ANATOMY,PHYSIOLOGY OF ADRENAL GLAND......ADRENAL TUMORS & THEIR MANAGEMENT

1. ADRENAL GLAND TUMORS
DR.SUNIL KAMBLE
ASSISTANT PROFESSOR
DEPT.OF GEN.SURGERY
MNR MEDICAL COLLEGE,SANGAREDDY

2. HISTORICAL BACKGROUND
• Eustachius provided the first accurate anatomic account of
the adrenals in 1563.
• The anatomic division of the adrenals into the cortex and
medulla was described by Cuvier in 1805.
• Thomas Addison in 1855 described the features of adrenal
insufficiency
• DeCreccio provided the first description of congenital adrenal
hyperplasia (CAH) occurring in a female
pseudohermaphrodite in 1865.
• Pheochromocytomas were first identified by Frankel in 1885,
but were not named as such until 1912 by Pick, who noted
the characteristic chromaffin reaction of the tumor cells.

3. • Adrenaline was identified as an agent from the adrenal
medulla that elevated blood pressure in dogs and was named
epinephrine in 1897.
• The first successful adrenalectomies for pheochromocytoma
were performed by Roux in Switzerland, and Charles Mayo in
the United States
• In 1932, Harvey Cushing described 11 patients who had moon
facies, truncal obesity, hypertension, and other features of the
syndrome that now bears his name.
• Cortisone was first synthesized by Kendall.
• Aldosterone was identified in 1952, and the syndrome
resulting from excessive secretion of this mineralocorticoid
was first described in 1955 by Conn.

4. EMBRYOLOGY
• The adrenal or suprarenal glands are two endocrine organs in
one; an outer cortex and an inner medulla, each with distinct
embryologic, anatomic, histologic, and secretory features.
• The cortex originates around the fifth week of gestation from
mesodermal tissue near the gonads on the adrenogenital
ridge .
• Therefore, ectopic adrenocortical tissue may be found in the
ovaries, spermatic cord, and testes.
• The cortex differentiates further into a thin, definitive cortex
and a thicker, inner fetal cortex.

5. • The latter is functional and produces fetal adrenal
steroids by the eighth week of gestation, but undergoes
involution after birth, resulting in a decrease in adrenal
weight during the first three postpartum months.
• The definitive cortex persists after birth to form the
adult cortex over the first 3 years of life.
• In contrast, the adrenal medulla is ectodermal in origin
and arises from the neural crest.
• At around the same time as cortical development, neural
crest cells migrate to the para-aortic and paravertebral
areas and toward the medial aspect of the developing
cortex to form the medulla.

6. • Most extra-adrenal neural tissue regresses but may persist at
several sites.
• The largest of these is located to the left of the aortic
bifurcation near the inferior mesenteric artery origin and is
designated as the organ of Zuckerkandl.
• Adrenal medullary tissue also may be found in neck, urinary
bladder, and para-aortic regions.
• Several factors are involved in adrenal development and
include insulin-like growth factor 2; gastric inhibitory peptide;
and the dosage-sensitive, sex-reversal adrenal hypoplasia
(DAX1) gene.

7. CROSS-SECTION OF THE EMBRYO
DEPICTING ADRENAL DEVELOPMENT
(1) Neural tube,
(2) Chorda,
(3) Aorta,
(4) Base of the mesentery,
(5) Digestive tube,
(6) Adrenal cortex,
(7) Undifferentiated gonad,
(8) Mesonephros, and
(9) Neural crest.
Cells migrate from the neural crest to
form the ganglia of the sympathetic
trunk (A), sympathetic plexi (B), and
the adrenal medulla and paraganglia
(C).

8. ANATOMY
• Anatomy was first described in 1563
• Paired retroperitoneal organs composed of a cortex and
medulla
• Contained in its own sub-compartment within Gerota’s fascia
• Gross examination reveals
– Cortex = spiculated, mustard yellow colour
– Medulla = central, brown colour
• Weight ~ 4 - 5 g each

9. • Size
– Length = 4 - 6 cm
– Width = 2 - 3 cm
• Right adrenal gland is triangular in shape
• Left adrenal gland is crescent shaped
• They may sit either immediately superior to kidney, “capping”
the upper pole, or superio-medially to upper pole, “cradled”
by kidney just above renal vessels.

14. Cross-section of a normal
adrenal gland
• The inner, very thin
layer between the two
dark lines (zona
reticularis) is the
adrenal medulla

15. RELATIONS
• Located within Gerota fascia at level of 11th and 12th ribs
• Gerota’s fascia connects them to upper pole of kidney
• Located cephalad to upper pole of kidneys and anterior to
crus of diaphragm
• The right adrenal gland tends to lie more cephalad than the
left adrenal gland

16. • Right adrenal is bounded
– Anteriorly = Liver
– Posterior = Diaphragm
– Superior = Diaphragm
– Inferio-laterally = Right Kidney
– Medially = IVC
– Medial aspect of the gland is often retrocaval
– Right adrenal vein enters IVC in a posterolateral position

18. • Position of the adrenal
glands (hatched) in the
retroperitoneum

21. • Left adrenal gland is bounded
– Anteriorly = Stomach, Pancreas (Body), Splenic
Vessels
– Posteriorly = Diaphragm
– Superiorly = Spleen
– Inferiorly = Kidney
– Medially = Aorta

22. • Left adrenal is more elongated than right and will lie in a
more superomedial position to the kidney. This tends to
place the gland closer to the left renal hilum, and these
structures must be accounted for during dissection.
• Close juxtaposition of these organs to adrenal explains why
lesions of adjacent organs, such as leiomyomas of greater
curvature of stomach, may be confused for an adrenal
mass.

