Thyroid Ultrasound: State of the Art. Part 2 – Focal Thyroid Lesions

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Review

DOI: 10.11152/mu-999

Thyroid Ultrasound: State of the Art. Part 2 – Focal Thyroid Lesions

Manjiri Dighe

¹

, Richard Barr

²

, Jörg Bojunga

³

, Vito Cantisani

⁴

, Maria Cristina Chammas

⁵

, David Cosgrove6, Xin-Wu Cui

⁷

, Yi Dong

⁸

, Franziska Fenner

⁹

, Maija Radzina

¹⁰

,

Sudhir Vinayak

¹¹

, Jun-Mei Xu

¹²

, Christoph F Dietrich

^13,14

1Department of Radiology, University of Washington, Seattle, USA, ²Department of Radiology, Northeastern Ohio Medical University, Rootstown, Ohio, USA and Southwoods Imaging, Youngstown, Ohio, USA, ³Department of Internal Medicine 1, Endocrinology and Diabetology, Goethe University Hospital, Frankfurt am Main, Germany, ⁴De- partment of Radiological Sciences, Oncology and Pathology, Policlinico Umberto I, University Sapienza, Rome, Italy,

5Ultrasound Division, Department of Radiology, Hospital das Clínicas, School of Medicine, University of São Paulo, São Paulo, Brazil, ⁶Division of Radiology, Imperial and Kings Colleges, London, UK, ⁷Department of Internal Medi- cine 2, Caritas-Krankenhaus Bad Mergentheim, Germany, ⁸Department of Ultrasound, Zhongshan Hospital, Fudan University, Shanghai, China, ⁹Department of Surgery, Caritas-Krankenhaus Bad Mergentheim, Germany, ¹⁰Diagnostic Radiology Institute, Paula Stradins Clinical University Hospital, Riga, Latvia, ¹¹Department of Imaging and Diag- nostic Radiology, Aga Khan University Hospital, Nairobi, Kenya, ¹²Department of Medical Ultrasound, Shanghai Tenth People’s Hospital, Ultrasound Research and Education Institute, Tongji University School of Medicine, China,

13Department of Internal Medicine 2, Caritas Hospital, Bad Mergentheim, Germany,¹⁴Sino-German Research Center of Ultrasound in Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

Received 20.11.2016 Accepted 22.12.2016 Med Ultrason

2017, Vol. 19, No 2, 195-210

Corresponding author: Prof. Dr. med. Christoph F. Dietrich Department of Internal Medicine 2, Caritas Krankenhaus, Uhlandstr. 7, D-97980 Bad Mergentheim, Germany Phone: 49 (0)7931 – 58 – 2201 / 2200 Fax: 49 (0)7931 – 58 – 2290 Email: [email protected]

Introduction

Focal thyroid lesions are common, with almost 50%

of the population having thyroid nodules as per the au- topsy database. The number of thyroid nodules also increases with age. Differentiation between benign and malignant nodules is important and even though fine nee-

dle aspiration (FNA) is the gold standard for diagnosis, pre-screening with ultrasound (US) is essential since per- forming FNA in all nodules is not feasible. US elastography is an additional non-invasive tool that is available and able to differentiate between benign and malignant nodules. This second part of the State of the Art Thyroid Ultrasound imaging deals with focal thyroid lesions and provides information about US and new techniques like elastography and contrast enhanced US (CEUS).

Benign thyroid nodules

In B-mode ultrasound, benign nodules generally present as isoechoic or hyperechoic, with well-defined margins, often with a hypoechoic halo, and with a variable vascularity at Doppler evaluation [1,2].

Abstract

Accurate differentiation of focal thyroid nodules (FTL) and thyroid abnormalities is pivotal for proper diagnostic and therapeutic work-up. In these two part articles, the role of ultrasound techniques in the characterization of FTL and evaluation of diffuse thyroid diseases is described to expand on the recently published World Federation in Ultrasound and Medicine (WFUMB) thyroid elastography guidelines and review how this guideline fits into a complete thyroid ultrasound exam.

Keywords: thyroid; ultrasonography; elastography; color Doppler; contrast enhanced ultrasound (CEUS); point of care (POC).

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Cysts and Pseudocysts

The majority (67.3%) of incidentally detected thyroid lesions in children are cysts. True cysts occur as a result of dilatation of the ducts or tubules lined by epithelium and pseudocysts lack epithelial lining. True epithelial-lined thyroid cysts are rare. Most cystic thyroid lesions are pseudocysts from hyperplastic nodules that have undergone extensive degeneration, necrosis and hemorrhage into the parenchyma with fluid accumulation (fig 1) [3]. Colloid cysts may contain bright echogenic foci with comet-tail artifacts caused by the presence of microcrystals (fig 2) [4-6].

Calcification

Macrocalcifications are encountered in up to 20%

of these lesions. To avoid false results at elastography, a macrocalcification must be excluded from the region of interest (ROI), as its stiffness alters the nodules stiffness assessment [7].

In addition to suspicious malignant nodules, a diffusely enlarged thyroid with numerous microcalcifications on US is defined as a thyroid malignancy and should be evaluated using FNA [8].

Multinodular goiter (MNG) (struma diffusa et nodosa)

Nodular goiters are clinically recognizable enlarge- ments of the thyroid gland characterized by excessive

growth and structural and/or functional transformation of one or several areas within the normal thyroid tissue. In the absence of thyroid dysfunction, autoimmune thyroid disease, thyroiditis, and thyroid malignancy, they consti- tute an entity described as simple nodular goiter [9].

