Bailey & Love Bailey & Love Bailey & Love

Bailey &50
Love Bailey & Love Bailey & Love
Chapter

The thyroid gland

Learning objectives
•• To understand the development and anatomy of the •• To know when to operate on a thyroid swelling
thyroid gland •• To describe thyroidectomy
•• To know the physiology and investigation of thyroid •• To know the risks and complications of thyroid surgery
function
•• To be able to select appropriate investigations for
thyroid swellings

EMBRYOLOGY junction of the anterior two-thirds and posterior one-third of

the tongue is the vestigial remnant of the duct. This initially
The embryology of the thyroid and parathyroid glands under- hollow structure migrates caudally and passes in close con-
lies the anatomical position, anatomical variations and con- tinuity with, and sometimes through, the developing hyoid
genital conditions of these structures and is therefore vital for cartilage. The parathyroid glands develop from the third and
surgery (Figure 50.1). The thyroglossal duct develops from fourth pharyngeal pouches. The thymus also develops from
the median bud of the pharynx. The foramen caecum at the the third pouch. As it descends, the thymus takes the asso-
ciated parathyroid gland with it, which explains why the
inferior parathyroid, which arises from the third pharyngeal
pouch, normally lies inferior to the superior gland. However,
Buccal cavity
the inferior parathyroid may be found anywhere along this
line of descent (see also Chapter 51). The developing thyroid
lobes amalgamate with the structures that arise in the fourth
Thyroid pharyngeal pouch, i.e. the superior parathyroid gland and the
II
ultimobranchial body. Parafollicular cells (C cells) from the
neural crest reach the thyroid via the ultimobranchial body.
III
IPG Path of
Thymus descent of SURGICAL ANATOMY
IV thyroid
The normal thyroid gland weighs 20–25 g. The functioning
SPG Path of unit is the lobule supplied by a single arteriole and consists of
UBB descent of 24–40 follicles lined with cuboidal epithelium. The follicle
IPG and
contains colloid in which thyroglobulin is stored (Figure 50.2).
thymus
The arterial supply is rich, and extensive anastomoses occur
Tracheo-oesophageal
tube
between the main thyroid arteries and branches of the tracheal
and oesophageal arteries (Figure 50.3). There is an extensive
Figure 50.1 Embryology of thyroid and parathyroid. Diagram of an lymphatic network within and around the gland. Although
anterior view of the pharynx in a 4-week embryo showing the rela-
tionship of the third and fourth pharyngeal pouches to final position
some lymph channels pass directly to the deep cervical nodes,
of the thyroid and parathyroid glands. IPG, inferior parathyroid; SPG, the subcapsular plexus drains principally to the central com-
superior parathyroid; UBB, ultimobranchial body. partment juxtathyroid – ‘Delphian’ and paratracheal nodes

Delphi, a sacred site near the Gulf of Corinth in Greece, is the place where Phythia, the snake-woman oracle, resided. She sat on a tripod clutching the ribbons of
the monolithic ‘omphalos’ of the world and after inhaling sulphurous fumes, would utter meaningless jargon which was interpreted equivocally by the attendent
priests for those who came to consult her. Formerly the purpose of these lymph nodes was uncertain, and they were therefore called ‘Delphic’.

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Surgical anatomy 801

ve Submandibular
gland Internal carotid
Digastric
muscle artery

Mylohyoid
muscle

Hyoid bone II
I
Internal jugular
vein
Omohyoid
muscle Internal carotid
III artery
Sternocleidomastoid
Cricoid
muscle
cartilage V
VI
IV Trapezius
Figure 50.2 Histology of the normal thyroid. muscle

Right common Anterior scalene

and nodes on the superior and inferior thyroid veins (level VI), carotid artery muscle
and from there to the deep cervical (levels II, III, IV and V) VII
and mediastinal groups of nodes (level VII) (Figure 50.4). Internal jugular
The relationship between the recurrent laryngeal nerve Manubrium vein
(RLN) and the thyroid is of supreme importance to the oper- Left common carotid
artery
ating surgeon. A branch of the vagus, the nerve recurs round
the arch of the aorta on the left and the subclavian artery Figure 50.4 Cervical lymph node levels.
on the right. The clinical significance of this is that on the
left the nerve has more distance in which to reach the tra- mately 2% of nerves on the right are non-recurrent and will
cheoesophageal groove and therefore runs in a medial plane. enter the larynx from above.
On the right, there is less distance and the nerve runs more The nerve runs posterior to the thyroid and enters
obliquely to reach the tracheoesophageal groove. Approxi- the ­larynx at the cricothyroid joint. This entry point is at

Left vagus Right vagus

nerve (X) nerve (X)
Common Superior
carotid parathyroid gland
artery

Thyroid gland
Title:Internal
Bailey & Love’s Short Practice of Surgery, 26th Ed ISBN: 9781444121278
(right lobe) Proof Stage: 2
jugular vein
www.cactusdesign.co.uk Inferior parathyroid
gland

Right recurrent
Inferior thyroid vein larygeal nerve

Inferior thyroid artery

Left recurrent
larygeal nerve

Figure 50.3 The thyroid gland from behind.

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802 CHAPTER 50  The thyroid gland
the level of Berry’s ligament, a condensation of pretracheal
fascia that binds the thyroid to the trachea. This is the point
at which the nerve is at most risk of injury during surgery. In
terms of surgical anatomy, the nerve can be located in the
­tracheosophageal groove where it forms one side of Beahrs’
triangle (the other two sides are the carotid artery and the
inferior thyroid artery) or at the cricothyroid joint. The nerve
will normally be found as the thyroid lobe is mobilised later­
ally, lying under the most posterolateral portion of the gland
called the tubercle of Zuckerkandl.
PHYSIOLOGY
Thyroxine
The hormones tri-iodothyronine (T3) and l-thyroxine (T4)
are bound to thyroglobulin within the colloid. Synthesis
within the thyroglobulin complex is controlled by several
enzymes, in distinct steps:
●● trapping of inorganic iodide from the blood;
●● oxidation of iodide to iodine;
●● binding of iodine with tyrosine to form iodotyrosine;
●● coupling of monoiodotyrosines and di-iodotyrosines to
form T3 and T4.
When hormones are required, the complex is resorbed
into the cell and thyroglobulin is broken down. T3 and T4 are
liberated and enter the blood, where they are bound to serum
proteins: albumin, thyroxine-binding globulin (TBG) and
thyroxine-binding prealbumin (TBPA). The small amount of
hormone that remains free in the serum is biologically active.
The metabolic effects of the thyroid hormones are due to
unbound free T4 and T3 (0.03% and 0.3% of the total cir-
culating hormones, respectively). T3 is the more important
physiological hormone and is also produced in the periph-
ery by conversion from T4. T3 is quick acting (within a few
hours), whereas T4 acts more slowly (4–14 days).
Calcitonin
The parafollicular C cells of the thyroid are of neuroendo-
crine origin and arrive in the thyroid via the ultimobranchial
body (Figure 50.1). They produce calcitonin.
TABLE 50.1 Results of thyroid function tests in normal and pathological states.
Thyroid functional state TSH (0.3–3.3 mU/L)
Euthyroid Normal
Thyrotoxic Undetectable
Myxoedema High
Suppressive T4 therapy Undetectable
T3 toxicity Low/undetectable
Sir James Berry, 1860–1946, surgeon, Royal Free Hospital, London, UK.
Oliver H Beahrs, 1914–2006, surgeon, Mayo Clinic, MN, USA.
Emil Zuckerkandl, 1849–1901, Austro-Hungarian anatomist, brother of urologist Otto Zuckerkandl.
Myxoedemawas first described in 1873 by Sir William Withey Gull, 1816–1890, physician, Guy’s Hospital, London, UK.
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The pituitary–thyroid axis
Synthesis and release of thyroid hormones from the thyroid is
controlled by thyroid-stimulating hormone (TSH) from the
anterior pituitary. Secretion of TSH depends upon the level
of circulating thyroid hormones and is modified in a negative
feedback manner. In hyperthyroidism TSH production is sup-
pressed, whereas in hypothyroidism it is stimulated. Regulation
of TSH secretion also results from the action of thyrotrophin-
releasing hormone (TRH) produced in the hypothalamus.
Thyroid-stimulating antibodies
A family of IgG immunoglobulins bind with TSH receptor
sites (TRAbs) and activate TSH receptors on the follicular
cell membrane. They have a more protracted action than
TSH (16–24 versus 1.5–3 hours) and are responsible for vir-
tually all cases of thyrotoxicosis not due to autonomous toxic
nodules. Serum concentrations are very low but their mea-
surement is not essential to make the diagnosis.
Serum thyroid hormones
Serum TSH
TSH levels can be measured accurately down to very low
serum concentrations with an immunochemiluminomet-
ric assay. Interpretation of deranged TSH levels depends on
knowledge of the T3 and T4 values. In the euthyroid state,
T3, T4 and TSH levels will all be within the normal range.
Florid thyroid failure results in depressed T3 and T4 levels,
with gross elevation of TSH. Incipient or developing thyroid
failure is characterised by low normal values of T3 and T4 and
elevation of TSH. In toxic states, the TSH level is suppressed
and undetectable (Table 50.1). T3 toxicity (with a normal T4)
is a distinct entity and may only be diagnosed by measuring
T3, although a suppressed TSH in the presence of normal T4
suggests the diagnosis.
Thyroid autoantibodies
Serum levels of antibodies against thyroid peroxidase
(TPO) and thyroglobulin are useful in determining the
cause of ­
thyroid dysfunction and swellings. Autoimmune
Free T4 (10–30 nmol/L) Free T3 (3.5–7.5 µmol/L)
Normal Normal
High High
Low Low
High High (often normal)
Normal High
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Physiology 803

thyroiditis may be associated with thyroid toxicity, failure (a)

or euthyroid goitre. Levels above 25 units/mL for TPO anti-
body and titres of greater than 1:100 for antithyroglobulin
are considered significant, although a proportion of patients
with histological evidence of lymphocytic (autoimmune)
thyroiditis are seronegative. The presence of antithyroglob-
ulin antibody interferes with assays of serum thyroglobulin,
with implications for follow-up of thyroid cancers. TSH
receptor antibodies (TSH-Rab or TRAB) are often present
in Graves’ disease. They are largely produced within the
thyroid itself.

Summary box 50.1

(b)
Thyroid investigations
Essential
●● Serum: TSH (T3 and T4 if abnormal); thyroid autoantibodies
●● FNAC of palpable discrete swellings; ultrasound guidance
may reduce the ‘Thy1’ rate

Optional
●● Corrected serum calcium
●● Serum calcitonin (carcinoembryonic antigen may be used as
an alternative screening test for medullary cancer)
●● Imaging: chest radiograph and thoracic inlet if tracheal
deviation/retrosternal goitre; ultrasound, CT and MRI scan
for known cancer, some reoperations and some retrosternal
goitres; isotope scan if discrete swelling and toxicity coexist Figure 50.5 Ultrasound scanning. (a) Transverse scan of normal
thyroid. R, right lobe; L, left lobe; T, trachea. (b) Longitudinal scan of
normal jugular lymph nodes (white arrows).

Thyroid imaging Contrast enhanced CT is useful for determining the extent of

The workhorse investigation in thyroid disease for the sur- airway invasion (Figure 50.7) and MRI is superior at deter-
geon is ultrasound. This modality allows assessment of the mining the presence of prevertebral fascia invasion.
gland and the regional lymphatics. Not only can the char- Positron emission tomography (PET) scans have limited
acteristics of the gland substance be quantified, but critically application in thyroid disease. They may be considered in the
the presence and features of thyroid nodules can be described. setting of recurrent thyroid cancer. This is particularly use-
Number, size, shape, margins, vascularity and specific features ful when the disease does not concentrate iodine, at which
such as the presence of microcalcifications can be used to pre- point fluorodeoxyglucose (FDG) uptake increases and lesions
dict the risk of malignancy within a specific nodule. Regional become positive on PET scans.
lymphatics, particularly in the lateral neck can be assessed
accurately for the presence of metastatic deposits. During
ultrasound, fine needle aspiration (FNA) can be performed
more accurately than free-hand techniques allow.
Ultrasound has the advantages that it is not associated
with ionising radiation and is non-invasive and cheap (Figure
50.5). Visualisation of the central neck nodes, in particular
those behind the sternum, is however limited. For this reason,
when metastatic disease is detected cross-sectional imaging
is required to fully stage the disease. Retrosternal extension,
which can often be predicted on plain chest x-ray (Figure
50.6), also requires more advanced techniques to determine
the extent adequately prior to considering management. For
most of these indications, the imaging modality of choice is
computed tomography (CT). Rapid acquisition times mini-
mise the artifact secondary to breathing and the lung fields
can be accurately assessed simultaneously.
In the setting of an invasive primary thyroid cancer, both Figure 50.6 Chest radiograph showing retrosternal goitre with
CT and magnetic resonance imaging (MRI) may have a role. ­tracheal displacement.

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804 CHAPTER 50  The thyroid gland

(a) (c)

(d)

(b)

Figure 50.7 (a) Scout film showing retrosternal goitre. (b) Axial
computed tomography (CT) section showing goitre extending to
below the aortic arch with tracheal compression. (c) Coronal CT sec-
tion showing goitre extending to the tracheal bifurcation. (d) Sagittal
CT section showing goitre filling the posterior mediastinum.

Isotope scanning out-patient department and is readily repeated. This technique,

The uptake by the thyroid of a low dose of either radiola- developed in Scandinavia 40 years ago, is now routine through-
belled iodine (123I) or the cheaper technetium (99mTc) will out the world. FNAC results should be reported using standard
demonstrate the distribution of activity in the whole gland. terminology (Table 50.2). As stated above there is a trend to
Routine isotope scanning is unnecessary and inappropriate
for distinguishing benign from malignant lesions because the
majority (80%) of ‘cold’ swellings are benign and some (5%)
functioning or ‘warm’ swellings will be malignant. Its princi-
pal value is in the toxic patient with a nodule or nodularity
of the thyroid. Localisation of overactivity in the gland will
differentiate between a toxic nodule with suppression of the
remainder of the gland, and toxic multinodular goitre with
several areas of increased uptake with important implications
for therapy (Figure 50.8).
Whole-body scanning is used to demonstrate metastases.
However, the patient must have all normally functioning thy-
roid tissue ablated either by surgery or radioiodine before the
scan is performed, because metastatic thyroid cancer tissue can-
not compete with normal thyroid tissue in the uptake of iodine.

Fine-needle aspiration cytology

Figure 50.8 Technetium thyroid scan showing appearance of a 1-cm
Fine-needle aspiration cytology (FNAC) is the investigation ‘toxic’ adenoma in the right thyroid lobe with suppression of uptake in
of choice in discrete thyroid swellings. FNAC has excellent the left lobe. The intense uptake gives a false impression of the size
patient compliance, is simple and quick to perform in the of the swelling.

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TABLE 50.2 Classification of fine-needle aspiration Summary box 50.2

cytology reports.
Thy1 Non-diagnostic Thyroid swellings
Thy1c Non-diagnostic cystic ●● Know how to describe thyroid swellings
●● Use appropriate investigations
Thy2 Non-neoplastic
●● Know the indications for surgery
Thy3 Follicular ●● Select the appropriate procedure
Thy4 Suspicious of malignancy ●● Describe and manage postoperative complications

Thy5 Malignant

Simple goitre
use ultrasound to guide the needle to achieve more accurate Aetiology
sampling and reduce the rate of unsatisfactory aspirates. Simple goitre may develop as a result of stimulation of the
thyroid gland by TSH, either as a result of inappropriate
THYROID ENLARGEMENT secretion from a microadenoma in the anterior pituitary
(which is rare), or in response to a chronically low level of
The normal thyroid gland is impalpable. The term goitre (from
circulating thyroid hormones. The most important factor in
the Latin guttur = the throat) is used to describe generalised
endemic goitre is dietary deficiency of iodine (see below),
enlargement of the thyroid gland. A discrete swelling (nodule)
but defective hormone synthesis probably accounts for many
in one lobe with no palpable abnormality elsewhere is termed an
sporadic goitres (see below).
isolated (or solitary) swelling. Discrete swellings with evidence
TSH is not the only stimulus to thyroid follicular cell pro-
of abnormality elsewhere in the gland are termed dominant.
liferation and other growth factors, including immunoglob-
A scheme for classifying thyroid enlargement is given in
ulins, exert an influence. The heterogeneous structural and
Table 50.3.
functional response in the thyroid resulting in characteristic
nodularity may be due to the presence of clones of cells par-
ticularly sensitive to growth stimulation.
TABLE 50.3 Classification of thyroid swellings.
Simple goitre Diffuse Physiological IODINE DEFICIENCY
(euthyroid) hyperplastic Pubertal The daily requirement of iodine is about 0.1–0.15mg. In
Pregnancy nearly all districts where simple goitre is endemic, there is a
Multinodular very low iodide content in the water and food. Endemic areas
goitre are in the mountainous ranges, such as the Rocky Mountains,
Toxic Diffuse (Graves’ the Alps, the Andes and the Himalayas and in the UK areas
disease) of Derbyshire and Yorkshire. Endemic goitre is also found in
Multinodular lowland areas where the soil lacks iodide or the water supply
Toxic adenoma comes from far away mountain ranges, e.g. the Great Lakes
of North America, the plains of Lombardy, the Struma val-
Neoplastic Benign
ley, the Nile valley and the Congo. Calcium is also goitro-
Malignant genic and goitre is common in low-iodine areas on chalk or
Inflammatory Autoimmune Chronic lymphocytic limestone, for example Derbyshire and Southern Ireland.
thyroiditis Although iodides in food and water may be adequate, failure
Hashimoto’s disease of intestinal absorption may produce iodine deficiency.
Granulomatous De Quervain’s thyroiditis DYSHORMONOGENESIS
Fibrosing Riedel’s thyroiditis Enzyme deficiencies of varying severity may be responsible
Infective Acute (bacterial for many sporadic goitres, i.e. in non-endemic areas (Figure
thyroiditis, viral thyroiditis, 50.9). There is often a family history, suggesting a genetic
‘subacute thyroiditis’) defect. Environmental factors may compensate in areas of
Chronic (tuberculous, high iodine intake; for example, goitre is almost unknown in
syphilitic) Iceland where the fish diet is rich in iodine. Similarly, a low
Other Amyloid intake of iodine encourages goitre formation in those with a
metabolic predisposition.

