The role of elastography in evaluating thyroid nodules: a literature review and meta-analysis.

Eur Arch Otorhinolaryngol DOI 10.1007/s00405-014-3155-7

REVIEW ARTICLE

The role of elastography in evaluating thyroid nodules: a literature review and meta-analysis Vik Veer • Srikanth Puttagunta

Received: 13 April 2014 / Accepted: 12 June 2014 Springer-Verlag Berlin Heidelberg 2014

Abstract To appraise the literature for studies involving the use of elastography to diagnose thyroid nodule pathology. Two independent reviewers performed a systematic review of the English medical literature for studies involving elastography diagnosing thyroid nodule pathology. Data gleaned from this process was used in a metaanalysis to summarise the results. Thirty-eight studies were used in the meta-analysis totalling 5,942 thyroid nodules examined with elastography. The pooled results were sensitivity = 87.0 % (95 % confidence intervals (CI) = 86.2–87.9 %), specificity = 80.6 % (CI = 79.5– 81.6 %), positive predictive value (PPV) = 48.9 % (CI = 47.6–50.2 %), negative predictive value (NPV) = 96.7 % (CI = 96.2–97.1 %), diagnostic accuracy = 81.7 % (CI = 80.7–82.7 %). Subgroup analysis of the data is also presented. Elastography has its limitations in the diagnosis of thyroid nodules; however, its high NPV is increasingly being used as an important investigation and may allow a reduction in the number of hemi-thyroidectomies with benign pathology. Subgroup analysis suggests that elastography techniques where compressive force is performed in a non-user-dependant method results in improved final results. Keywords

Thyroid nodules Ultrasound Elastography

V. Veer (&) James Cook University Hospital, Marton Rd, Middlesbrough TS4 3BW, England, UK e-mail: [email protected] S. Puttagunta Glasgow Royal Infirmary, 84 Castle St, Glasgow, Glasgow City G4 0SF, Scotland, UK

Introduction Thyroid nodules are a common medical pathology. Prospective studies of randomly selected patients have reported a prevalence of thyroid nodules found on ultrasound to be 19–67 % [1]. Current practice in the United Kingdom is to perform an ultrasound examination of these nodules and a fine-needle aspiration cytology (FNAc) [2]. Ultrasonography is a particularly useful tool in the detection and measurement of thyroid nodules as well as improving the quality of FNAc sampling [3, 4]. Ultrasound features that are significantly more common within malignant lesions include the presence of micro-calcifications, coarse internal calcifications, markedly hypoechoic components, mostly solid-to-solid contents, infiltrative or micro-lobulated margins, taller-than-wide shape, and a high aspect ratio (0.85 vs 0.71) [5]. These features, however, are not specific enough to reliably diagnose malignancy. FNAc is more accurate in the differentiation between malignant and benign nodules; however, a significant proportion of samples still cannot be clearly diagnosed as having a malignancy or not [6]. In nodules with indeterminate FNAc results, some studies have shown the carcinoma rate to be as low as 15 % on the surgical specimen histology (i.e. post hemi-thyroidectomy) [7]. Elastography is a general term for the dynamic use of ultrasonography to provide an estimation of tissue stiffness by measuring the degree of elasticity of a nodule. By measuring to what degree a mass deforms under compressive stress, an estimate of its relative stiffness is made. Elastography has been used in breast [8], cervix [9], prostate [10], liver [11], pancreas [12] and parotid [13] to differentiate between different pathologies. This article examines the studies that have used ultrasound elastography to differentiate between benign and malignant thyroid nodules.

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Materials and methods A systematic review of the literature was performed using the core search term ‘‘Elastography’’ coupled with ‘‘Thyroid’’. The databases searched were Medline (1966 to February 2013), and EMBASE (1980 to February 2013). In addition, the obtained papers were examined for further potentially relevant papers. The last search was performed on the 9th February 2013. The selection criteria used were all studies that used elastography to study thyroid nodules in live human patients. Autopsy studies were excluded, as were any studies that only provided subjective results (i.e. ‘‘elastography was found to be a useful adjunct’’). Studies that did not provide enough data to be included in the statistical calculation for meta-analysis were excluded. Studies that were not translated into English were also excluded. The two reviewers performed the searches, using the selection criteria above, and produced a list of abstracts. The reviewers independently examined the two lists of abstracts for variations or disparities, and together agreed upon a definitive list of abstracts to assess further. Some abstracts did not provide all the data required to exclude or Fig. 1 Overall pooled results from all studies included in the meta-analysis (n = 5,942)

include into the review (e.g. available published data for meta-analysis). In these cases, the study was included into the review for further appraisal and subsequently excluded if selection criteria were not met. Electronic copies of the journal articles were obtained and independently assessed by the two reviewers.

