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advocate for single mutation screening for theBRAF(V600E) mutation,21-25 and this practice continuesto gain popularity despite the recent commercialization of

at least one of the more sophisticated tests.19

As part of the conventional evaluation of FNA speci-mens, cytopathologists often note features of cytologicatypia such as nuclear grooves, pseudoinclusions, and ovalnuclei that are not prominent enough to make the diagno-sis of PTC. Such nodules are thereby categorized as a

follicular lesion of undetermined significance/atypia ofundetermined significance (Bethesda category III).6 Thisis a very heterogeneous group with an overall risk ofmalignancy ranging from 20% to 60%.26-30 Our group

recently demonstrated that not all descriptors of atypiaconfer an equal risk of malignancy; the presence of nucleargrooves, pseudoinclusions, or both, increases the risk of

malignancy to 55%, 65%, and 79%, respectively.31

The aims of this study were 3-fold: 1) to determineif certain features of cytologic atypia are independent riskfactors for harboring the BRAF(V600E) mutation, 2) todetermine if the additional knowledge of BRAF(V600E)status improves the sensitivity and specificity of FNA for

detecting malignancy, and 3) to determine if performingpreoperative BRAF(V600E) testing would alter the initialsurgical management of patients with indeterminatethyroid nodules.

MATERIALS AND METHODS

Patient Selection and Clinical Data Collection

Patients aged 18 years and older who had either a hemi-or total thyroidectomy at a single tertiary referral centerbetween January 2003 and March 2012 were prospec-tively enrolled. Patients whose preoperative FNAs identi-fied an indeterminate thyroid nodule (Bethesda categoriesIII, IV, or V) and had both cytologic and histopathologic

reports available were included in the final study popula-tion. The Institutional Review Board of Weill CornellMedical College approved this study, and informed, writ-ten consent was obtained from all patients.

Patient age, sex, preoperative FNA cytology, andfinal histopathological diagnosis were evaluated. All pre-operative FNAs and surgical specimens were reviewed by

a board-certified cytopathologist or surgical pathologist,respectively. Original FNA cytology reports were used tomaintain generalizability to other referral centers thatreview reports from multiple outside institutions. Forcases where multiple nodules were present, the FNA resultwas matched by location and size to the correct corre-

sponding nodule on the histopathology report. If theBethesda classification was not explicitly stated in the

biopsy report (ie, biopsies performed prior to 2009 andbiopsies performed at institutions that do not use theBethesda system in their reports), the appropriateBethesda category was assigned based on the findings

noted in the report. For this reason, Bethesda categoriesIII and IV were grouped together, because it was oftendifficult to distinguish these 2 groups on the basis of theterminology used in those reports.

The following features of cytologic atypia were tabu-lated for each biopsy: psammoma bodies, clear chromatin,

nuclear grooves, pseudoinclusions, enlarged nuclei,pinpoint nuclei, peripheral nucleoli, pleomorphic nuclei,and atypia not otherwise specified.

BRAF(V600E) Mutation Analysis

BRAF(V600E) mutation status was determined retro-spectively, using Sanger sequencing of frozen tissue sam-ples that were collected immediately after surgicalresection. All tissue samples were snap-frozen in liquid

nitrogen and stored at 80C until analysis. GenomicDNA was extracted using the QIAamp DNA Mini Kit(Qiagen, Valencia, Calif) according to manufacturerinstructions. The following primers were used as a tem-plate for a polymerase chain reaction (PCR) reactionunder standard conditions using the AmpliTaq Gold

PCR Kit (Applied Biosystems, Foster City, Calif): for-ward 50-TGCTTGCTCTGATAGGAAAATG-3 0,reverse 50-GACTTTCTAGTAACTCAGCAGC-3 0. The

PCR product was purified using the QIAQuick PCRPurification Kit (Qiagen) and visualized on a 2% agarosegel, which confirmed the presence of a single band ofapproximately 238 base pairs. The PCR product was then

direct-sequenced on an Applied Biosystems Automated3730xl DNA analyzer (Biotechnology Resource Center ofCornell University, Ithaca, NY) and read at position 1799for the presence of a mutant (A) allele. All malignant nod-ules and 18 of the 221 benign nodules were genotyped.The remaining benign nodules were assumed to be wild-

type, because the BRAF(V600E) mutation has never beendetected in a benign nodule.

Statistical Analysis

Univariate analysis was performed comparing demo-

graphic and cytologic features of BRAF(V600E) mutantsversus the wild type. Features of cytologic atypia that wereidentified on univariate analysis as having a significantassociation with the BRAF(V600E) mutation were thenentered into a multivariate logistic regression model toassess their influence on harboring the BRAF(V600E)

mutation. The sensitivity, specificity, positive predictivevalue (PPV), and negative predictive value (NPV) of, 1)

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BRAF(V600E) mutation testing, or 2) cytologic atypia orBethesda category V classification as surrogate markers formalignancy, were calculated both alone and in combina-tion to determine if the additional knowledge of the for-mer would have improved the diagnostic accuracy of thelatter.

