1. health and fitness
2. disease
3. thyroid disease

S P E C I A L
A p p r o a c h
F E A T U R E
t o
t h e
P a t i e n t
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
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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
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This Journal-based CME activity should be of substantial
interest to endocrinologists.
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The following individuals reported NO relevant financial
relationships:
Rebecca S. Bahn, M.D., M. Regina Castro, M.D., and Leonard Wartofsky, M.D., reported no relevant financial
relationships.
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content for this activity reported no relevant financial
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Activity release date: May 2011
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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 aspiration 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 measured to assess functional thyroid status and US examination to evaluate the
number, size, and sonographic features of the nodules and assist in the selection 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 suspicious (indeterminate) cytology, patients with such nodules are generally advised 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, choking sensation, or airway obstruction. Such patients will often require surgery
for alleviation of symptoms. In the absence of malignancy, asymptomatic patients may be observed. Radioactive iodine, commonly used in many parts of
Europe, is safe and effective and may be a reasonable option for many patients. Periodic follow-up with neck palpation and US exam is recommended
for all patients. (J Clin Endocrinol Metab 96: 1202–1212, 2011)
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.
1202
jcem.endojournals.org
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 utilization of ultrasound (US) for evaluation of nonthyroid
lesions of the neck, the incidental finding of unsuspected
thyroid nodules (“incidentalomas”) has dramatically increased, with some studies reporting a prevalence of up to
50% in individuals over the age of 50 yr (1). The prevalence of thyroid nodules is higher in women in areas of
T
Abbreviations: CT, Computed tomography; FNA, fine-needle aspiration; MNG, multinodular goiter; RAI, radioactive iodine; Rec., recommendation; rhTSH, recombinant human
TSH; Tg, thyroglobulin; US, ultrasound.
J Clin Endocrinol Metab, May 2011, 96(5):1202–1212
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J Clin Endocrinol Metab, May 2011, 96(5):1202–1212
iodine deficiency and increases with advancing age. Factors that increase the risk of malignancy include male gender, 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 solitary nodule is generally straightforward. Fine-needle aspiration (FNA) biopsy with or without US guidance should be
performed in these patients. However, US examination demonstrates the presence of additional nodules in up to 50% of
these patients (3). The evaluation and management of a patient 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 require FNA biopsy is important because cytological findings will usually help guide further management. In general, observation is appropriate in patients with benign
cytology and absence of pressure symptoms, and surgery
is preferred when there is concern or evidence of malignancy or bothersome pressure symptoms despite benign
cytology. However, the management of patients with nodules having “indeterminate” or “suspicious” cytology remains difficult, owing to a lack of reliable markers for
making a definitive preoperative diagnosis. This is particularly 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 section examination of such specimens is controversial, with
some institutions reporting significant value and cost savings in guiding the extent of the surgery with this approach
(11, 12), whereas others find it is not helpful or cost-effective (13–16).
jcem.endojournals.org
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cular nodule on the left lobe of the thyroid, measuring
1.8 cm, and a hypoechoic nodule on the right lobe measuring 1.4 cm, with internal microcalcifications and illdefined 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 history 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 reference to the recently revised American Thyroid Association (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 summary 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, either 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
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 discreet palpable nodules. A bruit was noted over the right carotid artery. Her physician diagnosed viral pharyngitis and
recommended symptomatic treatment. Carotid Doppler US
demonstrated mild (40%) stenosis of the right internal carotid artery and incidentally noted an isoechoic and avas-
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 scintigraphy (using either technetium 99mTc pertechnetate or
123
I) 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 generally not necessary (17).
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Nontoxic Multinodular Goiter
J Clin Endocrinol Metab, May 2011, 96(5):1202–1212
TABLE 1. Summary of recommendations from ATA referred to throughout the manuscript
Rec.
Rec. no.
Guideline recommendation
rating
1
Measure serum TSH in the initial evaluation of a patient with a thyroid nodule. If the serum TSH is subnormal,
A
a radionuclide thyroid scan should be performed using either technetium 99mTc pertechnetate or 123I.
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
B
located posteriorly in the thyroid lobe.
6b
Partially cystic nodules that repeatedly yield nondiagnostic aspirates need close observation or surgical
B
excision. Surgery should be more strongly considered if the cytologically nondiagnostic nodule is solid.
