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Treatment of benign obstructive or substernal goiter

Treatment of benign obstructive or substernal goiter
Author:
Douglas S Ross, MD
Section Editor:
David S Cooper, MD
Deputy Editor:
Jean E Mulder, MD
Literature review current through: Jan 2024.
This topic last updated: Jan 29, 2024.

INTRODUCTION — Goiter refers to abnormal growth of the thyroid gland. Patients with longstanding goiters (cervical or substernal) may develop symptoms of obstruction due to progressive compression of the trachea or sudden enlargement (usually accompanied by pain) secondary to hemorrhage into a nodule. The most common obstructive symptom is exertional dyspnea, which is present in 30 to 60 percent of cases; it usually occurs when the tracheal diameter is under 8 mm. Substernal goiter may be detected incidentally on chest radiograph or computed tomography (CT) scan or found because of obstructive symptoms such as dyspnea, wheezing, or cough.

Once goiter is detected (on physical examination or incidentally during a radiologic procedure performed for other purposes), an evaluation is performed to assess thyroid function and to identify the underlying cause, presence of obstructive symptoms, and presence of suspicious sonographic features in nodules within the goiter. These factors determine management.

The treatment of benign obstructive or substernal goiters will be reviewed here. The clinical manifestations and evaluation of suspected obstructive or substernal goiter is reviewed separately. The management of benign nonobstructive goiter, toxic multinodular goiter, and thyroid nodules with abnormal cytology is also discussed separately.

(See "Clinical presentation and evaluation of goiter in adults", section on 'Goiter with obstructive symptoms or suspected substernal goiter'.)

(See "Overview of the management of benign goiter".)

(See "Thyroid hormone suppressive therapy for thyroid nodules and benign goiter".)

(See "Treatment of toxic adenoma and toxic multinodular goiter".)

(See "Diagnostic approach to and treatment of thyroid nodules", section on 'FNA cytology'.)

ANATOMIC RELATIONSHIPS — Enlarging thyroid lobes usually grow outward because of their location in the anterior neck in front of the trachea, covered only by thin muscles, subcutaneous tissue, and skin. In patients with substantial enlargement of one lobe or asymmetric enlargement of both lobes, the trachea, esophagus, or blood vessels may be displaced or, less often, compressed. Bilateral lobar enlargement (especially if the goiter extends posterior to the trachea) may cause either compression or concentric narrowing of the trachea or compression of the esophagus or jugular veins. Exertional dyspnea is the most common obstructive symptom, occurring in 30 to 60 percent of such cases, typically when the tracheal diameter is under 8 mm. (See "Surgical anatomy of the thyroid gland".)

With some goiters, there is growth of one or both lobes through the thoracic inlet into the thoracic cavity, which can result in obstruction of any of the structures in the inlet (image 1A-B). Such goiters are referred to as substernal.

OUR APPROACH TO MANAGEMENT — Our approach described below is based on evidence from observational studies and from clinical experience (algorithm 1).

Goiter with obstructive symptoms — Patients with obstructive symptoms (eg, dysphagia, dyspnea, cough) from a cervical or substernal goiter require removal or ablation of the thyroid. Once obstructive symptoms are present, there is risk of further thyroid growth and progressive tracheal compression, which in some instances (eg, hemorrhage) may be rapid and fatal.

For the treatment of obstructive goiter, we suggest surgery rather than radioiodine (see 'Approach to surgery' below and 'Radioiodine administration' below). We prefer surgery because it eliminates the goiter and provides immediate relief of obstructive symptoms, whereas radioiodine only moderately reduces thyroid volume (40 to 60 percent) and provides reasonable relief of obstructive symptoms [1-10]. After radioiodine, the treated goiter requires continued monitoring for growth and malignancy. In addition, there are rare cases of radioiodine-induced radiation thyroiditis with acute worsening of airway obstruction [1]. (See 'Adverse effects of radioiodine' below.)

We reserve radioiodine for patients with obstructive symptoms who are poor surgical candidates or who want to avoid surgical risks (see 'Complications' below), particularly if the substernal or obstructive goitrous tissue is functional on thyroid radionuclide imaging. Radioiodine may be most efficacious in this setting. (See "Treatment of toxic adenoma and toxic multinodular goiter", section on 'Choice of therapy'.)

Radioiodine therapy is relatively infrequently used in the United States for the treatment of nontoxic goiter. Due to high dietary iodine intake, thyroid iodine uptake is typically low in patients with nontoxic goiter, and therefore, a relatively high dose of radioiodine is required for goiter reduction (see 'Dose' below). Radioiodine for the treatment of nontoxic nodular goiter is more commonly used in Europe, and in particular Denmark and the Netherlands. (See 'Radioiodine administration' below.)

