Thyroid nodules with indeterminate cytology: prospective comparison between 18F-FDG-PET/CT, multiparametric neck ultrasonography, 99mTc-MIBI scintigraphy and histology

in European Journal of Endocrinology
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  • 1 Nuclear Medicine Unit, Office of the Scientific Director, Galliera Hospital, Genoa, Italy
  • | 2 Clinical Trial Unit, Office of the Scientific Director, Galliera Hospital, Genoa, Italy
  • | 3 Department of Nuclear Medicine and PET/CT Centre, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
  • | 4 Internal Medicine, Galliera Hospital, Genoa, Italy
  • | 5 Department of Nuclear Medicine, University of Brescia and Spedali Civili di Brescia, Brescia, Italy
  • | 6 Department of Radiology, Galliera Hospital, Genoa, Italy
  • | 7 Department of Surgery, Thyroid Centre, Galliera Hospital, Genoa, Italy
  • | 8 Department of Pathology, Galliera Hospital, Genoa, Italy

Correspondence should be addressed to A Piccardo; Email: arnoldo.piccardo@galliera.it

(M Cabria and L Giovanella contributed equally to this work)

Free access

Purpose

To evaluate the role of 18F-flurodeoxiglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in predicting malignancy of thyroid nodules with indeterminate cytology.

Patients and methods

We analysed 87 patients who have been scheduled to undergo surgery for thyroid nodule with indeterminate cytology. All patients underwent 18F-FDG-PET/CT, multiparametric neck ultrasonography (MPUS), and 99mTc-methoxyisobutylisonitrile scintigraphy (99mTc-MIBI-scan). Histopathology was the standard of reference. We compared the sensitivity (SE), specificity (SP), accuracy (AC), positive (PPV) and negative predictive (NPV) values of 18F-FDG-PET/CT with those of 99mTc-MIBI-scan and MPUS in detecting cancer. Univariate and multivariate analyses evaluated the association between each diagnostic tool and histopathology.

Results

On histopathology, 69 out of 87 nodules were found to be benign and 18 to be malignant. The SE, SP, AC, PPV and NPV of 18F-FDG-PET/CT were 94, 58, 66, 37 and 98% respectively. The SE, AC and NPV of 18F-FDG-PET/CT were significantly higher than those of MPUS and 99mTc-MIBI-scan. The association of both positive 18F-FDG-PET/CT and MPUS (FDG+/MPUS+) showed significantly lower SE (61% vs 94%) and NPV (88% vs 98%) than 18F-FDG-PET/CT alone, but significantly higher SP (77% vs 58%). On univariate analysis, 18F-FDG-PET/CT and the combination of FDG+/MPUS+ and of FDG+/MIBI− were all significantly associated with histopathology. On multivariate analysis, only FDG+/MIBI− was significantly associated with histopathology.

Conclusion

The AC of 18F-FDG-PET /CT in detecting thyroid malignancy is higher than that of 99mTc-MIBI-scan and MPUS. A negative 18F-FDG-PET/CT correctly predicts benign findings on histopathology. The association of FDG+/MPS+ is significantly more specific than 18F-FDG-PET/CT alone in identifying differentiated thyroid cancer. A positive 18F-FDG-PET/CT is significantly associated with malignancy when qualitative 99mTc-MIBI-scan is rated as negative.

Abstract

Purpose

To evaluate the role of 18F-flurodeoxiglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in predicting malignancy of thyroid nodules with indeterminate cytology.

Patients and methods

We analysed 87 patients who have been scheduled to undergo surgery for thyroid nodule with indeterminate cytology. All patients underwent 18F-FDG-PET/CT, multiparametric neck ultrasonography (MPUS), and 99mTc-methoxyisobutylisonitrile scintigraphy (99mTc-MIBI-scan). Histopathology was the standard of reference. We compared the sensitivity (SE), specificity (SP), accuracy (AC), positive (PPV) and negative predictive (NPV) values of 18F-FDG-PET/CT with those of 99mTc-MIBI-scan and MPUS in detecting cancer. Univariate and multivariate analyses evaluated the association between each diagnostic tool and histopathology.

Results

On histopathology, 69 out of 87 nodules were found to be benign and 18 to be malignant. The SE, SP, AC, PPV and NPV of 18F-FDG-PET/CT were 94, 58, 66, 37 and 98% respectively. The SE, AC and NPV of 18F-FDG-PET/CT were significantly higher than those of MPUS and 99mTc-MIBI-scan. The association of both positive 18F-FDG-PET/CT and MPUS (FDG+/MPUS+) showed significantly lower SE (61% vs 94%) and NPV (88% vs 98%) than 18F-FDG-PET/CT alone, but significantly higher SP (77% vs 58%). On univariate analysis, 18F-FDG-PET/CT and the combination of FDG+/MPUS+ and of FDG+/MIBI− were all significantly associated with histopathology. On multivariate analysis, only FDG+/MIBI− was significantly associated with histopathology.

Conclusion

The AC of 18F-FDG-PET /CT in detecting thyroid malignancy is higher than that of 99mTc-MIBI-scan and MPUS. A negative 18F-FDG-PET/CT correctly predicts benign findings on histopathology. The association of FDG+/MPS+ is significantly more specific than 18F-FDG-PET/CT alone in identifying differentiated thyroid cancer. A positive 18F-FDG-PET/CT is significantly associated with malignancy when qualitative 99mTc-MIBI-scan is rated as negative.

