Conclusion

For the patient who presents with a nodule, the main concern is to exclude the possibilityof thyroid cancer, even though the vast majority of nodulesare benign. The initial evaluation should include measurement of the serum thyrotropin level and a fine-needle aspiration, preferably guided by ultrasonography. If the patienthas a family history of medullary thyroid carcinoma or multipleendocrine neoplasia type 2, the serum calcitonin level shouldalso be checked. If the thyrotropin level is suppressed, radionuclidescanning should be performed. In patients less than 20 yearsold and in the case of a high clinical suspicion for cancer(e.g., follicular neoplasia as diagnosed by fine-needle aspiration and a non-functioning nodule revealed on scanning), the patient should be offered hemithyroidectomy regardless of the resultsof fine-needle aspiration.

REFERENCES TO SECTION 3

[3.1] HEGEDÜS, L., BONNEMA, S.J., BENNEDBÆK, F.N., Management of simple nodular goiter: Current status and future perspectives, Endocr Rev 24 (2003) 102-132.

[3.2] BENNEDBÆK, F.N., PERRILD, H., HEGEDÜS, L., Diagnosis and treatment of the solitary thyroid nodule: Results of a European survey, Clin Endocrinol (Oxf) 50 (1999) 357-363.

[3.3] BENNEDBÆK, F.N., HEGEDÜS, L., Management of the solitary thyroid nodule:

Results of a North American survey, J Clin Endocrinol Metab 85 (2000) 2493-2498.

[3.4] SINGER, P.A., COOPER, D.S., DANIELS, G.H., et al., Treatment guidelines for patients with thyroid nodules and well-differentiated thyroid cancer, Arch Intern Med 156 (1996) 2165-2172.

[3.5] WONG, C.K.M, WHEELER, M.H., Thyroid nodules: Rational management, World J Surg 24 (2000) 934-941.

[3.6] KUMA, K., MATSUZUKA, F., KOBAYASHI, A., et al., Outcome of long standing solitary thyroid nodules, World J Surg 16 (1992) 583-587.

[3.7] BENNEDBÆK, F.N., NIELSEN, L.K., HEGEDÜS, L., Effect of percutaneous ethanol injection therapy vs. suppressive doses of L-thyroxine on benign solitary solid cold thyroid nodules: A randomised trial, J Clin Endocrinol Metab 83 (1998) 30-35.

[3.8] ALEXANDER, E.K., HURWITZ, S., HEERING, J.P., et al., Natural history of benign solid and cystic thyroid nodules, Ann Intern Med 138 (2003) 315-318.

[3.9] PAPINI, E., GUGLIELMI, R., BIANCHINI, A., et al., Risk of malignancy in nonpalpable thyroid nodules: Predictive value of ultrasound and color-Doppler features, J Clin Endocrinol Metab 87 (2002) 1941-1946.

[3.10] ITO, Y., URUNO, T., NAKANO, K., et al., An observation trial without surgical treatment in patients with papillary microcarcinoma of the thyroid, Thyroid 13 (2003) 381-387.

[3.11] JARLØV, A.E., NYGAARD, B., HEGEDÜS, L., HART-LING, S.G., HANSEN, J.M., Observer variation in the clinical and laboratory evaluation of patients with thyroid dysfunction and goiter, Thyroid 8 (1998) 393-398.

[3.12] HEGEDÜS, L., Thyroid ultrasound, Endocrinol Metab Clin North Am 30 (2001) 339-360.

[3.13] HAMMING, J.F., GOSLINGS, B.M., VAN STEENIS, F.J., et al., The value of fine-needle aspiration biopsy in patients with nodular thyroid disease divided into groups of suspicion of malignant neoplasms on clinical grounds, Arch Intern Med 150 (1990) 113-116.

[3.14] BISWAL, B.M., BAL, C.S., SANDHU, M.S., PADHY, A.K., RATH, G.K., Management of intracranial metastases of differentiated carcinoma of thyroid, J Neurooncol 22 (1994) 77-81.

[3.15] MAZZAFERRI, E.L., An overview of the management of papillary and follicular thyroid carcinoma, Thyroid 9 (1999) 421-427.

[3.16] SAMAAN, N.A., SCHULTZ, P.N., HICKEY, R.C., et al., The results of various modalities of treatment of well differentiated thyroid carcinomas: A retrospective review of 1599 patients, J Clin Endocrinol Metab 75 (1992) 714-720.

[3.17] DEGROOT, L.J., KAPLAN, E.L., MCCORMICK, M., STRAUS, F.H., Natural history, treatment, and course of papillary thyroid carcinoma, J Clin Endocrinol Metab 71 (1990) 414-424.

[3.18] SIMPSON, W.J., PANZARELLA, T., CARUTHERS, J.S., GOSPADOROVICH, M., SUTCLIFFE, S.P., Papillary and follicular thyroid cancer prognostic factors in 1578 patients, Am J Med 83 (1987) 479-488.

[3.19] FRANSILA, K., Is differentiation between papillary and follicular thyroid cancer valid? Cancer 32 (1973) 853-864.

