Thyroid Cancer: New Approaches To The Fastest Growing Cancer

Thyroid Cancer: Latest Approaches to Canada’s Fastest Growing Cancer

Alon Vaisman, H.B.Sc. (1T1), Faculty of Medicine, University of Toronto Steven Orlov, B.Sc. (1T0), Faculty of Medicine, University of Toronto Jonathan Yip, H.B.Sc. (1T3), Faculty of Medicine, University of Toronto David Orlov, H.B.Sc., M.D. (0T9), Faculty of Medicine, McMaster University

Abstract

Thyroid cancer is the most common endocrinological malignancy worldwide and its incidence is increasing faster than any other cancer. The majority of this increase has been in well differentiated thyroid carcinoma (i.e. papillary and follicular histology) which comprise 90% of all thyroid cancers. Recent advancements in the diagnosis, surgical treatment, and long-term monitoring have enhanced the detection of primary and recurrent disease, as well as treatment modalities. These developments have prompted institutions to revise their guidelines on the management of thyroid disorders. In the diagnosis of thyroid nodules, recommendations have been made regarding initial evaluation, use of TSH and radionuclide studies, clinical and ultrasound criteria for fine-needle aspiration biopsy (FNAB), and the interpretation of FNAB results. Thyroidectomy (removal of gross thyroid tissue) and lymph node dissection have been established as efficacious initial therapy to reduce disease recurrence; howeve, the extent of surgical resection is hotly debated. Following surgical therapy, appropriate use of radioactive iodine remnant ablation (RAI) to destroy microscopic disease has been advised. However, RAI decision-making has been controversial, as some groups base decisions on preoperative and intraoperative features, while others argue that these are not reliable predictors of disease. Guidelines for long-term management include recommendations on the use of TSH suppression therapy, surveillance of recurrent disease using ultrasound & serum thyroglobulin, and the treatment of recurrent/metastatic disease. Here, we review the recent developments and recommendations in the management of well differentiated thyroid carcinoma.

Introduction

In North America, the incidence of thyroid cancer is increasing faster than for any other cancer1. It is currently the most common endocrinological malignancy worldwide, and the most common carcinoma in young females, where its incidence has increased by 10% since 19971. In the United States, 37,200 new cases of thyroid cancer are diagnosed annually and incidence has increased almost three-fold since 19732, 3. The majority of this increase has been in well differentiated thyroid carcinoma (WDTC), which includes papillary and follicular cancers, and comprises 90% of all thyroid malignancies4. The increase in incidence can also be attributed to advancements in the detection of thyroid nodules through the use of ultrasound and needle biopsies. Fortunately, despite the significant rise in incidence, mortality rates have remained stable, with a 5-year relative survival ratio of 98% due to earlier diagnosis and improved treatment efficacy1. The focus of the present review is to examine the latest research in the diagnosis, treatment, and management of patients with WDTC. This includes recent developments in the diagnostic evaluation of thyroid nodules, the need for adequate surgery, and the use of radioactive iodine therapy following thyroidectomy.

Diagnosis The Thyroid Nodule

The diagnosis of thyroid cancer often begins with the detection of a thyroid nodule, either by palpation or neck ultrasound. A nodule is defined as a discrete lesion within the thyroid gland that is distinct from the surrounding thyroid tissue5. The detection of a thyroid nodule should be followed by a complete history and physical examination focusing on the thyroid gland and lymph nodes of the neck. The prevalence of thyroid nodules in adults is approximately 5% in women and 1% in men by palpation, but can be as high as 50% by high-resolution ultrasound6, 7. Non-palpable nodules (i.e. detected only on ultrasound) have the same risk of malignancy as palpable nodules of the same size8. The 2009 American Thyroid Association guidelines for the management of thyroid cancer state that generally, only nodules larger than 1 cm should be evaluated for their potential to become significant cancers5. Investigation of smaller nodules may be indicated in the presence of suspicious ultrasound findings and/or history that places an individual at higher risk for malignancy. History of head and neck irradiation, a first-degree relative with a history of thyroid carcinoma, and exposure to ionizing radiation or nuclear fallout are three risk factors that place an individual at higher risk for thyroid carcinoma9. Suspicious physical examination findings may include new-onset dysphonia secondary to vocal cord paralysis, cervical lymph node enlargement, and/or a fixed/irregular nodule.

