BRAF mutation in Fine Needle Aspiration Specimens as a Potential Predictor for Persistence/Recurrence in Patients with Classical Papillary Thyroid Carcinoma Larger than 10 mm at a BRAF Mutation Prevalent Area

BRAF and Recurrence of Papillary Thyroid Carcinoma

Hee Jung Moon, MD, PhD,1 Eun-Kyung Kim, MD, PhD,1 Woong Youn Chung, MD, PhD,2 Dong Yeob Shin, MD, 3 Jin Young Kwak, MD, PhD1

1

Department of Radiology, Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea 2

3

Department of Surgery, Yonsei University College of Medicine, Seoul, Korea

Endocrinology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea

Corresponding author: Jin Young Kwak, M.D. Department of Radiology, Research Institute of Radiological Science, Yonsei University College of Medicine 250 Seongsanno, Seodaemun-gu, 120-752 Seoul, Korea Tel: 82-2-2228-7400; Fax: 82-2-393-3035 E-mail: [email protected]

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/hed.23770

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BRAF mutation in Fine Needle Aspiration Specimens as a Potential Predictor for Persistence/Recurrence in Patients with Classical Papillary Thyroid Larger than 10 mm Carcinoma at a BRAF Mutation Prevalent Area

BRAF and Recurrence of Papillary Thyroid Carcinoma

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ABSTRACT:

Background.

The

association

between

the

BRAF

mutation

and

persistence/recurrence was investigated in patients with classical papillary thyroid carcinoma (PTC) at a BRAF mutation prevalent area. Methods. A total of 282 patients with total thyroidectomy and prophylactic central neck dissection were included. The BRAF mutation was evaluated with cytology specimen using dual priming oligonucleotide (DPO)-based multiplex PCR and direct sequencing preoperatively. Results. Thirty four patients (12%) had persistence/recurrence. In all PTC, the BRAF mutation on both methods was not associated with persistence/recurrence. In PTC > 10 mm, the BRAF mutation on DPO-based multiplex PCR was significantly associated with persistence/recurrence and a potential predictor for persistence/recurrence. In PTC ≤ 10 mm, none of the covariates were significantly different between patients with and without persistence/recurrence. Conclusions. The BRAF mutation was significantly associated with persistence/recurrence and a potential predictor in patients with classical PTC > 10 mm at a BRAF mutation prevalent area.

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INTRODUCTION

Papillary thyroid carcinoma (PTC) is usually indolent and cured with surgery and/or radioiodine ablation but persistence/recurrence is the main cause of mortality.1-6 About 5 to 15% of PTC patients have regional or distant metastasis and the 10 year survival rate is only 40% in patients with distant metastasis.7 Although every effort has been made to identify predicting factors for aggressive PTCs, no staging system has yet provided a perfect answer for differentiating indolent PTCs from aggressive ones. The BRAF V600E mutation is investigated as a prognostic factor in many studies. The mutation is strongly associated with persistent or recurrent disease8-15 and the mutation status helps decide the optimal extent of surgery.15,16 In contrast, the BRAF mutation is not associated with poor clinical or pathological factors in other studies.17-21 These opposite conclusions may arise from a variety of reasons such as heterogeneous inclusion criteria such as variable PTC subtypes (e.g. tall cell variant, classical variant, and follicular variant) and disease stages, and different methods for analyzing the BRAF V600E mutation, performances of prophylactic central lymph node dissection, definitions of persistence or recurrence of disease, races, and geographical areas. Thus, the association between persistence/recurrence and the BRAF mutation on dual

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priming oligonucleotide (DPO)-based multiplex PCR and direct sequencing was investigated in patients with classical PTC using US guided fine needle aspiration (US-FNA) specimens at a BRAF mutation prevalent area.

