Thyroid enlargement Surprisingly enough, iodides in large quantities are goitrogenic because they inhibit the organic binding
of iodine and produce an iodide goitre.
The normal thyroid gland is impalpable. The term goitre (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 categorising thyroid enlargement is given in Table 44.3.
Simple goitre
Aetiology
Simple goitre may develop as a result of stimulation of the thyroid gland by TSH, either as a result of
inappropriate secretion 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
dietary deficiency of iodine (see below) but defective hormone synthesis probably accounts for many
sporadic goitres (see below).TSH is not the only stimulus to thyroid follicular cell proliferation and other
growth factors including immunoglobulins exert an influence. The heterogeneous structural and
functional response in the thyroid resulting in characteristic nodularity may be due to the presence of
clones of cells particularly sensitive to growth stimulation.
Iodine deficiency
The daily requirement of iodine is about 0.1—0.15 mg. In nearly all districts where simple goitre is
endemic, there is a very low iodide content in the water and food. Endemic areas are in the
mountainous ranges, such as the Rocky Mountains, the Alps, the Andes and the Himalayas. In Great
Britain endemic goitre is found in the Mendips, Chilterns, Cotswolds and the Pennine chain of
Derbyshire and Yorkshire. 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 valley3, the Nile valley and the Congo.
Calcium is also goitrogenic and goitre is common in low-iodine areas on chalk or limestone, e.g.
Derbyshire and Southern Ireland. Although iodides in food and water may be adequate, failure of
intestinal absorption may produce iodine deficiency (McCarrison).
Defective hormone synthesis
Enzyme deficiency/dyshormonogenesis. It is probable that enzyme deficiencies of varying severity are
responsible for many sporadic goitres, i.e. in nonendemic areas. 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.
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, of course, 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.
The natural history of simple goitre
Stages in goitre formation are:
•persistent growth stimulation causes diffuse hyperplasia; all lobules are composed of active follicles
and iodine uptake is uniform. This is a diffuse hyperplastic goitre, which may persist for a long time but
is reversible if stimulation ceases;
•later, as a result of fluctuating stimulation, a mixed pattern develops with areas of active lobules and
areas of inactive lobules;
•active lobules become more vascular and hyperplastic until haemorrhage occurs, causing central
necrosis and leaving only a surrounding rind of active follicles;
•necrotic lobules coalesce to form nodules filled with either iodine-free colloid or a mass of new but
inactive follicles;
•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
Diffuse hyperplasia corresponds to the first stages of the natural history. The goitre appears in childhood
in endemic areas but, in sporadic cases, it usually occurs at puberty when metabolic demands are high
—puberty goitre (Fig. 44.12). If TSH stimulation ceases, the goitre may regress, but tends to recur later
at times of stress such as pregnancy. The goitre is soft, diffuse and may become large enough to cause
discomfort. A colloid goitre is a late stage of diffuse hyperplasia when TSH stimulation has fallen off and
when many follicles are inactive and full of colloid (Fig. 44.13).
Nodular goitre
Nodules are usually multiple, forming a multinodular goitre. 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 haemorrhage 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
goitre until the late 40s or 50s. All types of simple goitre are far more common in the female than in the
male and the presence of oestrogen receptors in normal thyroid tissue and in nodular goitre is relevant.
Diagnosis is usually straightforward. The patient is euthyroid: the nodules are palpable and often visible;
they are smooth, usually firm and not hard, and the goitre is painless and moves freely on swallowing.
Hardness and irregularity, due to calcification, 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. Differential diagnosis from autoimmune thyroiditis may be difficult.
Investigations. Tests of thyroid function are necessary to exclude mild hyperthyroidism, and the
estimation of titres of thyroid antibodies to differentiate from autoimmune thyroiditis. Plain radiographs
of the chest and thoracic inlet may show calcification and tracheal deviation or compression.
Complications.Tracheal obstruction is due to gross lateral displacement, or compression in a lateral or
anteroposterior plane by retrosternal extension of the goitre (Fig. 44.14). Acute respiratory obstruction
may follow haemorrhage into a nodule impacted in the thoracic inlet.
Secondary thyrotoxicosis. Many patients with nodulargoitres experience transient episodes of mild
hyperthyroidism. The incidence is difficult to estimate, but figures as high as 30 per cent have been
suggested.
Carcinoma,which is usually of follicular pattern. It is uncommon but an increased incidence has been
reported from endemic areas.
