Epidemiology—Increasing Incidence of Thyroid Cancer.
According to cancer statistics, there has been a substantial rise in thyroid carcinoma in the United States in recent years. Cancer statistics for 2012 estimate 56,460 new cases of thyroid cancer will occur. This is more than three times the number of thyroid cases reported 15 years earlier (Fig. 28-1
The mortality is increasing at a slower rate, with 1,780 deaths expected due to thyroid cancer in 2012.1
Were thyroid cancer outcomes more ominous, the public awareness of this significant trend would be widespread. In fact, the rise in incidence is of uncertain significance. Although this increased incidence may represent a true increase in disease, there are other possible explanations including reporting variability, increased diagnostic effort, and improved technology.
Although the reported incidence of thyroid cancer is alarming, these figures must be assessed in the context of data implying a much larger prevalence of these tumors. Several autopsy series around the world have suggested that the prevalence of occult papillary cancer (typically defined as tumors <1 cm in diameter) in patients dying of other causes ranges from 6% to 28%.2
In the United States, studies have shown the incidence of occult papillary cancer to be 6% to 13% in patients dying of other causes.2,3,4
If one were to make a very conservative estimate of occult thyroid cancer in the United States at 1 % of adults, it could be estimated that there are currently >3 million undiagnosed thyroid cancers. The Surveillance, Epidemiology, and End Results (SEER) database estimated a prevalence of thyroid cancer of 458,403 in 2010; therefore, it would appear that what is seen is only a minority of the total number of thyroid cancers in cancer statistical data.5
There are several suspected reasons for the increased incidence of thyroid cancer. These reasons include (a) an increased reporting of occult tumors, (b) an increased diagnostic suspicion due to increased awareness by clinicians, (c) an improvement in diagnostic skills through increased ultrasound surveillance, (d) an increased use of fine-needle aspiration (FNA), and (e) the growing use of ultrasound-guided FNA to evaluate small lesions of the thyroid. If any or all of these reasons were the cause of the increase in thyroid cancer incidence, one might expect that there would be an increase in the proportion of cancers diagnosed at lower stage.
Using SEER data from 1975 to 2002 and historical staging, there has been no change in the proportion of thyroid cancer that is confined to the thyroid, so it would not appear that increases are of low-stage tumors only.6
However, improvements to the SEER database beginning in 1988 lend further insight. First, it has been shown that the entire increase in incidence of thyroid cancer consists of papillary carcinomas. Secondly, as primary size has been better reported by SEER since 1988, 49% of the increased incidence between 1988 and 2002 consists of tumors <1 cm diameter, and 87%
of the increase consists of tumors <2 cm.6
Therefore, a significant portion of this “epidemic” of thyroid cancer would appear to be a reflection of increased investigation and assessment of small thyroid lesions. The controversy about this is not resolved as more recent analysis of SEER data shows that although the majority of the increase in thyroid cancer is among low-stage tumors, a measurable increased incidence can be shown for higher stage tumors as well.7
Although the diagnosis of small papillary cancers appears to be responsible for the majority of increase in thyroid cancer incidence, it is difficult to predict the natural history of even small papillary thyroid cancers and clinical judgment is important in the monitoring of such patients.8
Mazzaferri has cautioned that even patients with micropapillary cancer have a cancer-related mortality of approximately 1%, a risk of distant recurrence of approximately 2.5%, and a risk of local node recurrences of approximately 5.0%. These figures are why clinicians are uneasy as they try to address this epidemic.
The worldwide incidence of thyroid cancer varies as shown in Figure 28-2
, with the highest reported incidence in Polynesia, followed by North America. In general, the
incidence in more developed countries is higher than that in less developed countries.9
Worldwide incidence varies considerably, and even within Europe (Fig. 28-3
), wide variations are seen.10
FIGURE 28-1. Incidence of thyroid cancer in the United States, 1997-2012 (estimated).
Source: Adapted from American Cancer Society. Cancer Facts and Figures 1997-2012. Atlanta, GA: American Cancer Society; 2012, with permission.
