Preface

Thyroid cancer is being increasingly diagnosed nowadays. This situation has attracted the attention of scientists and physicians alike. This updated book deals with various aspects of thyroid cancer and has been written by various international authors who have devoted many long and meticulous hours to the subject.

> **Omer Engin** Izmir Tepecik Eğitim ve Araştırma Hastanesi, Turkey

**1**

**Chapter 1**

*Omer Engin*

**1. Introduction**

vical trunks [1].

into the superior vena cava [2, 3].

the complication rates may be different.

and indirect laryngoscopy may be used [9].

on Thyroid Cancer

Introductory Chapter: Knowledges

The thyroid gland is located in the neck in front of the trachea. The gland has right and left lobes. The lobes are connected by isthmus. The superior thyroid artery arises from the external carotid artery; inferior thyroid arteries arise from thyrocer-

Superior and middle veins of the thyroid gland drain into the internal jugular vein; the inferior vein of the gland drains into the brachiocephalic vein or directly

Another name for the inferior laryngeal nerve is the recurrent laryngeal nerve (RLN). RLN has internal and external branches. The internal branch of RLN supplies sensation of the vocal cords and subglottic areas. The external branch of this nerve sends motor fibres to the intrinsic laryngeal muscles except the cricothyroid muscle. These two nerves may be lacerated in thyroidectomy operations [6]. Thyroid cancer is one of the surgeries often performed in surgical practice. Among thyroidectomy indications, thyroid cancer has an important place. There are significant differences between thyroidectomy due to benign diseases and thyroidectomy due to malignant disease. Complications are also different as the surgical method is different. Oncological rules apply in thyroid cancer surgery. Therefore,

The symptoms of thyroid cancer may be silent as well as may be noticeable. Thyroid cancer can follow a quiet and slow clinical process. Or thyroid cancer can follow a rapid clinical process. Thyroid cancer may be associated with other clinical diseases. Care should be taken in such cases and thyroid cancer should not be overlooked. In general, a palpable nodule is palpated in the neck. Sometimes cervical pathologic lymphadenopathy is palpated or is found on ultrasonographic examination incidentally. In this situation, ultrasound-guided fine needle aspiration biopsy may be needed for histologic diagnosis in the preoperative stage. Thyroid malignancies may progress from the neck into the thorax, so intrathoracic goitre may develop. In general intrathoracic goitre is operated in the neck, but sometimes sternotomy may be needed [7, 8].

Hoarseness can be a sign of thyroid cancer. If the tumour invades the recurrent laryngeal nerve, the vocal cord is paralysed. For diagnosis, thyroid ultrasonography

There are noninvasive and invasive methods in the diagnosis of thyroid cancer. Ultrasound-guided fine needle aspiration biopsy can be used as an invasive method. Ultrasonography, one of the noninvasive methods, has been increasingly used in the

Superior and inferior laryngeal nerves are important in thyroid surgery. The superior laryngeal nerve divides into external and internal branches. The external branch stimulates the cricothyroid muscle, so when the nerve is injured, the vocal cord tension is decreased on the side of injury. The internal branch

provides sensor innervation to supraglottic and glottic larynx [4, 5].

#### **Chapter 1**

## Introductory Chapter: Knowledges on Thyroid Cancer

*Omer Engin*

#### **1. Introduction**

The thyroid gland is located in the neck in front of the trachea. The gland has right and left lobes. The lobes are connected by isthmus. The superior thyroid artery arises from the external carotid artery; inferior thyroid arteries arise from thyrocervical trunks [1].

Superior and middle veins of the thyroid gland drain into the internal jugular vein; the inferior vein of the gland drains into the brachiocephalic vein or directly into the superior vena cava [2, 3].

Superior and inferior laryngeal nerves are important in thyroid surgery.

The superior laryngeal nerve divides into external and internal branches. The external branch stimulates the cricothyroid muscle, so when the nerve is injured, the vocal cord tension is decreased on the side of injury. The internal branch provides sensor innervation to supraglottic and glottic larynx [4, 5].

Another name for the inferior laryngeal nerve is the recurrent laryngeal nerve (RLN). RLN has internal and external branches. The internal branch of RLN supplies sensation of the vocal cords and subglottic areas. The external branch of this nerve sends motor fibres to the intrinsic laryngeal muscles except the cricothyroid muscle. These two nerves may be lacerated in thyroidectomy operations [6].

Thyroid cancer is one of the surgeries often performed in surgical practice. Among thyroidectomy indications, thyroid cancer has an important place. There are significant differences between thyroidectomy due to benign diseases and thyroidectomy due to malignant disease. Complications are also different as the surgical method is different. Oncological rules apply in thyroid cancer surgery. Therefore, the complication rates may be different.

The symptoms of thyroid cancer may be silent as well as may be noticeable. Thyroid cancer can follow a quiet and slow clinical process. Or thyroid cancer can follow a rapid clinical process. Thyroid cancer may be associated with other clinical diseases. Care should be taken in such cases and thyroid cancer should not be overlooked. In general, a palpable nodule is palpated in the neck. Sometimes cervical pathologic lymphadenopathy is palpated or is found on ultrasonographic examination incidentally. In this situation, ultrasound-guided fine needle aspiration biopsy may be needed for histologic diagnosis in the preoperative stage. Thyroid malignancies may progress from the neck into the thorax, so intrathoracic goitre may develop. In general intrathoracic goitre is operated in the neck, but sometimes sternotomy may be needed [7, 8].

Hoarseness can be a sign of thyroid cancer. If the tumour invades the recurrent laryngeal nerve, the vocal cord is paralysed. For diagnosis, thyroid ultrasonography and indirect laryngoscopy may be used [9].

There are noninvasive and invasive methods in the diagnosis of thyroid cancer. Ultrasound-guided fine needle aspiration biopsy can be used as an invasive method. Ultrasonography, one of the noninvasive methods, has been increasingly used in the

#### *Knowledges on Thyroid Cancer*

diagnosis of thyroid cancer. Ultrasonography, scintigraphy, computerised tomography, magnetic resonance imaging and PET CT can be used for evaluation of the thyroid cancer and metastases. Preoperative evaluation with imaging tests gives us a route for therapeutic modalities [10, 11].

In thyroid cancer cases, a very good thyroid anatomy should be known. It is very important not to damage the anatomical structures during neck dissection. The anatomy of the thyroid and neck should be well known for a good surgical outcome.

Papillary thyroid cancer is the most common type in the thyroid cancers. Others are follicular thyroid cancer, medullary thyroid carcinomas, anaplastic thyroid carcinomas, primary thyroid lymphomas and primary thyroid sarcomas. Last two malignancies are seen rarely. Hurthle cell cancer is often accepted as a variant of follicular thyroid cancer. Thyroid cancer may have metastasis at the time of diagnosis [12, 13].

Nowadays, various technological innovations have been developed to reduce complications during thyroidectomy. Intraoperative nerve monitoring is one of these innovations. The nerve damage was reduced during thyroidectomy with the nerve monitoring. Do not forget that surgical skills are not an important thing for the prevention of nerve injury. Methylene blue dyeing is another method for identifying of the recurrent nerve. Methylene blue may be given intraarterially or by directly spraying on the tissue [14, 15].

In the thyroidectomy operation, different complications can occur such as hemorrhagia, recurrent nerve injury, trachea laceration, oesophageal laceration, etc. It is important that, if these complications are diagnosed in intraoperative or perioperative time, they may be corrected. For example, if the recurrent nerve is lacerated and is diagnosed by the surgeon, the surgeon can suture the lacerated nerve. But if the injured nerve is diagnosed in the postoperative period, nerve suturing cannot be used. So careful surgical dissection is most important for the prevention of the complications [16, 17]. Another important complication is oesophageal laceration. If the lacerated oesophagus is not diagnosed in the intraoperative period, this can lead to cervical sepsis. When esophagus is lacerated in the operation, intraoperative suturing can be performed intraoperatively. If esophageal laceration is minimal and it can not be recognized intraoperatively, endoscopic endoclips may be choosen as an alternative method [18].

In our book, the issues have been examined by the international elite authors. Our book is not a text book where each subject is processed, respectively. Information about thyroid cancer is given from different perspectives with the original approach.

I hope that our book will be useful to all physicians who are interested in the thyroid. With my love and respect.

#### **Author details**

Omer Engin Izmir Tepecik Eğitim ve Araştırma Hastanesi, Turkey

\*Address all correspondence to: omerengin@hotmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**3**

*Introductory Chapter: Knowledges on Thyroid Cancer DOI: http://dx.doi.org/10.5772/intechopen.86627*

> [9] Jin J. Screening for thyroid cancer. JAMA. 2017;**317**(18):1920-1920

fibromatosis? A retrospective analysis of 13 cases, focusing on the stromal area. Ultrasound International Open.

[10] Tajiri K et al. Can ultrasound alone predict papillary thyroid carcinoma with desmoid-type

[11] Vrachimis A et al. [18 F] FDG PET/CT outperforms [18 F] FDG PET/MRI in differentiated thyroid cancer. European Journal of Nuclear Medicine and Molecular Imaging.

[12] Agrawal N et al. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;**159**(3):676-690

[13] Kam BL et al. Treatment of patients with hurtle cell thyroid carcinoma using [Lu-177-DOTA0, Tyr3]

octreotate. Journal of Nuclear Medicine.

2016;**57**(supplement 2):208-208

[14] Lv B, Zhang B, Zeng Q-D. Total endoscopic thyroidectomy with intraoperative laryngeal nerve monitoring. International Journal of Endocrinology. 2016;**2016**:5. http:// dx.doi.org/10.1155/2016/7381792 Article

[15] Sari S, Erhan A, Muslumanoglu M et al. Safe thyroidectomy with intraoperative methylene blue spraying. Thyroid Research.

2012;**5**(1):15. https://doi. org/10.1186/1756-6614-5-15

[16] Muheremu A, AO Q. Past, present, and future of nerve conduits in the treatment of peripheral nerve injury. BioMed Research International.

2015;**2015**:6. http://dx.doi.

237507

org/10.1155/2015/237507 Article ID:

2018;**4**(02):E39-E44

2016;**43**(2):212-220

ID: 7381792

[1] Miller FR. Surgical anatomy of the thyroid and parathyroid glands. Otolaryngologic Clinics of North

[2] Maceroni P. Ultrasound features of thyroid, parathyroid, neck lymph nodes: Normal and pathologic pattern. In: Mini mally Invasive Therapies for Endocrine Neck Diseases. Cham: Springer; 2016.

[3] Sawant DA, Moore TF, Cashell AW. A cadaveric case report of dual thyroid: Ectopic and normal location thyroid with brief review of literature. International Journal of Endocrinology and Metabolism.

[4] Sun S-Q, Chang RWH. The superior laryngeal nerve loop and its surgical implications. Surgical and Radiologic

Anatomy. 1991;**13**(3):175-180

Italica. 2013;**33**(1):67-71

2004;**187**(2):249-253

2015;**100**(4):1316-1324

2015;**400**(3):301-306

[5] Marchese-Ragona R, Restivo DA, Mylonakis I, et al. The superior laryngeal nerve injury of a famous soprano, Amelita Galli-Curci. Acta Otorhinolaryngologica

[6] Ardito G et al. Revisited anatomy of the recurrent laryngeal nerves. The American Journal of Surgery.

[7] Viola D et al. Prophylactic central compartment lymph node dissection in papillary thyroid carcinoma: Clinical implications derived from the first prospective randomized controlled single institution study. The Journal of Clinical Endocrinology & Metabolism.

[8] Rolighed L, Rønning H, Christiansen P. Sternotomy for substernal goiter: Retrospective study of 52 operations. Langenbeck's Archives of Surgery.

America. 2003;**36**(1):1-7

**References**

pp. 3-13

2018;**6**(3):201-206

*Introductory Chapter: Knowledges on Thyroid Cancer DOI: http://dx.doi.org/10.5772/intechopen.86627*

#### **References**

*Knowledges on Thyroid Cancer*

route for therapeutic modalities [10, 11].

by directly spraying on the tissue [14, 15].

diagnosis of thyroid cancer. Ultrasonography, scintigraphy, computerised tomography, magnetic resonance imaging and PET CT can be used for evaluation of the thyroid cancer and metastases. Preoperative evaluation with imaging tests gives us a

important not to damage the anatomical structures during neck dissection. The anatomy of the thyroid and neck should be well known for a good surgical outcome. Papillary thyroid cancer is the most common type in the thyroid cancers. Others are follicular thyroid cancer, medullary thyroid carcinomas, anaplastic thyroid carcinomas, primary thyroid lymphomas and primary thyroid sarcomas. Last two malignancies are seen rarely. Hurthle cell cancer is often accepted as a variant of follicular thyroid cancer. Thyroid cancer may have metastasis at the time of diagnosis [12, 13]. Nowadays, various technological innovations have been developed to reduce complications during thyroidectomy. Intraoperative nerve monitoring is one of these innovations. The nerve damage was reduced during thyroidectomy with the nerve monitoring. Do not forget that surgical skills are not an important thing for the prevention of nerve injury. Methylene blue dyeing is another method for identifying of the recurrent nerve. Methylene blue may be given intraarterially or

In thyroid cancer cases, a very good thyroid anatomy should be known. It is very

In the thyroidectomy operation, different complications can occur such as hemorrhagia, recurrent nerve injury, trachea laceration, oesophageal laceration, etc. It is important that, if these complications are diagnosed in intraoperative or perioperative time, they may be corrected. For example, if the recurrent nerve is lacerated and is diagnosed by the surgeon, the surgeon can suture the lacerated nerve. But if the injured nerve is diagnosed in the postoperative period, nerve suturing cannot be used. So careful surgical dissection is most important for the prevention of the complications [16, 17]. Another important complication is oesophageal laceration. If the lacerated oesophagus is not diagnosed in the intraoperative period, this can lead to cervical sepsis. When esophagus is lacerated in the operation, intraoperative suturing can be performed intraoperatively. If esophageal laceration is minimal and it can not be recognized intraoperatively, endoscopic endoclips may be choosen as

In our book, the issues have been examined by the international elite authors.

I hope that our book will be useful to all physicians who are interested in the thyroid.

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Our book is not a text book where each subject is processed, respectively. Information about thyroid cancer is given from different perspectives with the

**2**

**Author details**

original approach.

an alternative method [18].

With my love and respect.

Izmir Tepecik Eğitim ve Araştırma Hastanesi, Turkey

provided the original work is properly cited.

\*Address all correspondence to: omerengin@hotmail.com

Omer Engin

[1] Miller FR. Surgical anatomy of the thyroid and parathyroid glands. Otolaryngologic Clinics of North America. 2003;**36**(1):1-7

[2] Maceroni P. Ultrasound features of thyroid, parathyroid, neck lymph nodes: Normal and pathologic pattern. In: Mini mally Invasive Therapies for Endocrine Neck Diseases. Cham: Springer; 2016. pp. 3-13

[3] Sawant DA, Moore TF, Cashell AW. A cadaveric case report of dual thyroid: Ectopic and normal location thyroid with brief review of literature. International Journal of Endocrinology and Metabolism. 2018;**6**(3):201-206

[4] Sun S-Q, Chang RWH. The superior laryngeal nerve loop and its surgical implications. Surgical and Radiologic Anatomy. 1991;**13**(3):175-180

[5] Marchese-Ragona R, Restivo DA, Mylonakis I, et al. The superior laryngeal nerve injury of a famous soprano, Amelita Galli-Curci. Acta Otorhinolaryngologica Italica. 2013;**33**(1):67-71

[6] Ardito G et al. Revisited anatomy of the recurrent laryngeal nerves. The American Journal of Surgery. 2004;**187**(2):249-253

[7] Viola D et al. Prophylactic central compartment lymph node dissection in papillary thyroid carcinoma: Clinical implications derived from the first prospective randomized controlled single institution study. The Journal of Clinical Endocrinology & Metabolism. 2015;**100**(4):1316-1324

[8] Rolighed L, Rønning H, Christiansen P. Sternotomy for substernal goiter: Retrospective study of 52 operations. Langenbeck's Archives of Surgery. 2015;**400**(3):301-306

[9] Jin J. Screening for thyroid cancer. JAMA. 2017;**317**(18):1920-1920

[10] Tajiri K et al. Can ultrasound alone predict papillary thyroid carcinoma with desmoid-type fibromatosis? A retrospective analysis of 13 cases, focusing on the stromal area. Ultrasound International Open. 2018;**4**(02):E39-E44

[11] Vrachimis A et al. [18 F] FDG PET/CT outperforms [18 F] FDG PET/MRI in differentiated thyroid cancer. European Journal of Nuclear Medicine and Molecular Imaging. 2016;**43**(2):212-220

[12] Agrawal N et al. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;**159**(3):676-690

[13] Kam BL et al. Treatment of patients with hurtle cell thyroid carcinoma using [Lu-177-DOTA0, Tyr3] octreotate. Journal of Nuclear Medicine. 2016;**57**(supplement 2):208-208

[14] Lv B, Zhang B, Zeng Q-D. Total endoscopic thyroidectomy with intraoperative laryngeal nerve monitoring. International Journal of Endocrinology. 2016;**2016**:5. http:// dx.doi.org/10.1155/2016/7381792 Article ID: 7381792

[15] Sari S, Erhan A, Muslumanoglu M et al. Safe thyroidectomy with intraoperative methylene blue spraying. Thyroid Research. 2012;**5**(1):15. https://doi. org/10.1186/1756-6614-5-15

[16] Muheremu A, AO Q. Past, present, and future of nerve conduits in the treatment of peripheral nerve injury. BioMed Research International. 2015;**2015**:6. http://dx.doi. org/10.1155/2015/237507 Article ID: 237507

#### *Knowledges on Thyroid Cancer*

[17] Erovic BM, Lercher P. Sural nerve grafting. In: Manual of Head and Neck Reconstruction Using Regional and Free Flaps. Vienna: Springer; 2015. pp. 63-65

[18] Young CA et al. CT features of esophageal emergencies. Radiographics. 2008;**28**(6):1541-1553

**5**

**Chapter 2**

**Abstract**

Thyroid Anatomy

to the practicing thyroid surgeon.

**1. Introduction**

*Sinan Binboga, Eyup Gemici and Elif Binboga*

In ancient times, the Celsius first identified the masses in the neck and reported that their surgical removal was fatal. The sources related to thyroid surgery show that the success of the neck masses with the surgical intervention was limited until the second half of the nineteenth century. Among the names leading the development of thyroid surgery in contemporary times are Emil Theodor Kocher, Theodor Billroth, William James Mayo, and William Stewart Halsted. In this chapter, we will be investigating thyroid gland embryology, histology, and anatomy that is essential

**Keywords:** thyroid gland, anatomy, embryology, histology, vascularization

This chapter will discuss the thyroid anatomy including macroscopic/microscopic structure, thyroid embryology, and also vascular composition and innervation. The nuclear medicine imaging, ultrasound, and biopsy of the thyroid in the evaluation of nodules and differentiation of benign from malignant disease have a very precious place. Generally, the neck is the part of the body that separates the head from the torso. The midline in front of the neck has a prominence of the thyroid cartilage termed the laryngeal prominence. Between the laryngeal prominence and the chin, the hyoid bone can be felt; below the thyroid cartilage, a further ring that can be felt in the midline is the cricoid cartilage. Between the cricoid cartilage and the suprasternal notch, the trachea and isthmus of the thyroid gland can be felt. The quadrangular area is on the side of the neck and is bounded superiorly by the lower border of the body of the mandible and the mastoid process, inferiorly by the clavicle, anteriorly by a midline in front of the neck, and posteriorly by the trapezius muscle. The main arteries in the neck are the common carotids, and the main veins of the neck that return the blood from the head and face are the external and internal jugular veins. The thyroid is located in front of the neck between the levels of the C5 and T1, joined by the isthmus, bridging to the trachea. The basic anatomy is best appreciated in **Figure 1**. The size and shape of the thyroid lobes vary widely in normal patients. The shape of lateral lobes is longitudinally elongated in tall subjects, whereas in shorter subjects, the gland is more oval. In the newborn the thyroid gland is approximately 19 mm, with an anteroposterior (AP) diameter of 8–9 mm. By 1 year of age, the mean length is 25 mm with 12–15 mm AP, whereas the mean length is approximately 40–60 mm, with mean 13–18 mm AP in adults. The thyroid gland is slightly larger and heavier in women. It shows a little more growth in pregnancy and menstruation [1–4]. The thyroid gland is an organ of the endocrine system that maintains body metabolism, growth, and development through the synthesis, storage, and secretion of thyroid hormones. These hormones include

## **Chapter 2** Thyroid Anatomy

*Sinan Binboga, Eyup Gemici and Elif Binboga*

#### **Abstract**

*Knowledges on Thyroid Cancer*

[17] Erovic BM, Lercher P. Sural nerve grafting. In: Manual of Head and Neck Reconstruction Using Regional and Free Flaps. Vienna: Springer; 2015. pp. 63-65

[18] Young CA et al. CT features of esophageal emergencies. Radiographics.

