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CHAPTER 6 Breast and endocrine surgery
262
Multiple endocrine neoplasia
Key facts
• Familial endocrine diseases constitute a group of rare conditions.
• Familial syndromes are autosomal dominant diseases involving tumours
of several endocrine glands in a synchronous or metachronous pattern.
Clinicopathological features
Multiple endocrine neoplasia type I (MEN-1)
A syndrome of the ‘3Ps’.
• Parathyroid gland tumours. By age 40, 95% of patients have
hypercalcaemia which is the commonest manifestation.
• Pancreatic islet cell tumours.
Prevalence of 30–75%.•
Usually multicentric, slow-growing.•
Secrete multiple polypeptides (insulin and gastrin commonest).•
Gastrinoma leads to Zollinger–Ellison syndrome (recurrent and •
multiple peptic ulcers, severe refl ux oesophagitis, and diarrhoea).
Rarer tumours are VIPoma, glucagonoma, somatostatinoma.•
• Anterior pituitary tumours.
Detected in 15–40%.•
Commonest is prolactinoma.•
Rarer are GH- (causes acromegaly) or ACTH- (causes Cushing’s •
disease) secreting tumours.
Carcinoid tumours (thymus, lungs, foregut), adrenal tumours, lipomas, and
pinealomas have also been reported to appear in MEN-1 patients.
MEN-1 gene, Chr11, encodes a nuclear protein, menin (role unclear).
Multiple endocrine neoplasia type II (MEN-2) Has two forms.
MEN-2A Syndrome with the following features.
• Medullary thyroid carcinoma (MTC).
Originates in the calcitonin-secreting parafollicullar C-cells •
(derivatives of the neuroectodermal tube);
Commonly multicentric and bilateral and appear on a background •
of C-cell hyperplasia;
Presents as unilateral or bilateral thyroid nodules with/without •
associated cervical lymphadenopathy;
Associated secretion of other (some unidentifi ed) peptides can •
lead to severe diarrhoea.
• Phaeochromocytoma (in 50% of patients; see b p. 268 for features).
• Primary hyperparathyroidism (15% of patients).
MEN-2B Syndrome with the following features.
• MTC.
• Phaeochromocytoma.
• ‘Marfanoid-specifi c body habitus’ (tall, slender, high arched palate, and
long extremities), 90% of patients.
MEN-2B is associated with mucosal neuromas and intestinal ganglioneuromatosis and characteristic facial appearance.
MULTIPLE ENDOCRINE NEOPLASIA
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MEN-2 gene, Chr10, encodes a cell surface glycoprotein member of
receptor tyrosine kinases (RET proto-oncogene). Point mutations in specifi c parts of the RET gene lead to specifi c clinical syndromes (genotype–
phenotype correlation). Because of near complete penetrance, all gene
carriers are likely to be affected.
Familial MTC A syndrome of isolated familial with MTC.
Diagnosis and investigations
MEN-1
• Biochemical screening from second decade in known families (serum
calcium, PTH, prolactin, and insulin growth factor-1 (IGF-1) for
pituitary lesions, and serum glucose, insulin, gastrin, and chromogranin
for pancreatic tumours).
• Genetic screening can be used for offspring of known index cases.
Because 10% of menin mutations are de novo, siblings of an index case
are not necessarily at risk.
MEN-2
• Genetic screening for point mutations of the RET gene has 100%
accuracy for identifying carriers (before biochemical abnormalities).
• Affected children are offered total thyroidectomy at an age related
to the individual risk of each mutation (as early as 3y old for some
aggressive mutations).
• Biochemical screening with 24h urine excretion of catecholamines and
metanephrines and serum calcium and PTH are measured annually.
Treatment
Surgical treatment
MEN-1
• Parathyroidectomy.
• Pancreatic tumours. Enucleation of individual tumours in the head of
the pancreas and distal pancreatectomy for tumours in the tail/body.
• Hypophysectomy and external beam irradiation are considered for
pituitary tumours.
MEN-2
• Total thyroidectomy (TT) indicated in patients identifi ed by genetic
screening. Symptomatic patients need TT and cervical nodal dissection
for the lymph nodes on the involved side.
• Laparoscopic adrenalectomy for phaeochromocytoma.
