ABSTRACT

Multinodular goiter (MNG) is the most common of all the disorders of the thyroid gland. MNG is the result of the genetic heterogeneity of follicular cells and apparent acquisition of new cellular qualities that become inheritable. Nodular goiter is most often detected simply as a mass in the neck, but sometimes an enlarging gland produces pressure symptoms. Hyperthyroidism develops in a large proportion of MNGs after a few decades, frequently after iodine excess. Diagnosis is based on the physical examination. Thyroid function test results are normal, or indicate subclinical or overt hyperthyroidism. Imaging procedures are useful to detect details such as distortion of the trachea, and to provide an estimation of the volume before and after therapy. From 4 to 17% of MNGs fulfill the criteria of malignant change, however, the majority of these lesions are not lethal. If a clinical and biochemically euthyroid MNG is small and produces no symptoms, treatment is controversial. T4 given to shrink the gland or to prevent further growth is effective in about one third of patients. If the clinically euthyroid goiter is unsightly, shows subclinical hyperthyroidism or is causing pressure symptoms, treatment with ¹³¹I preceded by recombinant human TSH is successful but causes hypothyroidism in varying degrees. This treatment can lead to 45-65% shrinkage of the MNG, even if in an intrathoracic position, with a relatively low cost, thus it is considered a good alternative to surgery. However, surgery is an acceptable option. The efficacy of T4 treatment after surgery, to prevent regrowth, is debatable although frequently usedt. For complete coverage of all related aeas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

The normal thyroid gland is a fairly homogenous structure, but nodules often

form within its substance. These nodules may be only the growth and fusion of localized colloid-filled follicles, or more or less discrete adenomas, or cysts. Nodules larger than 1 cm may be detected clinically by palpation. Careful examination discloses their presence in at least 4% of the general population. Nodules less than 1 cm in diameter not clinically detectable unless located on the surface of the gland, are much more frequent. The terms adenomatous goiter, nontoxic nodular goiter, and colloid nodular goiter are used interchangeably as descriptive terms when a multinodular goiter is found.

INCIDENCE

The incidence of goiter, diffuse and nodular, is very much dependent on the status of iodine intake of the population. In areas of iodine deficiency, goiter prevalence may be very high and especially in goiters of longstanding, multinodularity develops frequently (Figure 17-1). The incidence of multinodular goiter in areas with sufficient iodine intake has been documented in several reports (1-10). In a comprehensive population survey of 2,749 persons in northern England, Tunbridge et al (1) found obvious goiters in 5.9% with a female/male ratio of 13:1. Single and multiple thyroid nodules were found in 0.8% of men and 5.3% of women, with an increased frequency in women over 45 years of age. Routine autopsy surveys and the use of sensitive imaging techniques produce a much higher incidence. In three reports nodularity was found in 30% to 50% of subjects in autopsy studies, and in 16% to 67% in prospective studies of randomly selected subjects on ultrasound (2). In Framingham the prevalence of multinodular goiter as found in a population study of 5234 persons over 60 years was 1% (3). Results from Singapore show a prevalence of 2.8% (4). In an evaluation in 2,829 subjects, living in southwestern Utah and Nevada (USA, between 31 and 38 years) of age, 23% had non-toxic goiter, including 18 single nodules, 3 cysts, 38 colloid goiters and 7 without a histological diagnosis. No mention was made of multinodular goiters, although some might have been present in the colloid and unidentified group (5). In general, in iodine sufficient countries the prevalence of multinodular goiter is not higher than 4% (6). In countries with previous deficiency that was corrected by universal salt iodination, elderly subjects may have an incidence of, approximately, 10% of nodular and multinodular goiter, attributed to lack of nutritional iodine in early adult life (7).

ETIOLOGY

The first comprehensive theory about the development of multinodular goiter was proposed by David Marine (8) and studied further by Selwyn Taylor (9), and can be considered one of the classics in this field. Nodular goiter may be the result of any chronic low-grade, intermittent stimulus to thyroid hyperplasia. Supporting evidence for this view is circumstantial. David Marine first developed the concept, that in response to iodide deficiency, the thyroid first goes through a period of hyperplasia as a consequence of the resulting TSH stimulation, but eventually, possibly because of iodide repletion or a decreased requirement for thyroid hormone, enters a resting phase characterized by colloid storage and the histologic picture of a colloid goiter. Marine believed that repetition of these two phases of the cycle would eventually result in the formation of nontoxic multinodular goiter (8). Studies by Taylor of thyroid glands removed at surgery led him to believe that the initial lesion is diffuse hyperplasia, but that with time discrete nodules develop (9).

By the time the goiter is well developed, serum TSH levels and TSH production rates are usually normal or even suppressed (10). For example, Dige-Petersen and Hummer evaluated basal and TRH-stimulated serum TSH levels in 15 patients with diffuse goiter and 47 patients with nodular goiter (11). They found impairment of TRH-induced TSH release in 27% of the patients with nodular goiter, suggesting thyroid autonomy, but in only 1 of the 15 with diffuse goiter. Smeulers et al (12), studied clinically euthyroid women with multinodular goiter and found that there was an inverse relationship between the increment of TSH after administration of TRH, and size of the thyroid gland (Figure 17-1). It was also found that, while being still within the normal range, the mean serum T3 concentration of the group with impaired TSH secretion was significantly higher than the normal mean, whereas the mean value of serum T4 levels was not elevated (12). These and other results (13) are consistent with the hypothesis that a diffuse goiter may precede the development of nodules. They are also consistent with the clinical observation that, with time, autonomy may occur, with suppression of TSH release, even though such goiters were originally TSH dependent.

Figure 17-1

Relationship of TSH (after 400 mg TRH i.v.) and thyroid weight (g) in 22 women with clinically euthyroid multinodular goiter (with permission ref. 12)

Comprehensive reviews about insights into the evolution of multinodular goiter have been published by Studer and co-workers (14-16). An adapted summary of the major factors that are discussed is presented in Table 17-1 and will be referred to in the discussion that follows.

Table 17-1. Factors that may be involved in the evolution of multinodular goiter.

PRIMARY FACTORS

• Functional heterogeneity of normal follicular cells, most probably due to genetic and acquisition of new inheritable qualities by replicating epithelial cells. Gender (women) is an important factor.

• Subsequent functional and structural abnormalities in growing goiters.

