MCO Molecular and Clinical Oncology 2049-9450 2049-9469 D.A. Spandidos 10.3892/mco.2015.540 MCO-0-0-540 Articles Comparison of the clinicopathological behavior of the follicular variant of papillary thyroid carcinoma and classical papillary thyroid carcinoma: A systematic review and meta-analysis YANGJING 1 GONGYANPING 1 YANSHUPING 1 SHIQINGQUAN 2 ZHUJINGQIANG 1 LIZHIHUI 1 CHENQIANG 1 GONGRIXIANG 1 Department of Thyroid and Breast Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China Correspondence to: Professor Rixiang Gong, Department of Thyroid and Breast Surgery, West China Hospital, Sichuan University, 37 Guo Xue Xiang, Chengdu, Sichuan 610041, P.R. China, E-mail: gongrixiang@scu.edu.cn 07 2015 06 04 2015 3 4 753 764 16102014 25022015 Copyright © 2015, Spandidos Publications 2015

The follicular variant of papillary thyroid carcinoma (FV-PTC) is the second most common type of papillary thyroid carcinoma (PTC), and it has been increasingly diagnosed in recent years. However, whether FV-PTC behaves differently from classical PTC (C-PTC) remains controversial. To address this controversy, a meta-analysis was performed to determine the potential differences between FV-PTC and C-PTC in their clinicopathological behavior. The relevant published studies between January 1, 2003 and August 31, 2014 were reviewed according to the defined selection criteria using the PubMed database. Review Manager was used to calculate the pooled odds ratio (OR) or the mean difference (MD) with a 95% confidence interval (CI), using a random- or fixed-effect model for all analyses. In total, 112 studies were identified and examined; finally, only 36 studies met the inclusion criteria. In the 36 studies, compared to the clinicopathological behavior of patients with C-PTC, patients with FV-PTC had the following parameters: Similar mean age and similar prevalence of gender, tumor size ≥10 mm, multifocality, capsular invasion, vascular invasion, lymphocytic and/or Hashimoto's thyroiditis, and clinical stage; a larger mean tumor size and higher prevalence of age ≥45 years; and lower prevalence of extrathyroidal extensions, lymph node metastases, BRAF mutation and recurrence. The meta-analysis suggested that patients with FV-PTC have a more favorable clinicopathological behavior and improved prognosis compared to patients with C-PTC. Thus, patients with FV-PTC and C-PTC may be managed differently, and the two types of PTC should be clearly distinguished in future retrospective or prospective studies.

 thyroid carcinoma papillary follicular classical meta-analysis Introduction

Well-differentiated thyroid cancer is the most common endocrine tumor, and its prevalence is increasing worldwide (1). The majority of thyroid cancer cases (~85%) are papillary thyroid carcinoma (PTC) (2). A number of PTC variants have been described, including classical, follicular, oncocytic, solid, tall cell, columnar cell, diffuse sclerosing and cribriform (3,4). Among these variants, the conventional or classical type is the most common and accounts for ≤54.2% of all PTC cases in certain reported series (5–8). The follicular variant is the second most common subtype and constitutes 4.9–41.2% PTC cases in different series (7–12). Since the follicular variant of PTC (FV-PTC) was first described by Crile and Hazard in 1953 (13), FV-PTC has been increasingly diagnosed and accounts for 41–53% of PTC cases (7,14).

As FV-PTC exhibits a mixed histopathological picture of PTC and follicular thyroid carcinoma (FTC), certain investigators have hypothesized that FV-PTC has specific characteristics from the two types. Numerous studies have since investigated the clinical behavior of FV-PTC and the classical type of PTC (C-PTC) and compared the two; however, certain results were contradictory. In different studies, the incidence of aggressive clinical features was identified as higher, similar or lower in FV-PTC compared to C-PTC (5,7,8,10,12,15–20).

Meta-analysis is a powerful tool for summarizing the results of different studies by producing a single estimate of the major effect with enhanced precision. A major advantage of a meta-analysis is the increase in sample size, which may reduce the probability that a random error will produce false-positive or false-negative associations.

A meta-analysis was performed to quantify and compare the clinical parameters of C-PTC and FV-PTC and provide some guidance on the management and prognosis of FV-PTC. The following clinicopathological parameters were evaluated: Age, gender, tumor size, multifocality, capsular invasion, vascular invasion, extrathyroidal extension, lymph node metastasis, lymphocytic and/or Hashimoto's thyroiditis, clinical stage, BRAF mutation and recurrence.

 Materials and methods <sec> <title>Selection criteria

Studies that examined the associations of FV-PTC and C-PTC with clinicopathological parameters were searched for. The following criteria were considered when selecting the studies: i) Studies published in English between January 1, 2003 and August 31, 2014. ii) The criteria of C-PTC include classical, conventional and pure PTC. iii) Clinicopathological parameters with detailed data on C-PTC and FV-PTC tissue were included from the same studies that assessed different types of carcinoma, such as primary, follicular, anaplastic and medullary carcinomas. iv) Only studies analyzing at least two of the above categories of clinicopathological data and containing ≥5 cases reported FV-PTC and C-PTC. v) When multiple studies were published by the same investigators or groups, the newest or most informative single study was selected. The following studies were excluded: i) Review studies without original data; ii) absent or inappropriately reported clinicopathological data; iii) single or pure case reports; iv) animal research; and v) familial research studies.

 Collection of published studies

A literature search was carried out using the PubMed database (http://www.ncbi.nlm.nih.gov/pubmed). The search term combination was ‘follicular variant of papillary thyroid carcinoma’ OR ‘FV-PTC’ OR ‘FVPTC’ OR ‘FPTC’ OR ‘F-PTC.’ Relevant studies were selected on the basis of the summary analysis. Any duplication of data was carefully avoided by examining the names of all the authors and different medical centers involved in each publication. Overlapping studies or data and studies that were unrelated to the meta-analysis were excluded. Two investigators (J. Yang and Y.P. Gong) used the EndNote reference tool to independently screen and select studies. All the procedures conformed to the guidelines for the meta-analysis of observational studies in epidemiology (21).

