0021-972X/00/$03.00/0
The Journal of Clinical Endocrinology & Metabolism
Copyright © 2000 by The Endocrine Society
Vol. 85, No. 7
Printed in U.S.A.
Management of the Solitary Thyroid Nodule: Results of a
North American Survey*
FINN NOE BENNEDBÆK
AND
LASZLO HEGEDÜS
Department of Endocrinology, Odense University Hospital, DK-5000 Odense C, Denmark
ABSTRACT
The present survey evaluated current trends in the management
of the nontoxic solitary thyroid nodule by expert endocrinologists in
North America and compared their results with a similar European
Thyroid Association survey. A questionnaire was circulated to all
clinical members of the American Thyroid Association. An index case
(a 42-yr-old woman with a solitary 2 ⫻ 3-cm thyroid nodule and no
clinical suspicion of malignancy) and 11 variations were provided to
evaluate how each alteration would affect management. One hundred
and seventy-eight members replied and 142 responses were retained
for analysis, corresponding to a response rate of 43% of clinically
active members. Based on the index case, basal serum TSH was the
routine choice of 99%, and serum T4 and/or free T4 were included by
61% of the respondents. Thyroid peroxidase antibodies and serum
calcitonin were included by 30% and 5%, respectively. Thyroid scintigraphy was used by 23% (123I, 63%; 99mTc, 31%; 131I, 6%), and
ultrasonography was used by 34%. Fine needle aspiration biopsy was
A
LTHOUGH THYROID nodules are common, less than
5% prove to be malignant (1, 2). Physicians responsible for the care of patients with thyroid nodules are increasingly aware of the need for safe, expedient, and costeffective management of this common disorder. The optimal
evaluation and management, however, are still controversial. Early referral of patients with suspected thyroid nodules
to an endocrinologist results in significant savings in both
cost and patient’s time as well as increased precision of
diagnosis (3). On the other hand, experts disagree on the
predictive value of clinical factors supporting suspicion of a
malignant thyroid neoplasm and whether to operate regardless of benign cytological findings (4, 5).
A recent European survey [European Thyroid Association
(ETA)] demonstrated major differences in diagnostic approach and treatment in patients with a solitary thyroid
nodule (6). We chose to conduct a similar survey within the
U.S. and Canada. The objectives were: 1) to determine which
in vitro and in vivo tests are currently being used; 2) to determine trends for the recommended treatment in an index
patient with a benign-appearing nodule; 3) to determine the
impact of different clinical variations on management; and 4)
to compare results with the recent ETA survey (6).
Received January 26, 2000. Revision received March 17, 2000. Accepted April 4, 2000.
Address all correspondence and requests for reprints to: Finn Noe
Bennedbæk, M.D., Ph.D., Department of Endocrinology, Odense
University Hospital, DK-5000 Odense C, Denmark. E-mail: finn.
[email protected].
* This work was supported by the Agnes and Knut Mørk Foundation.
The results were presented in part at the 72nd Annual Meeting of the
American Thyroid Association, Palm Beach, Florida, September 29, 1999.
routinely used by all and was guided by palpation in 87%. Based on
the individually chosen diagnostic tests indicating a benign solitary
thyroid nodule in a euthyroid subject, L-T4 treatment was advocated
by 47%, no specific treatment and follow-up was advocated by 52%,
and surgery was advocated by 1%. Clinical factors suggesting thyroid
malignancy (e.g. rapid nodule growth and a large nodule of 5 cm) lead
a significant number of clinicians (40 - 50%; P ⬍ 0.00001) to disregard
biopsy results and to choose a surgical strategy. Nevertheless, North
American endocrinologists heavily rely on fine needle aspiration biopsy results. Compared to the European Thyroid Association survey,
North American endocrinologists use imaging [scintigraphy, 23% vs.