Results Seventy-three articles were reviewed, but only 38 ultimately met all the selection criteria. There was significant variation between the studies as there is no standard method of performing elastography. The main elements of heterogeneity of the studies are described below. Delivery of the compressive force To show elasticity or the stiffness of a thyroid nodule, it has to be mechanically deformed and then allowed to return to a resting state again. A popular method of delivering a compressive force was for the technician to periodically apply manual pressure to the mass using the ultrasound

100.0% NPV, 96.7%

90.0% Sensitivity, 87.0%

Accuracy, 81.7%

Specificity, 80.6%

80.0%

Low CI

70.0%

Mean High CI

60.0%

50.0%

PPV, 48.9%

40.0% Sensitivity

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Specificity

PPV

NPV

Accuracy

Eur Arch Otorhinolaryngol Table 1 Summary of heterogeneity of the studies included in meta-analysis Author

Device used

Compression source

Scoring systems

Diagnosis results

Rago 2007 [14] Asteria 2008 [15] Ferrari 2008 [16] Hong 2009 [17] Luo 2009 [18]

Hitachi LOGOS EUB 8500

Manual compression Manual compression Manual compression Manual compression Carotid pulsation Carotid pulsation Manual compression Manual compression

1 to 5 cut off above 3

Surgery histology results only


FNA cytology and surgical histology





DSVI cut off at 0.019%

Cytology alone

Type 1 (benign) or type 2 (cancer) 1 to 4 cut off above 2

FNA cytology and surgical histology (indeterminate FNAc results were excluded) FNA cytology and surgical histology







Threshold 65kPa







FNA cytology and surgical histology (indeterminate FNAc results were excluded) Surgery histology results only

Dighe 2010 [19] Friedrich-Rust 2010 [20] GietkaCzernel 2010 [21] Kagoya 2010 [22] Rago 2010 [23] Sebag 2010 [24] Vorla¨nder 2010 [25] Wang 2010 [26] Bhatia 2011 [27] Lippolis 2011 [28] Luo 2011 [29] Merino 2011 [30] ¨ nlu¨tu¨rk 2011 U [31] Bojunga 2012 [32] Cappelli 2012 [33] Castisani 2012 [34] Castisani 2012 [35] Ciledag 2012 [36] Friedrich-Rust 2012 [37] Gu 2012 [38] Hong 2012 [39] Mansor 2012 [40] Ragazzoni 2012 [41] Slapa 2012 [42]

Hitachi LOGOS EUB 8500 Hitachi LOGOS EUB 8500 Hitachi LOGOS EUB 8500 Hitachi HI VISION 5500 Hitachi HI VISION 5500 Hitachi EUB 900 Hitachi Hivision Preirus

Hitachi LOGOS EUB 7500 Hitachi LOGOS EUB 8500 Aixplorer SuperSonic Imagine Hitachi LOGOS EUB 7500 Hitachi LOGOS EUB 8500 Siemens Acuson S2000 Hitachi system Hitachi HI VISION 5500 Siemens Acuson S2000 Hitachi EUB 7000 Hitachi EUB 900 Hitachi EUB 900 Toshiba Aplio XVG Toshiba Aplio XVG Toshiba Aplio XVG Hitachi HI Vision 900 Siemens Acuson S2000 Hitachi LOGOS EUB 8500 Hitachi HI Vision 900 Hitachi LOGOS EUB 7500 Esaote My Lab 70XVG Aixplorer SuperSonic Imagine

Manual compression Manual compression ShearWave propagation Manual compression Manual compression Manual compression Manual compression Carotid pulsation Manual compression Manual compression Manual compression Manual compression Manual compression Manual compression Manual compression Manual compression ShearWave propagation Manual compression Manual compression Manual compression ShearWave propagation

1 to 4 cut off above 2 Type 1 (benign) Type 2 (cancer) Type 1 = soft, type 2 = intermediate, type 3 = hard Type 1 = soft, type 2 = intermediate, type 3 = hard 1 to 4 cut off above 2

FNA cytology and surgical histology FNA cytology and surgical histology FNA cytology and surgical histology FNA cytology and surgical histology



