Endocrine DOI 10.1007/s12020-014-0438-0
ORIGINAL ARTICLE
Diagnostic performance of elastography in cytologically indeterminate thyroid nodules Francesca Garino • Maurilio Deandrea • Manuela Motta • Alberto Mormile Federico Ragazzoni • Nicola Palestini • Milena Freddi • Guido Gasparri • Enrico Sgotto • Donatella Pacchioni • Paolo Piero Limone
•
Received: 13 June 2014 / Accepted: 23 September 2014 Springer Science+Business Media New York 2014
Abstract Cytological examination of material from fineneedle aspiration biopsy is the mainstay of diagnosis of thyroid nodules, thanks to its remarkable accuracy and scarcity of complications. However, follicular lesions (also called indeterminate lesions or Thy3 in the current classification), a heterogeneous group of lesions in which cytology is unable to give a definitive diagnosis to, represent its main limit. Elastography has been proposed as a potential diagnostic tool to define the risk of malignancy in the aforementioned nodules, but at present there is no conclusive data due to the small number of specifically addressed studies and the lack of concordance among them. The objective of our study was to evaluate the role of real-time
F. Garino (&) M. Deandrea A. Mormile F. Ragazzoni P. P. Limone Division of Endocrinology Diabetes and Metabolism, Department of Medicine, A.O. Ordine Mauriziano, Largo Turati 62, 10128 Turin, Italy e-mail: [email protected] M. Motta Department of Diagnostic and Clinical Pathology, S.C. Anatomy and Histopathology, A.O. Ordine Mauriziano, Largo Turati 62, 10128 Turin, Italy N. Palestini M. Freddi G. Gasparri Department of Surgery, S.C.U. General Surgery III, A.O.U. Citta` della Salute e della Scienza, Corso Bramante 88, 10126 Turin, Italy E. Sgotto Department of Surgery, SSD Thyroid Surgery, A.O. Ordine Mauriziano, Largo Turati 62, 10128 Turin, Italy D. Pacchioni Department of Laboratory Medicine, S.C.U. Diagnostic Anatomy and Histopathology, A.O.U Citta` della Salute e della Scienza, Corso Bramante 88, 10126 Turin, Italy
elastography (RTE) for refining diagnosis of Thy3 nodules, by integrating diagnostic information provided by traditional ultrasound (US). The study included 108 patients with Thy3 nodules awaiting for surgery, which were evaluated by US (considering hypoecogenicity, irregular margins, microcalcifications, halo sign, and intranodular vascularization) and RTE. Nodules were classified at RTE using a four-class color scale. At histologic examination, 75 nodules were benign and 33 malignant. As expected, none of the ultrasound parameters alone was adequate in predicting malignancy or benignity of the nodules; in the presence of at least two US risk factors, we obtained 61 % sensitivity, 83 % specificity, and 77 % accuracy with 6.8 OR (95 % CI 2.4–20.4). RTE scores 3 and 4 showed 76 % sensitivity, 88 % specificity, 74 % PPV, and 89 % NPV with diagnostic accuracy of 84 %; the data are statistically significant (p \ 0.0001) with a OR of 21.9 (95 % CI 7.1–76). By combining RTE with US parameters, the presence of at least 2 characters of suspicion had 88 % sensitivity and 94 % NPV with 23.8 OR (95 % CI 7–106.3). The use of combined RTE and US leads to the identification of two patients subpopulations which have a significantly different malignancy risk (6 vs. 63 %); further studies are needed to verify if it is possible to send only the first group to thyroidectomy and the other to follow-up. Keywords Radiology-Imaging Thyroid nodules Elastosonography Pathology-Thyroid Cytology Thyroid cancer-clinical Introduction Cytological examination of specimens from fine-needle aspiration biopsy (FNAB) is the mainstay of the diagnosis of thyroid nodules, due to its remarkable accuracy and low
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complications rate. Indeed, false-negative cytological diagnosis, generally due to inadequate sampling or interpretation errors, is rare, having a frequency of around 1–3 % [1]. False-positive diagnosis leading to the removal of benign lesions as a consequence of cytological misclassification are reported in a percentage between 1 and 8 %: they are mainly due to errors in interpretation, sample inadequacy, or inexperience on the part of the pathologist or to the presence of degenerative diseases (Hashimoto’s thyroiditis is the most commonly misunderstood disease) [2, 3]. Nevertheless, there are still some open issues such as follicular lesions, a heterogeneous group of lesions in which cytology is unable to put a definitive diagnosis to, because malignancy is defined by the morphological findings of vascular invasion and/or full-thickness infiltration of the capsule, features that cytology does not allow us to assess [4, 5]. On histological examination, these lesions may be follicular or H} urthle adenoma or carcinoma, follicular variant of papillary carcinoma, medullary cancer, microfollicular goiter, nodular hyperplasia, or thyroiditis. Various proposals have been made over time to improve the diagnostic accuracy of FNAB, but to date none has proved definitive. Indeed, clinical and ultrasound (US) criteria can be correlated with an increased risk of malignancy, but with a low predictive value [6, 7]; quite recent data on a small sample suggest irregular margins as a powerful predictor of malignancy [8], and an interesting meta-analysis showed a higher risk of cancer for patients who are male and have indeterminate thyroid nodules greater than 4 cm in diameter [9]. Immunohistochemistry [10] and biomolecular markers [11, 12] have improved the accuracy of cytological diagnosis but they are currently prerogative of specialized centres, and, therefore, their use is reserved only for selected patients [13]. Additional cytological criteria have been proposed to split indeterminate nodules (Thy3) into two subclasses with a different risk of malignancy [14]: indeed, according to the Bethesda System Classification, the risk of malignancy is 5–15 % for the so-called atypia/follicular lesion of undetermined significance, while it increases to 15–30 % in the so-called follicular neoplasms or suspicious for follicular neoplasm [15]. Such classification is now recommended in Great Britain and Italy [13, 16]. Core needle biopsy is one of the more promising tools to identify malignancy in Thy3 [17]; however, its use is not recommended, at present, in the routine management of follicular nodules [16]. Real-time elastography (RTE) is a dynamic US technique which differentiates tissues according to their stiffness or elasticity, as described in EFSUMB guidelines [18]; it has been proposed in several studies as an effective tool to predict the malignancy of unselected thyroid nodules ¨ nlu¨tu¨rk [19–30]; among them, only Rago, Ragazzoni, and U
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[20, 23, 25] evaluated RTE performances in a Thy3 nodule subgroups showing 71–100 % sensitivity (Se) and 44–96 % specificity (Sp). More recently, two studies have been specifically addressed to evaluate RTE utility in the management of Thy3 nodules, with contrasting results. Rago et al. in 2010 proposed a very promising future for elastography, showing 96.8 % Se, 91.8 % Sp, 76.9 % positive predictive value (PPV) and 92.9 % negative predictive value (NPV) in refining diagnosis on 142 Thy3 nodules. On the other hand, Lippolis et al. reported only 6 % Sp, 34 % PPV, and 50 % NPV for RTE; indeed, in 102 patients awaiting surgery for cytologically indeterminate nodules, they found only 8 elastic nodules out of 66 benign lesions which were diagnosed at final histological examination [31]. In our preliminary experience on 24 Thy3 nodules, RTE showed a slightly lower diagnostic performance than that obtained in unselected thyroid nodules, with 71.4 % Se, 64.7 % Sp, 84.6 % NPV, and 66 % accuracy [23]. The aim of this study was to evaluate the role of realtime elastography in refining the diagnosis of cytologically indeterminate thyroid nodules in comparison with traditional US, and to assess the diagnostic accuracy in this setting of the combination of both elastographic scores and traditional US parameters.