Introduction

The finding of an undetermined cytology result after thyroid nodule fine-needle aspiration biopsy still remains a challenging situation, the management of which is still under debate. On the one hand, in these nodules the risk of malignancy reaches 15 – 30% (1), and a conservative approach may not be completely safe. On the other, more aggressive clinical management may involve over-treatment (i.e. total thyroidectomy or lobectomy) in more than 70% of patients.

Although various immunohistochemical markers (e.g. thyroperoxidase, galectin-3 and E-cadherin) have been proposed for the pre-surgical identification of malignancy, none has high enough accuracy to be used in routine clinical practice (2, 3). Similarly, several molecular markers, such as RAS, BRAF, RET/PTC and Pax8/PPARγ, have been explored, but, despite their high specificity in detecting malignancies, their sensitivity is too low (4, 5).

In this field, imaging tools characterized by high sensitivity and high negative predictive value (NPV) may be able to substantially reduce the number of patients undergoing inappropriate thyroidectomy. Multiparametric ultrasonography (MPUS), 99mTc methoxyisobutylisonitrile scintigraphy (99mTc MIBI scan) and 18F-flurodeoxiglucose positron emission tomography/computed tomography (18F-FDG PET/CT) are the principal diagnostic tools to have been proposed in recent years.

Several studies have investigated the role of US features in diagnosing indeterminate thyroid nodules. Although several US features have been shown to identify thyroid nodules at higher risk of malignancy (e.g. marked hypoechogenicity, irregular margins and microcalcifications), no definitive evidence has been obtained, and US alone is not recommended in the clinical management of indeterminate thyroid lesions (1, 6, 7, 8). In addition, although real-time elastography (RTE) has recently been reported to increase the sensitivity of US, it has suboptimal accuracy in diagnosing thyroid nodules previously classified as indeterminate (9). 99mTc-MIBI scan may be useful in the pre-surgical evaluation of thyroid nodules with undetermined cytology, and it has proved to be a specific tracer in identifying malignancy in non-oncocytic follicular lesions. However, it has not proved specific enough to distinguish benign oncocytic follicular lesions from malignant ones (10).

18F-FDG PET/CT seems to be helpful in defining the nature of indeterminate nodules and has been reported to have a very high NPV (11, 12, 13, 14, 15, 16, 17). However, a recent study (18) on a considerable number of patients did not confirm the high NPV of 18F-FDG PET/CT, and the authors concluded that this imaging tool did not add any diagnostic benefit to conventional US.

The aim of this two-centre study was to better clarify the role of 18F-FDG PET/CT in detecting differentiated thyroid cancer (DTC) in patients with thyroid nodules with indeterminate cytology and to compare the results obtained with those of MPUS and 99mTc MIBI scan. We also assessed whether the combination of two of the three diagnostic tools could improve the accuracy of each single imaging test. A multivariate logistic analysis was also conducted to evaluate the association between malignancy and the results of each diagnostic tool, on adjusting for other clinical parameters such as age, nodule dimensions and thyroglobulin (Tg) levels. In addition, we tested the PPV of BRAF V600E mutation in patients with histologically proven DTC and the association between this mutation and 18F-FDG and 99mTc MIBI uptake.

Patients and methods

Patient population

In our two centres (Galliera Hospital, Genoa, Italy and Oncology Institute of Southern Switzerland, Bellinzona, Switzerland), between November 2012 and March 2015 we prospectively enrolled 87 patients (23 males, 64 females) who had been scheduled to undergo thyroidectomy for thyroid nodules with undetermined cytology according the Società Italiana di Anatomia e Citologia Patologica-International Academy of Pathology classification (2010) (1). The inclusion criteria were as follows: thyroid nodule with a diameter of >1 cm, TSH levels between 1 and 4 mUI/l and undetectable thyroperoxidase and Tg auto-antibodies. The study included 74 patients at Galliera Hospital and 13 patients at Oncology Institute of Southern Switzerland.

Our institutional review board approved the study and all patients gave their written informed consent.

Imaging modalities

All patients underwent MPUS, 99mTc MIBI scan and 18F-FDG PET/CT within 1 day of each other. Image acquisition was performed according to standard procedures.

First all patients were examined by using neck US (LOGIQ S8 General Electric Medical Systems, Milwaukee, WI, USA). The US parameters evaluated included, nodule diameters, structure (i.e. solid or mixed) echogenicity (hypoechoic, hyperechoic, isoechoic), presence or absence of irregular margins and presence or absence of microcalcifications. Following Power Doppler US analysis, nodule blood flow was classified as negative in case of absent or presence of marked peripheral blood flow and positive in case of intralesional blood flow. The elastic properties of thyroid nodules were assessed by means of RTE. This technique measures mechanically probe-induced deformation (strain) of structures and tissues examined in the B-mode ultrasound image, producing colour-coded maps of the strain distribution (i.e. elastograms) that reflect tissue elasticity (19, 20).

The RTE module implemented in our ultrasound system generates a colour map in which hard tissue areas appear blue, intermediate tissue areas are green, and soft tissue areas are red. Elastograms were obtained by placing the probe on the long axis of each thyroid nodule and RTE images were produced applying gentle pulse compression on the skin (19).

