Anatomic Pathology / REPEAT THYROID FINE-NEEDLE ASPIRATION
Repeat Thyroid Nodule Fine-Needle Aspiration
in Patients With Initial Benign Cytologic Results
Melina B. Flanagan, MD, MSPH,1 N. Paul Ohori, MD,1 Sally E. Carty, MD,2
and Jennifer L. Hunt, MD1
Key Words: Thyroid; Fine-needle aspiration; FNA; Repeat testing
DOI: 10.1309/4AXLDMN1JRPMTX5P
Fine-needle aspiration (FNA) is the standard of
care for the initial workup of thyroid nodules, but there
is no consensus algorithm to manage patients with
benign results. We examined performance
characteristics of initial and repeat satisfactory FNAs
for all 402 patients who underwent thyroid surgery
during a recent 22-month period. Of these patients, 267
had at least 1 satisfactory FNA and 70 had 2 or more.
After an initial benign FNA, 1 repeat FNA correctly
identified an unsuspected malignancy in 2 of 70
patients and was indeterminate in 17; of these, 7 of 17
were identified as malignant in the final pathologic
diagnosis. Overall, the use of 1 repeat FNA increased
the sensitivity for malignancy from 81.7% to 90.4% and
decreased the false-negative rate from 17.1% to 11.4%.
With more than 1 repeat FNA, there was no
improvement in performance characteristics. These
data make a strong argument for 1 repeat FNA
following an initial benign FNA diagnosis.
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DOI: 10.1309/4AXLDMN1JRPMTX5P
A clinically palpable thyroid nodule is present in 4% to 7%
of the adult population in North America1; however, it has been
estimated that only 5% to 10% of these are malignant.1,2 Fineneedle aspiration (FNA) has become the standard of care for the
initial diagnostic workup of a thyroid nodule. Although diagnostic categories for reporting thyroid cytology results are not
entirely standardized, most cytopathologists use 4 categories:
malignant, indeterminate, benign, and unsatisfactory.3 At our
institution, we subclassify the indeterminate category with
descriptions that include follicular lesion, Hürthle cell lesion,
atypical cells present, and “suspicious” for malignant cells.
Most clinicians use the results of a thyroid FNA in conjunction with clinical findings to guide patient management.
Patients with a malignant or an indeterminate FNA diagnosis
will be counseled to undergo surgery, whereas benign diagnoses in stable nodules do not usually warrant surgical intervention.2 Use of FNA to manage thyroid nodules has been
associated with a considerable decrease in the need for diagnostic thyroidectomy and an increase in the percentage of thyroid cancer found in surgical specimens.1
As with any screening test, the usefulness of thyroid FNA
depends on its accuracy. Estimates of FNA sensitivity range
from 65% to 98% and specificity from 72% to 100%. The
false-positive rate reportedly ranges from 0% to 7.7% and is
considered low. The false-negative rate is more concerning,
however, because it has been estimated to range from 1.3% to
11.5%1 and has been shown to be associated with a significant
delay in appropriate treatment.4 Although there is general
agreement on the management of patients with a malignant or
indeterminate FNA diagnosis, there is no consensus on clinical
management of patients with benign FNA results. Several studies have examined the usefulness of repeat thyroid FNA after
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Abstract
Anatomic Pathology / ORIGINAL ARTICLE
an initial benign result. Although some authors suggest that
repeat FNA reduces the false-negative rate and is, therefore, a
valuable tool,5-9 others find that the routine repeat aspiration of
cytologically benign nodules does not improve the detection of
malignancy and is not warranted.10-12 In most studies, however, the patients generally had only 1 repeat FNA, study sizes
were limited, and only small subsets were correlated with surgical specimens. The present study examined the role of 1 or
more repeat thyroid FNAs in a large cohort of patients undergoing thyroidectomy with an initial benign FNA diagnosis.