Hakaru Hashimoto, 1881–1934, Director of The Hashimoto Hospital, Mie, Japan, described chronic lymphocytic thyroiditis in 1912. The link to an autoimmune
basis was defined by Roitt and his co-workers.
Struma. The River Struma arises in the mountains of Bulgaria and flows into the Aegean Sea. Along its banks and those of its tributaries dwell peoples of several
nationalities among whom endemic goitre has long been prevalent. Struma is a European continental term for goitre.

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806 CHAPTER 50  The thyroid gland

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 (Figure
50.10).

Figure 50.9 Total thyroidectomy for dyshormonogenetic goitre in a
14-year-old girl.
NODULAR GOITRE
Nodules are usually multiple, forming a multinodular goitre
(Figure 50.11). 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 his or her late 40s or 50s. All types
of simple goitre are more common in the female than in the
male owing to the presence of oestrogen receptors in thyroid
tissue.

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 the anti-
thyroid drugs. Thiocyanates and perchlorates interfere with
iodide trapping; carbimazole and thiouracil compounds inter-
fere with the oxidation of iodide and the binding of iodine to
tyrosine.
Surprisingly, iodides in large quantities are goitrogenic
because they inhibit the organic binding of iodine and ­produce
an iodide goitre. Excessive iodine intake may be associated
with an increased incidence of autoimmune thyroid disease.

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, Figure 50.10 Colloid goitre.
which may persist for a long time but is reversible if stim-
ulation ceases.
●● Later, as a result of fluctuating stimulation, a mixed pat-
tern 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 either with
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 natu-
ral history. The goitre appears in childhood in endemic areas
but, in sporadic cases, it usually occurs at puberty when meta-
bolic demands are high. If TSH stimulation ceases the goitre
may regress, but tends to recur later at times of stress such as Figure 50.11 Large multinodular goitre.

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Diagnosis
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 calci-
fication, 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 and the two conditions frequently coexist.
Investigations
Thyroid function should be assessed to exclude mild hyper-
thyroidism, and the presence of circulating thyroid antibodies
tested to differentiate from autoimmune thyroiditis. Ultra-
sound is the gold standard assessment when undertaken by
a suitably trained and experienced operator. FNAC is only
required for a nodule within the goitre that demonstrates
ultrasonic features of concern. This may or may not be the
largest ‘dominant’ nodule. The biopsy should be performed
under ultrasonic guidance to ensure the correct nodule is sam-
pled. If there are swallowing or breathing symptoms then a
CT scan of the thoracic inlet is the best modality to assess
tracheal or oesophageal compression.
Complications
Tracheal obstruction may be due to gross lateral displacement
or compression in a lateral or anteroposterior plane by ret-
rosternal extension of the goitre (Figure 50.7). Acute respi-
ratory obstruction may follow haemorrhage into a nodule
impacted in the thoracic inlet.
SECONDARY THYROTOXICOSIS
Transient episodes of mild hyperthyroidism are common,
occurring in up to 30% of patients.
CARCINOMA
An increased incidence of cancer (usually follicular) has been
reported from endemic areas. Dominant or rapidly growing
nodules in longstanding goitres should always be subjected to
aspiration cytology.
Prevention and treatment of simple goitre
In endemic areas the incidence of goitre has been strikingly
reduced by the introduction of iodised salt.
In the early stages, a hyperplastic goitre may regress if thy-
roxine is given in a dose of 0.15–0.2 mg daily for a few months.
Although the nodular stage of simple goitre is irrevers-
ible, more than half of benign nodules will regress in size over
10 years. Most patients with multinodular goitre are asymp-
tomatic and do not require operation. Surgery is indicated for
nodular goitres with features of underlying malignancy, for
swallowing symptoms if other causes have been excluded or
for cosmetic reasons if the patient finds the goitre unsightly. If
the goitre is causing tracheal compression then surgery should
be considered. Many such patients are found incidentally
Sir Thomas Peel Dunhill, 1876–1957, surgeon, St Bartholomew’s Hospital, London, UK.
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Thyroid enlargement 807
and are asymptomatic and often very elderly. As these goitres
often grow very slowly the risks and benefits of surgery should
be considered carefully, particularly if a sternal split may be
required for access.
There is a choice of surgical treatment in multinodular
goitre: total thyroidectomy with immediate and lifelong
replacement of thyroxine or some form of partial resection
to conserve sufficient functioning thyroid tissue to subserve
normal function while reducing the risk of hypoparathyroid-
ism that accompanies total thyroidectomy. Subtotal thyroid-
ectomy involves partial resection of each lobe removing 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 complica-
tions. More often, however, the multinodular change is asym-
metrical, with one lobe more significantly involved than the
other. In these circumstances, particularly in older patients,
total lobectomy on the more affected side is the appropriate
management with either subtotal resection (Dunhill proce-
dure) 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, an increasing number
of thyroid surgeons favour total thyroidectomy in younger
patients. However, when the first operation comprised uni-
lateral lobectomy alone for asymmetric goitre, reoperation
and completion total thyroidectomy is straightforward if
required for progression of nodularity in the remaining lobe.
Total lobectomy and total thyroidectomy have the additional
advantage of being therapeutic for incidental carcinomas (see
below).
After subtotal resection, it has been customary to give
thyroxine to suppress TSH secretion, with the aim of prevent-
ing 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 radio-
active iodine may reduce the size of recurrent nodular goitre
after previous subtotal resection and, in some circumstances,
this may be a safer alternative than reoperation, particularly
if there has been more than one previous thyroid procedure.
Clinically discrete swellings
Discrete thyroid swellings (thyroid nodules) are common and
are palpable in 3–4% 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 is
dominant for a similar swelling in a gland with clinical evi-
dence of generalised abnormality in the form of a palpable
contralateral lobe or generalised mild nodularity. About 70%
of discrete thyroid swellings are clinically isolated and about
30% are dominant. The true incidence of isolated swellings is
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808 CHAPTER 50  The thyroid gland

s­omewhat less than the clinical estimate. Clinical classifica- Isolated

tion is inevitably subjective and overestimates the frequency thyroid swelling
of truly isolated swellings. When such a gland is exposed
at operation or examined by ultrasonography, CT or MRI,
Solid Cystic
clinically impalpable nodules are often detected. The true 24% 12%
frequency of thyroid nodularity compared with the clinical
detection rate by palpation is shown in Figure 50.12.
Male Female Male Female
48% 12% 24% 6%
70
60
50 Dominant
Prevalence

thyroid swelling
40
30
Solid Cystic
20
12% 6%
10

0 10 20 30 40 50 60 Male Female Male Female

Age (years) 24% 6% 12% 3%

Figure 50.12 The prevalence of thyroid nodules detected on palpa-

tion (broken line) or by ultrasonography or postmortem examination
(solid line) (after Mazzaferri). Generalised
thyroid swelling

Demonstrating the presence of impalpable nodules does

not change the management of palpable discrete swellings and
begs the question of the necessity of investigating incidentally
found nodules. The importance of discrete swellings lies in
the risk of neoplasia compared with other thyroid swellings.
Some 15% of isolated swellings prove to be malignant and
an additional 30–40% are follicular adenomas. The remain-
der are non-neoplastic, largely consisting of areas of colloid
degeneration, thyroiditis or cysts. Although the incidence
of malignancy or follicular adenoma in clinically dominant
swellings is approximately half of that of truly isolated swell-
ings, it is substantial and cannot be ignored (Figure 50.13).
Investigation
THYROID FUNCTION
Serum TSH and thyroid hormone levels should be measured.
If hyperthyroidism associated with a discrete swelling is con-
firmed biochemically, it indicates either a ‘toxic adenoma’ or a
manifestation of toxic multinodular goitre. The combination
of toxicity and nodularity is important and is an indication
for isotope scanning to localise the area(s) of hyperfunction.
AUTOANTIBODY TITRES
The autoantibody status may determine whether a swelling
is a manifestation of chronic lymphocytic thyroiditis. The
presence of circulating antibodies increases the risk of thyroid
failure after lobectomy.
ISOTOPE SCAN
Isotope scanning used to be the mainstay of investigation of
discrete thyroid swellings but has been abandoned except
when toxicity is associated with nodularity.
3%
Figure 50.13 The risk of malignancy in thyroid swellings (‘rule of
twelve’). The risk of cancer in a thyroid swelling can be expressed as a
factor of 12. The risk is greater in isolated versus dominant swellings,
solid versus cystic swellings and in men versus women.
ULTRASONOGRAPHY
This is gold standard investigation to determine the physi-
cal characteristics of thyroid swellings. There are a number
of ultrasonic features in a thyroid swelling associated with
thyroid neoplasia, including microcalcification and increased
vascularity, but only macroscopic capsular breach and nodal
involvement are diagnostic of malignancy. Ultrasound should
be used as the primary investigation of any thyroid nodule as
a reassuring appearance mitigates the need for an FNAC (see
below).
FINE-NEEDLE ASPIRATION CYTOLOGY
FNAC should be used, ideally under ultrasound guidance,
on all nodules that do not fulfil a fully benign (U2) clas-
sification on ultrasound. FNAC is reliable in identifying
papillary thyroid cancer but cannot distinguish between a
benign follicular adenoma (Figure 50.14) and follicular car-
cinoma, as this distinction is dependent not on cytology but
on histological criteria, which include capsular and vascular
invasion.
FNAC is both highly specific and sensitive. Using ultra-
sound improves this further, particularly in part cystic, part
solid nodules in which ultrasound allows targeting of the solid
element for biopsy.

Ernest L Mazzaferri, 1936–2013, endocrinologist, Ohio State University School of Medicine, Columbus, OH, USA.

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 PART 8 | BREAST AND ENDOCRINE
Thyroid enlargement 809

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 asso-
ciated 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, more so in males.

Thyroid cysts
Routine FNAC (or ultrasonography) shows that over 30%
of clinically isolated swellings contain fluid and are cystic or
Figure 50.14 Thy3 aspiration cytology. Follicular neoplasm showing
increased cellularity with a follicular pattern. 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
RADIOLOGY period of weeks if untreated. Aspiration yields altered blood
Plain films have previously been used to assess tracheal com- but reaccumulation is frequent. About 50% of cystic swellings
pression and deviation, but the modality of choice now is CT are the result of colloid degeneration, or of uncertain aeti-
scanning. CT scanning is also useful if ultrasound has iden- ology because of an absence of epithelial cells in the lining.
tified metastatic disease in the neck as it can assist surgical Although most of the remainder are the result of involution
planning and also assess the superior mediastinum and lungs. in follicular adenomas (Figure 50.15), some 10–15% of cys-
tic follicular swellings are histologically malignant (30% in
LARYNGOSCOPY men and 10% in women). Papillary carcinoma is often associ-
Flexible laryngoscopy has rendered indirect laryngoscopy ated with cyst formation (Figure 50.16).
obsolete and is widely used preoperatively to determine the Most patients with discrete swellings, however, are
mobility of the vocal cords. The presence of a unilateral cord women, aged 20–40 years, in whom the risk of malignancy,
palsy coexisting with an ipsilateral thyroid nodule of concern although significant, is low and the indications for operation
are not clear cut.
is usually diagnostic of malignant disease.
Ultrasound is the most useful tool for assessing cysts. If
CORE BIOPSY there is no discernable solid element then the cyst is almost
certainly benign and does not need to be further investigated.
Core biopsy is rarely indicated in thyroid masses due to the
If there is an associated solid element then ­consideration
vascularity of the thyroid gland and the risk of postprocedure
haemorrhage. It can be useful in the rapid diagnosis of widely
invasive malignant disease, for example anaplastic carcinoma,
or in the diagnosis of lymphadenopathy.
The main indication for operation is the risk of neoplasia,
which includes follicular adenoma as well as malignant swell-
ings. The reason for advocating the removal of all follicular
neoplasms is that it is seldom possible to distinguish between a
follicular adenoma and carcinoma cytologically. On this basis,
some 50% of isolated swellings and 25% of dominant swell-
ings should be removed on the grounds of neoplasia. Even Figure 50.15 Apparently simple cystic thyroid swelling, the wall of
when the cytology is negative, the age and sex of the patient which comprised follicular neoplastic tissue.
and the size of the swelling may be relative indications for sur-
gery, especially when a large swelling is responsible for symp-
toms. 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 as tense cystic swellings may
be suspiciously hard but a hard, irregular swelling with any
apparent fixity, which is unusual, is highly suspicious. Evidence
of RLN paralysis, suggested by hoarseness and a non-­occlusive
cough and confirmed by laryngoscopy, is almost pathogno-
monic. Deep cervical lymphadenopathy along the internal Figure 50.16 Cyst formation in a papillary carcinoma.

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 PART 8 | BREAST AND ENDOCRINE
810 CHAPTER 50  The thyroid gland

should be given to targeting that area with an ultrasound-­ Subtotal resections for colloid goitre run the risk of later
guided FNAC. growth of the remnant and, if a second operation is required
The indications for operation in isolated or dominant thy- years later, this greatly increases the risk to the RLN and para-
roid swellings are listed in Table 50.4. thyroid glands. In young patients, total thyroidectomy should
be considered. It may be preferable to leave the least affected
lobe untouched to permit a straightforward lobectomy in the
TABLE 50.4 Indications for operation in thyroid swellings.
future if required, rather than carry out subtotal resections.
Neoplasia FNAC positive Thy3–5 In Graves’ disease, preserving large remnants increases
Clinical suspicion Age the risk of recurrence of the toxicity and, in these cases, it is
better to err on the side of removing too much thyroid tissue
Male sex
rather than too little (Table 50.5). Thyroid failure should not
Hard texture be regarded as a failure of treatment, but recurrent toxicity is.
Fixity The relative merits of routine total versus selective total
thyroidectomy in differentiated thyroid cancer are discussed
Recurrent laryngeal
nerve palsy below.
Lymphadenopathy
Recurrent cyst Summary box 50.3
Toxic adenoma
Thyroid operations
Pressure
All thyroid operations can be assembled from three basic
symptoms
elements:
Cosmesis
1 Total lobectomy
Patient’s wishes 2 Isthmusectomy
3 Subtotal lobectomy
Total thyroidectomy = 2 × total lobectomy + isthmusectomy
Selection of thyroid procedure Subtotal thyroidectomy = 2 subtotal lobectomy + isthmusectomy
The choice of thyroid operation depends on: Near-total thyroidectomy = total lobectomy + isthmusectomy +
subtotal lobectomy (Dunhill procedure)
●● diagnosis (if known preoperatively); Lobectomy = total lobectomy + isthmusectomy
●● risk of thyroid failure;
●● risk of RLN injury;
●● risk of recurrence;
●● Graves’ disease;
●● multinodular goitre; Retrosternal goitre
●● differentiated thyroid cancer;
Retrosternal goitre tends to arise from the slow growth of
●● risk of hypoparathyroidism.
a multinodular gland down in to the mediastinum. As the
Total and near-total thyroidectomy do not conserve suffi- gland enlarges within the thoracic inlet, pressure may lead
cient thyroid tissue for normal thyroid function and thyroid to dysphagia, tracheal compression and eventually air-
replacement therapy is necessary. In most patients with neg- way symptoms. The vast majority of patients have minimal
ative antithyroid antibodies, one thyroid lobe will maintain symptoms. Patient should be considered for surgery if there
normal function. In subtotal thyroidectomy, the volume of is significant airway compression, if symptoms are present or
thyroid tissue preserved influences the risk of thyroid failure: in young patients in whom symptoms are likely to develop.
larger remnants have a better chance of normal function but In elderly patients with incidentally discovered retroster-
a higher risk of recurrence in Graves’ disease. nal goitres, most surgeons would observe rather than­treat

TABLE 50.5 Comparison of surgical options for Graves’ disease.

Total thyroidectomy Subtotal thyroidectomy
Control of toxicity Immediate Immediate
Return to euthyroid state Immediate Variable – up to 12 months
Risk of recurrence None Lifelong – up to 5%a
Risk of thyroid failure 100% Lifelong – up to 100% at 30 yearsa
Risk of permanent hypoparathyroidism 5% 1%
Need for follow-up Minimal Lifelong

a
The risk of recurrence and late failure are a function of the size of the remnant as a proportion of the total gland weight. Large remnants in small glands have a
higher risk of recurrence and a low risk of failure, and small remnants in large glands have a higher risk of thyroid failure but a low risk of recurrence.

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 PART 8 | BREAST AND ENDOCRINE
Hyperthyroidism 811

p­ rop­hylactically. Clearly a balance between risk and benefit

must be made.
If a decision is made to proceed to surgery, assessment of
the extent of disease is critical. The vast majority (>95%)
of retrosternal goitres can be removed transcervically. Those
at most risk of requiring conversion to an open sternotomy
approach include malignant or revision cases, those which
extend into the posterior mediastinum and those in which
the diameter of the goitre exceeds that of the thoracic inlet.
In such cases a joint case with thoracic surgery should be
planned.
All cases should have cross-sectional imaging. Ideally this
is performed in the surgical position and when interpreting
CT chest scans, the surgeon should pay attention to the arm
position. If the arms are up (as for standard CT chest) a great
deal of thyroid movement will be achieved when the arms are
down and the neck extended.
The approach to surgery is as described below. A longer
incision is required. The surgeon may mobilise the sternomas-
toid muscle from the strap muscles to improve access. The
ligamentous tissue between the sternal heads of the clavicles Figure 50.17 Graves’ disease.
may be gently divided to increase the opening for gland deliv-
ery. Blunt dissection on the capsule of the gland allows mobil-
isation. Gentle traction is applied to deliver the gland into whole of the functioning thyroid tissue is involved, and the
the neck. If the goitre has developed from a posteriorly posi- hypertrophy and hyperplasia are due to abnormal TSH-RAb
tioned nodule there is a risk that the RLN may be displaced that bind to TSH receptor sites and produce a disproportion-
anteriorly, so great care must be taken in dividing apparent ate and prolonged effect.
fascial bands that overlie the gland. The blood supply is from
the neck, reducing the risk of catastrophic bleeding from the Toxic nodular goitre
great vessels. Nonetheless, care should be taken in the region A simple nodular goitre is present for a long time before the
of the major blood vessels in the neck and chest. hyperthyroidism, usually in the middle-aged or elderly, and
If the gland is fixed and immobile or too large to deliver very infrequently is associated with eye signs. The syndrome
through a cervical approach, a midline sternotomy is per- is that of secondary thyrotoxicosis.
formed and the gland can be dissected from below to achieve In many cases of toxic nodular goitre, the nodules are
a safe total thyroidectomy. inactive, and it is the internodular thyroid tissue that is over-
active. However, in some toxic nodular goitres, one or more
nodules are overactive and here the hyperthyroidism is due to
HYPERTHYROIDISM autonomous thyroid tissue as in a toxic adenoma.
Thyrotoxicosis
Toxic nodule
The term thyrotoxicosis is retained because hyperthyroidism,
A toxic nodule is a solitary overactive nodule, which may be
i.e. symptoms due to a raised level of circulating thyroid hor-
part of a generalised nodularity or a true toxic adenoma. It is
mones, is not responsible for all manifestations of the disease.
autonomous and its hypertrophy and hyperplasia are not due
Clinical types are:
to TSH-RAb. TSH secretion is suppressed by the high level
●● diffuse toxic goitre (Graves’ disease); of circulating thyroid hormones and the normal thyroid tissue
●● toxic nodular goitre; surrounding the nodule is itself suppressed and inactive.
●● toxic nodule;
●● hyperthyroidism due to rarer causes. HISTOLOGY
The normal thyroid gland consists of acini lined with flat-
Diffuse toxic goitre tened cuboidal epithelium and filled with homogeneous col-
Graves’ disease, a diffuse vascular goitre appearing at the same loid (Figure 50.2). In hyperthyroidism (Figure 50.18), there
time as hyperthyroidism, usually occurs in younger women and is hyperplasia of acini, which are lined by high columnar epi-
is frequently associated with eye signs. The syndrome is that thelium. Many of them are empty, and others contain vacuo-
of primary thyrotoxicosis (Figure 50.17); 50% of patients lated colloid with a characteristic ‘scalloped’ pattern adjacent
have a family history of autoimmune endocrine diseases. The to the thyrocytes.