Although the use of ultrasound-guided thermal ablation techniques (eg, radiofrequency ablation, microwave ablation) for the treatment of thyroid nodules is expanding, there are few case reports describing successful ablation of thyroid nodules in patients with obstructive goiter (eg, tracheal compression) [11]. In centers with expertise in these procedures, thermal ablation of obstructive goitrous tissue situated above the sternal notch with the neck extended may be an option for patients who are poor surgical candidates or who want to avoid surgical risks. These techniques should be applied with caution given limited evidence in this patient population [12].

Substernal goiter — In the absence of obstructive symptoms, the choice of therapy depends upon the extent of substernal extension and patient characteristics.

Extension below the brachiocephalic vein — The author of this topic and others suggest surgery for most patients with substernal goiters that extend below the level of the brachiocephalic vein, assuming they are good surgical candidates (image 1B) [13-18] (see 'Approach to surgery' below). However, this is an area of controversy, and other experts prefer to monitor such patients.

The arguments for removing a substernal goiter in a patient who has no obstructive symptoms include:

Some goiters continue to enlarge and become more difficult to remove if obstructive symptoms do develop. (See "Clinical presentation and evaluation of goiter in adults", section on 'Obstructive symptoms'.)

Levothyroxine suppressive therapy is relatively ineffective and is associated with significant morbidity in older patients.

Approximately 42 percent of patients with evidence of upper airway obstruction on flow-volume loops are asymptomatic [19].

As patients age, surgical complications are more common and severe [20].

The substernal component could contain a cancer that cannot be palpated or biopsied (range of reported cancer risk 3 to 22 percent) [18,21].

There is a small risk of hemorrhage into the goiter that could result in acute airway obstruction. (See "Clinical presentation and evaluation of goiter in adults", section on 'Obstructive symptoms'.)

Extension to the level of the brachiocephalic vein or higher

Mild symptoms or signs or cosmetic concerns – For patients with substernal goiter (extending no further than the brachiocephalic vein) and mild symptoms (eg, pressure), mild signs (eg, tracheal deviations), or cosmetic concerns, treatment options include continued surveillance for progression of symptoms or signs, thyroid surgery, radioiodine ablation, or potentially ultrasound-guided thermal ablation (eg, radiofrequency ablation, where expertise is available). Management decisions should be individualized based upon patient factors, regional medical practices, and advantages and disadvantages of each modality (table 1). (See 'Surveillance for patients not receiving definitive therapy' below and 'Approach to surgery' below and 'Radioiodine administration' below and 'Ultrasound-guided thermal ablation techniques' below.)

If surveillance is chosen, ideally treatment should be pursued before symptoms increase or patient develops comorbidities that may preclude surgery.

Asymptomatic with no cosmetic concerns – We suggest surveillance rather than surgery for asymptomatic patients with normal flow-volume loops whose goiters end at the level of the brachiocephalic vein or higher. (See 'Surveillance for patients not receiving definitive therapy' below.)

This includes:

Patients without thyroid enlargement whose thyroid glands extend slightly substernally due to kyphosis.

Patients whose goiters extend only slightly substernally on a CT scan obtained without neck extension. The thyroid gland may not be substernal when the neck is extended. Their glands are also usually accessible for fine-needle aspiration (FNA) biopsy if indicated.

Patients who, in retrospect, have serial CT scans showing long-term stability of a substernal goiter, especially if the inferior extent is above the level of the brachiocephalic vein.

Levothyroxine may have a limited role in patients with asymptomatic substernal goiters. In a randomized trial, thyroid-stimulating hormone (TSH)-suppressive doses of levothyroxine reduced goiter size in approximately two-thirds of patients with sporadic, multinodular goiters [22]. However, most large goiters do not shrink sufficiently to alleviate symptoms [23], any reduction in size is not rapid, and levothyroxine is not effective in those patients who already have low serum TSH concentrations (ie, subclinical hyperthyroidism). Additionally, growth of the goiter may resume as soon as levothyroxine treatment is stopped. (See "Thyroid hormone suppressive therapy for thyroid nodules and benign goiter".)

Surveillance for patients not receiving definitive therapy — Patients who do not pursue definitive treatment of goiter should be monitored to detect thyroid function test abnormalities or evidence of growth.

We perform the following assessment annually, or sooner if the patient develops new symptoms:

Measurement of TSH and free thyroxine (T4)

Assessment for growth of goiter

Symptom development

Physical examination

Imaging

We obtain CT scans, usually noncontrast, initially after one year and, if stable, at increasing intervals. In patients with autonomous thyroid nodules, iodine-induced hyperthyroidism may occasionally occur after exposure to iodinated contrast agents during diagnostic radiography. (See "Iodine-induced thyroid dysfunction", section on 'Iodine-induced hyperthyroidism'.)

