3.5.3 Management of the single thyroid nodule

The main concern of patients and physicians alike, when dealing with the solitary thyroid nodule, is to diagnose the few cancers (approximately 5%) as rapidly and cost-effectively as possible, and to reduce superfluous thyroid surgery. Management has changed in recent years, but differences prevail as shown by an investigation among European thyroidologists (1). This chapter focuses on the palpably discrete swelling within an otherwise normal gland in the clinically and biochemically euthyroid patient (2, 3). The toxic nodule is dealt with in Chapter 3.3.11, and thyroid malignancy in Chapters 3.5.4–3.5.7.

The estimated life-time risk of developing a thyroid nodule is between 5% and 10% (2, 3), but factors such as sex (4 times more common in women), age (frequency increases with age), regional iodine intake (more prevalent in iodine-deficient areas), and whether the diagnosis is made clinically (palpation), by ultrasonography, or at autopsy (5–10 times more prevalent using the last two) are of importance when estimating prevalence (2, 3). The incidence of clinical disease has been estimated at 0.1% by palpation (2, 3).

Very little is known regarding the natural history of thyroid nodules since data are highly selective and generally concern patients with small nodules without suspicion of malignancy and not causing pressure symptoms or cosmetic complaints. With these restrictions, most nodules appear not to change appreciably over time. The nodules that increase in size are predominantly solid and carry a higher risk of harbouring thyroid carcinoma than those predominantly cystic, being more prone to decrease in size or even disappear.

In most patients, ultrasonography will identify nodules not evident clinically and, given time, most of these patients will be classified as having multinodular goitre. Therefore, the risk of thyroid malignancy is independent of whether the nodule is solitary or the dominant nodule in an otherwise multinodular gland (2–4).

Almost any thyroid disease can appear as a clinically solitary nodule. The differential diagnostic spectrum is given in Box 3.5.3.1. Although 42–77% of surgically removed nodules are colloid nodules, 15–40% are adenomas, and 8–17% are carcinomas, few patients undergo surgery. Therefore, the risk of a solitary nodule harbouring a thyroid carcinoma is no higher than 5–10% (2, 3).

History and physical examination are important and patients with a risk of thyroid carcinoma can be identified (Box 3.5.3.2). A positive family history of benign goitre suggests a benign disorder, whereas medullary thyroid carcinoma or even papillary or follicular thyroid carcinoma in the family should raise suspicion. Nodules occurring in the young or in the old are especially likely to be cancerous, the risk being higher in men than in women. Head or neck irradiation in childhood leads to clinically evident thyroid abnormality in 10–40% of patients 5–40 years later. Thyroid carcinomas, mainly papillary carcinomas, are seen in 30% of those with thyroid abnormality. Rapid tumour growth (weeks to months) and symptoms of local invasion, such as pain, dysphagia, hoarseness, or dyspnoea, suggests a carcinoma, but only a minority of patients have these symptoms. Furthermore, these symptoms can occur in patients with large multinodular benign goitres. Growth during l-thyroxine treatment should raise concern as to possible malignancy.

The physical examination is important in the work-up and certain signs and symptoms are highly suspicious of thyroid malignancy (Box 3.5.3.2), but inter- and intraobserver variation is alarmingly high (5) and the specificity and sensitivity of the diagnosis of a solitary thyroid nodule is low. Thus, nodules of 10 mm or more can usually be palpated depending on their localization in the neck. However, one-half of the nodules found by ultrasound examination escape clinical detection, one-third of which are more than 20 mm in diameter. A hard nodule is not necessarily a carcinoma (chronic thyroiditis), whereas a soft nodule may well be a cystic papillary cancer. Although generally believed to carry a higher risk of thyroid malignancy, the solitary thyroid nodule probably does not imply a higher risk of malignancy than that of a dominant nodule in a multinodular goitre (2–5). In view of this, fine-needle aspiration biopsy (FNAB) is mandatory but should be interpreted in the light of the history and the physical examination. As a consequence, several patients are operated on in spite of a benign cytology (1).

