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Special Articles

Application of the Bethesda Classification for Thyroid


Fine-Needle Aspiration
Institutional Experience and Meta-analysis
Elliot A. Krauss, MD; Megan Mahon, BS; Jean M. Fede, DO; Lanjing Zhang, MD, MS

 Context.Fine-needle aspiration (FNA) biopsies have Significant differences were noted in the frequencies of
been an important component in the preoperative evalu- cases in diagnostic categories Benign (II; P .003),
ation of thyroid nodules. Until the introduction of the Suspicious for follicular neoplasm/Follicular neoplasm
Bethesda System for Reporting Thyroid Cytopathology (IV; P , .001), and Malignant (VI; P .003) after the
(BSRTC) in 2008, individual institutions had developed introduction of the BSRTC. Eighteen published articles met
their own diagnostic categories. The BSRTC proposed 6 the criteria for inclusion in the meta-analysis. The risk of
categories in an attempt to standardize reporting of thyroid malignancy in each category in our institution was similar
FNA. to that determined in the meta-analysis, except for
Objective.To present a 15-year experience of thyroid
Insufficient for diagnosis (I; 20% versus 9%14%). Meta-
FNA at one institution, including data before and after
analysis showed an overlapping 95% CI of risk of
introduction of the BSRTC. The risk of malignancy is
compared with the meta-analysis of high-quality published malignancy between Atypia of undetermined signifi-
data. cance/Follicular lesion of undetermined significance (III;
Data Sources.Data sources were PubMed, a manual 11%23%) and Suspicious for follicular neoplasm/Follic-
search of references, and institutional data. ular neoplasm (IV; 20%29%), suggesting similar risks of
Conclusions.The diagnostic categories developed at malignancy. The use of newer molecular tests for these
our institution were similar to those proposed by the indeterminate cases may further refine risk assessment.
BSRTC, with best fit into the 6 categories easily accom- (Arch Pathol Lab Med. 2016;140:11211131; doi:
plished and reported in the final 2 years of the study. 10.5858/arpa.2015-0154-SA)

F ine-needle aspiration (FNA) of the thyroid gland has


proven to be an invaluable procedure for evaluating
patients with thyroid nodules. It has been in use for more
categories without consensus among reporting institutions.
Institutions reviewed their experiences with FNA of the
thyroid to determine its usefulness and predictive value for
than 50 years, first advocated in Sweden.1 However, not malignancy.35 In 1996, the Papanicolaou Society of
until the late 1970s was its use advocated in the United Cytopathology proposed guidelines and 10 diagnostic
States.2 As a method for triaging patients to distinguish groups for the cytologic interpretation of thyroid FNA.6 In
those who require surgery from those who do not, 2007, the National Cancer Institute hosted the NCI Thyroid
institutions developed their own cytologic diagnostic Fine Needle Aspiration State of the Science Conference. The
intention was to develop a system of classification of thyroid
FNA similar in scope to the Bethesda Classification for
Accepted for publication February 12, 2016. gynecologic cervical cytology. By the publication and
From the Department of Pathology, University Medical Center of
Princeton, Plainsboro, New Jersey (Drs Krauss, Fede, and Zhang); the
acceptance of what has become known as the Bethesda
Department of Pathology, Rutgers Robert Wood Johnson Medical System for Reporting Thyroid Cytopathology (BSRTC), it
School, New Brunswick, New Jersey (Drs Krauss, Fede, and Zhang, was hoped that there would be more effective communi-
and Ms Mahon); the Department of Chemical Biology, Rutgers Ernest cation among provider stakeholders, greater facilitation of
Mario School of Pharmacy, Piscataway, New Jersey (Dr Zhang); and cytologic-histologic correlations, and the easy and reliable
the Cancer Institute of New Jersey, Rutgers University, New
sharing of data between different laboratories.7 Further, the
Brunswick, New Jersey (Dr Zhang). Drs Krauss and Zhang equally
supervised this work. committee proposed morphologic criteria for each diagnos-
The authors have no relevant financial interest in the products or tic category.8 It was hoped that the proposed label of
companies described in this article. Bethesda Classification would lend credibility to the
Presented in part at the Princeton Integrated Pathology Sympo- classification by reference and similarity to the gynecologic
sium: Head and Neck Pathology; February 9, 2014; Princeton, New cytology classification. The BSRTC has 6 diagnostic catego-
Jersey.
Reprints: Elliot A. Krauss, MD, Department of Pathology, Univer- ries, including Nondiagnostic or Unsatisfactory (I); Benign
sity Medical Center of Princeton, 1 Plainsboro Rd, Plainsboro, NJ (II); Atypia of undetermined significance or follicular lesion
08536 (email: ekrauss@princetonhcs.org). of undetermined significance (AUS/FLUS; III); Suspicious
Arch Pathol Lab MedVol 140, October 2016 Bethesda Classification for Thyroid FNAKrauss et al 1121
Table 1. Distribution of Diagnoses Before and After Implementation of the Bethesda Classification
Diagnosis Bethesda Class 19992011, No. (%)a 20122013, No. (%) P Value
Total insufficient I 458 (10.3) 118 (10.4) .96b
Insufficient I 403 (9.1) 109 (9.6)
Cyst I 55 (1.2) 9 (0.8)
Total benign II 3211 (72.4) 875 (76.9) .003b
Chronic thyroiditis II 171 (3.9) 20 (1.8)
Benign nodule II 3040 (68.5) 855 (75.1)
Follicular lesion III 199 (4.5) 39 (3.4) .14b
Total class IV IV 322 (7.3) 21 (1.9) ,.001b
SuspFoll N IV 224 (5.0) 18 (1.6)
HCL/N IV 98 (2.2) 3 (0.3)
Total class V V 164 (3.7) 47 (4.1) .55b
Susp N/susp Malign V 55 (1.2) 43 (3.9)
Susp PTC V 109 (2.5) 4 (0.4)
Malignant (PTC and medullary carcinoma) VI 82 (1.8) 38 (3.3) .003b
Sum of Nodules 4436 1138 ,.001c
Abbreviations: HCL/N, Hurthle cell lesion/neoplasm; PTC, papillary thyroid carcinoma; SuspFoll N, Suspicious for follicular neoplasm; Susp N/susp
Malign, Suspicious for neoplasm/suspicious for malignancy.
a
Data through November 2011, when the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) was implemented.
b
Comparison of the frequencies of individual classifications in all cases before and after inclusion of BSRTC.
c
Comparison of the overall frequencies of major classifications before and after inclusion of BSRTC.