Conventional B-mode ultrasond

The benign thyroid nodule generally exhibits an iso- echo or hyper-echo, well-defined margin and, often, a hypo-echoic halo (fig 3) [10].

Color Doppler imaging

Color Doppler imaging (CDI) may be able to differentiate between an “autoimmune” form of toxic multinodular goiter from an non-autoimmune form due to multiple autonomous nodules. Boi et al found in their study that increased vascularization on CDI was consist- ently found in autonomous ‘hot’ thyroid nodules on scintigraphy [11].

Elastography

The value of thyroid elastography for predicting malignancy in patients with nodular goiters was investigated by several authors. Different elastographic techniques were used by these authors and they found that all methods has both good sensitivity and specificity for predicting malignancy in thyroid nodules (fig 4) [12-16]. Also, inter- and intra-operator reproducibility of ‘quasi-static’

elastography is considered acceptable [17,18]. Thyroid nodules with VTQ values <2.16 m/s were all benign, which accounted for 60.2% of all benign nodules [19].

Contrast enhanced ultrasound

To date, no specific papers, to the best of our knowledge have been published focusing on CEUS in multinodular goiter.

Tips and tricks

Hot thyroid nodules are rarely malignant and therefore fine needle aspiration biopsy (FNAB) is not rec- Fig 1. Cyst. A 29 year old female with multi-

ple known thyroid nodules and difficulty swal- lowing due to a mass like feeling in the neck.

A large anechoic cyst (arrow) was seen in the left lobe. No calcifications or ring down artifact were seen in this cyst.

Fig 2. Colloid cyst. A 53 year old male with an incidental mass in the right lobe seen on CT.

Transverse US shows a cystic mass in the right lobe with ring down artifact (arrowheads) seen in it consistent with a colloid cyst.

Fig 3. Benign isoechoic nodule in a 49 year old female with multiple thyroid nodules: a) B-mode and b) color Doppler US shows an isoechoic nodule (arrow) in the right lobe with regular margins, hypoechoic halo, well-defined margins and no calcifications (benign nodule at biopsy).

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Fig 5. Adenoma. A 53 year old female presented for follow up US for thyroid nodule. Sagittal US (a) through the right lobe showed a hypoechoic nodule with no internal calcifications and with minimal internal vascularity on transverse color Doppler image (b).

Fig 6. Benign adenoma – 2 cases. Case 1 – 45 year old male with an isoechoic nodule (a) in the left lobe with a halo around it. 2D SWE performed showed a predominantly soft lesion (b) with a stiffness value of 21.5kPa. FNA showed a benign adenoma. Case 2 (image c and d) – 56 year old with a hypoechoic nodule in the left lobe. ARFI measurement of nodule is 2.10 m/s (c). Shear wave velocity measurement by ROI (small box- es) in the color elastogram is 2.13m/s in the nodule and 1.57m/s in the adjacent thyroid gland (d).

Fig 4. Multinodular goiter in a 55 year old male. The nodule is displayed using different elastographic techniques (a-b) and contrast enhanced ultrasound: a) shows the architecture using quasi static strain elastography technique and b) displays the measurement values using shear wave elastography. Primarily a neoplastic lesion was suspected and surgery performed. Comparative data between different manufacturerers are not published so far. Contrast enhanced ultrasound revealed inhomogenous enhancement due to regressive changes (c).

ommended. Nevertheless, the presence of concomitant indifferent or cold nodules on thyroid scintigraphy (especially if they are clinically suspicious) should prompt further evaluation.

Hyperplastic adenomatous nodules, adenoma Autonomous thyroid adenomas occur unifocally, multifocally, or even in a disseminated fashion. Iodine deficiency and genetic disposition are etiological factors.

Focal thyroid adenomas grow very slowly, often over the course of many years. As a rule, clinical symptoms of hyperthyroidism must be expected only if the nodule has reached a critical diameter of about 2.5 cm, although symptoms might occasionally occur with smaller vol- umes [20].

Conventional B-mode ultrasound

The majority of the hyperplastic adenomatous nodules are hypoechoic and clearly delineated nodules (fig 5). The nodules might show cystic degeneration and, in this case, can only be recognized as adenomas because of the hypoechoic edge with minimal residual tissue [20].

Demonstration of increased peripheral and central blood flow is an important indicator of functional activ- ity, but only signifies autonomy to a certain extent in patients with hyperthyroidism. If a solitary adenoma is seen in the case of a hyperthyroid functional state, the prob- ability that this represents carcinoma is extremely low.

Regressive thyroid nodules, however, usually only show peripheral and not central vascularization [21].

Vascularization of a nodule must always be assessed in relationship to the surrounding ‘normal’ thyroid tissue. In accordance with rising hormone levels, perfusion of the autonomous nodules increases. Perfusion does not show a strict correlation with function, however, but is also dependent on the volume and grade of regressive change. The grade of perfusion (blood flow detected per unit of volume) of large nodules is smaller for equal func-

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tional states, especially in cases of regressive alteration.

If these areas are destroyed by radioiodine treatment or instillation of alcohol or if hormone release is reduced by thyreostatic therapy, perfusion rate decreases again [20].

