Approach to the Patient with Nontoxic Multinodular Goiter
Article in The Journal of Clinical Endocrinology and Metabolism · May 2011
DOI: 10.1210/jc.2010-2583 · Source: PubMed
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Approach to the Patient with Nontoxic Multinodular Goiter
Rebecca S. Bahn and M. Regina Castro
Division of Endocrinology and Metabolism, Mayo Clinic, Rochester, Minnesota 55905
Thyroid nodules are very common, and although the majority are benign, approximately 5% may harbor malignancy. The evaluation of the patient with solitary thyroid nodule is generally straightforward and will typically include measurement of serum TSH to assess thyroid function and fine-needle aspi- ration biopsy of the nodule, with or without ultrasound (US) guidance. The approach to the patient with nontoxic multinodular goiter represents a more difficult problem for the clinician. All patients should have serum TSH mea- sured to assess functional thyroid status and US examination to evaluate the number, size, and sonographic features of the nodules and assist in the se- lection of nodules that may need fine-needle aspiration biopsy. Patients with nodules yielding malignant cytology should be referred for surgery. Given the lack of reliable markers to predict biological behavior of nodules with suspi- cious (indeterminate) cytology, patients with such nodules are generally ad- vised to have surgery, unless autonomous function of these nodules can be confirmed by scintigraphy. Most of these patients, however, will ultimately prove to have benign follicular tumors. Many patients with benign but large goiters may experience clinical symptoms of pressure, such as dysphagia, chok- ing sensation, or airway obstruction. Such patients will often require surgery for alleviation of symptoms. In the absence of malignancy, asymptomatic pa- tients may be observed. Radioactive iodine, commonly used in many parts of Europe, is safe and effective and may be a reasonable option for many pa- tients. Periodic follow-up with neck palpation and US exam is recommended for all patients.(J Clin Endocrinol Metab96: 1202–1212, 2011)
T
hyroid nodules are very common in clinical practice, and although most are benign, approximately 5%harbor malignancy. Their prevalence depends to a great extent on the method used for detection. By palpation, the least sensitive method, approximately 5% of people are found to have nodules. However, with the increased uti- lization of ultrasound (US) for evaluation of nonthyroid lesions of the neck, the incidental finding of unsuspected thyroid nodules (“incidentalomas”) has dramatically in- creased, with some studies reporting a prevalence of up to 50% in individuals over the age of 50 yr (1). The preva- lence of thyroid nodules is higher in women in areas of
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A.
Copyright © 2011 by The Endocrine Society
doi: 10.1210/jc.2010-2583 Received November 10, 2010. Accepted February 23, 2011.
Abbreviations: CT, Computed tomography; FNA, fine-needle aspiration; MNG, multinod- ular goiter; RAI, radioactive iodine; Rec., recommendation; rhTSH, recombinant human TSH; Tg, thyroglobulin; US, ultrasound.
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The Endocrine Society designates this Journal-based CME ac- tivity for a maximum of 1AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Learning Objectives
Upon completion of this educational activity, participants should be able to
•Recognize ultrasound features of benign and malignant thyroid nodules to assist in the selection of nodules that require FNA biopsy
•Establish a diagnostic work up for patients with non toxic multinodular goiter
•Select among different therapeutic modalities for the treatment of patients with non toxic multinodular goiter based on clinical symptoms and physical findings Target Audience
This Journal-based CME activity should be of substantial interest to endocrinologists.
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Disclosures forJCEMEditors are found athttp://www.
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The following individuals reported NO relevant financial relationships:
Rebecca S. Bahn, M.D., M. Regina Castro, M.D., and Leon- ard Wartofsky, M.D., reported no relevant financial relationships.
Endocrine Society staff associated with the development of content for this activity reported no relevant financial relationships.
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This Journal-based CME activity is available in print and online as full text HTML and as a PDF that can be viewed and/or printed using Adobe Acrobat Reader. To receive CME credit, participants should review the learning objec- tives and disclosure information; read the article and reflect on its content; then go tohttp://jcem.endojournals.organd find the article, click on CME for Readers, and follow the instructions to access and complete the post-activity test questions and evaluation. The estimated time to complete this activity, including review of material, is 1 hour. If you have questions about this CME activity, please direct them to [email protected].