Prevention and treatment of simple goitre
In endemic areas, e.g. Switzerland, parts of the USA and Argentina, 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 mg daily
for a few months.
The nodular stage of simple goitre is irreversible. Most patients with multinodular goitre are
asymptomatic and do not require operation. Operation may be indicated on cos-metic grounds if the
goitre is unsightly. Retrosternal extension with actual or incipient tracheal compression is an indication
for operation, as is the presence of a dominant area of enlargement which may be neoplastic.
There is a choice of surgical treatment: (a) total thyroidectomy with immediate and life-long
replacement of thyroxine; or (b) some form of partial resection to conserve sufficient functioning
thyroid tissue to subserve normal function whilst eliminating the risk of hypoparathyroidism which
accom-panies total thyroidectomy. Partial resection aims to remove the bulk of the gland, leaving up to
8 g of relatively normal tissue in each remnant. The technique is essentially the same as described for
toxic goitre, as are the postoperative complications. More often, however, the multinodular change is
asymmetrically distributed, with one lobe more significantly involved than the other. Under these
circumstances total lobectomy on the more affected side is the appropriate management with either
subtotal resection or no intervention on the less affected side. In many cases the causative factors
persist and recurrence is likely. Reoperation for recurrent nodular goitre is more difficult and hazardous
and for this reason many thyroid surgeons favour total thyroidectomy in younger patients. When a
unilateral lobectomy alone has been performed for asymmetric goitre, reoperation is straight-forward
should it become necessary on the remaining lobe.
After subtotal resection ithas been customary to give thyroxine to suppress TSH secretion with the aim
of preventing recurrence. Whether this is either necessary or effective is uncertain, although the
evidence of benefit in endemic areas is better than elsewhere. There is some evidence that recur-rence
after surgery may reduce in size after treatment with radioactive iodine.
Clinically discrete swellings
Discrete thyroid swellings (thyroid nodules) are common and are present in 3—4 per cent of the adult
population in the UK and USA. They are three to four times more frequent in women than men.
Diagnosis
A discrete swelling in an otherwise impalpable gland is termed isolated or solitary, whereas the
preferred term 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 is dominant.About 70 per cent of
discrete thyroid swellings are clinically isolated and about 30 per cent dominant. The true incidence of
isolated swellings is somewhat less than the clinical estimate. Clinical classification is inevitably
subjective and overesti-mates the frequency of truly isolated swellings. When such a gland is exposed at
operation or examined by ultrasonography, computed tomography (CT) or magnetic resonance imaging
(MRI), clinically impalpable nodules are often detected. The true frequency of thyroid nodularity
compared with the clinical detection rate by palpation is shown in (Fig. 44.15).Establishing the presence
of such minor abnormality is unnecessary because the management of discrete swellings, be they
isolated or dominant, is similar.
The importance of discrete swellings lies in the risk of neoplasia compared with other thyroid swellings.
Some 15per cent of isolated swellings prove to be malignant, and an additional 30—40 per cent are
follicular adenomas. The remainder are non-neoplastic largely consisting of areas of colloid
degeneration, thyroiditis or cysts. Although the inci-dence of malignancy or follicular adenoma in
clinically domi-nant swellings is approximately half that of truly isolated swellings, it is substantial and
cannot be ignored.
Investigation
Thyroid function. The thyroid functional status should be established by estimation of serum thyroid
hormones and TSH. If hyperthyroidism associated with a discrete swelling is confirmed biochemically,
itindicates either a ‘toxic adenoma’ or a manifestation of toxic multinodular goitre. The combination of
toxicity and nodularity is important and constitutes the only indication for isotope scanning to localise
the area(s) of hyperfunction.
Autoantibody titres. The autoantibody status is important in determining which swellings may be a
manifestation of chronic lymphocytic thyroiditis.
Isotope scan. Isotope scanning used to be the mainstay of investigation of discrete thyroid swellings to
determine the functional activity relative to the surrounding gland according to isotope uptake.
On scanning, swellings are categorised as ‘hot’ (over-active), ‘warm’ (active) or ‘cold’ (underactive). A
hot nodule is one that takes up isotope, while the surrounding thyroid tissue does not. Here the
surrounding thyroid tissue is inactive because the nodule is producing such high levels of thyroid
hormones that TSH secretion is suppressed. A warm nodule takes up isotope and so does normal thyroid
tissue about it. A cold nodule takes up no isotope (Fig. 44.7).
