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Holzheimer RG, Mannick JA, editors. Surgical Treatment: Evidence-Based and Problem-Oriented. Munich: Zuckschwerdt; 2001.

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Surgical Treatment: Evidence-Based and Problem-Oriented.

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Benign nodular thyroid disease

, M.D., Ph.D.

http://rene-holzheimer.de/ Medical Faculty, Martin Luther University, Halle-Wittenberg, Germany

Introduction

We have performed a medline search with the following keywords: benign nodular thyroid disease, hypothyroidism, hyperthyroidism, Graves’ disease, benign solitary thyroid nodule, surgery, randomized controlled trial, clinical trial. Thyroiditis was not included in this review. The selected papers were evaluated with regard to study design, study population, number of patients, results and graded according to the published evidence grading.

Most of the evidence in the management of benign nodular thyroid disease is grade C; only few studies were rated grade A or B.

Definition, pathogenesis, and epidemiology

Nodular thyroid disease is common. Palpable thyroid nodules may be detected in 0.8–1.5% of men and 5.3–6.4% of women (1, 2). Most of these nodules are benign colloid nodules composed of irregularly enlarged follicles containing abundant colloid. Causes of benign solitary nodules are thyroid adenomas, cysts, thyroiditis or it may be the largest nodule of a small, clinically unrecognized multinodular goiter (3, 4, 5). Multinodular goiter is a structurally and functionally heterogeneous thyroid enlargement, most often caused by iodine deficiency (endemic goiter) or by medication, malnutrition, inherited defects in thyroid hormone synthesis, and growth stimulating antibodies. With increasing age thyroid function may become more autonomous and subclinical hyperthyroidism or overt hyperthyroidism may develop (6).

Hyperthyroidism is caused by increased levels of thyroid hormone with a loss of the normal feedback mechanism controlling the secretion of thyroid hormone. Common types of hyperthyroidism, are diffuse toxic goiter (Graves’ disease) and toxic adenoma or toxic multinodular goiter (Plummer's disease). Graves’ disease is a systemic autoimmune disorder with variable expression that includes goiter with hyperthyroidism, exophthalmia, pretibial myxedema, and acropachy. An adenoma may be described as benign neoplasia associated with a localized excessive secretion of thyroid hormone. The relative incidence of adenomatous hyperthyroidism and Graves’ disease varies geographically. Although the origin of Graves’ disease remains obscure, current evidence suggests it is an autoimmune disorder caused by thyroid-stimulating immunoglobulins (TSIs) that have been produced against an antigen in the thyroid. These polyclonal immunoglobulins appear to be directed to thyroid-stimulating hormone (TSH) receptors and can be detected by sensitive and specific radioreceptor assays. Toxic adenomas are often first recognized on a thyroid scan where they appear as hot nodules. Often the patient is still euthyroid, because even though the adenoma is hypersecreting independently of the pituitary feedback system, suppression of thyroid secretion from the normal gland maintains a physiologic net secretion rate of thyroid hormone (7). Thyroid storm is a feature of thyrotoxicosis which appears not only in patients after operation for thyrotoxicosis but also in unrecognized hyperthyroidism. It is considered to be an acute adrenergic reaction after thyroid hormone induction of myocardial catecholamine receptors (8, 9).

Diagnosis

Clinical features

Palpation of the thyroid gland may reveal the location, size, consistency, and mobility of nodules. Multinodularity is consistent with a benign nodular disease, especially when all nodules have a similar consistency. Symptoms of Graves’ disease are irritability, sweating, palpitations, shortness of breath, fatigue, muscle weakness, prominent eyes, increased appetite and weight loss, diarrhea, goiter with or without bruit, hair loss and pruritus. Toxic adenoma may be differentiated from Graves’ disease by lack of ophthalmopathy, pretibial myxedema, or acropachy. Rapid pulse rate may suggest hyperthyroidism. However, in older patients is may be difficult to detect hyperthyroidism; they may be mono- or asymptomatic and atrial fibrillation may be the only symptom. Manifestations of thyroid storm are hyperthermia, tachycardia, hypertension, sweating, irritability and anxiety. Hypertension may occur in the context of MEN type II (see relevant chapter in this book). The neck should be palpated for lymphadenopathy and deviation of the trachea should be noted. Nontoxic multinodular goiter may be accompanied by inspiratory stridor or dyspnea. This may be caused by tracheal compression or tracheal deviation which can be demonstrated by x-rays of the neck and thorax. A CT scan or magnetic resonance imaging is not warranted for the initial exam of the patient, but it may add important clinical information in case the goiter is located retrosternal (10).

