55 T_h e thyroid gland

Benign tumours
Calcitonin
Clinical features of thyroid cancers
Clinically discrete swellings
Diagnosis of thyroid neoplasms
EMBRYOLOGY
FURTHER READING
Follicular carcinoma
Granulomatous thyroiditis (subacute thyroiditis, d
Granulomatous thyroiditis (subacute thyroiditis, de Quervain’s thyroiditis)
HYPERTHYROIDISM Thyrotoxicosis
Introduction
Isotope scanning
Learning objectives
Malignant lymphoma
Malignant tumours
Medullary carcinoma
NEOPLASMS OF THE THYROID
PHYSIOLOGY Thyroxine
Prognosis in differentiated thyroid carcinoma
SURGICAL ANATOMY
Serum thyroid hormones
Simple goitre
Surgery for thyrotoxicosis
Surgical treatment for differentiated thyroid canc
Surgical treatment for differentiated thyroid cancer
THYROID ENLARGEMENT
THYROIDITIS Chronic lymphocytic (autoimmune) thyro
THYROIDITIS Chronic lymphocytic (autoimmune) thyroiditis (Hashimoto’s disease)
Thyroid autoantibodies
Thyroid imaging
Thyroid-stimulating antibodies
Treatment
Undifferentiated (anaplastic) carcinoma

Benign tumours

Follicular adenomas present as clinically solitary nodules us ( Figure 55.21 ) and the distinction between a follicular - carcinoma and an adenoma can only be made by histological examination; in the adenoma there is no invasion of the capsule or of pericapsular blood vessels. For this reason, FNA, which provides cytological detail but not tissue architecture, cannot di ﬀ erentiate between benign and malignant follicular lesions. Diagnosis and treatment is, therefore, by wide excision, i.e. total lobectomy . The remaining thyroid tissue is normal so that prolonged follow-up is unnecessary . - Benign tumours

Calcitonin

The parafollicular C cells of the thyroid are of neuroendocrine origin and arrive in the thyroid via the ultimobranchial body ( Figure 55.1 ). They produce calcitonin. Sir James Berry , 1860–1946, surgeon, Royal Free Hospital, London, UK. Oliver H Beahrs , 1914–2006, surgeon, Mayo Clinic, Rochester, MN, USA. Emil Zuckerkandl , 1849–1901, Austro-Hungarian anatomist, brother of urologist Otto Zuckerkandl. Myxoedema was ﬁrst described in 1873 by Sir William Withey Gull, 1816–1890, physician, Guy’s Hospital, London, UK. Synthesis and release of thyroid hormones from the thyroid is controlled by thyroid-stimulating hormone (TSH) from the - anterior pituitary . Secretion of TSH depends upon the level of circulating thyroid hormones and is modiﬁed in a nega - tive feedback manner. In hyperthyroidism TSH production is suppressed, whereas in hypothyroidism it is stimulated. , Regulation of TSH secretion also results from the action of thyrotr ophin-releasing hormone (TRH) produced in the hypothalamus.

TABLE 55.1 Results of thyroid function tests in normal and pathological states. Thyroid functional state TSH (0.3–3.3 /uni00A0 mU/L) Euthyroid Normal Thyrotoxic Undetectable Myxoedema High Suppressive T therapy Undetectable 4 T toxicity Low/undetectable 3 T , tri-iodothyronine; T , L -thyroxine; TSH, thyroid-stimulating hormone. 3 4

Calcitonin

Clinical features of thyroid cancers

The annual incidence is about 0.8 per million of the popula tion and the sex ratio is three females to one male. However, the incidence of PTC is increasing rapidly across the world. This Karl Hürthle , 1866–1945, histopathologist, Breslau, Germany (now Wroc ł aw , Poland). is mostly due to increased rates of imaging detecting previ - - ously occult disease. For that reason, although the incidence is increasing, the mortality rates remain static at over 80% 5-year survival for all groups. In particular, anaplastic carcinoma es predicts poor outcome with di ﬀ er entiated carcinomas gener - ally having excellent outcomes. The most common presenting - symptom is a thyroid swelling ( Figures 55.21 and 55.23 ). Enlarged cervical lymph nodes may be the presenta tion of PTC. RLN paralysis is very suggestive of locally advanced disease. - - - -

Figure 55.22 Metastasis in the humerus from thyroid carcinoma (courtesy of DS Devadatta, Vellore, India). Figure 55.23 Follicular neoplasm of the thyroid presenting as an isolated swelling.

ing. A di ﬀ erentiated carcinoma may be suspiciously ﬁrm and irregular, but is often indistinguishable from a benign swelling. Small papillary tumours may be impalpable, even when lym pha tic metastases are present. Pain, often referred to the ear, is suggestive of nerve involvement from inﬁltrating tumours. Clinical features of thyroid cancers

Figure 55.22 Metastasis in the humerus from thyroid carcinoma (courtesy of DS Devadatta, Vellore, India). Figure 55.23 Follicular neoplasm of the thyroid presenting as an isolated swelling.

Clinically discrete swellings

Discrete thyroid swellings (thyroid nodules) are common and are palpable in 3–4% of the adult population in the UK and USA. They are three to four times more frequent in women than in men. Diagnosis A discrete swelling in an otherwise impalpable gland is termed isolated or solitary , whereas the preferred term is dominant for a similar swelling in a gland with clinical evidence of gener - alised abnormality in the form of a palpable contralateral lobe - or generalised mild nodularity . About 70% of discrete thyroid swellings are clinically isolated and about 30% are dominant. The true incidence of isolated swellings is somewhat less than the clinical estimate. Clinical classiﬁca tion is inevitably subjec - tive and overestimates the frequency of truly isolated swellings. When such a gland is exposed at operation or examined by ultrasonography , CT or MRI, clinically impalpable nodules are often detected. The true frequency of thyroid nodularity compar ed with the clinical detection rate by palpation is shown in Figure 55.12 . Demonstrating the presence of impalpable nodules does not change the management of palpable discrete swellings and begs the question of the necessity of investigating incidentally found nodules. The importance of discrete swellings lies in the risk of neoplasia compared with other thyroid swellings. Some 15% of isolated swellings prove to be malignant and an additional 30–40% are follicular adenomas. The remain der are non-neoplastic, largely consisting of areas of colloid degeneration, thyroiditis or cysts. Although the incidence of malignancy or follicular adenoma in clinically dominant swell ings is approximately half of that of truly isolated swellings, it is substantial and cannot be ignored ( Figure 55.13 ). Investigation Thyroid function Serum TSH and thyroid hormone levels should be measured. If hyperthyroidism associated with a discrete swelling is conﬁrmed biochemically , it indicates either a ‘toxic adenoma’ or a manifestation of toxic multinodular goitre. The combina tion of toxicity and nodularity is important and is an indication for isotope scanning to localise the area(s) of hyperfunction. Autoantibody titres The autoantibody status may determine whether a swelling is a manifestation of chronic lymphocytic thyroiditis. The presence of circulating antibodies increases the risk of thyroid failure after lobectomy . Isotope scan Isotope scanning used to be the mainstay of investigation of discrete thyroid swellings but has been abandoned except when toxicity is associated with nodularity . Ultrasonography This is used to determine the physical characteristics of thyroid swellings. There are a number of ultrasonographic features in a thyroid swelling associated with thyroid neoplasia, including microcalciﬁcation and increased vascularity , but only macro scopic capsular breach and nodal involvement are diagnostic of malignancy . Ultrasonography should be used as the primary investigation of any thyroid nodule as a reassuring appearance Ernest L Mazzaferri , 1936–2013, endocrinologist, Ohio State University School of Medicine, Columbus, OH, USA. - - - mitigates the need for FNAC (see Fine-needle aspiration cytology ). Fine-needle aspiration cytology FNAC should be used, ideally under ultrasound guidance, on all nodules that do not fulﬁl a fully benign (U2) classiﬁcation on ultrasonography . FNAC is reliable in identifying papillary thyroid carcinoma (PTC) but cannot distinguish between a benign follicular adenoma ( Figure 55.14 ) and follicular carcinoma, as this distinction is dependent not on cytology but on histological criteria, which include capsular and vascular invasion. FNAC is both highly speciﬁc and sensitive. Using ultraso - nography improves this further, particularly in part cystic, part solid nodules in which ultrasonography allows targeting of the solid element for biopsy . Radiology Plain ﬁlms have previously been used to assess tracheal - compression and deviation, but the modality of choice now is CT scanning. CT scanning is also useful if ultrasonography has identiﬁed metastatic disease in the neck as it can assist surgical planning and also assess the superior mediastinum and lungs.

60 50 40 30 Prevalence 20 10 0 10 20 30 40 50 60 Age (years) Figure 55.12 The prevalence of thyroid nodules detected on palpation (dashed line) or by ultrasonography or postmortem examination (solid line) (after Mazzaferri). thyroid swelling Solid Cystic 24% 12% Male Female Female Male 48% 12% 6% 24% Dominant thyroid swelling Cystic Solid 6% 12% Male Male Female Female 12% 24% 3% 6% Generalised thyroid swelling 3% Figure 55.13 The risk of malignancy in thyroid swellings (‘rule of 12’). The risk of cancer in a thyroid swelling can be expressed as a factor of 12. The risk is greater in isolated versus dominant swellings, solid versus cystic swellings and in men versus women.

Laryngoscopy Flexible laryngoscopy has rendered indirect laryngoscopy obsolete and is widely used preoperatively to determine the mobility of the vocal cords. The presence of a unilateral cord palsy coexisting with an ipsilateral thyroid nodule of concern is usually diagnostic of malignant disease. Core biopsy Core biopsy is rarely indicated in thyroid masses owing to the vascularity of the thyroid gland and the risk of postprocedure haemorrhage. It can be useful in the rapid diagnosis of widely invasive malignant disease, for example anaplastic carcinoma, or in the diagnosis of lymphadenopathy . Indication for surgery The main indication for operation is the risk of neoplasia, which includes follicular adenoma as well as malignant swell ings. The reason for advocating the removal of all follicular neoplasms is that it is seldom possible to distinguish between a follicular adenoma and carcinoma cytologically . Even when the cytology is negative, the age and sex of the patient and the size of the sw elling may be relative indications for surgery , especially when a large swelling is responsible for symptoms. There are useful clinical criteria to assist in selection for operation according to the risk of neoplasia and malignancy . Hard texture alone is not reliable as tense cystic swellings may be suspiciously har d but a hard, irregular swelling with any apparent ﬁxity , which is unusual, is highly suspicious. Evidence of RLN paralysis, suggested by hoarseness and a non-occlusive cough and conﬁrmed by laryngoscopy , is almost pathogno monic. Cervical lymphadenopathy along the internal jugular vein in association with a clinically suspicious swelling is almost diagnostic of PTC. In most patients, however, suc h features are absent. The incidence of thyroid carcinoma in women is about three times that in men, but a discrete swelling in a male is much more likely to be malignant than in a female. The risk of carcinoma is increased at either end of the age range and a discrete swelling in a teenager of either sex must be provision ally diagnosed as carcinoma. Thyroid cysts Routine FNAC (or ultrasonography) shows that over 30% of clinically isolated swellings contain ﬂuid and are cystic or partly cystic. Tense cysts may be hard and mimic carcinoma. Bleeding into a cyst often presents with a history of sudden painful swell - ing, which resolves to a variable extent over a period of weeks if untreated. Aspiration yields altered blood but reaccumulation is frequent. About 55% of cystic swellings are the result of colloid degeneration or are of uncertain aetiology because of - an absence of epithelial cells in the lining. Although most of the remainder are the result of involution in follicular adenomas ( Figure 55.15 ), some 10–15% of cystic follicular swellings are histologically malignant (30% in men and 10% in women). PTC is often associated with cyst formation ( Figure 55.16 ). Most patients with discrete swellings, however, are women, aged 20–40 years, in whom the risk of malignancy , although signiﬁcant, is low and the indications for operation are not clear-cut. Ultrasonography is the most useful tool f or assessing cysts. If there is no discernible solid element, the cyst is almost certainly benign and does not need to be further investigated. As stated above, simple aspiration is associated with high rates - of reaccumula tion. However, ablation using either ethanol or thermal probes (radiofrequency , microwave, laser or high- frequency ultrasound) achieves cyst resolution in up to 90% of cases and should be considered for recurrent, symptomatic cysts. If there is an associated solid element, then consideration should be given to targeting that area with ultrasound-guided FNAC. The indications for operation in isolated or dominant thy - - roid swellings are listed in Table 55.4 .