23. BLOOD SUPPLY
ARTERIAL SUPPLY
• 3 Arterial sources of flow:
– Branches from Inferior Phrenic Artery  Superior Adrenal
A.
– Direct visceral branches from Aorta  Middle Adrenal
A.
– Branches from I/L Renal Artery  Inferior
Adrenal A.
• The main adrenal arteries  branch to form a subcapsular
plexus
• From subcapsular plexus
– Some branches continue directly  to medulla
– Others form sinusoids  to cortex

25. VENOUS DRAINAGE
• Medullary veins coalesce to form adrenal vein
• Adrenal vein is surrounded by medullary tissue within the gland.
• Single main vein on each side
• Most important surgical structure
• Right adrenal vein
– Short
– Drains directly into post IVC
• Left adrenal vein
– Long as compared to right adrenal vein
– Joined by Inferior Phrenic vein prior to draining into Left Renal Vein
• The overlapping of both arterial and venous anatomy makes partial
adrenalectomy possible with little risk of subsequent adrenal infarction

26. NERVE SUPPLY
• Sympathetic
– Medulla
• Preganglionic sympathetic fibers from sympathetic
trunk directly to chromaffin cells
– Cortex
• Postganglionic fibers from splanchnic ganglia
• Parasympathetic to adrenal cortex and medulla
– Not well defined
– Branches from Vagus nerve may be present

27. LYMPHATICS
• Right  Para-caval Lymph Nodes
• Left  Para-aortic Lymph Nodes
• lateral aortic

28. • Is divided into 3 zones in the adult gland:
– Zona Glomerulosa
– Zona Fasciculata
– Zona Reticularis
• Is divided onto 4 zones in the fetal gland:
– The three zones of the permanent adult cortex constitutes
only 20% of the fetal gland’s size.
– The remaining zone (fetal cortex) comprises up to 80% of
gland’s size during fetal life.
HISTOLOGY

29. • Each adrenal gland is enclosed within a fibrous capsule
• Directly beneath the capsule is the cortex, which comprises
three zones:
– Zona Glomerulosa (Outermost Layer)
• Small polyhedral cells with scant eosinophilic cytoplasm
and dark round nuclei.
– Zona Fasciculata
• Broad layer of large pale cells arranged in vertical
columns beneath glomerulosa
 Zona Reticularis (Innermost layer)
• Round dark staining cells

32. Adrenal
Histology
Capsule
Glomerulosa
Fasiculata
Reticularis
Medulla

34. LAYERS OF ADRENAL GLAND

36. ADRENAL PHYSIOLOGY

37. Adrenal
Cortex
Endocrine
Medulla
Neurocrine

38. ADRENAL PHYSIOLOGY
• Cholesterol, derived from the plasma or synthesized in
the adrenal, is the common precursor of all steroid
hormones derived from the adrenal cortex.
• Cholesterol initially is cleaved within mitochondria to 5--
pregnolone, which in turn is transported to the smooth
endoplasmic reticulum where it forms the substrate for
various biosynthetic pathways leading to steroidogenesis
.

40. SYNTHESIS OF ADRENAL STEROIDS
The enzymes involved are
• (1) p450scc (cholesterol side chain cleavage),
• (2) 3-hydroxysteroid dehydrogenase,
• (3) p450c21 (21-hydroxylase),
• (4) p450c11 (11-hydroxylase),
• (5) p450c11AS (aldosterone synthase),
• (6) p450c17 (17-hydroxylase activity),
• (7) p450c17 (17,20-lyase/desmolase activity), and
• (8) sulfokinase.
• DHEAS = Dehydroepiandrosterone sulfate.

41. ADRENAL GLAND TUMORS
• Divided into tumors arising from adrenal cortex and arising
from adrenal medulla
Adrenal cortex
1.Cushings syndrome
2.Primary hyperaldosteronism (Conn’s syndrome)
3.Adrenogenital syndrome
4.Adrenal carcinoma
5.Incidentalomas

42. TUMORS ARISING FROM ADRENAL
MEDULLA
Neoplasm of chromaffin cells
Pheochromocytoma
Neoplasms of the sympathetic neurons
i. Neuroblastoma
ii.Ganglioneuroma

43. 1.CUSHING’S SYNDROME
• Hypersecretion of cortisol caused by endogenous production
of corticosteroids is known as cushing’s syndrome
• It can be either ACTH-dependent or ACTH-independent in
origin.
• The most common cause (85%) of ACTH-dependent Cushing’s
syndrome is Cushing’s disease resulting from a pituitary
adenoma that secretes an excessive amount of ACTH.
• Ectopic ACTH-producing tumours (small cell lung cancer,
foregut carcinoid) and CRH-producing tumours (medullary
thyroidcarcinoma, neuroendocrine pancreatic tumour) are
more infrequent causes of ACTH-dependent Cushing’s
syndrome.

