Morphogenesis disturbances on establishment, migration and organization of thyroid primordium occurring during early stages of embryogenesis may results to generation of ectopic thyroid glands or ectopic thyroid tissues along the gland's embryological descending pathway from foramen cecum to the mediastinum, as well as distant areas [1] [2] [3]. Ectopic thyroid is formed when the thyroid primordium or a portion of it fails to descend along the normal migration pathway and results into the gland development in an anomalous position. Multiple ectopic foci of thyroid gland (tissues) are very rare and only few cases of dual and triple ectopic have been reported with frequent locations along the midline from base of the tongue to the mediastinum or sub diaphragmatic organs [4] [5] [6]. However, most of the reported cases are reporting the incidence of multiple ectopic being in various locations on the cervical region above or lateral to the normally located thyroid gland, or thyroid tissues embedded within other organs. Here, we are reporting a case of triple ectopic thyroid located inferior to the normally located thyroid gland and extending into superior mediastinum between great vessels and the trachea.

During routine head and neck dissection classes for the undergraduate medical students, we encountered variation on number and position of the thyroid gland of a 88-years-old formalin embalmed female cadaver. After the anterior cervical and upper thoracic regions skin and superficial and deep fascia were removed, we encountered a normally positioned pretracheal thyroid gland associated with three other inferiorly placed ectopic thyroid masses of which each had its own blood supply and venous drainage, and extending from the cervical to superior mediastinum displacing the aortic arch and great vessels anteriorly, and trachea laterally to the right.

Normal thyroid gland was located anterior to the trachea, inferior to the thyroid cartilage of the larynx and had a typical butterfly-shape appearance with two lobes (left and right) connected by an isthmus and extends inferiorly to fifth tracheal ring. Each lobe measured 4.5 cm long, 2.8 cm wide, 1.5 cm thick, and received blood supply from superior and inferior thyroid arteries originated from external carotid and common carotid arteries respectively (Figure 1) and (Figure 2).

Ectopic-thyroid-I was a tongue-shaped extending from left to right located inferior to the normally positioned thyroid gland and superior to the ectopic-thyroid-II. It measured 2.2 cm long, 4 cm wide with 2 cm thick at the broad end, and 1cm at its tapered end (Figure 2). It received blood supply from artery branched from the left inferior thyroid artery originating from left common carotid artery.

Ectopic-thyroid-II was triangular in shape bordered superiorly by normal thyroid and ectopic-thyroid-II, and ectopic-thyroid-III inferiorly and extended into superior mediastinum displacing laterally the carotid and subclavian arteries. It measured 2.4 cm thick, 4 cm on its longest side, 3 cm and 2.8 cm on other sides (Figure 2). It had dual blood supply from right common carotid artery and left inferior thyroid artery.

Ectopic-thyroid-III was a triangular in shape with its apex extending deep into the superior mediastinum intertwined between the aortic arch (anterior) and trachea (posterior) at the level of thoracic vertebral IV (Figure 1) and (Figure 2)and displacing the aortic arch anteriorly and the trachea posterolateral to the right. It received dual blood supply from right common carotid artery and a branch from left inferior thyroid artery.

Associated variations
The left common carotid artery and brachiocephalic arteries arises from a common arterial trunk from the aortic arch (Figure 2). Usually, the inferior thyroid arteries arise from the thyrocervical trunk, however, in the current case the multiple arteries were observed to rise from the common carotid arteries to supply the ectopic-thyroid masses.

Histology
Each thyroid mass as well as the normally located thyroid gland was sectioned and prepared for microscopic examination under hematoxylin and eosin staining. The histological results revealed the typical features of the thyroid gland (tissues) in all three masses similar to those preparations from normally positioned thyroid gland, displaying distinct thyroid follicles with the associated cells (Figure 3).

Thyroid ectopia are rarely encountered developmental anomalies although it is the most frequent form of thyroid dysgenesis [3] [7] and its presence may be symptomatic or asymptomatic clinically depending on location, size and functional activities. Dual thyroid ectopia has been reported to associate lingual and submandibular thyroid or intranasal and nasopharynx thyroid ectopia co-existing with normally located thyroid gland [5] [6]. Triple ectopic have been reported to involve lateral ectopic thyroid masses co-exist with eutopic thyroid gland, or sublingual-suprahyoid-subhyoid thyroids [4] or foramen cecum-suprahyoid-cricoid thyroids or lingual-hyoid-suprahyoid thyroids, all with the absence of normally located thyroid gland. However, altogether these cases are reporting the ectopic being on the lateral or superior to the normally located thyroid gland, and none of them are reporting three distinct independent thyroid masses located inferior to the normally located thyroid gland.