FIGURE 28-2. World age-standardized thyroid cancer incidence by gender and region.
Adapted from Ferlay J, Shin HR, Bray F, et al. GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 10 [Internet].
Lyon, France: International Agency for Research on Cancer; 2010. Available from: globocan.iarc.fr
, Accessed January 1, 2012, with permission.
With such a wide variation in incidence of thyroid cancer, the impact of environmental exposures may be considered. For the countries surrounding the Chernobyl nuclear facility, an increase in thyroid cancer incidence has been shown and more will be written on this later in the chapter.11
However, similar to the U.S. experience, multiple studies have demonstrated an increase in thyroid cancer incidence throughout the world. A relationship to the Chernobyl incident or to other radiation or environmental exposures has not been suspected in this increase.12
Instead, the increase in thyroid cancers has been explained by a changing management strategy in thyroid disease. A French multi-institutional study demonstrates a relationship to both the increased use of diagnostic ultrasound and to rigorous cytologic evaluations. The result has been an increase in the proportion of surgical cases that result in malignant pathology.13
Lithuania introduced ultrasound-guided FNA in 1997 and a recent retrospective evaluation shows a significant increase in the incidence of thyroid cancer beginning in 2000. Before this, the annual increase in thyroid cancer incidence was approximately 5 % per year. Since 2000, the annual increase in thyroid cancer is 28 % per year. The increased incidence is seen in both papillary and follicular cancers, but is confined to stage I disease only.12
Changes in Histology.
Over the last 50 years, there has been an increase in the frequency of papillary cancers primarily, with a decrease in follicular cancers and anaplastic cancers and essentially no change in medullary cancers.14
It has been proposed that the difference in the proportion of tumors of each histology is partly explained by variations in environmental iodine exposure. Iodine-deficient areas are associated with an increased risk of goiter and an increased proportion of follicular cancer and anaplastic cancer. Iodine-sufficient areas are associated with increased autoimmune thyroid disease and an increased proportion of papillary thyroid cancers with a decrease in follicular and anaplastic cancers. A dose-response relationship is indicated with the proportion of papillary to follicular cancers changing from approximately 5:1 in high iodine-intake areas, to 2.5:1 in moderate iodine areas to 1:1 in iodine-deficient areas.15
Changes in pathologic interpretation of thyroid cancers over time may confound our ability to make generalizations about the proportion of cancer histology over time and about the relationship between iodine and thyroid cancer histology. A review of previous thyroid cancer cases entered in the Geneva Cancer Registry over a 30-year period demonstrated that 45 % of follicular cancers diagnosed between 1970 and 1979 were reclassified as papillary cancers. Cases entered more recently, 1990 to 1998, were less likely to be reclassified, but the rate of reclassification was still 25 %. The possible explanation for this high rate of reclassification is not known but could relate to the development of stricter guidelines for microscopic characterization.16
A relationship between ionizing radiation and thyroid cancer was first described in 1950 by Duffy and Fitzgerald.17
A dose-response relationship has been established for lower doses of radiotherapy, particularly in individuals exposed in childhood.18
Between approximately 1920 and 1960, the use of low-dose irradiation was practiced for benign diseases of childhood
including acne, tinea capitis, impetigo, sinusitis, adenoid hypertrophy, thymic enlargement, and keloids. The practice has now been discontinued since the recognition that this practice contributed to an increased risk papillary thyroid cancer development. However, the risk of developing thyroid cancer in patients treated with low-dose radiotherapy is increased, even for doses as small as 0.1 Gy, and although the risk begins to decline at 30 years, it remains elevated far longer. The risk is greatest for those irradiated at younger than 15 years of age with an estimated relative risk of 7.7 per Gy.18
The risk of nodules in patients irradiated for benign disease has been reported at 38%19
and approximately a third of these nodules will be malignant.20,21,22
While the risk is significant for those patients irradiated, the numbers of irradiated patients is not felt to be large enough to explain the increase in cancer incidence across populations discussed earlier.