Materials and Methods
Results
During the 22-month period from January 2001 through
October 2002, 402 patients underwent thyroid surgery at our
institution for nodular thyroid disease. Patients had 0 to 5
FNAs preceding surgery, for a total of 394 FNAs ❚Figure 1❚.
(135)
0 FNAs (135)
(197)
FNA #1 (267)
(51)
FNA #2 (70)
(10)
FNA #3 (19)
(7)
FNA #4 (9)
(2)
FNA #5 (2)
Surgery (402 patients, 367 satisfactory FNAs)
❚Figure 1❚ From January 2001 through October 2002, 402
patients underwent thyroid surgery at our institution for
nodular thyroid disease; 0-5 FNAs were performed preceding
surgery for a total of 367 FNAs. Numbers indicate how many
patients had a certain number of aspirates and then proceeded
to surgery or a repeat aspirate. FNA, fine-needle aspiration.
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The pathology records of the University of Pittsburgh
Medical Center, Pittsburgh, PA, were reviewed to identify all
patients who underwent thyroid surgery for nodular thyroid
disease for the 22-month period from January 2001 through
October 2002. For each patient, diagnoses from the final surgical pathology report and all preceding cytopathology reports
were retrieved. The final histologic permanent section diagnoses were categorized as benign (including nodular goiter,
dominant hyperplastic nodule, chronic lymphocytic thyroiditis, follicular or Hürthle cell adenoma, and Graves disease) or
malignant (including follicular, papillary, Hürthle cell, and
medullary carcinomas). Similarly, the preoperative cytologic
diagnoses were categorized as benign, indeterminate, malignant (papillary and medullary carcinomas), or unsatisfactory.
The indeterminate category included diagnoses of follicular
lesion, Hürthle cell lesion, atypical, and suspicious for malignant cells (listed in increasing probability of malignant outcome). At our institution, FNA specimens that do not contain
sufficient diagnostic material (usually owing to a paucity of
follicular epithelial groups or to blood contamination) are
given the qualifier “unsatisfactory.” Because unsatisfactory
FNAs will be repeated, these samples were excluded from further statistical analysis in the present study. Pathologically
identified incidental microscopic papillary thyroid carcinomas
were not included, and for the purposes of this study, only
index lesions were examined for FNA predictive ability.
All FNAs were performed by University of Pittsburgh
physicians (including endocrine surgeons, ultrasound radiologists, and thyroid-specialized endocrinologists), all with substantial experience in the technique. Each specimen was divided between air-dried smears stained with rapid Romanowsky
stain and alcohol-fixed smears for Papanicolaou staining. All
thyroid FNA specimens were interpreted by experienced staff
cytopathologists. All surgical specimens were processed
according to standard procedures, with extensive sampling of
gross nodules (ie, fully submitted or at least 20 cassettes).
Histologic sections were interpreted by experienced staff surgical pathologists.
Performance characteristics (sensitivity, specificity, and
false-positive and false-negative rates) of FNA for the final histologic diagnoses were calculated. Because patients with an
indeterminate or malignant result usually are counseled to
undergo surgery, patients with these FNA diagnoses were
grouped as “positive” for the purposes of this analysis. All performance characteristics (sensitivity, specificity, and false-negative and false-positive rates) were calculated for the initial
FNA and then for each repeat aspirate before surgery. For calculations of characteristics on repeat aspirates, the most worrisome diagnosis was used. The false-negative rate was defined
as the number of patients with benign FNA diagnoses who at
surgery were found to have malignancy divided by the total
number of patients with benign FNA diagnoses. Again, unsatisfactory samples were not included in the calculations.
Statistics were performed using SPSS version 11.5 (SPSS,
Chicago, IL). This study was approved by the University of
Pittsburgh Institutional Review Board (IRB number 0307076).
Flanagan et al / REPEAT THYROID FINE-NEEDLE ASPIRATION
reaffirmed the original benign diagnosis in 34 cases (59.6%).
