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Eur Arch Otorhinolaryngol DOI 10.1007/s00405-013-2872-7

HEAD AND NECK

The association between BRAFV600E mutation and pathological features in PTC Xin Liu • Kangkang Yan • Xuejun Lin • Longyu Zhao • Wenxiu An • Chunpeng Wang Xiaodong Liu



Received: 11 August 2013 / Accepted: 19 December 2013 Ó Springer-Verlag Berlin Heidelberg 2014

Abstract The BRAFV600E mutation is a common genetic alteration in papillary thyroid carcinoma (PTC) and is associated with some pathological features. The association has been widely reported, but results were inconclusive. In this study a meta-analysis was done to explore the association between BRAFV600E mutation and pathological features in papillary thyroid carcinoma. Medline, PubMed and Web of Science were searched. A total of 69 studies that included 14,170 PTC patients were identified. The outcomes were from 2004 to October 2013. STATA12.0 software package was used to analyze the data. The result was assessed based on pooled odds ratios (ORs) with 95 % confidence intervals (CIs). The results showed that the BRAFV600E mutation was associated with extra-thyroidal extension (OR = 2.09, 95 % CI = 1.69–2.58), advanced TNM stage (OR = 1.90, 95 % CI = 1.62–2.22), lymph node metastasis (OR = 1.68, 95 % CI = 1.41–2.01), multifocality (OR = 1.22, 95 % CI = 1.06–1.40), and recurrence (OR = 2.50, 95 % CI = 1.73–3.59). The meta-

X. Liu  K. Yan  X. Lin  L. Zhao Epidemiology and Statistics, School of Public Health, Jilin University, Changchun, Jilin, China W. An Social Medicine, School of Public Health, Jilin University, Changchun, Jilin, China C. Wang (&) School of Mathematics and Statistics, Northeast Normal University, Changchun, Jilin, China e-mail: [email protected] X. Liu (&) Key Laboratory of Radiobiology, Ministry of Health, School of Public Health, Jilin University, Changchun 130021, China e-mail: [email protected]

analysis suggested the potential roles of BRAFV600E mutation in pathological features. BRAFV600E might provide prognostic and diagnostic information for papillary thyroid carcinoma. Keywords BRAFV600E  Association  Pathological features  Papillary thyroid carcinoma  Meta-analysis

Introduction Thyroid cancer is the most common endocrine malignancy, accounting for about 1 % of human tumors. Differentiated thyroid carcinoma (DTC) includes the papillary thyroid carcinoma (PTC) and follicular histotypes and their variants, accounting for more than 90 % of all thyroid cancers [1]. PTC is the most common one, characterized by slow growth and long existence. For PTC shares some pathological features in common with other benign thyroid tumors, the diagnostics mainly depend on B ultrasound and biomarkers. Immunohistochemical or molecular biological approaches must be combined with current cytological diagnostic techniques for the diagnosis of PTC [2]. Hughes DT found that central neck lymph node dissection contributed to the treatment of PTC in cases of recurrent disease [3]. BRAF, a cytoplasmic serine-threonine protein kinase, plays a critical role in cell signaling as an activator within the mitogen-activated protein kinase (MAPK) pathway. V600E transversion is the most common BRAF mutation and has been found in 44 % PTC. BRAFV600E can initiate follicular cell transformation, BRAFV600E detection is important for the diagnostic and prognostic management of PTC and can provide diagnostic information [4–9]. But Nam JK claimed that the effect of BRAFV600E detection for

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prediction of poor prognosis of PTC was not clear [10]. Elisei thought that the BRAFV600E positive (BRAFV600E mutation present) cases had a 4.18-fold increase in risk of advanced TNM stage than BRAFV600E negative (BRAFV600E mutation not present) cases [11]. Many studies have evaluated the association between BRAFV600E mutation and pathological features in PTC, but the results are inconclusive and incomplete. To overcome the shortage and to understand the real situation, now a meta-analysis was performed to get a realistic result.