45. • In about 15% of patients, an ACTH-independent Cushing’s
syndrome (low ACTH levels) is caused by a unilateral
adrenocortical adenoma.
• Adrenocortical carcinoma and bilateral macronodular or
micronodular hyperplasia represent rare causes of
hypercortisolism.
CLINICAL SYMPTOMS
• The typical patient is characterised by a facial plethora, a
buffalo hump and a moon face in combination with
hypertension, diabetes and central obesity
• However, clinical signs can be minimal or absent in patients
with subclinical Cushing’s syndrome.

46. CLINICAL FEATURES OF CUSHING’S
SYNDROME
• Weight gain/central obesity
• Diabetes
• Hirsuitism
• Hypertension
• Skin changes { abdominal striae , facial plethora ,ecchymosis ,
acne }
• Muscle weakness
• Menstrual irregularity/impotence
• Depression/mania
• Osteoporosis
• hypokalaemia

48. DIAGNOSIS
Biochemical test
1.Measurement of 24 hours urinary free cortisol
• Urinary excretion of free cortisol is directly proportional
to the amount of free cortisol in the plasma
2.Serum ACTH levels discriminate ACTH-dependent from
ACTH-independent disease.
• Elevated or normal ACTH levels provide evidence for an
ACTHproducing pituitary tumour (85%) or ectopic ACTH
production

49. 3.Urinary 17-ketosteroid levels help to distinguish an adrenal
adenoma from a carcinoma
• Low levels {<10mg/day} suggest an adrenal adenoma and
high levels {>60mg/day} suggest adrenal cancer or ectopic
ACTH syndrome
4.Dexamethasone suppression test is the most useful test in
establishing the cause of hypercortisolism and in determining
whether the cause is pituitary dependent or independent

50. RADIOLOGICAL INVESTIGATIONS
1.CT scan : Adrenal ct can reliably distinguish cortical hyperplasia from
tumor
• Ct has great sensitivity{>95%},less specific
• Can be used to image the primary tumor,plus local and distant
metastasis in patients with adrenocortical cancer
2.MRI : Used to distinguish adrenal adenoma and carcinoma and a
pheochromocytoma
• Adrenal adenomas appear darker than the liver on T2 weighted
imaging
• Carcinomas whether primary adrenocortical or metastatic appear
as bright or slightly brighter than the liver on T2 imaging
• Pheochromocytomas appear much brighter {3x} than liver on T2
weighted imaging

51. 3.Radio isotope imaging of the adrenals with labelled
iodocholesterol such as 131 1-6 beta –iodomethyl
norcholesterol,can be useful in distinguishing adrenal adenoma
from hyperplasia

52. TREATMENT
• Medical therapy with metyrapone or ketoconazole reduces
steroid synthesis and secretion and is used in patients with
severe hypercortisolism or if surgery is not possible.
• ACTH-producing pituitary tumours are treated by trans-
sphenoidal resection or radiotherapy.
• If an ectopic ACTH source is localised, resection will cure
hypercortisolism.

53. • Bilateral asymmetrical
hyperplasia of the adrenal
glands (arrows) in a patient
with Cushing’s syndrome

54. • A unilateral adenoma is treated by adrenalectomy.
• In cases of bilateral ACTH-independent disease , bilateral
adrenalectomy is the primary treatment.
• Patients with an ectopic ACTH-dependent Cushing’s
syndrome and an irresectable or unlocalised primary tumour
should be considered for bilateral adrenalectomy as this
controls hormone excess.
• Subclinical Cushing’s syndrome caused by unilateral adenoma
is treated by unilateral adrenalectomy.

55. PREOPERATIVE MANAGEMENT
1.Patients with Cushing’s syndrome are at an increased risk of
hospital-acquired infection and thromboembolic and
myocardialcomplications.
2.Therefore, prophylactic anti-coagulation and the use of
prophylactic antibiotics are essential.
3.Cushing-associated diseases (diabetes, hypertension) must be
controlled by medical therapy preoperatively.

56. POSTOPERATIVE MANAGEMENT
1.Supplemental cortisol should be given after surgery.
2.In total, 15 mg h–1 is required parenterally for the first 12
hours followed by a daily dose of 100 mg for 3 days, which is
gradually reduced thereafter.
3.After unilateral adrenalectomy, the contralateral suppressed
gland needs up to 1 year to recover adequate function.
4.In 10% of patients with Cushing’s disease who undergo a
bilateral adrenalectomy, the pituitary adenoma converts into an
aggressive tumour (Nelson’s syndrome).

57. ADRENAL METASTASES
• Adrenal metastases are discovered at autopsy in one-third of
patients with malignant disease (less frequently during life).
• In declining frequency, the most common primary tumours
are breast, lung, renal, gastric, pancreatic, ovarian and
colorectal cancer.
• In selected cases an adrenalectomy can be performed

58. 2.PRIMARY HYPERALDOSTERONISM-
CONN’S SYNDROME
Incidence
• Primary hyperaldosteronism (PHA) is defined by
hypertension, hypokalaemia and hypersecretion of
aldosterone.
• In PHA, plasma renin activity is suppressed.
• Among patients with hypertension the incidence of
hypokalaemic PHA is approximately 2%.
• Recent studies have revealed that up to 12% of
hypertensive patients have PHA with normal potassium
levels.

