Disorders Of Adrenal Cortex

Adrenal Glands/Suprarenal Glands

Describe applied anatomy of adrenal glands.

Adrenal Glands Anatomy:

• Weight of a normal gland is 4 g.
• Yellowish in colour.
• Surrounded by perinephric pad of fat.

Adrenal Glands  Physiology:

Read And Learn More: General Surgery Notes

Adrenal Glands  Histology and Adrenal Glands function:

Adrenal Glands Cortex:

• Derived from mesoderm
• Secretes corticosteroids, androgens, aldosterone.

Adrenal Glands Medulla:

• Derived from neural crest cells.
• It is a mass of nervous tissue associated with sympathetic system.

Parts: Two parts—cortex and medulla.

Adrenal Glands Blood Supply:

• Superior suprarenal arteries arise from inferior phrenic arteries.
• Middle suprarenal arteries arise from abdominal aorta.
• Inferior suprarenal arteries arise from renal artery.
• Suprarenal arteries branch before entering the gland so that 50 to 60 arteries penetrate the capsule.
• Venous drainage is through a single large suprarenal vein. On the right side, it is short and drains into IVC. On the left side, it is longer and joined by inferior phrenic vein and empties into left renal vein.

Adrenal Glands Surgical Importance:

• One has to clearly identify and ligate suprarenal vein especially on the right side because of its short course. Avulsion of right suprarenal vein can be catastrophic.
• Chromaffin cells of the medulla are related to sympathetic system.
• These cells secrete catecholamines (mostly epinephrine).

Adrenal Glands Lymphatics:

• Drain into caval or aortic lymph nodes.
• Describe the aetiology, clinical features and principles of management of disorders of adrenal gland.

Disorders Of Adrenal Cortex

Primary Hyperaldosteronism (Pha)

• Triad of PHA is hypertension, hypokalaemia and hypersecretion of aldosterone.
• PHA can be due to a single adrenocortical adenoma wherein it is called Conn’s syndrome.
• It can also be due to bilateral micronodular hyperplasia.
• Clinical features are headache, hypertension, hypokalaemia and weakness, commonly in women.
• Polyuria, polydypsia, nocturia are other features.
• The diagnosis is established by measuring potassium level and aldosterone to plasma renin activity ratio.
• CT scan is the most important test to locate the lesion (usually it is 1–2 cm).
• Treated by spironolactone and antihypertensive medications in bilateral hyperplasia.
• Laparoscopic adrenalectomy is an effective treatment in unilateral cases.

Aldosterone:

• Angiotensin II increases aldosterone secretion.
• Hyperkalaemia is another potent stimulator of aldosterone.
• It functions mainly to increase sodium reabsorption and potassium and hydrogen ion excretion.
• It acts at distal convoluted tubules.

Cushing’S Syndrome

• Refers to various clinical manifestations resulting from increased secretion of corticosteroids.
• When it is due to pituitary adenoma secreting large amount of ACTH—it is called Cushing’s disease.
• Ectopic ACTH producing tumours causing Cushing’s syndrome are:
  • Small cell lung cancers
  • Foregut carcinoid
  • Medullary carcinoma thyroid
  • Neuroendocrine pancreatic tumour.

Adrenal Gland Classification:

• ACTH—dependent (70% pituitary or ectopic ACTH producing tumours).
• ACTH—independent: Adrenal adenoma or hyperplasia.

Adrenal Gland Features:

They are mainly due to increased corticosteroids, aldosterone and androgens. The net result is typical cushingoid facies—with facial plethora, buffalo hump and moon face.

Adrenal Glands  Clinical Features:

• Central obesity
• Unusual site obesity: Supraclavicular space, posterior neck
• Secondary osteoporosis: Buffalo humps
• Hypertension, Hyperglycaemia, Hypokalaemia, Hirsutism Irregularity in menstruation
• Neurological: Depression, mania
• Gain in weight
• Skin changes: Abdominal striae, ecchymosis, acne, plethora due to thinning of subcutaneous tissues Remember as CUSHINGS

Adrenal Gland Investigations:

1. Morning and midnight plasma cortisol levels are increased.
2. Serum ACTH levels: If increased, it is from pituitary source or ectopic ACTH.
3. CT chest and abdomen to assess not only adrenals but also to detect ectopic sites.

