Curriculum in Urology
Adrenal Tumours
..................................
L. Jarolima,*, J. Brezab, H. Wunderlichc
 valu 84, 15006 Prague 5, Czech Republic
Department of Urology, Charles University, V U
Department of Urology, Derer's University Hospital, Bratislava, Slovak Republic
c
Department of Urology, Friedrick Schiller University, Jena, Germany
a
b
Abstract
Benign or malignant tumours within the
adrenal glands can give rise to of a number
of hypersecretion syndromes dependent
on where the tumour is located. These
include oversecretion of aldosterone
(Conn syndrome), cortisol (Cushing syndrome) or androgens (androgenital syndrome) and adrenaline or noradrenaline
(pheochromocytoma). It is very dif®cult
to distinguish benign and malignant adrenocortical tumours. However, a number of
criteria can be applied, including size;
benign tumours of the adrenal cortex are
generally smaller than malignant tumours.
Benign tumours tend to be homogeneous
in cross-section compared with heterogeneous malignant tumours. The presence of
distant metastases is an absolute indication
of malignancy.
*
Corresponding author. Tel. ‡420-22443-4804;
Fax: ‡420-22443-4820.
E-mail address: ladislav.jarolim@lfmotol.cuni.cz
(L. Jarolim).
Open adrenalectomy remains still a safe
and effective surgical technique for treatment of complicated and recurrent adrenal
tumours. However, in experienced hands,
laparoscopic adrenalectomy is a safe and
minimally invasive surgical technique with
a short hospitalization stay and minimal
complication rate.
Generally, adrenocortical carcinomas are
curable only when they are small and localized. Adjuvant treatment regimes for more
advanced adrenocortical carcinoma involves the chemotherapeutic agent mitotane,
while conventional multiagent chemotherapy still needs to be evaluated in randomized trials.
Physiology and pathophysiology
of the adrenal glands
Adrenal physiology
Each adrenal gland consists of the cortex
and the medulla, and under normal
circumstances the mass is of the order of
0302-2838/02/$ ± see front matter # 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 3 0 2 - 2 8 3 8 ( 0 2 ) 0 0 3 6 5 - 2
Eur Urol 2003;43 (Curric Urol I±X)
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3±7 g. With regard to aetiology, morphology and function, these two regions of the
gland act as entirely distinct organs. Three
zones can be identi®ed within the adrenal
cortex: the zona glomerulosa, the zona
fasciculate and the zona reticularis. The
main products of the peripheral zone of
the cortex, the zona glomerulosa, are
mineralocorticoids (mainly aldosterone),
while secretion of glucorticoids (mainly
cortisol) predominates in the zona fasciculata and the sex steroids (androgens, progesterone and oestrogens) are secreted by
the inner most zone, the zona reticularis.
The function of the zona glomerulosa is
under the control of the rennin±aldosterone system, whereas glucorticoid and
androgen production is controlled mainly
by hypophyseal adrenocorticotropic hormone (ACTH). ACTH secretion exhibits a
diurnal rhythm, with highest levels at 6 am
and lowest levels at 10 pm, which correlates with the oscillating pattern of cortisol
plasma levels. A common precursor of steroidal hormones of the adrenal cortex is
cholesterol; these hormones are metabolised by the liver and the metabolites are
secreted by the kidneys.
The arterial blood supply (Fig. 1) to the
adrenal glands consists of the:
superior adrenal artery (from the inferior
phrenic artery),
medial adrenal artery (from the abdominal aorta),
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inferior adrenal artery (from the renal
artery).
The venal blood supply (Fig. 1) is more
complicated depending on which side the
gland is located. In the case of the right
gland, the right adrenal vein is short and
empties into the inferior vena cava; the left
adrenal vein is longer and thicker and
empties into the left renal vein. In addition,
there are multiple smaller veins.
Mineralocorticoids. Mineralocorticoids, in
particular aldosterone, control the volume
and ion content of the extracellular and
intracellular fluids. Aldosterone stimulates
reabsorption of sodium and increases
secretion of K into urine. An excess of
aldosterone causes a rise of the extracellular fluid, hypertension, hypokaliaemia and
metabolic alkalosis.