Activity release date:May 2011 Activity expiration date:May 2012
A p p r o a c h t o t h e P a t i e n t
1202 jcem.endojournals.org J Clin Endocrinol Metab, May 2011, 96(5):1202–1212
iodine deficiency and increases with advancing age. Fac- tors that increase the risk of malignancy include male gen- der, history of head and neck irradiation, and very young or advanced age (⬍30 or⬎60 yr old) (2).
Evaluation of the euthyroid patient with a palpable soli- tary nodule is generally straightforward. Fine-needle aspira- tion (FNA) biopsy with or without US guidance should be performed in these patients. However, US examination dem- onstrates the presence of additional nodules in up to 50% of these patients (3). The evaluation and management of a pa- tient with a multinodular goiter (MNG) represents a much more difficult problem.
Nonpalpable nodules have the same risk of malignancy as palpable nodules of similar size (4), and several studies have shown that the risk of thyroid cancer is similar in patients with MNG and those with solitary nodules (2, 5, 6). Hence, appropriate selection of the nodules that re- quire FNA biopsy is important because cytological find- ings will usually help guide further management. In gen- eral, observation is appropriate in patients with benign cytology and absence of pressure symptoms, and surgery is preferred when there is concern or evidence of malig- nancy or bothersome pressure symptoms despite benign cytology. However, the management of patients with nod- ules having “indeterminate” or “suspicious” cytology re- mains difficult, owing to a lack of reliable markers for making a definitive preoperative diagnosis. This is partic- ularly difficult in patients with cytology “suspicious for follicular or Hu¨rthle cell neoplasms” in whom the risk of malignancy has been found to be between 20 and 30%
(7–10). Most such patients undergo surgery, but 70 to 80% are found to have benign lesions on final pathology.
Furthermore, the usefulness of intraoperative frozen sec- tion examination of such specimens is controversial, with some institutions reporting significant value and cost sav- ings in guiding the extent of the surgery with this approach (11, 12), whereas others find it is not helpful or cost-ef- fective (13–16).
The Patient
A 62-yr-old woman was referred for evaluation of nodular goiter. She presented to her local physician 6 wk earlier for evaluation of fever and sore throat. Examination revealed a slightly erythematous oropharynx without exudates and mild bilateral submandibular adenopathy. The thyroid was slightly enlarged at approximately 25–30 g without dis- creet palpable nodules. A bruit was noted over the right ca- rotid artery. Her physician diagnosed viral pharyngitis and recommended symptomatic treatment. Carotid Doppler US demonstrated mild (40%) stenosis of the right internal ca- rotid artery and incidentally noted an isoechoic and avas-
cular nodule on the left lobe of the thyroid, measuring 1.8 cm, and a hypoechoic nodule on the right lobe mea- suring 1.4 cm, with internal microcalcifications and ill- defined margins. A few other benign-appearing cystic lesions, all under 1 cm in size, were noted throughout both lobes. Serum TSH was normal at 4.0 mU/liter. The patient denies pressure symptoms or any previous his- tory of thyroid problems. She has no history of radiation to her head or neck and no known family history of thyroid disease.
We present a practical approach to this case, with ref- erence to the recently revised American Thyroid Associa- tion (ATA) guidelines for management of patients with thyroid nodules and differentiated thyroid cancer (17).
Whenever possible, the specific recommendation (Rec.) number and level of evidence will be noted (18). A sum- mary of all recommendations discussed in this manuscript is provided in Table 1.
Clinical Presentation
The clinical presentation of patients with MNG is variable and depends to a great extent on the size, location, and functional status of the thyroid. Most euthyroid patients with a small goiter are completely asymptomatic. Other patients may have a long-standing visible goiter in the absence of other clinical symptoms. Hyperthyroidism, ei- ther subclinical or overtly symptomatic, is present in up to 25% of these patients (19). However, occasionally, the thyroid may extend into the thoracic cavity (substernal goiter) resulting in obstruction or pressure of structures within the cavity. Tracheal compression (see Fig. 3) can result in exertional or positional dyspnea, most commonly amplified in the recumbent position (20 –22); dysphagia, cough, choking sensation, or hoarseness may also be seen in patients with large goiters.