Adrenal Gland Treatment:

1. Medical: Ketoconazole or metyrapone can reduce steroid synthesis. Thus, symptoms can be controlled. They are also indicated if surgery is not possible.
2. Trans-sphenoidal resection of ACTH producing pituitary tumours.
3. Unilateral adenoma: Adrenalectomy.
4. Bilateral tumours: Bilateral adrenalectomy. Postoperatively cortisol should be given.

Adrenal Insufficiency

Addison’S Disease Definition: Loss of function of adrenal cortex is also called Addison’s disease.

Diseases associated with Addison’s disease include:

1. After bilateral adrenalectomy
2. Tuberculosis
3. Metastases
4. Haemorrhage
5. Amyloidosis, Wilson’s disease
6. HIV infection

Addison’S Disease Types:

1. Acute Adrenal Insufficiency

• Shock
• Fever
• Abdominal pain, vomiting confused for acute abdomen Waterhouse-Friderichsen syndrome. It is a bilateral adrenal infarction associated with meningococcal sepsis.

2. Chronic Adrenal Insufficiency:

• Anorexia, weakness and nausea
• ACTH and POMC—pro-opiomelanocortin levels increase—resulting in hyperpigmentation of skin and oral mucosa
• Hypotension, hypercalcaemia and hyponatraemia.

Addison’S Disease Diagnosis:

• Basal ACTH levels are increased
• Cortisol levels are decreased
• ACTH tests: No rise in cortisol levels following administration of ACTH.

Addison’S Disease Treatment:

• Acute cases: 4 hydrocortisone 100 mg 6th hourly, saline transfusion, control of infections and cardiac care.
• Chronic cases: Oral hydrocortisone (10 mg/m2 body surface area) and fludrocortisone (0.1 mg).
• Lifelong treatment with glucocorticoid and mineralocorticoid replacement.

Describe the clinical features, principles of investigation and management of adrenal tumours.

Tumours Of The Adrenal Gland

1. Classification Of The Tumours Of The Adrenal Cortex

• Cortical carcinoma,
• Cortical adenoma,
• Sex cord stromal tumours,
• Adenomatoid tumour, mesenchymal and
• Stromal tumours (myelolipoma and schwannoma),
• Haematological tumours, and secondary tumours.

2. Tumours Of The Adrenal Medulla And Extra-Adrenal Paraganglia:

• Pheochromocytoma,
• Paraganglioma (head and neck paraganglioma and sympathetic paraganglioma),
• Neuroblastic tumours (neuroblastoma, nodular ganglioneuroblastoma, intermixed ganglioneuroblastoma, and ganglioneuroma),
• Composite pheochromocytoma, and composite paraganglioma.
• Adrenocortical carcinoma, neuroblastoma and phaeochromocytoma are discussed in more details here.

Adrenocortical Carcinoma

• Incidence: One in 1,000,000 cases.
• Age: Bimodal with a first peak in childhood and second between fourth and fifth decades.
• 60% of patients present with Cushing’s syndrome.
• Diagnosis of malignancy is (>6 cm) by size of the tumour, presence of necrosis or haemorrhage, capsular or vascular invasion.
• CT—heterogeneous tumour, irregular margins, haemorrhage, lymphadenopathy, metastasis in liver.
• MRI—angiography to exclude tumour thrombus in vena cava.
• Open radical tumour resection (Ro)—en bloc removal of tumour lymph nodes and involved organs is the treatment of choice.
• Adjuvant chemotherapy—mitotane alone (derivative of insecticide DDT) is used. It has adrenolytic activity.
• Etoposide, cisplatin and doxorubicin are also used.
• Steroid hypertension is managed by ketoconazole.