• Parathyroidectomy for MTC in patients belonging to families in which
hyperparathyroidism is frequently associated.
Medical treatment
MEN-1 Prolactinomas can be treated with dopamine agonists (bromocriptine/cabergoline).
263
CHAPTER 6 Breast and endocrine surgery
264
Cushing’s syndrome
Key facts
A syndrome of excess levels of plasma cortisol and associated clinical
features.
Causes
• Commonest cause is iatrogenic administration of steroids.
• Primary adrenal disease (50% of patients).
Unilateral. Cortical adenoma or cortical carcinoma.•
Bilateral. ACTH-independent macronodular adrenal hyperplasia or •
pigmented nodular adrenal cortical disease.
• Secondary adrenal disease.
ACTH-secreting pituitary adenoma (Cushing’s disease, 25%).•
Ectopic ACTH secretion (25%) from other malignant tumours (e.g. •
small cell lung carcinoma).
Clinical features
• Weight gain. Obesity is predominantly truncal with a protuberant
abdomen and a ‘buffalo hump’.
• Muscle weakness, especially thigh and upper arms (add to the overall
appearance, likened to a ‘lemon on sticks’).
• Menstrual irregularities, headache, and backache are common
presenting symptoms.
• Psychological changes are commonly overlooked: lethargy/depression,
paranoid ideas, hallucinations, and a tendency to suicide.
• Plethora, acne, striae, and multiple bruising are common, as is
hirsutism.
• Hypertension, osteoporosis, and impaired glucose tolerance/diabetes.
All these symptoms and signs are non-specifi c and not exclusively related
to Cushing syndrome.
Diagnosis and investigations
Diagnosis is by proving cortisol excess and then by establishing the cause.
• Loss of normal circadian rhythm of cortisol secretion. Samples taken
at 9 a.m. and midnight demonstrate a loss of the normal morning peak
and night nadir.
• Persistent increase in cortisol levels. 24h urine cortisol levels are
elevated, but false positive results can appear in obese patients,
athletes, and patients suffering stress.
• Overnight dexamethasone test. After administration of 1mg
dexamethasone in the evening, the morning cortisol is inhibited in
normal patients, but not in Cushing’s syndrome. It is a very valuable
outpatient screening test.
• Low dose dexamethasone test. Administration of 0.5mg dexamethasone
qds for 48h fails to inhibit plasma cortisol and urine cortisol and
metabolites.
• ACTH levels are inhibited in primary adrenal disease (see above)
and are increased in patients with pituitary adenomas and ectopic
secretion.
CUSHING’S SYNDROME
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• High dose dexamethasone test. Administration of 2mg dexamethasone
qds for 48h inhibits ACTH secretion from pituitary tumours and leads
to a drop in cortisol levels in such patients. The test is negative in
primary adrenal disease and in ectopic ACTH secretion.
• Imaging.
Abdominal CT or MRI scanning demonstrates whether there is a •
solitary adrenal tumour (with an atrophic contralateral gland) or
whether both adrenals are enlarged. Cancer should be strongly
suspected in tumours greater than 7cm.
Pituitary MRI usually demonstrates tumours over 10mm; small •
microadenomas may need confi rmation by measuring ACTH
concentrations in the inferior petrosal sinuses (to demonstrate
laterality of the tumour).
Treatment
Surgical treatment
• Unilateral adrenalectomy (may be laparoscopic). For patients with
primary adrenal disease.
• Bilateral adrenalectomy. For patients with pituitary ACTH-secreting
adenomas who failed pituitary surgery or gamma-knife treatment. It
is also needed for the very rare patients with ACTH-independent
bilateral adrenal hyperplasia.
Medical treatment
• Metyrapone and ketoconazole can be used preoperatively to decrease
cortisol synthesis, but their effi cacy is limited.
• Cortisol replacement after unilateral or bilateral adrenalectomy is vital.
Patients with solitary adrenal tumours have the contralateral •
adrenal gland atrophied and it may take up to 1y for a return
to normal function. Start on 50–100mg IV tds hydrocortisone
post-operatively. Maintenance dose is usually prednisolone orally
long-term.
Patients should be informed about the possibility of an Addisonian •
crisis triggered by any illness that could impair their ability to
continue medication (e.g. severe diarrhoea/vomiting episodes).
They should wear a bracelet and carry a card with details of their
condition.