About 80 per cent of discrete swellings are cold but only 15 per cent prove to be malignant and the use
of this criterion as an indication for operation lacks discrimination. Routine isotope scanning has been
abandoned except when toxicity is associated with nodularity.
Ultrasonography was formerly widely used as a noninva-sive supplement to clinical examination in
determining the physical characteristics of thyroid swellings. Although ultrasonography can demonstrate
subclinical nodularity and cyst formation, the former is clinically irrelevant and the latter apparent at
aspiration, which should be routine in all discrete swellings.
Fine-needle aspiration cytology (FNAC). FNAC has become established as the investigation of choice in
discrete thyroid swellings. FNAC has excellent patient compliance, is simple and quick to perform in the
out-patient department and is readily repeated. This technique, developed in Scandinavia some 30 years
ago, has become popular in the rest of Europe and North America in the last 20 years.
Thyroid conditions that may be diagnosed by FNAC include colloid nodules (Fig. 44.16), thyroiditis,
papillary carcinoma (Fig. 44.17), medullary carcinoma, anaplastic carcinoma and lymphoma. FNAC
cannot distinguish between a benign follicular adenoma (Fig. 44.18) and follicular carcinoma as this
distinction is dependent not on cytology but on histological criteria, which include capsular and vascular
invasion.
Although FNAC has been reported as highly accurate by Lowhagen and his colleagues at the Karolinska
Hospital, who were its pioneers, and by other authors, high accuracy has not always been reproducible,
especially when results are analysed critically. There are very few false positives with respect to
malignancy but there is a definite false-negative rate with respect to both benign and malignant
neoplasia.
FNAC is less reliable in cystic than in solid swellings, often yielding only cyst fluid with macrophages and
degenerate cells.After aspiration a further sample should be taken from the cyst wall, for cytology.
Relatively few cysts are permanently abolished by one or more aspirations and, because of the risk of
malignancy, recurrent cysts should be removed.
Radiology. Chest and thoracic inlet radiographs are only necessary when there is clinical evidence of
tracheal deviation or compression or retrosternal extension.
Other scans. CT and MRI scans give excellent anatomical detail of thyroid swellings but have no role in
the first line of investigation. They are occasionally useful in assessing recurrent and retrosternal
swellings. The increased use of these imaging modalities in other head and neck swellings has created a
new clinical conundrum which has been termed the ‘Thyroid Incidentaloma’. These are clinically
unsuspected and impalpable thyroid swellings which with few exceptions require no further
investigation or surgery.
Indirect laryngoscopy to determine the mobility of the vocal cords is widely used preoperatively,
although usually for medicolegal rather than clinical reasons.
Large-bore needle (Trucut) biopsy. Trucut biopsy has a high diagnostic accuracy but has poor patient
compliance and may be associated with complications such as pain, bleeding, tracheal and recurrent
laryngeal nerve damage. It has little application in routine assessment except in locally advanced,
surgically unresectable malignancy (either anaplastic carci-noma or lymphoma) when Trucut biopsy may
avoid operation.
The main indication for operation is the risk of neoplasia which includes follicular adenoma as well as
malignant swellings. The reason for advocating the removal of all follicular neoplasms is that itis
seldompossible to distinguish between a follicular adenoma and carcinoma cytologically. The distinction
usually depends on histological evidence of capsular or vascular invasion and FNAC cannot make this
distinction, although on occasion cellular nuclear features may be so abnormal as to suggest malignant
change. On this basis, some 50 per cent of isolated and25 per cent of dominant swellings should be
removed on the grounds of neoplasia. Even when the cytology is negative, the age and sex of the patient
and the size of the swelling may be relative indications for surgery, especially when a large swelling is
responsible for symptoms. Some patients are happier to have a swelling removed even when cytology is
negative.
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 since tense cystic swellings may be suspiciously hard but a
hard, irregular swelling with any apparent fixity, which is unusual, is highly suspicious. Evidence of
recurrent laryngeal nerve paralysis, suggested by hoarseness and a nonocclusive cough, and confirmed
by indirect laryngoscopy, is almost pathognomonic. Deep cervical lymphadenopathy along the internal
jugular vein in association with a clinically suspicious swelling is almost diagnostic of papillary carcinoma.
In most patients, however, such features are absent but there are risk factors associated with sex and
age. 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 and it is seldom justifiable to
avoid removing such a swelling in a man. 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 provisionally diagnosed as carcinoma.