TSH and Radionuclide Studies

Work-up for suspicious nodules should include a serum thyroid stimulating hormone (TSH) level and imaging studies. A high serum TSH warrants further investigation by ultrasound, as studies have shown that high serum TSH is associated with increased risk of malignancy10. An abnormally low serum TSH value indicates the need for radionuclide thyroid scanning, either with technetium (99mTc pertechnetate) or iodine (123I) isotopes. A “cold” (hypofunctioning) nodule on such a scan warrants further investigation by ultrasound to rule out malignancy, whereas a “warm” or “hot” (hyperfunctioning) nodule needs no further investigation. Currently, serum thyroglobulin and calcitonin measurements are not recommended in the diagnosis of thyroid cancer due to their poor sensitivity, specificity, and lack of cost effectiveness11, 12.

Ultrasound Guided Fine Needle Aspiration Biopsy

Thyroid ultrasonography should be performed in all patients with one or more suspicious thyroid nodules. This modality allows for accurate examination of the size and associated characteristics of the nodule itself. Worrisome qualities on ultrasound include solid/complex appearance, hypoechoicity, micro-calcifications, and blurry margins13 (Figure 1). Ultrasound also facilitates the most accurate method of thyroid nodule evaluation - fine needle aspiration biopsy (FNAB). Studies continue to show that biopsying suspicious nodules using ultrasound guidance is both cost-effective and highly accurate14. Ultrasound-guided FNAB is also recommended for nodules that are non-palpable, cystic, or posteriorly located in the thyroid gland. FNAB results are divided into four categories: (1) benign, (2) indeterminate or suspicious, (3) malignant (>95% risk of malignancy), and (4) non-diagnostic (i.e. repeat FNAB is required)13. Malignant cytology warrants surgical therapy, while benign nodules need no further investigation aside from serial follow-up with ultrasound. Nodules of indeterminate cytology—which have an approximately 25% chance of being malignant—may also require surgical treatment depending on the results of a radionuclide scan15. Recently, attempts to use 18fluorodeoxyglucose positron emission tomography (18FDG-PET) to distinguish between benign and malignant indeterminate nodules have shown the scan to be of high sensitivity but poor specificity, and is therefore not recommended at this time16, 17. Screening for malignant molecular markers such as BRAF, RAS, and RET/PTC in indeterminate nodules may be useful in helping guide further therapy. Unfortunately, these markers are not readily available in many clinical laboratories18-20.

Surgical Therapy Thyroidectomy

The initial therapy for malignant thyroid nodules is total (removal of all grossly visible thyroid tissue) or near-total (removal of grossly visible thyroid tissue leaving <1g of tissue remaining) thyroidectomy5, 13. Total thyroidectomy is also indicated for patients with indeterminate nodules on FNAB in the presence of high risk features on history or physical examination (described above)21. For primary tumours <1 cm in the absence of high-risk features, current guidelines mainly recommend a thyroid lobectomy (removal of one thyroid lobe)5, 13 although certain schools of thought favour total thyroidectomy on the basis of decreased cancer recurrence and health care costs22, 23. Another important consideration in determining the extent of a thyroid tissue resection is surgical expertise. The complication rate of thyroidectomy has been negatively associated with the experience of surgeons, and the reported rate is 2-3% in those who do more than 20 cases per year24, 25. Complications of a thyroidectomy include transient or permanent hypocalcemia, transient or permanent recurrent laryngeal nerve injury, and neck hematoma25.

