value was TN/FN + TN. As we were testing the accuracy of the Tg test, we could not include it as evidence that defined which patient was POS and which patient had NED.
Results
Patient and tumor characteristics
Three hundred and seventy-seven patients underwent routine rhTSH-assisted follow-up evaluations to monitor residual thyroid carcinoma between January 1, 1999, and December 31, 2000. Eleven patients had Tg autoantibodies and were eliminated from further analysis. The mean age at diagnosis was 47.8 yr, and 57.3% of the patients were female (Table 1
). The AJCC stage of disease was as follows: 163 patients were stage I, 56 patients were stage II, 90 were stage III, and 55 were stage IV. Initial stage was not available for 2 patients. Papillary thyroid carcinoma was the pathological type in 303 of the patients. The mean ± SD suppressed Tg level was 628.3 ± 3618 µg/liter, with a median of 1 µg/liter. The mean ± SD stimulated Tg 72 h after the last dose of rhTSH was 1137.6 ± 6404 µg/liter, with a median of 2.6 µg/liter. DxWBS uptake of 131I was seen in 46.7% of the patients. Of those, 69 of 170, or 40.6%, had uptake only in the thyroid bed. Based on all clinical testing, 46.4% of all patients had evidence for residual disease outside the thyroid bed.
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Diagnostic testing of the entire group (Fig. 1)
Of the 366 evaluable patients who received rhTSH, 175 (47.8%) had a stimulated Tg of 2 µg/liter or less. In this group, 31% had uptake of radioiodine on the DxWBS. When all other testing was accomplished, 35 (20%) were categorized as TB, and 24 (13.7%) as POS. The location of the metastases in these patients, their stimulated Tg levels, and the means by which the metastases were localized are provided in Table 2. Of note is the fact that the DxWBS was negative in 11 of the 24 patients who had residual cancer.
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If a threshold cut-off of 1 µg/liter or less was employed, 142 of the entire cohort would have been at or below this point. Sixteen of these 142 patients (11.3%) had evidence of metastatic disease compared with 24 of 175 (13.7%) when the higher cut-off of 2 µg/liter or less was used.
Results from the low risk group (Fig. 2)
In the low risk group, 90 (82.6%) of the 109 patients had a stimulated Tg of 2 µg/liter or less. From this group of 90, 12 had positive DxWBS; however, only 7 of the 12 (7.8% of the total group) had radioiodine uptake in metastases outside the thyroid bed (6 in the lateral neck and 1 in the mediastinum). Conversely, 9 of the 19 patients (47.4%) whose stimulated Tg was above 2 µg/liter had evidence of metastatic thyroid carcinoma. Interestingly, none of these 9 patients had abnormal DxWBS. Metastatic disease was identified on posttherapy scans in 3 of 19, by neck ultrasonography in 5 of 19, and by [18F]fluoro-2-deoxyglucose-PET scanning in 1.
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To determine the diagnostic accuracy of the stimulated Tg alone in the low risk group, we divided the patients into NED and POS groups. The TB patients were considered an indeterminate group, as one cannot unequivocally state that they do or do not have any residual cancer. Therefore, for accuracy testing the patients with TB (n = 6) were eliminated. Based on the data in Fig. 3, using a threshold of 2 µg/liter or less to predict metastatic disease, we found a sensitivity of 56.3% (9 of 16), a specificity of 88.5% (77 of 87), a positive predictive value of 47.4% (9 of 19), and a negative predictive value of 91.7% (77 of 84). Lowering the threshold cut-off to 1 µg/liter or less resulted in a higher sensitivity (68.8%), lower specificity (74.7%), and lower positive predictive value (33.3%), but no substantial change in the negative predictive value (92.8%).
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Although seven low risk patients had FN testing, all had had prior uptake outside the thyroid bed on their previous DxWBS. When we examined the 84 low risk individuals who had a stimulated Tg of 2 µg/liter or less, we found 25 whose most recent prior DxWBS was negative. All 25 were considered to be NED (TN) at the current evaluation. Therefore, a 100% negative predictive value existed in all low risk patients whose last DxWBS was negative.