Elastography

Multiple studies involving elastography in thyroid nodules have found that adenomas are usually softer than other lesions (fig 6). A small number of adenomas can be harder if they have had prior hemorrhage, calcification or fibrosis. Samir et al in their study involving follicular lesions, found that at a cutoff value with 2D-SWE (shear wave elastography) of 22.30 kPa, SWE had a sensitivity of 82% and a specificity of 88% with a positive predictive value of 75% and a negative predictive value of 91% [22].

CEUS has been used to differentiate between benign and malignant nodules. Some authors reported that hy- poenhancement is the most accurate US feature of malignancy on CEUS with high sensitivity, specificity and accuracy 82%, 85%, and 84%, respectively [23-27]. Three recent meta-analyses reported high-pooled accuracy of CEUS in diagnosing benign from malignant nodules with sensitivity, specificity, and positive and negative LR ranging 0.85-0.88, 0.87-0.90, 5.8-8.6 and 0.15-19 respectively [27-29].

Tips and tricks

In cases of doubt, biopsy or surgery must be performed. Scintigraphy might also be helpful, since cancer inside this lesion may be ruled out if there is an overac- tive (hot) nodule [30].

Malignant thyroid nodules

Ultrasound is essential in identifying suspicious nodules for cancer in the context of the high prevalence of benign lesions. Suspicious US features are: microcalcifications, marked hypoechogenicity, irregular margins with an absent halo, taller than wider shape, and intranodular vascularity greater than peripheral vascularity [31]. Se- bag et al investigated the efficiency of SWE in predicting malignancy in solitary or multiple thyroid nodules. Using a cut-off level of 65 kPa, they could predict malignancy with sensitivity of 85.2%, specificity of 93.9% and positive predictive value (PPV) of 92.3% [32].

Compared with B mode US features for predicting malignancy, SWV ≥3.54 m/s has a higher sensitivity (79.27%), specificity (71.52%), PPV (26.75%) and negative predictive value (NPV) (96.34%). Thyroid nodule stiffness measured by virtual touch tissue imaging quantification (VTIQ) generated SWE is an independent predictor of thyroid cancer [33]. Grazhdani et al showed that ARFI imaging is a reproducible method with good

diagnostic performance in differentiating benign and malignant nodules using the cut-off value of 2.455 m/s [34].

Studies with semi-quantitative Strain Elastography (SE) found that in benign nodules SR was 2.59±2.12 and in malignant ones 9.10±7.02 [28,35]. In another more recent study on 97 patients, the prediction of malignancy using strain ratio with cut-off value ≥2, sensitivity, specificity, PPV, and NPV of 97.3%, 91.7%, 87.8%, and 98.2% was obtained [7]. Strain index value greater than 4 on off-line processed elastograms was the strongest independent predictor of thyroid gland malignancy, with 96%

specificity and 82% sensitivity. Two other elastographic criteria, which were evaluated on real time elastograms:

a margin regularity score higher than 3 (88% specificity, 36% sensitivity) and a tumor area ratio higher than 1 (92% specificity, 46% sensitivity) also were associated with malignancy [12].

More recently, with the respect to the use of SR, two comprehensive meta-analysis were published. The first meta-analysis, in which qualitative and Strain-ratio results were provided, is the one published by Razavi et al [36]. In their paper, twenty-four studies provided rel- evant information on more than 2624 patients and 3531 thyroid nodules (927 malignant and 2604 benign). Six ultrasound features (echogenicity, calcifications, margins, halo sign, shape, and color Doppler flow pattern) were compared with elasticity score and strain ratio. The respective sensitivities and specificities were as follows:

elasticity score, 82% and 82%; strain ratio, 89% and 82%; hypoechogenicity, 78% and 55%; micro-calcifications, 50% and 80%; irregular margins, 66% and 81%;

absent halo sign, 56% and 57%; nodule vertical devel- opment, 46% and 77%; and intranodular vascularization, 40% and 61%. They showed and confirmed that ultrasound elastography appears to be both more sensitive and specific than each of the ultrasound features in thyroid nodule differentiation.

The second meta-analysis, published by Sun et al [37], assessed the diagnostic power of elastography in differentiating benign and malignant thyroid nodules for elasticity score and strain ratio assessment. A total of 5481 nodules in 4468 patients for elasticity score studies and 1063 nodules in 983 patients for strain ratio studies published until January 2013 were analyzed. The overall mean sensitivity and specificity of ultrasound elastography for differentiation of thyroid nodules were 0.79 (95% confidence interval [CI], 0.77-0.81) and 0.77 (95% CI, 0.76-0.79) for elasticity score assessment and 0.85 (95% CI, 0.81-0.89) and 0.80 (95% CI, 0.77-0.83) for strain ratio assessment, respectively. The areas under the curve for the elasticity score and strain ratio were 0.8941 and 0.9285.

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A meta-analysis of qualitative SE published by Trim- boli et al achieved AUC of 0.77 and concluded that SE has suboptimal diagnostic accuracy to diagnose thyroid nodules previously classified as indeterminate [38]. They advised for further studies using other elastographic ap- proaches and combined real-time tissue elastography (RTE) and B-mode ultrasonography. More recently, Can- tisani et al reported that ultrasound elastography (USE) with strain ratio should be considered a useful additional tool to colour Doppler US, since it improves characterization of thyroid nodules with indeterminate cytology [39].