Figure 55.14 Thy3 aspiration cytology ( Table 55.2 ). Follicular neo plasm showing increased cellularity with a follicular pattern. Figure 55.15 Apparently simple cystic thyroid swelling, the wall of which comprised follicular neoplastic tissue.

Figure 55.16 Cyst formation in a papillary carcinoma.

/uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF Selection of thyroid procedure The choice of thyroid operation depends on: /uni25CF diagnosis (if known preoperatively); /uni25CF risk of thyroid failure; /uni25CF risk of RLN injury; /uni25CF risk of recurrence; /uni25CF Graves’ disease; /uni25CF multinodular goitre; /uni25CF di ﬀ erentiated thyroid cancer; /uni25CF risk of hypoparathyroidism. Total and near-total thyroidectomy do not conserve suf ﬁcient thyroid tissue for normal thyroid function and thyroid replacement therapy is necessary . In two-thirds of patients with negative antithyroid antibodies , one thyroid lobe will maintain normal function. Subtotal resections for colloid goitre or Graves’ disease run the risk of later growth of the remnant and, if a second operation is required years later, this greatly increases the risk to the RLN and parathyroid glands. In young patients, total thyroidectomy should be considered. It may be preferable to leave the least a ﬀ ected lobe untouched to permit a straightfor ward lobectomy in the future if required, rather than carry out subtotal resections. In Graves’ disease, preserving large remnants increases the risk of recurrence of the toxicity and, in these cases, it is better to err on the side of r emoving too much thyroid tissue rather than too little ( Table 55.5 ). Thyroid failure should not be regarded as a failure of treatment, but recurrent toxicity is. thyroidectomy in di ﬀ erentiated thyroid cancer are discussed below . Summary box 55.2 Thyroid operations Retrosternal goitre Retrosternal goitre tends to arise from the slow growth of a multinodular gland down into the mediastinum. As the gland enlarges within the thoracic inlet, pressure may lead to dyspha - gia, tracheal compression and eventually airway symptoms. The vast majority of patients have minimal symptoms. Patients should be considered for surgery if there is signiﬁcant airway compression, if symptoms are present or in young patients - in whom symptoms are likely to develop. In elderly patients with incidentally discovered retrosternal goitres, most surgeons would observe rather than treat prophylactically . Clearly a balance between risk and beneﬁt must be made. If a decision is made to proceed to surgery , assessment of the extent of disease is critical. The vast majority (>95%) of retrosternal goitres can be removed transcervically . Patients most at risk of requiring conv ersion to an open sternotomy approach include those with malignant disease or who are undergoing revision, those whose goitres that extend into the - posterior mediastinum and those in whom the diameter of the goitre exceeds that of the thoracic inlet. In such cases a joint case with thoracic surgery should be planned. All patients should have cross-sectional imaging. Ideally this is performed in the surgical position and, when interpret - ing CT chest scans, the surgeon should pay attention to the arm position. If the arms are up (as for standard CT c hest)

Neoplasia FNAC positive Thy3–5 Clinical Age suspicion Male sex Hard texture Fixity Recurrent laryngeal nerve palsy Lymphadenopathy Recurrent cyst Toxic adenoma Pressure symptoms Cosmesis Patient’s wishes FNAC, /f_i ne-needle aspiration cytology; Thy3–5, see Table 55.2 TABLE 55.5 Comparison of surgical options for Graves’ disease. Total thyroidectomy Control of toxicity Immediate Return to euthyroid state Immediate Risk of recurrence None Risk of thyroid failure 100% Risk of permanent hypoparathyroidism 5% Need for follow-up Minimal a The risks of recurrence and late failure are a function of the size of the remnant as a proportion of the total gland weight. Large remnants in small glands have a higher risk of recurrence and a low risk of failure, and small remnants in large glands have a higher risk of thyroid failure but a low risk of recurrence. All thyroid operations can be assembled from three basic elements: 1. Total lobectomy 2. Isthmusectomy 3. Subtotal lobectomy Total thyroidectomy = 2 × total lobectomy + isthmusectomy Subtotal thyroidectomy = 2 × subtotal lobectomy + . isthmusectomy Near-total thyroidectomy = total lobectomy + isthmusectomy + subtotal lobectomy (Dunhill procedure) Lobectomy = total lobectomy + isthmusectomy Subtotal thyroidectomy Immediate Variable – up to 12 months a Lifelong – up to 5% a Lifelong – up to 100% at 30 years 1% Lifelong

pared with when the arms are down and the neck extended. The approach to surgery is as described in Surgical tech nique of thyroidectomy . A longer incision is required. The surgeon may mobilise the sternomastoid muscle from the strap muscles to improve access . The ligamentous tissue between the sternal heads of the clavicles may be gently divided to increase the opening for gland delivery . Blunt dissection on the capsule of the gland allows mobilisation. Gentle traction is applied to deliver the gland into the neck. If the goitre has developed from a posteriorly positioned nodule there is a risk that the RLN may be displaced anteriorly , so great care must be taken in dividing apparent fascial bands that overlie the gland. The blood supply is from the neck, reducing the risk of catastrophic bleeding from the great vessels. Nonetheless, care should be taken in the region of the major blood vessels in the neck and chest. If the gland is ﬁxed and immobile or too large to deliver through a cervical approach, a midline sternotomy is per formed and the gland can be dissected from below to achieve a safe total thyroidectomy . Clinically discrete swellings

Figure 55.14 Thy3 aspiration cytology ( Table 55.2 ). Follicular neo plasm showing increased cellularity with a follicular pattern. Figure 55.15 Apparently simple cystic thyroid swelling, the wall of which comprised follicular neoplastic tissue.

Figure 55.16 Cyst formation in a papillary carcinoma.

Diagnosis of thyroid neoplasms

Clinical history and examination continue to be the cornerstone of diagnosis of thyroid neoplasms. As previously mentioned, radiation exposure and family history should be discussed. Examination of the central neck and regional lymphatics should be combined with assessment of vocal cord function. Biochemical assessment of thyroid function should also be considered in this ﬁrst encounter, if not already performed. Following initial assessment, the next step is ultrasonogra phy . This non-invasive investigation is most accurate at assess ing thyroid swellings. Not only can a judgement be made on the presence, size and number of thyroid nodules present, but an estimate of risk of malignancy can be made depending on these ﬁndings. Following ultrasonog raphy , lesions can be categorised as benign, indeterminate or malignant. Benign lesions require no further assessment unless surgery is considered for compres sive symptoms. Indeterminate or malignant lesions should be investiga ted with FNAC. Occasionally , the surgeon will encounter a thyrotoxic patient. Such cases are one of the few indications for a radio iodine uptake scan. This allows assessment of the function of a nodule. Hot nodules are very rarely malignant. Cold nodules will require assessment as f or all other thyroid neoplasms. Following clinical, ultrasonographic and cytological assess ment, the vast majority of lesions will be characterised as benign, malignant or indeterminate. Further treatment will be planned accordingly . Certain situations require speciﬁc consideration. For patients with widespread nodal disease or suspicion of locally inv asive disease a ﬀ ecting the airway , contrast-enhanced imag ing should be considered. This should cover the neck and chest. This not only allows accurate assessment of any visceral invasion, but is superior to ultrasonography at deﬁning dis ease in the mediastinum and thorax. Concerns o ver the impact of iodine-containing contrast on delays to radioactive iodine therapy have been overplayed, and it is more critical that the surgeon has an accurate assessment of disease extent prior to sur gery . Patients with a rapidly growing thyroid mass, particularly if solid and ﬁxed, should be considered at risk of anaplastic car cinoma. However, this diagnosis can be di ﬃ cult to di ﬀ erentiate from thyroid lymphoma or occasionally thyroiditis. Despite the di ﬃ culty , an accurate diagnosis is critical as anaplastic carci noma is rapidly fatal and palliative measures are generally recommended, wher eas confounding disease processes may respond to therapy . In this setting, core or even open biopsy may be required to make a conﬁdent diagnosis. Max Askanazy , 1865–1940, Professor of Pathology , Geneva, Switzerland PTC is the most common thyroid malignancy . Interestingly , up to 30% of patients who die of non-thyroid disease have - deposits of PTC in autopsy studies, suggesting that many patients live with this disease undetected. Nonetheless, when PTC is diagnosed most patients will be o ﬀ ered treatment. The disease is known for its propensity for lymph node metastases. These are more common in younger patients, in whom they do not a ﬀ ect the otherwise excellent survival. This ﬁnding is in contrast to most malignancies, where the ﬁnding of metastatic disease confers a poor outcome. One contentious ﬁnding in patients with PTC is a high rate of occult micrometastases (as high as 40% of N0 patients in the central neck). Despite the presence of metastases, few patients progress to have clinically meaningful disease and the role of elective nodal surgery is in question. Distant metastases are uncommon in PTC. Recently , increasing interest has focused on ‘papillary - microcarcinoma’. This term is used to describe PTC that is - <10 /uni00A0 mm in size. These lesions are common (detected in about 10% of benign thyroid resections) and not associated with adverse outcomes, including recurrence or non-survival. As such, management and follow-up of patients with these lesions of doubtful clinical signiﬁcance is controversial. In Korea, for example, national screening has led to a signiﬁcant increase in these cases. In Japan groups are opting for an observational - approach without surgery . These studies have shown that at least two-thirds never progress. In the USA some groups are attempting non-surgical management with ablation techniques using ethanol or radiofrequency . In most of the world, however, - groups try to avoid diagnosing these small, insigniﬁcant lesions by limiting biopsies to >10 /uni00A0 mm lesions and being conservative in the management of lesions following their diagnosis. - Diagnosis of thyroid neoplasms

EMBRYOLOGY

The embryology of the thyroid and parathyroid glands underlies the anatomical position, anatomical variations and congenital conditions of these structures; it is therefore vital for surgery ( Figure 55.1 ). The thyroglossal duct develops from the median bud of the pharynx. The foramen caecum at the junc tion of the anterior two-thirds and posterior one-third of the tongue is the vestigial remnant of the duct. This initially hollow Delphi , a sacred site near the Gulf of Corinth in Greece, is the place where Pythia, the snake-woman oracle, resided. She sat on a tripod clutching the ribbons of the monolithic ‘omphalos’ of the world and, after inhaling sulphurous fumes, would utter meaningless jargon, which was interpreted equivocally by the attendant priests for those who came to consult her. Formerly the purpose of these lymph nodes was uncertain, and they were therefore called ‘Delphic’. structure migrates caudally and passes in close continuity with, and sometimes through, the developing hyoid cartilage. The parathyroid glands develop from the third and fourth pharyn - geal pouches. The thymus also develops from the third pouch. As it descends, the thymus takes the associated parathyroid gland with it, which explains wh y the inferior parathyroid, - which arises from the third pharyngeal pouch, normally lies inferior to the superior gland. However, the inferior para - thyroid may be found anywhere along this line of descent (see also Chapter 56 ). The developing thyroid lobes amalgamate with the structures that arise in the fourth pharyngeal pouc h, i.e. the superior parathyroid gland and the ultimobranchial body . Parafollicular cells (C cells) from the neural crest reach the thyroid via the ultimobranchial body .