1. Neoplasm Of The Sympathetic Neurons:

1. Ganglioneuroma: It is a benign neuronal tumour, commonly arising from retroperitoneal lumbar sympathetic trunk. FNAC, ultrasound followed by surgical excision is the management.
2. Neuroblastoma

2. Neoplasm Of The Chromaffin Cells:

• Phaeochromocytoma

Neuroblastoma

• It is a malignant tumour, derived from sympathetic nervous system and adrenal medulla.
• Since it originates from the neural crest, it may be found from orbit to pelvis where sympathetic nervous tissue is found.
• It occurs in 1 in 10,000 live births.
• It is the most common solid tumour of infancy in childhood.
• Adrenal gland is the most common site of neuroblastoma.
• As the name suggests, the tumour occurs due to malignant proliferation of the neuroblasts or failure of maturation of primitive sympathetic nerve cells, the neuroblasts.

Neuroblastoma:

• Most common solid tumour in infancy and childhood.
• Adrenal gland is the most common site.
• Mass abdomen and metastasis are common presenting features.
• Surgical excision is the best treatment.
• Younger the child, better the prognosis.
• Highest incidence of spontaneous remission.

Adrenal Tumours Pathology:

• Characterised by presence of immature cells derived from neuroectoderm of sympathetic nervous system.
• It is pale with grey surface and well-encapsulated.
• A few areas of calcification are seen.
• Necrosis and haemorrhage are late features.
• Microscopically, uniform round cells containing hyperchromatic speckled nucleus, Homer-Wright rosettes with central fibrillar core.

Adrenal Tumours Clinical Features:

• 50% of children present to the hospital under the age of one year and 80–90% are less than 3 years of age.
• An abdominal mass is the most common presenting feature. The mass has all the features of a renal mass but location is slightly higher. It is firm to hard, nodular and fixed.
• The child is sick with weight loss, fever, abdominal distension, anaemia, etc.

Tumours with Calcification:

• • Neuroblastoma
  • Chondrosarcoma
  • Papillary carcinoma thyroid
  • Phaeochromocytoma (10%)
• Functional tumours produce diarrhoea and hypokalaemia due to release of vasoactive intestinal polypeptide (VIP), sweating and flushing due to release of catecholamines.
• Proptosis and periorbital swellings are due to bony metastasis and subcutaneous nodules are quite common.
• Secondaries in retro-orbital region result in infraorbital ecchymosis—Raccoon’s eye sign.
• Posterior mediastinal neuroblastomas can produce cord compression and even paraplegia due to protrusion within the spinal canal (dumbbell tumours).

Types of Neuroblastoma:

1. Pepper type: Right-sided tumours with secondaries in the liver.
2. Hutchinson’s type: Left-sided tumour with metastasis in bones—orbit and skull.

Adrenal Tumours Investigations:

• Vanillylmandelic acid (VMA) and homovanillic acid (HVA) are the byproducts of catecholamines passed in the urine. 24-hour urinary excretion of catecholamines and these two metabolites will be very high.
• Plain X-ray abdomen shows fine stippled calcification. X-ray chest is done to rule out cannonball secondaries.
• Abdominal ultrasound and computed tomography (CT) can define the mass, nature and extent of the tumour and can detect hepatic metastasis.
• Magnetic resonance imaging (MRI) is better than CT scan in detecting the mass as well as bony metastasis. CT-/MRI-guided core biopsy can be done.
• Bone marrow aspiration is positive in around 60–70% of cases.

Adrenal Tumours Treatment:

• Intermediate- and high-risk cases can be managed by chemotherapy followed by surgery.
  Early cases respond very well to surgical excision.
• However, many children present with metastasis, and chemotherapy and radiotherapy are given first to control the disease followed by surgical excision.
• Autologous bone marrow transplantation has improved the outlook for patients with advanced disease.