Glucocorticoids. Glucocorticoids are of
vital importance and have numerous
effects on the metabolism of saccharides
(cortisol increases gluconeogenesis), proteins (catabolic effect, increasing proteolysis and leading to a loss of the muscular
mass, skin thinning, osteoporosis) and
lipids. Glucocorticoids influence the
immune system and have anti-inflammatory and immunosuppressive effects. Due
to the effect of cortisol, the blood inflow and
glomerular filtration increase in the kidneys.
Glucocorticoids cross the blood±brain
Fig. 1. Adrenal blood supply.
Eur Urol 2003;43 (Curric Urol I±X)
Jarolim/Breza/Wunderlich
barrier and directly affect the metabolism of
the brain.
Adrenal androgens. Adrenal androgens
are converted into active hormones
(testosterone and dihydrotestosterone)
and exhibit anabolical effects, unlike the
catabolic effect of glucocortocoids. In
males, the adrenal glands contribute to
the daily production of testosterone by
about 100 mg per day, while the testicles
produce about 7000 mg of testosterone a
day. In females, the adrenal glands produce
roughly 50% of circulating testosterone.
Hypersecretion syndromes
Depending on which zona of the adrenal
cortex is involved in tumour growth
(benign or malignant) one of four hypersecretion syndromes may be displayed
clinically. The pathoanatomical ®nding
on the adrenal glands has the same basic
variants: bilateral hyperplasia of the adrenal cortex, adrenocortical adenoma, or
adrenocortical carcinoma.
Primary hyperaldosteronism (Conn syndrome). Conn syndrome results from overproduction of aldosterone by the cells
of zona glomerulosa. It occurs in adult
patients, with women affected twice as
frequently as men. In approximately 80%
of cases, the cause is benign adrenocortical
adenoma (Fig. 2) and in 20% of cases by
bilateral hyperplasia of the adrenal cortex;
very rarely the syndrome is due to an
adrenocortical carcinoma. The symptoms
of the Conn syndrome include muscular
weakness, headache, polydipsia and polyuria, arterial hypertension, hypocalaemia,
metabolic alkalosis and low plasma rennin
levels.
Cushing syndrome. Cushing syndrome is
a complex phenomenon caused by hypersecretion of cortisol. It has a typical
symptomatology, including: trunk obesity,
plethora and moon-shaped face, purple
striae on the belly, breasts and thighs,
hirsutism, acne, sexual malfunction, arterial hypertension, hyperglycaemia and
osteoporosis. Cushing syndrome can be
classified into five categories. The central
form is typified by bilateral diffuse hyperplasia of the adrenal cortex and hyperproduction of cortisol due to permanently
increased ACTH secretion. Paraneoplastic
Cushing syndrome has the same aetiopathology; the only difference is that
ACTH is produced by ACTH-producing
tumours and not by the hypophysis.
Macronodular hyperplasia of the adrenal
cortex independent of ACTH is characterized by the presence of large nodules
in the adrenal cortex and concomitant
bilateral hyperplasia of the adrenal cortex
Fig. 2. Conn's syndrome caused by small benign adenoma of the adrenal cortex.
Adrenal Tumours
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Fig. 3. Macronodular hyperplasia of the adrenal cortex in Cushing's syndrome characterized by large nodules in the
adrenal cortex and concomitant bilateral hyperplasia of the adrenal cortex.
(Fig. 3). About 20±30% of all cases of the
Cushing syndrome are the peripheral type
caused by a benign or malignant tumour of
the adrenal cortex, be (Fig. 4). In pubertal
girls, Cushing syndrome is always a
consequence of this form of tumour. The
fifth form is iatrogenic type and is typically
seen in patients receiving large doses of
corticosteroids as in organ transplantation.
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Adrenogenital syndrome. Adrenogenital
syndrome is nearly always caused by a
tumour within the zona reticularis, which
produces excessive amounts of androgens
or oestrogens and sometimes also cortisol.
Approximately 50% of cases are in children and adolescents. At postpubertal
age, the adrenogenital syndrome is far
more frequent in females than in males.
Fig. 4. Peripheral type of Cushing syndrome caused by a malignant tumour of the adrenal cortex.