While childhood radiation for benign conditions is no longer used, there remains a cohort of patients who are treated in childhood for malignancy with radiation therapy. This is a population that has been shown to be at increased risk of thyroid cancer. Estimates of increased risk ratio (RR) of 4.6 to 14.6 have been reported.23,24
The risk increases with increasing thyroid radiation dose up to about 20 Gy and then tapers off.24
The risk is greater with younger age of treatment and in females. Subsequent thyroid cancer risk is most often associated with Hodgkin and non-Hodgkin Lymphoma23
For lymphomas, the field of radiation includes the thyroid bed whereas for the latter tumor the early age of treatment is a major factor influencing thyroid cancer risk. The relative risk of developing thyroid cancer peaks at 20 years after treatment,23,24
but lifelong monitoring is recommended.23
There has been evidence of increased rates of differentiated thyroid cancer (DTC) in areas downwind from nuclear test sites.24
Following atomic testing in the United States between 1950 and 1958, the estimated average cumulative dose of radiation from environmental iodine-131 ( 131
I) has been estimated to range from 1 to 4 rads per individual across the United States. Some areas are estimated to have had exposures up to 16 rads. In contrast, the average annual background radiation is 0.1 rad.26
A careful evaluation of thyroid cancer rates attributable to atmospheric nuclear testing found that the risk of thyroid cancer was only suggested for individuals exposed before the age of 1. Older children and adults did not demonstrate an increased risk.26
The risk of environmental exposure from radiation has been clearly documented following the Chernobyl nuclear disaster in the Ukraine in 1986.27,28,29
The pattern of development, however, is quite different from that seen in childhood therapeutic radiation exposure. In childhood low-dose therapeutic radiation exposure, the risk of thyroid cancer rises after a latency of approximately 10 years and peaks at 25 to 30 years as shown in Figure 28-4
Following Chernobyl, the increase in thyroid cancers was seen as early as 1989, only 3 years after the accident.27,28,29
The impact of the Chernobyl disaster may not be yet fully known. Data from Belarus (whose border is <20 miles from Chernobyl) indicate a significantly higher incidence of thyroid cancer in high-exposure areas when compared with low-exposure areas. The rate of thyroid cancers continues to increase in individuals who were between 0 and 15 years of age at the time of the disaster.11
Other environmental factors that might lead to an increase in thyroid cancer development are not clear. In a thorough case-control study using the Swedish Cancer Registry and an extensive review of lifetime diagnostic radiograph exposures, there was no evidence of an increased exposure to diagnostic radiographs in patients with DTC.31
Similarly, there is no strong indication that irradiation from the use of therapeutic 131
I leads to an increased risk of thyroid cancer.32,33,34,35
One exception is work by Franklyn et al. which evaluated patients with hyperthyroidism given 131
I and found a higher incidence and mortality rate of thyroid cancers as well as a higher incidence of small bowel tumors, although the absolute incidence rates were low.36
FIGURE 28-4. Incidence and timing of papillary thyroid carcinoma in patients exposed to ionizing radiation during childhood.
Source: Adapted from DeGroot M, Sternberg T. The Thyroid and Its Diseases. 5th ed. New York, NY: Churchill Livingstone; 1984, with permission.
Associations between thyroid cancer and other exposures have been investigated. Owing to the fact that thyroid cancer is a relatively common disease in young women and the increased incidence of thyroid cancer is greatest in women, multiple studies have investigated the relationship between thyroid cancer and reproductive history and exogenous hormone use. The data are mixed but describe an increased risk of thyroid cancer with early menarche,37
early first pregnancy,38
late first pregnancy,39
and late last pregnancy.39,40
Other studies show no relationship to reproductive history.41,42
The relationship between oral contraceptive use and thyroid cancer has been positive, negative, or unrelated depending on the study,37,43,44
although there is a suggestion from pooled data that oral contraceptives can act as a promoter of thyroid cancer.43
The risk of oral contraceptive use appears to be eliminated after the hormone is discontinued.43
Genetic causes of thyroid malignancy are well known for medullary cancer, and this will be discussed in detail later in the chapter. For papillary cancer, there are a handful of syndromes that manifest this cancer. These include Gardner syndrome, Cowden disease, and Carney complex, all autosomal dominantly inherited.45,46
Embryology. The thyroid gland develops from the endodermal tissues of the primitive gastrointestinal tract. The site of origin ultimately is the foramen cecum at the tongue base and descent of the thyroid occurs by the seventh gestational week to lie anterior to the cricoid and cervical trachea. The thyroid is able to concentrate iodine and form thyroid hormone by the 11th gestational week. It reaches its full size of 15 to 25 g in adulthood.
