Endocrine (2014) 46:52–59 DOI 10.1007/s12020-013-0057-1

META-ANALYSIS

Clinical characteristics as predictors of malignancy in patients with indeterminate thyroid cytology: a meta-analysis Pierpaolo Trimboli • Giorgio Treglia • Leo Guidobaldi • Enrico Saggiorato Giuseppe Nigri • Anna Crescenzi • Francesco Romanelli • Fabio Orlandi • Stefano Valabrega • Ramin Sadeghi • Luca Giovanella



Received: 25 July 2013 / Accepted: 5 September 2013 / Published online: 3 October 2013 Ó Springer Science+Business Media New York 2013

Abstract Indeterminate thyroid nodules (ITN) constitute the gray zone of thyroid fine-needle aspiration cytology (FNAC). About 70–80 % of ITN are later diagnosed as benign; therefore, it is very important to identify the predictors of malignancy. Aim of the study was to summarize published data about clinical risk factors for malignancy in patients with ITN and thereby provide more robust estimates of the effect of these risk factors. Sources comprised studies published through December 2012. Original articles that investigated clinical parameters as potential predictors of malignancy in ITN were identified. Two authors performed the data extraction independently. A meta-analysis of 19 relevant studies was conducted that included 3,494 patients with ITN according to FNAC. The pooled prevalence of malignancy was 28 % (95 % CI 23–33), 26 % in

females and 34 % in males. The pooled OR was 1.51 (95 % CI 1.2–1.83) for males and 0.68 (95 % CI 0.53–0.88) for females. Regarding the nodule’s size, the pooled OR was 2.10 (95 % CI 1.26–3.50) for nodules [4 cm in diameter. Analysis of the patient age as a risk factor was not feasible because of marked difference found between the studies. In patients with indeterminate thyroid nodules diagnosed at FNAC, the pooled rate of malignancy from 19 studies was 28 %. Patients that are male and have ITN greater than 4 cm in diameter should be considered at higher risk of cancer. Keywords Thyroid  Cytology  Age  Gender  Thy 3

Pierpaolo Trimboli and Giorgio Treglia share the first authorship. P. Trimboli Section of Endocrinology and Diabetology, Ospedale Israelitico, Rome, Italy

G. Nigri  S. Valabrega Department of Medical and Surgical Sciences, Ospedale S. Andrea, Sapienza University, Rome, Italy

G. Treglia  L. Giovanella Thyroid Centre, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland

F. Romanelli Department of Experimental Medicine, Sapienza University, Rome, Italy

G. Treglia (&)  L. Giovanella Department of Nuclear Medicine and PET/CT Centre, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland e-mail: [email protected]

R. Sadeghi Nuclear Medicine Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

L. Guidobaldi  A. Crescenzi Section of Pathology, Ospedale Israelitico, Rome, Italy E. Saggiorato  F. Orlandi Section of Endocrinology, Division of Internal Medicine, Department of Clinical and Biological Sciences, University of Turin, Turin, Italy

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Endocrine (2014) 46:52–59

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Introduction Fine-needle aspiration cytology (FNAC) is the primary diagnostic tool in evaluating thyroid nodules because of its high accuracy [1, 2]. FNAC is very reliable in detecting papillary thyroid cancer (PTC) and anaplastic thyroid cancer. However, indeterminate thyroid nodules (ITN), defined at FNAC as monotonous cellular population with scant or absent colloid, constitute the gray zone of thyroid cytology. In these lesions, FNAC evaluation cannot discriminate malignant (i.e., follicular carcinoma and follicular variant of PTC) from benign (i.e., follicular adenoma and nodular adenomatous goiter) tumors [3]. As a consequence, the uncertain outcome of thyroid nodule is assessed as Thy 3 according to British Thyroid Association Guidelines [2], Class 3 by American Association Clinical Endocrinologists/Associazione Medici Endocrinologi and European Thyroid Association guidelines [1], or Categories III–IV of the Bethesda System for Reporting Thyroid Cytopathology [4]. The latter [4] divides the uncertain reports into two categories at different cancer risk. The majority (70–80 %) of these nodules are diagnosed as benign at histology after surgery; therefore, the identification of parameters as potential markers of malignancy should be of great clinical value. Many molecular, cytological, ultrasound, and clinical studies that examine such predictors have been conducted, with controversial findings [5–7]. In particular, although several articles report conflicting results about the clinical features that correlate with malignancy, no systematic reviews of this topic exist to date. The objective of our study was to conduct a meta-analysis of published data about clinical risk factors for malignancy, in patients with indeterminate thyroid nodules according to FNAC, and thereby provide more robust estimates of the effect of these risk factors.