2008;**28**(6):1541-1553

**4**

In ancient times, the Celsius first identified the masses in the neck and reported that their surgical removal was fatal. The sources related to thyroid surgery show that the success of the neck masses with the surgical intervention was limited until the second half of the nineteenth century. Among the names leading the development of thyroid surgery in contemporary times are Emil Theodor Kocher, Theodor Billroth, William James Mayo, and William Stewart Halsted. In this chapter, we will be investigating thyroid gland embryology, histology, and anatomy that is essential to the practicing thyroid surgeon.

**Keywords:** thyroid gland, anatomy, embryology, histology, vascularization

#### **1. Introduction**

This chapter will discuss the thyroid anatomy including macroscopic/microscopic structure, thyroid embryology, and also vascular composition and innervation. The nuclear medicine imaging, ultrasound, and biopsy of the thyroid in the evaluation of nodules and differentiation of benign from malignant disease have a very precious place. Generally, the neck is the part of the body that separates the head from the torso. The midline in front of the neck has a prominence of the thyroid cartilage termed the laryngeal prominence. Between the laryngeal prominence and the chin, the hyoid bone can be felt; below the thyroid cartilage, a further ring that can be felt in the midline is the cricoid cartilage. Between the cricoid cartilage and the suprasternal notch, the trachea and isthmus of the thyroid gland can be felt. The quadrangular area is on the side of the neck and is bounded superiorly by the lower border of the body of the mandible and the mastoid process, inferiorly by the clavicle, anteriorly by a midline in front of the neck, and posteriorly by the trapezius muscle. The main arteries in the neck are the common carotids, and the main veins of the neck that return the blood from the head and face are the external and internal jugular veins. The thyroid is located in front of the neck between the levels of the C5 and T1, joined by the isthmus, bridging to the trachea. The basic anatomy is best appreciated in **Figure 1**. The size and shape of the thyroid lobes vary widely in normal patients. The shape of lateral lobes is longitudinally elongated in tall subjects, whereas in shorter subjects, the gland is more oval. In the newborn the thyroid gland is approximately 19 mm, with an anteroposterior (AP) diameter of 8–9 mm. By 1 year of age, the mean length is 25 mm with 12–15 mm AP, whereas the mean length is approximately 40–60 mm, with mean 13–18 mm AP in adults. The thyroid gland is slightly larger and heavier in women. It shows a little more growth in pregnancy and menstruation [1–4]. The thyroid gland is an organ of the endocrine system that maintains body metabolism, growth, and development through the synthesis, storage, and secretion of thyroid hormones. These hormones include

**Figure 1.**

*a) General thyroid gland histology including fibrous capsule,septum, follicules and reticular fiber meshwork b) Thyroid gland cell types; parafollicular and follicular cells*

triiodothyronine (T3), thyroxine (T4), and calcitonin. Food-energy metabolism of cells is stimulated by T3 and T4. Calcitonin has a minor role in regulation of calcium levels. Disorders of the thyroid may result from thyroid gland dysfunction, which is regulated by the pituitary and hypothalamus glands. An appreciation of the embryological development of the thyroid and parathyroid glands facilitates comprehension of some of the various anatomical and pathological processes. The worldwide guides of various associations such as the American Thyroid Association (ATA), American Association of Clinical Endocrinologists (AACE), American College of Endocrinology (ACE), and Associazione Medici Endocrinologi (AME) are used in the evaluation of the pathological processes [5].

#### **2. Embryology of the thyroid gland**

The primordial thyroid gland is one the earliest endocrine organs. It is detectable during the starting day 24 in the embryo. Throughout the 4th to 7th weeks of gestation, it slowly migrates to the final location. It is developed from pharyngeal endoderm cells and derived from the foramen caecum in the tongue base and also connected to the tongue base via thyroglossal duct until week 10. It consists of two lobes, and both lobes (lobus dexter and lobus sinister) are connected together with isthmus. There is a small lobe known as "the pyramidal lobe" mostly derived from the left lobe of the thyroid and attached to the hyoid bone. Calcitonin-secreting parafollicular thyroid ("C") cells are derived from a combination of cells migrating from the neural crest and a fifth pharyngeal pouch structure [5, 6].

There are clinically relevant various pathologic consequences of this embryogenesis, for example, hypothyroidism, thyroglossal duct cyst, medullary carcinoma, and fistulas.

#### **3. Histology of the thyroid gland**

The thyroid gland is a unique endocrine gland with follicles and extracellular components storing large amounts of hormone in an inactive form [7]. The gland is enveloped by a fibrous capsule, and a fine collagenous septum divides the thyroid gland into lobules consisting of numerous thyroid follicles which are closely packed ring-shaped structures with an average diameter of about 200 μm [8]. The follicles are embedded within the meshwork of reticular fibers (**Figure 1a**) [9].

**7**

(**Figure 2b**).

*Thyroid Anatomy*

*DOI: http://dx.doi.org/10.5772/intechopen.85194*

reduced in amount but also shows vacuoles [9].

colloidal resorption droplets [10].

The thyroid follicles are the main functional and structural components of the gland which synthesize and release T3 and T4 in the center of follicles. Each follicle is filled with colloid, which is a gelatinous substance containing the stored form of T3 and T4. In active glands, the colloid is predominantly basophilic, whereas in inactive glands, it is acidophilic. In highly activated glands, this colloid is not only

There are types of thyroid cells, i.e., follicular cells and parafollicular cells. The follicular or principal cells are responsible for T3 and T4 production. These cells are usually simple cuboidal cells but may change to simple squamous (inactive) or columnar cells (active) depending on their states of secretion (**Figure 1b**). H&E staining of thyroid gland shows that the follicular cells have basophilic cytoplasm and a round nucleus with one or more distinct nucleoli. Golgi apparatus is located in the supranuclear position. Ultrastructurally, the cells contain the organelles showing both secretory and absorptive characteristics and short microvilli on the apical surface of cells. In basal location, cells contain a large number of rough endoplasmic reticulum. In apical location, cells contain small vesicles morphologically related to Golgi apparatus and a large number of endocytotic vesicles lysosomes defined as

Parafollicular or clear cells (C cells) are the second type of thyroid cells, located within the follicular epithelium or as small clumps adjacent to the follicles. These cells are relatively large oval or ellipsoid cells with round nuclei and pale cytoplasm and are found lying on the basal follicular membrane. These cells have an extensive unstained cytoplasm often difficult to distinguish in H&E sections and therefore called "C" cells [7]. These cells produce calcitonin hormone released in response to

The thyroid gland is enveloped by the fascia consisting of the anterior and posterior parts of the deep cervical fascia. The gland weighs approximately 10–20 g, and each lobe measures an average of 5 cm in length, 2.5 cm in width, and 1.5 cm in depth [12]. The gland is slightly heavier and bigger in size during menstruation and pregnancy [13]. Thyroid lobes are located lateral to the trachea and esophagus, anteromedial to the carotid sheath, and posteromedial to the strap muscles (sternohyoid, sternothyroid, and superior belly of the omohyoid) and are innervated by the ansa cervicalis (ansa hypoglossi), overlying from the level of the fifth cervical vertebra down to the first thoracic vertebra (**Figure 2a**) [13, 14]. The shape of the gland varies from an H to a U form, consisted of two elongated lateral lobes with superior and inferior poles that are joined at the midline by an isthmus. The length of the isthmus is in between 12 and 15 high, connecting the two lobes. Occasionally, the isthmus may be absent, and the gland exists as two separate lobes

A pyramidal lobe presents in approximately 50% of patients extending toward the hyoid bone, to which it may be attached by a fibrous or fibromuscular band [14]. The most lateral extension of the thyroid lobes is the Zuckerkandl tubercles (ZTs). These tubercles are condensed thyroid parenchyma located in the cricothyroid junction, at the junction point of the medial thyroid with the ultimobranchial bodies, and have an important vicinity with the recurrent laryngeal nerve (RLN). ZTs develop from the embryologic fusion of the ultimobranchial body with the median anlage and the lateral thyroid anlages of the fourth pharyngeal pouch. The dissection of this tissue is important because the RLN is located below the ZTs

high blood calcium and inhibits the activity of the osteoclasts [11].

**4. Macroscopic anatomy of the thyroid gland**

located in the posterolateral of the thyroid gland [15, 16].

#### *Thyroid Anatomy DOI: http://dx.doi.org/10.5772/intechopen.85194*

*Knowledges on Thyroid Cancer*

**Figure 1.**

triiodothyronine (T3), thyroxine (T4), and calcitonin. Food-energy metabolism of cells is stimulated by T3 and T4. Calcitonin has a minor role in regulation of calcium levels. Disorders of the thyroid may result from thyroid gland dysfunction, which is regulated by the pituitary and hypothalamus glands. An appreciation of the embryological development of the thyroid and parathyroid glands facilitates comprehension of some of the various anatomical and pathological processes. The worldwide guides of various associations such as the American Thyroid Association (ATA), American Association of Clinical Endocrinologists (AACE), American College of Endocrinology (ACE), and Associazione Medici Endocrinologi (AME)

*a) General thyroid gland histology including fibrous capsule,septum, follicules and reticular fiber meshwork* 

The primordial thyroid gland is one the earliest endocrine organs. It is detectable during the starting day 24 in the embryo. Throughout the 4th to 7th weeks of gestation, it slowly migrates to the final location. It is developed from pharyngeal endoderm cells and derived from the foramen caecum in the tongue base and also connected to the tongue base via thyroglossal duct until week 10. It consists of two lobes, and both lobes (lobus dexter and lobus sinister) are connected together with isthmus. There is a small lobe known as "the pyramidal lobe" mostly derived from the left lobe of the thyroid and attached to the hyoid bone. Calcitonin-secreting parafollicular thyroid ("C") cells are derived from a combination of cells migrating

There are clinically relevant various pathologic consequences of this embryogenesis, for example, hypothyroidism, thyroglossal duct cyst, medullary carcinoma,

The thyroid gland is a unique endocrine gland with follicles and extracellular components storing large amounts of hormone in an inactive form [7]. The gland is enveloped by a fibrous capsule, and a fine collagenous septum divides the thyroid gland into lobules consisting of numerous thyroid follicles which are closely packed ring-shaped structures with an average diameter of about 200 μm [8]. The follicles

are used in the evaluation of the pathological processes [5].

from the neural crest and a fifth pharyngeal pouch structure [5, 6].

are embedded within the meshwork of reticular fibers (**Figure 1a**) [9].

**2. Embryology of the thyroid gland**

*b) Thyroid gland cell types; parafollicular and follicular cells*

**3. Histology of the thyroid gland**

**6**

and fistulas.

The thyroid follicles are the main functional and structural components of the gland which synthesize and release T3 and T4 in the center of follicles. Each follicle is filled with colloid, which is a gelatinous substance containing the stored form of T3 and T4. In active glands, the colloid is predominantly basophilic, whereas in inactive glands, it is acidophilic. In highly activated glands, this colloid is not only reduced in amount but also shows vacuoles [9].

There are types of thyroid cells, i.e., follicular cells and parafollicular cells. The follicular or principal cells are responsible for T3 and T4 production. These cells are usually simple cuboidal cells but may change to simple squamous (inactive) or columnar cells (active) depending on their states of secretion (**Figure 1b**). H&E staining of thyroid gland shows that the follicular cells have basophilic cytoplasm and a round nucleus with one or more distinct nucleoli. Golgi apparatus is located in the supranuclear position. Ultrastructurally, the cells contain the organelles showing both secretory and absorptive characteristics and short microvilli on the apical surface of cells. In basal location, cells contain a large number of rough endoplasmic reticulum. In apical location, cells contain small vesicles morphologically related to Golgi apparatus and a large number of endocytotic vesicles lysosomes defined as colloidal resorption droplets [10].

Parafollicular or clear cells (C cells) are the second type of thyroid cells, located within the follicular epithelium or as small clumps adjacent to the follicles. These cells are relatively large oval or ellipsoid cells with round nuclei and pale cytoplasm and are found lying on the basal follicular membrane. These cells have an extensive unstained cytoplasm often difficult to distinguish in H&E sections and therefore called "C" cells [7]. These cells produce calcitonin hormone released in response to high blood calcium and inhibits the activity of the osteoclasts [11].

#### **4. Macroscopic anatomy of the thyroid gland**

The thyroid gland is enveloped by the fascia consisting of the anterior and posterior parts of the deep cervical fascia. The gland weighs approximately 10–20 g, and each lobe measures an average of 5 cm in length, 2.5 cm in width, and 1.5 cm in depth [12]. The gland is slightly heavier and bigger in size during menstruation and pregnancy [13]. Thyroid lobes are located lateral to the trachea and esophagus, anteromedial to the carotid sheath, and posteromedial to the strap muscles (sternohyoid, sternothyroid, and superior belly of the omohyoid) and are innervated by the ansa cervicalis (ansa hypoglossi), overlying from the level of the fifth cervical vertebra down to the first thoracic vertebra (**Figure 2a**) [13, 14]. The shape of the gland varies from an H to a U form, consisted of two elongated lateral lobes with superior and inferior poles that are joined at the midline by an isthmus. The length of the isthmus is in between 12 and 15 high, connecting the two lobes. Occasionally, the isthmus may be absent, and the gland exists as two separate lobes (**Figure 2b**).

A pyramidal lobe presents in approximately 50% of patients extending toward the hyoid bone, to which it may be attached by a fibrous or fibromuscular band [14]. The most lateral extension of the thyroid lobes is the Zuckerkandl tubercles (ZTs). These tubercles are condensed thyroid parenchyma located in the cricothyroid junction, at the junction point of the medial thyroid with the ultimobranchial bodies, and have an important vicinity with the recurrent laryngeal nerve (RLN). ZTs develop from the embryologic fusion of the ultimobranchial body with the median anlage and the lateral thyroid anlages of the fourth pharyngeal pouch. The dissection of this tissue is important because the RLN is located below the ZTs located in the posterolateral of the thyroid gland [15, 16].

**Figure 2.** *a)Thyroid gland in computed tomography b) Macroscopic anatomy of the thyroid gland*

Thyroglossal duct extends along the path of thyroid descending from the foramen cecum at the base of the tongue to the lower neck. The cysts of this duct are the most commonly encountered congenital cervical anomalies in humans. They are usually asymptomatic but occasionally become infected by oral bacteria. The carcinomas of the duct are extremely rare, and approximately 1–2% of are found to be cancer, which are usually papillary carcinomas (85%) [12, 17, 18].

A thin layer of the front and back of the deep cervical fascia wraps the thyroid lobes. This fascia joins the capsule by two suspensory ligaments, namely, the anterior and posterior suspensory ligaments. The anterior suspensory ligament extends from the superior medial aspect of each thyroid lobe to the cricoid and thyroid cartilage. The posterior ligament, known as the Berry ligament, connects the thyroid to the cricoid cartilage and upper rings of the trachea. The ligament of Berry is closely attached to the cricoid cartilage and has important surgical implications due to its connection to the RLN. The RLN usually enters deep into the posterior suspensory ligament [14]. During the retracting of the thyroid gland on the medial side, it should not be compelling, because it may cause RLN to be stretched and injured. In addition, rupture of the vena thyroidea media may occur bleeding. Care should be taken not to cause nerve damage during the dissection and hemostasis to control bleeding. There are two superior and two inferior parathyroid glands. The parathyroid glands are small structures adjacent to or occasionally embedded in the thyroid gland. Usually, two pairs of parathyroid glands lie in proximity to the thyroid gland. The inferior glands migrate further and have more chance of being in ectopic sites [19, 20].

#### **5. Microscopic anatomy of the thyroid gland**

The thyroid gland is a highly vascular organ, among other endocrine organs, in a sense that there is a rich blood flow with large amounts of anastomosis in the gland. Arterial supply is bilateral from both the external carotid system and superior thyroid artery and subclavian system with the lower thyroid branch of the thyrocervical trunk. It may be a single thyroid ima artery arising from the brachiocephalic artery [21].

The superior thyroid arteries originate from the ipsilateral external carotid arteries and are divided into anterior and posterior branches in the apex of the thyroid lobes. Inferior thyroid arteries originate from the thyrocervical shortly after the origin of the subclavian arteries. The inferior thyroid arteries extend from the

**9**

**Figure 3.**

*Thyroid Anatomy*

*DOI: http://dx.doi.org/10.5772/intechopen.85194*

internal jugular or brachycephalic veins [12].

to be attached to this artery (**Figure 3**) [23, 24].

*Thyrid gland location with nerve and parathyroid gland*

tracheobronchial arteries [22].

**5.1 Innervation of the thyroid**

neck to the back of the carotid sheath and enter the thyroid lobes at the midpoints. Thyroidea ima, the arteries born directly from the aorta or innominate, enters the isthmus or replaces a missing lower thyroid artery in 1–4% of individuals. The inferior thyroid artery passes through the recurrent laryngeal nerve (RLN) and requires the identification of RLN before the arterial branches are ligated. The inferior thyroid artery provides an arterial supply of the cervical esophagus with subclavian artery and branches directly from the aorta, intercostal arteries, and

There are three main venous pathways of the thyroid: superior, middle, and inferior thyroid veins. The superior thyroid vein accompanies the superior thyroid artery and drains to the internal jugular vein but not accompanied by the middle thyroid vein. There are several inferior thyroid vessels that frequently flow into the

RLN is a branch of the vagus nerve, responsible from the laryngeal motor function and feeling. The left RLN is looped from the vagus nerve to the back of the aorta, and the right RLN revolves around the right subclavian artery. During thyroidectomy, since these nerves rise along the trachea near the thyroid gland, the surgeon should pay attention to protect them. The inferior thyroid artery and its terminal branches are closely related to the RLN at the entrance point of the thyroid gland. Sometimes, the nerve can be confused with a branch of the artery. Compared to the artery, it is less regular, rounded, and elastic [23]. A small, red, curved vein called vasa nervorum is usually seen in the wall of the nerve. The left RLN rises straight along the tracheoesophageal groove, while the right RLN is more inclined and lateral than the left one. However, numerous variations have been defined, so care should be taken in every case. In the two upper tracheal rings, the RLN is embedded at the back of the suspensory ligament, called the Berry ligament. This ligament extends to backward of the recurrent nerve and tightly connects the thyroid to the trachea and esophagus. At this point, there is a posterior artery near the recurrent nerve, which gives a small branch to the thyroid gland and is not easy

The superior laryngeal nerve is also a branch of the vagus nerve. On the pharynx side, the internal carotid descends from the back of the artery and is divided into

#### *Thyroid Anatomy DOI: http://dx.doi.org/10.5772/intechopen.85194*

*Knowledges on Thyroid Cancer*

**Figure 2.**

Thyroglossal duct extends along the path of thyroid descending from the foramen cecum at the base of the tongue to the lower neck. The cysts of this duct are the most commonly encountered congenital cervical anomalies in humans. They are usually asymptomatic but occasionally become infected by oral bacteria. The carcinomas of the duct are extremely rare, and approximately 1–2% of are found to

A thin layer of the front and back of the deep cervical fascia wraps the thyroid lobes. This fascia joins the capsule by two suspensory ligaments, namely, the anterior and posterior suspensory ligaments. The anterior suspensory ligament extends from the superior medial aspect of each thyroid lobe to the cricoid and thyroid cartilage. The posterior ligament, known as the Berry ligament, connects the thyroid to the cricoid cartilage and upper rings of the trachea. The ligament of Berry is closely attached to the cricoid cartilage and has important surgical implications due to its connection to the RLN. The RLN usually enters deep into the posterior suspensory ligament [14]. During the retracting of the thyroid gland on the medial side, it should not be compelling, because it may cause RLN to be stretched and injured. In addition, rupture of the vena thyroidea media may occur bleeding. Care should be taken not to cause nerve damage during the dissection and hemostasis to control bleeding. There are two superior and two inferior parathyroid glands. The parathyroid glands are small structures adjacent to or occasionally embedded in the thyroid gland. Usually, two pairs of parathyroid glands lie in proximity to the thyroid gland. The inferior glands migrate further and have more chance of being

The thyroid gland is a highly vascular organ, among other endocrine organs, in a sense that there is a rich blood flow with large amounts of anastomosis in the gland. Arterial supply is bilateral from both the external carotid system and superior thyroid artery and subclavian system with the lower thyroid branch of the thyrocervical trunk. It may be a single thyroid ima artery arising from the brachiocephalic

The superior thyroid arteries originate from the ipsilateral external carotid arteries and are divided into anterior and posterior branches in the apex of the thyroid lobes. Inferior thyroid arteries originate from the thyrocervical shortly after the origin of the subclavian arteries. The inferior thyroid arteries extend from the

be cancer, which are usually papillary carcinomas (85%) [12, 17, 18].

*a)Thyroid gland in computed tomography b) Macroscopic anatomy of the thyroid gland*

**8**

artery [21].

in ectopic sites [19, 20].

