The thyroid gland
Background
Embryology, surgical anatomy and physiology
Recurrent laryngeal nerve and external branch of superior laryngeal nerve anatomy
The recurrent laryngeal nerve (RLN), also known as the inferior laryngeal nerve, is a branch of the vagus nerve. After winding around the aortic arch on the left, and the right subclavian artery, the RLNs course superomedially from the root of the neck to continue in the tracheo-oesophageal groove. The right RLN has an oblique course and the left a more vertical course, in the neck. The posteromedial aspect of the gland is therefore in close approximation to the last extralaryngeal segment of the nerve. In the last 1–2 cm of its extralaryngeal course, the RLN is juxtaposed between the lateral side of the ligament of Berry and the medial side of the TZ, plastered in place by an overlying fascia containing the tertiary branches of the inferior thyroid artery. It is here, just before entering the larynx under the cover of the cricopharyngeus muscle, that the RLN is most constant in position and also most prone to injury during thyroid surgery due to the difficulty in freeing it from the structures enveloping it. Up to 72% of RLNs divide into two or more branches before entering the larynx. The anterior-most branch carries most of the motor fibres to the laryngeal muscles, and therefore is the most important branch to preserve.1
The external branch of the superior laryngeal nerve (EBSLN), also a branch of the vagus nerve, is the motor supply of the cricothyroid muscle. In its course from the carotid sheath to the cricothyroid muscle, it comes close to the junction of the upper pole and the upper pole vessels. The Cernea Classification describes the various variations, which have relevance in surgical dissection (Fig. 2.1).
Figure 2.1 Anatomical variations of the external branch of the superior laryngeal nerve, in relation to the superior pole of the thyroid lobe. Type 1 nerve crosses the superior thyroid vessels > 1 cm above the superior pole, while type 2 nerve crosses the superior thyroid vessels < 1 cm above (type 2a) or below (type 2b) the superior pole.
Parathyroid anatomy
Parathyroid cell masses from the third and fourth pharyngeal pouches form the inferior and superior parathyroid glands respectively. They descend from their pouch origins to the final positions in close association with the developing thyroid and thymus glands. Therefore, it is not surprising that they maintain such close relationships with these glands. The majority of non-pathological superior parathyroid glands are found in the vicinity of the cricothyroid junction (77%), often closely related to the TZ and RLN, or under the capsule on the posterior surface of the superior thyroid pole (22%). The superior glands lie posterior to the RLNs. The inferior parathyroid glands, having travelled a longer distance, are more variable in their locations. They can be found on the surface of the inferior thyroid pole (42%), in the uppermost part of the thymic horn (39%), lateral to the inferior thyroid pole (15%) or in other ectopic locations (2%).2 They lie anterior to the RLNs.
Thyroid physiology
Thyroid hormone secretion in health is dependent upon a classical feedback loop. Reduced levels of T3 and T4 induce thyroid-stimulating hormone (TSH) release directly from the anterior pituitary and also indirectly through hypothalamic stimulation of thyrotropin-releasing hormone (TRH) release (which in turn induces TSH secretion). Such pathways are suppressed in periods of thyroid hormone excess. TSH exerts its effect via TSH receptors to increase iodide trapping, Tg synthesis, as well as T3/T4 production and secretion (Fig. 2.2).
Clinical history and examination
Pathologies of the endocrine organs, including the thyroid gland, give rise to a broad spectrum of symptoms and signs. The clinician must be thorough in both history-taking and physical examination, not only of the organ in question, but also other organ systems that the endocrinopathy may affect. A schema for assessing patients with thyroid complaints is suggested in Box 2.1, while Box 2.2 lists the questions that are essential to keep in mind when formulating a management plan. Some symptoms and signs of thyroid pathologies are listed in Tables 2.1 and 2.2. These are by no means exhaustive. A grading system for goitre size has been published by the World Health Organisation (Table 2.3).