SECONDARY FACTORS

• Elevated TSH (induced by iodine deficiency, natural goitrogens, inborn errors of thyroid hormone synthesis)

• Smoking, stress, certain drugs

• Other thyroid-stimulating factors (IGF-1 and others)

• Endogenous factor (gender)

PRIMARY FACTORS

Genetic heterogeneity of normal follicular cells and acquisition of new inheritable qualities by replicating epithelial cells. (Figure 17-2).It has been shown cells of many organs, including, the thyroid gland, are often polyclonal, rather than monoclonal of origin. Also from a functional aspect it appears that through developmental processes the thyroid epithelial cells forming a follicle are functionally polyclonal and possess widely differing qualities regarding the different biochemical steps leading to growth and to thyroid hormone synthesis like e.g. iodine uptake (and transport), thyroglobulin production and iodination, iodotyrosine coupling, endocytosis and dehalogenation. As a consequence there is some heterogeneity of growth and function within a thyroid and even within a follicle Studer et al (14-16) demonstrated the existence of monoclonal and polyclonal nodules in the same multinodular gland. They analyzed 25 nodules from 9 multinodular goiters and found 9 to be polyclonal and 16 monoclonal. Three goiters contained only polyclonal nodules and 3 contained only monoclonal nodules. In 3 goiters poly- and monoclonal nodules coexisted in the same gland (17).

Figure 17-2

Heterogeneity of morphology and function in a human multinodular goiter. Autoradiographs of two different areas of typical multindular euthyroid human goiter excised after administration of radioiodine tracer to the patient. There are enormous differences of size, shape and function among the individual follicles of the same goiter. Note also that there is no correlation between the size or any other morphological hallmark of a single follicle and its iodine uptake. (with permission ref.15).

Newly generated cells may acquire qualities not previously present in mother cells. These qualities could subsequently be passed on to further generations of cells. A possible example of this process is the acquired abnormal growth pattern that is reproduced when a tissue sample is transplanted into a nude mouse (16). Other examples are acquired variable responsiveness to TSH (13). These changes may be related to mutations in oncogenes which do not produce malignancy per se, but that can alter growth and function. An example of acquisition of genetic qualities is the identification in the last few years of constitutively activating somatic mutations not only in solitary toxic adenoma, but also in hyperfunctioning nodules of toxic multinodular goiters (18). So far these mutations in MNG have only been found in the TSH-receptor (TSHR) gene, and not in the Gs-alpha gene. Different somatic mutations are found in exon 9 and 10 of the TSHR gene and the majority of mutations that are present in toxic adenomas are also found in toxic nodules in multinodular goiter (19-21).

SECONDARY FACTORS

The secondary factors discussed below stimulate thyroid cell growth and / or function and, because of differences in cellular responsiveness that are presumed to exist, aggravate the expression of heterogeneity which leads to further growth and focal autonomic function of the thyroid gland. Local necrosis, cyst formation sometimes with bleeding and fibrosis may be the anatomical end stage of such processes (Figure 17-3).

Figure 17-3

Mild iodine deficiency associated or not with smoking, presence of natural goitrogenic, drugs, familial goiter, genetic markers and gender (women) will decrease the inhibition of serum T4 on the pituitary thyrotrophs. Increased TSH production will cause diffuse goiter followed by nodule formation. Finally, after decades of life, a large multinodular goiter is present with cystic areas, hemorrhage, fibrosis and calcium deposits.

Iodine Deficiency

Stimulation of new follicle generation seems to be necessary in the formation of simple goiter. (Figure 17-3) Evidence accumulated from many studies indicates that iodine deficiency or impairment of iodine metabolism by the thyroid gland, perhaps due to congenital biochemical defects, may be an important mechanism leading to increases in TSH secretion (30,53). Since in experimental animals the level of iodine per se may modulate the response of thyroid cells to TSH, this is an additional mechanism by which relatively small increases in serum TSH level may cause substantial effects on thyroid growth in iodine-deficient areas (53). It was found that the thyroidal iodine clearance of patients with nontoxic nodular goiter was, on overage, higher than that in normal persons (Fig. 17-3). This finding was interpreted as a reflection of a suboptimal iodine intake by such patients. When data published from various major cities in Western Europe, regarding thyroid volume and iodine excretion are put together (54) and inverse relation is found between urinary iodine excretion and thyroid volume (Fig. 17-4). Physiologic stresses, such as pregnancy, may increase the need for iodine and require thyroid hypertrophy to increase iodine uptake that might otherwise satisfy minimal needs. An elevated renal clearance of iodine occurs during normal pregnancy (24). It has been suggested that in some patients with endemic goiter there are similar increases in renal iodine losses (53). Increased need for thyroxin during pregnancy may also lead to thyroid hypertrophy when iodine intake as limited. Iodide need in pregnancy is increased by increased iodide loss through the kidneys, but also because of significant transfer of thyroid hormone from the mother to the fetus (24). In areas of moderate iodine intake, thyroid volume increase is predominantly affected by a higher HCG serum concentration during the first trimester of pregnancy, and by a slightly elevated serum TSH level present at delivery (24). Finally mutations in the thyroglobulin gene may impair the efficiency of thyroid hormone synthesis and release, leading to a decreased rate of inhibition of TSH at pituitary level. The relatively high TSH released from the thyrotrophs will continuously stimulate the thyroid gland growth (55).

Figure 17-4Relationship between nontoxic goiter and thyroidal iodine clearance.

Figure 17-5Correlation between thyroid volume and urinary iodine excretion in normal population from various areas.

Inherited defects in thyroid hormone synthesis and resistance to thyroid hormone action

Inherited goiter and congenital hypothyroidism were first described by Stanbury and associated (30) in two goitrous siblings with defective thyroperoxidase action resulting in impaired iodine organification. Both siblings were mentally retarded and had enormous multinodular goiters. In the next fifty years a number of genetic defects in every step of thyroid hormone synthesis have been described in detail. If not diagnosed at birth the impaired thyroid hormone synthesis would result in an elevated TSH secretion and diffuse goiter could progressively appears. Other factors might be of importance regarding goiter formation. The level of nutritional iodine seems to be quite important in patients with the defective sodium iodine symporter (NIS), thyroglobulin gene mutations and the defective dehalogenase system (DEHAL gene). If a relatively high intake of iodine is provided goiter formation may be slowed down to a certain extent. On the contrary in marginally low nutritional iodine intake goiter will progress to a very large size and nodules will appear (multinodular goiter). It has been proposed that mutations of certain genes involved in thyroid hormone synthesis that do not entirely affect the physiological action of the translated protein may cause goiter later on life and more frequently in women (55). Thus the variable phenotype resulting from genetically documented mutations may be quite variable depending on environmental factors (iodine). Individual adaptation to the defective protein, rapid hydrolysis of defective TG, serum level of TSH and response of the thyroid epithelial cells to the growth-promoting effect of TSH are other factors to be considered.