**5. Microscopic anatomy of the thyroid gland**

neck to the back of the carotid sheath and enter the thyroid lobes at the midpoints. Thyroidea ima, the arteries born directly from the aorta or innominate, enters the isthmus or replaces a missing lower thyroid artery in 1–4% of individuals. The inferior thyroid artery passes through the recurrent laryngeal nerve (RLN) and requires the identification of RLN before the arterial branches are ligated. The inferior thyroid artery provides an arterial supply of the cervical esophagus with subclavian artery and branches directly from the aorta, intercostal arteries, and tracheobronchial arteries [22].

There are three main venous pathways of the thyroid: superior, middle, and inferior thyroid veins. The superior thyroid vein accompanies the superior thyroid artery and drains to the internal jugular vein but not accompanied by the middle thyroid vein. There are several inferior thyroid vessels that frequently flow into the internal jugular or brachycephalic veins [12].

#### **5.1 Innervation of the thyroid**

RLN is a branch of the vagus nerve, responsible from the laryngeal motor function and feeling. The left RLN is looped from the vagus nerve to the back of the aorta, and the right RLN revolves around the right subclavian artery. During thyroidectomy, since these nerves rise along the trachea near the thyroid gland, the surgeon should pay attention to protect them. The inferior thyroid artery and its terminal branches are closely related to the RLN at the entrance point of the thyroid gland. Sometimes, the nerve can be confused with a branch of the artery. Compared to the artery, it is less regular, rounded, and elastic [23]. A small, red, curved vein called vasa nervorum is usually seen in the wall of the nerve. The left RLN rises straight along the tracheoesophageal groove, while the right RLN is more inclined and lateral than the left one. However, numerous variations have been defined, so care should be taken in every case. In the two upper tracheal rings, the RLN is embedded at the back of the suspensory ligament, called the Berry ligament. This ligament extends to backward of the recurrent nerve and tightly connects the thyroid to the trachea and esophagus. At this point, there is a posterior artery near the recurrent nerve, which gives a small branch to the thyroid gland and is not easy to be attached to this artery (**Figure 3**) [23, 24].

The superior laryngeal nerve is also a branch of the vagus nerve. On the pharynx side, the internal carotid descends from the back of the artery and is divided into

**Figure 3.** *Thyrid gland location with nerve and parathyroid gland*

two arms: the external laryngeal nerve as the motor nerve and the internal laryngeal nerve as the sensory nerve. The superior laryngeal nerve contributes to the pitch of voice, and its paralysis can lead to significant contraction of pitch range, vocal fold vibratory phase asymmetry, and acoustic aperiodicity, thus leading to an overall poor vocal quality [24]. There is a close relationship between the superior thyroid artery and the external branch of the superior laryngeal nerve. This nerve injury may cause high-pitched noises. In order to prevent damage to the external branch of the superior laryngeal nerve, it is recommended to ligate the superior thyroid arteries as low as possible during thyroidectomy. The cricothyroid artery, a branch of the superior thyroid artery, is located in the cephalic portion of the upper pole and moves toward the midline on the cricothyroid ligament. This vessel may be damaged during cricothyroidotomy and may cause bleeding. Care should be taken in large area hemostasis to control bleeding. Ligating the veins one by one prevents nerve damage. Classification of the external branch of the superior laryngeal nerve according to the risk of potential damage [12] is given below.

Type 1: The nerve crosses the superior thyroid vessels more than 1 cm above the border of the thyroid upper pole.

Type 2a: The nerve crosses the vessels less than 1 cm above the border of the thyroid upper pole.

Type 2b: The nerve crosses the vessel below the border of the thyroid upper pole.

The recurrent laryngeal nerve (on the right, after exiting the superior thoracic cavity) may be located in the neck root, in the lateral carotid artery, in the medial trachea, and in the triangle formed by the superior thyroid lobe.

The right recurrent laryngeal nerve usually enters the larynx at an angle of 0–30° in the tracheoesophageal groove. In the left recurrent laryngeal nerve, this angle is about 15–45°. Recurrent laryngeal nerve passes through the posterior of the inferior thyroid artery in 61% of cases, anterior in 32%, and the branches of the artery in 7% of cases. The lower parathyroid glands are located proximal to the inferior laryngeal nerve, and the upper parathyroid glands are located distal to the nerve. Recurrent laryngeal nerve is found in 60–70% of cases in the tracheoesophageal groove, 20–25% in the lateral of the trachea, and 5% in the posterior of the trachea.

In 35–80% of cases, RLS is divided into branches before entering the larynx. Typically, extralaryngeal branching is in two forms as motor and sensory branch. However, two to eight extralaryngeal branches have been described in the literature. Its linear extension and its light yellow color make it known macroscopically.

The right inferior laryngeal nerve is 32 cm long, and the left is approximately 43 cm long. Since the left inferior laryngeal nerve has a longer course in the tracheoesophageal groove, the majority of nerve injuries occur in this side.

Nonrecurrent laryngeal nerve was reported in 0.3–0.8% of cases. Nonrecurrent laryngeal nerve exits the cervical section of the vagus at the level of the larynx or thyroid gland and directly enters the larynx at the level of the cricothyroid joint without forming a loop [25].

The intraoperative methylene blue spraying technique could be used in thyroid surgery. Methylene blue will be sprayed over the thyroid lobe and perilober area. Tissues, especially parathyroides, the recurrent laryngeal nerve, and the inferior thyroid artery could be evaluated [26].

Recurrent nerve damage after thyroid surgery varies between 0 and 11%. Complications are more frequently seen in subtotal thyroidectomies and secondary surgeries than total thyroidectomies and primary surgeries, whereas they are inversely correlated with surgeon experience. Posterior cricoarytenoid muscle palpation without electromyography provided that follow-up of glottic pressure applications and peroperative observation of vocal folds. However, the fact that the practice is both difficult and does not give very healthy results is an important

**11**

the lymph node [38].

*Thyroid Anatomy*

surgeon [27].

anesthesia is important.

*DOI: http://dx.doi.org/10.5772/intechopen.85194*

izing neuromuscular blocking agent [28].

reaction in the perineural tissues [32].

**5.2 Lymphatics of the thyroid**

posterior drainage [35].

limitation of this method. Postoperative complications were reduced, and surgical duration was significantly reduced by the use of peroperative recurrent nerve monitoring. Measurements are made with surface electrodes integrated in endotracheal intubation tubes. The device alerts the surgeon with sound. In addition, the current changes in the device screen can be recorded and provide legal basis for the

In patients undergoing peroperative recurrent nerve monitoring, selection of

The continued effect of the muscle relaxant agent will affect the results completely. Intubation can be done without using any muscle relaxant. And also, it can be done with using agents which effect in a short time and break down in a short time. For this purpose, succinylcholine is often preferred as a short-acting depolar-

If there is a nerve injury, different methods of recurrent nerve repair, such as microsuturing gluing and grafting, have been proposed [29]. Direct microsuture is preferable when the defect is no longer than 5 mm and the primary repair can be completed without tension [30]. After transection of RLN, immediate reconstruction could be performed by a direct, "end-to-end" anastomosis of neural stamps, by three to four perineural stitches of 7-0 nylon thread, using microsurgical instruments [31]. Cyanoacrylate glue has also been proposed for nerve repair but has been criticized for its toxicity, excessively slow resorption, and risk of inflammatory

When the proximal stump of the RLN cannot be used, grafting should be done using the transverse cervical nerve, supraclavicular nerve, or ansa cervicalis [33]. First, start to identify ansa cervicalis on the surface of the internal jugular vein, and branches to the sternothyroid muscles could be dissected. The proximal end of the

The lymphatic drainage of the thyroid gland is wide and flows in a versatile pattern. The Hollinshead pattern of drainage is divided into four different ways as the median superior drainage, median inferior drainage, right/left lateral drainage, and

The median superior drainage passes through three to six lymphatic vessels originating from the upper edge of the isthmus and the upper middle edge of the lateral lobes. These lymphatic veins move upward in the direction of the larynx and end in the digastric nodes. Some of the lymphatics can flow into one or two (Delphian) nodes in the throat immediately above the isthmus [23]. Secondarily, the anterior tracheal nodes under the thyroid through the lymphatic channels move downward from the upper jugular nodes on either side of the neck or from the

The median inferior drainage consists of several lymphatic vessels draining to the inferior portion of the isthmus and the lower medial parts of the lateral lobes [36, 37]. These lymphatic channels follow the inferior thyroid veins to terminate before the tracheal and brachycephalic nodes [12, 13]. Right and left lateral drainage patterns originate from the lymphatic bodies at the lateral border of each lobe [12, 25]. The superior thyroid artery and vein are ascended, followed by the lower thyroid artery at the bottom [13, 36]. Between these two groups, the lymphatic ducts move lateral, anterior, or posterior to the carotid sheath to reach the lymph nodes of the internal jugular vein [12–14, 36]. In rare cases, these lymphatic vessels drain directly into the subclavian vein, jugular vein, or thoracic duct without flowing to

major branch could anastomosed to the distal RLN stump [34].

Delphian nodes to the frontal side of the thyroid gland [12, 36].

#### *Thyroid Anatomy DOI: http://dx.doi.org/10.5772/intechopen.85194*

*Knowledges on Thyroid Cancer*

border of the thyroid upper pole.

without forming a loop [25].

thyroid artery could be evaluated [26].

thyroid upper pole.

two arms: the external laryngeal nerve as the motor nerve and the internal laryngeal nerve as the sensory nerve. The superior laryngeal nerve contributes to the pitch of voice, and its paralysis can lead to significant contraction of pitch range, vocal fold vibratory phase asymmetry, and acoustic aperiodicity, thus leading to an overall poor vocal quality [24]. There is a close relationship between the superior thyroid artery and the external branch of the superior laryngeal nerve. This nerve injury may cause high-pitched noises. In order to prevent damage to the external branch of the superior laryngeal nerve, it is recommended to ligate the superior thyroid arteries as low as possible during thyroidectomy. The cricothyroid artery, a branch of the superior thyroid artery, is located in the cephalic portion of the upper pole and moves toward the midline on the cricothyroid ligament. This vessel may be damaged during cricothyroidotomy and may cause bleeding. Care should be taken in large area hemostasis to control bleeding. Ligating the veins one by one prevents nerve damage. Classification of the external branch of the superior laryngeal nerve

Type 1: The nerve crosses the superior thyroid vessels more than 1 cm above the

Type 2b: The nerve crosses the vessel below the border of the thyroid upper pole. The recurrent laryngeal nerve (on the right, after exiting the superior thoracic cavity) may be located in the neck root, in the lateral carotid artery, in the medial

The right recurrent laryngeal nerve usually enters the larynx at an angle of 0–30° in the tracheoesophageal groove. In the left recurrent laryngeal nerve, this angle is about 15–45°. Recurrent laryngeal nerve passes through the posterior of the inferior thyroid artery in 61% of cases, anterior in 32%, and the branches of the artery in 7% of cases. The lower parathyroid glands are located proximal to the inferior laryngeal nerve, and the upper parathyroid glands are located distal to the nerve. Recurrent laryngeal nerve is found in 60–70% of cases in the tracheoesophageal groove, 20–25% in the lateral of the trachea, and 5% in the posterior of the trachea. In 35–80% of cases, RLS is divided into branches before entering the larynx. Typically, extralaryngeal branching is in two forms as motor and sensory branch. However, two to eight extralaryngeal branches have been described in the literature. Its

Type 2a: The nerve crosses the vessels less than 1 cm above the border of the

according to the risk of potential damage [12] is given below.

trachea, and in the triangle formed by the superior thyroid lobe.

linear extension and its light yellow color make it known macroscopically.

esophageal groove, the majority of nerve injuries occur in this side.

The right inferior laryngeal nerve is 32 cm long, and the left is approximately 43 cm long. Since the left inferior laryngeal nerve has a longer course in the tracheo-

Nonrecurrent laryngeal nerve was reported in 0.3–0.8% of cases. Nonrecurrent laryngeal nerve exits the cervical section of the vagus at the level of the larynx or thyroid gland and directly enters the larynx at the level of the cricothyroid joint

The intraoperative methylene blue spraying technique could be used in thyroid surgery. Methylene blue will be sprayed over the thyroid lobe and perilober area. Tissues, especially parathyroides, the recurrent laryngeal nerve, and the inferior

Recurrent nerve damage after thyroid surgery varies between 0 and 11%. Complications are more frequently seen in subtotal thyroidectomies and secondary surgeries than total thyroidectomies and primary surgeries, whereas they are inversely correlated with surgeon experience. Posterior cricoarytenoid muscle palpation without electromyography provided that follow-up of glottic pressure applications and peroperative observation of vocal folds. However, the fact that the practice is both difficult and does not give very healthy results is an important

**10**

limitation of this method. Postoperative complications were reduced, and surgical duration was significantly reduced by the use of peroperative recurrent nerve monitoring. Measurements are made with surface electrodes integrated in endotracheal intubation tubes. The device alerts the surgeon with sound. In addition, the current changes in the device screen can be recorded and provide legal basis for the surgeon [27].

In patients undergoing peroperative recurrent nerve monitoring, selection of anesthesia is important.

The continued effect of the muscle relaxant agent will affect the results completely. Intubation can be done without using any muscle relaxant. And also, it can be done with using agents which effect in a short time and break down in a short time. For this purpose, succinylcholine is often preferred as a short-acting depolarizing neuromuscular blocking agent [28].

If there is a nerve injury, different methods of recurrent nerve repair, such as microsuturing gluing and grafting, have been proposed [29]. Direct microsuture is preferable when the defect is no longer than 5 mm and the primary repair can be completed without tension [30]. After transection of RLN, immediate reconstruction could be performed by a direct, "end-to-end" anastomosis of neural stamps, by three to four perineural stitches of 7-0 nylon thread, using microsurgical instruments [31]. Cyanoacrylate glue has also been proposed for nerve repair but has been criticized for its toxicity, excessively slow resorption, and risk of inflammatory reaction in the perineural tissues [32].

When the proximal stump of the RLN cannot be used, grafting should be done using the transverse cervical nerve, supraclavicular nerve, or ansa cervicalis [33]. First, start to identify ansa cervicalis on the surface of the internal jugular vein, and branches to the sternothyroid muscles could be dissected. The proximal end of the major branch could anastomosed to the distal RLN stump [34].

#### **5.2 Lymphatics of the thyroid**

The lymphatic drainage of the thyroid gland is wide and flows in a versatile pattern. The Hollinshead pattern of drainage is divided into four different ways as the median superior drainage, median inferior drainage, right/left lateral drainage, and posterior drainage [35].

The median superior drainage passes through three to six lymphatic vessels originating from the upper edge of the isthmus and the upper middle edge of the lateral lobes. These lymphatic veins move upward in the direction of the larynx and end in the digastric nodes. Some of the lymphatics can flow into one or two (Delphian) nodes in the throat immediately above the isthmus [23]. Secondarily, the anterior tracheal nodes under the thyroid through the lymphatic channels move downward from the upper jugular nodes on either side of the neck or from the Delphian nodes to the frontal side of the thyroid gland [12, 36].

The median inferior drainage consists of several lymphatic vessels draining to the inferior portion of the isthmus and the lower medial parts of the lateral lobes [36, 37]. These lymphatic channels follow the inferior thyroid veins to terminate before the tracheal and brachycephalic nodes [12, 13]. Right and left lateral drainage patterns originate from the lymphatic bodies at the lateral border of each lobe [12, 25]. The superior thyroid artery and vein are ascended, followed by the lower thyroid artery at the bottom [13, 36]. Between these two groups, the lymphatic ducts move lateral, anterior, or posterior to the carotid sheath to reach the lymph nodes of the internal jugular vein [12–14, 36]. In rare cases, these lymphatic vessels drain directly into the subclavian vein, jugular vein, or thoracic duct without flowing to the lymph node [38].

#### *Knowledges on Thyroid Cancer*

The posterior drainage pattern begins in the lymphatic vessels draining to the inferomedial parts of the lateral lobes to discharge into the lymph nodes along the RLN track [12, 36]. Rarely, a lymphatic body that rises posteriorly to the upper part of the lobe reaches to the retropharyngeal nodes [36].

Several models of lymphatic drainage of the thyroid gland have been proposed, and all of them are true and comprehended from the same basis. Another simplified drainage model is that emergency lymphatic drainage enters the periglandular nodes, followed by the preterminal and paratracheal nodes along with the RLN and then to the mediastinal lymph nodes [14, 36].

Although lymph node metastasis is known to increase recurrence, its effect on prognosis and survival is still being discussed [39, 40]. All patients with lateral LN recurrence could be therapeutic neck dissection and RAI ablation therapy as adjuvant treatment [41].

### **Author details**

Sinan Binboga1 \*, Eyup Gemici<sup>2</sup> and Elif Binboga<sup>3</sup>

1 General Surgery Department, Alsancak Nevvar Salih Isgoren Hospital, Izmir, Turkey

2 Bakirkoy Dr.Sadi Konuk Training and Research Hospital, Istanbul, Turkey

3 Faculty of Medicine, Department of Intensive Care, Dokuz Eylul University, Izmir, Turkey

\*Address all correspondence to: dr.binboga@hotmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**13**

pp. 325-334

*Thyroid Anatomy*

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[2] Hoyes AD, Kershaw DR. Anatomy and development of the thyroid gland. Ear, Nose, & Throat Journal.

[3] Lai SY, Mandel SJ, Weber RS. Chapter 119: Management of thyroid neoplasms. In: Cummings Otolaryngology: Head and Neck Surgery. 4th ed. Philadelphia:

### **References**

*Knowledges on Thyroid Cancer*

adjuvant treatment [41].

**Author details**

Sinan Binboga1

Izmir, Turkey

Turkey

**12**

provided the original work is properly cited.

\*, Eyup Gemici<sup>2</sup>

\*Address all correspondence to: dr.binboga@hotmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

and Elif Binboga<sup>3</sup>

1 General Surgery Department, Alsancak Nevvar Salih Isgoren Hospital, Izmir,

2 Bakirkoy Dr.Sadi Konuk Training and Research Hospital, Istanbul, Turkey

3 Faculty of Medicine, Department of Intensive Care, Dokuz Eylul University,

The posterior drainage pattern begins in the lymphatic vessels draining to the inferomedial parts of the lateral lobes to discharge into the lymph nodes along the RLN track [12, 36]. Rarely, a lymphatic body that rises posteriorly to the upper part

Several models of lymphatic drainage of the thyroid gland have been proposed, and all of them are true and comprehended from the same basis. Another simplified drainage model is that emergency lymphatic drainage enters the periglandular nodes, followed by the preterminal and paratracheal nodes along with the RLN and

Although lymph node metastasis is known to increase recurrence, its effect on prognosis and survival is still being discussed [39, 40]. All patients with lateral LN recurrence could be therapeutic neck dissection and RAI ablation therapy as

of the lobe reaches to the retropharyngeal nodes [36].

then to the mediastinal lymph nodes [14, 36].

