Thyroid Stimulating Hormone Suppression and Thyroid Cancer

Controversy exists in thyroid cancer management about the extent of surgery, the use of 131I ablation therapy, the place of thyroglobulin assay in follow-up, and the role and level of TSH suppressant treatment. Further, there is debate about the degree of TSH dependence of differentiated thyroid carcinomas and the importance of other thyroid growth factors.

Thyroid Growth Factors and Thyroid Carcinoma

Thyroid tumors vary markedly in prognosis, and the natural history of differentiated tumors is long. The control of thyroid cell growth is complex and is influenced by many hormones and growth factors operating through distinctly different cell signal transduction systems. Classically, TSH is considered the major thyroid growth hormone, and, although there is no dispute about its role in stimulating thyroid gland function, its effects on thyroid growth and particularly abnormal growth are in question. TSH stimulates "differentiated" thyroid functions, most notably iodine uptake and organification as well as thyroglobulin synthesis, by activating a membrane-bound adenylate cyclase system and increasing intracellular cyclic adenosine monophosphate; this results in cytoplasmic protein phosphorylation and increased nuclear transcription.177 In general, follicular thyroid neoplasms have enhanced adenylate cyclase activity in response to TSH stimulation and tend to have an inverse correlation with the state of aggressiveness of the tumor.178 It is also evident that TSH functions through the phosphatidyl inositol phosphokinase C-intracellular calcium system because it is known that high dietary calcium, particularly in areas of endemic iodine deficiency, promotes goiter formation.179180 Elevated levels of TSH promote thyroid tumors in rats, and these tumors can be prevented by treating with thyroid hormone (TSH suppression).181

TSH is generally considered a relatively weak factor for human thyroid cell growth in tissue culture.182 The cells tend to be very heterogeneous in their response,183 and transplanted human thyroid tumors ultimately demonstrate TSH independence in vitro.165 The fact remains that thyroid tumor tissue has demonstrable TSH receptor sites, although the importance of these sites clinically is another matter.184

The list of known thyroid growth factors is quite long (Table 8-5) and includes TSIs, epidermal growth factor, epidermal growth factor receptor (EGFr), insulin-like growth factors, and prostaglandin E2. Inhibitors of thyroid growth in vitro include transforming growth factor somatostatin, and vitamin A.185187

EGF functions as a powerful thyroid growth stimulant, possibly more active than TSH and perhaps acting synergisti-cally with TSH, promoting cell growth but inhibiting cellular differentiated functions.188,189 Further, EGFr expression has been shown to be associated with reduced disease-free survival in differentiated tumors.190,191

Thyroid cell proliferation is further affected by growth-promoting oncogenes and inhibited by tumor suppressor genes.

TABLE 8-5. Putative Factors Affecting Thyroid Growth

Stimulators Inhibitors

TSHi82.i83 Transforming growth

Thyroid-stimulating factor-ß185

immunoglobulins111113 Vitamin A1B7

Epidermal growth factor196196 Insulin-like growth factors Growth hormone

Platelet-derived growth factor201202 Prostaglandin E2 Oncogenes c-erb B2192

Epidermal growth factor receptor188'189 c-myc194196 c-fos ras196,197

TSH = thyioid-stimujating hormone.

Their protein products presumably replace known specific growth regulators, growth factor receptors, and signal transducers. TSIs and fibroblast growth factor function as circulating growth factors. The protooncogene c-erb B2 (HER-2/new) is a plasma membrane receptor and the ras oncogene a signal transducer for thyroid growth.192 c-erb B2 is a surface growth receptor that has been shown to be frequently overexpressed in a proportion of breast and ovarian cancers and to correlate with poor prognosis.193

Oncogenes, whether natural (protooncogenes) or viral, encode protein products, which act in either the nucleus or cytoplasm. Both ras and c-myc oncogenes are overexpressed in about 60% of differentiated thyroid neoplasms; prognosis is worse in the cases in which c-myc is heavily encoded.194195 Frauman, Lemoine, Wyllie, and Clark196'200 and their colleagues have discussed the subject in great depth. Both the tumor suppressor gene p53, which has been heavily implicated in the tumorigenesis of colorectal carcinoma, and platelet-derived growth factor have been found to be overexpressed in anaplastic tumors.201-202 It is evident then that TSH suppression in thyroid cancer is likely to have only a partial role in tumor control, perhaps similar to that of tamoxifen therapy in women with breast cancer.