Eur Urol 2003;43 (Curric Urol I±X)
Jarolim/Breza/Wunderlich
Overproduction of androgens in women
leads to virilisation manifesting itself
through hirsutism, breast atrophy, oligomenorrhagia and clitoridomegalia. In
boys, overproduction of androgens results
in pubertas praecox, while in adult men the
adrenogenital syndrome virtually cannot be
detected. Overproduction of oestrogens
causes feminization of adult men, which
may manifests itself through gynaecomasty, atrophy of the testicles and
decreased libido. In prepubertal girls, the
consequence of overproduction of oestrogens by a tumour of the adrenal gland is
precocious puberty.
The ®rst subjective symptom of adrenocortical carcinoma is pain, which may be of
the blunt persistent type caused by the
pressure of the tumour on the neighbouring organs or by of in®ltration into the
nerve bundles. Another, less frequent type
of pain is severe abdominal pain due to
acute bleeding into the tumour or from a
rupture of the adrenocortical carcinoma.
A relatively large group of adrenocortical
tumours (around 15%) comprises the socalled adrenal gland incidentalomas. These
are asymptomatic and hormonally inactive
tumours, which are found incidentally by
sonographic or radiological examination of
the abdominal organs.
Myelipoma. Myelipoma is not a true neoplasia of the adrenal gland, but rather a
metaplasia. It arises from both the adrenal
cortex and the adrenal medulla and is
completely benign, with no symptomatology. As such, it is usually detected
incidentally or when it reaches excessive
size, causing pain. It consists of lipid
cells and haematopoietic cells. It is again
totally benign and never occurs before
puberty.
Adrenomedullar tumours
The adrenal medulla is part of the sympathico-adrenal system and is composed of
chromo®nic cells, which are in principle
neurons without efferent ®bres. Theses
cells produce catecholamines, the principal ones being adrenaline and noradrenaline, which in¯uence the regulation of
numerous physiological and metabolic
Adrenal Tumours
functions. The most signi®cant disease of
the adrenal medulla is pheochromocytoma, which causes the ®fth adrenal hypersecretion
syndrome
(adrenaline or
noradrenaline). If the tumour arises from
extra-adrenal chroma®ne cells, it is referred
to as an extra-adrenal pheochromocytoma
or paraganglioma. In 80±90% of cases, the
pheochromocytoma occurs as a solitary
tumour and is considered to be an
acquired disease. In 10% of cases, it occurs
extra-adrenally, in 10% of cases, bilaterally
(sometimes as part of familial multiple
endocrine neoplasia syndrome MEN2A
and MEN2B), and in 10% of cases, it has
histological features of malignancy. A
pathognomic sign of the pheochromocytoma is paroxysmal hypertension appearing in approximately 50% of patients.
Diagnosis of adrenal lesions
The diagnosis of adrenal lesions involves
the taking of a patient medical history and
the physical examination in the ®rst
instance, followed by laboratory tests
aimed at proving overproduction of hormones of the adrenal cortex and hypophysis, their metabolites and main stimulators
of their biosynthesis (ACTH, renin).
Laboratory tests. To evaluate the disorder
of the secretion of corticoids, the level of
cortisol in plasma is assessed. It changes in a
broad physiological range (100±650 nmol/
l) and exhibits a circadian rhythm. Free
cortisol in urine is a sensitive indicator of
the concentration of free cortisol in plasma;
values range between 70 and 170 nmol per
day and rise markedly with Cushing syndrome. Further examinations are stimulation tests (ACTH tests, metopirone test,
corticoliberin test) and inhibition tests
(dexamethason test).
To evaluate the secretion of mineralocorticoids, the assessment of aldosterone in
plasma and urine, plasma renin activity
and concentration of angiotensin II are
used. To evaluate the secretion of androgens, plasma values of androstendione and
dehydroandrostendione, free testosterone
and 17-ketosteroid in urine are assessed.
With regard to pheochromocytoma, the
detection of >100 nmol per 24 h adrenaline
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and >500 nmol per 24 h noradrenaline in
urine is diagnostic.