Lymph Node Dissection Lymph node metastases are common in WDTC. Standard histological examination of lymph nodes removed at the time of thyroidectomy reveals metastases in 20-50% of patients, and the incidence of palpable lymph node disease is 5-10%26. Though lymph node involvement has been shown to increase recurrence rates, its impact on survival is relatively small25. Consequently, lymph node dissections are usually performed at the time of thyroidectomy, and serve to aid in local control and future disease prevention. Current surgical guidelines recommend the removal of nodal groups in the central and/or lateral neck compartments only when there is clinical or pathologic indication of lymph node abnormalities as evidenced on physical examination, preoperative ultrasound, and/or intraoperative assessment5, 25. Features suggestive of metastatic lymph nodes on preoperative ultrasound include loss of the fatty hilus, rounded shape, hypoechogenicity, cystic change, calcifications, and peripheral vascularity. Intraoperative lymphadenopathy or positive frozen section pathology also warrant excision27, 28. The role of prophylactic lymph node dissections, involving the extensive removal of lymph nodes with no clinical evidence of disease, is a hotly debated topic25. A consensus on the benefits in recurrence rates with this approach has not been reached, as this practice appears to be associated with high morbidity, including recurrent laryngeal nerve damage and transient hypoparathyroidism,29.

Post-Operative Staging Accurate postoperative staging of patients permits: (1) assessment of prognosis, (2) tailoring of adjuvant therapy, and (3) facilitation of decision-making regarding frequency and intensity of follow-up5, 13. The most commonly used staging system for WDTC is the pTNM (pathological tumour-node-metastasis) staging developed by the American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC)30 (Table 1).

Radioactive Iodine Therapy Following initial surgical therapy, radioactive iodine (RAI) remnant ablation is commonly used as adjuvant treatment to destroy residual microscopic disease. This therapy also facilitates the detection of recurrent disease with serum thyroglobulin (see below) by ablating normal remaining thyroid tissue 31. Although large retrospective studies have shown that RAI can decrease the rate of disease recurrence32, 33 and cause-specific mortality33, 34, a recent meta- analysis could not confirm the same benefit for early stage thyroid cancers35, which make up the majority of all thyroid carcinomas. Currently, prescription of RAI therapy is largely based on advanced patient age, larger tumour size, and the presence of local and/or distant metastases5. A recent study has explored the utility of a post-surgical TSH-stimulated thyroglobulin (discussed below) to improve RAI decision-making36. Once patients are selected to undergo post-surgical RAI therapy, they should adhere to a low-iodine diet and discontinue any oral thyroid hormone supplementation (T4 or T3). Such action results in a stimulated level of serum TSH (>30mU/L) via negative feedback on the hypothalamic-pituitary-thyroid axis and facilitates greater radioactive iodine uptake at the time of RAI therapy37. Alternatively, an elevated level of serum TSH can be achieved using an injection of recombinant human TSH (rhTSH)38. Although radioactive iodine doses generally range from 30-100 mCi, higher doses may be required for more extensive disease5.

Long Term Follow-up The goal of long term follow-up is to monitor for cancer recurrence and/or metastatic spread following initial surgical and radioactive therapies. Follow-up generally relies on measuring serum thyroglobulin (Tg) - a protein involved in thyroid hormone synthesis, which is increased when stimulated by TSH and should be undetectable in individuals without thyroid tissue35. Thyroglobulin can be measured while patients are on thyroid hormone replacement (TSH-suppressed Tg) or when thyroid hormone is discontinued (TSH-stimulated Tg). Alternatively, an injection of rhTSH can be used to measure TSH-stimulated Tg. Increased levels of serum Tg suggest the presence of residual or recurrent diseased tissue. Annual neck ultrasound is also a common modality to monitor for residual or recurrent disease21, 39. Patients appropriately treated for thyroid cancer have excellent outcomes, in terms of life span and mortality. Recent studies have shown that the life span of those treated with total thyroidectomy and RAI therapy is similar to the general population40.