P values were calculated using Fishers exact test

(dichotomous variables) or Student t test (continuousvariables) as appropriate. All continuous variablesfollowed a normal distribution and are presented as mean standard deviation. P values < .05 were considered

statistically significant. All statistical analyses were per-formed using STATA 12.0 (Stata Corporation, CollegeStation, Tex).

RESULTS

A total of 960 patients were enrolled in this study, ofwhich 310 (32%) had indeterminate nodules (Bethesdacategories III, IV, or V) and were included in the finalstudy population (Fig. 1). Among this population, 274

(88%) nodules were Bethesda category III or IV, and 36(12%) were Bethesda category V. In addition, 89 of the

indeterminate nodules were malignant, making the over-all risk of malignancy 29%. A total of 145 nodules (47%)had at least 1 feature of cytologic atypia, which increasedthe risk of malignancy to 42%. Thirteen BRAF(V600E)-mutant nodules were identified, all of which were malig-nant. There were no significant differences in age, sex, ornodule size between BRAF(V600E) mutants and the wild

type (Table 1).The various histologic subtypes identified among

the total study population as well as several subgroups areshown in Table 2. The most common malignant histo-

logic subtype overall was follicular variant of PTC(fvPTC). Bethesda category III or IV nodules that weremalignant were most likely to be of the fvPTC subtype,whereas Bethesda category V malignant nodules were

most likely to be classic PTCs. Eleven (85%) of theBRAF(V600E)-mutant nodules were classic PTCs,whereas 2 (15%) were fvPTCs.

Eleven of the BRAF(V600E)-mutant nodules hadcytologic atypia, whereas 2 did not (P .005). Nodules

with cytologic atypia were 6.7 times more likely to harborthe BRAF(V600E) mutation than those without atypia

Figure 1. Flowchart shows Bethesda classification of all patients and breakdown of the study population by atypia/no atypia, final

diagnosis (malignant versus benign), and BRAF(V600E) status of the malignancies. Asterisk (*) indicates the study population.Abbreviations: Mut, mutant; WT, wild-type.

BRAF Testing of FNAs and Initial Surgery/Kleiman et al

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(95% confidence interval [CI] 1.5-30.7, P .004).Similarly, nodules with cytologic atypia were 3.6 timesmore likely to be malignant than nodules without atypia

(95% CI 2.1-6.0, P< .001).Nuclear grooves (P .030), intranuclear pseudoin-

clusions (P< .001), and oval nuclei (P .022) were allmore common in BRAF(V600E)-mutant nodules com-pared with wild-type nodules (Table 1). Multivariatelogistic regression analysis revealed that pseudoinclusions

and oval nuclei were independent risk factors for harbor-

ing the BRAF(V600E) mutation, with odds ratios 11.2(95% CI 3.0-42.2) and 10.0 (95% CI 1.4-72.0),respectively (Table 3). Nuclear grooves showed a trend

toward increased risk but did not reach significance (oddsratio 2.3, 95% CI 0.6-8.3). The area under thereceiver operating curve (ROC) for a multivariate modelincluding all 3 descriptors was 0.749, but the areadecreased to 0.705 when the factor of nuclear grooves wasremoved, thus indicating that nuclear grooves contributed

to the overall predictive value of the model despite notreaching statistical significance independently.

The incidence of the BRAF(V600E) mutationamong Bethesda category III or IV nodules that were

found to be malignant on final pathologic analysis was3%, whereas the incidence among Bethesda categoryV nodules that were malignant was 42% (P < .001,

Table 4). The sensitivity of BRAF(V600E) testing fordetecting malignancy in all indeterminate nodules was15%. The sensitivity among Bethesda III or IV noduleswas 3.2% and among Bethesda V nodules was 42%.

Among nodules with cytologic atypia, the sensitivity was18%, whereas among Bethesda category III or IV nodules

without atypia, the sensitivity was only 4%. The specific-ity of BRAF(V600E) testing was 100% for all subgroups.

TABLE 1. Patient and Nodule Characteristics

Grouped by BRAF(V600E) Status

Characteristic

BRAF Mut

(n 13)BRAF WT

(n 297) P

Age, ya 47.2 14.3 48.6 13.4 .722

Females 12 (5%) 233 (95%) .315

Males 1 (2%) 64 (98%)

Nodule size, cma 1.8 0.9 2.6 1.7 .080

Bethesda category

III or IVb 2 (1%) 272 (99%)

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The sensitivity, specificity, PPV, and NPV ofBRAF(V600E) mutation testing compared with, or incombination with, use of cytologic atypia or Bethesda cat-egory V classification as surrogate markers for malignancyare displayed in Figure 2. When BRAF(V600E) testingwas added to these conventional cytologic markers ofmalignancy, there was no meaningful improvement insensitivity, specificity, NPV, or PPV.