[3.20] EZAKI, H., Analysis of thyroid carcinoma based on materials registered in Japan during 1977-86, Cancer 70 (1992) 808-814.

[3.21] SAMUEL, A.M., SHAH, D.H., “Clinical presentation of thyroid cancer”, Thyroid Cancer: An Indian Perspective, Quest Publications (1999) 77-90.

[3.22] BAL, C.S., “Radioiodine therapy in thyroid cancer: AIIMS experience”, A Monograph on Thyroid Cancer (MISHRA S.K., Ed.), JICA Publication, Lucknow (1997) 179-189.

[3.23] OGBAC, R., OBALDO, J., CRUZ, F., A review of current applications of ¹³¹I for thyroid cancer therapy at the UP-PGH – A five year study, unpublished data (2001).

4. THYROGLOBULIN

Thyroglobulin is a large (660 kd) homodimeric glycoprotein molecule, encoded by a gene on chromosome 8 that is secreted uniquely by thyroid follicular cells [4.1]. The factors controlling Tg gene expression include thyrotropin (TSH), insulin and insulin-like growth factor-l (IGF-l), which act synergistically to stimulate transcription of the 8.5 kilobase (kb) Tg mRNA, whereas epidermal growth factor (EGF), interferon-γ, tumour necrosis factor (TNF-α), and retinoic acid are inhibitors of transcription [4.2-4.8]. Thyroglobulin is synthesized in the endoplasmic reticulum, modified in the golgi apparatus, and transported to the colloid for storage. The formation of mature Tg requires complex processing that involves dimerization and folding, glycosylation and modification, followed by incorporation into exocytotic vesicles for export into the lumen of thyroid follicles, after which thyroid peroxidase catalyses iodination of tyrosyl residues. (Tg gets iodinated at the apical membrane of the cell where a conformational change takes place depending upon the iodine content) and coupling of some of them within the Tg polypeptide to form thyroxine (T4) and triiodothyronine (T3) [4.9-4.12].

Synthesis and secretion of Tg is regulated by TSH as is evident from studies in humans where exogenous injection of TSH or endogenously raised TSH after administration of thyrotropin releasing hormone results in a rise in serum Tg level. Moreover, the administration of thyroid hormones results in lowering of Tg levels with a concomitant fall in TSH level.

Thyroglobulin in thyroid tissue and serum is heterogeneous [4.13]. All the steps involved in post-translational processing can affect the ultimate conformation and immunoreactivity of Tg. Antibodies used in Tg immunoassays are conformational, that is, directed against discontinuous regions of the protein [4.14]. Conformational differences in Tg arising from differences in its composition of carbohydrate [4.15, 4.16] or iodine [4.17, 4.18] can expose or mask epitopes [4.19] and cause antibody-dependent differences in immunoactivity [4.20, 4.21]. Some monoclonal antibodies detect differences between the Tg isoforms present in the glandular extracts used for assay standardization as compared with Tg isoforms in the circulation [4.20]. This can have clinical consequences when using serum Tg as a marker for thyroid carcinomas that secrete conformationally abnormal Tg molecules [4.19, 4.20, 4.22].

The processes involved in the release of Tg into and clearance from the circulation are poorly understood. Tg in the follicular lumen is internalized by micropinocytosis and undergoes proteolytic cleavage in lysosomes, a process that liberates T4 and T3 while degrading 90% or more of the Tg molecules [4.23-4.25]. Undigested Tg enters the circulation via thyrolymphatic system by a poorly understood mechanism, either because lysosomal hydrolysis is incomplete or as a result of short-loop secretion that does not involve luminal storage [4.26]. The latter may represent the major route of secretion by thyroid carcinomas in which both glandular and circulating forms of Tg are poorly iodinated.

During steady-state conditions, the serum Tg concentration is determined by the balance between its secretion and metabolism. The mechanisms for clearing Tg from the circulation are poorly understood, but they are thought to be influenced by the sialic acid content of the molecule; its presence appears to facilitate clearance. Hepatocytes are thought to mediate most extrathyroidal Tg metabolism; Tg binds to B-lymphocytes and other cells, but the metabolic importance of this binding is unclear. In normal subjects the secretion rate and plasma half-life of Tg are 100 mg/60 kg/day and 29.6+2.8 hours, respectively. In general, 1 g of normal thyroid tissue results in a serum Tg of approximately 1 µg/litre when the TSH is in the normal range and about 0.5 µg/litre when TSH is suppressed [4.27]. The half-life after thyroidectomy is shorter in patients with Graves' disease or differentiated thyroid carcinoma and longer in patients with nodular goitre. The different Tg half-life estimates, ranging from

2.5 hours to 6 days may be due to variations in clearance resulting from release of Tg molecules of different size or sialic acid content [4.16]. In addition, there may be differences in immunoreactivity between the exogenously administered Tg preparations used for some clearance studies as compared with endogenous Tg measured in the post-thyroidectomy studies. In the case of Graves' disease, it is postulated that formation of Tg-TgAb complexes might increase Tg clearance.