preoperative diagnosis of thyroid nodules using the bethesda system for reporting thyroid...

Preoperative diagnosis ofthyroid nodules using theBethesda System for ReportingThyroid Cytopathology: acomprehensive review andmeta-analysisExpert Rev. Endocrinol. Metab. Early online, 1–14 (2014)

Brandon S Sheffield1,Hamid Masoudi1,Blair Walker1 andSam M Wiseman*2

1Department of Pathology and

Laboratory Medicine, St. Paul’s Hospital

and University of British Columbia,

Vancouver, British Columbia, Canada2Department of Surgery, St. Paul’s

Hospital and University of British

Columbia, Vancouver, British Columbia,

Canada

*Author for correspondence:

Tel.: +1 604 806 9108

Fax: +1 604 806 9957

[email protected]

Fine-needle aspiration biopsy (FNAB) is the test of choice for the evaluation of nodules, arrivingat a cancer diagnosis, and guiding surgical management. This review and meta-analysis aims toobjectively evaluate the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) basedupon literature reports of histopathological outcomes following cytopathological diagnoses.Thirteen studies were reviewed and the risk of malignancy (ROM) for each of the BSRTCdiagnostic categories were calculated as: Non-diagnostic 11–26%, Benign 4–9%, AUS/FLUS19–38%, FN/SFN 27–40%, SFM 50–79%, and Malignant 98–100%. In typical clinical utilization,the sensitivity and specificity of thyroid FNAB diagnosis using the BSRTC were 96% and 46%,respectively. The BSRTC represents an important advance in standardizing thyroid FNABcytopathological reporting. Close attention should be paid to the observation that the AUS-FLUSand FN-SFN DCs have overlapping ROMs, and the potential clinical implications of this finding onpatient management.

KEYWORDS: Bethesda • BSRTC • cytology • fine-needle biopsy • needle biopsy • thyroid cancer • thyroid neoplasm

The thyroid nodule, a palpably discrete swell-ing in an otherwise normal thyroid gland,varies in incidence from 1 to 10% in iodine-sufficient populations [1]. This incidence risesto 67% when non-palpable lesions that aredetected by high-resolution ultrasound areincluded [2]. Cancer is the primary concern forany patient who presents with a thyroid nod-ule, either palpable or incidentally detected byimaging, and as few as 3.9% [2] of theselesions may actually represent cancer in indi-viduals who lack any other clinical risk factors.The rising incidence of thyroid cancer that hasbeen observed in western society over the lastseveral decades [3] suggests that an increasingnumber of thyroid nodules have been under-going clinical evaluation.

Papillary thyroid carcinoma accounts for85% of all thyroid cancer cases and generally

has an excellent prognosis with a 20-yearcause-specific mortality rate that is less than1% [4]. The mainstay of treatment for thyroidcancer is total or near-total resection of thethyroid gland, postoperative adjuvant radioac-tive iodine therapy and life-long thyroid hor-mone replacement with thyroid-stimulatinghormone suppression [5]. By contrast, manybenign nodules may be followed clinically.Given these two very different treatment algo-rithms for thyroid nodules, their accurate pre-operative cancer risk-stratification is of criticalclinical importance.

While history and physical examination,laboratory testing, and imaging are all impor-tant parts of the evaluation of an individualwho presents with a thyroid nodule, it is fine-needle aspiration biopsy (FNAB) that is thesingle most useful test to either confirm or

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exclude a cancer diagnosis. The proportion of cases diagnosedwith cancer in thyroid surgical specimens prior to the wide-spread adoption of FNAB was reported to be 14% [6], andafter its introduction this proportion more than doubled androse to approximately 40% [7]. Over the past decade, the pro-portion of thyroid surgical specimens that are given a cancerdiagnosis has further risen to approximately 56% [8]. Althoughthe technique for FNAB has remained largely unchanged, inno-vations such as the widespread adoption of ultrasound guid-ance, liquid-based cytology preparations and improvedtechnical and interpretive skills, may in part explain this risingFNAB accuracy.

FNAB has significantly influenced the management of thy-roid nodules and will continue to be the test of choice forguiding the treatment of thyroid nodules in the foreseeablefuture. Despite its widespread utilization, FNAB is an imperfecttest, with established false-positive and false-negative rates thatare approximately 5% for each [9], and may lead to nodule over-treatment or undertreatment, respectively [10]. These apparentdeficiencies in the test characteristics of FNAB may be largelyattributable to specimens that are given an ‘indeterminate’ diag-nosis, or a cytopathological diagnosis that is associated with acancer risk, but is not definitively benign or malignant.

Terminology is a modifiable factor with regards to thereporting of thyroid cytopathology, and miscommunicationbetween the pathologist and the clinician may occur, especiallyfor indeterminate diagnoses. Surveys have shown that patholo-gists report thyroid cytopathology with very heterogeneous ter-minology [11,12], and that clinicians act variably based uponthese reports [11]. Apart from its impact on patient care, incon-sistent cytopathological nomenclature blurs the relationshipbetween FNAB diagnosis and outcome, hampers the analysis ofthe test itself as well as understanding of the pathophysiologyof the processes for which it has been utilized.

To address the inconsistencies and the limitations of the termi-nology employed for thyroid cytopathology, the National CancerInstitute hosted the 2007 ‘National Cancer Institute ThyroidFine Needle Aspiration State of the Science Conference’ that ledto the development and publication of The Bethesda System forReporting Thyroid Cytopathology (BSRTC) [13]. The BSRTCis composed of a set of 6 diagnostic categories (DCs) thatare each accompanied with descriptive information andphoto-micrographic examples for pathologists, as well as a risk ofmalignancy (ROM) and recommended course of action for clini-cians [14]. The 6 DCs are: non-diagnostic (including cyst fluid,acellular, or excessively bloody specimens), benign (includingfollicular nodules and thyroiditis), atypia of undetermined signif-icance or follicular lesion of undetermined significance(AUS-FLUS), follicular neoplasm or suspicious for a follicularneoplasm (FN-SFN), suspicious for malignancy (SFM) andmalignant (including papillary carcinoma, medullary carcinoma,undifferentiated thyroid cancer, and metastatic disease). For acomplete description, with definitions and criteria for each DCplease refer to BSRTC [13]. The cancer risk and recommendedmanagement associated with each of the DCs are as follows:

non-diagnostic (1–4% cancer risk, recommend repeat FNABwith ultrasound guidance), benign (0–3% cancer risk, recom-mend clinical follow-up), AUS-FLUS (5–15% cancer risk, rec-ommend repeat FNAB), FN-SFN (15–30% cancer risk,recommend surgical lobectomy), SFM (60–75% cancer risk, rec-ommend surgical lobectomy or near-total thyroidectomy), andmalignant (97–99% cancer risk, recommend near-total thyroid-ectomy) [13,14].