Finally, the extent of initial surgical resection per-formed on the 13 patients with the BRAF(V600E) mutation

was reviewed to determine if the initial operative plan wouldhave changed if the presence of the BRAF(V600E) mutationhad been known preoperatively (ie, if a total thyroidectomywould have been recommended instead of a hemithyroidec-tomy initially). Eleven of the 13 BRAF(V600E) mutantpatients had Bethesda category V nodules and thus alreadyunderwent a total thyroidectomy as their initial operation, asis the standard recommendation at our institution. Onepatient had a Bethesda category III nodule with pseudoin-clusions and enlarged nuclei and, therefore, that patient wasalso advised to undergo a total thyroidectomy due to theincreased risk of malignancy that those atypical features

imparted. One patient underwent a hemithyroidectomy andisthmusectomy for a 2.7-cm follicular neoplasm (Bethesdacategory IV) with no cytologic atypia that was found to be aBRAF(V600E)-mutant fvPTC. Therefore, the initial surgi-cal plan would have been altered in only 1 of the 310patients with indeterminate nodules if BRAF(V600E) test-ing had been performed preoperatively.

DISCUSSION

Preoperative screening for the BRAF(V600E) mutation asa way to refine the accuracy of FNA of indeterminate

TABLE 4. Correlation Between BRAF(V600E) Status and Outcome Among Various Subgroups of the Study

Population

Subgroup Malignant (n 89) Benign (n 221)

All indeterminate nodules BRAF(V600E) 13 (15%) 0 (0%) Sensitivity: 15%

Specificity: 100%(Bethesda III, IV or V) Wild-type 76 (85%) 221 (100%) PPV: 100%

NPV: 74%

Malignant (n 63) Benign (n 211)

Bethesda III or IV BRAF(V600E) 2 (3%) 0 (0%) Sensitivity: 3%

Specificity: 100%

(FLUS/AUS or follicular neoplasm) Wild-type 61 (97%) 211 (100%) PPV: 100%

NPV: 78%


Bethesda V (suspicious for PTC) BRAF(V600E) 11 (42%) 0 (0%) Sensitivity: 42%

Specificity: 100%

Wild-type 15 (58%) 10 (100%) PPV: 100%

NPV: 40%


Any atypia BRAF(V600E) 11 (18%) 0 (0%) Sensitivity 18%

Specificity 100%

Wild-type 50 (82%) 84 (100%) PPV 100%

NPV 63%


Bethesda III or IV without atypia BRAF(V600E) 1 (4%) 0 (0%) Sensitivity 4%

Specificity 100%

Wild-type 22 (96%) 135 (100%) PPV 100%

NPV 86%

Abbreviations: AUS, atypia of undetermined significance; BRAF(V600E), B-type Raf kinase Val600Glu mutation; FLUS, follicular lesion of undetermined signifi-

cance; NPV, negative predictive value; PPV, positive predictive value.

Figure 2. Histograms show sensitivity, specificity, positive

predictive value (PPV), and negative predictive value (NPV)of BRAF(V600E) mutation analysis compared with, or in

combination with, using cytologic atypia or Bethesda V clas-sification as surrogate markers for malignancy.



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thyroid nodules is rapidly gaining popularity.11,16,21,22,32

However, in this study, we found that 92% of indetermi-nate nodules that harbor the BRAF(V600E) mutation

have other conventional cytologic markers of malignancy(cytologic atypia or Bethesda V classification) thatalready warrant a total thyroidectomy, and therefore,BRAF(V600E) screening is unlikely to alter their initialmanagement. Furthermore, the sensitivity ofBRAF(V600E) screening is lowest among nodules for

which it would be hoped to be most helpful (Bethesda IIIor IV nodules without atypia which normally warrantonly a diagnostic hemithyroidectomy), thus limiting itspotential value as a preoperative screening test. As such,

this is the first study to report that cytologic atypiapredicts the presence of the BRAF(V600E) mutation, andalso that preoperative BRAF(V600E) screening does not

improve the evaluation of indeterminate nodules if oneconsiders cytologic atypia.

The low sensitivity of BRAF(V600E) screeningis the main limitation of single-mutation analysis fordetecting malignancy among indeterminate FNAs. Toovercome this limitation, Nikiforov and colleagues have

developed a genetic screening panel for molecular analysisof preoperative FNAs that detects not onlyBRAF(V600E), but also point mutations ofNRAScodon61, HRAS codon 61, and KRAS codons 12/13, and

rearrangements of RET/PTC1, RET/PTC3, and PAX8/PPARc.10 Testing positive for any mutation on the panel

has a sensitivity of 62%, specificity of 99.7%, and PPV of97% for malignancy. However, very few centers as of yethave the ability to screen for the full panel of mutations,and most that have begun or are considering adding muta-tion analysis only test for BRAF(V600E).