Serum Thyroglobulin (Tg)

Serial serum Tg measurement is the cornerstone of thyroid cancer follow-up. Unfortunately, up to 20% of the population has anti-Tg antibodies that interfere with the validity of existing Tg assays41. Without the interference of antibodies, serum Tg has high sensitivity and specificity for the detection of recurrent thyroid cancer following total thyroidectomy and RAI therapy42-44. The sensitivity of serum Tg for recurrent thyroid cancer can be further improved by performing a TSH-stimulated Tg using thyroid hormone withdrawal or an injection of rhTSH. Specifically, rhTSH-stimulated serum Tg values less than 0.5 ng/mL (undetectable levels) identifies 99.5% of tumour free patients45. Further, a single undetectable TSH-stimulated Tg test does not require subsequent simulation testing46. A TSH-stimulated Tg performed after thyroidectomy but prior to RAI therapy may also predict disease free remission, future recurrence, metastases, and mortality47-49. This association forms the basis of a strategy to use TSH-stimulated Tg to help identify patients who subsequently require RAI and those who may not (i.e. surgery alone may have been curative)36.

TSH Suppression

Since thyroid tissue growth relies on thyroid stimulating hormone (TSH), long-term TSH suppression (below 0.1 mU/L) has become a commonly used practice to treat post-operative patients50. TSH suppression is accomplished by using supra-physiologic doses of thyroid hormones which downregulates TSH via negative feedback in the hypothalamic-pituitary-thyroid axis. A meta-analysis has shown that TSH suppression can prevent disease recurrence and is particularly effective in patients diagnosed with advanced stage thyroid cancer51.

Disease Recurrence/Metastatic Disease

Patients found to have elevated or rising serum Tg levels after thyroidectomy must be investigated for the possibility of recurrent or metastatic disease5. Ultrasound studies are helpful in identifying recurrent disease in the neck and all suspicious lymph nodes (described above) should be biopsied to assess for malignancy. 18FDG-PET scanning has proven helpful in patients with suspected metastatic disease as part of staging, prognosis, and to evaluate the effectiveness of therapy52. In the event that metastatic/recurrent disease has been confirmed, additional surgery and RAI is required. In patients with incurable metastatic cancer, surgery may also be used to eliminate disease in important locations such as the central nervous system or aerodigestive locations5. As well, external beam irradiation can be used in such patients to treat painful bone metastases and metastatic lesions in critical locations53. Althought there is a limited for the adjunctive use of chemotherapy in patients with WDTC, other treatments such as radiofrequency ablation, ethanol ablation, or chemo-embolization may be used instead13. Distant metastatic thyroid cancer foci (brain, bone, lung) that do not respond to surgery or radiotherapy have poor outcome54.

Conclusion According to Canadian Cancer Society statistics, thyroid cancer accounted for 2.7% of all new Canadian cancer cases in 2009, placing it eighth behind prostate, lung, breast, colorectal cancer, Non-Hodgkin’s lymphoma, bladder cancer, and melanoma, respectively1. Although its incidence continues to climb faster than for any other malignancy, it is highly treatable and currently ranks high in terms of survival post-diagnosis. Developments over the past few decades have drastically improved diagnostic efficacy and treatment modalities for this entity. As such, cases of thyroid cancer are diagnosed earlier, managed multi-modally, and followed longitudinally for recurrence with serial measurement of serum thyroglobulin. Stable survival despite a rising incidence is a testament to the current success in treatment of this condition. Current thyroid cancer research has turned to discovering novel biomarkers to improve diagnosis and follow-up, risk-stratification of patients post-thyroidectomy to potentially bypass RAI therapy and its associated side-effects, and further elucidation of thyroid cancer mechanisms on a molecular level. In all, it is hopeful that all of these future avenues will further improve the success of managing thyroid malignancy for future patients.