Materials and methods Patients Between March 2011 and April 2013, 108 patients awaiting surgery for cytologically indeterminate thyroid nodules were prospectively enrolled. Cystic or calcified lesions and nodular goiters with large or merging nodules were excluded from the study to avoid possible bias due to the technical limits of RTE technique. Surgery was performed at the Mauriziano Hospital Department of Surgery (25 patients) and at the Citta` della Salute Hospital Department of Surgery (83 patients). The study protocol was approved by the Institutional Ethical Committee, and all patients gave written informed consent before enrolment.
FNAB and cytology FNABs were carried out at the Citta` della Salute Hospital Department of Surgery or at the Mauriziano Hospital Department of Endocrinology, under US guidance through 21 or 23 Gauge needle. The cytological examination of the specimens was subsequently performed at the Departments of Pathology of both the Institutions. All patients awaiting surgery for Thy3 nodules underwent US and RTE.
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Fig. 1 Examples of four categories of elastographic images: a score 1: green (homogeneously elastic nodule), b score 2: red zones interposed to green and gray areas (prevalence of elastic tissue with some greater rigid areas which were not constantly present during
real-time evaluation), c score 3: prevalence of red with some green/ gray, generally at the periphery (prevalence of rigid areas), d score 4: prevalence of red (uniformly rigid nodule)
Ultrasound and elastography
microcalcifications, macrocalcifications, and calcification of the wall). Vascularization was classified into type I (absent), type II (peripheral), and type III (peripheral and intranodal). US signs of thyroiditis were also reported for each patient. In the second part of the examination, elastography was performed using the same probe after the activation of the elastographic module; the probe was used to slightly compress the tissue in the longitudinal axis, and the images obtained were compared with the previous frames. Elastograms were displayed using a chromatic scale, which could be superimposed or juxtaposed to the B-mode. The region-of-interest for elastography included the nodule and the surrounding thyroid parenchyma or subcutaneous tissue in order to have a real-time comparison between the elasticity of the nodule and that of the surrounding thyroid tissue. The software did not give, prior to the study, the absolute measurement of elasticity in kPa. Before starting the study, operators agreed to use
Thyroid US, Doppler US, and elastography were performed using Esaote MyLab 70XVG (Esaote SpA, Genoa, Italy) with 7.5–13 MHz linear probe and module ElaXto with CAM software. All patients were examined by endocrinologists (operator 1 M.D. or operator 2 A.M.) with more than 10 years’ experience in thyroid US and more than 3 years in elastography. The first part of the examination, carried out with the patient lying down with their head slightly hyperextended, was aimed at identifying the suspicious node and at evaluating its sonographic features and vascularization. For each of the selected nodules we analyzed, according to the Society of Radiologists in Ultrasound [32]: echogenicity (isoechoic, hypoechoic, hyperechoic, and anechoic), composition (solid, cystic, mixed, mainly mixed, predominantly cystic, or solid), margins (regular or irregular), halo (present, absent, and thickened), and calcifications (absent,
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Statistical analysis
Table 1 Type of surgery and histological features Surgery type Emythyroidectomy Emythyroidectomy ? radicalization Total thyroidectomy
20 6 82
Histologic diagnosis Benign
75
Malignant
33
Benign Adenoma
28
Nodular goiter
44
Thyroiditis
3
Malignant Follicular variant of papillar carcinoma
Results 12
Classical papillar carcinoma
9
Follicular carcinoma H}urthle cells carcinoma
8 3
Trabecolar carcinoma
1
a chromatic scale in which greater deformation (the elastic zone) was represented in green, lower deformation (rigid areas) in red and regions with a medium degree of deformability in gray. RTE was performed according to the technique previously described by Tranquart et al. [33]; elastographic images were classified into four categories, depicted in Fig. 1: • •
• •
Score 1: homogeneously elastic (green). Score 2: prevalence of elastic tissue with some greater rigid areas which were not constantly present during real-time evaluation (red zones interposed to green and gray areas). Score 3: prevalence of rigid areas (prevalence of red with some green/gray, generally on the periphery). Score 4: uniformly rigid (red nodules).
During examination, a real-time indication of the pressure applied by the probe on the basis of a six point scale was represented on the screen by a spring, in order to certify the extent of the pressure; only images obtained with a score greater than 4 were used to reduce interoperator variability and to ensure image quality. Surgery and histology All patients underwent surgery within 4 months of the exam. Histological examination was performed on sections of paraffin-embedded material which was colored using hematoxylin/eosin; neoplasms were classified according to WHO guidelines.
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Data with a normal distribution were expressed as mean and standard deviation, the other as median and InterQuartile Range (IQR). Sonographic and elastographic features were analyzed with v2 test and, when appropriate, with Fisher’s exact test. The predictivity test was obtained according to Galen and Gambino. Odds ratios with 95 % confidence intervals were used to determine the association of single parameters with malignancy risk. Statistical significance was set at p \ 0.05.