Robert James Graves, 1796–1853, physician, Meath Hospital, Dublin, Ireland, published an account of exopthalmic goitre in 1835. He was President of the Royal
College of Physicians of Ireland and elected Fellow of The Royal Society of London in 1849. There is a statue of him in the Royal College of Physicians in Ireland.

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 PART 8 | BREAST AND ENDOCRINE
812 CHAPTER 50  The thyroid gland
Figure 50.18 Histology of thyrotoxicosis.
Principles of treatment of thyrotoxicosis
Non-specific measures are rest and sedation and in established
thyrotoxicosis should be used only in conjunction with spe-
cific measures, i.e. the use of antithyroid drugs, surgery and
radioiodine.
ANTITHYROID DRUGS
Those in common use are carbimazole and propylthiouracil.
Antithyroid drugs are used to restore the patient to a euthyroid
state and to maintain this for a prolonged period in the hope
that a permanent remission will occur, i.e. that production
of thyroid-stimulating antibodies (TSH-RAb) will diminish
or cease. Antithyroid drugs cannot cure a toxic nodule. The
overactive thyroid tissue is autonomous and recurrence of the
hyperthyroidism is certain when the drug is discontinued.
●● Advantages. No surgery and no use of radioactive materials.
●● Disadvantages. Treatment is prolonged and the failure
rate is at least 50%. The duration of treatment may be
tailored to the severity of the toxicity, with milder cases
being treated for only 6 months and severe cases for
2 years before stopping therapy.
SURGERY
In diffuse toxic goitre and toxic nodular goitre with over­
active internodular tissue, surgery cures by reducing the mass
of overactive tissue by reducing the thyroid below a criti-
cal mass. After subtotal thyroidectomy the patient should
return to a euthyroid state, albeit after a variable period of
hypothyroidism. There are however, the long-term risks of
recurrence and eventual thyroid failure. In contrast total/
near total thyroidectomy accepts immediate thyroid failure
and lifelong thyroxine replacement to eliminate the risk of
recurrence and simplify follow-up. Operation may result in
a reduction in TSH-RAb. In the autonomous toxic nodule,
and in toxic nodular goitre with overactive autonomous
toxic nodules, surgery cures by removing all the overactive
thyroid tissue; this allows the suppressed normal tissue to
function again.
●● Advantages. The goitre is removed, the cure is rapid and
the cure rate is high if surgery has been adequate.
08_50B-B&L27_Pt8_Ch50.indd 812
●● Disadvantages. Recurrence of thyrotoxicosis occurs in at
least 5% of cases when subtotal thyroidectomy is carried
out. There is a risk of permanent hypoparathyroidism and
nerve injury. Young women tend to have a poorer cos-
metic result from the scar.
Every operation carries a risk, but with suitable prepara-
tion and an experienced surgeon the mortality is negligible
and the morbidity low.
RADIOIODINE
Radioiodine destroys thyroid cells and, as in thyroidectomy,
reduces the mass of functioning thyroid tissue to below a crit-
ical level.
●● Advantages. No surgery and no prolonged drug therapy.
●● Disadvantages. Isotope facilities must be available. The
patient must be quarantined while radiation levels are
high and avoid pregnancy and close physical contact, par-
ticularly with children. Eye signs may be aggravated.
Choice of therapy
Each case must be considered individually. Below are listed
guiding principles on the most satisfactory treatment for a
particular toxic goitre at a particular age; these must, how-
ever, be modified according to the facilities available and the
personality and wishes of the individual patient, business or
family commitments and any other coexistent medical or sur-
gical condition. Access to post-treatment care and availabil-
ity of replacement thyroxine can be important considerations
in resource-poor countries.
In advising treatment, compliance, influenced by social
and intellectual factors, is important; many patients cannot
be trusted to take drugs regularly if they feel well, and indefi-
nite follow-up, which is essential after radioiodine or subtotal
thyroidectomy is a burden for all.
DIFFUSE TOXIC GOITRE
Most patients have an initial course of antithyroid drugs with
radioiodine for relapse. Exceptions are those who refuse radi-
ation, have large goitres, progressive eye signs or are pregnant.
TOXIC NODULAR GOITRE
Toxic nodular goitre is often large and uncomfortable and
enlarges still further with antithyroid drugs. A large goitre
should be treated surgically because it does not respond as
well or as rapidly to radioiodine or antithyroid drugs as does a
diffuse toxic goitre.
TOXIC NODULE
Surgery or radioiodine treatment is appropriate. Resection is
easy, certain and with a low risk of morbidity. Radioiodine is a
good alternative for patients over the age of 45 years because
the suppressed thyroid tissue does not take up iodine and thus
there is minimal risk of delayed thyroid insufficiency.
FAILURE OF PREVIOUS TREATMENT WITH
ANTITHYROID DRUGS OR RADIOIODINE
In this case, surgery or thyroid ablation with 123I is appropriate.
25/10/2017 09:10

Surgery for thyrotoxicosis
Preoperative preparation
Traditional preparation aims to make the patient biochemi-
cally euthyroid at operation. Preparation is as an out-patient
and only rarely is admission to hospital necessary on account
of severe symptoms at presentation, failure to control the
hyperthyroidism or non-compliance with medication. Care
should be coordinated with endocrinology input.
Carbimazole 30–40 mg per day is the drug of choice for
preparation. When euthyroid (after 8–12 weeks), the dose
may be reduced to 5 mg 8-hourly or a ‘block and replace’
regime used. In this case, the high dose of carbimazole is con-
tinued to inhibit T3 and T4 production and a maintenance
dose of 0.1–0.15 mg of thyroxine is given daily. The last dose
of carbimazole may be given on the evening before surgery.
Iodides are not used alone because, if the patient needs pre-
operative treatment, a more effective drug should be given.
An alternative method of preparation is to abolish the
clinical manifestations of the toxic state, using β-adrenergic
blocking drugs. These act on the target organs and not on
the gland itself. Propranolol also inhibits the peripheral con-
version of T4 to T3. The appropriate dosages are propranolol
40 mg t.d.s. or the longer acting nadolol 160 mg once daily.
Clinical response to β-blockade is rapid and the patient may
be rendered clinically euthyroid and operation arranged in a
few days rather than weeks. The dose of β-adrenergic block-
ing drug is increased to achieve the required clinical response
and quite often larger doses (propranolol 80 mg t.d.s. or nado-
lolol 320 mg once daily) are necessary.
β-adrenergic blocking drugs do not interfere with syn-
thesis of thyroid hormones, and hormone levels remain high
during treatment and for some days after thyroidectomy. It
is, therefore, important to continue treatment for 7 days
­postoperatively.
Iodine may be given with carbimazole or a β-adrenergic
blocking drug for 10 days before operation. Iodide alone
produces a transient remission and may reduce vascularity,
thereby marginally improving safety. The use of iodine prepa-
rations is not universal because of more effective alternatives.
Iodine gives an additional measure of safety in case the early
morning dose of β-adrenergic blocking drug is mistakenly
omitted on the day of operation.
The extent of the resection depends on the size of the
gland, the age of the patient, the experience of the surgeon,
the need to minimise the risk of recurrent toxicity and the
wish to avoid postoperative thyroid replacement (Table 50.5).
SURGICAL TECHNIQUE OF THYROIDECTOMY
Having made the decision to proceed to surgery, the first step is
informed consent. Patients should understand the risk of scar,
RLN damage, bleeding, hypocalcaemia and hypo­thyroidism.
Endotracheal intubation is performed, and if a nerve mon-
itor is to be used its position should be confirmed once the
patient is in the surgical position (see New technology in thy-
roidectomy, below).
The patient lies supine with the neck extended. Surgical
preparation extends from the mandible on to the chest. A
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PART 8 | BREAST AND ENDOCRINE
Hyperthyroidism 813
skin crease incision is placed around the level of the cricoid
cartilage. Classically those patients with ‘pendulous’ breasts
should have an incision placed more superiorly as it will tend
to migrate inferiorly over years and a sternal wound is less
attractive.
Subplatysmal flaps are raised to an extent that allows access
to the goitre, often from thyroid notch to sternal notch. The
midline is identified between the strap muscles. The plane
is developed to dissect between the muscle layers, elevating
sternohyoid laterally until ansa cervicalis is visualised. The
sternothyroid muscle is then mobilised from the gland, taking
great care with the delicate vasculature. If required, the strap
muscles may be divided superiorly to afford greater exposure.
Attention is turned first to the superior pole. A plane
between the larynx and superior pole is developed and the
branching divisions of the superior vascular pedicle are dis-
sected. As these insert onto the gland they are dissected,
controlled with ties or bipolar diathermy and divided individ-
ually. Not only does this mobilise the superior pole, but pre-
serves the blood supply to the superior parathyroid gland. In
addition, this minimises risk to the superior laryngeal nerve,
which can often be seen passing medially towards the crico-
thyroid muscle. Gradually the superior pole is mobilised tak-
ing care not to dissect below the cricoid cartilage, at which
point the RLN is at risk.
By now, the fascia around the thyroid has been clearly
identified. This plane is followed over the anterolateral aspect
of the gland to the inferior pole. The tracheoesophageal
groove should not be entered at this point as the RLN is yet
to be identified. Inferiorly the trachea should be dissected in
order to confirm the anatomical landmark.
At this point structures inferior and superior to the RLN
have been identified and careful dissection toward the lateral
aspect of the gland allows the gland to be rotated medially,
displaying the tracheoesophageal groove. Careful dissection
of this area proceeds being sure not to divide any structure
that could be the nerve. The fascia from the thyroid is mobil-
ised, being vigilant throughout. The RLN is identified and
confirmed by the anatomical location, direction of travel and
the nerve monitor, if in use. The nerve is then traced towards
the larynx, allowing mobilisation of the lateral aspect of the
gland.
During this part of the dissection the surgeon must prior-
itise identification of the nerve, preservation of the inferior
parathyroid and its blood supply, as well as control of branches
of the inferior thyroid artery. Again, these should be divided
in a controlled manner as close as possible to gland in order to
preserve parathyroid blood supply.
At this stage the nerve should be traced towards the cri-
cothyroid joint as it enters the larynx. This point is the area
where the nerve is most commonly damaged. The pretracheal
fascia condenses into Berry’s ligament at this stage. Small ves-
sels within the ligament retract if not controlled with bipolar
diathermy or ties, and the resulting bleeding can disorientate
the surgeon placing the nerve at risk (Figure 50.19).
In order to avoid this, pre-emptive diathermy to the
ligament and careful layer by layer dissection allows final
­
mobilisation of the thyroid lobe. Some surgeons prefer to iso-
late the ligament and apply a careful tie to achieve haemostasis.
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 PART 8 | BREAST AND ENDOCRINE
814 CHAPTER 50  The thyroid gland
Figure 50.19 Identification of the recurrent laryngeal nerve. Note
how rotating the gland medially anteriorly kinks the nerve that is
­normally intimately related to the terminal branches of the inferior
­thyroid artery.
Whichever method is preferred, great care must be taken at this
point. The lobe is then mobilised medially and the nerve falls
laterally.
If total thyroidectomy is indicated the procedure is
repeated on the contralateral side. If, however, lobectomy
alone is indicated, the isthmus should be divided between
clamps and oversewn. The surgical bed is then inspected to
confirm the integrity of the nerve and the state of the para-
thyroid glands. Consideration may be given to reimplantation
of parathyroids to the sternomastoid muscle if they appear
devascularised. Irrigation followed by meticulous haemostasis
should follow and no bleeding is acceptable. Ideally this is
performed with a Valsalva manouvre with the head down.
Following complete haemostasis the strap muscles are
loosely reapproximated in order to avoid a water tight seal but
to prevent adhesion between skin and trachea. The wound is
then closed in layers with absorbable suture to platysma and
skin closure. This may be with clips, non-absorbable sutures
or subcuticular closure. It is important that those involved
in postoperative care know how the wound was closed and
how to perform a bedside reopening in the event of a life-­
threatening bleed.
The patient is then returned to the recovery room and
the postoperative area for overnight monitoring. Not only
is the wound regularly reviewed, but for total thyroidectomy
patients postoperative calcium should be checked to identify
hypocalcaemia.
NEW TECHNOLOGY IN THYROIDECTOMY
The major immediate risk following thyroidectomy is haem-
orrhage; conventionally, artery forceps, ligatures and sutures
have been used to secure the meticulous haemostasis neces-
sary to minimise the risk of this potentially life-threatening
complication. Ultrasonic shears, enhanced bipolar diathermy
and harmonic vessel sealing devices are increasingly used
in ­thyroid surgery and may be advantageous in complex
­procedures.
Monitoring of the RLN and vagus nerve has become
available over the last few years. By placing electrodes on the
endotracheal tube between the vocal cords, movements can
08_50B-B&L27_Pt8_Ch50.indd 814
be detected when the nerve is stimulated. Such intermittent
nerve monitoring is gaining in popularity. Advocates consider
the monitor particularly useful in recurrent operations where
scar tissue makes the nerve difficult to identify. In addition,
some authors find operative time is reduced and that this is
a valuable tool for training. There is also some support for
the use of nerve monitoring during bilateral thyroid surgery,
as the information provided can aid in the identification of
a unilateral palsy to prevent bilateral palsy that can require
tracheostomy. Those who do not support the use of the nerve
monitor highlight the lack of evidence that any real differ-
ence in outcome associated with this practice. In addition,
there is the expense of the base machine and the electrodes.
In contrast to intermittent nerve monitoring that allows
identification of a damaged nerve, continuous nerve moni-
toring has now been developed. In theory, this provides the
opportunity to identify a nerve when function is threatened
(by excessive traction for example). This technique, although
theoretically advantageous, requires an electrode placed on
the vagus nerve and has not gained widespread acceptance
(Figure 50.20).
Figure 50.20 Diagram of continuous monitoring of the vagus nerve
(adapted from an image provided by Inomed UK Ltd).
ALTERNATIVE SURGICAL TECHNIQUES
Over the past two decades, increasing experience has been
gained in alternative approaches to thyroid surgery. Mini-
mally invasive video assisted techniques have been developed,
which allow surgeons to operate through an incision <2 cm in
length. With appropriately modified dissectors, experienced
operators and advanced haemostatic electrosurgical devices,
such procedures offer reduced scar length. However, they are
only appropriate for small volume disease and as such are not
suitable for many thyroid cases.
Robots have found a role in many aspects of modern surgi-
cal practice. In the Far East, a neck scar is found to be socially
unacceptable. Robotic techniques have been developed that
allow access to the thyroid via an axillary incision. Such ‘max-
imally invasive’ techniques require extended dissection over
the chest wall and again are most suitable for small volume
disease. Experienced centres continue to expand the indica-
tions for these techniques. However, they are associated with
great cost and significant time, which currently limits their
application to thyroid surgical practice.
25/10/2017 09:10