 Data analyses and statistical methods

Review Manager (version 5.1; http://tech.cochrane.org/revman) was used to perform all the statistical analyses, including the calculation of the summary odds ratio (OR) or the mean difference (MD) with a 95% confidence interval (CI), using a random- or fixed-effect model for all the analyses. The choice of each individual statistical method depended on whether the measured event was dichotomous or continuous, whereas the choice of a random- or fixed-effect model depended on the tests for heterogeneity. The heterogeneity of the studies was assessed using the χ2 test of heterogeneity and the I2 measure of inconsistency. When the heterogeneity in the χ2 test showed a P-value of <0.10 or when the I2 measure was >50%, the random-effect model was chosen, otherwise the fixed-effect model was used. The 95% CI was constructed around the effect size to establish its significance.

For the OR of dichotomous events, if the 95% CI of an OR included 1, the two groups were not considered statistically different, otherwise they were considered statistically different. For the MD of continuous events, if the 95% CI crossed the null point (zero), then the possibility that the difference should be attributed to chance could not be ruled out. When the null point fell outside the 95% CI of an MD, the observed difference was considered statistically significant. The potential publication bias was assessed using Begg's funnel plot and Egger's test by Stata 12.0 software (Stata Corporation, College Station, TX, USA). P<0.05 was considered to indicate a statistically significant difference.

 Results <sec> <title>Clinicopathological parameters

Fig. 1 summarizes the study selection process. A total of 495 abstracts and titles were obtained using a PubMed search, of which 81 were published before January 1, 2003 and 1 duplicate study was excluded. Of the remaining 413, 112 full-text studies were deemed relevant and were examined in detail. Eventually, following the application of all the inclusion and exclusion criteria, 36 studies (7,8,10,12,14,16,17,19,20,22–48) fulfilled the eligibility criteria. The main features of the eligible studies are summarized in Table I. In each category of clinicopathological parameters, some heterogeneity was present. In terms of tumor size, multifocality, capsular invasion, vascular invasion, extrathyroidal extension and lymph node metastasis, their heterogeneity was assessed using χ2 tests and the P-value was <0.10 (or I2 measures were >50%). The random-effect models were selected, but for the remaining parameters, fixed-effect models were used. The combined results of the meta-analysis and the heterogeneity test are shown in Table II.

 Gender

In total, 33 studies were comparable in terms of gender. The prevalence of females among patients with FV-PTC and C-PTC was 80.1 (1,136/1,418) and 81.9% (5,627/6,872), respectively, and the difference was not statistically significant (OR, 1.09; 95% CI, 0.93–1.29; P=0.29; Fig. 2A). No statistical heterogeneity was detected among the studies (χ2=29.61, P=0.59, I2=0%).

 Age

Nineteen studies included mean age in the patient clinical data. The mean age of patients with FV-PTC ranged from 27 to 50.9 years, whereas those of the patients with C-PTC ranged from 26.3 to 52.88 years, and the difference was not significant (MD, −0.61; 95% CI, −1.75–0.53; P=0.29; Fig. 2B). No statistical heterogeneity was identified among the studies (χ2=31.36, P=0.03, I2=43%). In addition, 11 studies presented the prevalence of patients aged ≥45 years, which overall was 56.4 (219/388) and 51.5% (371/720) in patients with FV-PTC and C-PTC, respectively, and the difference was statistically significant (OR, 1.45; 95% CI, 1.11–1.90; P=0.007; Fig. 2C). There was no significant statistical heterogeneity among the studies (χ2=8.90, P=0.54, I2=0%).

 Tumor size

Seventeen studies presented clinical data that included mean tumor size. The mean tumor size of patients with FV-PTC ranged from 14.4 to 34.7 mm, whereas that of patients with C-PTC ranged from 9.7 to 35.0 mm; this difference was statistically significant (MD, 2.88; 95% CI, 0.26–5.51; P=0.03; Fig. 2D). Significant statistical heterogeneity was present among the studies (χ2=50.73, P<0.0001, I2=68%). Ten studies presented the prevalence of the tumor size of patients with FV-PTC and C-PTC being ≥10 mm, which overall was 63.4 (251/396) and 45.8% (496/1,084), respectively, and the difference was not significant (OR, 1.25; 95% CI, 0.77–2.03; P=0.36; Fig. 2E). There was significant statistical heterogeneity among the studies (χ2=21.73, P=0.010, I2=59%).

 Multifocality

In 17 studies that analyzed multifocality, the overall percentage of patients with multifocality in FV-PTC and C-PTC was 31.6 (257/813) and 30.7% (1,411/4,593), respectively, and the difference was not statistically significant (OR, 0.88; 95% CI, 0.64–1.22; P=0.44; Fig. 2F). No statistical heterogeneity was detected among the studies (χ2=40.85, P=0.0006, I2=61%).

 Capsular invasion

In 6 studies that assessed the capsular invasion of the tumor, the percentages of patients with capsular invasion in FV-PTC and C-PTC were 28.1 (115/409) and 30.2% (281/932), respectively, and the difference was not statistically significant difference (OR, 0.82; 95% CI, 0.48–1.39; P=0.46; Fig. 2G). There was no statistical heterogeneity among the studies (χ2=14.60, P=0.01, I2=66%).

 Vascular invasion

In 9 studies, the percentages of cases with vascular invasion in FV-PTC and C-PTC were reported; these were 19.8 (85/430) and 12.2% (86/704), respectively, and the difference was not significant (OR, 1.38; 95% CI, 0.56–3.42; P=0.49; Fig. 2H). Significant statistical heterogeneity was detected among the studies (χ2=31.84, P<0.0001, I2=75%).

 Extrathyroidal extension

Eighteen studies presented the prevalence of cases with extrathyroidal extension in FV-PTC and C-PTC, which overall was 15.1 (144/951) and 46.1% (2,157/4,682), respectively, and the difference was statistically significant (OR, 0.40; 95% CI, 0.25–0.64; P=0.0001; Fig. 2I). Significant statistical heterogeneity was detected among the studies (χ2=56.75, P<0.00001, I2=70%).