Table 2.3
Simplified classification of goitre by palpation (WHO)
| Grade 0 | No palpable or visible goitre |
| Grade 1 | A goitre that is palpable but not visible when the neck is in the normal position (i.e. the thyroid is not visibly enlarged) |
| Grade 2 | A swelling in the neck that is clearly visible when the neck is in the normal position and is consistent with an enlarged thyroid when the neck is palpated |
Investigation of the thyroid
Blood tests
Thyroid function tests: Thyroid function homeostasis is dependent upon the pituitary–thyroid axis feedback loop (Fig. 2.2). Thyroid function tests (TFTs) identify hypo- or hyperfunction through quantification of not only circulating thyroid hormones (T3 and T4) but, more importantly, thyroid-stimulating hormone (TSH or thyrotropin). In keeping with the negative feedback loop, thyroid hyperfunction results in a suppressed TSH, in the presence of increased circulating T3 and T4. Conversely, reduced hormone levels lead to an increase in TSH.3 (also see section on hyperthyroidism).
Thyroglobulin antibody: Thyroglobulin antibody (TgAb) is a highly sensitive marker of Hashimoto’s disease and over 99% of patients with this condition will have elevated antibodies.4 Elevated levels may also be seen in Graves’ disease. The presence of TgAb should also be noted when monitoring Tg levels for surveillance after treatment of papillary or follicular thyroid cancer. TgAb may interfere with Tg assays and lead to spurious levels.
Thyroid peroxidase antibody: Thyroid peroxidase antibody (TPOAb) is commonly elevated in Graves’ disease but may also be seen in cases of thyroiditis. The test lacks sensitivity and specificity for Graves’ disease and is therefore only useful with a clear clinical suspicion of disease.5 Systemic autoimmune diseases may also lead to TPOAb positivity that may not be of any clinical significance.
TSH receptor antibody: TSH receptor antibodies (TRAbs) may be directly stimulatory or exert an inhibitory action on thyroid TSH receptors, leading to related changes in thyroid hormone secretion. Stimulatory antibodies are encountered in Graves’ disease and are particularly useful where the clinical diagnosis proves difficult to make. TRAbs are also identified in euthyroid Graves’ opthalmopathy, unilateral Graves’ eye disease, subclinical hyperthyroidism and thyroiditis. TRAbs can also cross the placenta and, in pregnancy, a positive test predicts for neonatal thyroid dysfunction.5
Biomarkers of malignant disease:
Thyroglobulin: Assessment of serum Tg is employed in surveillance of patients who have undergone total thyroidectomy and radioactive iodine ablation for differentiated thyroid cancers. Thyroglobulin serves as a biochemical marker of disease recurrence or progression in those with residual disease.
Calcitonin: Calcitonin is produced by the parafollicular C cells of the thyroid gland. These cells represent the cellular origin of medullary thyroid carcinoma (MTC), and calcitonin is elevated in cases of this disease. Calcitonin serves as a sensitive marker of disease recurrence and progression in MTC, and progressively higher levels at diagnosis are associated with larger tumours, regional lymph node metastases and distant metastases.6 Routine measurement of calcitonin in the work-up of thyroid nodules is recommended by the European Thyroid Cancer Taskforce; however, the American Thyroid Association (ATA) has not made a recommendation for or against this practice in their updated guidelines.7,8
Imaging studies
Ultrasonography: Ultrasound (US) is the imaging modality of choice for evaluation of the thyroid gland and associated lymph nodes. It is accessible, inexpensive, non-invasive and well tolerated. Surgeon-performed thyroid US is increasingly becoming a standard skill set and it has been shown that surgeon-performed US leads to beneficial changes in diagnosis and management.10 It also affords the clinician the added advantage of an intimate anatomical knowledge of the region to be dissected, which is of particular benefit in re-operative surgery or where selective lymph node dissection is anticipated.
US features that are suspicious for malignancy include microcalcifications, intranodular hypervascularity, hypoechoeic nodules, irregular margins and extracapsular extension (see Box 2.3).
Nuclear medicine studies: Thyroid isotope scanning employs intravenous radiolabelled iodine (131I or 123I) or technetium pertechnetate (99mTc), which are taken up by active thyroid cells and detected by gamma-ray cameras. Isotope scanning may be used in determining the cause of hyperthyroidism, identifying ectopic thyroid tissue or postoperative remnant tissue and detecting metastases of differentiated thyroid cancers. It is also used for surveillance after treatment of differentiated thyroid cancers.