RTE images were assessed by means of a dychotomous qualitative analysis, dividing thyroid nodules into soft and hard groups. A nodule softer than, or with the same stiffness of the surrounding parenchyma, was considered soft (with a green, yellow or green appearance on the colour-coded map). By converse, a nodule harder/stiffer than the adjacent thyroid parenchyma (with a blue appearance on the colour-coded map) was considered hard.

99mTc MIBI scans were obtained 20 and 120 min after the injection of 400 MBq of 99mTc MIBI (Cardiolite, Bristol-Myers-Squibb, North Billerica, MA, USA). All scan images were obtained in the anterior projection of the neck using a gamma camera (Millenium, GE Medical Systems, Milwaukee, WI, USA or ECAM, Siemens Medical Solutions, Knoxville, TN, USA) equipped with a high-resolution, parallel-hole, low-energy high-resolution collimator. The images were obtained in a 256 × 256 matrix using a digital zoom of 1.8. The acquisition time was set to 900 s with a 20% window centred at 140 keV in all cases.

18F-FDG PET/CT of the neck was performed 50 min after the injection of tracer; data were acquired in the three-dimensional mode by means of two dedicated 16-slice PET/CT system (in one Nuclear Medicine Department with Discovery ST, GE Medical Systems; in the second with Biograph 16 Siemens Medical Solutions). The activity administered was 111 MBq. 18F-FDG PET of the neck was performed in one bed positions (5-min emissions per bed position) and images were reconstructed by using an iterative algorithm. A non-diagnostic CT scan (low-dose CT with 120 kV, 80 mA, 0.6 s per rotation) was used for attenuation correction and anatomical localization of the hot spots of the 18F-FDG PET study. Motion correction software was not available.

Image interpretation

MPUS US was considered positive in the presence of at least three of these characteristics; solid nodule, hypoechoic nodule, irregular margins, microcalcifications, intralesional blood flow and increased nodule stiffness.

18F-FDG-PET/CT was interpreted visually and semiquantitatively using the maximum standardized uptake value (SUV-max). However, no SUV-max cut-off value has been introduced and SUV was calculated for each lesion just to support visual interpretation. On 18F-FDG-PET/CT, any focal uptake above thyroid parenchyma, corresponding to the nodule with cytological undetermined results, was considered as positive. In addition nodule/normal thyroid gland SUV-max (SUV ratio) was quantitatively assessed by using regions of interest (ROIs) drawn on the images. On 99mTc-MIBI image any early and late focal uptake above thyroid parenchyma (i.e. nodule/thyroid parenchyma ratio >1), corresponding to the nodule with cytological undetermined results, was considered as positive (21, 22).

Diagnostic patterns

In order to evaluate the additional value of diagnostic associations between MPUS, 99mTc-MIBI scan and 18F-FDG-PET/CT, we defined three different patterns as follows:

Standard of reference and BRAF mutation analysis

For all patients histopathological results were available. In all 18 DTC patients, DNA was extracted from samples after micro-dissection by using the QIAamp DNA FFPE Tissue Kit (Qiagen, Hilden, Germany) according to the manufacturer’s instructions and amplified through Rotor-Gene 6000 real time PCR machine (Corbett Research, Eaton Socon, St. Neots, U.K.). BRAF mutation analysis was performed by means of Pyrosequencing platform ‘PyroMark Q96 ID System’ (Qiagen) using the commercial ‘Anti-EGFR MoAb Response (BRAF status)’ Kit (Diatech Pharmacogenetics, Jesi, Italy). This system allows to identify all variants of codon 600 of exon 15, including the most frequent one V600E (Val600Glu). Thus, all DTC patients were classified as BRAF V600E mutated or BRAF wild-type.

Statistical analysis

Descriptive statistics used for continuous factors where mean and standard deviation, median and interquartile range; in case of categorical factors, absolute and relative frequencies (%) were adopted. Sensitivity (SE), specificity (SP), positive predictive value (PPV), NPV and accuracy (AC, defined as the number of ((true positives)+(true negatives))/total) were calculated and compared between the each diagnostic techniques and the gold standard, as previously defined (histopathology). Fisher's exact test was used to compare independent diagnostics indicators (PPV, NPV); McNemar test was used for comparison of paired diagnostics indicators (SE, SP, AC).

Logistic regression modelling was adopted to calculate odds ratios (ORs) and Wald test to estimate and test the association between the histopathology assessment (positive/negative) and each of the diagnostic techniques/parameters considered. ORs from univariate models were adjusted only for age and dimensions of nodule; ORs from multivariate models were adjusted for age, dimensions of nodule and for all other factors with a Wald P-value <0.3 in the univariate analysis. In case of high correlated factors, to avoid multicollinearity, we included in the multivariate model only the most significant factors from the univariate analysis.

All analyses were conducted using Stata (version 13, StataCorp, College Station, TX, USA) software. Two-tailed probabilities were reported and the P value of 0.05 was used to define nominal statistical significance.