 Lymph node metastasis

Twenty-three studies reported the prevalence of lymph node metastasis in patients with FV-PTC and C-PTC, which overall was 22.8 (257/1,125) and 46.4% (2,965/6,386), respectively, and this difference was statistically significant (OR, 0.35; 95% CI, 0.25–0.49; P<0.00001; Fig. 2J). Significant statistical heterogeneity was detected among the studies (χ2=65.94, P<0.00001, I2=67%).

 Lymphocytic and/or Hashimoto's thyroiditis

Nine studies presented the prevalence of lymphocytic and/or Hashimoto's thyroiditis in patients with FV-PTC and C-PTC. The overall prevalence was 19.8 (97/490) and 30.0% (1,279/4,261), respectively, and the difference was not statistically significant (OR, 0.79; 95% CI, 0.61–1.02; P=0.07; Fig. 2K). There was no significant statistical heterogeneity among the studies (χ2=13.94, P=0.08, I2=43%).

 Clinical stage

Twelve studies included clinical stage in their analyses. The stage of the tumor was I or II in 422/527 (80.1%) patients with FV-PTC and in 913/1,195 (76.4%) patients with C-PTC; the difference was not statistically significant (OR, 1.17; 95% CI, 0.0–1.52; P=0.25; Fig. 2L). There was no significant statistical heterogeneity among the studies (χ2=10.29, P=0.50, I2=0%).

 BRAF mutation

Thirteen studies presented the prevalence of BRAF mutation in patients with FV-PTC and C-PTC, which overall was 23.8 (116/487) and 71.7% (2,734/3,814), respectively, and the difference was statistically significant (OR, 0.19; 95% CI, 0.15–0.24, P<0.00001; Fig. 2M). There was no significant statistical heterogeneity among the studies (χ2=8.15, P=0.77, I2=0%).

 Recurrence

Eight studies evaluated the recurrence of tumor while following up patients with FV-PTC and C-PTC for varying periods. The overall percentage of recurrence was 9.4 (31/329) and 15.8% (129/814), respectively, and the difference was statistically significant (OR, 0.52; 95% CI, 0.34–0.80; P=0.003; Fig. 2N). There was no significant statistical heterogeneity among the studies (χ2=5.46, P=0.60, I2=0%).

 Publication bias

Funnel plots and Begg's test were performed to access the publication bias. All the Begg's funnel plots did not show evident asymmetry (Begg's funnel plots not shown), and the results of Egger's test were confirmed for the comparison of clinical parameters of FV-PTC and C-PTC (all P>0.05 for Egger's test; Table II). The results of Begg's funnel plot and Egger's test did not show any publication bias.

 Discussion

Following a systematic review of the recent literature, it was observed that FV-PTC has been increasingly diagnosed in recent years, and an increasing amount of research is being performed concerning FV-PTC. The majority of studies comparing the clinicopathological behavior of FV-PTC and C-PTC have limitations, such as inclusion of relatively few cases, incomprehensive categories of clinical parameters and single-institution bias. Thus, their conclusions were mutually conflicting. Therefore, it is necessary to acquire a more comprehensive view of FV-PTC from population-based studies, and a meta-analysis can achieve this. To the best of our knowledge, this is the first study of a meta-analysis comparing the clinicopathological behavior of FV-PTV and C-PTC.

The findings reveal that the following clinicopathological parameters are significantly different between patients with FV-PTC and those with C-PTC: Patient age (≥45 years), mean tumor size, extrathyroidal extension, lymph node metastasis, BRAF mutation and recurrence. By contrast, no significant differences were identified in gender, mean age, tumor size (≥10 mm), multifocality, capsular invasion, vascular invasion, lymphocytic and/or Hashimoto's thyroiditis, and clinical stage.

Patients with FV-PTC and C-PTC have similarly high prevalence of females, and this finding is consistent with nearly all the relevant studies. When analyzing age and tumor size, the meta-analysis was performed in two ways. The mean age of patients with FV-PTC was similar to that of patients with C-PTC, but the former were more likely to be ≥45 years old. The number of patients with FV-PTC and C-PTC in the analysis of mean age was 656 and 972 (total 1,628) respectively, which is a larger population of patients in the analysis of age ≥45 years being 219 and 371 (total 590). Logically, the mean age analysis may be more reliable. The findings were not consistent in the mean tumor size and the prevalence of tumor size ≥10 mm. The mean tumor size of patients with FV-PTC was larger than that of the patients with C-PTC, which is in agreement with the results of studies by Chang et al (10), Ozdemir et al (17), Burningham et al (19), Jain et al (49) and Kim et al (50). Ozdemir et al (17) and Kim et al (50) also reported that compared to C-PTC, FV-PTC has more benign sonographic features, a lower incidence of a sonographically malignant grade and a lower diagnostic rate of PTC on fine-needle aspiration biopsy (FNAB). Thus, the lower rate of suspicious findings in FV-PTC lesions may have caused evaluation of larger FV-PTC lesions by FNAB, resulting in the detection of these lesions at a later stage. In addition, FV-PTC lesions may have become larger when patients with FV-PTC underwent surgery. However, the present study identified that the prevalence of tumor size ≥10 mm was similar between the two types. By contrast, Tielens et al (5) reported that tumor size of FV-PTC tends to be smaller than that of C-PTC. The present study showed similar prevalence of multifocality, capsular invasion, vascular invasion, lymphocytic and/or Hashimoto's thyroiditis, and clinical stage between patients with FV-PTC and C-PTC.

The prevalence of the above results has been controversial. Passler et al (12) suggested that there was a significantly higher prevalence of multifocality in patients with FV-PTC compared to patients with C-PTC, but the opposite was reported by Gao et al (31) and Trovisco et al (47). Certain studies reported a higher prevalence of capsular invasion and vascular invasion in the FV-PTC (10,20,51), whereas others did not (17,43,47). Although the majority of the C-PTCs do not have a tumor capsule, patients with C-PTC (28.1%) and patients with FV-PTC (30.2%) showed a similar high prevalence of capsular invasion of tumor in the present meta-analysis. As C-PTC is more inclined to show infiltrative growth, the tumor easily invades the capsule once containing the tumor capsule. When histopathologically comparing the presence of concomitant lymphocytic and/or Hashimoto's thyroiditis in patients with FV-PTC and C-PTC, Tielens et al (5) reported a higher rate in the former, whereas Yuksel et al (16) reported a higher rate in the latter.