Buccal cavity Thyroid II III IPG Path of Thymus descent of thyroid IV SPG Path of UBB descent of IPG and thymus Tracheo-oesophageal tube Figure 55.1 Embryology of the thyroid and parathyroid. Diagram of an anterior view of the pharynx in a 4-week embryo showing the relation ship of the third and fourth pharyngeal pouches to the /f_i nal position of the thyroid and parathyr oid glands. IPG, inferior parathyroid; SPG, superior parathyroid; UBB, ultimobranchial body. To be able to select appropriate investigations for thyroid • swellings To know when to operate on a thyroid swelling • To describe thyroidectomy • To know the risks and complications of thyroid surgery •

EMBRYOLOGY

Follicular carcinoma

Follicular carcinoma can normally only be di ﬀ erentiated from follicular adenoma by the architecture on histology . For this reason, follicular lesions on FNA are unable to be diagnosed as malignant in the absence of clinical features such as metastases - ( Figure 55.24 ). Multiple foci of follicular carcinoma are seldom seen and lymph node involvement is much less common than in PTC. Blood-borne metastases are more common and the - eventual mortality rate, although still low , is twice that of PTC ( Figure 55.25 ). Hürthle cell tumours are a rare variant of follicular neo - plasm in which oxyphil (Hürthle, Askanazy) cells predominate histologically . Hürthle cell cancers are associated with a poor prognosis. - Follicular carcinoma

Granulomatous thyroiditis (subacute thyroiditis, d

Granulomatous thyroiditis (subacute thyroiditis, de Quervain’s thyroiditis)

This may follow a viral infection. In a typical subacute presen tation, there is pain in the neck, fever, malaise and a ﬁrm, irregular enlargement of one or both thyroid lobes. There are tory markers, absent thyroid antibodies, the raised inﬂamma 123 is high normal or slightly raised and the I uptake serum T 4 of the gland is low . The condition is self-limiting and, in a few months, the goitre subsides and there may be a period of months of hypothyroidism before eventual recovery . In 10% of cases the onset is acute, the goitre is very painful and tender and there may be symptoms of hyperthyroidism. One-third of cases are asymptomatic but for the presence of diagnosis is in doubt, it may be conﬁrmed by the goitre. If FNAC, radioactive iodine uptake and a rapid symptomatic response to prednisone. The speciﬁc treatment for the acute patient with severe pain is to give prednisone l0–20 /uni00A0 mg daily for 7 days and the dose is then gradually reduced over the next month. If thyroid failure is prominent, treatment with thyrox ine may be required until function recovers. This is very rare, accounting for 0.5% of goitres. Thyroid tissue is replaced by cellular ﬁbrous tissue, which inﬁltrates through the capsule into muscles and adjacent structures, including parathyroids, recurrent nerves and the carotid sheath. It may occur in association with retroperitoneal and mediastinal ﬁbrosis and is most probably a collagen disease. The goitre may be unilateral or bilateral and is very hard and ﬁxed. The di ﬀ er - ential diagnosis from anaplastic carcinoma can be made with certainty only by biopsy , when a wedge of the isthmus should also be removed to free the trachea. If unilateral, the other ypothyroidism lobe is usually involved later and subsequent h is common. Treatment is with high-dose steroids, tamoxifen and thyroxine replacement. Reduction in the size of the goitre and long-term improvement in symptoms are to be expected if treatment is commenced early .

Granulomatous thyroiditis (subacute thyroiditis, de Quervain’s thyroiditis)

HYPERTHYROIDISM Thyrotoxicosis

The term thyrotoxicosis is retained because hyperthyroidism, i.e. symptoms due to a raised level of circulating thyroid hormones, is not responsible for all manifestations of the disease. Clinical types are: /uni25CF di ﬀ use toxic goitre (Graves’ disease); /uni25CF toxic nodular goitre; /uni25CF toxic nodule; /uni25CF hyperthyroidism due to rarer causes. Diffuse toxic goitre Graves’ disease, a di ﬀ use vascular goitre appearing at the same time as hyperthyroidism, usually occurs in younger women and is frequently associated with eye signs ( Figure 55.17 syndrome is that of primary thyrotoxicosis; 55% of patients have a family history of autoimmune endocrine diseases. The whole of the functioning thyroid tissue is involved, and the hypertrophy and hyperplasia are due to abnormal TSH-RAb that bind to TSH receptor sites and produce a disproportionate and prolonged e ﬀ ect. Toxic nodular goitre A simple nodular goitre is present for a long time before the hyperthyroidism, usually in the middle-aged or elderly , and very infrequently is associated with eye signs. The syndrome is that of secondary thyrotoxicosis. In many cases of toxic nodular goitre, the nodules are inactive, and it is the internodular thyroid tissue that is overactive. However, in some toxic nodular goitr es, one or more nodules are overactive and here the hyperthyroidism is due to autonomous thyroid tissue as in a toxic adenoma. Toxic nodule A toxic nodule is a solitary overactive nodule, which may be part of a generalised nodularity or a true toxic adenoma. It is - - autonomous and its hypertrophy and hyperplasia are not due to TSH-RAb. TSH secretion is suppressed by the high level of circulating thyroid hormones and the normal thyroid tissue surrounding the nodule is itself suppressed and inactive. Histology The normal thyroid gland consists of acini lined with ﬂattened cuboidal epithelium and ﬁlled with homogeneous colloid ( Figure 55.2 ). In hyperthyroidism ( Figure 55.18 ), there is hyperplasia of acini, which are lined by high columnar epithelium. Many of them are empty , and others contain vacuolated colloid with a characteristic ‘scalloped’ pattern adjacent to the thyrocytes. Principles of treatment of thyrotoxicosis Non-speciﬁc measures are rest and sedation and in established thyrotoxicosis should be used only in conjunction with speciﬁc measures, i.e. the use of antithyroid drugs, surgery and radio - iodine. ). The Antithyroid drugs Those in common use are carbimazole and propylthiouracil. Antithyroid drugs are used to restore the patient to a euthyroid

Figure 55.17 Graves’ disease. Figure 55.18 Histology of thyrotoxicosis.

that a permanent remission will occur, i.e. that production of TSH-RAb will diminish or cease. Antithyroid drugs cannot cure a toxic nodule. The overactive thyroid tissue is autono mous and recurrence of the hyperthyroidism is certain when the drug is discontinued. /uni25CF Advantages . No surgery and no use of radioactive mate rials. /uni25CF Disadvantages . Treatment is prolonged and the failure rate is at least 55%. The duration of treatment may be tailored to the severity of the toxicity , with milder cases being treated for only 6 months and severe cases for 2 years before stopping therapy . Surgery In di ﬀ use toxic goitre and toxic nodular goitre with overactive internodular tissue, surgery cures by reducing the mass of overactive tissue by reducing the thyroid below a critical mass. After subtotal thyroidectomy the patient should return to a euthyroid state, albeit after a variable period of hypothyroid ism. There are, however, long-term risks of recurrence and eventual thyroid failure. In contrast total/near-total thyroidec tomy accepts immediate thyroid failure and lifelong th yroxine replacement to eliminate the risk of recurrence and simplify follow-up . Operation may result in a reduction in TSH-RAb. In the autonomous toxic nodule, and in toxic nodular goitre with overactive autonomous toxic nodules, surgery cures by removing all the overactive thyroid tissue; this allows the suppressed normal tissue to function again. /uni25CF Advantages . The goitre is removed, the cure is rapid and the cure rate is high if surgery has been adequate. /uni25CF Disadvantages . Recurrence of thyrotoxicosis occurs in at least 5% of cases when subtotal thyroidectomy is carried out. There is a risk of permanent hypoparathyroidism and nerve injury . Y oung women tend to have a poorer cosmetic result from the scar. Every operation carries a risk, but with suitable preparation and an experienced surgeon the mortality is negligible and the morbidity low . Radioiodine Radioiodine destroys thyroid cells and, as in thyroidectomy , reduces the mass of functioning thyroid tissue to below a critical level. /uni25CF Advantages . No surgery and no prolonged drug therapy . /uni25CF Disadvantages . Isotope facilities must be available. The patient must be quarantined while radiation levels are high and avoid pregnancy and close physical contact, particu larly with children. Eye signs may be aggravated. Choice of therapy Each case must be considered individually . Below are listed guiding principles on the most satisfactory treatment for a particular toxic goitre at a particular age; these must, however, be modiﬁed according to the facilities available and the personality and wishes of the individual patient and any other coexistent medical or surgical condition. Access to can be important considerations in some areas. Diffuse toxic goitre - Most patients have an initial course of antithyroid drugs with radioiodine for relapse. Exceptions are those who refuse radia - tion, those who have large goitres or progressive eye signs and - those who are pregnant. Toxic nodular goitre Toxic nodular goitre is often large and uncomfortable and enlarges still further with antithyroid drugs. Large goitres should be treated surgically because they do not respond as well or as rapidly to radioiodine or antithyroid drugs as does a di ﬀ use toxic goitre. Toxic nodule Surgery or radioiodine treatment is appropriate. Resection is easy , certain and has limited morbidity . Radioiodine is a good alternative for patients over the age of 45 years because the - suppressed thyroid tissue does not take up iodine and thus there is minimal risk of delayed thyroid insu ﬃ ciency . - Failure of previous treatment with antithyroid drugs or radioiodine 123 In this case, surgery or thyroid ablation with I is appropriate. HYPERTHYROIDISM Thyrotoxicosis

Figure 55.17 Graves’ disease. Figure 55.18 Histology of thyrotoxicosis.

Introduction

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Isotope scanning

The uptake by the thyroid of a low dose of either radiolabelled 123 99m I) or the cheaper technetium ( Tc) will demonstrate iodine ( the distribution of activity in the whole gland. Routine isotope scanning is unnecessary and inappropriate for distinguishing benign from malignant lesions because the majority (80%) of ‘cold’ swellings are benign and some (5%) functioning or ‘warm’ swellings will be malignant. Its principal value is in the toxic patient with a nodule or nodularity of the thyroid. Local isation of overactivity in the gland will di ﬀ erentiate between a toxic nodule with suppression of the remainder of the gland and toxic multinodular goitre with several areas of increased Figure 55.8 uptake with important implications for therapy ( Whole-body scanning is used to demonstrate metastases. However, the patient must have all normally functioning y either surgery or radioiodine before thyroid tissue ablated b ) the scan is performed because metastatic thyroid cancer tissue - cannot compete with normal thyroid tissue in the uptake of iodine. - - ).

(d) Figure 55.7 (a) Scout /f_i lm showing retrosternal goitre. (b) Axial com

puted tomography (CT) section showing goitre extending to below the aortic arch with tracheal compression. (c) Coronal CT section showing goitre extending to the tracheal bifurcation. (d) Sagittal CT section showing goitre /f_i lling the posterior mediastinum. Figure 55.8 Technetium thyroid scan showing the appearance of a 1-cm ‘toxic’ adenoma in the right thyroid lobe with suppression of uptake in the left lobe. The intense uptake gives a false impression of the size of the swelling.

FNAC is the investigation of choice in discrete thyroid swell ings. FNAC has excellent patient compliance, is simple and quick to perform in the outpatient department and is readily repeated. This technique, developed in Scandinavia 40 years ago, is now r outine throughout the world. FNAC results should be reported using standard terminology ( Table 55.2 ). Ultra sound guidance allows more accurate sampling and reduces the rate of unsatisfactory aspirates.