Computed tomography: Computed tomography (CT) scanning gives detailed anatomical definition of the thoracic inlet and associated structures, and is therefore of utility in the management of retrosternal disease. The degree of tracheal compression and distortion of adjacent structures by a bulky retrosternal goitre can be adequately defined (Fig. 2.3). The presence of mediastinal, pulmonary or more distant metastases in thyroid cancer can also be quantified. Often, CT scanning will dictate the surgical approach, with a large retrosternal goitre or low mediastinal metastases being indications for sternotomy. In locally aggressive cancers, CT scanning is a useful modality in assessing invasion of the aerodigestive tract and internal jugular veins (Fig. 2.4).
Tissue diagnosis
The interpretation of FNAC results has recently been standardised with the introduction of the Bethesda classification, which divides FNAC results into six categories (Table 2.4, Fig. 2.5). Each category correlates with an estimated risk of malignancy, which aids surgical decision-making (see section on management of differentiated thyroid cancers).11,12
Figure 2.5 Fine-needle aspiration cytology (FNAC) showing Bethesda II, IV and VI. (a) Bethesda II – abundant colloid with some benign follicular cells arranged as microfollicles or fragments of follicles. (b) Bethesda IV – cytological preparation with high cellularity with scant colloid. The follicular cells are usually in microfollicular or trabecular arrangements. (c) Bethesda VI – nuclei showing prominent pseudo-inclusions and grooves. Images courtesy of Dr Anthony Gill.
Surgical pathologies of the thyroid
Benign goitre
Causes of multinodular goitre:
Iodine deficiency: Goitre is considered endemic when its prevalence in a region is over 10%, and iodine deficiency is the primary cause of endemic MNG. Iodine deficiency is mainly due to a low dietary intake in areas of iodine-poor soil, regardless of altitude. While some of the most severely iodine-deficient regions are high up in the mountains, such as the Pyrenees, the Himalayas and the Cordillera of the Andes, populations in coastal areas, large cities and highly developed countries can also be found to be iodine deficient. The Sydney basin on Australia’s eastern coast is one example.
Genetics: Although no single causative gene with a clear mode of inheritance has been described, the familial clusters and higher concordance rates in monozygotic twins with sporadic MNG point towards a genetic aetiology. Genes implicated in familial goitre include the thyroglobulin gene, the thyroid-stimulating hormone receptor gene, the Na+/I− symporter gene and the MNG marker 1 on chromosome 14. A defect in any of these genes can result in dyshormonogenesis, leading to compensatory goitre formation. Further studies are required for the significance of these genes to be extrapolated to the general population.13
Goitrogens: Thiocyanate is the goitrogen found in cassava and vegetables of the brassica family (e.g. cabbage, Brussels sprouts, cauliflower, mustard and turnip). Their goitrogenic effects are usually seen in areas where these food types are the staple, and especially where the iodine intake is also borderline.14
Pathogenesis: There are two stages in the development of MNG, which may be separated by a long period of time, sometimes as long as decades. The early stimulus for generalised thyroid hyperplasia is most commonly due to iodine deficiency in endemic areas, whereas in sporadic MNG, genetic predisposition or ingested goitrogens may be the stimulus. The second stage of MNG formation is due to focal somatic mutations. Although most of the mutations result in enlarged colloid follicles, focal hyperplasia, hypertrophy, adenoma or even carcinoma can all contribute to the MNG. Over time, these nodules become intersected by areas of fibrosis.15–17
Management of benign MNG: Surgery is the only effective way of treating compressive symptoms of the aerodigestive tract caused by MNG. As such, this constitutes the main indication for surgery. Other indications include MNG with nodules suspicious of malignancy on FNA, toxic MNG and retrosternal goitre.
Total thyroidectomy (TTx) has replaced subtotal thyroidectomy (STTx) as the procedure of choice for benign MNG. The major issue with STTx is recurrence, with long-term follow-up data showing eventual recurrence in up to 50% of patients.18 Furthermore, if secondary surgery is subsequently required for symptomatic recurrent goitre, the risk of complications rises. A significantly higher complication rate has been reported in patients undergoing re-operative thyroidectomy for recurrence after initial STTx, compared to those who had a primary TTx.19
Thyroid cysts
Thyroid cysts are usually benign and account for up to a third of surgically excised solitary thyroid lesions. However, up to 10% of mixed solid and cystic thyroid lesions can be malignant in nature. FNA under US guidance and targeting the solid component of a mixed solid/cystic lesion ensures optimal cellular harvest. Indications for surgery include malignant or suspicious cytology, large cyst (> 4 cm), rapid refill after aspiration, heavily bloodstained aspirate, and a history of head and neck irradiation.20
Malignant conditions
The incidence of thyroid cancer has increased exponentially over the last three or so decades according to data from countries such as Australia, the USA, Canada and France.21–24 This steep rise in incidence is due to increased diagnosis of papillary thyroid carcinoma (PTC), especially microcarcinomas, with mortality due to thyroid cancer remaining consistently low (5-year relative survival of 96%).22,25 Females are four times more likely to be diagnosed with thyroid cancer than males.