59. PATHOLOGY
• The most frequent cause of PHA with hypokalaemia is a
unilateral adrenocortical adenoma (Conn’s syndrome).
• In 20–40% of cases, bilateral micronodular hyperplasia is
causative.
• Rare causes of PHA are bilateral macronodular hyperplasia,
glucocorticoid-suppressible hyperaldosteronism or
adrenocortical carcinoma.
• In the subset of patients with normokalaemic PHA, 70% have
hyperplasia and 30% unilateral adenoma.

60. • A Conn’s adenoma (arrow)
of the left adrenal gland;
note the V-shaped normal
adrenal tissue.

61. CAUSES OF PRIMARY
HYPERALDOSTERONISM (%)
SCREENING
CAUSE SELECTIVE NONSELECTIVE
Aldosterone producing adenoma 60 30
Bilateral adrenal hyperplasia {ideopathic
hyperaldosteronism}
35 65
Aldosterone –producing adrenocortical carcinoma <1 <1
Familial hyperaldosteronism
Type 1 {glucocorticoid remediable aldosteronism} <1 <1
Type 2 {non-glucocorticoid remediable aldosteronism} <1 <1

62. CLINICAL FEATURES
• Most patients are between 30 and 50 years of age with a
female predominance.
• Apart from hypertension and hypokalaemia, patients
complain of non-specific symptoms: headache, muscle
weakness, cramps, intermittent paralysis, polyuria, polydypsia
and nocturia.

63. DIAGNOSIS
• The key feature of the biochemical diagnosis is the
assessment of potassium level and the aldosterone to plasma
renin activity ratio.
• Antihypertensive and diuretic therapy, which
causehypokalaemia and influence the renin–angiotensin–
aldosterone system, have to be discontinued.
• Once the biochemical diagnosis is confirmed, MRI or CT
should be performed to distinguish unilateral from bilateral
disease.
• Conn’s adenomas usually measure between 1 and 2 cm and
are detected by CT with a sensitivity of 80–90% .
• Micronodular changes and small adenomas are often
underdiagnosed.

64. • An apparent unilateral mass could be a non-functioning
tumour in a patient with bilateral micronodular hyperplasia.
• Therefore, selective adrenal vein catheterisation is warranted
before a decision on non-surgical or surgical treatment is
made.
• During selective adrenal vein catheterisation, samples are
obtained from the vena cava and from both adrenal veins and
the aldosterone to cortisol ratio (ACR) is determined in each
sample.
• A significant difference in the ACR ratio on one side indicates
unilateral disease

65. • Computerised tomography
scan of a Conn’s adenoma
of the left adrenal gland
(arrowheads).

66. Appearance of aldosteronoma
on anatomic imaging
• A, Venous phase, contrast-
enhanced CT demonstrating
a 2-cm left aldosteronoma
(arrow).
• B, Late arterial phase,
coronal CT demonstrating a
1.7-cm left aldosteronoma
(arrow) and a normal right
adrenal gland (arrowhead).

67. TREATMENT
• The first-line therapy for PHA with bilateral hyperplasia is
medical treatment with spironolactone.
• In most cases supplemental antihypertensive medication is
necessary.
• Unilateral laparoscopic adrenalectomy is an effective therapy
in patients with clear evidence of unilateral or asymmetrical
bilateral disease.
• A subtotal resection is favoured in the case of a typical Conn’s
adenoma.
• In 10–30% of patients who undergo an adrenalectomy,
hypertension persists despite adequate diagnostic work-up
and treatment.

68. 3.CONGENITAL ADRENAL HYPERPLASIA
(ADRENOGENITAL SYNDROME)
• Virilisation and adrenal insufficiency in children are pathognomonic
of congenital adrenal hyperplasia (CAH).
• Autosomal recessive disorder caused by a variety of enzymatic
defects in the synthetic pathway of cortisol and other steroids from
cholesterol.
• The most frequent defect (95%) is the 21-hydroxylase deficiency,
which has an incidence of 1 in 5000 live births.
• Excessive ACTH secretion is caused by the loss of cortisol and this
leads to an increase in androgenic cortisol precursors and to CAH.
• CAH may present in girls at birth with ambiguous genitalia or as
late-onset disease at puberty.
• Hypertension and short stature, caused by the premature
epiphyseal plate closure, are common symptoms.
• Affected patients are treated by replacement of cortisol and with
fludrocortisone.

69. 4.ADRENOCORTICAL CARCINOMA
Incidence
• Adrenocortical carcinoma is a rare malignancy with an
incidence of 1–2 cases per 1 000 000 population per year
and a variable but generally poor prognosis.
• A slight female predominance is observed (1.5:1).
• The age distribution is bimodal with a first peak in
childhood and a second between the fourth and fifth
decades.

70. PATHOLOGY
• Criteria for malignancy are tumour size, the presence of
necrosis or haemorrhage and microscopic features such as
capsular or vascular invasion.
• These should be assessed in terms of a microscopic diagnostic
score.
• Additional information is provided by immunohistochemistry.
• The macroscopic features are commonly multinodularity and
heterogeneous structure.

71. • Adrenocortical carcinoma
that caused Cushing’s
syndrome and virilisation in
a female patient.