TABLE 55.2 Classi /f_i cation of /f_i ne-needle aspiration cytology reports. Thy1 Non-diagnostic Thy1c Non-diagnostic cystic Thy2 Non-neoplastic Thy3 Follicular Thy4 Suspicious of malignancy Thy5 Malignant

Isotope scanning

(d) Figure 55.7 (a) Scout /f_i lm showing retrosternal goitre. (b) Axial com

Learning objectives

To understand the development and anatomy of the • thyroid gland To know the physiology and investigation of thyroid • function Learning objectives

To understand the development and anatomy of the • thyroid gland To know the physiology and investigation of thyroid • function

Malignant lymphoma

In the past, many malignant lymphomas were diagnosed as small round-cell anaplastic carcinomas. Response to irradiation is dramatic ( Figure 55.27 ) and radical surgery is unnecessary Antoine Marfan , 1858–1942, paediatrician, University of Paris, France. Bosselated: covered in multiple bosses (small protuberences). - once the diagnosis is established by biopsy . In patients with tracheal compression, isthmusectomy is the most appropriate - form of biopsy , although the response to therapy is so rapid - that this should rarely be necessary unless there has been di ﬃ culty in making a histological diagnosis. The prognosis is good, particularly if there is no involvement of cervical lymph nodes. Rarely , the tumour is part of widespread malignant lymphoma disease and the prognosis in these cases is worse. Most lymphomas occur against a background of lymphocytic thyroiditis.

(b) Figure 55.27 Magnetic resonance imaging scans of extensive malignant lymphoma (a) before and (b) after 7 days of external beam radiotherapy (courtesy of Dr FW Smith, Aberdeen, UK).

Malignant lymphoma

(b) Figure 55.27 Magnetic resonance imaging scans of extensive malignant lymphoma (a) before and (b) after 7 days of external beam radiotherapy (courtesy of Dr FW Smith, Aberdeen, UK).

Malignant tumours

The vast majority of primary malignancies are carcinomas derived from the follicular cells ( Table 55.6 ). Such tumours were thought of as di ﬀ erentiated (papillary , follicular and Hürthle cell) and undi ﬀ erentiated (anaplastic). However, now an intermediate class of ‘poorly di ﬀ erentiated carcinoma’ is recognised, which is likely to represent a state of dedi ﬀ erentiated – between classic di ﬀ erentiated and undi ﬀ erentiated diseases. The parafollicular C cells can undergo malignant transfor mation into medullary carcinoma, and thyroid lymphoma is another primary thyroid malignancy . In addition, the thyroid can be involv ed by direct spread from surrounding structur (larynx and oesophagus) or metastases (most commonly from renal cell carcinoma). Lymph node and blood-borne metas tases of thyroid cancer occur primarily to bone and lung and may be the mode of presentation ( Figure 55.22 ). Aetiology of malignant thyroid tumours The great majority of thyroid cancers have no known aetiolog ical factor. The most important identiﬁable aetiological factor in di ﬀ erentiated thyroid carcinoma (particularly papillary) is irradiation of the thyroid under 5 years of age. In the town of Gomel, Ukraine , the incidence of childhood thyroid cancer rose from <1 per million to 96 per million following the Chernobyl nuclear disaster. Short latency aggressive PTC is associated with the ret / PTC3 oncogene and later developing, possibly less aggres sive, cancers with ret / PTC1 . The incidence of follicular carci noma is high in endemic goitrous areas, possibly because of TSH stimulation. Malignant lymphomas sometimes develop in autoimmune thyroiditis, and the lymphocytic inﬁltration in the autoimmune process ma y be an aetiological factor.

Figure 55.21 Isolated swelling in the upper pole of the right thyroid lobe.

Malignant tumours

Figure 55.21 Isolated swelling in the upper pole of the right thyroid lobe.

Medullary carcinoma

These are tumours of the parafollicular (C cells) derived from the neural crest that are not unlike those of a carcinoid tumour ( Figure 55.26 ). High levels of serum calcitonin and carcinoembryonic antigen are produced. Calcitonin levels fall after resection and rise again with recurrence, making it a valuable tumour marker in the follow-up of patients with this disease. Diarrhoea is a feature in 30% of cases and this may - be due to 5-hydroxytryptamine or prostaglandins produced by the tumour cells. Medullary carcinoma may occur in combination with adrenal phaeochromocytoma and hyperparathyroidism - (usually due to hyperplasia) in the syndrome known as multiple endocrine neoplasia type 2A (MEN-2A). The familial form of the disease frequently a ﬀ ects c hildren and young adults, whereas the sporadic cases occur at any age with no sex predominance. When the familial form is associated with prominent mucosal neuromas involving the lips, tongue and inner aspect of the eyelids, with a Marfanoid habitus, the syndrome is referred to as MEN type 2B (see Chapter 57 ). Involvement of lymph nodes occurs in 55–60% of cases and blood-borne metastases are common. Tumours are not TSH dependent and do not take up radioactive iodine. The prognosis is variable and depends on the stage at diagnosis. volvement virtually eliminates the prospect of Any nodal in cure and, unfortunately , even small tumours conﬁned to the thyroid gland may have spread by the time of diagnosis, par ticularly in familial cancers. In common with many endocrine tumours the progression of disease may be very slow , with a characteristically indolent course and long survival, even in the . absence of cure In familial cases of medullary thyroid cancer, genetic screening of relatives should be recommended and the infor mation used to make recommendations concerning prophy . Some relatives may be monitored into lactic thyroidectomy adulthood with serial calcitonin monitoring. In contrast, the highest risk mutations are associated with early-onset disease and total thyroidectomy is recommended during infancy .

Figure 55.26 Histology of medullary carcinoma showing characteris tic ‘cell balls’ and amyloid (courtesy of Dr SWB Ewen, Aberdeen, UK).

Medullary carcinoma

Figure 55.26 Histology of medullary carcinoma showing characteris tic ‘cell balls’ and amyloid (courtesy of Dr SWB Ewen, Aberdeen, UK).

NEOPLASMS OF THE THYROID

Classiﬁcation of thyroid neoplasms is presented in Table 55.6 and the relative incidence of malignancies in Table 55.7 . - - -

TABLE 55.6 Classi /f_i cation of thyroid neoplasms. Benign Follicular adenoma Malignant Primary Follicular epithelium – Follicular differentiated Papillary Follicular epithelium – Anaplastic poorly differentiated Parafollicular cells Medullar Lymphoid cells Secondary Metastatic Local in /f_i ltration TABLE 55.7 Relative incidence of primary malignant tumours of the thyroid gland. Malignancy Relative incidence (%) Papillary carcinoma 80 Follicular carcinoma 10 Poorly differentiated/anaplastic 5 carcinoma Medullary carcinoma 2.5 Lymphoma 2.5

NEOPLASMS OF THE THYROID

Classiﬁcation of thyroid neoplasms is presented in Table 55.6 and the relative incidence of malignancies in Table 55.7 . - - -

PHYSIOLOGY Thyroxine

The hormones tri-iodothyronine (T ) and /l.sc -thyroxine (T 3 bound to thyroglobulin within the colloid. Synthesis within the thyroglobulin complex is controlled by several enzymes, in distinct steps: /uni25CF trapping of inorganic iodide from the blood; /uni25CF oxidation of iodide to iodine; /uni25CF binding of iodine with tyrosine to form iodotyrosine; /uni25CF coupling of monoiodotyrosines and di-iodotyrosines to form T and T . 3 4 When hormones are required, the complex is resorbed into the cell and thyroglobulin is broken down. T and T are lib 3 4 erated and enter the blood, where they are bound to serum proteins: albumin, thyroxine-binding globulin (TBG) and thyroxine-binding prealbumin (TBPA). The small amount of hormone tha t remains free in the serum is biologically active. The metabolic e ﬀ ects of the thyroid hormones are due to unbound free T and T (0.3% and 0.03% of the total 3 4 circulating hormones, respectively). T is the more important 3 physiological hormone and is also produced in the periphery by conversion from T . T is quick acting (within a few hours), 4 3 whereas T acts more slowly (4–14 days). 4 PHYSIOLOGY Thyroxine

Prognosis in differentiated thyroid carcinoma

The prognosis in di ﬀ erentiated thyroid cancers is generally excellent. In terms of survival, older patients, those with large tumours or those with extrathyroid extension or distant metas - tases have worse outcomes. A system of risk stratiﬁcation can be used to predict the risk on an individual basis. In a young patient with a low-risk tumour, the risk of death following appropriate treatment is almost zero. In an older patient with a high-risk tumour (extrathyroid extension or distant metasta ses), the risk is as high as 55% at 5 years. Older patients with low-risk tumours and younger patients with high-risk tumours are an intermediate-risk group. Nodal metastases deserve special mention. In younger patients they predict for r rence but not for death. This is because recurrent neck disease in young patients can almost always be successfully salvaged. In contrast, for older patients neck metastases (particularly in the lateral neck) are a marker of distant metastases in some, recurrence and death. The American Joint Committee on Cancer system stages all patients <55 years as stage I unless they have distant metas - tases, when they are stage II. Older T1N0M0 pa tients are stage I and T2N0M0 patients are stage II. The pr esence of nodal disease upstages older patients to stage II, as does T3 disease. All older patients with locally invasive primary disease (T4) or distant metastases are stage IV .

Figure 55.24 Histology of follicular thyroid carcinoma showing vas cular (red arrow) and capsular (black arrow) invasion (courtesy of Dr SWB Ewen, Aberdeen, UK). Figure 55.25 Follicular carcinoma of the thyroid with skull secondaries.

Prognosis in differentiated thyroid carcinoma

The prognosis in di ﬀ erentiated thyroid cancers is generally excellent. In terms of survival, older patients, those with large tumours or those with extrathyroid extension or distant metas - tases have worse outcomes. A system of risk stratiﬁcation can be used to predict the risk on an individual basis. In a young patient with a low-risk tumour, the risk of death following appropriate treatment is almost zero. In an older patient with a high-risk tumour (extrathyroid extension or distant metasta ses), the risk is as high as 55% at 5 years. Older patients with low-risk tumours and younger patients with high-risk tumours are an intermediate-risk group. Nodal metastases deserve special mention. In younger patients they predict for r rence but not for death. This is because recurrent neck disease in young patients can almost always be successfully salvaged. In contrast, for older patients neck metastases (particularly in the lateral neck) are a marker of distant metastases in some, recurrence and death. The American Joint Committee on Cancer system stages all patients <55 years as stage I unless they have distant metas - tases, when they are stage II. Older T1N0M0 pa tients are stage I and T2N0M0 patients are stage II. The pr esence of nodal disease upstages older patients to stage II, as does T3 disease. All older patients with locally invasive primary disease (T4) or distant metastases are stage IV .

SURGICAL ANATOMY

The normal thyroid gland weighs 20–25 /uni00A0 g. The functioning unit is the lobule supplied by a single arteriole and consists of 24–40 follicles lined with cuboidal epithelium. The follicle contains colloid in which thyroglobulin is stored ( Figure 55.2 ). The arterial supply is rich, and extensive anastomoses occur between the main thyroid arteries and the branches of the tracheal and oesophageal arteries ( Figure 55.3 ). There is an extensive lymphatic network within and around the gland. Although some lymph channels pass directly to the deep cervical nodes, the subcapsular plexus drains principally to the central compartment juxtathyroid – ‘Delphian’ and paratra - cheal nodes and nodes on the superior and inferior thyroid veins (level VI) – and from there to the deep cervical (levels II, III, IV and V) and mediastinal g roups of nodes (level VII) ( Figure 55.4 ). The relationship between the recurrent laryngeal nerve (RLN) and the thyroid is of supreme importance to the

operating surgeon. A branch of the vagus, the nerve recurs round the arch of the aorta on the left and the subclavian artery on the right. The clinical signiﬁ cance of this is that on the left the nerve has more distance in which to reach the tracheo-oesophageal groove and therefore runs in a medial plane. On the right, there is less distance and the nerve runs more obliquely to reach the tracheo-oesophageal groove. Approximately 2% of nerves on the right are non-recurrent and will enter the larynx from above. The nerve runs posterior to the thyroid and enters the larynx at the cricothyroid joint. This entry point is at the level