Acknowledgements

The authors would like to acknowledge the support for their research into thyroid cancer from the Joseph Mildred Sonshine Centre for Head and Neck Diseases at Mount Sinai Hospital, under the mentorship of Dr. Paul G. Walfish, Alex and Simona Shnaider Research Chair in Thyroid Oncology. They would also like to acknowledge the Comprehensive Research Experience for Medical Students, who previously provided funding for the research two of the authors of this review (A.V., S.O.). Figures

Table 1. Pathological tumour-node-metastasis (pTNM) staging for well-differentiated thyroid carcinoma (WDTC). Figure 1. Thyroid ultrasound showing an isoechoic nodule with well-defined margins and microcalcifications. References 1. Society CC. Canadian Cancer Society's Steering Committee: Canadian Cancer Statistics. 2009. 2. Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973- 2002. Jama. May 10 2006;295(18):2164-2167. 3. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. Jan-Feb 2007;57(1):43-66. 4. Sherman SI. Thyroid carcinoma. Lancet. Feb 8 2003;361(9356):501-511. 5. Cooper DS, Doherty GM, Haugen BR, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. Nov 2009;19(11):1167-1214. 6. Tunbridge WM, Evered DC, Hall R, et al. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol (Oxf). Dec 1977;7(6):481-493. 7. Tan GH, Gharib H. Thyroid incidentalomas: management approaches to nonpalpable nodules discovered incidentally on thyroid imaging. Ann Intern Med. Feb 1 1997;126(3):226-231. 8. Hagag P, Strauss S, Weiss M. Role of ultrasound-guided fine-needle aspiration biopsy in evaluation of nonpalpable thyroid nodules. Thyroid. Nov 1998;8(11):989-995. 9. Pacini F, Vorontsova T, Demidchik EP, et al. Post-Chernobyl thyroid carcinoma in Belarus children and adolescents: comparison with naturally occurring thyroid carcinoma in Italy and France. J Clin Endocrinol Metab. Nov 1997;82(11):3563-3569. 10. Boelaert K, Horacek J, Holder RL, Watkinson JC, Sheppard MC, Franklyn JA. Serum thyrotropin concentration as a novel predictor of malignancy in thyroid nodules investigated by fine-needle aspiration. J Clin Endocrinol Metab. Nov 2006;91(11):4295- 4301. 11. Choi JY, Lee KS, Kim HJ, et al. Focal thyroid lesions incidentally identified by integrated 18F-FDG PET/CT: clinical significance and improved characterization. J Nucl Med. Apr 2006;47(4):609-615. 12. Cheung K, Roman SA, Wang TS, Walker HD, Sosa JA. Calcitonin measurement in the evaluation of thyroid nodules in the United States: a cost-effectiveness and decision analysis. J Clin Endocrinol Metab. Jun 2008;93(6):2173-2180. 13. Cooper DS, Doherty GM, Haugen BR, et al. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. Feb 2006;16(2):109-142. 14. Alexander EK, Heering JP, Benson CB, et al. Assessment of nondiagnostic ultrasound- guided fine needle aspirations of thyroid nodules. J Clin Endocrinol Metab. Nov 2002;87(11):4924-4927. 15. Baloch ZW, LiVolsi VA. Fine-needle aspiration of the thyroid: today and tomorrow. Best Pract Res Clin Endocrinol Metab. Dec 2008;22(6):929-939. 16. Kim JM, Ryu JS, Kim TY, et al. 18F-fluorodeoxyglucose positron emission tomography does not predict malignancy in thyroid nodules cytologically diagnosed as follicular neoplasm. J Clin Endocrinol Metab. May 2007;92(5):1630-1634. 17. Sebastianes FM, Cerci JJ, Zanoni PH, et al. Role of 18F-fluorodeoxyglucose positron emission tomography in preoperative assessment of cytologically indeterminate thyroid nodules. J Clin Endocrinol Metab. Nov 2007;92(11):4485-4488. 