72. CLINICAL PRESENTATION
• Approximately 60% of patients present with evidence of
steroid hormone excess (Cushing’s syndrome).
• Patients with nonfunctioning tumours frequently complain of
abdominal discomfort or back pain caused by large tumours.
• However, with increasing use of abdominal imaging, a
growing number of adrenocortical carcinomas are detected
incidentally.

73. DIAGNOSIS
• The diagnostic work-up should include measurements of
DHEAS, cortisol and catecholamines to exclude a
phaeochromocytoma and a dexamethasone suppression test.
• MRI and CT are equally effective in distinguishing
adrenocortical adenoma from carcinoma.
• MRI angiography is useful to exclude tumour thrombus in the
vena cava, which must be excluded before adrenalectomy.
• As distant metastases are frequentlypresent, a CT scan of the
lung is recommended.

74. • The World Health Organization classification of 2004 is based
on the McFarlane classification and defines four stages:
• Tumours < 5 cm(stage I)
• > 5 cm (stage II),
• Locally invasive tumours (III)
• Tumours with distant metastases (IV)

75. • Axial magnetic resonance
imaging of an
adrenocortical carcinoma
on the right side invading
the inferior vena cava and
invading the superior aspect
of the kidney displacing the
liver laterally and
superiorly{d}

76. • CT scan demonstrating a 10-
cm left adrenocortical
carcinoma.
• Note the areas of central
necrosis (arrow).

77. • Magnetic resonance
imaging of adrenocortical
carcinoma (arrow) in a
patient with cortisol and
testosterone excess.

78. TREATMENT
• Complete tumour resection (R0) is associated with favourable
survival and should be attempted whenever possible.
• In order to prevent tumour spillage and implantation
metastases, the capsule must not be damaged.
• En bloc resection with removal of locally involved organs is
often required and in case of tumour thrombus in the vena
cava the assistance of a cardiac surgeon is sometimes needed.
• Laparoscopic adrenalectomy is associated with a high
incidence of local recurrence and cannot be recommended.
• Tumour debulking plays a role in functioning tumours to
control hormone excess.

79. • Patients should be treated postoperatively with mitotane
alone or in combination with etoposide, doxorubicin and
cisplatin in 30% and 50% of cases respectively.
• Adjuvant radiotherapy may reduce the rate of local
recurrence.
• After surgery, restaging every 3 months is required as the risk
of tumour relapse is high.
• Prognosis depends on the stage of disease and complete
removal of the tumour.
• Patients with stage I or II disease have a 5-year survival rate
of 25% whereas patients with stage III and stage IV disease
have 5-year survival rates of 6% and 0% respectively.

80. 5.INCIDENTALOMA
Definition
• A clinically unapparent mass detected incidentally by
imaging studies conducted for other reasons.
Incidence
• The prevalence of adrenal masses in autopsy studies
ranges from 1.4% to 8.7% and increases with age.
• Incidentalomas may be detected on imaging studies in
4% of patients.
• More than 75% are non-functioning adenomas but
Cushing’s adenomas, phaeochromocytomas and even
adrenocortical carcinomas may be present.

81. PREVALENCE OF NON-FUNCTIONING AND FUNCTIONING TUMOURS IN
PATIENTS WITH INCIDENTALOMAS
Tumour Prevalence{%}
Non-functioning adenoma 78
Cushing’s adenoma 7
Adrenocortical carcinoma 4
Phaeochromocytoma 4
Myelolipoma 2
Cyst 2
Metastasis 2
Conn’s adenoma 1

82. DIAGNOSIS
• When an incidentaloma is identified, a complete history and clinical
examination are required.
• A biochemical work-up for hormone excess and sometimes additional
imaging studies are also needed
• The main goal is to exclude a functioning or malignant adrenal tumour.
Hormonal evaluation includes:
• Morning and midnight plasma cortisol measurements;
• A 1-mg overnight dexamethasone suppression test;
• 24-hour urinary cortisol excretion (optional);
• 24-hour urinary excretion of catecholamines, metanephrines
or plasma-free metanephrines;
• Serum potassium, plasma aldosterone and plasma renin activity;
• Serum DHEAS, testosterone or 17β-hydroxyestradiol (virilising
or feminising tumour).

83. • For evaluation of malignancy, computerised tomography (CT)
or magnetic resonance imaging (MRI) should be performed in
all patients with adrenal masses, followed by fine-needle
aspiration cytology after a phaeochromocytoma has been
excluded.
• The likelihood of an adrenal mass being an adrenocortical
carcinoma increases with the size of the mass (25% > 4 cm).
• Adrenal metastases are likely in patients with a history of
cancer elsewhere.

84. Adrenal gland biopsy
• Never biopsy an adrenal mass until
phaeochromocytoma has been biochemically
excluded
• The indication for adrenal biopsy is to confirm
adrenal gland metastasis

85. ADRENAL MEDULLA
1.Phaeochromocytoma
(adrenal paraganglioma)
Definition
• This is a tumour of the
adrenal medulla, which is
derived from chromaffin
cells and which produces
catecholamines.

86. AETIOLOGY
• The prevalence of phaeochromocytoma in patients with
hypertension is 0.1–0.6% with an overall prevalence of 0.05% in
autopsy series.
• In total, 4% of incidentalomas are phaeochromocytomas.
• Sporadic phaeochromocytomas occur after the fourth decade
whereas patients with hereditary forms are diagnosed earlier.
• Phaeochromocytoma is known as the ‘10% tumour’
• as 10% of tumours are inherited,
• 10% are extra-adrenal,
• 10% are malignant,
• 10% are bilateral and
• 10% occur in children.