66% (P ⬍ 0.0001); ultrasonography, 34% vs. 80% (P ⬍ 0.0001)] and
serum calcitonin (5% vs. 43%; P ⬍ 0.0001) less frequently. A nonsurgical strategy prevails in North America, and despite controversies on
the effect of L-T4, this treatment is supported by more than 40% in
both Europe and North America. (J Clin Endocrinol Metab 85: 2493–
2498, 2000)
Materials and Methods
Survey methods
The questionnaire was initially distributed to all American Thyroid
Association (ATA) members participating in the 71st Annual Meeting of
ATA in Portland, OR, September 16 –20, 1998, and was also sent to
members not participating in the meeting. Subsequently, one reminder
was sent by air-mail to all nonresponders identified from the membership list.
Structure of the questionnaire
The questionnaire was based on a well defined case: “A 42-year-old
Caucasian woman is seen in your hospital/clinic due to a palpable mass
in the left thyroid lobe. It is clinically judged to be a solitary 2 ⫻ 3 cm
mobile nodule. There is no lymphadenopathy and no symptoms of
thyroid dysfunction or anterior neck pain. The nodule has been present
for 3 months and the patient reports moderate local neck discomfort.
There is no family history of thyroid disease and no positive information
of previous external irradiation.” The questions asked related to the
diagnostic investigations (in vitro and in vivo tests) and the choice of
therapy. The basic treatment advocated was based on the premise that
the preceding (individually chosen) in vitro and in vivo investigations
were indicative of a benign condition in a euthyroid subject, and that if
chosen, scintigraphy showed a cold nodule. Furthermore, it was assumed that the decision of therapy was left entirely to the clinician.
In the second part of the questionnaire, 11 variations of the initial case
report were listed, but only 1 variable was changed in each case (Table
1). The clinicians were then asked to indicate whether the management
plan would alter given each variation and to detail the altered diagnostic
procedures and treatment.
Statistical methods
Results are predominantly given as frequencies. McNemar’s test was
employed in each variation to compare the altered therapeutic attitude
with the basic treatment advocated, e.g. P ⫽ 1 means that the therapeutic
attitude was unchanged, given that particular variation. The ␹2 test was
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2494
TABLE 1. Patient variations
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
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BENNEDBÆK AND HEGEDÜS
TABLE 2. Frequency of employment of in vitro tests
TSH suppressed
Patient aged 18 yr
Patient aged 75 yr
Male
Family history of benign nodular thyroid disease
Family history of thyroid cancer
History of external ionizing irradiation
Rapid nodule growth and very firm at palpation
Large nodule of 4 ⫻ 5 cm and major discomfort
Small nodule of 1 ⫻ 1 cm and no discomfort
The nodule cystic
used to test for differences between the present survey and the ETA
survey. P ⬍ 0.05 was considered significant. All variables were registered in a computer-operated database (Paradox 5.0, Borland International), and the statistical software used was SPSS 8.0 (SPSS, Inc., Evanston, IL).
Results
Survey response
The questionnaire was initially distributed to 568 North
American members of the ATA. Fifty-eight responses were
received at the meeting in Portland. We then identified 307
nonresponding, supposedly clinically active, ATA members
from the membership list, all of whom were sent a reminder.
A total of 178 responses were received. Thirty-six originated
from nonclinicians, clinicians who had retired, or clinicians
who had not regularly seen patients with nodular thyroid
disease. The remaining 142 responses, corresponding to a
response rate of 43% (142 of 365) of clinically active North
American ATA members, were retained for analysis. There
was no significant difference between respondents and nonrespondents with regard to type of practice or state in which
they practiced. The 142 responses represented clinicians (endocrinology, 90.9%; surgery, 6.3%; nuclear medicine, 2.8%)
from the U.S. (133, 93.7%) and Canada (9, 6.3%) who had
diagnosed and treated more than 50 (41%) or less than 50
(59%) patients with nodular thyroid disease within the last
6 months. The vast majority (96.5%) stated that their patients
live in an area of iodine sufficiency.
In vitro diagnostic procedures (Table 2)
The index patient was investigated as an out-patient by all
respondents. Serum TSH was the routine choice of 99.3%.
