2015 HSC Section 1 Book of Articles

presence of the mutation with aggressive disease charac-

teristics, but no general consensus has been reached. A

recent meta-analysis in adults, including 14 studies and

2,470 patients reported that the BRAF mutation was sig-

nificantly associated with recurrence, lymphatic metasta-

ses, extrathyroidal extension, and advanced stage.

Thyroid cancer is rare in pediatric populations, and

these patients often present at a more advanced stage.

Few studies in children have examined the prevalence of

the BRAF gene mutation, or its association with aggres-

sive disease characteristics. In our study, tumor speci-

mens from 19 pediatric patients with PTC were

analyzed for the presence of the BRAF gene mutation.

The BRAF mutation was present in 7/19 patients

(36.8%) overall, and in 7/11 patients (63.6%) with classic

PTC. All patients with variant pathology were wild type,

which is similar to previous reports of a very low inci-

dence of the BRAF mutation in histologic variants of

PTC.

Previous studies of pediatric patients with PTC

demonstrated a BRAF mutation prevalence of 0% to

37%.

10–14

The prevalence of the BRAF gene mutation in

our sample of patients with classic PTC (63.6%) is much

higher than previously reported in the pediatric litera-

ture (Table III), and higher than the prevalence reported

in two recent meta-analyses of adult patients (45% and

50.9%),

7,8

but similar to rates published in individual

studies in adults (27%–73%).

7,18

This study is the most

comprehensive of its type in that it attempts to deter-

mine an association of the BRAF V600E mutation with

aggressive disease features commonly seen in pediatric

PTC. Only two previous studies from the US popula-

tion

12,13

have examined the BRAF prevalence in the

pediatric population, and these studies did not comment

on aggressive disease characteristics (Table III). The

studies from Europe and Japan that did review the clini-

cal course of their patients did not find any association

with some aggressive characteristics.

11,14

This question

is important to answer in the US population, because

oncogene mutations may display variable prevalence in

different geographical regions.

The BRAF V600E mutation was significantly associ-

ated with malignancy, specifically PTC histology

(

.013), as has been reported previously in the adult

literature.

No patients with other variant pathology,

including seven follicular variants of PTC (FVPTC), one

tall cell variant, and one oncocytic variant were BRAF

V600E mutants. FVPTC histology was significantly neg-

atively associated with BRAF V600E (

.017). This is

in agreement with findings from a recent meta-analysis

of the adult literature,

and is important because this

mutation could serve as a diagnostic adjunct in FNA

biopsy. Gene panel assays are currently in early phases

of use for thyroid cancer diagnosis.

19,20

Some authors

have recommended escalating therapy (such as perform-

ing a total thyroidectomy instead of lobectomy) in

patients with a thyroid nodule that have a known

genetic mutation.

In contrast to the adult population, we did not find

that the BRAF mutation was associated with other

markers of aggressive disease such as lateral neck

metastases (

.633), central neck metastases (

.617),

pulmonary metastases (

.106), tumor size (

.863),

lymphovascular invasion (

.580), or extrathyroidal

extension (

1.00). It was also not associated with

older age (

.239). Interestingly, there was a negative

association between the BRAFV600E mutation and a

higher MACIS score (

.087). This association

approached statistical significance, and could become

significant with a higher sample size.

MACIS score was chosen as a surrogate for more

advanced disease because, unlike the AGES and AMES

scoring systems for prognosis, it does not rely as heavily

on age to calculate the score. MACIS score is calculated

with numerical points added for age, tumor size, incom-

plete resection, local invasion, and distant metastases.

This system has been previously validated in children

and adolescents

as a useful prognostic indicator. A

TABLE III.

Literature Review.

Study and Year

Patients With

BRAF Mutation Percentage

Association With Aggressive Disease Characteristics

Country of Origin

Kumagai 2004

1 of 31

3.2% Factors not associated with BRAF V600E: tumor size, lymphatic

or distant metastases, extrathyroidal extension.

Japan

Nikiforova 2004

30 of 82

36.6% Not examined.

Belarus and

Ukraine

Penko 2005

0 of 14

0% Not examined.

U.S.A.

Rosenbaum 2005

4 of 20

20% Not examined.

U.S.A.

Sassoulas 2012

21 of 56

20.3% Factors not associated with BRAF V600E: lymphatic metastases

or extrathyroidal extension.

France, Italy

Givens 2014

(current study)

7 of 19

36.8% BRAF V600E is associated with PTC histology and is negatively

associated with FVPTC histology. Factors not associated with

BRAF V600E: lymphatic or distant metastases, age, tumor size,

extrathyroidal extension, lymphovascular invasion, MACIS score,

microcarcinoma. Prevalence in patients with classical PTC is 63.6%.

U.S.A.

Cumulative

prevalence

63 of 222

28.4%

FVPTC

follicular variant of papillary thyroid carcinoma; MACIS

metastases, age at diagnosis, completeness of resection, invasion, size of the tumor

scoring; PTC

papillary thyroid carcinoma.

Givens et al.: BRAF V600E and Pediatric Thyroid Carcinoma

Laryngoscope

124:

September

2014

236