When dealing with quasistatic strain USE with elasticity contrast index (ECI), values above 3 were the most accurate values cut-off for predicting the malignant nature of the nodules [40], This technique showed excellent inter-observer agreement [18].

Papillary thyroid carcinoma (PTC)

Papillary carcinoma is the most common form (80%) of thyroid malignancies [41].

PTC is diagnosed by conventional US based on its characteristic calcification, irregular shape, and heterogeneous internal echogenicity (fig 7) [42].

CDI of thyroid tumors is not useful for diagnosing papillary cancer, but it was reported to be clinically useful for diagnosing follicular cancer [43]. However, the diagnostic value of CDI remains controversial, probably due to its qualitative nature, poor inter-observer agreement and dependence on the sensitivity of the US technology and device settings. The 2015 ATA guidelines do not consider vascularity as an independent risk factor of malignancy on US [44].

Elastography

Dighe et al found good accuracy of carotid artery SE in diagnosing micropapillary carcinomas in small nodules (< 1 cm in transverse), ECI with a cut-off of 3.6 had a sensitivity of 100% and a specificity of 60% [45,46].

Thyroid stiffness index (TSI) calculated with elastography using carotid arterial pulsation, as the compression source was effective in helping distinguish between papillary carcinomas and other lesions because papillary carcinomas were stiffer than other lesions. Multiple nodules in a patient can be evaluated with elastography to select probable papillary carcinoma [45]. A semi-quantitative SE contrast index was effective in distinguishing small papillary thyroid carcinomas [46,47] (fig 8).

Ultrasound thyroid elastography using carotid artery pulsation appears to have the potential for noninva- sively differentiating papillary carcinoma from benign nodular goiter. The TSI or papillary carcinoma was higher comparing with benign nodular goiter, indicating

Fig 7. Papillary carcinoma in a 25 year old male presented with a palpable nodule in the right lobe. Transverse US image (a) showed a large hypoechoic nodule with multiple micro and macro calcifications and mild internal vascularity (b). FNA performed confirmed a papillary carcinoma.

Fig 8. Carotid Pulsation based Elastography in a 40 year old female presented with an incidentally detected nodule in the left lobe. Transverse US (a) through the right lobe shows a mixed solid and cystic nodule in close proximity to the carotid artery. CA – carotid artery. Carotid artery based elastography (b) shows areas of increased stiffness within this nodule in the soft tissue portion of the nodule. This was shown to be a papillary carcinoma on FNA.

that papillary carcinoma is stiffer than a benign nodular goiter [48].

With regard to the thyroid nodules, the SWVs of papillary thyroid carcinoma were significantly higher than those of benign nodules. The AUROC curve was 0.83 and the SWV cut-off value was 2.36 m/s. The sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy were 70.0%, 84.3%, 28.6%, 96.1%. and 65.6%, respectively [49] (fig 9, fig 10). The most accurate SWE cut-off, 34.5 kPa for a 2 mm region of interest, achieved 76.9% sensitivity and 71.1%

specificity for discriminating papillary cancer from benign nodules [50].

More recently Zhou et al reported that CEUS with quantitative evaluation was useful to predict papillary carcinomas. Compared with the peripheral parenchyma, 60 PTC nodules showed low heterogeneous enhancement and 2 nodules showed slightly high enhancement, and the peak intensity of CEUS in PTC was lower than in peripheral parenchyma [51].

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Tips and tricks

The cytological analysis based on Bethesda System (category IV) [52] is an independent predictor for malignancy in indeterminate thyroid nodules. Maia et al in their study showed that border irregularity and Bethesda System category IV were predictive factors of malignancy in indeterminate thyroid nodules, with an accuracy of 76.9%. This study confirmed a significant increase of risk for malignancy in thyroid nodules with indeterminate cytology showing Bethesda System category IV and suspi-

cious features at US. These findings enhance our current limited predictive armamentarium and can be used to guide surgical decision making [53].

Follicular carcinoma

Follicular carcinoma accounts for approximately 5.1% of thyroid cancers and is more common in females than males [54,55]. The distinction between a benign and malignant follicular neoplasm can only be made by evaluating the presence of capsular or vascular invasion during a histological examination. The estimated rate of malignancy for follicular neoplasm is variable, ranging from 10-30 % [56].

The follicular variant of PTC, the second most common variant of thyroid carcinoma shows oval-to-round shapes more frequently compared with conventional PTCs, which usually have a typical taller-than-wide shape (fig 11). In addition, follicular PTCs may show isoechogenicity or hypoechogenicity rather than marked hypoechogenicity. A hypoechoic rim is more commonly seen in the follicular variant than in conventional PTC.

Anuradha et al describes in a large retrospective study the usefulness off “nodule in nodule” sign and „hypoechoic internal septae“ in differentiating follicular variant of PTC from benign thyroid nodules [57].

High-velocity pulsatile blood flow penetrating the tumor was found to be the characteristic finding of follicular carcinoma [43]. In thyroid follicular neoplasms, there were significant positive associations between predominantly central flow and malignancy and between predominantly peripheral flow and benign disease. How- ever, power Doppler characteristics could not be used to rule out malignancy because 20% of malignant nodules had predominantly peripheral flow. For predicting malignancy a resistivity index cutoff of 0.75 showed good ac- Fig 10. A 53 year old male patient with hypoechoic mass in the

right thyroid lobe with irregular margins and heterogenous appearance. Strain elastography showed a relatively hard nodule with a strain ratio with the surrounding parenchyma of 3.98 and hence suspicious for malignancy. Histopathology after thyroidectomy showed a papillary thyroid carcinoma.