Patients and histology The study population was of 108 patients (81 females and 27 males) with a median age of 50 years old (IQR 40–60). Among these patients, we observed 57 multinodular goiters and 24 thyroiditis. Table 1 shows the type of surgery and the histological features. Ultrasound and elastography Sixty one examinations were carried out by M.D. and 47 by A.M. For each US risk factor (hypoechogenicity, irregular margins, altered peripheral halo, microcalcifications, and type 3 vascularization), Se, Sp, PPV, and NPV were calculated; diagnostic accuracy, as a predictor of malignancy, was determined, and odds ratio (OR) was calculated for each of them (Table 2). Hypoechogenicity is the most sensitive parameter, but it has unsatisfactory specificity; the opposite occurs in the presence of an altered peripheral halo and of microcalcifications. Irregular margins and type 3 vascularization provided a better diagnostic performance with good Sp (93 and 92 %, respectively) and NPV (74 and 77 %, respectively) and acceptable PPV (64 and 67 %); these two sonographic parameters were significant predictors of malignancy (p value 0.0097 and 0.0006, respectively), with an OR of 5.1 and 6.4, respectively (Table 2). There were no significant differences between the results of tests carried out by the two operators. The same analysis was performed by creating a panel with the US risk factors (Table 3). If we considered all the nodules which had any of the US risk factors as suspicious, we obtained the highest Se (97 %) and NPV (95 %), but Sp and diagnostic accuracy were very low (24 and 46 %, respectively). On the other hand, if we considered two altered parameters in order to predict malignancy, an acceptable Se (61 %), NPV (83 %), and PPV (61 %) were maintained with greater Sp and accuracy (83 and 76 %,
Endocrine Table 2 Diagnostic performance of ultrasound parameters Ultrasound parameters
Se (%)
Hypoechogenicity
88
24
Microcalcifications
18
95
3
Irregular margins Vascularization type 3
Halo sign
Sp (%)
PPV (%)
NPV (%)
Accuracy (%)
p
OR (95 % CI)
34
82
44
0.1999
2.3 (0.7–10)
60
72
71
0.0647
3.9 (0.8–20.2)
100
100
70
70
0.3056
27
93
64
74
73
0.0097
5.1 (1.4–21.6)
36
92
67
77
75
0.0006
6.4 (1.9–23.6)
–
p-values and OR reaching statistical significance are reported in italics Se sensitivity, Sp specificity, PPV positive predictive value, NPV negative predictive value, OR odds ratio, 95 % CI 95 % confidence interval
Table 3 Diagnostic performance of ultrasound parameters integration Ultrasound parameters
Se (%)
Sp (%)
PPV (%)
NPV (%)
Accuracy (%)
p
OR (95 % CI)
Number =/[ 1
97
24
36
95
46
0.0065
Number =/[ 2
61
83
61
83
76
\0.0001
– 6.8 (2.4–20.4)
p-values and OR reaching statistical significance are reported in italics Se sensitivity, Sp specificity, PPV positive predictive value, NPV negative predictive value, OR odds ratio, 95 % CI 95 % confidence interval Table 4 Prevalence of malignancy in thyroid nodules according to the elastographic score RTE score Score 1
Prevalence of cancer (%) 0/7 (0)
Score 2
8/67 (12)
Score 3
19/27 (70)
Score 4
6/7 (86)
respectively); moreover, suspicious nodules had a malignancy risk of 6.8 times higher than non-suspicious nodules (OR 6.8 with CI 95 % 2.4–20.4). At elastography, 7 nodules had score 1, 67 nodules had score 2, 27 nodules had score 3, and 7 nodules had score 4; all nodules with score 1 were benign on histology, while malignancy was found, respectively, in 8 nodules (12 %) which had score 2, 19 nodules (70 %) which had score 3, and 6 nodules (86 %) which had score 4 (Table 4). The distribution did not change regardless of which operator performed the examination. Considering scores 1 and 2 as predictors of benignity and scores 3 and 4 as suspicious for malignancy, elastography showed 76 % Se, 88 % Sp, 74 % PPV, and 89 % NPV with 84 % accuracy; the data are statistically significant (p \ 0.0001) with a 21.9 times higher risk of malignancy for rigid nodules than for those which are elastic (OR 21.9 with 95 % CI 7.1–76) (Table 5). Finally, we performed the statistical analysis including elastography in the US panel. By combining the presence of a suspicious elastographic score with the US B-mode parameters of suspicion, a significant increase in Se was obtained compared to that of using US alone, with a slight decrease in Sp. The presence of at least two characters of
suspicion either from US or elastography led to an improvement in the prediction of malignancy (Table 5). In this case, the risk of malignancy for suspicious nodules was 23.8 times higher than that of other nodules; indeed the NPV was 94 % and the association with elastography led to the identification of eight tumors which otherwise would not have been identified by B-mode US alone.
Discussion Cytology on material from FNAB is the main tool for the differential diagnosis of thyroid nodules; however, one of its fundamental limits is that of indeterminate lesions (10–25 % of all cytological results, depending on the series [34, 35]), for which guidelines suggest a surgical approach, despite a risk of malignancy not exceeding 20–30 %; it follows that in 70–80 % of the patients thyroidectomy is an exclusively diagnostic procedure and can, therefore, be regarded as unnecessary. In our study, the percentage of malignant nodules was 29 %, substantially in line with the most recent series concerning indeterminate lesions, in which malignancy was reported in 22–38 % of cases [27, 31, 36]; small differences among the series can be attributed to the selection criteria for surgery. The study population of patients we chose awaiting surgery may not represent the whole Thy3 group, as a number of subjects harboring Thy3 nodules do not undergo surgery but only follow-up; however, since our purpose was to evaluate the amount of diagnostic surgery that could be avoided using US ? RTE, we had to select patients with Thy3 nodules for which surgery was advised and histological diagnosis was available; moreover, to
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Endocrine Table 5 Diagnostic performance of elastography and of ultrasound/elastographic parameters integration Parameters
Se (%)
Sp (%)
PPV (%)
NPV (%)
Accuracy (%)
p
OR (95 % CI)
76
88
74
89
84
\0.0001
US/E number =[1
100
23
36
100
46
0.0013
US/E number =[2
88
77
63
94
81
\0.0001
Elastography
21.9 (7.1–76.0) – 23.8 (7–106.3)
p-values and OR reaching statistical significance are reported in italics Se sensitivity, Sp specificity, PPV positive predictive value, NPV negative predictive value, OR odds ratio, 95 % CI 95 % confidence interval
avoid further possible selection bias patients were consecutively enrolled. As to the rather elevated percentage of papillary carcinomas among our patients, at a glance this could be a surprising finding; however, we have to note that in other published series from centres with great experience in this field, the percentage of papillary cancers among nodules with THY3 cytology is even higher: in particular, in Rago’s series of 31 carcinomas 26 were papillary [36], in Lippolis’s report 34 out of 36 malignant nodules were papillary [31]; finally Trimboli et al. in 2012 reported on 14 papillary carcinomas among 16 malignant nodules [27]. Over time several procedures have been proposed to identify two groups of lesions at different risk of malignancy among Thy3 nodules, one to be sent to surgery and the other to follow-up, in order to reduce the number of ‘‘diagnostic’’ thyroidectomies. A recent report [17] point out core needle biopsy as an accurate tool in the identification of malignancies, however, more data are needed to confirm this. US is unhelpful in this case; indeed, high sensitivity parameters such as hypoechogenicity or solid composition have low specificity and predictive value, as these characteristics are also frequently found in benign nodules. Microcalcifications have high specificity and predictive value and are significantly associated with the diagnosis of malignancy [37], however, they are present in a small number of carcinomas. The combination of multiple parameters improves specificity and predictive value, though it reduces sensitivity [7]. The study of vascularity by Doppler and, more recently, power Doppler, added further elements of discrimination, although its actual diagnostic value is still being debated [38, 39]. To date, numerous studies have shown that malignant thyroid nodules are more rigid than benign nodules [19– 28]; therefore, elastography has been proposed as a new diagnostic tool to identify malignant lesions by assessing their elasticity. Data from different studies, reviewed in a recent meta-analysis, confirmed good sensitivity (92 %) and specificity (90 %) of the method on 639 nodules, despite a considerable variability of specificity between individual studies [29]. Some limits of RTE are represented by false positive, for example the nodules in acromegalic patients [40] or those previously treated by thermal