[1] Gray H. Anatomy of the Human Body. Philadelphia: Lea & Febiger, 1918; 2000

[2] Hoyes AD, Kershaw DR. Anatomy and development of the thyroid gland. Ear, Nose, & Throat Journal. 1985;**64**(10):318-332

[3] Lai SY, Mandel SJ, Weber RS. Chapter 119: Management of thyroid neoplasms. In: Cummings Otolaryngology: Head and Neck Surgery. 4th ed. Philadelphia: Mosby; 2005. pp. 2687-2718

[4] Ahuja AT, Antonio GE, editors. Diagnostic and Surgical Imaging Anatomy: Ultrasound. Manitoba, Canada: Amirsys; 2007

[5] Arrangoiz R, Cordera F, Caba D, Muñoz M, Moreno E, León EL. Comprehensive review of thyroid embryology, anatomy, histology, and physiology for surgeons. International Journal of Otolaryngology and Head & Neck Surgery. 2018;**7**(4): 160-188. DOI: 10.4236/ijohns.2018.74019

[6] Dominique Dorion Thyroid Anatomy. Available from: https:// reference.medscape.com/article/ 835535-overview

[7] Young B, Heath JW. Wheater's Functional Histology. 4th ed. Edinburg: Churchill-Livingstone; 2000. pp. 315-317

[8] Singh I. Human Embryology. 6th ed. India: Jaypee Brothers Medical Publishers; 2005. pp. 119-123

[9] Cui D. Endocrin system. In: Atlas of Histology with Functional and Clinical Correlations. First ed. Baltimore: Lippincott Williams & Wilkins, a Wolters Kluwer business; 2011. pp. 325-334

[10] Ross MH, Pawlina W. Endocrine organs. In: Histology: A Text and Atlas, with Correlated Cell and Molecular Biology. 6th ed. Baltimore: Lippincott Williams & Wilkins, a Wolters Kluwer business; 2010. p. 755

[11] Lokanadham S, Subhadra Devi V. Thyroid Gland—Morphology & Histogenesis. Germany: LAP LAMBERT Academic Publishing; 2013. pp. 20-21

[12] Skandalakis JE. Neck: Thyroid gland. In: Skandalakis JE, editor. Surgical Anatomy. The Embryologic and Anatomic Basis of Modern Surgery. 14th ed. Vol. 1. Athens: Paschalidis Medical Publications; 2004

[13] Cummings CW. Thyroid anatomy. In: Cummings CW, editor. Head and Neck Surgery. 3rd ed. St. Louis: Mosby; 1998

[14] Williams PL, Bannister LH. Thyroid gland. In: Gray's Anatomy. 38th ed. New York: Churchill Livingstone; 1995

[15] Sheahan P, Murphy MS. Thyroid tubercle of Zuckerkandl: Importance in thyroid surgery. Laryngoscope. 2011;**121**(11):23357. DOI: 10.1002/ lary.22188PMid:21898449

[16] Costanzo M, Caruso LA, Veroux M, et al. The lobe of Zuckerkandl: An important sign of recurrent laryngeal nerve. Annali Italiani di Chirurgia. 2005;**76**(4):337-340. PMID: 16550870

[17] Plaza CP, Lopez ME, Carrasco CE, Meseguer LM, Perucho Ade L. Management of well-differentiated thyroglossal remnant thyroid carcinoma: Time to close the debate? Report of five new cases and proposal of a definitive algorithm for treatment. Annals of Surgical Oncology. 2006;**13**:745-752

[18] Doshi SV, Cruz RM, Hilsinger RL Jr. Thyroglossal duct carcinoma: A large case series. The Annals of

Otology, Rhinology, and Laryngology. 2001;**110**:734-738

[19] Fancy T, Gallagher D, Hornig JD. Surgical anatomy of the thyroid and parathyroid glands. Otolaryngologic Clinics of North America. 2010;**43**: 221-227. DOI: 10.1016/j.otc.2010.01.001

[20] Akerström G, Malmaeus J, Bergström R. Surgical anatomy of human parathyroid glands. Surgery. 1984;**95**:14

[21] Toni R, Della Casa C, et al. Anthropological variations in the anatomy of the human thyroid arteries. Thyroid. 2003;**13**:183-192

[22] Lal G, Clark OH. Thyroid, parathyroid, and adrenal. In: Schwartz Principles of Surgery. 10th ed. pp. 1523-1524

[23] Orestes MI, Chhetri DK. Superior laryngeal nerve injury: Effects, clinical findings, prognosis, and management options. Current Opinion in Otolaryngology & Head and Neck Surgery. 2014;**22**(6):439-443

[24] Youn YK, Lee KE, Choi JY. Color Atlas of Thyroid Surgery. South Korea: Springer Heidelberg; 2014. pp. 5-6

[25] Miller FR. Surgical anatomy of the thyroid and parathyroid glands. Otolaryngologic Clinics of North America. 2003;**36**:1-7

[26] Tian W, Jiang Y, Gao B, Zhang X, Zhang S, Zhao J, et al. Application of nano-carbon in lymph node dissection for thyroid cancer and protection of parathyroid glands. Medical Science Monitor. 2014;**20**:1925-1930

[27] Dralle H, Sekulla C, Lorenz K, Brauckhoff M, Machens A, the German IONM Study Group. Intraoperative monitoring of the recurrent laryngeal nerve in the thyroid surgery. World Journal of Surgery. 2008;**32**:1358-1366

[28] Chu KS, Wu SH, Lu IC, et al. Feasibility of intraoperative neuromonitoring during thyroid surgery after administration of nondepolarizing neuromuscular blocking agents. World Journal of Surgery. 2009;**33**:1408-1413

[29] Miyauchi A, Inoue H, Tomoda C, et al. Improvement in phonation after reconstruction of the recurrent laryngeal nerve in patients with thyroid cancer invading the nerve. Surgery. 2009;**146**:1056-1062

[30] Sanuki T, Yumoto E, Minoda R, et al. The role of immediate recurrent laryngeal nerve reconstruction for thyroid cancer surgery. Journal of Oncology. 2010;**2010**:846235

[31] Dzodic R, Markovic I, Santrac N, et al. Recurrent laryngeal nerve liberations and reconstructions: A single institution experience. World Journal of Surgery. 2016;**40**:644-651

[32] Choi BH, Kim BY, Huh JY, et al. Microneural anastomosis using cyanoacrylate adhesives. International Journal of Oral and Maxillofacial Surgery. 2004;**33**:777-780

[33] Gurrado A, Pasculli A, Pezzolla A, et al. A method to repair the recurrent laryngeal nerve during thyroidectomy. Canadian Journal of Surgery. 2018; **61**(4):278-282

[34] Miyauchi A, Masuoka H, Tomoda C, et al. Laryngeal approach to the recurrent laryngeal nerve involved by thyroid cancer at the ligament of Berry. Surgery. 2012;**152**:57-60

[35] Zollinger R et al. Atlas of Surgical Operations. 9th ed. New York: McGraw-Hill; 2010

[36] Hollinshead WH. Anatomy for Surgeons. 3rd ed. Vol. 1. Philadelphia: Lippincott Williams and Wilkins; 1982

**15**

*Thyroid Anatomy*

2011. pp. 372-374

*DOI: http://dx.doi.org/10.5772/intechopen.85194*

[37] Larsen WJ. Human Embryology. 3th ed. Philadelphia: Churchill Livingstone;

[39] Mazefferi EL, Jhiang SM. Long term impact of initial surgical and medical therapy on papillary and folliculary thyroid cancer. The American Journal of

[38] Stephen C, Munnoch DA. Lymphoedema of the upper limb: A rare complication of thyroid surgery? BML Case Reports. 2016;**2016**. DOI:

10.1136/bcr-2016-214376

Medicine. 1994;**97**:418-428

1997;**80**(12):2268-72

[40] Yamashita, H, Noguchi S, Murakami N, Kawamoto H,

Watanabe S. Extracapsular invasion of lymph node metastasis is an indicator distant metastasis and poor prognosis in patients with thyroid papillary carcinoma.Cancer. Dec 15

[41] Lim YC, Liu L, Chang JW, Koo BS. Lateral lymph node recurrence after total thyroidectomy and central neck dissection in patients with papillary thyroid cancer without clinical

evidence of lateral neck metastasis. Oral

Oncology. 2016;**62**:109-113

*Thyroid Anatomy DOI: http://dx.doi.org/10.5772/intechopen.85194*

*Knowledges on Thyroid Cancer*

2001;**110**:734-738

Otology, Rhinology, and Laryngology.

[28] Chu KS, Wu SH, Lu IC, et al. Feasibility of intraoperative neuromonitoring during thyroid surgery after administration of nondepolarizing neuromuscular blocking agents. World Journal of Surgery. 2009;**33**:1408-1413

[29] Miyauchi A, Inoue H, Tomoda C, et al. Improvement in phonation after reconstruction of the recurrent laryngeal nerve in patients with thyroid cancer invading the nerve. Surgery.

[30] Sanuki T, Yumoto E, Minoda R, et al. The role of immediate recurrent laryngeal nerve reconstruction for thyroid cancer surgery. Journal of Oncology. 2010;**2010**:846235

[31] Dzodic R, Markovic I, Santrac N, et al. Recurrent laryngeal nerve

[32] Choi BH, Kim BY, Huh JY, et al. Microneural anastomosis using cyanoacrylate adhesives. International Journal of Oral and Maxillofacial

[33] Gurrado A, Pasculli A, Pezzolla A, et al. A method to repair the recurrent laryngeal nerve during thyroidectomy. Canadian Journal of Surgery. 2018;

[34] Miyauchi A, Masuoka H, Tomoda C,

[35] Zollinger R et al. Atlas of Surgical Operations. 9th ed. New York: McGraw-

[36] Hollinshead WH. Anatomy for Surgeons. 3rd ed. Vol. 1. Philadelphia: Lippincott Williams and Wilkins; 1982

et al. Laryngeal approach to the recurrent laryngeal nerve involved by thyroid cancer at the ligament of Berry.

Surgery. 2012;**152**:57-60

Surgery. 2016;**40**:644-651

Surgery. 2004;**33**:777-780

**61**(4):278-282

Hill; 2010

liberations and reconstructions: A single institution experience. World Journal of

2009;**146**:1056-1062

[19] Fancy T, Gallagher D, Hornig JD. Surgical anatomy of the thyroid and parathyroid glands. Otolaryngologic Clinics of North America. 2010;**43**: 221-227. DOI: 10.1016/j.otc.2010.01.001

Bergström R. Surgical anatomy of human parathyroid glands. Surgery. 1984;**95**:14

[20] Akerström G, Malmaeus J,

[21] Toni R, Della Casa C, et al. Anthropological variations in the anatomy of the human thyroid arteries.

[22] Lal G, Clark OH. Thyroid,

Principles of Surgery. 10th ed.

Surgery. 2014;**22**(6):439-443

parathyroid, and adrenal. In: Schwartz

[23] Orestes MI, Chhetri DK. Superior laryngeal nerve injury: Effects, clinical findings, prognosis, and management options. Current Opinion in Otolaryngology & Head and Neck

[24] Youn YK, Lee KE, Choi JY. Color Atlas of Thyroid Surgery. South Korea: Springer Heidelberg; 2014. pp. 5-6

[25] Miller FR. Surgical anatomy of the thyroid and parathyroid glands. Otolaryngologic Clinics of North

[26] Tian W, Jiang Y, Gao B, Zhang X, Zhang S, Zhao J, et al. Application of nano-carbon in lymph node dissection for thyroid cancer and protection of parathyroid glands. Medical Science

America. 2003;**36**:1-7

Monitor. 2014;**20**:1925-1930

[27] Dralle H, Sekulla C, Lorenz K, Brauckhoff M, Machens A, the German IONM Study Group. Intraoperative monitoring of the recurrent laryngeal nerve in the thyroid surgery. World Journal of Surgery. 2008;**32**:1358-1366

Thyroid. 2003;**13**:183-192

pp. 1523-1524

**14**

[37] Larsen WJ. Human Embryology. 3th ed. Philadelphia: Churchill Livingstone; 2011. pp. 372-374

[38] Stephen C, Munnoch DA. Lymphoedema of the upper limb: A rare complication of thyroid surgery? BML Case Reports. 2016;**2016**. DOI: 10.1136/bcr-2016-214376

[39] Mazefferi EL, Jhiang SM. Long term impact of initial surgical and medical therapy on papillary and folliculary thyroid cancer. The American Journal of Medicine. 1994;**97**:418-428

[40] Yamashita, H, Noguchi S, Murakami N, Kawamoto H, Watanabe S. Extracapsular invasion of lymph node metastasis is an indicator distant metastasis and poor prognosis in patients with thyroid papillary carcinoma.Cancer. Dec 15 1997;**80**(12):2268-72

[41] Lim YC, Liu L, Chang JW, Koo BS. Lateral lymph node recurrence after total thyroidectomy and central neck dissection in patients with papillary thyroid cancer without clinical evidence of lateral neck metastasis. Oral Oncology. 2016;**62**:109-113

**17**

**Chapter 3**

Advanced Ultrasound Techniques

The most precise evaluation of thyroid masses is by high-sensitive ultrasound. Complementary to B-mode ultrasound, elastography can add valuable information by determining tissue stiffness—an important predictor for malignancy. All major guidelines recommend nodules with high suspicious ultrasound characteristics larger than 1 cm to be addressed to ultrasound-guided fine needle aspiration biopsy (FNAB) to rule out malignancy. The main limitation of this procedure is represented by indeterminate cytology, which accounts for up to 20–25% of biopsy results. Molecular markers imply elevated costs and their performance needs further study. Elastography may be helpful in establishing the optimal therapeutic attitude for this cytological category. Currently, there are two ultrasound elastography methods available for assessing tissue stiffness using the parallel deformation to the applied force direction (strain) or the perpendicular deformation to the force direction (shear wave). These methods will be presented and compared in this chapter, with their indications and limitations for a better understanding of their

**Keywords:** thyroid cancer, ultrasound, elastography, strain, shear wave,

to surgery, and which to follow by means of ultrasound evaluation [2, 4].

procedure such as carotid ultrasound or computed tomography of the neck [5].

"A thyroid nodule is defined as a discrete lesion within the thyroid gland that is ultrasonographically distinct from the surrounding thyroid parenchyma" [4]. Nodules are usually noticed either by the patient when causing clinical disturbances or compressive symptoms, or by the clinician when performing a thyroid screening or a radiologic

Thyroid cancer incidence increased in the last three decades by up to 211%, not only as a result of a better ability to detect very small lesions, by means of highresolution ultrasonography, but also secondary to a real increase of thyroid cancer incidence, regardless of size, gender, or age groups [1, 2]. Even in these conditions, the prevalence of thyroid cancer, in the entire group of thyroid nodules, reaches a percentage of 15% [3], the main challenge for clinicians being the correct identification of which nodules to refer to fine needle aspiration cytology (FNAC) or directly

in Preoperative Diagnostic of

*Andreea Borlea, Laura Cotoi, Ioana Mozos* 

Thyroid Cancers

application in nodular thyroid pathology.

malignancy risk assessment

**1. Introduction**

*and Dana Stoian*

**Abstract**

#### **Chapter 3**

## Advanced Ultrasound Techniques in Preoperative Diagnostic of Thyroid Cancers

*Andreea Borlea, Laura Cotoi, Ioana Mozos and Dana Stoian*

#### **Abstract**

The most precise evaluation of thyroid masses is by high-sensitive ultrasound. Complementary to B-mode ultrasound, elastography can add valuable information by determining tissue stiffness—an important predictor for malignancy. All major guidelines recommend nodules with high suspicious ultrasound characteristics larger than 1 cm to be addressed to ultrasound-guided fine needle aspiration biopsy (FNAB) to rule out malignancy. The main limitation of this procedure is represented by indeterminate cytology, which accounts for up to 20–25% of biopsy results. Molecular markers imply elevated costs and their performance needs further study. Elastography may be helpful in establishing the optimal therapeutic attitude for this cytological category. Currently, there are two ultrasound elastography methods available for assessing tissue stiffness using the parallel deformation to the applied force direction (strain) or the perpendicular deformation to the force direction (shear wave). These methods will be presented and compared in this chapter, with their indications and limitations for a better understanding of their application in nodular thyroid pathology.

**Keywords:** thyroid cancer, ultrasound, elastography, strain, shear wave, malignancy risk assessment

#### **1. Introduction**

Thyroid cancer incidence increased in the last three decades by up to 211%, not only as a result of a better ability to detect very small lesions, by means of highresolution ultrasonography, but also secondary to a real increase of thyroid cancer incidence, regardless of size, gender, or age groups [1, 2]. Even in these conditions, the prevalence of thyroid cancer, in the entire group of thyroid nodules, reaches a percentage of 15% [3], the main challenge for clinicians being the correct identification of which nodules to refer to fine needle aspiration cytology (FNAC) or directly to surgery, and which to follow by means of ultrasound evaluation [2, 4].

"A thyroid nodule is defined as a discrete lesion within the thyroid gland that is ultrasonographically distinct from the surrounding thyroid parenchyma" [4]. Nodules are usually noticed either by the patient when causing clinical disturbances or compressive symptoms, or by the clinician when performing a thyroid screening or a radiologic procedure such as carotid ultrasound or computed tomography of the neck [5].

#### *Knowledges on Thyroid Cancer*

When evaluating a thyroid nodule, first line step is represented by running laboratory tests (thyroid-stimulating hormone and thyroid hormones) and performing ultrasound evaluation of the gland. Evaluation goals include identification of the small percentage of malignant nodules, of those that impair thyroid function and of compressive symptoms (dysphonia and dyspnea) [6, 7].

Personal or family history of thyroid cancer, significant exposure to radiations, increases the malignancy risk of the nodule and should be screened for [8].

It is desired to have uniform and standardized reports, given the increased accessibility of the ultrasound equipment and considerable number of clinicians that perform this type of evaluation. Reports will always record nodule position, number, extracapsular relations, and the following features of the lesions: size, shape, margins, echogenicity, echo texture, internal composition (solid, cystic, or mixed), presence of calcifications, and vascular pattern [2].

There are some US features described that are considered highly specific for malignancy, as the presence of microcalcifications, rim calcifications, infiltrative margins, extrathyroidal extension, mostly solid composition, marked hypoechoic texture, and "taller than wide" shape, respectively, the vertical diameter bigger than the transverse diameter. Spongiform appearance, smooth margins, and cystic composition are associated with benignity [6].

Vascularization assessment is considered to have poor interobserver agreement and it has highly dependent on the US equipment used [9].

Additionally, abnormal cervical lymph nodes should be assessed, especially in patients with intermediate- and high-risk thyroid nodules [10].

Various authors and societies proposed risk-stratification systems for thyroid nodules on US. They were initially introduced by classifying thyroid nodules which displayed any suspicious feature as malignant. Thus, starting with Kim et al. in 2002, risk-stratification systems were conceived as qualitative grading systems.

Assessment based on a combination of US features has been proposed as a better method of risk stratification. The system developed into a quantitative scoring system, on which the concept of thyroid imaging reporting and data system (TI-RADS) is based. Horvath et al., inspired by the previously existing breast imaging reporting and data system (BI-RADS) score, introduced it in 2009. Since then, the concept has permanently developed; each new concept proposed having its advantages and limitations regarding their practical application [11]. There are also data suggesting TI-RADS quantification is better than individual assessment of the US characteristics [12].

Different diagnostic qualities are described for each model: Park model: Se = 82%, Sp = 65% [13]; Kwak model: Se = 97.4%, Sp = 29.3% [14, 15].

Diagnostic accuracy for Russ' TI-RADS model was evaluated comparatively on gray scale alone and associated with elastography score. When compared to cytological results, the study showed Se = 95.7, Sp = 61%, and NPV = 99.7% for gray scale only; Se = 98.5%, Sp = 44.7%, and NPV = 99.8% for the combined model using gray scale + elastography. For the operated group, these models were also compared to pathology results showing Se = 93.2% for gray-scale TI-RADS and Se = 96.7% for gray scale + elastography. It was estimated that the number of nodules sent to FNAB decreased by 33.8% [9, 10, 16].

Stoian model also calculated strain ratio for each nodule, apart from qualitative SE scoring, with excellent diagnostic value (AUC = 0.95761, 95% confidence interval (CI)). In this case, Se = 97.93%, Sp = 86.20%, and NPV = 97.26%. Nodules required for FNAB decreased by 43.7% [17].

**19**

*Advanced Ultrasound Techniques in Preoperative Diagnostic of Thyroid Cancers*

US-guided FNAB represents the next step in thyroid nodule evaluation and is considered to be the most accurate and cost-efficient preoperative method for identifying malignancy in thyroid nodular lesions, but its indications are broad and differ in the guidelines [19, 20]. Complications are rare and are usually represented by local pain or minor hematomas, but patients are still sometimes reluctant to undergo this procedure [21]. Prior the FNAB, the patients can be questioned for the use of blood thinner drugs and hematologic disease such as bleeding-clotting

A category-based reporting system was developed and standardized for thyroid FNAB specimens by The Bethesda System for Reporting Thyroid Cytopathology (and it has been broadly adopted). Based on this reporting system, thyroid nodule cytology can be classified in one of the following six categories: (I) nondiagnostic, (II) benign, (III) atypia or follicular lesion of undetermined significance (AUS or FLUS), (IV) (suspicion of) follicular neoplasm, (V) suspicious for malignancy, and

Each category has its evidence-based recommendation for further clinical behavior according to its estimated malignancy risk. The real challenge concerns the management of indeterminate cytology lesions (Bethesda categories III–V) [22]. Benign cytology accounts for 60–70% of FNAs, malignant findings for about 5%—papillary thyroid carcinoma (PTC) being the most common, and indeterminate cytology for 10–20% of specimens—atypical modifications, follicular or Hurthle cell cancers. The indeterminate category has anywhere from 15 to 60% risk of malignancy, depending on the specifics of the report. Studies recently showed that molecular markers can help future distinction between benign and malignant nodules in this

cytological category but there are no recommendations currently in use [20].

The American Association of Clinical Endocrinology 2016 guidelines recommend FNAB for nodules with high US risk if they are ≥10 mm, for intermediate US risk nodules ≥20 mm, and low US risk lesions >20 mm that are increasing in size or have thyroid cancer history. For nodules between 5 and 10 mm in diameter with high-risk US characteristics, they recommend FNAC or watchful waiting. Functioning nodules on scintigraphy that lack suspicious US characteristics do not

The American Thyroid Association (ATA) Management Guidelines refer to

There are some drawbacks regarding FNAC results. About 5% of cases are considered qualitative or quantitative insufficient for diagnostic, and Bethesda III and IV categories are inconclusive for a final treatment recommendation. In the presence of indeterminate cytology, the clinical judgment relies again on patient background (clinical risk categories) and ultrasonography aspect [22, 26].

