Understanding normal development of the thyroid and its microscopic anatomy allows for comprehension of a number of disorders of the thyroid gland. Embryology also explains the diversity of certain thyroidal conditions, ranging from the lingual thyroid to the superior vena cava syndrome due to a mediastinal goiter. Understanding the histology of the thyroid gland explains how medullary thyroid cancer differs from other thyroid malignancies. Hence, knowledge of the embryology and anatomy of the thyroid gland will improve one'S diagnostic and therapeutic acumen related to disorders that affect the thyroid gland.
DEVELOPMENT OF THE THYROID GLAND
The thyroid gland is the first of the body'S endocrine glands to develop. The morphogenesis of the thyroid gland, the anteriormost organ that buds from the gut tube, begins with a thickening of the endodermal epithelium in the foregut, which is referred to as thyroid anlage. The human thyroid anlage is first recognizable at embryonic day 16 or 17. This median thickening deepens and forms first a small pit and then, an outpouching of the endoderm adjacent to the developing myocardial cell. The site of the initial development which lies between two key structures, the tuberculum impar and the copula is known as the foramen cecum.1
The foramen cecum begins rostral to the copula, also known as the hypobranchial eminence. This median embryologic swelling consists of mesoderm that arises from the second pharyngeal pouch (although the third and fourth pouches are also involved). The thyroid gland, therefore, originates from between the first and second pouches.
The thyroid primordium, starts as a simple midline thickening and develops to form the thyroid diverticulum. This structure is initially hollow, although it later solidifies and becomes bilobed. The two lobes are located on either side of the midline and are connected via an isthmus. With continuing development, the median diverticulum is displaced caudally, following the myocardial cells in their descent.
The primitive stalk connecting the primordium with the pharyngeal floor elongates into the thyroglossal duct. During its caudal displacement, the primordium assumes a bilobate shape, coming into contact and fusing with the ventral aspect of the fourth pharyngeal pouch when it reaches its final position at about embryonic day 50 (Fig. 1).2
Thyroid stimulating hormone (TSH) and thyroxine (T4) levels increase from the 12th week of gestation until delivery, whereas triiodothyronine levels remain relatively low. At birth, a cold-stimulated, short-lived TSH surge is observed, followed by a TSH decrease until day 3 or 4 of life by T4 feedback inhibition. Disorders of thyroid gland development and/or function are relatively common, affecting approximately one newborn infant in 2,000–4,000.3
DESCENT OF THE THYROID GLAND
The thyroid gland originates from the foramen cecum, and by 7 weeks gestation, descends ventrally in the midline of the neck. During its descent, a patent diverticulum, the thyroglossal duct, connects the gland to the base of the tongue.4
The initial descent of the thyroid gland occurs anterior to the pharyngeal gut. At this point, the thyroid is still connected to the tongue via the thyroglossal duct. The foramen cecum represents the opening of the thyroglossal duct into the tongue; its remains may be observed as a small blind pit in the midline between the anterior two thirds and the posterior third of the tongue. The tubular duct later solidifies and subsequently obliterates entirely (during gestational weeks 7–10).