Discussion
Routine surveillance to detect early thyroid cancer recurrences is recommended by numerous clinical organizations (12, 13), based on the principle that it easier to treat small volume disease. The National Comprehensive Cancer Network guidelines, for instance recommend that DxWBS be repeatedly performed until one or two scans are completely negative (7). Of the various tools available to detect recurrences, the most sensitive and specific appears to be serum Tg (10). Multiple investigators agree that the serum Tg is a more sensitive index of residual disease when the TSH is elevated compared with when TSH is suppressed (14).
Since 1950, the DxWBS has also been a central surveillance tool for monitoring thyroid cancer survivors. By itself, the DxWBS has approximately 70% sensitivity to detect residual thyroid carcinoma (4, 15, 16). Studies using either thyroid hormone withdrawal or rhTSH suggest that the stimulated Tg response may be a more sensitive and specific response than the DxWBS (9, 10, 17, 18, 19). In the context of thyroid hormone withdrawal, the sensitivity of the stimulated Tg is clearly higher than that of the DxWBS. However, analysis of both tests together almost always results in better diagnostic accuracy than either test alone (10, 20, 21, 22, 23).
Callieux et al. (24) recently proposed that the DxWBS may not be necessary in the follow-up of thyroid cancer patients after radioiodine remnant ablation unless serum Tg exceeds 10 µg/liter after thyroid hormone withdrawal. We examined the hypothesis that the serum Tg response to rhTSH could by itself serve as an accurate and sensitive means to detect residual thyroid carcinoma without the need to perform DxWBS. This hypothesis was tested in an unselected large group of thyroid cancer survivors at a tertiary referral center and in a low risk subset that more closely reflects patients seen by general endocrinologists.
Unfortunately, there is no uniformity in reporting serum Tg levels in the medical literature. Most publications cannot be compared directly, as few use an international standard as a benchmark. The manufacturers of the Dynotest TgS assay used in this report have found a 2:1 ratio of CRM457 material to their standards (see Subjects and Methods). This 2:1 ratio must be considered when comparing our results with those who calibrate their results to CRM457. For instance, the serum Tg results from the large Phase III Genzyme trial (9) used an assay that was standardized and calibrated on the CRM457 (1:1) reference material.
The exact cut-off level of serum Tg that suggests residual thyroid carcinoma has been debated, but is taken by many investigators to be 2 µg/liter with the currently available assays (9). When we considered a stimulated Tg of over 2 µg/liter to be abnormal, we were able to verify the presence of residual thyroid cancer in 76% of all 366 patients and in 47% of the low risk group. Conversely, 13.7% of the entire cohort with a stimulated Tg of 2 µg/liter or less had evidence of metastatic disease. If the threshold was lowered further to 1 µg/liter or less, 11.3% of those below this level had evidence of metastatic disease. Even at 0.3 ng/ml, our functional sensitivity, 8% of patients still had evidence of metastatic disease. The lack of detectable Tg, even in the presence of demonstrable disease, may be due to several possibilities. First, some metastatic thyroid cancers simply do not produce any Tg, or they produce a form that is not measured in our assay. Secondly, small deposits of thyroid cancer may not produce sufficient Tg to raise the serum level above our functional sensitivity.
We developed the low risk group to minimize referral pattern biases that occur at tertiary cancer centers and to focus on the more typical kind of patient seen in routine practice. Of the low risk patients whose Tg did not rise above 2 µg/liter, we found that 7.8% (n = 7) had evidence of residual thyroid cancer. In all seven of these patients, the DxWBS after rhTSH was positive in either the neck or the mediastinum. Interestingly, all of these individuals had had a positive DxWBS during their prior evaluation. Including these patients, we found that a stimulated Tg of 2 µg/liter or less had high specificity (88.5%) and high negative predictive value (91.7%). If we had included a prior negative DxWBS as an inclusion criterion to define the low risk group, we would have had a 100% negative predictive value.