Laboratory tests

The most effective measure of thyroid activity is the third generation TSH assay. Serum thyrotrophin (Thyroid-stimulating hormone) is used to differentiate among euthyroid, hypothyroid (elevated TSH), and hyperthyroid (suppressed TSH). If serum thyrotrophin is elevated, serum antithyroperoxidase (formerly antimicrosomal antibodies) should be determined to detect Hashimotos thyroiditis. If TSH is suppressed measurement of free thyroxine should be obtained to document the presence and degree of hyperthyroidism. In case of normal free thyroxine and suppressed thyrotrophin levels a serum total triiodothyronine (T3) or free T3 may be obtained to rule out T3 toxicosis. A suppressed thyrotrophin level, with or without an elevation in free thyroxine or free T3 suggests a benign disease. Hyperthyroidism is usually confirmed by measuring circulating thyroid hormone concentrations of total thyroxine (TT4). Resin uptake of 125I-triiodothyronine (T3) is concomitantly assessed for determining the free T4 index, because the increased TT4 may reflect a familial increase in thyroid-binding globulin. Serum T3 is almost always enhanced in conjunction with an elevated T4 level; however, the frequency of hyperthyroidism due to excess T3 with a normal concentration of T4 is sufficient to warrant a measurement of T4. Measurement of thyroid uptake of radioiodine (131I) is not routinely performed. It may be useful if the T3 and T4 levels are not clearly elevated but are at the upper limit of normal. An iodine 123-labeled scan should be performed to confirm the presence of a hyperfunctioning hot nodule, since a hypofunctioning nodule may coexist in the context of underlying hyperthyroidism. The diagnostic approach for toxic nodular goiter(TNG) includes the thyroid function test mentioned above. The absence of thyroid antibodies may help to differentiate TNG from Graves’ disease. Radioiodine uptake and thyroid scan may be useful in patients with TNG to determine whether a dominant nodule is hypofunctioning, suggesting the need for needle aspiration to rule out thyroid carcinoma. There are no specific laboratory findings distinguishing thyroid storm from uncomplicated hyperthyroidism. A basal serum calcitonin should be obtained in search for medullary thyroid carcinoma (see relevant chapter in this book) (11, 12).

Ultrasound is critical for evaluating changes in nodule or goiter volume in studies of therapy. Furthermore it may be used to for evaluation of cystic nodules which do not disappear or recur after aspiration (13). According to the guidelines of the American Thyroid Association ultrasonosound may be useful in selected patients who are undergoing Fine Needle Aspiration Biopsy (FNAB) and in multinodularity (12). In European guidelines it is emphasized that ultrasonographic evaluation of the patient is mandatory for the preoperative evaluation of size, structure, and extrathyroid manifestations, e.g., lymph nodes, or nodules (14). Ultrasound may be followed by FNAB when carcinoma is suspected. Although in unselected cases with multinodular goiter the prevalence of clinically important carcinoma may be less than 1% (13), there are reports on the incidence of carcinoma ranging from 1 to 10% (15, 16, 17).

Fine-needle aspiration biopsy which is influenced by the skills and experience of the treating physician and the pathologist is indicated in all patients who present with solitary thyroid nodules suspicious of carcinoma. Approximately 70% of nodules are found to be cytologically benign (false negative rate 1 to 2%) and approximately 4% to be malignant (18, 19). Indeterminate cytological findings or inadequate cytological findings may account for the remaining patients. In these cases surgery is indicated to establish a final diagnosis. In Europe fine-needle aspiration biopsy is considered useful (14)

  • in solitary nodules above 1 cm diameter and suspicion of malignancy
  • in fast growing nodules of the thyroid
  • as therapeutic measure in large cysts
  • in acute suppurative thyroiditis without indication for surgery
  • in unclear cases of subacute thyroiditis
  • in unclear cases of chronic lymphocytic thyroiditis.