It is conceivable that multinodular goiter could result from a defect in any step of thyroid hormone synthesis, and to resistance to thyroid hormone action. In both groups of defects in the thyroid hormone system serum TSH would be elevated and goiter would be the logical consequence of a prolonged stimulation to growth. In the context of other factor that might induce multinodular goiters the defective thyroid hormone system and resistance to thyroid hormone action are relatively rare conditions as compared to other factors.

IOD Iodine organification defect; PIOD: Partial IOD;TIOD: Total IOD; RAI: radioactive iodine. Source: modified from “Genetic causes of dyshormonogenesis. Grasberger and Refetoff, 2011.

PATHOLOGY

Although it is rare to obtain pathological examination of thyroid glands in the early phase of development of multinodular goiters, such glands should show areas of hyperplasia with considerable variation in follicle size. The more typical specimen coming to pathologists is the goiter that has developed a nodular consistency. Such goiters characteristically present a variegated appearance, with the normal homogeneous parenchymal structure deformed by the presence of nodules (Figure 17-6). The nodules may vary considerably in size (from a few millimeters to several centimeters); in outline (from sharp encapsulation in adenomas to poorly defined margination for ordinary nodules); and in architecture (from the solid follicular adenomas to the gelatinous, colloid-rich nodules or degenerative cystic structures). The graphic term “Puddingstone goiter” has been applied. Frequently the nodules have degenerated and a cyst has formed, with evidence of old or recent hemorrhage, and the cyst wall may have become calcified. Often there is extensive fibrosis, and calcium may also be deposited in these septae. Scattered between the nodules are areas of normal thyroid tissue, and often-focal areas of lymphocytic infiltration. Radioautography shows a variegated appearance, with RAI localized sometimes in the adenomas and sometimes in the paranodular tissue. Occasionally, most of the radioactivity is confined to a few nodules that seem to dominate the metabolic activity of the gland.

Figure 17-6

(A) Cross section of multinodular goiter. (B) Cross radioautograph of

The thyroid in part a. Observe the variation in 131I uptake indifferent areas.

If careful sections are made of numerous areas, 4-17% of these glands removed at surgery will be found to harbor microscopic papillary carcinoma (56-60). The variable incidence can most likely be attributed to the different criteria used by the pathologists and the basis of selection of the patients for operation by their physicians. These factors are discussed below.

NATURAL HISTORY OF THE DISEASE

Multinodular goiter is probably a lifelong condition that has its inception in adolescence or at puberty. Minimal diffuse enlargement of the thyroid gland is found in many teenage boys and girls, and is almost a physiologic response to the complex structural and hormonal changes occurring at this time. It usually regresses, but occasionally (much more commonly in girls) it persists and undergoes further growth during pregnancy. This course of events has not been documented as well as might be desired in sporadic nodular goiter, but it is the usual evolution in areas where mild endemic goiter is found.

Patients with multinodular goiter seek medical attention for many reasons. Perhaps most commonly they consult a physician because a lump has been discovered in the neck, or because a growth spurt has been observed in a goiter known to be present for a long time. Sometimes the increase in the size of the goiter will cause pressure symptoms, such as difficulty in swallowing, cough, respiratory distress, or the feeling of a lump in the throat. Rarely, an area of particularly asymmetrical enlargement may impinge upon or stretch the recurrent laryngeal nerve. Commonly the goiter is discovered by a physician in the course of an examination for some other condition. An important scenario is for the patient to seek medical attention because of cardiac irregularities or congestive heart failure, which proves to be the result of slowly developing thyrotoxicosis. (The issue is discussed more fully later in this chapter). Many times the goiter grows gradually for a period of a few too many years, and then becomes stable with little tendency for further growth. It is rare for any noteworthy spontaneous reduction in the size of the thyroid gland to occur, but patients often describe fluctuation in the size of the goiters and the symptoms they give. These are usually subjective occurrences, and more often than not the physician is unable to corroborate the changes that the patient describes. On the other hand, it could be that changes in blood flow through the enlarged gland account for the symptoms.

Occasionally, a sudden increase in the size of the gland is associated with sharp pain and tenderness in one area. This event suggests hemorrhage into a nodular cyst of the goiter, which can be confirmed by ultrasound. Within 3-4 days the symptoms subside, and within 2-3 weeks the gland may revert to its previous dimensions. In such a situation, acute thyrotoxicosis may develop and subside spontaneously.

Rarely, if ever, do the patients become hypothyroid and if they do, the diagnosis is more probably Hashimoto´s thyroiditis than nodular goiter. In a study in clinically euthyroid subjects with multinodular goiter, 13 out of 22 had subnormal TSH release after TRH. (12) If the goiter is present for long time, thyrotoxicosis develops in a large number of patients. In a series collected many years ago at the Mayo Clinic, 60% of patients with MNG over 60 were thyrotoxic. The average duration of the goiter before the onset of thyrotoxicosis was 17 years; the longer the goiter had been present the greater was the tendency for thyrotoxicosis to develop. This condition appears to occur because with the passage of time, autonomous function of the nodules develops. In a study of patients with euthyroid multinodular goiter, thyroid function was autonomous in 64 and normal in 26. After a mean follow-up of 5.0 years (maximum 12 years) 18 patients with autonomous thyroid function became overtly hyperthyroid and in 6 patients with primarily normal thyroid function autonomy developed (25-26). Thyroid function tests is illustrated in a patient with multinodular goiter starting from complete euthyroidism on to overt thyrotoxicosis. Occasionally a single discrete nodule in the thyroid gland becomes sufficiently active to cause thyrotoxicosis and to suppress the activity of the rest of the gland. (see Chap13). If these patients are given thyroid hormone, continued function of nodules can be demonstrated by radioiodine scanning techniques. Thus, these nodules have become independent of pituitary control. When patients with euthyroid multinodular goiter are frequently tested, it appears that in some of them occasional transient increases of serum T3 and / or T4 are seen. The possibility that the abrupt development of hyperthyroidism may follow administration of large amounts of iodine to these patients was reviewed by Stanbury and collaboration (61). In several areas of the world previously iodine deficiency the introduction of iodine supplementation lead to an increase of hyperthyroidism (non-autoimmune) possibly by excessive thyroid hormone production by “hot” thyroid nodules.