9
If the cytology reports a follicular neoplasm, a 123I thyroid scan may be considered, if not already done,
C
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.
12a
In the presence of two or more thyroid nodules larger than 1 cm, those with a suspicious sonographic
B
appearance should be aspirated preferentially.
12b
If none of the nodules has a suspicious sonographic appearance and multiple sonographically similar
C
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.
B
13
A low or low-normal serum TSH concentration may suggest the presence of autonomous nodule(s). A
technetium 99mTc pertechnetate or 123I 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.
C
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.
14b
If there is evidence of nodule growth either by palpation or sonographically (⬎50% change in volume or a
B
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.
16
Routine suppression therapy of benign thyroid nodules in iodine-sufficient populations is not recommended.
F
A
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.
27b
Prophylactic central-compartment neck dissection (ipsilateral or bilateral) may be performed in patients with
C
papillary thyroid carcinoma with clinically uninvolved central neck lymph nodes, especially for advanced
primary tumors (T3 or T4).
B
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.
A
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.
B
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.
Adapted from revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer
(DTC) (17).
Patients with autoimmune (Hashimoto’s) thyroiditis may
present with a high-normal to elevated TSH and apparent
nodularity, which may represent focal lymphocytic infiltration (pseudonodules). US evaluation is often helpful in distin-
guishing these findings from true thyroid nodules. The measurement 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.
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J Clin Endocrinol Metab, May 2011, 96(5):1202–1212
jcem.endojournals.org
TABLE 2. Predictive value of ultrasonographic features
in detection of thyroid cancer
Ultrasound feature
Microcalcifications
(28, 81– 86)
Absence of halo
(28, 52, 83, 86 – 87)
Irregular margins
(5, 28, 52, 70, 81– 83)
Hypoechogenicity
(5, 28, 70, 81– 84, 87)
Increased vascularity
(5, 28, 82, 84, 86)
Sensitivity
% (range)
52 (26 –73)
Specificity
(range)
83 (69 –96)
66 (46 –100)
54 (30 –72)
55 (17–77)
79 (63– 85)
81 (49 –90)
53 (36 – 66)
67 (57–74)
81 (49 – 89)
Reproduced with permission from S. A. Fish et al.: Endocrinol Metab
Clin North Am 37:401– 417, 2008 (29).
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 malignancy 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 addition to serum TSH levels, that positive serum thyroglobulin (Tg) antibodies were an independent predictor of malignancy 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 evaluation of patients with nodular goiter.
Ultrasonography
Although neck palpation is inexpensive, widely available, and simple to perform, it is notoriously imprecise and
insensitive in the detection and estimation of size and number of thyroid nodules. Current US technology using highresolution 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 incidentally 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 performed (27). Because the frequency of malignancy is sim-
1205
ilar in patients with single or multiple nodules (5, 28),
selection of the nodule(s) that will require biopsy in patients with MNG needs careful consideration. Many studies have shown that certain ultrasonographic features are
associated with increased risk of malignancy. Such features 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 aspirated (Rec. 12a-B) (17) (Fig. 1). The combination of several of these sonographic features increases the specificity.
Because in the absence of these features malignancy cannot 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 hoarseness, 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 aspirated, and the rest should be observed with serial US
(Rec. 12b-C) (17).
Because a false-negative rate of up to 5% has been reported in patients with previous benign cytology (30), patients with MNG should be followed with US within 6 to
18 months of initial FNA and periodically thereafter (every 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 biopsy when there is at least a 50% increase in nodule vol-
FIG. 1. US image of malignant thyroid nodule (papillary thyroid
carcinoma). Note hypoechogenicity, irregular/indistinct margins, and
the presence of microcalcifications (arrow).
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Nontoxic Multinodular Goiter
FIG. 2. US image showing a benign thyroid nodule. Note the presence
of peripheral halo, well-defined borders, isoechogenicity, and absence
of microcalcifications.
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 technetium 99mTc pertechnetate or 123I (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 scintigraphy in the evaluation of thyroid nodules is limited to
confirming the functional status of suspected autonomously 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 nonfunctioning nodules, particularly those with suspicious sonographic 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 considered (Rec. 9-C) (17).
J Clin Endocrinol Metab, May 2011, 96(5):1202–1212
FIG. 3. CT scan of patient with large substernal goiter showing
narrowing of tracheal lumen and deviation of the trachea to the left.