• Mineralocorticoid replacement (fl udrocortisone 0.1mg) is also
necessary after bilateral adrenalectomy.
265
CHAPTER 6 Breast and endocrine surgery
266
Conn’s syndrome
Key facts
• Syndrome of hypertension, severe hypokalaemia, and aldosterone
hypersecretion with suppression of plasma renin activity.
• Originally described in 1954 by Dr Jerome Conn; caused by a benign
adrenocortical tumour.
Causes and pathological features
• Aldosterone-producing adenomas are usually solitary tumours
involving only one adrenal gland. Most adenomas are small (<2cm in
diameter). Aldosterone-producing adenomas (APA) account for about
50–75% of cases of primary hyperaldosteronism (PAL).
• Other causes are idiopathic bilateral adrenal hyperplasia (25–30% of
cases) and familial hyperaldosteronism (very rare cases).
Type I familial hyperaldosteronism.• Autonomous aldosterone
hypersecretion that is suppressible by dexamethasone (mutation
in the ACTH-responsive regulatory portion of the 11b-hydroxylase
gene).
Type II familial hyperaldosteronism.• Autosomal dominant
autonomous aldosterone hypersecretion that is not suppressible by
dexamethasone.
Clinical features
PAL is characterized by:
• Hypertension. Moderate to severe and indistinguishable from other
forms of hypertension (up to 10% of new diagnoses of hypertension);
• Hypokalaemia. Signs include muscle weakness, cramping, intermittent
paralysis, headaches, polydipsia, polyuria, and nocturia.
Diagnosis and investigations
• Serum and urinary K+ levels. PAL suspected if serum K+ <3mmol/L
and urinary K
ACE inhibitors should be stopped prior to testing and any K
corrected).
• Ratio of plasma aldosterone concentration to plasma renin activity,
PAC/PRA (i.e. aldosterone/renin ratio, ARR).
Aldosterone is elevated in all cases (normal 2.2–15ng/dL).•
In PAL, plasma renin activity is suppressed.•
PAC:PRA ratio of >50 is diagnostic for PAL.•
False positive due to beta-blockers, clonidine, NSAIDS, renal •
impairment, and the contraceptive pill.
False negative due to diuretics, ACE inhibitors, renovascular •
hypertension, malignant hypertension, calcium blockers, and very
low Na
• Aldosterone suppression test.
Inability to suppress aldosterone with a high Na•
Oral Na•
and a 24h urine sample obtained.
+
excretion >40mmol/L per day. (Spironolactone or
+
diets.
+
+
(9g/day for 3 days) and 0.5mg of fl udrocortisone are given
diet.
+
defi cit
CONN’S SYNDROME
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Na+ values >200mEq with aldosterone levels >12micrograms/L are •
diagnostic.
Normokalaemia should be ensured prior to testing as the test •
may precipitate hypokalaemia. The test is positive in only 3 of 10
patients with Conn’s syndrome.
• Posture test.
• i PAC after standing for 4h in bilateral adrenal hyperplasia.
• d PAC after standing for 4h in unilateral disease (i.e. adrenocortical
adenoma, Conn’s syndrome).
APAs are unresponsive to angiotensin, but still follow the circadian •
rhythm of ACTH/cortisol.
• Adrenal imaging.
CT scan. To localize the cause.•
If a solitary unilateral macroadenoma (>1cm), no other localization •
studies are necessary and treatment is unilateral adrenalectomy.
• Adrenal venous sampling (AVS) is useful when CT localization has
failed.
Patients in whom localization is not achieved may have bilateral adrenal
hyperplasia and should be treated medically.
Treatment
Surgical treatment
Laparoscopic adrenalectomy for aldosterone-secreting adenomas.
Hypokalaemia should be corrected before the operation by the use
of spironolactone, oral potassium, or both. Normalization of BP after
treatment with spironolactone is a good predictor of the successful treatment of hypertension after unilateral adrenalectomy.
Medical treatment Spironolactone can control hypertension and correct
+
levels in the preparation for surgical treatment.
K
267
CHAPTER 6 Breast and endocrine surgery
268
Phaeochromocytoma
Key facts
• Rare—incidence of 2–8 cases per million population/year.
• Many cases probably remain undiagnosed.