49.3% added free T4 (direct measurement or based on T3 resin
uptake), and only 12.0% and 9.2%, respectively, would measure total T4 and total T3 (Table 2). Serum thyroid peroxidase
antibodies or microsomal antibodies were determined routinely by 35.9%, and calcitonin was included by 4.9%. Thirtyseven percent of the clinicians indicated the routine use of
one test only (TSH), whereas 42% used 2 or 3 tests, and the
remaining 21% used 4 or more tests. A combination of TSH
and free T4 and/or total T4 was used by 53%.
In vivo diagnostic procedures (Table 3)
Initial diagnosis in the index patient included imaging by
43.6% of the respondents, whereas 56.4% would leave out
diagnostic imaging (Table 3). Thyroid scintigraphy and ultrasonography (US) were used by 23.2% and 33.8%, respec-
Tests
Frequency (%)
TSH
Free T4 measurement (or index)
Thyroid peroxidase (TPO) antibodies
Thyroglobulin antibodies
Total T4
Total T3
Free T3 measurement (or index)
Sedimentation rate
Microsomal antibodies
Calcitonin
Thyroglobulin
Other tests
99.3
49.3
30.3
18.3
12.0
9.2
6.3
6.3
5.6
4.9
4.2
0.7
Listed in decreasing order of frequency.
tively, and 13.4% would employ both imaging modalities.
I was used by 62.5%, and 99mTc (technetium pertechnetate)
was used by 31.3%, whereas 6.2% preferred 131I. A radioiodine uptake measurement was performed by 34.4% of the
clinicians, and a suppression test was performed by 9.4%.
Timing of uptake varied with the isotope used. US was used
for determination of thyroid/nodule size by 81.3%, for specification of morphological characteristics (Gray scale) by
72.9%, and for Doppler investigations by 18.8% of the 48
clinicians using thyroid US.
Regional differences were analyzed for Canada (nine
responses) and those states represented by nine or more
respondents. In California, 90.9%, compared to an overall
average of 56.4%, do not use imaging. In Michigan and Massachusetts, 45.5% and 30.0%, respectively, use scintigraphy
as the only imaging modality compared to an overall 9.8%.
In New York and Illinois, US is used as the only imaging
modality by 33.4% and 30.0%, respectively, compared to an
average of 20.4% in the survey.
Fine needle aspiration biopsy (FNAB) was advised by all
respondents and was performed guided by palpation in
86.6% and by US in 13.4%. Most often it was performed by
endocrinologists (68.3%), and 16.2% stated that two or more
specialties attended to this function. In 6.3% of the cases a
cytopathologist performed the biopsy, and less frequently a
radiologist did so (2.1%). In the institutions of 35.9%, 23.9%,
and 32.4% of the respondents, the biopsies were performed
by one to three, four or five, and six or more persons, respectively. Large needle biopsy was recommended by none.
Of those clinicians who had performed scintigraphy, all
would perform FNAB given a single nodule without uptake,
whereas 97% of the respondents chose this option in the case
of a single nodule without uptake in a multinodular gland.
In the case of a single nodule with uptake equaling the rest
of the gland, 73% would perform FNAB. Only 3% would
suggest FNAB in the case of an autonomously functioning
nodule.
123
Therapeutic choices (Table 4)
In the index patient, the majority of physicians (52.1%)
refrained from treatment, but suggested follow-up (surveillance) in the patient’s own clinic/institution (50%) or by the
primary care physician (2.1%; Table 4). l-T4 treatment was
recommended by 46.5%. Surgery was chosen by only two
respondents (1.4%). l-T4 treatment with the intention to treat
MANAGEMENT OF THE SOLITARY THYROID NODULE
TABLE 3. Frequency of employment of in vivo diagnostic
procedures in the index case
2495
TABLE 4. Treatment advocated in the index case
Frequency (%)
Frequency (%)
Imaging
Scintigraphy and ultrasonography
Scintigraphy
Scintigraphy as only imaging modality
Primary isotopea
123
I
99m
Tc
131
I
Ultrasonography
Ultrasonography as only imaging
modality
Ultrasound modeb
Size
Gray scale
Doppler
Radioiodine uptake measurement
Thyroid suppression test
X-Ray (chest/trachea)
No imaging
Biopsy
Fine needle aspiration biopsy (FNAB)
Specialty attending to FNABc
Endocrinology
Cytopathology
Surgery
Radiology
Nuclear medicine
Not stated
ⱖ2 specialties
No. of persons performing FNABc
1–3
4 –5
6–8
⬎9
Not stated
13.4
23.2
9.8
62.5
31.3
6.2
33.8
20.4
81.3
72.9
18.8
34.4
9.4
0.7
56.4
100.0
68.3
6.3
4.2
2.1
1.4
1.4
16.2
35.9
23.9
16.2
16.2
7.8
a
Percentages of clinicians performing radionuclide scan.