Results

At histopathology 69 out of 87 nodules (79%) were found to be benign (48 follicular hyperplasia and 21 follicular adenomas) and 18 (21%) were malignant, including 13 papillary carcinomas and five follicular carcinomas (FTC). Six patients with pT1, six patients with pT2, and six patients with pT3 were found. Patients’ characteristics are summarized in Table 1. Out of 41, only one patient with negative 18F-FDG-PET/CT had final histological diagnosis of malignancy. In 69 out of 87 patients concordant findings were detected by 18F-FDG-PET/CT and 99mTc-MIBI-scan. The SE, SP, AC, positive (PPV), and negative predictive (NPV) values of 18F-FDG-PET/CT in detecting cancer were 94, 58, 66, 37 and 98%, respectively. The SE, AC and NPV of 18F-FDG-PET/CT were significantly higher than those of MPUS and 99mTc-MIBI-scan (Table 2 and Figs 1 and 2). When each US parameter was separately considered, the sensitivity of 18F-FDG-PET was significantly higher than that related to the presence of microcalcifications, irregular margins, intralesional blood flow and increased nodule stiffness (Table 3). On the contrary, the specificity of microcalcifications and irregular margins was higher than that of 18F-FDG-PET/CT (Tables 3 and 4).

Figure 1
Figure 1

(A) 13 mm isoechoic solid nodule characterized by well-defined margins and without microcalcifications, located in the inferior part of the right thyroid lobe in the subcapsular region (A). The vascularization of the nodule was peripheral on colour-Doppler evaluation (B) and the only suspected feature was the increased stiffness found on real-time elastography (C). 99mTc-methoxyisobutylisonitrile scintigraphy scan did not show focal uptake in the right thyroid lobe either 20 min (D) or 1 h after tracer injection (E). By contrast, 18F-flurodeoxiglucose positron emission tomography/computed tomography showed focal uptake (F) corresponding to the small thyroid nodule detected by US. Histopathology (haematoxylin-eosin stain, 4× (G) and (H) haematoxylin-eosin stain, 10×) revealed a small subcaspular papillary carcinoma.

Citation: European Journal of Endocrinology 174, 5; 10.1530/EJE-15-1199

Figure 2
Figure 2

(A) 25 mm hypoechoic solid nodule of the left lobe, characterized by undefined margins and multiple microcalcifications (A). The vascularization of the nodule was not significantly increased on colour-Doppler evaluation (not shown) and increased stiffness was found on real-time elastography (B). 99mTc-methoxyisobutylisonitrile scintigraphy scan did not show uptake in the left thyroid lobe either 20 min (C) or 1 h (D) after tracer injection. 18F-flurodeoxiglucose positron emission tomography/computed tomography (E) did not show any uptake corresponding to the thyroid nodule detected by US. Histopathology revealed a hyperplastic nodule characterized by micro- and macrocalcifications (haematoxylin-eosin stain, 4×) (F).

Citation: European Journal of Endocrinology 174, 5; 10.1530/EJE-15-1199

Table 1

Patients’ characteristics.

Mean

(± s.d.)
Median

(IQR)
Oncocytic lesions (n = 15)Nononcocytic lesions (n = 72)
Age (years)57 ± 1356 (49 – 67)
TSH levels (IU/L)1.7 ± 0.91.6 (1.0 – 3.4)
Tg levels (ng/mL)202 ± 44571 (27.5 – 182)
Dimensions of the nodule (mm)24 ± 13.420 (13 – 30)
Dimensions of the thyroid carcinomas (mm)26 ± 1623 (13 – 30)
DTC, n (%)3 (20)15 (21)
Follicular adenomas, n (%)8 (53)13 (18)
Follicular hyperplasia, n (%)4 (27)44 (61)
Table 2

Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy in detecting thyroid malignancy using multiparametric ultrasonography (MPUS) alone 18F-FDG-PET/CT alone and 99mTc-methoxyisobutylisonitrile scintigraphy-scan alone.

PET/CT

(%)
MPUS

(%)
99mTc-MIBI-scan

(%)
Sensitivity 9450 (0.02)56 (0.01)
Specificity5852 (0.6)52 (0.4)
PPV3721 (0.1)23 (0.17)
NPV9880 (0.01)82 (0.03)
Accuracy6652 (0.01)53 (0.02)

Values in parentheses indicate P value vs PET/CT.

Table 3

Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy in detecting thyroid malignancy using 18F-flurodeoxiglucose positron emission tomography/computed tomography alone and each feature of multiparametric ultrasonography.

Multiparametric US
PET/CT

(%)
Solid lesion

(%)
Hypoechogenicity

(%)
Irregular margins

(%)
Microcalcification

(%)
Hypervascularization

(%)
Stiffness

(%)
Sensitivity9494 (1)67 (0.12)33 (0.001)28 (0.001)22 (0.00001)47 (0.03)
Specificity5813 (0.0001)43 (0.13)77 (0.04)75 (0.04)65 (0.48)49 (0.07)
PPV3722 (0.09)24 (0.18)27 (0.58)23 (0.28)14 (0.06)20 (0.14)
NPV9890 (0.35)83 (0.04)82 (0.01)80 (0.008)76 (0.003)77 (0.007)
Accuracy6630 (0.0001)48 (0.003)68 (0.7)66 (1)56 (0.3)49 (0.006)

Values in parentheses indicate P value vs PET/CT.

Table 4

Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy in detecting thyroid malignancy using 18F-flurodeoxiglucose positron emission tomography/computed tomography alone and the diagnostic associations between MPUS, 99mTc-MIBI scan and 18F-FDG-PET/CT.

