Thyroid swellings - principles and approach to treatment

Siu-Kwan Ng 吳少君, Bertrand C H Leung 梁知行, Terry C W Hung 洪致偉, Alexander C Vlantis 屈力行, Michael C F Tong 唐志輝

HK Pract 2005;27:424-432

Summary

Thyroid swellings are common in clinical practice. A systematic approach to their management is recommended. An excisional biopsy for every patient with a thyroid swelling is impractical and would expose them to unnecessary risks. A good clinical assessment with appropriate use of special investigations will lead to the correct diagnosis and minimize the risks of an invasive procedure. This article is a broad overview of the approach to thyroid swellings.

摘要

甲狀腺腫物是常見的臨床問題。為每位患者施行組織切除活檢不單不可行， 還令病人承擔不必要的危險，所以系統性的診治方法非常重要。好的臨床評核配合適當的特別檢查， 既可做出正確診斷又可以減少創傷性檢查。本文就甲狀腺腫物的診斷及治療做了廣泛，全面回顧。

Introduction

Thyroid swellings are commonly encountered in clinical practice. The management of patients with thyroid swellings is complicated by the possible differential diagnoses as well as by the large number of diagnostic tools available. In simple terms, the important task when evaluating a patient with a thyroid swelling is to determine whether the swelling is benign or malignant. If the thyroid swelling is benign, the need for active management is based on the clinical assessment and biochemical thyroid function tests. Indications for the active management of a benign thyroid swelling include a swelling that is:

1. associated with thyroid hormone imbalance.
2. causing compressive symptoms e.g. dysphagia, shortness of breath, etc.
3. unsightly from the patient's point of view.

Most benign swellings can be managed conservatively. As the typical clinical signs and symptoms of thyroid hormone imbalance may sometimes be lacking, thyroid stimulating hormone (TSH) levels should be checked in all patients with a thyroid swelling to determine if they are euthyroid, hyperthyroid or hypothyroid. Malignant lesions should be actively treated with surgery, radiotherapy, radioactive iodine or with a combination of these. The flow chart in Figure 1 summarizes the overall management.

The initial clinical examination is used to determine whether there is a diffuse thyroid swelling or a solitary thyroid nodule.

Diffuse thyroid swellings

The majority of diffuse thyroid swellings are due to either a multinodular goiter or Graves' disease. Other less common but nevertheless equally important causes include various types of thyroiditis and malignancies such as anaplastic carcinoma and lymphoma. The typical characteristics and important diagnostic features of these diseases are described in the following paragraphs.

Multinodular goiter

It is believed that the thyroid gland has an inherent propensity to form nodules with age. Multinodular goiter (MNG) represents an enhancement of this tendency due to environmental factors such as iodine deficiency, diet and lithium treatment. The diagnosis can usually be made on clinical grounds alone or with ultrasonography (USG). MNG often presents as a long-standing or slowly enlarging thyroid swelling. Surface nodules may be palpable. MNG may require active treatment if it is associated with hormonal disturbances, compression symptoms or appears unsightly.

Hyperthyroidism associated with MNG is usually due to autonomous nodules. Unlike thyrotoxicosis due to Graves' disease, where the level of stimulating auto-antibodies can spontaneously decrease, excessive thyroxine production by autonomous nodules does not normally go into spontaneous remission. It is inappropriate to prescribe anti-thyroid drugs for an extended period of time as the thyrotoxicosis will recur after cessation of the medication. Anti-thyroid medication can further promote the growth of the thyroid gland due to elevated TSH levels which result from the suppression of thyroxine production. Treatment options include a thyroidectomy or a course of radioactive iodine. As the dose of radioactivity required is large, surgery is the treatment of choice. A total thyroidectomy is advised to avoid the problems associated with a subtotal thyroidectomy when any remaining nodular tissue can grow again under the influence of raised TSH levels.

Non-toxic compressive goiters can be treated surgically, resulting in an immediate and effective relief of obstruction, and allowing for histological examination of the thyroid tissue. Although radioactive iodine has been shown to be effective in reducing the size of a MNG in some series,^1-3 its use has not become popular because concerns of an acute swelling threatening the airway remain.