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ablation [41], and false negative such as intrathyroidal renal cell carcinoma metastasis [42] or medullary thyroid cancer [43]. Encouraging data have come from the small number of Thy3 lesions analyzed in studies aimed at evaluating the diagnostic role of elastography in the general population of thyroid nodules [20, 23, 25, 44–46]; further significant data emerged from the aforementioned study by Rago [36]; in sharp contrast, however, Lippolis [31] did not report any improvement in diagnostic accuracy by elastography in Thy3 nodules. In our experience [23], elastography was shown to have a role in the evaluation of thyroid nodules, leading to a better identification of those for which FNAB was advised; even in the population of cytologically indeterminate nodules, elastography seemed to be able to maintain interesting performance, though this data were obtained retrospectively on a small number of patients. The four-class score system was chosen because of its good sensitivity and NPV, as well as the good agreement between investigators [23, 27]; indeed intraoperator variability, which was one of the most worrying issues regarding ES clinical use, was confirmed as not relevant in our hands and in other experience [23, 47]. The present data obtained prospectively on a substantial number of nodules with indeterminate cytology attribute an important role to elastography in the clinical management of these lesions; indeed, an increased stiffness (score 3 or 4) was found in slightly less than 30 % of the population, and the majority of carcinomas (25 out of 33, 75 %) were found in this population, with a 22 times higher risk of malignancy (OR). Elastography alone showed an interestingly better diagnostic performance than that obtained by the best combination of US criteria (about 40 % of nodules were considered as suspicious, with correct identification of 21 out of 33 carcinomas, accounting for 63 %, with an OR of 6.8). Comparing these results with those of the two abovementioned studies, the elasticity distribution of nodules was substantially in line with the data reported by Rago (27 % of rigid or intermediate nodules) [36], differing markedly from that reported by Lippolis (92 % of rigid nodules) [31]. It is difficult to ascribe this difference to a different presence of cystic nodules in the various series, due to the fact that also in our series, as in that of Lippolis, most of the nodules were
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solid (87 %), and the remaining had a cystic portion which did not exceed 20 %. Diagnostic performance was still lower than that obtained by Rago, especially in terms of sensitivity (76 vs. 96 %), but was substantially similar in terms of specificity and NPV (both were slightly less than 90 %) with a slightly lower PPV (74 vs. 76 %). From a clinical point of view, the aim of a diagnostic test in this population should be to identify a subgroup with a very low risk of cancer, and then to reduce the number of unnecessary thyroidectomies. Due to the natural history of thyroid tumors, a minimal risk is acceptable in patients submitted to follow-up (especially considering that those nodules with benign cytology still have a cancer risk of around 2–3 %), thus maintaining acceptable cost-effectiveness. Completely elastic nodules (score 1) all had a benign histology (NPV 100 %). The main limitation, however, is that only 7 out of 108 nodules showed score 1; so that, only a few patients would benefit from follow-up instead of surgery. The group of nodules with score 2 was far larger (67 nodules), but a 12 % risk of malignancy in this group did not allow us to submit all those patients to follow-up. Traditional US involved roughly the same issues: if we consider those nodules which have no suspicious feature as benign, we can identify a population with a very low risk of malignancy (NPV 95 %), though this group is rather small (19 nodules out of 108); on the other hand, if we consider those nodules with one feature of malignancy as probably benign, the population significantly increases (74 nodules), although in this case the risk of malignancy (16.2 %) does not allow us to send patients to follow-up. The best performance was achieved integrating the two methods: indeed, if we consider those nodules that present no more than one feature of suspicion (either from US or from elastography) as benign, we obtain a population of 62 nodules (57 %) with a malignancy risk of 6.4 % (4 unidentified carcinomas), which could undergo followup; in the remaining 43 % of the nodules, 29 out of 33 carcinomas (88 %) are included, with a 63 % risk of malignancy. For these patients, thyroidectomy is advised.
Conclusions The results of this study provide useful information to improve clinical management of patients with nodular thyroid disease with cytological diagnosis of ‘‘follicular neoplasm.’’ On this basis, and in agreement with other literature data [36, 48], information provided by traditional ultrasonography can be integrated by elastography, a non-invasive and inexpensive test, which demonstrated good reproducibility among different trained operators [22, 23, 28, 31, 36].
In summary, patients with cytological diagnosis of ‘‘follicular neoplasm’’ should undergo to an US exam associated to real-time elastography; in the presence of two or more characters of suspicion (considering hypoechoic, irregular margins, altered peripheral halo, microcalcifications, type 3 vascularization, and score 3 or 4 at elastography), the patients should be sent to thyroidectomy, keeping in mind that even in this population about 40 % of interventions would be purely diagnostic: however, the number of ‘‘diagnostic’’ surgeries would be markedly reduced in respect to a surgical indication for the whole Thy 3 population. In the presence of no more than a single character of suspicion, patients should be sent to follow-up, due to the low residual risk of cancer (6 %), substantially similar to Thy1 nodules and slightly higher than those found in thyroid nodules with benign cytology. On this basis, the use of combined US and RTE improves the management of Thy3 leading to an important reduction in diagnostic surgery. However, interpretation of the results derived from the combination of US B-mode with elastography and the consequent therapeutic decisions cannot be made without first taking into account both clinical evaluation and laboratory criteria (high serum calcitonin, hard and fixed on deep layer thyroid nodules, the presence of suspicious lymphadenopathy, and solid nodules increasing in size) which, being suggestive of malignancy, constitute an indication for thyroidectomy, regardless of the US examination. Acknowledgments This study was Compagnia di San Paolo di Torino. Disclosure
partially
supported
by
No competing financial interests exist.