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). Because these imaging modalities are expensive and CT imaging of patients with MNG may require iodine-containing contrast agents for better definition, they are not
recommended for routine evaluation of patients with thyroid nodules.
FNA biopsy
Thyroid FNA biopsy is the single most valuable, costeffective, and accurate method in the evaluation of a patient with a nodular goiter. Most centers using this procedure have achieved a 35 to 75% reduction in the number
of patients requiring surgery, while still doubling or tri-
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.
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J Clin Endocrinol Metab, May 2011, 96(5):1202–1212
pling the malignancy yield at thyroidectomy (36 –38). Selection 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 sample the solid component while avoiding cystic areas of
central necrosis that often yield insufficient specimens
(39). In the hands of experienced operators, adequate samples can be obtained from solid nodules in 90 –97% of
aspirations (31, 40). Although the management of clinically proven benign (observation) or malignant nodules
(surgery) is relatively straightforward, nodules with indeterminate or “suspicious” cytology continue to pose a clinical challenge without reliable markers to accurately predict 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 considered nondiagnostic or unsatisfactory, and care must be
taken not to label them as “negative for malignancy.”
Because about 50% of cases initially classified as nondiagnostic 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 nondiagnostic 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 findings 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.
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Thyroid hormone suppressive therapy
Because TSH has been regarded as a growth factor for
thyroid epithelial cells (46, 47), treatment with levothyroxine 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 controversial. 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%) reduction 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 better 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 thyroidectomy 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 adequate TSH suppression.
Because of the known deleterious effects on the skeleton associated with subclinical hyperthyroidism resulting
from levothyroxine suppressive therapy and the increased
risk of atrial fibrillation and other cardiovascular complications, 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 uncertain benefits (53, 54).
Radioiodine therapy
Radioactive iodine (RAI) has been extensively and successfully 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 European 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 obstructive symptoms (dyspnea, dysphagia) in the majority
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Nontoxic Multinodular Goiter
of patients (59, 60). Some patients develop transient hyperthyroidism in the first 2 wk after RAI, and up to 45%
become permanently hypothyroid and require lifelong
thyroid hormone replacement (58). Although not FDAapproved for this purpose in the United States, pretreatment 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 enhancing 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 efficacy (65). Moreover, because the side effects are dose dependent, 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 radiationinduced malignancy (65).
Painful transient thyroiditis and transient mild thyrotoxicosis (67) may occur within the first month after treatment, and there is an increased incidence of subsequent
hypothyroidism. Development of Graves’ hyperthyroidism (with high levels of TSH receptor antibodies) in patients 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 patients. Complications of surgery such as injury to the recurrent laryngeal nerve, trachea, and parathyroid glands
are more common in patients with large and substernal
goiters than in those undergoing thyroidectomy for cervical goiters (20, 69). To minimize the risk of such complications, 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 challenging. The finding of “suspicious” or “indeterminate”
J Clin Endocrinol Metab, May 2011, 96(5):1202–1212
cytology (for follicular and Hu¨rthle cell neoplasms) poses
a clinical dilemma. Most patients with this cytological diagnosis 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, PAX8PPAR␥), microRNA, or immunohistochemical marker (Galectin 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 malignant 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 demonstrating more than a 50% increase in volume over a 6to 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 studies 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 upgrading 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 represent 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 thyroid 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
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J Clin Endocrinol Metab, May 2011, 96(5):1202–1212
of sufficient evidence, owing in part to the lack of availability 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, dysphagia) should be referred for surgery (Fig. 5).
Although several other treatment modalities are currently available for the management of patients with
jcem.endojournals.org
1209
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 papillary carcinoma on the right lobe, confined to the thyroid. 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 nodule 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 antibodies, and her neck US showed no evidence of recurrence (Rec. 43-A and 44-B) (17).
Acknowledgments
FIG. 5. Algorithm for evaluation and management of patient with
nodular goiter.
Address all correspondence and requests for reprints to: M. Regina
Castro, M.D., Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. E-mail: [email protected].
This work was supported by a Write-up and Publish (WRAP)
grant from the Department of Medicine, Mayo Clinic (Rochester, MN).
Disclosure Summary: The authors have no relevant disclosures.
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1210
Bahn and Castro
Nontoxic Multinodular Goiter
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