MULTINODULAR GOITER AND CANCER

If surgical specimens of multinodular goiters are examined carefully, 4-17% are found to harbor a carcinoma (56-60, 62-64). The use of ultrasound-guided fine needle aspiration (FNA) for evaluating these patients is not clearly defined. The biopsy of all the numerous nodules is impractical. Recently, a retrospective study with 134 patients showed a significant incidence (46,3%) of thyroid cancer in patients with multinodular goiter and benign FNA (65).These carcinomas vary widely in size and are typically of the papillary variety. Similar tumors are occasionally found in thyroid glands affected by Hashimoto´s thyroiditis and in otherwise normal glands. Bisi et al (59) reported that 13% of the glands resected in thyroid operations for any reason contained papillary adenocarcinoma. In Japan, routine autopsies of patients who were not suspected of having thyroid disease and who had no known irradiation experience, 17% were found to have small carcinomas when careful serial sections of the thyroid glands were done (62). If the figures of Bisi et al (59) were confirmed (63, 64) truly represent the prevalence of invasive carcinoma, one would certainly be forced to conclude that all multinodular goiters should be resected in order to prevent dissemination of malignant disease. However, it seems quite unlikely that all lesions that appear to satisfy the histological criteria for malignant neoplasia are potentially lethal. This view is strongly supported by the final report of the study on the significance of nodular goiter carried out in Framingham (see ref. 24). They followed for 15 years all 218 nontoxic thyroid nodules previously detected in a total population of approximately 5,000 persons. None of these lesions showed any clinical evidence of malignancy at the end of that time. Despite of the low-quality, the evidence suggests a lower prevalence of thyroid caner in multinodular goiter compared to single nodules, particularly in iodine-deficient areas (66, 67).

A strong case can be made for the view that there is only minimal risk from carcinoma in multinodular goiter. The prevalence of clinical nodularity of the thyroid is at least 4%, or 40,000 per 1,000,000 populations. Use of a much higher figure can be justified by the autopsy studies described above. Despite the high frequency of nodular goiter, only 36-60 thyroid tumors appear per 1,000,000 persons each year or by analysis of reported statistics on thyroid surgical specimens (57-60). A recent national cancer survey in the United States found an incidence of 40 per 1,000,000. An overview of the incidence of thyroid cancer in 409 countries, both with and free of endemic goiter was reported previously (58). The range of incidence varied between 7.5 and 56 per 1,000,000 persons each year. The prevalence of significant thyroid carcinoma at routine autopsy is less than 0.1% and persons with this type of tumor are probably examined as frequently as are those with other forms of neoplasia. The United States mortality figures for thyroid carcinoma are constant at about 6 per 10-6 population each year. Riccabona also summarized death rates from thyroid cancer in non-endemic and in endemic countries. (64) For Austria this was 16 per 10-6 per year in 1952 and 10 per 10-6 per year in 1983. For Switzerland this was in 1952, 18 per 10-6 per year and in 1979, 9 per 10-6 per year. The death rate per year for the United States in 1979 was 3 per 10-6, for Israel in 1952 1 per 10-6 per year and for the UK 7 per 10-6 in 1963. Death rates from thyroid cancer in endemic goiter areas from regions in Austria, Yugoslavia, Finland and Israel were between 10 and 16 per 10-6 per year between 1980 and 1984.

Lastly, it should be recognized that meticulous examination of autopsy specimens from persons dying of nonthyroid disease may show small (less than 0.5 cm) papillary lesions in4-24% of human thyroid glands (63,64). A report of 1020 sequential autopsies revealed the presence of microscopic papillary carcinoma in 6%. (60) Although the prevalence of this type of lesion increases with age, there is no question that such lesions may be present even in younger persons. The proportion of these lesions that even become clinically apparent is unknown, but their presence in otherwise normal thyroid glands should be kept in mind when evaluating reports of similar prevalences of thyroid carcinoma in multinodular thyroid glands.

If 4% of patients with nodular goiter actually have thyroid carcinoma, the prevalence of tumor in the general population would be 1,600 per 1,000,000. It is remarkable that only about 25 of these 1,600 hypothetical tumors would become apparent each year, or that only about 10 would prove fatal. Thus, there appears to be a gross discrepancy between the mortality form thyroid carcinoma and its reported frequency in surgical specimens of multinodular goiters. Reasonable arguments can be mustered in an effort to reconcile the information. Perhaps the most important single factor is selection. Persons with nodular goiter who come to operation are not representative of the general population but are patients with clinically significant thyroid disease who have been selected by their physicians for thyroid surgery. One of the factors controlling the selection process is the suspicion of malignant tumor. In fact, the selection process is especially good, as reflected by the high recovery of malignant thyroid tumors in patients operated on with this presumptive diagnosis. A second factor is that the histologic diagnosis of thyroid carcinoma may not correlate well with true invasiveness. It is impossible to prove this thesis, but pathologists agree that the criteria for judging malignancy are variable and that it is exceedingly difficult to predict with any degree of certainty the growth potential of a particular thyroid lesion.

Other arguments may be used to defend a conservative therapeutic position. In the first place, the tumors that are usually found in multinodular goiters are papillary tumors, and their degree of invasiveness is low. Indeed, the survival rate for intrathyroid papillary carcinoma is only slightly less than that for normal persons of the same age and sex (69-74). Furthermore, prophylactic subtotal thyroidectomy is not a guarantee of protection from cancer arising in a nodular goiter, since the process is usually diffuse, and it may be assumed that abnormal tissue is left in the neck after operation. In fact, unless replacement therapy is given, partial thyroidectomy might be expected to induce a tremendous growth stimulus in the remaining gland (75-80). A further point is that thyroidectomy, even in the best of hands, carries its own risk and its own morbidity, with dimensions comparable to those of missing a small papillary carcinoma within a multinodular goiter (81-84). Obviously this last possibility does not apply when a focus of unusual induration or rapid growth rate is detected clinically.

Treatment of multinodular goiter

In the past iodine supplementation seems to be an adequate approach because goiter development is associated with mild iodine deficiency in many countries worldwide. The effect of iodine once a multinodular goiter has developed a limited value in reducting the MNG. A major problem of iodine supplementation is the risk for inducing subclinical / clinical hyperthyroidism (Jod-Basedow). Therefore aside from a few European Countries iodine is no longer used alone or associated with L-T4 to treat thyroid enlargement (24).