Nearly all the relevant literature on clinical stages shows the same ratio of clinical stage I + II in patients with FV-PTC and C-PTC, thereby suggesting that clinical stages of patients with FV-PTC and C-PTC are similar. The present meta-analysis reveals that the incidence of associated extrathyroidal extension, lymph node metastases, BRAF mutation and recurrence is significantly lower in patients with FV-PTC compared to patients with C-PTC. As described in the majority of the studies, the frequencies of extrathyroidal extension and lymph node metastases are lower in patients with FV-PTC compared to patients with C-PTC; however, a few studies reported opposing findings (20,24). Consistently, all the relevant studies on the BRAF gene shows the lower ratio of BRAF mutation in patients with FV-PTC compared to patients with C-PTC. The majority of meta-analysis studies showed that the BRAF mutation was associated with the majority of vital clinicopathological characteristics in PTC, and the BRAF mutation may be used as an important prognostic marker of patients with PTC (52–56). However, when analyzing FV-PTC and C-PTC respectively, Gao et al (31) and Oler et al (42) identified that the BRAF mutation was associated with the clinicopathological characteristics in patients with C-PTC, but not in patients with FV-PTC.

After the similar follow-up periods, the rate of recurrence in patients with FV-PTC was significantly lower than that in the patients with C-PTC, which may be associated with the above finding that patients with FV-PTC are at a lower risk of extrathyroidal extension, lymph node metastases or BRAF mutation. Aggressive clinicopathological behavior of patients with PTC is associated with old age, and include the following: Presence of extrathyroidal extension, lymph node metastases, advanced clinical stages and BRAF mutation. Therefore, poor prognosis in patients with PTC is associated with certain aggressive clinicopathological characteristics. Therefore, patients with FV-PTC have an improved prognosis compared to patients with C-PTC. However, it may be affected by treatment factors such as type of surgery, I-131 ablation and use of external radiotherapy.

Patients with FV-PTC have a lower prevalence of extrathyroidal extension, lymph node metastases, BRAF mutation and recurrence compared to patients with C-PTC. The mean tumor size is larger and the incidence of patients aged ≥45 years are higher in the former. Thus, as reported in a previous study (8) and in the present meta-analysis, patients with FV-PTC exhibit a more favorable clinicopathological behavior and improved prognosis compared to patients with C-PTC. Thus, the lower incidence of extrathyroidal extension, lymph node metastases, BRAF mutation and recurrence would appear to be distinct clinicopathological behavior of FV-PTC. Patients with FV-PTC and C-PTC are clearly two different groups. As was also reported by Yu et al (57) and Chang et al (10), the clinicopathological behavior of FV-PTC is unique and represents an intermediate entity between C-PTC and FTC. Different approaches may be used for their clinical management. More invasive treatment strategies, such as total thyroidectomy or central lymph node dissection, may be considered in patients with C-PTC presenting extrathyroidal extension, lymph node metastasis or BRAF mutation to decrease recurrence.

The present study has several limitations. One primary limitation is that reporting of FV-PTC is not a standard practice in certain hospitals, leading to a reporting bias. There may be an interpretational difference among pathologists, as FV-PTC may be confused with FTC. Additionally, stratified analyses of summary data from the reported studies could not be performed, and the present study was unable to identify the diverse sources of heterogeneity of the effect size. In addition, multiple outcome variables require cautious interpretation as the outcomes may be interrelated. For instance, the patients with extrathyroidal extension tend to have a more advanced clinical stage and a higher risk of recurrence than those with no extension. However, this limitation is unlikely to have a significant impact on the present study as the sample size in the meta-analysis is sufficiently large.

The meta-analysis suggested that, patients with FV-PTC present more favorable clinicopathological behaviors and improved prognosis than patients with C-PTC. Patients with FV-PTC and C-PTC may be managed differently, and the two types of PTC should be clearly distinguished in future retrospective or prospective studies. For instance, it may not be necessary for patients with FV-PTC to undertake the invasive strategies that are appropriate in patients with C-PTC, if the FV-PTC is diagnosed prior to or during surgery. However, more valuable studies on a large cohort of cases are required to evaluate the clinicopathological behavior in patients with FV-PTC and patients with C-PTC.

 Acknowledgements

The present study was supported by a grant from the Department of Sichuan Province, Science and Technology Support Program (no. 2013SZ0041).