Diagnostic association
PET/CT

(%)
FDG+/MIBI+

(%)
FDG+/MIBI−

(%)
FDG+/MPUS+

(%)
Sensitivity9456 (0.01) 39 (0.002) 61 (0.03)
Specificity5864 (0.12) 94 (0.0001) 77 (0.002)
PPV3729 (0.48) 64 (0.17) 41 (0.8)
NPV9885 (0.03) 86 (0.05) 88 (0.14)
Accuracy6662 (0.54) 83 (0.01) 74 (0.17)

Values in parentheses indicate P value vs PET/CT.

The FDG+/MIBI+ pattern (Fig. 3) presented similar accuracy (62% vs 66%) but a significantly lower sensitivity (56% vs 94%) and NPV (85% vs 98%) than that of 18F-FDG-PET/CT alone (Table 4). On the other hand, the FDG+/MIBI− (Fig. 4) presented a significantly higher specificity (94% vs 58%) and accuracy (83% vs 66%) than that of 18F-FDG-PET/CT alone but a significantly lower sensitivity (39% vs 94%) (Table 4).

Figure 3
Figure 3

(A) 39 mm isoechoic solid nodule of the left thyroid lobe, characterized by well-defined margins and without microcalcifications (A). The vascularization of the nodule was significantly increased on colour-Doppler evaluation (B) and a high level of elasticity was found on real-time elastography (C). 99mTc-methoxyisobutylisonitrile scintigraphy scan showed intense uptake in the left thyroid lobe 20 min (D) and 1 h after tracer injection (E). 18F-flurodeoxiglucose positron emission tomography/computed tomography showed focal uptake corresponding to the thyroid nodule detected by US (F). Histopathology revealed a follicular adenoma (haematoxylin-eosin stain, 4 × (G) and haematoxylin-eosin stain, 10 × (H).

Citation: European Journal of Endocrinology 174, 5; 10.1530/EJE-15-1199

Figure 4
Figure 4

(A) 12 mm hypoechoic solid nodule characterized by irregular margins located in the inferior part of the right thyroid lobe in the subcapsular region (A). The vascularization of the nodule was absent on colour-Doppler evaluation (B) and stiffness was mildly increased on real-time elastography (C). 99mTc-methoxyisobutylisonitrile scintigraphy scan did not show focal uptake in the right thyroid lobe either 20 min (D) or 1 h (E) after tracer injection. By contrast, 18F-flurodeoxiglucose positron emission tomography/computed tomography (F) showed focal uptake corresponding to the thyroid nodule detected by US. Histopathology (haematoxylin-eosin stain, 4 ×) revealed a papillary carcinoma (G).

Citation: European Journal of Endocrinology 174, 5; 10.1530/EJE-15-1199

The FDG+/MPUS+ pattern (Fig. 5) showed a significantly lower sensitivity (61% vs 94%) and NPV (88% vs 98%) but a significantly higher specificity (77% vs 58%) than that of 18F-FDG-PET/CT alone (Table 4).

Figure 5
Figure 5

(A) 35 mm hypoechoic solid nodule of the isthmus, characterized by defined margins and without microcalcifications (A). The vascularization of the nodule was not significantly increased on colour-Doppler evaluation (B) and increased stiffness was found on real-time elastography (C). 99mTc-methoxyisobutylisonitrile scintigraphy scan showed intense uptake in the left thyroid lobe 20 min (D) and 1 h after tracer injection (E). 18F-flurodeoxiglucose positron emission tomography/computed tomography (F) showed focal uptake corresponding to the thyroid nodule detected by US. Histopathology (haematoxylin-eosin stain, 4 × (G) and 10 × (H)) revealed a follicular carcinoma.

Citation: European Journal of Endocrinology 174, 5; 10.1530/EJE-15-1199

BRAF V600E mutation status was analysed in all 18 histologically proven DTC patients and we found only four BRAF-mutated and 14 wild-type (PPV 22%) patients. We did not find any significant difference (P = 0.9) in terms of SUV ratio between BRAF-mutated and the wild-type patients. On the other hand, when MIBI uptake was taken into account, we found that BRAF-mutated patients presented a significantly lower MIBI ratio (P = 0.047) than wild-type patients. Only FDG-negative DTC patient did not show BRAF mutation.

On univariate analysis, 18F-FDG-PET/CT positive results, FDG+/MIBI− and FDG+/MPUS+ patterns were all significantly associated with malignancy at histopathology (Table 5 and Fig. 3). Neither SUV ratio nor MIBI ratio was significantly associated with malignancies. In a multivariate logistic regression model adjusted for age, dimensions of nodule and all other factors which had a P value < 0.3 in the univariate analysis, we found that only the FDG+/MIBI− pattern (P = 0.05) was associated with DTC. Moreover, a trend towards the level of statistical significance was found between Tag levels and DTC (P = 0.09; Table 5).

Table 5

Logistic regression analysis: dependent variable: positive(=‘1’)/negative (=‘0’) histology.