18. Haugen BR, Woodmansee WW, McDermott MT. Towards improving the utility of fine- needle aspiration biopsy for the diagnosis of thyroid tumours. Clin Endocrinol (Oxf). Mar 2002;56(3):281-290. 19. Sapio MR, Guerra A, Posca D, et al. Combined analysis of galectin-3 and BRAFV600E improves the accuracy of fine-needle aspiration biopsy with cytological findings suspicious for papillary thyroid carcinoma. Endocr Relat Cancer. Dec 2007;14(4):1089- 1097. 20. Sapio MR, Posca D, Raggioli A, et al. Detection of RET/PTC, TRK and BRAF mutations in preoperative diagnosis of thyroid nodules with indeterminate cytological findings. Clin Endocrinol (Oxf). May 2007;66(5):678-683. 21. Mazzaferri EL. Management of low-risk differentiated thyroid cancer. Endocr Pract. Sep 2007;13(5):498-512. 22. Udelsman R, Shaha AR. Is total thyroidectomy the best possible surgical management for well-differentiated thyroid cancer? Lancet Oncol. Jul 2005;6(7):529-531. 23. Pitt SC, Sippel RS, Chen H. Contralateral papillary thyroid cancer: does size matter? Am J Surg. Mar 2009;197(3):342-347. 24. Stavrakis AI, Ituarte PH, Ko CY, Yeh MW. Surgeon volume as a predictor of outcomes in inpatient and outpatient endocrine surgery. Surgery. Dec 2007;142(6):887-899; discussion 887-899. 25. Sippel RS, Chen H. Controversies in the surgical management of newly diagnosed and recurrent/residual thyroid cancer. Thyroid. Dec 2009;19(12):1373-1380. 26. Grodski S, Cornford L, Sywak M, Sidhu S, Delbridge L. Routine level VI lymph node dissection for papillary thyroid cancer: surgical technique. ANZ J Surg. Apr 2007;77(4):203-208. 27. Lim YC, Choi EC, Yoon YH, Koo BS. Occult lymph node metastases in neck level V in papillary thyroid carcinoma. Surgery. Feb;147(2):241-245. 28. Slough CM, Randolph GW. Workup of well-differentiated thyroid carcinoma. Cancer Control. Apr 2006;13(2):99-105. 29. Roh JL, Park JY, Park CI. Total thyroidectomy plus neck dissection in differentiated papillary thyroid carcinoma patients: pattern of nodal metastasis, morbidity, recurrence, and postoperative levels of serum parathyroid hormone. Ann Surg. Apr 2007;245(4):604- 610. 30. Loh KC, Greenspan FS, Gee L, Miller TR, Yeo PP. Pathological tumor-node-metastasis (pTNM) staging for papillary and follicular thyroid carcinomas: a retrospective analysis of 700 patients. J Clin Endocrinol Metab. Nov 1997;82(11):3553-3562. 31. Cobin RH, Gharib H, Bergman DA, et al. AACE/AAES medical/surgical guidelines for clinical practice: management of thyroid carcinoma. American Association of Clinical Endocrinologists. American College of Endocrinology. Endocr Pract. May-Jun 2001;7(3):202-220. 32. DeGroot LJ, Kaplan EL, McCormick M, Straus FH. Natural history, treatment, and course of papillary thyroid carcinoma. J Clin Endocrinol Metab. Aug 1990;71(2):414- 424. 33. Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med. Nov 1994;97(5):418-428. 34. Tuttle RM, Leboeuf R. Follow up approaches in thyroid cancer: a risk adapted paradigm. Endocrinol Metab Clin North Am. Jun 2008;37(2):419-435, ix-x. 35. Sawka AM, Brierley JD, Tsang RW, et al. An updated systematic review and commentary examining the effectiveness of radioactive iodine remnant ablation in well- differentiated thyroid cancer. Endocrinol Metab Clin North Am. Jun 2008;37(2):457-480, x. 36. Vaisman A, Orlov S, Yip J, et al. Application of Post-Surgical Stimulated Thyroglobulin for Radioiodine Remnant Ablation Selection in Low-Risk Papillary Thyroid Carcinoma. Head and Neck. 2010; (In Press). 37. Edmonds CJ, Hayes S, Kermode JC, Thompson BD. Measurement of serum TSH and thyroid hormones in the management of treatment of thyroid carcinoma with radioiodine. Br J Radiol. Nov 1977;50(599):799-807. 