The only relevant biochemical test that is routinely needed is serum thyroid-stimulating hormone (TSH) measured with a sensitive assay. Subnormal serum TSH values should lead to determination of free thyroxine (T₄) and free triiodothyronine (T₃). In the presence of normal thyroid hormone levels, a suppressed serum TSH on repeat examination should lead to treatment, especially in older patients (Chapter 3.3.4). Scintigraphy is advised and will most likely demonstrate a hot or a toxic nodule (Chapters 3.1.6 and 3.3.11) in such patients. Most patients are euthyroid, including those with thyroid malignancy. It seems that the risk of malignancy in a thyroid nodule increases with serum TSH concentration, within the normal range, at presentation, and thus serves as an adjunctive and independent predictor of malignancy (6). Hypothyroidism suggests that the patient has Hashimoto’s thyroiditis.

Thyroglobulin in serum is positively correlated with thyroid size but has no place in the routine investigation or in the follow-up of benign nodules. Calcitonin is the only clinically relevant biochemical marker of medullary thyroid carcinoma. Routine determination has been suggested by European guidelines (7). It allows the detection of unsuspected medullary thyroid carcinoma with a frequency of 1 in 200–300 thyroid nodules, with better sensitivity than FNAB (7). However, there remains unresolved issues of sensitivity, specificity, assay performance, and cost-effectiveness. Thyroid autoantibodies against thyroid peroxidase cannot differentiate between malignant and benign disease. In our opinion, they should be determined routinely in the work-up to identify patients with possible Hashimoto’s thyroiditis. These antibodies are markers of an increased risk of developing hypo- or hyperthyroidism (Graves’ disease) spontaneously or secondary to surgery or radio-iodine treatment (8). TSH-receptor antibodies are rarely present and should not be determined routinely.

No method of imaging can differentiate benign and malignant nodules accurately. However, 88% of European thyroidologists use either scintigraphy (66%), ultrasonography (80%), or both (58%) in the evaluation of patients with a clinically solitary thyroid nodule, illustrating that the diagnosis is not always straightforward and that they believe diagnostic imaging gives valuable information (see also Chapters 3.1.6 and 3.1.6.1) (1).

There is no consensus on the use of scintigraphy in the euthyroid patient. Since most have a cold nodule—increasing the risk of thyroid malignancy at least 10-fold—many investigators, mainly in the USA, advocate the use of FNAB as the first step (2, 3). Imaging, if performed, can be with ¹²³I, ¹³¹I, or ^99mTc pertechnetate, the last being preferred (86%) among European thyroidologists (1), although iodine should be used if the aim is also to reduce the risk of overlooking malignancy. A clinically dominant nodule that is cold on scintigraphy, should be treated as a solitary cold nodule, the risk of malignancy being the same (2–5), and FNAB should be performed. In case of suppressed serum TSH or overt hyperthyroidism, the risk of malignancy is thought to be much lower as is the need for FNAB.

Ultrasonography, often used in Europe (80%) and less so in the USA, allows determination of total thyroid volume, individual nodule size and echogenicity, morphology of extranodular tissue, and investigation of regional lymph nodes (1). Supplemental colour flow Doppler adds information regarding regional blood flow and nodule vascularity. Ultrasonography aids in performing accurate biopsies and cyst punctures, as well as therapeutic procedures such as percutaneous ethanol injection and laser therapy of solid as well as cystic nodules (2, 9, 10). There is no ultrasound pattern, alone or in combination with other techniques, that may be considered specific for thyroid cancer. For the objective determination of thyroid or nodule size, whether initially or during follow-up, it is the technique of choice. CT and MRI are generally of little value except in the evaluation of the intrathoracic goitre or in the evaluation and follow-up of malignant thyroid disease.

FNAB provides the most direct and specific information about a thyroid nodule, and it is used by 99% of European Thyroid Association members on an outpatient basis (1). As the cornerstone in the evaluation it is virtually without complications, inexpensive, and easy to learn to perform. Its use reduces the number of thyroidectomies by approximately 50% (2, 3), roughly doubles the surgical yield of carcinoma, and reduces the overall cost of medical care in these patients by 25% (2, 3).