The objective of developing the BSRTC was to create a uni-form thyroid cytopathology reporting system that could facili-tate: effective communication between pathologists andclinicians, cytologic-histologic correlation of cases, research andallow for comparison of data between institutions. Since theBSRTC was first published in 2007, it has become adopted bymany centers and its clinical utility has been extensivelyscrutinized [15–18]. Controversies have arisen over the recom-mended management of certain DCs, such as the appropriatesurgical management of AUS-FLUS [19], or the need for rou-tine second-opinion on all indeterminate diagnoses (AUS-FLUS, FN-SFN, SFM) [20,21]. Some authors have even sug-gested revising the 6-DC system into a 4-DC system [22], orsubdividing the AUS-FLUS DC into two separate DCs [23].Overall, the BSRTC has been well received, with the majorityof controversy focused upon the AUS-FLUS DC [24,25].

This review and meta-analysis aims to evaluate institutionaldata published in the medical literature regarding the rate ofmalignancy for each of the 6 BSRTC DCs that have beenfollowed-up with a thyroid operation and a definitive histo-pathologic diagnosis. Though similar reviews have been under-taken in the past [15,16], our study represents a contemporaryand comprehensive review of the current published literaturethat has reported on the BSRTC.

Materials & methodsA review of the Medline database was carried out throughPubMed and Ovid in order to identify relevant studies formeta-analysis. Studies were identified based upon a comparisonof the cytological diagnosis with the histological diagnosis afterthyroid surgery, and only studies using BSRTC terminologyfor reporting the cytological diagnosis were included. Addi-tional inclusion criteria were English language publication, andpublication availability (search performed online 31 December2012). Thirteen studies meeting the above inclusion criteriawere identified and are summarized in TABLE 1 [8,26–37]. Publica-tions focusing only upon specific BSRTC DCs were excludedfrom the analysis [38]. Publications meeting the inclusion crite-ria, but presenting data in a manner such that extraction formeta-analysis was not possible, were also excluded [18,39].A recent report by Wong and Baloch [15] reviewed the experi-ence of six institutions with the BSRTC and all six of theirsource publications were included in the current review.Another recent review by Bongiovanni et al. [16] analyzed datareported by seven institutions using the BSRTC, and all butone of these studies were included in the current review.A single report was excluded because they utilized a system

Review Sheffield, Masoudi, Walker & Wiseman

doi: 10.1586/17446651.2014.887435 Expert Rev. Endocrinol. Metab.

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‘similar to BSRTC’ and because the data were presented in amanner that it could not readily be assigned into BSRTCDCs [40].

The following elements were extracted from the includedreports: total number of FNAB cases, distribution of cytologi-cal diagnoses into the 6 DCs, total number of cases with

histological follow-up and their distribution across 6 DCs,the number of cases in each DC having malignant histologyat follow-up and the rate of surgical intervention. Statisticalanalysis was carried out, and tables and figures were gener-ated using Microsoft Excel (Microsoft Corporation, Red-mond, WA, USA). The mean ROM scores and 95% CIs

Table 1. Demographics of studies selected for review.

Study(year)

Institution Method Total FNABs Total FNABswith follow-uphistology

Ref.

1

(2012)

Charleston Area Medical

Center

Randomly selected 100 cases with

available histology performed blind,

retrospective cytology diagnosis using

BSRTC

99 99 [26]

2

(2012)

Ball Memorial Hospital Retrospective review of consecutive

FNAB cases

1382 221 [27]

3

(2012)

Cleveland Clinic Prospective series of consecutive FNAB

cases

1000 451 [28]

4

(2011)

Vanderbuilt University

Medical Center

Retrospective review of consecutive

surgical cases comparing outcomes

pre-BSRTC with those after

implementation of the BSRTC

282 282 [29]

5

(2011)

University of Alabama at

Birmingham


FNAB cases comparing outcomes pre-

BSRTC with those after implementation

of the BSRTC

562 110 [30]

6

(2010)

University of Virginia

Health System


FNAB cases with retrospective BSRTC

diagnosis based on previous descriptive

terminology

3080 882 [31]

7

(2010)

Yale-New Haven Hospital Prospective series of consecutive FNAB

cases

2468 378 [32]

8

(2011)

Istanbul University Retrospective review of consecutive

FNAB cases spanning implementation

of BSRTC; retrospective reclassification

of pre-BSRTC indeterminate diagnoses

442 442 [33]

9

(2010)

Baptist Hospital,

Homestead Hospital


FNAB cases with retrospective

reclassification according to BSRTC

7089 1331 [34]

10

(2011)

Konkuk Medical Center Prospective series of consecutive FNAB

cases, studying impact of ancillary

molecular testing on malignancy rate

865 193 [35]

11

(2012)

Multi-institutional

collaboration


cases from five institutions comparing

BSRTC to 5-tiered Italian system

3724 1361 [36]

12

(2007)

Long-Island Jewish

Medical Center

University of Texas

Medical Branch


FNAB cases and reclassification using

BSRTC

4703 1052 [37]

13

(2007)

Brigham and Women’s

Hospital

Prospective series of consecutive FNAB

cases

3589 1242 [8]

BSRTC: Bethesda System for Reporting Thyroid Cytopathology; FNAB: Fine-needle aspiration biopsy.

Preoperative diagnosis of thyroid nodules using the BSRTC Review

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were calculated (using a sample size of 13) based upon aver-ages of individually reported ROMs in the source material.Weighted means were additionally calculated, however, thisstatistic was not amenable to presentation with 95% CIs, andtherefore the average of individual ROMs was the preferredstatistic for evaluation.

Test characteristics, including sensitivity (SN) (true positives/[true positives + false negatives]), specificity (SP) (true nega-tives/[false positives + true negatives]), positive predictive value(PPV) (true positives/total positives), negative predictive value(NPV) (true negatives/total negatives) and both positive andnegative likelihood ratios (LR+ and LR-) (SN/[1 - SP] and[1 - SN]/SP), were computed for multiple cases interpretingdifferent combinations of DCs as being positive or negativetest results (95% CIs calculated using x ± [1.96 � sqrt(x � (1 - x)/n)] for SN, SP, PPV, NPV and exp [log(LR) ± (1.96 � standard error)] for LR+ and LR-). Post-testprobabilities were calculated for illustrative cases (post-testprobability = [p/(1 - p) � LR]/[1 + (p/[1 - p] � LR)], where

p = pre-test probability). Test characteristics were computedwith the aid of CatMaker software available through the Centrefor Evidence Based Medicine [41].