If growth is detected on serial CT scans and the trajectory suggests that the patient is likely to develop obstructive symptoms in their lifetime, we suggest surgery, if possible (see 'Approach to surgery' below). Radioiodine therapy or ultrasound-guided ablation techniques (if the goiter is accessible by ultrasound with extension of the neck) may be options for patients who are unable or unwilling to undergo surgery. (See 'Radioiodine administration' below and 'Ultrasound-guided thermal ablation techniques' below.)

Ideally, definitive treatment should be pursued before development of symptoms or patient comorbidities that may preclude surgery. For patients with minimally substernal goiters, the goal is to treat before the goiter extends into the chest.

APPROACH TO SURGERY

Preoperative assessment — Patients with symptomatic or substernal goiter who are undergoing thyroid surgery should be referred to an experienced thyroid surgeon as complication rates appear to be lower in high-volume centers [24]. Patients who may require sternotomy should be referred to an experienced thoracic surgeon [25].

Once the decision to proceed with surgery has been made, preoperative assessment includes measurement of serum TSH to identify hyperthyroidism or hypothyroidism, additional thyroid imaging (ultrasound, CT) if not performed recently, and laryngoscopy to visualize the tracheal lumen and vocal cords. (See "Clinical presentation and evaluation of goiter in adults", section on 'Goiter with obstructive symptoms or suspected substernal goiter' and "Thyroidectomy", section on 'Preoperative evaluation and preparation'.)

If overt hypothyroidism or hyperthyroidism are present and the surgery is elective, surgery should be delayed until the patient is euthyroid. For overtly hypothyroid or hyperthyroid patients in whom surgery cannot be postponed (eg, severe obstructive symptoms), preoperative treatment of hypothyroidism or hyperthyroidism should be initiated as soon as possible. Patients with subclinical hypothyroidism or subclinical hyperthyroidism can typically proceed with elective or urgent surgery. (See "Surgical management of hyperthyroidism", section on 'Preoperative preparation' and "Treatment of primary hypothyroidism in adults", section on 'Standard replacement therapy'.)

Extent of resection — The extent of surgery for benign goiter depends upon the expertise of the surgeon, the extent of the goiter, and whether the patient has obstructive symptoms and signs. Because of the risk of recurrent goiter, a total or near-total thyroidectomy should be performed unless during the procedure the surgeon feels that a less extensive operation is prudent because of an increased risk of recurrent laryngeal nerve injury or hypoparathyroidism due to anatomic considerations. In a meta-analysis of four randomized trials in people with cervical nontoxic multinodular goiter, recurrent goiter was less common after total than subtotal thyroidectomy [26].

If a more limited operation is done, we suggest:

Patients with large, relatively symmetric goiters should have a bilateral subtotal thyroidectomy.

Patients with asymmetric goiters should have a hemithyroidectomy on the more involved side and a subtotal thyroidectomy on the contralateral side. If the patient already has vocal cord paralysis on the more involved side and the contralateral thyroid lobe is not very large, we suggest doing only a hemithyroidectomy and isthmusectomy.

In patients with chronic autoimmune thyroiditis who have concentric tracheal compression, excision of the isthmus alone may be sufficient to alleviate the compression. These fibrous glands may be difficult to dissect free from nerves and parathyroid glands, and more extensive surgery may result in complications.

Most obstructive and substernal goiters can be excised through a standard cervical incision [27,28], while partial or complete sternotomy or even thoracotomy may be required in patients with previous cervical thyroidectomy, very large substernal goiters, or invasive cancer [25,29,30]. In an Italian study of 19,662 patients undergoing total thyroidectomy at six centers, 1055 had substernal goiters and only 69 (6.5 percent) required sternotomy [31]. Patients requiring sternotomy were more likely to have a malignancy (36 compared with 22 percent of those excised through a cervical incision). Similar results were noted in two single-center studies [18,32] and in a systematic review [21]; recurrent or ectopic goiter in addition to malignancy were associated with the need for sternotomy. In one analysis, extension more than 5 cm below the sternal notch correlated with the need for sternotomy [33].

Complications — The major complications of surgery for large goiters and substernal goiters are injury to the recurrent laryngeal nerves, trachea, and parathyroid glands [13-16,18,25,29,34].