Nonetheless, in some individuals, remnants of this duct may still persist which differentiate into thyroid tissue, forming the pyramidal lobe of the gland. The pyramidal lobe itself may be attached to the hyoid bone, similar to a thyroglossal duct cyst or may be incorporated into a thyroglossal duct cyst. At the same time, the lobes contact the ultimobranchial glands, leading to incorporation of C cells into the thyroid (Fig. 2). Concomitantly, histologic alterations occur throughout the gland. Complex, interconnecting, cord-like arrangements of cell interspersed with vascular connective tissue replace the solid epithelial mass and become tubule-like structures at about the third month of fetal life; shortly thereafter, follicular arrangements devoid of colloid appear, and by 13–14 weeks, follicles begin to fill with colloid.5
Further descent of the thyroid gland carries it anterior (or ventral) to the hyoid bone, and subsequently, anterior (or ventral) to the laryngeal cartilages. As the thyroid gland descends, it forms its mature shape, with a median isthmus connecting two lateral lobes. The thyroid completes its descent in the 7th gestational week, coming to rest in its final location immediately anterior to the trachea.6
THYROID EMBRYOLOGY: CLINICAL CORRELATIONS
If the thyroglossal duct does not atrophy, then the remnants can manifest clinically as a thyroglossal duct cyst. While half of these, generally midline cystic masses, are located at or just below the level of the hyoid bone, they may be located and can track anywhere from the thyroid cartilage up the base of the tongue. If the cyst ruptures, it may go on to form a thyroglossal duct sinus or thyroglossal duct fistula that exits through the overlying skin. Because the hyoid bone develops in an anterior direction and may surround the thyroglossal duct, the surgeon should resect the central portion on the hyoid bone along with the cyst (the Sistrunk procedure), unless the thyroglossal duct tract can clearly be observed coursing away from the bone.5
This reflects the complexity of the thyroid anatomical correlates, and hence, thyroid surgery has been fraught with complications. Injury to the recurrent laryngeal nerve, superior laryngeal nerve, or the parathyroid glands may result in profound life-long consequences for the patient.7
An aberrant or ectopic thyroid gland may occur anywhere along the path of initial descent of the thyroid, although it is most common at the base of the tongue, just posterior to the foramen cecum. In this location, an aberrant or ectopic thyroid gland is known as a lingual thyroid and represents a failure of the thyroid to descend. This failure to descend contrasts with the incomplete descent of the thyroid, in which case the resulting final resting point of the gland may be high in the neck or just below the hyoid bone. Accessory thyroid tissue can also occur, arising from remnants of the thyroglossal duct. While the accessory thyroid tissue may be functional, it is generally insufficient for normal function if the main thyroid gland is entirely removed. This accessory tissue may appear anywhere along the path of the thyroglossal duct tract.8 The thyroglossal cyst is the most common nonodontogenic cyst in the neck. This cyst may also occur in the lingual or submental areas, though more rarely.9
Minimally invasive thyroidectomy utilizing endoscopic techniques may also affect the practice of thyroid surgery.7 The understanding of the surgical anatomy of the thyroid gland is valuable to aid the thyroid surgeon in appropriate identification and preservation of the function of these structures and to avoid the pitfalls of the operation. Importantly, the knowledge of the possible variations is paramount to safe and effective surgery.8
The ontogeny of thyroid function and its regulation in the human fetus are fairly well-defined. Fetal and maternal thyroid physiology differ, but the systems interact by means of the placenta and amniotic fluid, which modulate the transfer of iodine, and small but important amounts of thyroid hormone from mother to fetus.10
Follicular cells acquire the capacity to form thyroglobulin as early as the 29th day of gestation, whereas the capacities to concentrate iodine and synthesize are delayed until about the 11th week. Radioactive iodine inadvertently given to the mother would be accumulated by the fetal thyroid soon thereafter. Early growth and development of the thyroid do not seem to be TSH-dependent, because the capacity of the pituitary to synthesize and secrete TSH is not apparent until the 14th week.1 Subsequently, rapid changes in pituitary and thyroid function take place. Probably as a consequence of hypothalamic maturation and increasing secretion of thyrotropin releasing hormone (TRH), the serum TSH concentration increases between 18 and 26 weeks’ gestation, after which levels remain higher than those in the mother. The higher levels may reflect a higher set-point of the negative feedback control of TSH secretion during fetal life than at maturity. Thyroxine binding globulin (TBG), the major thyroid hormone binding protein in plasma, is detectable in the serum by the 10th gestational week and increases in concentration progressively to term. This increase in TBG concentration accounts in part for the progressive increase in the serum T4 concentration during the second and third trimesters, but increased secretion of T4 must also play a role, because the concentration of free T4 also rises.1
ANATOMY AND HISTOLOGY
The thyroid is one of the largest of the endocrine organs. Moreover, the potential of the thyroid for growth is tremendous. The normal thyroid is made up of two lobes joined by a thin band of tissue, the isthmus, which is approximately 0.5 cm thick, 2 cm wide, and 1–2 cm high. The individual lobes normally have a pointed superior pole and a poorly defined, blunt inferior pole hat merges medially with the isthmus. Each lobe is approximately 2.0–2.5 cm in thickness and width at its largest diameter, and it is approximately 4.0 cm in length.