US elastography noninvasively evaluates the stiffness of a thyroid nodule by measuring the distortion that appears when the nodule is compressed by external

**2. Ultrasound elastography—nodule stiffness as a malignancy** 

The Korean Thyroid Association (KTA) 2016 Revised Guideline recommends that highly suspicious nodules <1 cm should undergo FNAC in order to avoid unnecessary long-term follow-up, given that 20–40% of nodules in this category are benign [25]. The number of nodules addressed to FNAC could be reduced, as 60–80% of FNACs reveal benign lesions; this low percentage of malignancy detected in the nodules sent to FNAC based on US imaging criteria points out the real need for a

*DOI: http://dx.doi.org/10.5772/intechopen.83032*

disorders.

(VI) malignant [22–24].

have recommendation for FNAC [4].

FNAC also for intermediate risk nodules >10 mm [19].

more accurate US diagnostic evaluation [4, 6].

**risk-stratification parameter**

The 2017 ACR–TIRADS applied on 100 thyroid nodules showed an overall Se = 92% and Sp = 44%, with a 29% reduction in the number of nodules that require biopsy [18].

#### *Advanced Ultrasound Techniques in Preoperative Diagnostic of Thyroid Cancers DOI: http://dx.doi.org/10.5772/intechopen.83032*

US-guided FNAB represents the next step in thyroid nodule evaluation and is considered to be the most accurate and cost-efficient preoperative method for identifying malignancy in thyroid nodular lesions, but its indications are broad and differ in the guidelines [19, 20]. Complications are rare and are usually represented by local pain or minor hematomas, but patients are still sometimes reluctant to undergo this procedure [21]. Prior the FNAB, the patients can be questioned for the use of blood thinner drugs and hematologic disease such as bleeding-clotting disorders.

A category-based reporting system was developed and standardized for thyroid FNAB specimens by The Bethesda System for Reporting Thyroid Cytopathology (and it has been broadly adopted). Based on this reporting system, thyroid nodule cytology can be classified in one of the following six categories: (I) nondiagnostic, (II) benign, (III) atypia or follicular lesion of undetermined significance (AUS or FLUS), (IV) (suspicion of) follicular neoplasm, (V) suspicious for malignancy, and (VI) malignant [22–24].

Each category has its evidence-based recommendation for further clinical behavior according to its estimated malignancy risk. The real challenge concerns the management of indeterminate cytology lesions (Bethesda categories III–V) [22].

Benign cytology accounts for 60–70% of FNAs, malignant findings for about 5%—papillary thyroid carcinoma (PTC) being the most common, and indeterminate cytology for 10–20% of specimens—atypical modifications, follicular or Hurthle cell cancers. The indeterminate category has anywhere from 15 to 60% risk of malignancy, depending on the specifics of the report. Studies recently showed that molecular markers can help future distinction between benign and malignant nodules in this cytological category but there are no recommendations currently in use [20].

The American Association of Clinical Endocrinology 2016 guidelines recommend FNAB for nodules with high US risk if they are ≥10 mm, for intermediate US risk nodules ≥20 mm, and low US risk lesions >20 mm that are increasing in size or have thyroid cancer history. For nodules between 5 and 10 mm in diameter with high-risk US characteristics, they recommend FNAC or watchful waiting. Functioning nodules on scintigraphy that lack suspicious US characteristics do not have recommendation for FNAC [4].

The American Thyroid Association (ATA) Management Guidelines refer to FNAC also for intermediate risk nodules >10 mm [19].

The Korean Thyroid Association (KTA) 2016 Revised Guideline recommends that highly suspicious nodules <1 cm should undergo FNAC in order to avoid unnecessary long-term follow-up, given that 20–40% of nodules in this category are benign [25].

The number of nodules addressed to FNAC could be reduced, as 60–80% of FNACs reveal benign lesions; this low percentage of malignancy detected in the nodules sent to FNAC based on US imaging criteria points out the real need for a more accurate US diagnostic evaluation [4, 6].

There are some drawbacks regarding FNAC results. About 5% of cases are considered qualitative or quantitative insufficient for diagnostic, and Bethesda III and IV categories are inconclusive for a final treatment recommendation. In the presence of indeterminate cytology, the clinical judgment relies again on patient background (clinical risk categories) and ultrasonography aspect [22, 26].

#### **2. Ultrasound elastography—nodule stiffness as a malignancy risk-stratification parameter**

US elastography noninvasively evaluates the stiffness of a thyroid nodule by measuring the distortion that appears when the nodule is compressed by external

*Knowledges on Thyroid Cancer*

When evaluating a thyroid nodule, first line step is represented by running laboratory tests (thyroid-stimulating hormone and thyroid hormones) and performing ultrasound evaluation of the gland. Evaluation goals include identification of the small percentage of malignant nodules, of those that impair thyroid function and of

Personal or family history of thyroid cancer, significant exposure to radiations,

There are some US features described that are considered highly specific for malignancy, as the presence of microcalcifications, rim calcifications, infiltrative margins, extrathyroidal extension, mostly solid composition, marked hypoechoic texture, and "taller than wide" shape, respectively, the vertical diameter bigger than the transverse diameter. Spongiform appearance, smooth margins, and cystic

Vascularization assessment is considered to have poor interobserver agreement

Additionally, abnormal cervical lymph nodes should be assessed, especially in

Various authors and societies proposed risk-stratification systems for thyroid nodules on US. They were initially introduced by classifying thyroid nodules which displayed any suspicious feature as malignant. Thus, starting with Kim et al. in 2002, risk-stratification systems were conceived as qualitative grading systems. Assessment based on a combination of US features has been proposed as a better method of risk stratification. The system developed into a quantitative scoring system, on which the concept of thyroid imaging reporting and data system (TI-RADS) is based. Horvath et al., inspired by the previously existing breast imaging reporting and data system (BI-RADS) score, introduced it in 2009. Since then, the concept has permanently developed; each new concept proposed having its advantages and limitations regarding their practical application [11]. There are also data suggesting TI-RADS quantification is better than individual assessment of

Different diagnostic qualities are described for each model: Park model:

Diagnostic accuracy for Russ' TI-RADS model was evaluated comparatively on gray scale alone and associated with elastography score. When compared to cytological results, the study showed Se = 95.7, Sp = 61%, and NPV = 99.7% for gray scale only; Se = 98.5%, Sp = 44.7%, and NPV = 99.8% for the combined model using gray scale + elastography. For the operated group, these models were also compared to pathology results showing Se = 93.2% for gray-scale TI-RADS and Se = 96.7% for gray scale + elastography. It was estimated that the number of nodules sent to FNAB

Stoian model also calculated strain ratio for each nodule, apart from qualitative SE scoring, with excellent diagnostic value (AUC = 0.95761, 95% confidence interval (CI)). In this case, Se = 97.93%, Sp = 86.20%, and NPV = 97.26%. Nodules

The 2017 ACR–TIRADS applied on 100 thyroid nodules showed an overall Se = 92% and Sp = 44%, with a 29% reduction in the number of nodules that

Se = 82%, Sp = 65% [13]; Kwak model: Se = 97.4%, Sp = 29.3% [14, 15].

increases the malignancy risk of the nodule and should be screened for [8]. It is desired to have uniform and standardized reports, given the increased accessibility of the ultrasound equipment and considerable number of clinicians that perform this type of evaluation. Reports will always record nodule position, number, extracapsular relations, and the following features of the lesions: size, shape, margins, echogenicity, echo texture, internal composition (solid, cystic, or

compressive symptoms (dysphonia and dyspnea) [6, 7].

mixed), presence of calcifications, and vascular pattern [2].

and it has highly dependent on the US equipment used [9].

patients with intermediate- and high-risk thyroid nodules [10].

composition are associated with benignity [6].

the US characteristics [12].

decreased by 33.8% [9, 10, 16].

require biopsy [18].

required for FNAB decreased by 43.7% [17].

**18**

#### *Knowledges on Thyroid Cancer*

pressure (strain elastography) or by assessing the attenuation of the shear waves (shear-wave elastography) generated by the transducer [10].

Elasticity is the ability of tissue to resist deformation when an external force is applied, or to resume its original shape after the force is removed [27]. Loss of elasticity of a tissue on palpation or elastography ("virtual palpation") generates suspicion of malignancy. Most solid tumors are mechanically different from adjacent tissues, presenting increased stiffness (decreased elasticity) owing to desmoplastic transformation—more collagen and myofibroblasts [27, 28].

There are some fibrous benign tumors that can be hard on elastography (histiocytofibromas) and some malignant nodules with nonmodified elasticity that can be missed by elastography (follicular carcinomas) [28, 29].

The different US elastography techniques that are currently available carry various limitations in relation to the tissue shear properties and they may be in some cases complementary [30]. Elastography can be easily used in the evaluation of the thyroid gland considering its conveniently superficial location, but it is still not widely adopted in practice or included in all the risk-stratification systems [31].

Presently, only one thyroid US elastography guideline has been published the "European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) Guidelines and Recommendations." Recommendations are in favor of using elastography as an extra tool to gray-scale ultrasound and for the follow-up of nodules formerly benign in FNAB [32].

#### **2.1 Strain (quasistatic) elastography**

Strain elastography (SE) was the first to be used and most implemented technique on US systems. Usually, very slight external pressure is applied by the operator (or by acoustic radiation force impulse (ARFI)), or more recently, it has the sensitivity to detect minimal endogenous physiological motion (vascular beam movements and muscle contraction) [28, 30]. The imaging methods are a little different for each manufacturer so each equipment will display images with slightly different characteristics [33].

SE equipment does not offer direct quantification of stress. Elastograms illustrate relative stiffness and are calculated from the signal differences previously and after compression, being displayed in parallel with B-mode image (split-screen) or overlaid on the conventional B-mode image. Stiffness of the tissue is displayed usually in a continuous color map from red (soft or no strain) to green (intermediate or equal strain) to blue (hard or no strain). There are some systems available on the market that use a reverse color scale [34, 35].

A visual colorimetric analysis based on the displayed qualitative map image will be made [32]. Two scoring systems have been proposed for the qualitative assessment of nodule elasticity: the Asteria and Rago systems. Asteria classifies nodules on a scale from 1 (entirely elastic nodule) to 4 (entirely stiff nodule). Rago includes the first four Asteria classes with the addition of the fifth score (entirely stiff nodule, infiltrating in the posterior shadowing area) [35]. Lesions that appear homogenous or with low stiffness are considered benign, while lesions that present increased stiffness are considered to have high malignancy risk [28].

SE machines use special software for an objective semiquantitative determination providing a numeric value: *the strain ratio* (*SR*). This method of elasticity assessment represents the ratio between strain value in the neighboring thyroid parenchyma and the mean nodule strain (parenchyma-to-nodule ratio) or between the strain in a neighboring strap muscle and the thyroid nodule (muscle-to-nodule ratio) [32]. Probability of cancer grows with a higher strain ratio [35]. A study conducted by Aydin et al. in 2014 showed that there are no significant differences

**21**

*Advanced Ultrasound Techniques in Preoperative Diagnostic of Thyroid Cancers*

between muscle-to-nodule ratio and parenchyma-to-nodule ratio, suggesting that the first ratio could be safely used instead of last ratio in evaluating malignancy risk when the thyroid parenchyma is abnormal [36]. SR is considered to be more accurate than qualitative elasticity assessment. The final value will represent the

Widely different cutoff values have been described for the SR (between 1 and 5), currently there is no general agreement: ≥ 2 (Se = 97.3%, Sp = 91.7%) [38]; ≥ 2.09 (Se = 90.6%; Sp = 93%) [39]; ≥ 2.73 (Se = 89.3%; Sp = 73.2%) [40]; and ≥ 3.79 (Se = 97.8%; Sp = 85.7%) [41]. Most of these studies included only solid nodules. **Elastography imaging to B-mode size ratio (EI/B ratio)** has been suggested to

**The area ratio (AR)** is a semiquantitative assessment for SE in virtual touch equipment that compares the nodule area on virtual touch image and B-mode, calculating the mean of the three most accurate measurements. A malignancy cutoff

**Hard area ratio** is the ratio between the nodule hard area and the whole nodule area. Different cutoff values for malignancy have been proposed: ≥ 0.45 (Se = 98.2%; Sp =81.2%) [40] and ≥0.6 (Se = 92.9%, Sp = 91.3%). This parameter is

**The elasticity contrast index** is available on Samsung machines and measures the strain oscillation within a nodule and then uses complex calculation to determine local contrast. In a malignant lesion, there are large differences between low

When choosing the place of the ROI, some aspects have to be taken into consideration. It should be as proximal to the transducer as possible, it should cover the entire nodule and "as much of the adjacent parenchyma as possible." Manual compression is quantified on most of the machines for better reproducibility: optimal compression in Hitachi machines is considered between 3 and 4 and > 50 in

There is a huge body of evidence regarding the diagnostic qualities of the SE

In a meta-analysis conducted in 2010 by Bojunga et al. that included eight studies (639 nodules), RTE recognized thyroid malignancy with overall mean Se = 92% (88–96 CI) and mean Sp = 90% (85–95 CI). A significant heterogeneity was found

Rago et al. conducted a study on 195 nodules, which concluded that RTE elastography had Se = 94.9%, Sp =90.3%, PPV = 71.1%, and NPV = 98.6% in predicting malignancy in nodules with indeterminate or nondiagnostic cytology. Worth mentioning is the high NPV of high elasticity-score nodules, which strongly predicts

Another valuable study from Italy evaluated SE diagnostic accuracy on 498 nodules showing Se = 97% and NPV = 97% when at least one suspicious US parameters

A meta-analysis that included 20 studies evaluating SE diagnostic value in benign or malignant nodules showed a pooled Se = 85% (95% CI, 79–90%),

Sp = 80% (95% CI, 73–86%), NPV = 97% (95% CI, 94–98%), and PPV = 40% (95%

Some of SE limitations are represented by its subjectivity, operator-dependency,

Increased stiffness can be found in benign nodules with coarse calcification or

When the evaluated lesion is located deeper, an elastogram can be obtained if lesion can be visualized in the B-mode image, but it may require application of

highly dependent on the examiner and has poor reproducibility [37].

and high strain regions, inducing important local contrast [44].

method in defining benign versus malignant lesion.

for specificity of the different studies [45].

and compressibility-dependency [49].

fibrosis, leading to false-positive results [45, 50].

*DOI: http://dx.doi.org/10.5772/intechopen.83032*

average of three measurements [37].

of 1.08 was suggested [43].

Siemens machines [32, 37].

benignity [46].

was also present [47].

CI, 34–48%) [48].

be useful in evaluation of breast lesions [42].

between muscle-to-nodule ratio and parenchyma-to-nodule ratio, suggesting that the first ratio could be safely used instead of last ratio in evaluating malignancy risk when the thyroid parenchyma is abnormal [36]. SR is considered to be more accurate than qualitative elasticity assessment. The final value will represent the average of three measurements [37].

Widely different cutoff values have been described for the SR (between 1 and 5), currently there is no general agreement: ≥ 2 (Se = 97.3%, Sp = 91.7%) [38]; ≥ 2.09 (Se = 90.6%; Sp = 93%) [39]; ≥ 2.73 (Se = 89.3%; Sp = 73.2%) [40]; and ≥ 3.79 (Se = 97.8%; Sp = 85.7%) [41]. Most of these studies included only solid nodules.

**Elastography imaging to B-mode size ratio (EI/B ratio)** has been suggested to be useful in evaluation of breast lesions [42].

**The area ratio (AR)** is a semiquantitative assessment for SE in virtual touch equipment that compares the nodule area on virtual touch image and B-mode, calculating the mean of the three most accurate measurements. A malignancy cutoff of 1.08 was suggested [43].

**Hard area ratio** is the ratio between the nodule hard area and the whole nodule area. Different cutoff values for malignancy have been proposed: ≥ 0.45 (Se = 98.2%; Sp =81.2%) [40] and ≥0.6 (Se = 92.9%, Sp = 91.3%). This parameter is highly dependent on the examiner and has poor reproducibility [37].

**The elasticity contrast index** is available on Samsung machines and measures the strain oscillation within a nodule and then uses complex calculation to determine local contrast. In a malignant lesion, there are large differences between low and high strain regions, inducing important local contrast [44].

When choosing the place of the ROI, some aspects have to be taken into consideration. It should be as proximal to the transducer as possible, it should cover the entire nodule and "as much of the adjacent parenchyma as possible." Manual compression is quantified on most of the machines for better reproducibility: optimal compression in Hitachi machines is considered between 3 and 4 and > 50 in Siemens machines [32, 37].

There is a huge body of evidence regarding the diagnostic qualities of the SE method in defining benign versus malignant lesion.

In a meta-analysis conducted in 2010 by Bojunga et al. that included eight studies (639 nodules), RTE recognized thyroid malignancy with overall mean Se = 92% (88–96 CI) and mean Sp = 90% (85–95 CI). A significant heterogeneity was found for specificity of the different studies [45].

Rago et al. conducted a study on 195 nodules, which concluded that RTE elastography had Se = 94.9%, Sp =90.3%, PPV = 71.1%, and NPV = 98.6% in predicting malignancy in nodules with indeterminate or nondiagnostic cytology. Worth mentioning is the high NPV of high elasticity-score nodules, which strongly predicts benignity [46].

Another valuable study from Italy evaluated SE diagnostic accuracy on 498 nodules showing Se = 97% and NPV = 97% when at least one suspicious US parameters was also present [47].

A meta-analysis that included 20 studies evaluating SE diagnostic value in benign or malignant nodules showed a pooled Se = 85% (95% CI, 79–90%), Sp = 80% (95% CI, 73–86%), NPV = 97% (95% CI, 94–98%), and PPV = 40% (95% CI, 34–48%) [48].

Some of SE limitations are represented by its subjectivity, operator-dependency, and compressibility-dependency [49].

Increased stiffness can be found in benign nodules with coarse calcification or fibrosis, leading to false-positive results [45, 50].

When the evaluated lesion is located deeper, an elastogram can be obtained if lesion can be visualized in the B-mode image, but it may require application of

*Knowledges on Thyroid Cancer*

pressure (strain elastography) or by assessing the attenuation of the shear waves

Elasticity is the ability of tissue to resist deformation when an external force is applied, or to resume its original shape after the force is removed [27]. Loss of elasticity of a tissue on palpation or elastography ("virtual palpation") generates suspicion of malignancy. Most solid tumors are mechanically different from adjacent tissues, presenting increased stiffness (decreased elasticity) owing to desmoplastic transformation—more collagen and myofibroblasts [27, 28].

There are some fibrous benign tumors that can be hard on elastography (histiocytofibromas) and some malignant nodules with nonmodified elasticity that can be

The different US elastography techniques that are currently available carry various limitations in relation to the tissue shear properties and they may be in some cases complementary [30]. Elastography can be easily used in the evaluation of the thyroid gland considering its conveniently superficial location, but it is still not widely adopted in practice or included in all the risk-stratification systems [31]. Presently, only one thyroid US elastography guideline has been published the "European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) Guidelines and Recommendations." Recommendations are in favor of using elastography as an extra tool to gray-scale ultrasound and for the follow-up of

Strain elastography (SE) was the first to be used and most implemented technique on US systems. Usually, very slight external pressure is applied by the operator (or by acoustic radiation force impulse (ARFI)), or more recently, it has the sensitivity to detect minimal endogenous physiological motion (vascular beam movements and muscle contraction) [28, 30]. The imaging methods are a little different for each manufacturer so each equipment will display images with slightly

SE equipment does not offer direct quantification of stress. Elastograms illustrate relative stiffness and are calculated from the signal differences previously and after compression, being displayed in parallel with B-mode image (split-screen) or overlaid on the conventional B-mode image. Stiffness of the tissue is displayed usually in a continuous color map from red (soft or no strain) to green (intermediate or equal strain) to blue (hard or no strain). There are some systems available on the

A visual colorimetric analysis based on the displayed qualitative map image will be made [32]. Two scoring systems have been proposed for the qualitative assessment of nodule elasticity: the Asteria and Rago systems. Asteria classifies nodules on a scale from 1 (entirely elastic nodule) to 4 (entirely stiff nodule). Rago includes the first four Asteria classes with the addition of the fifth score (entirely stiff nodule, infiltrating in the posterior shadowing area) [35]. Lesions that appear homogenous or with low stiffness are considered benign, while lesions that present

SE machines use special software for an objective semiquantitative determination providing a numeric value: *the strain ratio* (*SR*). This method of elasticity assessment represents the ratio between strain value in the neighboring thyroid parenchyma and the mean nodule strain (parenchyma-to-nodule ratio) or between the strain in a neighboring strap muscle and the thyroid nodule (muscle-to-nodule ratio) [32]. Probability of cancer grows with a higher strain ratio [35]. A study conducted by Aydin et al. in 2014 showed that there are no significant differences

increased stiffness are considered to have high malignancy risk [28].

(shear-wave elastography) generated by the transducer [10].

missed by elastography (follicular carcinomas) [28, 29].

nodules formerly benign in FNAB [32].

**2.1 Strain (quasistatic) elastography**

different characteristics [33].

market that use a reverse color scale [34, 35].