Phaeochromocytoma

• Phaeochromocytoma Definition: These are catecholamine producing tumours arising from adrenal medulla and sympathetic ganglia which are derived from chromaffin cells.
• As the name suggests, phaeo (dusty) chromo (chromaffin cells)—phaeochromocytoma is a neoplasm arising from chromaffin cells.
• 90% of the tumour occurs in adrenal glands.
• When phaeochromocytoma occurs in extra-adrenal sites, it is called paraganglioma.
• Extra-adrenal sites include organ of Zuckerkandl (the most common site), urinary bladder, renal hilum, chest, neck, etc. These are the sites of paraganglionic system.
• In about 5% of cases, the tumour can be a component of multiple endocrine neoplasia (MEN) type IIa or type IIb.
• Other syndrome associated with phaeochromocytoma is von Hippel-Lindau syndrome.
• The clinical manifestations are due to release of adrenaline and noradrenaline. When the level of noradrenaline is high, symptoms are severe.

Adrenal Tumours Pathology:

It is a soft, highly vascular tumour consisting of large sympathetic ganglionic cells. Most of the cells are differentiated.

Phaeochromocytoma:

• 10% Bilateral
• 10% Malignant
• 10% Extra-adrenal This 10% rule has
• 10% Multiple been challenged
• 10% Familial
• 10% Children

Other Neuroectodermal Anomalies with Phaeochromocytoma:

• • Neurofibromatosis (NF) type 1
  • Acoustic neuroma
  • Meningioma, glioma, haemangioblastoma (von Hippel-Lindau (vHL)) syndrome
  • Astrocytoma
  • MEN type 2—hereditary phaeochromocytoma
  • Familial paraganglioma syndrome along with carotid body tumours
• Usually, it is small in size and well-encapsulated.
• Sometimes, it can present as a large abdominal mass.
• Microscopic features are polygonal or spheroidal chromaffin cells within a vascularised fibrous stroma.
• Presence of high number of Ki-67 positive cells, vascular invasion or breached capsule and PASS— phaeochromocytoma of the adrenal gland scale score suggests metastasis.

Adrenal Tumours Clinical Features:

• Sporadic cases peak at 40–50 years, whereas familial tend to occur early.
• The most common presenting feature is paroxysmal or persistent hypertension (80–90%). It is associated with palpitation (50–70%), fever, pallor, tremors, sweating and severe headache (60–90%).
• The paroxysmal attack may last for a few minutes to a few hours.
• The factors which stimulate an attack are
  • Surgery
  • Anaesthesia
  • Invasive procedure
  • Late pregnancy
  • Drugs—histamine, glucagon, etc.
  • Palpation of the mass
• Classical triad consisting of headache, diaphoresis and palpitations is seen in only a few patients.
• A high index of suspicion is necessary to diagnose phaeochromocytoma in a hypertensive patient.

Adrenal Tumours Investigations:

1. Urinary levels of free catecholamines, vanillylmandelic acid (VMA) in excess of 7 mg/24 hours and meta-adrenaline 1–3 mg/24 hours are suggestive of phaeochromocytoma.

Hypertension in Phaeochromocytoma:

• Paroxysmal Persistent
• Palpitations Pallor
• Profuse sweating Pain abdomen
• Palpation of the mass

2. Plasma metanephrines: A fractionated plasma-free metanephrine level may be measured. Blood sample drawn after 15–20 minutes of IV catheter insertion (not immediately).

3. Computed tomography:

• Noninvasive, safe investigation
• It has a high degree of accuracy
• It can pick up lesions of less than 1 cm in size.

4. MRI is preferred because contrast media used for CT scan can provoke paroxysms.

5. ¹³¹I Metaiodobenzylguanidine (MIBG) scan:

Iodine labelled MIBG (radionuclide) scan is found to be very specific for phaeochromocytoma. This radionuclide scan locates only abnormal adrenal tissue and is more useful in detecting ectopic sites of phaeochromocytoma (Fig. 38.13).

Adrenal Tumours Treatment:

• Surgical removal is the treatment.1 However, a good preoperative preparation is essential before doing surgery. It includes control of blood pressure and tachycardia, by α- and β-blockers.
• Contraction of vascular bed which occurs due to catecholamines results in hypovolaemia which must be corrected with 4 fluids.