Thyroid-Stimulating Hormone Suppressive Therapy in Thyroid Cancer

TSH suppressive therapy was first advocated for thyroid carcinoma by Dunhill in 1937203 and was used extensively in the treatment of disseminated differentiated thyroid cancer by Crile.204 The rationale for its use has subsequently been the demonstration of TSH receptors in malignant tissue from differentiated thyroid cancers of follicular cell origin and the noted increase in adenylate cyclase activity in response to TSH stimulation in vitro.205,206 Thyroid tumors, however, that already have increased basal TSH adenylate cyclase activity are unlikely to be particularly responsive to TSH suppression.207

It is clear that 80% of patients with papillary thyroid cancer and many cases of follicular thyroid cancer do well almost regardless of how they are treated.208,209 TSH suppression has been shown to date to have no proven benefit in patients with medullary thyroid carcinoma.

The use of TSH suppressive therapy has to show survival advantage over prolonged follow-up for the patients deemed to have poor prognoses and, in view of the potential side effects of long-term suppressive treatment, it seems sensible to individualize its use on the basis of expected likelihood of local or systemic recurrence. Factors associated with a particularly poor prognosis in differentiated thyroid cancer include poor 131I uptake (such as Hiirthle cell variants),210 decreased adenylate cyclase response to TSH,178 DNA aneuploidy,211 the expression of EGFr,191 and the extent of initial surgical treatment.212 This has been complemented by the AGES classification devised by Hay and colleagues to classify patients as high risk and low risk on the basis of age, histologic grade, extent of primary tumor, and primary size.213 Notably, patients older than 40 years at diagnosis with tumors larger than 4 cm with marked DNA aneuploidy have been shown to have markedly worse disease-free and overall survival.214

In this sense, it is advocated that TSH suppressive therapy should be adjusted to individual prognostic factors to avoid unnecessary radical surgery, radiation exposure, and the costs associated with monitoring patients at minimal risk for recurrent disease.

The use of TSH suppression is very much aligned with the view that differentiated thyroid carcinoma should be treated by total thyroidectomy. The advantage of total thyroidectomy in such cases is to permit both diagnostic and, where appropriate, ablative radioactive 131I to be administered without the problem of a competing thyroid lobe as well as to diminish the likelihood of troublesome recurrence in the central neck, which is difficult to treat and whose surgical therapy is fraught with considerable morbidity.215,216 Other advantages of total thyroidectomy in this setting include the removal of the contralateral lobe, which has as much as an 80% chance of containing a microscopic focus of carcinoma,217 as well as the elimination of the very small risk of a differentiated tumor dedifferentiating into an anaplastic cancer.218 Total thyroidectomy permits better potential ablation of metastatic disease and allows serum thyroglobulin levels to be more reflective of recurrence.

The evidence for T4 treatment actually improving survival in differentiated carcinoma is at best uncontrolled. Mazzaferri219,220 and Massin221 and their coworkers showed the best long-term survival in the patients treated by total thyroidectomy, ablative radioiodine, and deliberate TSH suppression. A beneficial effect has been reported in both papillary and follicular cancer,222 in papillary cancer alone,220 and in neither.223 The most convincing evidence comes from Mazzaferri, who was able to show a cumulative recurrence rate for papillary carcinoma of 17% for patients receiving T4 compared with 34% when no T4 was used over a 10-year follow-up period.224 This retrospective series was neither controlled nor randomized. However, another large study failed to show any improvement in survival with thyroid hormone therapy.225

T4 is probably tumor static and not tumoricidal. The dose requirements and level of required TSH suppression are simply not known.226 No study has documented conclusively the optimal degree of TSH suppression, and patients' compliance is an issue that remains largely unexplored.

Because of the heterogeneity of thyroid cancers, their variable prognostic indicators, the required length of follow-up needed to demonstrate survival advantage, and a general failure to record uniformly both the presence and extent of TSH suppression, it seems unlikely that such a controlled, randomized, prospective trial assessing the value of levothyroxine, particularly in carcinoma subgroups, will ever be conducted.223

Suppression of TSH to less than 0.1 mU/L is recommended. The average daily dose of T4 to achieve this level of suppression is usually 2.2 to 2.5 p.g/kg. Because low-risk cases represent about 75% of all patients227 and the incidence of local recurrence is greatest within the first 5 years after thyroidectomy,214 it is recommended that high-level TSH suppression be used for this initial period, allowing the TSH concentration to rise to between 0.1 and 0.3 mU/L if no recurrences are demonstrable at 5 years.

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