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43. M. Andrioli, P. Trimboli, S. Amendola, S. Valabrega, N. Fukunari, M. Mirella, L. Persani, Elastographic presentation of medullary thyroid carcinoma. Endocrine 45, 153–155 (2014) 44. C. Vorla¨nder, J. Wolff, S. Saalabian, R.H. Lienenlu¨ke, R.A. Wahl, Real-time ultrasound elastography—a noninvasive diagnostic procedure for evaluating dominant thyroid nodules. Langenbecks Arch. Surg. 395, 865–871 (2010) 45. B. Cakir, C. Aydin, B. Korukluog˘lu, D. Ozdemir, I.C. Sisman, D. Tu¨zu¨n, A. Oguz, G. Gu¨ler, G. Gu¨ney, A. Kus¸ demir, S.Y. Sanisoglu, R. Ersoy, Diagnostic value of elastosonographically determined strain index in the differential diagnosis of benign and malignant thyroid nodules. Endocrine 39, 89–98 (2011) 46. M. Friedrich-Rust, A. Sperber, K. Holzer, J. Diener, F. Gru¨nwald, K. Badenhoop, S. Weber, S. Kriener, E. Herrmann, W.O. Bechstein, S. Zeuzem, J. Bojunga, Real-time elastography and contrast-enhanced ultrasound for the assessment of thyroid nodules. Exp. Clin. Endocrinol. Diabetes 118, 602–609 (2010) 47. V. Cantisani, H. Grazhdani, P. Ricci, K. Mortele, M. Di Segni, V. D’Andrea, A. Redler, G. Di Rocco, L. Giacomelli, E. Maggini, C. Chiesa, S.M. Erturk, S. Sorrenti, C. Catalano, F. D’Ambrosio, Q-elastosonography of solid thyroid nodules: assessment of diagnostic efficacy and interobserver variability in a large patient cohort. Eur. Radiol. 24, 143–150 (2014) 48. V. Cantisani, S. Ulisse, E. Guaitoli, C. De Vito, R. Caruso, R. Mocini, V. D’Andrea, V. Ascoli, A. Antonaci, C. Catalano, F. Nardi, A. Redler, P. Ricci, E. De Antoni, S. Sorrenti, Q-elastography in the presurgical diagnosis of thyroid nodules with indeterminate cytology. PLoS ONE 7, e50725 (2012)
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ORIGINAL ARTICLE
Diagnostic performance of elastography in cytologically indeterminate thyroid nodules Francesca Garino • Maurilio Deandrea • Manuela Motta • Alberto Mormile Federico Ragazzoni • Nicola Palestini • Milena Freddi • Guido Gasparri • Enrico Sgotto • Donatella Pacchioni • Paolo Piero Limone
•
Received: 13 June 2014 / Accepted: 23 September 2014 Springer Science+Business Media New York 2014
Abstract Cytological examination of material from fineneedle aspiration biopsy is the mainstay of diagnosis of thyroid nodules, thanks to its remarkable accuracy and scarcity of complications. However, follicular lesions (also called indeterminate lesions or Thy3 in the current classification), a heterogeneous group of lesions in which cytology is unable to give a definitive diagnosis to, represent its main limit. Elastography has been proposed as a potential diagnostic tool to define the risk of malignancy in the aforementioned nodules, but at present there is no conclusive data due to the small number of specifically addressed studies and the lack of concordance among them. The objective of our study was to evaluate the role of real-time
F. Garino (&) M. Deandrea A. Mormile F. Ragazzoni P. P. Limone Division of Endocrinology Diabetes and Metabolism, Department of Medicine, A.O. Ordine Mauriziano, Largo Turati 62, 10128 Turin, Italy e-mail: [email protected] M. Motta Department of Diagnostic and Clinical Pathology, S.C. Anatomy and Histopathology, A.O. Ordine Mauriziano, Largo Turati 62, 10128 Turin, Italy N. Palestini M. Freddi G. Gasparri Department of Surgery, S.C.U. General Surgery III, A.O.U. Citta` della Salute e della Scienza, Corso Bramante 88, 10126 Turin, Italy E. Sgotto Department of Surgery, SSD Thyroid Surgery, A.O. Ordine Mauriziano, Largo Turati 62, 10128 Turin, Italy D. Pacchioni Department of Laboratory Medicine, S.C.U. Diagnostic Anatomy and Histopathology, A.O.U Citta` della Salute e della Scienza, Corso Bramante 88, 10126 Turin, Italy
elastography (RTE) for refining diagnosis of Thy3 nodules, by integrating diagnostic information provided by traditional ultrasound (US). The study included 108 patients with Thy3 nodules awaiting for surgery, which were evaluated by US (considering hypoecogenicity, irregular margins, microcalcifications, halo sign, and intranodular vascularization) and RTE. Nodules were classified at RTE using a four-class color scale. At histologic examination, 75 nodules were benign and 33 malignant. As expected, none of the ultrasound parameters alone was adequate in predicting malignancy or benignity of the nodules; in the presence of at least two US risk factors, we obtained 61 % sensitivity, 83 % specificity, and 77 % accuracy with 6.8 OR (95 % CI 2.4–20.4). RTE scores 3 and 4 showed 76 % sensitivity, 88 % specificity, 74 % PPV, and 89 % NPV with diagnostic accuracy of 84 %; the data are statistically significant (p \ 0.0001) with a OR of 21.9 (95 % CI 7.1–76). By combining RTE with US parameters, the presence of at least 2 characters of suspicion had 88 % sensitivity and 94 % NPV with 23.8 OR (95 % CI 7–106.3). The use of combined RTE and US leads to the identification of two patients subpopulations which have a significantly different malignancy risk (6 vs. 63 %); further studies are needed to verify if it is possible to send only the first group to thyroidectomy and the other to follow-up. Keywords Radiology-Imaging Thyroid nodules Elastosonography Pathology-Thyroid Cytology Thyroid cancer-clinical Introduction Cytological examination of specimens from fine-needle aspiration biopsy (FNAB) is the mainstay of the diagnosis of thyroid nodules, due to its remarkable accuracy and low
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complications rate. Indeed, false-negative cytological diagnosis, generally due to inadequate sampling or interpretation errors, is rare, having a frequency of around 1–3 % [1]. False-positive diagnosis leading to the removal of benign lesions as a consequence of cytological misclassification are reported in a percentage between 1 and 8 %: they are mainly due to errors in interpretation, sample inadequacy, or inexperience on the part of the pathologist or to the presence of degenerative diseases (Hashimoto’s thyroiditis is the most commonly misunderstood disease) [2, 3]. Nevertheless, there are still some open issues such as follicular lesions, a heterogeneous group of lesions in which cytology is unable to put a definitive diagnosis to, because malignancy is defined by the morphological findings of vascular invasion and/or full-thickness infiltration of the capsule, features that cytology does not allow us to assess [4, 5]. On histological examination, these lesions may be follicular or H} urthle adenoma or carcinoma, follicular variant of papillary carcinoma, medullary cancer, microfollicular goiter, nodular hyperplasia, or thyroiditis. Various proposals have been made over time to improve the diagnostic accuracy of FNAB, but to date none has proved definitive. Indeed, clinical and ultrasound (US) criteria can be correlated with an increased risk of malignancy, but with a low predictive value [6, 7]; quite recent data on a small sample suggest irregular margins as a powerful predictor of malignancy [8], and an interesting meta-analysis showed a higher risk of cancer for patients who are male and have indeterminate thyroid nodules greater than 4 cm in diameter [9]. Immunohistochemistry [10] and biomolecular markers [11, 12] have improved the accuracy of cytological diagnosis but they are currently prerogative of specialized centres, and, therefore, their use is reserved only for selected patients [13]. Additional cytological criteria have been proposed to split indeterminate nodules (Thy3) into two subclasses with a different risk of malignancy [14]: indeed, according to the Bethesda System Classification, the risk of malignancy is 5–15 % for the so-called atypia/follicular lesion of undetermined significance, while it increases to 15–30 % in the so-called follicular neoplasms or suspicious for follicular neoplasm [15]. Such classification is now recommended in Great Britain and Italy [13, 16]. Core needle biopsy is one of the more promising tools to identify malignancy in Thy3 [17]; however, its use is not recommended, at present, in the routine management of follicular nodules [16]. Real-time elastography (RTE) is a dynamic US technique which differentiates tissues according to their stiffness or elasticity, as described in EFSUMB guidelines [18]; it has been proposed in several studies as an effective tool to predict the malignancy of unselected thyroid nodules ¨ nlu¨tu¨rk [19–30]; among them, only Rago, Ragazzoni, and U
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[20, 23, 25] evaluated RTE performances in a Thy3 nodule subgroups showing 71–100 % sensitivity (Se) and 44–96 % specificity (Sp). More recently, two studies have been specifically addressed to evaluate RTE utility in the management of Thy3 nodules, with contrasting results. Rago et al. in 2010 proposed a very promising future for elastography, showing 96.8 % Se, 91.8 % Sp, 76.9 % positive predictive value (PPV) and 92.9 % negative predictive value (NPV) in refining diagnosis on 142 Thy3 nodules. On the other hand, Lippolis et al. reported only 6 % Sp, 34 % PPV, and 50 % NPV for RTE; indeed, in 102 patients awaiting surgery for cytologically indeterminate nodules, they found only 8 elastic nodules out of 66 benign lesions which were diagnosed at final histological examination [31]. In our preliminary experience on 24 Thy3 nodules, RTE showed a slightly lower diagnostic performance than that obtained in unselected thyroid nodules, with 71.4 % Se, 64.7 % Sp, 84.6 % NPV, and 66 % accuracy [23]. The aim of this study was to evaluate the role of realtime elastography in refining the diagnosis of cytologically indeterminate thyroid nodules in comparison with traditional US, and to assess the diagnostic accuracy in this setting of the combination of both elastographic scores and traditional US parameters.