Imaging techniques. A series of imaging
techniques of the adrenal glands may be
employed if biochemical and hormonal
abnormalities are detected. At present
the method of choice is computed
tomography (CT), in particular, spiral CT,
which can detect tumours as small as
0.5 cm in diameter. The application of
contrast during CT examination allows an
assessment of the vascularity of the tumour.
Magnetic resonance imaging (MRI) allows
the adrenal glands to be visualized in
numerous planes. Additionally, paramagnetic contrast substances can be used,
which makes it possible to resolve solid
tumours from cystic formations and to
ascertain the vascularity of the tumour. In
clinical practice, if a tumour of the adrenal
glands is proven by CT and MRI, usually no
further visualizing examinations are needed
before surgery.
In selected cases, angiography may be
performed as it provides information on
the vascular supply of the tumour as well as
information useful for surgical decisions.
Large palpable masses in right upper quadrant have been detected with this technique.
Adrenalectomy
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Adrenalectomy is indicated for syndromes of hyperfunction of either the adrenal cortex or the medulla caused by a
tumour or cortical hypertrophy (with the
exception of congenital adrenal hyperplasia), or for adrenal tumours >3 cm in diameter with no hormonal activity where
malignancy is suspected. Good surgical
results can be expected if certain rules are
adhered to. Correct pre-operative diagnosis
is essential, with con®rmation of the exact
form of the hypersecretion and its lateralization. If the macroscopic changes on the
adrenal glands are not too signi®cant, the
surgeon must work in an operative ®eld
with high visibility and haemostasis must
be optimal in order to differentiate minor
aberrations in the physiological anatomical
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relationships. In addition, pre- and postoperative care should allow the avoidance
or rapid action to be taken in the case of a
critical state due to the removal of a hormonal hyperfunction [8].
Surgical approach
The choice of incision site is made
dependent on: the size of the lesion; the
type of disease; patient habitus; and the
experience and preference of the surgeon.
The surgical technique chosen is dependent of the vascularisation of the adrenal
gland. The lateral approach is used with
smaller tumours (<5 cm). The posterior
approach goes direct to the adrenal gland,
but does not allow widening of the ®eld in
case of complications; this approach
through the 10th intercostals space is
used infrequently. The thoracoabdominal
approach is used for very large tumours,
particularly those on the right side, and is
through the eighth intercostal space. The
drawback with this incision technique is
that the pleural cavity has to be opened
and it is used mostly on the right side.
Transperitoneal approach. The transperitoneal incision is used for large tumours,
especially malignancies or pheochromocytomas due to the possibility of multifocality
(10% of cases). This approach can be used
in bilateral hyperplasias and in some
patients with Cushing's syndrome who
have extreme osteoporosis with multiple
fractures, this is the only one possible.
Sufficient time must be allowed with this
technique because the approach to the
adrenal glands is not direct.
There are a number of transperitoneal
approaches, including middle laparotomy, which has the advantage of simplicity and little bleeding and being suitable
in bilateral disease. One disadvantage is
the high post-operative rate of hernias.
Other approaches include the subcostal
incision (suited to large tumours), the
transabdominal or Chevron incision. This
is a bilateral subcostal incision, which gives
wide access to both adrenal glands; it is not
necessary to extend the incision of the
contralateral side in the case of unilateral
disease.
Jarolim/Breza/Wunderlich
Right adrenalectomy. For adrenalectomy
on the right, the posterior peritoneum is
cut just under the liver and the duodenum
freed. Gerot's fascia is opened and the
incision continued along the inferior
vena cava superiorly, taking care not to
cause injury to it (a Satinsky clamp
should be used in such cases of injury).
During a right adrenalectomy, one or two
suprarenal arteries and veins are ligated,
followed by the small medial veins and
arteries and then the central adrenal vein.
Left adrenalectomy. For adrenalectomy
on the left, after making the incisions as
for the right side, the phrenocolic
ligament is cut and the descending colon
mobilized medially. The inferior mesenteric
vein is ligated and the ligament of Treitz cut
in the case of a large tumour. At the lower
edge of the pancreas, the posterior peritoneum is cut and Gerot's fascia opened.