MATERIALS AND METHODS Patients Our institutional review board approved this retrospective study, and informed consent was waived. However, informed consent for both US-FNA and BRAF mutation analysis was still obtained separately from all patients. From April to July 2008, 487 consecutive patients with thyroid malignancy underwent staging ultrasonography (US) for the evaluation of extrathyroidal extension (ETE, T classification), multiple tumors, and lymph node metastasis (LNM, N classification) according to the sixth AJCC edition of the TNM classification, the most current edition at that time22, which is not different from the 7th edition23 except for the T1a classification (tumor equal or less than 1cm). These patients underwent US-FNA to evaluate the BRAF mutation during staging US.24-26 Of 487 patients, 184 who underwent hemithyroidectomy (n=53) or hemithyroidectomy and subtotal thyroidectomy (n=131) were excluded. Twenty patients with PTC other than classical subtypes were excluded. One patient who did not undergo any follow-up after total

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thyroidectomy was excluded. A total of 282 patients with total thyroidectomy, prophylactic central neck dissection, and classical PTC on histopathology were included. A portion of the study population was included in previous studies.24-26 One hundred fifty patients were included in a study by Kwak et al. in 2009, which was about the detection methods of DPO-based multiplex PCR, direct sequencing, and PCR-restriction fragment length polymorphism.25 Thirty two patients were included in a study by Kwak et al. in 2009, which discussed the associations between the BRAF mutation and ETE, LNM, and stage, and the associations between the BRAF mutation and US features.24 Thirty two patients were also included a study by Moon et al. in 2009, which was about the role of BRAF mutations in the management of thyroid nodules with suspicious for malignancy on cytology.26 The mean age of the 282 patients was 46.5 years old (range, 19-79 years). Of the 282 patients, 240 (85.1%, 240 of 282) were women and 42 (14.9%, 42 of 282) were men.

Fine needle aspiration and BRAF mutation analysis by DPO-based multiplex PCR and direct sequencing US examination and US-FNA were performed by one of two radiologists (K.E.K. and K.J.Y. with 11 and 7 year experiences in thyroid imaging). Index tumor size, ETE, and LNM on US were prospectively recorded in radiological reports.27 US-FNA was performed for the index

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PTC using a 23-gauge needle and a 2-mL disposable plastic syringe with the freehand biopsy technique. Materials obtained from FNA were rinsed with 1 mL of normal saline, and the washout was subjected to BRAF mutation analysis. The BRAF mutation was analyzed using genomic DNA by both DPO-based multiplex PCR and direct sequencing which were previously described in other studies.24-26

Surgery Before thyroid surgery, all patients underwent staging US and neck computed tomography (CT).28 Total thyroidectomy was performed in patients with an age ≥ 45 years, ETE, multiple tumors, or LNM on preoperative or intraoperative findings. Two hundred eighty two patients underwent total thyroidectomy. In our institution, prophylactic central neck dissection is routinely performed in patients with no LNM found clinically and radiologically. Therapeutic dissection is performed in patients with LNM found clinically or radiologically. Of the 282 patients, prophylactic bilateral central lymph node dissection was performed on 145 patients and therapeutic central neck dissection was performed on 137 patients. Lateral lymph node dissection was selectively performed in patients with LNM on prior US –FNA.28 If suspicious lymph nodes were found during surgery, lymph node sampling and frozen sections were done. If LNM was present, the surgeon routinely dissected the lateral compartment including level 2, 3,

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4, and anterior 5.28 Thirty patients underwent therapeutic unilateral lateral compartment dissection and four underwent therapeutic bilateral lateral compartment dissection.

Postoperative follow-up and persistence/recurrence After surgery, all patients underwent thyroid stimulating hormone (TSH) suppressive therapy with levothyroxine. In patients with ETE or LNM on histopathology,

131

I radioiodine ablation

was usually performed after withdrawal of levothyroxine for 2 or 3 weeks or after preparing recombinant human TSH. Afterwards, 131I whole body scintigraphy (WBS) was performed. Two hundred thirty five patients (83.3%, 235 of 282) underwent radioiodine ablation therapy after surgery (195 patients with 30mCi, 35 with 150mCi, 1 with 180mCi, and 4 with 200 mCi). The mean interval from surgery to radioiodine ablation therapy was 119 days (range, 31 - 198 days). Patients were followed every 6 months in the first 3 years after surgery and every 12 months after then. The routine follow-up consisted of a clinical examination every 6 months, and the measurement of serum TSH, free thyroxine, thyroiglobulin (Tg) and anti-Tg antibody (TgAb), a chest x-ray, and a neck US examination every 12 months. WBS, chest CT, or fluorodeoxyglucose positron emission tomography with computed tomography (PET/CT) was performed in selective cases (e.g., detectable or persistent serum Tg and TgAb without recurrence on a chest x-ray or neck US). WBS was performed after withdrawal of levothyroxine

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for 2 or 3 weeks or after preparing recombinant human TSH. No clinical evidence of disease was defined as suppressed Tg 10 mm. In classical PTCs > 10 mm on US, exact multivariate logistic regression analysis was performed. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Statistical significance was determined with a two-sided P value of less than 0.05. Statistical analyses were performed with SAS statistical software (SAS system for Windows, version 9.2; SAS institute, Cary, NC).