Fig. 1 Plot on the literature search and selection strategy of the included studies

references of the retrieved articles were also screened to identify additional studies. Study selection Original articles that investigated clinical parameters to predict malignancy of thyroid nodules with indeterminate FNAC were eligible for inclusion. The main exclusion criteria were articles that did not provide clear study characteristics and reports with overlapping patient data. Cases reported in the studies with no histological outcome were excluded. Two researchers (PT, GT) independently reviewed the titles and abstracts of the retrieved articles, applying the inclusion and exclusion criteria previously described. Then, the same two researchers independently reviewed the full-text version of the remaining articles to determine their eligibility for inclusion.

Materials and methods

Data extraction

Search strategy

For each included study, information was abstracted concerning study data (authors, year of publication, and country of origin); instrumentation used; number, gender, and age of patients evaluated; number of thyroid lesions with histological follow-up; and number and rate of cancers and benign neoplasms detected.

Initially, we identified studies that evaluated the association between any clinical features and the definitive histological outcome of ITN (according to FNAC). A comprehensive computer literature search of the PubMed/ MEDLINE, Embase, and Scopus databases was conducted to find published articles that addressed this association. The search algorithm was based on the combinations of the terms ‘‘thyroid,’’ ‘‘indeterminate,’’ ‘‘fine-needle aspiration,’’ and ‘‘cytology.’’ A beginning date limit was not used, the search was updated until December 31, 2012 and no language restriction was used. To expand our search,

Statistical analysis The prevalence of malignant outcomes was calculated from individual studies using this formula: number of patients with a malignant nodule/number of patients evaluated with a thyroid nodule of indeterminate FNAC 9 100.

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54 Table 1 Characteristics of the series included in the study

Endocrine (2014) 46:52–59

First author

Year

Journal

Patients

Gender F

All included cases had a histological follow-up

M

n

% 38.5

Davis [8]

1991

Am J Surg

395

295

100

152

Chen [9]

1998

Ann Surg

57

51

6

20

35.1

Tuttle [10]

1998

Thyroid

103

81

22

22

21.4

Mc Henry [11]

1999

Surgery

75

64

11

17

22.7

Raber [12]

2000

Thyroid

120

103

17

21

17.5

Baloch [13]

2002

Diagn Cytopathol

122

107

15

37

30.3

Kim [14]

2003

Korean J Intern Med

215

196

19

102

Giorgadze [15]

2004

Diagn Cytopathol

169

136

33

76

Smith [16]

2005

Am J Surg

24

20

4

7

29.2

Pu [17]

2006

Diagn Cytopathol

303

242

61

87

28.7

Sahin [18] Rago [19]

2006 2007

Clin Endocrinol Clin Endocrinol

86 505

61 398

15 107

34 125

39.5 24.8 12.7

47.4 45

Paramo [20]

2008

Endocr Pract

71

55

16

9

Trimboli [21]

2008

Clin Endocrinol

47

36

11

8

Gulcelik [22]

2008

Arch Otolaryngol Head Neck Surg

98

82

16

26

26.5

Mihai [23]

2008

Thyroid

201

167

34

57

28.4

Sorrenti [24]

2009

Thyroid

603

502

101

106

17.6

Lubitz [25]

2010

Thyroid

144

112

32

16

11.1

Asari [26]

2010

Surgery

Pooled

Whenever possible, the malignancy risk of the analyzed parameters (age and gender of patients, size of the lesion) was obtained from individual studies and a pooled odds ratio (OR) was calculated for these parameters. A random-effects model was used for statistical pooling of the data; pooled data represented weighted OR that were related to the sample size of each study. Pooled data were presented with their respective 95 % CI and data were displayed using plots. An I2 statistic was also calculated to test heterogeneity between studies. An Egger test and a funnel plot were performed to assess the presence of publication bias. Statistical analyses were performed using StatsDirect statistical software (StatsDirect Ltd, Altrincham, UK).