The second FNA diagnosis was upgraded to indeterminate in
21 cases (36.8%), 7 of which were determined to be malignant
by final histologic examination. Two cases (3.5%) were
upgraded to malignant, and both were malignant on final histologic examination. Overall, 1 repeat FNA of thyroid nodules
diagnosed as benign on initial FNA detected 9 previously
undetected malignant neoplasms and, thus, changed the clinical plan in 9 (15.8%) of 57 patients.
Nineteen patients with benign diagnoses on the first 2
FNAs had up to 3 additional FNAs before surgery. Five of
these were upgraded to an indeterminate diagnosis, but all of
these were determined to be benign by final histologic examination. Two patients were given a malignant diagnosis by
final histologic examination, despite having had 3 or 4 benign
FNA results.
Performance characteristics for 1, 2, 3, 4, and 5 FNAs are
shown in ❚Table 2❚ (this analysis includes all satisfactory
repeat FNAs). With the second FNA, the overall sensitivity
increased from 81.7% to 90.4%, and the false-negative rate
decreased from 17.1% to 11.4%. In the subset of patients with
❚Table 1❚
Diagnoses for Each Fine-Needle Aspirate and for Final Surgical Specimen Histology
Fine-Needle Aspirate No.
Final Surgical Specimen
1
2
3
4
5
Benign
N
B
B
B
B
B
B
B
B
B
B
I
I
I
I
M
M
N
N
B
B
B
B
B
B
B
I
M
N
B
I
M
N
M
N
N
N
B
B
B
B
B
I
N
N
N
N
N
N
N
N
N
N
N
N
B
B
I
I
N
N
N
N
N
N
N
N
N
N
N
N
N
N
B
N
I
N
N
N
N
N
N
N
N
N
110
48
13
7
4
1
2
1
2
14
0
63
1
7
0
0
0
Malignant
Total
25
6
2
1
1
0
0
0
0
7
2
47
0
2
2
33
1
135
54
15
8
5
1
2
1
2
21
2
110
1
9
2
33
1
B, benign; I, indeterminate; M, malignant; N, none.
❚Table 2❚
Performance Characteristics for 1, 2, 3, 4, and 5 Fine-Needle Aspirations*
Fine-Needle Aspirate
Sensitivity (%)
Specificity (%)
False-negative rate (%)
False-positive rate (%)
*
1
1 and 2
1-3
1-4
1-5
81.7
56.4
17.1
45.5
90.4
47.9
11.4
47.5
90.4
47.2
11.5
47.8
90.4
44.8
12.0
48.9
90.4
44.8
12.0
48.9
The analysis includes all satisfactory repeated fine-needle aspirations.
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DOI: 10.1309/4AXLDMN1JRPMTX5P
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The indication for repeat FNA was almost always given as the
persistence of a dominant lesion. Of the 394 aspirates, 367
samples (93.2%) were satisfactory and included in this analysis. Of the 402 cases, 267 patients had at least 1 satisfactory
FNA, 70 patients had 2 or more, 19 had 3 or more, 9 had 4 or
more, and 2 had 5 FNAs. In this study 197 (49.0%) had exactly 1 FNA, 51 (12.7%) had 2, 10 (2.5%) had 3, 7 (1.7%) had 4,
and 2 (0.5%) had 5 FNAs.
In ❚Table 1❚, results are displayed by cytologic diagnostic
categories for all preoperative satisfactory aspirates and for the
final surgical pathology results. Of 267 patients with 1 or more
FNAs, the first FNA was benign in 111 (41.6%), malignant in
34 (12.7%), and indeterminate in 122 (45.7%). Of the 70
patients who had a second FNA, in 44 (62.9%), the repeat
FNA results were concordant with the first FNA result.
To assess the importance of a second FNA after a benign
diagnosis, the analysis was limited to the cases in which the
initial FNA diagnosis was benign (ie, excluding cases with a
malignant or indeterminate diagnosis). There were 111
patients with an initial benign diagnosis, and 57 of these had
1 or more additional aspirates. In this subset, the second FNA
Anatomic Pathology / ORIGINAL ARTICLE
initially benign cytologic results, 1 repeated FNA resulted in
an overall false-negative rate of 11.4%. Additional repeat
FNAs did not improve sensitivity. Additional repeat FNAs
also increased the overall false-negative rate.