Surgery for substernal goiter appears to be associated with higher complication rates than surgery for cervical goiter [20,35], as illustrated by a statewide database of cervical (n = 32,777) and substernal thyroidectomies (n = 1153) performed between 1998 and 2004. Patients who underwent substernal thyroidectomy were more likely to be older, have a comorbid condition, be uninsured, be undergoing total thyroidectomy, and have surgery at a low-volume center [20]. After adjusting for these variables, patients undergoing substernal thyroidectomy were still at higher risk for the following:

Recurrent laryngeal nerve injury (odds ratio [OR] 2.4, 95% CI 1.5-3.8)

Postoperative bleeding (OR 1.9, 95% CI 1.2-2.9)

Deep venous thrombosis (OR 5.9, 95% CI 2.4-15.2)

Respiratory failure (OR 4.2, 95% CI 2.8-6.2)

Red blood cell transfusion (OR 5.7, 95% CI 3.8-8.5)

Mortality (OR 8.3, 95% CI 4.2-16.3)

In the same database, complication rates were significantly lower at hospitals that performed a high volume of substernal thyroidectomies [24].

Of note, this study did not report how many patients with substernal goiter required sternotomy, a procedure that may be associated with higher surgical complication rates [31,36]. In the Italian study of 1055 patients with substernal goiter, 69 patients who required a sternotomy were compared with 986 patients whose goiters were excised through a cervical incision [31]; only phrenic nerve palsy was more common in the sternotomy group. In a study from the National Surgical Quality Improvement Program database of 2716 patients with substernal goiter, the 14 percent who required a sternal split or transthoracic approach had a higher incidence of unplanned intubation (OR 2.70, 95% CI 1.17-6.25) and bleeding (OR 5.56, 95% CI 2.38-13.0); a higher incidence of death (1.9 versus 0.3 percent) was not statistically significant [36]. Together, these studies suggest that surgery for substernal goiter (using a cervical approach or sternotomy) is associated with higher complication rates than surgery for cervical goiter.

Recurrent laryngeal nerve injury — Transient recurrent laryngeal nerve injury has been reported to occur in 2 to 9 percent of patients undergoing surgery for substernal goiter [18,29,30,34]. Permanent nerve injury occurs less commonly: 0 and 0.03 percent in the two largest studies [18,34] and 3 percent in two other reports [29,30]. Patients with bilateral nerve injury and therefore bilateral vocal cord paralysis require tracheostomy to provide an adequate airway.

Hypocalcemia — Hypocalcemia due to hypoparathyroidism is the most frequent complication of near-total thyroidectomy and is more common when the goiter is extensive and anatomic landmarks are displaced and obscured. Hypocalcemia may be transient or permanent. In one series, transient hypoparathyroidism occurred in 12 of 170 patients (7 percent) undergoing cervical thyroidectomy for substernal goiter [18].

Current requirements for short hospital stays argue for early treatment of hypocalcemia. Our approach to the management of hypocalcemia is summarized in the table and reviewed in detail separately (table 2). (See "Differentiated thyroid cancer: Surgical treatment", section on 'Hypoparathyroidism' and "Hypoparathyroidism", section on 'Acute hypoparathyroidism: Postsurgical'.)

Tracheomalacia — In patients who have tracheomalacia due to pressure-induced destruction of tracheal rings by the goiter, the airway may collapse during the postoperative period. In one study, 10 percent of patients could not be immediately extubated, although all were successfully extubated by 10 days [37]. These patients were older, had larger goiters, and were more likely to have tracheal compression. If recognized at the time of surgery, tracheomalacia may, in some cases, be treated by partial tracheal resection and reconstruction; otherwise, tracheostomy is necessary.

In a systematic review, the presence of a substernal goiter for more than five years causing tracheal compression was a risk factor for tracheomalacia and tracheostomy. However, in this review, tracheomalacia was an infrequent occurrence (3 percent) and was managed without tracheostomy in approximately 50 percent of cases [21].

Levothyroxine after surgery — Patients who undergo total thyroidectomy for benign disease should start a replacement dose of levothyroxine daily at an approximate dose of 1.6 mcg/kg body weight. Patients over 65 years should be started at a 10 to 15 percent lower dose. Serum TSH should be tested approximately six weeks after starting the replacement therapy. The TSH should be kept in a normal range. (See "Treatment of primary hypothyroidism in adults".)

We generally do not prescribe postoperative TSH suppressive therapy with levothyroxine. However, the author of this topic discusses a trial of suppressive therapy with young patients who have no contraindications to TSH suppression and who experience growth of a surgical remnant.

