TREATMENT OF BENIGN NODULAR THYROID DISEASE

thyroid disease is common. Palpable thyroid nodules were detected in 0.8 percent of NODULAR adult men and 5.3 percent of adult women in Whickham, northeast England,1 and in 1.5 percent of men and 6.4 percent of women between 30 and 59 years of age in Framingham, Massachusetts. In the latter population, new nodules appeared in 0.1 percent per year during a 15- year follow-up period. Thyroid nodules are even more commonly detected when the thyroid is examined by ultrasonography. The overwhelming ma- jority of these nodules are benign. Several reviews describe diagnostic strategies to distinguish between benign and malignant nodules 5-9 or address the treatment of thyroid cancer. Here, we focus on the treatment of patients with benign nodular thyroid disease. CLINICALLY SOLITARY THYROID NODULES A clinically solitary thyroid nodule is a discrete swelling within an otherwise palpably normal thyroid gland. With time, solitary thyroid nodules may enlarge, shrink, or even disappear spontaneously,13,14 but most do not change appreciably.3 Most of these nodules are benign colloid nodules composed of ir- regularly enlarged follicles containing abundant col- loid. Most are actually the largest of multiple colloid nodules in small, clinically unrecognized multinod- ular goiters.15 Other causes of benign solitary nod- ules are thyroid adenomas, cysts, and thyroiditis. Ap- proximately 5 percent of all solitary thyroid nodules are thyroid carcinomas.5-9 A strong clinical suspicion of carcinoma (e.g., when there is a firm, fixed nodule, enlarged cervical lymph nodes, or hoarseness) is in itself an indication for surgical treatment. Fine-needle aspiration biopsy is indicated in all patients with solitary thyroid nod- ules and is especially helpful in patients in whom there are no obvious symptoms or signs of carcino- ma. When this technique is used, approximately 70 percent of nodules are found to be cytologically be- nign (with a false negative rate of 1 to 2 percent) and approximately 4 percent to be malignant.8,16 In the remaining patients, either the distinction can- not be made on the basis of cytologic findings (in- determinate cytologic findings) or the aspirate con- tains an insufficient number of follicular cells for a reliable diagnosis (inadequate cytologic findings). Surgery is advised for patients with indeterminate or repeatedly inadequate cytologic findings. An ex- ception can be made for patients with low serum thyrotropin concentrations, in whom thyroid scin- tigraphy with iodine-123 (or iodine-131) should demonstrate hyperfunctioning of the nodule and little or no uptake in the extranodular tissue. These autonomously functioning nodules are rarely malig- nant.6 Given the imprecision of palpation, ultrasonogra- phy is critical for evaluating changes in nodule or

goiter volume in studies of therapy, but it is not indicated for routine clinical management. Ultrasonography is of value when cystic nodules do not disappear completely or when they recur after aspiration. In these cases, ultrasonographic guidance can be used to obtain adequate cytologic findings from the solid components. Patients with cystic le- sions that disappear permanently after aspiration need no further diagnostic evaluation, even when the cytologic findings in the aspirated fluid are inad- equate.17 MULTINODULAR GOITER A multinodular goiter may be defined as a struc- turally and functionally heterogeneous thyroid enlargement. Worldwide, such goiters are most often caused by iodine deficiency. In the early phase of goitrogenesis, the thyroid may be diffusely enlarged, but with time diffuse goiters tend to grow and be- come more nodular. Thyroid function often becomes more autonomous with increasing age,18,19 and eu- thyroidism may gradually change to subclinical hy- perthyroidism (defined as a low serum thyrotropin concentration and normal serum free thyroxine and triiodothyronine concentrations) and eventually into overt hyperthyroidism. In patients with multinodular goiter, serum thyro- tropin and free thyroxine should be measured to identify those with subclinical or overt hyperthy- roidism. Thyroid scintigraphy and ultrasonography are not routinely indicated. Fine-needle aspiration biopsy may be helpful when carcinoma is suspected: cytologic examination should focus on the domi- nant nodule or nodules or those that have a different consistency from other nodules within the gland.20 In surgical series of patients with multinodular goi- ter, the reported incidence of carcinoma was as high as 10 percent.21 However, the patients were highly selected, and most of the carcinomas were tiny pap- illary carcinomas. In less highly selected groups of patients with multinodular goiter, such as those presenting to a thyroid clinic, the incidence of carcino- ma was 1 to 4 percent.22,23 In unselected patients with multinodular goiter, the prevalence of clinically important carcinoma must be less than 1 percent, given the high prevalence of multinodular goiter and the very low incidence of clinically evident thyroid carcinoma. TREATMENT OF NONTOXIC UNINODULAR THYROID DISEASE The main indications for treatment of a euthyroid patient with a benign thyroid nodule that is not hyperfunctioning are compression of the trachea or esophagus, growth of the nodule, and recurrence of a cystic nodule after aspiration. Other indications for treatment are neck discomfort, cosmetic con- cern, and the patients anxiety about the nodule. The main therapeutic options are surgery and thy- roxine treatment. Surgery

