Diseases of adrenal cortex & medulla Ali Al Khader, M.D. Faculty of Medicine Al-Balqa’ Applied University Email: ali.alkhader@bau.edu.jo

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

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

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

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

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

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

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

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

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

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

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)

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

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

Thank You