87. HEREDITARY PHAEOCHROMOCYTOMAS
Multiple endocrine neoplasia type 2 (MEN 2)
An autosomal dominant inherited disorder that is caused
by activating germline mutations of the RET proto-
oncogene.
Familial paraganglioma (PG) syndrome
Glomus tumours of the carotid body and extra-adrenal
paraganglioma are characteristic in this hereditary tumour
syndrome, which is caused by germline mutations within the
succinate dehydrogenase complex subunit B (SDHB) and SDHD
genes.

88. Von Hippel–Lindau (VHL) syndrome
• Those affected can develop early-onset bilateral kidney
tumours, phaeochromocytomas, cerebellar and spinal
haemangioblastomas and pancreatic tumours. Patients
have a germline mutation in the VHL gene.
Neurofibromatosis (NF) type 1
• Phaeochromocytomas in combinationwith fibromas on the
skin and mucosae (‘café-au-lait’ skin spots) are indicative of a
germline mutation in the NF1 gene

89. PATHOLOGY
• Phaeochromocytomas are greyish-pink on the cut surface and
are usually highly vascularised.
• Areas of haemorrhage or necrosis are often observed.
• Microscopically, tumour cells are polygonal but the
configuration varies considerably.
• The differentiation between malignant and benign tumours is
difficult, except if metastases are present.
• An increased PASS (phaeochromocytoma of the adrenal
gland scale score) indicates malignancy as does a high number
of Ki-67-positive cells, vascular invasion or a breached capsule

90. • Phaeochromocytomas may also produce calcitonin,
ACTH,vasoactive intestinal polypeptide (VIP) and parathyroid
hormone-related protein (PTHrP).
• In patients with MEN 2, the onset of phaeochromocytoma is
preceded by adrenomedullary hyperplasia, usually bilateral.
• Phaeochromocytoma is rarely malignant in MEN 2.

91. CLINICAL FEATURES
• Symptoms and signs are caused by catecholamine excess and can
be continuous or intermittent .
• In total, 90% ofpatients with the combination of headache,
palpitations and sweating have a phaeochromocytoma.
• Paroxysms may be precipitated by physical training, induction of
general anaesthesia and numerous drugs and agents (contrast
media, tricyclic antidepressive drugs, metoclopramide and opiates).
• Hypertension may occur continuously, be intermittent or absent.
• A subset of patients is asymptomatic.
• More than 20% of apparently sporadic phaeochromocytomas are
caused by germline mutations in the RET, SDHB, SDHD and NF1
genes; genetic testing for these genes is therefore generally
recommended

92. CLINICAL SIGNS OF PHAEOCHROMOCYTOMA
Symptoms Prevalence{%}
Hypertension 80-90
paroxysmal 50-60
continuous 30
Headache 60-90
Sweating 50-70
Palpitation 50-70
Pallor 40-45
Weight loss 20-40
Hyperglycemia 40
Nausea 20-40
Psychological effects 20-40

93. DIAGNOSIS
• The first step in the diagnosis of a phaeochromocytoma is the determination of
adrenaline, noradrenaline, metanephrine and normetanephrine levels in a 24-hour
urine collection.
• Catecholamine levels that exceed the normal range by 2–40 times will be found in
affected patients.
• Determination of plasma-free metanephrine and normetanephrine levels is a
recently available test that has a high sensitivity.
• Biochemical tests should be performed at least twice.
• The biochemical diagnosis is followed by the localisation of the
phaeochromocytoma and/or metastases.
• MRI is preferred because contrast media used for CT scans can provoke paroxysms.
• Classically, phaeochromocytomas show a ‘Swiss cheese’ configuration .
• 123I-MIBG (metaiodobenzylguanidine) single-photon emission computerised
tomography (SPECT) will identify about 90% of primary tumours and is essential
for the detection of multiple extra-adrenal tumours and metastases .

94. • Magnetic resonance
imaging of a sporadic
phaeochromocytoma of the
left adrenal gland
(arrowheads).

95. • Meta-iodobenzylguanidine
(MIBG) single-photon
emission computerised
tomography scan of a
phaeochromocytoma of the
left adrenal gland (arrow)

96. • Coronal view of a 10 cm left
adrenal
pheochromocytoma.
• Despite this large mass, it is
well circumscribed and can
be removed
laparoscopically via hand
port incision.

97. TREATMENT
• Laparoscopic resection is now routine in the treatment of
phaeochromocytoma.
• If the tumour is larger than 8–10 cm or radiologicalsigns of
malignancy are detected an open approach should be
considered

98. PREOPERATIVE
• Once a phaeochromocytoma has been diagnosed, an α-
adrenoreceptor blocker (phenoxybenzamine) is used to block
catecholamine excess and its consequences during surgery.
• With adequate medical pre-treatment, the perioperative
mortality rate has decreased from 20–45% to less than 3%.
• A dose of 20 mg of phenoxybenzamine initially should be
increased daily by 10 mg until a daily dose of 100–160 mg is
achieved and the patient reports symptomatic postural
hypotension.
• Additional β- blockade is required if tachycardia or
arrhythmias develop; this should not be introduced until the
patient is α-blocked.