The right lobe is normally more vascular than the left; it is often the larger of the two and tends to enlarge more in disorders associated with a diffuse increase in gland size. Two pairs of vessels constitute the major arterial blood supply: the superior thyroid artery, which rises from the external carotid artery, and the inferior thyroid artery, which arises from the subclavian artery. Estimates of thyroid blood flow range from 4 to 6 mL/min/g, well in excess of the blood flow to the kidney (3 mL/min/g).10
Under the middle layer of deep cervical fascia, the thyroid has an inner true capsule, which is thin and adheres closely to the gland. Extensions of this capsule within the substance of the gland form numerous septae, which divide it into lobes and lobules. The lobules are composed of follicles, the structural units of the gland, which consist of a layer of simple epithelium enclosing a colloid-filled cavity.11
The follicles are invested with a rich capillary network. The interior of the follicle is filled with clear, proteinaceous colloid that normally is the major constituent of the total thyroid mass. On the cross-section, thyroid tissue appears as closely packed, ring shaped structures consisting of a single layer of thyroid cells surrounding a lumen. The diameter of the follicle varies considerably, even within a single gland, but averages about 200 nm. The follicular cells vary in height with the degree of glandular stimulation, becoming columnar when active and cuboidal when inactive. The epithelium rests on the basement membrane that is rich with glycoproteins and separates the follicular cells from the surrounding capillaries. About 20–40 follicles are demarcated by connective tissue septa to form a lobule supplied by a single artery. The function of a given lobule may differ from that of its neighbors.
On electron microscope, the thyroid follicular epithelium has many features in common with other secretory cells and some are peculiar to the thyroid. Thyroid follicular cells show a neutrophilic cytoplasm, a basal nucleus, and para-aminosalicylic acid-positive vacuoles (phagosomes). From the apex of the follicular cell, numerous microvilli extend into the colloid. It is at or near this surface of the cell that iodination, exocytosis, and the initial phase of hormone secretion (i.e., colloid resorption) occur. The nucleus has no distinctive features, and the cytoplasm contains an extensive endoplasmic reticulum laden with microsomes. The endoplasmic reticulum is composed of network of wide irregular tubules that contains the precursor of thyroglobulin. The carbohydrate component of thyroglobulin is added to this precursor in the golgi apparatus, which is located apically. Lysosomes and mitochondria are scattered throughout the cytoplasm. Stimulation by TSH results in enlargement of the golgi apparatus and formation of pseudopodia in the apical portion of the cells. The smaller (150–200 nm) vesicles are exocytotic vesicles containing newly synthesized thyroglobulin. The fusion of these vesicles with the apical plasma membrane leads to the delivery of thyroglobulin into the follicle lumen. Thyroid peroxidase (TPO) and hydrogen peroxide producing enzymes are localized to the luminal side of the follicular cell membrane, thus allowing the iodination process to occur. The larger vesicles (500–4,000 nm) are filled with dense material called colloid droplets that are the result of the uptake of the iodinated thyroglobulin store in the follicular lumen. Thyroid stimulating hormone induces the uptake of thyroglobulin from the follicle lumen, increasing the number of colloid droplets. The reabsorption of the colloid involves a macropinocytosis mechanism whose first step is the formation of pseudopods at the apical pole. The pseudopods close, and a portion of the colloid is internalized into the cell.1
At the molecular level, a follicular cell can be identified by the presence of a specific set of proteins and corresponding messenger ribonucleic acids—indispensable for its specialized functions. Among such proteins, thyroglobulin and TPO are remarkable specific, being detectable exclusively in thyroid follicular cells. Other proteins, such as TSH receptor, sodium iodide symporter, pendrin, and dual oxidases, though expressed in thyroid follicular cells, are also present in other tissues.