Materials and methods Search strategy, selection criteria and data extraction The following pathological features of PTC were selected to evaluate the possible association with BRAFV600E mutation: (1) extra-thyroidal extension; (2) multifocality; (3) lymph node metastasis; (4) advanced TNM stage; (5) disease recurrence; (6) distant metastasis; (7) age. A comprehensive search strategy was conducted in the PubMed, Medline and Web of Science from 2004 to October 2013. Search terms included ‘‘papillary thyroid carcinoma’’, ‘‘PTC’’, ‘‘BRAFV600E’’, ‘‘BRAFT1799A, synonym of BRAFV600E’’, ‘‘mutation’’, ‘‘papillary thyroid carcinoma’’. The retrieval of literature was performed by two independent reviewers. The studies meeting the following criteria were accepted: (1) the study must offer detailed information about BRAFV600E mutation and pathological features; (2) all cases were diagnosed by hospital; (3) BRAFV600E mutations were determined by direct sequencing; (4) when multiple publications reported on the same or overlapping data, we used the most recent or largest population; (5) publication language was English. The following information was extracted: first author, country, publishing year, the information about BRAFV600E positive cases and BRAFV600E negative cases. If there was disagreement between the two reviewers, a third reviewer was involved to make the decision. Statistical analysis Pooled ORs with 95 % CIs were used to evaluate the association between pathological features and BRAFV600E mutation. Chi square test and I-square were used to assess the heterogeneity. The random effects model or fixed effects model was selected to analyze the result on the heterogeneity of the studies. If the P value\0.10 or I2 [ 50 %, the heterogeneity was defined. Subgroup analyses were performed to analyze the country effect if the heterogeneity was significant. The potential publication bias was assessed using Begg’s funnel plot and Egger’s test. A P value of 0.05 for

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Fig. 1 The process of study selection

Egger’s was considered significant. STATA12.0 software package was used to calculate the result.

Results The characteristics of eligible studies All studies retrieved were carefully screened and 69 studies [5, 7–74] met the criteria, among which 14,170 PTC cases were included (Fig. 1). The main characteristics of 69 studies are shown in Table 1. If the study was conducted by different universities or hospitals, the multi-institutional studies were determined. The studies of Sykorova V, Ulisse S, and Fugazzola L were multi-institutional studies [29, 34, 58]. Of the 69 studies, 37 studies evaluated the association of BRAFV600E mutation with extra-thyroidal extension; 45 studies evaluated the association of BRAFV600E mutation with advanced TNM stage; 49 studies evaluated the association of BRAFV600E mutation with LNM; 38 studies evaluated the association of BRAFV600E mutation with multifocality; 30 studies evaluated the association of BRAFV600E mutation with age; 9 studies evaluated the association of BRAFV600E mutation with disease recurrence; and 13 studies evaluated the association of BRAFV600E mutation with distant metastasis. Meta-analysis The combined results of this meta-analysis and the heterogeneity test are shown in Table 2. Random effects model

Eur Arch Otorhinolaryngol Table 1 Characteristics of individual studies First author

Country

The institutions where the studies were conducted

Source of PTC

Positive/ PTC

Fugazzola et al. [72]

Italy

Institute of Endocrine Sciences, University of Milan

Ospedale Maggiore IRCCS

18/65

Liu et al. [73]

China

Division of Metabolism, Chang Gung Memorial Hospital

Chang Gung Memorial Hospital

49/105

Kim et al. [46]

Korea

Departments of Internal Medicine, Sciences, Asan Medical Centre, University of Ulsan College of Medicine

Asan Medical Centre

31/60

Jo et al. [71]

Korea

Department of Internal Medicine, Chungnam National University School of Medicine

Chungnam National University Hospital

102/161

RiescoEizaguirre et al. [69]

Spain

Hospital Universitario LaPaz

28/67

Park et al. [14]

Korea

Instituto de Investigaciones Biome0 dicas ‘Alberto Sols’ Consejo Superior de Investigaciones Cientı0 ficas y Universidad Auto0 noma de Madrid Department of Pathology, Seoul National University Bundang Hospital