The descent of the thyroid through the anterior midline neck explains several anomalies that relate to thyroid pathology. These include ectopic thyroid located at the tongue base, termed a lingual thyroid.
Lingual thyroid tissue has been reported in up to 10% of children.47,48
When noted, this may represent the only thyroid tissue in patients and evaluation of the neck for additional thyroid tissue is important. Along the pathway of thyroid descent, a cyst of ciliated pseudostratified epithelium and variable amounts of thyroid tissue may remain. These thyroglossal duct cysts are usually closely related to the central portion of the hyoid bone, and it is generally accepted that this bone must be resected to successfully remove the cyst. The cyst, or similarly located ectopic thyroid tissue, may give rise to thyroid neoplasia
on occasion. The most inferior point on the pathway of normal thyroid descent would be represented by the pyramidal lobe, thyroid tissue located just cephalad to the thyroid isthmus.
Other ectopic locations of thyroid tissue have been noted including mediastinum, heart, liver, esophagus, larynx and trachea, and ovary.49,50,51,52,53,54
These structures are obviously beyond the range of the typical descent of thyroid tissue and represent true ectopic locations. Thyroid rests in cervical lymph nodes deserve special mention. Although these have been described previously in cervical lymph nodes,55
the concern when thyroid tissue is identified in these nodes is that this represents well-DTC metastatic to that node. As a general rule, thyroid rests in nodes along the jugular chain (i.e., lateral neck nodes) are considered diagnostic for thyroid malignancy. On the other hand, thyroid rests in central compartment lymph nodes are felt to represent benign thyroid rests if no suspicion of malignancy is noted in the thyroid itself. These guidelines may not apply to all patients and each patient’s context should be reviewed to determine when additional testing for the presence of malignancy must proceed.
While the thyroid follicular tissue develops from the embryologic foregut, the calcitonin producing (C or parafollicular) cells of the thyroid develop from neural crest ectoderm related to the fourth and fifth branchial pouches. These tissues, known as the ultimobranchial body, migrate anteriorly and merge with the descending follicular thyroid tissues, thus explaining their designation as parafollicular cells. Analysis of thyroid tissues has shown that these C cells lie in greater concentration in the superior and posterior aspect of the thyroid, a location similar to the superior parathyroid, which also arises from the fourth brachial pouch.
The parathyroid glands develop as two paired structures from the third and fourth branchial pouches. The third pouch gives rise to the inferior parathyroid and the more inferior thymus gland. This relationship explains the fact that ectopic parathyroid tissues may be located within the thymus. As stated, the superior parathyroid develops from the fourth branchial pouch along with the ultimobranchial body, which gives rise to the C cells.
The thyroid consists of two lobes, each approximately 8 to 10 mL in size connected by a thin isthmus lying over the trachea. A pyramidal lobe of any significant size is present in a minority of cases. The average gland weighs 15 to 25 g. The thyroid isthmus is often easily palpated, just below the cricoid cartilage. The thyroid lobes are palpable lateral to this, with the examination made easier when the patient swallows. The left and right lobes of the thyroid lie just deep to the sternothyroid muscles. The gland is encased by a thin layer of fascia, but the posterior attachment of the gland to the trachea is quite dense and lies just medial to the area where the recurrent laryngeal nerve enters the cricothyroid membrane. It has been estimated that up to two-thirds of thyroid glands may have a tubercle of Zuckerkandl, a posterior, lateral extension of the thyroid lobe that may be an important landmark in identifying the recurrent laryngeal nerve and the superior parathyroid gland.56,57,58
Vascular and Lymphatic Anatomy.