Figure 55.2 Histology of the normal thyroid. Left vagus nerve (X) Common carotid artery Internal jugular vein Inferior thyroid vein Left recurrent laryngeal nerve Figure 55.3 The thyroid gland from behind. Submandibular gland Internal carotid Digastric artery muscle Mylohyoid muscle II Hyoid bone I Internal jugular vein Omohyoid Internal carotid muscle artery III Sternocleidomastoid Cricoid muscle cartilage V VI IV Trapezius muscle Right common Anterior scalene carotid artery muscle VII Internal jugular vein Manubrium Left common carotid artery Figure 55.4 Cervical lymph node levels. Right vagus nerve (X) Superior oid gland parathyr Thyroid gland (right lobe) Inferior parathyroid gland Right recurr ent laryngeal nerve Inferior thyr oid artery

binds the thyroid to the trachea. This is the point at which the nerve is at most risk of injury during surgery . In terms of surgical anatomy , the nerve can be located in the tracheo oesophageal groove, where it forms one side of Beahrs’ triangle (the other two sides are the carotid artery and the inferior thyroid artery) or at the cricothyroid joint. The nerve will normally be found as the thyroid lobe is mobilised laterally lying under the most posterolateral portion of the gland called the tubercle of Zuckerkandl. SURGICAL ANATOMY

Serum thyroid hormones

Serum thyroid-stimulating hormone TSH levels can be measured accurately down to very low serum concentrations with an immunochemiluminometric assay . - Interpretation of deranged TSH levels depends on knowledge of the T and T values. In the euthyroid state, T , T and TSH 3 4 3 4 levels will all be within the normal range. Florid thyroid failure results in depressed T and T levels, with gross elevation of 3 4 TSH. Incipient or developing thyroid failure is characterised by low normal values of T and T and elevation of TSH. In 3 4 toxic states, the TSH level is suppressed ( Table 55.1 ). Serum thyroid hormones

Simple goitre

Aetiology Simple goitre may develop as a result of stimulation of the thyroid gland by TSH, either as a result of inappropriate secre tion from a microadenoma in the anterior pituitary (which is rare) or in response to a chronically low level of circulating thyroid hormones. The most important factor in endemic goitre is dietar y deﬁciency of iodine (see Iodine deﬁciency but defective hormone synthesis probably accounts for many sporadic goitres (see Dyshormonogenesis ). TSH is not the only stimulus to thyroid follicular cell pro liferation as other growth factors, including immunoglobulins, exert an inﬂuence. The heterogeneous structural and func tional response in the thyroid resulting in characteristic nodu larity may be due to the presence of clones of cells particularly sensitive to g rowth stimulation. Hakaru Hashimoto , 1881–1934, Director, The Hashimoto Hospital, Mie, Japan, described chronic lymphocytic thyroiditis in 1912. Friedrich Joseph de Quervain , 1868–1940, Professor of Surgery , Berne, Switzerland, described this form of thyroiditis in 1902. Bernhard Riedel , 1846–1916, Surgeon, University of Jena, Thuringia, Germany Struma . The River Struma arises in the mountains of Bulgaria and ﬂows into the Aegean Sea. Along its banks and those of its tributaries dwell peoples of several nationalities, among whom endemic goitre has long been prevalent. Struma is a European continental term for goitre. /uni25CF - /uni25CF /uni25CF - Iodine deﬁciency The daily requirement of iodine is about 0.1–0.15 /uni00A0 mg. In nearly all districts where simple goitre is endemic, there is a very low iodide content in the water and f ood. Endemic areas are in the mountainous ranges, such as the Rocky Mountains, the Alps, the Andes and the Himalayas, and in the UK areas of Derbyshire and Y orkshire. Endemic goitre is also found in lowland areas where the soil lacks iodide or the water supply comes from far away mountain ranges, e.g. the Great Lakes of North America, the plains of Lombardy , the Struma Valley , the Nile Valley and the Congo. Calcium is also goitrogenic and goitre is common in low-iodine areas on chalk or limestone, for - example Derbyshire and southern Ireland. Although iodides in food and water may be adequate, failure of intestinal absorption may produce iodine deﬁciency . Dyshormonogenesis ), Enzyme deﬁciencies of varying severity may be responsible for many sporadic goitres, i.e. in non-endemic areas ( Figure 55.9 ). - There is often a family history , suggesting a genetic defect. Environmental factors may compensate in areas of high - iodine intake; for example, goitre is almost unknown in Iceland - where the ﬁsh diet is rich in iodine. Similarly , a low intake of iodine encourages goitre formation in those with a metabolic predisposition.

Simple goitre Diffuse Physiological (euthyroid) hyperplastic Pubertal Pregnancy Multinodular goitre Toxic Diffuse (Graves’ disease) Multinodular Toxic adenoma Neoplastic Benign Malignant In /f_l ammatory Autoimmune Chronic lymphocytic thyroiditis Hashimoto’s disease Granulomatous de Quervain’s thyroiditis Fibrosing Riedel’s thyroiditis Infective Acute (bacterial thyroiditis, viral thyroiditis, ‘subacute thyroiditis’) Chronic (tuberculous, syphilitic) Other Amyloid

Goitrogens Well-known goitrogens are the vegetables of the brassica family (cabbage, kale and rape), which contain thiocyanate, drugs such as para-aminosalicylic acid (PAS) and the antithyroid drugs. Thiocyanates and perchlorates interfere with iodide trapping; carbimazole and thiouracil compounds interfere with the oxidation of iodide and the binding of iodine to tyrosine. Surprisingly , iodides in large quantities are goitrogenic because they inhibit the organic binding of iodine and produce an iodide goitre. Excessive iodine intake may be associated with an increased incidence of autoimmune thyr oid disease. The natural history of simple goitre Stages in goitre formation are: /uni25CF Persistent growth stimulation causes di ﬀ use hyperplasia; all lobules are composed of active follicles and iodine uptake is uniform. This is a di ﬀ use hyperplastic goitre, which may persist but is reversible if stimulation ceases. /uni25CF Later, as a result of ﬂuctuating stimulation, a mixed pat tern develops with areas of active lobules and areas of inactive lobules. /uni25CF Active lobules become more vascular and hyperplastic until haemorrhage occurs, causing central necrosis and leaving only a surrounding rind of active follicles. /uni25CF Necrotic lobules coalesce to form nodules ﬁlled either with iodine-free colloid or a mass of new but inactive follicles. /uni25CF Continual repetition of this process results in a nodular goitre. Most nodules are inactive, and active follicles are present only in the internodular tissue. Diffuse hyperplastic goitre Di ﬀ use hyperplasia corresponds to the ﬁrst stages of the natu ral history . The goitre appears in childhood in endemic areas; in sporadic cases, it usually occurs at puberty , when metabolic demands are high. If TSH stimulation ceases the goitr regress, but tends to recur later at times of stress such as preg nancy . The goitre is soft, di ﬀ use and may become large enough to cause discomfort. A colloid goitre is a late stage of di ﬀ use many follicles are inactive and full of colloid ( Figure 55.10 ). Nodular goitre Nodules are usually multiple, forming a multinodular goitre ( Figure 55.11 ). Occasionally , only one macroscopic nodule is found, but microscopic changes will be present throughout the gland; this is one form of a clinically solitary nodule. Nodules may be colloid or cellular, and cystic degeneration and haem - orrhage are common, as is subsequent calciﬁcation. Nodules appear early in endemic goitre and later (between 20 and 30 years) in sporadic goitre, although the patient may be unaware of the goitr e until his or her late forties or ﬁfties. All types of simple goitre are more common in the female than in the male owing to the presence of oestrogen receptors in thyroid tissue. Diagnosis Diagnosis is usually straightforward. The patient is euthyroid and the nodules are palpable and often visible; they are smooth, usually ﬁrm and not hard and the goitre is painless and moves - - e may -

Figure 55.9 Total thyroidectomy for dyshormonogenetic goitre in a 14-year-old girl. Figure 55.10 Colloid goitre. Figure 55.11 Large multinodular goitre.

ﬁcation, may simulate carcinoma. A painful nodule, sudden appearance or rapid enlargement of a nodule raises suspicion of carcinoma but is usually due to haemorrhage into a simple nodule. Di ﬀ erential diagnosis from autoimmune thyroiditis may be di ﬃ cult and the tw o conditions frequently coexist. Investigations Thyroid function should be assessed to exclude hyperthyroid ism, and the presence of circulating thyroid antibodies tested to di ﬀ erentiate from autoimmune thyroiditis. Ultrasonography is the gold standard assessment when undertaken by a suitab trained and experienced operator. FNAC is only required for a nodule within the goitre that demonstrates ultrasonographic features of concern. This may or may not be the largest ‘dominant’ nodule. The biopsy should be performed under ultrasound guidance to ensure that the correct nodule is sampled. If there are swallowing or breathing symptoms then a CT scan of the chest and neck is the best modality to assess tracheal or oesophageal deviation or compression. Complications Tracheal obstruction may be due to gross lateral displace ment or compression in a lateral or anteroposterior plane by retrosternal extension of the goitre ( Figure 55.7 ). Acute r espiratory obstruction may follow haemorrhage into a nodule impacted in the thoracic inlet. Secondary thyrotoxicosis Transient episodes of mild hyperthyroidism are common, occurring in up to 30% of patients. Carcinoma An increased incidence of cancer (usually follicular) has been reported from endemic areas. Dominant or rapidly growing nodules in longstanding goitres should always be subjected to aspiration cytology . Prevention and treatment of simple goitre In endemic areas the incidence of goitre has been strikingly reduced by the introduction of iodised salt. In the early stages, a hyperplastic goitre may regress if thyroxine is given in a dose of 0.15–0.2 /uni00A0 mg daily for a few months. Although the nodular stage of simple goitre is irreversible, more than half of benign nodules will regress in size over 10 years. Most patients with multinodular goitre are asymptom a tic and do not require operation. Surgery is indicated for nodular goitres with features of underlying malignancy , for pressure symptoms if other causes have been excluded or for cosmetic reasons if the pa tient ﬁnds the goitre unsightly . If the goitre is causing tracheal compression then surgery should be considered. Many such patients are found incidentally and are asymptomatic and often very elderly . As these goitres often grow very slowly the risks and beneﬁts of surgery should be considered carefully , particularly if a sternal split may be required for access. Sir Thomas Peel Dunhill , 1876–1957, surgeon, St Bartholomew’s Hospital, London, UK. lar goitre: total thyroidectomy with immediate and lifelong replacement of thyroxine or some form of partial resection to conserve su ﬃ cient functioning thyroid tissue to subserve nor - mal function while reducing the risk of hypoparathyroidism that accompanies total thyroidectomy . Historically subtotal thyroidectomy involves partial resection of eac h lobe, remov - ing the bulk of the gland and leaving up to 8 /uni00A0 g of relatively - normal tissue in each remnant. The technique is essentially the same as described for toxic goitre, as are the postopera - tive complications. A signiﬁcant problem with this approach is ly the propensity for regrowth. Therefore, unless there is a local shortage of thyroxine, most sur geons now favour total thyroid - ectomy in the setting of bilateral disease. More often, however, the multinodular change is asymmetrical, with one lobe more signiﬁcantly involved than the other. In these circumstances, particularly in older patients, total lobectomy on the more a ﬀ ected side is the appropriate management. Although this can be used in combination with subtotal r esection of the con - tralateral lobe (Dunhill procedure), most surgeons now prefer no intervention on the less a ﬀ ected side because of the poten - tial for regrowth and the increased rate of complications asso - - ciated with reoperation. In many cases , the causative factors persist and recurrence is likely . Reoperation for recurrent nodular goitre is more di ﬃ cult and hazardous and, for this reason, an increasing n umber of thyroid surgeons favour total thyroidectomy in younger patients. Ho wever, when the ﬁrst operation comprised uni - lateral lobectomy alone for asymmetric goitre, reoperation and completion total thyroidectomy is straightforward if required for progression of nodularity in the remaining lobe. Total lobectomy and total th yroidectomy have the additional advan - tage of being therapeutic for incidental carcinomas. Simple goitre

Figure 55.9 Total thyroidectomy for dyshormonogenetic goitre in a 14-year-old girl. Figure 55.10 Colloid goitre. Figure 55.11 Large multinodular goitre.