Fig 11. Follicular variant of papillary carcinoma in a 42 year old female with a palpable mass in the left lower lobe. Trans- verse US (a) of the left lobe showed a large hypoechoic mass with small cystic areas and some micro-calcifications and internal vascularity on color Doppler (b). Histopathology performed after resection showed the lesion to be a follicular variant of papillary carcinoma.

Fig 9. A 61 year old female with a 3.2 cm hypoechoic nodule seen in the right lobe on transverse image (a) that has markedly increased blood flow on color Doppler (b), a very stiff nodular component on strain elastography (c). On 2D-SWE (d) the nodule within the lesion had a stiffness value of 7.0m/s while the majority of the lesion has a stiffness of 2.28m/s. On biopsy the nodule was diagnosed to be a papillary carcinoma

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curacy, specificity, and negative predictive value but low sensitivity and positive predictive value (respectively, 91%, 97%, 92%, 40%, and 67%) [59].

Elastography

An important limitation of elastography is the lack of sensitivity for follicular thyroid carcinoma which showed an elastographic pattern similar to that found in benign nodules (fig 12) [60]. Follicular carcinomas can be soft and difficult to be differentiated from benign nodules, although some good results have also been reported both with SR SE [61] and with SWE [22]. In the latter paper a cut-off value of 22.30 kPa can help differentiate malignant from benign follicular thyroid lesions with sensitivity of 82%, specificity of 88%, and positive and negative predictive values of 75% and 91%, respectively.

In the study of Zhang et al the authors stated that heterogeneous enhancement correlated highly with a malignant diagnosis (sensitivity 88.2%, specificity, 92.5%

positive predictive value, 91.8%, negative predictive value 89.1%, and accuracy 90.4%). In both mixed and solid nodules, ring enhancement is highly predictive of a benign finding [62].

Clinical decision making (biopsy, scintigraphy, etc) Follicular carcinoma (fig 13) is less common and differentiating follicular carcinoma from adenomas is not possible with imaging. Because there are no specific imaging features the fine needle aspiration is required in these cases.

Anaplastic carcinoma

Anaplastic carcinoma is a highly aggressive form of thyroid cancer and accounts for 1-2% of primary thyroid malignancies. It typically occurs in elderly women with a peak incidence at 6^th to 7^th decades of life. A large number of these patients have a history of concurrent multinodular goiter [63,64].

Ultrasound features of anaplastic carcinoma include hypoechoic tumor, diffusely involving the entire lobe or gland, ill-defined margins, areas of necrosis, nodal or distant metastases, and extracapsular spread and vascular invasion (fig 14) [65]. In elderly women with common malignant features on ultrasound, the thyroid nodules with a maximum diameter greater than 5 cm, anteroposterior-to-transverse diameter ratio less than 1, and microcalcifications are highly likely to be anaplastic thyroid carcinoma [66]. Punctate calcifications are more commonly seen in anaplastic carcinoma compared to papillary carcinomas [66] but Suh et al found no difference in imaging features between anaplastic carcinoma and other types of aggressive thyroid carcinomas [67].

Fig 12. Ultrasound elastography in follicular variant of papillary carcinoma. A 63 year old male patient with markedly hypoechoic mass in the left thyroid lobe with a taller than wide shape and slightly irregular margins. Share wave elastography showed a very hard nodule with stiffness measurement of 7.3m/s. Histopathology after thyroidectomy showed a papillary thyroid carcinoma.

Fig 13. A 38 year old female patient with a isoechoic nodule in the left thyroid lobe with a halo and regular margins (a). SWE imaging showed a predominantly soft nodule (blue green on SWE color map (b)) with a few stiff areas in it (red – yellow on SWE color map), a mean stiffness of 29.5kPa and maximum stiffness of 75.6 kPa. FNA showed an indeterminate follicular nodule and histopathology after resection showed a follicular carcinoma.

Multiple small intranodular vessels are seen on color Doppler imaging [65].

Elastography

To date, no specific papers, to the best of our knowledge have been published focusing on anaplastic carcinoma. From personal experience in a series of 6 anaplastic carcinomas, the tumors are uniquely very hard on SE.

To date, no specific papers, to the best of our knowledge have been published focusing on anaplastic carcinoma

Tips and tricks

Patients with anaplastic carcinoma usually present later and have extensive involvement of surrounding

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structures. Due to the fibrotic nature of this carcinoma, FNA may not be adequate and core biopsy may be required for diagnosis.

Medullary carcinoma

Medullary carcinoma (MTC) is thought to arise from parafollicular C-cells that secrete thyrocalcitonin. Only 5% of thyroid carcinomas are MTC, however 10-20% of patients with MTC have a family history of pheochromo- cytomas or hypercalcemia. MTC may be associated with MEN II-syndrome [68].

Ultrasound features of MTC include solid hypoechoic nodule with echogenic foci in 80-90% due to amyloid dep- osition or calcification (fig 15) [65]. Trimboli et al reported that MTC is frequently associated with features of aggres-

siveness, suggesting that careful preoperative US of MTC patients may better plan their surgical approach [69].

Chaotic intranodular vessels are seen in the tumor on color flow imaging [65].