Using the lower threshold of 1 µg/liter for the low risk group increases the sensitivity of detecting metastatic disease (from 56% to 69%), but lowers both the specificity (from 88% down to 75%) and the positive predictive value (from 47% down to 33%). The negative predictive value remains high (93% compared with 92%).
Some investigators and clinicians consider any measurable Tg, after total thyroidectomy and radioiodine ablation, as evidence for residual thyroid carcinoma. This perspective would not allow the possibility for a false positive test. This would make calculations of specificity, sensitivity, and positive predictive value impossible using our statistical conventions. The negative predictive value, however, would remain the same. In this report we designated one group of patients as NED. This does not imply cure, but only the inability to detect residual disease. Furthermore, this NED status does not preclude a recurrence in the future, only the inability to detect residual disease at present.
Pacini et al. (25) have examined the use of rhTSH-stimulated Tg level in the follow-up of thyroid cancer survivors who have suppressed Tg levels on T4. They found no extrathyroid uptake on DxWBS in all 41 patients whose Tg levels did not stimulate above 1 µg/liter. Of 31 patients who had a rise in Tg after rhTSH, 11 had metastases on DxWBS, 12 had thyroid bed uptake only, and 8 were totally negative. Reanalysis of their data using the convention that we used to calculate accuracy, at the 1 µg/liter level, showed very similar positive predictive value and specificity levels. They had 100% NPV and sensitivity based on the fact that there were no false negatives in their cohort. Our NPV and sensitivity were lower due to 5 of 103 FN results. They concluded that no DxWBS was necessary in patients whose Tg does not rise above 1 µg/liter after rhTSH. A cut-off of 0.5 µg/liter in our assay would correspond to 1 µg/liter in the Pacini assay. Forty-seven of our low risk patients had stimulated Tg levels less than 0.5 µg/liter. Four of these patients (8%) had radioiodine uptake in regional lymph nodes, which we categorize as false negatives.
We conclude that the serum Tg response to rhTSH alone is a not a sufficient test for surveillance in unselected thyroid cancer patients, as we found that 13% of those who did not stimulate above 2 µg/liter had evidence for metastatic disease. Using a threshold of 1 µg/liter, 11% of those below this level had evidence for metastatic disease. We believe that these levels are too high to endorse the use of the stimulated Tg alone as the only follow-up tests in all thyroid cancer survivors.
However, in a low risk subset, as defined in this report, a low stimulated Tg has a very high negative predictive value. Importantly, none of the seven patients in the low risk group who were false negatives had distant metastases. Finally, a stimulated Tg of 2 µg/liter or less in low risk patients who have had a prior negative DxWBS was clearly sufficient by itself to monitor for residual disease. However, for thyroid cancer survivors who are not low risk, we advise that routine rhTSH-assisted surveillance should include both DxWBS and a stimulated Tg level (10).
Acknowledgments
We are grateful for the superb assistance the Nuclear Medicine staff, especially Wayne Vorphal and Upendra Bhatt; to clinical care provided by Drs. Alexandra Dimich, Martin Sonenberg, Sam Yee, Chaitanya Divgi, and Henry Yeung; to the editorial assistance of Cherryl Murray-Marone; to the Epidemiology and Biostatistics Department; and to the expertise of the Clinical Chemistry technical staff.
Footnotes
Abbreviations: AJCC, American Joint Commission on Cancer; DxWBS, diagnostic radioiodine whole body scan; FN, false negative; FP, false positive; MSKCC, Memorial Sloan-Kettering Cancer Center; NED, no evidence of disease; PET, positron emission tomography; POS, positive metastatic disease; rhTSH, recombinant human TSH; TB, thyroid bed uptake only; Tg, thyroglobulin; TN, true negative; TP, true positive.
Received September 24, 2001.
Accepted April 9, 2002.
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