This leaves in essence three modalities of therapy:

(1). L-T4 suppressive therapy

(2). Radioiodine (¹³¹I) alone or preceded by rhTSH

(3). Surgery

The use of rhTSH for improving ¹³¹I therapy of nontoxic multinodular goiter

(1). Increased uptake and goiter volume reduction

In recent years, pretreatment with rhTSH has been used in patients with MNG (which typically have only a fraction of the normal RAIU) to increase ¹³¹I uptake in the goiter and allow treatment with lower doses of ¹³¹I to induce thyroid volume reduction (125-129). Accordingly, in a study of 15 patients with nontoxic MNG, pretreatment with a single low dose of rhTSH (0.01 or 0.03 mg 24 h before ¹³¹I administration) resulted in a doubling of RAIU (130). In addition, the single dose of rhTSH caused a more homogeneous distribution of ¹³¹I by stimulating more uptake in relatively cold areas than in hot areas, particularly in patients with low serum TSH levels (Figure 17- 7).

Various studies have demonstrated the effect of rhTSH on ¹³¹I therapy for MNG. Twenty-two patients with MNG were treated with ¹³¹I 24h after administration of 0.01 or 0.03 mg rhTSH (131). In this study, the dose of ¹³¹I was adjusted to the increase in uptake induced by rhTSH, aimed at 100 µCi/g thyroid tissue retained at 24h. Pretreatment with 0.01 and 0.03 mg rhTSH resulted in reductions in the ¹³¹I dose by a factor of 1.9 and 2.4, respectively. One year after treatment, there was a reduction in thyroid volume of 35% and 41% in the two groups, respectively. Despite delivering a good therapeutic response, the administration of ¹³¹I 100 µCi/g of thyroid tissue corrected for 24-h RAIU raises concerns of irradiation of the surrounding neck structures and potential risk for stomach, bladder, and breast cancer, which have been reported after ¹³¹I therapy for toxic nodular goiter (24). In another study (132), 16 patients with MNG were treated with a fixed dose of ¹³¹I (30 mCi) 72h after pretreatment with 0.3 mg rhTSH, or 24h after pretreatment with 0.9 mg rhTSH. The two regimens were equally effective, leading to a 30 to 40% reduction in thyroidal volume at 3 to 7 months. Giusti et al compared the 12-months outcome after RAI and rhTSH arbitrarily chosen (0.1mg for 24-h RAIU > 30 %; 0.2 mg for RAIU<30 %) between patients with basal non-toxic (TSH>0.3 mIU/l)) and non autimmune pre-toxic MNG (TSH<0.3 mIU/l). They confirmed the effectiveness of rhTSH adjuvant treatment in reducing thyroid volume after low RAI dose (<600 MBq) independently of the baseline TSH level. A more severe thyrotoxic phase after rhTSH was observed in patients with TSH<0.3 mIU/L, while L-T4 therapy was more frequently needed when initial TSH levels were > 0.3 mIU/l (133)

As mentioned, rhTSH was administered 24h before ¹³¹I therapy in most studies. However, results from a study published by Duick and Baskin (134, 135) suggested that the time interval may be even longer to achieve a maximum stimulation of the thyroid RAIU.

Recently in a phase II, single blinded, placebo-controlled study with 95 patients evaluating two low doses (0.01 and 0.03mg) of modified-release rhTSH, no statistical significant enhancement of thyroid volume reduction was achieved at three years follow-up (41% to 53%) . The modified-release rhTSH was developed to minimize the side effects related to thyroid hormone excess, (136).

(2). Tracheal compression and pulmonary function

Many elderly patients have significant intrathoracic extension of the MNG, which may cause tracheal compression with subsequent airflow reduction. Bonnema et al (137) evaluated upper airway obstruction by flow volume loops in 23 patients with very large goiter. In one third of the patients, there was impairment of the forced inspiratory flow at 50% of the vital capacity (FIF50%).The authors found a significant correlation between FIF50% and the smallest tracheal cross-sectional area. Reduction of the MNG volume after high dose of ¹³¹I had a remarkable effect in enlarging tracheal cross-sectional area and consequently improving inspiratory capacity in these patients.

(3). Transient hyperthyroidism after ¹³¹I ablation

Other studies using different doses of rhTSH and showing comparable RAIU increases with lower doses, demonstrated significant goiter reduction, but also transient hyperthyroidism after ¹³¹I therapy (131-144). A study in which 34 patients with large MNGs were randomized to receive ¹³¹I therapy (100 µCi/g of thyroid tissue) alone or following a single relatively high dose of rhTSH (0,45 mg) 24h before ¹³¹I administration, showed that patients who received rhTSH had transient elevations in thyroid hormone levels lasting a few weeks, a greater reduction in goiter size (60% vs. 40%), and a higher incidence of hypothyroidism (65% vs. 21%) (142). In another study, 18 patients received two 0.1 mg doses of rhTSH followed by 30 mCi of ¹³¹I. RAIU increased from 12 to 55%, free T 4 increased from 1.3 to 3.2 ng/dL, and goiter size reduced from 97 to 65 mL. However, about 30% of the patients experienced painful thyroiditis and 39% had mild hyperthyroidism (137). In a randomized trial of ¹³¹I treatment calculated to deliver a thyroidal absorbed dose of 100 Gy (10 mrads) and administered 24h after rhTSH (0.3 mg) or placebo, patients with MNG (mean goiter volume of 55 cm³) who received rhTSH had more symptoms of hyperthyroidism and neck pain during the first week after treatment, a greater reduction in goiter size (52% vs. 46%), and a higher frequency of hypothyroidism (62% vs. 11%) (145). Using a similar study design, Bonnema et al (141) compared the effects of rhTSH (0.3 mg) or placebo, followed by a maximum dose of ¹³¹I 100 mCi on goiter volume reduction in 29 patients with very large goiters (median volume of 160 mL). After 12 months, the median goiter volume (monitored by magnetic resonance imaging) was reduced by 34% in the placebo group and by 53% in the rhTSH group. In the placebo group, the goiter reduction correlated positively with the retained thyroidal ¹³¹I dose, whereas this relationship was absent in the rhTSH group. Adverse effects, mainly related to thyroid pain and cervical compression, were more frequent in the rhTSH group. At 12 months, goiter-related complaints were significantly reduced in both groups without any between-group difference. One patient in the placebo group and three patients in the rhTSH group developed hypothyroidism.