for follicular neoplasm or Follicular neoplasm (SFN/FN; IV); Center of Princeton at Plainsboro, New Jersey (formerly University
Suspicious for malignancy (V); and Malignant (VI). Medical Center at Princeton, Princeton, New Jersey) were recorded
Beginning in 1999, our institution embarked on a program prospectively into a database. Thyroid nodules were localized with
palpation and ultrasound. The aspirates were prepared as direct
of FNA sampling of thyroid nodules. The program was a
smears and were alcohol fixed. Excess material from the aspirates
coordinated effort among a small group of physicians, was placed in Saccomanno or formalin (10%) fixative and a cell
including a pathologist, interventional radiologists, endocri- block prepared, when possible. The smears were stained with the
nologists, and thyroid surgeons. A system of classification standard Papanicolaou stain. Immediate diagnosis of adequacy was
based on the Papanicolaou Societys report6 was agreed upon not provided. The material was submitted by clinicians from their
by the providers. The system that developed was similar to office practice and from radiologists performing the procedure in
that later proposed by the BSRTC, which enabled a smooth the hospital outpatient setting. Interpretation of the aspirates was
transition to that classification system. In this report, we have performed by pathologists only, not cytologists. During the 15
summarized our 15-year experience, with comparison to the years of the study, 3735 of 5574 nodules (67%) were interpreted by
one pathologist, 1616 (29%) by another, and 223 (4%) by a third.
BSRTC and an emphasis on the cytologic-histologic correla-
No retrospective review was performed on cases prior to analysis of
tion. We also conducted a meta-analysis of high-quality the data.
published studies for comparison to our data. Our major aim The cytologic diagnoses were classified into 9 categories with the
was to reappraise the value of BSRTC and seek areas of following criteria:
potential improvement or update.
1. Unsatisfactory. Fewer than 6 groups containing at least 10 well-
MATERIALS AND METHODS preserved cells on each of at least 2 slides. Colloid only and
hypocellular aspirates from cysts were considered unsatisfactory
Prospective Correlation Study with a descriptive comment.
Beginning January 1, 1999, through December 31, 2013, all 2. Benign thyroid nodule. Variable numbers of unremarkable
results of thyroid FNA interpretations at the University Medical follicular cells in flat sheets, large clusters, and macrofollicles.

Table 2. Cytologic-Histologic Correlation 19992013


Surgical Diagnosis, No.
Cytologic Diagnosis Benign Cyst CT FA HCA FC HCC PTC Med Para SCC Totals
Insufficient 23 2 1 6 1 1 0 7 0 0 0 41
Benign 160 1 3 16 1 0 1 7 0 0 0 189
Follicular lesion 24 0 2 15 0 3 1 10 0 0 0 55
FN/Susp FN 47 0 1 38 0 3 0 15 0 0 0 104
HC lesion/neoplasm 15 0 1 1 6 3 12 0 0 0 0 38
Susp neoplasm/SuspMalig 11 0 0 10 0 9 1 34 1 3 1 70
Medullary carcinoma 0 0 0 0 0 0 0 0 1 0 0 1
Susp PTC 5 0 0 0 0 0 1 62 0 0 0 68
PTC 0 0 0 0 0 0 0 68 0 0 0 68
Total 634
Abbreviations: CT, chronic thyroiditis; FA, follicular adenoma; FC, follicular carcinoma; FN, follicular neoplasm; HC, Hurthle cell; HCA, Hurthle cell
adenoma; HCC, Hurthle cell carcinoma; Med, medullary carcinoma; Para, parathyroid gland; PTC, papillary thyroid carcinoma; SCC, squamous cell
carcinoma.
1122 Arch Pathol Lab MedVol 140, October 2016 Bethesda Classification for Thyroid FNAKrauss et al
Table 3. Cytologic-Histologic Correlation Risk of Malignancy
Bethesda Risk of Risk of Malignancy,
Cytology Diagnosis, 19992013 Category Malignancy, % BSRTC, %a
Insufficient I 20 14
Benign II 4 03
Follicular lesion III 25 515
FN/Susp FN IV 17 1530
HC lesion/neoplasm IV 39
Susp neoplasm/Susp Malig V 66 6075
Susp PTC V 93
Medullary carcinoma VI 100
PTC VI 100 9799
Abbreviations: BSRTC, Bethesda System for Reporting Thyroid Cytopathology; FN, follicular neoplasm; HC, Hurthle cell; Malig, malignancy; PTC,
papillary thyroid carcinoma; Susp, suspicious for.
a
Risk of malignancy as reported in the BSRTC.8