Percentages of clinicians performing ultrasonography. The sum
exceeds 100.
c
Percentages of clinicians performing FNAB.
b
symptoms and arrest further growth was recommended by
62.1% and by another 18.2% also as evidence of benign pathology. The initial dose recommended varied considerably, but
aimed at a suppressed serum TSH level just below the normal
range (60.6%) or low, but still within the normal range (18.2%).
Only 9.1% aimed at total or near-total suppression of serum
TSH. US was used routinely by 34.8% during follow-up. l-T4
treatment for 12 months or less was the choice of 54.6%, and
21.2% would treat for years or indefinitely.
Regional differences regarding the preferred treatment were
observed. Thus, surveillance was more often chosen by endocrinologists in California, Michigan, and Canada (72.7–77.8%),
whereas l-T4 was more often recommended in Illinois (70.0%).
Surgery
No treatment indicated and follow-up by
primary care physician
No treatment indicated and follow-up in your
clinic/institution
L-T4 treatment
Details of L-T4 treatment
Indication
Trial as evidence of benign pathology
To treat symptoms and arrest further
growth
Both of the above
TSH (normal, 0.3– 4.0 arbitrary U/mL)
aiming at
⬍0.1
0.1– 0.3
0.3–1.0
Not stated
US used in follow-up
Duration of treatment
3– 6 months
6 months
6 –12 months
12 months
12–24 months
24 –36 months
Yr or indefinitely
Not stated
1.4
2.1
50.0
46.5
19.7
62.1
18.2
9.1
60.6
18.2
12.1
34.8
7.6
6.1
22.7
18.2
10.6
3.0
21.2
10.6
Furthermore, 80.7% by whom a radionuclide scan was not
obtained initially would now perform this test.
Serum calcitonin was included by 34.8% in the case of a
family history of thyroid cancer (variation 6). In the case of the
patient being 75 yr (variation 3) and in the case of a family
history of benign nodular thyroid disease (variation 5), the
initial treatment was not modified (P ⫽ 1; Fig. 1). Medical
treatment was changed to surgery by approximately 10% in the
young patient (variation 2) and in the male patient (variation 4)
and by 18% in the case of suppressed serum TSH. Sixteen
percent would prefer radioiodine treatment in variation 1.
Given a small nodule (variation 10), 63.4% would prefer surveillance, whereas the remaining 36.6% would suggest l-T4
treatment. In the case of a cystic nodule (variation 11), the
majority (94.4%) chose a nonsurgical approach, primarily surveillance, but 7% stated that they would reaspirate in the case
of recurrence and eventually treat with a sclerosing agent.
In variations 6 –9, where clinical information favored thyroid malignancy, medical treatment was changed to surgery
by 14 –50% (P ⬍ 0.000001). The preferred surgical technique
was hemithyroidectomy (55.6%, 41.7%, 56.3%, and 66.7% in
variations 6, 7, 8, and 9, respectively). Approximately one
third (31.3–36.1%) would use l-T4 postoperatively in variations 6 –9.
Clinical variations: altered management (Table 5 and
Fig. 1)
Comparison with ETA survey (Table 6)
Suppressed serum TSH (variation 1) most frequently resulted in an altered diagnostic approach (Table 5). Some
61.1% of clinicians, by whom a free T4 had not been performed in the index case, would recommend that this test be
performed, and 9.2% and 13.2%, respectively, would include
TSH receptor antibodies and thyroid peroxidase antibodies.