ResultsAll studies reported consecutive series of cytological diagnoseswith the exceptions of Richmond et al. [26], who evaluated arandom selection of 100 cases with available histological fol-low-up, and Broome and Solorzano [29], who reported on aconsecutive series of surgical cases. The remaining 11 studiesreported results from consecutive series of FNABs with histo-pathological follow-up and their distribution across the6 BSRTC DCs, is summarized in TABLE 2.

The broadest variation in DC utilization was within thebenign DC, with a frequency that ranged from 39.00% asreported by Wu et al. to 77.76% as reported by Crowe et al.The DC with the second-most common variation in propor-tion was the AUS-FLUS DC, with rates that ranged from0.80%, as reported by Bohacek et al., to 27.21% as reported

Table 2. Incidence of each Bethesda System for Reporting Thyroid Cytopathology diagnostic categoryin studies evaluated.

Study† TotalFNAB

Non-diagnostic I(%)

Benign II(%)

AUS-FLUS III(%)

FN-SFN IV(%)

Suspicious V(%)

Malignant VI(%)

2 1382 278

20.12%

539

39.00%

376

27.21%

116

8.39%

36

2.60%

37

2.68%

3 1000 56

5.60%

671

67.10%

8

0.80%

172

17.20%

24

2.40%

69

6.90%

5 562 16

2.85%

437

77.76%

71

12.63%

21

3.74%

2

0.36%

15

2.67%

6 3080 574

18.64%

1817

58.99%

104

3.38%

298

9.68%

71

2.31%

216

7.01%

7 2468 230

9.32%

1799

72.89%

89

3.61%

166

6.73%

39

1.58%

145

5.88%

8 442 36

8.14%

223

50.45%

25

5.66%

35

7.92%

42

9.50%

81

18.33%

9 7089 1671

23.57%

3829

54.01%

548

7.73%

606

8.55%

134

1.89%

301

4.25%

10 865 16

1.85%

504

58.27%

141

16.30%

10

1.16%

54

6.24%

140

16.18%

11 3724 110

2.95%

2064

55.42%

248

6.66%

886

23.79%

224

6.02%

192

5.16%

12 4703 488

10.38%

3036

64.55%

152

3.23%

544

11.57%

124

2.64%

359

7.63%

13 3589 269

7.50%

2361

65.78%

144

4.01%

328

9.14%

314

8.75%

173

4.82%

Total

Mean

(95% CI)

28,904 3744

10.08%

(9.83–10.33%)

17,280

60.39%

(60.23–60.54%)

1906

8.29%

(7.93–8.65%)

3182

9.80%

(9.58–10.03%)

1064

4.03%

(3.86–4.19%)

1728

7.41%

(7.16–7.66%)†Studies 1 and 4 are excluded as they do not report consecutive case series of FNAB.AUS: Atypia of undetermined significance; FLUS: Follicular lesion of undetermined significance; FN: Follicular neoplasm; FNAB: Fine-needle aspiration biopsy;SFN: Suspicious for a follicular neoplasm.



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by Wu et al. The malignant and SFM DCs were diagnosedmost consistently. Not surprisingly, the majority of FNABswere diagnosed in the benign DC, 60.39 ± 0.15% (mean± 95% CI). The malignant DC comprised 7.41 ± 0.25% oftotal FNABs, and 22.12% of diagnoses were from one of theindeterminate DCs (AUS-FLUS, FN-SFN or SFM). FN-SFNwas most commonly diagnosed (9.80 ± 0.23%) and SFM wasleast commonly diagnosed, accounting for fewer than 5% oftotal FNAB diagnoses (TABLE 2).

Of all the histopatholigcal results available for review fromthe source publications, 27.05% of the cases had an initialbenign FNAB diagnosis, 16.82% of the cases had malignantcytology, 48.16% of cases had indeterminate cytology and7.97% of cases were non-diagnostic FNABs.

TABLE 3 summarizes the ROM for each of the 6 BSRTC DCsas they were presented in the 13 publications reviewed. Asexpected, the highest ROM was associated with a malignantcytopathological diagnosis (97.74–99.53% [95% CI]), and thelowest ROM was associated with a benign cytopathologicaldiagnosis (4.47–8.57%). The remaining 4 DCs had ROMsthat were between these two extremes. These observations arepresented in FIGURE 1, showing individual study means, overallmean ± 95% CI and the BSRTC expected ROM.

Considering thyroid FNAB that utilizes the BSRTC termi-nology as a diagnostic test, and applying follow-up histopatho-logical diagnosis as the gold standard, the test characteristicswere calculated. A positive or negative test result depends uponhow the indeterminate cases are grouped. For this reason, testcharacteristics were calculated with multiple interpretations ofboth positive and negative results. Two illustrative cases arepresented in FIGURE 2.

If only malignant FNABs are considered as being positivetest results, and only benign FNABs are considered negativetest results, and all other results (ND, AUS-FLUS, FN-SFN,SFM) are excluded, then the SN, SP, PPV and NPV ofBSRTC would be 92, 99, 99 and 94%, respectively. Con-versely, if malignant, SFM, FN-SFN, AUS-FLUS* DCs areconsidered to be positive test results, with only benign FNABsinterpreted as negative results, and all non-diagnostic cases areexcluded, the SN, SP, PPV, NPV are calculated as 96, 46,54 and 95%, respectively (FIGURE 2).

While the first case may represent the ideal scenario, the sec-ond case may more accurately reflect current clinical reality. Tovalidate the decision to exclude non-diagnostic FNABs fromthis calculation, the non-diagnostic population is interpretedsequentially as either positive or negative, showing that the testcharacteristics remain relatively stable with the SN and SPranging from 93 to 96% and 52 to 41%, respectively. Thus,the test characteristics are minimally impacted by the groupingof the non-diagnostic DC.

DiscussionBSRTC utilization

The 13 studies included in this review well illustrate how numer-ous institutions have adopted the BSRTC with variable results.These reports comprise data from Europe, Asia and North Amer-ica, and from both the academic and community hospital set-tings. It is clear that the utilization of the BSRTC DCs variessignificantly from one center to another (TABLE 2). Notable exam-ples include an extremely high rate of AUS-FLUS (27%)reported by Wu et al. [27], compared with the extremely low rateof this DC reported by Bohacek et al. [28] (0.8%). Non-diagnostic rates reported by Wu et al. [27], Jo et al. [31] andRenshaw [34] were 20, 19 and 24%, respectively, and were all sig-nificantly higher than the 10% overall group mean. These obser-vations may suggest that the BSRTC, and that the AUS-FLUSDC in particular, may not be consistently utilized by all institu-tions. This variation in DC incidence may have several possibleexplanations. It is possible that the incidence of the 6 DCs variesgeographically in different thyroid nodule patient populations.There may also be a referral bias, wherein academic institutionsmay report on a higher proportion of diagnostically challengingcases. Finally, it is possible that different pathologists, at differentcenters, have different experience and thresholds for making aspecific BSRTC diagnosis. Both Wu et al. [27] and Layfield et al.[42] have reported that there is a wide variation in individualpathologist utilization of the AUS-FLUS DC, and they havefound that individuals who lack specific cytopathology trainingmay be more likely to utilize this DC.