Diagnostic Evaluation
Serum TSH
Patients presenting with a nodular goiter should have a complete history and physical exam, and serum TSH levels should be measured (Rec. 1-A) (17). If low, a thyroid scin- tigraphy (using either technetium99mTc pertechnetate or
123I) should be performed as the next step to determine the functional status of the nodules because low serum levels of TSH suggest overt or subclinical hyperthyroidism and suggest the presence of hyperfunctioning (“hot”) nodules (Rec. 1-A) (17). Because “hot” nodules are very seldom malignant, cytological evaluation in this setting is gener- ally not necessary (17).
Patients with autoimmune (Hashimoto’s) thyroiditis may present with a high-normal to elevated TSH and apparent nodularity, which may represent focal lymphocytic infiltra- tion (pseudonodules). US evaluation is often helpful in distin-
guishing these findings from true thyroid nodules. The mea- surement of serum thyroid peroxidase antibody levels may also be helpful in these patients because moderate to high levels are indicative of coexisting autoimmune thyroid disease.
TABLE 1. Summary of recommendations from ATA referred to throughout the manuscript
Rec. no. Guideline recommendation
Rec.
rating 1 Measure serum TSH in the initial evaluation of a patient with a thyroid nodule. If the serum TSH is subnormal,
a radionuclide thyroid scan should be performed using either technetium99mTc pertechnetate or123I.
A 2 Thyroid sonography should be performed in all patients with known or suspected thyroid nodules. A 4 The panel cannot recommend either for or against the routine measurement of serum calcitonin. I
5a FNA is the procedure of choice in the evaluation of thyroid nodules. A
5b US guidance for FNA is recommended for those nodules that are nonpalpable, predominantly cystic, or located posteriorly in the thyroid lobe.
B 6b Partially cystic nodules that repeatedly yield nondiagnostic aspirates need close observation or surgical
excision. Surgery should be more strongly considered if the cytologically nondiagnostic nodule is solid.
B 9 If the cytology reports a follicular neoplasm, a123I thyroid scan may be considered, if not already done,
especially if the serum TSH is in the low-normal range. If a concordant autonomously functioning nodule is not seen, lobectomy or total thyroidectomy should be considered.
C
12a In the presence of two or more thyroid nodules larger than 1 cm, those with a suspicious sonographic appearance should be aspirated preferentially.
B 12b If none of the nodules has a suspicious sonographic appearance and multiple sonographically similar
coalescent nodules with no intervening normal parenchyma are present, the likelihood of malignancy is low and it is reasonable to aspirate the largest nodules only and observe the others with serial US examinations.
C
13 A low or low-normal serum TSH concentration may suggest the presence of autonomous nodule(s). A technetium99mTc pertechnetate or123I scan should be performed and directly compared to the US images to determine functionality of each nodule greater than 1–1.5 cm. FNA should then be considered only for those isofunctioning or nonfunctioning nodules, among which those with suspicious sonographic features should be aspirated preferentially.
B
14a It is recommended that all benign thyroid nodules be followed with serial US examinations 6 –18 months after the initial FNA. If nodule size is stable (i.e. no more than 50% change in volume or less than 20%
increase in at least two nodule dimensions in solid nodules or in the solid portion of mixed cystic-solid nodules), the interval before the next follow-up clinical examination or US may be longer,e.g.every 3–5 yr.
C
14b If there is evidence of nodule growth either by palpation or sonographically (⬎50% change in volume or a 20% increase in at least two nodule dimensions with a minimal increase of 2 mm in solid nodules or in the solid portion of mixed cystic-solid nodules), the FNA should be repeated, preferably under US guidance.
B
16 Routine suppression therapy of benign thyroid nodules in iodine-sufficient populations is not recommended. F 26 For patients with thyroid cancer larger than 1 cm, the initial surgical procedure should be a near-total
thyroidectomy unless there are contraindications to this surgery. Thyroid lobectomy alone may be sufficient treatment for small (⬍1 cm), low-risk, unifocal, intrathyroidal papillary carcinomas in the absence of prior head and neck irradiation or radiologically or clinically involved cervical nodal metastases.
A
27b Prophylactic central-compartment neck dissection (ipsilateral or bilateral) may be performed in patients with papillary thyroid carcinoma with clinically uninvolved central neck lymph nodes, especially for advanced primary tumors (T3 or T4).