**20**

more stress by the examiner, which could alter the color map for more superficial structures. If nodules are too deep, a false-positive stiff image can appear as a result of reduced stress transmission [32].

Nodule size is not considered to interfere with SE evaluation accuracy, although there are some studies that reported affected performance on nodules larger than 3 cm or very small lesions. WFUMB guidelines consider nodules larger than 3 cm cannot be evaluated correctly because of their deeper parts and lack of healthy adjacent tissue. Coalescent nodules can also not be assessed by SE [32, 37, 51].

Carotid pulsations interfere when external pressure is applied, particularly in transverse incidence, the incidence being preferred for elastography with internal force [32].

The reference surrounding parenchyma in the ROI should have at least 50% green color to obtain an accurate strain ration [37].

Other limitations of SE are presence of peripheral rim calcification—increased stiffness; large cystic component—SE in nodules with cystic components should be assessed only for the solid component; necrosis—can present soft areas; nodules under 5 mm—although a low size limit for SE use was not established; and obese patients [50, 51].

It is clear that strain elastography accuracy is highly dependent on the examiner's training. The interobserver variability has been evaluated by several studies that recently showed excellent agreement between multiple observers [32]. It seems that strain ratio is easily learned compared to elasticity score interpretation [52].

Different pathologies of the thyroid nodules can have an impact on SE appearance. Currently, it is known that follicular carcinomas may appear elastic on SE, so elastography is not a useful tool for evaluating this type of thyroid malignancy (44% false-negative findings). Other particular pathologies that appear soft on elastography and may lead to false-negative results are medullary carcinomas and metastatic carcinomas [32, 45].

#### **2.2 Shear-wave elastography**

Shear waves are defined as transverse elements of particle displacement which are very quickly attenuated by the tissue. Shear represents a modification of shape, without a modification of volume [35, 53]. Tissue propagation of shear waves is much slower in comparison to longitudinal waves. They do not propagate well in water, being rapidly attenuated, but they do propagate in elastic media [54].

Shear-wave elastography (SWE) is more operator-independent, and therefore, more reproducible [35]. Quantitative and qualitative assessment of tissue elasticity can be obtained by measuring the shear wave speed. Several applicable methods are available [27].

**1D Transient elastography** is widely used for estimating liver fibrosis (Fibroscan and Echosens). It cannot be performed with a standard transducer on regular ultrasound equipment. The probe used by this device incorporates an US transducer as well as a vibrating device that exerts an external vibrating "punch" to generate shear waves that will propagate through tissues [27].

**In monoplane shear-wave elastography (pSWE)**, ARFI mechanically excites the tissue in the region of interest (ROI) using acoustic push pulses which generate localized tissue displacements in the US axial direction—perpendicular to the surface. Shear wave speed measurements can be made up to 8 cm in depth (m/s) [14, 30]. This approach is implemented on devices produced by Phillips (ElastPQ ) and Siemens (VitualTouch Quantification, VTQ ) [27].

**Biplane shear-wave elastography (SWE, 2D SWE, 3D SWE**) offers a realtime display of a color quantitative elastogram overlaid on a B-mode image and

**23**

*Advanced Ultrasound Techniques in Preoperative Diagnostic of Thyroid Cancers*

stiffness, mean stiffness, and standard deviation (SD) [35].

78.2–91.7) and Sp = 89.5% (95% CI: 83.3–93.6) [56].

assessment of shear wave speed [27]. Supersonic shear wave uses focused ultrasonic beams that spread through the whole imaging area, displaying on a color map the velocity (m/s) of the shear wave or directly the elasticity (kilopascals) for every pixel in the ROI. A series of parameters in the ROI can be measured: maximum

The following 2D-SWE technologies are currently available on US machines by: Siemens (Virtual Touch Imaging Quantification, VTIQ ), SuperSonic Imagine (SWE), Philips (SWE), Toshiba (Acoustic Structure Quantification), and GE

The largest recent meta-analysis by Zhang et al. included 16 studies that used ARFI-generated SWE to evaluate 2436 nodules had mean Se = 0.80 (95% CI, 0.73–0.87) and Sp = 0.85 (95% CI, 0.80–0.90) in detecting malignancy. Both Se and

Another meta-analysis (Dong et al.) on 13 retro/prospective studies detected high

Cutoff values again range widely and have been reported for shear-wave velocity

One study on 476 nodules established an EI cutoff mean value of above 85 kPa (Se = 95%) or one maximum value of above 94 kPa [58]. Another study on VTQ of ARFI reported a cutoff point for velocity = 2.87 m/s and for SWV ratio = 1.59. The study also pointed out this SWE method has highest diagnostic value for nodules

Other studies reviewed in the WFUMB guidelines showed cutoff values ranging

Interobserver and intraobserver reproducibility were reported to be high. One study conducted by Grazhdani et al. showed high concordance rate (k = 0.75)

For the characterization of the thyroid lesion, a quantitate measurement for the mean value or maximum value of an elasticity is used. Similar to SE, an SR can be obtained by comparing adjacent normal parenchyma or surrounding muscle [32].

The size of the ROI is fixed (5 × 6 mm or 20 × 20 mm)—small nodules cannot be accurately measured. Also for nodules smaller than 20 mm, wave velocity is not stable. Composition of nodules: cystic composition or calcifications cannot be evaluated—it is impossible to place the ROI inside the nodule. Depth is an important limitation for both pSWE and 2D SWE—the ARFI cannot penetrate nodules deeper than 4–5 cm; ARFI can measure velocities only up to 9 m/s—harder nodules

Nodules that are located on the thyroid isthmus are a challenge due to their interpo-

Again, not all malignant nodules are elastic. Follicular carcinomas are described

Some of ARFI technique limitations will be briefly presented.

or areas will not be evaluated properly: the value "x.xx m/s" will be shown.

as soft lesions and are difficult to differentiate from benign lesions. A study by Samir et al. proposed a cutoff value of 22.3 kPa for distinguishing thyroid follicular

sition between the stiff trachea and the skin [32, 37].

cancer from benign follicular lesions (Se = 82%; Sp = 88%) [65].

ARFI VTQ efficacy in detecting thyroid cancer, with pooled Se = 86.3% (95% CI,

A meta-analysis by Lin et al. included 15 studies that used point-SWE or 2D SWE to investigate 1867 nodules. The pooled Se = 84.3% (95% CI, 76.9–89.7%), Sp = 88.4% (95% CI, 84.0–91.7%), PPV = 27.7–44.7%, and NPV = 98.1–99.1% [57]. All the mentioned meta-analyses concluded that SWE (pSWE and 2-D SWE) are useful in detecting thyroid malignancy as a complementary tool to gray-scale US, which is also a stated recommendation of WFUMB 2017 guidelines [32]. Five to ten consecutive measurements are needed in order to obtain a valid

Sp were found significantly heterogeneous in all the included studies [55].

*DOI: http://dx.doi.org/10.5772/intechopen.83032*

Healthcare (2D-SWE) [27].

median result [32].

>20 mm [59].

between 2.4 and 4.7 m/s [32].

from 2.55 to 2.75 m/s [60–63].

between two observers [64].

*Advanced Ultrasound Techniques in Preoperative Diagnostic of Thyroid Cancers DOI: http://dx.doi.org/10.5772/intechopen.83032*

assessment of shear wave speed [27]. Supersonic shear wave uses focused ultrasonic beams that spread through the whole imaging area, displaying on a color map the velocity (m/s) of the shear wave or directly the elasticity (kilopascals) for every pixel in the ROI. A series of parameters in the ROI can be measured: maximum stiffness, mean stiffness, and standard deviation (SD) [35].

The following 2D-SWE technologies are currently available on US machines by: Siemens (Virtual Touch Imaging Quantification, VTIQ ), SuperSonic Imagine (SWE), Philips (SWE), Toshiba (Acoustic Structure Quantification), and GE Healthcare (2D-SWE) [27].

The largest recent meta-analysis by Zhang et al. included 16 studies that used ARFI-generated SWE to evaluate 2436 nodules had mean Se = 0.80 (95% CI, 0.73–0.87) and Sp = 0.85 (95% CI, 0.80–0.90) in detecting malignancy. Both Se and Sp were found significantly heterogeneous in all the included studies [55].

Another meta-analysis (Dong et al.) on 13 retro/prospective studies detected high ARFI VTQ efficacy in detecting thyroid cancer, with pooled Se = 86.3% (95% CI, 78.2–91.7) and Sp = 89.5% (95% CI: 83.3–93.6) [56].

A meta-analysis by Lin et al. included 15 studies that used point-SWE or 2D SWE to investigate 1867 nodules. The pooled Se = 84.3% (95% CI, 76.9–89.7%), Sp = 88.4% (95% CI, 84.0–91.7%), PPV = 27.7–44.7%, and NPV = 98.1–99.1% [57].

All the mentioned meta-analyses concluded that SWE (pSWE and 2-D SWE) are useful in detecting thyroid malignancy as a complementary tool to gray-scale US, which is also a stated recommendation of WFUMB 2017 guidelines [32].

Five to ten consecutive measurements are needed in order to obtain a valid median result [32].

Cutoff values again range widely and have been reported for shear-wave velocity between 2.4 and 4.7 m/s [32].

One study on 476 nodules established an EI cutoff mean value of above 85 kPa (Se = 95%) or one maximum value of above 94 kPa [58]. Another study on VTQ of ARFI reported a cutoff point for velocity = 2.87 m/s and for SWV ratio = 1.59. The study also pointed out this SWE method has highest diagnostic value for nodules >20 mm [59].

Other studies reviewed in the WFUMB guidelines showed cutoff values ranging from 2.55 to 2.75 m/s [60–63].

Interobserver and intraobserver reproducibility were reported to be high. One study conducted by Grazhdani et al. showed high concordance rate (k = 0.75) between two observers [64].

For the characterization of the thyroid lesion, a quantitate measurement for the mean value or maximum value of an elasticity is used. Similar to SE, an SR can be obtained by comparing adjacent normal parenchyma or surrounding muscle [32].

Some of ARFI technique limitations will be briefly presented.

The size of the ROI is fixed (5 × 6 mm or 20 × 20 mm)—small nodules cannot be accurately measured. Also for nodules smaller than 20 mm, wave velocity is not stable. Composition of nodules: cystic composition or calcifications cannot be evaluated—it is impossible to place the ROI inside the nodule. Depth is an important limitation for both pSWE and 2D SWE—the ARFI cannot penetrate nodules deeper than 4–5 cm; ARFI can measure velocities only up to 9 m/s—harder nodules or areas will not be evaluated properly: the value "x.xx m/s" will be shown. Nodules that are located on the thyroid isthmus are a challenge due to their interposition between the stiff trachea and the skin [32, 37].

Again, not all malignant nodules are elastic. Follicular carcinomas are described as soft lesions and are difficult to differentiate from benign lesions. A study by Samir et al. proposed a cutoff value of 22.3 kPa for distinguishing thyroid follicular cancer from benign follicular lesions (Se = 82%; Sp = 88%) [65].

*Knowledges on Thyroid Cancer*

force [32].

patients [50, 51].

metastatic carcinomas [32, 45].

**2.2 Shear-wave elastography**

available [27].

of reduced stress transmission [32].

green color to obtain an accurate strain ration [37].

more stress by the examiner, which could alter the color map for more superficial structures. If nodules are too deep, a false-positive stiff image can appear as a result

Nodule size is not considered to interfere with SE evaluation accuracy, although there are some studies that reported affected performance on nodules larger than 3 cm or very small lesions. WFUMB guidelines consider nodules larger than 3 cm cannot be evaluated correctly because of their deeper parts and lack of healthy adjacent tissue. Coalescent nodules can also not be assessed by SE [32, 37, 51]. Carotid pulsations interfere when external pressure is applied, particularly in transverse incidence, the incidence being preferred for elastography with internal

The reference surrounding parenchyma in the ROI should have at least 50%

Other limitations of SE are presence of peripheral rim calcification—increased stiffness; large cystic component—SE in nodules with cystic components should be assessed only for the solid component; necrosis—can present soft areas; nodules under 5 mm—although a low size limit for SE use was not established; and obese

It is clear that strain elastography accuracy is highly dependent on the examiner's training. The interobserver variability has been evaluated by several studies that recently showed excellent agreement between multiple observers [32]. It seems that

Different pathologies of the thyroid nodules can have an impact on SE appearance. Currently, it is known that follicular carcinomas may appear elastic on SE, so elastography is not a useful tool for evaluating this type of thyroid malignancy (44% false-negative findings). Other particular pathologies that appear soft on elastography and may lead to false-negative results are medullary carcinomas and

Shear waves are defined as transverse elements of particle displacement which are very quickly attenuated by the tissue. Shear represents a modification of shape, without a modification of volume [35, 53]. Tissue propagation of shear waves is much slower in comparison to longitudinal waves. They do not propagate well in water, being rapidly attenuated, but they do propagate in elastic media [54].

Shear-wave elastography (SWE) is more operator-independent, and therefore, more reproducible [35]. Quantitative and qualitative assessment of tissue elasticity can be obtained by measuring the shear wave speed. Several applicable methods are

**In monoplane shear-wave elastography (pSWE)**, ARFI mechanically excites the tissue in the region of interest (ROI) using acoustic push pulses which generate localized tissue displacements in the US axial direction—perpendicular to the surface. Shear wave speed measurements can be made up to 8 cm in depth (m/s) [14, 30]. This approach is implemented on devices produced by Phillips (ElastPQ )

**Biplane shear-wave elastography (SWE, 2D SWE, 3D SWE**) offers a realtime display of a color quantitative elastogram overlaid on a B-mode image and

**1D Transient elastography** is widely used for estimating liver fibrosis (Fibroscan and Echosens). It cannot be performed with a standard transducer on regular ultrasound equipment. The probe used by this device incorporates an US transducer as well as a vibrating device that exerts an external vibrating "punch" to

generate shear waves that will propagate through tissues [27].

and Siemens (VitualTouch Quantification, VTQ ) [27].

strain ratio is easily learned compared to elasticity score interpretation [52].

**22**

For accurate results, an experimented examiner should always perform SWE evaluation of the thyroid. The pressure applied on the transducer can influence the evaluation results [32].

There are also clear recommendations that in the presence of a stiff nodule, the FNAB is recommended, regardless the conventional US characteristics.

In the AACE guidelines, a nodule with high stiffness is directly included in the intermediate risk group, elevated stiffness being listed as one of the AACE criteria for FNAB. There is a grade-B recommendation for nodules that are stiff on elastography to be addressed to FNAB [7].

Also, in the presence of indeterminate cytology findings, they suggest that elastography to be considered for extra information. Combined elastography and B-mode US is presented to be more trustworthy when excluding nodules from biopsy evaluation [7].

ATA guidelines acknowledge usefulness of US elastography for noninvasive assessment of malignancy risk when accurate evaluation can be made, but it can neither recommend its universal adoption, nor its replacement of classic US assessment [19].

European Thyroid Association (ETA) guidelines also state that elastography, with its high NPV, can be a helpful instrument for thyroid nodule evaluation and it may be used together with gray-scale US, but not replace it [10].

#### **2.3 RTE versus SWE elastography**

As mentioned in the EFSUMB guidelines and showed in literature data, both SE and SWE represent a useful tool in thyroid nodule stratification of malignancy risk, complementary to gray-scale evaluation [32].

Different studies have reported a wide range of values for Se and Sp when comparing the two-elastographic methods.

A big meta-analysis on 71 studies with a total of 16,624 patients showed that RTE is slightly better in differentiating benignancy from malignancy in thyroid lesions, with pooled Se = 82.9% for RTE; Se = 78.4% for SWE and Sp = 82.8% for RTE; and Sp = 82.4% for SWE [66].

A head-to-head comparison of two elastographic methods was made only in a few studies.

In a publication by Liu et al., 49 patients (64 nodules) underwent both SWE and RTE evaluation and results were compared to pathology results. For SE, qualitative assessment was made using Rago classification (score 4–5 considered as malignancy suspicious) and for SWE—min and max mean elasticity were measured, cutoff mean value was 38.3 kPa, with Sp = 68.4%; Se = 86.7%; NPV = 86.7%; PPV = 68.4% for SWE and Sp = 79%; Se = 84.4%; NPV = 83.3%; PPV = 64.7% for RTE. The study established that SWE is a promising method for the evaluation of thyroid malignancy risk, with similar value to RTE, its sensitivity being a little lower and its specificity a little higher [67].

A 2017 meta-analysis (Hu et al.) is evaluating 22 studies, which simultaneously evaluated diagnostic performance for thyroid malignancy using both RTE and SWE techniques. The results showed that the pooled Se = 0.79 (95% CI, 0.73–0.84), Sp = 0.87 (95% CI, 0.79–0.92) for SWE compared with Se = 0.84 (95% CI, 0.76–0.90), Sp = 0.90 (95% CI, 0.85–0.94) for RTE, was significant lower for SWE technique (p < 0.05) [49].

Another study evaluated 138 nodules using gray-scale US, ARFI imaging and qualitative strain elastography. Combination of ARFI and RTE specificity for detecting malignancy increased by 20% (Sp = 92 vs. 72% for RTE only), but sensitivity decreased by 28% (Se = 48 vs. 76% for RTE alone). When ARFI cutoff was adapted

**25**

*Advanced Ultrasound Techniques in Preoperative Diagnostic of Thyroid Cancers*

for the combined methods (ES 3–4 and ARFI ≥1.11 m/s), sensitivity was unchanged, specificity increased by just 3%. Therefore, there was no significant change in accuracy of finding malignant nodules when combining the two methods [63].

Although most literature data suggest RTE is slightly more powerful in differentiating thyroid cancer, there is currently no consensus about which method is better and both SE and SWE proved to add important value to classic US evaluation in the

Nondiagnostic and indeterminate cytology represent the great limitations of FNAC and gray-scale US can sometimes be poorly predictive. About half of these nodules can avoid surgery by performing a second biopsy [68]. There was one study that reported higher prevalence of cancer on repeat FNAB, maybe as a consequence

For the clearance of this cytological category, there is currently a general proposal to use molecular markers, but there is still no consensus regarding which

Several molecular markers have been studied in indeterminate FNAB cytology findings. The most studied mutations/rearrangements include BRAF, RAS, RET/ PTC, and PAX8/PPARγ. These markers can predict ("rule in") malignancy with very high sensitivity, having a high positive predictive value (PPV) but if they are not present, malignancy cannot be "ruled out," having a low sensitivity and nega-

The most common molecular tests used in this rapidly developing field will be shortly presented. The Afirma Gene Expression Classifier (GEC) is a microarray test which investigates mRNA expression of 167 genes [72]. This test has been reported to have high NPV (up to 95%) in the Bethesda III and IV categories, but low PPV (14–57%), which makes it useful only as a "rule-out" test [72, 73]. ThyGenX test identifies over 100 mutations associated with thyroid cancer, using a next-generation-sequencing (NGS). ThyraMIR is a newer test (used complementary to the ThyGenX) that analyzes 10 different microRNA molecules that are considered to contribute to cell differentiation and proliferation in thyroid pathology. Combining ThyGenX and ThyraMIR in nodules with indeterminate cytology showed Se = 89%, Sp = 85%, NPV = 94%, and PPV = 74% [72, 74]. ThyroSeq v2 includes analysis of a panel of >1000 mutations and RNA alterations, with Se = 90%, Sp = 93%, PPV = 83%, and NPV = 96%, suggesting that this test may be useful as both "rule-in" and "rule-out" test for Bethesda III and IV cytology [72, 75]. It has been suggested that the thyrotropin receptor (TSHR) mRNA test can be useful in indeterminate nodules, its expression being helpful for early

Currently, there is no individual molecular marker that can certainly rule out malignancy in indeterminate nodules and it is still debatable if there is a cost-

Elastography has been suggested to define more accurately the presurgical malignancy risk in this cytological category to help clinician's decision whether to

A study by Rago et al. tried to refine diagnosis in this category of nodules (142 indeterminate and 53 nondiagnostic). All patients have been examined by grayscale US, color Doppler, and qualitative RTE (modified Ueno score). Indeterminate cytology score 1—highly elastic nodule—was found strongly predictive of benignity (p < 0.0001); combination of scores 2 and 3 showed Se = 96.8%, Sp = 91.8%, and NPV = 99.0% for predicting malignancy. In nondiagnostic cases, Sp, Se, and NPV

effective combination of these markers that can be used [4, 70, 71].

*DOI: http://dx.doi.org/10.5772/intechopen.83032*

preoperative approach of thyroid nodules.

panel should be used [70].

tive predictive value (NPV) [70, 71].

diagnosis of PTC [72, 76, 77].

repeat biopsy or follow-up [32].

**2.4 Elastography: place in indeterminate cytology results**

of the class of high-risk nodules that underwent second FNAB [69]*.*

#### *Advanced Ultrasound Techniques in Preoperative Diagnostic of Thyroid Cancers DOI: http://dx.doi.org/10.5772/intechopen.83032*

for the combined methods (ES 3–4 and ARFI ≥1.11 m/s), sensitivity was unchanged, specificity increased by just 3%. Therefore, there was no significant change in accuracy of finding malignant nodules when combining the two methods [63].