Seoul National University Bundang Hospital

29/37

Sapio et al. [31]

Italy

Department of Scienze Biomorfologiche e Funzionali, Universita‘ Federico II, Naples

Relevant department at the University of Naples

18/43

Fugazzola et al. [29]

Italy

The endocrine surgery units of the Universities of Milan, Perugia and Pisa (M*)

Endocrine surgery units of the Universities of Milan

99/260

Kim et al. [45]

Korea

Departments of Internal Medicine, Sciences, Asan Medical Centre, University of Ulsan College of Medicine

Asan Medical Centre

149/203

Abrosimov [74]

Russian

Department of International Health and Radiation Research, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences

Russian Academy of Medical Sciences

23/40

Zuo et al. [36]

Japan

The ethical committee of Wakayama Medical University

Kuma Hospital

28/42

Nakayama et al. [53]

Japan

Department of General Surgery, Yokohama City University Hospital

Kanagawa Cancer Center

26/40

Lupi et al. [67]

Italy

Departments of Surgery, University of Pisa

Department of Pathology, University of Pisa

219/500

Goutas et al. [68]

Greek

Histopathology Department, Evgenidion Hospital, University of Athens

Not Available

15/55

Elisei et al. [11]

Italy

Departments of Endocrinology and Metabolism,University Hospital of Pisa

University Hospital of Pisa

38/102

Guan et al. [56]

China

Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine

People’s Hospital in Shenyang

19/38

Frasca et al. [61]

Italy

Sezione di Endocrinologia, Dipartimento Clinico-Sperimentale di Medicina e Farmacologia, Azienda Ospedaliera Universitaria Policlinico, University of Messina

Island of Sicily

125/323

Ito et al. [18]

Japan

Kuma Hospital

Kuma Hospital

242/631

Sheu et al. [37]

Germany

The Institute of Pathology and Neuropathology, University Hospital of Essen, University of Duisburg-Essen

University Hospital of Essen

92/221

Moon et al. [51]

Korea

Severance Hospital

Severance Hospital

42/84

Oler et al. [57]

Brazil

Genetic Basis of Thyroid Tumor Laboratory, Division of Genetics, Federal University of Sao Paulo

Hospital Sao Paulo

48/73

Xing et al. [60]

USA

Division of Endocrinology and Metabolism, Departments of Medicine, Pathology, Surgery, and Otolaryngology-Head and Neck Surgery, the Johns Hopkins University School of Medicine

Johns Hopkins Hospital

61/134

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Eur Arch Otorhinolaryngol Table 1 continued First author

Country

The institutions where the studies were conducted

Source of PTC

Positive/ PTC

Gu et al. [63]

China

Department of Endocrine and Metabolic Diseases, Rui-jin Hospital

Shanghai and Zhejiang

42/123

Guan et al. [70]

China

Division of Endocrinology and Metabolism, Johns Hopkins University School of Medicine

From Shenyang, Shanghai, and Qingdao

639/ 1032

O’Neill et al. [21]

Australia

Endocrine Surgical Unit, University of Sydney

Local human research ethics committee

60/101

Zerilli et al. [25]

Italy

Department of Genetic, University of Palermo, Palermo

Not Available

13/27

Basolo et al. [7]

Italy

Departments of Surgery, University of Pisa, Pisa

Department of Surgical Pathology, University of Pisa

486/ 1060

Jung et al. [47]

Korea

The Institutional Review Board of Seoul, St Mary’s Hospital, the Catholic University of Korea

Seoul St Mary’s Hospital

162/210

Hwang et al. [41]

Korea

Department of Radiology and Center for Imaging Science, Samsung Medical Center

Not Available

106/135

Sykorova et al. [58]

Czech

The Department of Otorhinolaryngology and Head and Neck Surgery of the Faculty Hospital Motol; Department of Surgery of the 2nd Faculty of Medicine and collected at the Department of Pathologu and Molecular Medicine, Faculty Hospital Motol (M*)