38. Pacini F, Ladenson PW, Schlumberger M, et al. Radioiodine ablation of thyroid remnants after preparation with recombinant human thyrotropin in differentiated thyroid carcinoma: results of an international, randomized, controlled study. J Clin Endocrinol Metab. Mar 2006;91(3):926-932. 39. Schlumberger M, Pacini F, Wiersinga WM, et al. Follow-up and management of differentiated thyroid carcinoma: a European perspective in clinical practice. Eur J Endocrinol. Nov 2004;151(5):539-548. 40. Links TP, van Tol KM, Jager PL, et al. Life expectancy in differentiated thyroid cancer: a novel approach to survival analysis. Endocr Relat Cancer. Jun 2005;12(2):273-280. 41. Spencer CA, Lopresti JS. Measuring thyroglobulin and thyroglobulin autoantibody in patients with differentiated thyroid cancer. Nat Clin Pract Endocrinol Metab. Apr 2008;4(4):223-233. 42. Black EG, Cassoni A, Gimlette TM, et al. Serum thyroglobulin in thyroid cancer. Lancet. Aug 29 1981;2(8244):443-445. 43. Blahd WH, Drickman MV, Porter CW, Hill VA, Baumgartner WA. Serum thyroglobulin, a monitor of differentiated thyroid carcinoma in patients receiving thyroid hormone suppression therapy: concise communication. J Nucl Med. Jun 1984;25(6):673-676. 44. Eustatia-Rutten CF, Smit JW, Romijn JA, et al. Diagnostic value of serum thyroglobulin measurements in the follow-up of differentiated thyroid carcinoma, a structured meta- analysis. Clin Endocrinol (Oxf). Jul 2004;61(1):61-74. 45. Kloos RT, Mazzaferri EL. A single recombinant human thyrotropin-stimulated serum thyroglobulin measurement predicts differentiated thyroid carcinoma metastases three to five years later. J Clin Endocrinol Metab. Sep 2005;90(9):5047-5057. 46. Castagna MG, Brilli L, Pilli T, et al. Limited value of repeat recombinant human thyrotropin (rhTSH)-stimulated thyroglobulin testing in differentiated thyroid carcinoma patients with previous negative rhTSH-stimulated thyroglobulin and undetectable basal serum thyroglobulin levels. J Clin Endocrinol Metab. Jan 2008;93(1):76-81. 47. Heemstra KA, Liu YY, Stokkel M, et al. Serum thyroglobulin concentrations predict disease-free remission and death in differentiated thyroid carcinoma. Clin Endocrinol (Oxf). Jan 2007;66(1):58-64. 48. Sawka AM, Orlov S, Gelberg J, et al. Prognostic value of postsurgical stimulated thyroglobulin levels after initial radioactive iodine therapy in well-differentiated thyroid carcinoma. Head Neck. Jun 2008;30(6):693-700. 49. Toubeau M, Touzery C, Arveux P, et al. Predictive value for disease progression of serum thyroglobulin levels measured in the postoperative period and after (131)I ablation therapy in patients with differentiated thyroid cancer. J Nucl Med. Jun 2004;45(6):988- 994. 50. Brabant G. Thyrotropin suppressive therapy in thyroid carcinoma: what are the targets? J Clin Endocrinol Metab. Apr 2008;93(4):1167-1169. 51. McGriff NJ, Csako G, Gourgiotis L, Lori CG, Pucino F, Sarlis NJ. Effects of thyroid hormone suppression therapy on adverse clinical outcomes in thyroid cancer. Ann Med. 2002;34(7-8):554-564. 52. Larson SM, Robbins R. Positron emission tomography in thyroid cancer management. Semin Roentgenol. Apr 2002;37(2):169-174. 53. Kim TH, Yang DS, Jung KY, Kim CY, Choi MS. Value of external irradiation for locally advanced papillary thyroid cancer. Int J Radiat Oncol Biol Phys. Mar 15 2003;55(4):1006-1012. 54. Ronga G, Filesi M, Montesano T, et al. Lung metastases from differentiated thyroid carcinoma. A 40 years' experience. Q J Nucl Med Mol Imaging. Mar 2004;48(1):12-19.