Strain ratio [2


Strain ratio [2


1 to 5 cut off above 2.31 1 to 4 cut off above 2

FNA cytology (with 12 month follow up) and surgical histology FNA cytology and surgical histology









Threshold 65kPa


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Eur Arch Otorhinolaryngol Table 1 continued Author

Device used

Compression source

Scoring systems

Diagnosis results

Shuzhen 2012 [43] Stoian 2012 [44] Veyrieres 2012 [45] Azizi 2013 [46] Dighe 2013 [47] Mehrotra 2013 [48] Rivo-Vazquez 2013 [49] Russ 2013 [50] Shweel 2013 [51]

Hitachi HI Vision 900

Manual compression Manual compression ShearWave propagation Manual compression Carotid pulsation Manual compression Manual compression Manual compression Manual compression





Threshold 66kPa




Elasticity contrast index [3.6 = malignancy 0 to 2 cut off at 1




Quantitative strain value cut off at 0.045 1 to 5 with benign = 1?2 intermediate = 3 and malignant = 4?5


Hitachi EUB 7500 Aixplorer SuperSonic Imagine Siemens Acuson S2000 Hitachi HI VISION 5500 Hitachi EUB 7500 Siemens Acuson S2000 Toshiba Aplio XVG Siemens Acuson S2000

transducer. This however introduces an inherent variability between measurements, and variability between technicians as they would naturally apply different levels of force. Alternative methods of delivering the compressive force included utilising the pulsation from the carotid artery, or Shear waveTM imaging. Shear wave imaging involves measuring the velocity of device-generated Shear waves as they propagate in tissue. Shear wave propagation speed in tissue is directly related to tissue stiffness. Also, quantitative assessment of the true tissue elasticity, a reading in KPa, can be obtained with Shear wave elastography. These methods attempted to reduce the potential inter-observer variability. Table 1 describes the differing methods to apply a compressive force in the studies reviewed. Elastography device A surprising array of different elastography devices are currently being used by ultrasonographers. Each uses a different calculation formula, and technology to provide the elasticity measurement. Table 1 provides information about the ultrasound machines used in each study. Scoring systems Scoring the thyroid nodules elasticity was also a highly variable factor in the articles reviewed. Many studies required the technician to make a judgement on the elasticity from the image produced from the device. For example, the Ueno system showed softer tissues represented as blue, whereas stiffer tissues are coloured red. This again increases intra- and inter-observer variability and further degrades the

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confidence one may have in this technique. To reduce this variability, several devices produce an elasticity grade or class typically 1–4 or similar simple systems. Again this calculation is different in most devices. Other devices provide a raw value of KPa and use a cut-off value as the point where one should be suspicious of malignancy. Table 1 summarises the reviewed studies included in this review. Validation of results The highest level of validation accuracy for the elastography results was found when compared against thyroidectomy histological sampling. Since a significant number of thyroid nodules which are investigated, do not then go on to have a thyroidectomy, most studies elected to follow up those patients who did not have a histological specimen to compare against. Again, this data is summarised in Table 1. To perform an accurate calculation with the inherent heterogeneity described above, the reviewers used the absolute numbers of patients in each study and produced a contingency table with the collected data. The cut-off values and scores used in each individual study were used to delineate where patient numbers were placed in this table. The calculations were performed using Microsoft Excel statistical tools. The pooled results of all the studies included in the meta-analysis are provided below (n = 5,942). • •

Mean overall sensitivity = 87.0 % (95 % Confidence intervals (CI) = 86.2–87.9 %) Mean overall specificity = 80.6 % (95 % CI = 79.5– 81.6 %)


• • •

Mean overall positive predictive value (PPV) = 48.9 % (95 % CI = 47.6–50.2 %) Mean overall negative predictive value (NPV) = 96.7 % (95 % CI = 96.2–97.1 %) Mean overall diagnostic accuracy = 81.7 % (95 % CI = 80.7–82.7 %) These results are graphically represented in Fig. 1.

Subgroup analysis was performed in response to the heterogeneity found in these studies. The various methods of delivering the compressive force were individually compared and the results are provided below. The studies that only used surgical histology pathology results to validate their results were also analysed and the results are also provided below.