The vascular anatomy of the thyroid is described as two paired arteries and three paired veins. These include superior and inferior thyroid arteries and superior, middle, and inferior thyroid veins. Although this is true, the practical application of this information is significantly limited by the surgical anatomy of the thyroid. The superior thyroid vein, and to a lesser extent the artery, anastomose with the thyroid through several small branches. The superior laryngeal nerve may be intertwined with these branches, so meticulous dissection of individual branches of the superior thyroid artery and vein is required when dissecting the superior pole of the thyroid. Likewise, the inferior vein is always divided into multiple branches at the margin of the thyroid gland. Individual ligation of these branches is required due to the fact that the inferior parathyroid is often located on the thyroid capsule in this area. Finally, the inferior thyroid artery has been shown to contribute the major blood supply to both the inferior and superior parathyroid glands. Preservation of the vascularity of these glands is felt to be important in order to preserve their function after thyroidectomy. Therefore, dissection and ligation of only the distal branches of this artery as they enter the thyroid has been felt to be most judicious. Regarding the last point, however, there may be some debate as two randomized studies looking at subtotal thyroidectomy found no difference in postoperative hypocalcemia whether or not the inferior arteries were ligated at the main trunk.59,60
Whether these studies apply to the performance of total thyroidectomy is unclear.
The superior thyroid artery arises as the first branch of the external carotid artery in the vast majority of individuals. From this point, it descends to the upper thyroid pole by passing deep to the omohyoid muscle and superficial to the superior constrictor muscle and cricothyroid muscle. The superior laryngeal nerve arises from the vagus nerve high in the neck and passes deep to the carotid artery to reach the larynx. The internal branch of the superior laryngeal nerve enters the thyrohyoid membrane just inferior to the hyoid whereas the external branch travels parallel and deep to the superior thyroid artery and then passes medially to the cricothyroid muscle.
The relationship between the superior thyroid artery and nerve is variable. This variability was emphasized in a recent anatomic study that included review of previous data. In this, the nerve was shown to cross the plane of the superior thyroid artery over 1 cm above the superior thyroid pole in 18% to 68% of cases. The nerve crossed within 1 cm of the superior thyroid pole in 11% to 60%. However, the more important, and most consistent, anatomic relationship for surgical dissection was the finding that the nerve crosses the artery below the upper pole of the thyroid in 14% to 20% of patients.61
In addition to this study, recent work has shown that in almost half of all thyroidectomies the superior laryngeal nerve may be located below the superior pole of the thyroid gland and be at risk for injury,62
with oversized glands having a higher risk.63
The inferior thyroid artery is a branch of the thyrocervical trunk and passes deep to the common carotid artery to reach the thyroid. In this orientation, it is roughly perpendicular to the recurrent laryngeal nerve. The relationship between the inferior thyroid artery and this nerve is variable, but is stated to demonstrate the nerve as deep to the artery in 70% of cases. A distinction has been suggested between the two sides of the larynx with the right nerve most often passing between branches of the inferior thyroid artery and the left nerve most often passing behind the artery.64
Lymphatics of the thyroid consist of a rich intraglandular network as well as extraglandular drainage. The intraglandular network has been thought to explain the high rate of multifocality in papillary thyroid cancers by allowing tumor emboli to travel through the thyroid and metastasize to other intrathyroidal sites. The extraglandular network passes through the medial compartment of the neck and also follows the arterial supply in a retrograde manner as it exits this medial compartment. The medial or central compartment of the neck, shown in Figure 28-5
, represents the primary echelon nodal drainage from the thyroid gland. Surgical dissection of the central compartment in the treatment of thyroid papillary carcinoma has been shown to yield an average of eight nodes per patient.65
Secondary echelon nodal drainage is to the lateral neck compartment and posterior triangle lymph nodes. The retrograde lymphatic drainage following the arterial supply to the thyroid
is demonstrated by work on subcentimeter papillary thyroid cancers. Small tumors of the upper portion of the thyroid are as likely to spread to level II in the upper jugular chain (presumably through lymphatics along the superior thyroid artery) as to lower neck nodes.66
FIGURE 28-5. Primary and secondary echelon lymphatic drainage from the thyroid gland.