The risk increases as age advances beyond 50 years, and more so in males.
Thyroidcysts
Routine FNAC (or ultrasonography) shows that over 30 per cent 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 swelling which resolves to a variable extent over a period
of weeks if untreated. Aspiration yields altered blood but re accumulation is frequent. About 50 per
cent of cystic swellings are the result of colloid degeneration, or 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 (Fig. 44.19) some 10—15 per cent of cystic follicular swellings are histo-logically
malignant (30 per cent in males and 10 per cent in females). Papillary carcinoma is often associated with
cyst formation (Fig. 44.20).
Most patients with discrete swellings, however, are females aged 20—40 years in whom the risk of
malignancy, although significant, is low and the indications for operation are not clear cut. FNAC is the
most appropriate investigation to aid selection.
The indications for operation in isolated or dominant thyroid swellings are listed in Table 44.4.
Retrosternal goitre
Very few retrosternal goitres arise from ectopic thyroid tissue; most arise from the lower pole of a
nodular goitre. If the neck is short and the pretracheal muscles are strong, as in men, the negative
intrathoracic pressure tends to draw these nodules into the superior mediastinum.
Clinical features
A retrosternal goitre is often symptomless and is discovered on a routine chest radiograph. There may,
however, be severe symptoms:
dyspnoea, particularly at night, cough and stridor (harsh sound on inspiration). Many of these patients
may attend a chest clinic with a diagnosis of asthma before the true nature of the problem is discovered;
• dysphagia;
• engorgement of neck veins and superficial veins on the chest wall. In severe cases there may be
obstruction of the superior vena cava (Fig. 44.21);
• recurrent nerve paralysis is rare. The goitre may also be malignant or toxic.
Radiographs show a soft-tissue shadow in the superior mediastinum — sometimes with calcification —
and often causing deviation and compression of the trachea (Fig. 44.14). Radio-graphs of the thoracic
inlet give better definition than a chest radiograph. Significant tracheal compression and obstruction
may be demonstrated objectively by a flow—volume loop pulmonary function test in which the rate of
flow is plotted against the volume of air inspired and then expired. Deterioration in flow due to increase
in tracheal compression either acutely or in the long term may be used to monitor progression of the
disease and indicate the need for surgery. The changes are reversed by operation (Fig. 44.22).
Treatment
If obstructive symptoms are present in association with thyrotoxicosis it is unwise to treat a retrosternal
goitre withantithyroid drugs or radioiodine as these may enlarge the goitre. Resection can almost always
be carried out from the neck and a midline sternotomy is hardly ever necessary. The cervical part of the
goitre should first be mobilised by ligation and division of the superior thyroid vessels, and by ligature
and division of the middle thyroid veins and the inferior thyroid artery. The retrosternal goitre can then
be delivered by traction and finger mobilisation. Haemorrhage is rarely a problem because the goitre
takes its blood supply with it from the neck. The recurrent laryngeal nerve should be identified if
possible before delivering the retrosternal goitre, as it may be abnormally displaced and is particularly
vulnerable to injury from traction or tearing. If a large multinodular goitre cannot be delivered intact
from the retrosternal position it may be broken with the fingers and delivered piecemeal, but this
should never he done if the lesion is solitary and there is the possibility of carcinoma.
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 papillaryadenoma and all papillary
tumours should be considered asmalignant 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, itis 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 popu-lation 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
presentingsymptom is a thyroid swelling (Fig. 44.36) and a 5-year history is far from uncommon
indifferentiated 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. Smallpapillary
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 1231in 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 lobec-tomy is essential when indoubt.
Incisional biopsy may cause seeding of cells and local recurrence, and is most inadvisable ina 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 papil-lary
projections and characteristic pale, empty nuclei (Orphan Annie-eyed8 nuclei) (Fig. 44.37). Papillary
carci-nomasare 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 com-mon 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 byhistological type, is much
more dependent onage, 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 con-servative 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 carci-noma 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 carci-noma, particularly since 90 per cent fall into a
group with a 2 per cent mortality rate, is appropriately treated by lobecto-my with isthmusectomy on
the affected side. At the same time clinically obvious nodes, which may be pretracheal, para-tracheal 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 resec-tion 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 dis-crete thyroid swelling and for most patients with
differentiated carci-noma. 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 hypopara-thyroidism
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 con-firmed 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 lym-phomas 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. Tracheo-stomy 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 hyper-parathyroidism (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.