Treatment with higher doses of levothyroxine to suppress serum TSH to prevent goiter recurrence in patients who have already had surgery for obstructive goiter (versus no thyroid hormone therapy or replacement therapy if needed to normalize the serum TSH concentration) is controversial. In one study with 10 years of follow-up, the recurrence rate was lower in the patients treated with levothyroxine (5 versus 42 percent in the untreated group had recurrent goiter) [38]. However, this benefit was not confirmed in a report with 30 years of follow-up; the recurrence rates were similar (41 and 45 percent) in treated and untreated patients [39]. (See "Thyroid hormone suppressive therapy for thyroid nodules and benign goiter".)

RADIOIODINE ADMINISTRATION

Efficacy — There are several observational studies, mostly from Europe, describing the effects of radioiodine therapy in over 300 patients with nontoxic multinodular goiter (average goiter size ranging from 60 to 269 mL) [1-10]. In most studies, the patients were older; had respiratory symptoms, dysphagia, or recent thyroid growth; and were considered poor surgical candidates or had refused surgery. Overall, the reported reduction in goiter size (as measured by ultrasound) ranged from 40 to 60 percent within one to two years of therapy, with most of the effect occurring in the first three months [3]. Obstructive symptoms improved in most patients with increases in tracheal luminal diameter.

As examples:

In one series of 14 patients with large multinodular goiters, eight of whom had respiratory symptoms and eight of whom had substernal extension, all improved after treatment with 200 to 400 microcuries/g of radioiodine (total dose range 20 to 100 millicuries [740 to 3700 megabecquerels]), and no patient had an acute exacerbation of obstructive symptoms [7].

Similar improvements in obstructive symptoms were seen in a series of 19 older patients treated with 100 microcuries/g tissue (average total dose 70 millicuries [2590 megabecquerels]). Goiter volume decreased by 40 percent [4].

In other series, goiter volume decreased by 36 percent [40], and volume reduction of the cervical and substernal components was similar (30 percent in one study) [41].

The factors determining outcome were analyzed in one study of 50 patients (goiter size 17 to 325 mL) in whom the mean reduction in goiter size was 47 percent (median follow-up 41 months) [42]. Among the 50 patients, 11 (22 percent) had no decrease in goiter size or a transient decrease and then re-enlargement of their goiter. The reduction in goiter size was greater in younger patients; those with smaller goiters, a shorter history of goiter, or dominant nodules; and those given higher doses of radioiodine. In general, very large goiters require larger doses of radioiodine to effectively decrease goiter volume [10,42]. The baseline serum TSH concentration was not a determinant of reduction in goiter size, but a higher (but still normal) value was associated with a higher risk of hypothyroidism.

Dose — In observational studies, the dose of radioiodine delivered to the thyroid ranged from 75 to 400 microcuries/g thyroid tissue (2.8 to 14.8 megabecquerels/g) [1-10]. Most patients received doses between 100 and 200 microcuries/g thyroid tissue (3.7 and 7.4 megabecquerels/g), similar to the desired radioiodine delivery to the thyroid during treatment of hyperthyroidism. (See "Radioiodine in the treatment of hyperthyroidism".)

In observational studies, the total dose was usually calculated by the following formula:

 Dose (activity)  =  (thyroid weight  x  desired radioiodine delivery to thyroid/g)  ÷  radioiodine uptake

The units are grams for thyroid weight and microcuries/g thyroid tissue for radioiodine delivery; radioiodine uptake is expressed as a decimal (ie, 20 percent = 0.20).

The 24-hour thyroid radioiodine uptake is considerably lower in patients with nontoxic multinodular goiter than in patients with Graves' hyperthyroidism or toxic multinodular goiter, particularly in patients with high dietary iodine intake (eg, in the United States). Therefore, a relatively high dose of radioiodine is required for goiter reduction. As a result, the dose of radioiodine needed may exceed that permissible for outpatients, which varies from state to state in the United States and also among other countries. Efforts to improve radioiodine uptake and thereby reduce the radioiodine include pretreatment with recombinant human TSH (rhTSH, thyrotropin alfa) or methimazole. (See 'Pretreatment with recombinant human TSH to increase the radioiodine uptake' below and 'Pretreatment with methimazole to increase the radioiodine uptake' below.)

An alternative approach is to use multiple fractionated doses of radioiodine. When 60 millicuries (2.22 gigabecquerels) was given in four divided monthly doses to patients with obstructive goiter in one report, 71 percent had improvement in symptoms related to compression of neck structures and 92 percent had a reduction in goiter size, but 66 percent became hypothyroid [43]. Slightly over one-half of the patients had toxic nodular goiter. Thus, it is uncertain whether the higher rate of hypothyroidism was due to the fractionated doses or higher retention of isotope in the hyperthyroid patients.