 References HowladerNNooneAMKrapchoMGarshellJMillerDAltekruseSFKosaryCLYuMRuhlJTatalovichZMariottoALewisDRChenHSFeuerEJCroninKASEER Cancer Statistics Review1975–2011National Cancer InstituteBethesda, MDhttp://seer.cancer.gov/csr/1975_2011/September172014 SiposJAMazzaferriELThyroid cancer epidemiology and prognostic variablesClin Oncol (R Coll Radiol)22395404201010.1016/j.clon.2010.05.00420627675 CarcangiuMLZampiGPupiACastagnoliARosaiJPapillary carcinoma of the thyroidA clinicopathologic study of 241 cases treated at the University of Florence, ItalyCancer55805828198510.1002/1097-0142(19850215)55:4<805::AID-CNCR2820550419>3.0.CO;2-Z3967175 Albores-SaavedraJWuJThe many faces and mimics of papillary thyroid carcinomaEndocr Pathol17118200610.1385/EP:17:1:116760576 TielensETShermanSIHrubanRHLadensonPWFollicular variant of papillary thyroid carcinoma: a clinicopathologic studyCancer73424431199410.1002/1097-0142(19940115)73:2<424::AID-CNCR2820730230>3.0.CO;2-I8293410 SebastianSOGonzalezJMParicioPPPerezJSFloresDPMadronaAPRomeroPRTebarFJPapillary thyroid carcinoma: prognostic index for survival including the histological varietyArch Surg135272277200010.1001/archsurg.135.3.27210722027 ZidanJKarenDSteinMRosenblattEBasherWKutenAPure versus follicular variant of papillary thyroid carcinoma: clinical features, prognostic factors, treatment and survivalCancer9711811185200310.1002/cncr.1117512599223 LangBHLoCYChanWFLamAKWanKYClassical and follicular variant of papillary thyroid carcinoma: a comparative study on clinicopathologic features and long-term outcomeWorld J Surg30752758200610.1007/s00268-005-0356-716680590 LamAKLoCYLamKSPapillary carcinoma of thyroid: A 30-yr clinicopathological review of the histological variantsEndocr Pathol16323330200510.1385/EP:16:4:32316627919 ChangHYLinJDChouSCChaoTCHsuehCClinical presentations and outcomes of surgical treatment of follicular variant of the papillary thyroid carcinomasJpn J Clin Oncol36688693200610.1093/jjco/hyl09317000702 LinHWBhattacharyyaNClinical behavior of follicular variant of papillary thyroid carcinoma: presentation and survivalLaryngoscop120712716201010.1002/lary.20828 PasslerCPragerGScheubaCNiederleBEKasererKZettinigGNiederleBFollicular variant of papillary thyroid carcinoma: a long-term follow-upArch Surg13813621366200310.1001/archsurg.138.12.136214662540 CrileGJHazardJBRelationship of the age of the patient to the natural history and prognosis of carcinoma of the thyroidAnn Surg1383338195310.1097/00000658-195307000-0000513058300 ErtekSYilmazNCCiceroAFVurupalmazODemirozASErdoganGIncreasing diagnosis of thyroid papillary carcinoma follicular variant in south-east Anatolian region: comparison of characteristics of classical papillary and follicular variant thyroid cancersEndocr Pathol23157160201210.1007/s12022-012-9216-922711546 LiVolsiVAAsaSLThe demise of follicular carcinoma of the thyroid glandThyroid4233236199410.1089/thy.1994.4.2337920009 YukselOKurukahveciogluOEgeBEkinciOAydinAPoyrazATezelETaneriFThe relation between pure papillary and follicular variant in papillary thyroid carcinomaEndocr Regul422933200818333702 OzdemirDErsoyRCuhaciNArpaciDErsoyEPKorukluogluBGulerGCakirBClassical and follicular variant papillary thyroid carcinoma: comparison of clinical, ultrasonographical, cytological and histopathological features in 444 patientsEndocr Pathol225865201110.1007/s12022-011-9160-021556739 ChengSSerraSMercadoMEzzatSAsaSLA high-throughput proteomic approach provides distinct signatures for thyroid cancer behaviorClin Cancer Res1723852394201110.1158/1078-0432.CCR-10-283721389096 BurninghamARKrishnanJDavidsonBJRingelMDBurmanKDPapillary and follicular variant of papillary carcinoma of the thyroid: Initial presentation and response to therapyOtolaryngol Head Neck Surg132840844200510.1016/j.otohns.2005.02.00215944551 HagagPHodNKummerECohenpourMHorneTWeissMFollicular variant of papillary thyroid carcinoma: clinical-pathological characterization and long-term follow-upCancer J12275282200610.1097/00130404-200607000-0000516925971 StroupDFBerlinJAMortonSCOlkinIWilliamsonGDRennieDMoherDBeckerBJSipeTAThackerSBMeta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of observational studies in epidemiology (MOOSE) groupJAMA2832008201210.1001/jama.283.15.2008 AbrosimovASaenkoVMeirmanovSNakashimaMRogounovitchTShkurkoOLushnikovEMitsutakeNNambaHYamashitaSThe cytoplasmic expression of MUC1 in papillary thyroid carcinoma of different histological variants and its correlation with cyclin D1 overexpressionEndocr Pathol186875200710.1007/s12022-007-0012-x17916995 BrzezianskaEPastuszak-LewandoskaDWojciechowskaKMigdalska-SekMCyniak-MagierskaANawrotELewinskiAInvestigation of V600E BRAF mutation in papillary thyroid carcinoma in the Polish populationNeuro Endocrinol Lett28351359200717693984 CostaAMHerreroAFresnoMFHeymannJAlvarezJACameselle-TeijeiroJGarcia-RostanGBRAF mutation associated with other genetic events identifies a subset of aggressive papillary thyroid carcinomaClin Endocrinol (Oxf)68618634200810.1111/j.1365-2265.2007.03077.x18070147 Daglar-AdayAToptasBOzturkTSeyhanFSaygiliNEronatAPAkadam-TekerBYilmaz-AydoganHAksoyFOzturkOInvestigation of BRAF V600E mutation in papillary thyroid carcinoma and tumor-surrounding nontumoral tissuesDNA Cell Biol321318201310.1089/dna.2012.177623157614 DarrEAPatelADYuGKomorowskiZMcCormickSTiwariRSchantzSPGeliebterJReduced Cx43 gap junction plaque expression differentiates thyroid carcinomas from benign diseaseArch Otolaryngol Head Neck Surg13711611165201110.1001/archoto.2011.18622106244 DettmerMPerrenAMochHKomminothPNikiforovYENikiforovaMNComprehensive MicroRNA expression profiling identifies novel markers in follicular variant of papillary thyroid carcinomaThyroid2313831389201310.1089/thy.2012.063223427895 Di CristofaroJMarcyMVaskoVSebagFFakhryNWynford-ThomasDDe MiccoCMolecular genetic study comparing follicular variant versus classic papillary thyroid carcinomas: association of N-ras mutation in codon 61 with follicular variantHum Pathol37824830200610.1016/j.humpath.2006.01.03016784981 EloyCSantosJSoaresPSobrinho-SimoesMThe preeminence of growth pattern and invasiveness and the limited influence of BRAF and RAS mutations in the occurrence of papillary thyroid carcinoma lymph node metastasesVirchows Arch459265276201110.1007/s00428-011-1133-721796448 EspadinhaCSantosJRSobrinhoLGBugalhoMJExpression of iodine