Materials and methods Patients Between March 2011 and April 2013, 108 patients awaiting surgery for cytologically indeterminate thyroid nodules were prospectively enrolled. Cystic or calcified lesions and nodular goiters with large or merging nodules were excluded from the study to avoid possible bias due to the technical limits of RTE technique. Surgery was performed at the Mauriziano Hospital Department of Surgery (25 patients) and at the Citta` della Salute Hospital Department of Surgery (83 patients). The study protocol was approved by the Institutional Ethical Committee, and all patients gave written informed consent before enrolment.
FNAB and cytology FNABs were carried out at the Citta` della Salute Hospital Department of Surgery or at the Mauriziano Hospital Department of Endocrinology, under US guidance through 21 or 23 Gauge needle. The cytological examination of the specimens was subsequently performed at the Departments of Pathology of both the Institutions. All patients awaiting surgery for Thy3 nodules underwent US and RTE.
Endocrine
Fig. 1 Examples of four categories of elastographic images: a score 1: green (homogeneously elastic nodule), b score 2: red zones interposed to green and gray areas (prevalence of elastic tissue with some greater rigid areas which were not constantly present during
real-time evaluation), c score 3: prevalence of red with some green/ gray, generally at the periphery (prevalence of rigid areas), d score 4: prevalence of red (uniformly rigid nodule)
Ultrasound and elastography
microcalcifications, macrocalcifications, and calcification of the wall). Vascularization was classified into type I (absent), type II (peripheral), and type III (peripheral and intranodal). US signs of thyroiditis were also reported for each patient. In the second part of the examination, elastography was performed using the same probe after the activation of the elastographic module; the probe was used to slightly compress the tissue in the longitudinal axis, and the images obtained were compared with the previous frames. Elastograms were displayed using a chromatic scale, which could be superimposed or juxtaposed to the B-mode. The region-of-interest for elastography included the nodule and the surrounding thyroid parenchyma or subcutaneous tissue in order to have a real-time comparison between the elasticity of the nodule and that of the surrounding thyroid tissue. The software did not give, prior to the study, the absolute measurement of elasticity in kPa. Before starting the study, operators agreed to use
Thyroid US, Doppler US, and elastography were performed using Esaote MyLab 70XVG (Esaote SpA, Genoa, Italy) with 7.5–13 MHz linear probe and module ElaXto with CAM software. All patients were examined by endocrinologists (operator 1 M.D. or operator 2 A.M.) with more than 10 years’ experience in thyroid US and more than 3 years in elastography. The first part of the examination, carried out with the patient lying down with their head slightly hyperextended, was aimed at identifying the suspicious node and at evaluating its sonographic features and vascularization. For each of the selected nodules we analyzed, according to the Society of Radiologists in Ultrasound [32]: echogenicity (isoechoic, hypoechoic, hyperechoic, and anechoic), composition (solid, cystic, mixed, mainly mixed, predominantly cystic, or solid), margins (regular or irregular), halo (present, absent, and thickened), and calcifications (absent,
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Statistical analysis
Table 1 Type of surgery and histological features Surgery type Emythyroidectomy Emythyroidectomy ? radicalization Total thyroidectomy
20 6 82
Histologic diagnosis Benign
75
Malignant
33
Benign Adenoma
28
Nodular goiter
44
Thyroiditis
3
Malignant Follicular variant of papillar carcinoma
Results 12
Classical papillar carcinoma
9
Follicular carcinoma H}urthle cells carcinoma
8 3
Trabecolar carcinoma
1
a chromatic scale in which greater deformation (the elastic zone) was represented in green, lower deformation (rigid areas) in red and regions with a medium degree of deformability in gray. RTE was performed according to the technique previously described by Tranquart et al. [33]; elastographic images were classified into four categories, depicted in Fig. 1: • •
• •
Score 1: homogeneously elastic (green). Score 2: prevalence of elastic tissue with some greater rigid areas which were not constantly present during real-time evaluation (red zones interposed to green and gray areas). Score 3: prevalence of rigid areas (prevalence of red with some green/gray, generally on the periphery). Score 4: uniformly rigid (red nodules).
During examination, a real-time indication of the pressure applied by the probe on the basis of a six point scale was represented on the screen by a spring, in order to certify the extent of the pressure; only images obtained with a score greater than 4 were used to reduce interoperator variability and to ensure image quality. Surgery and histology All patients underwent surgery within 4 months of the exam. Histological examination was performed on sections of paraffin-embedded material which was colored using hematoxylin/eosin; neoplasms were classified according to WHO guidelines.
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Data with a normal distribution were expressed as mean and standard deviation, the other as median and InterQuartile Range (IQR). Sonographic and elastographic features were analyzed with v2 test and, when appropriate, with Fisher’s exact test. The predictivity test was obtained according to Galen and Gambino. Odds ratios with 95 % confidence intervals were used to determine the association of single parameters with malignancy risk. Statistical significance was set at p \ 0.05.