Recently, an uncontrolled study (140) demonstrated the effect of rhTSH (0.1 mg, single dose) followed by ¹³¹I 30mCi 24h later in 17 patients with MNG (mean thyroid volume of 106 cm³). Pretreatment with rhTSH resulted in a mean RAIU increase from 18 to 50% and an increase in free T4 of 55% at 24h. Mean T3 levels increased by 86% and peaked at 48h, and median TG levels increased about 600% and peaked on the fifth day. Symptomatic tachycardia was promptly relieved with ß-blocker administration. After 12 months, mean thyroid volume measured by computed tomography had reduced by 46%. The adverse effects observed were transient hyperthyroidism (17.6%), painful thyroiditis (29.4%), and hypothyroidism (52.9%).

(4). Degree of goiter reduction, ¹³¹I dose, and rhTSH

Most investigators (Table 17-7) could not find any correlation of thyroid volume reduction with post-rhTSH RAIU, area under the curve of TSH, basal thyroid volume, or effective activity of ¹³¹I. Also, in the placebo-controlled study by Bonnema et al (141), no significant correlation was found, in either the placebo group of the rhTSH-treated group, between the degree of goiter reduction and the initial goiter size. However, in the placebo group, there was a correlation (r = 0.74) between the degree of goiter reduction and the retained ¹³¹I thyroid dose, an observation in agreement with previous reports (135). At variance, Albino et al (131) found a positive correlation (r = 0.68) between the degree of goiter volume reduction and the effective activity of administered post-rhTSH ¹³¹I dose. This issue, therefore, needs further clarification, but overall, these studies suggest that goiter reduction may be dependent on other factors caused by rhTSH pre-stimulation and not only on the applied ¹³¹I thyroid dose. For example, rhTSH could induce reactivation of inactive thyroid tissue or render the thyrocytes more vulnerable to ionizing radiation. Generally, the dose of ¹³¹I in these studies ranged from 75 to 400 µCi/g tissue, and most patients received doses between 100 and 200 µCi/g, similar to those used to treat hyperthyroidism.

Figure 17-7

– Goiter reduction volume (%) at last follow-up of patients treated only with radioiodine (left bars) as compared with patients that received recombinant human TSH plus radioiodine (right bars). Note the significant and early volume reduction with radioiodine preceded by rh TSH (146)

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Table 17-7. Studies on the effect of recombinant human TSH on goiter reduction

in multinodular goiter patients.

No. of subjects

Dose of rhTSH (mg)

Time interval between rhTSH and radioiodine (123I or 131I)

Therapeutic dose of 131I (mCi)

Peak increase in thyroid hormones (%)

Goiter reduction(%)

Time of follow-up

Goiter size estimation (Methods)

Remarks

Nieuwlaat et al. (128)

12

0.01

24 h

~39 (mean)

Free T4: 47 Free T3: 41

35

1 year

MRI

0.01 mg: 131I activity reduced by a factor 1.9

10

0.03

24 h

~23 (mean)

Free T4: 52 Free T3: 59

41

0.03 mg: 131I activity reduced by a factor 2.4; Hypothyroidism: 36%

Duick & Baskin (134)

6

0.3

72 h

30

NI

NI

7 m

Palpation

0.3 mg: increase in 4 h RAIU 72 h after rhTSH: from 3.9 to 17

10

0.9

24 h

30

NI

30-40

0.9 mg: remission of compressive symptoms in 69% Hypothyroidism: 56%

Silva et al. (142)

17

none

~96 (mean)

Free T4: 34 T3: 33

40

1 year

CT

131I: Hypothyroidism: 23%

17

0.45

24 h

~90 (mean)

Free T4: 594 T3: 73

58

131I + rhTSH: Hypothyroidism: 64%; hyperthyroidism: 100%

Albino et al. (131)

18

2 x 0.1

24 h

30

Free T4: 146 T3: 191

39

6 m

CT

24 h RAIU increased from 12 – 53%; Hypothyroidism: 65%; hyperthyroidism: 39%

Giusti et al. (140)

8

none

NM

NM

25

20 m

US + CT

12

2x0.2

24 h

NM

Free T4: 290* Free T3: 340*

44

22 m

US + CT

Cohen et al. (132)

17

0.03

24 h

~30

Free T4: 46 T3: 33

34

6 m

CT

24 h RAIU increased from 26% to 43%; Hypothyroidism: 18%; hyperthyroidism: 18%

Nielsen et al. (145)

29

none

14 (median)

NM

46

1 year

US

131I: 24 h RAIU decreased from 32 to 29; Hypothyroidism: 11%; hyperthyroidism: 21%

28

0.3

24 h

~16 (median)

NM

62

131I + rhTSH: 24 h RAIU increased from 34 to 47; Hypothyroidism: 62%; hyperthyroidism: 36%

Bonnema et al. (141)

15

none

24 h

~42 (median)

NM

34

1 year

MRI

131I: hypothyroidism: 7%

14

0.3

~38 (median)

NM

53

131I + rhTSH: hypothyroidism: 21%

Paz-Filho et al. (137)

17

0.1

24 h

30

Free T4: 56 T3: 87

46

1 year

CT

24 h RAIU increased from 18 to 50%; Hypothyroidism: 53%; hyperthyroidism: 18%

Cubas et al. (147)

28

A: 0.1 B: 0.005 C: NONE

24 h

30

Free T4: 31 Free T4: 23 Free T4: 19

37.2 39.3 15.3

2 years

CT

43% had hypothyroid signs 25.9% had persistant hypothyroidism

Romão et al. (148)

Eu: 18 SCH: 18 CH: 6

0.1

24h

30

Free T4: 67 Free T4: 106 Free T4: 170

79.5 70.6 68.7

3 years

CT

Hypothyroidism: 50% 11% 16% Side effects more commonly find in SCH and CH

Fast et al

Clontrol

24h

rh TSH>

1 year

see Figure 17-7

(146)

Rh TSH

X control

Fast et al. (136)

95

Placebo 0.01 0.03

24hs

100Gy

NM

44 41 53

3 years

CT

Hypothyroidism: more frequently in 0.03 mg group

Giusti et al (133)

26

TSH>0.3mlU/l TSH<0.3mlU/l

24hs

600 MBq

NM

67,1 61.7

55.3 ± 4.1m 57.2 ± 5.1m

Ultrasonography

Several side effects in both groups

M: months

(5). Increase in goiter size immediately after ablation

It is worth mentioning the possibility of increase in goiter size with rhTSH (142, 145). In a study of 10 patients with MNG who were given 0.3 mg of rhTSH, it was shown that 24h after rhTSH, the mean goiter volume increased by 9.8% and after 48h, by 24%, reverting to baseline at 1 week. This suggests that rhTSH may lead to significant cervical compression in patients with near obstructive goiters, when used for improving ¹³¹I therapy in patients with goiter (145). All side effects related to acute thyroid enlargement causing tenderness and dyspnea due to possible obstruction of tracheal airway were promptly resolved with corticosteroid therapy.