While the published description of the BSRTC does notspecify a target incidence for any of the specific DCs, the chap-ter dedicated to AUS-FLUS suggests that pathologists shouldaim for an incidence that is approximately 7% of allFNABs [43]. Our review found a mean incidence of 8.3% forthe AUS-FLUS DC. This observation is similar to the BSRTCrecommendation, and the mean does fall within this rangewhen outliers are excluded from the analysis (6.4% whenexcluding Wu et al. [27]). Apart from the 7% reporting recom-mendation for the AUS-FLUS DC, there is a paucity of evi-dence regarding the appropriate distribution of other BSRTCDCs. Krane et al. [44] have suggested the utilization of an AUS:malignant ratio as a benchmark to ensure laboratories achievean appropriate distribution of BSRTC DCs. Currently, thereexists no recommendation for, or system to facilitate, internalvalidation for laboratories newly adopting the BSRTC.

Cancer risk

Comparing the ROMs calculated in the current study withROMs reported for the BSRTC (FIGURE 1), our review found anincreased cancer risk for non-diagnostic DC (11–26% in currentreview compared with 1–4% reported by the BSRTC) and AUS-FLUS DC (19–38% in current review compared with the5–15% reported by the BSRTC). Our observed cancer risk isalso slightly higher for the benign and FN-SFN DCs. Both themalignant and SFM DCs have calculated ROMs that are consis-tent with those reported by the BSRTC (TABLE 1).

*The test characteristics for this specific scenario (positivetest = Malignant or SFM or FN-SFN or AUS-FLUS) are presented

here because these diagnoses are most likely to undergo surgery, basedon data collected in this study.



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Table

3.Riskofmalignancy

instudiesevaluatedwithsu

mmary

statistics.

Study

TotalFN

AB

withfollow-up

histology

Non-diagnostic

ITotalcases

Malignant

histology

(%)

BenignII

Totalcases

Malignant

histology

(%)

AUS/FLU

SIII

Totalcases

Malignant

histology

(%)

FN/SFN

/HCN

IVTotalcases

Malignant

histology

(%)

Susp

iciousV

Totalcases

Malignant

histology

(%)

MalignantVI

Totalcases

Malignant

histology

(%)

199

6 1 16.67%

54

6 11.11%

10

4 40.00%

25

10

40.00%

3 1 33.33%

1 1 100.00%

2221

21

3 14.29%

63

6 9.52%

51

11

21.57%

49

13

26.53%

18

12

66.67%

19

19

100.00%

3451

19

5 26.32%

173

12

6.94%

8 1 12.50%

160

33

20.63%

24

14

58.33%

67

65

97.01%

4282

11

0 0.00%

96

9 9.38%

82

16

19.51%

33

12

36.36%

29

15

51.72%

31

30

96.77%

5110

2 1 50.00%

35

3 8.57%

44

8 18.18%

16

3 18.75%

0 0 0.00%

13

13

100.00%

6882

135

12

8.89%

307

20

6.51%

53

9 16.98%

177

45

25.42%

56

39

69.64%

154

151

98.05%

7378

25

8 32.00%

82

8 9.76%

27

13

48.15%

102

35

34.31%

30

26

86.67%

112

112

100.00%

8442

36

9 25.00%

223

22

9.87%

25

9 36.00%

35

23

65.71%

42

34

80.95%

81

77

95.06%

91331

235

47

20.00%

361

6 1.66%

204

50

24.51%

287

80

27.87%

75

73

97.33%

169

169

100.00%

10

193

0 0 0.00%

8 0 0.00%

33

24

72.73%

7 3 42.86%

33

33

100.00%

112

112

100.00%

11

1361

28

8 28.57%

158

4 2.53%

132

19

14.39%

698

224

32.09%

183

137

74.86%

162

161

99.38%

AUS:Atypia

ofundeterm

ined

significance;FLUS:Follicularlesionofundeterm

ined

significance;FN

:Follicularneo

plasm

;FN

AB:Fine-needle

aspirationbiopsy;HCN:Hurthle

cellneo

plasm

;SFN

:Su

spiciousfora

follicularneo

plasm

.



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A potential explanation for the elevated ROMs we observedin the current study is the bias introduced when only consider-ing cases that have undergone a thyroid operation. This is bestdemonstrated in the benign DC that we found had a 7% can-cer risk (TABLE 3), a higher cancer risk than was suggested by theBSRTC (0–3% cancer risk). Clinical follow-up is often recom-mended for benign thyroid nodules, leading to the inferencethat the 2176 cytologically benign cases that underwent anoperation must have had an alternative surgical indication.Unfortunately, these specific surgical indications were not elab-orated upon in the source publications, but may have included:symptomatic goiters, cosmesis, malignant imaging characteris-tics, thyroid cancer predisposing inherited conditions such asMEN2, surgery performed for a different or higher risk thyroidlesion or hyperthyroidism.

In order to determine the true cancer risk, we would need toapply the gold standard, or thyroid histopathology following sur-gery, to all thyroid nodules undergoing FNAB, which for benignpreoperative diagnoses, is not clinically feasible. In the currentstudy, histopathology after surgery was the only diagnostic goldstandard for definitive diagnosis that we utilized. Other possiblediagnostic gold standards could include histopathology afterautopsy, and possibly long-term clinical follow-up of benignlesions. Future studies may choose to utilize these or other crite-ria in order to better evaluate the true risk of cancer for DCs thatdo not necessarily require an operation. While this ‘surgicalfollow-up’ bias is most apparent for the non-diagnostic andbenign DCs, it should be absent in the malignant and SFMDCs, both of which require surgical treatment. The ROMs forthese categories were 98–100% and 50–79%, respectively, andthese observations are consistent with the reported BSRTCROMs. It is unknown what proportion of the elevated ROM,that is present in the AUS-FLUS category, may be attributed tothis bias.

Another potential study bias is the inclusion of papillarymicrocarcinomas (tumors less than 1 cm in greatest dimension)in the study populations. These were occasionally mentionedin the studies evaluated, and where the incidence of papillarymicrocarcinoma was stated separately from incidence of papil-lary carcinoma, both were interpreted as cancer in the currentreview. The majority of studies did not specifically state howmicrocarcinomas were interpreted when calculating their malig-nancy rates. According to a review of international autopsydata, subclinical papillary microcarcinomas may be present inup to 39% of individuals [45].