For the left adrenalectomy, the inferior
adrenal vein is ligated followed by the
inferior adrenal artery and the central adrenal vein. Finally, the superior adrenal vein
and artery (sometimes several branches
from the inferior phrenic vein and artery
are present) are ligated, as well as the
group of medial arteries and veins.
Laparoscopic adrenalectomy. Laparoscopic adrenalectomy has been developed
in recent years and is an ideal approach
for smaller tumours, particularly those
located in the left. The technique may
involve a retroperitoneal approach using
tissue dilation and this is the most common
technique. The major advantage of the
laparoscopic technique is comfortable
recovery with a shorter period of
hospitalisation; transfusion requirements
are less and there are fewer perioperative
complications with trained staff [4].
Laproscopic adrenalectomy is indicated
for any adrenal mass in the case of:
Hormone-inactive mass.
Hormone-active solid mass.
Recurrent central forms of Cushing's syndrome.
The procedure is contraindicated in
patients with:
Adrenal Tumours
Hernias following abdominal operations.
Severe obesity.
Concurrent significant intraperitoneal
tumours.
Coagulopathy.
Serious ischaemic heart or bronchopneumonic disease.
Advanced pregnancy.
In terms of anaesthesia, minimal use
should be made of nitrous oxide due to
the risk of overdistension. The patient
should also be catheterised. For right side
adrenalectomy, the patient is placed in the
lumbotomic position. The liver is folded cranio-medially and suf®cient diathermy of
ligamentum triangulare conducted. The
vena cava should be suf®ciently exposed
and a careful dissection conducted between
the adrenal gland and the inferior vena
cava. Careful coagulation of smaller vessels
with the monopolar scissors as well as bipolar forceps is applied. The thick central adrenal vein is isolated and clipped without any
diathermy. For left side adrenalectomy the
patient is placed in the same position as for
the right side. To proceed, lateral freeing of
the colon is conducted followed by the
freeing of the spleen and pancreas and then
careful dissection along the splenic vein.
The renal vein is localized and the incoming
main adrenal vein is isolated and freed of all
connecting tissue and clipped. When cutting the adrenal vein no diathermy is
applied. Smaller vessels including arteries
are diathermed by bipolar forceps. The
freed adrenal gland is pushed out using a
collecting bag, which is introduced through
one of the ports and removed through the
abdominal wall.
Comparative studies have demonstrated
the advantages of the laparoscopic
approach compared with traditional open
approaches. These include a more rapid
recovery, shorter hospitalisation and fewer
complications.
Partial adrenalectomy. An adrenal-sparing
technique was introduced in 1985 by
Linehan. It can be applied to patients with
von Hippel-Lindau disease who have developed multiple bilateral adrenal pheochromocytoma. The partial adrenalectomy
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technique can preserve normal adrenal
function and avoid the morbidity associated with medical adrenal replacement
[5±7].
Pre- and post-operative preparation. Preand post-operative preparation of the
patient is important. For those patients
treated for hypercortisolism and patients
undergoing
bilateral
adrenalectomy
cortisol substitution should be applied
consisting of 100 mg during surgery and
100 mg at 6 h intervals for the first day.
Parenteral administration of cortisol is
followed by peroral substitution in
descending dosage from 50 to 30 mg per
day divided in two dosages (morning 30±
20 mg; midday 20±10 mg). For patients
with pheochromocytoma or conditions
involving over production of catecholamine the situation is more complicated.
There is a potential danger from flooding of
the system with catecholamines during
tumour manipulation, resulting in a very
rapid increase in blood pressure. Consequently, attempts should be made to
dissect and ligate the central suprarenal
vein; fentolamine (Regitine) should be
applied in the case of a rapid blood
pressure rise. Dispensarization after surgery for pheochromocytoma is necessary,
with measurement of urinary metabolites of
catecholamines. Anaesthesia in these
patients also has to be modified; the use
of atropine in the pre-medication is not
advised. Halothane and curare should not
be used, whereas methoxyflurane, succinylcholine and nitrous oxide are considered suitable. Lidocaine may be applied
in the event of arrhythmias during surgery.
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Pre- and post-operative complications.