Colloid and histiocytes were a common accompaniment. The cellular specimens with atypical nuclei, including nuclear
differential diagnosis for the group included hyperplastic enlargement, mild nuclear pleomorphism, and pale nuclei. The
nodule, adenomatous follicular nodule, and macrofollicular differential diagnosis included a benign nodule, a follicular
adenoma. neoplasm, and papillary carcinoma. Generally, the features of the
3. Chronic thyroiditis. Generally cellular specimens with abundant specimen were insufficient to reach a more definitive diagnosis.
lymphocytes or lymphoid tangles and follicular cells showing a 5. Follicular neoplasm/suspicious for follicular neoplasm. Hyper-
variety of changes in the same nodule, including variable cellular specimens with a predominance of microfollicles in 3-
oxyphilic change, nuclear pleomorphism, and nuclear anisocy- dimensional, overlapping structures. Abundant isolated, intact,
tosis. Histiocytes were common. Colloid was variable. individual cells with syncytial microbiopsies. Little colloid was
4. Follicular lesion. Hypercellular specimens with colloid and present. Cytologic nuclear changes of papillary thyroid carci-
variably sized follicles, predominantly microfollicles. Fewer noma were lacking. The differential diagnosis included benign

Figure 1. Forest plot of meta-analysis on the risk of malignancy of Bethesda classification I for thyroid fine-needle aspiration (I2 42.1%, P .04).
The reference numbers of the included articles are listed in the parentheses. Abbreviation: ES, estimated.
Arch Pathol Lab MedVol 140, October 2016 Bethesda Classification for Thyroid FNAKrauss et al 1123
Figure 2. Forest plot of meta-analysis on the risk of malignancy of Bethesda classification II for thyroid fine-needle aspiration (I2 93.6%, P , .001).
The reference numbers of the included articles are listed in the parentheses. Abbreviation: ES, estimated.

thyroid nodule, follicular adenoma, and well-differentiated 9. Malignant. Generally hypercellular with cytologic features
follicular carcinoma. qualitatively and quantitatively definitive for papillary carcino-
6. Hurthle cell lesion/suspicious for Hurthle cell neoplasm. ma as described in Suspicious for papillary carcinoma. This
Variable cellularity with predominantly follicular cells showing category also would include anaplastic carcinoma, medullary
abundant granular and eosinophilic cytoplasm. Enlarged nuclei carcinoma, lymphoma, squamous cell carcinoma, and other
with or without prominent nucleoli. Variably sized follicles or carcinomas, such as metastatic carcinoma.
sheets of follicular cells. Absence of lymphocytes. Colloid
variable, but generally scant. The differential diagnosis included In November 2011, our institution modified its reporting
hyperplastic nodule, Hurthle cell adenoma, and Hurthle cell categories to include the BSRTC category with a best fit to the
carcinoma. categories that had been in use.
7. Suspicious for neoplasm. Generally hypercellular with cytologic This study has been approved by the Institutional Review Board
features suggestive of papillary carcinoma, such as enlarged at our institution.
nuclei, atypical nuclei with irregular nuclear membranes,
nuclear grooves, overlapping and crowding of nuclei, nuclear The Meta-analysis
molding, and fine granular or powdery nuclear chromatin. We searched PubMed with the term cytology AND thyroid
These features were quantitatively and qualitatively insufficient AND Bethesda AND accuracy in May 2014. Additional articles
for a more definitive diagnosis of malignancy. The differential were also found or removed by manually reviewing the full text and
diagnosis included benign thyroid nodule and papillary thyroid references of the matched articles. Two of the coauthors (M.M. and
carcinoma. L.Z.) cross-checked the accuracy and relevance of the articles. Only
8. Suspicious for papillary carcinoma. Generally hypercellular with studies meeting the following criteria were considered to have
cytologic features suggestive of papillary carcinoma, such as high-quality data and to be relevant to the subject, and were
enlarged nuclei, atypical nuclei with irregular nuclear mem- included: (1) the studies were indexed in PubMed; (2) the studies
branes, nuclear grooves, overlapping and crowding of nuclei, reported correlations between thyroid cytology Bethesda classifi-
nuclear molding, fine granular or powdery nuclear chromatin, cation and respective surgical pathology diagnosis of thyroid
and intranuclear pseudoinclusions. These specimens usually nodules; (3) the studies included both classes II and VI, and one
lacked 1 or 2 of the cytologic features of papillary thyroid or more additional other categories, or included categories III, IV,
carcinoma, preventing a definitive diagnosis. The differential and V. The criterion 3 is particularly important for ensuring that the
diagnosis included benign thyroid nodule and papillary thyroid included data represent a wide spectrum of pathology between
carcinoma. benign and malignant cases. This criterion in our view would
1124 Arch Pathol Lab MedVol 140, October 2016 Bethesda Classification for Thyroid FNAKrauss et al
Figure 3. Forest plot of meta-analysis on the risk of malignancy of Bethesda classification III for thyroid fine-needle aspiration (I2 93.2%, P , .001).
The reference numbers of the included articles are listed in the parentheses. Abbreviation: ES, estimated.