The Department of Otorhinolaryngology and Head and Neck Surgery of the Faculty Hospital Motol; Department of Surgery of the 2nd Faculty of Medicine and collected at the Department of Pathologu and Molecular Medicine, Faculty Hospital Motol

81/242

Smith et al. [49]

Australia

Department of Pathology, Griffith Medical School, Gold Coast, Queensland

Different hospitals in Australia

34/76

Howell et al. [15]

USA

Department of Surgery, University of Pittsburgh, Pittsburgh

Department of Surgery, University of Pittsburgh

86/219

Pelttari [16]

Finland

Division of Endocrinology, Department of Medicine, Helsinki University Central Hospital

Helsinki University Central Hospital

34/51

Bommarito et al. [19]

Italy

The IRB of the University of Palermo

Sicilian Registry of Thyroid Tumors

28/56

Patel et al. [20]

Ukraine

Department of Pediatrics, Uniformed Services University of the Health Sciences

The Center for Endocrine Surgery, Kiev

47/104

Stanojevic et al. [38]

Serbia

The Institute of Oncology and Radiology of Serbia, Belgrade

The Institute of Oncology and Radiology of Serbia

84/266

Kim et al. [44]

Korea

Departments of Internal Medicine, Konkuk University School of Medicine

Konkuk Medical Center

154/169

Joo et al. [66]

Korea

Chungnam National University Hospital, Daejeon, Korea

Not Available

79/148

Guerra et al. [12]

Italy

The Ospedale S. Paolo and Fondazione IRCCS Ca’Granda

Fondazione IRCCS Ca’Granda

62/168

Moon et al. [17]

Korea

Department of Radiology, Konkuk University School of Medicine

Not available

141/164

Chakraborty et al. [5]

India

Radiation Medicine Centre, Tata Memorial Hospital

Tissue Repository of Tata Memorial Hospital

46/86

Ahn et al. [22]

Korea

Department of Otorhinolaryngology, Head and Neck Surgery, School of Medicine, Kyungpook National University Hospital

Not Available

85/107

Lee [24]

Korea

Samsung Medical Center

Samsung Medical Center

403/605

Kurtulmus et al. [26]

Turkey

Department of Endocrinology, Acibadem Maslak Hospital

The thyroid disease clinic of the authors

43/109

Kim et al. [8]

Korea

Seoul National University Hospital

Seoul National University Hospital

381/547

Zheng et al. [9]

China

Tianjin Medical University Cancer Institute and Hospital

Tianjin Medical University Cancer Institute and Hospital

263/512

Lee et al. [28]

Korea

Thyroid Nodule Clinic of the Samsung Medical Center

Samsung Medical Center

342/429

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Eur Arch Otorhinolaryngol Table 1 continued First author

Country

The institutions where the studies were conducted

Source of PTC

Positive/ PTC

Jeong et al. [30]

Korea

Department of Pathology, Soonchunhyang University College of Medicine

Korea cell line bank

178/200

Lee et al. [32]

Korea

The Center for Endocrine Surgery, Chungnam National University Hospital, Daejeon

Chungnam National University Hospital

123/166

Koperek et al. [33]

Austria

Department of Clinical Pathology of the Medical University of Vienna

Medical University of Vienna

76/144

Ulisse et al. [34]

Italy

The Department of Surgical Sciences, ‘Sapienza’ University of Rome; The Department of Medical and Surgical Sciences, University of Padova (M*)

‘Sapienza’ University of Rome

44/91

Nam et al. [10]

Korea

The Institutional Review Board of the Seoul St. Mary’s Hospital, Catholic University of Korea

Seoul St. Mary’s Hospital

335/424

Lee et al. [35]

USA

The Johns Hopkins Hospital

The Johns Hopkins Hospital

44/63

Park et al. [39]

Korea

Departments of Surgery, College of Medicine, The Catholic University of Korea

Seoul St. Mary’s Hospital

152/181

Finkelstein et al. [40]

USA

Departments of Pathology, Hartford Hospital, Hartford

Not Available

34/56

Wang et al. [42]

China

The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou

First Affiliated Hospital, Zhejiang University School of Medicine

115/208

Zheng et al. [43]

China

Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital

Tianjin Medical University Cancer Institute and Hospital.