Surgery for thyrotoxicosis

Preoperative preparation Traditional preparation aims to make the patient biochemi - cally euthyroid at operation. Preparation is as an outpatient and only rarely is admission to hospital necessary on account of severe symptoms at presentation, failure to control the hyperthyr oidism or non-compliance with medication. Care should be coordinated with endocrinology input. Carbimazole 30–40 /uni00A0 mg/day is the drug of choice for preparation. When euthyroid (after 8–12 weeks), the dose may be reduced to 5 /uni00A0 mg 8-hourly or a ‘block and replace’ regime used. In this case, the high dose of carbimaz ole is continued to inhibit T and T production and a maintenance dose of 3 4 0.1–0.15 /uni00A0 mg thyroxine is given daily . The last dose of carbi - mazole may be given on the evening before surgery . Iodides are not used alone because, if the patient needs preoperative trea tment, a more e ﬀ ective drug should be given. An alternative method of preparation is to abolish the clinical manifestations of the toxic state, using β -adrenergic - blocking drugs. These act on the target organs and not on the gland itself. Propranolol also inhibits the peripheral conversion of T to T . The appropriate dosages are propranolol 40 /uni00A0 mg 4 3 three times daily . Clinical response to β -blockade is rapid and the patient may be rendered clinically euthyroid and operation arranged in a few days rather than weeks. The dose of β -adrenergic blocking drug is increased to achieve the required clinical response and quite often larger doses (propranolol 80 /uni00A0 mg three times daily or nadolol 320 /uni00A0 mg once daily) are necessary . of thyroid hormones, and hormone levels remain high during treatment and for some days after thyroidectomy . It is, there fore, important to continue treatment for 7 days postopera tively . Iodine may be given with carbimazole or a β -adrenergic blocking drug for 10 days before operation. Iodide alone pro duces a transient remission and may reduce vascularity , thereby marginally impro ving safety . The use of iodine preparations is not universal because of more e ﬀ ective alternativ es. Iodine gives an additional measure of safety in case the early morning dose of β -adrenergic blocking drug is mistakenly omitted on the day of operation. The extent of the resection depends on the size of the gland, the age of the patient, the experience of the surgeon, the need to minimise the risk of recurrent toxicity and the wish to avoid postoperative thyroid r eplacement ( Table 55.5 Surgical technique of thyroidectomy The aim of thyroidectomy is to remove the entire thyroid lobe (bilaterally if total thyroidectomy), encompassing all disease and preserving the cervical strap muscles, external branches of the superior laryngeal nerve, the RLN, parathyroid glands and their blood supply in each case while minimising cosmetic impact. With the patient under general anaesthesia, supine, arms at their side, with their head on a ring and neck extended with a shoulder roll or the head of the table extended with the head of the bed raised (reverse Trendelenburg), the opera ﬁeld is prepared from lower lip to upper chest. A nerve monitor endotracheal tube or electrode wrap can be used (see New technology in thyroidectomy ). The posi tion of the tube should be checked after positioning the patient as extending the neck can withdraw the tube and compromise the contact of the electrodes in the larynx. Either use a head drape or square o ﬀ the surgical site. If head draping , include the nerve monitor leads in the head drape. Alter natively , squaring o ﬀ the surgical site can giv ier access to the endotracheal tube if required. The skin incision is placed in a skin crease as close as possible to the cricoid at the superior edge of the thyroid isthmus, w hich is usually palpable. The length of the incision is determined by the size of the thyroid; however, there is little beneﬁt in extending the incision much beyond the medial edge of the sternocleidomastoid muscle. Mark the incision before prepping and inﬁltrate with local anaesthetic and adrenaline (epinephrine). A scalpel is used for the skin incision. Incise through the dermis, making sure to use the full extent of the incision. Monopolar diathermy can be used to expose and divide the platysma. This plane is then used to raise a subplatysmal ﬂap to the thyroid notch of the thyr oid cartilage superiorly and to the suprasternal notch inferiorly . Friedrich Trendelenburg , 1844–1924, successively Professor of Surgery at Rostock (1875–1882), Bonn (1822–1895) and Leipzig (1895–1911), Germany . The Trendelenburg position was ﬁrst described in 1885. Bernhard Rudolf Konrad von Langenbeck , 1810–1887, Professor of Surgery , successively at Kiel and Berlin, Germany . riorly as, often, the sternohyoid muscles separate around the thyroid eminence. The sternohyoid muscles are raised with - toothed forceps and monopolar diather my is used to divide - the fascia, avoiding injury to the anterior jugular veins. A Lan - genbeck retractor helps dissect superior and inferior limits. The plane is developed to dissect between the muscle lay - - ers, elevating sternohyoid laterally until the ansa cervicalis is visualised. The sternothyroid muscle is then mobilised from the gland, taking great care with the delicate vasculature. If requir ed, the strap muscles may be divided superiorly to a ﬀ ord greater exposure. There is usually an artery and a vein travel - ling between the two strap muscles superiolaterally; these can be injured if overly enthusiastic blunt dissection is used. Once the internal jugular vein is identiﬁed dissection medial and deep to this will allow identiﬁcation of the common carotid artery , and between the vessels the vagus nerve. This should ). be stimulated to prove that the nerve monitor is functioning properly . If the latency reading on the nerve monitor is unex - pectedly short on the right side then consider a non-recurrent right laryngeal nerve. At this point the gland is exposed and ready for dissection. Minimal blood loss should have been encountered. The assistant now places Langenbeck retractors under ster nohyoid, one lateral to the upper pole and one medial. This displays the superior thyroid v ascular pedicle, which is controlled with ties or a bipolar energy device. T his not only mobilises the superior pole but also preserves the blood supply to the superior parathyroid gland. In addition, tive it minimises risk to the superior laryngeal nerve, which can often be seen passing medially towards the cricothyroid muscle. Gradually the superior pole is mobilised, taking care not to - dissect below the cricoid cartilage, at which point the RLN is at risk ( Figure 55.19 ) . Gentle traction on the fascia over the gland, immediately next to the superior plane, will show a plane to follow over the main thyroid. This is e eas - followed inferior ly , avoiding excessive lateral dissection to prevent inadvertent damage to the RLN. Blunt dissection will allow much of this fascia to be mobilised. Occasional vessels require bipolar cautery . Next, the trachea is identiﬁed in the midline below the isth - mus, staying on the cartilage and close to the gland in order to prevent damage to vessels that may contribute to arcades supplying the inferior para thyroid gland. At this point, the RLN is superior and lateral to the trachea and inferior to the plane developed superiorly . Depending on just how compliant the fascia is and how large the lobe is, much of the dissection may now be complete. A pledget may be used to brush fascia laterally . It is not uncommon that the RLN can be seen at this point. Assuming

Set-up. Exposure. Upper pole. Mobilising the rest of the gland. Identi /f_i cation of the recurrent laryngeal nerve.

it is not, dissection proceeds by gently mobilising the fascia around the gland, staying directly on the gland and not dividing anything that could be neural. The RLN will be close, often but not always behind the inferior thyroid artery (approximately 70%). By remaining vigilant, never dividing any structure that could remotely be neural and slowly dissecting fascia, the lobe can be delivered from above and below , mobilising in the direc tion of Berry’s ligament. Using this approach, the RLN will be identiﬁed and can be conﬁrmed with the nerve stimulator. Once the nerve has been identiﬁed a number of approaches are possible. Ideally the nerve is largely lateral to the gland. T his allows dissection to progress until only Berry’s ligament remains. However, if the nerve lies medially , it may actually lie on the thyroid and require gentle dissection to free it from the thyroid surface. If this is the case, stay directly on the nerve and slowly dissect the nerve free of the surrounding tissue, endeav ouring not to injure the nerve by direct pressure. The nerve should be traced towards the cricothyroid joint as it enters the larynx. The pretracheal fascia condenses into Berry’s ligament at this point. Small vessels within the ligament retract if not controlled with bipolar cautery or ties, and the r esulting bleeding can disorientate the surgeon, placing the nerve at risk. In order to avoid this, pre-emptive diathermy to the ligament and careful layer-by-layer dissection allows ﬁnal mobilisation of the thyroid lobe. Some surgeons prefer to iso late the ligament and apply a careful tie to achieve haemostasis. Whichever method is preferred, great care must be taken at this point. The exact anatomy her e will depend on how extensive the condensation of fascia (Berry’s ligament) is and how it rela tes to the RLN. This is are. In some the ligament is distant from the nerve. In others the nerve runs up to and even through the ligament. Keeping the nerv e in direct vision, minimal division of the ligament allows the RLN to move back and expose more of the liga - ment, allowing the process to continue, layer by layer, until the nerve is well lateral and the ligament has been divided. If, during this process, bleeding is encountered the use of targeted pressure and occasionally ﬁne-tip suction to identify the speciﬁc bleeding point and careful use of bipolar cautery will achie ve haemostasis. This must be meticulous as re-exploration of this ar ea for bleeding puts the RLN at signiﬁcant risk. Loose pretrachea fascia can now be opened with monopolar diathermy over the trachea to the midline and beyond to remove the isthmus, which is divided, encompassing any pyramidal lobe tissue . The residual isthmus is either oversewn or sealed with bipolar cautery . If a total thyroidectomy is required, the procedure is repeated on the other side. The operative ﬁeld should be inspected. Irrigation with saline helps identiﬁcation of small bleeding points. The anatomy should be conﬁrmed, ideally with conﬁrmation of neural integrity by stimulating the v agus (if previously located). Bipolar cautery is used carefully to avoid nerve or parathyroid injury . Most surgeons do not place a drain. Interrupted sutures are placed through the sternohyoid muscle to prevent adhesion betw een the trachea and skin. The aim is not to perform a watertight closure of the muscle in case this promotes pressure in the event of a haematoma. The platysma closure is followed by subcuticular skin clo - sure with an absorbable suture. - New technology in thyroidectomy The major immediate risk following thyroidectomy is haem - orrhage; conventionally , artery forceps, ligatures and sutures have been used to secure the meticulous haemostasis necessary to minimise the risk of this potentially life-threatening compli - cation. Ultrasonic shears , enhanced bipolar diathermy and harmonic vessel sealing devices are increasingly used in thyroid surgery and may be advantageous in complex procedures. - Monitoring of the RLN and v agus nerve has become available over the last few years. By placing electrodes on the endotracheal tube between the vocal cords, movements can be detected when the nerv e is stimulated. Such intermittent nerve monitoring is gaining in popularity . Advocates consider the monitor particularly useful in recurrent operations where scar tissue makes the nerve di ﬃ cult to identify . In addition, some ﬁnd that operative time is reduced and that this is a valuable tool for training. There is also some support for the use of nerve - monitoring during bilateral thyroid surgery , as the information provided can aid in the identiﬁcation of a unilateral palsy to prevent bilateral palsy that can require tracheostomy . Those who do not support the use of the nerve monitor highlight the lack of evidence that there is any real di ﬀ erence in outcome associated with this practice. In addition, there is the expense of the base machine and the electrodes.

artery External branch superior laryngeal nerve Superior parathyroid gland Recurrent laryngeal nerve Inferior thyroid artery Inferior parathyroid gland Thyroid ima artery Figure 55.19 General anatomy of a thyroidectomy. Management of Berry’s ligament. Delivery of the gland. Closure.