Discussion
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Whether FNA of thyroid nodules should be interpreted as
a screening tool or a diagnostic procedure is not clear and
depends on the diagnosis given. However, the ultimate goal of
thyroid FNA should be to differentiate between nodules that
are definitely nonneoplastic and those that definitely are
malignant or that must be examined histologically for diagnosis. The ability of FNA to identify patients who will benefit
from surgery is entirely dependent on the accuracy of the test.
Thyroid FNA has been estimated to have a sensitivity for
malignancy between 65% and 98% (mean, 83%), a specificity between 72% and 100% (mean, 92%), a false-positive rate
of 0% to 7.7% (mean, 2.9%), and a false-negative rate of 1.3%
to 11.5% (mean, 5.2%).1
Estimates of these performance characteristics are highly
dependent on excellent follow-up data, which can be difficult
to acquire, and on the “gold standard” used for comparison. In
reported studies, the gold standard compared with FNA is variable and has included repeat FNA, clinical impression, and histologic diagnoses from thyroidectomies. There are disadvantages to each of these outcome measures. Repeat FNA suffers
from the same problems of sampling and interpretation as first
FNA and, therefore, is not a reliable outcome measure. Clinical
data are notoriously difficult to obtain and must include very
long follow-up time because thyroid malignant neoplasms can
be indolent. Histologic data generally are seen as the true gold
standard for comparison but, because most patients with
benign cytologic findings do not undergo surgery, such information is not readily available. The ideal study would include
initial and repeat FNA data and histologic analysis of all thyroid nodules in all patients; however, this study is not possible
as the standard of care has been established.
It is well established that FNA has revolutionized the care
of patients with thyroid nodules. The need for a diagnostic
lobectomy has decreased greatly because many patients can
be triaged based on their FNA results. However, the false-negative rate for initial thyroid FNA has important clinical implications. One false-negative result delays appropriate surgical
treatment by more than 2 years, and additional false-negative
diagnoses confer an even longer delay. This delayed treatment
is associated with capsular and vascular invasion, both of
which predict a poorer outcome.4 Thus, the clinical significance of a false-negative FNA result certainly fuels the issue
of how to manage patients with a thyroid nodule diagnosed as
benign on the first FNA.
Several studies support the view that 1 repeat FNA in
cytologically benign nodules is valuable. In studies of 246,
196, and 235 patients with 1 repeat FNA and histologic followup on a limited subset, Hamburger,5 Dwarakanathan et al,6 and
Chehade et al7 reported that repeat FNA upgraded 18, 13, and
12 benign diagnoses, respectively, to suspicious or malignant,
and that 6 of 10, 4 of 10, and 2 of 9, respectively, of these who
underwent thyroidectomy had a malignancy found by histologic evaluation. These authors concluded that 1 repeat FNA
reduces the false-negative rate and, therefore, is useful.
Two studies examined multiple repeat FNAs and reported that either 2 or 3 FNAs are useful. Erdogan et al8 reviewed
multiple repeat aspiration specimens from 216 euthyroid
patients with cytologically benign nodules (257 second FNAs,
137 third, 46 fourth, and 17 fifth). The second FNA upgraded
3 cases to malignant, and all were malignant by histologic
examination; with 4 FNAs, 16 cases were upgraded to suspicious, but all 6 of these that underwent thyroidectomy were
benign. The authors concluded that a second FNA in patients
with initially cytologically benign thyroid nodules may detect
a few previously missed malignant neoplasms but that additional repeat FNAs are not indicated routinely. More recently,
Orlandi et al9 examined up to 5 repeat FNA specimens in 306
patients and reported that repeat FNA upgraded 4 cases from
benign to malignant (1 in the second FNA and 3 in the third).