POSTOPERATIVE COMPLICATIONS
Haemorrhage Haemorrhage is the most frequent
life-threatening complication of thyroidectomy. Around 1 in
50 patients will develop a haematoma, and in almost all cases
this will develop in the first 24 hours. If an arterial bleed
occurs, the tension in the central compartment pressure can
rise until it exceeds venous pressure. Venous oedema of the
larynx can then develop and cause airway obstruction lead-
ing to death. Although improvements in understanding of
the blood supply to the larynx and technical developments in
terms of haemostatic technologies have been made, this com-
plication has not been eliminated. Although many surgeons
worldwide practice day case thyroidectomy, bleeding is the
reason that, in the UK, thyroidectomy remains an inpatient
procedure.
Intraoperative attention to detail in terms of haemostasis
is critical. When closing the wound, avoiding a watertight
closure of the strap muscles may allow a haematoma to escape
into the subcutaneous tissues. Wound drains have not been
shown to have a protective effect. Close monitoring of the
wound is advised postoperatively. If a haematoma develops,
clinical staff should know to remove skin sutures in order to
release some pressure and seek senior advice immediately.
Endotracheal intubation should be used to secure the airway
while the haematoma is evacuated and the bleeding point
controlled.
Recurrent laryngeal nerve paralysis and voice
change RLN injury may be unilateral or bilateral, tran-
sient or permanent. Early routine postoperative laryngoscopy
reveals a much higher incidence of transient cord paralysis
than is detectable by simple assessment of the integrity of the
voice and cough. Such temporary dysfunction is not clinically
important however, but voice and cord function should be
assessed at first follow-up 4 weeks postoperatively. The Brit-
ish Association of Endocrine Surgeons audit revealed a RLN
palsy rate of 1.8% at 1 month, declining to 0.5% at 3 months
for first time operations. Permanent paralysis is rare if the
nerve has been identified at operation.
If a RLN is injured during surgery and the transected ends
are identified, they should be reanastomosed. In the event that
a length of nerve is excised (due to invasion by malignancy
for example), anastomosis of the ansa cervicalis may be con-
sidered. This does not return mobility of the vocal cord but
maintains neurological input to the muscles of the larynx. By
avoiding denervation and related muscle atrophy, the vocal
quality is improved. Permanent vocal cord paralysis should be
treated conservatively with speech therapy. If voice quality
is unacceptable, medialisation procedures can be performed.
Nerve grafting has shown promise but experience is limited.
Injury to the external branch of the superior laryngeal
nerve is more common because of its proximity to the supe-
rior thyroid artery. This leads to loss of tension in the vocal
cord with diminished power and range in the voice. Patients,
particularly those who use their voice professionally, must be
advised that any thyroid operation will result in change to the
voice even in the absence of nerve trauma. Fortunately, for
most patients the changes are subtle and only demonstrable
on formal voice assessment.
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PART 8 | BREAST AND ENDOCRINE
Hyperthyroidism 815
Thyroid insufficiency Following total thyroidectomy,
clearly thyroxine replacement will be required. Around one
in three patients who has a lobectomy will require supplemen-
tation; rates are higher in those with thyroid autoantibodies.
Subtotal thyroidectomy was at one time performed with the
aim of leaving sufficient tissue to maintain thyroid function.
However, this is difficult to judge and over years, the benign
process that necessitated primary surgery may recur, requir-
ing difficult revision procedures. For this reason, the practice
of subtotal thyroidectomy has been more or less abandoned
outside of environments where exogenous thyroxine is not
available.
Parathyroid insufficiency This is due to removal of the
parathyroid glands or infarction through damage to the para-
thyroid end arteries; often both factors occur together. Vas-
cular injury is probably far more important than inadvertent
removal. The incidence of permanent hypoparathyroidism
should be less than 1% and most cases present dramatically
2–5 days after operation but, very rarely, the onset is delayed
for 2–3 weeks or a patient with marked hypocalcaemia may
be asymptomatic. The complication is limited to total thy-
roidectomy, as when lobectomy is performed the contralateral
parathyroid glands are sufficient to maintain calcium levels.
In particular, total thyroidectomy with central neck dissection
places the parathyroid glands and their vascular supply at great
risk and should only be performed when there is evidence of
metastatic disease or high risk of occult disease in the regional
lymph nodes.
Thyrotoxic crisis (storm) This is an acute exacerbation of
hyperthyroidism. It occurs if a thyrotoxic patient has been
inadequately prepared for thyroidectomy and is now extremely
rare. Very rarely, a thyrotoxic patient presents in a crisis and
this may follow an unrelated operation. Symptomatic and
supportive treatment is for dehydration, hyperpyrexia and
restlessness. This requires the administration of intravenous
fluids, cooling the patient with ice packs, administration of
oxygen, diuretics for cardiac failure, digoxin for uncontrolled
atrial fibrillation, sedation and intravenous hydrocortisone.
Specific treatment is by carbimazole 10–20 mg 6-hourly,
Lugol’s iodine 10 drops 8-hourly by mouth or sodium iodide
1g i.v. Propranolol intravenously (1–2 mg) or orally (40 mg
6-hourly) will block β-adrenergic effects.
Wound infection Cellulitis requiring prescription of antibi-
otics, often by the general practitioner, is more common than
most surgeons appreciate. A significant subcutaneous or deep
cervical abscess is exceptionally rare and should be drained.
Hypertrophic or keloid scar This is more likely to form if
the incision overlies the sternum and in dark skinned indi-
viduals. Intradermal injections of corticosteroid should be
given at once and repeated monthly if necessary. Scar revision
rarely results in significant long-term improvement.
Stitch granuloma This may occur with or without sinus
formation and is seen after the use of non-absorbable, partic-
ularly silk, suture material. Absorbable ligatures and sutures
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 PART 8 | BREAST AND ENDOCRINE
816 CHAPTER 50  The thyroid gland

should be used throughout thyroid surgery. Some surgeons use

a subcuticular absorbable skin suture rather than the tradi-
tional skin clips or staples.

POSTOPERATIVE CARE
Following surgery, the patient should be returned to the
recovery room and nursed overnight on the ward. Wound care
should include vigilance for signs of a haematoma. Following
total thyroidectomy, calcium levels should be checked post-
operatively. Not all patients develop immediate hypocalcae-
mia and they should be educated about the signs (parasthesia
of the fingers and toes or round the mouth). Serial calcium
monitoring should be recommended for those at highest risk.
Those patients who had a total thyroidectomy require thyrox-
ine replacement, which should start day 1 postoperatively. On
clinic review, in addition to checking the histology report,
the wound should be inspected and the larynx examined for
vocal cord function. Biochemical assessment of thyroid func-
tion and calcium, if required, should be arranged. Figure 50.21 Isolated swelling in the upper pole of the right thyroid
lobe.

NEOPLASMS OF THE THYROID lesions. Diagnosis and treatment is therefore, by wide exci-
Classification of thyroid neoplasms is presented in Table 50.6 sion, i.e. total lobectomy. The remaining thyroid tissue is nor-
and the relative incidence of malignancies in Table 50.7. mal so that prolonged follow-up is unnecessary.

TABLE 50.6 Classification of thyroid neoplasms. Malignant tumours

Benign Follicular
adenoma
The vast majority of primary malignancies are carcinomas
derived from the follicular cells (Table 50.6). Such tumors
Malignant Primary Follicular epithelium – Follicular
differentiated Papillary
were thought of as differentiated (papillary, follicular and
Hürthle cell) and undifferentiated (anaplastic). However,
Follicular epithelium – Anaplastic
poorly differentiated
now an intermediate class of ‘poorly differentiated carcinoma’
is recognised, which is likely to represent a state of dediffer-
Parafollicular cells Medullary
entiated, between classic differentiated and undifferentiated
Lymphoid cells Lymphoma diseases. The parafollicular C cells can undergo malignant
Secondary Metastatic transformation into medullary carcinoma, and thyroid lym-
Local infiltration
phoma is another primary thyroid malignancy. In addition,
the thyroid can be involved by direct spread from surround-
ing structures (larynx and oesophagus) or metastases (most
TABLE 50.7 Relative incidence of primary malignant commonly from renal cell carcinoma). Lymph node and
tumours of the thyroid gland. blood-borne metastases of thyroid cancer occur primarily to
Malignancy Relative incidence bone and lung and may be the mode of presentation (Figure
Papillary carcinoma 80% 50.22).
Follicular carcinoma 10% Aetiology of malignant thyroid tumours
Poorly differentiated/anaplastic carcinoma 5% The great majority of thyroid cancers have no known aeti-
Medullary carcinoma 2.5% ological factor. The most important identifiable aetiological
Lymphoma 2.5% factor in differentiated thyroid carcinoma (particularly papil-
lary) is irradiation of the thyroid under 5 years of age. In the
town of Gomel, Ukraine, the incidence of childhood thyroid
cancer rose from <1 per million to 96 per million following
Benign tumours the Chernobyl nuclear disaster.
Follicular adenomas present as clinically solitary nodules Short latency aggressive papillary cancer is associated with
(Figure 50.21) and the distinction between a follicular car- the ret/PTC3 oncogene and later developing, possibly less
cinoma and an adenoma can only be made by histological aggressive, cancers with ret/PTC1. The incidence of follicular
examination; in the adenoma there is no invasion of the cap- carcinoma is high in endemic goitrous areas, possibly due to
sule or of pericapsular blood vessels. For this reason, FNA, TSH stimulation. Malignant lymphomas sometimes develop
which provides cytologic detail but not tissue architecture, in autoimmune thyroiditis, and the lymphocytic infiltration
cannot differentiate between benign and malignant follicular in the autoimmune process may be an aetiological factor.

08_50B-B&L27_Pt8_Ch50.indd 816 25/10/2017 09:10


Figure 50.22 Metastasis in the humerus from thyroid carcinoma
­(courtesy of DS Devadatta, Vellore, India).
Clinical features of thyroid cancers
The annual incidence is about 0.6 per million of the popu-
lation and the sex ratio is three females to one male. How-
ever, the incidence of papillary thyroid cancer is increasing
rapidly across the world. This is mostly due to increased rates
of imaging detecting previously occult disease. For that rea-
son, although the incidence is increasing, the mortality rates
remain static at over 80% 5-year survival for all groups. In
particular, anaplastic carcinoma predicts poor outcome with
differentiated carcinomas generally having excellent out-
comes. The most common presenting symptom is a thyroid
swelling (Figures 50.21 and 50.23). Enlarged cervical lymph
nodes may be the presentation of papillary carcinoma (PTC).
RLN paralysis is very suggestive of locally advanced disease.
Figure 50.23 Follicular neoplasm of the thyroid presenting as an iso-
lated swelling.
08_50B-B&L27_Pt8_Ch50.indd 817
PART 8 | BREAST AND ENDOCRINE
Neoplasms of the thyroid 817
Anaplastic growths are usually hard, irregular and infil-
trating. A differentiated carcinoma may be suspiciously firm
and irregular, but is often indistinguishable from a benign
swelling. Small papillary tumours may be impalpable, even
when lymphatic metastases are present. Pain, often referred
to the ear, is suggestive of nerve involvement from infiltrating
tumours.
Diagnosis of thyroid neoplasms
Clinical history and examination continue to be the cor-
nerstone of diagnosis of thyroid neoplasms. As previously
mentioned, radiation exposure and family history should be
discussed. Examination of the central neck and regional lym-
phatics should be combined with assessment of vocal cord
function. Biochemical assessment of thyroid function should
also be considered in this first encounter, if not already per-
formed.
Following initial assessment, the next step is ultrasound.
This non-invasive investigation is most accurate at assessing
thyroid swellings. Not only can a judgement be made on the
presence, size and number of thyroid nodules present, but an
estimate of risk of malignancy can be made depending on
these findings.
Following ultrasound, lesions can be categorised as benign,
indeterminate or malignant. Benign lesions require no further
assessment unless surgery is considered for compressive symp-
toms. Indeterminate or malignant lesions should be investi-
gated with FNAC.
Occasionally, the surgeon will encounter a thyrotoxic
patient. Such cases are one of the few indications for a radio-
iodine uptake scan. This allows assessment of the function of
a nodule. Hot nodules are very rarely malignant. Cold nod-
ules will require assessment as for all other thyroid neoplasms.
Following clinical, ultrasound and cytological assess-
ment, the vast majority of lesions will be characterised as
benign, malignant or indeterminate. Further treatment will
be planned accordingly.
Certain situations require specific consideration. For
patients with widespread nodal disease or suspicion of locally
invasive disease affecting the airway, contrast enhanced
imaging should be considered. This should cover the neck
and chest. Not only does this allow accurate assessment of
any visceral invasion, but is superior to ultrasound at defining
disease in the mediastinum and thorax. Concerns over the
impact of iodine-containing contrast on delays to radioactive
iodine therapy have been overplayed, and it is more critical
that the surgeon has an accurate assessment of disease extent
prior to surgery.
Patients with a rapidly growing thyroid mass, particularly
if solid and fixed, should be considered at risk of anaplastic
carcinoma. However, this diagnosis can be difficult to dif-
ferentiate from thyroid lymphoma or occasionally thyroid-
itis. Despite the difficulty, an accurate diagnosis is critical as
anaplastic carcinoma is rapidly fatal and palliative measure
are general recommended, whereas confounding disease pro-
cesses may respond to therapy. In this setting, core or even
open biopsy may be required to make a confident diagnosis.
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818 CHAPTER 50  The thyroid gland

Papillary carcinoma
Papillary carcinoma is the most common thyroid malignancy.
Interestingly, up to 30% of patients who die of non-thyroid
disease have deposits of PTC in autopsy studies, suggesting
that many patients live with this disease undetected. None-
theless, when papillary cancer is diagnosed most patients will
be offered treatment. The disease is known for its propen-
sity for lymph node metastases. These are more common in
younger patients, in whom they do not affect the otherwise
excellent survival. This finding is in contrast to most malig-
nances, where the finding of metastatic disease confers a poor
outcome. One contentious finding in patients with PTC is
a high rate of occult micrometastases (as high as 40% of N0
patients in the central neck). Despite the presence of metas-
Figure 50.24 Histology of follicular thyroid carcinoma showing vas-
tases, few patients progress to have clinically meaningful cular (red arrow) and capsular (black arrow) invasion (courtesy of Dr
disease and the role of elective nodal surgery is in question. SWB Ewen, Aberdeen, UK).
Distant metastases are uncommon in PTC.
Recently, increasing interest has focused on ‘papillary
microcarcinoma’. This term is used to describe PTC that is
<10 mm in size. These lesions are common (detected in about
10% of benign thyroid resections) and not associated with
adverse outcomes, including recurrence or non-survival. As
such, management and follow-up of patients with these lesions
of doubtful clinical significance is controversial. In Korea, for
example, national screening has led to a significant increase
in these cases. In Japan groups are opting for an observational
approach without surgery. These studies have shown that at
least two-thirds never progress. In the USA some groups are
attempting non-surgical management with ablation techniques
using ethanol or radiofrequency. In most of the world however,
groups try to avoid diagnosing these small, insignificant lesions
by limiting biopsies to >10 mm lesions and being conservative
in the management of lesions following their diagnosis.

Follicular carcinoma
Follicular carcinoma can normally only be differentiated from
follicular adenoma by the architecture on histology. For this
reason, follicular lesions on FNA are unable to be diagnosed
as malignant in the absence of clinical features such as metas-
tases (Figure 50.24). Multiple foci of follicular carcinoma are
seldom seen and lymph node involvement is much less com-
mon than in papillary carcinoma. Blood-borne metastases are
more common and the eventual mortality rate, although still
low, is twice that of papillary cancer (Figure 50.25).
Hürthle cell tumours are a rare variant of follicular neo-
plasm in which oxyphil (Hürthle, Askanazy) cells predomi-
nate histologically. Hürthle cell cancers are associated with a
poorer prognosis.
Prognosis in differentiated thyroid
carcinoma
The prognosis in differentiated thyroid cancers is generally
excellent. In terms of survival, older patients, those with large
Figure 50.25 Follicular carcinoma of thyroid with skull secondaries.
tumors or extrathyroid extension or distant metastases have
worse outcomes. A system of risk stratification can be used
to predict the risk on an individual basis. In a young patient
with a low-risk tumour, the risk of death following appropriate
treatment is almost zero. In an older patient with a high-risk
tumour (extrathyroid extension or distant metastases), the
risk is as high as 50% at 5 years. Older patients with low-
risk tumours and younger patients with high-risk tumours are
an intermediate risk group. Nodal metastases deserve special
mention. In younger patients they predict for recurrence but
not for death. This is because recurrent neck disease in young

Karl Hürthle, 1866–1945, German histopathologist, first drew attention to these cells.
Max Askanazy, 1865–1940, described these cells while working at the Pathological Anatomy Institute, Tübingen, Germany.