FIGURE 28-6. The various relationships of the inferior thyroid artery to the recurrent laryngeal nerve. A: View of the right neck with the inferior artery dividing to straddle the recurrent laryngeal nerve. B: Cross-sectional diagram of the neck showing the various relationships between the inferior thyroid artery and the recurrent laryngeal nerve (1, artery superficial to nerve; 2, artery deep to nerve; 3, artery dividing around nerve). ASM, anterior scalene muscle; PVF, prevertebral fascia; PVM, prevertebral muscle; CS, carotid sheath; ITA, inferior thyroid artery; RLN, recurrent laryngeal nerve; J, jugular vein; VN, vagus nerve; C, carotid artery; E, esophagus; TG, thyroid gland; TR, trachea; SCM, sternocleidomastoid muscle; STM, sternohyoid muscle; PLM, platysma; SHM, sternohyoid muscle; IF investing fascia; PTF, pretracheal fascia.
The nerves important in thyroid anatomy and thyroid surgery are those of the larynx. The superior laryngeal nerve and recurrent laryngeal nerve are branches of the vagus nerve. This nerve exits the skull base at the jugular foramen, and just below this point, the superior laryngeal nerve branches off to pass deep to the carotid artery and medially toward the larynx. The internal branch of this nerve enters the thyrohyoid membrane to supply sensory innervation to the supraglottic larynx. The superior location of this branch means that is it not at risk in thyroid surgery unless a large cephalad extension of the thyroid is present. The external branch of the nerve is of greater concern in thyroid surgery. This branch innervates the cricothyroid muscle, a nerve important in vocal fold stretch and in vocalizing at high pitch. The nerve travels to this muscle along the superior thyroid artery, to which it lies deep. Near the upper pole of the thyroid and occasionally between branches of the superior thyroid artery, the nerve travels medially to the cricothyroid muscle. En route
, the nerve may penetrate the inferior constrictor muscle and, in fact, has been shown to travel deep to this muscle throughout its course in 10% of patients.61
The nerve is quite small and even with significant effort can prove difficult to identify. In fact, one study reported an effort to identify the nerve in 50 cases using a nerve stimulator and was only able to identify the nerve in 20% of cases.67
Other surgeons have been more successful and have reported success in identifying the nerve in >90% of cases.68
The recurrent laryngeal nerve branches from the vagus nerve in the thoracic cavity. On the left side, the nerve passes around the aortic arch and then superiorly up along the tracheoesophageal groove to the Berry ligament. On the right side, the nerve passes around the subclavian artery and then passes in a more oblique direction toward the larynx. The nerve passes deep to the inferior thyroid artery in most cases (Fig. 28-6
). As the nerve proceeds cephalad, small branches may be seen that enter the
trachea and esophagus. These include sensory branches to the upper trachea and subglottic larynx. The motor component of the recurrent laryngeal nerve may divide into a posterior and anterior division below the level of the Berry ligament. Katz describes branching of the nerve over 5 mm below the lower border of the cricoid cartilage in 63% of >1,100 thyroidectomies.69
In addition, recent work suggests that in 1% of cases the recurrent nerve or its branches may enter the larynx in a higher-thanexpected location making the nerve more prone to injury.70
It is important to recognize this branching of the nerve during thyroid surgery. Failure to recognize this anatomy may result in injury to a branch of the nerve. The function of the motor branches of the recurrent laryngeal nerve is to supply all of the muscles of the larynx except the cricothyroid. These include both the abductors and the adductors of the larynx. Injury to the nerve can result in significant laryngeal incompetence. When disruption of those sensory fibers from the recurrent laryngeal nerve to the upper trachea and subglottic larynx occurs in conjunction with motor injury to the recurrent nerve, the combination of vocal cord incompetence and hemitracheal anesthesia can make the postoperative course of such a patient much more problematic.