C
40 Initial TSH suppression to below 0.1 mU/liter is recommended for high-risk and intermediate-risk thyroid cancer patients, whereas maintenance of the TSH at or slightly below the lower limit of normal (0.1– 0.5 mU/liter) is appropriate for low-risk patients who have not undergone remnant ablation,i.e. serum TSH 0.1– 0.5 mU/liter.
B
43 Serum Tg should be measured every 6 –12 months by an immunometric assay that is calibrated against the CRM-457 standard. Ideally, serum Tg should be assessed in the same laboratory, using the same assay during follow-up of patients with DTC who have undergone total or near-total thyroidectomy with or without thyroid remnant ablation. Tg antibodies should be quantitatively assessed with every measurement of serum Tg.
A
44 Periodic serum Tg measurements and neck US should be considered during follow-up of patients with DTC who have undergone less than total thyroidectomy and in patients who have had a total thyroidectomy but not RAI ablation. While specific cutoff levels during TSH suppression or stimulation that normally distinguish normal residual thyroid tissue from persistent thyroid cancer are unknown, rising Tg values over time are suspicious for growing thyroid tissue or cancer.
B
Adapted from revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer (DTC) (17).
Recent studies have suggested that serum TSH levels are an independent predictor of malignancy in patients with thyroid nodules (23, 24). In a study of 1500 patients evaluated for thyroid nodules, the prevalence of malig- nancy increased from 2.8% when TSH was less than 0.4 mU/liter to up to 29.7% when TSH was greater than 5.5 mU/liter (23). Furthermore, another study showed that in patients diagnosed with thyroid cancer, a higher TSH was associated with a more advanced stage of the disease (24).
More study is needed to determine whether elevated TSH can be considered a prognostic indicator in the evaluation of thyroid nodules. Another recent study found, in addi- tion to serum TSH levels, that positive serum thyroglob- ulin (Tg) antibodies were an independent predictor of ma- lignancy in patients with thyroid nodules, despite the concurrent presence of autoimmune thyroid disease (25).
Further studies are needed to validate and better define the utility of serum anti-Tg antibody measurement in the eval- uation of patients with nodular goiter.
Ultrasonography
Although neck palpation is inexpensive, widely avail- able, and simple to perform, it is notoriously imprecise and insensitive in the detection and estimation of size and num- ber of thyroid nodules. Current US technology using high- resolution transducers is the most sensitive method available (approaching 95%) and is capable of detecting nodules as small as 1–2 mm (26). Thyroid US has become an extension of the physical examination, resulting in an epidemic of in- cidentally discovered thyroid nodules.
All patients with a nodular thyroid should be evaluated with US (Rec. 2-A) (17) to confirm the presence of a mass, assess whether the lesion is single or multiple, determine whether it is of thyroidal origin, and guide FNA biopsy. Up to 50% of patients with a single palpable thyroid nodule will demonstrate additional nodules when US exam is per- formed (27). Because the frequency of malignancy is sim-
ilar in patients with single or multiple nodules (5, 28), selection of the nodule(s) that will require biopsy in pa- tients with MNG needs careful consideration. Many stud- ies have shown that certain ultrasonographic features are associated with increased risk of malignancy. Such fea- tures include nodule hypoechogenicity, the presence of microcalcifications, increased vascular flow, irregular borders, and the absence of a halo (5, 29) (Table 2), and when present, such nodules should be preferentially aspi- rated (Rec. 12a-B) (17) (Fig. 1). The combination of sev- eral of these sonographic features increases the specificity.
Because in the absence of these features malignancy can- not definitively be excluded, patients with MNG should be followed with periodic neck examination and US, and a repeat biopsy should be considered if significant growth of a nodule or other worrisome clinical (persistent hoarse- ness, dysphagia, adenopathy,etc.) or sonographic features develop on follow-up.
On the other hand, if each of the nodules has benign sonographic appearance (i.e. well-defined borders, a peripheral halo, iso- or hyperechogenicity) (Fig. 2), only the largest or “dominant” nodule(s) should be aspi- rated, and the rest should be observed with serial US (Rec. 12b-C) (17).