36/86

Kang et al. [54]

Korea

Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine

Not Available

226/299

Yim et al. [55]

Korea

Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine

Asan Medical Center

17/35

Elisei et al. [11]

Italy

Departments of Endocrinology and Metabolism, University of Pisa

Department of Endocrinology of Pisa University

106/319

Pyo et al. [13]

Korea

Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul

Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine

110/122

Jeong et al. [23]

Korea

Department of Pathology, Soonchunhyang University College of Medicine

Korea cell line bank

189/211

Virk et al. [27]

USA

Department of Pathology, Yale School of Medicine

Yale New Haven Hospital

90/129

Zagzag et al. [48]

USA

Department of Surgery, Division of Endocrine Surgery, New York University School of Medicine, New York

New York University Langone Medical Center

25/37

Ito et al. [50]

Japan

Department of Surgery, Kuma Hospital

Lived in Japan

281/766

Kang et al. [52]

Korea

Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine

Samsung Medical Center

118/159

Kleiman et al. [59]

USA

New York Presbyterian Hospital – Weill Cornell Medical College, Department of Surgery, Division of Endocrine and Minimally Invasive Surgery, New York

Not Available

24/47

Kang et al. [64]

Korea

Department of Laboratory Medicine, Chosun University Medical School

Gangnam Severance Hospital

77/100

Fernandez et al. [65]

Italy

Sant’Orsola–Malpighi Hospital of Bologna

University Hospital of Bologna

173/297

M* the study is multi-institutional study

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Eur Arch Otorhinolaryngol Table 2 Meta-analyses of association between pathological features and BRAFV600E mutation OR (95 % CI)

P*

P**

Model selection

[45 versus B45 (30 studies)

1.00 (0.86, 1.17)

0.033

0.052

Random effects model

Asian (14 studies)

1.03 (0.80, 1.32)

Caucasian (11 studies)

0.88 (0.73, 1.06)

Advance TNM stage (44 studies)

1.90 (1.62, 2.22)

0.000

0.070

Random effects model

Asian (24 studies)

1.60 (1.31, 1.95)

Caucasian (15 studies)

2.29 (1.80, 2.91)

Disease recurrence (9 studies)

2.50 (1.73, 3.59)

0.160

0.491

Fixed effects model

Distant metastasis (13 studies)

1.09 (0.55, 2.15)

0.033

0.073

Random effects model

Asian (7 studies)

1.84 (1.12, 3.01)

Extra-thyroidal extension (37 studies)

2.09 (1.69, 2.58)

0.000

0.670

Random effects model

Asian (19 studies)

1.76 (1.36, 2.29)

Caucasian (11 studies)

2.66 (2.06, 3.42)

Lymph node metastasis (49 studies)

1.68 (1.41, 2.01)

Asian (26 studies)

1.55 (1.25, 1.93)

Caucasian (16 studies)

1.73 (1.23, 2.44)

Multifocality (36 studies)

1.22 (1.06, 1.40)

Asian (15 studies)

1.21 (0.99, 1.48)

Caucasian (15 studies)

1.24 (0.97, 1.59)

Discussion 0.000

0.011

0.666

0.228

Random effects model

Random effects model

P* value for heterogeneity P** value for Egger’s test

was selected for extra-thyroidal extension, LNM, advanced TNM stage, multifocality, distant metastasis, and age (for extra-thyroidal extension, P of heterogeneity was 0.000; for LNM, P of heterogeneity was 0.000; for advanced TNM stage, P of heterogeneity was 0.000; for multifocality, P of heterogeneity was 0.011; for distant metastasis, P of heterogeneity was 0.033; and for age, P of heterogeneity was 0.033). Fixed effects model was selected for disease recurrence (for disease recurrence, P of heterogeneity was 0.160). Overall, there were statistical associations between the BRAFV600E mutation and extra-thyroidal