RESULTS The BRAF mutation was present in 85.1% (240 of 282) of patients with classical PTCs on DPO-based multiplex PCR and 68.4% (193 of 282) on direct sequencing. The mean followup from surgery to last follow-up or persistence/recurrence was 46.6 months (range, 6 - 55.2 months). The mean interval from surgery to persistence/recurrence was 23.2 months (median interval, 13.9 months; range, 8.5-51.8 months). The median follow-up interval from surgery to the last follow-up in patients with persistence/recurrence was 47.7 months, which was not

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statistically different from the 48.2 months of patients without persistence/recurrence (P value, 0.9705). Thirty four patients (12.1%, 34 of 282) had persistence/recurrence. Thirteen patients were detected by WBS, 9 were detected biochemically, 6 were detected by WBS and biochemical study, 4 were detected by US and US-FNA (2 underwent surgery), and 2 were detected by WBS and PET/CT. In all

PTC, lateral

LNM on US

was

significantly found

in patients with

persistence/recurrence (P value, 0.007) (Table 1). The BRAF mutations on DPO-based multiplex PCR and direct sequencing were not statistically different (P value, 0.115 and 0.283). The ETE, lateral lymph node metastasis, and higher stages on histopathology were significantly found in patients with persistence/recurrence (P value, 0.006, 0.003, and 0.002). The BRAF mutations on DPO-based multiplex PCR and direct sequencing were not independent factors for predicting persistence/recurrence (OR, 3.27 (95% CI, 0.73-14.60) and 1.45 (95% CI, 0.61-3.46)) (Table 2). Lateral LNM on US was an independent factor (ORs, 2.67 (95% CI, 1.11-6.42) and 2.54 (95% CI, 1.06-6.06)). The ETE and lateral LNM on histopathology were also independent factors (ORs, 3.03 (95% CI, 1.10 - 8.33) and 3.43 (95% CI, 1.34 - 8.77)). In PTC > 10 mm on US, the BRAF mutation was found in 83.3% and 72.9% on DPO-based multiplex PCR and direct sequencing. The BRAF mutation on DPO-based multiplex PCR was

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100% in PTC patients with persistence/recurrence, significantly different from 81% in those without

(P value, 0.044). Lateral

LNM

was significantly found

in PTC with

persistence/recurrence (P value, 0.005) (Table 3). In PTC ≤ 10 mm on US, no covariates were significantly different between the two groups. In PTC > 10 mm on histopathology, PTC with persistence/recurrence was significantly larger than PTC without (P value, 0.009) and had lateral LNM significantly (P value, 0.006) (Table 4). In PTC ≤ 10 mm on histopathology, no covariates were significantly different between the two groups. In PTC > 10 mm on US or histopathology, the BRAF mutation on DPO-based multiplex PCR was a potential predictor for persistence/recurrence (OR, 5.12 (95% CI, 0.80->999.999; P value, 0.095)) (Table 5). Lateral LNM on US and on histopathology were independent factors for predicting persistence/recurrence (OR, 4.47 (95% CI, 1.48- 13.58; P value, 0.008) and OR of 4.21 (95% CI, 1.22 – 14.52; P value, 0.023)).