The anatomy of the recurrent laryngeal nerve results in some specific risks during thyroid surgery. The nerve can be placed under significant stress during the surgery as dissection proceeds along the lateral aspect of the thyroid and the gland is retracted medially to expose the path of the nerve. During this medial retraction of the gland, the nerve may become compressed by a distal branch of the inferior thyroid artery or by a fascial band stretched across the nerve. At the ligament of Berry, the nerve courses posteriorly to enter the larynx behind the cricothyroid joint. This fixed relationship between the nerve and the cricothyroid joint and the medial traction of the gland described earlier can also contribute to stretch on the recurrent laryngeal nerve during the dissection. Inadvertent transection of the recurrent laryngeal nerve is not a significant risk for an experienced thyroid surgeon. However, stretch injuries of the nerve may still occur. Almost all of these are temporary. The use of intraoperative recurrent nerve monitoring has been suggested to decrease the risk of injury. However, in recent review of the literature, Dralle et al.71
found that in six studies comparing intraoperative recurrent nerve monitoring with postoperative laryngoscopic findings, nerve monitoring had a high negative predictive value (NPV; 92%-100%), but relatively low and variable positive predictive values (PPVs; 10%-90%), potentially limiting the role of nerve monitoring. International study guidelines have recently been published on the role of intraoperative nerve monitoring.72
FIGURE 28-7. Pathologic evaluation following thyroidectomy revealed that this patient’s left (A) and right (B) inferior parathyroid glands were both located within the thyroid parenchyma. This example demonstrates the relative symmetry that may be seen in parathyroid anatomy.
A special anatomic relationship should be mentioned in the case of the right recurrent laryngeal nerve. This nerve may be nonrecurrent in a small number of patients, typically estimated at well below 1 %. This occurs when there is an aberrant takeoff of the right subclavian artery. This anomaly represents an anomaly of the fourth branchial arch resulting in the right subclavian to arise from the aorta and pass deep to the esophagus. The recurrent laryngeal nerve will then pass deep to the carotid and directly toward the larynx. The authors have seen nonrecurrent nerves that travel parallel (and deep) to the superior thyroid artery and others that resemble a recurrent nerve except that they travel behind the carotid at the level of the inferior thyroid artery.
Parathyroid Anatomy. Normal parathyroid glands are each approximately 40 to 70 mg in weight, meaning a size of approximately 4 × 6 mm at surgery. The location of these glands is variable. The typical location of the superior parathyroid gland is behind the thyroid at the cricoid level, lateral to the recurrent laryngeal nerve. The inferior glands are located on or adjacent to the lower pole of the thyroid in 50% of cases. The inferior glands may lie within thymic tissue in up to 40% of cases.
In the treatment of primary hyperparathyroidism, the surgeon must be familiar with various ectopic locations of parathyroid tissue in order to identify and resect adenomas or hyperplastic glands in these locations. The treatment of malignant diseases of the thyroid does not typically require direct application of this knowledge. However, the surgeon should be aware that 4% of parathyroid glands are found embedded within the thyroid gland.73 Figure 28-7
shows such a case where both inferior parathyroid glands were identified within the thyroid on pathologic study. This case emphasizes both the possibility of intrathyroidal parathyroid gland and the symmetry often seen when searching for parathyroid glands at surgery. Beyond identification and preservation of parathyroid glands while dissecting the thyroid gland, the treatment of thyroid malignancy will often require a medial compartment neck dissection. Here, the parathyroid glands are at significantly greater risk of devascularization or inadvertent removal during the dissection process and surgeons must be facile at parathyroid gland identification, dissection, and preservation of the parathyroid vascular pedicle, and when necessary, perform parathyroid autotransplantation, usually into an adjacent muscle.
