Thyroid function tests: Thyroid function homeostasis is dependent upon the pituitary–thyroid axis feedback loop (Fig. 2.2). Thyroid function tests (TFTs) identify hypo- or hyperfunction through quantification of not only circulating thyroid hormones (T₃ and T₄) but, more importantly, thyroid-stimulating hormone (TSH or thyrotropin). In keeping with the negative feedback loop, thyroid hyperfunction results in a suppressed TSH, in the presence of increased circulating T₃ and T₄. Conversely, reduced hormone levels lead to an increase in TSH.³ (also see section on hyperthyroidism).

Thyroid antibodies:

Biomarkers of malignant disease:

Ultrasonography: Ultrasound (US) is the imaging modality of choice for evaluation of the thyroid gland and associated lymph nodes. It is accessible, inexpensive, non-invasive and well tolerated. Surgeon-performed thyroid US is increasingly becoming a standard skill set and it has been shown that surgeon-performed US leads to beneficial changes in diagnosis and management.¹⁰ It also affords the clinician the added advantage of an intimate anatomical knowledge of the region to be dissected, which is of particular benefit in re-operative surgery or where selective lymph node dissection is anticipated.

US features that are suspicious for malignancy include microcalcifications, intranodular hypervascularity, hypoechoeic nodules, irregular margins and extracapsular extension (see Box 2.3).

Nodules and lymph nodes may also be aspirated under US guidance, ensuring precise sampling and avoidance of complications. US-guided fine-needle aspiration (FNA) has been shown to produce lower rates of non-diagnostic and false-negative cytology specimens, when compared to FNA performed by palpation only.

Nuclear medicine studies: Thyroid isotope scanning employs intravenous radiolabelled iodine (¹³¹I or ¹²³I) or technetium pertechnetate (^99mTc), which are taken up by active thyroid cells and detected by gamma-ray cameras. Isotope scanning may be used in determining the cause of hyperthyroidism, identifying ectopic thyroid tissue or postoperative remnant tissue and detecting metastases of differentiated thyroid cancers. It is also used for surveillance after treatment of differentiated thyroid cancers.

Computed tomography: Computed tomography (CT) scanning gives detailed anatomical definition of the thoracic inlet and associated structures, and is therefore of utility in the management of retrosternal disease. The degree of tracheal compression and distortion of adjacent structures by a bulky retrosternal goitre can be adequately defined (Fig. 2.3). The presence of mediastinal, pulmonary or more distant metastases in thyroid cancer can also be quantified. Often, CT scanning will dictate the surgical approach, with a large retrosternal goitre or low mediastinal metastases being indications for sternotomy. In locally aggressive cancers, CT scanning is a useful modality in assessing invasion of the aerodigestive tract and internal jugular veins (Fig. 2.4).

Causes of multinodular goitre:

Pathogenesis: There are two stages in the development of MNG, which may be separated by a long period of time, sometimes as long as decades. The early stimulus for generalised thyroid hyperplasia is most commonly due to iodine deficiency in endemic areas, whereas in sporadic MNG, genetic predisposition or ingested goitrogens may be the stimulus. The second stage of MNG formation is due to focal somatic mutations. Although most of the mutations result in enlarged colloid follicles, focal hyperplasia, hypertrophy, adenoma or even carcinoma can all contribute to the MNG. Over time, these nodules become intersected by areas of fibrosis.15–17

Management of benign MNG: Surgery is the only effective way of treating compressive symptoms of the aerodigestive tract caused by MNG. As such, this constitutes the main indication for surgery. Other indications include MNG with nodules suspicious of malignancy on FNA, toxic MNG and retrosternal goitre.