Graves' disease

Graves' disease is the most common form of thyrotoxicosis and is a female-predominant autoimmune disease. The underlying pathophysiological mechanism is the generation of auto-antibodies against TSH receptors on thyrocytes. Apart from signs and symptoms of thyrotoxicosis, patients may develop a diffuse goiter, sometimes with a bruit, and have characteristic infiltrative ophthalmopathy and pre-tibial myxoedema. The diagnosis is usually made on clinical grounds and blood tests, which show a suppressed TSH level and elevated levels of free thyroxine (free T4). Patients are initially treated with a course of anti-thyroid drugs and those who fail are offered surgery or radioactive iodine.

Thyroiditis

Thyroiditis encompasses a group of inflammatory disorders of the thyroid gland including Hashimoto's thyroiditis and subacute thyroiditis.

Hashimoto's thyroiditis is an autoimmune disease which causes progressive thyroid cell damage. There is an associated goiter and thyroid dysfunction. It usually presents as a painless, diffuse, firm and lumpy goiter in young or middle aged women. It is characterized by a high level of autoantibodies against thyroid perioxidase, previously called microsomal antigen. The diagnosis can be confirmed by fine-needle aspiration cytology (FNAC). Patients with this condition are treated with thyroid hormone replacement. Surgery is reserved for large compressive goiters.

Subacute thyroiditis is a common cause of a painful thyroid gland. Women are more frequently affected than men, with a peak incidence in the 4^th and 5^th decades. A viral aetiology is implicated as it often follows an upper respiratory tract infection or has a prodrome of muscle aches and pains, fever and malaise. The onset of thyroid pain can be gradual or sudden. The thyroid gland is tender on palpation. The blood erythrocyte sedimentation rate is markedly elevated. Patients with this condition may undergo a period of thyrotoxicosis followed by a euthyroid and hypothyroid state as a result of ongoing thyrocyte damage. Fortunately, it is usually a self-limiting disease. Treatment is symptomatic with analgesics and sometimes beta-blockers during the thyrotoxic phase.

Anaplastic thyroid carcinoma

Anaplastic thyroid carcinoma is one of the most lethal solid tumours. With rare exceptions, it is rapidly fatal. It occurs more commonly in an elderly person who has a long-standing goiter. It presents as a rapid increase in the size of a pre-existing goiter and may be associated with pain and symptoms of surrounding tissue invasion such as hoarseness. The mainstay of treatment is radiotherapy with or without chemotherapy. If the diagnosis cannot be made by FNAC, an incisional biopsy is necessary. The role of surgery is to relieve airway obstruction if present.

Lymphoma

Lymphoma is an uncommon disease of the thyroid gland and is usually of the non-Hodgkin's type. It commonly occurs in older women who have pre-existing hypothyroidism or Hashimoto's thyroiditis. The presentation can mimic anaplastic thyroid carcinoma. The diagnosis is made with FNAC or an incisional biopsy. The tissue diagnosis is important to make as the treatment of lymphoma is different from and carries a better prognosis than anaplastic thyroid carcinoma.

Solitary thyroid nodules

Differentiating a malignant from a benign lesion remains the objective in patients presenting with a solitary thyroid nodule. There is however, unfortunately, no consensus on their management. As the risk of malignancy of a dominant nodule in a MNG is similar to that of a truly solitary nodule,⁴ they should be investigated and managed as such. While an excisional biopsy would be the gold standard for diagnosis, it is not practical to subject every patient to this considering the potential risks and costs involved.

Except for thyroid isthmus lesions, the minimum surgery on the thyroid gland is a lobectomy. A palpable solitary nodule is common, affecting about 4-7% of the population in America.⁵ The incidence of ultrasound-detected thyroid nodules is even higher.⁶ The chance of a solitary nodule being malignant is low, in the range of 5-10%.⁷ Thus the important goal in the evaluation of a solitary nodule is to identify those that are malignant while avoiding surgery in those that are benign.

Clinical assessment

Suspicious features of a malignant nodule include:

1. Male gender. The male:female ratio of a malignant nodule is 2:1.
2. Extremes of age, i.e. less than 20-years and older than 60-70 years.
3. Family history of thyroid cancer.
4. Neck irradiation during childhood.
5. Rapid, but not sudden, enlargement of a thyroid nodule.
6. Hoarseness, dysphagia or other obstructive symptoms.
7. Hard, firm, fixed irregular mass.
8. Enlarged lymph node(s).
9. A previous history of thyroid cancer.

