Neoplasms of the thyroid

Thyroid neoplasms are classified in Table 44.5.

Benign tumours

Follicular adenomas present as clinically solitary nodules 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. Treatment is, therefore, by wide excision preferably a lobectomy. The remaining thyroid tissue is normal so that prolonged follow up is unnecessary. It is doubtful whether there is such an entity as a papillary adenoma and all papillary tumours should be considered as malignant even if encapsulated.

Malignant tumours

The vast majority of primary growths is carcinomas (Table 44.6). Dunhill classified them histologically as differentiated and undifferentiated: and the differentiated carcinomas are now subdivided into follicular and papillary. Secondary growths are rare but blood-borne metastases occur (Figs 44.34 and 44.35). Blood borne metastases more usually occur from primary carcinomas of breast, colon and kidney and from melanomas.

Aetiology of malignant thyroid tumours

Differentiated thyroid carcinoma, particularly papillary, frequently follows accidental irradiation of the thyroid in childhood7. The incidence of follicular carcinoma is high in endemic goitrous areas, possibly owing to TSH stimulation. Malignant lymphomas can present in a patient known to have autoimmune thyroiditis, so that the lymphocytic infiltration in the autoimmune process may be an aetiological factor. Indeed, it is likely that all lymphomas of the thyroid arise in glands affected by such thyroiditis.

Clinical features of thyroid neoplasms

The annual incidence is about 3.7 per 100 000 of the popu­lation and the sex ratio is three females to one male. The mortality should only be of the order of 2—3 per cent. The commonest presenting symptom is a thyroid swelling (Fig. 44.36) and a 5-year history is far from uncommon in differentiated growths. Enlarged cervical lymph nodes may be the presentation of papillary carcinoma. Recurrent laryngeal nerve paralysis may be a presenting feature of locally advanced disease.

Anaplastic growths are usually hard, irregular and infiltrating. A differentiated carcinoma may be suspiciously firm and irregular, but is often indistinguishable from a benign swelling. Small papillary tumours may be impalpable (occult carcinoma) even when lymphatic metastases are present (so-called lateral aberrant thyroid). Pain, often referred to the ear, is frequent in infiltrating growths.

Diagnosis of thyroid neoplasms

Diagnosis is obvious on clinical examination in most cases of anaplastic carcinoma, although Riedel’s thyroiditis (see later) is indistinguishable. The localised forms of granulomatous thyroiditis and lymphadenoid goitre may simulate carcinoma. It is not always easy to exclude a carcinoma in a multinodular goitre, and solitary nodules, particularly in the young male, are always suspect. Failure to take up radio-iodine is characteristic of almost all thyroid carcinomas [only very rarely will differentiated carcinoma (primary or secondary) take up 1231 in the presence of normal thyroid tissue], but occurs also in degenerating nodules and all forms of thyroiditis. Thyroid antibody titres are often raised in carcinoma. The role of FNAC in preoperative diagnosis has already been discussed. No diagnostic test is absolutely certain, and exploration with excision in the form of lobec­tomy is essential when in doubt. Incisional biopsy may cause seeding of cells and local recurrence, and is most inadvisable in a resectable carcinoma. In an anaplastic and obviously irremovable carcinoma, however, incisional or needle biopsy is justified.

Papillary carcinoma

Most papillary tumours contain a mixture of papillary and colloid-filled follicles, and in some the follicular structure predominates. Nevertheless, if any papillary structure is present, the tumour will behave in a predictable fashion as a papillary carcinoma. Histologically the tumour shows papil­lary projections and characteristic pale, empty nuclei (Orphan Annie-eyed8 nuclei) (Fig. 44.37). Papillary carci­nomas are very seldom encapsulated. Multiple foci may occur in the same lobe as the primary tumour or, less commonly, in both lobes. They may be due to lymphatic spread in the rich intrathyroidal lymph plexus, or to multicentric growth. Spread to the lymph nodes is com­mon but blood-borne metastases are unusual unless the tumour is extrathyroidal. The term extrathyroidal indicates that the primary tumour has infiltrated through the capsule of the thyroid gland.