(6). Radioactive iodine and rhTSH in elderly with hyperthyroidism

Treatment with ¹³¹I following rhTSH stimulation is also an attractive alternative in elderly patients considered poor surgical candidates or who refuse surgery. The prevalence of MNG rises in the elderly, a population in whom comorbities prevail. Of even greater concern in iodine repleted areas is the development of subclinical or overt hyperthyroidism, since thyroid hyper-function may increase the mortality risk in these patients (148). An Italian study assessed 20 elderly patients with large goiters and compared treatment with ¹³¹I (10 to 15 mCi fixed dose) following two consecutive 0.2 mg doses of rhTSH (n = 12; 3 patients had subclinical hyperthyroidism with TSH <0.3 µU/ml) with treatment with ¹³¹I alone (n = 8; subclinical hyperthyroidism recorded in 5). Patients who received rhTSH had higher transient elevations in free T4 and Free T3 lasting 2 weeks, a greater reduction in goiter size (44% vs. 25%). Both groups had a 17% incidence of hypothyroidism ~ 2 years after ¹³¹I therapy. Symptomatic relief occurred in all but 1 patient following rhTSH with a 50% median reduction on thyroid volume after about 2 years (140). In study conducted by Silva et al (142), 17 elderly subjects with MNG treatment with ¹³¹I 24h after pretreatment with 0.45 mg rhTSH and were compared with 17 elderly controls treated with ¹³¹I alone. In patients pretreated with rhTSH, serum TSH and T3 levels rose to a peak level in 24h, returning to normal at 72h. Serum free T4 concentrations rose significantly at 48h returning to normal at 7 days. Serum TG increased and remained elevated during the following 12 months. Patients pretreated with rhTSH had a 58% reduction in goiter volume when compared with 40% in patients treated with ¹³¹I alone. Hypothyroidism was more frequent in pretreated patients (65% versus 21% in non-pretreated) after 1 year. No symptoms of hyperthyroidism were observed in these patients. Four years after ¹³¹I therapy, additional thyroid volume reduction was similar for patients treated with rhTSH prior to ¹³¹I or with ¹³¹I alone, but it was significantly more pronounced in the rhTSH group, mainly in the first year (149). Although no additional benefit of rhTSH was observed after a long follow-up, the initial difference in thyroid volume reduction was maintained, denoting the advantage of using rhTSH pretreatment to achieve higher thyroid volume reduction during the first treatment (Table 17-6).

In another report of a short-term observational study, the investigators assessed the efficacy of a low-dose (0.03 mg) rhTSH stimulation on a fixed therapeutic activity of ~ 30 mCi ¹³¹I in 17 patients with large nodular goiters (12 with overt or subclinical hyperthyroidism / TSH <0.5 µU/ml and five on treatment with thionamides) (147). RAIU increased from 26% to 43%, free T4 increased from 1.4 to 2.0 ng/dl, and goiter size decreased from 170 to 113 cm³ by 6 months. Symptomatic relief, improved well-being and / or reduction, or elimination of anti-hyperthyroid drug was seen in 76% of the patients. However, 3 (18%) patients presented transient neck pain or tenderness, 1 experienced asymptomatic thyroid enlargement, and 3 became hypothyroid by 3 months (Table 17-6). A recent paper (146) compared the results of RAI alone and RAI preceded by rhTSH (see Figure 17-8) clearly demonstrating the efficacy of pre-treatment with rh TSH.

(7). Cardiovascular events after RAI ablation

Cardiovascular parameters to detect transient elevation of serum thyroid hormones were evaluated in 27 of 42 patients (age range 42-80 years) with large MNGs who were treated with rhTSH before receiving ¹³¹I 30 mCi (150). All patients presented a transient surge in serum levels of free T4 and total T3 into the hyperthyroid range following therapy. However, post-treatment cardiovascular evaluation did not show significant changes when compared with baseline evaluation, suggesting that treatment of MNGs with RAI after rhTSH stimulation does not affect structural and functional parameters of the heart. These findings are reassuring, particularly when considering treatment for older adults with comorbidities that preclude surgery.

(8). Thyroid autoantibodies occurrence after ¹³¹I therapy

Some studies have reported the development of thyroid antibodies associated with ¹³¹I therapy (151), however a direct cause-effect linking to rhTSH has not been demonstrated. These observations have been interpreted as an immunological response caused by the release of thyroid antigens from destroyed follicular cells. In a study published by Rubio et al (152), it was found that rhTSH pretreatment had no significant effect in the development of antibodies (TSH receptor and TPO) when compared with treatment with ¹³¹I alone. As noted below, up to 5% of individuals develop auto-immune hyperthyroidism after 131-I therapy.

(9). Potential induction of malignancy

Although generally ignored, treatment with large doses of 131-I obviously raises the possibility of induction of malignancy. This has not so far been recorded in relation to therapy of MNG. Depending on functionality of the thyroid tissue, dose administered, size of the goiter, and size of the patient, whole body radiation could be up to 1 rad/mCi given, a dosage similar to that obtained during therapy of thyroid cancer. Perhaps the major use of this treatment will be in older individuals, with a shorter potential life span after treatment, which would presumably make this less of a concern.

Conclusions and comments

Given the limited experience published in the literature so far, before considering the routine use of rhTSH administration before ¹³¹I treatment of MNG, several issues must be taken into consideration (153-157).