The rate of growth of the nodule is important. Thyroid carcinomas usually grow slowly over weeks or more often over months. Sudden growth is usually due to thyroid cyst formation, haemorrhage into a previously undetected nodule or subacute thyroiditis. Rapid enlargement on the other hand would suggest an anaplastic carcinoma or lymphoma.

While some of these features are quite helpful, clinical evaluation is neither sensitive nor specific enough to differentiate a malignant from a benign lesion with certainty. Special investigations are needed to supplement the history and clinical examination.

Fine needle aspiration cytology

Fine needle aspiration cytology (FNAC) has become the standard investigation for the evaluation of a thyroid nodule. The limitation of FNAC is that it runs the risk of sampling error. It is also an operator-dependent test; its accuracy is highly dependent on the skill and experience of the cytopathologist. Moreover, FNAC is also unable to differentiate between a follicular adenoma and a follicular carcinoma. Nevertheless, in experienced hands, it has a pre-operative predictive accuracy of more than 90%.^7,8 The results of FNAC will usually be one the following:⁹

1. Non-diagnostic or quantity insufficient The clinician should arrange for another FNAC to be done, preferably under ultrasound guidance to improve the yield and obtain a more representative sample.
2. Non-neoplastic or benign The patient can be monitored and have the FNAC repeated 6 month later to reduce the risk of a false negative FNAC. For patients in the high risk group (i.e., male gender, extremes of age, family history of thyroid carcinoma, etc), the decision to proceed to a lobectomy may be made even with a benign FNAC result if it is clinically indicated. Surgery can also be considered if there are pressure symptoms or there has been rapid growth. In addition, the patient may choose to have the lesion removed despite it being diagnosed as a benign lesion on FNAC.
3. Follicular lesion As the diagnosis of a follicular carcinoma relies on the identification of thyroid capsule or vascular invasion, FNAC is unable to differentiate between a follicular adenoma and a follicular carcinoma. Lobectomy, an excisional biopsy, is offered for this diagnosis.
4. Abnormal or a suspicion of malignancy If a differentiated carcinoma, papillary or follicular, is suspected, surgery is indicated to obtain a definitive diagnosis and for treatment. If an anaplastic thyroid carcinoma, lymphoma or metastatic tumour is suspected, further investigations such as an incisional biopsy are indicated.
5. Diagnostic of malignancy Surgery is indicated for differentiated thyroid carcinomas. Further management will depend on other factors such as the age of the patient, extent of disease, histological findings, etc.
   An anaplastic thyroid carcinoma, lymphoma or metastatic tumour would be treated appropriately once all relevant investigations were completed. This may include radiotherapy or chemotherapy.

Ultrasonography

An ultrasound scan is useful in differentiating pure cysts, mixed cysts, and solid lesions. Features of malignancy may be identified with USG e.g. punctuate calcification in a papillary carcinoma, the presence of abnormal lymph nodes, etc. One value of USG is to guide and improve the yield of FNAC in cases where the first FNAC was inadequate for diagnosis.

Radionuclide scan

A hot nodule on a radionuclide scan is invariably benign. Less than 10% of all thyroid nodules will be hot. Malignancy cannot be excluded in the remaining warm or cold nodules, although they are usually benign.¹⁰ For this reason, many endocrinologists no longer advocate a radionuclide scan as part of the routine initial work up of a nodular goiter. However, it is still useful in the diagnosis of thyrotoxicosis due to a solitary toxic nodule.

Computerised tomography and magnetic resonance imaging

Computerised tomography (CT) and magnetic resonance imaging (MRI) modalities have little place in the initial evaluation of a solitary nodule. As intravenous contrast medium commonly used for contrast in a CT scan contains a high concentration of iodine, it may interfere with future radioiodine scanning or treatment of the thyroid gland for weeks or months.

In a nutshell, the clinical assessment, biochemical thyroid function tests, FNAC and ultrasound scan are the key elements in the initial assessment of a solitary thyroid nodule.