Notably, the ROM for the AUS-FLUS DC was calculated tobe 19–38%, which is higher than the 5–15% risk reported by theBSRTC. The ROM in this DC also overlaps with the ROM forthe BSRTC FN-SFN DC that was calculated to range from 27 to40%. These observations are best appreciated in FIGURE 1, wherethe individual study means and the overall means for each DCare presented. FIGURE 3 presents the ROM statistic for the AUS-FLUS DC as compared with the ROM statistic for FN-SFNDC. Two studies (Richmond et al. [27] [study 1] and Croweet al. [30] [study 5]), reported very similar ROM statistics forT

able

3.Riskofmalignancy

instudiesevaluatedwithsu

mmary

statistics(cont.).

Study

TotalFN

AB

withfollow-up

histology

Non-diagnostic

ITotalcases

Malignant

histology

(%)

BenignII

Totalcases

Malignant

histology

(%)

AUS/FLU

SIII

Totalcases

Malignant

histology

(%)

FN/SFN

/HCN

IVTotalcases

Malignant

histology

(%)

Susp

iciousV

Totalcases

Malignant

histology

(%)

MalignantVI

Totalcases

Malignant

histology

(%)

12

1052

46

5 10.87%

247

18

7.29%

52

10

19.23%

326

105

32.21%

105

68

64.76%

276

272

98.55%

13

1242

77

8 10.39%

369

6 1.63%

84

20

23.81%

268

74

27.61%

288

173

60.07%

156

152

97.44%

Total

8044

641

107

16.69%

2176

120

5.51%

805

194

24.10%

2183

660

30.23%

886

625

70.54%

1353

1334

98.60%

Mean

(95%

CI)

18.69%

(11.16–26.22%

)

6.52%

(4.47–8.57%

)

28.27%

(19.02–37.53%

)

33.10%

(26.56–39.65%)

64.95%

(50.41–79.49%)

98.64%

(97.74–99.53%)

AUS:Atypia

ofundeterm

ined

significance;FLUS:

Follicularlesionofundetermined

significance;FN

:Follicularneo

plasm

;FN

AB:Fine-needle

aspirationbiopsy;HCN:Hurthle

cellneo

plasm

;SFN

:Suspiciousfora

follicularneo

plasm

.



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0%

012345678910111213

10%

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50%

RO

M (

%)

Study

60%

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90%

100%

0%

012345678910111213

10%

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50%

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M (

%)

Study

60%

70%

80%

90%

100%

0%

012345678910111213

10%

20%

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50%

RO

M (

%)

Study

60%

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0%

012345678910111213

10%

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M (

%)

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60%

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012345678910111213

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M (

%)

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60%

70%

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0%

012345678910111213

10%

20%

30%

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50%

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M (

%)

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60%

70%

80%

90%

100%

AB D

C

FE

Figure

1.Fo

rest

plots

ofrisk

ofmalignancy

forthesixBethesd

aSystem

forReportingThyroid

Cytopathologydiagnostic

categories.

Vertical

linesshow

ROM

as

predictedbyBethesdaSystem

forReportingThyroid

Cytopathology.

Diamondsshow

individualstudies’reportedROM.Largecirclesshow

meanofindividually

reportedstudies

ROM

±95%

CI(n

=13).(A

)DCInon-diagnostic.(B)DCIIben

ign.(C)DCIIIatypia

ofundeterm

inedsignifican

ceorfollicularlesionofundeterm

ined

significance.(D

)DCIV

follicularneoplasm

orsuspiciousforfollicularneoplasm

.(E)DCVsuspiciousformalignancy.(F)DCVImalignant.

DCs:Diagnosticcategories;ROM:Riskofmalignan

cy.



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these DCs. Furthermore, Theoharis et al. [32] (study 7) andKim et al. [35] (study 10) reported higher ROMs for the AUS-FLUS DC than for the FN-SFN DC. These observations raisedoubts regarding the validity of 5–15% ROM for the AUS-FLUS DC presented by the BSRTC. Additionally, the recom-mended clinical management for nodules in the AUS-FLUSDC is repeat FNAB, whereas for FN-SFN the recommendedmanagement is a diagnostic thyroid lobectomy. The major dif-ference in the clinical management of these DCs is interesting,since we found that they both have an almost equivalent cancerrisk. This discrepancy seems to have already been recognized bytreating clinicians. In the current review, all the included studieswere evaluated for the rate of surgical intervention for the AUS-FLUS DC. This statistic was available for 8 of 13 studiesreviewed and is presented in TABLE 4. These findings clearly sug-gest that a significant proportion of nodules diagnosed as AUS-FLUS undergo a diagnostic operation. Thus, not only is thecancer risk similar in the AUS-FLUS DC to other DCs, but itsclinical management may also be similar.

Test characteristics

As already discussed, measuring the test characteristics of thy-roid FNABs is challenging, as there is no clearly accepted

definition for a ‘positive’ or ‘negative’ result. Lewis et al. [12]

reported a wide variation in thyroid FNAB test characteristicspublished in the medical literature. The explanation for hetero-geneity in observed results was that for each calculation theindeterminate cytopathology results were treated variably, aseither being positive or negative results, or being excluded fromthe calculation entirely. In this review, we calculated test char-acteristics for thyroid FNABs with every possible combinationof interpretations as to what could be considered a positive ora negative test result, and all our calculations used final histopa-thology as the gold standard for diagnosis. Two of these com-binations are selected and shown in FIGURE 2 with Case Aillustrating an ‘ideal’ scenario, and Case B depicting the more‘real-world’ scenario. Overall, the cytopathological diagnosis ofthyroid nodules is generally quite reliable if the diagnosis iseither benign or malignant, and fortunately the majority (67%)of all FNABs are within these 2 DCs (data from this review).The remaining third of all thyroid nodules that are given anindeterminate diagnosis present the treating clinician with amanagement dilemma. Given that AUS-FLUS DC cases arelikely to undergo surgical intervention, perhaps it is more clini-cally appropriate that a ‘positive test’, or test result that suggeststhe need for surgical intervention, includes the malignant,