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Subgroup analysis of studies included in meta-analysis that used manual compression to assess the elasticity of thyroid nodules (n = 4,926) • • • • •

Mean sensitivity for manual compression subgroup = 86.5 % (95 % CI = 85.6–87.5 %). Mean specificity for manual compression subgroup = 79.7 % (95 % CI = 78.6–80.8 %) Mean positive predictive value (PPV) for manual compression subgroup = 46.9 % (95 % CI = 45.5–48.3 %) Mean negative predictive value (NPV) for manual compression subgroup = 96.6 % (95 % CI = 96.1–97.1 %) Mean diagnostic accuracy for manual compression subgroup = 80.9 % (95 % CI = 79.8–82.0 %)

These results are graphically represented in Fig. 2. Subgroup analysis of studies included in meta-analysis that used Shear wave propagation as the compressive force to assess the elasticity of thyroid nodules (n = 527) • •

Mean group Mean group

sensitivity for Shear = 85.9 % (95 % CI = specificity for Shear = 89.1 % (95 % CI =

Fig. 2 Subgroup analysis of studies included in metaanalysis that used manual compression to assess the elasticity of thyroid nodules (n = 4,926)

wave propagation sub82.9–88.9 %) wave propagation sub86.5–91.8 %)

•

•

•

Mean positive predictive value (PPV) for Shear wave propagation subgroup = 60.3 % (95 % CI = 56.2– 64.5 %) Mean negative predictive value (NPV) for Shear wave propagation subgroup = 97.0 % (95 % CI = 95.6– 98.5 %) Mean diagnostic accuracy for Shear wave propagation subgroup = 88.6 % (95 % CI = 85.9–91.3 %)

These results are graphically represented in Fig. 3. Subgroup analysis of studies included in meta-analysis that used carotid pulsation as the compressive force to assess the elasticity of thyroid nodules (n = 241) • • • • •

Mean sensitivity for carotid pulsation subgroup = 100.0 % (95 % CI = 100–100 %) Mean specificity for carotid pulsation subgroup = 77.2 % (95 % CI = 71.9–82.5 %) Mean positive predictive value (PPV) for carotid pulsation subgroup = 52.2 % (95 % CI = 45.9–58.5 %) Mean negative predictive value (NPV) for carotid pulsation subgroup = 100 % (95 % CI = 100–100 %) Mean diagnostic accuracy for carotid pulsation subgroup = 81.7 % (95 % CI = 76.9–86.6 %)

100.0% NPV, 96.6%

90.0%

Sensitivity, 86.5%

80.0%

Accuracy, 80.9%

Specificity, 79.7%

Low CI

70.0%

Mean High CI

60.0%

50.0% PPV, 46.9%

40.0% Sensitivity

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Specificity

PPV

NPV

Accuracy

Eur Arch Otorhinolaryngol Fig. 3 Subgroup analysis of studies included in metaanalysis that used Shear wave propagation as the compressive force to assess the elasticity of thyroid nodules (n = 527)

100.0% NPV, 97.0% 95.0%

90.0%

85.0%

Specificity, 89.1%

Accuracy, 88.6%

Sensitivity, 85.9%

80.0%

Low CI

75.0%

Mean High CI 70.0%

65.0%

PPV, 60.3%

60.0%

55.0%

50.0% Sensitivity

These results are graphically represented in Fig. 4. Subgroup analysis of studies included in meta-analysis that only used surgical histology results to validate their findings (n = 2,301). • • • • •

Mean sensitivity for histology only subgroup = 89.8 % (95 % CI = 88.6–91.0 %) Mean specificity for histology only subgroup = 80.3 % (95 % CI = 78.6–81.9 %) Mean positive predictive value (PPV) for histology only subgroup = 59.3 % (95 % CI = 57.3–61.3 %) Mean negative predictive value (NPV) for histology only subgroup = 96.1 % (95 % CI = 95.3–96.9 %) Mean diagnostic accuracy for histology only subgroup = 82.6 % (95 % CI = 81.0–84.1 %)

These results are graphically represented in Fig. 5. Further analysis of the data found that there was no significance found between studies that used elastography to assess only nodules that had an indeterminate or nondiagnostic FNAc result compared to the overall pooled result. Equally, this group was compared against the studies that did not assess nodules based upon FNAc result and again no significant difference was observed.