The false-negative rate should be less than 5% and the false-positive rate approximately 1%. 1 of 4 types of interpretations are reported: benign, malignant, suspicious for a follicular or Hürthle cell tumor, insufficient. Follicular or Hürthle cell tumor requires further evaluation and management (12). According to the results of a clinical study FNAB was a significantly better predictor of malignancy than thyroid scan (20) (grade C).

Thyroid scintigraphy with administration of 131I is useful for the diagnosis of toxic adenoma. When the diagnosis is in doubt, a suppression test can be warranted with administration of TSH. In the presence of an autonomous nodule TSH stimulates suppressed thyroid tissue to accumulate 131I, so that the entire thyroid, including the autonomous nodule is visualized on the scan. Approximately 70% of adenomas do not accumulate radioactive iodine and are thus cold on scan; 20% demonstrate uptake roughly equivalent to the remaining normal thyroid tissue and are therefore designated warm. 5–10% of adenomas are hyperfunctional and may produce thyrotoxicosis, particularly when the lesion exceeds 3 cm in diameter (21). Iodine123 or technetium Tc99 pertechnetate are useful imaging agents. Most specialists in the US use iodine123. Occasionally a nodule that is functioning with technetium Tc99m pertechnetate will be hypofunctioning with iodine123. Therefore, all nodules that are hot with technetium Tc99m pertechnetate should be rescanned with iodine123. Nodules that are either hypofunctioning or eufunctioning with iodine123 or technetium Tc99m pertechnetate are also usually benign, but malignancy cannot be excluded. With the exception of hyperfunctioning nodules, the thyroid scan will not distinguish benign from malignant nodules (12).

Nontoxic uninodular thyroid disease

Indications for treatment are

1.

compression of trachea or esophagus

2.

growth of the nodule

3.

recurrence of a cystic nodule after aspiration

4.

neck discomfort

5.

cosmetic concern

6.

patient's anxiety about the nodule

Therapeutic options are:

1.

surgery

2.

thyroxine treatment

Surgery

The surgical treatment may be either excision of the nodule or unilateral thyroid lobectomy. The decision to operate or not may also depend on the reliability of diagnosis, the stability of the size of the nodule, the risk of subsequent dysfunction and the presence of other medical diseases. Solitary nodules may disappear in 38% of all cases (grade C). A thyroid nodule which is larger than 3 cm, cystic/solid or large and cystic/solid may have a higher probability of malignancy (grade C) (22). The intraoperative diagnosis by frozen section may be correct in 92% of cases (23). Unilateral thyroid lobectomy is the preferred therapy for patients with benign solitary nodules (24, 25) (grade C). For the nodule with malignant or indeterminate cytology surgical resection is indicated. Surgical resection is also indicated for cysts that recur after aspiration (26).

Thyroxine treatment

The results of several studies ( modest short-term results of thyrotrophin-suppression therapy, absence of data on long-term efficacy, possible adverse effects) are controversial. The benefit for patients is not established (13, 2733). The nodule volume did not decrease significantly in a randomized controlled study when L-thyroxine was given (grade B) (34). Long term TSH suppression induced volume reduction only in a subgroup of thyroid nodules. L-T4 therapy should be reserved for small nodules in younger patients (grade B) (35).

Radioiodine therapy or surgery is indicated in case of local effects of the nodule or when the nodule is 3 cm or more in asymptomatic patients because of the risk of hyperthyroidism (36). Thyrotrophin-suppression therapy is not indicated in euthyroid patients with autonomously functioning thyroid nodules, as it may induce hyperthyroidism.

Nontoxic multinodular goiter

Indications for treatment are:

1.

compression of the trachea or esophagus

3.

venous-outflow obstruction

3.

growth of the goiter

4.

neck discomfort

5.

cosmetic issues

Therapeutic options are:

1.

Surgery

2.

Thyroxine Therapy

3.