08_50B-B&L27_Pt8_Ch50.indd 818 25/10/2017 09:10


patients can almost always be successfully salvaged. In con-
trast, for older patients neck metastases (particularly in the
lateral neck) are a marker of distant metastases in some, and
therefore carry a negative prognostic implication for both
recurrence and death.
The AJCC staging system is in the process of modifica-
tion. However, the current edition stages all patients <45
years as stage I unless they have distant metastases, when they
are stage II. Older T1N0M0 patients are stage I and T2N0M0
are stage II. The presence of nodal disease in the central neck
nodes (N1a) upstages older patients to stage III, as does T3
disease. All older patients with lateral neck disease (N1b),
locally invasive primary disease (T4) or distant metastases are
stage IV.
The AJCC 8th edition will raise the age cut-off to 55 years.
It will also formally recognise that extrathyroid extension is
less significant if identified microscopically but not evident
during surgery. The extent of nodal involvement will also
be included, with small numbers of low-volume nodes being
considered less significant than multiple large-volume nodes.
Surgical treatment for differentiated
thyroid cancer
This subject has many contentious aspects. For the vast
majority of patients, outcome is excellent irrespective of the
extent of surgery. The low number of recurrences and death
has made prospective trials difficult and, as such, very few
exist.
The aim of surgery is to rid the patient of macroscopic
disease and minimise the chance of recurrence and death. An
additional aim is to minimise surgical morbidity. Achieving
a balance between these aims is critical. In addition, the sur-
geon must consider whether radioactive iodine is to be rec-
ommended. In low-risk cases this is rarely indicated, whereas
in high-risk patients it is used almost universally. Risk stratifi-
cation is therefore critical.
In high-risk patients with nodal or distant metastases,
total thyroidectomy will be performed to eradicate disease in
the thyroid and prepare the patient for radioactive iodine. For
low-risk patients with a single focus of disease limited to the
thyroid, a thyroid lobectomy can be offered. This has the sig-
nificant advantage of protecting the contralateral RLN and
parathyroid glands. This approach is now considered appro-
priate unless there are high-risk features of disease.
In terms of the neck, when metastatic disease is present, a
therapeutic compartment-orientated neck dissection should
be performed to remove disease from the central or lateral
neck, depending on the site of involvement. The role of elec-
tive neck surgery, when no disease in the nodes is detected
preoperatively, is far more controversial. Lateral neck dissec-
tion carries significant morbidity and despite high rates of
occult metastases in papillary carcinoma, has been abandoned.
The reason is that even in patients who are thought to have
occult metastases, very few progress to clinically meaningful
disease. In contrast, the morbidity of central neck dissection
is lower, and the compartment has to be opened during a thy-
roidectomy. In addition, salvage surgery in the central neck
08_50B-B&L27_Pt8_Ch50.indd 819
PART 8 | BREAST AND ENDOCRINE
Neoplasms of the thyroid 819
carries a high risk to the RLN and parathyroid glands. For
these reasons elective central neck dissection has been pop-
ular in the last few decades. However, increased recognition
that performing such surgery in all patients with PTC leads
to high rates of morbidity and the lack of evidence that out-
comes improve due to more aggressive surgery, has led to a
move away from this practice. At this point, patients who are
considered at highest risk of having occult metastases in the
central neck (those with extrathyroid extension for example)
are ­considered most likely to see benefit from elective surgery
and it is not recommended routinely in low-risk patients.
Many patients will only be diagnosed with their thyroid
cancer following a diagnostic lobectomy. In this setting, risk
assessment is again critical. If the patient is considered low
risk, further surgery is unlikely to be beneficial. If, however,
patient or tumour features are considered high risk, radioac-
tive iodine may be recommended, in which case completion
thyroidectomy may be required.
Given the complexity of decision making in thyroid
cancer and the different groups involved (surgeons, endocri-
nologists, radiologists, cytologists, pathologists and nuclear
medicine physicians), all cases should be discussed in a multi-
disciplinary setting.
Thyroxine
Following surgery, thyroid cells (both normal and malignant)
can be suppressed using high doses of thyroxine. This was once
considered routine for all differentiated thyroid cancers during
follow-up. Again, risk stratification has modified our approach
to these patients. Following surgery, patients can be considered
high or low risk. For those patients at high risk from disease,
thyroxine will be prescribed at levels which suppress TSH
without making the patient biochemically hyperthyroid. In
contrast, low-risk patients may be considered for thyroxine
replacement at physiological levels. In this patient group, a
balance of benefit (remember these patients have extremely
low rates of recurrence or death) versus risk must be made. In
particular, long-term TSH suppression can result in cardiac
arrhythmia and osteoporosis. As such the treating team should
consider all risks during follow-up to strike this balance.
Low-risk patients who have had lobectomy alone may
require no thyroxine at all. Patients who had a total thyroid-
ectomy will clearly require replacement and those considered
high risk should be managed with suppression, in order to
minimise the chance of disease recurrence.
Radioiodine
Thyroid tissue concentrates iodine. For this reason, 131I can
be given in order to deliver tumoricidal doses of radioactivity
directly to thyroid tissue, both benign and malignant. In the
setting of thyroid cancer, all normal tissue should be removed
(total thyroidectomy) along with any gross neck disease (neck
dissection) in order for any residual microscopic disease or
distant metastases to receive an optimal dose. Radioiodine
treatment is not an alternative to surgical resection for gross
resectable disease.
As with many aspects of differentiated thyroid cancer
management, indications for radioiodine treatment are con-
troversial. Again, low-risk patients have little to gain and
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 PART 8 | BREAST AND ENDOCRINE
820 CHAPTER 50  The thyroid gland
may be safely managed without adjuvant therapy. High- risk
patients, however, remain candidates.
In order to effectively drive the radioiodine into cells,
high levels of TSH are required. This can be achieved by
rendering the patient hypothyroid (off thyroxine) or by using
recombinant TSH, which is injected prior to radioiodine
administration.
Following radioiodine administration, an uptake scan is
performed. This demonstrates areas of iodine uptake in the
whole body and can be used to identify any metastatic disease
not recognised on initial imaging. This information is useful
in the ongoing process of risk stratification of patients follow-
ing initial therapy.
Outside the setting of primary treatment, radioiodine
treatment may be considered in cases of recurrence, particu-
larly if not used initially. Multiple doses can be used in order
to treat unresectable disease, distant metastases or even a ris-
ing thyroglobulin in the absence of structural disease.
Most differentiated thyroid cancers will concentrate
iodine. However, with advancing patient age and particu-
larly if disease is multiply recurrent the tumour will lose its
iodine avidity. This is called radioiodine refractory disease.
Such cases may be considered for external beam radiotherapy,
although this is uncommon.
Thyroglobulin
Thyroglobulin is a tumour marker produced by normal thy-
roid cells and most differentiated thyroid cancer. As such,
this offers an extremely accurate method of following patients
postoperatively. If a lobectomy has been performed the level
will not be undetectable, but trends can be used to monitor
for recurrence. Following total thyroidectomy, the aim is to
have an undetectable thyroglobulin. Patients who achieve
this point are at extremely low risk of recurrence. Serial thy-
roglobulin measurement (6–12 monthly) combined with
ultrasound assessment of the neck can then be used to moni-
tor patients during follow-up.
If an undetectable level is not achieved, the thyroglobulin
can be followed. If it increases, imaging should be performed
to look for gross recurrent disease. Resectable disease should
be addressed surgically and normally further radioactive
iodine (RAI) would be indicated. The role of RAI in a rising
thyroglobulin without structural disease is controversial.
Undifferentiated (anaplastic)
carcinoma
This is one of the most aggressive malignancies in humans.
Thankfully it is rare. It may develop de novo, or present as
dedifferentiation of a papillary or poorly differentiated carci-
noma. The disease is characterised by rapid growth, visceral
invasion and distant metastases. The surgeon’s role in this
disease is crucial. Thyroid lymphoma can be incorrectly diag-
nosed as anaplastic cancer and so biopsy is critical. This can
be done using a core or open technique.
Management is controversial. Almost all patients will be
dead within 6 months. Radiotherapy and chemotherapy have
not been shown to improve survival. Occasional patients may
08_50B-B&L27_Pt8_Ch50.indd 820
present with disease limited to the neck, which appears resect-
able on imaging. Such patients seem to have a slightly better
outcome if treated with aggressive surgery and postoperative
adjuvant therapy (radiotherapy +/- chemotherapy). However,
solid evidence is lacking and the majority of patients will not
be considered for curative treatment.
Those patients who have a known diagnosis and develop
airway symptoms are generally better managed without tra-
cheostomy, despite the potentially distressing mode of death.
In patients who present with airway signs and without a diag-
nosis, a tracheostomy may be required to buy time to con-
firm the diagnosis and in order to allow a few more days for
patients to ‘get their affairs in order’.
Medullary carcinoma
These are tumours of the parafollicular (C cells) derived from
the neural crest. rather than the cells of the thyroid follicle
as are other primary thyroid carcinomas. The cells are not
unlike those of a carcinoid tumour and on histological anal-
ysis a characteristic amyloid stroma is seen (Figure 50.26).
High levels of serum calcitonin and carcinoembryonic anti-
gen are produced by many medullary tumours, which should
be tested for in suspected cases. Calcitonin levels fall after
resection and rise again with recurrence, making it a valuable
tumour marker in the follow-up of patients with this disease.
Diarrhoea is a feature in 30% of cases and this may be due
to 5-hydroxytryptamine or prostaglandins produced by the
tumour cells.
Some tumours are familial and account for 10–20% of
all cases. Medullary carcinoma may occur in combination
with adrenal phaeochromocytoma and hyperparathyroidism
(HPT) (usually due to hyperplasia) in the syndrome known as
multiple endocrine neoplasia type 2A (MEN-2A). The famil-
ial 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 and
inner aspect of the eyelids, with a Marfanoid habitus, the syn-
drome is referred to as MEN type 2B (see Chapter 52).
Figure 50.26 Histology of medullary carcinoma showing character-
istic ‘cell balls’ and amyloid (courtesy of Dr SWB Ewen, Aberdeen,
UK).
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 PART 8 | BREAST AND ENDOCRINE
Thyroiditis 821

Involvement of lymph nodes occurs in 50–60% of cases (a)

of medullary carcinoma and blood-borne metastases are com-
mon. As would be expected, tumours are not TSH dependent
and do not take up radioactive iodine. The prognosis is variable
and depends on the stage at diagnosis. Any nodal involvement
virtually eliminates the prospect of cure and, unfortunately,
even small tumours confined to the thyroid gland may have
spread by the time of diagnosis, particularly in familial cancers.
In common with many endocrine tumours the progression of
disease may be very slow, with a characteristically indolent
course and long survival, even in the absence of cure.
In familial cases of medullary thyroid cancer, genetic
screening of relatives should be recommended. This is a com-
plex subject but individuals identified can be risk stratified
dependent on the genetic abnormality. This information
can be used to make recommendations concerning prophy-
(b)
lactic thyroidectomy. Some relatives may be monitored into
adulthood with serial calcitonin monitoring. In contrast, the
­highest-risk mutations are associated with early-onset disease
and total thyroidectomy is recommended during infancy.

Treatment
When medullary carcinoma is diagnosed, staging of the neck
and chest should be performed. For those patients with disease
confined to the thyroid, total thyroidectomy is recommended
to remove all C cells. In addition, elective dissection of the
central neck nodes is also performed to optimise the chance of
cure. If there is evidence of nodal metastases, cure is unlikely. Figure 50.27 Magnetic resonance imaging scans of extensive
In this setting, gross disease should be excised but the surgeon malignant lymphoma (a) before and (b) after 7 days of external beam
should be mindful of morbidity. Such patients are highly likely radiotherapy (courtesy of Dr FW Smith, Aberdeen, UK).
to recur and a pragmatic approach should be adopted.

or with established or subclinical thyroid failure. The diagno-

Malignant lymphoma sis often follows investigation of a discrete swelling. Features
In the past, many malignant lymphomas were diagnosed as of chronic lymphocytic (focal) thyroiditis are commonly
small round-cell anaplastic carcinomas. Response to irradia- present on histological examination in association with other
tion is dramatic (Figure 50.27) and radical surgery is unnec- thyroid disease, notably toxic goitre (Figure 50.28). Primary
essary once the diagnosis is established by biopsy. In patients
with tracheal compression, isthmusectomy is the most appro-
priate form of biopsy although the response to therapy is so
rapid that this should rarely be necessary unless there has
been difficulty in making a histological diagnosis. The prog-
nosis is good, particularly if there is no involvement of cer-
vical lymph nodes. Rarely, the tumour is part of widespread
malignant lymphoma disease and the prognosis in these cases
is worse. Most lymphomas occur against a background of lym-
phocytic thyroiditis.

THYROIDITIS
Chronic lymphocytic
(autoimmune) thyroiditis
This common condition is usually associated with raised titres Figure 50.28 Autoimmune thyroiditis (Hashimoto’s disease; struma
of thyroid antibodies. It commonly presents as a goitre, which lymphomatosa). Intense lymphocytic-plasma cell infiltration, acinar
may be diffuse or nodular with a characteristic ‘bosselated’ feel destruction and fibrosis.

Friedrich Joseph de Quervain, 1868–1940, Professor of Surgery, Berne, Switzerland, described this form of thyroiditis in 1902.

08_50B-B&L27_Pt8_Ch50.indd 821 25/10/2017 09:10

 PART 8 | BREAST AND ENDOCRINE
822 CHAPTER 50  The thyroid gland
myxoedema without detectable thyroid enlargement rep-
resents the end stage of the pathological process.
Granulomatous thyroiditis (subacute
thyroiditis, de Quervain’s thyroiditis)
This may follow a viral infection. In a typical subacute pre-
sentation, there is pain in the neck, fever, malaise and a firm,
irregular enlargement of one or both thyroid lobes. There are
raised inflammatory markers, absent thyroid antibodies, the
serum T4 is high normal or slightly raised, and the 123I uptake
of the gland is low. The condition is self-limiting and, in a
few months, the goitre subsides and there may be a period of
months of hypothyroidism before eventual recovery. In 10%
of cases the onset is acute, the goitre very painful and tender
and there may be symptoms of hyperthyroidism. One-third of
cases are asymptomatic but for the presence of the goitre. If
diagnosis is in doubt, it may be confirmed by FNAC, radio-
active iodine uptake and by a rapid symptomatic response to
prednisone. The specific treatment for the acute case with
severe pain is to give prednisone l0–20 mg daily for 7 days
and the dose is then gradually reduced over the next month.
If thyroid failure is prominent, treatment with thyroxine may
be required until function recovers.
Riedel’s thyroiditis
This is very rare, accounting for 0.5% of goitres. Thyroid
tissue is replaced by cellular fibrous tissue, which infiltrates
through the capsule into muscles and adjacent structures,
including parathyroids, recurrent nerves and carotid sheath.
It may occur in association with retroperitoneal and medi-
astinal fibrosis and is most probably a collagen disease. The
Bernhard Moritz Carl Ludwig Riedel, 1846–1916, Professor of Surgery, Jena, Germany, described this form of thyroiditis in 1896.
08_50B-B&L27_Pt8_Ch50.indd 822
goitre may be unilateral or bilateral and is very hard and fixed.
The differential diagnosis from anaplastic carcinoma can be
made with certainty only by biopsy, when a wedge of the isth-
mus should also be removed to free the trachea. If unilateral,
the other lobe is usually involved later and subsequent hypo-
thyroidism is common. Treatment is with high-dose steroid,
tamoxifen and thyroxine replacement. Reduction in the size
of the goitre and long-term improvement in symptoms are to
be expected if treatment is commenced early.
FURTHER READING
Chadwick D, Kinsman R, Walton P. The British Association of Endo-
crine and Thyroid Surgeons Fourth National Audit Report, Den-
drite Clinical Systems Ltd: Henley-on-Thames, 2012.
Chen A, Bernet V, Carty SE et al. American Thyroid Association state-
ment on optimal surgical management of goiter. Thyroid 2014; 24:
181–9.
Gharib H, Papini E, Valcavi R et al. American Association of Clinical
Endocrinologists and Associazione Medici Endocrinologi medical
guidelines for clinical practice for the diagnosis and management of
thyroid nodules. Endocr Pract 2006; 12: 63–102.
Haugen BRM, Alexander EK, Bible KC et al. American Thyroid Associ-
ation management guidelines for adult patients with thyroid nodules
and differentiated thyroid cancer. Thyroid 2016; 26: 1–133.
Perros P, Boelaert K, Colley S et al. Guidelines for the management of
thyroid cancer. Clin Endocrinol 2014; 81(Suppl 1): 1–122.
Smallridge RC, Ain KB, Asa SL et al. American Thyroid Association
guidelines for management of patients with anaplastic thyroid can-
cer. Thyroid 2012; 22: 1104–39.
Wells SA, Jr, Asa SL, Dralle H et al. Revised American Thyroid Associa-
tion guidelines for the management of medullary thyroid carcinoma.
Thyroid 2015; 25: 567–610.
Yeh MW, Bauer AJ, Bernet VA et al. American Thyroid Association
statement on preoperative imaging for thyroid cancer surgery. Thy-
roid 2015; 25: 3–14.
25/10/2017 09:10
ve Bailey & Love Bailey & Love Bailey & Love
51Love
ve Bailey & Love Bailey & Love Bailey &
The parathyroid glands
Learning objectives
To understand:
•• The anatomy of the parathyroid glands
•• The physiology of calcium regulation
•• The underlying causes of hypercalcaemia and
appropriate emergency management
•• The aetiology, presentation, investigation and
management of primary hyperparathyroidism and
associated special cases
INTRODUCTION
The parathyroid glands were first described by Sir Richard
Owen in a neck dissection of an Indian rhinoceros at the Lon-
don Zoological Gardens in 1850. Credit for recognition of the
‘glandulae parathyreoidae’ goes, however, to SandstrÖm who
published a monograph in 1887 on dissection of the para-
thyroid glands and their blood supply in animals and human
cadavers. Unfortunately, Sandström committed suicide at the
age of 37 and it was not until the 1890s that his work was
rediscovered by Gley, who associated tetany following thy-
roid surgery with removal of the parathyroid glands. In 1905,
MacCallum found that he could relieve postoperative tetany
by the injection of parathyroid extract. While the associa-
tion between parathyroid enlargement and bone disease was
reported in 1907, it was not until 1925 that the first para-
thyroidectomy was performed by Mandl in Vienna on Albert
Gahne, a tram conductor with severe primary hyperparathy-
roidism (PHPT) and osteitis fibrosa cystica.
ANATOMY OF THE
PARATHYROID GLANDS
The developmental embryology and surgical anatomy of the
parathyroid glands are intimately linked, and knowledge of
Sir Richard Owen, 1804–1892, English comparative anatomist and palaeontologist. First director of the Natural History Museum, London and Hunterian Pro-
fessor at Royal College of Surgeons of England.
Ivar Viktor Sandström,1852–1889, medical student, Uppsala, Sweden.
Marcel Eugene Gley, 1857–1930, French pathologist.
William J MacCallum, 1874–1944, Professor of Pathology, Johns Hopkins Hospital, USA.
Felix Mandl, 1892–1957, Professor of Surgery, Vienna, Austria.
08_51-B&L27_Pt8_Ch51.indd 823
Chapter
•• The aetiology, presentation, investigation
and management of secondary and tertiary
hyperparathyroidism
•• The aetiology and management of parathyroid
carcinoma
both is essential for successful surgical treatment of parathy-
roid disease.
The parathyroid glands, of which there are four, develop
from the third and fourth pharyngeal pouches between
the fifth and twelfth week of gestation. They are typically
described as ‘Portland brick’ (yellow/brown) in colour and
weigh approximately 30 mg. Approximately 13% of the pop-
ulation have abnormal parathyroid tissue, with 5% having a
true supernumerary gland. The blood supply of both the supe-
rior and inferior parathyroid glands arises from the inferior
thyroidal artery. While the location of the individual glands
may vary significantly, there appears to be a degree of symme-
try between opposite sides that can be helpful during surgical
dissection.
The inferior parathyroid gland and the thymus arise from
the third pharyngeal pouch. As a result of the longer normal
embryological descent, there is correspondingly more vari-
ation in their anatomical position. However, in more than
50% of cases they are located at the inferior pole of the thy-
roid gland, on the anterior, lateral or posterior surface. The
gland itself is freely mobile within a globule of fat adjacent to
the lower pole (Figure 51.1a).
The superior parathyroid glands arise from the dorsal
portion of the fourth pharyngeal pouch. As a result of their
more limited embryological descent they are more constant in
25/10/2017 09:21
 PART 8 | BREAST AND ENDOCRINE
824 CHAPTER 51  The parathyroid glands

(a)

Undescended 2%
(above ITA)

2% Intrathyroidal
3%

Below intersection 56% Related to lower

ITA and RLN pole of thyroid

28% In thyrothymic
tract
Mediastrial 9%

(b)

Related to upper
11% pole of thyroid

In carotid sheath 1% Around intersection

77% of ITA and RLN

1% Intrathyroidal
Paraoesophageal 10%
and below ITA

Figure 51.1 Potential locations of the inferior (a) and superior (b) parathyroid glands. ITA, inferior thyroid artery; RLN, recurrent laryngeal
nerve.

p­ osition. In more than 80% of patients, the superior parathy-
roid glands are located at the posterior aspect of the thyroid
lobe in an area 2 cm in diameter, centred 1 cm around the
junction of the inferior thyroid artery and the recurrent laryn-
geal nerve in strict proximity to the cricothyroid junction
(Figure 51.1b). The parathyroid glands are closely associated
with, but contained within, a halo of fat that is freely mobile
over the thyroid capsule.
CALCIUM AND PARATHYROID
HORMONE REGULATION
The parathyroid glands play a central role in the regulation
of serum calcium levels through the production of the active
84 amino-acid peptide, parathyroid hormone (PTH). PTH
is secreted in response to low serum calcium or high serum
magnesium levels. It is initially cleaved in the liver yielding