Factorn (%)ORu (P value)ORm (P value)
US structure
 Cystic10 (11)1.01.0
 Solid77 (89)3.5 (0.3)33.4 (0.3)
Ecogenity
 Iso-hyperechogenity36 (41)1.0
 Hypoechogenity51 (59)1.6 (0.4)
Microcalcifications
 Absence65 (75)1.0
 Presence22 (25)1.1 (0.8)
Margins
 Regular65 (75)1.0
 Irregular22 (25)1.6 (0.4)
Hypervascularization
 Absence59 (68)1.01.0
 Presence28 (32)0.5 (0.2)0.8 (0.9)
Elastography
 Softness35 (50)1.0
 Stiffness35 (50)0.8 (0.8)
Multiparametric US
 Negative45 (52)1.0
 Positive42 (48)1.2 (0.8)
MIBI
 No uptake44 (51)1.0
 Uptake43 (49)1.2 (0.8)
PET
 No uptake41 (47)1.01.0
 Uptake46 (53)28.4 (0.002)6.2 (0.16)
FDG+/MPUS+
 Negative60 (69)1.01.0
 Positive27 (31)6.5 (0.002)2.3 (0.3)
FDG+/MIBI+
 Negative52 (60)1.0
 Positive35 (40)2.2 (0.2)
FDG+/MIBI−
 Negative76 (87)1.01.0
 Positive11 (13)21.3 (< 0.001)7.5 (0.05)
 SUV ration = 861.006 (0.9)
 MIBI ration = 781.4 (0.7)
 Tg*n = 721.0007 (0.2)1.0008 (0.09)

ORu, odds ratios from a univariate logistic regression model adjusted for age and dimensions of nodule; ORm, odds ratios from a multivariate logistic regression model adjusted for age, dimensions of nodule and all other factors which had a P value < 0.3 in the univariate analysis. In case of high correlated factors, to avoid multicollinearity, we included in multivariate model only the most significant factors in the univariate analysis.

*Tg, SUV ratio and MIBI ratio were continuous factors: consequently the OR stands for 1-unit increase.

Discussion

We prospectively compared the ability of 18F-FDG PET/CT, MPUS and 99mTc-MIBI-scan to characterize thyroid nodules with indeterminate cytology in 87 patients. To the best of our knowledge, this is the first time that such a comparison has been made.

First our study showed that the overall SE and AC of 18F-FDG PET/CT are significantly higher than those of both MPUS and 99mTc-MIBI-scan. The most important datum that we want to underline is the very high NPV of 18F-FDG PET/CT (98%), which is significantly higher than those of MPUS, each single US and 99mTc-MIBI-scan. By contrast, as expected, we found a low PPV of 18F-FDG PET/CT (38%) confirming previous data (23, 24). All in all, a negative 18F-FDG PET/CT significantly reduces inappropriate thyroidectomies while positive nodules deserve lobectomy and histological examination. The full implementation of this diagnostic and clinical approach in patients with indeterminate thyroid nodules may reduce costs and increase the patients’ quality of life (25).

In our patients MPUS had suboptimal levels of sensitivity (50%) and specificity (52%) while in a similar series Deandreis et al. (18) found higher sensitivity (82%) and lower specificity (47%). This finding is probably related to the higher prevalence of malignancies and less stringent definition of suspicious thyroid nodules on MPUS in the latter study. Considering each single US feature, we found, in agreement with Yoo et al. (26), that the most sensitive US parameters were solid nodule structure (94%) and hypoechogenicity (67%) with no difference in terms of sensitivity from 18F-FDG PET/CT. Interestingly, irregular margins and microcalcifications were the most specific US parameters and showed a significantly higher specificity than that of 18F-FDG PET/CT. Like Yoo et al. (26), we found that nodule internal hypervascularity was not sensitive and specific enough to correctly identify thyroid malignancy. This finding is probably related to the intense internal hypervascularity of follicular adenomas (24% of all nodules in our patients) commonly detected on US (27). At the same time, we confirmed (9) that RTE has suboptimal accuracy in diagnosing thyroid nodules previously classified as indeterminate and is unable to select patients for surgery.

Secondly, we found that 99mTc-MIBI-scan had levels of AC (53%) and SE (56%) significantly lower than those of 18F-FDG PET/CT. Although one meta-analysis has reported the diagnostic performance of 99mTc-MIBI-scan in predicting the malignancy of thyroid nodules (28), only two prospective studies (10, 29) have evaluated the diagnostic role of 99mTc-MIBI-scan in thyroid nodules with indeterminate cytology. The authors found higher SE and AC than those reported in our series. Some possible explanations of these discrepancies may be cited. In their paper, the authors included only patients with cold nodules on 99mTc-pertechnetate thyroid scan. Moreover, selecting patients with class IV Bethesda at cytology (i.e. follicular proliferations ‘sensu strictu’) (30), their series were characterized by a higher prevalence of DTC (26 – 37%). Indeed, most neoplasms were follicular cancers. In this study, a different cytological classification was adopted, resulting in a lower prevalence of malignancy with more papillary cancers than follicular cancers detected. Finally, Saggiorato et al. (10) and Giovanella et al. (29) assessed the tracer washout by a semi-quantitative analysis to calculate the retention or washout index, respectively. Of importance, only semi-quantitative analysis of tracer kinetic proved to be able to rule-out surgery.

The only one other paper (31) comparing 99mTc-MIBI-scan and 18F-FDG PET/CT in the preoperative evaluation of thyroid nodules reported, using interpretation criteria similar to that adopted by Saggiorato et al. and Giovanella et al., that these imaging techniques had the same SE and similar NPV. Indeed, Sager et al. (31) studied a limited number of patients (n = 23) who presented larger thyroid nodules (median 32 mm vs 24 mm) and larger thyroid malignancies (median 30 mm vs 23 mm) than those of our series and cytology was not considered in patient selection.