Treatment of solitary thyroid nodules

Euthyroid benign nodule

Simple cysts can be aspirated and the content sent for cytological examination to confirm the benign nature of the cyst. Up to half of all such cysts disappear permanently after one or more aspirations. Those that recur are usually larger, more than 4 cm, and should be considered for surgery.⁷

Patients with a solid nodule with clinical features and investigations indicating a benign nature can be managed conservatively with follow-up. They can be re-investigated if progressive enlargement, new symptoms or thyroid hormonal dysfunction occur. A second FNAC can also be done after a period of 6-12 months to further reduce the chance of a false negative FNAC diagnosis.

Toxic benign nodule

A toxic nodule will usually not be malignant and is effectively managed with either radioactive iodine (¹³¹I) or surgical excision. Since radioactive iodine treatment is simple and does not involve the risks of surgery, it is preferred by many clinicians and patients.

Radioactive iodine is contraindicated during pregnancy and breast feeding.

Malignant nodule

The majority of malignant thyroid nodules will be either papillary or follicular thyroid carcinoma, collectively known as differentiated thyroid carcinomas (DTC). Medullary thyroid cancer is rare, accounting for only 1.3% in one local series of over 1600 thyroid cancer patients,¹¹ and 5-10% of all thyroid cancers in some western countries.⁹ Thyroid lymphoma and anaplastic carcinomas are also rare.

There is controversy about the aggressiveness of treatment for early disease. As the prognosis of these patients is usually good and the mortality rate low, more aggressive treatment should be avoided as it is associated with a higher rate of complications such as hypoparathyroidism and vocal cord palsy. Many would agree that lobectomy alone, with or without an isthmusectomy, may be appropriate treatment for patients known to be at low risk (e.g. female who is younger than 45 years old) with early favourable disease (e.g. a tumour less than 1 cm in size without extracapsular invasion) i.e. a favourable patient with favourable tumour factors. For other cases, the consensus is less well-established. The justification for a total thyroidectomy is based on the fact that papillary carcinoma is often multifocal. Removing the gland decreases the chance of local and distant disease, decreases the risk of anaplastic transformation and allows the use of ¹³¹I and thyroglobulin to monitor the thyroid state. The treatment of more advanced differentiated thyroid carcinomas entails a total thyroidectomy and excision of involved and probably-involved cervical lymph nodes, followed by radioactive iodine ablation and postoperative TSH suppression. External radiotherapy may be used to improve the loco-regional control in certain cases. The long term outcome of patients treated for differentiated thyroid carcinoma is usually favourable. The overall 10-year survival rate for middle aged adults with differentiated thyroid carcinoma is 80-90%. Four principle variables are independently poor prognostic factors: extremes of age, male gender, poorly differentiated histological features of the tumour and tumour stage.⁹ Treatment will also influence the prognosis. Treatment involves a combination of total thyroidectomy, selective lymph node dissection, postoperative ¹³¹I therapy and thyroid hormone suppression therapy.

Medullary thyroid carcinoma arises from parafollicular or C cells. Parafollicular cells secrete calcitonin which can be used as a valuable tumour marker. Medullary carcinoma may occur as part of the MEN syndrome, as familial non-MEN disease or be sporadic. Affected patients should undergo genetic studies and screening for familial medullary carcinoma. The principal treatment entails total thyroidectomy, central neck node dissection and removal of any enlarged lymph nodes.

Conclusion

Thyroid swelling is a common clinical entity. It is important to determine whether the swelling is benign or malignant, and whether it is associated with thyroid hormonal imbalance. Other indications for active treatment as aforementioned should also be sought. A systematic approach is required for the proper management of this group of patients. This often involves multiple disciplines.

Key messages

1. Universal open biopsy of thyroid swelling is impractical as the minimal surgery for thyroid, except for small isthmus lesion, would be a thyroid lobectomy and the yield is low.
2. Fine needle aspiration cytology is a standard investigation for evaluation of thyroid nodule with high diagnostic accuracy in experienced hands.
3. The thyroid hormonal status should be determined and confirmed by biochemical thyroid function test.
4. Indications of surgery for euthyroid benign thyroid swelling include compressive symptoms, cosmetic concern and patients' anxiety.
5. Anaplastic carcinoma of thyroid represents one of the most lethal solid malignancies of the human body but it is rare.
6. Papillary and follicular carcinomas make up majority of thyroid cancers. They are treated by thyroidectomy and usually with other adjuvant treatments. The prognosis is generally very good with a overall 10-year survival rate of 80-90%.