Thyroid gland organogenesis results in an organ, the shape, size, and position of which are largely conserved among adult individuals of the same species, thus suggesting that genetic factors must be involved in controlling these parameters.12
The exclusive or prevalent expression of genes necessary for thyroid hormone biosynthesis in thyroid follicular cells appears to be due to a combination of transcription factor unique to this cell type. These transcription factors (NKX2-1/TTF-1, PAX-8, FOXE-1) have subsequently been found to be important in controlling not only differentiation but also the morphogenesis of the gland.13
The parafollicular cells arise from the ultimobranchial body. This body represents the last structure derived from the branchial pouches, hence its name. The ultimobranchial body arises from the fifth pharyngeal pouch, which is alternately described as the ventral portion of the fourth pharyngeal pouch.1 Migrating cells from the neural crest region infiltrate the ultimobranchial body. This structure is then incorporated into the thyroid gland, as the ultimobranchial body fuses with the thyroid gland and disseminates its cells into it. The C cells of the thyroid, therefore, are of neural crest origin. The C cells synthesize and secrete calcitonin, a polypeptide hormone involved in calcium metabolism. In lower vertebrates, C cells form an organ called the ultimobranchial gland that is separate from the thyroid gland.13
The C cells are known as parafollicular cells because of their distribution among follicular cells. However, in spite of their name, not all C cells are located between follicular cells and the basement membrane (a real parafollicular position); they are also found among the follicles (interfollicular) or in an intrafollicular position. In fact, C cells are found dispersed as individual cells in small groups closely associated to follicular cells, and in more complex structures, consisting of both follicular and C cells. The number of parafollicular cells in the thyroid differs among species. In humans, the number of C cells decreases with age: the neonatal thyroid has 10 times more C cells than the adult thyroid. These cells are usually distributed in the upper two-third of the lateral lobe in intra- and parafollicular position.
The C cells are characterized by clear cytoplasm and small compact nuclei. Electron microscopy reveals that these cells contain cytoplasmic secretory granules 100–200 nm in diameter. At the molecular level, C cells are identified by the presence of calcitonin. The calcitonin/calcitonin gene related peptide (CGRP) gene encodes four proteins: calcitonin, CGRP, and katacalcin I and II.14
The unusual association of adipose tissue and cartilage as well as the results of the extended immunohistochemical study provides further support to the belief that solid cells nests (SCN) and “mixed thyroid follicles” represent remnants of the ultimobranchial body and should be considered normal components of the thyroid gland.14,15
Parafollicular cells share several biological features with other neuroendocrine cells that originate from the neural crest. Indeed parafollicular cells express neuroendocrine markers, such as neurospecific enolase and chromogranin A, and a large number of regulatory peptides and their receptors, including somatostatin, serotonin, cholecystokinin 2 receptor, gastrin releasing peptide, TRH, and helodermin. Whether different subpopulations of parafollicular cells synthesize different sets of regulatory factors has not yet been demonstrated.12
Ultimobranchial Body-derived Epithelial Cells
In humans, ultimobranchial body remnants known as SCN are frequently present in the thyroid gland and are preferentially located in the middle and upper third of the lobes. Solid cells nests appear as para- or intrafollicular clusters and cords of epithelial cells clearly separated from the follicles by the basal lamina.
Solid cells nests are composed of two cell types: C cells and “main” cells, the most important cell population of these structures. The presence of C cells is consistent with the common ultimobranchial derivation of both SCN and C cells. In most cases, the SCN are found mixed with another structure known as a mixed follicle, in which follicular cells and main cells underline a lumen filled with colloid-like material.13
The thyroid gland is the first of the body's endocrine glands to develop. The normal thyroid gland is immediately caudal to the larynx and encircles the anterolateral portion of the trachea and is bordered by the trachea and esophagus medially, the carotid sheath laterally, and the sternocleidomastoid, sternohyoid, and sternothyroid muscles anteriorly and laterally. Very rarely the thyroid fails to descend from the tongue area resulting in a lingual thyroid. Incomplete descent, which is rare, may result in a cervical thyroid that is seen in the neck at or just below the hyoid bone. Accessory thyroid tissue often is fully functional, originates from remnants of the thyroglossal duct, thus can be found anywhere from the level of the tongue to where the thyroid gland comes to rest in the neck. Cysts can form anywhere along the course of the developing thyroglossal duct during descent of the developing thyroid gland from the tongue. Remnants of the duct may persist and give rise to cysts in the tongue or in the midline of the neck, usually below the hyoid bone. A detailed understanding of the thyroid embryology helps in making a better medical clinical decision regarding diagnosis and treatment of thyroid disorders and also helps the surgical outcomes.