Results Eligible articles The comprehensive computer literature search revealed 412 articles. Review of titles and abstracts excluded 401 articles according to the above criteria. Eleven articles were selected and their full-text version retrieved; however, 4 of these were not included because they did not analyze clinical parameters. Twelve additional studies were found by screening the references of these papers. Altogether 19

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Cancers

17

156

131

25

55

35.3

3,494

2,839

645

977

27.8

studies, reporting 3,494 patients with a ITN at FNAC, were included in our meta-analysis [8–26] (Fig. 1). The main characteristics of the included studies are shown in Table 1. Qualitative analysis Overall, the studies included 3,494 patients with a female/ male ratio of 4.4. About 1 in 4 nodules was malignant at histological follow-up. Overall, 26 % (range 11–51 %) of females and 34 % (range 12–75 %) of males had cancer. In two papers [10, 17], male gender gave a significant risk of malignancy. Parameters evaluating age of patients were not homogeneous; 40, 45, 50, or 60 years as a cut-off point, or mean age in cancer and benign nodules were investigated. Similarly, inhomogeneous characteristics were found regarding the size of the lesion; the studies evaluated different cutoffs (2, 3 or 4 cm) or mean nodule’s size. Then, findings that were discrepant between the 19 studies were noted. Quantitative analysis (meta-analysis) The pooled prevalence of malignancy of indeterminate thyroid nodules in the 19 included studies was 28 % (95 CI 23–33). The included studies were statistically heterogeneous (I2:[75 %) for the prevalence of malignancy, which ranged from 11 to 47 % (Fig. 2).

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Fig. 2 Left Plot on the pooled prevalence of malignancy in indeterminate thyroid nodule at cytology, including 95 % confidence intervals. The size of the squares indicates the weight of each study.

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Right Bias assessment plot on publication bias. The symmetry of this plot demonstrated the absence of a significant publication bias

Fig. 3 Plot on the pooled odd ratio of the male and female genders, including 95 % confidence intervals. The size of the squares indicates the weight of each study

A significant publication bias was not found using a specific bias assessment plot (Fig. 2) and Egger test (Egger bias 2.17; 95 % CI –1.53 to 5.89; p = 0.23). The pooled OR for the male gender was 1.51 (95 % CI 1.24–1.83) (Fig. 3), whereas the pooled OR for the female

gender was 0.68 (95 % CI 0.53–0.88) (Fig. 3). Therefore, the male gender represented a risk factor for malignancy in ITN. The included studies were quite homogeneous regarding this association (I2: 0 % for male gender and 25 % for female gender), without significant publication

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Fig. 4 Plot on the pooled odd ratio of size\or[4 cm, including 95 % confidence intervals. The size of the squares indicates the weight of each study

bias for male gender (Egger bias –0.16; 95 % CI –1.23 to 0.91; p = 0.75) and female gender (Egger bias 0.31; 95 % CI –0.99 to 1.62; p = 0.6). A pooled analysis of OR for patients age was not feasible, because the included studies reported different age categories. Furthermore, because it was not possible to retrieve for the age of each patient, the correlation between the age of the patients and the malignancy status could not be calculated from the included studies. Likewise, different cut-off values for the size of the thyroid nodule were reported in the included studies. A pooled analysis was possible only for the most frequently reported cut-off value, [4 cm [12, 20, 22, 23, 26]. The pooled OR for nodule size [4 cm was 2.10 (95 % CI 1.26–3.50) (Fig. 4); the pooled OR for a size B4 cm was 0.48 (95 % CI 0.29–0.79) (Fig. 4). Therefore, the size [4 cm represented a risk factor for malignancy in ITN diagnosed by FNAC. The included studies were quite homogeneous regarding the effect of nodule size [4 (I2: 20 % for size[4 or\4 cm), without significant publication bias revealed by the Egger test.

Discussion ITN represent a major dilemma for thyroidologists, amounting to about 15 % of citologies. Benignancy is highly prevalent (80 %) in the histological follow-up of ITN. Consequently, a large number of single-center studies investigated clinical parameters as potential predictors of malignancy, with discrepant findings. Here, we systematically reviewed 19 studies on this topic [8–26] and data from these papers were meta-analyzed. In this meta-analysis the rate of malignancy ranged from 11 to 47 %, with a pooled value of 28 %. This agrees with