08_51-B&L27_Pt8_Ch51.indd 824 25/10/2017 09:21


an inactive C-terminal that is cleared by the kidneys. The
N-terminal fragment is responsible for the biological activity
of PTH on peripheral tissues. The active circulating molecule
has a half life of approximately 3–5 minutes in patients with
normal renal function.
PTH acts directly on the kidneys, bone and the gastro-
intestinal tract to activate intracellular second messengers,
including cyclic AMP and calcium. In the kidneys, PTH
increases serum calcium levels by increasing resorption of cal-
cium from the renal tubules and increasing the hydroxylation
of 25-hydroxyvitamin D to the biologically active 1,25-dihy-
droxyvitamin D. Active vitamin D increases both the resorp-
tion of phosphorus in the kidneys and the absorption of
calcium from the gastrointestinal tract. In the bone, PTH
acts on osteoblasts and osteoclasts to increase bone turnover,
thereby increasing the amount of calcium in the extracellular
space (Figure 51.2).
Calcitonin, which is synthesised by the parafollicular C
cells of the thyroid gland, acts as the physiological antagonist
to PTH. Calcitonin decreases serum calcium by decreasing
bone turnover.
PRIMARY
HYPERPARATHYROIDISM
The early descriptions of patients with PHPT were domi-
nated by those with osteitis fibrosa cystica. Brown tumours
of the long bones and associated subperiostal bone reabsorp-
tion, distal tapering of the clavicles and the classical ‘salt and
pepper’ erosions of the skull were typical findings. Over 80%
of patients had associated renal stones, significant neuromus-
cular dysfunction and muscle weakness. This led to the tra-
ditional mnemonic that patients with PHPT presented with
‘bones, stones, abdominal groans and psychiatric overtones’.
The introduction of the automated serum chemical autoanal-
yser in the 1970s as well as radioimmune assay to accurately
measure circulating PTH levels radically improved early
+/–
Plasma Ca2+ Parathyroid Parathyroid
concentration glands hormone
Activation of Renal tubular
Ca2+ mobilised
vitamin D absorption from bones
of Ca2+
Ca2+ absorption
in intestine
Plasma Ca2+
concentration
Figure 51.2 Schematic diagram of actions of parathyroid hormone.
08_51-B&L27_Pt8_Ch51.indd 825
PART 8 | BREAST AND ENDOCRINE
Primary hyperparathyroidism 825
diagnosis of PHPT, such that the majority of patients are now
identified incidentally on routine biochemical investigations
and are asymptomatic. The current controversies therefore,
centre on the indications for intervention, either surgically
or medically.
Presentation
PHPT is defined as hypercalcaemia in the presence of an
unsuppressed and therefore relatively, or absolutely, elevated
PTH level. Prevalence of the disease is reported to be 0.2–
0.5% with approximately 100 000 new cases per year in the
USA. The majority of PHPT is sporadic in nature. Familial
disease can occur in multiple endocrine neoplasia (MEN)
type 1 or type 2A or as a familial cluster. Patients usually pres-
ent in the 5th or 6th decades and there is a female predomi-
nance with a ratio of 3:1.
Patients are typically identified incidentally with an ele-
vated total calcium or following routine assessment of bone
densitometry (DEXA scan). Most patients will, however,
have some vague constitutional symptoms, such as fatigue,
muscle weakness, depression or some mild memory impair-
ment on questioning. The presence of kidney stones remains
the most common clinical manifestation of symptomatic
PHPT. Between 15% and 20% of patients will have neph-
rolithiasis and over 40% of patients will have hypercalciuria.
Increasingly, postmenopausal women present with significant
osteopenia or osteoporosis in the distal one-third of the radius
with a minimal reduction in the lumbar spine, which prompts
further investigation. This distribution arises as PTH appears
to be catabolic at cortical sites (distal one-third of the radius)
and anabolic at cancellous sites (lumbar spine).
PHPT may present with pancreatitis, although it is rarely
seen in patients with milder forms of the disease. Common
epidemiologically linked disorders, such as hypertension and
peptic ulcer disease, are often encountered. Clinical examina-
tion is usually normal. Band keratopathy, pathognomonic of
the disease and due to deposition of calcium phosphate crys-
tals in the cornea, is now rarely identified.
The differential diagnosis of PHPT includes other causes
of hypercalcaemia, which are usually readily distinguishable
(Table 51.1). It is important to exclude the presence of a wide-
spread malignancy, in which patients will typically have other
symptoms. The exception to this rule is multiple myeloma,
in which hypercalcaemia can be the presenting complaint.
Improvements in the immuno-radiometric and immuno-
chemiluminometric assays for PTH can help to distinguish
these conditions, as in malignancy PTH levels are typically
suppressed.
Hypercalcaemic crisis: presentation
and management
Hypercalcaemia is documented in 0.5% of the general pop-
ulation and in up to 5% of hospitalised patients. The vast
majority are asymptomatic with a mild to moderate elevation
of serum calcium (<3 mmol/L and 3–3.5 mmol/L, respec-
tively) and respond to treatment of the underlying aetiology
with associated dietary modification. A small proportion of
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 PART 8 | BREAST AND ENDOCRINE
826 CHAPTER 51  The parathyroid glands

TABLE 51.1 Causes of hypercalcaemia. seen. Finally, glucocorticoids (prednisolone) can be used to
enhance the action of calcitonin. They increase calciuresis
Endocrine Primary hyperparathyroidism
Thyrotoxicosis and decrease intestinal absorption of calcium. As a result,
Phaeochromocytoma they may also play a role in diseases associated with vitamin
Renal failure Secondary hyperparathyroidism D excess.
Tertiary hyperparathyroidism
Malignant disease Skeletal metastatic disease
Multiple myeloma, lymphoma, leukaemia
Pathology
Solid tumours (PTH-related peptide The underlying aetiology of PHPT is usually a solitary para-
mediated): lung, renal, squamous thyroid adenoma; however, in a small number of patients
cell carcinoma of the head and neck,
oesophagus, genital tract (2–4%) there are double adenomas. It may occur in a sporadic
fashion or it can be familial (MEN type 1 or type 2A, hyper-
Nutritional Excessive vitamin D ingestion
Vitamin A intoxication parathyroidism-jaw tumour syndrome (HPT-JT)) in nature.
Milk-alkali syndrome The only known risk factor for the development of PHPT is
Aluminium intoxication a history of prior neck irradiation. The underlying molecu-
Granulomatous Sarcoidosis lar basis of PHPT is heterogeneous; however, upregulation of
Tuberculosis cyclin D may lead to a clonal proliferation within the para-
Inherited disease Hypercalciuric hypercalcaemia thyroid glands. This does not alter the set point of calcium
Immobilisation
but the hyperplasic nature of the parathyroid cells themselves
causes excessive secretion of PTH.
Paget’s disease
Multigland disease is less common, occurring in approx-
Drug related Lithium imately 15% of patients. No clinical features differentiate
single from multigland disease, although multigland disease
is more commonly associated with familial syndromes such
patients will present symptomatically with a total calcium of as MEN types 1 and 2A, as well as the chronic ingestion of
>3.5 mmol/L. This is referred to as a hypercalcaemic crisis and lithium.
requires aggressive medical management.
Although symptoms can be varied, the typical presenta-
tion is of acute confusion, abdominal pain, vomiting, dehy- Diagnosis
dration and anuria. Prolongation of the P–R interval with a PHPT is a biochemical diagnosis. Only when the disease has
shortened Q–T interval can be identified on an electrocardio- been confirmed biochemically should localisation studies be
gram (ECG) prior to potentially lethal cardiac arrhythmias. undertaken. Positive imaging does not confirm the diagnosis
Where the calcium is >4.5 mmol/L, coma and cardiac arrest and negative findings cannot rule it out.
can occur. PHPT is defined as an elevated total, or more specifically
Treatment revolves around increasing renal excretion of ionised, calcium, in the presence of an inappropriately elevated
calcium, reducing skeletal release of calcium and treatment of or unsuppressed PTH. It is associated with a low serum
the underlying cause. Aggressive rehydration plays a p­ ivotal phosphate in the setting of normal creatinine and vitamin D
role. Typically, 200–500 mL/h of normal saline is given to levels; 24-hour urinary excretion of calcium may be normal or
maintain a urine output >100 mL/h, with the caveat that this elevated. It is important to perform a 24-hour urinary collection
may be modified to account for associated patient comorbidi- to rule out the presence of the rare familial hypocalciuric
ties. Once intravascular volume has been adequately restored, hypercalcaemia. Alkaline phosphatase may be elevated in
loop diuretics, such as furosemide, can be used to enhanced patients in whom there is concomitant bone disease. This is
the renal excretion of calcium. The majority of patients important to recognise preoperatively, as the surgeon should
will have normalisation of their calcium with these simple anticipate significant postoperative hypocalcaemia due to the
­measures. development of hungry bone syndrome.
In patients with advanced malignancy and a serum cal-
cium level >3 mmol/L, agents that blunt the release of cal-
cium from skeletal stores may be required. First-line treatment Localisation studies
includes administration of bisphosphonates. These are pyro- “In my opinion, the only localising study required in a
phosphate analogues that inhibit osteoclast activity in areas patient with untreated primary hyperparathyroidism is to
of high bone turnover. In the acute setting, these are given localise an experienced parathyroid surgeon.”
intravenously due to poor absorption in the gastrointestinal John Doppman, 1986
tract. Calcitonin can be used to both decrease osteoclastic
activity and increase renal excretion of calcium. It has a short Historically, preoperative localisation studies for PHPT were
duration of action and is usually used as a bridge to reduce considered less important than identifying an experienced
calcium until the sustained action of the bisphosphonates is surgeon. However, with a shift away from the traditional four-

John L Doppman, 1928–2000, radiologist, National Institutes of Health, USA, developed the technique of selective venous sampling for parathyroid localisation.

08_51-B&L27_Pt8_Ch51.indd 826 25/10/2017 09:21


gland (cervical neck) exploration to more minimally invasive
procedures, accurate preoperative identification is critically
important to guide surgical strategy.
There are a variety of both non-invasive and invasive
studies commonly is use. Non-invasive radiology includes
nuclear medicine-based studies, ultrasonography and 4D
computed tomography (CT) scanning. Invasive imaging is
largely reserved for reoperative surgery and includes ultra-
sound or CT-guided fine-needle aspiration with concomitant
PTH assays, parathyroid angiography or selective venous sam-
pling for the PTH gradient.
Nuclear medicine-based studies (sestamibi
scanning)
The use of sestamibi (2-methoxy-2-methylpropylisonitrile
(MIBI)) for parathyroid localisation was first described in
1989 and is now regarded as the most accurate and reliable
method for imaging the parathyroid glands. It is safe and
reproducible and while it has a sensitivity and specificity
simi­lar to ultrasound, it may image glands in ectopic positions
better (Figure 51.3a).
(a)
(b)
Karl Hürthle, 1866–1945, histopathologist, Breslau, Germany.
08_51-B&L27_Pt8_Ch51.indd 827
PART 8 | BREAST AND ENDOCRINE
Primary hyperparathyroidism 827
Sestamibi accumulates in mitochondria and therefore
washes out at differential rates depending on the number of
mitochondria within individual tissues. Parathyroid adenomas
often have a high concentration of oxyphilic cells with high
mitochondrial content. These retain tracer and adenomas
are therefore associated with a slow washout when compared
with the thyroid gland. There are three different protocols
for sestamibi scanning: single-isotope dual-phase scan, dual
isotope subtraction imaging and single-photon emission com-
puted tomography (SPECT). The sensitivity and specificity of
sestamibi, regardless of the protocol used, are 79% and 90%,
respectively. False positives are rare but may arise from some
solid thyroid nodules, such as Hürthle cell nodules, that are
associated with high oxyphilic content. These can be reduced
by the addition of a thyroid-specific radioactive tracer, such as
99
Tc-pertechnetate and subsequent subtraction images.
Ultrasonography
Ultrasonography is a non-invasive, inexpensive method of
imaging the parathyroid glands (Figure 51.3b). Parathyroid
adenomas are typically oval or elongated, bi- or multilobed
Figure 51.3 Sestamibi scan (a) demonstrating right inferior ade-
noma, with concordant ultrasound (b).
25/10/2017 09:21
 PART 8 | BREAST AND ENDOCRINE
828 CHAPTER 51  The parathyroid glands

hypoechoic structures. Rarely, adenomas may be cystic or (a)

heterogeneous in nature. Giant adenomas are described as
those over 3 cm in size. Ultrasound is not associated with
any radiation exposure and has the advantage of being able
to identify and facilitate biopsy of any concomitant thyroid
pathology. However, ultrasonography is operator, lesion size
and location dependent. Critically, ultrasound may miss ade-
nomas located in retro-oesophageal, retrosternal or retrotra-
cheal areas. It can also be difficult to differentiate between
a small parathyroid gland and a normal appearing lymph
node. A recent meta-analysis of preoperative localisation
techniques in PHPT demonstrated that ultrasound and
sestamibi-SPECT have comparable accuracy, with pooled
sensitivities of 76.1% and 78.9% respectively, and positive
predictive values (PPVs) of 93.2% and 90.7% respectively
(Krakauer et al., 2016).
(b)

4D Computed tomography scanning

Multiphase CT imaging (4D-CT) has become widely uti-
lised to localise disease (Figure 51.4). It gives both anatom-
ical as well as functional information about the parathyroid
glands. Using precontrast, postcontrast and delayed images,
it demonstrates not only detailed anatomic localisation but,
combined with rapid uptake and wash-out, allows hyperfunc-
tioning glands to be differentiated from lymph nodes, which
demonstrate a progressive enhancement pattern. The poten-
tial disadvantage of 4D-CT scanning is the higher radiation
dose when compared with traditional imaging modalities.
Modification of the protocol now allows fewer phases to be
obtained without compromising outcomes. The initial study
in 2006 reported a sensitivity of 88% for lateralisation and
70% for localisation of parathyroid adenomas (Rodgers et al.,
2006). A more recent meta-analysis, although limited by the
small number of studies, demonstrated a sensitivity and PPV
of 89.4% and 93.5% respectively, when 4D-CT was used as
the primary imaging modality. This was reduced to 71.8% and
74.9% respectively in cases of negative or inconclusive prior
imaging (Cheung et al., 2012).
Figure 51.4 (a, b) 4D Computed tomography scanning demonstrat-
ing a right inferior parathyroid adenoma (arrows).
Magnetic resonance imaging
Magnetic resonance imaging (MRI) is not commonly used
to image the parathyroid glands. However, on T2-weighted
images, enlarged parathyroid glands demonstrate significantly
imaging modalities. It involves examination of both thyro-
increased intensity. In reoperative cases or where the ade-
cervical trunks, both internal mammary arteries and carotids,
noma is located in the mediastinum, MRI may be beneficial,
with occasional selective superior thyroid artery catheterisa-
with higher reported sensitivities (50–88%). While the sensi-
tion. Vascular parathyroid adenomas appear as a persistent
tivity of MRI is slightly better than CT (64–88%) in primary
oval or round ‘stain’ on angiography. Serious complications
disease, it has significant limitations. It is expensive, patients
such as contrast-induced renal failure, embolisation and neu-
can be poorly compliant due to claustrophobia and the reso-
rological damage have limited its utility.
lution for normal glands or adenomas <5 mm is poor. Simi-
Selective venous sampling for PTH can allow accurate
larly, it can be difficult to localise superior glands due to their
localisation of adenomas but an experienced interventional
posterior location, which allows them to be obscured by the
radiologist is vital for success. The venous drainage of the
thyroid gland.
lesion is established when there is a two-fold drop in the
PTH between the sampled blood and the serum PTH. The
Parathyroid angiography and venous sensitivity is reported to be 80% and is equally effective in
sampling for PTH localising cervical and mediastinal adenomas. However, the
Parathyroid angiography is reserved for reoperative cases and false-positive rate of between 6% and 18% limits its utility to
is now rarely required due to improvements in non-invasive reoperative cases.

08_51-B&L27_Pt8_Ch51.indd 828 25/10/2017 09:21

 PART 8 | BREAST AND ENDOCRINE
Primary hyperparathyroidism 829

Management strategies or recurrent hyperparathyroidism. Persistent disease is defined

Surgical management
The mainstay of treatment for PHPT is surgery, addressing
the underlying aetiology and allowing not only resolution of
biochemical abnormalities but also sustained improvements
in end-organ damage. Traditionally a bilateral cervical explo-
ration was performed with reported cure rates of 95–98%.
With improvements in preoperative radiological localisation,
a more minimally invasive approach has been developed and
widely adopted (Figure 51.5).
All symptomatic patients should be offered surgery. An
expert panel recently published recommendations on which
asymptomatic patients should be considered for surgical inter-
vention (Table 51.2) (Bilezikian et al., 2014). When criteria
have been met and where a single adenoma has been confi-
dently identified by radiological means, a minimally invasive
parathyroidectomy may be offered. Conversely, where there
is discordant imaging or where imaging fails to identify any
parathyroid abnormalities, then a bilateral neck exploration
and three and a half-gland parathyroidectomy or a four-
gland parathyroidectomy and autotransplantation should be
performed.
Consent for a parathyroidectomy must include the pos-
sibility of recurrent laryngeal nerve damage (risk <1%), per-
manent hypoparathyroidism (requiring lifelong calcium and
vitamin D supplementation, risk 0.5%), and persistent (5%)
as an elevated serum calcium within 6 weeks of surgical inter-
vention and recurrent disease is defined as an increase in cal-
cium levels after 6 months but with an intervening period of
normocalcaemia.
MINIMALLY INVASIVE (FOCUSED)
PARATHYROIDECTOMY
Minimally invasive approaches are based on the principle that
over 80% of individuals with PHPT have a single adenoma.
Although there is no strict definition of the procedure, it
commonly refers to the removal of a localised abnormal para-
thyroid gland through an incision less than 3 cm in length
(Figure 51.6). The term encompasses open approaches (cen-
tral and lateral incisions), video-assisted and radio-guided
parathyroidectomies. A number of randomised studies have
shown that the focused approach has similar cure rates to a
cervical exploration but with reduced rates of postoperative
hypocalcaemia, shorter operating times, potentially less pain
and better cosmesis.
The need to convert from a focused to a cervical exploration
may be guided by the use of intraoperative PTH measurements.
Routine use is, however, controversial due to high false-­positive
and false-negative rates. The basic concept is that the half life
of circulating PTH is 3–5 minutes and there should therefore
be a significant drop detected in the plasma PTH following
resection of a single adenoma. If no such drop is detected, then

TABLE 51.2 Consensus guidelines for surgical (a)

intervention in asymptomatic primary hyperparathyroidism.
(Adapted from Bilezikian et al., 2014.)
Measurement of 0.25 mmol/L (1.0 mg/dL) above the upper
serum calcium limit of normal
Skeletal BMD by DEXA; T score –2.5 at lumbar spine,
total hip, femoral neck or distal 1/3 of radius
Vertebral fracture
Renal Creatinine clearance <60 mL/min
24-hour urinary calcium >10 mmol/dL
(>400 mL/d) or increased risk of stone
formation by risk analysis
Age <50 years

Discordant MIBI and US Concordant

imaging imaging (b)

Pre-op
4D CT marking
with US

4 gland Pre-op
exploration marking with MIP
US and MIP

Figure 51.5 Localisation paradigm and management strategies. CT,

computed tomography; MIP, minimally invasive parathyroidectomy; Figure 51.6 (a) Minimally invasive parathyroidectomy through a lat-
US, ultrasound. eral approach; (b) the excised parathyroid adenoma.