The most serious complication during
adrenalectomy is damage to the inferior
vena cava. Using the lateral approach it
is possible to open the pleural cavity
giving rise to a pneumothorax. In right
sided adrenalectomy, there is a further
danger of damage to the duodenum,
liver, hepatic veins, pancreas, stomach,
spleen and renal hilus; in the case of the
latter, a nephrectomy may sometimes
be required. Blood pressure fluctuations
Eur Urol 2003;43 (Curric Urol I±X)
during pheochromocytoma are an impor±
tant complication and have been discussed
above.
With regard to post-operative complications, poor healing may occur in patients
with hypercorticolism. In these patients, it is
necessary to remove cutaneous stitches
after the 14th day or even later. There is
also a tendency towards wound infection in
patients with steroidal diabetes and hypoglycaemia is possible in patients treated for
pheochromocytoma. Haematoma infection requiring drainage is common after
the removal of large tumours with a large
residual cavity. Intestinal adhesions and problems with peristalsis and ileus are also
potential post-operative complications.
Adrenocortical carcinoma
Demographics
Small asymptomatic adrenocortical
nodes with an average size of 2±2.5 cm
are found relatively often at autopsy, however, actual adrenocortical tumours,
benign or malignant, are rare in clinical
practice. Adrenocortical carcinomas occur
mostly in the ®rst decade of life as well as
the fourth and ®fth decades, and are
slightly more common in women.
Abnormalities of the adrenal morphology
(masses larger than one cm in diameter)
are found incidentally in approximately
1% of all patients undergoing abdominal
CT. As many as 2% of all autopsies show
adenomatous changes of the adrenal
glands and up to 38% of patients with
primary extra-adrenal malignancies have
adrenal metastases at the time of autopsy.
Adrenocortical masses are among the
most common tumours in humans. However, only a small proportion of these
tumours cause endocrine diseases such
as primary hyperaldosteronism, hypercortizism, hyperandrogenism and/or hyperoestrogenism. Adrenocortical carcinoma
is a rare tumour with an incidence of
0.5±2% of adenomas of the adrenal gland
per year. Adrenal cortical tumours producing excessive levels of steroid hormones
have an estimated incidence of approximately 4 per million people per year and
Jarolim/Breza/Wunderlich
are represented in 50% of the cases each
by adenomas and carcinomas.
In a review of about 87 series containing
1891 patients with adrenocortical carcinoma, Wooten and King [1] found a slight
female predominance (4:3); the incidence
of left adrenal tumours was 52.8% and
bilateral tumours occurred in 2.4% of
patients. Of the carcinomas detected,
59.3% were functional lesions; female
patients developed functional tumours
more often than male patients. Patients
with untreated adrenocortical carcinoma
have a very poor prognosis; the mean
survival time being only 3 months. Overall,
5-year survival in treated patients ranges
from 16 to 43%.
Aetiology
The aetiology of adrenocortical carcinoma is unknown, although one opinion
is that it arises de novo from the adrenal
cortex. Another view is that the carcinomas
develop from hyperplastic nodules in the
adrenal gland. Alterations in intercellular
communication, local production of
growth factors and cytokines, and aberrant
expression of ectopic receptors on adrenal
tumour cells have been implicated in adrenal cell growth, hyperplasia, tumour formation
and
autonomous
hormone
production. Neoplastic transformation of
the tissue of the adrenal cortex may also
be caused by chronic excessive stimulation
of ACTH. Genetic aberrations and chromosomal abnormalities, including several
chromosomal loci (loss of heterozygosity
on chromosomes l1p, 13q and 17p) and
the genes coding for p53, p57 and insulinlike growth factor II, have been reported in
adrenal tumours and may be important in
pathogenesis.
Classification and symptoms
Adrenocortical carcinoma has been classi®ed as either functional (75%) or nonfunctional (25%) tumours. Functional carcinomas are classi®ed according to
whether they produce an excess of corticosteriod, sex hormone(s), or mineralocorticoid. Excess production of corticosteroid,
androgen and oestrogen occurs more frequently than mineralocorticoid excess. In
Adrenal Tumours
Table 1. The TNM staging system for adrenocortical
carcinomas
Stage
Criteria
I
II
III
IV
<5 cm; confined to adrenal gland
>5 cm; confined to adrenal gland
Local invasion or positive lymph nodes
Local invasion and positive lymph nodes or
distant metastases
contrast to adult tumours, over 95% of
paediatric tumours are functional and
are frequently associated with congenital
abnormalities and secondary tumours.