Intrathoracic thyroid ectopia has been also reported previously in the mediastinum, lungs, and heart and mostly were discovered incidentally on chest radiograph or during autopsy. However, the reported mediastinal thyroid ectopia were located in the anterior or posterior mediastinum [8] and none in the superior mediastinum as observed in the current case displacing the aortic arch, great vessels and the trachea.

Embryologically, the thyroid primordium develops about 24th day post-fertilization as median endodermal thickening in the floor of primitive hypopharynx which then descend along the migration pathway from foramen caecum towards its normal position. Definitive thyroid gland cells develop as a result of merging of migrating cells from thyroid anlage (follicular cells) and ultimobranchial bodies (parafollicular cells) from fourth pharyngeal pouch. Ectopic thyroid tissues may rise as a faulty embryogenesis which could be due to mutation of thyroid transcription factors required for descending migration [3][4] or developmental defects other than abnormal migration of the thyroid primordium. Genetic defects involving mutations in the paired box transcription factors PAX8 and thyroid transcription factors TTF1 and TTF2 has been linked with thyroid dysgenesis [3] [9]. Mediastinal ectopia or other anomaly position could be due displacement of the mesenchymal tissue during the course of embryonic development. In the current case, three independent ectopic thyroids located inferior to the normally located thyroid but along the midline of the neck to the superior mediastinum between trachea and aortic arch were observed. Conceivable clarifications for this entity could be due to the division of the thyroid primordium caused by the developing trachea and its cartilage rings. The condition may also be hypothesized to arise as a result of aberrant migration and differentiation of uncommitted endodermal cells of the thyroid primordium along the midline.

Alterations in signaling or defects during early embryogenesis of thyroid gland generate thyroid ectopia along its embryological pathway or distant areas. Multiple ectopic thyroid tissue are rare developmental defects and could be difficult to diagnose since most cases are asymptomatic. In the present case, three independent ectopic thyroid tissues extend from the neck inferior to the normally positioned thyroid gland to the superior mediastinum could be due to the developmental defects other than migration defects such as division of the developing thyroid gland caused by trachea and its cartilage rings or by aberrant migration and differentiation of uncommitted endodermal cells from the thyroid primordium. Understanding of this rare entity could benefit the physician, surgeons and radiologists during their routine procedures performed within or closely to the superior mediastinum and also in differentiating the mediastinal masses.

We expressing thanks to Prof. Yoh-ichi Satoh and Prof. Sumio Isogai for their moral and material support and all members in the Department of Anatomy, Iwate Medical University for their encouragement.

1. Batsakis JG, El-Naggar AK, Luna MA. Thyroid gland ectopias. Ann Otol Rhinol Laryngol 1996 Dec;105(12):996–1000.   [Pubmed]    
2. Takahashi T, Ishikura H, Kato H, Tanabe T, Yoshiki T. Ectopic thyroid follicles in the submucosa of the duodenum. Virchows Arch A Pathol Anat Histopathol 1991;418(6):547–50.   [CrossRef]   [Pubmed]    
3. De Felice M, Di Lauro R. Thyroid development and its disorders: genetics and molecular mechanisms. Endocr Rev 2004 Oct;25(5):722–46.   [CrossRef]   [Pubmed]    
4. Jain A, Pathak S. Rare developmental abnormalities of thyroid gland, especially multiple ectopia: A review and our experience. Indian J Nucl Med 2010 Oct;25(4):143–6.   [CrossRef]   [Pubmed]    
5. Kumar Choudhury B, Kaimal Saikia U, Sarma D, et al. Dual ectopic thyroid with normally located thyroid: a case report. J Thyroid Res 2011;2011:159703.   [CrossRef]   [Pubmed]    
6. Hussain D, Waheed S, Haider G, Ibrahim M, Hartung R. Dual Ectopy of Thyroid Tissue: Intratracheal and in Nasopharynx, Associated with Normally Located Thyroid. J Coll Physicians Surg Pak 2015 Oct;25 Suppl 2:S86–8.   [CrossRef]   [Pubmed]    
7. Olivieri A, Stazi MA, Mastroiacovo P, et al. A population-based study on the frequency of additional congenital malformations in infants with congenital hypothyroidism: data from the Italian Registry for Congenital Hypothyroidism (1991-1998). J Clin Endocrinol Metab 2002 Feb;87(2):557–62.   [CrossRef]   [Pubmed]    
8. Guimarães MJ, Valente CM, Santos L, Baganha MF. Ectopic thyroid in the anterior mediastinum. [Article in English, Portuguese]. J Bras Pneumol 2009 Apr;35(4):383–7.   [CrossRef]   [Pubmed]    
9. Kousta E, Konstantinidis K, Michalakis C, et al. Ectopic thyroid tissue in the lower neck with a coexisting normally located multinodular goiter and brief literature review. Hormones (Athens) 2005 Oct-Dec;4(4):231–4.   [CrossRef]   [Pubmed]    