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extension (OR = 2.09, 95 % CI = 1.69–2.58), advanced TNM stage (OR = 1.90, 95 % CI = 1.62-2.22), lymph node metastasis (LNM) (OR = 1.68, 95 % CI = 1.41–2.01), multifocality (OR = 1.22,95 % CI = 1.06–1.40), and recurrence (OR = 2.50, 95 % CI = 1.73–3.59), but the associations were not found between the BRAFV600E mutation and age (OR = 1.00, 95 % CI = 0.86–1.17), distant metastasis (OR = 1.09, 95 % CI = 0.55–2.15). Sensitive analyses were conducted to determine the influence of single study on the overall meta-analysis, and the omission of any study made no difference, indicating that the results were statistically robust. Funnel plots and Begg’s test were performed to access the publication bias. The all Begg’s funnel plots did not show obvious asymmetry (Begg’s funnel plots not shown), and the results of Egger’s test were confirmed for the association between BRAFV600E mutation and pathological features (P of Egger’s test is 0.670 for extra-thyroidal extension; 0.228 for multifocality; 0.666 for lymph node metastasis; 0.070 for advanced TNM stage; 0.491 for disease recurrence; 0.073 for distant metastasis; 0.052 for age). The results of Begg’s funnel plot and Egger’s test did not show the publication bias.

Sixty-nine studies including 14,170 PTC cases from 2004 to October 2013 were used to explore the association between BRAFV600E mutation and pathological features in PTC. This meta-analysis suggested that extra-thyroidal extension, multifocality, LNM, disease recurrence, and advanced TNM were associated with BRAFV600E mutation in PTC. Kim et al. [75] once made a similar meta-analysis; his studies were from 2003 to 2010, but there were only three studies in 2010. He found that extra-thyroidal invasion, LNM, advanced TNM stage, and disease recurrence/persistent were associated with BRAFV600E mutation. Compared with the conclusion of Kim, our study was based on papers from 2004 to October 2013; among the 69 studies, 45 studies were from 2010 to 2013. This study not only compared the associations of BRAFV600E mutation and extra-thyroidal extension, LNM, advanced TNM stage, disease recurrence/persistent, but also evaluated the associations of BRAFV600E mutation and multifocality, distant metastasis. The results about the associations of BRAFV600E mutation and extra-thyroidal extension, LNM, advance TNM stage, disease recurrence were consistent. The incidence of BRAFV600E mutation ranged from around 27.3 to 90.2 %, and the average prevalence rate of BRAFV600E mutation was 56.3 % in this sdudy. Some pathological features are the risk factors of PTC. Recently,

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Fig. 2 Forest plot for the association between BRAFV600E mutation and extra-thyroidal extension (a), age (b), disease recurrence (c), distant metastasis (d), lymph node metastasis (e), multifocality (f), advanced TNM stage (g). ORs with corresponding 95 % CIs of

individual studies for association BRAFV600E mutation associated with extra-thyroidal extension are shown in the figure. The forest plot displays the effect size and 95 % CIs for each study and overall

some scientists have found the correlations of BRAFV600E mutation with nodal metastasis, extra-thyroidal invasion, higher risk of recurrent and advanced TNM stage. The studies of Howell GM and Lee JI agreed that there were associations between advanced TNM stage and BRAFV600E mutation [15, 24]. The classic PTC (CPTC) and the follicular variant of PTC (FVPTC) are the most frequently diagnosed variants. CPTC and FVPTC present distinct cytoarchitectural features. Eloy C separately compared the risk factors of BRAFV600E mutation for CPTV and FVPTC [76]; the results were consistent between the two groups. BRAFV600E mutation status can identify the risk of central

compartment lymph node metastasis (CLNM). BRAFV600E mutation could predict the CLNM in PTC and could guide the extent of initial surgery. Besides above-mentioned pathological features, a few researchers evaluated the associations between BRAFV600E mutation and other pathological features; they found no association between BRAFV600E mutation and lymphatic invasion [8, 35]. Elisei R studied 102 PTC patients with a median follow-up of 15 years, which demonstrated a significant correlation between the BRAFV600E mutations and a worse outcome of patients with PTC [11]. Ito et al. [18] reported that there existed differences between Japan and some Western

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Fig. 2 continued

countries on BRAFV600E mutation. For Koreans, the prevalence of the BRAFV600E mutations in PTC is high, and iodine-rich diet might be one possible reason [9]. From Fig. 2 we found that the association between the

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BRAFV600E mutations and distant metastasis is stable and credible, the BRAFV600E mutations might provide diagnostic information of distant metastasis for papillary thyroid carcinoma.