Staging
The TNM system is used for staging of
adrenocortical carcinomas (Table 1).
Approximately 60% of carcinomas diagnosed are stage IV, with only 2% being
stage I. Unfortunately, many of the carcinomas, in particular the non-functional
type, have a large tumour size. Metastases
in adrenocortical carcinoma are common,
with the most common sites being liver,
lung and lymph nodes; other less frequent
sites are bone, omentum and diaphragm
(Table 2).
Identification of malignant
adrenocortical tumours
It is very dif®cult to distinguish benign
and malignant adrenocortical tumours.
Even in well-differentiated tumours, many
of them simultaneously exhibit morphological characteristics of both benign and
malignant tissues of the adrenal cortex.
However, a number of criteria can be
applied, including size; benign tumours
of the adrenal cortex are generally smaller
than malignant tumours. Benign tumours
tend to be homogeneous in cross-section
compared with heterogeneous malignant
Table 2. Location of metastatic disease in adrenocortical
carcinoma [3]
Site of metastases
Frequency (%)
Liver
Lung
Lymph nodes
Bone
Omentum/peritoneum
Diaphragm
Others
47
43
25
15
9
6
26
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tumours. On CT, benign adrenocortical
adenomas are a uniformly yellow, dark
red or even black colour on cross-section,
depending on fat and lipofuscin content of
the cells. In contrast, adrenocortical carcinomas, which on cross-section have a lobar
nature, are non-uniform with regions of
necroses and bleeding. This is apparent
through different tissue colours, from yellow, whitish and red to brown and dark.
Nevertheless, the presence of distant
metastases are the absolute indication of
malignancy.
Treatment
Surgical treatment has been described
above. In terms of chemotherapy for the
disease, the most commonly used agent is
mitotane, which causes necroses after
being taken up by the adrenal glands.
The speci®c cytotoxic activity of mitotane
on the adrenal glands has lead to its use in
both primary and adjuvant therapy settings. Response rates of 14±35% have been
reported from a number of trials. Survival
rates of 13% after 2 years have been
reported by Venkatesh et al. [2], however,
signi®cantly longer survival bene®ts were
possible when mitotane serum blood levels
were maintained above 14 mg/l.
Mitotane therapy has been associated
with signi®cant toxicity. Gastrointestinal
symptoms include nausea and anorexia,
while neuromuscular toxicity includes
lethargy, dizziness, somnolence and depression. Almost all patients on this mitotane
therapy will experience adrenal insuf®ciency and steroid replacement should be
routinely used. Fludrocortisone acetate
should be given at an initial dose of
0.1 mg three times per week, adjusted to
0.1 mg per day according to serum electrolytes and weight gain. Other therapeutic
regimens that have been evaluated include
the cisplatin and etosposide combination
and suramin. However, none have proved
as effective as mitotane.
Follow-up
Recurrences and metastases in adrenocortical carcinoma are common and occur
in 85% of patients after complete resection. In the follow-up, careful histories and
physical examination as well as CT of the
abdomen and chest X-ray should be performed four times each year for the ®rst 2
years and thereafter twice each year.
Patients with an elevated serum level of
dehydroepiandrosterone can be followed
with this marker. Patients with a tumour
producing elevated levels of urinary corticosteroids should have their urine checked
every 3±6 months. A rise of urinary steroid
levels often signals a recurrence ahead of
symptom appearance, clinical ®ndings or
®ndings in radiological examinations.
References
[1] Wooten MD, King DK. Adrenal cortical carcinoma.
Cancer 1993;72:3145±55.
[2] Venkatesh S, Hickey RC, Sellin RV, Fernandez JF,
Samaan NA. Adrenal cortical carcinoma. Cancer
1989;64:765±9.
[3] Pommier RF, Brennan MF. An eleven-year experience
with adrenocortical carcinoma. Surgery 1992;112:
963±71.
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Jarolim/Breza/Wunderlich