Radioiodine therapy

Surgery

Bilateral subtotal thyroidectomy is standard therapy for patients with nontoxic multinodular goiter. If only one lobe is enlarged, unilateral lobectomy and isthmectomy may suffice. The surgical mortality rate associated with bilateral thyroid operations in patients with non-toxic multinodular goiter is less than 1% (37)

Causes of surgical morbidity are:

  • Postoperative tracheal obstruction due to hemorrhage or tracheomalacia
  • Injury to recurrent laryngeal nerve (1–2% of cases when surgeon is experienced)
  • Hypoparathyroidism (0.5–5% of cases)
  • Voice changes due to superior-laryngeal-nerve damage
  • Hypothyroidism

Surgical morbidity depends on extend of resection, seize of goiter, and reoperation for recurrent goiter (38). Recurrence of goiter increases with time. Recurrence rate after 10 years may be approximately 10% (39). Routine thyroxine therapy after surgery is not recommended. Several uncontrolled studies have yielded no evidence; randomized studies with long follow-up are not existing (13, 40).

Thyroxine therapy

Before treatment with thyroxine serum thyrotrophin should be measured because patients may have autonomous thyroid hormone production and subclinical hyperthyroidism. Cave - this may cause overt hyperthyroidism (41). There is no evidence that long-term thyroxine therapy alters the natural history of multinodular goiter (13). Randomized, placebo-controlled trials using objective volume measurements are rare. Goiter size was relatively small in one study and returned to base line after discontinuation of treatment (grade B) (42). Cystic and autonomously (thyrotrophin-independent) lesions rarely shrink with thyrotrophin suppression. In deciding whether thyroid hormone therapy is appropriate the following factors should be considered: pattern of growth and stability of nodule, degree of diagnostic certainty, patients perioperative risk, risk to develop other medical conditions that might be exacerbated by thyroid hormone therapy, e.g., cardiac disease or osteoporosis (12).

Radioiodine therapy

Radioiodine therapy (iodine-131) is effective in most patients with non-toxic multinodular goiter (4347). Compressive symptoms decreased in the majority of patients. Side effects (pain, radiation thyroiditis, esophagitis, increase in compressive symptoms) are rare (48). Development of autoimmune hyperthyroidism (Graves’) occurs several months after therapy in approximately 5% of patients (49). Post-treatment hypothyroidism incidence is reported to be 20% to 30% at five years. The risk of induction of carcinoma is not established by studies (44).

Toxic uninodular and multinodular goiter

Indications for treatment are:

  • overt hyperthyroidism
  • subclinical hyperthyroidism in elderly patients and in younger patients who are at risk for cardiac disease or osteoporosis

Treatment options are:

  • antithyroid drugs (ATDs)
  • surgery
  • radioiodine

The treatment plan should take into consideration age, type of goiter, degree of hyperthyroidism, and patient wishes.

Medical therapy

The antithyroid drug therapy is often a life-long therapy; recurrence may follow immediately when the treatment is stopped. It may lower operative risk if given before surgery, and sometimes before and after radioiodine treatment to achieve faster euthyroidism. If a change in the administration of thyroxine may have a significant effect on hyperthyroidism, remains to be elucidated. However, there is evidence (grade B) that during weekly administration of T4, autoregulatory mechanisms may maintain euthyroidism (50).