Clinicopathological features
• Said to follow the ‘10% rule’:
10% are multifocal.•
10% are bilateral.•
10% are extra-adrenal.•
10% are malignant.•
10% occur in children.•
• Originate from the neural crest tissue that forms the adrenal medulla,
sympathetic chain, and visceral autonomic tissue.
• Most common active products are catecholamines (adrenaline,
dopamine, and noradrenaline), but vasopression, somatostatin, ACTH,
and oxytocin may also be secreted.
• Excess catecholamine secretion leads to characteristic episodes
(‘attacks’) of:
Headache.•
Sweating.•
Palpitations.•
Paroxysmal hypertension, tachydysrrhythmias, and a feeling of •
‘impending doom or death’ may also occur.
• Attacks can be triggered by activities causing mechanical pressure
on the tumour (e.g. physical exercise, defecation, intercourse),
by ingestion of alcohol, labour, general anaesthesia, and surgical
procedures.
• Only 50% of patients have persistent hypertension. The other 50%
have normal BP or are hypotensive between the acute episodes.
Diagnosis and investigations
Consider the diagnosis in patients with characteristic paroxysmal episodes, those with unusually labile or intermitted hypertension, those with
a family history of phaeochromocytoma or related conditions (see MEN
syndromes), and in hypertensive children.
• 24h urine collection and assessment for vanillylmandelic acid (VMA)
and noradrenaline is most accurate for diagnosis (97% sensitive).
• Clonidine suppression test (failure of urine levels to fall after clonidine
dose) confi rms the diagnosis where urine levels are borderline.
• Provocative testing (e.g. stimulation with bolus IV glucagon) is rarely
necessary and not without risk.
Localizing studies
• Thoraco-abdominal CT or MRI scanning. First-line test, especially for
adrenal and sympathetic chain tumours.
• MIBG (meta-iodo-benzyl-guanidine) scanning localizes extra-adrenal
sites not seen on CT or MRI.
PHAEOCHROMOCYTOMA
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Treatment
Medical treatment
• It is imperative to control BP prior to contemplating any surgical
intervention.
• Alpha-blockade (e.g. phenoxybenzamine 10mg bd/tds up to the
maximum dose tolerated) until hypertension controlled.
• Beta-blockade (e.g. propranolol) can be added after hypertension
controlled to control the beta-adrenergic effects (tachycardia).
• Alternative treatments with doxazosin (alpha-/beta-blocker) or calcium
channel blockers have been described, but are not widely used.
Surgical treatment
• The principle of surgery is complete resection of the tumour (with
clear negative margins if suspected of malignancy).
• Laparoscopic adrenalectomy is the treatment of choice for smaller
adrenal tumours (<8cm); open adrenalectomy for larger tumours.
• Local or radical excision is appropriate for extra-adrenal tumours.
Key revision points—anatomy of the adrenal gland
• Two main regions—cortex (steroid producing) and medulla
(catecholamine-producing).
• Three cortical zones.
Glomerulosa (outer)—mineralocorticoids (aldosterone).•
Fasciculata (middle)—glucocorticoids (cortisol).•
Reticularis (inner)—sex hormones (andosterone).•
• Blood supply.
Arterial supply is triple—mainly suprarenal artery, some from •
renal artery and inferior phrenic artery.
Venous drainage—usually single vein to the vena cava (right •
suprarenal vein is very short).
• Innervation.
Autonomic—sympathetic from greater splanchnic nerve (T12), •
parasympathetic from vagus (X) via coeliac plexus.
Somatic—from pudendal nerve (S2, 3, 4) to supply external •
urethral sphincter.
269
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Chapter 7
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Upper gastrointestinal
surgery
Upper gastrointestinal endoscopy 272
Oesophageal motility disorders 274
Pharyngeal pouch 276
Hiatus hernia 278
Gastro-oesophageal refl ux disease 280
Oesophageal tumours 282
Peptic ulcer disease 284
Gastric tumours 286
Chronic intestinal ischaemia 288
Surgery for morbid obesity 290
Small bowel tumours 292
Acute haematemesis 294
Acute upper GI perforation 296
Acute appendicitis 298
Acute peritonitis 300
Acute abdominal pain 302
Gynaecological causes of lower abdominal pain 306
Intra-abdominal abscess 308
271
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