Hyperte Phaeochromocytoma (Preoperative Preparation):

• • Phenoxybenzamine: 20–60 mg/day for 3–4 weeks before surgery to control hypertension—increased to 10 mg/day—total of 100–160 mg.
  • Propranolol: 20–60 mg/day for 5–7 days before surgery to control tachycardia and arrhythmias.
  • Plenty of fluids before surgery to correct hypovolaemia.
• First, alpha-adrenergic blockers such as phenoxybenzamine is given to control hypertension and to permit re-expansion of intravascular volume. Only after the complete alpha-adrenergic blockade, betaadrenergic blockade may be added.

Ten Commandments Of Phaeochromocytoma

1. MRI is better because CT scan provokes paroxysm
2. MIBG—123I single-photon emission CT will diagnose about 90% of cases
3. Should not do FNAC/biopsy of adrenals
4. α-adrenergic blockers should be started first
5. β-blockade is always given after α-blockade
6. CVP and intra-arterial monitoring is a must, as they may hold a large volume of fluids
7. Should also look on the contralateral side for phaeochromocytoma
8. Ligate adrenal vein first
9. Never allow vaginal delivery in patients who have phaeochromocytoma
10. Laparoscopic adrenalectomy is the ‘Gold standard’

Surgery (see ten commandments given above)

Excision is the treatment. Certain steps of excision (adrenalectomy) are as follows:

• Sodium nitroprusside must be kept ready to treat hypertension during surgery as it is a direct arterial vasodilator (0.5 to 10 µg/kg/minute).
• Thorough search in the abdomen for other sites, due to the possibility of multiple tumours.
• Postoperative hypotension can be a serious problem which needs to be treated with large volume of plasma expanders, blood transfusions, corticosteroids and vasopressors.

Precautions During Surgery:

• Midline incision for familial cases
• Anterior or posterior approach for sporadic cases
• Careful positioning
• Ligation of adrenal vein first
• Gentle handling
• Haemodynamic monitoring—CVP, arterial monitoring
• Avoid rupture of the tumour to prevent recurrence
• Laparoscopic adrenalectomy is very popular now

Metastatic Pheochromocytoma

It was called malignant phaeochromocytoma earlier.

• 10% of phaeochromocytomas are malignant.
• Rate is higher in extra-adrenal tumours.
• Malignancy is suspected when metastasis or vascular invasion is present or when a capsule is breached.
• Open adrenalectomy is the choice for excision.
• Debulking should be done even if metastasis is present, so as to decrease tumour burden and to control catecholamine excess.

Incidentalomas

• Incidentally detected adrenal masses.
• Detected by ultrasound or CT scan (1 to 5% of patients undergoing CT abdomen for evaluation of abdominal pain).
• Some patients may have subclinical Cushing’s syndrome or aldosteronism.
• Nonfunctioning situations may be metastatic cancer (primary from breast, kidney, melanoma, lung).
• Myelolipoma
• Adrenal cysts
• Majority of such tumours are nonfunctioning cortical adenomas of no clinical significance.
• Indication to do adrenal gland biopsy is to rule out/ diagnose metastasis.
• Absolute contraindication to do adrenal biopsy in phaeochromocytoma.
• Any nonfunctioning adrenal incidentaloma should be resected.
• Majority of incidentalomas are nonfunctional adenomas.
• Refer to clinical notes.

Clinical Notes:

• An 18-year-old girl was admitted for tonsillectomy. This girl suffered from occasional headache. She was diagnosed to have migraine.
• Preoperative blood pressure showed mild elevations which were thought to be due to anxiety.
• During tonsillectomy, there was a rise in BP, which was controlled well. However, in the postoperative period, there was severe tachycardia, hypertension, arrhythmias and hypovolaemia.
• Within 8 hours of surgery, the patient died even as the diagnosis of phaeochromocytoma was being considered.