Because a false-negative rate of up to 5% has been re- ported in patients with previous benign cytology (30), pa- tients with MNG should be followed with US within 6 to 18 months of initial FNA and periodically thereafter (ev- ery 3–5 yr) to evaluate for nodule growth (Rec. 14a-C) (17, 31, 32). Although there is no consensus on the definition of “clinically significant growth” of a thyroid nodule, the ATA task force guidelines recommend repeating the bi- opsy when there is at least a 50% increase in nodule vol- TABLE 2. Predictive value of ultrasonographic features
in detection of thyroid cancer Ultrasound feature
Sensitivity
% (range)
Specificity (range) Microcalcifications
(28, 81– 86)
52 (26 –73) 83 (69 –96) Absence of halo
(28, 52, 83, 86 – 87)
66 (46 –100) 54 (30 –72) Irregular margins
(5, 28, 52, 70, 81– 83)
55 (17–77) 79 (63– 85) Hypoechogenicity
(5, 28, 70, 81– 84, 87)
81 (49 –90) 53 (36 – 66) Increased vascularity
(5, 28, 82, 84, 86)
67 (57–74) 81 (49 – 89)
Reproduced with permission from S. A. Fishet al.:Endocrinol Metab Clin North Am37:401– 417, 2008 (29).
FIG. 1. US image of malignant thyroid nodule (papillary thyroid carcinoma). Note hypoechogenicity, irregular/indistinct margins, and the presence of microcalcifications (arrow).
ume within the first 6 –18 months after initial FNA (Rec.
14b-B) (17).
Thyroid scintigraphy
In patients with a nodular goiter and suppressed serum TSH levels, thyroid scanning should be performed using either technetium99mTc pertechnetate or123I (Rec. 1-A) (17) because this imaging modality provides a measure of the iodine-trapping function in a nodule compared with the surrounding thyroid tissue and thus best assesses the functional status of a particular nodule.
The sensitivity of 123I scanning to detect functioning nodules is about 83% (33), whereas that of technetium scanning is about 91% (34). The specificity of thyroid scans is low (5 to 25%), mostly because other thyroid lesions (i.e.cystic nodules, the cystic component of mixed nodules) or superimposed normal functioning tissue may interfere with uptake of the radioisotopes. Because of its very low diagnostic accuracy, the utility of thyroid scin- tigraphy in the evaluation of thyroid nodules is limited to confirming the functional status of suspected autono- mously functioning thyroid nodules (35). The results of scintigraphy should then be compared with the US images, and FNA should be considered only for iso- or nonfunc- tioning nodules, particularly those with suspicious sono- graphic features (Rec. 13-B) (17). Thyroid scintigraphy may also be used to determine whether a substernal mass represents functioning thyroid tissue (35). In patients with cytology “suspicious” for a follicular neoplasm, thyroid scintigraphy is recommended, especially if serum TSH is in the low-normal range. If a concordant autonomously functioning nodule is not seen, surgery should be consid- ered (Rec. 9-C) (17).
Other imaging modalities
Computed tomography (CT) and magnetic resonance imaging are helpful in the assessment of patients with large goiters, those with suspected substernal extension, and/or those with obstructive or pressure symptoms because they provide a good assessment of goiter size and its positional relationship to surrounding structures (Figs. 3 and 4). Be- cause these imaging modalities are expensive and CT im- aging of patients with MNG may require iodine-contain- ing contrast agents for better definition, they are not recommended for routine evaluation of patients with thy- roid nodules.
FNA biopsy
Thyroid FNA biopsy is the single most valuable, cost- effective, and accurate method in the evaluation of a pa- tient with a nodular goiter. Most centers using this pro- cedure have achieved a 35 to 75% reduction in the number of patients requiring surgery, while still doubling or tri-
FIG. 3. CT scan of patient with large substernal goiter showing narrowing of tracheal lumen and deviation of the trachea to the left.
FIG. 4. Coronal view of the same patient with MNG as shown in Fig.
3, demonstrating tracheal deviation to the left and substernal extension of the goiter into the upper mediastinum.