Positive = malignant; negative = benign

Histology 95% CIMalignant Benign Total Sensitivity 91.75% 90.84% 92.65%

FN

A

+ 1334 19 1353 Specificity 99.08% 98.77% 99.40%

- 120 2056 2176Pre-testprobability 41.20%†

Total 1454 2075 3529 PPV 98.60% 98.21% 98.98%NPV 94.49% 93.73% 95.24%

LR + 100.1973Post test + 98.60%‡

LR - 0.083294Post test - 5.51%‡

Positive = malignant, SFM, FN-SFN, AUS-FLUS; negative = benign

Histology 95% CIMalignant Benign Total Sensitivity 95.91% 95.46% 96.36%

FN

A

+ 2813 2414 5227 Specificity 46.00% 44.86% 47.13%

- 120 2056 2176Pre-testprobability 39.62%†

Total 2933 4470 7403 PPV 53.82% 52.68% 54.95%NPV 94.49% 93.97% 95.01%

LR + 1.775939Post test + 53.82%‡

LR - 0.088952Post test - 5.51%‡

A

B

Figure 2. Test characteristics of thyroid FNAB. (A) Positive FNAB interpreted as malignant (Bethesda VI). (B) Positive FNAB interpretedas malignant or SFM or FN-SFN or AUS-FLUS (Bethesda III, IV, V, VI).†Based on the population used to calculate the test characteristics.‡Based on the pre-test probability presented in each case. Post-test probabilities can be calculated using different pre-testprobabilities using an appropriate nomogram.AUS: Atypia of undetermined significance; FLUS: Follicular lesion of undetermined significance; FNAB: Fine-needle aspiration biopsy;SFM: Suspicious for malignancy.



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SFM, FN-SFN and AUS-FLUS DCs, since these DCs usuallyall lead to an operative intervention. The test characteristics ofFNABs that utilize the BSRTC under these conditions are pre-sented in FIGURE 2B.

If a FNAB was carried out (using test characteristics calcu-lated in FIGURE 2B) on three illustrative patients, one with a low,another with an intermediate and another with a high pre-testthyroid cancer risk, the post-test cancer risks are summarizedin FIGURE 4. In the patient with a low pre-test cancer risk (5%cancer risk), a positive FNAB result is unable to definitivelydiagnose cancer, while a negative FNAB is sufficient to excludecancer. In the intermediate-risk patient (40% pre-test cancer

risk, the approximate incidence of cancerin the follow-up histology specimens inthis study) even though a benign FNABdiagnosis may be able to exclude cancer(6% post-test cancer risk), a positive resultcannot definitively diagnose malignancy(54% post-test cancer risk). In the theoret-ical high-risk patient (80% pre-test cancerrisk, chosen for illustrative purposes),FNAB is unable to definitively diagnose orexclude cancer (88%, 26% post-test +/-cancer risk). As seen here, the test charac-teristics of FNAB break down when thetest is applied to the illustrative high-riskpatient, thus bringing the clinical utility ofthe BSRTC in this specific setting intoquestion. Based upon the calculationsshown in FIGURES 2B & 4, we can concludethat the only truly diagnostic use of preop-erative FNAB is to rule out cancer in alow-risk patient. For all other scenarios,the test leaves significant room for error. Itshould also be noted that in other clinical

scenarios, such as for the high-risk patient, FNAB may still beuseful in establishing less common diagnoses such as lymphomaor thyroid cancer in lymph node metastases, which have differentclinical management algorithms.

Future directions

Despite recent advances in medicine, thyroid nodules continueto present a diagnostic and management dilemma for patholo-gists, endocrinologists, surgeons and other clinicians who areinvolved in their treatment. Operative decision-making isheavily influenced by the FNAB diagnosis, which in itself isbased upon morphologic criteria. As demonstrated in thisreview, thyroid cytopathology has limitations and is unable todefinitively diagnose approximately a third of thyroid nodules.Future endeavors may include the further refinement of termi-nology and DCs, with updated cancer risk estimation as well asclinical management recommendations. More recently, toaddress the limitations of thyroid cytopathology much attentionhas also been paid to non-morphological elements as adjunctsto traditional cytomorphology. These non-morphological ele-ments include immunocytochemistry (ICC) and molecularscreening methodologies.

ICC is a derivation of the well-established technique ofimmunohistochemistry that is commonly applied to surgicalspecimens. ICC is an antibody-based assay that allows the cyto-pathologist to determine whether a given antigen or molecularmarker is present, its location within the cellular compartmentand its level of expression. A review of studies investigating theuse of immunocytochemical markers in thyroid FNABs haspreviously been reported by our group [46].

Molecular analysis is yet another diagnostic avenue that hasbeen explored in order to reduce the number of indeterminate

ROM (AUS-FLUS + FN-SFN )

0

1

2

3

4

5

6

7

8

9

10

11

12

13

0.00% 20.00% 40.00% 60.00% 80.00% 100.00%

ROM

Study

Figure 3. Risk of malignancy for both atypia of undetermined significancefollicular lesion of undetermined significance (squares) and follicular neoplasmor suspicious for a follicular neoplasm (triangles). Grand means are shown as study0 with error bars representing 95% CIs.AUS: Atypia of undetermined significance; FLUS: Follicular lesion of undeterminedsignificance; FN-SFN: Follicular neoplasm or suspicious for a follicular neoplasm;ROM: Risk of malignancy.

Table 4. Rate of surgical intervention for atypiaof undetermined significance-follicular lesion ofundetermined significance diagnosis†.

Study Percent treated surgically

3 100%

5 62%

6 52%

7 30.3%

9 37%

11 53.2%

12 40.6%

13 58.3%

Mean (95% CI) 54.18% (39.28–69.07%)†Includes only studies who explicitly stated the rate of surgical follow-up or thosepublishing data in a manner that facilitated extraction.



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thyroid FNABs that undergo surgical intervention. This gener-ally involves the analysis of FNAB specimens using moleculartechniques such as the PCR. Variations of this technique canidentify mutations in oncogenes that are highly specific for thy-roid cancer such as BRAF. Nikiforov et al. [47] reported onhow indeterminate BSRTC DC cases could be reassigned tohigher- or lower-risk groups by evaluating a panel of genesusing a PCR-based test. While molecular changes such asBRAF mutations have proven highly specific for thyroid can-cer, targeted molecular assays have generally had limited successin accurately identifying benign thyroid lesions. Anothermolecular-based strategy that has been developed to boost thediagnostic accuracy of FNABs is nucleic acid array-based test-ing. These techniques usually evaluate the RNA content of aFNAB specimen from a cytologically indeterminate thyroidlesion. Using bioinformatic classification analyses, which com-pares the tested material to known benign and malignant refer-ence standards, these assays are able to differentiate benign andmalignant RNA-expression profiles. Alexander et al. [48]

recently reported the results of a gene-expression classifier thatwas used to evaluate cases with indeterminate BSRTC diagno-ses. For thyroid lesions with BSRTC diagnoses that were AUS-FLUS, FN-SFN and SFM, the assay had NPVs that were 95,94 and 85%, respectively. The ability to exclude cancer incytologically indeterminate specimens could potentially signifi-cantly reduce the number of diagnostic thyroid operations.