significantly reduce the selection bias introduced by the studies that inclusion of the BSRTC (P , .001), particularly within the
included only one or two classes. Benign (II) and Suspicious for malignancy (V) categories (P
We used the best-fit approach to extract data and reclassify cases, , .001 for both). No frequency difference was found
mostly for the works published prior to the publication of BSRTC. between before and after inclusion of the BSRTC in the
Specifically, the acceptable alternative terminologies for AUS/FLUS
categories Insufficient for diagnosis (I), AUS/FLUS (III),
(III) category were indeterminate for neoplasm, indeterminate cells
of undetermined significance, atypical cellular lesion, atypical cells SFN/FN (IV), and Malignant (VI; Table 1).
of undetermined significance, atypical follicular cells, abnormal, Of the 576 FNAs with Insufficient for diagnosis (which
indeterminate, indeterminate follicular lesion, and inconclusive or included cysts), 193 patients (42%) had reaspirations, of
indeterminate. The acceptable alternative terminologies for SFN/ whom 165 (85%) resolved into a more specific category. Of
FN (IV) category were neoplasm, follicular/Hurthle cell neoplasm, the 238 Follicular lesion diagnoses in 236 patients, only 6
suspicious for neoplasm, suspicious for follicular or oncocytic patients (2.5%) had repeat aspirations of the nodules. All 6
neoplasm, Hurthle cell, indeterminate Hurthle cell, and Hurthle (100%) had a diagnosis of Follicular lesion on the repeat
cell neoplasm. aspiration, which was separated from the first aspiration by
The statistical analyses, including meta-analysis, were carried out
as much as 6 years. Of the 343 Suspicious for follicular
by using STATA version 12.0 (Stata Corp, College Station, Texas) as
described previously by Zhang et al.9 Random efforts were applied neoplasm/follicular neoplasm diagnoses, which included
to the meta-analysis. A random-effect model was used for meta- those nodules with Hurthle cell features, in 324 patients,
analysis when I2 . 50% or P , .05 in the heterogeneity test; only 6 patients (1.8%) had repeat aspirations of the nodules.
otherwise, a fixed-effect model was used. P , .05 was considered All 6 (100%) had a diagnosis of Suspicious for follicular
statistically significant. neoplasm/follicular neoplasm on the repeat aspiration,
which was separated from the first aspiration by as much as
RESULTS 7 years. Only 1 of these 6 patients (16.6%) had Hurthle cell
Between January 1, 1999, and December 31, 2013, a total features, which was present on both the original as well as
of 5574 nodules were sampled during 4338 patient the repeat aspiration.
encounters. Table 1 shows the distribution of diagnoses According to the BSRTC, although Hurthle cell lesions/
before and after the inclusion of the BSRTC category, with neoplasms are included in the category SFN/FN (IV), it was
the descriptive diagnosis for each FNA. There was also recommended to specifically note the presence of
significant frequency difference between before and after Hurthle cell changes. At our institution, Hurthle cell lesion/
Arch Pathol Lab MedVol 140, October 2016 Bethesda Classification for Thyroid FNAKrauss et al 1125
Figure 4. Forest plot of meta-analysis on the risk of malignancy of Bethesda classification IV for thyroid fine-needle aspiration (I2 91.0%, P ,
.001). The reference numbers of the included articles are listed in the parentheses. Abbreviation: ES, estimated.

neoplasm has always been considered a distinct category, carcinoma. Within each category, except Hurthle cell lesion/
and although indicated as BSRTC SFN/FN (IV), it is neoplasm, papillary thyroid carcinoma was the dominant
presented in Table 1 as a separate line category. type of cancer identified, including 10 of the 14 cases
Similarly, Suspicious for papillary carcinoma had always (71.4%) within the follicular lesion category and 15 of the 18
been considered by us as a separate category, and it is cases (83.3%) within the follicular neoplasm category.
presented as a BSRTC category V lesion, Suspicious for Table 3 presents the cytologic-histologic correlations
malignancy. charted in Table 2 as risk of malignancy (ROM) given the
The distribution of several diagnoses showed a significant cytologic diagnosis. Malignancy included follicular carcino-
change after the introduction of the BSRTC classification. ma, Hurthle cell carcinoma, papillary carcinoma, medullary
Benign (II) showed a modest but significant increase in carcinoma, and squamous cell carcinoma. Although other
percentage of cases, whereas SFN/FN (IV), Hurthle cell carcinomas can be seen in the thyroid gland, these were the
lesion/neoplasm (IV), and Suspicious for papillary carcino-
only malignancies identified in our patients. The ROM was
ma (V) all showed significant decreases.
calculated by dividing the number of malignancies detected
A total of 556 patients underwent a partial or total
by thyroidectomy, by the number of thyroidectomies, in a
thyroidectomy. Among them, 634 nodules were identifiable
based on the clinical or ultrasonographic description, and diagnostic category, 3 100. The ROM was higher for
were correlated with their cytologic diagnosis. The distri- insufficient (I; 20%) and AUS/FLUS (III; 25%) than that
bution of the cytologic-histologic correlation of the nodules reported in the BSRTC.8 Of those insufficient cases which on
within the excised thyroid glands is presented in Table 2. subsequent aspiration resolved into more definitive catego-
The 2 diagnostic categories Hurthle cell lesion/Neoplasm ries (n 165), 16 (10%) came to surgery. Of these 16, an
and Suspicious for papillary thyroid carcinoma are present- additional 5 (31%) malignancies were identified. If these
ed as separate line categories. cases had surgery on the first Insufficient for diagnosis,
There were 241 malignant nodules identified, of which 19 the ROM of Insufficient for diagnosis would have been
(7.9%) were follicular carcinoma, 16 (6.6%) Hurthle cell 23%. In Table 3, these 16 cases were categorized in their
carcinoma, 203 (84.2%) papillary thyroid carcinoma, 2 more definitive categories, not in the Insufficient for
(0.8%) medullary carcinoma, and 1 (0.4%) squamous cell diagnosis category.
1126 Arch Pathol Lab MedVol 140, October 2016 Bethesda Classification for Thyroid FNAKrauss et al
Figure 5. Forest plot of meta-analysis on the risk of malignancy of Bethesda classifications III and IV (combined) for thyroid fine-needle aspiration (I2
94.2%, P , .001). The reference numbers of the included articles are listed in the parentheses. Abbreviation: ES, estimated.