Total thyroidectomy (TTx) has replaced subtotal thyroidectomy (STTx) as the procedure of choice for benign MNG. The major issue with STTx is recurrence, with long-term follow-up data showing eventual recurrence in up to 50% of patients.¹⁸ Furthermore, if secondary surgery is subsequently required for symptomatic recurrent goitre, the risk of complications rises. A significantly higher complication rate has been reported in patients undergoing re-operative thyroidectomy for recurrence after initial STTx, compared to those who had a primary TTx.¹⁹

Papillary thyroid carcinoma: The molecular studies over the last two decades have led to the observation that PTC is characterised by genetic lesions that activate the mitogen-activated protein kinase (MAPK) signalling pathway. These genetic lesions can be produced by chromosomal rearrangements such as RET/PTC, TRK and AKAP9/BRAF oncogenes, or point mutations such as BRAF and RAS oncogenes.²⁶

The RET proto-oncogene encodes a receptor-type tyrosine kinase. In PTC, RET is mutated by chromosomal rearrangements where the tyrosine kinase domain is fused to a variety of donor genes causing constitutive activation of the tyrosine kinase domain. RET/PTC1 and RET/PTC3 are the commonest combinations, and they account for over 90% of all RET rearrangements in PTC. Tumours with RET/PTC rearrangements are typically of the classical variant of PTC.²⁶

The BRAF protein is the B-isoform of the intracellular Raf kinase within the MAPK signalling cascade. The BRAF gene is mutated in a variety of human cancers, and by far the commonest mutation involves a valine-to-glutamate substitution at residue 600 (BRAF^V600E). This substitution results in constitutive activation of Raf kinase and subsequently up-regulation of the MAPK pathway. BRAF^V600E is detected in 29–69% of PTC cases, and can be associated with the classical and tall cell variants of PTC, as well as poorly differentiated and anaplastic thyroid carcinomas. Some studies report association of BRAF^V600E with more aggressive clinicopathological features; however, this view is not universal.²⁶

Follicular thyroid carcinoma: The common genetic mutations associated with FTCs are RAS mutations, PAX8/PPAR-γ rearrangement and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway deregulation.

Oncogenic mutations may involve any of the three members of the RAS gene family. RAS mutations reportedly occur in up to 50% of FTCs, 40% of follicular adenomas, 25% of Hurthle cell carcinomas (HCCs) and 20% of follicular variant PTCs. They are also seen frequently in PDTC and ATC. The presence of RAS mutations in follicular adenomas is a clue to the adenoma–carcinoma sequence in the pathogenesis of FTCs. Significant correlation between RAS mutations to metastases and poor prognosis has been found.²⁶

The PAX8/PPAR-γ rearrangement results in a fusion of the DNA-binding domain of PAX8 to the peroxisome proliferator-activated receptor PPAR-γ. The fusion protein stimulates proliferation of thyrocytes by an unknown mechanism. The PI3K/Akt pathway is central for many cellular events such as growth, proliferation and apoptosis. Its constitutive activation by mutations is a common feature in many cancers, including FTC.²⁶

Risk factors: The most well-established environmental risk factor for thyroid cancer is exposure to ionising radiation.²⁷ PTC is the type of thyroid cancer that is associated with radiation exposure, which induces damage to cellular DNA, commonly causing RET/PTC chromosomal rearrangements. The effect is most pronounced in children, and the latency period ranges from 5 to 30 years. In a patient with a history of radiation exposure, the overall risk of malignancy in a nodule is 30–40%; therefore, an initial TTx is recommended.²⁸

No susceptibility gene for hereditary non-medullary thyroid cancer (HNMTC) has been identified; however, epidemiological studies have shown that they are more aggressive than sporadic disease. The risk of developing thyroid cancer is 5 to 10 times higher in patients with a first-degree relative who has thyroid cancer, when compared to the general population. Features such as early age at presentation, reversed gender distribution, large tumour size, tumour multicentricity and aggressive tumour biology are clues to suspect such a kindred. Until specific gene(s) are identified, a detailed family history is the only way to identify these at-risk families. HNMTC may also be part of another familial syndrome, such as familial adenomatous polyposis (APC), Cowden syndrome (PTEN), Carney complex type 1 (PRKAR1α), McCune–Albright syndrome (GNAS1) and Werner syndrome (WRN) (see Chapter 4 for further details).²⁹

Pathology:

Staging: As many as 17 staging and prognostic systems for DTC have been reported in the literature since 1979.³⁵ The sixth edition AJCC/IUCC staging system is currently one of the most commonly used systems. Other commonly used systems include AMES (Age, Metastasis, Extent, Size) from the Lahey Clinic, AGES (Age, Grade, Extent, Size) and MACIS (Metastasis, Age, Completeness of resection, Invasion, Size) from the Mayo Clinic, and EORTC staging from the European Organisation for Research and Treatment of Cancer. Some interesting observations can be made from these systems. Like all other staging systems, pathological features such as tumour size, grade, extent and presence of metastasis feature uniformly throughout the different classification systems. However, nodal status is notably absent in many of these systems apart from the AJCC system. This relates to the fact that these systems were mostly developed to predict disease-specific survival, and so far most studies do not correlate nodal status with survival, although the evidence is not conclusive at this stage. This must be borne in mind when using these prognostic systems during patient follow-up for recurrence. The ATA published a three-tier risk stratification that is useful for the purpose of surveillance (Table 2.5). Another unique factor in the AJCC staging for DTC is the inclusion of age. Patients under the age of 45 have excellent prognosis regardless of nodal status, and a small decrease in survival in the presence of metastases. As such, the highest stage for patients under 45 years of age is Stage II.

Work-up: Patients with thyroid cancer most commonly present with a neck lump. They can also be completely asymptomatic and be diagnosed incidentally on imaging or on the operative specimen where the indication for thyroidectomy was for a benign condition. A thorough history and examination, followed by appropriate investigations, is required when a patient presents with a complaint related to the thyroid. Certain clinical features should raise the suspicion of malignant thyroid disease (Box 2.3).

Surgery of DTC: Various guidelines have been developed based on mostly retrospective data (Box 2.4). Due to the overall high rate of long-term survival of patients with thyroid DTC, prospective randomised data are near impossible to obtain. This has resulted in difficulties in resolving some of the controversies in the management of DTC.

It is important to recognise the various goals of initial treatment for DTC. Besides the usual goals of complete resection and accurate pathological staging, minimising treatment morbidity and facilitating long-term surveillance are more important than in other cancers due to the excellent long-term survival of patients with DTC. The management goals are listed in Table 2.6.

Adjuvant treatments: Patients with thyroid cancer should be managed in a multidisciplinary setting, involving endocrine surgeons, endocrinologists, nuclear medicine physicians, radiologists and oncologists.

Radioactive iodine (RAI) ablation is recommended for patients with known distant metastases, gross extrathyroidal extension, primary tumour > 4 cm, regional lymph node metastases, or presence of high-risk features. It is not recommended for patients with unifocal cancer < 1 cm without high-risk features, or patients with multifocal cancer all < 1 cm and without high-risk features. TSH suppression therapy with thyroxine is also recommended.

Follow-up: Initial follow-up is recommended 6–12 months after initial treatment, with Tg measurements, diagnostic whole-body nuclear medicine scan and neck US. Disease-free status is defined by absence of clinical evidence of disease, absence of imaging evidence of disease and undetectable Tg level during TSH suppression and stimulation, in the absence of Tg antibodies.

Surveillance of recurrence is also by means of Tg measurements, diagnostic nuclear medicine scan and neck US. The frequency depends on the patient’s ATA risk category (Table 2.5).

1. Presence of a trabecular/insular/solid growth pattern.

2. Absence of the classical PTC nuclear features.

3. Presence of convoluted nuclei, mitotic activity  > 3 × 10HPF (high-power field) or tumour necrosis.⁴⁷

Pathology: Medullary thyroid carcinoma is a disease of the neuroendocrine-derived, calcitonin-producing, parafollicular C cells (Fig. 2.8). Whilst primarily characterised by discovery of the RET proto-oncogene, up to 50% of cases do not harbour an identifiable mutation.⁵¹ The RET mutation is thought to trigger constitutive phosphorylation of the tyrosine kinase receptor, leading to an increase in intracellular messaging and unregulated cellular proliferation. This typically leads to C-cell hyperplasia as a precursor to development of carcinoma. Characteristic histopathology is supplemented by immunohistochemistry showing calcitonin positivity. Cases of MTC are not uncommonly identified by FNAC.