metabolism genes in human thyroid tissues: evidence for age and BRAFV600E mutation dependencyClin Endocrinol (Oxf)70629635200910.1111/j.1365-2265.2008.03376.x18710471 GaoWLWieLLChaoYGWieLSongTLPrognostic prediction of BRAF (V600E) and its relationship with sodium iodide symporter in classic variant of papillary thyroid carcinomasClin Lab58919926201223163107 HuntJLFowlerMLomagoDNiehouseLSasatomiESwalskyPFinkelsteinSTumor suppressor gene allelic loss profiles of the variants of papillary thyroid carcinomaDiagn Mol Pathol134146200410.1097/00019606-200403000-0000715163008 IgciYZErkilicSIgciMArslanAMCM3 Protein expression in follicular and classical variants of papillary thyroid carcinomaPathol Oncol Res208791201310.1007/s12253-013-9662-923821456 IgciYZErkilicSArslanASeptin 7 immunoexpression in papillary thyroid carcinoma: a preliminary studyPathol Res Pract210426431201410.1016/j.prp.2014.02.00924685401 ItoYHirokawaMUrunoTKiharaMHigashiyamaTTakamuraYMiyaAKobayashiKMatsuzukaFMiyauchiAPrevalence and biological behaviour of variants of papillary thyroid carcinoma: experience at a single institutePathology40617622200810.1080/0031302080232063018752130 LassalleSHofmanVIlieMBonnetaudCPuissegurMPBrestPLoubatierCGuevaraNBordoneOCardinaudBLebrigandKRiosGSantiniJFrancBMariBAl GhuzlanAVielhPBarbryPHofmanPCan the microRNA signature distinguish between thyroid tumors of uncertain malignant potential and other well-differentiated tumors of the thyroid gland?Endocr Relat Cancer18579594201110.1530/ERC-10-028321778212 LeeSHanBKKoEYOhYLChoeJHShinJHThe ultrasonography features of hyalinizing trabecular tumor of the thyroid are more consistent with its benign behavior than cytology or frozen section readingsThyroid21253259201110.1089/thy.2010.020221190434 LimJYHongSWLeeYSKimBWParkCSChangHSChoJYClinicopathologic implications of the BRAF (V600E) mutation in papillary thyroid cancer: a subgroup analysis of 3130 cases in a single centerThyroid2314231430201310.1089/thy.2013.003623496275 LiuZLiuDBojdaniEEl-NaggarAKVaskoVXingMIQGAP1 plays an important role in the invasiveness of thyroid cancerClin Cancer Res1660096018201010.1158/1078-0432.CCR-10-162720959410 MinHSLeeCJungKCCorrelation of immunohistochemical markers and BRAF mutation status with histological variants of papillary thyroid carcinoma in the Korean populationJ Korean Med Sci28534541201310.3346/jkms.2013.28.4.53423580256 Nechifor-BoilaABordaASassolasGHafdi-NejjariZBorson-ChazotFLifanteJ, CSturmNLaverriereMHBergerNDecaussin-PetrucciMImmunohistochemical markers in the diagnosis of papillary thyroid carcinomas: The promising role of combined immunostaining using HBME-1 and CD56Pathol Res Pract209585592201310.1016/j.prp.2013.06.01223910176 OlerGCeruttiJMHigh prevalence of BRAF mutation in a Brazilian cohort of patients with sporadic papillary thyroid carcinomas: correlation with more aggressive phenotype and decreased expression of iodide-metabolizing genesCancer115972980200910.1002/cncr.2411819152441 RiveraMTuttleRMPatelSShahaAShahJPGhosseinRAEncapsulated papillary thyroid carcinoma: a clinico-pathologic study of 106 cases with emphasis on its morphologic subtypes (histologic growth pattern)Thyroid19119127200910.1089/thy.2008.030319191744 SchultenHJSalamaSAl-MansouriZAlotibiRAl-GhamdiKAl-HamourOASayadiHAl-AradatiHAl-JohariAHuwaitEGariMAl-QahtaniMHAl-MaghrabiJBRAF mutations in thyroid tumors from an ethnically diverse groupHered Cancer Clin Pract1010201210.1186/1897-4287-10-1022925390 SheuSYGrabellusFSchwertheimSWormKBroecker-PreussMSchmidKWDifferential miRNA expression profiles in variants of papillary thyroid carcinoma and encapsulated follicular thyroid tumoursBr J Cancer102376382201010.1038/sj.bjc.660549320029416 SlosarMVohraPPrasadMFischerAQuinlanRKhanAInsulin-like growth factor mRNA binding protein 3 (IMP3) is differentially expressed in benign and malignant follicular patterned thyroid tumorsEndocr Pathol20149157200910.1007/s12022-009-9079-x19449140 TroviscoVSoaresPPretoAde CastroIVLimaJCastroPMaximoVBotelhoTMoreiraSMeirelesAMMagalhaesJAbrosimovACameselle-TeijeiroJSobrinho-SimoesMType and prevalence of BRAF mutations are closely associated with papillary thyroid carcinoma histotype and patients' age but not with tumour aggressivenessVirchows Arch446589595200510.1007/s00428-005-1236-015902486 WreesmannVBGhosseinRAHezelMBanerjeeDShahaARTuttleRMShahJPRaoPHSinghBFollicular variant of papillary thyroid carcinoma: genome-wide appraisal of a controversial entityGenes Chromosomes Cancer40355364200410.1002/gcc.2004915188460 JainMKhanAPatwardhanNRealeFSafranMFollicular variant of papillary thyroid carcinoma: a comparative study of histopathologic features and cytology results in 141 patientsEndocr Pract77984200110.4158/EP.7.2.7911421549 KimDSKimJHNaDGParkSHKimEChangKHSohnCHChoiYHSonographic features of follicular variant papillary thyroid carcinomas in comparison with conventional papillary thyroid carcinomasJ Ultrasound Med2816851692200919933483 SalajeghehAPetcuEBSmithRALamAKFollicular variant of papillary thyroid carcinoma: a diagnostic challenge for clinicians and pathologistsPostgrad Med J847882200810.1136/pgmj.2007.06488118322127 LeeJHLeeESKimYSClinicopathologic significance of BRAF V600E mutation in papillary carcinomas of the thyroid: a meta-analysisCancer1103846200710.1002/cncr.2275417520704 KimTHParkYJLimJAAhnHYLeeEKLeeYJKimKWHahnSKYounYKKimKHChoBYPark doJThe association of the BRAF (V600E) mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer: a meta-analysisCancer11817641773201210.1002/cncr.2650021882184 TufanoRPTeixeiraGVBishopJCarsonKAXingMBRAF mutation in papillary thyroid cancer and its value in tailoring initial treatment: a systematic review and meta-analysisMedicine (Baltimore)91274286201210.1097/MD.0b013e31826a9c7122932786 LiCLeeKCSchneiderEBZeigerMABRAF V600E mutation and its association with clinicopathological features of papillary thyroid cancer: a meta-analysisJ Clin Endocrinol Metab9745594570201210.1210/jc.2012-210423055546 LiuXYanKLinXZhaoLAnWWangCLiuXThe association between BRAF V600E mutation and pathological features in PTCEur Arch Otorhinolaryngol271Jan42014(Epub ahead of print)10.1007/s00405-013-2872-724389984 YuXMSchneiderDFLeversonGChenHSippelRSFollicular variant of papillary thyroid carcinoma is a unique clinical entity: a population-based study of 10,740 casesThyroid2312631268201310.1089/thy.2012.045323477346