Unilateral thyroid lobectomy is the preferred ther- apy for patients with benign solitary thyroid nodules. The operative risk is lower than that of subtotal thyroidectomy for multinodular goiter, because the resection is less extensive. As an alternative, patients with recurrent cystic nodules can be treated by in- jection of a sclerosing agent, such as tetracycline24 or ethanol,25,26 into the nodule. Thyroxine Therapy Thyroxine is the most widely used treatment for patients with benign solitary thyroid nodules. It is given to suppress the secretion of thyrotropin. The assumption underlying this treatment is that the growth of thyroid nodules, like that of normal thy- roid tissue, is dependent on thyrotropin, and there- fore that suppression of thyrotropin secretion will result in a decrease in nodule size. Nonrandomized studies suggested that thyroxine treatment induced a decrease of 50 percent or more in nodule diameter in approximately 30 percent of patients.27 However, these studies lacked adequate control groups, nodule volumes were often not meas- ured objectively, and patients with subclinical hy- pothyroidism were not always excluded. There have been four randomized, prospective tri- als in euthyroid patients with benign, clinically soli- tary nodules that compared the effect of thyroxine given at thyrotropin-suppressive doses for 6 to 12 months with the effect of placebo or no treatment on nodule size as determined by ultrasonography (Table 1). Three studies were limited to patients with colloid nodules,28-30 but the fourth study in- cluded patients with degenerative, hyperplastic, and fibrotic nodules.31 Thyroxine therapy was of no ben- efit in two studies.28,29 In the third study,30 more pa- tients receiving thyroxine than patients receiving placebo had a decrease in nodule volume (45 per- cent vs. 26 percent), but the percentages of patients with a greater than 50 percent decrease in nodule volume did not differ significantly between the groups. In the fourth study,31 nodule volume de- creased by 50 percent or more in 39 percent of the thyroxine-treated patients and in no untreated pa- tients, but only nodules with a volume of 10 ml or less at base line decreased by 50 percent or more. In this study the cytologic characteristics of the nodule predicted the effect of thyroxine therapy, the chance of shrinkage being highest in patients with colloid or degenerative nodules.32 Given the at best modest short-term results of thyrotropin-suppression therapy, the absence of data on its long-term efficacy, and the possible adverse effects (see below), the value of thyroxine treatment in patients with benign solitary thyroid nodules is controversial. Some have completely abandoned this therapy, and others restrict it to men and premeno- pausal women, with postmenopausal women being treated only when growth of the nodule is demon- strated.33 Another controversial issue is the appropri- ate level of thyrotropin suppression; we do not know whether marked suppression of thyrotropin secre- tion is more effective than mild suppression.

Management of Autonomously Functioning Thyroid Nodules Because of the risk of inducing hyperthyroidism, thyrotropin-suppression therapy is not indicated in euthyroid patients with autonomously functioning thyroid nodules. Most of these nodules do not sub- stantially change in size with time; in one study, 86 percent of nodules remained stable during a follow- up period of 1 to 15 years.34 Approximately 5 per- cent of the patients become hyperthyroid each year34,35; the risk is highest when the nodule is 3 cm or more in diameter at the time of diagnosis.34 Ra- dioiodine therapy or surgery may be indicated in case of local effects of the nodule. Because of the risk of hyperthyroidism, therapy should also be con- sidered in asymptomatic patients with nodules 3 cm or more in diameter, especially in elderly patients. TREATMENT OF NONTOXIC MULTINODULAR GOITER The main indications for the treatment of patients with nontoxic multinodular goiter are compression of the trachea or esophagus and venous-outflow ob- struction. Another indication is growth of the goi- ter, especially where there is intrathoracic extension. Such goiters are inaccessible to palpation and fine- needle aspiration biopsy, and they may cause acute airway symptoms. Sometimes treatment is sought because of neck discomfort or cosmetic issues. Patients who have symptoms and signs of tracheal compression (inspiratory stridor and dyspnea) should undergo radiography, computed tomography (CT), or magnetic resonance imaging (MRI) of the neck and upper thorax and pulmonary-function tests, es- pecially flow-volume loop studies. The sensitivity of both CT and MRI for the detection of intratho- racic extension of a goiter is 100 percent. When CT is used, iodinated contrast agents should not be given, because of the risk of inducing hyperthy- roidism. The available treatment options are surgery, thy- roxine, and radioiodine (Table 2). Even when iodine deficiency is the cause of the goiter, iodine supple- mentation is not advisable in patients with nontoxic multinodular goiter, because it may induce hyper- thyroidism. Surgery Bilateral subtotal thyroidectomy is standard ther- apy for patients with nontoxic multinodular goiter.36,37 It leads to rapid decompression of vital struc- tures. If only one thyroid lobe is enlarged, treatment may consist of unilateral lobectomy and isthmecto- my. Nearly all such goiters can be removed through a collar incision, even those that extend well into the thorax, and therefore thoracotomy is rarely needed. However, isolated intrathoracic goiters, which are extremely rare, must be removed by a thoracic ap- proach.36