European endocrinologists perform a larger number of
laboratory tests in the index patient [3.5 (2;5.25) vs. 2 (1;3);
median (quartiles); P ⬍ 0.0001] compared to North American
endocrinologists (Table 6). The percentage of clinicians using
only one laboratory test (TSH) was 9% in the ETA survey
compared to 37% in the ATA survey (P ⬍ 0.0001). Most
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BENNEDBÆK AND HEGEDÜS
TABLE 5. Addition of diagnostic tests in the clinical variations
Variations
Blood analysis
Free T4
Free T3
Total T4
Total T3
Sedimentation rate
TRAb
TPOab
Calcitonin
Imaging
Scintigraphy
Ultrasonography
No. 1
61.1
25.6
29.5
12.0
8.3
9.2
13.2
80.7
11.7
No. 6
No. 7
0.7
1.0
2.0
34.8
0.9
1.1
4.6
5.3
No. 8
No. 9
1.4
0.8
1.4
3.0
8.3
2.0
6.7
2.0
5.9
2.8
4.3
7.3
9.6
No. 11
0.9
6.4
Percentage of the respondents using additional tests in each of the variations (refer to Table 1 for specification). Values more than 5% are
in bold. Variations 2–5 and 10 did not elicit a significantly altered diagnostic approach. TRAb, TSH receptor antibodies.
FIG. 1. Percentage choosing surgery
(䡺) or nonsurgical treatment (surveillance, LT4, radioiodine, and sclerotherapy) (u) in the index case as well as in
variations 1–11. Each variant was compared statistically with the index case
using McNemar test.
TABLE 6. Major differences in management between the present survey and the ETA survey
Diagnostic evaluation (index case)
Number of laboratory testsa
Serum calcitonin
Scintigraphy
US
Both scintigraphy and US
Treatment (index case)
Surgery
Surveillance
Treatment (variation no. 9)
Surgery
ATA survey
ETA survey
P value
2 [1;3]
5
23
34
13
3.5 [2;5.25]
43
66
80
58
⬍0.0001
⬍0.0001
⬍0.0001
⬍0.0001
⬍0.0001
1
52
23
30
⬍0.0001
0.001
50
91
⬍0.0001
Frequency of employment of tests or advocated treatment.
a
Median number of tests [quartiles] employed. Comparison by t test.
strikingly serum calcitonin was included routinely by 43% in
the ETA survey compared to only 5% in the ATA survey (P ⬍
0.0001). Imaging, i.e. radionuclide scan, US, or both, was used
more frequently in Europe than in North America (see Table
6 for details). Surgery was the basic treatment recommended
by only 1% in the U.S. and Canada compared to nearly one
in four in Europe (P ⬍ 0.0001). In the case of clinical factors
favoring thyroid malignancy, e.g. a large nodule of 5 cm
(variation 9), more than 90% of ETA members disregarded
biopsy results and chose a surgical approach compared to
half of the ATA members (P ⬍ 0.0001) (1).
Discussion
The present survey represents an effort to analyze strategies for management of the nontoxic solitary thyroid nodule
MANAGEMENT OF THE SOLITARY THYROID NODULE
within the U.S. and Canada. The major flaw is a poor overall
response rate, which may limit generalizations. However,
one in three of those responses (n ⫽ 36) not retained for
analysis originated from members who actually did not treat
such patients. The fact that they were identified as supposedly clinically active according to the membership list makes
it likely that a number of the 187 (365–178) nonresponders
were, in fact, not clinically active or did not see such patients.
In this case the true response rate would be higher. Furthermore, based on the diversity of geographical locations represented, we believe the results to represent current trends
on how management is implemented by thyroid specialists.