DISCUSSION The BRAF mutation is significantly associated with the mortality in patients with PTC and synergistically increased the mortality in patients older than 60 years or with ETE or LNM.30,31 Many studies have reported that the BRAF mutation is significantly associated with

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poor clinico-pathologic factors and poor outcome.8-15,20,30-35 In our study, patients with classical PTC, total thyroidectomy, prophylactic central lymph node dissection, and/or radioiodine ablation were included and the BRAF mutation of classical PTC was 85.1%, comparable to Korean prevalence.24-26,36 In classical PTC > 10 mm on US, the BRAF mutation on DPO-based multiplex PCR was significantly associated with persistence/recurrence (P value, 0.044). The OR of the BRAF mutation was 5.12 (95% CI, 0.80->999.999) and the P value was 0.095. The upper limit of the 95% CI was infinite because all PTC with persistence/recurrence had the BRAF mutation, the number of persistence/recurrence was small, and none of the PTC without the BRAF mutation had persistence/recurrence. Clinically, the BRAF mutation on DPO-based multiplex PCR was a potential predictor for persistence/recurrence in PTC > 10 mm on US at a BRAF mutation prevalent area. This result is comparable to many studies8-10,13-15,20,34 but a contrast to others.17-19,31 The BRAF mutation as a prognostic factor is still under debate. The mutation has been significantly associated with ETE, LNM, higher stages, or multifocal cancers.9-12,14,15,19,20,31-35 However, other studies have stated that the BRAF mutation is not associated with any of these.18,21,31,37-41 In terms of recurrence, the association between the BRAF mutation and recurrence has also been under debate. Some results show that the BRAF mutation is strongly associated with recurrence,8-11,13-15,34,35 whereas others show that there is no association between

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the BRAF mutation and recurrence.17-20,38,39 The reasons for these apparently conflicting results are thought to be due to heterogeneous study populations with different definitions of persistence/recurrence, initial stages, or subtypes of PTCs (tall cell, classical, or follicular variant of PTC, etc), and due to different methods and specimens of BRAF mutation analysis and BRAF prevalence (Table 6). The persistence/recurrence rate in our study was 12.1%, which was within the wide range from 8.2% to 29% of previous studies.8-10,13-15,17-20,34 There are different definitions of recurrence according to previous studies. Sometimes, recurrence was defined when only new structural recurrence was found13 or when recurrence on imaging studies only was considered.19 Some studies included patients with distant metastasis initially or a portion of those with initial advanced stages.8,10,19,20,34 The extent of initial surgery can also impact recurrence rates.42 Prophylactic

central

lymph

node

dissection

was

routinely

performed

and

the

persistence/recurrence rate was 12.1% in our study, comparable to 8.2% of a previous study in the same situation.19 The variable inclusion criteria and extent of surgery can affect persistence/recurrence rates, which may also impact conclusions about the association between the BRAF mutation and recurrence. The tall cell variant of PTC is known to have more ETE, LNM, recurrence, or distant metastasis, compared with the classical and follicular variant of PTCs.12 The BRAF mutation

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prevalence of the tall cell variant of PTC is 50% to 88%, higher than 39.5% to 68.3% of the classical PTC, and 14% to 20% of the follicular variant of PTC.14,19,33,34 A mixture of the tall cell, classical, and follicular variant of PTCs may skew the results towards a strong association between the BRAF mutation and persistence/recurrence.12 Thus, results from studies including all the diverse subtypes of PTCs cannot be applied in predicting the recurrence of each subtype of PTC. Patients with classical PTC only were included in our study and the BRAF mutation on DPO-based multiplex PCR in classical PTC > 10 mm on US was significantly associated with persistence/recurrence and a potential predictor for recurrence/recurrence, comparable to previous studies about classical PTC.10,20 In patients with PTC > 10 mm, all eighteen patients with persistence/recurrence had the BRAF mutation, whereas, none of the patients without the BRAF mutation had persistence/recurrence. In a high BRAF mutation prevalent area, it is clinically significant that not having the BRAF mutation is associated with no persistence/recurrence. In patients with PTC ≤ 10 mm, the BRAF mutation was not associated with persistence/recurrence, which was comparable to previous studies.20,39 Different methods for BRAF mutation analysis result in a variable range of prevalence, 36.9 to 81% although the prevalence itself is different from country to country (Table 6).8-10,1215,17-20,34