FIG. 2. US image showing a benign thyroid nodule. Note the presence of peripheral halo, well-defined borders, isoechogenicity, and absence of microcalcifications.
pling the malignancy yield at thyroidectomy (36 –38). Se- lection of nodules that require biopsy in patients with MNG is challenging. Because patients with MNG have the same risk of malignancy as those with solitary thyroid nodules (5, 6), biopsy of only the “dominant” nodule may not detect an existing thyroid cancer (6). US guidance has proven extremely helpful in selecting the best targets for FNA and is most helpful in small (⬍1.5 cm), partly cystic, and nonpalpable nodules (Rec. 5b-B) (17). In complex or mostly cystic nodules, US guidance helps to properly sam- ple the solid component while avoiding cystic areas of central necrosis that often yield insufficient specimens (39). In the hands of experienced operators, adequate sam- ples can be obtained from solid nodules in 90 –97% of aspirations (31, 40). Although the management of clini- cally proven benign (observation) or malignant nodules (surgery) is relatively straightforward, nodules with inde- terminate or “suspicious” cytology continue to pose a clin- ical challenge without reliable markers to accurately pre- dict the nature of such lesions. Occasionally, a thyroid scan may be helpful if autonomous function is suspected.
However, in the absence of autonomous function, surgical excision of these nodules is recommended (Rec. 9-C) (17), despite only 20 –30% of these nodules showing evidence of malignancy on final pathology (1, 8, 41, 42). Fixed lesions, those larger than 4 cm, male gender, and younger age at diagnosis have been shown to convey increased risk for malignancy (9, 42).
Aspirates with insufficient number of cells are consid- ered nondiagnostic or unsatisfactory, and care must be taken not to label them as “negative for malignancy.”
Because about 50% of cases initially classified as nondi- agnostic will produce a satisfactory specimen when FNA is repeated under US guidance (43), the ATA guidelines recommended repeat biopsy in this setting (Rec. 5a-A) (17). Because the incidence of malignancy in the subset (5–10%) of patients with nodules remaining nondiagnos- tic has been found to be between 2 and 9% (44, 45), such nodules should be followed closely or surgery considered, particularly if the nodule is solid (Rec. 6b-B) (17).
Treatment Considerations for Patients with Benign MNG
In the absence of clinical, sonographic, or cytological find- ings suggestive of malignancy, the selection of the best therapeutic option for a patient with MNG will depend on several factors, including size and location of the goiter, the presence and severity of compressive symptoms, and the presence or absence of thyrotoxicosis.
Thyroid hormone suppressive therapy
Because TSH has been regarded as a growth factor for thyroid epithelial cells (46, 47), treatment with levothy- roxine in doses sufficient to suppress TSH has long been used to prevent or reduce growth of thyroid nodules.
However, the effectiveness of this practice remains con- troversial. Although some studies have shown efficacy (48), others have failed to show a clear benefit (49), likely owing to differences in study design, the population being evaluated, and epidemiological factors such as prevalence of iodine insufficiency, nature of the nodular goiter (single vs.multinodular), adequacy of TSH suppression, duration of treatment,etc.(49).
Some studies have shown a moderate (50 – 60%) re- duction in goiter volume with the use of levothyroxine.
Although this occurs primarily within the first 3 months of treatment and patients with diffuse goiters responded bet- ter than those with nodular goiters, the effect is lost after therapy is discontinued (50, 51).
The efficacy of levothyroxine suppressive therapy in preventing recurrence of goiter growth after partial thy- roidectomy is less clear. Although several nonrandomized trials suggest that levothyroxine therapy is effective for this purpose, randomized trials have failed to confirm such benefit (51). Some of these studies, however, were small and of short duration, and many failed to achieve ade- quate TSH suppression.
Because of the known deleterious effects on the skele- ton associated with subclinical hyperthyroidism resulting from levothyroxine suppressive therapy and the increased risk of atrial fibrillation and other cardiovascular compli- cations, this treatment modality is not recommended by the ATA (Rec. 16-F) (17). It should be particularly avoided in postmenopausal women with evidence of low bone mass, in the elderly, and in those with cardiac disease, in whom the risk of this therapy generally outweighs its un- certain benefits (53, 54).
Radioiodine therapy
Radioactive iodine (RAI) has been extensively and suc- cessfully used for the treatment of toxic MNG. For the majority of patients with this condition, a single orally administered dose will lead to the destruction of the toxic nodules and restoration of euthyroidism over a 2- to 4-month period.