Pretreatment with recombinant human TSH to increase the radioiodine uptake — We do not administer rhTSH for the purpose of increasing radioiodine uptake. Neither regular nor modified-release rhTSH is approved by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA) for use with radioiodine in the treatment of multinodular goiter. It is only available in kits of two vials of 0.9 mg (for use prior to administration of radioiodine to athyreotic thyroid cancer patients), and it is costly. The proposed rhTSH dosing for treatment of nontoxic multinodular goiter is much lower than for thyroid cancer, and a preparation designed for use in patients with nontoxic goiter is not currently available. (See "Differentiated thyroid cancer: Radioiodine treatment", section on 'Recombinant human TSH'.)

Nevertheless, pretreatment of nontoxic nodular goiter with rhTSH (thyrotropin alfa) prior to radioiodine administration has been evaluated for the purpose of increasing radioiodine uptake and reducing radioiodine dose or frequency of repeat radioiodine treatment.

Efficacy of rhTSH – The addition of recombinant human thyroid-stimulating hormone (rhTSH, thyrotropin alfa) to radioiodine in patients with obstructive goiters appears to allow treatment with lower doses of radioiodine and results in a greater reduction in thyroid volume than radioiodine alone [44,45]. The reduction in radioiodine dose may facilitate outpatient treatment and reduce the risk of side effects.

As examples:

In meta-analyses of trials, radioiodine with rhTSH (eg, 0.005 to 0.45 mg administered 24 hours prior to radioiodine) was significantly more effective in reducing goiter volume than radioiodine alone (weighted mean difference 11.9 to 19.66 percent) [46,47].

In one of the trials in the meta-analysis, 90 patients with nontoxic nodular goiter (median size 63 mL) were randomly assigned to either 0.1 mg rhTSH and radioiodine (50 grays) or placebo and radioiodine (100 grays) [44]. After 12 months, the mean reduction in goiter volume was identical (35 percent), even though the rhTSH group received one-half the dose of radioiodine as the placebo group. Both groups reported improvement in goiter symptoms.

With longer-term follow-up (mean 71 months), the reduction in goiter volume remained higher in the rhTSH group (70 versus 56 percent in the group who received radioiodine without rhTSH), and the number of patients requiring additional therapy for obstructive symptoms was lower in the rhTSH group (5 versus 20 percent in the group who were not pretreated with rhTSH) [48-50].

Adverse effects of rhTSH – Compared with radioiodine alone, the use of rhTSH prior to radioiodine is associated with a higher incidence of hypothyroidism (62 versus 11 percent in one trial [48]). However, in the trial described above in which patients who were pretreated with rhTSH received one-half the dose of radioiodine, the difference in the prevalence of hypothyroidism one year after treatment was not significant (12 versus 7 percent) [44].

Another potential concern about pretreatment with rhTSH is an increase in goiter size after administration of rhTSH. This was illustrated in a study of 10 patients with nodular goiter given 0.3 mg of rhTSH who then experienced an increase in mean goiter size at 24 hours of 9.8 percent and at 48 hours of 24 percent, returning to baseline at one week, suggesting that rhTSH could cause obstructive symptoms in patients with near obstructive goiters and that candidates for this treatment should be carefully screened for near-critical obstructive signs or symptoms [51].

In another study using rhTSH to reduce goiter size in 14 patients with large goiters, the smallest cross-sectional area of the trachea measured by magnetic resonance imaging (MRI) was found to be 10.5 percent greater one week after radioiodine administration, although the forced vital capacity was slightly reduced [52]. A modified-release, very-low-dose rhTSH preparation (0.01 to 0.03 mg) has been studied that results in lower peak serum TSH levels and, therefore, might be associated with less risk of goiter enlargement [53].

Pretreatment with methimazole to increase the radioiodine uptake — Methimazole increases TSH by reducing thyroid hormone synthesis. One would anticipate that the higher level of TSH would be associated with a higher radioiodine uptake. This was demonstrated in a small randomized trial (mean goiter volume 65 mL) comparing methimazole 10 mg daily or placebo for six weeks prior to radioiodine administration (21.6 millicuries [800 megabecquerels]) [54]. Methimazole increased the TSH from 2.1 to 7.9 mIU/L, and the rate of radioiodine uptake from 29 to 65 percent. Reduction in gland size was 34 percent greater in the group that received methimazole, while there was no change in the rate of hypothyroidism at one year (31 versus 27 percent in the treatment versus placebo group, respectively).