Surgery

Surgery is the treatment of choice in patients of fertile age, large goiters or severe hyperthyroidism and all patients with toxic nodular goiters (23). Hyperthyroidism and solitary autonomously functioning thyroid nodule may be treated by lobectomy or nodulectomy. European guidelines stress the importance of a selective resection of diseased thyroid tissue and leaving normal thyroid tissue in place (14). Recurrence is then rare, hypothyroidism occurs in 10 to 20% of patients (5153). For toxic multinodular goiter the surgical therapy may consist of bilateral subtotal thyroidectomy, or in selected cases it will be the near-total resection. The operative risk is similar to nontoxic multinodular goiter. The combined incidence of persistent and recurrent hyperthyroidism may be less than 10 to 20%. Post-treatment hypothyroidism was reported in up to 70% (54, 55). Hyperthyroidism can be treated by hemithyroidectomy plus contralateral resection without increasing the risk of complications (grade B) (56). The widely held assumption that surgical trauma stimulates the release of thyroid hormones may not be true. In a recent study it was demonstrated that surgery did not induce any intraoperative increase in fT3 or fT4 in patients with untreated severe hyperthyroidism (57). The indication for total thyroidectomy remains a subject of dispute. There is no grade A or B evidence to recommend total thyroidectomy in patients with toxic goiter or Graves’ disease. Several studies reported conflicting results in the evaluation of total thyroidectomy. In a retrospective analysis of 825 patients the rate of recurrent nerve palsy was 0.5%, the rate of permanent hypoparathyroidism 0.6%. The low complication rate was attributed to the capsular dissection technique. The authors conclud that total thyroidectomy should be used for most benign diseases such as multinodular goiter, thyroiditis, and goiters affected by thyrotoxicosis (-grade C) (58). In a retrospective analysis the nodular recurrence occurred in 36 of 1456 patients who underwent thyroidectomy. Since nodular recurrence occurred in only 2.5% of patients systematic total thyroidectomy was not recommended in multinodular goiter (grade C) (59).

Ethanol injection

Ethanol injection therapy has been the subject of several investigations. There is evidence (grade A) that ethanol injection induces necrosis and reduces the volume of benign solitary solid thyroid nodules. An additive effect of two additional doses of ethanol is insignificant. However, the procedure is quite painful despite local anesthesia and routine use may not be recommended (60).

Graves’ disease (M. Basedow)

The American Thyroid Association recommends thyroidectomy for patients with Graves’ disease in case of specific indication which include very large goiters who may be relatively to 131I, those who have coincidental thyroid nodules, pregnant patients allergic to ATDs and patients who are allergic to ATDs and/or do not wish 131I therapy. Approximately two months after surgery, thyroid status should be assessed. Recurrent hyperthyroidism can occur after surgery, but hypothyroidism is far more common. If levothyroxine is necessary patients should be followed at yearly intervals. Patients who are euthyroid should also be followed yearly measuring serum TSH (61). Europe guidelines offer both subtotal resection of both lobes (< 5 ml remnant thyroid) or hemithyroidectomy and contralateral subtotal resection. Recurrence rate is then below 5%. A postoperative substitution of thyroxine is indicated in most patients (14).

Most surgical studies in goiter, hyperthyroidism or Graves’ disease evaluating surgical technique are case series or retrospective analysis (grade C) (table I).

Table I. Clinical studies in benign thyroid disease evaluating surgical technique.

Table I

Clinical studies in benign thyroid disease evaluating surgical technique.

Radioiodine therapy

Radioactive iodine (131I) is the most commonly used form of treatment in the United States. It is considered to be effective as surgery for treatment of patients with autonomously functioning thyroid nodules and those with toxic multinodular goiters (13). The size of the goiter may be a criterion for exclusion of radioiodine therapy. Reversal of hyperthyroidism is more gradual. The principal side effect is hypothyroidism (61) . The incidence of hypothyroidism is approximately 10% (53). Hypothyroidism in patients with toxic nodular goiter less common than in those with Graves’ hyperthyroidism. In a large follow-up study the risk of thyroid carcinoma was not increased (62).

Medical therapy

Antithyroid drugs may be started as initial therapy or to lower thyroid hormone levels before surgery or radioiodine therapy (methimazole 10–40 mg or propylthiouracil 100–600 mg). Duration of treatment is 6 months to two years. Adverse reactions may be itching, rash, arthralgias or hepatic abnormalities (61).

Conclusion

Subtotal thyroidectomy in case of benign nodular thyroid disease is by far the most often used operation. However, in recent years there is a trend for a more sophisticated surgical therapy, e.g., lobectomy plus contralateral subtotal lobectomy. The significance of total thyroidectomy for benign nodular thyroid disease remains a subject of dispute unless clear evidence is present. The identification of recurrent laryngeal nerve (RLN) and parathyroid glands is accepted by most authors. Special surgical techniques, e.g., capsular dissection technique and neuromonitoring, may further improve the results of surgery and avoid complications. It is obvious that most evidence in benign thyroid disease is grade C.

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