Overall, accuracy of 99mTc-MIBI-scan may have been underestimated in our patients and no conclusions can be drawn on the superiority of 18F-FDG PET/CT over 99mTc-MIBI-scan. However, the MIBI semiquantitative analysis is time-consuming and, at least partially, an operator-dependent technique, especially with regard to the definition of the ROIs. Furthermore, this technique is partially dependent on the instruments used and the peculiarities of the local patient population. Therefore, each laboratory needs to optimize the protocol and to define its normal reference values. 18F-FDG PET/CT procedure is more standardized and qualitative analysis is relatively simple when compared with 99mTc-MIBI quantification and interpretation.

Anyway, molecular imaging (99mTc-MIBI-scan) proved superior to molecular testing in differentiating benign from malignant follicular neoplasm also in terms of cost-effectiveness (29, 32).

Thirdly, on considering the combined pattern of FDG+/MPUS+, we found that the specificity in detecting DTC was significantly higher than that of 18F-FDG PET/CT alone. This finding, which has never been reported before, may improve the well-known low specificity of 18F-FDG PET/CT, suggesting which patients are more suitable for thyroidectomy. A similarly important finding emerged when we considered FDG+/MIBI−. The specificity of this metabolic pattern, which reached 94%, was significantly higher than that of 18F-FDG PET/CT alone. In particular, when we conducted a logistic analysis to evaluate the association between malignancy and the results of each diagnostic tool or diagnostic association, after adjusting for other clinical parameters such as age, nodule dimensions and Tg levels, we found that, at the univariate level, 18F-FDG PET/CT, FDG+/MIBI− and FDG+/MPUS+ were all significantly associated with histopathology. However, on multivariate analysis, only the FDG+/MIBI− pattern was associated with malignancy. However, in order to better evaluate the real diagnostic impact of this pattern (FDG+/MIBI−) and to ascertain a real pathophysiological substrate, further studies on a larger sample population are needed.

On multivariate analysis, we found an interesting trend towards a significant association between Tg levels (expressed as a continuous variable) and malignancy. This is in agreement with what was reported by a recent meta-analysis (33), in which the preoperative Tg value was deemed to be an independent predictor of thyroid cancer and should be considered especially in the case of thyroid nodules with indeterminate cytology.

Fourthly, considering the connection between BRAF V600E mutation and mortality (34) and the inverse correlation between survival and FDG uptake in DTC patients (35, 36), we tested the association between primary thyroid tumour uptake (expressed in terms of SUV ratio) and BRAF V600E mutation in vivo; to our knowledge, this was the first such test. Although this association has recently been reported in patients with DTC metastases (37), we did not find any correlation between BRAF V600E mutation and FDG uptake. However, we tested this association only on a relatively small number of patients with DTC, a high percentage of which were FTC, mostly at an early stage, and often characterized by an indolent behaviour (38); in such cases, a low number of BRAF V600E mutations should be expected a priori, as indeed we found (22%).

By contrast, patients with BRAF mutations presented a significantly lower MIBI ratio than wild-type patients. This association may have been influenced by the low numbers of BRAF mutations; nevertheless, in this case, we found a significant P value. One possible, albeit speculative, explanation could be related to the low MIBI ratio evaluated in the late images. This tracer behaviour may be associated with the multi-drug resistance protein often expressed by DTC and, in some cases, related to poor prognosis (39). In this setting, DTC with low MIBI uptake in late images might be more aggressive, thus presenting BRAF mutation. However, as previously stated, absolute wash-out assessment is mandatory to prove an efflux of the tracer from the tumour while our analysis was based on relative uptake of normal thyroid and tumour tissue, respectively. As a consequence further studies are required to test this hypothesis.

Finally, we found that BRAF mutation had low NPV in detecting DTC. Thus, we confirmed what was reported in a recent systematic review, i.e. a marginal value of this biomarker in detecting malignancy in nodules with indeterminate cytology reports (4).

Limitations

Despite our encouraging results, some limitations should be noted. Although the number of patients included in this study was high, the number of DTC patients, as expected, was relatively low. A higher number of DTC could have helped to better evaluate the real diagnostic impact of 18F-FDG PET/CT in this challenging scenario. However, this is an intrinsic limitation of all studies investigating the role of imaging in thyroid nodules with indeterminate cytology.

The diagnostic sensitivity of 99mTc-MIBI-scan and, more generally its accuracy, may have been affected by our analysis. In addition, as we did not preselect patients on the basis of cold nodule on 99mTc-pertechnetate scintigraphy, we could not apply the visual analysis proposed by Hurtado-Lopez et al. (i.e. any nodular uptake of 99mTc-MIBI   > 99mTc-pertechnetate is considered positive), which significantly increases the SE and NPV of 99mTc-MIBI thyroid scan (40).

Conclusion

The accuracy of 18F-FDG-PET/CT in detecting thyroid malignancy is higher than that of qualitative 99mTc-MIBI-scan and MPUS. A negative 18F-FDG-PET/CT correctly predicts a benign finding on histopathology. The pattern FDG+ is significantly associated with malignancy when qualitative MIBI scan is rated as negative. The association of FDG+/MPUS+ is significantly more specific than 18F-FDG-PET/CT alone in identifying DTC.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

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    (A) 13 mm isoechoic solid nodule characterized by well-defined margins and without microcalcifications, located in the inferior part of the right thyroid lobe in the subcapsular region (A). The vascularization of the nodule was peripheral on colour-Doppler evaluation (B) and the only suspected feature was the increased stiffness found on real-time elastography (C). 99mTc-methoxyisobutylisonitrile scintigraphy scan did not show focal uptake in the right thyroid lobe either 20 min (D) or 1 h after tracer injection (E). By contrast, 18F-flurodeoxiglucose positron emission tomography/computed tomography showed focal uptake (F) corresponding to the small thyroid nodule detected by US. Histopathology (haematoxylin-eosin stain, 4× (G) and (H) haematoxylin-eosin stain, 10×) revealed a small subcaspular papillary carcinoma.