99. PEROPERATIVE
• With adequate α-blockade preoperatively, anaesthesia should
not differ from that used in patients with a non-functioning
adrenal tumour; however, in some patients, dramatic changes
in heart rate and blood pressure may occur and require
sudden administration of pressor or vasodilator agents.
• A central venous catheter and invasive arterial monitoring are
essential.
• Special attention is required when the adrenal vein is ligated
as a sudden drop in blood pressure may occur.
• Rarely, the infusion of large volumes of fluid or even
administration of adrenaline can be necessary

100. GROSS APPEARANCE OF
PHEOCHROMOCYTOMA
• A, Open resection of a left
para-aortic extra-adrenal
pheochromocytoma via an
infracolic approach.
• The patient’s head is to the
right.
• The tumor is being rotated
medially by the surgeon’s
hand to reveal the left
ureter, indicated by forceps.
• B, Left adrenal
pheochromocytoma.

101. POSTOPERATIVE
• Patients should be observed for 24 hours in the intensive care
unit (ICU) as hypovolaemia and hypoglycaemia may occur.
• Biochemical cure should be confirmed by an assessment of
catecholamines 2–3 weeks postoperatively.
• Lifelong yearly biochemical tests should be performed to
identify recurrent, metastatic or metachronous
phaeochromocytoma.

102. PHEOCHROMOCYTOMA
• Obtain a secure biochemical diagnosis
• Exclude family history
• Diagnosis confirmed , treat with alpha-blockers
• Plan surgical excision
• Yearly lifelong follow-up

103. DIAGNOSTIC TESTS FOR VARIOUS
CATEGORIES OF ADRENAL NEOPLASMS

104. MALIGNANT PHAEOCHROMOCYTOMA
Definition
• Approximately 10% of phaeochromocytomas are
malignant.
• This rate is higher in extra-adrenal tumours
(Paragangliomas).
• The diagnosis of malignancy implies metastases of
chromaffin tissue, most commonly to lymph nodes, bone
and liver.
• About 8% of patients with an apparently benign
phaeochromocytoma subsequently develop metastases.

105. TREATMENT
• Surgical excision is the only chance for cure.
• Even in patients with metastatic disease, tumour debulking
can be considered to reduce the tumour burden and to
control the catecholamine excess.
• Symptomatic treatment can be obtained with α-blockers.
• Mitotane should be started as adjuvant or palliative
treatment.
• Treatment with 131I-MIBG or combination chemotherapy has
resulted in a partial response in 30% and an improvement of
symptoms in 80% of patients.
• The natural history is highly variable with a 5-year survival
rate of less than 50%

106. PHAEOCHROMOCYTOMA IN PREGNANCY
• Phaeochromocytomas in pregnancy may imitate an amnion
infection syndrome or Pre-eclampsia.
• Without adequate α-blockade, mother and unborn child are
threatened by hypertensive crisis during vaginal delivery.
• In the first and second trimesters the patient should be
scheduled for laparoscopic adrenalectomy after adequate α-
blockade; the risk of a miscarriage during surgery is high.
• In the third trimester, elective Caesarean with consecutive
adrenalectomy should be performed.
• The maternal mortality rate is 50% when a
phaeochromocytoma remains undiagnosed.

107. 2.NEUROBLASTOMA
Definition
• A neuroblastoma is a malignant tumour that is derived from
the sympathetic nervous system in the adrenal medulla (38%)
or from any site along the sympathetic chain in the
paravertebral sites of the abdomen (30%), chest (20%) and,
rarely, the neck or pelvis

108. PATHOLOGY
• Neuroblastomas have a pale and grey surface, are
encapsulated and show typical areas with calcification.
• With increased tumour size, necrosis and haemorrhage may
be detected.
• They are characterised by the presence of immature cells
derived from the neuroectoderm of the sympathetic nervous
system.
• Mature cells are found only in ganglioneuroblastomas.

109. CLINICAL FEATURES
• Predominantly newborn infants and young children (< 5 years
of age) are affected.
• Symptoms are caused by tumour growth or by bone
metastases.
• Patients present with a mass in the abdomen, neck or chest,
proptosis, bone pain, painless bluish skin metastases,
weakness or paralysis.
• Metastatic disease is present in 70% of patients.
• The catecholamine excess is asymptomatic and an excess of
ACTH or VIP may occur.

110. DIAGNOSIS
• Biochemical evaluation should include urinary excretion (24-
hour urine) of vanillylmandelic acid (VMA), homovanillic acid
(HVA), dopamine and noradenaline, as increased levels are
present in about 80% of patients.
• Accurate staging requires CT/MRI of the chest and abdomen,
a bone scan, bone marrow aspiration and core biopsies as
well as an MIBG scan.
• Staging is established according to the International
Neuroblastoma Staging System (INSS).

111. TREATMENT
• Prognosis can be predicted by the tumour stage and the age at
diagnosis.
• Patients are classified as low, intermediate or high risk.
• Low-risk patients are treated by surgery alone (the addition of 6–12
weeks of chemotherapy is optional) whereas intermediate risk
patients are treated by surgery with adjuvant multi-agent
chemotherapy (carboplatin, cyclophosphamide, etoposide,
doxorubicin).
• High-risk patients receive high-dose multi-agent chemotherapy
followed by surgical resection in responding tumours and
myeloablative stem cell rescue.
• Patients assigned to the low-risk, intermediate-risk and high-risk
groups have overall 3-year survival rates of 90%, 70–90% and 30%
respectively.