Molecular biology of thyroid cancers
The underlying molecular mechanisms that result in thyroid cancer development have gradually been elucidated in the last 20 years. A brief summary is given here.26
Papillary thyroid carcinoma: The molecular studies over the last two decades have led to the observation that PTC is characterised by genetic lesions that activate the mitogen-activated protein kinase (MAPK) signalling pathway. These genetic lesions can be produced by chromosomal rearrangements such as RET/PTC, TRK and AKAP9/BRAF oncogenes, or point mutations such as BRAF and RAS oncogenes.26
The RET proto-oncogene encodes a receptor-type tyrosine kinase. In PTC, RET is mutated by chromosomal rearrangements where the tyrosine kinase domain is fused to a variety of donor genes causing constitutive activation of the tyrosine kinase domain. RET/PTC1 and RET/PTC3 are the commonest combinations, and they account for over 90% of all RET rearrangements in PTC. Tumours with RET/PTC rearrangements are typically of the classical variant of PTC.26
The BRAF protein is the B-isoform of the intracellular Raf kinase within the MAPK signalling cascade. The BRAF gene is mutated in a variety of human cancers, and by far the commonest mutation involves a valine-to-glutamate substitution at residue 600 (BRAFV600E). This substitution results in constitutive activation of Raf kinase and subsequently up-regulation of the MAPK pathway. BRAFV600E is detected in 29–69% of PTC cases, and can be associated with the classical and tall cell variants of PTC, as well as poorly differentiated and anaplastic thyroid carcinomas. Some studies report association of BRAFV600E with more aggressive clinicopathological features; however, this view is not universal.26
Follicular thyroid carcinoma: The common genetic mutations associated with FTCs are RAS mutations, PAX8/PPAR-γ rearrangement and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway deregulation.
Oncogenic mutations may involve any of the three members of the RAS gene family. RAS mutations reportedly occur in up to 50% of FTCs, 40% of follicular adenomas, 25% of Hurthle cell carcinomas (HCCs) and 20% of follicular variant PTCs. They are also seen frequently in PDTC and ATC. The presence of RAS mutations in follicular adenomas is a clue to the adenoma–carcinoma sequence in the pathogenesis of FTCs. Significant correlation between RAS mutations to metastases and poor prognosis has been found.26
The PAX8/PPAR-γ rearrangement results in a fusion of the DNA-binding domain of PAX8 to the peroxisome proliferator-activated receptor PPAR-γ. The fusion protein stimulates proliferation of thyrocytes by an unknown mechanism. The PI3K/Akt pathway is central for many cellular events such as growth, proliferation and apoptosis. Its constitutive activation by mutations is a common feature in many cancers, including FTC.26
Differentiated thyroid cancers (PTC and FTC)
Risk factors: The most well-established environmental risk factor for thyroid cancer is exposure to ionising radiation.27 PTC is the type of thyroid cancer that is associated with radiation exposure, which induces damage to cellular DNA, commonly causing RET/PTC chromosomal rearrangements. The effect is most pronounced in children, and the latency period ranges from 5 to 30 years. In a patient with a history of radiation exposure, the overall risk of malignancy in a nodule is 30–40%; therefore, an initial TTx is recommended.28
No susceptibility gene for hereditary non-medullary thyroid cancer (HNMTC) has been identified; however, epidemiological studies have shown that they are more aggressive than sporadic disease. The risk of developing thyroid cancer is 5 to 10 times higher in patients with a first-degree relative who has thyroid cancer, when compared to the general population. Features such as early age at presentation, reversed gender distribution, large tumour size, tumour multicentricity and aggressive tumour biology are clues to suspect such a kindred. Until specific gene(s) are identified, a detailed family history is the only way to identify these at-risk families. HNMTC may also be part of another familial syndrome, such as familial adenomatous polyposis (APC), Cowden syndrome (PTEN), Carney complex type 1 (PRKAR1α), McCune–Albright syndrome (GNAS1) and Werner syndrome (WRN) (see Chapter 4 for further details).29