Study selection process. FV-PTC, follicular variant of papillary thyroid carcinoma. C-PTC, classical, conventional or pure papillary variant of papillary thyroid carcinoma; SEER, the Surveillance, Epidemiology and End Results database.

Forest plot for the comparison of (A) female, (B) mean age and (C) aged ≥45 years between follicular variant of papillary thyroid carcinoma (FV-PTC) and classical papillary thyroid carcinoma (C-PTC). ORs or MDs with corresponding 95% CIs of individual studies for comparison of clinicopathological characteristics are shown. The forest plot shows the effect size and 95% CIs for each study and overall. OR, odds ratio; MD, mean difference; CI, confidence interval.

(D) Mean tumor size, (E) the tumor size being ≥10 mm, (F) multifocality and (G) capsular invasion between follicular variant of papillary thyroid carcinoma (FV-PTC) and classical papillary thyroid carcinoma (C-PTC). ORs or MDs with corresponding 95% CIs of individual studies for comparison of clinicopathological characteristics are shown. The forest plot shows the effect size and 95% CIs for each study and overall. OR, odds ratio; MD, mean difference; CI, confidence interval.

(H) Vascular invasion, (I) extrathyroidal extension and (J) lymph node metastasis between follicular variant of papillary thyroid carcinoma (FV-PTC) and classical papillary thyroid carcinoma (C-PTC). ORs or MDs with corresponding 95% CIs of individual studies for comparison of clinicopathological characteristics are shown. The forest plot shows the effect size and 95% CIs for each study and overall. OR, odds ratio; MD, mean difference; CI, confidence interval.

(K) Lymphocytic and/or Hashimoto's thyroiditis, (L) stages I + II, (M) BRAF mutation and (N) recurrence between follicular variant of papillary thyroid carcinoma (FV-PTC) and classical papillary thyroid carcinoma (C-PTC). ORs or MDs with corresponding 95% CIs of individual studies for comparison of clinicopathological characteristics are shown. The forest plot shows the effect size and 95% CIs for each study and overall. OR, odds ratio; MD, mean difference; CI, confidence interval.

Characteristics of individual studies included in the meta-analysis.