Clinical features: Patients undergoing genetic testing may be brought to the clinician’s attention before development of clinical features, and this is the most common mode of presentation in HMTC. Sporadic disease, by contrast, is more likely to manifest clinically with local symptoms or even problems related to metastases. Identification of a thyroid nodule or mass is the most common presenting complaint. Compressive symptoms of neck fullness, dysphagia, shortness of breath or hoarse voice may occur with more advanced disease. Systemic symptoms such as bone pain, flushing or diarrhoea may be encountered as the presenting feature in 10% of patients. Distant metastases most commonly occur in bone, liver and lung.⁵²

Patients with SMTC typically present later than those with HMTC (47 years vs. 30 years).⁵² The burden of disease at diagnosis is dependent upon the mode of presentation. In patients with palpable disease at diagnosis, two-thirds will have involved ipsilateral cervical lymph nodes and one-third will have contralateral nodal involvement.⁵³

Diagnosis: Diagnosis follows the general schema for investigation of a thyroid nodule. Imaging should include assessment of the cervical lymph nodes. If suspicious for MTC, FNAC of the thyroid nodule or cervical lymph node should also be stained for calcitonin. Identification of MEN-associated pathology such as phaeochromocytoma or hyperparathyroidism should prompt investigation to identify a related MTC.

A diagnosis of MTC should prompt baseline serum measurements of known biomarkers, namely calcitonin and CEA. RET mutation testing and investigations to delineate MEN-related pathologies (phaeochromocytoma and parathyroid adenoma) should also be performed. A phaeochromocytoma must always be excluded before proceeding to thyroid surgery and, if present, it should take clinical precedence. A dedicated neck ultrasound should be performed to detect nodal disease prior to thyroid surgery.

In general, all first-degree relatives of an individual with MTC in association with an identified germline RET mutation should undergo genetic testing. This should be performed under the guidance of a genetic counsellor or experienced endocrinologist.

Treatment: Management of MTC is based on the extent of disease at presentation. A preoperative diagnosis should be treated with TTx and bilateral CLND (level VI).⁵⁴ Any lateral nodal disease evident clinically, radiologically or proven by biopsy should be managed with an ipsilateral compartmental LLND (levels II, III, IV and V).

In the presence of metastatic disease, a palliative TTx and CLND should also be carried out to reduce the burden of local mass effect. Where curative resection is not possible, a debulking operation may be undertaken while avoiding the sacrifice of functionally important structures such as the RLNs and parathyroid glands. Surgical debulking can offset ongoing morbidity associated with incurable MTC, and may even extend to sternotomy and/or thoracotomy for surgical management of chest metastases.

Often, a diagnosis of MTC is only made postoperatively following pathological examination of a thyroid resected for an alternative indication. If this is the case, the previously mentioned staging investigations should still be performed and a plan of appropriate treatment developed based on the same principles.

During thyroidectomy, resected or devascularised parathyroid glands should be autografted but the preferred site of transplantation differs according to genetic mutation status if known, owing to the possibility of future parathyroid pathology. Autografts should be in the neck for RET-negative, MEN2B and familial MTC (FMTC) patients, and in a heterotopic site (e.g. brachioradialis muscle) for MEN2A patients.⁵⁴

Medical therapy for advanced disease with tyrosine kinase inhibitors has shown promise in recent clinical trials.⁵⁵ Radiotherapy is controversial and has not been shown to lead to improved survival outcomes, but may be utilised in selected cases for locoregional control of disease.⁵⁴

Prophylactic thyroidectomy for RET-positive family members of the index case may need to be undertaken. This may involve operating upon paediatric patients, often under the age of 1 year, depending on the inherited mutation. TTx in these circumstances is technically challenging and should only ever be undertaken in tertiary centres by experienced surgeons. ATA guidelines provide a schema that identifies when patients should be offered a total thyroidectomy based on the inherited RET mutation.⁵⁴

Prognosis: Overall 10-year survival of patients with MTC averages 75%.⁵² It can, however, be a heterogeneous disease, with some patients living years with bulky and persistent disease. Numerous clinical (age, gender), histopathological (tumour size, lymphovascular invasion), biochemical (calcitonin, CEA) and genetic (RET mutation) variables have been evaluated as potential markers of prognostic significance.