08_51-B&L27_Pt8_Ch51.indd 829 25/10/2017 09:21

 PART 8 | BREAST AND ENDOCRINE
830 CHAPTER 51  The parathyroid glands

multigland disease may be suspected and conversion to a bilat- (a)

eral neck exploration should be considered. The Miami criteria
were developed to determine the extent of resection. A drop in
the PTH into the normal range and to less than half the max-
imum preoperative PTH at 10 minutes appears to accurately
predict single-gland disease (Figure 51.7).

BILATERAL NECK EXPLORATION

A traditional cervical neck exploration is required where
imaging is negative or discordant, in MEN (type 1 or type
2A) or in lithium-induced PHPT. A transverse collar (Koch-
er’s) incision is made and the subplatysmal plane developed.
The deep cervical fascia is divided between the strap muscles
and these are retracted. The thyroid lobes are mobilised and
the middle thyroid vein may be divided when present.
Identification of the recurrent laryngeal nerve and the
middle thyroid artery allows a starting point for a systematic
exploration. All four glands are identified. Three and a half
glands are resected, with half of a vascularised parathyroid left
in situ. The other half of the gland should be sent for frozen
section to confirm the presence of parathyroid tissue (Fig-
ure 51.8). Ideally the most normal appearing parathyroid is
left in situ. With this caveat in mind, where possible an infe-
rior gland should be left. It is marked with a non-absorbable
suture to aid identification in the presence of recurrent dis-
ease, where resection can be achieved without increasing the (b)
risk of damage to the recurrent laryngeal nerve. Alternatively,
all four glands can be resected and a forearm autotransplant
created. Small pieces of parathyroid are sutured into pockets
created in the brachioradialis muscle. Cure rates, persistent
and recurrent disease appear to be similar, regardless of the
type of procedure use. However, in recurrent disease it can be
difficult to identify the location of the recurrent tissue when
an autotransplant is performed.

THYMECTOMY AND RESECTION OF MEDIASTINAL

ADENOMAS
The incidence of clinically significant supernumerary glands
is increased in patients with multigland disease or those with
hereditary syndromes. A thymectomy should be routinely
undertaken for patients with MEN 1-associated PHPT or in
secondary hyperparathyroidism. A cervical thymectomy is
performed by dissecting close to the thymic capsule, explor-
ing the cervical part of the gland. The mediastinal part of
the gland can be removed by gentle upwards traction, with
120
100
% PTH remaining
Figure 51.8 Parathyroidectomy with exposure of the left superior
and inferior parathyroid glands (white arrows) in situ (a) and left supe-
rior gland mobilised on its vascular pedicle (b).
ligation of the veins draining into the innominate vein. The
end of the gland is tapered and rarely requires formal ligation.
A median sternotomy is not required where a prophylactic
thymectomy is being performed.
Mediastinal adenomas are rare, accounting for less than
1% of all parathyroid adenoma. They will be typically iden-

tified on preoperative imaging. Resection can either be

80 achieved by an open sternotomy or increasingly by a thora-
60 coscopic approach. A minimally invasive approach can be
40 particularly effective where the abnormal gland lies immedi-
20 ately deep to the mediastinal pleura. It can confer significant
advantages in length of hospital stay and complication rates.
0
0 5 10 15
Time (min)
Permanent hypoparathyroidism
Figure 51.7 Miami criteria for intraoperative parathyroid hormone
(PTH) measurement. Drop of PTH into the normal range and less than Permanent hypoparathyroidism is defined as the continuing
half the maximum value at 10 min postresection. need for calcium and/or vitamin D replacement at 1 year

08_51-B&L27_Pt8_Ch51.indd 830 25/10/2017 09:21


postoperatively. It is a rare complication when surgery is
undertaken for PHPT (0.5%), but in secondary hyperpara-
thyroidism it can range from 4% to 12%. Symptoms and
signs relate to serum calcium levels. Symptoms include mild
circumoral or digital numbness and paraesthesia, carpopedal
or laryngeal spasms and cardiac arrhythmias. Chvostek’s and
Trousseau’s signs may be elicited. Chvostek’s sign refers to
contraction of the ipsilateral facial muscles on percussion of
the facial nerve below the zygoma. Trousseau’s sign refers to
the development of carpopedal spasm secondary to occlusion
of the arm (usually with a blood pressure cuff).
Biochemical investigations include total and ionised
calcium levels as well as serum magnesium levels. An ECG
may demonstrate a prolonged QT interval or QRS complex
changes. Mild hypocalcaemia can be treated with oral cal-
cium and vitamin D supplementation. Acute symptomatic
hypocalcaemia is an emergency and should be corrected with
intravenous as well as oral calcium and vitamin D replace-
ment. Traditionally, 10 mL of 10% calcium gluconate is
administered slowly intravenously. Supplemental magnesium
may also be required, due to the synergistic action of trans-
porters for calcium and magnesium.
Medical management
Medical management is warranted in patients who are
deemed unfit or who have contraindications to surgical inter-
vention, in patients with failed surgical intervention or in the
long-term management of parathyroid carcinoma. The aims
are to prevent skeletal complications (improve bone mineral
density and reduce fracture risk) and to stabilise biochemi-
cal parameters. There are only limited data on the long-term
efficacy of such an approach as surgery is known to provide
durable responses.
BISPHOSPHONATES
Bisphosphonates are pyrophosphate analogues that are
concentrated in areas of high bone turnover. They inhibit
osteoclast activity and apoptosis, thereby increasing bone
mineralisation and reducing bone turnover. Studies looking
at the management of PHTP utilising bisphosphonates are
limited by small numbers and short follow-up. However, use
does appear to stabilise bone mineral density without mark-
edly altering the underlying serum biochemistry.
HORMONE REPLACEMENT THERAPY AND
SELECTIVE OESTROGEN RECEPTOR ANTAGONISTS
Hormone replacement therapy (HRT) has been shown to
improve bone mineral density and reduce the associated frac-
ture risk in postmenopausal women by reducing bone turn-
over. Two non-randomised controlled trials have shown a
durable and similar response to surgery for PHTP at 4 years,
with improvements in bone mineral density but without any
improvement in the underlying serum biochemistry. The
rational for the use of selective oestrogen receptor antagonists
(SERMs) is that they should confer the benefits of HRT but
Frantisek Chvostek, 1835–1884, physician, The Jasefsacademie, Vienna, Austria.
Armand Trousseau, 1801–1867, physician, Hôtel Dieu, Paris, France.
08_51-B&L27_Pt8_Ch51.indd 831
PART 8 | BREAST AND ENDOCRINE
Special cases 831
without the potential adverse vascular and breast effects. The
effect on the bone mineral, however, appears to be less signif-
icant than that of HRT.
CALCIMIMETICS
The extracellular calcium sensing receptor (CaR) on the
parathyroid cell surface negatively regulates secretion of
PTH. Activation of the receptor decreases secretion of PTH,
thereby decreasing bone turnover. Calcimimetics, such as
cinacalcet, amplify the sensitivity of the CaR to extracellular
calcium, altering the set point and thereby decreasing PTH
production. The use of calcimimetics has gained widespread
acceptance in secondary hyperparathyroidism, but use in
PHTP is largely limited to patients unfit for surgery. Despite
this, a number of small studies have shown normalisation of
PTH levels and a reduction in bone remodelling, with durable
results at 2 years, with the use of cinacalcet. Drug tolerance,
especially gastrointestinal side effects, can be problematic and
may limit the duration of usage.
SPECIAL CASES
Lithium-induced
hyperparathyroidism
Lithium-induced hyperparathyroidism occurs in 10–15% of
patients treated with long-term lithium. It is generally associ-
ated with a mild elevation in calcium with failure to suppress
PTH. The underlying aetiology can be either gland hyper-
plasia, with lithium originally thought to stimulate all para-
thyroid tissue, or a single adenoma which has been shown to
occur in 33–49% of cases. It has recently been suggested that
the hyperparathyroidism may be caused by interference with
the parathyroid kinase C signal transduction system and the
Wnt pathway. Biochemical abnormalities may resolve with
discontinuation of lithium. Surgery is indicated where ongo-
ing treatment with lithium is required or where abnormalities
persist following withdrawal of lithium. Minimally invasive
surgery is relatively contraindicated in these patients due to
the high incidence of multigland disease. Excision, however,
should be limited to those glands that are obviously enlarged
at exploration rather than a formal three and a half-gland
excision.
Familial syndromes
Familial hyperparathyroidism can be part of a well-recognised
endocrine disorder, but it may also occur in isolation in a
non-syndromic form. PHPT occurs as a central facet in mul-
tiple MEN 1, MEN 2A, HPT-JT and familial hypocalciuric
hypercalcaemia (FHH).
Familial isolated hyperparathyroidism
Isolated familial hyperparathyroidism occurs when patients
have PHPT without any other associated endocrinopathies.
25/10/2017 09:21
 PART 8 | BREAST AND ENDOCRINE
832 CHAPTER 51  The parathyroid glands
The underlying genetic abnormality has yet to be fully elu-
cidated, but the syndrome has been linked to known muta-
tions in the MEN 1 gene, the HRPT2 gene as well as the
calcium-sensing receptor gene. A significant proportion of
patients will belong to the MEN 1 family, with documented
recognised mutations but without expression of other endo-
crinopathies. Hyperparathyroidism should be treated with
a formal bilateral neck exploration and management as per
patients with MEN.
MEN 1-associated hyperparathyroidism
MEN 1 is a rare autosomal dominant syndrome consisting of
tumours of the parathyroids, endocrine pancreas–duodenum
and the pituitary (the three Ps). It occurs in approximately
1 per 30 000 individuals. It can also be associated with adre-
nal adenomas or carcinoma, foregut carcinoids and lipomas.
Mutations, of which there are over 1000 identified in differ-
ent families, occur in the MEN 1 gene, which encodes the
protein menin. Menin acts as a tumour suppressor. Patients
typically present with young onset (20–30 years of age) of
symptomatic hyperparathyroidism and over 95% of patients
will have PHPT before the age of 40 years.
Surgical intervention in MEN aims to obtain and main-
tain normocalcaemia for the longest time possible. In
general, it is associated with the presence of multigland para-
thyroid disease and as such has mandated a bilateral cervical
exploration with at least a subtotal parathyroidectomy and
cervical thymectomy. A total parathyroidectomy and fore-
arm autotransplantation is an acceptable alternative. Half of
the most normal appearing parathyroid should be left in situ
with a marking stitch to facilitate reoperative intervention.
Detailed intraoperative notes, including diagrams, should
be kept. Despite meticulous and extensive surgery, the rates
of both persistent and recurrent disease remain high in this
group of patients (up to 62%) regardless of the type of sur-
gery performed. Unfortunately, the rates of postoperative
­permanent hypocalcaemia are also high, with published rates
up to 47%.
MEN 2A-associated hyperparathyroidism
MEN 2A consists of medullary thyroid carcinoma, unilateral
or bilateral phaeochromocytomas and PHPT. PHPT occurs in
approximately 20% of patients and is associated with muta-
tions in codon 634 in the RET proto-oncogene. The major-
ity of patients will be asymptomatic, with a mild elevation in
calcium and asymmetrically enlarged parathyroid glands. It
is extremely important that the presence of a phaeochromo-
cytoma is excluded prior to surgical intervention. Surgery is
usually performed for medullary thyroid carcinoma (MTC),
with the parathyroid enlargement often being a coincidental
intraoperative finding. In this setting, with extensive surgery
for MTC, the primary aim of treatment is to avoid hypopara-
thyroidism. A conservative stance is adopted with resection
of grossly enlarged glands, but with preservation of parathy-
roid tissue where possible and identification with a marking
stitch in the neck.
Max Wilms, 1867–1918, Professor of Surgery, University of Heidelberg, Germany.
08_51-B&L27_Pt8_Ch51.indd 832
Hyperparathyroid-jaw tumour syndrome
HPT-JT is a rare cause of PHPT. It arises due to inactivat-
ing mutations in the HRPT2 gene on chromosome 1 q21-32,
encoding parafibromin. It classically presents with early-onset
PHPT (mean age of 32 years), the aetiology of which can be
either single- or multiple-gland disease but is predominantly
cystic in nature. It presents with severe hypercalcaemia and
is associated with an increased risk of an underlying parathy-
roid carcinoma. Approximately 40% of patients will have the
pathognomonic ossifying jaw fibromas of the maxilla or man-
dible. Other associated abnormalities include renal pathology
(hamartomas, polycystic kidney disease and adult Wilms’
tumours) and female patients may have uterine malignancies.
Surgical intervention involves removal of all enlarged para-
thyroid glands.
Where there is concern for a parathyroid carcinoma, great
care must be taken to avoid tumour spillage. Whether or not
an en bloc resection of the enlarged suspicious parathyroid and
the adjacent thyroid lobectomy is required remains contro-
versial.
Familial hypocalciuric hypercalcaemia
FHH is not a surgical disease and therefore preoperative diag-
nosis is imperative for the surgeon. FHH arises as a result of
heterozygous mutations in the calcium receptor gene (CASR)
on chromosome 3. Benign familial hypocalciuric hypercal-
caemia typically presents with mild hypercalcaemia in young
(<10 years of age) asymptomatic patients. Patients with FHH
have a normal or slightly elevated PTH level, increased serum
magnesium levels and hypocalciuria. A low urinary calcium/
creatinine clearance ratio is used to discriminate between
FHH and mild PHPT. Patients rarely require intervention
and surgical intervention is not indicated.
Summary box 51.1
Primary hyperparathyroidism
●● Presentation is now typically asymptomatic rather than the
classical ‘bones, stones, abdominal groans and psychiatric
overtones’
●● The diagnosis of primary hyperparathyroidism is a
biochemical one
●● Presence of an elevated ionised calcium with an
inappropriately elevated/not suppressed PTH level confirms
the diagnosis
●● Sestimibi and focused neck ultrasound are the first-line
radiological investigations
●● 85% of cases are due to a single adenoma
●● Minimally invasive parathyroidectomy is a safe and
acceptable alternative to a four-gland exploration in the
presence of localised disease
●● Familial syndromes and disease that is not localised require
a formal four gland exploration and three and a half gland
parathyroidectomy
25/10/2017 09:21
 PART 8 | BREAST AND ENDOCRINE
Secondary hyperparathyroidism 833

SECONDARY
HYPERPARATHYROIDISM
Secondary hyperparathyroidism is defined as a derangement in
calcium homeostasis, which leads to a compensatory increase
in PTH secretion. It occurs primarily as a result of chronic
kidney disease and is therefore sometimes referred to as renal
hyperparathyroidism. Other underlying causes include gastro-
intestinal malabsorption, vitamin D deficiency, liver disease
or chronic lithium usage.
The pathogenesis of secondary hyperparathyroidism is
related to renal dysfunction. Abnormalities in the renal tubu-
lar absorption of phosphate lead to hyperphosphataemia. This
acts directly on the parathyroid cells and stimulates PTH
secretion. More recent translational research has identified
a novel phosphaturia hormone, fibroblast growth factor 23
(FGF 23). This is progressively secreted from osteocytes to
compensate for chronic phosphate retention that in turn
leads to a reduction in 1,25-dihydroxyvitamin D, which by
reducing the intestinal absorption of calcium, also acts to
increase secretion of PTH. Previous studies in patients with
chronic renal disease have shown that there is a reduction in
the expression of the vitamin D receptor and the CaR, with
associated skeletal resistance to PTH. These factors interact
to form the complex pattern leading to progressive secondary
hyperparathyroidism in the setting of chronic renal disease.
The pathological characteristics associated with second-
ary hyperparathyroidism include hyperplasia, asymmetrical
glandular enlargement or nodularity. This differentiation is
important, as when the parathyroid gland becomes nodular
it loses expression of the vitamin D and Ca receptors. It has
Figure 51.9 Secondary hyperparathyroidism. X-ray showing ectopic
been proposed that nodular parathyroid glands may be resis- calcification.
tant to calcimimetics and therefore be refractory to medical
management.
recurrent disease, in order to identify ectopic parathyroid tis-
sue, especially in the mediastinum. In cases of recurrent dis-
Diagnosis ease, when there is no evidence of active disease in the neck,
The classical symptoms associated with secondary hyper- and a previous allograft has been used to the forearm, then
parathyroidism are seen less commonly now, with greater selective venous sampling for PTH in the neck and the bra-
awareness of the disease and the resultant earlier medical chial vein on the side of the graft can be useful. This is known
intervention. However progressive bone disease, especially as the Casanova test and to prove that the recurrent disease
bone pain, can occur with associated soft tissue calcium is located in the grafted arm (graft hyperplasia) the ratio must
deposits (Figure 51.9). be greater than 20:1.
The diagnosis of secondary hyperparathyroidism is char-
acterised by hypocalcaemia or normocalcaemia with an ele-
vated PTH. Patients have a high serum phosphate and a low Calciphylaxis
vitamin D. Traditional plain x-rays now rarely demonstrate Calciphylaxis (calcific uraemic arteriolopathy) is a syndrome
the pathognomonic osteitis fibrosa cystica. However, bone of disseminated calcification resulting in both vascular cal-
densitometry (DEXA scan) typically demonstrates osteope- cification and skin necrosis. It accounts for approximately
nia or osteoporosis. 4% of patients undergoing surgical intervention for second-
The diagnosis of secondary hyperparathyroidism is a bio- ary hyperparathyroidism. It presents with expanding painful
chemical one. In general, localisation studies are not under- cutaneous purpuritic lesions, predominantly on the extrem-
taken as minimally invasive surgery is not indicated. However, ities, although it can also be seen on the lower abdomen.
a neck ultrasound can be performed to identify patients with The underlying tissue calcification within the arteriolar and
nodular hyperplasia who may be refractory to medical man- small vascular walls leads to ischaemic necrosis and the devel-
agement. Localisation studies are helpful in patients with opment of gangrene, which in turn leads to overwhelming

Daniel Casanova, contemporary, University of Cantabria, Santander, Spain.