There was consensus regarding the patient with a solitary
thyroid nodule being diagnosed and treated in an out-patient
setting, and that initial diagnosis included a serum TSH and
FNAB. Approximately 60% would routinely measure T4
and/or free T4, and one in three of the clinicians would also
determine thyroid autoantibodies. This is in agreement with
the results of a previous ATA survey stating that the initial
assessment of a similar index patient would be conducted in
an ambulatory care setting and included a serum TSH
(⬎90%) and FNAB (96%) (7). Some researchers recommend
serum calcitonin routinely in the clinical work-up of nodules
(8), and others consider its use in the older patients (9). In the
present survey less than 5% would include serum calcitonin
measurement, and this is in agreement with recent ATA and
clinical practice guidelines stating that the test is not costeffective if the family history is noncontributory (10, 11).
Only in the case of a family history of thyroid cancer (variation 6) did a significant number of clinicians include the test.
Variations in imaging were evident. In the initial diagnosis
one in three and one in four, respectively, routinely included
US and radionuclide scan. On the other hand, the majority
(at least two of three) would leave out imaging in the
work-up of the index patient, in concordance with North
American guidelines recommending radionuclide scan depending on FNAB results and US in selected patients only,
e.g. to guide biopsy and in cystic nodules. However, only 6%
of the respondents who did not recommend US in the index
case would add this technique given a cystic nodule (variation 11). Only in the case of suppressed TSH would the vast
majority recommend a radionuclide scan, with 123I being the
preferred isotope. Compared to the previous ATA survey
from 1996, significantly fewer would include a thyroid scan
(23% vs. 56%) (7), possibly as a consequence of the publication of management guidelines (10, 11).
FNAB has become the initial diagnostic test in the evaluation of nontoxic solitary thyroid nodules, based on the fact
that FNAB has proved to be a better predictor of thyroid
malignancy than radionuclide scan; the latter provides little
additional information about cytological findings (12). All
respondents included a FNAB in the initial diagnosis. Furthermore, FNAB results are heavily relied upon, as evidenced by the fact that an additional diagnostic surgery was
recommended by only 1% of physicians for the index patient.
In the case of clinical factors raising the suspicion of malignancy, still less than 50% resorted to surgery.
Once malignancy was excluded or determined to be improbable, the preferred strategy was that of surveillance, in
accordance with the existing guidelines (10, 11). However,
2497
despite controversies regarding l-T4 suppressive treatment
(13) and ambiguous recommendations on its use in the
above-mentioned guidelines (10, 11), it was preferred by a
large number of clinicians (47%). Despite regional differences, with more frequent use of l-T4 in some states, the
treatment is widely distributed throughout North America.
Furthermore, when surgery was recommended (variations
6 –9), routine postoperative l-T4 treatment in the euthyroid
patient was recommended by approximately one third of the
physicians, although evidence of an effect on recurrence rate
is questioned (14).
Compared to European endocrinologists, ATA members
use fewer laboratory tests and less frequently perform imaging (radionuclide scan and/or US) in the index patient. 123I
is preferred, in contrast to the situation in Europe, where
99m
Tc is the preferred isotope. FNAB is the cornerstone in the
initial diagnosis, but whereas North American endocrinologists heavily rely on FNAB results, European endocrinologists perform supplementary testing, primarily diagnostic
imaging and serum calcitonin measurement, and turn to
surgery in the case of clinical factors favoring thyroid malignancy despite benign FNAB results. A strategy of surveillance, implying careful follow-up of the patient with a benign-appearing nodule, was recommended by the majority
of ATA members compared to less than one in three ETA
members. The fact is, however, that l-T4 treatment is supported by more than 40% of physicians in both North America and Europe, although evidence of its effect is lacking, at
least in iodine-sufficient regions (15).
Thus, even though a patient with a solitary thyroid nodule
is managed differently by North American endocrinologists,
a cost-effective diagnostic approach seems, in general, to
prevail and largely reflects implementation of the recommendations in the official guidelines (10, 11).
Acknowledgments
We thank the executive committee of the ATA for supporting the
implementation of the survey, as well as all the members of the ATA who
participated in this survey. The help of Martin I. Surks, who critically
reviewed the manuscript, is gratefully acknowledged. The Agnes and
Knut Mørk Foundation is thanked for sponsoring the distribution of the
questionnaire.
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