Of the 628 articles identified in PubMed, 7 articles met the ROM in each diagnostic category, and comparison with the
inclusion criteria. An additional 11 qualified articles were pooled ROM through a meta-analysis on high-quality
identified by searching the references of those articles and published data.
personal article collections. A total of 18 articles therefore The results of this thyroid FNA study confirm the
were included for the meta-analysis and subject to the usefulness and comparability of this technique in our
heterogeneity test (Figures 1 through 7; Table 4). Our meta- institution to the experience at other institutions.1017 The
analysis found that AUS/FLUS (III) and SFN/FN (IV) had distribution of diagnoses is similar to that reported as
similar ROMs, as shown by overlapping 95% CIs (average expected when using the BSRTC and our meta-analysis
[95% CI], 0.24 [0.160.32] and 0.25 [0.190.31], respectively; results.8
Figures 3 and 5 and Table 5). The ROM of the combined
After the implementation of the BSRTC, the distribution
AUS/FLUS (III) and SFN/FN (IV) was 0.24 (0.190.30;
of several diagnoses showed a significant change. Benign
Figure 4 and Table 5) and did not overlap the 95% CIs of
(II) showed a modest but significant increase, whereas SFN/
Benign (II) or Suspicious for malignancy (V). The pooled
ROMs of categories Benign (II), Suspicious for malignancy FN (IV), Hurthle cell lesion/Neoplasm (IV), and Suspicious
(V), and Malignant (VI) were significantly different from for Papillary Carcinoma (V) all showed significant decreases.
each other, and from AUS/FLUS (III) and SFN/FN (IV) or The publication by Baloch et al8 of diagnostic criteria for
combined from AUS/FLUS (III) and SFN/FN (IV). Of note, each category aided us in refining our interpretations and
the pooled ROM from meta-analysis was slightly different may account for the change in distributions from 19992011
from the crude malignancy rate in cases combined because versus 20122013. However, our experience with reporting
weighted ROMs from the included studies were used for the BSRTC encompassed only 2 years versus 13 years. The
calculation (Figures 1 through 7 and Table 4). distribution could regress to the results of the previous 13
years as time and the number of aspirates progresses
DISCUSSION forward.
In the past 40 years, thyroid FNA has been recognized as The recognition that the BSRTC category of Papillary
the most useful diagnostic tool in triaging those patients Carcinoma accepted a less than 100% ROM influenced us to
most at risk of harboring a malignant lesion. We have progressively eliminate the category of Suspicious for
reported our 15 years of experience with the technique, papillary carcinoma, in which we had a 93% ROM, in favor
Arch Pathol Lab MedVol 140, October 2016 Bethesda Classification for Thyroid FNAKrauss et al 1127
Figure 6. Forest plot of meta-analysis on the risk of malignancy of Bethesda classification V for thyroid fine-needle aspiration (I2 93.3%, P , .001).
The reference numbers of the included articles are listed in the parentheses. Abbreviation: ES, estimated.