In patients with nontoxic MNG, RAI has not widely been considered a treatment option. However, several Eu- ropean studies have shown that it is both safe and effective (55–57). It resulted in significant goiter size reduction when compared with levothyroxine suppressive therapy, which offered no benefit (58), and improvement in ob- structive symptoms (dyspnea, dysphagia) in the majority
of patients (59, 60). Some patients develop transient hy- perthyroidism in the first 2 wk after RAI, and up to 45%
become permanently hypothyroid and require lifelong thyroid hormone replacement (58). Although not FDA- approved for this purpose in the United States, pretreat- ment with a single dose of 0.1 mg of recombinant human TSH (rhTSH) has been occasionally used successfully for carefully selected patients in some centers in Europe as adjuvant to RAI. It improves the efficacy of RAI by en- hancing uptake in nontoxic thyroid tissue and allowing the use of lower doses of RAI, while still resulting in greater reduction of goiter size (61– 64). It has also been shown that rhTSH not only increases thyroid RAI uptake but also potentiates the effect of RAI. This allows for a significant reduction in the RAI dose without compromising its effi- cacy (65). Moreover, because the side effects are dose de- pendent, they are rare after doses of rhTSH of 0.1 mg or less (66). This approach also minimizes posttherapeutic restrictions and reduces the potential risk of radiation- induced malignancy (65).
Painful transient thyroiditis and transient mild thyro- toxicosis (67) may occur within the first month after treat- ment, and there is an increased incidence of subsequent hypothyroidism. Development of Graves’ hyperthyroid- ism (with high levels of TSH receptor antibodies) in pa- tients with preexisting high thyroid peroxidase antibody concentrations has also been described after treatment of euthyroid MNG with RAI (68).
Surgery
Surgery is the preferred treatment modality for patients with euthyroid large, obstructive, and substernal nontoxic MNG (see Figs. 3 and 4) and those with continued growth, if they have an acceptable surgical risk. Near-total or total thyroidectomy is the procedure of choice for these pa- tients. Complications of surgery such as injury to the re- current laryngeal nerve, trachea, and parathyroid glands are more common in patients with large and substernal goiters than in those undergoing thyroidectomy for cer- vical goiters (20, 69). To minimize the risk of such com- plications, all patients requiring surgery, especially those with substernal goiter, should be referred to experienced thyroid surgeons in high-volume centers.
Controversies/Areas of Uncertainty
Despite advances made over the past few decades with the advent of high-resolution US allowing improved detection and selection of nodules for biopsy, some aspects of the management of patients with nodular goiter remain chal- lenging. The finding of “suspicious” or “indeterminate”
cytology (for follicular and Hu¨rthle cell neoplasms) poses a clinical dilemma. Most patients with this cytological di- agnosis are referred for surgical excision, but only 20 – 30% ultimately prove to have a malignant lesion on final pathology (8, 71). Although much work is currently under way to attempt to identify better predictors of malignancy, no single molecular/genetic (BRAF, RET/PTC, RAS, PAX8- PPAR␥), microRNA, or immunohistochemical marker (Ga- lectin 3, HBME-1, CK19) or set of markers has been found to have sufficient accuracy and negative predictive value to allow the clinician to comfortably recommend observation rather than surgery (72).
Other areas of uncertainty include when to recommend rebiopsy of a nodule with previously benign FNA cytology that enlarges in size in the absence of other concerning changes. It has been shown that both benign and malig- nant nodules grow over time (73, 74), and although rapid growth is generally seen as suggestive of malignancy, some studies have shown that the rate of growth is not always a useful determinant (75). In light of these uncertainties, current ATA guidelines advise rebiopsy of nodules dem- onstrating more than a 50% increase in volume over a 6- to 18-month period after initial FNA (Rec. 14b-B) (7) and recommend that clinical or US follow-up be carried out 3–5 yr after nodule biopsy with benign findings in the absence of further changes (Rec. 14a-C) (17). Future stud- ies of the rate of growth over time of presumably benign nodules and the incidence of malignancy diagnosed in nodules previously determined to be benign on biopsy will help to clarify these issues so that unnecessary follow-up and rebiopsy can be avoided.