The surgical mortality rate associated with bilat- eral thyroid operations in patients with nontoxic multinodular goiter is less than 1 percent.36,37 Surgical morbidity includes postoperative tracheal ob- struction due to hemorrhage or tracheomalacia, in- jury to the recurrent laryngeal nerve (in 1 to 2 percent of cases when the operation is performed by an experienced thyroid surgeon), hypoparathy- roidism (0.5 to 5 percent of cases), voice changes due to superior-laryngeal-nerve damage, and hypo- thyroidism.36,37 The rate of postoperative hypothy- roidism depends on the extent of surgery. Surgical morbidity is highest in patients with very large goi- ters and in those who undergo reoperation because of recurrent goiter.38 The rate of goiter recurrence after surgery increas- es with time. With adequate surgery, the recurrence rate should not be higher than approximately 10 percent after 10 years.39 Thyroxine is frequently pre- scribed postoperatively to decrease the chance of goiter recurrence, but several large, uncontrolled studies have yielded no convincing evidence that this therapy is effective, and no randomized studies with sufficient follow-up times and objective measure- ments of goiter have been performed.40 Therefore, routine thyroxine therapy after surgery for nodular goiter cannot be advised. Thyroxine Therapy Suppression therapy with thyroid hormone is ef- fective in reducing the volume of diffuse nontoxic goiters, as measured by ultrasonography.41,42 Several nonrandomized studies suggest that this therapy is also effective in patients with multinodular goiters.40 However, in most of the studies, patients with iodine deficiency or subclinical hypothyroidism were not excluded, and none had adequate control groups and objective measurements of thyroid volume. Only one randomized, placebo-controlled trial using ob- jective volume measurements has been reported.43 In this study of patients with relatively small, non- toxic, predominantly multinodular goiters (mean vol- ume, 53 ml), a decrease in goiter size, defined as a decrease in thyroid volume of more than 13 percent, occurred in 58 percent of the patients treated with thyroxine and in only 5 percent of those given pla- cebo. The mean decrease in thyroid volume in the patients with a response was 25 percent after nine months of thyroxine treatment. Goiter size returned to base line after the discontinuation of therapy. The effect of thyroxine treatment in patients with larger multinodular goiters is probably smaller. Further- more, there is no evidence that long-term thyroxine therapy alters the natural history of multinodular goiter. Before thyroxine therapy is begun in patients with multinodular goiter, serum thyrotropin should be measured, because many patients with large multi- nodular goiters have autonomous thyroid hormone production and subclinical hyperthyroidism. In such patients, thyroxine therapy is inadvisable because it may cause overt hyperthyroidism, and no shrinkage of the goiter can be