of the more definitive diagnostic category Papillary Carci- FLUS to total thyroid FNAs) and incorporate a consensus
noma. review for lesions falling into indeterminate categories
Indeed, combining our Suspicious for papillary carcinoma (AUS/FLUS [III] and SFN/FN [IV]). It is interesting to note
category, primarily used before the introduction of the that there was a wide CI for the Suspicious for malignancy
BSRTC, with our Papillary Thyroid Carcinoma category (V) category in the meta-analysis, indicating significant
would have produced a ROM of 96%, similar to that subjectivity here as well.
reported in the BSRTC8 category Malignant (VI). The usefulness of FNA of the thyroid is in its ability to aid
Of the 576 insufficient for diagnosis patients, 193 (34%) clinicians in their decision on how best to treat patients.
had repeat aspirations, with 85% of them resolving into Thus, Benign (I), Suspicious for malignancy (V), and
more definitive diagnostic categories. A total of 41 patients Malignant (VI) categories have sufficient ROMs, in our
went on to have partial or total thyroidectomy, with 8 (20%) institution (4%, 66%, and 96%, respectively) and other
of them showing malignancy. The meta-analysis also reports summarized by our meta-analysis, as to give
identified a 12% (95% CI, 9%14%) ROM in this category. clinicians clear treatment directions.
The higher rate of malignancy in our series may reflect other The more problematic categories of AUS/FLUS (III), SFN/
suspicious clinical features that prompted the election of FN (IV), and Hurthle cell lesion/Neoplasm (IV) have ROMs
surgical excision. It is noteworthy to recognize that that are in an indeterminate range, 17% to 39%, and
insufficient for diagnosis does not mean negative for therefore do not give clinicians a clear direction. In our
malignancy, and these patients should have close clinical series, very few of these cases had repeat aspirations, which
follow-up. have been reported in other series to resolve the dilemma in
The ROMs of our categories Suspicious for malignancy up to 50% of cases of AUS/FLUS (III).18 However, the ROM
(V) and Malignant (VI) are similar to that of the meta- for an AUS/FLUS (III) diagnosis with a subsequent Benign
analysis. AUS/FLUS (III) is slightly higher (25%) and SFN/ (II) diagnosis on a follow-up FNA is not the same as a single
FN (IV) is slightly lower (17%) than the ranges seen in the Benign (II) diagnosis, but rather falls somewhere in between
meta-analysis (95% CIs, 11%23% and 20%29%, respec- the two (15%29%).19,20 This would seem to preclude the
tively). This likely reflects subjective differences in how we use of a second aspiration in cases of AUS/FLUS (III) for
interpreted the criteria for these categories. This subjectivity additional risk stratification. The presented meta-analysis
was mirrored as well by the wide 95% CIs seen in the meta- shows overlapping ROMs for AUS/FLUS (III) and SFN/FN
analysis. It might be useful for laboratories to create a (IV). On the surface, AUS/FLUS (III) and SFN/FN (IV) have
standardized performance measure (such as ratio of AUS/ different diagnostic criteria, but the ROM is what drives a
1128 Arch Pathol Lab MedVol 140, October 2016 Bethesda Classification for Thyroid FNAKrauss et al
Figure 7. Forest plot of meta-analysis on the risk of malignancy of Bethesda classification VI for thyroid fine-needle aspiration (I2 25.1%, P .24).
The reference numbers of the included articles are listed in the parentheses. Abbreviation: ES, estimated.

Table 4. The List of the Studies Qualified and Included in the Meta-analysis
Source, y Article Title
Banks et al,24 2008 A diagnostic predictor model for indeterminate or suspicious thyroid FNA samples
Blansfield et al,25 2002 Recent experience with preoperative fine-needle aspiration biopsy of thyroid nodules in a
community hospital
Bohacek et al,26 2012 Diagnostic accuracy of surgeon-performed ultrasound-guided fine-needle aspiration of thyroid
nodules
Bozhok et al,27 2009 A cohort study of thyroid cancer and other thyroid diseases after the Chernobyl accident: Cyto-
histopathologic correlation and accuracy of fine needle aspiration biopsy in nodules detected
during the first screening in Ukraine
Faquin and Baloch,28 2010 Fine-needle aspiration of follicular patterned lesions of the thyroid: Diagnosis, management, and
follow-up according to National Cancer Institute (NCI) recommendations
Jo et al,29 2010 Malignancy risk for fine-needle aspiration of thyroid lesions according to the Bethesda System For
Reporting Thyroid Cytopathology
Mufti and Molah,30 2012 The Bethesda System for Reporting Thyroid Cytopathology: A five-year retrospective study of one
center experience
Nayar and Ivanovic,31 2009 The indeterminate thyroid fine-needle aspiration
Oertel et al,32 2007 Value of repeated fine needle aspirations of the thyroid: An analysis of over ten thousand FNAs
Poller et al,33 2000 Fine-needle aspiration of the thyroid: Importance of an indeterminate diagnostic category
Renshaw,34 2011 Subclassification of atypical cells of undetermined significance in direct smears of fine-needle
aspirations of the thyroid
Sclabas et al,35 2003 Fine-needle aspiration of the thyroid and correlation with histopathology in a contemporary series of
240 patients
Smith et al,36 2013 Indeterminate pediatric thyroid fine needle aspirations: A study of 68 cases
Theoharis et al,37 2009 The Bethesda Thyroid Fine-Needle Aspiration Classification System: Year 1 at an academic institution
Wu et al,15 2006 Fine-needle aspiration cytology of the thyroid: Ten year experience in a community teaching hospital
Wu et al,38 2012 The Bethesda System for Reporting Thyroid Cytopathology: An experience of 1,382 cases in a
community practice setting with the implication for risk of neoplasm and risk of malignancy
Yang et al,39 2007 Fine-needle aspiration of thyroid nodules: A study of 4703 patients with histologic and clinical
correlations
Yassa et al,40 2007 Long-term assessment of a multidisciplinary approach to thyroid nodule diagnostic evaluation

