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Division of Endocrinology (E.L.M.), Shands Hospital, Gainesville, Florida 32610; Endocrine Service, Department of Medicine (R.J.R.), Memorial Sloan-Kettering Cancer Center, New York, New York 10021; Department of Medicine (C.A.S.), University of Southern California, Los Angeles, California 90033; Section of Endocrinology, Diabetes, and Nutrition (L.E.B.), Boston Medical Center, Boston, Massachusetts 02118; Division of Endocrinology (F.P.), University of Siena, 53100 Siena, Italy; Department of Medicine (L.W.), Washington Hospital Center, Washington, D.C. 20010; Division of Endocrinology (B.R.H.), University of Colorado Health Sciences Center, Denver, Colorado 80262; Department of Endocrine Neoplasia and Hormonal Disorders (S.I.S.), University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; Division of Endocrinology (D.S.C.), Sinai Hospital, Baltimore, Maryland 21215; Department of Medicine (G.D.B.), Cedars Sinai Medical Center, Los Angeles, California 90048; Section of Endocrinology, Diabetes, and Nutrition (S.L.), Boston Medical Center, Boston, Massachusetts 02118; Division of Endocrinology and Metabolism (T.F.D.), Mount Sinai Medical Center, New York, New York 10029-6574; Division of Clinical and Molecular Endocrinology (B.M.A.), University Hospitals of Cleveland, Cleveland, Ohio 44106; Division of Endocrinology (P.W.L.), Johns Hopkins Hospital, Baltimore, Maryland 21278; and Division of Endocrinology (A.P.), University of Pisa, 56124 Pisa, Italy
Address all correspondence and requests for reprints to: Dr. Ernest L. Mazzaferri, 4020 SW 93rd Drive, Gainesville, Florida 32608-4653. E-mail: mazz01{at}bellsouth.net.
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Abstract |
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There is growing recognition of the value of serum thyroglobulin (Tg) as part of routine surveillance. An undetectable serum Tg measured during thyroid hormone suppression of TSH (THST) is often misleading. Eight studies show that 21% of 784 patients who had no clinical evidence of tumor with baseline serum Tg levels usually below 1 µg/liter during THST had, in response to recombinant human TSH (rhTSH), a rise in serum Tg to more than 2 µg/liter. When this happened, 36% of the patients were found to have metastases (36% at distant sites) that were identified in 91% by an rhTSH-stimulated Tg above 2 µg/liter. Diagnostic whole body scanning, after either rhTSH or thyroid hormone withdrawal, identified only 19% of the cases of metastases. Ten studies comprising 1599 patients demonstrate that a TSH-stimulated Tg test using a Tg cutoff of 2 µg/liter (either after thyroid hormone withdrawal or 72 h after rhTSH) is sufficiently sensitive to be used as the principal test in the follow-up management of low-risk patients with DTC and that the routine use of diagnostic whole body scanning in follow-up should be discouraged. On the basis of the foregoing, we propose a surveillance guideline using TSH-stimulated Tg levels for patients who have undergone total or near-total thyroidectomy and 131I ablation for DTC and have no clinical evidence of residual tumor with a serum Tg below 1 µg/liter during THST.
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Introduction |
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Debate concerning management of DTC has been fueled by its low incidence, prolonged clinical course, and the paucity of prospective randomized trials. It has been estimated, for example, that a randomized study to detect a 10% reduction in thyroid cancer mortality rates 25 yr after 131I therapy would require 4000 patients in each arm of the study and would take 10 yr or more to enroll, making results available after 35 yr (15). At present, the core information about the efficacy of initial therapy accordingly derives from large retrospective cohort studies of patients observed for decades. This is the basis for the clinical management guidelines offered by a number of organizations, including the American Association of Clinical Endocrinologists (16), the American Association of Endocrine Surgeons (16), the American Thyroid Association (17), the British Thyroid Association (18), and the National Cancer Center Network (NCCN; Ref. 8).