Unfortunately, neither ICC nor molecular analysis hasbecome routinely adopted into the clinical management ofthyroid nodules. Undoubtedly, the adoption of ICC andmolecular testing into the algorithm of thyroid nodule man-agement, as a means to overcome the limitations of cytopa-thology shows promise, but will importantly also need totake economic considerations into account as these tests maylead to increased healthcare-related costs. A recent report byour group [49] evaluated the cost–effectiveness of a thyroidcancer molecular diagnostic test used adjunctively withFNAB, showed a slight benefit in both cost and quality oflife, though these conclusions are drawn based upon theassumption that the molecular test had excellent performancecharacteristics (SN, SP >95%).

ConclusionThe BSRTC represents an important advance in the establish-ment of a standardized system for reporting thyroid cytopathol-ogy. It has already, and will continue to have a positive impacton patient care as well as research in the field of thyroid cancerdiagnosis. This review validates several elements of the BSRTC,including the cancer rate in malignant, SFM, FN-SFN, benignand non-diagnostic DCs, suggesting that these diagnoses arereproducible at different institutions, in different patient popu-lations and at different geographic locations. The currentreview also suggests that the risk of cancer is significantlyhigher than has been previously suggested for the AUS-FLUSDC, and its recommended BSRTC clinical managementshould be reconsidered. Most importantly, by computing the

test characteristics of FNABs, we have highlighted the need forcaution in making clinical decisions based solely upon thecytopathologic diagnosis.

Expert commentaryThyroid nodules are common and FNAB represents the singlemost important test for their diagnosis. The BSRTC representsan important advancement in the field because it provides astandardized system for the reporting of thyroid FNABs. How-ever, currently one-third of all FNABs are diagnosed as indeter-minate, with no clearly established clinical managementguidelines. Molecular analysis of these indeterminate aspirateshas become of increasing importance, and we are beginning tosee its early adoption in the clinic. The role of molecular diag-nostics is currently being filled at most centers by clinical judg-ment, a tried and tested, but not always an objective orscientific technique. In this review, the BSRTC has been vali-dated and the test characteristics of this system are reported tofacilitate its clinical utilization. The BSRTC will continue toprove useful in both the clinical management and study ofthyroid nodules.

Five-year viewThe BSRTC has already been adopted into routine clinicalpractice by many institutions worldwide. As individual centersreport and validate their experiences with the BSRTC, addi-tional institutions will continue to adopt the system, and fur-ther refinements may make it more widely accepted andadopted by other centers. It was the aim of this review to eval-uate the true cancer risk associated with each BSRTC DC sothat the medical team involved in thyroid nodule managementmay incorporate this information into their treatment plan. Asutilization of the BSRTC becomes more widespread, and avail-able outcome data for analysis increases, further refinement ofthe cancer risk and recommended clinical actions associatedwith each cytopathological DC will be possible. Expanded

Pre-FNAB cancer risk FNAB Post-FNAB cancer risk

5%9%

<1%

40%54%

6%

80%88%

26%

+-

+-

+-

Figure 4. Post-test cancer risk for three pre-test cancer risks†.†Based on likelihood ratios calculated in FIGURE 2B (FNAB isinterpreted as positive if: malignant, suspicious for malignancy,follicular neoplasm or suspicious for a follicular neoplasm, atypiaof undetermined significance-follicular lesion of undeterminedsignificance and interpreted as negative if benign).FNAB: Fine-needle aspiration biopsy.



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utilization of the BSRTC will also facilitate both intra- andinter-laboratory quality assurance endeavors, adding to thereproducibility of the system and allow further improvement inthe accuracy of FNAB.

Even though FNAB has remained the cornerstone of pre-operative thyroid nodule diagnostic evaluation, in the futurein addition to cytomorphological data, for indeterminatecases adjunctive ICC and/or molecular analysis will assistthe cytopathologist in establishing a definitive diagnosis.The current revised American Thyroid Association Guide-lines specifically state that molecular markers may beemployed in cases of indeterminate FNAB cytology [50]. Asthese novel techniques undergo further refinement and vali-dation, and with decreasing costs per test, their clinical util-ity will increase and they will emerge with a more definitiverole in the management algorithm of thyroid nodules. Theavailability of such specialized tests may also have an impact

on the performance and interpretation of thyroid FNABs atsmaller volume centers, and potentially lead to the migra-tion of diagnostic thyroid cytology to reference centers forcytopathological evaluation and ancillary testing. Thus, theongoing evolution and refinement of thyroid nodule cytopa-thology, of which the BSRTC represents an important earlystep, will undoubtedly lead to improved management andoutcomes of individuals diagnosed with both benign andmalignant disease.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with

any organization or entity with a financial interest in or financial conflict

with the subject matter or materials discussed in the manuscript. This

includes employment, consultancies, honoraria, stock ownership or options,

expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Fine-needle aspiration biopsy is currently the best diagnostic test for the preoperative evaluation of a thyroid nodule.

• Clear communication of cytopathological results from the pathologist to the treating clinician(s) is of critical importance for optimal

patient management.

• The Bethesda System for Reporting Thyroid Cytopathology (BSRTC) provides a well-defined framework for communicating

cytopathological diagnoses from the pathologist to the clinician.

• The BSRTC consists of 6 diagnostic groups, each having an associated specific cancer risk, and estimates of these risks based upon

clinical reports have been calculated in this review.

• The atypia of undetermined significance or follicular lesion of undetermined significance diagnostic group confers a cancer risk that is

significantly higher than the cancer risk suggested by the BSRTC, and this finding must be considered when managing cases in this group.

• In typical clinical utilization, the BSRTC is highly sensitive (96%), but lacks specificity (46%) for thyroid cancer diagnosis.

• Decisions regarding the surgical management of cases with indeterminate cytopathology should incorporate the specific cytopathologic

diagnosis, as well as other relevant clinical parameters.

• Ancillary tests for accurately diagnosing indeterminate cases are being actively investigated, and are currently available at select

institutions, over time these modalities will become increasingly incorporated into the clinical management algorithm of thyroid nodules.

References

Papers of special note have been highlighted as:

• of interest

•• of considerable interest

1. Maitra A. The endocrine system. In:

Kumar V, Abbas AK, Fausto N, Aster JC,

editors. Pathologic basis of disease (1107-

1126). Elsevier; Philadelphia, PA, USA: 2010

• An excellent, concise textbook-chapter

review of thyroid pathophysiology.

