1. Diseases of adrenal cortex & medulla
Ali Al Khader, M.D.
Faculty of Medicine
Al-Balqa’ Applied University

2. Lecture outline Tumors of the adrenal medulla:
Adrenocortical hyperfunction (Hyperadrenalism):
-Hypercortisolism (Cushing syndrome)
-Primary hyperaldosteronism
-Adrenogenital (virilizing) syndromes…excess androgens
Adrenocortical insufficiency
Adrenocortical neoplasms
Tumors of the adrenal medulla:
-Pheochromocytoma
-Neuroblastoma

3. Hypercortisolism (Cushing syndrome)
Endogenous
Exogenous (Iatrogenic)
The most common
Immunodeficiency
Hypertension
Diabetes
ACTH-independent
ACTH-dependent
Less common than
-Adrenal adenoma
-Adrenal carcinoma
-Hyperplasia (a subset
of them is seen in
McCune-Albright
syndrome (GNAS
mutations))
-Pituitary
tumor (mostly
ACTH-secreting
microadenoma)
-Rarely: increased
CRH (from
hypothalamus)
Ectopic ACTH
…e.g., lung
small cell
carcinoma
Menstrual abnormality
Middle-aged
males more
Mental/psychological
manifestations
= Cushing disease
Young adult
females more

4. Cushing syndrome, laboratory diagnosis
Cushing disease
Ectopic ACTH
Adrenal tumor
-ACTH is not suppressed
with low-dose dexamethasone
…urinary steroid secretion
is not decreased
-ACTH is suppressed with
high-dose dexamethasone
is decreased
No response to high-
or low-dose dexamethasone
ACTH is already low
and cortisol excretion
is not affected by low-
or high-dose
dexamethasone

5. Primary hyperaldosteronism
The most common cause of 2ry hypertension
Autonomous overproduction of aldosterone, with resultant suppression of the renin-angiotensin system and decreased plasma renin activity
Causes:
Bilateral idiopathic hyperaldosteronism…the most common
Bilateral nodular hyperplasia
Adenoma (Conn syndrome)
or carcinoma
Older age & less severe hypertension than
hyperaldosteronism due to adrenal tumor
Middle-aged women more
2ry Hyperaldosteronism:
…in response to activation of the renin-angiotensin system
…characterized by increased levels of plasma renin
…seen in conditions of decreased renal perfusion

6. Primary hyperaldosteronism, clinical features & diagnosis
Hypertension with resulting left ventricular hypertrophy and cardiovascular compromise, strokes & MIs
Hypokalemia (weakness, paresthesias, visual disturbances, and occasionally frank tetany)
Elevated plasma aldosterone to renin ratio
…if this screening test is positive, a confirmatory aldosterone
suppression test (by salt or captopril for example) must be performed
…if the aldosterone levels are still high and the renin levels are still low
after the suppression test, the diagnosis is confirmed

7. Adrenogenital (virilizing) syndromes
Adrenocortical neoplasms
Congenital adrenal hyperplasia (CAH)
Carcinomas more than adenomas
The most common enzymatic defect in CAH is 21-hydroxylase deficiency…a spectrum of severity depending on the mutation
21-hydroxylase is required for synthesis of
cortisol and aldosterone but not sex steroids
Cortisol is not synthesized
(&/or aldosterone)
In response to ACTH, no cortisol will be synthesized but the androgen
synthesis pathway will be activated instead
ACTH is increased

8. Adrenogenital (virilizing) syndromes, clinical features
The onset of clinical symptoms may occur in the perinatal period, later childhood, or (less commonly) adulthood
In 21-hydroxylase deficiency:
-Masculinization (virilization) in females:
-In males:
Enlargement of the external genitalia, precocious puberty in young patients. Most men with CAH are fertile but some have failure of Leydig cell development and oligospermia
1/3: aldosterone deficiency and some may have risk
for acute adrenal insufficiency
Clitoral hypertrophy and pseudohermaphroditism in infants or oligomenorrhea, hirsutism, and acne
in postpubertal girls …an ovarian tumor must also be excluded
Always rule out CAH in any neonate with ambiguous genitalia

9. Adrenocortical insufficiency
No hyperpigmentation
Normal aldosterone
Hyperpigmentation
Primary
Secondary
= Adrenal crisis
…due to ACTH deficiency
= Addison disease
Fatigue
Vomiting
Diarrhea
Anorexia, nausea & weight loss
Hypoglycemia
Hyperkalemia
Hyponatremia
Hypotension
…mainly: lung & breast

10. Notes on adrenocortical adenoma and carcinoma
The most common adrenal malignancy is metastases (especially from the lung or breast)
Adenoma is usually nonfunctional and is usually discovered incidentally (incidentaloma)
“Functional” or “nonfunctional” cannot be predicted from morphology
Behavior is more important than morphology to differentiate between adenoma and carcinoma

11. Pheochromocytoma A tumor of chromaffin cells
Catecholamine cardiomyopathy, or catecholamine-induced myocardial instability and ventricular arrhythmias and cerebrovascular accidents are serious complications
A tumor of chromaffin cells
A cause of 2ry hypertension…mainly paroxysmal (with palpitations, sweating & tremor)
Rule of 10s:
10% of pheochromocytomas are extraadrenal… = paragangliomas
10% of adrenal pheochromocytomas are bilateral
10% of adrenal pheochromocytomas are malignant
10% of adrenal pheochromocytomas are not associated with hypertension
25% are familial…6 known genes (RET, NF1, VHL, SDHB, SDHC, SDHD)
There is usually base-line hypertension
Lab results: Increased urinary excretion of free catecholamines and their metabolites, such as vanillylmandelic acid and metanephrines

13. Neuroblastoma The most common extracranial solid tumor of childhood
…most commonly during the first 5 years of life and may arise during
infancy
It arises from primordial neural crest cells
Neuroblastomas may occur anywhere in the sympathetic nervous system and occasionally within the brain, but they are most common in the abdomen (esp., adrenal medulla)

14. A small round blue cell tumor
Necrosis is common
Mitoses are numerous
Apoptotic activity is high

15. Neuroblastoma *Age <18 months: favorable prognosis
Unfortunately, most (60% to 80%) children present
with stage 3 or 4
4S tumors have an excellent prognosis with minimal therapy, and it is not uncommon for the primary or metastatic 4S tumors to undergo spontaneous regression
*Age <18 months: favorable prognosis
*Certain genetic/chromosomal abnormalities are important in the prognosis (e.g., MYCN oncogene amplification is bad)
*Certain histological features are important in the prognosis (Gangliocytic differentiation is associated with favorable prognosis, high mitotic activity is bad)
*Stages 1, 2A, 2B & 4S are better than 3 & 4

16. Thank You