Occult carcinoma

Papillary carcinoma may present as an enlarged lymph node in the jugular chain with no palpable abnormality of the thyroid. The primary tumour may be no more than a few millimetres in size and is termed occult. Such primary foci of papillary carcinoma may also be discovered in thyroid tissue resected for other reasons, e.g. Graves’ disease. The term occult is now applied to all papillary carcinomas less than 1.5 cm in diameter. These have an excellent prognosis and are regarded as of little clinical significance.

Follicular carcinoma

These appear to be macroscopically encapsulated but microscopically there is invasion of the capsule and of the vascular spaces in the capsular region (Fig. 44.38). Multiple foci are seldom seen and lymph node involvement is much less common than in papillary carcinoma. Blood-borne metastases are almost twice as common and the eventual mortality rate is twice as high (Fig. 44.39). Hurthle cell tumours are a variant of follicular neo plasm in which oxyphil (Hurthle, Askanazy) cells predominate histologically. It is doubtful whether Hurthle cell neoplasms are ever benign and they may be associated with a poorer prognosis.

Differences between papillary and follicular carcinoma

The major differences between papillary (including mixed papillary and follicular) and follicular carcinoma have been set out by Cady on the basis of an analysis of 40 years’ experience at the Lahey Clinic (Table 44.7).

Prognosis in differentiated thyroid carcinoma

The prognosis of differentiated thyroid carcinoma , although influenced by histological type, is much more dependent on age, the presence of extrathyroidal spread or major capsular transgression (in follicular carcinoma), and the size of the tumour. Recently, several scoring systems based on multi-factorial analysis of risk factors from retrospectively gathered data have been devised. On the basis of age, tumour spread, size and histology, these allow separation of patients into low-and high-risk groups with 25-year mortality rates of 2 per cent and 46 per cent, respectively. With regard to age, the prognosis is much worse in males over the age of 40 years and in females over 50 years. Distant metastatic disease is obviously an adverse prognostic factor but lymph node metastases are not associated with worse prognosis. Definitions of low- and high-risk groups based on data from the Lahey Clinic are given in Table 44.8.

Patients in the low-risk group account for 90 per cent of cases of differentiated thyroid carcinoma.

Surgical treatment

There is continuing disagreement on the most appropriate operation for differentiated thyroid carcinoma. The con­servative approach advocates lobectomy with isthmusectomy in most patients with total thyroidectomy reserved for specific indications (viz, those with bilateral disease or judged to be in a high-risk category). The more radical approach advocates routine total thyroidectomy often as a staged procedure depending on the pathological findings of the initial lobectomy.

The case for a policy of total thyroidectomy is theoretically based on the prevalence of multifocality in papillary carci­noma and on the feasibility thereafter of using radioiodine scanning to detect metastases, the thyroid having been ablated (Fig. 44.40). However, the clinical significance of multifocality is low as local recurrence is infrequent after unilateral resection. In addition, in those selected patients in whom scanning may be indicated, the remaining thyroid tissue may be ablated safely with a preliminary dose of radioiodine. Most importantly there is no evidence that the long-term results of routine total thyroidectomy as a policy are better than those of more conservative operations, and there is a substantial risk of permanent hypoparathyroidism. Clearly the risk of parathyroid damage varies according to expertise and the frequency with which the operation is done but, even at the Mayo Clinic, where thyroid surgery is frequently and expertly done, the rate of hypoparathyroidism is significant (Hay).

The large majority of patients with differentiated carci­noma, particularly since 90 per cent fall into a group with a 2 per cent mortality rate, is appropriately treated by lobecto­my with isthmusectomy on the affected side. At the same time clinically obvious nodes, which may be pretracheal, para­tracheal or in the jugular chain, are removed. If the jugular nodes are extensively involved, a modified neck dissection with preservation of the accessory nerve and sternomastoid muscle may be carried out through extension of the thyroidectomy incision. Very occasionally it may be necessary to sacrifice the recurrent laryngeal nerve if it is completely encircled and, on even more rare occasions, extrathyroidal spread may require resection of part of the trachea.