Arch Pathol Lab MedVol 140, October 2016 Bethesda Classification for Thyroid FNAKrauss et al 1129
Table 5. Meta-analysis of the Risk of Malignancy in the Bethesda Classes
Included Risk of Malignancy
Class Studies, No. (95% Cls) Malignancy/Total Cases (%)a I2, % P Valueb
I 10 0.12 (0.090.14) 94/748 (13) 34.9 .13
II 11 0.05 (0.030.07) 102/2366 (4) 75.3 ,.001
III 10 0.17 (0.110.23) 147/1101 (13) 83.8 ,.001
III and IV 14 0.24 (0.180.29) 703/3188 (22) 89.7 ,.001
IV 14 0.25 (0.200.29) 556/2230 (25) 91.3 ,.001
V 12 0.72 (0.610.84) 568/840 (68) 94.1 ,.001
VI 7 0.98 (0.970.99) 909/929 (98) 7.6 .37
a
Some studies may be excluded in the meta-analysis.
b
Heterogeneity v2 P values.

clinicians decision, not the terminology. Newer molecular 14. Ravetto C, Colombo L, Dottorini ME. Usefulness of fine needle aspiration
in the diagnosis of thyroid carcinoma: a retrospective study in 37,895 patients.
tests have been developed and in particular assist in triaging Cancer Cytopathol. 2000;90(6):357363.
these indeterminate (AUS/FLUS [III] and SFN/FN [IV]) 15. Wu HH, Jones JN, Osman J. Fine-needle aspiration cytology of the thyroid:
cases.21,22 These initial papers appear encouraging, but ten year experience in a community teaching hospital. Diagn Cytopathol. 2006;
34(2):8788.
further refinement and development of additional molecular 16. Bakhos R, Selvaggi SM, DeJong S, et al. Fine-needle aspiration of the
markers may enable an even more accurate categorization. thyroid: rate and causes of cytohistopathologic discordance. Diagn Cytopathol.
In its latest guidelines, the American Thyroid Association 2000;23(4):233237.
indicates that investigations such as repeat FNA or 17. Al-Hureibi KA, Al-Hureibi AA, Abdulmughni YA, et al. The diagnostic
value of fine needle aspiration cytology in thyroid swellings in a University
molecular testing may be used to supplement malignancy Hospital, Yemen. Saudi Med J. 2003;24(5):499503.
risk assessment data, in lieu of proceeding directly with a 18. Ratour J, Polivka M, Dahan H, et al. Diagnosis of follicular lesions of
strategy of either surveillance or diagnostic surgery for undetermined significance in fine-needle aspirations of thyroid nodules. J Thyroid
Res. 2013;2013:250347.
AUS/FLUS (III), and molecular testing may be used to 19. Renshaw AA. Does a repeated benign aspirate change the risk of
supplement malignancy risk assessment data, in lieu of malignancy after an initial atypical thyroid fine-needle aspiration? Am J Clin
proceeding directly with surgery for SFN/FN (IV).23 The use Pathol. 2010;134(5):788792.
20. Marchevsky AM, Walts AE, Bose S, et al. Evidence-based evaluation of the
of these molecular markers as a reflex to initially indeter- risks of malignancy predicted by thyroid fine-needle aspiration biopsies. Diagn
minate cytologic diagnoses may therefore lead to, in the Cytopathol. 2010;38(4):252259.
future, the collapse of the AUS/FLUS (III) and SFN/FN (IV) 21. Nikiforov YE, Ohori NP, Hodak SP, et al. Impact of mutational testing on
categories into a single indeterminate category with a the diagnosis and management of patients with cytologically indeterminate
thyroid nodules: a prospective analysis of 1056 FNA samples. J Clin Endocrinol
consistent and unified set of management recommenda- Metab. 2011;96(11):33903397.
tions. However, prospective studies and high-quality data 22. Alexander EK, Kennedy GC, Baloch ZW, et al. Preoperative diagnosis of
are needed to validate our findings and proposals. benign thyroid nodules with indeterminate cytology. N Engl J Med. 2012;367(8):
705715.
References 23. Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid
1. Einhorn J, Franzen S. Thin-needle biopsy in the diagnosis of thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and
disease. Acta Radiol. 1962;58:321336. Differentiated Thyroid Cancer: the American Thyroid Association Guidelines Task
2. Miller JM, Hamburger JI, Kini SR. The impact of needle biopsy on the Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;
preoperative diagnosis of thyroid nodules. Henry Ford Hosp Med J. 1980;28(2 26(1):1133.
3):145148. 24. Banks ND, Kowalski J, Tsai HL, et al. A diagnostic predictor model for
3. Gharib H, Goellner JR, Johnson DA. Fine-needle aspiration cytology of the indeterminate or suspicious thyroid FNA samples. Thyroid. 2008;18(9):933941.
thyroid: a 12 year experience with 11,000 biopsies. Clin Lab Med. 1993;13(3): 25. Blansfield JA, Sack MJ, Kukora JS. Recent experience with preoperative
699709. fine-needle aspiration biopsy of thyroid nodules in a community hospital. Arch
4. Bisi H, de Camargo RY, Longatto Filho A. Role of fine-needle aspiration Surg. 2002;137(7):818821.
cytology in the management of thyroid nodules: review of experience with 1,925 26. Bohacek L, Milas M, Mitchell J, Siperstein A, Berber E. Diagnostic accuracy
cases. Diagn Cytopathol. 1992;8(5):504510. of surgeon-performed ultrasound-guided fine-needle aspiration of thyroid
5. Baloch ZW, Sack MJ, Yu GH, Livolsi VA, Gupta PK. Fine-needle aspiration nodules. Ann Surg Oncol. 2012;19(1):4551.
of the thyroid: an institutional experience. Thyroid. 1998;8(7):565569. 27. Bozhok Y, Greenebaum E, Bogdanova TI, et al. A cohort study of thyroid
6. Guidelines of the Papanicolaou Society of Cytopathology for the cancer and other thyroid diseases after the Chernobyl accident: cyto-histopath-
examination of fine-needle aspiration specimens from thyroid nodules: the ologic correlation and accuracy of fine needle aspiration biopsy in nodules
Papanicolaou Society of Cytopathology Task Force on standards of practice. Mod detected during the first screening in Ukraine. Cancer. 2009;117(2):7381.
Pathol. 1996;9(6):710714. 28. Faquin WC, Baloch ZW. Fine-needle aspiration of follicular patterned
7. Cibas ES, Ali SZ. The Bethesda System for Reporting Thyroid Cytopathol- lesions of the thyroid: diagnosis, management, and follow-up according to
ogy. Am J Clin Pathol 2009;132(5):658665. National Cancer Institute (NCI) recommendations. Diagn Cytopathol. 2010;
8. Baloch ZW, LiVolsi VA, Asa SL, et al. Diagnostic terminology and 38(10):731740.
morphologic criteria for cytologic diagnosis of thyroid lesions: a synopsis of the 29. Jo VY, Stelow EB, Dustin SM, Hanley KZ. Malignancy risk for fine-needle
National Cancer Institute thyroid fine needle aspiration state of the science aspiration of thyroid lesions according to the Bethesda System for Reporting
conference. Diagn Cytopathol. 2008;36(6):425437 Thyroid Cytopathology. Am J Clin Pathol. 2010;134(3):450456.
9. Zhang L, Chen Z, Fukuma M, Lee LY, Wu M. Prognostic significance of race 30. Mufti ST, Molah R. The Bethesda System for Reporting Thyroid
and tumor size in carcinosarcoma of gallbladder: a meta-analysis of 68 cases. Int Cytopathology: a five-year retrospective study of one center experience. Int J
J Clin Exp Pathol. 2008;1(1):7583. Health Sci. 2012;6(2):159173.
10. Amrikachi M, Ramzy I, Rubenfield S, Wheeler TM. Accuracy of fine- 31. Nayar R, Ivanovic M. The indeterminate thyroid fine-needle aspiration.
needle aspiration of thyroid: a review of 6226 cases and correlation with surgical Cancer Cytopathol. 2009;117(3):195202.
or clinical outcome. Arch Pathol Lab Med. 2001;125(4):484488. 32. Oertel YC, Miyahara-Felipe L, Mendoza MG, Yu K. Value of repeated fine
11. Arda IS, Yildirim S, Demirhan B, Firat S. Fine needle aspiration biopsy of needle aspirations of the thyroid: an analysis of over ten thousand FNAs. Thyroid.
thyroid nodules. Arch Dis Child. 2001;85(4):313317. 2007;17(11):10611066.
12. Greaves TS, Olvera M, Florentine BD, et al. Follicular lesions of thyroid: a 33. Poller DN, Ibrahim AK, Cummings MH, Mikel JJ, Boote D, Perry M. Fine-
5-year fine-needle aspiration experience. Cancer Cytopathol. 2000;90(6):335 needle aspiration of the thyroid: importance of an indeterminate diagnostic
341. category. Cancer Cytopathol. 2000;90(4):239244.
13. Sidawy MK, Del Vecchio DM, Knoll SM. Fine needle aspiration of thyroid 34. Renshaw AA. Subclassification of atypical cells of undetermined signifi-
nodules: correlation between cytology and histology and evaluation of discrepant cance in direct smears of fine-needle aspirations of the thyroid. Cancer
cases. Cancer Cytopathol. 1997;81(4):253259. Cytopathol. 2011;119(5):322327.