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The average prevalence rate of the disease recurrence is 12.89 % for PTC patients, 15.63 % for group of BRAFV600E mutation, and 9.38 % for group of BRAFV600E wild. The meta-analysis illustrated that there was an association between BRAFV600E mutation and disease recurrence (OR = 2.50, 95 % CI = 1.73-3.59), suggesting that the PTC in patients with BRAFV600E mutation was more dangerous in disease recurrence than in the PTC patients without BRAFV600E mutation. Some studies made survival analysis to explore the differences in recurrencefree survival in PTC patients with BRAFV600E mutation versus BRAFV600E wild type. Tae YK made a Kaplan– Meier survival analysis and founded that the cumulative survival was different between BRAFV600E positive and BRAFV600E negative (P = 0.037) [45], the cumulative survival of BRAFV600E negative patients was higher than that of BRAFV600E positive. Xing et al. got the same conclusion [60], while the conclusion of Lee JI [24] was different from Tae YK. The Kaplan–Meier survival analysis of Ji et al. proved that there was no difference in tumor persistence/recurrence-free between PTC patients with and without the BRAFV600E mutation (P = 0.095), and the tumor persistence/recurrence-free survival at 24 months of PTC patients with BRAFV600E mutation was not different from those without BRAFV600E mutation (P = 0.259). Ulisse S also made a Kaplan–Meier survival analysis, and the PTC patients were followed up from 6 to 64 months, he failed to identify difference of cumulative survival between BRAFV600E positive and BRAFV600E negative (P = 0.9375) [34]. Stanojevic et al. [38] got the same conclusion. Thus, more studies were needed to get the correct conclusion. Some researches have proved the association between BRAFV600E mutation and prognosis. Costa AM illustrated BRAF ‘alone’ did not represent a marker for prognosis [77]. Elisei et al. [11] drew the opposite conclusion and proved the BRAF mutation was demonstrated to be a prognostic factor independent from other pathological features. Whether BRAF can be used as independent factor for prognosis is controversial. Subgroup analyses of patient’s country were performed to explore possible causes of heterogeneity. When the number of studies was more than five and the number of PTC patients was more than 1,000, we would explore the influence of geographical regions, which could make the conclusion more credible. There was no association between BRAFV600E mutation and distant metastasis, but in subgroup analyses, the association was found in Asian. There was association between multifocality and BRAFV600E mutation in pooled meta-analysis, but the association was not found in Asian and Caucasian. The above two different conclusions might be caused by the ethnicity or geographical regions. The other conclusions of subgroup analysis were consistent with the pooled meta-analysis.

Some limitations should be considered when interpreting the conclusion. Firstly, the number of cases in some studies was small, so the related studies could not provide strong evidence about the results [14, 25, 31, 55, 74]. Secondly, subgroup analyses were restricted because of inadequate information. Thirdly, the selection of BRAFV600E negative cases and BRAFV600E positive cases was not random, which could cause selection bias. In conclusion, our meta-analysis suggested that extrathyroidal extension, lymph node metastasis, disease recurrence, and advanced TNM stage were associated with BRAFV600E mutation. Large well-designed studies should be necessary to explore the association between BRAFV600E mutation and other pathological features. Acknowledgments This study was supported by Jilin Provincial Science and Technology Development Project (Grant No. 201205008), Science and Technology Project of the Department of Health of Jilin Province (Grant No. 2013Z034) and Postdoctoral Scientific Research Project of Jilin Province (Grant No. RB201343).

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