Elastography

To date only few papers on MTC tumors have been reported. Andrioli et al recently reported their experience on 18 histologically proven MCTs, showing that at qualitative SE most of MTCs presented as soft elastographic pattern, more than half having a low-intermediate grade of elasticity. Therefore, qualitative elastography was reported to have no added value in these cases [70] (fig 16).

Future technical developments to reduce the inter-observer and intra-observer variability are warranted. Most of the MTCs present an elastographic pattern of benignity suggesting that most of the MTC lesions are not hard. In- deed, the hardest medullary lesions (ES4) were those with other US features suggestive of malignancy in our series.

To date, no specific papers, to the best of our knowledge have been published focusing on MTC.

Fig 14. A 53 year old female with growing thyroid nodule.

Anaplastic carcinoma was revealed by core needle biopsy.

Color Doppler revealed only few vessels (a). Hypovascularity was proven by two contrast techniques, conventional (b) and using so-called microbubble tracing imaging (c). Elastography revealed stiff cervical lymph nodes (d).

Fig 15. Medullary carcinoma in a 37 year old male with incidentally detected nodule on CT scan. Transverse US (a) of the right lobe showed a large hypoechoic predominantly solid nodule with mild internal vascularity on color Doppler (b). FNA showed cells suspicious for medullary carcinoma and this was confirmed on histopathology.

Fig 16. Ultrasound elastography in medullary thyroid carcinoma in a 72-year-old woman. A 20 mm thyroid nodule that appears as hypo-echogenicity, well defined margin, presence of halo sign, and rich intranodular and peripheral flow was found in left lobe of the thyroid at conventional US (a,b). The EI score 3 (c, the nodule is displayed predominantly in blue with few green areas/spots), VTI grade IV (d, most lesion is displayed in black with a small amount of white) and SWV of 2.71 m/s (e) on VTQ are assigned at elastography.

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Tips and tricks

Calcifications are commonly seen in MCT.

Lymphoma

Primary thyroid lymphoma (PTL) is a rare malignant disease (1-3% of all thyroid malignancies), which can be- come life threatening because of airway obstruction due to rapidly growing mass. Patients usually have a history of prior Hashimoto’s disease. Non-Hodgkin’s lymphoma can more often involve the thyroid gland than Hodgkin’s disease. Typical presentation is an elderly female with a rapidly increasing mass. Involvement may be focal or diffuse with commonly extrathyroidal spread and vascular invasion [71,72].

The sonographic patterns of PTL could be classified into diffuse and nodular or segmental types, based on the distri- bution of hypoechoic and echogenic structures within the lesions. Some common US characteristics suggesting thyroid malignancy could not facilitate differentiation of PTL from nodular goiter. However, a central blood flow pattern would favor the diagnosis of primary thyroid lymphoma, whereas a peripheral pattern would suggest the diagnosis of nodular goiter [73]. Other authors report that although some common features were found, the sonographic appearance of PTL is nonspecific, especially for the diffuse type [74]. Yang et al showed in 12 patients with PTL diffuse heterogeneous hypoechoic parenchyma with interven- ing echogenic septa-like structures in 3 patients (25.0%), markedly hypoechoic masses in 8 patients (66.7%), and a mixed pattern in one patient (8.3 %) (fig 17) [75].

A central blood flow pattern would highly suggest the diagnosis of PTL rather than nodular goiter [73].

Elastography

To date, no specific papers, to the best of our knowledge have been published focusing on thyroid lymphoma, though some author’s speculate that elastography may be able to differentiate between nodules due to chronic autoimmune thyroiditis and lymphoma, however data regarding this is lacking [76].

To date, no specific papers, to the best of our knowledge have been published focusing on thyroid lymphoma

Tips and tricks

Prompt and accurate detection and diagnosis in the early phase of PTL are crucial for the treatment of this disease. However, due to lack of standardized diagnostic procedures and methods, PTL can be easily missed or misdiagnosed [75].

Sarcoma

Ultrasound evaluation of proved primary thyroid sarcomas (PTS) was reported for 36 patients in systematic re-

view by Surov et al [77]. The following data were retrieved for the identified sarcomas: localization, size, homogeneity, internal texture, and margin characteristics. In most cases, PTS occurred in patients over 40 years of age, with a peak incidence for the group aged 60-79 years. Angiosarcoma was diagnosed in 29 cases (20.4%), followed by malignant hemangioendothelioma (n=23, 16.3%), malignant fibrous histiocytoma (n=20, 14.1%), leiomyosarcoma (n=16, 11.3%), and fibrosarcoma (n=13, 9.2%). In most patients (n=113, 79.6%), PTS manifested clinically as a painless goiter. On ultrasound, PTS were predominantly mixed hypo-to-hyperechoic in comparison to the normal thyroid tissue. In 26.8%, infiltration of the adjacent organs was seen.

The trachea or esophagus was affected more frequently in patients with malignant histiocytoma and liposarcoma.

The described features should be taken into consideration in the differential diagnosis of thyroid tumors.

Metastasis

Metastatic carcinomas to the thyroid are rare in daily clinical practice. However, when encountered, they represent a diagnostic challenge, since it is difficult to distinguish them from primary thyroid lesions, especially when occurring in patients with occult malignant history [78].

There are no specific clinical features and few characteristic findings of metastatic thyroid carcinoma on imaging studies such as US and computed tomography (CT) [79].