Adverse effects of radioiodine — Radioiodine is generally well tolerated (table 1). Concerns that radioiodine therapy in patients with nontoxic multinodular goiter might cause early goiter enlargement, thereby leading to acute airway obstruction, have not materialized [1,8]. However, in a study of patients with nonobstructive, toxic multinodular goiter given radioiodine, 8 percent had an increase in goiter size (mean increase 23 percent) [55], suggesting caution and careful monitoring in patients with severe tracheal narrowing.

In studies of radioiodine for the treatment of nontoxic goiter with compressive symptoms or cosmetic concerns, the following findings were noted:

Hypothyroidism – Hypothyroidism occurred in 22 to 58 percent of patients within one to eight years after treatment [1,5,6,42,56]. An additional 10 to 40 percent of patients had subclinical hypothyroidism [6,7,9,42], and treatment with levothyroxine after radioiodine probably masked hypothyroidism in some other patients.

Transient hyperthyroidism – Approximately 5 percent of patients had transient hyperthyroidism [4,6,7,9,56]. The mean serum free T4 and triiodothyronine (T3) concentrations transiently increased by 13 and 20 percent, respectively, in the first two weeks after treatment [8].

Two groups found that 4 to 5 percent of patients with nontoxic multinodular goiter treated with radioiodine developed Graves' hyperthyroidism, with high serum concentrations of TSH receptor antibodies 3 to 10 months later [57,58]. Another study of over 1350 patients found only 1.1 percent of patients developed autoimmune hyperthyroidism [59]. However, this occurred up to 10 times more commonly in patients with high serum antithyroid peroxidase antibody concentrations before treatment (TSH receptor antibody tests were negative then in all patients) [58,59]. These patients were treated with an antithyroid drug or additional radioiodine. (See "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment".)

Radiation thyroiditis – Symptomatic radiation thyroiditis (thyroid pain and tenderness) was uncommon, occurring in 2 of 69 patients (3 percent) in one series [6] and 4 of 32 patients (13 percent) in another series [60]. (See "Overview of thyroiditis".)

Risk of nonthyroid cancer – Based on measurements of whole-body radiation exposure, one group calculated slightly increased estimated lifetime risk of nonthyroid cancer of approximately 1.6 percent because of the large doses of radioiodine used in patients with very large goiters (mean size 222 g) [61]. The risk is much less (approximately 0.5 percent) in patients above the age of 65 years, the age of most patients with nontoxic multinodular goiters large enough to require therapy. The risk of nonthyroid and thyroid cancer after radioiodine treatment of hyperthyroidism is discussed separately. (See "Radioiodine in the treatment of hyperthyroidism", section on 'Cancer'.)

Monitoring after radioiodine therapy — We monitor for the development of hypothyroidism and for evidence of thyroid growth or malignancy:

Hypothyroidism – We measure TSH initially after three to six months. If the patient remains euthyroid, serum TSH should be measured at yearly intervals for the patient's lifetime because of the ongoing risk of hypothyroidism. If hypothyroidism develops, levothyroxine should be initiated and the dose adjusted to maintain a normal TSH level. (See "Treatment of primary hypothyroidism in adults", section on 'Dose and monitoring'.)

Evidence of growth or malignancy – We monitor annually for evidence of growth (eg, symptom development, physical examination findings, CT imaging). The development of nodule(s) warrants thyroid ultrasound and fine-needle aspiration (FNA) biopsy. (See "Diagnostic approach to and treatment of thyroid nodules", section on 'Fine-needle aspiration biopsy'.)

ULTRASOUND-GUIDED THERMAL ABLATION TECHNIQUES — The American Thyroid Association statement suggests that patients with large obstructive or substernal goiters are best treated surgically and that thermal ablation techniques (where available) be used with caution [12].

There are few case reports describing successful thermal ablation (eg, radiofrequency ablation, microwave ablation) of thyroid nodules in patients with obstructive or substernal nodular goiter [11,62,63]. Thermal ablation of substernal nodules is more difficult due to the effect of respiratory variation on ultrasound visualization [12].

Thermal ablation techniques for benign nodules are reviewed separately. (See "Diagnostic approach to and treatment of thyroid nodules", section on 'Symptomatic benign nodules'.)

SUMMARY AND RECOMMENDATIONS

Anatomic relationships – Bilateral thyroid lobe enlargement (especially if the goiter extends posterior to the trachea) may cause either compression or concentric narrowing of the trachea or compression of the esophagus or jugular veins. Obstructive symptoms usually occur when the tracheal diameter is <8 mm. With some goiters, there is growth of one or both lobes through the thoracic inlet into the thoracic cavity, which can result in obstruction of any of the structures in the inlet. Such goiters are referred to as substernal (image 1A-B). (See 'Anatomic relationships' above.)