identiﬁcation of a damaged nerve, continuous nerve moni toring has now been developed. In theory , this provides the opportunity to identify a nerve when function is threatened (by excessive traction, for example). This technique, although theoretically advantageous, requires an electrode to be placed on the vagus nerve and has not gained widespread acceptance ( Figure 55.20 ). Alternative surgical techniques Over the past two decades, increasing experience has been gained in alternative approaches to thyroid surgery . Minimally invasive video-assisted techniques have been developed that allow surgeons to operate through an incision <2 /uni00A0 cm in length. With appropriately modiﬁed dissectors, experienced operators and advanced haemostatic electrosurgical devices, such procedures o ﬀ er reduced scar length. However, they are only appropriate for small-volume disease and as such are not suitable for many thyroid cases. Remote access thyroid surgery is of increasing interest. A number of approaches have been developed via axillary or breast incisions and also through the oral cavity . These approaches can be used with laparoscopic or r obotic tech niques to allow a magniﬁed view of the operative site. Such ‘maximally invasive’ techniques require extended dissection over the chest wall or neck and again are most suitable for small-volume disease. Experienced centres contin ue to expand the indications for these techniques. However, they are associ ated with increased and signiﬁcant time, which currently limits their application to most thyroid surgical practice. P o s t o p e r a t i v e c o m p l i c a t i o n s Haemorrhage is the most frequent life-threatening complica tion of thyroidectomy . Around 1 in 50 patients will develop a haematoma, and in almost all cases this will develop in the ﬁrst 24 hours. If an arterial bleed occurs, the tension in the central compartment pressure can rise until it exceeds venous pressure . V enous oedema of the larynx can then develop and cause airway obstruction, leading to death. Although improve ments in understanding of the blood supply to the larynx and technical developments in terms of haemostatic technologies - Although many surgeons worldwide practise da y case thyroid - ectomy , bleeding is the reason that, in the UK, thyroidectom y emains an inpatient procedure. r Intraoperative attention to detail in terms of haemostasis is critical. When closing the wound, avoiding a watertight closure of the strap muscles ma y allow a haematoma to escape into the subcutaneous tissues. Wound drains have not been shown to hav e a protective e ﬀ ect. Close monitoring of the wound is advised postoperatively . If a haematoma develops, clinical sta ﬀ should know to remove skin sutures in order to release some pressure and seek senior advice immediately . Endotra - cheal intubation should be used to secure the airway while the haematoma is evacuated and the bleeding point controlled. RLN paralysis and voice change RLN injury may be unila teral or bilateral, transient or permanent. Early routine postoperative laryngoscopy reveals a much higher incidence of transient cord paralysis than is detectable b y simple assess - ment of the integrity of the voice and cough. Such tempo - rary dysfunction is not clinically important, however, but voice and cord function should be assessed at ﬁrst follow-up 4 weeks postoperatively . A British Association of Endocrine and Thyroid Surgeons audit re vealed an RLN palsy rate of 1.8% at 1 month, declining to 0.5% at 3 months for ﬁrst-time operations. Permanent paralysis is rare if the nerve has been identiﬁed at operation. If an RLN is injured during surgery and the transected ends are identiﬁed, they should be reanastomosed. In the event that a length of nerve is excised (owing to invasion by malig - nancy , for e xample), anastomosis of the ansa cervicalis may be considered. This does not return mobility of the vocal cord but maintains neurological input to the muscles of the larynx. By avoiding denervation and rela ted muscle atrophy , the vocal quality is improved. Permanent vocal cord paralysis should be treated conservatively with speech therapy . If voice quality is unacceptable, medialisation procedures can be performed. Nerve grafting has shown promise but experience is limited. Injury to the external branch of the superior laryngeal nerve is more common because of its proximity to the superior - thyroid artery . This leads to loss of tension in the vocal cord with diminished power and range in the voice. P atients, particularly those who use their voice professionally , must be advised that any thyroid operation will result in change to the voice even in the absence of nerve trauma. Fortunately , for most patients - the changes are subtle and only demonstrable on formal voice assessment. Thyroxine replacement will be required following total thyroidectomy . Around one in three - patients who has a lobectomy will require supplementation; rates ar e higher in those with thyroid autoantibodies. Subtotal thyroidectomy was at one time performed with the aim of leaving su ﬃ cient tissue to maintain thyroid function. However, this is di ﬃ cult to judge and, over the years, the benign process that necessitated primary surgery may recur, requiring di ﬃ cult - revision procedures. For this reason, the practice of subtotal thyroidectomy has been more or less abandoned outside envi - ronments where exogenous thyroxine is not available.

Figure 55.20 Continuous monitoring of the vagus nerve (adapted from an image provided by Inomed UK Ltd). Thyroid insuf /f_i ciency.

thyroid glands or infarction through damage to the parathyroid end arteries; often both factors occur together. Vascular injury is probably far more important than inadvertent removal. The incidence of permanent hypopara thyroidism should be less than 1% and most cases present dramatically 2–5 days after operation; very rarely , the onset is delayed for 2–3 weeks or a patient with marked hypocalcaemia may be asymptomatic. The complication is limited to total thyroidectomy , as when lobectomy is performed the contralateral parathyroid glands are su ﬃ cient to maintain calcium levels. In particular, total thyroidectomy with central neck dissection places the parathy roid glands and their vascular supply at great risk and should only be performed when there is evidence of metastatic disease or high risk of occult disease in the regional lymph nodes. This is an acute exacerbation of hyperthyr oidism. It occurs if a thyrotoxic patient has been inadequately prepared for thyroidectom y and is now extremely rare. V ery rarely , a thyrotoxic patient presents in a crisis and this may follow an unrelated operation. Symptomatic and supportive treatment is for dehydration, hyperpyrexia and restlessness. This requires the administration of intravenous ﬂuids, cooling the patient with ice packs, administration of oxygen, diuretics for cardiac failure, digoxin for uncontrolled atrial ﬁbrillation, sedation and intravenous hydrocortisone. Speciﬁc treatment is by carbimazole 10–20 /uni00A0 mg 6-hourly , Lugol’s iodine 10 drops 8-hourly by mouth or sodium iodide 1 /uni00A0 g intravenously . Propranolol intravenously (1–2 /uni00A0 mg) or orally (40 /uni00A0 g 6-hourly) will block β -adrenergic e ﬀ ects. Cellulitis requiring prescription of anti biotics, often by the general practitioner, is more common than most surgeons appreciate. A signiﬁcant subcutaneous or deep cervical abscess is exceptionally rare and should be drained. This is more likely to form if the incision ov erlies the sternum and in dark-skinned individu als. Intradermal injections of corticosteroid should be given at once and repeated monthly if necessar y . Scar revision rarely results in signiﬁcant long-term improvement. This may occur with or without sin formation and is seen after the use of non-absorbable, partic ularly silk, suture material. Absorbable ligatures and sutures should be used throughout thyr oid surgery . Postoperative care Following surgery , the patient should be returned to the recovery room and nursed overnight on the ward. Wound care should include vigilance for signs of a haematoma. Following total thyroidectomy , calcium levels should be checked postop eratively . Not all patients develop immediate hypocalcaemia and they should be educated about the signs (paraesthesia of the ﬁngers and toes or around the mouth). Serial calcium monitoring should be recommended for those at highest risk. Jean Guillaume Auguste Lugol , 1786–1851, Physician, Hôpital Saint-Louis, Paris, France. replacement, which should start on day 1 postoperatively . On clinic review , in addition to checking the histology report, the wound should be inspected and the larynx e xamined for vocal cord function. Biochemical assessment of thyroid function and calcium, if required, should be arranged.

Thyrotoxic crisis (storm). Wound infection. Hypertrophic or keloid scar. Stitch granuloma.

Surgery for thyrotoxicosis

Set-up. Exposure. Upper pole. Mobilising the rest of the gland. Identi /f_i cation of the recurrent laryngeal nerve.

Figure 55.20 Continuous monitoring of the vagus nerve (adapted from an image provided by Inomed UK Ltd). Thyroid insuf /f_i ciency.

Thyrotoxic crisis (storm). Wound infection. Hypertrophic or keloid scar. Stitch granuloma.

Surgical treatment for differentiated thyroid canc

Surgical treatment for differentiated thyroid cancer

This subject has many contentious aspects. For the vast major - ity of patients, outcome is excellent irrespective of the extent of surgery . The low number of recurrences and deaths has made prospective trials di ﬃ cult; as such, ver y few exist. The aim of surgery is to rid the patient of macroscopic disease, reduce the chance of recurrence and minimise surgical morbidity . Achieving a balance between these aims is critical. In addition, the surgeon must consider whether radioactive iodine is to be recommended. In low-risk cases this is rarely indicated, whereas in high-risk patients it is used almost uni - versally . Risk stratiﬁcation is therefore critical. In high-risk patients with nodal or distant metastases, total thyroidectomy will be performed to eradicate disease in the thyroid and prepare the patient for radioactive iodine. For low- risk pa tients with a single focus of disease limited to the thyroid, a thyroid lobectomy can be o ﬀ ered. This has the signiﬁcant advantage of protecting the contralateral RLN and para - thyroid glands. This approach is now considered appropriate unless there are high-risk features of disease. In terms of the neck, when metastatic disease is present, a therapeutic compartment-orientated neck dissection should be performed to remove disease fr om the central or lateral neck, depending on the site of involvement. The role of elective neck sur gery when no disease in the nodes is detected preoperatively is far more controversial. Lat - eral neck dissection carries signiﬁcant morbidity and, despite high rates of occult metastases in PTC, has been abandoned. The reason for this is tha t, even in patients who are thought to have occult metastases, very few pr ogress to clinically meaning - ful disease. In contrast, the morbidity of central neck dissec - tion is lower, and the compartment has to be opened during a thyroidectomy . In addition, salvage surgery in the central neck carries a high risk to the RLN and parathyroid glands. For these reasons elective central neck dissection has been pop - ular in the last few decades . However, increased recognition that performing such surgery in all patients with PTC leads to - high rates of morbidity and the lack of evidence that outcomes improve as a result of more aggressive surgery have led to a move away from this practice. At this point, patients who are considered at highest risk of having occult metastases in the ecur - central neck (those with extrathyroid extension, for example) are considered most likely to beneﬁt from elective surgery . It is not recommended routinely in low-risk patients. Many patients will only be diagnosed with their thyroid cancer following a diagnostic lobectomy . In this setting, risk

risk, further surgery is unlikely to be beneﬁcial and active sur veillance should be considered. This approach, pioneered in Japan, has been adopted in a number of centres for PTCs <1 /uni00A0 cm as only 30% of patients develop tumour growth that requires interv ention. Larger tumours and younger patients are at higher risk and radioactive iodine may be recommended, in which case completion thyroidectomy may be required. Given the complexity of decision making in thyroid cancer and the di ﬀ erent groups involved (surgeons, endocrinologists, radiologists, cytologists, pathologists and nuclear medicine physicians), all cases should be discussed in a multidisciplinary setting. Thyroxine Following surgery , thyroid cells (both normal and malignant) can be suppressed using high doses of thyroxine. This was once considered routine for all di ﬀ erentiated thyroid cancers during follow-up. Again, risk stratiﬁcation has modiﬁed the approach to these patients. Following surgery , patients can be considered high or low risk. For those patients at high risk from disease, thyroxine will be prescribed at levels that suppress TSH without making the patient biochemically hyperthyroid. In contrast, low-risk patients may be considered for thyroxine replacement at physiological levels. In this patient group, a balance of beneﬁt (remember these patients have extremely low rates of recurrence or death) versus risk must be made. In particular, long-term TSH suppression can result in cardiac arrhythmia and osteoporosis. As such the multidisciplinary team should consider all risks during follow-up to strike this balance. Radioiodine 131 I can be given to deliver tumoricidal doses of radioactivity directly to thyroid tissue, both benign and malignant. In the setting of thyroid cancer, all normal tissue should be removed (total thyroidectomy) along with any gross neck disease (neck dissection) in order for any residual microscopic disease or distant metastases to receive an optimal dose. Radioiodine treatment is not an alternative to surgical resection for resect able disease. In order to e ﬀ ectively drive the radioiodine into cells, high levels of TSH are required. This can be achieved by rendering the patient hypothyroid (o ﬀ thyr oxine) or by using recombinant TSH, which is injected prior to radioiodine administration. Following radioiodine administration, an uptake scan is performed. This demonstrates areas of iodine uptake in the whole body and can be used to identify any metastatic disease not recognised on initial imaging. This infor mation is useful for risk stratiﬁcation following initial therapy . Outside the setting of primary treatment, radioiodine treat ment may be considered in cases of recurrence. Multiple doses can be used to treat unresectable disease or distant metastases. Most di ﬀ erentiated thyroid cancers will concentrate iodine. However, with adv ancing patient age and particularly if dis ease is multiply recurrent the tumour will lose iodine avidity . This is called radioiodine refractory disease. Such cases may be considered for external beam radiotherapy , although this is uncommon. - Thyroglobulin is a tumour marker produced by normal thyroid cells and most di ﬀ erentiated thyroid cancers and o ﬀ ers an extremely accurate method of following patients postoperatively . If a lobectomy has been performed the level will not be undetectable, but trends can be used to monitor for recurrence. Following total thyroidectomy , the aim is to have an undetectable thyroglobulin. Patients who achieve this point are at extremely low risk of recurrence. Serial thyroglobulin measurement (6- to 12-monthly) combined with ultrasono - graphic assessment of the neck can then be used to monitor patients during follow-up. If an undetectable level is not achieved, the thyroglobulin can be follow ed. If it increases, imaging should be performed to look for gross recurrent disease. Resectable disease should be addr essed surgically , and normally further radioactive iodine would be indicated. The role of radioactive iodine in a rising thyroglobulin without structural disease is controversial.