The authors concluded that it is useful to perform 3 FNAs, but
that in the absence of clinical changes, additional cytologic
follow-up after 3 FNAs with benign diagnoses is unnecessary.
Conversely, several studies support the opposing view
that repeat FNAs are not useful. Lucas et al10 reported that in
repeat FNAs on 116 euthyroid patients (2 in 116 patients, 3 in
19), no cases were upgraded from benign to malignant. In an
analysis of 490 patients with cytologically benign nodules,
Aguilar et al11 reported that 2 of 90 patients who underwent
thyroidectomy for clinical reasons were found to have a
malignancy, 1 of 184 benign diagnoses was upgraded to
malignant by repeat FNA and then confirmed histologically,
and 216 patients remained free of cancer as assessed by clinical follow-up. Finally, in an analysis of repeat FNA specimens
in 45 patients with initially benign diagnoses (41 with 1 repeat
FNA, 4 with 2), Merchant et al12 reported that all cases
remained categorized as benign and 7 of 7 cases that underwent thyroidectomy for clinical reasons were histologically
benign. These authors concluded that repeat FNA does not
improve detection of malignant neoplasms.
The present study examined the role of 1 or more satisfactory thyroid FNA specimens in 267 patients, including repeat
FNA in 70 patients. In 57 patients with an initial benign diagnosis, 1 repeat FNA diagnosed 2 additional malignant neoplasms
(both were malignant by final histologic examination) and 21
indeterminate cases (7 of which were malignant by final histologic examination). Thus, 2 repeat FNAs of thyroid nodules
Flanagan et al / REPEAT THYROID FINE-NEEDLE ASPIRATION
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9. Orlandi A, Puscar A, Capriata E, et al. Repeated fine-needle
aspiration of the thyroid in benign nodular thyroid disease:
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2005;15:274-278.
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cytology of benign nodular thyroid disease: value of reaspiration. Eur J Endocrinol. 1995;132:677-680.
11. Aguilar J, Rodriguez JM, Flores B, et al. Value of repeated fineneedle aspiration cytology and cytologic experience in the
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From the Departments of 1Pathology and 2Surgery, University of
Pittsburgh, Pittsburgh, PA.
Address reprint requests to Dr Hunt: Dept of Anatomic
Pathology, the Cleveland Clinic, 9500 Euclid Ave, L25, Cleveland,
OH 44195.
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diagnosed as benign on initial FNA detected 9 previously
undetected malignant neoplasms. Overall, a second FNA
decreased the false-negative rate from 17.1% to 11.4% and
increased sensitivity from 81.7% to 90.4%. Unlike previous
studies that have tried to address this issue, our study is based
on histologic analysis of all cases. The strength of this design
is that it allowed us to correlate cytologic with histologic findings for the entire sample. However, the surgical subset of
patients that we studied is likely to have a greater percentage of
malignant outcomes than the general population. Thus, our
performance characteristics for 1 FNA and multiple FNAs
should be interpreted as applicable to the subset of patients
offered surgery by their clinicians, and the benefit of a second
FNA in the general population might be somewhat lower.
The present study further examined the usefulness of
more than 1 repeat thyroid FNA. Despite extensive sampling,
no further malignant neoplasms were detected after the first
repeat FNA in up to 3 additional FNA specimens. Overall, the
false-negative rate increased from 11.4% for 2 aspirates to
11.5% for 3 and 12.0% for 4 or 5. It is interesting that there
were 2 cases in which thyroid nodules diagnosed as benign on
3 consecutive FNAs were diagnosed histologically as malignant: 1 papillary carcinoma and 1 follicular carcinoma. These
cases highlight that even repeat FNAs will have false-negative
results, and the ultimate decision to proceed to surgery must
include clinical factors as well as FNA results.
Our data strongly support the clinical usefulness of 1
repeat FNA after an initial benign aspiration. The data also
highlight the fact that management decisions for patients with
thyroid nodules must include the FNA result and clinical suspicion, because false-negative results are not eliminated with
repeat FNA of thyroid nodules.