Defining the most effective follow-up paradigm has been more elusive. Few large studies have focused on optimal surveillance strategies, resulting in less explicit follow-up guidelines that do not clearly separate the roles for various tests (8, 17, 18). The NCCN 2001 guidelines, for example, advise that patients with papillary thyroid carcinoma undergo physical examination every 3–6 months for 2 yr, then annually if disease-free. For patients who have undergone total thyroidectomy with 131I ablation, the guidelines advise thyroglobulin (Tg) measurement at 6 and 12 months, on or off THST, and a TSH-stimulated radioiodine diagnostic whole body scan (DxWBS) every 12 months, until one or two are negative. Serum Tg determinations and DxWBS are less accurate in patients with a large thyroid remnant, because both require high serum TSH levels, usually above 25 mIU/ml, for optimal sensitivity (8, 17, 18).
A number of recently published studies using recombinant human TSH (rhTSH) with sensitive Tg measurements and newer imaging techniques provide fresh insight into optimal long-term surveillance strategies of patients who appear to be free of disease. This is especially important because the prevalence of DTC is so high, affecting more than 200,000 patients in the United States alone (3). New explicit follow-up paradigms thus would likely have an important and beneficial impact on the management of many of these patients. Sparked by these issues, a group of thyroid cancer experts met on June 18, 2002, in San Francisco, California, in an attempt to seek a consensus concerning follow-up management. Although all authors did not agree on every point, this article represents the consensus of the 15 attendees of that meeting.
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The Questions Addressed |
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). What follows is the rationale for this recommendation.
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The consensus is that this follow-up paradigm should only be applied to those who are at low risk for persistent or recurrent disease or cancer death.
The guideline is intended for patients who have undergone total or near-total thyroidectomy and 131I ablation for DTC, who have no clinical evidence of tumor, and who have undetectable serum Tg levels (<1 µg/liter) during THST (Fig. 1
). The majority will have had tumors smaller than 4 cm (pT3), not of a virulent subtype, which were completely resected with or without nodal metastases, but without distant metastases. These are low-risk patients in the Age-Metastasis-Extent-Size scoring system (19), or they usually have Metastasis-Age-Completeness scores of less than 6 (20), or they are American Joint Commission/International Union Against Cancer (AJCC/UICC) stage I if younger than 45 yr or stage I or II if 45 yr of age or older (21).
2) What is the minimal acceptable performance standard of Tg assays used in the detection of residual thyroid cancer?
The consensus is that the physician using this paradigm must have a good working knowledge of the serum Tg assay that is being used, which should meet the minimum performance standards outlined by the U.S. National Academy of Clinical Biochemistry (NACB).
Accuracy of the serum Tg measurement, which is the keystone of the algorithm shown in Fig. 1, is essential (22). A reliable serum Tg measurement can identify patients with residual tumor, preventing unnecessary additional testing in those who are cured (23, 24). Several things may interfere with the accurate measurement of Tg, which is discussed in detail by the NACB (22).
In general, 1 g of normal thyroid tissue results in a serum Tg of approximately 1 µg/liter when the TSH is in the normal range and about 0.5 µg/liter when TSH is suppressed (22). Serum Tg levels rise with TSH stimulation, but the duration of stimulation is generally longer in the hypothyroid state, resulting in higher serum Tg levels than occur 72 h after the last of two 0.9-mg doses of rhTSH in the euthyroid state (22).
The accurate measurement of Tg is technically challenging (25, 26). The most popular commercial assays are immunometric (IMA), but the results are influenced by: 1) the use of the CRM-457 international standard, 2) assay functional sensitivity low enough to detect small amounts of thyroid tissue when TSH is suppressed, 3) interassay precision across monitoring intervals up to 12 months, 4) hook effects1 that can falsely lower Tg results, and 5) anti-Tg antibodies (TgAb) that also can falsely lower IMA Tg results (25, 26). It is thus strongly recommended that serial Tg measurements in a patient be made in the same laboratory using the same assay method because Tg values are not interchangeable among laboratories, even when using the international Tg standard. The assay should have a functional sensitivity of at least 1 µg/liter (22), with a normal lower Tg limit of 3 µg/liter, and the results should be standardized to the CRM-457 standard, which reduces but does not eliminate biases between Tg methods (26).