1130 Arch Pathol Lab MedVol 140, October 2016 Bethesda Classification for Thyroid FNAKrauss et al
35. Sclabas GM, Staerkel GA, Shapiro SE, et al. Fine-needle aspiration of the 38. Wu HH, Rose C, Elsheikh TM. The Bethesda System for Reporting Thyroid
thyroid and correlation with histopathology in a contemporary series of 240 Cytopathology: an experience of 1,382 cases in a community practice setting
patients. Am J Surg. 2003;186(6):702709. with the implication for risk of neoplasm and risk of malignancy. Diagn
36. Smith M, Pantanowitz L, Khalbuss WE, Benkovich VA, Monaco SE. Cytopathol. 2012;40(5):399403.
39. Yang J, Schnadig B, Wasserman PG. Fine-needle aspiration of thyroid
Indeterminate pediatric thyroid fine needle aspirations: a study of 68 cases. Acta
nodules: a study of 4703 patients with histologic and clinical correlations. Cancer
Cytol. 2013;57(4):341348. Cytopathol. 2007;111(5):306315.
37. Theoharis CGA, Schofield KM, Hammers L, Udelsman R, Chhieng DC. The 40. Yassa L, Cibas ES, Benson CB, et al. Long-term assessment of a
Bethesda Thyroid Fine-Needle Aspiration Classification System: year 1 at an multidisciplinary approach to thyroid nodule diagnostic evaluation. Cancer
academic institution. Thyroid. 2009;19(11):12151223. Cytopathol. 2007;111(6):508516.

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