Patients and histology The study population was of 108 patients (81 females and 27 males) with a median age of 50 years old (IQR 40–60). Among these patients, we observed 57 multinodular goiters and 24 thyroiditis. Table 1 shows the type of surgery and the histological features. Ultrasound and elastography Sixty one examinations were carried out by M.D. and 47 by A.M. For each US risk factor (hypoechogenicity, irregular margins, altered peripheral halo, microcalcifications, and type 3 vascularization), Se, Sp, PPV, and NPV were calculated; diagnostic accuracy, as a predictor of malignancy, was determined, and odds ratio (OR) was calculated for each of them (Table 2). Hypoechogenicity is the most sensitive parameter, but it has unsatisfactory specificity; the opposite occurs in the presence of an altered peripheral halo and of microcalcifications. Irregular margins and type 3 vascularization provided a better diagnostic performance with good Sp (93 and 92 %, respectively) and NPV (74 and 77 %, respectively) and acceptable PPV (64 and 67 %); these two sonographic parameters were significant predictors of malignancy (p value 0.0097 and 0.0006, respectively), with an OR of 5.1 and 6.4, respectively (Table 2). There were no significant differences between the results of tests carried out by the two operators. The same analysis was performed by creating a panel with the US risk factors (Table 3). If we considered all the nodules which had any of the US risk factors as suspicious, we obtained the highest Se (97 %) and NPV (95 %), but Sp and diagnostic accuracy were very low (24 and 46 %, respectively). On the other hand, if we considered two altered parameters in order to predict malignancy, an acceptable Se (61 %), NPV (83 %), and PPV (61 %) were maintained with greater Sp and accuracy (83 and 76 %,
Endocrine Table 2 Diagnostic performance of ultrasound parameters Ultrasound parameters
Se (%)
Hypoechogenicity
88
24
Microcalcifications
18
95
3
Irregular margins Vascularization type 3
Halo sign
Sp (%)
PPV (%)
NPV (%)
Accuracy (%)
p
OR (95 % CI)
34
82
44
0.1999
2.3 (0.7–10)
60
72
71
0.0647
3.9 (0.8–20.2)
100
100
70
70
0.3056
27
93
64
74
73
0.0097
5.1 (1.4–21.6)
36
92
67
77
75
0.0006
6.4 (1.9–23.6)
–
p-values and OR reaching statistical significance are reported in italics Se sensitivity, Sp specificity, PPV positive predictive value, NPV negative predictive value, OR odds ratio, 95 % CI 95 % confidence interval
Table 3 Diagnostic performance of ultrasound parameters integration Ultrasound parameters
Se (%)
Sp (%)
PPV (%)
NPV (%)
Accuracy (%)
p
OR (95 % CI)
Number =/[ 1
97
24
36
95
46
0.0065
Number =/[ 2
61
83
61
83
76
\0.0001
– 6.8 (2.4–20.4)
p-values and OR reaching statistical significance are reported in italics Se sensitivity, Sp specificity, PPV positive predictive value, NPV negative predictive value, OR odds ratio, 95 % CI 95 % confidence interval Table 4 Prevalence of malignancy in thyroid nodules according to the elastographic score RTE score Score 1
Prevalence of cancer (%) 0/7 (0)
Score 2
8/67 (12)
Score 3
19/27 (70)
Score 4
6/7 (86)
respectively); moreover, suspicious nodules had a malignancy risk of 6.8 times higher than non-suspicious nodules (OR 6.8 with CI 95 % 2.4–20.4). At elastography, 7 nodules had score 1, 67 nodules had score 2, 27 nodules had score 3, and 7 nodules had score 4; all nodules with score 1 were benign on histology, while malignancy was found, respectively, in 8 nodules (12 %) which had score 2, 19 nodules (70 %) which had score 3, and 6 nodules (86 %) which had score 4 (Table 4). The distribution did not change regardless of which operator performed the examination. Considering scores 1 and 2 as predictors of benignity and scores 3 and 4 as suspicious for malignancy, elastography showed 76 % Se, 88 % Sp, 74 % PPV, and 89 % NPV with 84 % accuracy; the data are statistically significant (p \ 0.0001) with a 21.9 times higher risk of malignancy for rigid nodules than for those which are elastic (OR 21.9 with 95 % CI 7.1–76) (Table 5). Finally, we performed the statistical analysis including elastography in the US panel. By combining the presence of a suspicious elastographic score with the US B-mode parameters of suspicion, a significant increase in Se was obtained compared to that of using US alone, with a slight decrease in Sp. The presence of at least two characters of
suspicion either from US or elastography led to an improvement in the prediction of malignancy (Table 5). In this case, the risk of malignancy for suspicious nodules was 23.8 times higher than that of other nodules; indeed the NPV was 94 % and the association with elastography led to the identification of eight tumors which otherwise would not have been identified by B-mode US alone.
Discussion Cytology on material from FNAB is the main tool for the differential diagnosis of thyroid nodules; however, one of its fundamental limits is that of indeterminate lesions (10–25 % of all cytological results, depending on the series [34, 35]), for which guidelines suggest a surgical approach, despite a risk of malignancy not exceeding 20–30 %; it follows that in 70–80 % of the patients thyroidectomy is an exclusively diagnostic procedure and can, therefore, be regarded as unnecessary. In our study, the percentage of malignant nodules was 29 %, substantially in line with the most recent series concerning indeterminate lesions, in which malignancy was reported in 22–38 % of cases [27, 31, 36]; small differences among the series can be attributed to the selection criteria for surgery. The study population of patients we chose awaiting surgery may not represent the whole Thy3 group, as a number of subjects harboring Thy3 nodules do not undergo surgery but only follow-up; however, since our purpose was to evaluate the amount of diagnostic surgery that could be avoided using US ? RTE, we had to select patients with Thy3 nodules for which surgery was advised and histological diagnosis was available; moreover, to
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Endocrine Table 5 Diagnostic performance of elastography and of ultrasound/elastographic parameters integration Parameters
Se (%)
Sp (%)
PPV (%)
NPV (%)
Accuracy (%)
p
OR (95 % CI)
76
88
74
89
84
\0.0001
US/E number =[1
100
23
36
100
46
0.0013
US/E number =[2
88
77
63
94
81
\0.0001
Elastography
21.9 (7.1–76.0) – 23.8 (7–106.3)
p-values and OR reaching statistical significance are reported in italics Se sensitivity, Sp specificity, PPV positive predictive value, NPV negative predictive value, OR odds ratio, 95 % CI 95 % confidence interval
avoid further possible selection bias patients were consecutively enrolled. As to the rather elevated percentage of papillary carcinomas among our patients, at a glance this could be a surprising finding; however, we have to note that in other published series from centres with great experience in this field, the percentage of papillary cancers among nodules with THY3 cytology is even higher: in particular, in Rago’s series of 31 carcinomas 26 were papillary [36], in Lippolis’s report 34 out of 36 malignant nodules were papillary [31]; finally Trimboli et al. in 2012 reported on 14 papillary carcinomas among 16 malignant nodules [27]. Over time several procedures have been proposed to identify two groups of lesions at different risk of malignancy among Thy3 nodules, one to be sent to surgery and the other to follow-up, in order to reduce the number of ‘‘diagnostic’’ thyroidectomies. A recent report [17] point out core needle biopsy as an accurate tool in the identification of malignancies, however, more data are needed to confirm this. US is unhelpful in this case; indeed, high sensitivity parameters such as hypoechogenicity or solid composition have low specificity and predictive value, as these characteristics are also frequently found in benign nodules. Microcalcifications have high specificity and predictive value and are significantly associated with the diagnosis of malignancy [37], however, they are present in a small number of carcinomas. The combination of multiple parameters improves specificity and predictive value, though it reduces sensitivity [7]. The study of vascularity by Doppler and, more recently, power Doppler, added further elements of discrimination, although its actual diagnostic value is still being debated [38, 39]. To date, numerous studies have shown that malignant thyroid nodules are more rigid than benign nodules [19– 28]; therefore, elastography has been proposed as a new diagnostic tool to identify malignant lesions by assessing their elasticity. Data from different studies, reviewed in a recent meta-analysis, confirmed good sensitivity (92 %) and specificity (90 %) of the method on 639 nodules, despite a considerable variability of specificity between individual studies [29]. Some limits of RTE are represented by false positive, for example the nodules in acromegalic patients [40] or those previously treated by thermal