According to NACB guidelines, Tg should be measured in sera free of TgAb, which must be determined in the same serum sample in which Tg is measured (25, 26). The presence of TgAb usually invalidates the serum Tg result (23, 27). There is some controversy, however, over the use of recovery assays used by some thyroid cancer experts that measure serum Tg levels in serum samples containing TgAb, which the NACB disapproves of (7, 25, 26, 28). Sera should be analyzed for TgAb with a sensitive immunoassay rather than hemagglutination tests, which are too insensitive to detect low TgAb levels (1–10 IU/ml) that may interfere with Tg measurement (25, 26). Using sensitive detection methods, TgAb is found in 25%2 of patients with DTC compared with 10% in the general population (23). With TgAb in sera, there is a significant discordance between serum Tg results measured simultaneously by RIA and IMA, the former measuring higher Tg values than the latter. Although this effect is more severe with high serum TgAb concentrations, it is unpredictable, occurring with TgAb levels as low as 1–2 IU/ml, whereas sometimes not occurring with TgAb values higher than 1000 IU/ml (23).
3) Is an undetectable serum THST-Tg level sufficiently sensitive to consistently identify patients who are free of residual tumor?
The consensus is that an undetectable serum Tg measured during thyroid hormone suppression is misleading in a large proportion of patients with residual DTC. An undetectable serum Tg during THST is usually achieved only by total or near-total thyroidectomy and 131I ablation. For example, one study (29) of 180 patients with DTC found that THST-Tg levels were often above 10 µg/liter after partial thyroidectomy, with or without 131I ablation. Even after near-total or total thyroidectomy and 131I ablation, Tg levels were higher than 10 µg/liter in almost 2% of patients during THST (29).
On the other hand, among patients displaying a low or undetectable serum Tg level during THST, the Tg often rises to above 2 µg/liter after TSH stimulation. In the Phase III rhTSH study (30), for example, a serum Tg lower than 2 µg/liter measured during THST failed to identify 23% of evaluable patients with metastatic disease, yet a TSH-stimulated Tg above 2 µg/liter (rhTSH or THW) identified all patients with metastases (Table 1 and Fig. 2).
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). When this occurred, almost 36% had metastases, of which over 36% were at distant sites.
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The consensus is that hypothyroid and euthyroid rhTSH-stimulated serum Tg levels (measured 72 h after the last dose of rhTSH) are comparable in detecting metastases when a cutoff of 2 µg/liter is used.
Considerable evidence supports the notion that the two methods used to stimulate Tg, THW-induced hypothyroidism and euthyroid rhTSH stimulation, are equally effective in detecting metastatic thyroid cancer. In the large Phase III rhTSH study (30), the median serum Tg values were 0.5 µg/liter during THST, 1.1 µg/liter 72 h after the last of two 0.9-mg doses of rhTSH, and 1.8 µg/liter during THW; however, using a Tg cutoff of 2 µg/liter, all metastases were identified with either an rhTSH- or THW-stimulated Tg test. Robbins et al. (37) were unable to demonstrate a difference in the diagnostic accuracy of serum Tg concentrations in the detection of metastases among patients prepared by either THW (161 patients) or rhTSH (128 patients). Pacini et al. (35), comparing peak rhTSH- and THW-stimulated serum Tg concentrations in the same patients, found that none of those with a TSH-stimulated Tg less than 1 µg/liter had metastases, whereas an elevated TSH-stimulated Tg identified 100% of the patients with local or distant metastases, regardless of whether the TSH stimulation was by rhTSH or THW. In eight recent studies (28, 30, 31, 32, 33, 34, 35, 36), an rhTSH-stimulated Tg above 2 µg/liter identified 91% of the 58 patients with metastases (Table 2).