Goiter with obstructive symptoms – For patients with obstructive cervical or substernal goiter, we suggest surgery rather than radioiodine (Grade 2C). Surgery eliminates the goiter and provides immediate relief of obstructive symptoms, whereas radioiodine only moderately reduces thyroid volume (40 to 60 percent) and provides reasonable relief of obstructive symptoms. After radioiodine, the treated goiter requires continued monitoring for growth and malignancy. In addition, there are rare cases of radioiodine-induced radiation thyroiditis with acute worsening of airway obstruction. We reserve radioiodine for patients with obstructive symptoms who are poor surgical candidates or who want to avoid surgical risks, particularly if the substernal or obstructive goitrous tissue is functional on thyroid radionuclide imaging (algorithm 1). (See 'Goiter with obstructive symptoms' above.)

In centers with expertise in thermal ablation procedures, thermal ablation of obstructive nodular goitrous tissue situated above the sternal notch with the neck extended may also be an option for patients who are poor surgical candidates or who want to avoid surgical risks. These techniques should be applied with caution given limited evidence in this patient population. (See 'Goiter with obstructive symptoms' above and 'Ultrasound-guided thermal ablation techniques' above.)

Substernal goiter

Extension below the brachiocephalic vein – In the absence of obstructive symptoms, recommendations for patients with goiters that extend below the level of the brachiocephalic vein are controversial. The author of this topic suggests surgical excision for most patients except older patients and those who are poor operative candidates, while other experts suggest observation of asymptomatic patients. (See 'Extension below the brachiocephalic vein' above.)

Extension to the level of the brachiocephalic vein or higher

-Asymptomatic – For asymptomatic patients with normal flow-volume loops whose goiters end at the level of the brachiocephalic vein or higher, we suggest surveillance rather than surgery (Grade 2C). (See 'Extension to the level of the brachiocephalic vein or higher' above.)

-Mild symptoms or signs or cosmetic concerns – For patients with substernal goiter and mild symptoms (eg, pressure), mild signs (eg, tracheal deviations), or cosmetic concerns, treatment options include continued surveillance for progression of symptoms or signs, thyroid surgery, radioiodine ablation, or potentially thermal ablation (where expertise is available) (algorithm 1). Thermal ablation techniques should be applied with caution given limited evidence in this patient population.

Management decisions should be individualized based upon patient factors, regional medical practices, and advantages and disadvantages of each modality (table 1). (See 'Extension to the level of the brachiocephalic vein or higher' above.)

Surveillance – For patients not treated with definitive therapy, we monitor annually for thyroid function test abnormalities and for evidence of growth (eg, symptom development, physical examination findings, imaging). We obtain CT scans, initially after one year and, if stable, at increasing intervals. (See 'Surveillance for patients not receiving definitive therapy' above.)

Surgery

Surgical approach – For most patients undergoing surgery, we suggest a total or near-total thyroidectomy, rather than subtotal thyroidectomy (Grade 2C). More extensive surgery reduces the risk of recurrence, but may have a higher risk of complications depending on the extent of the goiter and the experience of the surgeon; thus, a more limited operation may be selected in some patients. All patients requiring surgery for substernal goiter should be referred to experienced thyroid surgeons in high-volume centers to minimize complication rates. (See 'Extent of resection' above.)

Complications – The major complications of surgery for large goiters and substernal goiters are injury to the recurrent laryngeal nerves, trachea, and parathyroid glands. Surgery for substernal goiter is often associated with higher complication rates than surgery for cervical goiter. (See 'Complications' above.)

Postoperative thyroid hormone replacement – Patients who undergo total thyroidectomy for benign disease should start a replacement dose of levothyroxine daily at an approximate dose of 1.6 mcg/kg body weight. Patients over 65 years should be started at a 10 to 15 percent lower dose. We typically do not prescribe suppressive doses of levothyroxine to prevent recurrence. However, the author of this topic discusses a trial of suppressive therapy with young patients who have no contraindications to suppression and who experience growth of a surgical remnant. (See 'Levothyroxine after surgery' above.)

Radioiodine administration – Radioiodine is generally well tolerated. Adverse effects may include transient hyperthyroidism, hypothyroidism, and radiation thyroiditis (table 1). The lifetime risk of nonthyroid cancer may be increased in people with very large goiters due to the large doses of radioiodine used in such patients. The risk is much less (approximately 0.5 percent) in patients above the age of 65 years, the age of most patients with nontoxic multinodular goiters large enough to require therapy. After radioiodine therapy, we monitor for the development of hypothyroidism and for evidence of thyroid growth or malignancy. (See 'Radioiodine administration' above.)

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Topic 7820 Version 17.0

References

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