  • View in gallery

    (A) 25 mm hypoechoic solid nodule of the left lobe, characterized by undefined margins and multiple microcalcifications (A). The vascularization of the nodule was not significantly increased on colour-Doppler evaluation (not shown) and increased stiffness was found on real-time elastography (B). 99mTc-methoxyisobutylisonitrile scintigraphy scan did not show uptake in the left thyroid lobe either 20 min (C) or 1 h (D) after tracer injection. 18F-flurodeoxiglucose positron emission tomography/computed tomography (E) did not show any uptake corresponding to the thyroid nodule detected by US. Histopathology revealed a hyperplastic nodule characterized by micro- and macrocalcifications (haematoxylin-eosin stain, 4×) (F).

  • View in gallery

    (A) 39 mm isoechoic solid nodule of the left thyroid lobe, characterized by well-defined margins and without microcalcifications (A). The vascularization of the nodule was significantly increased on colour-Doppler evaluation (B) and a high level of elasticity was found on real-time elastography (C). 99mTc-methoxyisobutylisonitrile scintigraphy scan showed intense uptake in the left thyroid lobe 20 min (D) and 1 h after tracer injection (E). 18F-flurodeoxiglucose positron emission tomography/computed tomography showed focal uptake corresponding to the thyroid nodule detected by US (F). Histopathology revealed a follicular adenoma (haematoxylin-eosin stain, 4 × (G) and haematoxylin-eosin stain, 10 × (H).

  • View in gallery

    (A) 12 mm hypoechoic solid nodule characterized by irregular margins located in the inferior part of the right thyroid lobe in the subcapsular region (A). The vascularization of the nodule was absent on colour-Doppler evaluation (B) and stiffness was mildly increased on real-time elastography (C). 99mTc-methoxyisobutylisonitrile scintigraphy scan did not show focal uptake in the right thyroid lobe either 20 min (D) or 1 h (E) after tracer injection. By contrast, 18F-flurodeoxiglucose positron emission tomography/computed tomography (F) showed focal uptake corresponding to the thyroid nodule detected by US. Histopathology (haematoxylin-eosin stain, 4 ×) revealed a papillary carcinoma (G).

  • View in gallery

    (A) 35 mm hypoechoic solid nodule of the isthmus, characterized by defined margins and without microcalcifications (A). The vascularization of the nodule was not significantly increased on colour-Doppler evaluation (B) and increased stiffness was found on real-time elastography (C). 99mTc-methoxyisobutylisonitrile scintigraphy scan showed intense uptake in the left thyroid lobe 20 min (D) and 1 h after tracer injection (E). 18F-flurodeoxiglucose positron emission tomography/computed tomography (F) showed focal uptake corresponding to the thyroid nodule detected by US. Histopathology (haematoxylin-eosin stain, 4 × (G) and 10 × (H)) revealed a follicular carcinoma.

  • 1

    Fadda G, Basolo F, Bondi A, Bussolati G, Crescenzi A, Nappi O, Nardi F, Papotti M, Taddei G, Palombini L & SIAPEC-IAP Italian Consensus Working Group. Cytological classification of thyroid nodules. Proposal of the SIAPEC-IAP Italian Consensus Working Group. Pathologica 2010 102 405408.

    • Search Google Scholar
    • Export Citation
  • 2

    Orlandi F, Saggiorato E, Pivano G, Puligheddu B, Termine A, Cappia S, De Giuli P, Angeli A. Galectine-3 is a presurgical marker of human thyroid carcinoma. Cancer Research 1998 58 30153020.

    • Search Google Scholar
    • Export Citation
  • 3

    Bartolazzi A, Gasbarri A, Papotti M, Bussolati G, Lucante T, Khan A, Inohara H, Marandino F, Orlandi F & Nardi F et al. Application of an immunodiagnostic method for improving preoperative diagnosis of nodular thyroid lesions. Lancet 2001 357 16441650.

    • Search Google Scholar
    • Export Citation
  • 4

    Trimboli P, Treglia G, Condorelli E, Romanelli F, Crescenzi A, Bongiovanni M, Giovanella L. BRAF-mutated carcinomas among thyroid nodules with prior indeterminate FNA report: a systematic review and meta-analysis. Clinical Endocrinology 2016 84 315320. (doi:10.1111/cen.12806).

    • Search Google Scholar
    • Export Citation
  • 5

    Ohori NP, Nikiforova MN, Schoedel KE, LeBeau SO, Hodak SP, Seethala RR, Carty SE, Ogilvie JB, Yip L, Nikiforov YE. Contribution of molecular testing to thyroid fine-needle aspiration cytology of ‘‘follicular lesion of undetermined significance/atypia of undetermined significance’’. Cancer Cytopathology 2010 25 1723. (doi:10.1002/cncy.20063)

    • Search Google Scholar
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  • 6

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