5) Is TSH-stimulated serum Tg measurement sufficiently sensitive to be used alone in the follow-up of patients with DTC?
The consensus is that a TSH-stimulated Tg alone is sufficient for follow-up of low-risk patients with no clinical evidence of disease and suppressed serum Tg levels during THST.
Although serum Tg and DxWBS have been considered complementary in identifying residual tumor (38), an undetectable TSH-stimulated Tg alone, whether by THW or rhTSH, is usually sufficient to do this (Table 2 and Fig. 3). Little information is added by performing a DxWBS in the evaluation of patients at low-risk of having persistent disease. Tumor is rarely found when the serum Tg value is less than 2 µg/liter after rhTSH stimulation (28, 30, 31, 32, 33, 34, 35, 36) or THW (7, 39). Two THW studies show that TSH-stimulated serum Tg measurement consistently identifies patients with residual tumor (7, 39). Eight other studies (28, 30, 31, 32, 33, 34, 35, 36) show that metastatic tumor is almost always identified by an rhTSH-stimulated serum Tg above 2 µg/liter. Six of the eight studies (28, 31, 32, 33, 34, 35) show the extent to which unsuspected tumor is detected by rhTSH-Tg and DxWBS. When 784 patients underwent testing, 36% of those with an rhTSH-Tg above 2 µg/liter were found to have unsuspected metastases that were usually not detected by DxWBS (Table 2). Almost all (91%) of the patients with metastases were identified by an rhTSH-stimulated Tg above 2 µg/liter, whereas only 19% were identified by a positive rhTSH-stimulated or hypothyroid THW DxWBS (Table 2). Thus, 10 studies (7, 28, 30, 31, 32, 33, 34, 35, 36, 39) comprising 1599 patients demonstrate that TSH-stimulated Tg testing (either rhTSH or THW) is sufficiently sensitive to be used alone in the follow-up management of low-risk patients with DTC.
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The consensus is that serum Tg measurements during thyroid hormone suppression are sufficiently sensitive to forgo further testing in a low-risk patient who is clinically free of disease and has had an undetectable (< 1 µg/liter) serum Tg level during THST and after rhTSH or THW. A Tg that remains undetectable after either THW or rhTSH stimulation is strong evidence of complete tumor ablation (7, 28, 30, 32, 33, 34, 35, 36, 39). Such patients usually require nothing more than annual physical examination and serum Tg measurement during THST, unless there is clinical evidence of tumor or other compelling reasons for performing TSH-stimulated testing.
7) Can any recommendations be made concerning the frequency and type of long-term follow-up testing?
The consensus is that many patients do not require annual TSH-stimulated serum Tg measurement. Information garnered from the prior Tg response to rhTSH stimulation can form the basis of recommendations for further testing (Fig. 3).
Among patients with an undetectable THST-Tg who undergo rhTSH stimulation, there are three possible scenarios using a Tg cutoff of 2 µg/liter:
and 3) and may not call for immediate evaluation but usually warrants periodic rhTSH stimulation studies, perhaps as often as once yearly. Neck ultrasonography plays an important diagnostic role in this group. In some patients, the high TSH-stimulated serum Tg level will spontaneously decline over one or more years, and in others it will steadily rise, and metastases will become apparent (7, 29, 40). ) and usually indicates a substantial thyroid remnant or residual cancer. Patients with this pattern usually require further testing to localize the source of the Tg (Fig. 1 and Tables 1 and 2). |
Discussion |
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The algorithm we propose does not require a patient to become hypothyroid at the 1-yr follow-up evaluation, instead recommending preparation by rhTSH. Two large studies (30, 37) have now confirmed that the sensitivity of the rhTSH-stimulated Tg is similar to the hypothyroid-stimulated Tg for the detection of metastatic disease, despite the greater elevation of Tg that prolonged hypothyroidism may produce (35). Ultrasonography performed by expert endocrinologists or radiologists is particularly useful in patients with high Tg levels.