expected when thyrotropin se- cretion is already suppressed.44 Radioiodine Therapy Radioiodine (iodine-131) treatment is effective in reducing thyroid volume in most patients with nontoxic multinodular goiter.45-49 In the reported stud- ies, the average initial thyroid volumes ranged from 73 to 269 ml. Approximately 100 mCi (3.7 MBq) of radioiodine per gram of thyroid tissue (corrected for the percentage uptake of radioiodine in the thyroid at 24 hours) was administered. Radioiodine treat- ment resulted in a mean reduction in thyroid vol- ume of approximately 40 percent after one year45-49 and 50 to 60 percent after three to five years (Fig. 1).46,50 More important was the finding that com- pressive symptoms decreased in the majority of pa- tients. In one study, there was significant tracheal widening as measured by MRI (Fig. 1 and 2),47 and this widening was accompanied by improvement in respiratory function (Fig. 3).47,51 Early side effects (pain in the thyroid region, ra- diation thyroiditis, increase in compressive symptoms, and esophagitis) are rare, and when present they are usually mild and transient.47,50,52 The devel- opment of autoimmune (Graves) hyperthyroidism, probably triggered by the radiation induced release of thyroid antigens, is the most important complica- tion, occurring several months after therapy in ap- proximately 5 percent of patients.53,54 The incidence of post-treatment hypothyroidism is 20 to 30 per- cent at five years.46 No follow-up data are available on the risk of in- duction of carcinoma by the high doses of radioiodine needed for the treatment of patients with large multinodular goiters. The lifetime risk of radiation- induced carcinoma depends not only on the admin- istered dose of radioiodine but also on the age of the patient. It has been estimated that the lifetime risk of radiation-induced carcinoma in extrathyroidal tis- sues in people 65 years of age or older who are treat- ed with high doses of radioiodine is similar to the mortality rate associated with subtotal thyroidec- tomy.55 Adverse Effects of Suppression Therapy with Thyroid Hormone Thyroxine therapy in doses sufficient to suppress serum thyrotropin may have adverse effects. A meta- analysis of all controlled cross-sectional studies of the effects of thyroid hormone therapy on bone mineral density that were published between 1982 and 1994 demonstrated substantial decreases (5 to 9 percent) in bone mineral density at the lumbar spine, the proximal femur, and the radius in post- menopausal women receiving long-term suppression therapy with thyroid hormone.56 No negative effect of therapy on bone mineral density was found in premenopausal women or in men. Estrogen-replace- ment therapy in postmenopausal women ameliorates thyroid hormoneassociated bone loss.57

A low serum thyrotropin concentration in persons 60 years of age or older is associated with a tripling of the risk of atrial fibrillation in the subsequent decade.58 Therefore, it is not unreasonable to assume that suppression therapy with thyroid hormone might have adverse cardiac effects. The therapy increases left ventricular mass,59-61 but whether it causes cardi- ac dysfunction is not clear. In one study the patients treated with thyroid hormone had a normal heart rate, no atrial arrhythmias, and normal left ventricu- lar function,61 whereas in another study similarly treat- ed patients had an increased heart rate, an increased incidence of atrial arrhythmias, and decreased left ven- tricular function.59 TREATMENT OF TOXIC UNINODULAR AND MULTINODULAR GOITER In patients with nodular thyroid disease, treatment is always indicated when overt hyperthyroidism is present. In cases of subclinical hyperthyroidism, treat- ment is advisable in elderly patients and in younger ones who are at risk for cardiac disease or osteoporo- sis. The available treatment options are antithyroid drugs, surgery, radioiodine, and, in patients with au- tonomously functioning thyroid nodules, percutane- ous ethanol injection (Tables 3 and 4). Antithyroid-Drug Therapy Hyperthyroidism caused by nodular thyroid dis- ease is reversible by antithyroid-drug treatment. However, for most patients this therapy is not attrac- tive, because it must be lifelong; hyperthyroidism nearly always recurs after the antithyroid drug is dis- continued.62 Antithyroid-drug therapy is indicated before thyroid surgery because it lowers operative risk. In addition, it is recommended before and sometimes after radioiodine treatment in elderly pa- tients and those with other health problems, because euthyroidism is achieved more quickly with drug therapy and the risk of exacerbation of hyperthy- roidism after radioiodine treatment is likely to be lower. The antithyroid drug should be discontinued for at least three days before and three days after radioiodine therapy. Surgery In patients with hyperthyroidism who have soli- tary autonomously functioning thyroid nodules, either lobectomy or nodulectomy is simple and effec- tive. As in euthyroid patients with solitary thyroid nodules, the operative risk is lower than that of sur- gery for multinodular goiter. Recurrences after sur- gery are rare.63,64 Hypothyroidism develops in 10 to 20 percent of patients.63,65 Patients with toxic multinodular goiter may be treated by bilateral subtotal thyroidectomy. Among adequately prepared patients, the operative risk is similar to that of surgery for nontoxic multinodular goiter. After adequate surgery, the combined inci- dence of persistent and recurrent