The technique involves the use of a 5- to 20-ml plastic syringe with a 22- to 27-gauge needle. The skin is cleaned with alcohol and may be infiltrated with 1–2 ml 1% lidocaine, but, in general, local anaesthesia is not needed for FNAB of palpable nodules. The needle, attached to the syringe, is quickly inserted perpendicularly to the anterior surface of the neck (Fig. 3.5.3.1). Rapid (three excursions per second) sampling motions with brief dwell time within the nodule may diminish bloody dilution (11). Negative pressure is only applied if no fluid appears in the hub of the needle. Production of one or two slides per biopsy reflects an appropriate dwell time. No fluid should enter the syringe. If the nodule is a cyst or partly cystic, the aspiration should be followed by FNAB of any residual solid component. Investigation of the cyst sediment rarely gives useful information.

Diagnostically useful FNAB specimens are obtained in about 80% of cases (Box 3.5.3.1). The number of insufficient samples depends on operator experience, number of aspirations, the character of the nodule (cystic/solid), the experience of the cytopathologist, and especially the criteria used for adequacy of a sample. The number of sufficient samples increases if FNAB is guided by ultrasound. Rebiopsy will typically halve the number of insufficient biopsies. Needle-steering devices and pistol-grip equipment are used by some. The specimens should be smeared immediately (pull-apart technique) and most are air dried. Staining is with May-Giemsa-Grünwald stain, which is good for cytoplasmic details, or alternatively Papanicolaou’s stain, which is good for nuclear details.

Diagnostic accuracy of FNAB depends upon the handling of suspicious lesions. If considered negative, sensitivity will decrease and specificity will increase. If suspicious results are regarded as positive, the converse is true. In our opinion, patients with suspicious, malignant, and nondiagnostic cytology (after reaspiration) should be operated on (Table 3.5.3.1). The relevant question is what the false-negative rate is in the remaining 70–80% of cases in which nonsurgical treatment is an option. This has generally been estimated at 1% (2). Repeat FNAB during follow-up, to decrease the false-negative rate, will virtually eliminate the risk of overlooking thyroid malignancy.

Large-core needle biopsies can be considered when cytopathology expertise is not available. Its limitations include the need for local anaesthesia, local discomfort, and decreasing patient acceptance of repeat biopsies (11).

The optimal therapy for patients with thyroid nodules varies with the lesion and whether or not it is functioning (Table 3.5.3.1).

The main indications for surgery are malignant or suspicious cytological features and symptoms due to the nodule itself. Certain clinical features raising the suspicion of thyroid malignancy (Box 3.5.3.2) are an indication for surgery despite a benign cytology as recommended by most European thyroidologists (1). The frequency of complications due to surgery decreases with increasing experience and specialized training. Results from a specialist department for thyroid surgery indicate very low rates of complications: temporary and permanent unilateral vocal cord paralysis (2% and 0.7%, respectively), temporary and permanent hypocalcaemia (0.6% and 0.7%, respectively), and wound haematomas and infections (0.5% and 0.3%, respectively) (13). The likelihood of surgical complications increases proportionally with the extent of operation. Patients with benign cytology, in whom clinical suspicion results in referral for surgery, may generally be managed with lobectomy (hemithyroidectomy). Endoscopic surgery has the advantage of improved cosmetic results but is limited due to decreased ability to control bleeding and evaluate nodal status and to perform definitive procedures when a frozen section is reported malignant. l-thyroxine postoperatively to prevent regenerative hyperplasia is not recommended routinely (1, 2, 14).