Only age and stage of disease at diagnosis have been found to be statistically significant predictors of survival on multivariate analyses, with 5-year survival rates ranging from 100% (Stage I) to 56% (Stage IV). The presence of cervical node metastases is associated with persistent or recurrent disease but does not appear to confer negatively upon survival and is therefore not considered an independent risk factor. Overall 5- and 10-year cause-specific mortality has been shown to be 13–33% and 22–39%, respectively.⁵²

Follow-up: Serum calcitonin (and/or CEA) estimation at 3 months allows stratification of patients into one of two groups: those negative for disease and patients with elevated calcitonin who are considered to have ‘persistent’ disease. Persistent and recurrent cases can be considered to have ‘residual’ disease. In general, most patients can be monitored 3-, 6- and 12-monthly, with annual clinical examination and biomarker estimation. Ultrasound may be used as an adjunct to investigate clinical or biochemical suspicion of local disease recurrence or where residual disease is being monitored. Assessment of metastatic disease is typically with multimodal imaging, including US, CT, magnetic resonance imaging (MRI) and bone scan where appropriate.

Primary thyroid lymphoma: Primary thyroid lymphoma accounts for less than 5% of all thyroid malignancy. It is important to differentiate it from other forms of thyroid cancer, as a prompt diagnosis leads to potentially curative treatment without the need for surgery. It generally presents in older patients with a rapidly enlarging painless neck mass and associated local compressive symptoms. A history of autoimmune thyroiditis is important and this is thought to be the means by which lymphoid aggregates develop within the thyroid parenchyma, as in health there is no lymphatic tissue within the gland itself. Thus, Hashimoto’s disease is a strong risk factor. Non-Hodgkin B-cell lymphoma is the most common pathology encountered. Fine-needle biopsy yields mixed results and a biopsy dominated by lymphocytes (particularly if atypical) should arouse suspicion, but may still be difficult to distinguish from Hashimoto’s disease. Core or open surgical biopsy with histology, immunohistochemistry and flow cytometry is the preferred means of diagnosis.⁵⁷

Treatment consists of chemoradiation. The role of surgery is controversial and should be considered on an individual basis primarily for palliative debulking of compressive neck disease. Prognosis is dependent upon the specific subtype of lymphoma and the associated grade and stage of disease. In general, a 60% overall 5-year survival can be expected.⁵⁸

Squamous cell carcinoma: Primary squamous cell carcinoma of the thyroid is a rare and aggressive disease. When identified, distinguishing primary disease from a metastatic deposit is important relative to further investigation and management. The prognosis for primary disease is poor; palliative, supportive therapy may be the only option at diagnosis.⁵⁹

Metastatic carcinoma to the thyroid: Metastatic disease to the thyroid from another primary site may occur with a range of malignancies. The use of modern PET scanning, for instance, is leading to detection of small metastatic deposits in thyroid tissue during staging for other cancers. Management is dependent on the primary disease, with the indication for thyroidectomy or debulking entirely hinging on the prognosis of the disease.

Diagnosis of thyrotoxicosis: The most sensitive and specific single blood test in the evaluation of thyroid function status is serum TSH, and it can be used as a screening test. This is due to the inverse log-linear relationship between TSH and free T₄ (FT₄) in patients with an intact pituitary–thyroid axis. That is, small changes of FT₄ result in large changes in TSH. With the addition of serum FT₄, the diagnostic accuracy is enhanced for patients with suspected hyperthyroidism. Typical thyroid function test (TFT) profiles are shown in Table 2.8.

Determination of aetiology: In most situations, after thorough history, examination and review of the medication list, TRAb levels and thyroid uptake scans are sufficient to establish the common underlying aetiology of thyrotoxicosis. Graves’ disease is suspected in a patient with a diffuse goitre, recent onset of ophthalmopathy, and moderate to severe hyperthyroidism (undetectable TSH and significantly elevated FT₄). The diagnosis can be confirmed by elevated TRAb levels. No uptake scan is required in this situation. However, if the diagnosis is still uncertain or other causes of thyrotoxicosis are considered, a thyroid scan is indicated in the setting of suppressed TSH. The pattern of tracer uptake in the thyroid gland provides clues to the likely aetiology. However, it should always be interpreted in conjunction with the clinical presentation and other investigations. Table 2.9 and Figure 2.10 show the various patterns of tracer uptake and their likely diagnosis.