The application of thyroid physiology in the treatment of patients with thyroid cancer is one of the basic tools of the clinician. These applications include the possible use of exogenous thyroid hormone to suppress stimulation of benign and malignant thyroid tissue, withdrawal of thyroid hormone to allow intrinsic stimulation to be maximized in anticipation of radioactive iodine, and, more recently, the use of exogenous thyroid stimulation to prepare patients for radioactive iodine without the need for exogenous thyroid hormone withdrawal.
The basic functional unit of the thyroid is the thyroid follicle, which consists of a space filled with colloid and lined by thyroid follicular cells. These cells avidly trap iodide molecules through sodium iodide symporter channels and transport this iodide to the follicular lumen. Meanwhile, follicular cells also synthesize thyroglobulin (Tg), a glycoprotein that serves as the backbone and storage molecule for thyroid hormone. On the luminal side of the follicular cell plasma membrane, iodide molecules are oxidized and attached to tyrosyl peptides of the Tg molecule. Subsequent coupling of iodinated tyrosyl residues leads to the formation of the functional thyroid hormones, still embedded within the Tg glycoprotein through these tyrosyl residues.74
The two active thyroid hormones, thyroxine (T4) (3,5,3′,5′-tetraiodo-thyronine) and 3,5,3′-triiodothyronine (T3), are stored in this manner within the thyroid colloid until released into circulation. Release of active hormone occurs by reverse pinocytosis from the intrafollicular space back through the follicular cell where the Tg molecule is cleaved to release the T3 and T4 hormones into the plasma.
Tg itself may leak out or be released from follicular cells into the circulation, and the serum measurement of Tg has become an important tumor marker. The molecule is present in serum in normal and pathologic conditions. Increased serum Tg concentrations may be seen in the hyperthyroid phase of silent or subacute thyroiditis; multinodular thyroid disease; and in papillary, follicular, and anaplastic thyroid cancers. The use of serum Tg measures in previously untreated patients (with intact thyroid glands) is limited by its lack of specificity to distinguish benign from malignant conditions. However, in patients previously treated for DTC, in whom there is little or no residual normal thyroid tissue, Tg has become an essential indicator of residual or recurrent DTC (i.e., papillary or follicular thyroid cancer).
In plasma, T3 and T4 are bound to thyroxine-binding globulin (TBG) as well as prealbumin and albumin. Thyroxine-binding globulin is a protein made in the liver and is the dominant thyroid hormone-binding protein. T4 mainly acts as a prohormone and is metabolized to the active form of thyroid hormone, T3, in the liver and kidney primarily. Actions of thyroid hormones influence growth, development, and metabolism. In adulthood, the major effects of thyroid hormone are in the regulation of metabolism, including changes in oxygen consumption and protein, carbohydrate, lipid, and vitamin metabolism.75
Iodine and thyroid-stimulating hormone (TSH) are the major influences on thyroid hormone secretion and thyroid stimulation. TSH is excreted from the anterior pituitary and is in turn regulated by thyrotropin-releasing hormone (TRH) from the hypothalamus. Both TSH and thyrotropin-releasing hormone excretion are influenced by feedback from serum levels of thyroid hormones (Fig. 28-8
). TSH has been shown to increase thyroid hormone production through multiple mechanisms, from increasing iodine uptake by the sodium-iodine symporter to expediting Tg reuptake by thyrocytes as well as multiple steps in thyroid hormone production.74
TSH also stimulates thyrocyte proliferation. It is this effect that has led to the use of TSH suppression as an adjunct in the treatment of thyroid malignancy. Consistent TSH suppression therapy, interrupted only for short periods of TSH stimulation, in order to perform diagnostic studies or ablative treatment with radioactive iodine has long been the mainstay of papillary and follicular thyroid cancer treatment. TSH stimulation has traditionally required withdrawal of exogenous thyroid hormone for several weeks. More recently, however, this stimulation can be obtained through the use of recombinant human TSH (rhTSH) injections without the need for thyroid hormone withdrawal.
FIGURE 28-8. Autoregulatory feedback system for thyroid activity. TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone.