Seminar presentation by group C 5th year medical student under supervision Dato Imi, endocrine specialist in HRPZ II. Reference as mentioned at the end of the slide presentation

1. ADRENAL NEOPLASIA
& MEN SYNDROME
SUBGROUP C

2. OUTLINES
1 . AN ATOMY AN D PH YSIOLOGY
2 . C LASSIFIC ATION
3 . C ON N ’S SYN D R OME
4 . C U SH IN G SYN D R OME
5 . PH EOC H R OMOC YTOMA
6 . MEN SYNDROME

3. ANATOMY

4. ANATOMY
 retroperitoneal
structures
 2–6 gram
 located on either side
of the vertebral column
within Gerota’s fascia,
in close proximity to
the crura of the
diaphragm and the
superior poles of the
kidneys
 The right adrenal gland is
triangular or pyramidal in
shape, located between the
right liver lobe and the
diaphragm, close to and
partly behind the inferior
vena cava.
 The left adrenal gland is
crescentic in shape, lies close
to the upper pole of the left
kidney and the renal pedicle.
It is covered by the
pancreatic tail and the
spleen.

5.  Arterial supply is
drawn from the aorta,
renal artery and
inferior phrenic artery.
 Main venous drainage
on the right side is via
a short adrenal vein
(5mm) directly to the
inferior vena cava. On
the left side drainage
is directly to the left
renal vein.
ANATOMY

6. HISTOLOGY

7. PHYSIOLOGY

9. PHYSIOLOGY

10. PHYSIOLOGY

11. REMEMBER!

12. HYPERALDOSTERONISM
(CONN’S SYNDROME)

13. HYPERALDOSTERONISM
 Hyperaldosteronism is a disease caused by problems in the
adrenal glands.
 Aldosterone is one of the hormones produced. It is an
integral part of Hyperaldosteronism.
 Its overproduction leads to retention of salt and loss of potassium,
which then leads to hypertension (high blood pressure).
 People in their 30’s-50’s (adulthood), with prevalence increasing
with age
 Females are more likely to be affected than males
 African Americans have a significantly greater risk of fatality from
the disease than other races
 Rare in children (It is more likely to have been inherited if
diagnosed in a child

14. HYPERALDOSTERONISM

15. CLASSIFICATION

16. CONN’S SYNDROME
 Conn’s syndrome is a disease of the adrenal
gland characterized by excessive production of
aldosterone (hyperaldosteronism).
 What causes Conn’s Syndrome?
 Adenoma (benign tumor) on the adrenal gland 50-60%
cases
 Idiopathic (unknown cause) hyperaldosteronism 40-
50% cases

17. CONN’S SYNDROME
 Hypertension
 Hypokalemia
 Headache
 Muscle Weakness
 Cramps
 Intermittent Paralysis
 Polyuria
 Polydipsia
 Nocturia
CLINICAL FEATURES
Decreased potassium in the blood due to
increased excretion of potassium in the urine
REMEMBER!
hypokalaemia and hypertension.

18. DIAGNOSIS

19. DIAGNOSIS

20. LABORATORY TEST
– In a blood test, PRA(Plasma renin activity),
is used to distinguish between primary
(low PRA) and secondary
Hyperaldosteronism (high PRA).
– Plasma aldosterone concentration (PAC).
 24 hour urine potassium and aldosterone
measurement

21.  PAC:PRA ratio
 The first test used in patients suspected to have
primary hyperaldosteronism measures the plasma
aldosterone concentration (PAC) to plasma renin
activity (PRA) ratio. The levels of aldosterone and
renin are measured in the blood. A high ratio of PAC to
PRA suggests primary hyperaldosteronism; however,
additional testing may be needed to confirm the
diagnosis.
SCREENING TEST

22. CONFIRMATORY TEST
CONFIRMATORY TESTS:
Captopril Suppression Test
 Captopril is a medication for high blood pressure. A patient is given a single
dose of captopril, after which the levels of aldosterone and renin in the blood
are measured. In patients with primary hyperaldosteronism, the level of
aldosterone in the blood is still high and the level of renin is low even after
captopril administration.
24-Hour Urinary Excretion of Aldosterone Test:
 In the 24-hour urinary excretion of aldosterone test, a patient eats a high-salt
diet for 5 days before measuring the amount of aldosterone in the urine over a
24-hour period. In patients with primary hyperaldosteronism, aldosterone will
not be suppressed by the salt load, and the level of aldosterone in the urine will
be high.
Saline Suppression Test:
 In the saline suppression test, the patient is given a salt solution through an IV,
after which the levels of aldosterone and renin in the blood are measured. In
patients with primary hyperaldosteronism, the level of aldosterone in the blood
is still high and the level of renin is low even after this salt loading.

23. ADRENAL VENOUS
SAMPLING
 This procedure is performed in the operating room and
involves taking blood samples to measure the aldosterone
levels directly from the adrenal glands
 by placing a catheter in the left and right adrenal veins.
High hormone levels from one gland but not the other
suggests unilateral disease.
 If the blood levels are the same on both sides, then the
patient likely has bilateral disease.
 When performed by an experienced physician, adrenal
venous sampling is very accurate at determining if the
patient has unilateral or bilateral disease.
 Patients can usually go home the same day of the
procedure.

24. MANAGEMENT

25. TREATMENT
 Patients with unilateral disease should have an
adrenalectomy.
 The operation usually is performed using minimally invasive techniques
(i.E. Laparoscopic surgery), but may require a traditional operation in
cases of large, difficult to remove tumors.
 Patients with primary hyperaldosteronism caused by
bilateral adrenal hyperplasia are treated with
medications
 (I.E. Aldosterone-antagonists) that control high blood pressure and
normalize levels of sodium, potassium, and water in the blood. A low-
salt diet also is recommended
 Complications include heart attack and heart failure,
kidney damage and kidney failure, and stroke. Prevent
this condition by treating symptomatically.

27. CUSHING’S SYNDROME

28. DEFINITION
• 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.

29. CLASSIFICATION
• 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.
• 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.

30. CLINICAL FEATURES
• Weight gain/central obesity
• Diabetes
• Hirsutism
• Hypertension
• Skin changes (abdominal striae,
facial plethora, ecchymosis, acne)
• Muscle weakness
• Menstrual irregularity/impotence
• Depression/mania
• Osteoporosis
• Hypokalaemia

31. DIAGNOSIS
• Complete a drug history to exclude iatrogenic Cushing’s.
• Perform one of:
1. 24 hour urine free cortisol. ↑
2. Dexamethasone suppression test. ↓
3. Late night salivary cortisol. ↑
• Serum ACTH levels discriminate ACTH-dependent from
ACTH-independent disease.
• In patients with suppressed ACTH levels, a CT or MRI
scan is performed to assess the adrenal glands.
• Subclinical Cushing’s syndrome is diagnosed if clinical
symptoms are absent in the face of abnormal cortisol
secretion.

32. DIAGNOSIS

33. DIAGNOSIS

34. TREATMENT
• 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.
• 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.

35. • Pre-Op Management
• Biochemical abnormalities should be corrected.
• Patients with Cushing’s Syndrome are at an increased risk of hospital
acquired infection and thromboembolic and myocardial
complications. Therefore, prophylactic anticoagulation and the use
of prophylactic antibiotics are essential.
• Post-Op Management
• Supplementary Cortisol should be give after surgery. In total 15 mg h-
1 is required parentally for the first 12 hr followed by a daily dose of
100 mg for 3 days which is gradually reduced thereafter.
• After Unilateral adrenalectomy, the contralateral suppressed gland need
up to 1 year to recover adequate function.
TREATMENT

36. PHEOCHROMOCYTOMA

37.  Catecholamine-producing tumor derived from
the sympathetic and parasympathetic nervous
system, usually located in the adrenal gland.
 May also produce Calcitonin, ACTH, VIP, PTHrP
 Prevalence in Hypertensive patients is 0.1 – 0.6%
with over all prevalence of 0.05% In autopsy series.
 Sporadic Phaechromocytoma occur after the fourth
decade whereas patients with hereditary form are
diagnosed early.
 Also known as the 10% Tumour i-e
 10% are inherited
 10% Extraadrenal
 10% Malignant
 10% Bilateral
 10% Occur in Children
 Hereditary Phaechoromocytoma are Usually
Associated with Syndromes like
 Multiple Endocrine Neoplasia Type 2
 Medullay thyroid Carcina
 Primary Hyperparathyroi
 Phaechromoctoma
 Familial paraganglioma Syndrome
 Von Hippel-Lindau Syndrome
 Neurofibromatosis Type I
PHEOCHROMOCYTOMA

38.  Can be continuous or Intermittent.
 Headache
 Palpitation
 Sweating
 Hypertension ( Paroxysmal or continuous)
 Pallor
 Weight loss
 Nausea
 Hyperglycemia
 Psychological effects
 Paroxysms may be precipitated by physical
training, induction of anesthesia and drugs like
TCA, Metochlopramide, Opiates or contrast media
CLINICAL FEATURES

39.  Complete History
 Clinical Examination
 Biochemical evaluation
 Determination of Adrenaline, Noradrenaline, Metanephrine
and Normetanephrine levels in a 24-hr Urine Collection. Level
exceeding Normal range by 2-40 times will be found in affected
patients.
 Determination of plasma free Metanephrine and
Normetanephine Levels has a high sensitivity
 Biochemical tests should be performed at least twice
 Imaging
 For Localization of Tumour and/or Metastases MRI is preferred
because Contrast Media used for CT scans can provoke
paroxysms.
 123I-MIBG (meta-Iodobenzyl guanidine) single- photon
emission computerized tomography SPECT will identify about
90% of primary tumours. And is essential for the detection of
Multiple Extra-Adrenal Tumours and Metastases.
DIAGNOSIS

40. IMAGING: CT SCAN

41.  Laparoscopic resection.
 If tumour larger than 8-10cm or radiological signs of malignancy are
detected, then an open approach should be considered.
________________________________________________________
 Pre Operative Care
• Once Diagnosed, An alpha adrenergic Blocker
(Phenoxybenzamine) is used to block Catecholamine excess
and its consequences during Surgery.
• A dose of 20 mg of Phenoxybenzamine initially, should be
increased daily by 10mg until a daily dose of 100-160 mg is
achieved and the patient reports symptomatic postural
hypotension.
• Additional Beta-Blocker is required if tachycardia or
arrhythmias develops, and this should not be introduced
until the patient is on alpha blocker.
• In some patients, a 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.
MANAGEMENT

42.  Post Operative Care
•Patient should be observed for 24 hr in the
ICU as Hypovolemia and hypoglycemia may
occur.
 Follow Up
•Biochemical cure should be confirmed by an
assessment of catecholamine 2-3 weaks
postoperatively.
•Lifelong Yearly Biochemical tests should be
performed to identify recurrent, metastatic or
metachronous phaeochromocytoma.
MANAGEMENT

43.  10% of Phaechromocytoma are malignant
 Rate is higher in Extra-adrenal tumours (Paraganliomas).
 Diagnosis of Malignancy Implies Mets to Lymph Node, bone and
liver.
 About 8% apparently benign tumour subsequently develop
metastasis.
_____________________________________________________
Treatment:
• Surgical excision Is only chance of cure.
• Even in patient with metastatic disease, tumour debulking can be
considered to reduce the tumour burden and to control the
catecholamine excess.
• Symtomatic treatment can be obtained with alpha-blockers.
• Mitotane should be started as Adjuvent Or Pallistive treatment.
• Treatment with 131I-MIBG or combination chemotherapy has
resulted In a partial response in 30% and an improvement of
symtoms in 80% of patients.
• The natural History is highly Variable with a 5 year survival rate of
< 50%.
MALIGNANT PHEOCHROMOCYTOMA

44.  This condition may mimic amnion infection
syndrome or pre-eclampsia.
 Without adequate Alpha blockade, mother
and unborn child are threatened by
hypertensive crisis during delivery.
 In the first and second trimester, laparoscopic
adrenalectomy can be done while in the third
trimester, Elective caesarean section with
consecutive adrenalectomy should be
performed.
 The mortality rate is 50% when a
phaechromocytoma remains undiagnosed.
PHEOCHROMOCYTOMA IN PREGNANCY

45. MULTIPLE ENDOCRINE
NEOPLASIA

46. ▪ Hormones are chemical messengers that travel
through the bloodstream and regulate the function
of cells and tissues throughout the body.
▪ Multiple endocrine neoplasia is a group of disorders
that affect the body's network of hormone-
producing glands called the endocrine system
▪ Multiple endocrine neoplasia typically involves
tumors (neoplasia) in at least two endocrine glands;
tumors can also develop in other organs and tissues.
▪ These growths can be non cancerous (benign) or
cancerous (malignant).
▪ If the tumors become cancerous, the condition can
be life-threatening.
MULTIPLE ENDOCRINE NEOPLASIA

47.  Multiple endocrine neoplasia type 1 affects
about 1 in 30,000 people; multiple endocrine
neoplasia type 2 affects an estimated 1 in
35,000 people.
 Among the subtypes of type 2, type 2A is the
most common form, followed by FMTC.
 Type 2B is relatively uncommon, accounting for
about 5 percent of all cases of type 2.
 The prevalence of multiple endocrine neoplasia
type 4 is unknown, although the condition
appears to be rare.
FREQUENCY

48. ▪ The major forms of multiple endocrine neoplasia are called
type 1 and type 2.
▪ These types are distinguished by the genes involved, the
types of hormones made, and the characteristic signs and
symptoms.
▪There are specific genetic causes for each of the three
types of MEN.
▪Any particular MEN family will have only one type of
MEN, either;
 MEN 1
 MEN 2a or
 MEN 2b.
▪Therefore, families with one type of MEN do not have
an increased risk of developing an other type of MEN.
MULTIPLE ENDOCRINE NEOPLASIA

50. • Type 1 frequently involves tumors of the parathyroid
glands, the pituitary gland, and the pancreas.
▪ Tumors in these glands can lead to the
overproduction of hormones.
▪ The most common sign of multiple endocrine
neoplasia type 1 is overactivity of the parathyroid
glands (hyperparathyroidism).
▪ Hyperparathyroidism disrupts the normal balance of
calcium in the blood, which can lead to :
o -Kidney stones,
o -Thinning of bones,
o -Nausea and vomiting,
o -High blood pressure (hypertension),
o -Weakness, and fatigue.
MEN 1

51.  Mutations in the MEN1 gene cause multiple endocrine neoplasia
type 1.
 This gene provides instructions for producing a protein called
menin. Menin acts as a tumor suppressor, which means it normally
keeps cells from growing and dividing too rapidly or in an
uncontrolled way. It localized to chromosome band 11q13
 Although the exact function of menin is unknown, it is likely involved
in cell functions such as copying and repairing DNA and regulating
the activity of other genes. When mutations inactivate both copies
of the MEN1 gene, menin is no longer available to control cell
growth and division.
 The loss of functional menin allows cells to divide too frequently,
leading to the formation of tumors characteristic of multiple
endocrine neoplasia type 1. It is unclear why these tumors
preferentially affect endocrine tissues.
MEN 1

52. • Zollinger-Ellison syndrome (hypergastrinaemia)
• hypoglycaemia (hyperinsulinaemia)
• Prolactinoma: amenorrhoea (hyperprolactinaemia)
• Acromegaly (excess growth hormone).
• Tumors of the pituitary gland may cause symptoms by mass
effects. Angiofibromas, collagenomas, and lipomas do not
typically cause symptoms, and they are mostly of cosmetic
concern
• Age of onset of endocrine tumors is usually in the teenage
years, but symptoms from these tumors may not appear for
several years, and the diagnosis is frequently delayed until the
fourth decade of life
• Cutaneous tumors may develop prior to the manifestation of
overt clinical symptoms resulting from endocrine tumors. The
earliest cutaneous tumors appear in the teenage years.
CLINICAL PRESENTATION

53. ▪ Clinical diagnostic criteria for MEN1 syndrome include the presence of two
endocrine tumors that are parathyroid, pituitary, or GEP tract tumors.
▪ Biochemical testing detects an :
o -increased serum concentration of parathyroid hormone and calcium in
primary hyperparathyroidism,
o -increased serum concentrations of prolactin from a prolactinoma,
o -increased serum concentrations of gastrin, insulin, and VIP from tumors of the
GEP tract.
▪ Prolactinomas are imaged by MRI,
▪ Neuroendocrine tumors (NETs) are detected by somatostatin receptor
scintigraphy,
▪ Pancreatic endocrine tumors are detected by endoscopic ultrasound.
▪ Molecular genetic testing of MEN1, the only gene in which mutation is
known to cause MEN1 syndrome, detects MEN1 pathogenic variants in
approximately 80%-90% of probands with familial MEN1 syndrome and in
approximately 65% of simplex cases (i.e., a single occurrence of MEN1
syndrome in the family).
DIAGNOSIS