Early detection of tumor affects thyroid cancer mortality (1). The outcome of patients with metastatic disease is highly dependent on the size and extent of neoplastic foci when detected, with survival dramatically decreasing if foci remain unidentified until they become large and/or widespread (41). When serum Tg rises above 2 µg/liter after rhTSH, our algorithm suggests further evaluation and possibly 131I therapy if the THW-Tg rises above some arbitrary limit, without performing a DxWBS, relying on the posttherapy whole body scan (RxWBS) for localizing the tumor and confirming its uptake of 131I.
The choice of a 2 µg/liter cutoff to identify tumor is supported by studies that show a substantial likelihood of residual disease in patients with TSH-stimulated serum Tg levels above 2 µg/liter, whether induced by rhTSH or by endogenous TSH (7, 39). Eight studies (28, 30, 31, 32, 33, 34, 35, 36) comprising 1028 patients showed that almost 90% of those with metastases were identified using an rhTSH-Tg cutoff of 2 µg/liter. However, because different Tg assays return different Tg levels from the same serum specimen, the choice of the optimum cutoff may vary depending on the unique characteristics of individual Tg assays as outlined earlier in this report.
An elevated serum Tg may be the only indication of metastases ultimately found on the RxWBS after administering 131I therapy. The Tg cutoff for empiric 131I therapy, albeit arbitrary, is about 10 µg/liter after THW in many centers (8, 42, 43). The frequency of lung metastases in patients empirically treated with 131I for a high serum Tg and negative DxWBS ranges from nearly 6% in one study (44) to 9% in another (1), and from 35–55% of selected patients in two other studies (45, 46). Schlumberger (41) reported 100% 10-yr survival after empiric 131I treatment of lung metastases found by an elevated serum Tg level and negative DxWBS, but positive RxWBS. In contrast, 10-yr survival was 91% with a normal chest x-ray and a positive DxWBS and RxWBS, and it was considerably worse with a positive chest x-ray, i.e. 63% with micronodules and 11% with macronodules. Pineda et al. (46), after treating 17 Tg-positive and DxWBS-negative patients, found that the serum Tg decreased in 81% after the first 131I treatment, 90% after the second treatment, and 100% after the third treatment. These studies show that empiric 131I therapy may be useful for diffuse lung uptake, especially in young and middle-aged patients with negative chest x-rays and DxWBS. It is, however, of little benefit in patients with macronodular lung metastases, especially when they do not concentrate 131I or when they are visualized on FDG-PET (47, 48). Pacini et al. (40) emphasize that once tumor 131I uptake cannot be demonstrated on RxWBS, further 131I treatment is not indicated. Treating patients with large cumulative doses of 131I for tumors that do not concentrate the isotope has a potential for harm that outweighs any minor benefit it might have. Pacini et al. (49) also recommend that repeat 131I treatments should not be given for trivial thyroid bed uptake, whereas if lung metastases concentrate 131I on the first RxWBS after empiric treatment, 131I therapy should be continued until remission. Optimal therapy for lymph node metastases is often surgery (8).
Omitting follow-up DxWBS studies in low-risk patients after initial surgery and 131I ablation has important cost implications. The price for a DxWBS varies by region and ranges from $1022 to $1844 (Table 3). The cost for rhTSH is approximately $900, but this varies among providers. The cost of performing rhTSH-stimulated serum Tg measurements without DxWBS thus would be about the same as performing THW-stimulated serum Tg measurements and DxWBS. The least costly approach insofar as direct medical costs are concerned is to simply withdraw thyroid hormone and proceed with the algorithm shown in Fig. 1; however, this requires the patient to become hypothyroid, with its attendant problems, including indirect costs of hypothyroidism such as lost work and productivity. Although we have not performed a detailed pharmacoeconomic analysis, we believe the proposed paradigm using rhTSH-stimulated serum Tg measurements alone is a cost-effective and sensitive means of detecting early metastases in patients who clinically appear to be free of disease and who have undetectable serum Tg concentrations while taking TSH-suppressive doses of thyroid hormone. Follow-up paradigms are likely to be substantially different in patients who have not undergone total or near-total thyroidectomy and 131I ablation who have a thyroid remnant.