Specificity

PPV

NPV

Accuracy

Discussion The results of the meta-analysis show that the NPV (96.7 %) of elastography is very good when assessing a thyroid nodule for malignancy. Subgroup analysis would suggest that the differing methods of delivering a compressive force to these nodules had a significant impact in the ability of the elastography technique to evaluate malignant potential in thyroid nodules. In particular, carotid pulsation and Shear wave elastography produced better results. Firstly, carotid pulsation, when used as the compressive force, provided excellent results with 100 % sensitivity and NPV. Secondly, Shear wave elastography provided excellent overall results with 85.9 % sensitivity, 89.1 % specificity, 97 % NPV and a diagnostic accuracy of 91.3 %. Shear wave elastography is an attractive option as it gives a true tissue elasticity quantitative measurement in KPa, as well as qualitative information, facilitating numerical cut-offs [24, 42, 45]. It is a technology with potentially the least operator dependance and also has the option, ahead of carotid pulsation technology, for being applied to other tissues e.g. breast. An added advantage of using techniques that minimise

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Eur Arch Otorhinolaryngol Fig. 4 Subgroup analysis of studies included in metaanalysis that used carotid pulsation as the compressive force to assess the elasticity of thyroid nodules (n = 241)

100.0%

Sensitivity, 100.0%

NPV, 100.0%

90.0%

Accuracy, 81.7% 80.0% Specificity, 77.2%

Low CI

70.0%

Mean High CI

60.0%

PPV, 52.2% 50.0%

40.0% Sensitivity

Fig. 5 Subgroup analysis of studies included in metaanalysis that only used surgical histology results to validate their findings (n = 2,301)

Specificity

PPV

NPV

Accuracy

100.0% NPV, 96.1%

95.0%

90.0%

Sensitivity, 89.8%

85.0% Accuracy, 82.6%

Specificity, 80.3%

80.0%

Low CI

75.0%

Mean High CI 70.0%

65.0%

60.0%

PPV, 59.3%

55.0%

50.0%

Sensitivity

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Specificity

PPV

NPV

Accuracy


manual compression of thyroid nodules is that it reduces the risk of releasing malignant cells into the blood stream or lymphatic system. Many surgeons limit the handling of possibly malignant tissue in an effort to avoid circulation of tumour cells, and therefore, pre-operative manual compression of thyroid masses may be considered counter intuitive. In this respect, utilisation of carotid pulsation as the ‘compressive force’ would be the preferred technique. Therefore, on the basis of this meta-analysis, further investigation and evidence with these forms of elastography is suggested. The nodules that yielded non-diagnostic or indeterminate FNAc results seemed not to significantly alter the ability of elastography to assess these thyroid nodules. An area of uncertainty with regards to elastography is its use in predominantly cystic thyroid nodules. Firstly, nodules that are predominantly cystic were excluded in many studies. Rago [14] and Bhatia [27] have stated there is no role of elastography in cystic nodules. Some of the studies included in the meta-analysis excluded predominantly cystic nodules from their results. Overall, the benefits and evidence for this technique is rapidly growing particularly in the assessment of lowrisk cases. In a low-risk case, with an indeterminate or non-diagnostic FNAc result, one could use a negative elastography result to reassure a patient and initiate a period of observation, rather than electing for a hemithyroidectomy. Elastography could conceivably be used to triage 2-week wait cancer referred patients in a busy head and neck clinic. Obtaining a negative score on elastography for a thyroid mass in clinic, may allow the head and neck department to automatically remove that patient from the cancer waiting time. This would free up limited resources for patients with more suspicious lesions. For elastography to earn a place in the Head and Neck clinic, one would have to procure a device with low interobserver variability. The device would need minimal technical ability to handle it, and it should removal all ambiguity in the reporting of these nodules, for example a device with simple ‘benign’ or ‘suspicious’ result outcome value. Currently, elastography is an addition to high-specification ultrasound machines used by senior radiologists. Certainly the current gold standard initial radiological investigation for a thyroid mass is ultrasonography performed by a senior technician. The sole use of elastography in an outpatient setting is not currently possible. Its continued use, however, will undoubtedly increase, allowing radiologists to provide more definitive reports, and possibly reduce the number of FNAcs performed.

Conclusion Elastography is a promising technique, and the high NPV may be used to reassure patients and surgeons alike. There are clear limitations with the use of elastography and the authors suspect familiarity with technique and its results will delineate these advantages and disadvantages with greater clarity. The authors hope that its future use will reduce the number of hemi-thyroidectomies performed for benign thyroid nodules. At the very least, however, our hope is that this article will promote discussion of this technique amongst the surgical fraternity. Acknowledgments Dr Andrew McQueen, Consultant Head & Neck Radiologist, Freeman hospital, Newcastle, England for his invaluable advice and for providing the images of elastography scans. Ali Nikkar, ENT StR, Nottingham general hospital, England for procuring some of the publications for the meta-analysis. Conflict of interest There was no sponsorship or funding for this project, and no conflict of interest to declare.

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