Although most literature data suggest RTE is slightly more powerful in differentiating thyroid cancer, there is currently no consensus about which method is better and both SE and SWE proved to add important value to classic US evaluation in the preoperative approach of thyroid nodules.

#### **2.4 Elastography: place in indeterminate cytology results**

Nondiagnostic and indeterminate cytology represent the great limitations of FNAC and gray-scale US can sometimes be poorly predictive. About half of these nodules can avoid surgery by performing a second biopsy [68]. There was one study that reported higher prevalence of cancer on repeat FNAB, maybe as a consequence of the class of high-risk nodules that underwent second FNAB [69]*.*

For the clearance of this cytological category, there is currently a general proposal to use molecular markers, but there is still no consensus regarding which panel should be used [70].

Several molecular markers have been studied in indeterminate FNAB cytology findings. The most studied mutations/rearrangements include BRAF, RAS, RET/ PTC, and PAX8/PPARγ. These markers can predict ("rule in") malignancy with very high sensitivity, having a high positive predictive value (PPV) but if they are not present, malignancy cannot be "ruled out," having a low sensitivity and negative predictive value (NPV) [70, 71].

The most common molecular tests used in this rapidly developing field will be shortly presented. The Afirma Gene Expression Classifier (GEC) is a microarray test which investigates mRNA expression of 167 genes [72]. This test has been reported to have high NPV (up to 95%) in the Bethesda III and IV categories, but low PPV (14–57%), which makes it useful only as a "rule-out" test [72, 73]. ThyGenX test identifies over 100 mutations associated with thyroid cancer, using a next-generation-sequencing (NGS). ThyraMIR is a newer test (used complementary to the ThyGenX) that analyzes 10 different microRNA molecules that are considered to contribute to cell differentiation and proliferation in thyroid pathology. Combining ThyGenX and ThyraMIR in nodules with indeterminate cytology showed Se = 89%, Sp = 85%, NPV = 94%, and PPV = 74% [72, 74]. ThyroSeq v2 includes analysis of a panel of >1000 mutations and RNA alterations, with Se = 90%, Sp = 93%, PPV = 83%, and NPV = 96%, suggesting that this test may be useful as both "rule-in" and "rule-out" test for Bethesda III and IV cytology [72, 75]. It has been suggested that the thyrotropin receptor (TSHR) mRNA test can be useful in indeterminate nodules, its expression being helpful for early diagnosis of PTC [72, 76, 77].

Currently, there is no individual molecular marker that can certainly rule out malignancy in indeterminate nodules and it is still debatable if there is a costeffective combination of these markers that can be used [4, 70, 71].

Elastography has been suggested to define more accurately the presurgical malignancy risk in this cytological category to help clinician's decision whether to repeat biopsy or follow-up [32].

A study by Rago et al. tried to refine diagnosis in this category of nodules (142 indeterminate and 53 nondiagnostic). All patients have been examined by grayscale US, color Doppler, and qualitative RTE (modified Ueno score). Indeterminate cytology score 1—highly elastic nodule—was found strongly predictive of benignity (p < 0.0001); combination of scores 2 and 3 showed Se = 96.8%, Sp = 91.8%, and NPV = 99.0% for predicting malignancy. In nondiagnostic cases, Sp, Se, and NPV

*Knowledges on Thyroid Cancer*

evaluation results [32].

biopsy evaluation [7].

assessment [19].

raphy to be addressed to FNAB [7].

**2.3 RTE versus SWE elastography**

Sp = 82.4% for SWE [66].

specificity a little higher [67].

few studies.

(p < 0.05) [49].

complementary to gray-scale evaluation [32].

comparing the two-elastographic methods.

For accurate results, an experimented examiner should always perform SWE evaluation of the thyroid. The pressure applied on the transducer can influence the

There are also clear recommendations that in the presence of a stiff nodule, the

In the AACE guidelines, a nodule with high stiffness is directly included in the intermediate risk group, elevated stiffness being listed as one of the AACE criteria for FNAB. There is a grade-B recommendation for nodules that are stiff on elastog-

Also, in the presence of indeterminate cytology findings, they suggest that elastography to be considered for extra information. Combined elastography and B-mode US is presented to be more trustworthy when excluding nodules from

ATA guidelines acknowledge usefulness of US elastography for noninvasive assessment of malignancy risk when accurate evaluation can be made, but it can neither recommend its universal adoption, nor its replacement of classic US

European Thyroid Association (ETA) guidelines also state that elastography, with its high NPV, can be a helpful instrument for thyroid nodule evaluation and it

As mentioned in the EFSUMB guidelines and showed in literature data, both SE and SWE represent a useful tool in thyroid nodule stratification of malignancy risk,

A big meta-analysis on 71 studies with a total of 16,624 patients showed that RTE is slightly better in differentiating benignancy from malignancy in thyroid lesions, with pooled Se = 82.9% for RTE; Se = 78.4% for SWE and Sp = 82.8% for RTE; and

A head-to-head comparison of two elastographic methods was made only in a

A 2017 meta-analysis (Hu et al.) is evaluating 22 studies, which simultaneously evaluated diagnostic performance for thyroid malignancy using both RTE and SWE techniques. The results showed that the pooled Se = 0.79 (95% CI, 0.73–0.84), Sp = 0.87 (95% CI, 0.79–0.92) for SWE compared with Se = 0.84 (95% CI, 0.76–0.90), Sp = 0.90 (95% CI, 0.85–0.94) for RTE, was significant lower for SWE technique

Another study evaluated 138 nodules using gray-scale US, ARFI imaging and qualitative strain elastography. Combination of ARFI and RTE specificity for detecting malignancy increased by 20% (Sp = 92 vs. 72% for RTE only), but sensitivity decreased by 28% (Se = 48 vs. 76% for RTE alone). When ARFI cutoff was adapted

In a publication by Liu et al., 49 patients (64 nodules) underwent both SWE and RTE evaluation and results were compared to pathology results. For SE, qualitative assessment was made using Rago classification (score 4–5 considered as malignancy suspicious) and for SWE—min and max mean elasticity were measured, cutoff mean value was 38.3 kPa, with Sp = 68.4%; Se = 86.7%; NPV = 86.7%; PPV = 68.4% for SWE and Sp = 79%; Se = 84.4%; NPV = 83.3%; PPV = 64.7% for RTE. The study established that SWE is a promising method for the evaluation of thyroid malignancy risk, with similar value to RTE, its sensitivity being a little lower and its

Different studies have reported a wide range of values for Se and Sp when

may be used together with gray-scale US, but not replace it [10].

FNAB is recommended, regardless the conventional US characteristics.

**24**

showed poorer Se, Sp, and NPV for all elastography scores. When considering both indeterminate and nondiagnostic, the overall Se = 94.9%, Sp = 90.3%, and NPV = 91.3% for scores 2 and 3 [46].

In another study, qualitative RTE failed to make a correct distinction between benignity and malignancy in thyroid nodules, cancer was found in 50% of nodules scored 1 or 2 on elastogram and in 34% of score 3 nodules. Quantitative assessment of elasticity was suggested [78].

A comparison between 2D-SWE (VTIQ ) and molecular testing (Afirma GEC) was made in a prospective study in nodules with indeterminate FNAC. SWV cutoff for malignancy risk was defined at above 3.59 m/s with Se = 83.9% and Sp = 79.2%. SWV measurements were made in the stiffest section; authors mention that measurements of a larger area may result in a decreased SWV. The GEC-suspicious group had Se = 90.3% and Sp = 74.2% (PPV of only 47.5%, but NPV of 96.7%). The study concluded that both SWV and GEC can independently predict thyroid cancer with similar diagnostic value and are particularly useful in this cytological category [79].

A more complex study compared diagnostic efficiency of SWE, semiquantitative SE (strain index), classic US, CEUS, and BRAF mutation test in indeterminate cytology, but the number of evaluated nodules was relatively small. The study outcomes confirmed a slightly better efficiency for RTE compared to SWE in distinguishing malignancy; strain index was the one parameter that showed significant correlation with pathology results. RTE and SWE do not seem interchangeable but may be used complementary. Interestingly, when strain index, SWV, and BRAF mutation were considered together, Sp was enhanced, but Se was lower compared to US findings alone [68].

This cytological category still remains uncertain in diagnosis, and in some cases, a strategy that combines advanced ultrasound methods was documented to provide higher accuracy in diagnosis than use of a single technique [68]. More studies are required concerning this approach.

#### **2.5 Contrast-enhanced ultrasound (CEUS)**

The use of contrast agents in ultrasonography has widely expanded in clinical use and may play an important role in identifying thyroid cancers by evaluating tumor microcirculation. New-generation contrast agents (SonoVue) are administered intravenously and contain sulfur hexafluoride microbubbles that stay in the blood flow for a while. The examiner focuses the US image on the ROI and a contrastenhanced image is displayed, detecting microvascular changes in the lesion that classic Doppler cannot display [80].

CEUS has already changed approach in management of liver lesions, significantly improving the number of unnecessary biopsy indications [81].

In studies where CEUS was performed on thyroid lesions, malignity was indicated by hypoenhancement and heterogeneity [80]. Hypoenhancement can be explained by the absence of blood supply in the central area of the tumor, due to thrombus formation, vascular compression, and necrosis. Neovascularization is mainly marginal, promoting tumor expansion [82]. Heterogeneity is explained by the complex and aberrant composition of cancerous lesions (fibrotic, presence of calcifications, and necrosis areas) [80, 82].

Other indicators of malignancy are the time of wash-in and wash-out, but results are controversial. Some studies described early wash-in and wash-out in malignant lesions [83, 84], while others have shown late-phase enhancement for thyroid cancers compared to perinodular tissue [85] or no significant difference in the time of enhancement for benign versus malignant nodules [86].

**27**

category.

by an experienced operator.

There is no conflict of interest.

**Conflict of interest**

*Advanced Ultrasound Techniques in Preoperative Diagnostic of Thyroid Cancers*

Adenomas are characterized by homogeneity and peripheral ring enhancement [80]. Two recent meta-analyses on CEUS diagnostic accuracy showed the pooled Se = 0.88 (95% CI, 0.85–0.91); pooled Sp = 0.90 (95% CI, 0.88–0.92) [87]; and a

Some benign nodules showed pattern described for malignant ones and vice versa, so an assessment of both elastography and CEUS was combined in some

A study by Zhan et al. aimed to evaluate the aid of CEUS in diagnosis of thyroid malignancy. First, 200 thyroid nodules were evaluated using ARFI technique. A number of 40 nodules that were in the "gray zone" underwent CEUS. ARFI accurately diagnosed 82% of the total nodules, while CEUS accuracy was 90% (p < 0.05) [89]. Cantisani et al. compared Q-elastography with CEUS in thyroid cancer assessment. Study results showed that both methods outclassed gray-scale US, but Q-elastography was more sensitive than CEUS (Se = 95%, Sp = 88% for

However, more studies are required for evaluating the true usefulness of this relatively new and promising technique in the differentiation of malignant from

Given the great number of thyroid lesions and the rising incidence of thyroid cancer, a correct preoperative distinction between benignity and malignancy in

Ultrasound elastography represents the most important advance in US imaging since Doppler. It proved to serve as an important tool in selecting candidates for surgery. Elastography is a noninvasive, nonirradiating method that can be easily learned, adds only a few minutes to classic US evaluation, but provides truly valuable additional information. Unfortunately, this technique is still quite new and not widely used in clinical practice, so its universal adoption cannot be recommended by the guidelines, but there is important evidence of its clinical utility and its application in current practice is increasing. As any imaging technique, it holds

This technique cannot replace the classic, gray-scale ultrasound, and should be

Due to its high NPV, thyroid nodules that are scored soft on elastography are highly likely to be noncancerous and can be followed-up, avoiding FNAB [91]. Therefore, elastography reduces the need for FNA by up to 43% of cases compared to gray-scale risk stratification [17]. It also identifies stiff nodules that need biopsy and can be missed by gray-scale US alone. Even lesions with low-risk features, but

In the case of indeterminate cytology, clinical judgment can be a real challenge for practitioners. Elastography proved to predict malignancy better than B-mode parameters and can be essential in further management decision for nodules in this

For an accurate result, it is important that the evaluation should be performed

*DOI: http://dx.doi.org/10.5772/intechopen.83032*

pooled Se = 0.853, pooled Sp = 0.87 [88].

Q-elastography; Se = 79%, Sp = 91% for CEUS) [83].

articles.

benign thyroid nodules.

nodular pathology is crucial.

**3. Conclusions**

its limitations [90].

used complementary to it [7, 10, 25].

high stiffness, are recommended for FNAB [91].

*Advanced Ultrasound Techniques in Preoperative Diagnostic of Thyroid Cancers DOI: http://dx.doi.org/10.5772/intechopen.83032*

Adenomas are characterized by homogeneity and peripheral ring enhancement [80].

Two recent meta-analyses on CEUS diagnostic accuracy showed the pooled Se = 0.88 (95% CI, 0.85–0.91); pooled Sp = 0.90 (95% CI, 0.88–0.92) [87]; and a pooled Se = 0.853, pooled Sp = 0.87 [88].

Some benign nodules showed pattern described for malignant ones and vice versa, so an assessment of both elastography and CEUS was combined in some articles.

A study by Zhan et al. aimed to evaluate the aid of CEUS in diagnosis of thyroid malignancy. First, 200 thyroid nodules were evaluated using ARFI technique. A number of 40 nodules that were in the "gray zone" underwent CEUS. ARFI accurately diagnosed 82% of the total nodules, while CEUS accuracy was 90% (p < 0.05) [89].

Cantisani et al. compared Q-elastography with CEUS in thyroid cancer assessment. Study results showed that both methods outclassed gray-scale US, but Q-elastography was more sensitive than CEUS (Se = 95%, Sp = 88% for Q-elastography; Se = 79%, Sp = 91% for CEUS) [83].

However, more studies are required for evaluating the true usefulness of this relatively new and promising technique in the differentiation of malignant from benign thyroid nodules.

#### **3. Conclusions**

*Knowledges on Thyroid Cancer*

NPV = 91.3% for scores 2 and 3 [46].

of elasticity was suggested [78].

this cytological category [79].

US findings alone [68].

required concerning this approach.

classic Doppler cannot display [80].

calcifications, and necrosis areas) [80, 82].

**2.5 Contrast-enhanced ultrasound (CEUS)**

showed poorer Se, Sp, and NPV for all elastography scores. When considering both indeterminate and nondiagnostic, the overall Se = 94.9%, Sp = 90.3%, and

was made in a prospective study in nodules with indeterminate FNAC. SWV cutoff for malignancy risk was defined at above 3.59 m/s with Se = 83.9% and Sp = 79.2%. SWV measurements were made in the stiffest section; authors mention that measurements of a larger area may result in a decreased SWV. The GEC-suspicious group had Se = 90.3% and Sp = 74.2% (PPV of only 47.5%, but NPV of 96.7%). The study concluded that both SWV and GEC can independently predict thyroid cancer with similar diagnostic value and are particularly useful in

In another study, qualitative RTE failed to make a correct distinction between benignity and malignancy in thyroid nodules, cancer was found in 50% of nodules scored 1 or 2 on elastogram and in 34% of score 3 nodules. Quantitative assessment

A comparison between 2D-SWE (VTIQ ) and molecular testing (Afirma GEC)

A more complex study compared diagnostic efficiency of SWE, semiquantitative SE (strain index), classic US, CEUS, and BRAF mutation test in indeterminate cytology, but the number of evaluated nodules was relatively small. The study outcomes confirmed a slightly better efficiency for RTE compared to SWE in distinguishing malignancy; strain index was the one parameter that showed significant correlation with pathology results. RTE and SWE do not seem interchangeable but may be used complementary. Interestingly, when strain index, SWV, and BRAF mutation were considered together, Sp was enhanced, but Se was lower compared to

This cytological category still remains uncertain in diagnosis, and in some cases, a strategy that combines advanced ultrasound methods was documented to provide higher accuracy in diagnosis than use of a single technique [68]. More studies are

The use of contrast agents in ultrasonography has widely expanded in clinical use and may play an important role in identifying thyroid cancers by evaluating tumor microcirculation. New-generation contrast agents (SonoVue) are administered intravenously and contain sulfur hexafluoride microbubbles that stay in the blood flow for a while. The examiner focuses the US image on the ROI and a contrastenhanced image is displayed, detecting microvascular changes in the lesion that

CEUS has already changed approach in management of liver lesions, signifi-

In studies where CEUS was performed on thyroid lesions, malignity was indicated by hypoenhancement and heterogeneity [80]. Hypoenhancement can be explained by the absence of blood supply in the central area of the tumor, due to thrombus formation, vascular compression, and necrosis. Neovascularization is mainly marginal, promoting tumor expansion [82]. Heterogeneity is explained by the complex and aberrant composition of cancerous lesions (fibrotic, presence of

Other indicators of malignancy are the time of wash-in and wash-out, but results are controversial. Some studies described early wash-in and wash-out in malignant lesions [83, 84], while others have shown late-phase enhancement for thyroid cancers compared to perinodular tissue [85] or no significant difference in

cantly improving the number of unnecessary biopsy indications [81].

the time of enhancement for benign versus malignant nodules [86].

**26**

Given the great number of thyroid lesions and the rising incidence of thyroid cancer, a correct preoperative distinction between benignity and malignancy in nodular pathology is crucial.

Ultrasound elastography represents the most important advance in US imaging since Doppler. It proved to serve as an important tool in selecting candidates for surgery. Elastography is a noninvasive, nonirradiating method that can be easily learned, adds only a few minutes to classic US evaluation, but provides truly valuable additional information. Unfortunately, this technique is still quite new and not widely used in clinical practice, so its universal adoption cannot be recommended by the guidelines, but there is important evidence of its clinical utility and its application in current practice is increasing. As any imaging technique, it holds its limitations [90].

This technique cannot replace the classic, gray-scale ultrasound, and should be used complementary to it [7, 10, 25].

Due to its high NPV, thyroid nodules that are scored soft on elastography are highly likely to be noncancerous and can be followed-up, avoiding FNAB [91]. Therefore, elastography reduces the need for FNA by up to 43% of cases compared to gray-scale risk stratification [17]. It also identifies stiff nodules that need biopsy and can be missed by gray-scale US alone. Even lesions with low-risk features, but high stiffness, are recommended for FNAB [91].

In the case of indeterminate cytology, clinical judgment can be a real challenge for practitioners. Elastography proved to predict malignancy better than B-mode parameters and can be essential in further management decision for nodules in this category.

For an accurate result, it is important that the evaluation should be performed by an experienced operator.

#### **Conflict of interest**

There is no conflict of interest.

## **Abbreviations**


### **Author details**

Andreea Borlea1 , Laura Cotoi1 , Ioana Mozos2 and Dana Stoian1 \*

1 Department of Endocrinology, "Victor Babes University for Medicine", Timisoara, Romania

2 Department of Functional Science, "Victor Babes University for Medicine", Timisoara, Romania

\*Address all correspondence to: stoian.dana@umft.ro

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**29**

*Advanced Ultrasound Techniques in Preoperative Diagnostic of Thyroid Cancers*

Associazione Medici Endocrinologi Medical Guidelines For Clinical Practice For The Diagnosis And Management Of Thyroid Nodules – 2016 Update. Endocrine Practice. 2016;**22**(Supplement 1):1-60

[8] Remonti LR, Kramer CK, Leitão CB, Pinto LCF, Gross JL. Thyroid Ultrasound Features and Risk of Carcinoma: A Systematic Review and Meta-Analysis of Observational Studies.

[9] Russ G. Risk stratification of thyroid nodules on ultrasonography with the French TI-RADS: Description and reflections. Ultrasound (Seoul, Korea).

[10] Russ G, Bonnema SJ, Erdogan MF, Durante C, Ngu R, Leenhardt L.

European thyroid association guidelines

for ultrasound malignancy risk stratification of thyroid nodules in adults: The EU-TIRADS. European Thyroid Journal. 2017;**6**(5):225-237

[11] Ha EJ, Baek JH, Na DG. Risk stratification of thyroid nodules on ultrasonography: Current status and perspectives. Thyroid. 2017;**27**(12):1463-1468. DOI: 10.1089/

[12] Albair Ashamallah G, EL-Adalany MA. Risk for malignancy of thyroid nodules: Comparative study between TIRADS and US based classification system. Egyptian Journal of Radiology

[13] Park J-Y, Lee HJ, Jang HW, Kim HK, Yi JH, Lee W, et al. A proposal for a thyroid imaging reporting and data system for ultrasound features of thyroid carcinoma. Thyroid.