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Footnotes |
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Abbreviations: DTC, Differentiated thyroid carcinoma; DxWBS, diagnostic whole body scanning; IMA, immunometric assay; rhTSH, recombinant human TSH; RxWBS, posttherapy whole body scanning; Tg, thyroglobulin; TgAb, anti-Tg antibodies; THST, thyroid hormone suppression of TSH; THW, thyroid hormone withdrawal.
Received October 31, 2002.
Accepted January 14, 2003.
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S. Hu, M. Ewertz, R. P. Tufano, M. Brait, A. L. Carvalho, D. Liu, A. P. Tufaro, S. Basaria, D. S. Cooper, D. Sidransky, et al. Detection of Serum Deoxyribonucleic Acid Methylation Markers: A Novel Diagnostic Tool for Thyroid Cancer J. Clin. Endocrinol. Metab., January 1, 2006; 91(1): 98 - 104. [Abstract] [Full Text] [PDF]
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J. R. Stockigt Ambiguous Thyroglobulin Assay Results in the Follow-Up of Differentiated Thyroid Carcinoma J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5904 - 5905. [Full Text] [PDF]
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S. Leboulleux, C. Rubino, E. Baudin, B. Caillou, D. M. Hartl, J.-M. Bidart, J.-P. Travagli, and M. Schlumberger Prognostic Factors for Persistent or Recurrent Disease of Papillary Thyroid Carcinoma with Neck Lymph Node Metastases and/or Tumor Extension beyond the Thyroid Capsule at Initial Diagnosis J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5723 - 5729. [Abstract] [Full Text] [PDF]
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C. Ma, A. Kuang, J. Xie, and T. Ma Possible Explanations for Patients with Discordant Findings of Serum Thyroglobulin and 131I Whole-Body Scanning J. Nucl. Med., September 1, 2005; 46(9): 1473 - 1480. [Abstract] [Full Text] [PDF]
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R. T. Kloos and E. L. Mazzaferri A Single Recombinant Human Thyrotropin-Stimulated Serum Thyroglobulin Measurement Predicts Differentiated Thyroid Carcinoma Metastases Three to Five Years Later J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5047 - 5057. [Abstract] [Full Text] [PDF]
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E. L. Mazzaferri Empirically Treating High Serum Thyroglobulin Levels J. Nucl. Med., July 1, 2005; 46(7): 1079 - 1088. [Full Text] [PDF]
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C. Ma, J. Xie, and A. Kuang Is Empiric 131I Therapy Justified for Patients with Positive Thyroglobulin and Negative 131I Whole-Body Scanning Results? J. Nucl. Med., July 1, 2005; 46(7): 1164 - 1170. [Abstract] [Full Text] [PDF]
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M. G. Castagna, A. Pinchera, A. Marsili, M. Giannetti, E. Molinaro, P. Fierabracci, L. Grasso, F. Pacini, F. Santini, and R. Elisei Influence of Human Body Composition on Serum Peak Thyrotropin (TSH) after Recombinant Human TSH Administration in Patients with Differentiated Thyroid Carcinoma J. Clin. Endocrinol. Metab., July 1, 2005; 90(7): 4047 - 4050. [Abstract] [Full Text] [PDF]
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T. Y. Kim, W. B. Kim, E. S. Kim, J. S. Ryu, J. S. Yeo, S. C. Kim, S. J. Hong, and Y. K. Shong Serum Thyroglobulin Levels at the Time of 131I Remnant Ablation Just after Thyroidectomy Are Useful for Early Prediction of Clinical Recurrence in Low-Risk Patients with Differentiated Thyroid Carcinoma J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1440 - 1445. [Abstract] [Full Text] [PDF]
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S. M. Larson and E. P. Krenning A Pragmatic Perspective on Molecular Targeted Radionuclide Therapy J. Nucl. Med., January 1, 2005; 46(1_suppl): 1S - 3S. [Full Text] [PDF]