• Adelchi C, Mara P, Melissa L, De Stephano A, Cesare M. Ectopic thyroid tissue in the head and neck: a case series. BMC Res Notes. 2014; 7:790. Doi: 10.1186/1756-0500-7-790.
• Akanmu IN, Adewale OM. Lateral cervical ectopic thyroid masses with eutopic multinodular goiter: an unusual presentation. Hormones 2009; 8(2):150–3.
• Barai S, Bandopadhayaya GP, Kumar R, Malhotra A, Halanaik D. Multiple ectopic thyroid masses in a hypothyroid child. Pediatr Radiol 2004; 34:584. DOI 10.1007/s00247–004–1156–1.
• Casanova JB, Daly RC, Edwards BS, Tazelaar HD, Thompson GB. Intracardiac ectopic thyroid. Ann Thorac Surg 2000;70:1694–6.
• Di Mari N, Barbagli L, Mourmouras V, Miracco C. Ectopic thyroid of the lung. An additional case. Pathologica 2010; 102:102–3.
• Ghanem N, Bley T, Altehoefer C, Hogerle S, Langer M. Ectopic thyroid gland in the porta hepatis and lingua. Thyroid 2003; 13:503–7.
• Guerra G, Cinelli M, Mesolella M, Tafuri D, Rocca A. Morphological, diagnostic and surgical features of ectopic thyroid gland: A review of literature. Int J Surg 2014;12:S3-S11
• Harach HR. Ectopic thyroid tissue adjacent to the gallbladder. Histopathology 1998; 32:90–1.
• Ibrahim NA, Oludara MA. Lateral cervical ectopic thyroid masses with eutopic multinodular goiter: an unusual presentation. Hormones 2009; 8(2):150–3.
• Nilegaonkar, Sujit; Naik, Chetna; Sonar, Sameer; Hirawe, Deepti. Triple ectopic thyroid: A rare entity. Indian J Nucl Med. 2011 Oct; 26(4):194–5.
• Noussios G, Anagnostis P, Goulis DG, Lappas D, Natsis K. Ectopic thyroid tissue: anatomical, clinical, and surgical implications of a rare entity. European Journal of Endocrinology 2011; 165:375–82.
• Rosai J. Rosai and Ackerman's Surgical Pathology, 10ed. Elsevier Mosby. 2011(Vol 1).p.488–91.
• Sakorafas GH, Vlachos A, Tolumis G, Kassaras GA, Anagnostopoulos GK, Gorgogiannis D. Ectopic intrathoracic thyroid: case report. Mt Sinai J Med 2004; 71:131–3.
• Shah BC, Ravichand CS, Juluri S, Agarwal A, Pramesh CS, Mistry RC. Ectopic thyroid cancer. Annals of Thoracic and Cardiovascular Surgery 2007; 13:122–4.
• Ting-Shuo H, Huang-Yang C. Dual thyroid ectopia with a normally located Pretracheal thyroid gland: case report and literature review. Head Neck 2007; 29:885–8. doi: 10.1002/hed.20604.
• Van VG. Development of the thyroid gland: lessons from congenitally hypothyroid mice and men. Clin Genet 2003; 63:445-55.
• Wang J, Fang J. Ectopic thyroid mass in the left lateral neck and anterior mediastinum: a case report. J Med Case Rep. 2014; 8:351. doi: 10.1186/1752–1947–8–351
• Weller G. Development of the thyroid, parathyroid and thymus glands in man. Contrib Embryol 1933; 24:93–140.