Several other groups have recently developed molec-ular profiling tests that use multiple molecular markers to

refine the preoperative diagnosis of indeterminate nod-ules. The Veracyte Afirma thyroid FNA analysis systemmeasures expression of 142 genes to classify indeterminatenodules as benign or suspicious with 92% sensitivity and

52% specificity.

19

Our group has recently developed apanel of 4 micro-RNAs (miR-222, miR-328, miR-197,and miR-21) that has been preliminarily shown to dis-

criminate between benign and malignant indeterminatenodules with 100% sensitivity and 86% specificity.20

Future studies that combine existing knowledge ofconventional cytologic risk factors and multiple molecularmarkers of thyroid cancer are warranted.

Nuclear grooves, pseudoinclusions, and oval nuclei

were found to be associated with the BRAF(V600E)mutation on univariate analysis, and pseudoinclusions

and oval nuclei maintained significance on multivariatelogistic regression. These findings are consistent with ourgroups recent study that showed that grooves and

pseudoinclusions are independent risk factors for malig-nancy.31 It also supports the findings of Adeniran et al.who found that the incidence of the BRAF(V600E) muta-tion among indeterminate nodules with cytologic atypiawas 23% whereas the incidence among nodules withoutatypia was 0%.21 This suggests that these features of cyto-

logic atypia may be used as surrogate markers for theBRAF(V600E) mutation.

The incidence of the BRAF(V600E) mutation variesgreatly according to Bethesda category; the incidence in

Bethesda category III and IV nodules is < 5% whereas therate among Bethesda category VI (malignant) nodules isroughly 70%.11,22,23,32 One explanation for this differ-

ence is that the majority of Bethesda category III and IVnodules that are found to be malignant are of the fvPTCsubtype (as was the case in this study), and only approxi-mately 10% to 15% of fvPTCs harbor the BRAF(V600E)mutation.8,17,33 Therefore, the likelihood of finding theBRAF(V600E) mutation among Bethesda category III or

IV nodules is quite low which limits the potential contri-bution of preoperative mutation analysis for thesenodules.

A similar yet distinct research question is whether

preoperative BRAF(V600E) screening of indeterminatenodules would influence the decision to perform a pro-

phylactic central compartment lymph node dissection inaddition to a total thyroidectomy at the time of the initialoperation. Two recently published studies found that theBRAF(V600E) mutation is an independent risk factorfor occult central compartment lymph node metastases,and therefore, the authors suggest that preoperativeBRAF(V600E) screening should be used to guide the

extent of initial surgery.24,25 Both of these studies, how-ever, only included Bethesda category VI (malignant)nodules, a subgroup characterized by a significantly higherincidence of the BRAF(V600E) mutation (discussed

above) and a larger proportion of aggressive histologicsubtypes than Bethesda categories III, IV, and V nod-ules.34 Furthermore, it remains unclear whether perform-

ing a prophylactic central compartment lymph nodedissection improves outcomes or if the overall benefits ofthe procedure outweigh the increased risk of complica-tions such as permanent hypocalcemia.35-39

There are at least 2 limitations to this study. First,this was a single-center study and, as such, the choice of

initial surgery is reflective of the practice patterns of the 2participating surgeons (T.J.F. and R.Z.). At our center,

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we typically recommend a total thyroidectomy for allpatients whose risk of malignancy is 70%, whichincludes Bethesda category V nodules and nodules with

nuclear grooves and pseudoinclusions. Centers that followa more thyroid-preserving approach may observe a morefrequent change in initial operative plans if preoperativeBRAF testing is performed. Second, BRAF(V600E)testing was performed retrospectively using frozen tissuesamples and not prospectively using cytologic material

from an FNA biopsy. However, several authors havepreviously demonstrated the feasibility of performingmutation analysis using FNA material.8,11,15,16

In conclusion, the BRAF(V600E) mutation is most

common in nodules with other cytologic risk factors formalignancy, which already warrant a total thyroidectomy.Therefore, single-mutation screening for BRAF(V600E)

does not meaningfully improve preoperative risk stratifi-cation and is unlikely to alter the initial management ofpatients with indeterminate nodules.

FUNDING SOURCES

This study was supported in part by grant TL1RR024998 of theClinical and Translational Science Center at Weill Cornell Med-ical College, and by a donation from the Dancers CareFoundation.

CONFLICT OF INTEREST DISCLOSURE

The authors made no disclosure.

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