In our study, the 83.3% of BRAF mutation on DPO-based multiplex PCR was a

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potential predictor for persistence/recurrence in 144 PTCs > 10 mm on US but the 72.9% of BRAF mutation on direct sequencing was not associated with persistence/recurrence. These results were comparable to a study by Guerra et al., in which 53.6% of the BRAF mutation on pyrosequencing was significantly associated with recurrence but 36.9% of the BRAF mutation on direct sequencing was not.9 Even at a BRAF mutation prevalent area, the BRAF mutation was a potential predictor for persistence/recurrence. Most studies used a paraffin block for BRAF mutation analysis.8-10,13,14,17,19,20,34 Genetic materials degrade over time in paraffin blocks,13 causing bias in a study population and also impacting the BRAF mutation prevalence. The concordance rate of the BRAF mutation status on FNA specimens and histopathology is 69 to 94%43,44 because of intratumor genetic heterogeneity.45 Different prevalence are obtained from different specimens for BRAF mutation analysis, thus, it is one of the reasons that the association between the BRAF mutation and recurrence is still under debate. However, preoperative risk stratification is essential to plan the extent of surgery and our study used FNA specimens for the BRAF mutation analysis. There are some limitations to our study. First, our study was of retrospective design and follow-up

periods

were

variable.

A longer

follow-up

period

might

change

the

persistence/recurrence rate. A persistent disease might change to no evidence of clinical disease over time.46 Remission can be obtained without further treatment after two or three years in

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patients with clinically insignificant biological persistence disease.46,47 Also, with a longer follow-up, more cases of recurrence might be observed. Second, the BRAF mutation was investigated qualitatively. A quantitative analysis, a cut-off 30% on pyrosequencing is significantly associated with recurrence.9 Considering that the BRAF mutation prevalence is 85.1%, a quantitative analysis may provide a more strong positive association between the BRAF mutation and recurrence. A large series study is needed. In summary, the BRAF mutation was significantly associated with persistence/recurrence and a potential predictor for persistence/recurrence in patients with classical PTC > 10 mm on US at a BRAF mutation prevalent area.

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TABLE 1. Demographic, clinical, and pathological characteristics of 282 patients with or without persistence/recurrence. Persistent/Recurrence

No persistent/recurrence

(No.=34)

(No.=248)

46.5 (19-72)

46.5 (19-79)

Mean age (years, range) Gender

P value 0.983 0.320

Female

27 (79.4)

213 (85.9)

Male

7 (20.6)

35 (14.1)

14.8 (4-45)

12.5 (3-65)

0.147

ETE

30 (88.2)

199 (80.2)

0.263

Central LNM

12 (35.3)

65 (26.2)

0.265

Lateral LNM

11 (32.4)

35 (14.1)

0.007

BRAF on DPO

32 (94.1)

208 (83.9)

0.115

BRAF on sequencing

26 (76.5)

167 (67.3)

0.283

13.0 (2-35)

10.8 (2-45)

0.174

ETE

29 (85.3)

152 (61.3)

0.006

Central LNM

18(52.9)

119 (48.0)

0.588

Lateral LNM

10 (29.4)

24 (9.7)

0.003

RIA

32 (94.1)

203 (81.9)

0.072

Preoperative US Mean size (mm, range)

Postoperative Pathology Mean size (mm, range)

Stages

0.002

1

16 (47.1)

155 (62.5)

3

13 (38.2)

87 (35.1)

4a

5 (14.7)

6 (2.4)

The numbers in parenthesis were percentages. No.; number ETE; extrathyroidal extension LNM; lymph node metastasis DPO; dual priming oligonucleotide-based multiplex PCR RIA; radioiodine ablation

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Head & Neck

TABLE 2. Covariates for predicting persistence/recurrence in papillary thyroid carcinoma. Preoperative US

Odds ratio

95% CI

P value

Size

1.02

0.98 - 1.06

0.463

ETE

1.38

0.44 - 4.31

0.58

Central LNM

1.22

0.53 - 2.79

0.638

Lateral LNM

2.67

1.11 - 6.42

0.028

DPO

3.27

0.73 - 14.60

0.121

Odds ratio

95% CI

P value

Size

1.01

0.97 - 1.06

0.490

ETE

1.45

0.47 - 4.52

0.518

Central LNM

1.22

0.52 - 2.70

0.692

Lateral LNM

2.54

1.06 - 6.06

0.036

DS

1.45

0.61 - 3.46

0.398

Odds ratio

95% CI

P value

Size

1.01

0.96 - 1.06

0.808

ETE

3.03

1.10 - 8.33

0.032

Central LNM

0.82

0.37 - 1.80

0.613

Lateral LNM

3.43

1.34 - 8.77

0.010

RIA

2.18

0.48 - 9.98

0.314

Preoperative US

Postoperative setting

CI; confidence interval ETE; extrathyroidal extension LNM; lymph node metastasis DPO; dual priming oligonucleotide-based multiplex PCR RIA; radioiodine ablation