When there is clinically obvious bilateral disease at operation, bilateral resection is clearly indicated and bilateral resection may also be indicated in the few patients classified as high risk, although the evidence at present for improved prognosis is rather weak. Retrospective analysis of outcome in 860 patients with papillary carcinoma treated at the Mayo Clinic between 1946 and 1970 showed improved survival in high-risk patients undergoing bilateral resection, compared with lobectomy alone, although the difference was not statistically significant (Hay). There was no advantage for total compared with near-total thyroidectomy in which 1—2 g of thyroid tissue is preserved on the contralateral side to protect the blood supply to one or more parathyroid glands.

Surgical operations

Isthmusectomy. Swellings confined to the thyroid isthmus, including small differentiated carcinomas, may be appropriately removed by resec­tion of the isthmus alone. Isthmusectomy is also an effective method of relieving tracheal obstruction and obtaining tissue for diagnosis in anaplastic carcinoma and lymphoma.

Thyroid lobectomy. Total lobectomy on the- affected side together with isthmusectomy is the appropriate operation for removal of a dis­crete thyroid swelling and for most patients with differentiated carci­noma. The procedure, if performed meticulously by an experienced surgeon, is associated with very little risk of postoperative complications such as recurrent laryngeal nerve injury. The parathyroid glands should be seen and preserved in situ if possible; although the intact glands on the contralateral side will ensure normal function, removal of the contralateral lobe may occasionally be necessary in the future. It is unnecessary to ligate the main trunks of the inferior thyroid arteries. Instead, the individual arterial branches supplying the thyroid gland should be ligated close to the thyroid, preserving the parathyroid blood supply. The recurrent laryngeal nerve is carefully exposed throughout the dissection. It is particularly vulnerable close to where it angulates posteriorly to enter the larynx, at which site it is intimately related to the lateral thyroid ligament (ligament of Berry).

Near-total thyroidectomy. This consists of total thyroid lobectomy on the affected side, with conservation of 1—2 g of thyroid tissue on the contralateral side, which preserves the blood supply to one or both parathyroids.

Total thyroidectomy. The technique is essentially that of bilateral lobectomy and, if meticulous, the risk of complications is very low except for permanent hypoparathyroidism. The risk of hypopara­thyroidism is variable but may be appreciable even in experienced hands.

Additional measures

Thyroxine. It is standard practice to prescribe thyroxine in a dose of 0.1—0.2 mg daily, to suppress endogenous TSH production, for all patients after operation for differentiated thyroid carcinoma on the basis that some tumours are TSH dependent. Suppression of the TSH level should be con­firmed by measurement. Failure of suppression to a level of <0.1 i.t/litre may indicate an inadequate dose of thyroxine or more usually that the patient is noncompliant. However, suppressive thyroxine is probably not of value in follicular carcinoma, and is unlikely to be of benefit in low-risk patients treated by lobectomy. Thyroid hormone replacement is obviously necessary after total thyroidectomy and in the majority of patients after near-total thyroidectomy, and is usually given in the form of thyroxine. Patients with potential or actual distant metastases who may require repeated radioiodine administration for scanning and therapy should be given tri-iodothyronine (60—8 0 mg/day) because it is much shorter acting, and on stopping it, increased TSH secretion and thyroid avidity for iodine recover quickly so that radioiodine may be given after several days. The patient is thereby spared weeks of developing thyroid insufficiency after stopping thyroxine before radioiodine may be given.

Radioiodine. If metastases take up radioiodine they may be detected by scanning and may be treated with large doses of radioiodine. For effective scanning, all thyroid tissue must have been ablated by either surgery or preliminary radioiodine and the patient must be hypothyroid to improve uptake. The indications for scanning after operations for differentiated carcinoma are disputed, but it is probably only indicated in patients with unresectable local recurrence or metastatic disease, high-risk patients, and in those with a rising serum thyroglobulin level. In addition, if metastases take up radioiodine they are likely to be suppressed as effectively by treatment with thyroxine as by radioiodine. Cases in which suppression has failed and radioiodine has given permanent control appear to be uncommon.

If metastases have been treated, the scan should be repeated at annual intervals and further therapeutic doses of radioiodine given as necessary. Solitary distant metastases may be treated by external radiotherapy.