112. 3.GANGLIONEUROMA
Definition
• A ganglioneuroma is a benign adrenal neoplasm that arises
from neural crest tissue.
• Ganglioneuromas occur in the adrenal medulla and are
characterised by mature sympathetic ganglion cells and
Schwann cells in a fibrous stroma.

113. CLINICAL FEATURES
• Ganglioneuroma is found in all age groups but is more
common before the age of 60.
• Ganglioneuromas occur anywhere along the paravertebral
sympathetic plexus and in the adrenal medulla (30%).
• Most often they are identified incidentally by CT or MRI
performed for other indications.
TREATMENT
• Treatment is by surgical excision, laparoscopic when
adrenalectomy is indicated

114. SURGERY OF THE ADRENAL GLANDS
• Since its introduction in the 1990s, laparoscopic or retroperitoneoscopic
adrenalectomy has become the ‘gold standard’ in the resection of adrenal
tumours, except for tumours with signs of malignancy.
• The more popular approach is the laparoscopic transperitoneal
approach, which offers a better view of the adrenal region and may be
easier to learn.
• The advantage of the retroperitoneoscopic approach is the minimal
dissection required by this extra-abdominal procedure.
• In the case of small, bilateral tumours or in patients with hereditary
tumour syndromes a subtotal resection is warranted.
• The mortality rate ranges from 0 to 2% in specialised centres.
• An open approach should be considered if radiological signs, distant
metastases, large tumours (> 8–10 cm) or a distinct hormonal pattern
suggest malignancy.
• The surgical access in such cases should be thoracoabdominal.

115. LAPAROSCOPIC ADRENALECTOMY
• Knowledge of the anatomy of the adrenal region is essential
as anatomical landmarks guide the surgeon during operation.
• If these landmarks are respected, injury to the vena cava or
renal vein, the pancreatic tail or the spleen can be avoided.
• Careful haemostasis is essential as small amounts of blood
can impair the surgeon’s view.
• To prevent tumour spillage, direct grasping of the adrenal
tissue/tumour has to be avoided.

116. Patient positioning for left lateral transabdominal laparoscopic
adrenalectomy.

118. • Laparoscopic view during a
right adrenalectomy.
• Arrow indicates the adrenal
vein. AT, adrenal tumour;
VC, vena cava

119. RIGHT ADRENALECTOMY
• After mobilisation of the right liver lobe the adrenal vein is
identified and divided.
• The dissection continues at the level of the periadrenal fat
using careful coagulation and is finished by the complete or
subtotal removal of the adrenal gland.

120. Port placement for right laparoscopic adrenalectomy.
The patient is lying right-side up, with the head toward the right. The
marked line denotes the costal margin. Ports are placed approximately
2 cm inferior to the costal margin, spaced about 4 fingerbreadths
apart.

121. Patient positioning for open right adrenalectomy

122. LEFT ADRENALECTOMY
• With the patient positioned on his or her right side,
mobilisation of the spleen will displace the pancreatic tail
medially.
• The incision of Gerota’s fascia is followed by identification of
the adrenal vein, which runs into the renal vein in the space
between the medial aspect of the kidney and the posterior
aspect of the pancreatic tail.
• The resection is completed by the transection of the adrenal
gland at the level of the periadrenal fat

123. RETROPERITONEOSCOPIC
ADRENALECTOMY
• The first port is placed at the distal end of the 12th rib with
the patient in the prone position.
• After a digital dissection into theretroperitoneum, Gerota’s
fascia is displaced ventrally.
• The right adrenal vein is covered by the retrocaval posterior
aspect of the adrenal gland.
• The left adrenal vein is usually located at the medial inferior
pole of the adrenal gland.

124. OPEN ADRENALECTOMY
• An open adrenalectomy through a thoracoabdominal approach is
almost exclusively performed when a malignant adrenal tumour is
suspected.
• On the right side the hepatic flexure of the colon is mobilised and
the right liver lobe is cranially retracted to achieve an optimal
exposure of the inferior vena cava and the adrenal gland.
• On the left side the adrenal gland can be exposed after mobilisation
of the splenic flexure of the colon, through the transverse
mesocolon or through the gastrocolic ligament.
• The remaining dissection is the same as in laparoscopic
adrenalectomy.
• A resection of regional lymph nodes is recommended in malignant
adrenal tumours and should include resection of the tissue
between the renal pedicle and the diaphragm.

125. REFERENCES
1.Bailey and Love short practice of surgery-26th edition
2.Sabiston textbook of Surgery , 20th edition
3.Schwartz textbook of Principles of Surgery, 10th edition
4.Principles and Practice of Oncology, De Vita, 9th edition
5.Lee McGregor’s synopsis of surgical anatomy-12th edition
6.Clark,Duh,Kebebew textbook of endocrine surgery-2nd edition
7.Surgical endocrinology by Grenard M. Doherty & Britt Skogseid
8.Atlas of procedures in surgical oncology by Riccardo A Audisio
9.Textbook of surgical oncology by by Graeme J poston
10. Campbell-Walsh Urology 11th edition.