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Page 28 of 34

TABLE 3. Demographic and clinical characteristics of patients with persistence/recurrence according to preoperative US. Lesions ≤ 10 mm Mean age (years, range)

Persistent/Recurrence

No persistent/recurrence

(No.=16)

(No.=122)

46.8 (34-60)

48.3 (19-69)

Gender

P value 0.576 0.112

Female

12 (75.0)

109 (89.3)

Male

4 (25.0)

13 (10.7)

Mean size (mm, range)

6.9 (4-10)

7.3 (3-10)

0.436

ETE

12 (75.0)

86 (70.5)

> 0.9999

Central LNM

3 (18.8)

28 (23.0)

>0.9999

Lateral LNM

3 (18.8)

17 (13.9)

0.704

BRAF on DPO

14 (87.5)

106 (86.9)

>0.9999

BRAF on sequencing

11 (68.8)

77 (63.1)

0.659

Stages

0.082

1

9 (56.3)

67 (54.9)

3

4 (25.0)

49 (40.2)

4a

3 (18.8)

6 (4.9)

Persistent/Recurrence

No disease (n=126)

P value

44.7 (21-79)

0.650

Lesions > 10 mm

(n=18) Median age (years, range)

46.2 (19-72)

Gender

>0.9999

Female

15 (83.3)

104 (82.5)

Male

3 (16.7)

22 (17.5)

21.8 (11-40)

17.6 (11-65)

0.057

18 (100.0)

113 (89.7)

0.372

Central LNM

9 (50.0)

37 (29.4)

0.079

Lateral LNM

8 (44.4)

18 (14.3)

0.005

BRAF on DPO

18 (100.0)

102 (81.0)

0.044

BRAF on sequencing

15 (83.3)

90 (71.4)

0.399

Median size (mm, range) ETE

Stages

0.023

1

8 (44.4)

74 (58.7)

3

6 (33.3)

46 (36.5)

4a

4 (22.2)

6 (4.8)

The numbers in parenthesis were percentages. No.; number

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ETE; extrathyroidal extension LNM; lymph node metastasis DPO; dual priming oligonucleotide-based multiplex PCR

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Page 30 of 34

TABLE 4. Demographic and pathological characteristics of patients with persistence/recurrence. Persistent/Recurrence

No persistent/recurrence

(No.=20)

(No.=145)

45.0 (27-60)

47.5 (19-68)

0.320

Female

16 (80.0)

127 (87.6)

0.312

Male

4 (20.0)

18 (12.4)

6.56 (2-10)

6.56 (2-10)

0.986

ETE

16 (80.0)

83 (57.2)

0.052

Central LNM

8 (40.0)

58 (40.0)

>.9999

Lateral LNM

3 (15.0)

8 (5.5)

0.133

RAI

18 (90.0)

112 (77.2)

0.252

Size ≤ 10 mm Mean age (years, range)

P value

Gender

Mean size (mm, range)

Stages

0.364

1

11 (55.0)

88 (60.7)

3

8 (40.0)

55 (37.9)

4a

1 (5.0)

2 (1.4)

Persistent/Recurrence

No persistent/recurrence

(n=14)

(n=103)

48.6 (19-72)

45.1 (21-79)

Size > 10 mm Mean age (years, range) Gender

P value 0.356 0.706

Female

11 (78.6)

86 (83.5)

Male

3 (21.4)

17 (16.5)

22.2 (12-35)

16.7 (11-45)

0.009

ETE

13 (92.9)

69 (67.0)

0.062

Central LNM

10 (71.4)

61 (59.2)

0.380

Lateral LNM

7 (50.0)

16 (15.5)

0.006

14 (100.0)

91 (88.3)

0.356

Mean size (mm, range)

RIA Stages

0.006

1

5 (35.7)

67 (65.0)

3

5 (35.7)

32 (31.1)

4a

4 (28.6)

4 (3.9)