54. Treatment of manifestations
 Hyperparathyroidism is treated with subtotal
parathyroidectomy and cryopreservation of parathyroid tissue
or total parathyroidectomy and autotransplantation of
parathyroid tissue;
o - Recent studies suggest that long-acting release octreotide or
calcimimetic could also be effective;
o - Prior to surgery, bone anti-resorptive agents are used to reduce
hypercalcemia and limit bone resorption.
 Prolactinomas are treated with dopamine agonists (cabergoline
is the drug of choice).
 Growth hormone-secreting tumors causing acromegaly are
treated by transsphenoidal surgery;
o - Medical therapy for growth hormone-secreting tumors
includes somatostatin analogs, octreotide, and lanreotide.
MANAGEMENT

55.  ACTH-secreting pituitary tumors associated with
Cushing syndrome are surgically removed;
 Non-secreting pituitary adenomas are treated by
transsphenoidal surgery.
 Proton pump inhibitors or H2-receptor blockers
reduce gastric acid output caused by gastrinomas.
 Surgery is indicated for insulinoma and most other
pancreatic tumors.
 Long-acting somatostatin analogs can control the
secretory hyperfunction associated with carcinoid
syndrome.
 Surgical removal of adrenocortical tumors that exceed
3.0 cm in diameter can prevent malignancy.
MANAGEMENT

56.  The most common sign of multiple endocrine neoplasia type 2
is a form of thyroid cancer called medullary thyroid carcinoma.
▪ Some people with this disorder also develop a
pheochromocytoma, which is an adrenal gland tumor that can
cause dangerously high blood pressure.
▪ Multiple Endocrine Neoplasia Type 2 is divided into three
subtypes:
o - Type 2A,
o -Type 2B (formerly called type 3),
o -Familial medullary thyroid carcinoma (FMTC).
▪ These subtypes differ in their characteristic signs and symptoms
and risk of specific tumors;
o - For example, hyperparathyroidism occurs only in type 2A,
o - Medullary thyroid carcinoma is the only feature of FMTC.
▪ The signs and symptoms of multiple endocrine neoplasia type 2
are relatively consistent within any one family.
MEN 2A & MEN 2B

57.  Mutations in the RET proto-oncogene, at band 10q11.2
 This gene provides instructions for producing a protein
that is involved in signaling within cells.
 The RET protein triggers chemical reactions that instruct
cells to respond to their environment, for example by
dividing or maturing.
 Mutations in the RET gene overactivate the protein's
signaling function, which can trigger cell growth and
division in the absence of signals from outside the cell.
 This unchecked cell division can lead to the formation of
tumors in endocrine glands and other tissues.
MEN 2A & MEN 2B

58. ● The diagnosis of MEN 2 is established in a proband
who fulfills existing diagnostic clinical criteria.
● Molecular genetic testing to identify a heterozygous
germline RET pathogenic variant is indicated in all
individuals with a diagnosis of primary C-cell
hyperplasia or MTC or a clinical diagnosis of MEN 2.
● Identification of a heterozygous germline RET
pathogenic variant on molecular genetic testing
establishes the diagnosis if clinical features are
inconclusive.
DIAGNOSIS

59.  Treatment of manifestations
 Treatment for MTC is surgical removal of the thyroid gland and
lymph node dissection.
 External beam radiation therapy (EBRT) or intensity-modulated
radiation therapy (IMRT) can be considered for advanced
locoregional disease.
 Kinase inhibitors may be used in metastatic MTC.
 Pheochromocytomas detected by biochemical testing and
radionuclide imaging are removed by adrenalectomy.
 Primary hyperparathyroidism is treated with surgery to remove
one or more parathyroid glands, or more rarely, medications to
reduce parathyroid hormone secretion.
MANAGEMENT

60. REFERENCES
 http://endocrinediseases.org/adrenal/hypera
ldosteronism_diagnosis.shtml
 Bailey and Loves Short Practice Of Surgery 26th Edition
 Margulies, Paul. "Adrenal Diseases - Hyperaldosteronism The
Facts You Need To Know." NADF (National Adrenal Diseases
Foundation). NADF, 1987. Web.
http://www.nadf.us/diseases/hyperaldosteronism.htm

61. THANK YOU