When an observational strategy is chosen, the duration of follow-up is uncertain. No convincing evidence exists to demonstrate that prolonged follow-up for several years, including repeat FNA, is cost effective. In fact, a recent retrospective study demonstrated little diagnostic upgrad- ing value in repeat FNA in patients with previously benign cytology (1.7% false-negative rate of initial FNA). They found substantially increased costs associated with this approach owing to repeat FNA biopsy with or without US guidance and surgical procedures that were performed for indeterminate cytology that was ultimately found to rep- resent benign disease (76). These authors recommended repeat FNA only in cases in which clinically suspicious signs or complaints develop on follow-up. Prospective studies are needed to answer these important questions.
Routine measurement of serum calcitonin as a means to screen for medullary thyroid cancer in patients with thy- roid nodules is advocated in Europe for early detection of C-cell hyperplasia and medullary thyroid cancer (77, 78).
However, current ATA guidelines do not recommend for or against routine measurement of calcitonin due to lack
of sufficient evidence, owing in part to the lack of avail- ability of pentagastrin in the United States and unresolved issues of sensitivity, specificity, and assay performance (Rec. 4-I) (17).
Conclusion
The evaluation and management of a patient with a MNG is generally more difficult than that of a patient with a solitary thyroid nodule. Serum TSH measurement should be the initial step in the evaluation of these patients to exclude hyperfunctioning nodules (which have very low risk for malignancy). US examination and FNA biopsy (preferably under US guidance) when suspicious nodules are seen are essential to exclude malignancy. Continued follow-up with periodic US can detect clinically significant growth of nodules that may warrant reaspiration. The selection of nodules requiring FNA biopsy should be guided by sonographic features, clinical history, and rate of growth. Euthyroid patients with asymptomatic, benign nodular goiters (confirmed by FNA biopsy) can be safely observed and followed with periodic neck examination and US. Patients with confirmed malignant nodules and those with benign symptomatic goiters (pressure, dyspha- gia) should be referred for surgery (Fig. 5).
Although several other treatment modalities are cur- rently available for the management of patients with
multinodular goiters one must carefully weigh the risk/
benefit of each option because some of these treatments, such as levothyroxine suppressive therapy, offer benefits that are less clear and may pose undue risk for certain patient populations. Other therapies, such as the use of rhTSH in the pretreatment of patients with nontoxic MNG receiving RAI (79) appear promising in preliminary studies but are still not FDA-approved in the United States.
Nevertheless, this approach has occasionally been used in some centers in Europe for treatment of nontoxic benign goiters and may be considered a suitable option in selected patients.
Back to the Patient
The patient underwent US-guided FNA of the smaller (1.4 cm) hypoechoic nodule because this nodule had several worrisome sonographic features (Rec. 12a-B) (17). Cytology was read as positive for papillary thyroid cancer. FNA of the larger nodule was also performed, and its cytology was consistent with benign thyroid nodule. She underwent a near-total thyroidectomy (Rec. 26-A) (17) and was found to have a 1.5-cm pap- illary carcinoma on the right lobe, confined to the thy- roid. A prophylactic central compartment (level VI) neck dissection was performed (Rec. 27b-C) (17), and six lymph nodes were excised and found to be negative for metastatic disease. Accordingly, staging was T1N0M0-Stage I (American Joint Committee on Cancer Staging) (MACIS score, 5.4) (80). The larger 1.8-cm nod- ule was benign on final pathology, demonstrating only adenomatous hyperplasia. If FNA had been performed on only the “dominant” nodule, papillary thyroid cancer would have been missed. Levothyroxine suppressive therapy was started (Rec. 40-B) (17), and 6 months later, the patient had suppressed serum TSH (0.15 mU/
liter) and Tg (⬍0.1 ng/ml) in the absence of Tg anti- bodies, and her neck US showed no evidence of recur- rence (Rec. 43-A and 44-B) (17).
Acknowledgments
Address all correspondence and requests for reprints to: M. Regina Castro, M.D., Mayo Clinic, 200 First Street SW, Rochester, Min- nesota 55905. E-mail: [email protected].
This work was supported by a Write-up and Publish (WRAP) grant from the Department of Medicine, Mayo Clinic (Roches- ter, MN).
Disclosure Summary: The authors have no relevant disclosures.
FIG. 5. Algorithm for evaluation and management of patient with nodular goiter.
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