Thyroid suppression is intended to shrink or slow the growth of thyroid nodules, and also to prevent the occurrence of new nodules. However, most evidence suggests that changes in nodule size are similar in TSH suppressed and control groups and treatment seems at best beneficial in a subgroup of patients with smaller solid nodules (15). Twenty per cent or less of solitary nodules will actually regress as a result of l-thyroxine treatment, and regrowth is seen after cessation of therapy (8, 15). Long-term results confirm that the nodule-reducing effect of l-thyroxine is insignificant (16). Growth can be suppressed or slowed and the formation of new nodules may be prevented. Nodules grow less if serum TSH is suppressed to less than 0.1 mU/l, than if TSH is more than 0.1 mU/l (16). This degree of TSH suppression may, however, have adverse effects. Because suppressive treatment (by definition) produces subclinical hyperthyroidism, treated patients are at increased risk of atrial fibrillation, other cardiac abnormalities, and reduced bone density. These side effects, combined with the questionable efficacy, have led to recommendations that vary depending upon the age, sex, and menopausal status of the patient. l-thyroxine suppressive therapy is least tempting in elderly patients and in postmenopausal women. It should be reserved for small nodules—where treatment is least necessary—in younger patients living in borderline iodine-deficient areas. Based on management guidelines and meta-analyses, routine suppression therapy of benign thyroid nodules is discarded (2, 7, 12, 17).

Absolute ethanol (70–100%) can cause permanent tissue ablation due to coagulative necrosis and local small vessel thrombosis. It has proved useful in the treatment of autonomously functioning thyroid nodules, cystic thyroid nodules, and solid cold thyroid nodules (8). Using multiple ethanol injections, complete cure (normalization of scintigraphy and serum TSH) can be achieved in two-thirds of patients with toxic nodules and three-quarters of patients with pretoxic nodules. A single ethanol instillation in thyroid cysts prevents recurrence in 80% of patients (18). A single small dose of ethanol injected into benign cold solitary solid thyroid nodules results in relief of clinical symptoms in 50% of patients based on a nodule volume reduction of about one-half (2, 8).

Limitations are the need to repeat ethanol injections to achieve complete cure in toxic and pretoxic nodules and to prevent renewed growth in solid cold nodules. Furthermore, the procedure is often painful despite local anaesthesia. To minimize the risk of complications, each dose should be no more than 20% of the pretreatment nodule volume. The special technical skill obtained at a centre familiar with interventional ultrasonography reduces the risk of complications.

Following an approximately 10-min session of ultrasound-guided laser thermal ablation, a 50% reduction (very similar to that of ethanol injection) in nodule volume can be achieved (10, 19). This effect seems independent of whether the nodule is hot or cold. One or two additional sessions augment this effect by up to 30% (10). Side effects are mainly related to various degrees of local and irradiating pain, which is much milder than with ethanol injection. Laser treatment has only been introduced in a few centres and, while awaiting long-term follow-up data, it should be considered experimental (10, 19).

In the clinically euthyroid patient, autonomous thyroid nodules may present as a hot lesion on scintigraphy with varying degrees of extranodular suppression. Most of these patients have suppressed serum TSH (see also Chapters 3.3.4 and 3.3.11). Treatment may be dictated either by the nodule size, causing compression of the adjacent structures, or cosmetic disturbances. Additionally, treatment is given to prevent thyrotoxicosis (annual risk about 5%), particularly in patients with heart disease or older patients (8, 20). A cure rate (normalization of scintigraphy and serum TSH) of 75% and volume reduction of 40% following a single dose of radio-iodine can be anticipated (8, 20). Side effects are few and consist of hypothyroidism in about 10% after 5 years and seem unrelated to any type of dose planning (20). Treatment must be individualized based on the patient’s preference and risk factors for adverse effects. Table 3.5.3.1 summarizes the advantages and drawbacks of the treatment options.

Recommendations on management of the single thyroid nodule are based on fair evidence and FNAB has been as the cornerstone for almost 30 years, despite significant shortcomings in sensitivity and specificity. The recent application of microarray analysis to tumour biology has provided a novel opportunity for classifying tumours based on gene expression profiles (21). This might provide a foundation for the future addition of gene profiling to thyroid FNAB and ultimately improve the distinction between follicular carcinomas and adenomas.