The use of preoperative FNAB, with low morbidity and reasonable cost, has been emphasized as an effective and useful procedure for the diagnosis of metastatic thyroid cancer. Contrary to the wide consensus that FNAB is an accurate diagnostic tool, Chung et al reviewing the litera- ture of metastasis reported a high false negative rate of 28.7%. Thus, one should remain suspicious for metastatic disease to the thyroid gland when FNAB is negative or indeterminate for malignant cells [80].

No specific information has been published about color Doppler imaging of metastases.

Fig 17. Diffuse large B cell lymphoma in a 53 year old female with a large rapidly growing mass in the left thyroid lobe with irregular margins and heterogeneous appearance and central blood flow pattern. Strain elastography showed a hard nodule.

Core needle biopsy showed a diffuse large B cell lymphoma.

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Elastography

Metastatic carcinoma might also present as soft and might not be diagnosed with elastography (fig 18) [81].

To date, no specific papers, to the best of our knowledge have been published focusing on thyroid metastases.

Tips and tricks

Metastatic carcinoma has nonspecific imaging features and should be suspected if there is a history of malignancy in the patient. FNA might have to be modified to include core biopsy in case of suspicion of metastasis.

The contrast behavior may mimic the typical enhancement pattern of the original tumor [44,54,82].

Differential diagnosis of focal thyroid disease Rago et al evaluated tissue stiffness by elastography in a large group of patients with thyroid nodules who un- derwent surgery for compressive symptoms or suspicion of malignancy at FNA. Elastography displayed a sensitivity of 97%, a specificity of 100%, a positive predictive value of 100 % and a negative predictive value of 98%, independently from nodule size [83].

Monitoring after thyroidectomy

If indicated, percutaneous ethanol installation therapy (PEIT) may result in contraction of thyroid cysts or may be used for the treatment of autonomous lesions of the thyroid.

The value of scintigraphy

The clinical indications for thyroid scintigraphy, according to American Association of Clinical Endo- crinologists medical guidelines for clinical practice for the diagnosis and management of thyroid nodules, are:

1- TSH level below the normal range, 2- Iodine-deficient areas even if the TSH level is in the low-normal range, 3- Suspected ectopic thyroid tissue or retrosternal goiter.

Findings on thyroid scintigraphy are unspecific. A cold nodule may represent a benign lesion (like adenoma, cyst or hemorrhage) or a malignant one (well differentiated carcinoma, medullary or anaplastic carcinoma). Less than 20 % of cold nodules are actually malignant. A hot nodule is generally an autonomous or hypertrophic adenoma [84].

Although thyroid scintigraphy remains a standard ra- diologic study, thyroid US can be a practical alternative in many cases and the primary imag ing modality in some situations such as during pregnancy and lactation and for evaluation and management of ami odarone-induced thy- rotoxicosis.

The value of biopsy

FNA remains the most useful method of obtaining cellular diagnosis of any thyroid abnormality before treatment. In most situations it is the single most cost- effective investigation of a thyroid nodule. US guid- ance of the FNAB is an excellent means of ensuring accurate sampling of the area of interest. It provides greater accuracy as it enables the needle to be guided into impalpable nodules as well is into the solid component of a complex nodule. It has been report increased accuracy of FNAB by repeated biopsies after 3 months [85].

Although it is an effective and safe tool, FNA cytology does not alone provide all of the necessary information for clinical decision-making regarding thyroid nodules. Expert cytologists using the definitions established at the Bethesda conference report that between 2 % and 20 % of punctures are not satisfactory or do not provide diagnostic information. Furthermore, a portion of the re- maining punctures do not provide conclusive results regarding benignancy or malignancy [86].

Stiffness can vary inside the nodule, which may be related to different tissue types, such as follicular cells, colloid, fibrosis, and necrosis. Elastography could guide the thyroid FNA biopsy to improve the sensitivity and specificity of the FNA in thyroid cancer detection and reduce the number of cases having an insufficient number of tissue samples for diagnosis [48].

Fig 18. A 62 year old male patient with metachronic re-recurrence of thyroid metastases shown by contrast enhanced ultrasound with typical non enhancing areas (a) and heterogenous elastographic characteristics (b) corresponding to the typical finding of renal cell carcinoma.

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Lymphadenopathy

US may demonstrate tumor spread by identifying enlarged lymph nodes (LN), vascular invasion, and local recurrence after surgery. US is frequently advocated as an useful imaging modality in LN evaluation with sensitivity and specificity close to other imaging techniques, and because it can also be used to guide biopsies (fig 19) [87]. Several US criteria have been reported: nodal size, shape, site, outline, internal appearance, and behavior after contrast administration. However, there is not unani- mous consent about these criteria and the introduction of USE and CEUS have opened new possibilities. Lyshchik et al reported their study to assess the diagnostic accuracy of strain elastography by evaluating 141 LN [12].

Using a strain ratio cut-off value of >1.5, strain elastography showed sensitivity, specificity, and accuracy values of 85%, 98%, and 92%, respectively. The 4-point color- coded US-elastography scale is frequently used for detecting malignant LN. In general, metastatic LN demonstrate higher stiffness than benign LN. So, elastographic scale scores of 1-2 indicate benign LN, and elastographic scale scores of 3-4 indicate malignant LN [88].