• ¹³³I treatment alone can lead to a 15-25% transient increase in thyroid volume during the first week after treatment;
• rhTSH administration alone occasionally can lead to a significant increase, albeit transient, in thyroid volume, of up to 100% in normal subjects with 48h.
• The combination of the two modalities may lead to a substantial acute increase in thyroid volume;
• ¹³¹I treatment of MNG leads to transient hyperthyroidism during the first 2-3 weeks after therapy and the combination with rhTSH administration can enhance this effect, with potential consequences particularly for the elderly patients (148);
• The optimal dose of rhTSH for pretreatment of MNG remains to be determined. Studies have used different doses and regimens or rhTSH administration, from as low as 0.01 or 0.03 mg to as high as 0.45 mg or 0.9 mg 24h before RAI treatment;
• There is a significant occurrence of hypothyroidism after ¹³¹I treatment following rhTSH stimulation;
• Although rare, autoimmune hyperthyroidism (approximate reported incidence of 4-5%) can develop after treatment of MNG with ¹³¹I;
• Currently, rhTSH is not approved by the FDA as an adjuvant for ¹³¹I treatment of goiter.

Based on these results, pretreatment with rhTSH seems a promising alternative to thyroid surgery for the management of nontoxic MNG, particularly in elderly individuals. However, the optimal dose and timing of both, rhTSH and ¹³¹I as well as the criteria for patient eligibility remain to be determined.

Figure 17-8 – An elderly woman with a large and longstanding MNG that migrated to the upper mediastinal region with subsequent compression of the subclavian system. Note the subcutaneous enlarged venous circulation (a). In the next panel (b), it is presented the scintilographic studies after a tracer dose of 131I before and (c) after stimulation by 0.45 mg of recombinant human TSH. (ref. 142.).

SUMMARY

Perhaps the most common of all the disorders of the thyroid gland is multinodular goiter. Even in non-endemic regions it is clinically detected in about 4% of all adults beyond the age of 30. Pathologically it is much more frequent, the percentage incidence being roughly the same as the age of the group examined. The disease is much more common in women than in men.

Multinodular goiter is thought to be the result of primarily two factors. The first factor is genetic heterogeneity of follicular cells with regard to function (i.e. thyroid hormone synthesis) and growth. The second factor is the acquisition of new qualities that were not present in mother cells and become inheritable during further replication. Mutations may occur in follicular cells leading to constitutively activated adenomas and to hyperthyroidism. These factors may lead to loss of anatomical and functional integrity of the follicles and of the gland as a whole. These processes ultimately lead to goiter formation and are accelerated by stimulatory factors. These stimulatory factors are basically an elevated serum TSH, brought about by events such as iodine deficiency, inborn errors of thyroid hormone synthesis, goitrogens or local tissue growth-regulating factors. These basic and secondary factors may cause the thyroid to grow and gradually evolve into an organ containing hyperplastic islands of normal glandular elements, together with nodules and cysts of varied histologic pattern.

Nodular goiter is most often detected simply as a mass in the neck, but at times an enlarging gland produces pressure symptoms on the trachea and the esophagus. Occasionally tenderness and a sudden increase in size herald hemorrhage into a cyst. Hyperthyroidism develops in a large proportion of these goiters after a few decades frequently after iodine excess. Rare complications are paralysis of the recurrent laryngeal nerve, and pressure on the superior sympathetic ganglion causes a Horner´s syndrome.

The diagnosis is based on the physical examination. Thyroid function test results are normal or disclose subclinical or overt hyperthyroidism. Thyroid autoantibodies are usually absent or low, excluding Hashimoto´s thyroidits. Imaging procedures may reveal distortion of the trachea, calcified cysts, or impingement of the goiter on the esophagus. Sonographic studies, Scintilography (¹³¹I), CT and MRI are useful to detect details of the MNG and to provide an estimation of the volume before and after therapy.

From 4 to 17% of multinodular thyroids removed at operation contain foci that on microscopic examination fulfill the criteria of malignant change. The infrequency of thyroid cancer as a cause of death clearly proves that the vast majority of these lesions are not lethal or even clinically active. One of the reasons for the high incidence of cancer in surgical specimens is that patients with multinodular goiters were often selected for surgery because of a concern for carcinoma.

If a clinical and biochemically euthyroid multinodular goiter is small and produces no symptoms, treatment is controversial. T4 given in an effort to shrink the gland or to prevent further growth is effective in about one third of the patients. This therapy is more likely to be effective if begun at an early age while the goiter is still diffuse than in older patients in whom certain nodules may have already become autonomous. If the clinically euthyroid goiter is unsightly, shows subclinical hyperthyroidism or is causing, pressure symptoms, treatment with ¹³¹I preceded by recombinant human TSH is successful in virtually all cases but causes hypothyroidism at varying degree. Surgery is an acceptable alternative. The efficacy of T4 treatment after surgery, to prevent regrowth, is frequently used albeit debatable.

Overt toxic nodular goiter is usually treated with radioiodine. A gratifying reduction in the size of the goiter and control of the hyperthyroidism may be expected. Hypothyroidism often ensues.

During the past few years the use of recombinant human TSH has been used to enhance the uptake of radioiodine and to provide a more homogenous distribution of the radionuclide. Results have been rewarding with a 45-65% shrinkage of the MNG, even with an intrathoracic position. A surge of high levels of serum Free T4, total T3 and serum TG is observed in the first weeks after therapy. Clinically hyperthyroid patients seem to have more unwanted signs and symptoms as compared to euthyroid patients. Hypothyroidism (permanent) is commonly observed at 6-12 months after rhTSH plus RAI treatment. Taking all into account, this modality of treatment of MNG has a relatively low cost and it is considered a good alternative to surgery that might not be available for all patients with MNG in many centers around the world.

The term colloid is applied to glands composed of uniformly distended follicles appearing as a diffuse enlargement of the thyroid gland. The condition is found almost exclusively in young women. With time and due to a number of primary and secondary factors it may gradually develop into a multinodular goiter which becomes increasingly prominent as the decades pass. Appropriate therapy, if required, is the timely administration of thyroid hormone that may be continued for several years.

An intrathoracic goiter is usually an acquired rather than a development abnormality. It may come about in embryonic life by a carrying downward into the thorax of the developing thyroid anlage, or in adult life by protrusion of an enlarging thyroid through the superior thoracic inlet into the yielding mediastinal spaces. These lesions may produce pressure symptoms and may also be associated with hyperthyroidism. If too large for treatment with ¹³¹I, the appropriate therapy is resection of the goiter through the neck, if possible. Attachment of the intrathoracic goiter to the gland in the neck ordinarily proves the site of origin and provides a method for its easy surgical removal. In many of these patients a safe and easily performed therapy, in an outpatient mode, is the administration of a fixed dose of radioiodine (¹³¹I) of 30 mCi preceded by rhTSH.

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