No.; number #

; Mann Whitney test

The numbers in parenthesis were percentages. ETE; extrathyroidal extension LNM; lymph node metastasis

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DPO; dual priming oligonucleotide-based multiplex PCR RIA; radioiodine ablation

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Page 32 of 34

TABLE 5. Covariates for predicting persistence/recurrence in papillary thyroid carcinoma > 10 mm on ultrasonography or histopathology. Preoperative US

Odds ratio

95% CI

P value

Size

1.03

0.97 - 1.08

0.327

Lateral LNM

4.47

1.48- 13.58

0.008

DPO

5.12

0.80 - >999.999

0.095

Odds ratio

95% CI

P value

Size

1.06

0.99 - 1.13

0.114

ETE

5.73

0.66 - 45.60

0.113

Lateral LNM

4.21

1.22 - 14.52

0.023

Postoperative setting

CI; confidence interval LNM; lymph node metastasis DPO; dual priming oligonucleotide-based multiplex PCR

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TABLE 6. Studies about the association between the BRAF mutation and persistence/recurrence. Author

Year

Total

Inclusion (C, %)

(No.) 9

Guerra

2012

168

ETE

LNM (%)

(%) PTC sub (87.5)

46.7

57.9

BRAF (%)

BRAF

Recur

Follow-

Uni- or multivariate

(Method)

Specimen

(%)

up

analysis (95% CI)

36.9 (DS)

F, P

22.8

5.1 yr

DS; NA

53.6 (PS)

PS; OR=1.04 (1.01-1.07) and 5.31 (1.9-14.9)

Prescott

13

2012

205

PTC sub

18.4

Central 30.2

a

57.6 (DS)

P

15.4

> 5 yr

HR 2.51 (1.11-5.66)

37.3 (DS)

P

12.7

15 yr

OR 14.63 (1.28-167.29)

Lateral 13.2 Elisei

8

2008 10

102

PTC sub (86.3)

11.8

39.2

Kebebew

2007

347

PTC sub, FTC

26

37

51 (DS)

F, P

29

72 mo

OR 4.2 (1.2-14.6)b

Xing14

2005

219

PTC sub (57.1)

38b

52b

65b (DS)

P

21b

> 14 yrs

4.4 (1.3-14)

2009

190

PTC sub (70.5)

15.8

25.8

38.4 (DS)

FNA

10

3 yr

OR 3.06 (1.10-8.47)

2006

67

PTC sub (52.2)

43.3

26.9

41.7 (DS)

15

Xing

34

Riesco-E 20

Kim Ito19

17

2006

203

cPTC, only*

2009

631

PTC sub (92.4)

2008

Costa

18

49

PTC sub (32.7)

b

59

b

b

P

18

3 yr

P value, 0.02

b

65.4

b

73.4 (DS)

P

18

b

4.0 yr

0.037b

39.6

38.4 (DS)

P

8.2

80 mo

NA

P

b

140 mo

NA

b

50

b

75 b

81 (DS) b

b

25

b

Fugazzola

2004

47

cPTC, only

57.4

53.2

38.3 (DS)

F

21.3

Our study

2013

282

cPTC, only

64.2b

Central 48.6b

85.1 (DPO)b

FNA

12.1%

Lateral 12.1b

68.4 (DS)b

No.; number ETE; extrathyroidal extension LNM; lymph node metastasis CI; confidence interval

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NAb 46.6 mo

P value, 0.044b ORb 5.12 (0.80->999.999)

Head & Neck

PTC; papillary thyroid carcinoma PTC sub; PTC subtypes FTC; follicular thyroid carcinoma cPTC; classical papillary thyroid carcinoma DS; directing sequencing PS; pyrosequencing DPO; dual priming oligonucleotide-based multiplex PCR F; fresh frozen tissue P; paraffin embedded tissue FNA; fine needle aspiration yr; years mo; months OR; odds ratio HR; hazard ratio NA; not significant association a

; recurrence on biopsy or surgery only

b

; subgroup analysis of classical PTC

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Page 34 of 34

recurrence in patients with classical papillary thyroid carcinoma larger than 10 mm at a BRAF mutation prevalent area.

The association between the BRAF mutation and persistence/recurrence was investigated in patients with classical papillary thyroid carcinoma (PTC) at ...
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