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R. J. Robbins and M. J. Schlumberger The Evolving Role of 131I for the Treatment of Differentiated Thyroid Carcinoma J. Nucl. Med., January 1, 2005; 46(1_suppl): 28S - 37S. [Abstract] [Full Text] [PDF]
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R. J. Robbins, S. Srivastava, A. Shaha, R. Ghossein, S. M. Larson, M. Fleisher, and R. M. Tuttle Factors Influencing the Basal and Recombinant Human Thyrotropin-Stimulated Serum Thyroglobulin in Patients with Metastatic Thyroid Carcinoma J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6010 - 6016. [Abstract] [Full Text] [PDF]
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E. Mazzaferri A Randomized Trial of Remnant Ablation--In Search of an Impossible Dream? J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3662 - 3664. [Full Text] [PDF]
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C. A. Spencer Challenges of Serum Thyroglobulin (Tg) Measurement in the Presence of Tg Autoantibodies J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3702 - 3704. [Full Text] [PDF]
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P. Chinnappa, L. Taguba, R. Arciaga, C. Faiman, A. Siperstein, A. E. Mehta, S. K. Reddy, C. Nasr, and M. K. Gupta Detection of Thyrotropin-Receptor Messenger Ribonucleic Acid (mRNA) and Thyroglobulin mRNA Transcripts in Peripheral Blood of Patients with Thyroid Disease: Sensitive and Specific Markers for Thyroid Cancer J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3705 - 3709. [Abstract] [Full Text] [PDF]
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P. W. S. do Rosario, T. A. Fagundes, F. F. R. Maia, A. C. H. M. Franco, M. B. Figueiredo, and S. Purisch Sonography in the Diagnosis of Cervical Recurrence in Patients With Differentiated Thyroid Carcinoma J. Ultrasound Med., July 1, 2004; 23(7): 915 - 920. [Abstract] [Full Text] [PDF]
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M. Toubeau, C. Touzery, P. Arveux, G. Chaplain, G. Vaillant, A. Berriolo, J.-M. Riedinger, C. Boichot, A. Cochet, and F. Brunotte Predictive Value for Disease Progression of Serum Thyroglobulin Levels Measured in the Postoperative Period and After 131I Ablation Therapy in Patients with Differentiated Thyroid Cancer J. Nucl. Med., June 1, 2004; 45(6): 988 - 994. [Abstract] [Full Text] [PDF]
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M. D. Ringel Molecular Detection of Thyroid Cancer: Differentiating "Signal" and "Noise" in Clinical Assays J. Clin. Endocrinol. Metab., January 1, 2004; 89(1): 29 - 32. [Full Text] [PDF]
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R. Elisei, A. Vivaldi, L. Agate, E. Molinaro, C. Nencetti, L. Grasso, A. Pinchera, and F. Pacini Low Specificity of Blood Thyroglobulin Messenger Ribonucleic Acid Assay Prevents Its Use in the Follow-Up of Differentiated Thyroid Cancer Patients J. Clin. Endocrinol. Metab., January 1, 2004; 89(1): 33 - 39. [Abstract] [Full Text] [PDF]
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B. B. Chin, P. Patel, C. Cohade, M. Ewertz, R. Wahl, and P. Ladenson Recombinant Human Thyrotropin Stimulation of Fluoro-D-Glucose Positron Emission Tomography Uptake in Well-Differentiated Thyroid Carcinoma J. Clin. Endocrinol. Metab., January 1, 2004; 89(1): 91 - 95. [Abstract] [Full Text] [PDF]
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C. Menzel, F. Grunwald, and H. J. Biersack Monitoring of Low-Risk Patients with Papillary Thyroid Carcinoma J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4507 - 4507. [Full Text] [PDF]
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