08_51-B&L27_Pt8_Ch51.indd 833 25/10/2017 09:21

 PART 8 | BREAST AND ENDOCRINE
834 CHAPTER 51  The parathyroid glands
sepsis and death. The majority of these patients will have an
elevated calcium × phosphate product but it is not usually
associated with an extremely high PTH level. The underlying
aetiology remains unclear but a number of potential factors
have been postulated. A reduction in the serum levels of a
calcification inhibitory protein, α-2-Heremans–Schmid gly-
coprotein, and abnormalities in smooth muscle cell biology
in uraemic patients may play a role in the development of
the syndrome. Prognosis for these patients is extremely poor,
with a mortality of up to 87%. An urgent parathyroidectomy
has been shown to decrease pain, improve wound healing and
reduce the risk of amputation in these patients. It has also
been associated with an increase in median survival.
Management
Renal transplantation remains the only definite treatment for
secondary hyperparathyroidism. Other therapies are a bridge
to this or aim to provide symptom relief. Standard manage-
ment includes replacement of calcium and vitamin D and the
reduction of phosphate levels by the use of phosphate binders.
Treatment of this disease changed radically with the intro-
duction of calcimimetic drugs, such as cinacalcet. Calcimi-
metics alter the set point of the CaR, thereby reducing the
constant stimulation of the parathyroid glands and lowering
the PTH level. This obviously does not address the underly-
ing renal disease. It remains controversial as to which patients
may benefit from the use of calcimimetics and which patients
may benefit from earlier surgical intervention. Indications for
pursing medical management include those patients who are
deemed non-surgical candidates by reason of medical comor-
bidities. Similarly, where there is persistent or recurrent dis-
ease, the origin of which cannot be clearly elucidated, surgical
management should be avoided. However, there are definite
indications for surgical intervention in secondary hyperpara-
thyroidism (Table 51.3) although these have been modified
to reflect the current use, where available, of calcimimetics
(Table 51.4).
TABLE 51.3 Indications for surgical intervention in
secondary hyperparathyroidism.
Essential components
1. Persistently high serum level of intact PTH >500 pg/mL
2. Hyperphosphataemia (serum P >6 mg/dL) or hypercalcaemia
(serum Ca >2.5 mmol/L or 10 mg/dL) which is refractory to
medical management
3. Estimated volume of the largest gland >300–500 mm3 or long
axis >1 cm
Clinical findings
If patients have one of these symptoms, parathyroidectomy should
be recommended:
Severe osteitis fibrosa with associated high bone turnover
Subjective symptoms (bone and joint pain, arthralgia, muscle
weakness, irritability, purititis, depression)
Progressive ectopic calcification
Calciphylaxis
Progressive reduction in bone mineral content
Anaemia resistant to erythropoietin stimulating agent (ESA)
Dilated cardiomyopathy/cardiac failure
08_51-B&L27_Pt8_Ch51.indd 834
TABLE 51.4 Proposed indications for surgical
management of secondary hyperparathyroidism (SHPT) in
the era of calcimimetics.
When SHPT is refractory to vitamin D replacement or vitamin D
analogues and prolonged survival is anticipated
Severely impaired quality of life due to either SHPT or intolerance
to calcimimetics
When sufficient reduction in parathyroid hormone cannot be
achieved with use of calcimimetics
Thyroid surgery is also required (thyroid carcinoma)
There are a wide variety of operations that can be utilised
for the management of secondary hyperparathyroidism, none
of which appears significantly superior in terms of clinical
outcomes (persistent or recurrent disease). These include a
subtotal parathyroidectomy, a total parathyroidectomy with
autograft or a total parathyroidectomy without autograft.
Cryopreservation of resected tissue, where available, should
be performed in case of significant postoperative hypocalcae-
mia. The first two procedures are most widely accepted and
the type of operation performed depends upon the surgeon.
A subtotal parathyroidectomy is where three and a half
parathyroid glands are excised, with the remnant being
marked with a non-absorbable stitch to facilitate identifica-
tion in the event of recurrent disease. A biopsy of the final
gland that is to be left in situ is mandatory to confirm the pres-
ence of residual parathyroid tissue. Ideally an inferior gland
is left in situ to facilitate reoperative surgery and minimise
potential damage to the recurrent laryngeal nerve in that set-
ting (Figure 51.10). A total parathyroidectomy with a fore-
arm autograft involves removal of all parathyroid tissue in the
neck, with reimplantation of a small amount of morcellated
tissue within a pocket formed in the brachoradialis muscle.
Overall, regardless of the operative approach utilised the cure
rate ranges between 90% and 96%, with similar complication
rates. A randomised study looking at 40 patients who either
underwent a subtotal or total parathyroidectomy with auto-
transplant demonstrated no significant difference between
the two operations in terms of efficacy and recurrence rate
(Rothmund et al., 1991).
Figure 51.10 Subtotal parathyroidectomy for parathyroid hyperpla-
sia. Right inferior gland biopsied and half left in situ.
25/10/2017 09:21

The response to surgical intervention is often dramatic.
The biochemical parameters may resolve almost immediately
and appear to be sustained for up to 3 years postoperatively.
Patients subjectively report improvements in the symptoms of
secondary hyperparathyroidism including bone pain, pruritus,
fatigue and depression. Finally, bone metabolism is improved
with an approximate 10% increase in trabecular bone, with
almost immediate suppression of bone resorption and acceler-
ation of new bone formation.
Summary box 51.2
Secondary hyperparathyroidism
●● Primarily due to underlying chronic kidney disease
●● Associated with parathyroid hyperplasia
●● Diagnosis is made biochemically with a low or normal calcium
and an elevated PTH. High phosphate levels and low vitamin
D levels are seen
●● No localisation studies are required
●● Mainstay of treatment is renal transplantation. Medical
management with calcium and vitamin D replacements and
phosphate binders is a bridge to transplantation
●● Use of calcimimetics has reduced the requirement for surgical
intervention
●● Subtotal parathyroidectomy remains the surgical intervention
of choice when indicated
TERTIARY
HYPERPARATHYROIDISM
Tertiary hyperparathyroidism is a persistent autonomous
hypercalcaemic hyperparathyroidism occurring after kidney
transplantation. A number of proposed factors may prevent
involution of the hyperplastic parathyroid glands following
resolution of the underlying renal impairment. These include
impaired graft function, non-suppressible PTH secretion,
slow involution of enlarged glands or insufficient calcitriol
conversion by the transplanted kidney.
The biochemical diagnosis is confirmed by an elevated
total or ionised calcium, with an associated elevated or
unsuppressed PTH and a reduced phosphate occurring at least
1-year post renal transplantation. Differentiation from PHPT
can be difficult. Fewer than 1% of patients with tertiary
hyperparathyroidism will require surgical intervention (Table
51.5). The only new evidence for intervention is the presence
of nodular hyperplasia of the glands themselves. Traditionally,
localisation studies or imaging of the neck was not indicated in
tertiary hyperparathyroidism. However, increasing knowledge
TABLE 51.5 Indications for surgical intervention in tertiary
hyperparathyroidism.
Subacute severe hypercalcaemia (>3 mmol/L)
Impaired graft function
Nodular hyperplasia of the parathyroid gland(s)
Progressive symptoms (>2 years following transplantation)
Worsening bone disease (pain, fractures, bone loss)
Renal stones/nephrocalcinosis
Soft tissue or vascular calcifications
08_51-B&L27_Pt8_Ch51.indd 835
PART 8 | BREAST AND ENDOCRINE
Parathyroid carcinoma 835
of the clonal nature of gland hyperplasia suggests that where
there is a nodule within the parathyroid with a volume of
tissue greater than 500 mm3, then resolution of electrolyte
abnormalities is unlikely.
The use of calcimimetics in tertiary hyperparathyroid-
ism remains controversial and has not been approved for
this indication. However, isolated reports have documented
control of hypercalcaemia with minimal side effects in indi-
vidual patients. Surgical intervention remains the definitive
management strategy. Subtotal parathyroidectomy or total
parathyroidectomy with autotransplantation are acceptable
surgical options. The majority of endocrine surgeons will
opt for a subtotal parathyroidectomy in this setting, leaving
a gland approximately four times normal in volume to min-
imise postoperative complications. Total parathyroidectomy
without an autograft is not a treatment option due to the
postoperative and persistent difficulties in managing the asso-
ciated hypocalcaemia.
Summary box 51.3
Tertiary hyperparathyroidism
●● Persistent autonomous hypercalcaemic hyperparathyroidism
occurring after kidney transplantation
●● Diagnosis is made by demonstrating an elevated total or
ionised calcium with an associated elevated or unsuppressed
PTH and a reduced phosphate occurring at least 1-year post
renal transplantation
●● Localisation studies are not required but a focused neck
ultrasound may confirm the presence of nodular enlargement
●● Surgical intervention remains the mainstay of treatment and
involves a subtotal parathyroidectomy
PARATHYROID CARCINOMA
Parathyroid carcinoma is a rare malignancy occurring in
approximately 1% of cases of PHPT, with an estimated prev-
alence of 0.005% of all cancers. While the aetiology remains
unclear, recent advances in molecular biology suggest that
there may be an underlying genetic basis. Currently, a history
of previous neck irradiation remains the only known environ-
mental risk factor. However, given that it can arise in patients
with end-stage renal disease as well as in those with MEN
type 1, malignant transformation in hyperplastic glands may
also occur.
A significant proportion of patients (>10%) with a para-
thyroid carcinoma will have HPT-JT. The underlying muta-
tion is in the HRPT2 gene at 1q25-32, a tumour suppressor
gene that encodes the protein parafibromin. Parafibromin is
involved in the regulation of cellular transcription and his-
tone modification. HRPT2 mutations, leading to inactiva-
tion of parafibromin, are therefore an important contributor
to the pathogenesis of parathyroid carcinoma.
Parathyroid carcinoma remains difficult to diagnose pre-
operatively as it biochemically resembles PHPT. There are,
however, a number of suggestive features. Firstly, the diagno-
sis is typically made a decade earlier, with an equal gender
preponderance (female:male 1:1) when compared to PHPT.
25/10/2017 09:21
 PART 8 | BREAST AND ENDOCRINE
836 CHAPTER 51  The parathyroid glands
Secondly, a greater proportion of these patients will be symp-
tomatic at presentation. A palpable neck mass is found in
36–52% of patients with parathyroid carcinomas but rarely
(<5%) in cases of PHPT. Finally, the biochemical abnormal-
ities tend to be exaggerated with an average total calcium of
between 3.75 and 3.97 mmol/L and a PTH level 5–10 times
the normal range.
The leading cause of morbidity and mortality from para-
thyroid carcinoma is hypercalcaemia, due to inappropriate
PTH secretion. Treatment is focused on controlling hyper-
calcaemia and removal of the carcinoma where possible.
Surgery remains the mainstay of treatment for primary pre-
sentations and locally recurrent disease. Complete resection
of the tumour avoiding spillage is vital in preventing seeding
and thus recurrent disease. En bloc resection of the tumour,
associated thyroid lobectomy and central neck dissection
remains controversial. Traditionally, complete R0 resection
was thought to provide the only means of a cure. However,
a number of recent studies have failed to demonstrate an
improvement in local recurrence rates with such comprehen-
sive resection. Adjuvant chemotherapy has not been shown
to confer a disease-free or overall survival benefit. Use of
external beam radiotherapy should be considered on an indi-
vidual basis. Traditionally, it has not been deemed effective,
but more recent single institution case series appear to chal-
lenge this assumption. It may be considered where it is diffi-
cult to achieve a complete surgical resection or in patients
with multifocal recurrent soft tissue deposits.
Histological confirmation of a parathyroid carcinoma
remains difficult. The classical description included trabec-
ular architecture, mitotic figures, thick fibrous bands and
capsular and vascular invasion. However, these findings can
be non-significant and new molecular markers may aid the
diagnosis and stratify patients for more intensive follow-up
(Figure 51.11). Immunohistochemical evidence of down-­
regulation of parafibromin has a sensitivity of 67% and a
specificity of 100% for detecting parathyroid carcinoma and
the protein gene product 9.5 (PGP 9.5). Parafibromin immu-
nohistochemistry may be used with immunohistochemistry
for PGP 9.5. This is a protein encoded by ubiquitin carboxyl-­
terminal esterase L1. It is upregulated in parathyroid carci-
noma and has a sensitivity of 78% and a specificity of 100%
Atypical parathyroid
tumour
Parafibromin Parafibromin
NEGATIVE POSITIVE
PGP 9.5 PGP 9.5
POSITIVE NEGATIVE
High risk of Low risk of
Carcinoma
malignancy malignancy
Figure 51.11 Proposed decision tree for atypical parathyroid
tumours using parafibromin and PGP 9.5 immunostaining.
08_51-B&L27_Pt8_Ch51.indd 836
(­ Figure 51.11). All parafibromin-negative and PGP 9.5-
positive tumours should be considered for genetic screening.
Parathyroid carcinoma is an indolent but progressive
disease. Metastatic spread can occur to the lungs, liver and
bones. Recurrence rates range from 33% to 80% and it typi-
cally occurs in the first 3 years. Overall survival is reported to
be 85–90% at 5 years and 49–77% at 10 years.
Summary box 51.4
Parathyroid carcinoma
●● Accounts for approximately 1% of all cases of primary
hyperparathyroidism
●● A history of previous neck irradiation remains the only known
environmental risk factor
●● The tumours remain difficult to diagnose preoperatively as
they biochemically resemble primary hyperparathyroidism
●● Treatment is focused on controlling hypercalcaemia and
removal of the carcinoma where possible
●● Surgery remains the mainstay of treatment for primary
presentations and locally recurrent disease. Complete
resection of the tumour avoiding spillage is vital in preventing
seeding and thus recurrent disease
PERSISTENT
HYPERPARATHYROIDISM
Persistent hyperparathyroidism is defined as an elevated
calcium within 6 weeks of surgical intervention. For all
parathyroid operations (minimally invasive parathyroidec-
tomy (MIP) and bilateral exploration) the rate of persistent
hypercalcaemia is approximately 6% in sporadic disease and
between 16% and 20% in hereditary disease. It usually arises
as a result of a technical error during the first operation, either
due to a missed adenoma or asymmetrical disease. When
this occurs all preoperative biochemistry, radiological imag-
ing, intraoperative findings and pathology must be carefully
reviewed. If reoperation is appropriate, repeat imaging of the
neck and mediastinum is required (sestamibi, ultrasound and
4D-CT scanning). Surgical intervention can be straightfor-
ward where there are intact tissue planes, such as following
a minimally invasive parathyroidectomy. Complications,
including recurrent laryngeal nerve damage and permanent
hypocalcaemia, are increased when extensive previous dissec-
tion has occurred and the patient must be consented appro-
priately.
RECURRENT
HYPERPARATHYROIDISM
Recurrent hyperparathyroidism is defined as hypercalcaemia
occurring 6 months after surgery but with an intervening
period of normocalcaemia. Common causes include missed
pathology at the first operation; hyperplasia in remaining or
autotransplanted tissue; parathyromatosis or, very rarely, the
development of a second parathyroid adenoma. Parathyroma-
tosis refers to disseminated parathyroid tissue within the soft
25/10/2017 09:21

tissues of the neck and superior mediastinum due to rupture of
the parathyroid gland during the primary surgery. A definitive
indication for surgical intervention must be present prior to
embarking on localisation studies. Surgical intervention will
be guided by the radiological imaging. Complication rates of
recurrent laryngeal nerve damage and permanent hypocalcae-
mia are higher in reoperative surgery.
FURTHER READING
Agarwal A, Mishra AK, Lombardi CP, Raffaelli M. Applied embryo­logy
of the thyroid and parathyroid glands. In: G.W. Randolph surgery
of the thyroid and parathyroid glands. Philadelphia: Saunders, 2013,
15–24.
Barczynski M, BränstrÖm R, Dionigi G, Mihai R. Sporadic multiple
parathyroid gland disease – a consensus report of the European
Society of Endocrine Surgeons. Langenbecks Arch Surg 2015; 400(8):
887–905.
Bilezikian JP, Brandi ML, Eastell R et al. Guidelines for the management
of asymptomatic primary hyperparathyroidism: summary statement
from the Fourth International Workshop. J Clin Endocrinol Metab
2014; 99: 3561–9.
Carneiro-Pla D, Pellitteri PK. Intraoperative PTH monitoring during
parathyroid surgery. In: G.W. Randolph surgery of the thyroid and para-
thyroid glands. Philadelphia: Saunders, 2013, 605–12.
Certani F, Pardi E, Marcocci C. Update on parathyroid carcinoma.
J Endocrinol Invest 2016; 39(6): 595–606.
Cheung K, Wang TS, Farrokhyar F, Roman SA, Sosa JA. A meta-­
analysis of preoperative localisation techniques for patients with
primary hyperparathyroidism. Ann Surg Oncol 2012; 19(2): 577–83.
08_51-B&L27_Pt8_Ch51.indd 837
PART 8 | BREAST AND ENDOCRINE
Further reading 837
Howell VM, Gill A, Clarkson A et al. Accuracy of combined protein
gene product 9.5 and parafibromin markers for immunohistochem-
ical diagnosis of parathyroid carcinoma. J Clin Endocrinol Metab
2009; 94(2): 434–41.
Iacobone M, Carnaille B, Palazzo FF, Vriens M. Hereditary hyperpara-
thyroidism – a consensus report of the European Society of Endo-
crine Surgeons. Langenbecks Arch Surg 2015; 400(8): 867–86.
Jeong HS, Dominguez AR. Calciphylaxis: controversies in pathogenesis,
diagnosis and treatment. Am J Med Sci 2016; 351(1): 217–27.
Krakauer M, Wieslander B, Myschetzky PS et al. A prospective com-
parative study of parathyroid dual-phase scintigraphy, dual-isotope
subtraction scintigraphy, 4D-CT, and ultrasonography in primary
hyperparathyroidism. Clin Nucl Med 2016; 41(2): 93–100.
Mihai R, Simon D, Hellman P. Imaging for primary hyperparathyroidism
– an evidence-based analysis. Langenbecks Arch Surg 2009; 394(5):
765–84.
Pitt SC, Sipple RS, Chen H. Secondary and tertiary hyperparathyroid-
ism: state of the art surgical management. Surg Clin North Am 2009;
89(5): 1227–39.
Rodgers SE, Hunter GJ, Hamberg LM et al. Improved pre-operative
planning for directed parathyroidectomy with 4-dimensional com-
puted tomography. Surgery 2006; 140(6): 932–40.
Rothmund M, Wagner PK, Schark C. Subtotal parathyroidectomy ver-
sus total parathyroidectomy and autotransplantation in secondary
hyperparathyroidism: a randomized trial. World J Surg 1991; 15(6):
745–50.
Silverberg SJ, Clarke BL, Peacock M et al. 2014. Current issues in the
presentation of asymptomatic primary hyperparathyroidism. Pro-
ceedings of the Fourth International Workshop 2014; 99: 3580–94.
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