Patients, no. Mean age (years) ± SD and/or ≥ (>) 45, no. (%) Mean tumor size (mm) ± SD and/or ≥ (>)10, no. (%)
First author, year Country FV-PTC C-PTC FV-PTC C-PTC FV-PTC C-PTC (Refs.)
Abrosimov, 2007a Japan 34 148 NA NA >10±11 (32.4) >10±71 (47.3) (22)
Brzezianska, 2007 Poland 8 14 49 (20.4) 47.57 (17) NA NA (23)
≥45±5 (62.5) ≥45±7 (50.0)
Burningham, 2005 USA 46 114 46 (17)b 47 (26)b 15 (19)b 10 (16)b (19)
Chang, 2006 China 85 170 NA NA 27 (18.4) 23 (13.0) (10)
Costa, 2008 Portugal 17 16 37 (10) 45 (25) 34 (25) 35 (15) (24)
Daglar-Aday, 2013 Turkey 36 72 44.94 (15.21) 52.88 (17.11) NA NA (25)
Darr, 2011 USA 6 7 43 (15) 44 (14) >20±5 (16.7) >20±6 (14.3) (26)
Dettmer, 2013 USA 17 27 50.9 (17.73) 47.8 (15.58) NA NA (27)
Di Cristofaro, 2006 France 24 26 38.5 (13) 43.3 (17.3) 21.5 (8.5) 25.7 (11.3) (28)
Eloy, 2011 Portugal 31 42 42.73 (12.94) 39 (17.75) 22.3 (18) 22.4 (17.1) (29)
≥45±15 (48.4) ≥45±14 (33.3) >10±23 (74.2) >10±32 (76.2)
Ertek, 2012 Turkey 56 42 39.1 (10.6) 46.7 (12.9) 34.7 (31.7) 13.9 (12.2) (14)
Espadinha, 2009 Portugal 17 21 35.41 (25.37) 39.24 (25.17) NA NA (30)
≥45±6 (35.3) ≥45±14 (33.3)
Gao, 2012 China 25 84 ≥45±13 (52) ≥45±54 (64.3) >10±20 (80) >10±61 (72.6) (31)
Hagag, 2006 Israel 92 99 46 (19.18) 44 (9.95) 22 (19.2) 20 (9.9) (20)
≥45±52 (56.5) ≥45±54 (54.5)
Hunt, 2004 USA 16 8 50.38 (11.63) 46.75 (11.5) 30.1 (23.7) 15.6 (13.7) (32)
≥45±11 (68.8) ≥45±5 (62.5) >10±11 (68.8) >10±4 (50)
Igci, 2013 Turkey 10 11 38.5 (12.75) 50.09 (19.61) 30.6 (16.9) 30.6 (16.6) (33)
≥45±5 (50) ≥45±4 (36.4) >10±9 (90) >10±11 (100)
Igci, 2014 Turkey 25 15 46.76 (13.72) 48.73 (15.66) 14.4 (9.7) 16.4 (10) (34)
≥45±15 (60) ≥45±9 (60) ≥10±16 (64) ≥10±9 (60)
Ito, 2008 Japan 100 1,313 >55±41 (41) >55±403 (30.7) >40±6 (6) >40±158 (12) (35)
Lang, 2006 China 67 308 38.5 (14–83)c 42.0 (11–81)c 25 (10–85)c 25 (10–100)c   (8)
Lassalle, 2011 France 5 11 39 (8.06) 44.45 (18.05) 22.4 (8.4) 17.7 (7.8) (36)
Lee, 2011 Korea 30 30 49.27 (12.8) 47.83 (9.65) 17.4 (9.6) 9.7 (6.4) (37)
Lim, 2013 Korea 85 2,947 45 (13–84)c 47 (24–74)c 8.2 (0.5–)c 10 (2–65)c (38)
Liu, 2010 USA 73 114 NA NA NA NA (39)
Min, 2013 Korea 58 312 >45±44 (75.9) >45±172 (55.1) >10±15 (25.9) >10±101 (32.4) (40)
Nechifor-Boila, 2013 Romania 90 98 27 (6.1) 26.3 (5.5) 27 (16) 21 (11) (41)
Oler, 2009 Brazil 47 73 ≥45±23 (53.5) ≥45±31 (43.7) ≥10±35 (74.5) ≥10±50 (70.4) (42)
Ozdemir, 2011 Turkey 90 354 43.98 (12.46) 45.82 (12.24) 16.9 (13.9) 10.6 (9.7) (17)
>10±55 (61.1) >10±127 (35.9)
Passler, 2003 Austria 37 117 46.4 (10.9–74.8)c 47.5 (18.1–79.3)c 17.9 (17.6) 24.2 (21) (12)
Rivera, 2009 USA 63 43 >45±30 (47.6) >45±14 (32.6) ≥40±22 (35.5) ≥40±2 (4.7) (43)
Schulten, 2012 Saudi Arabia 42 115 NA NA NA NA (44)
Sheu, 2010 Germany 30 10 46.4 (15.4) 48.1 (14.0) 28.5 (18.1) 26.2 (18.8) (45)
Slosar, 2009 USA 60 37 NA NA ≥10±56 (93.3) ≥10±30 (81.1) (46)
Trovisco, 2005 Portugal 54 69 41.5 (19.11) 37.2 (17.44) 27 (13.6) 32 (21) (47)
Wreesmann, 2004 USA 17 25 40 (25–75)c 41 (20–77)c 25 (8–65)c 20 (6–45)c (48)
Yuksel, 2008 Turkey 41 158 >40±31 (75.6) >40±37 (23.4) 16.5 (10.8) 13.4 (10) (16)
Zidan, 2003 Israel 100 143 44 (17–81)c 43 (11–78)c 35 (3–100)c 34 (4–90)c   (7)

There were two PTCs with a conventional variant in one patient, two PTCs with conventional and follicular variants in two patients and two microcarcinomas (≤10 mm) with a conventional pattern in one patient

median (IQR, interquartile range reported as the range around the median)

continuous data are expressed as median, with the range in parentheses. NA, not available; FV-PTC, follicular variant of papillary thyroid carcinoma; C-PTC, classical, conventional or pure papillary variant of papillary thyroid carcinoma; SD, standard deviation.

Meta-analyses of the clinicopathological parameters between FV-PTC and C-PTC.

Clinicopathological characteristics Included study, n Heterogeneity test Effects model selection OR/MD (95% confidence interval) Combined effect test Statistical significance Egger's test
χ2 P-value I2, % Z P-value P-value
Female 33 29.61 0.59 0 Fixed 1.09 (0.93–1.29) 1.06 0.29 No 0.707
Age, years
  Mean 19 31.36 0.03 43 Fixed −0.61 (−1.75–0.53)a 1.05 0.29 No 0.413
  ≥45 11 8.90 0.54 0 Fixed 1.45 (1.11–1.90) 2.69 <0.01 Yes 0.754
Tumor size, mm
  Mean 17 50.72 <0.01 68 Random 2.88 (0.26–5.51)a 2.15 0.03 Yes 0.485
  ≥10 10 21.73 0.01 59 Random 1.25 (0.77–2.03) 0.92 0.36 No 0.473
Multifocality 17 40.85 <0.01 61 Random 0.88 (0.64–1.24) 0.77 0.44 No 0.522
  CI 6 14.60 0.01 66 Random 0.82 (0.48–1.39) 0.74 0.46 No 0.577
  VI 9 31.84 <0.01 75 Random 1.38 (0.56–3.42) 0.69 0.49 No 0.555
  EE 18 56.75 <0.01 70 Random 0.40 (0.25–0.64) 3.86 <0.01 Yes 0.609
  LNM 23 65.94 <0.01 67 Random 0.35 (0.25–0.49) 6.12 <0.01 Yes 0.450
  LT or/and HT 9 13.94 0.08 43 Fixed 0.79 (0.61–1,02) 1.82 0.07 No 0.419
  CS (I+II) 12 10.29 0.50 0 Fixed 1.17 (0.90–1.52) 1.16 0.25 No 0.605
  BRAF mutation 13 8.15 0.77 0 Fixed 0.19 (0.15–0.24) 13.34 <0.01 Yes 0.247
  Recurrence 8 5.46 0.60 0 Fixed 0.52 (0.34–0.80) 2.98 <0.01 Yes 0.991

MD with a 95% confidence interval. FV-PTC, follicular variant of papillary thyroid carcinoma; C-PTC, classical papillary thyroid carcinoma; OR, odds ratio; MD, standardized mean difference; CI, capsular invasion; VI, vascular invasion; EE, extrathyroidal extension; LNM, lymph node metastasis; LT, lymphocytic thyroiditis; HT, Hashimoto's thyroiditis; CS, clinical stage.