2015 HSC Section 1 Book of Articles

TABLE III. Literature Review.

Patients With BRAF Mutation Percentage

Study and Year

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 4 of 20 21 of 56

0% Not examined. 20% Not examined.

U.S.A. U.S.A.

Rosenbaum 2005 Sassoulas 2012

20.3% Factors not associated with BRAF V600E: lymphatic metastases or extrathyroidal extension. 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%.

France, Italy

U.S.A.

Givens 2014

7 of 19

(current study)

Cumulative

63 of 222

28.4%

prevalence

FVPTC 5 follicular variant of papillary thyroid carcinoma; MACIS 5 metastases, age at diagnosis, completeness of resection, invasion, size of the tumor scoring; PTC 5 papillary thyroid carcinoma.

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. 7 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. 13 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. 14 The BRAF V600E mutation was significantly associ- ated with malignancy, specifically PTC histology ( P 5 .013), as has been reported previously in the adult literature. 8 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 ( P 5 .017). This is in agreement with findings from a recent meta-analysis of the adult literature, 8 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. 21 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 ( P 5 .633), central neck metastases ( P 5 .617), pulmonary metastases ( P 5 .106), tumor size ( P 5 .863), lymphovascular invasion ( P 5 .580), or extrathyroidal extension ( P 5 1.00). It was also not associated with older age ( P 5 .239). Interestingly, there was a negative association between the BRAFV600E mutation and a higher MACIS score ( P 5 .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 22 as a useful prognostic indicator. A

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