2. Tan GH, Gharib H. Thyroid

incidentalomas: management approaches to

nonpalpable nodules discovered incidentally

on thyroid imaging. Ann Intern Med 1997;

126(1):226-331

3. Davies L, Welch HG. Increasing incidence

of thyroid cancer in the United States

1973-2002. JAMA 2006;295(18):2164-7

4. Randolph GW, Thompson GB,

Branovan DI, Tuttle M. Treatment of

thyroid cancer: 2007 - a basic review. Int J

Radiat Oncol Biol Phys 2007;69(2):92-7

5. Sosa JA, Udelsman R. Total thyroidectomy

for differentiated thyroid cancer. J Surg

Oncol 2006;94(8):701-7

6. Hamberger B, Gharib H, Melton LJ,

et al. Fine-needle aspiration biopsy of

thyroid nodules. Impact on thyroid

practice and cost of care. Am J Med 1982;

73(3):381-4

7. Hadi M, Gharib H, Goellner JR,

Heerden JA. Has fine-needle aspiration

biopsy changed thyroid practice? Endocr

Pract 1997;3(1):9-13

8. Yassa L, Cibas ES, Benson CB, et al.

Long-term assessment of a multidisciplinary

approach to thyroid nodule diagnostic

evaluation. Cancer 2007;111(1):508-16

• One of 13 articles included for meta-

analysis. This report is the basis for many

of the cancer risks published in

association with the Bethesda System for

Reporting Thyroid Cytopathology

(BSRTC).

9. Gharib H, Papini E, Valcavi R, et al.

American association of clinical

endocrinologists and associazione medici

endocrinology medical guidelines for clinical

practice or the diagnosis and management

of thyroid nodules: AACE/AME task force

on thyroid nodules. Endocr Pract 2006;

12(1):63-102

• Contains clinical management guidelines,

also see Reference 51.



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www.ncbi.nlm.nih.gov/pubmed/9027275?dopt=Abstract



















10. Kitano M, Sugitani I, Toda K, et al.

Cytopathological review of patients that

underwent thyroidectomies based on the

diagnosis of papillary thyroid carcinoma by

fine needle aspiration cytology but were later

found to have benign tumors by

histopathology. Surg Today 2013;43(6):632-7

11. Redman R, Yoder BJ, Massoll NA.

Perceptions of diagnostic terminology and

cytopathologic reporting of fine-needle

aspiration biopsies of thyroid nodules:

a survey of clinicians and pathologists.

Thyroid 2006;16(10):1003-8

•• This is an interesting report, which

highlights the role for the BSRTC. This

study consists of a survey of pathologists

and clinicians, asking about diagnostic

terminology used, as well as asking

clinicians how they perceive and react to

specific terminology.

12. Lewis CM, Chang KP, Pitman M, et al.

Thyroid fine-needle aspiration biopsy:

variability in reporting. Thyroid 2009;19(7):

717-23

•• This report examines published test

characteristics of fine-needle aspiration

biopsy (FNAB). Heterogeneity in the

methods used in literature reporting of

thyroid FNAB test characteristics is nicely

demonstrated.

13. Ali SZ, Cibas ES. editors. The Bethesda

system for reporting thyroid cytopathology.

Springer; NY: USA; 2010

•• An essential reference describing the

BSRTC.

14. Baloch ZW, Alexander EK, Gharib H,

Raab SS. Overview of diagnostic

terminology and reporting. In: Ali SZ,

Cibas ES, editors. The Bethesda system for

reporting thyroid cytopathology. Springer;

NY, USA; 2010

15. Wong LQ, Baloch ZW. Analysis of the

Bethesda system for reporting thyroid

cytopathology and similar precursor thyroid

cytopathology reporting schemes. Adv Anat

Pathol 2012;19(5):313-19

• Review and meta-analysis examining data

sets from both before and after adoption

of the BSRTC, showing calculated test

characteristics for each individual report.

A nice comparison with the current

study.

16. Bongiovanni M, Spitale A, Faquin WC,

et al. The Bethesda system for reporting

thyroid cytopathology: a meta-analysis. Acta

Cytol 2012;56(1):333-9

• This meta-analysis of the BSRTC has

essentially the same results to the current

study, though different statistical

methodologies and inclusion criteria are

employed to arrive at similar conclusions.

17. Chen JC, Pace SC, Chen BA, et al. Yield of

repeat fine-needle aspiration biopsy and rate

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18. Rabaglia JL, Kabbani W, Wallace L, et al.

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21. Davidov T, Trooskin SZ, Shanker BA,

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23. Horne MJ, Chhieng DC, Theoharis C,

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25. Bongiovanni M, Krane JF, Cibas ES,

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33. Ozluk Y, Pehlivan E, Gulluoglu MG, et al.

The use of the Bethesda terminology in

thyroid fine-needle aspiration results in a

lower rate of surgery for non-malignant

nodules: a report from a reference center in

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761-71

34. Renshaw AA. Should “atypical follicularcells” in thyroid fine-needle aspirates be

subclassified? Cancer Cytopathol 2010;

118(1):186-9

35. Kim SK, Hwant TS, Yoo YB, et al. Surgical

results of thyroid nodules according to a

management guideline based on the BRAF

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36. Bongiovanni M, Crippa S, Baloch Z, et al.

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38. VanderLaan PA, Marqusee E, Krane JF.

Features associated with locoregional spread

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39. Marchevsky AM, Walts AE, Bose S, et al.

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CATmaker �. The Centre for Evidence

Based Medicine. 2004. Available form

www.cebm.net/

•• The Centre for Evidence Based Medicine

is based out of Oxford University, the

website (above) provides excellent

reference material for physicians and

researchers. Specifically the CATmaker

program facilitates calculation of test

characteristics such as sensitivity

specificity, positive predictive value,

negative predictive value and both

positive and negative likelihood ratios.

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710-14

• Interesting examination of variability in

reporting of the atypia of undetermined

significance or follicular lesion of

undetermined significance diagnostic

category.

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NY, USA: 2010

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diagnosis and management of patients with

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J Clin Endocrinol Metab 2011;96(11):

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• Interesting demonstration of PCR-based

molecular assay for thyroid cancer.

48. Alexander EK, Kennedy GC, Baloch ZW,

et al. Preoperative diagnosis of benign

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•• Demonstration of array-based molecular

testing. Results indicate that a microarray

with classifier can effectively identify

benign RNA expression signature in

thyroid FNAB specimens.

49. Najafzadeh M, Marra CA, Lynd LD,

Wiseman SM. Cost-effectiveness of using a

molecular diagnostic test to improve

preoperative diagnosis of thyroid cancer.

Value Health 2012;15(8):1005-13

•• Analysis of the cost and benefit of a novel

molecular assay. This paper shows

potential for a test used in adjunct with

FNAB to have a wide-scale impact on

patient care. Highlights both the cost of

the test as well as the test characteristics

that are rate limiting.

50. Cooper DS, Doherty GM, Haugen BR,

et al. Revised American Thyroid Association

management guidelines for patients with

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