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the important study by Mihai et al. [23], which reported that up to one in four patients with Thy 3 has a cancer. Two papers raised the question if increased risk of cancer is present in Hu¨rthle neoplasms with respect to follicular neoplasms, and no difference was recorded [17, 24]. Many papers reported that male sex is a risk factor for malignancy in patients with ITN, especially in those with Hu¨rthle cells [13, 15, 17], but this was not confirmed by others [8, 19, 21]. Here, the pooled data showed that males had higher cancer risk. Notably, the largest study of this topic reported that the frequency of more aggressive subtypes of PTC (sclerosing, oncocytic, tall cell) were higher in females, conversely classical and follicular variants were more prevalent in males [24]. Different methods to evaluate patient’s age as a risk factor in ITN were reported (i.e., mean age, 40 or 50 years old). Also, these data are not consistently detailed. Therefore, whether age of patients is a parameter that predicts malignancy in ITN is still a matter of debate. Of note, a paper that was not included in the present review [27] found that the risk of malignancy decreased in adult subjects 0.7-fold for every 10 years of age. In contrast, two studies reported that patients above 40 years [8] or 50 [28] years had a higher incidence of malignancy. In addition, some reports [14, 21, 24, 29] found that the risk of malignancy increases at the extremes of age. Whether nodule size represents a risk factor for malignancy in ITN is still a controversial topic. Several authors noted that large size is associated with malignancy [8, 10, 28, 30, 31], being this not confirmed by other [14, 19, 21, 29]. One study found that increased nodule size was associated with more aggressive cancer types [24]. Among the 19 included studies, five evaluated nodule size of [4 cm diameter as a risk for malignancy, so we metaanalyzed those homogeneous studies [12, 20, 22, 23, 26].

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The results showed that a diameter [4 cm should be considered as a risk predictor while a diameter below 4 cm was associated with a benign outcome. Publication bias and heterogeneity may represent potential sources of bias in our meta-analysis. However, significant publication bias was not found in our meta-analysis as demonstrated by a specific bias assessment plot (view Fig. 2). The studies included in our pooled analysis were statistically heterogeneous regarding the prevalence of malignancy of ITN, but not about gender or size ( [4 or \4 cm) as risk factors for malignancy. This heterogeneity in malignancy rate may be due to baseline sociodemographic characteristics of patients, including referral patterns, and diversity in methodology of studies. Such variability was accounted for in a random-effects model used in our meta-analysis. In the last decade, several diagnostic tools have been investigated as predictors of malignancy in ITN. Ultrasound examination is the standard method in risk stratification of thyroid lesions, thus determining the need for biopsy [1]. However, while several features at US and color flow Doppler (such as hypoechoic appearance, microcalcifications, irregular margins, and intranodular vascularization) suggest malignancy in thyroid nodule [1], discordant results of these parameters were obtained in ITN [6]. More recently, an elastographic score of hardness was associated with cancer [32], but this was not confirmed by other reports [33, 34]. To date, there are no reliable ultrasound predictors of malignancy in ITN. A recent meta-analysis reported 95 % sensitivity and 48 % specificity for (18F)-fluoro-2deoxy-glucose (18FDG) positron emission tomography (PET) combined with X-ray computed tomography (18FDG-PET/CT); in particular, sensitivity increased to 100 % in 164 lesions larger than [15 mm, and negative 18 FDG-PET or PET/CT might exclude cancer when size is [15 mm [35]. These results deserve further investigation [36, 37]. Similarly, many studies reported data on Technetium-99m-MIBI scan in thyroid nodules [38–40] and a recent meta-analysis has recorded high sensitivity and negative predictive value of this scan [41]. Finally, many molecular (e.g., RET/PTC, BRAF, RAS, PAX8/PPARg, miRNA) [42–44] and/or immunocytochemical markers (e.g., galectin-3, HBME1, Cytokeratin-19, CITED-1) [5, 45, 46] have been investigated, and none of these alone resulted accurate in ITN. More recently encouraging results have been provided by core needle biopsy, but these findings need to be confirmed [47–49]. To date, no definitive criteria to discriminate malignant from benign lesions among ITN have been reported [1, 2, 4]. As a consequence, guidelines do not recommend for or against the use of these aforementioned tools in the workup of patients with inconclusive thyroid cytology [1, 2, 4, 50]. The present pooled analysis suggests that male gender confers a 51 % increase of cancer risk, and nodules larger than 4 cm in

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diameter augmented risk by 110 %. These findings should contribute to the risk assessment of patients with ITN. Future prospective studies, ideally in a multi-center setting, are required to confirm that. In conclusion, the pooled rate of malignancy from 19 studies of cytologically indeterminate thyroid nodules was 28 %. Patients that are male and have nodules greater than 4 cm in diameter should be considered to be at higher risk for cancer. Conflict of interest declare.

The authors have no conflicts of interest to

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Clinical characteristics as predictors of malignancy in patients with indeterminate thyroid cytology: a meta-analysis.

Indeterminate thyroid nodules (ITN) constitute the gray zone of thyroid fine-needle aspiration cytology (FNAC). About 70-80 % of ITN are later diagnos...
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