Ultrasonography of the thyroid gland can provide further anatomical information, in particular regarding gland nodularity, echogenicity and vascularity. In some European centres, sonography can provide enough information for the diagnosis of the aetiology of hyperthyroidism without thyroid scintigraphy. This technique is of particular value in situations where thyroid scintigraphy is not appropriate, such as during pregnancy.⁶¹

End-organ effects: Cardiac function in the elderly is especially affected by long-term hyperthyroidism, in particular due to GD. Evaluation of cardiac function may be necessary, and is essential prior to undergoing surgery. Cardiac function assessment can be achieved by way of echocardiogram, electrocardiogram, Holter monitor and/or myocardial perfusion studies.

Referral to an ophthalmologist for assessment and management of Graves’ ophthalmopathy (GO) may be required.

Symptomatic management: Beta-adrenergic blockade is the first-line treatment for patients with symptomatic thyrotoxicosis. It not only decreases heart rate, systolic blood pressure, muscle weakness and tremor, but also the degree of irritability, emotional lability and improves exercise tolerance. Commonly used beta-blockers include propranolol, atenolol and metoprolol. Alternatives or adjuncts to beta-blockers are calcium channel blockers such as verapamil and diltiazem.

Management – Graves’ disease: Graves’ disease can be treated in one of three ways – ¹³¹I therapy, antithyroid drugs (ATDs) or TTx. There are regional differences in preference around the world. For example, in the USA, RAI is the preferred therapy, whereas in Europe and Japan there is greater preference for ATDs and/or surgery. A detailed discussion between the treating doctor and patient regarding the strengths and weaknesses of each modality is required to reach a treatment decision (Table 2.10). There is no difference in the long-term quality of life in patients with GD treated with any of the three modalities.

Management – TMNG: Although both surgery and ¹³¹I are recommended options in the ATA guidelines, a 20% risk of recurrence following ¹³¹I therapy is considered unacceptably high in some centres, hence surgery is the preferred treatment for TMNG. Recurrence after total thyroidectomy by experienced endocrine surgeons should be < 1%. Likely sites of recurrence are at the pyramid, tubercle of Zuckerkandl and retrosternal rests.⁶²

Management – TA: Again, the treatment options for TA are surgery and ¹³¹I therapy. Surgery carries a < 1% risk of recurrence, while ¹³¹I therapy is associated with a 6–18% risk of persistence and 5.5% risk of recurrence.

Preoperative considerations: Patients with hyperthyroidism should be rendered euthyroid before submitting to surgery. This is best achieved with carbimazole. Beta-blockers can be used as supplementary symptomatic control, while iodine is given for 10 days before surgery for patients with GD. Treatment with iodine (in the form of Lugol’s solution or saturated solution of potassium iodide or inorganic iodine) facilitates surgery by decreasing thyroid vascularity. Iodine treatment is not necessary in patients with TMNG. Corticosteroids can also be administered in addition to iodine, especially in cases of emergency surgery requiring rapid preparation. Close monitoring of the patients after surgery is still required as thyroid storm can occur up to 24 hours after removal of the thyroid gland.

Operative considerations: Total thyroidectomy is the procedure of choice for the treatment of GD and TMNG. When performed by experienced surgeons it is associated with a very high cure rate and low morbidity. Subtotal thyroidectomy (such as Dunhill’s procedure) carries an 8% risk of persistence or recurrence, and a 50% chance of requiring thyroid hormone supplementation. Therefore, in most endocrine surgical centres, subtotal thyroidectomy for hyperthyroidism is now mostly historical.^63,64 In the case of TA, a unilateral lobectomy (or hemithyroidectomy) is usually all that is required.

Postoperative considerations: Patients with severe GD may develop ‘bone hunger’ postoperatively, requiring large amounts of calcium supplementation. However, oral calcium and calcitriol supplementation is usually adequate. Routine measurements of serum corrected calcium and intact PTH (iPTH) should guide calcium supplementation for all patients after TTx. Serum magnesium level should be measured and supplemented as required if intravenous calcium is required to maintain adequate serum calcium levels in the postoperative period.