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ablation [41], and false negative such as intrathyroidal renal cell carcinoma metastasis [42] or medullary thyroid cancer [43]. Encouraging data have come from the small number of Thy3 lesions analyzed in studies aimed at evaluating the diagnostic role of elastography in the general population of thyroid nodules [20, 23, 25, 44–46]; further significant data emerged from the aforementioned study by Rago [36]; in sharp contrast, however, Lippolis [31] did not report any improvement in diagnostic accuracy by elastography in Thy3 nodules. In our experience [23], elastography was shown to have a role in the evaluation of thyroid nodules, leading to a better identification of those for which FNAB was advised; even in the population of cytologically indeterminate nodules, elastography seemed to be able to maintain interesting performance, though this data were obtained retrospectively on a small number of patients. The four-class score system was chosen because of its good sensitivity and NPV, as well as the good agreement between investigators [23, 27]; indeed intraoperator variability, which was one of the most worrying issues regarding ES clinical use, was confirmed as not relevant in our hands and in other experience [23, 47]. The present data obtained prospectively on a substantial number of nodules with indeterminate cytology attribute an important role to elastography in the clinical management of these lesions; indeed, an increased stiffness (score 3 or 4) was found in slightly less than 30 % of the population, and the majority of carcinomas (25 out of 33, 75 %) were found in this population, with a 22 times higher risk of malignancy (OR). Elastography alone showed an interestingly better diagnostic performance than that obtained by the best combination of US criteria (about 40 % of nodules were considered as suspicious, with correct identification of 21 out of 33 carcinomas, accounting for 63 %, with an OR of 6.8). Comparing these results with those of the two abovementioned studies, the elasticity distribution of nodules was substantially in line with the data reported by Rago (27 % of rigid or intermediate nodules) [36], differing markedly from that reported by Lippolis (92 % of rigid nodules) [31]. It is difficult to ascribe this difference to a different presence of cystic nodules in the various series, due to the fact that also in our series, as in that of Lippolis, most of the nodules were
Endocrine
solid (87 %), and the remaining had a cystic portion which did not exceed 20 %. Diagnostic performance was still lower than that obtained by Rago, especially in terms of sensitivity (76 vs. 96 %), but was substantially similar in terms of specificity and NPV (both were slightly less than 90 %) with a slightly lower PPV (74 vs. 76 %). From a clinical point of view, the aim of a diagnostic test in this population should be to identify a subgroup with a very low risk of cancer, and then to reduce the number of unnecessary thyroidectomies. Due to the natural history of thyroid tumors, a minimal risk is acceptable in patients submitted to follow-up (especially considering that those nodules with benign cytology still have a cancer risk of around 2–3 %), thus maintaining acceptable cost-effectiveness. Completely elastic nodules (score 1) all had a benign histology (NPV 100 %). The main limitation, however, is that only 7 out of 108 nodules showed score 1; so that, only a few patients would benefit from follow-up instead of surgery. The group of nodules with score 2 was far larger (67 nodules), but a 12 % risk of malignancy in this group did not allow us to submit all those patients to follow-up. Traditional US involved roughly the same issues: if we consider those nodules which have no suspicious feature as benign, we can identify a population with a very low risk of malignancy (NPV 95 %), though this group is rather small (19 nodules out of 108); on the other hand, if we consider those nodules with one feature of malignancy as probably benign, the population significantly increases (74 nodules), although in this case the risk of malignancy (16.2 %) does not allow us to send patients to follow-up. The best performance was achieved integrating the two methods: indeed, if we consider those nodules that present no more than one feature of suspicion (either from US or from elastography) as benign, we obtain a population of 62 nodules (57 %) with a malignancy risk of 6.4 % (4 unidentified carcinomas), which could undergo followup; in the remaining 43 % of the nodules, 29 out of 33 carcinomas (88 %) are included, with a 63 % risk of malignancy. For these patients, thyroidectomy is advised.
Conclusions The results of this study provide useful information to improve clinical management of patients with nodular thyroid disease with cytological diagnosis of ‘‘follicular neoplasm.’’ On this basis, and in agreement with other literature data [36, 48], information provided by traditional ultrasonography can be integrated by elastography, a non-invasive and inexpensive test, which demonstrated good reproducibility among different trained operators [22, 23, 28, 31, 36].
In summary, patients with cytological diagnosis of ‘‘follicular neoplasm’’ should undergo to an US exam associated to real-time elastography; in the presence of two or more characters of suspicion (considering hypoechoic, irregular margins, altered peripheral halo, microcalcifications, type 3 vascularization, and score 3 or 4 at elastography), the patients should be sent to thyroidectomy, keeping in mind that even in this population about 40 % of interventions would be purely diagnostic: however, the number of ‘‘diagnostic’’ surgeries would be markedly reduced in respect to a surgical indication for the whole Thy 3 population. In the presence of no more than a single character of suspicion, patients should be sent to follow-up, due to the low residual risk of cancer (6 %), substantially similar to Thy1 nodules and slightly higher than those found in thyroid nodules with benign cytology. On this basis, the use of combined US and RTE improves the management of Thy3 leading to an important reduction in diagnostic surgery. However, interpretation of the results derived from the combination of US B-mode with elastography and the consequent therapeutic decisions cannot be made without first taking into account both clinical evaluation and laboratory criteria (high serum calcitonin, hard and fixed on deep layer thyroid nodules, the presence of suspicious lymphadenopathy, and solid nodules increasing in size) which, being suggestive of malignancy, constitute an indication for thyroidectomy, regardless of the US examination. Acknowledgments This study was Compagnia di San Paolo di Torino. Disclosure
partially
supported
by
No competing financial interests exist.
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