Surgical treatment for differentiated thyroid cancer

THYROID ENLARGEMENT

The normal thyroid gland is impalpable. The term goitre (from the Latin guttur = the throat) is used to describe generalised enlargement of the thyroid gland. A discrete swelling (nodule) in one lobe with no palpable abnormality elsewhere is termed an isolated (or solitary) swelling. Discrete swellings with evidence of abnormality elsewhere in the gland are termed dominant. A scheme for classifying thyroid enlargement is given in Table 55.3 . THYROID ENLARGEMENT

THYROIDITIS Chronic lymphocytic (autoimmune) thyro

THYROIDITIS Chronic lymphocytic (autoimmune) thyroiditis (Hashimoto’s disease)

This common condition is usually associated with raised titres of thyroid antibodies. It commonly presents as a goitre, which may be di ﬀ use or nodular with a characteristic ‘bosselated’ feel or with established or subclinical thyroid failure. The diagno - sis often follows investigation of a discrete swelling. Features of chronic lymphocytic (focal) thyroiditis are commonly with other present on histological examination in association thyroid disease, notably toxic goitre ( Figure 55.28 ). Primary myxoedema without detectable thyroid enlargement represents the end stage of the pathological process.

Figure 55.28 Autoimmune thyroiditis (Hashimoto’s disease; struma lymphomatosa). Intense lymphocytic–plasma cell in /f_i ltration, acinar destruction and /f_i brosis.

THYROIDITIS Chronic lymphocytic (autoimmune) thyroiditis (Hashimoto’s disease)

Figure 55.28 Autoimmune thyroiditis (Hashimoto’s disease; struma lymphomatosa). Intense lymphocytic–plasma cell in /f_i ltration, acinar destruction and /f_i brosis.

Thyroid autoantibodies

Serum levels of antibodies against thyroid peroxidase (TPO) and thyroglobulin are useful in determining the cause of thyroid dysfunction and swellings. Autoimmune thyroiditis may be asso - ciated with thyroid toxicity , failure or euthyroid goitre. Levels above 25 /uni00A0 units/mL for TPO antibody and titres of greater than 1:100 for antithyroglobulin are considered signiﬁcant,

(10–30 /uni00A0 nmol/L) Free T (3.5–7.5 /uni00A0/uni03BC mol/L) Free T 4 3 Normal Normal High High Low Low High High (often normal) Normal High

of lymphocytic (autoimmune) thyroiditis are seronegative. The presence of antithyroglobulin antibody interferes with assays of serum thyroglobulin, with implications for follow-up of thyroid cancers. TSH receptor antibodies (TSH-RAb or TRAB) are often present in Graves’ disease. They are largely produced within the thyroid itself. Summary box 55.1 Thyroid investigations /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF

Essential Serum: TSH (T and T if abnormal); thyroid autoantibodies 3 4 Fine-needle aspiration cytology (FNAC) of palpable discrete swellings Optional Corrected serum calcium Serum calcitonin (carcinoembryonic antigen may be used as an alternative screening test for medullary cancer) Imaging: chest radiograph and thoracic inlet if tracheal deviation/retrosternal goitre; ultrasonography, computed tomography (CT) and magnetic resonance imaging (MRI) scan for known cancer, some reoperations and some retrosternal goitres; isotope scan if discrete swelling and toxicity coexist

Thyroid autoantibodies

(10–30 /uni00A0 nmol/L) Free T (3.5–7.5 /uni00A0/uni03BC mol/L) Free T 4 3 Normal Normal High High Low Low High High (often normal) Normal High

Thyroid imaging

The workhorse investigation in thyroid disease for the surgeon is ultrasonography . This modality allows assessment of the gland and the regional lymphatics. Not only can the characteristics of the gland substance be quantiﬁed, but critically the presence and features of thyroid nodules can be described. Number, size, shape, margins, vascularity and speciﬁc features such as the presence of microcalciﬁcations can be used to predict the risk of malignancy within a speciﬁc nodule. Regional lymphatics, particularly in the lateral neck, can be assessed accurately for the presence of metastatic deposits. During ultrasonography , ﬁne-needle aspiration (FNA) can be performed more accurately than free-hand techniques allow . Ultrasonography has the advantages that it is not asso ciated with ionising radiation and is non-invasive and cheap ( Figure 55.5 ). Visualisation of the central neck nodes, in par ticular those behind the sternum, is however limited. For this oss-sectional reason, when metastatic disease is detected cr imaging is required to fully stage the disease. Retrosternal extension, which can often be predicted on a plain chest radio graph ( Figure 55.6 ), also requires more advanced techniques to determine the extent adequately prior to considering man agement. For most of these indications, the imaging modality of choice is CT . Rapid acquisition times minimise artefacts secondary to breathing and the lung ﬁelds can be accurately assessed simultaneously . In the setting of an invasive primary thyroid cancer, both y have a role. Contrast-enhanced CT is useful CT and MRI ma Robert James Graves , 1796–1853, physician, Meath Hospital, Dublin, Ireland, published an account of exophthalmic goitre in 1835. He was President of the Royal College of Physicians of Ireland and elected Fellow of the Royal Society (London, UK) in 1849. - - - -

(b) Figure 55.5 Ultrasonography. (a) Transverse scan of a normal thyroid. R, right lobe; L, left lobe; T, trachea. (b) Longitudinal scan of normal jugular lymph nodes (white arrows). Figure 55.6 Chest radiograph showing a retrosternal goitre with calci

/f_i cation and tracheal displacement (courtesy of Dr Achleshwar Dayal, Hoshangabad, MP , India).

for determining the extent of airway invasion ( Figure 55.7 and MRI is superior at determining the presence of preverte bral fascia invasion. Positron emission tomography (PET) scans have limited application in thyroid disease. They may be considered in the setting of recurrent thyroid cancer. This is particularly use ful when the disease does not concentrate iodine, at which point ﬂuorodeoxyglucose (FDG) uptake increases and lesions become positive on PET scans.

(b)

Thyroid imaging

(b) Figure 55.5 Ultrasonography. (a) Transverse scan of a normal thyroid. R, right lobe; L, left lobe; T, trachea. (b) Longitudinal scan of normal jugular lymph nodes (white arrows). Figure 55.6 Chest radiograph showing a retrosternal goitre with calci

/f_i cation and tracheal displacement (courtesy of Dr Achleshwar Dayal, Hoshangabad, MP , India).

(b)

Thyroid-stimulating antibodies

A family of IgG immunoglobulins bind with TSH receptor sites (TRAbs) and activate TSH receptors on the follicular cell ) are 4 membrane. They have a more protracted action than TSH (16–24 versus 1.5–3 hours) and are responsible for virtually all cases of thyrotoxicosis not due to autonomous toxic nodules. Serum concentrations are very low but their measurement is not essential to make the diagnosis. Thyroid-stimulating antibodies

Treatment

When medullary carcinoma is diagnosed, staging of the neck and chest should be performed. For patients with disease conﬁned to the thyroid, total thyroidectomy is recommended to remove all C cells with elective dissection of the central neck nodes. If there is evidence of nodal metastases, gross disease should be excised but the surgeon should be mindful of morbidity . Such patients are highly likely to develop recurrent disease, hence a pragmatic approach should be adopted (see Chapter 56 ). Treatment

Undifferentiated (anaplastic) carcinoma

This is one of the most aggressive malignancies in humans. Thankfully it is rare. It may develop de novo or present as dedif - ferentiation of a papillary or poorly di ﬀ erentiated carcinoma. The disease is characterised by rapid growth, visceral invasion and distant metastases. The surgeon’s role in this disease is crucial. Thyroid lymphoma can be incorrectly diagnosed as anaplastic cancer and so biopsy is critical. This can be done using a core or open technique. Management is controversial because of the extremely poor prognosis. Occasional patients may present with disease limited to the neck, which appears resectable on imaging. Such patients seem to have a slightly better outcome if trea ted with aggressive surgery and postoperative adjuvant therapy (radiotherapy with/without chemotherapy). However, in the majority , treatment is palliative. Those who develop airway symptoms are generally better managed without tracheostomy , - despite the potentially distressing mode of death. Undifferentiated (anaplastic) carcinoma

55 T_h e thyroid gland

Benign tumours

Calcitonin

Clinical features of thyroid cancers

Clinically discrete swellings

Figure 55.14 Thy3 aspiration cytology ( Table 55.2 ). Follicular neo plasm showing increased cellularity with a follicular pattern. Figure 55.15 Apparently simple cystic thyroid swelling, the wall of which comprised follicular neoplastic tissue.

Figure 55.14 Thy3 aspiration cytology ( Table 55.2 ). Follicular neo plasm showing increased cellularity with a follicular pattern. Figure 55.15 Apparently simple cystic thyroid swelling, the wall of which comprised follicular neoplastic tissue.

Diagnosis of thyroid neoplasms

EMBRYOLOGY

FURTHER READING

Follicular carcinoma

Granulomatous thyroiditis (subacute thyroiditis, d

Granulomatous thyroiditis (subacute thyroiditis, de Quervain’s thyroiditis)

HYPERTHYROIDISM Thyrotoxicosis

Introduction

Introduction

Isotope scanning

(d) Figure 55.7 (a) Scout /f_i lm showing retrosternal goitre. (b) Axial com

(d) Figure 55.7 (a) Scout /f_i lm showing retrosternal goitre. (b) Axial com

Learning objectives

Malignant lymphoma

Malignant tumours

Medullary carcinoma

NEOPLASMS OF THE THYROID

PHYSIOLOGY Thyroxine

Prognosis in differentiated thyroid carcinoma

SURGICAL ANATOMY

Serum thyroid hormones

Simple goitre

Surgery for thyrotoxicosis

Surgical treatment for differentiated thyroid canc

Surgical treatment for differentiated thyroid cancer

THYROID ENLARGEMENT

THYROIDITIS Chronic lymphocytic (autoimmune) thyro

THYROIDITIS Chronic lymphocytic (autoimmune) thyroiditis (Hashimoto’s disease)

Thyroid autoantibodies

Thyroid imaging

(b) Figure 55.5 Ultrasonography. (a) Transverse scan of a normal thyroid. R, right lobe; L, left lobe; T, trachea. (b) Longitudinal scan of normal jugular lymph nodes (white arrows). Figure 55.6 Chest radiograph showing a retrosternal goitre with calci

(b) Figure 55.5 Ultrasonography. (a) Transverse scan of a normal thyroid. R, right lobe; L, left lobe; T, trachea. (b) Longitudinal scan of normal jugular lymph nodes (white arrows). Figure 55.6 Chest radiograph showing a retrosternal goitre with calci

Thyroid-stimulating antibodies

Treatment

Undifferentiated (anaplastic) carcinoma