Rubaltelli studied 53 patients, 28 of whom had malignant forms of lymphadenopathy (metastatic in 21 cases, non-Hodgkin lymphomas in 7) [89]. Compared with cytological and/or histological diagnosis, US-elastography achieved a sensitivity of 75%, specificity of 80%, and accuracy of 77% with positive and negative predictive values of 80% and 70%, respectively. More recently Ying et al reported results of a meta-analysis, based on 9 studies that showed analyzed 835 LN pooled sensitivity and specificity values for detecting malignancies 74%

and 90% for elastographic scale and 88% and 81% using strain ratios, respectively [90]. According to those results, they concluded that SE could potentially help to

select suspicious LN for biopsy. About SWE and ARFI there are relatively few clinical studies that have compared ARFI imaging and supersonic shear imaging. Bha- tia et al have reported that the median elastic modulus of malignant LN is higher than that of benign lymph nodes [50]. However, discrimination was low because the optimal cut-off value of 30.2 kPa demonstrated sensitivity, specificity, and accuracy values of 41.9%, 100%, and 61.8%, respectively. Another study has reported that the maximum elastic modulus can be used to differentiate malignant LN, and that a cut-off value of 19.4 kPa result- ed in accuracy, sensitivity, and specificity values of 94%, 91%, and 97%, respectively (fig 20) [91]. At CEUS, reac- tive nodes usually present with intense homogeneous enhancement, whereas perfusion defects are a sign of metastatic involvement [92,93]. Scant or absent perfusion can be observed in widespread metastatic infiltration, reflect- ing presence of large areas of necrosis. Based on these features, Rubaltelli et al found a specificity, sensitivity, and accuracy in differentiation between benign and metastatic nodes of 93%, 92%, and 93%, respectively [94].

Furthermore, when signal time-intensity curves are generated and parametric images are calculated the perfusion parameters, such as the arrival time, time to peak, and peak signal intensity, the difference between peak signal intensity in hyper enhancing and hypo enhancing regions are higher in metastatic LN [95].

However, cervical LN diagnosis relies on FNA, which crucially depends on the experience and ability of the cytopathologist, and may be a challenging diagnostic category as cervical LN could harbor metastasis from a multiplicity of extrathyroidal malignancies or be affected by several non-tumoral diseases [96,97].

Parathyroid

Four parathyroid glands are normally present, 2 on each side, one superior and one inferior. They are located posterior to the thyroid gland. Ectopic and super- numerary parathyroid glands can occur as well. Ectopic superior glands may be undescended, parapharyngeal Fig 19. Abnormal lymph nodes – 45 year old male with known

papillary carcinoma post resection presented for routine follow up. Oblique sagittal US (a) through the left neck showed a large hypoechoic nodule with internal calcifications (arrow) and abnormal internal vascularity (b). This was confirmed to be papillary carcinoma metastasis on FNA.

Fig 20. A 17 year old female with metastatic papillary carcinoma lymph nodes. Note the stiff lymph nodes.

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near the piriform sinus, retropharyngeal, or retrotra- cheal. Ectopic inferior glands are more variable and can be undescended near the carotid bulb, within the carotid sheath, inferolateral to the lower pole of the thyroid in the thyrothymic tract, intrathyroidal, or in the thymus or mediastinum [98]. The blood supply to the superior and inferior parathyroid glands comes from the inferior thyroidal artery in most patients and tracing an enlarged inferior thyroidal branch is often of help in locating a parathyroid adenoma [2].

Parathyroid adenomas are typically uniformly hypoechoic relative to the thyroid gland and appear as well- circumscribed oval nodules (fig 21). Large adenomas may assume a bilobed or lobulated configuration or de- velop internal cystic changes. When seen immediately adjacent to the thyroid, the curvilinear echogenic margin of the thyroid capsule should be appreciable and will help in localizing the nodule as external to the thyroid [6].

Parathyroid adenomas are highly vascular lesions supplied by a prominent extrathyroidal feeding artery, usually the inferior thyroid artery. The feeding artery enters the adenoma at one pole along its long axis. The vascularity of an adenoma is peripheral in nature, encir- cling 90 to 270 degrees of the gland, however the internal vascular flow is variable [2,82,98].

Elastography

Limited information is available about the utility of US elastography in parathyroid diseases. A single study by Ünlütürk et al involving 72 patients with 93 parathyroid lesions found elasticity scores of 3 and 4 in all the parathyroid adenomas. The median strain ratio of parathyroid lesions showed that parathyroid adenomas showed a significantly higher level of stiffness compared to hyperplasias [30].

Agha et al have shown a sensitivity of 97% in detection of correct quadrant of the pathological parathyroid gland and 99% for correct side in comparison with 70%

for conventional US [99]. In a follow up study, Agha et al showed that CEUS had a sensitivity of 95.9% for the detection of pathological parathyroid glands in comparison to 60.8% for (99m) Technetium-sestamibi scintigraphy.

Sensitivity of CEUS in patients with negative scintigraphy was 96.3% [100,101].

Tips and tricks

Exophytic thyroid nodules can be mistaken for parathyroid lesions and rarely some parathyroid adenomas are located within the thyroid gland. If there is a suspicion for an intrathyroid parathyroid adenoma, samples from the FNA should also be sent for measurement of tissue parathyroid hormone levels; which will be diagnostic for parathyroid adenoma [102].

Conclusion

This chapter in the two part series describes the utility of ultrasound and new techniques in ultrasound like elastography and ultrasound contrast in evaluation of thyroid nodules, lymph nodal disease and parathyroid lesions [103-104].

Conflict of interest: none

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