[14] Kwak JY, Han KH, Yoon JH, Moon HJ, Son EJ, Park SH, et al. Thyroid

and Nuclear Medicine. 2016

2009;**19**(11):1257-1264

Thyroid. 2015;**25**(5):538-550

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thy.2016.0654

*DOI: http://dx.doi.org/10.5772/intechopen.83032*

[1] Lim H, Devesa SS, Sosa JA, Check D, Kitahara CM. Trends in thyroid cancer incidence and mortality in the United States, 1974-2013. Journal of the American Medical Association.

[2] Andrioli M, Carzaniga C, Persani L. Standardized ultrasound report for thyroid nodules: The endocrinologist's viewpoint. European Thyroid Journal.

[3] Pellegriti G, Frasca F, Regalbuto C, Squatrito S, Vigneri R. Worldwide increasing incidence of thyroid cancer: Update on epidemiology and risk factors. Journal of Cancer Epidemiology.

[4] Gharib H, Papini E, Garber JR, Duick DS, Harrell RM, Hegedüs L, et al. Amerıcan Assocıatıon of clınıcal endocrınologısts, Amerıcan college of endocrınology, and Assocıazıone Medıcı Endocrınologı medıcal guıdelınes for clınıcal practıce for the dıagnosıs and management of thyroıd nodules – 2016 update. Endocrine Practice. 2016;**22**(Suppl 1):1-60. DOI: 10.4158/

[5] Popoveniuc G, Jonklaas J. Thyroid nodules. The Medical Clinics of North

America. 2012;**96**(2):329-349

2018;**25**(11):1388-1397

[6] Gregory A, Bayat M, Kumar V, Denis M, Kim BH, Webb J, et al. Differentiation of benign and malignant thyroid nodules by using comb-push ultrasound shear elastography: A preliminary two-plane view study. Academic Radiology.

[7] Gharib H, Papini E, Garber JR, Duick DS, Harrell RM, Hegedüs L, et al. American Association Of Clinical Endocrinologists, American College Of Endocrinology, And

2017;**317**(13):1338-1348

2013;**2**(1):37-48

**References**

2013;**2013**:965212

EP161208.GL

*Advanced Ultrasound Techniques in Preoperative Diagnostic of Thyroid Cancers DOI: http://dx.doi.org/10.5772/intechopen.83032*

#### **References**

*Knowledges on Thyroid Cancer*

Se sensitivity Sp specificity

AR area ratio

FNAB fine needle biopsy

US ultrasonography conventional

ATA American Thyroid Association ETA European Thyroid Association

ARFI acoustic radiation force impulse

AACE American Association of Clinical Endocrinology

FLUS follicular lesion of undetermined significance

EI/B ratio elastography imaging to B-mode size ratio

EFSUMB European Federation of Societies for Ultrasound in Medicine and

WFUMB World Federation for Ultrasound in Medicine and Biology

NPV negative predictive value PPV positive predictive value

Biology

SE strain elastography SWE shear-wave elastography CEUS contrast-enhanced ultrasound AUS atypia of undetermined significance

ROI region of interest

**Abbreviations**

**28**

**Author details**

Andreea Borlea1

Timisoara, Romania

Romania

provided the original work is properly cited.

, Laura Cotoi1

\*Address all correspondence to: stoian.dana@umft.ro

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

, Ioana Mozos2

2 Department of Functional Science, "Victor Babes University for Medicine",

1 Department of Endocrinology, "Victor Babes University for Medicine", Timisoara,

and Dana Stoian1

\*

[1] Lim H, Devesa SS, Sosa JA, Check D, Kitahara CM. Trends in thyroid cancer incidence and mortality in the United States, 1974-2013. Journal of the American Medical Association. 2017;**317**(13):1338-1348

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nih.gov/pubmed/29068996

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[65] Samir AE, Dhyani M, Anvari A, Prescott J, Halpern EF, Faquin WC, et al. Shear-wave elastography for the preoperative risk stratification of follicular-patterned lesions of the thyroid: Diagnostic accuracy and optimal measurement plane. Radiology. 2015;**277**(2):565-573

[66] Tian W, Hao S, Gao B, Jiang Y, Zhang X, Zhang S, et al. Comparing the diagnostic accuracy of RTE and SWE in differentiating malignant thyroid nodules from benign ones: A meta-analysis. Cellular Physiology and Biochemistry. 2016;**39**(6):2451-2463

[67] Liu B-X, Xie X-Y, Liang J-Y, Zheng Y-L, Huang G-L, Zhou L-Y, et al. Shear wave elastography versus real-time elastography on evaluation thyroid nodules: A preliminary study. European Journal of Radiology. 2014;**83**(7): 1135-1143. DOI: 10.1016/j.ejrad. 2014.02.024

[68] Gay S, Schiaffino S, Santamorena G, Massa B, Ansaldo G, Turtulici G, et al. Role of strain elastography and shear-wave elastography in a multiparametric clinical approach to indeterminate cytology thyroid nodules. Medical Science Monitor. 2018;**24**:6273- 6279. Available from: https://www.ncbi. nlm.nih.gov/pubmed/30194820

[69] Kuru B, Atmaca A, Kefeli M. Malignancy rate associated with Bethesda category III (AUS/ FLUS) with and without repeat fine needle aspiration biopsy. Diagnostic Cytopathology. 2016;**44**(5):394-398

[70] Sahli ZT, Smith PW, Umbricht CB, Zeiger MA. Preoperative molecular markers in thyroid nodules. Frontiers in Endocrinology (Lausanne). 2018;**9**:179

[71] Ward LS, Kloos RT. Molecular markers in the diagnosis of thyroid nodules. Arquivos Brasileiros de Endocrinologia e Metabologia. 2013;**57**(2):89-97

[72] Zhang M, Lin O. Molecular testing of thyroid nodules: A review of current available tests for fine-needle aspiration specimens. Archives of Pathology & Laboratory Medicine. 2016;**140**(12):1338-1344. DOI: 10.5858/ arpa.2016-0100-RA

[73] Alexander EK, Kennedy GC, Baloch ZW, Cibas ES, Chudova D, Diggans J, et al. Preoperative diagnosis of benign thyroid nodules with indeterminate cytology. The New England Journal of Medicine. 2012;**367**(8):705-715

[74] Labourier E, Shifrin A, Busseniers AE, Lupo MA, Manganelli ML, Andruss B, et al. Molecular testing for miRNA, mRNA, and DNA on fine-needle aspiration improves the preoperative diagnosis of thyroid nodules with indeterminate cytology. The Journal of Clinical Endocrinology and Metabolism. 2015;**100**(7):2743-2750

[75] Nikiforov YE, Carty SE, Chiosea SI, Coyne C, Duvvuri U, Ferris RL, et al. Highly accurate diagnosis of cancer in thyroid nodules with follicular neoplasm/suspicious for a follicular neoplasm cytology by ThyroSeq v2 next-generation sequencing assay. Cancer. 2014;**120**(23):3627-3634

[76] Liu R, Hao S, Zhang H, Ma J, Liu X, Xu J, et al. Correlation of thyroid

stimulating hormone receptor mRNA expression levels in peripheral blood with undesirable clinicopathological features in papillary thyroid carcinoma patients. Oncotarget. 2017;**8**(43):74129-74138. Available from: https://www.ncbi.nlm.nih.gov/ pubmed/29088773

[77] Wagner K, Arciaga R, Siperstein A, Milas M, Warshawsky I, Sethu S, et al. Thyrotropin receptor/thyroglobulin messenger ribonucleic acid in peripheral blood and fine-needle aspiration cytology: Diagnostic synergy for detecting thyroid cancer. The Journal of Clinical Endocrinology and Metabolism. 2005;**90**(4):1921-1924. DOI: 10.1210/ jc.2004-1793

[78] Lippolis PV, Tognini S, Materazzi G, Polini A, Mancini R, Ambrosini CE, et al. Is elastography actually useful in the presurgical selection of thyroid nodules with indeterminate cytology? The Journal of Clinical Endocrinology and Metabolism. 2011;**96**(11):E1826-E1830. DOI: 10.1210/jc.2011-1021

[79] Azizi G, Keller JM, Mayo ML, Piper K, Puett D, Earp KM, et al. Shear wave elastography and AfirmaTM gene expression classifier in thyroid nodules with indeterminate cytology: A comparison study. Endocrine. 2018;**59**(3):573-584. Available from: https://www.ncbi.nlm.nih.gov/ pubmed/29350311

[80] Zhan J, Ding H. Application of contrast-enhanced ultrasound for evaluation of thyroid nodules. Ultrasound (Seoul, Korea). 2018;**37**(4):288-297. Available from: https://www.ncbi.nlm.nih.gov/ pubmed/30213158

[81] Nolsøe CP, Lorentzen T. International guidelines for contrast-enhanced ultrasonography: Ultrasound imaging in the new millennium. Ultrasound (Seoul, Korea). 2016;**35**(2):89-103. Available

**35**

*Advanced Ultrasound Techniques in Preoperative Diagnostic of Thyroid Cancers*

[88] Yu D, Han Y, Chen T. Contrastenhanced ultrasound for differentiation of benign and malignant thyroid lesions: Meta-analysis. Otolaryngology

and Head and Neck Surgery.

[89] Zhan J, Diao X-H, Chen L, Jin J-M, Chen Y. Role of contrastenhanced ultrasound in diagnosis of thyroid nodules in acoustic radiation force impulse "Gray Zone". Ultrasound in Medicine & Biology. 2017;**43**(6):1179-1186. DOI: 10.1016/j.

ultrasmedbio.2017.02.006

pubmed/27103947

cen.12077

[90] Menzilcioglu MS, Duymus M, Avcu S. Sonographic elastography of the thyroid gland. Polish Journal of Radiology. 2016;**81**:152-156. Available from: https://www.ncbi.nlm.nih.gov/

[91] Mehrotra P, McQueen A, Kolla S, Johnson SJ, Richardson DL. Does elastography reduce the need for thyroid FNAs? Clinical Endocrinology. 2012;**78**(6):942-949. DOI: 10.1111/

2014;**151**(6):909-915

*DOI: http://dx.doi.org/10.5772/intechopen.83032*

from: https://www.ncbi.nlm.nih.gov/

[82] Galiè M, D'Onofrio M, Montani M, Amici A, Calderan L, Marzola P, et al. Tumor vessel compression hinders perfusion of ultrasonographic contrast agents. Neoplasia. 2005;**7**(5):528-536. Available from: https://www.ncbi.nlm.

[83] Cantisani V, Consorti F, Guerrisi A, Guerrisi I, Ricci P, Di Segni M, et al. Prospective comparative evaluation of quantitative-elastosonography (Q-elastography) and contrast-

enhanced ultrasound for the evaluation

[84] Jiang J, Shang X, Wang H, Xu Y-B, Gao Y, Zhou Q. Diagnostic value of contrast-enhanced ultrasound in thyroid nodules with calcification. The Kaohsiung Journal of Medical Sciences.

[85] Wu Q, Wang Y, Li Y, Hu B, He Z-Y. Diagnostic value of contrast-enhanced ultrasound in solid thyroid nodules with and without enhancement. Endocrine.

[86] Wiesinger I, Kroiss E, Zausig N, Hornung M, Zeman F, Stroszczynski C, et al. Analysis of arterial dynamic micro-vascularization with contrastenhanced ultrasound (CEUS) in

thyroid lesions using external perfusion

software: First results. Clinical Hemorheology and Microcirculation.

[87] Sun B, Lang L, Zhu X, Jiang F, Hong Y, He L. Accuracy of

contrast-enhanced ultrasound in the identification of thyroid nodules: A meta-analysis. International Journal of Clinical and Experimental Medicine.

of thyroid nodules: Preliminary experience. European Journal of Radiology. 2013;**82**(11):1892-1898

2015;**31**(3):138-144

2016;**53**(2):480-488

2016;**64**(4):747-755

2015;**8**(8):12882-12889

pubmed/26867761

nih.gov/pubmed/15967105

*Advanced Ultrasound Techniques in Preoperative Diagnostic of Thyroid Cancers DOI: http://dx.doi.org/10.5772/intechopen.83032*

from: https://www.ncbi.nlm.nih.gov/ pubmed/26867761

*Knowledges on Thyroid Cancer*

[69] Kuru B, Atmaca A, Kefeli M. Malignancy rate associated with Bethesda category III (AUS/ FLUS) with and without repeat fine needle aspiration biopsy. Diagnostic Cytopathology. 2016;**44**(5):394-398

[70] Sahli ZT, Smith PW, Umbricht CB, Zeiger MA. Preoperative molecular markers in thyroid nodules. Frontiers in Endocrinology (Lausanne). 2018;**9**:179

stimulating hormone receptor mRNA expression levels in peripheral blood with undesirable clinicopathological

[77] Wagner K, Arciaga R, Siperstein A, Milas M, Warshawsky I, Sethu S, et al. Thyrotropin receptor/thyroglobulin messenger ribonucleic acid in peripheral

[78] Lippolis PV, Tognini S, Materazzi G, Polini A, Mancini R, Ambrosini CE, et al. Is elastography actually useful in the presurgical selection of thyroid nodules with indeterminate cytology? The Journal of Clinical Endocrinology and Metabolism. 2011;**96**(11):E1826-E1830.

DOI: 10.1210/jc.2011-1021

pubmed/29350311

pubmed/30213158

[81] Nolsøe CP, Lorentzen T. International guidelines for

[79] Azizi G, Keller JM, Mayo ML, Piper K, Puett D, Earp KM, et al. Shear wave elastography and AfirmaTM gene expression classifier in thyroid nodules with indeterminate cytology: A comparison study. Endocrine. 2018;**59**(3):573-584. Available from: https://www.ncbi.nlm.nih.gov/

[80] Zhan J, Ding H. Application of contrast-enhanced ultrasound for evaluation of thyroid nodules. Ultrasound (Seoul, Korea).

2018;**37**(4):288-297. Available from: https://www.ncbi.nlm.nih.gov/

contrast-enhanced ultrasonography: Ultrasound imaging in the new millennium. Ultrasound (Seoul, Korea). 2016;**35**(2):89-103. Available

blood and fine-needle aspiration cytology: Diagnostic synergy for detecting thyroid cancer. The Journal of Clinical Endocrinology and Metabolism. 2005;**90**(4):1921-1924. DOI: 10.1210/

features in papillary thyroid carcinoma patients. Oncotarget. 2017;**8**(43):74129-74138. Available from: https://www.ncbi.nlm.nih.gov/

pubmed/29088773

jc.2004-1793

[71] Ward LS, Kloos RT. Molecular markers in the diagnosis of thyroid nodules. Arquivos Brasileiros de Endocrinologia e Metabologia.

[72] Zhang M, Lin O. Molecular testing of thyroid nodules: A review of current available tests for fine-needle aspiration specimens. Archives of Pathology & Laboratory Medicine. 2016;**140**(12):1338-1344. DOI: 10.5858/

[73] Alexander EK, Kennedy GC, Baloch ZW, Cibas ES, Chudova D, Diggans J, et al. Preoperative diagnosis of benign thyroid nodules with indeterminate cytology. The New England Journal of

[74] Labourier E, Shifrin A, Busseniers AE, Lupo MA, Manganelli ML, Andruss B, et al. Molecular testing for miRNA, mRNA, and DNA on fine-needle aspiration improves the preoperative diagnosis of thyroid nodules with indeterminate cytology. The Journal of Clinical Endocrinology and Metabolism.

[75] Nikiforov YE, Carty SE, Chiosea SI, Coyne C, Duvvuri U, Ferris RL, et al. Highly accurate diagnosis of cancer in thyroid nodules with follicular neoplasm/suspicious for a follicular neoplasm cytology by ThyroSeq v2 next-generation sequencing assay. Cancer. 2014;**120**(23):3627-3634

[76] Liu R, Hao S, Zhang H, Ma J, Liu X, Xu J, et al. Correlation of thyroid

Medicine. 2012;**367**(8):705-715

2015;**100**(7):2743-2750

2013;**57**(2):89-97

arpa.2016-0100-RA

**34**

[82] Galiè M, D'Onofrio M, Montani M, Amici A, Calderan L, Marzola P, et al. Tumor vessel compression hinders perfusion of ultrasonographic contrast agents. Neoplasia. 2005;**7**(5):528-536. Available from: https://www.ncbi.nlm. nih.gov/pubmed/15967105

[83] Cantisani V, Consorti F, Guerrisi A, Guerrisi I, Ricci P, Di Segni M, et al. Prospective comparative evaluation of quantitative-elastosonography (Q-elastography) and contrastenhanced ultrasound for the evaluation of thyroid nodules: Preliminary experience. European Journal of Radiology. 2013;**82**(11):1892-1898

[84] Jiang J, Shang X, Wang H, Xu Y-B, Gao Y, Zhou Q. Diagnostic value of contrast-enhanced ultrasound in thyroid nodules with calcification. The Kaohsiung Journal of Medical Sciences. 2015;**31**(3):138-144

[85] Wu Q, Wang Y, Li Y, Hu B, He Z-Y. Diagnostic value of contrast-enhanced ultrasound in solid thyroid nodules with and without enhancement. Endocrine. 2016;**53**(2):480-488

[86] Wiesinger I, Kroiss E, Zausig N, Hornung M, Zeman F, Stroszczynski C, et al. Analysis of arterial dynamic micro-vascularization with contrastenhanced ultrasound (CEUS) in thyroid lesions using external perfusion software: First results. Clinical Hemorheology and Microcirculation. 2016;**64**(4):747-755

[87] Sun B, Lang L, Zhu X, Jiang F, Hong Y, He L. Accuracy of contrast-enhanced ultrasound in the identification of thyroid nodules: A meta-analysis. International Journal of Clinical and Experimental Medicine. 2015;**8**(8):12882-12889

[88] Yu D, Han Y, Chen T. Contrastenhanced ultrasound for differentiation of benign and malignant thyroid lesions: Meta-analysis. Otolaryngology and Head and Neck Surgery. 2014;**151**(6):909-915

[89] Zhan J, Diao X-H, Chen L, Jin J-M, Chen Y. Role of contrastenhanced ultrasound in diagnosis of thyroid nodules in acoustic radiation force impulse "Gray Zone". Ultrasound in Medicine & Biology. 2017;**43**(6):1179-1186. DOI: 10.1016/j. ultrasmedbio.2017.02.006

[90] Menzilcioglu MS, Duymus M, Avcu S. Sonographic elastography of the thyroid gland. Polish Journal of Radiology. 2016;**81**:152-156. Available from: https://www.ncbi.nlm.nih.gov/ pubmed/27103947

[91] Mehrotra P, McQueen A, Kolla S, Johnson SJ, Richardson DL. Does elastography reduce the need for thyroid FNAs? Clinical Endocrinology. 2012;**78**(6):942-949. DOI: 10.1111/ cen.12077

**37**

**Chapter 4**

**Abstract**

Correlation

thyroid-stimulating hormone

**1. Introduction**

Papillary Thyroid Carcinoma

Intertwined with Hashimoto's

Illustrating the ancient link connecting inflammation with cancer, the correlation of papillary thyroid carcinoma (PTC) with Hashimoto's thyroiditis (HT) has long been pursued as intersection of autoimmunity-induced chronic inflammation and tumor-induced immunity. The dramatic rise of the incidence of PTC οver the last decades—the main culprit for "thyroid cancer (TC) epidemic"—parallels the increasing incidence of HT, potentially reflecting a pathogenetic link that could be harnessed in diagnostics and therapeutics. Prompted by this perspective, in the present chapter, we dissect the hitherto elusive interrelationship of PTC with HT, focusing on four issues: firstly, an unresolved conundrum is whether PTC emerges due to or notwithstanding immune response or mirrors the "tumor defense-induced autoimmunity." Secondly, the interrelationship of HT with PTC may be merely epiphenomenon of selection bias inherent in thyroidectomy series. Thirdly, the impact of HT on coexistent PTC is equivocal—host protective versus tumor protective. Fourthly, translating serum concentrations of thyroid autoantibodies and thyroidstimulating hormone (TSH) into predictive and prognostic PTC biomarkers dichotomizes, till now, the researchers. In the era of precision medicine, illuminating whether HT precipitates PTC or *vice versa* is awaited with anticipation in order to refine the preventive and therapeutic policy counteracting "TC epidemic."

Thyroiditis: An Intriguing

*Maria V. Deligiorgi and Dimitrios T. Trafalis*

**Keywords:** papillary thyroid carcinoma, hashimoto's thyroiditis,

anti-thyroglobulin autoantibodies, anti-thyroperoxidase autoantibodies,

Initially reported by Dailey et al. in 1955, the correlation of papillary thyroid carcinoma (PTC)—the most common thyroid cancer (TC) histotype—with Hashimoto's thyroiditis (HT) [1] has long been pursued, rekindling the ancient link between inflammation and cancer [2]. Bearing in mind the rising incidence of PTC over the last decades [3], establishing causality between PTC and HT an issue highly contested—could lay the groundwork for a preventive policy. Moreover, harnessing the interrelationship of PTC with HT could refine therapeutics with respect to PTC. The present chapter dissects the correlation of PTC

#### **Chapter 4**