Thyroglobulin. The measurement of serum thyroglobulin is of value in the follow-up and in the detection of metastatic disease in patients who have undergone surgery for differentiated thyroid cancer. This measurement may obviate the need for serial radioactive iodine scanning but when a rise occurs, a scan will be indicated to confirm and locate the metastatic disease. Thyroglobulin levels are, however, only an adjunct to careful clinical palpation of the neck because local recurrence detectable clinically may be present with a low thyroglobulin.

Undifferentiated (ana plastic) carcinoma

This occurs mainly in elderly women and is much less often diagnosed now than in the past when many thyroid lym­phomas were mistakenly classified histologically as anaplastic carcinomas. Local infiltration is an early feature of these tumours with spread by lymphatics and by the bloodstream. They are extremely lethal tumours and survival for more than 1—2 years after presentation is most unusual. In most cases death occurs within months rather than within years. An attempt at curative resection is only justified if there is no infiltration through the thyroid capsule and no evidence of metastases. Many of these aggressive lesions present in an advanced stage with tracheal obstruction and require urgent tracheal decompression. The trachea may be decompressed and tissue obtained for histology by isthmusectomy. Tracheo­stomy is best avoided. Radiotherapy should be given in all cases and may provide a worthwhile period of palliation as may combination chemotherapy [including doxorubicin (Adriamycin)].

Medullary carcinoma

These are tumours of the parafollicular (C)-cells derived from the neural crest and not from the cells of the thyroid follicle as are other primary thyroid carcinomas. The cells are not unlike those of a carcinoid tumour and there is a characteristic amyloid stroma (Fig. 44.41). High levels of serum calcitonin (>0.08 ng/ml) are produced by many medullarv tumours. These levels fall after resection of a tumour and will rise again if the tumour recurs. This is a valuable tumour marker in the follow-up of patients with this disease. Diarrhoea is a feature in 30 per cent of cases and this may be due to 5-hydroxytryptamine or prostaglandins produced by the tumour cells.

Some tumours are familial and may account for 10—20 per cent of all cases. Medullary carcinoma may occur in combination with adrenal phaeochromocytoma and hyper­parathyroidism (usually due to hyperplasia) in the syndrome known as multiple endocrine neoplasia type ha (MEN IIa). The familial form of the disease frequently affects children 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 (Fig. 44.42) and inner aspect of the eyelids, with occasionally a Marfanoid hahitus, the syndrome is referred to as MEN type IIb.

Involvement of lymph nodes occurs in 50—60 per cent of cases of medullary carcinoma and blood-borne metastases are common. As would be expected, tumours are not hormone dependent and do not take up radioactive iodine. The course of the tumour is unpredictable; in general, life expectancy is excellent if the tumour is confined to the thyroid gland, good as long as metastases are confined to the cervical lymph nodes and poor once blood-borne metastases are present.

Treatment is by total thyroidectomy and resection of involved lymph nodes with either a radical or modified radical neck dissection. Familial cases are now detected by genetic screening for the RET oncogene mutations which identifies individuals who will develop medullary cancer later in life (Fig. 44.43). The genetic tests are supplemented by estimating serum calcitonin levels in the basal state and after stimulation by either calcium or pentagastrin. A rise in calcitonin levels under these circumstances should lead to a prophylactic thyroidectomy but even then the disease may be beyond the preinvasive C-cell hyperplasia stage (Fig. 44.44).

Phaeochromocytoma must be excluded by measurement of urinary catecholamine levels (Chapter 45) in all cases before embarking upon thyroid surgery to avoid the potential hazards associated with this condition.

Malignant lymphoma

In the past, many malignant lymphomas were diagnosed as small round-cell anaplastic carcinomas. Response to irradia­tion is good (Fig. 44.45) and radical surgery is unnecessary once the diagnosis is established by biopsy. Although the diagnosis may be made or suspected on FNAC, sufficient material is seldom available for immunocytochemical classification, and large-needle (Trucut) or open biopsy is usually necessary. In patients with tracheal compression, isthmusectomy is the most appropriate form of biopsy. The prognosis is good 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.