Papillary thyroid carcinoma: Papillary thyroid carcinoma is an epithelial malignant tumour of the thyroid gland, which still retains follicular cell differentiation and is characterised by unique nuclear features. The nuclei typically show a clear or ground-glass appearance, and irregularities of the nuclear contours can often be seen as nuclear grooves and pseudo-inclusions.30
Papillary thyroid microcarcinoma (PTMC) is defined by the World Health Organisation (WHO) as a PTC that is 1.0 cm or less in largest dimension.30 Its prevalence in autopsy series varies widely, from 6–7% in the USA to 35% in Finland.31 It is being diagnosed with increasing frequency due to the widespread use of US and FNA biopsy, as well as the improved resolution of ultrasonography.32,33 This increase has contributed significantly to the overall increase in incidence of newly diagnosed PTC.25 The prognosis for this group of patients had been shown to be excellent in a large study, despite 30% nodal involvement on presentation.34 A study from the Mayo Clinic also showed that PTMC does not affect overall survival, and that neither postoperative radioactive iodine (RAI) nor total thyroidectomy (or completion thyroidectomy) reduced recurrence rates compared to unilateral lobectomy. However, multifocal tumours and nodal positivity were predictors of recurrence.34
The follicular variant of PTC can be a challenge for pathologists to diagnose accurately. This variant displays follicular architecture, but retains the nuclear features of PTC (Fig. 2.6). It can be confused with follicular adenoma or carcinoma. However, it is important to distinguish the follicular variant of PTC from FTC because the prognosis of these patients is similar to that of patients with PTC rather than FTC.
Figure 2.6 Follicular variant of PTC histology. Although the cells show follicular architecture, the nuclei features are diagnostic of PTC. Examples of nuclear clearing (‘orphan Annie eyes’) are shown by blue arrows, nuclear grooving by yellow arrows and follicular architecture by white arrows. Image courtesy of Dr Anthony Gill.
The tall cell variant is an uncommon variant that is usually found in older patients. It has a more aggressive clinical behaviour, and is often associated with necrosis, mitotic activity and extrathyroidal extension (which are all aggressive features). Columnar and diffuse sclerosing variants are two other variants associated with more aggressive disease behaviour.30
Follicular thyroid carcinoma: Like PTC, FTC is a malignancy of the epithelial follicular cells. However, unlike PTC, it lacks diagnostic nuclear features, so the diagnosis of FTC can only be made on histological examination (Fig. 2.7). Aspirates that are hypercellular, with a microfollicular pattern and scant colloid, suggest follicular neoplasm (adenoma or carcinoma). FTC can only be diagnosed by histological confirmation of capsular invasion and/or vascular invasion. The main variants are conventional or oncocytic types. The oncocytic type is also known as Hurthle cell carcinoma.
Staging: As many as 17 staging and prognostic systems for DTC have been reported in the literature since 1979.35 The sixth edition AJCC/IUCC staging system is currently one of the most commonly used systems. Other commonly used systems include AMES (Age, Metastasis, Extent, Size) from the Lahey Clinic, AGES (Age, Grade, Extent, Size) and MACIS (Metastasis, Age, Completeness of resection, Invasion, Size) from the Mayo Clinic, and EORTC staging from the European Organisation for Research and Treatment of Cancer. Some interesting observations can be made from these systems. Like all other staging systems, pathological features such as tumour size, grade, extent and presence of metastasis feature uniformly throughout the different classification systems. However, nodal status is notably absent in many of these systems apart from the AJCC system. This relates to the fact that these systems were mostly developed to predict disease-specific survival, and so far most studies do not correlate nodal status with survival, although the evidence is not conclusive at this stage. This must be borne in mind when using these prognostic systems during patient follow-up for recurrence. The ATA published a three-tier risk stratification that is useful for the purpose of surveillance (Table 2.5). Another unique factor in the AJCC staging for DTC is the inclusion of age. Patients under the age of 45 have excellent prognosis regardless of nodal status, and a small decrease in survival in the presence of metastases. As such, the highest stage for patients under 45 years of age is Stage II.
Table 2.5
ATA risk stratification for DTC8