hyperthyroidism should be less than 10 to 20 percent.66,67 Widely varying rates of post-treatment hypothyroidism (up to 70 percent) are reported in the literature; the variation is probably due to variation in the extent of surgery.66 Radioiodine Therapy Traditionally, patients with toxic uninodular or multinodular goiter have been treated with relatively high doses of radioiodine. For patients with solitary autonomously functioning nodules, doses of 200 to 400 mCi (7.4 to 14.8 MBq) per gram of nodular tis- sue are advised.64 For patients with toxic multinod- ular goiter, the usual dose is 150 to 200 mCi (5.5 to 7.4 MBq) per gram of thyroid tissue.68 However, we and others have found that lower doses result in similar cure rates,69,70 so we now treat patients who have toxic multinodular goiter with doses of 80 to 100 mCi (3.0 to 3.7 MBq) per gram of thyroid tissue. Radioiodine therapy is as effective as surgery for the treatment of patients with autonomously functioning thyroid nodules and those with toxic multi- nodular goiters. The reversal of hyperthyroidism af- ter radioiodine therapy is, however, more gradual than that after surgery. For patients with autono- mously functioning thyroid nodules, radioiodine re- sults in a one-dose cure rate of 90 percent, on aver- age.63,65 Radioiodine therapy is effective in 80 to 100 percent of patients with toxic multinodular goiter, although more than one treatment may be neces- sary.69 In most patients, radioiodine treatment re- sults not only in the reversal of hyperthyroidism but also in a substantial reduction in thyroid (or nodule) volume.71 Hypothyroidism after radioiodine treatment is con- siderably less common in patients with toxic nodular goiter than in those with Graves hyperthyroidism. Among patients with autonomously functioning thy- roid nodules, the cumulative incidence of subclinical and clinical hypothyroidism is 10 percent, on aver- age, after mean follow-up ranging from 1 to 10 years.63,65 The frequency of hypothyroidism appears to be inversely related to the degree of suppression of thyrotropin secretion at the time of treatment and the resultant reduction in radioiodine uptake in the normal paranodular tissue.64 Among patients with toxic multinodular goiter, hypothyroidism occurred in less than 20 percent in most studies, even after long-term follow-up. The frequency of hypothyroid- ism is highest among patients who also have thyroid autoimmunity.72 Theoretically, patients treated with radioiodine have an increased risk of thyroid carcinoma, because the paranodular tissue may receive sublethal mu- tagenic doses of radiation.73 However, in a large fol- low-up study, the risk of thyroid carcinoma was not increased and the risk of carcinoma elsewhere was not increased or only marginally increased.74 Percutaneous Injection of Ethanol

Percutaneous injection of ethanol is a recently proposed alternative to radioiodine therapy and surgery for patients with autonomously functioning thyroid nodules. The procedure involves the instillation of ethanol directly into the nodule under ultrasound guidance. Multiple injections, usually causing mild-to-moderate pain, are required, and a few pa- tients have transient paralysis of the recurrent laryn- geal nerve. Of patients with overt hyperthyroidism in a large Italian multicenter study, 67 percent had normal serum thyrotropin concentrations and iodine uptake in the previously suppressed extranodular tissue 12 months after the injections were completed.75 In an- other study from Italy, 78 percent of patients with overt hyperthyroidism were cured after a median fol- low-up of 2.5 years.76 In both studies, nodule vol- ume decreased in the majority of patients. CONCLUSIONS Several medical and surgical treatment options are available for patients with benign nodular thyroid disease. Surgery is indicated in euthyroid patients with benign solitary thyroid nodules that cause tra- cheal compression. When treatment is sought by eu- thyroid patients with solitary nodules that do not cause tracheal compression, we offer a 6-to-12- month trial of thyroxine therapy, provided that the nodule is not functioning autonomously. We inform patients that the data on the efficacy of thyroxine therapy are controversial, and we discourage postmenopausal women who are not taking estrogen from trying thyroxine therapy. Surgery is standard therapy for patients with non- toxic multinodular goiter, especially when rapid de- compression of vital structures is required. Thyrox- ine may be tried in young patients with small goiters (not larger than 50 ml) who have normal serum thy- rotropin concentrations. Radioiodine treatment is an attractive alternative to surgery in elderly patients and those with cardiopulmonary disease. Adults with solitary hyperfunctioning thyroid nod- ules are usually treated with radioiodine, although some prefer surgery. For children and adolescents with solitary hyperfunctioning thyroid nodules, sur- gery is advised.77 For the treatment of patients with toxic multinodular goiters, radioiodine is usually rec- ommended, but surgery is more appropriate for pa- tients with large goiters when rapid decompression of vital structures is needed.