1. Arthur S. Schneider, M.D. Department of Pathology
Adrenal Disorders
Arthur S. Schneider, M.D. Department of Pathology

2. Adrenal hyperfunction

3. Diffuse hyperplasia of adrenal (bottom illustration) from Robbins-Cotran PBD, 8e

4. Cushing syndrome hypercorticism regardless of cause
medical use of exogenous adrenal corticoids – most frequent cause
hyperproduction of ACTH by corticotrophs of the pituitary (“Cushing disease”)
Ectopic ACTH production
primary adrenal causes 

5. Adrenal hypercorticism secondary to pituitary disease (Cushing Disease)
corticotropic adenoma (basophilic adenoma) hypersecretion of adrenocorticotropic hormone (ACTH) increased production of adrenal cortical hormones
also may be caused by basophilic microadenomas– often multiple

6. Other causes of Cushing syndrome
adrenal causes
adrenal cortical adenoma
adrenal carcinoma (less common than adenoma)
ectopic ACTH production
small cell lung carcinoma
various other tumors
Hypercorticism autonomous--not suppressed by exogenous adrenal steroids as in dexamethasone suppression tests

7. Dexamethasone suppression tests
test given at low (usually 1–2 mg) and high (8 mg) doses of dexamethasone
levels of cortisol are measured
low dose dexamethasone suppresses cortisol when there is no pathology in endogenous cortisol production
high dose dexamethasone exerts negative retro-control on pituitary ACTH producing cells but not on ectopic ACTH producing cells or adrenal adenoma

8. ACTH measurements in hypercorticism
increased in pituitary hypercorticism and in ectopic ACTH production
low when hypercorticism is of adrenal origin

9. Morphologic changes bilateral hyperplasia of adrenal zona fasciculata
occurs when syndrome results from ACTH stimulation
adrenal cortical atrophy when exogenous glucocorticoid medication is cause
adrenal cortical adenoma or carcinoma: adenoma more common

10. Cushing syndrome from Robbins-Cotran PBD, 8e

11. Cushing syndrome – clinical characteristics
round moon face
dorsal “buffalo hump”
relatively thin extremities
muscle wasting and weakness
skin atrophy
easy bruising and purplish striae over abdomen
hirsutism
muscle weakness
osteoporosis, amenorrhea, hypertension, hyperglycemia, psychiatric dysfunction

12. Summary—Pituitary Cushing disease
Increased corticotropin (ACTH)
corticotropic (basophilic) adenoma or multiple corticotropic microadenomas

13. Summary -- Cushing syndrome (hypercorticism)
Bilateral hyperplasia of adrenal zona fasciculata secondary to hyperactivity of pituitary corticotrophs or to ectopic ACTH-like production by a variety of tumors; adrenal cortical adenoma
May be of pituitary, adrenal, or ectopic origin; can also result from administration of exogenous hormone

14. From Rubin’s Pathology

15. From Rubin’s Pathology

16. Primary aldosteronism (Conn syndrome)
primary hyperproduction of adrenal mineralocorticoids.
usual cause: adrenocortical adenoma (aldosteronoma)
also can result from hyperplasia of zona glomerulosa
adrenocortical carcinoma much less common than adenoma or hyperplasia.

17. Clinical characteristics -- primary aldosteronism
hypertension
sodium and water retention
hypokalemia
decreased serum renin
negative feedback of increased blood pressure on renin secretion

18. Primary aldosteronism from Robbins-Cotran PBD, 8e

19. Secondary aldosteronism
secondary to renal ischemia, renal tumors, and profound edema of any cause such as cirrhosis, nephrotic syndrome, cardiac failure
caused by stimulation of renin-angiotensin system
serum renin increased (contrast to primary aldosteronism)

20. Serum renin in secondary aldosteronism
increased (contrast to primary aldosteronism)
synthesized in juxtaglomerular apparatus
promotes conversion of angiotensinogen to angiotensin I
angiotensin I converted by angiotensin-converting enzyme (mainly in the lung) to angiotensin II
angiotensin II facilitates release of aldosterone

21. Summary -- hyperaldosteronism (aldosteronism)
primary
adenoma or hyperplasia of zona glomerulosa
serum renin decreased
secondary
bilateral hyperplasia of zona glomerulosa caused by stimulation of renin-angiotensin system
serum renin increased; frequently secondary to edema, regardless of the cause

22. Adrenal virilism (adrenogenital syndrome)
congenital enzyme defects lead to diminished cortisol production
compensatory increased ACTH adrenal hyperplasia androgenic steroid production
21-hydroxylase deficiency most common. in most severe “salt-wasting” form  salt loss and hypotension
11-hydroxylase deficiency, much less common salt retention and hypertension.

23. Adrenogenital syndrome clinical characteristics
virilism in females
precocious puberty in males

24. 21-hydroxylase deficiency from Robbins-Cotran PBD, 8e

25. Summary--adrenal virilism
adenoma, carcinoma, or hyperplasia of zona reticularis
Can be due to hyperplasia resulting from congenital enzyme deficiencies such as 21-hydroxylase and 11-hydroxylase deficiencies

26. Adrenal hypofunction

27. Deficiency of pituitary ACTH
adrenal failure is secondary
no hyperpigmentation of the skin
lack of b-melanocyte-stimulating hormone (β-MSH ) as well as ACTH
contrasts with primary adrenal failure (Addison disease) in which ACTH and β-MSH is increased and hyperpigmentation is the rule

28. Hypocorticism (adrenal hypofunction)
cause is primary in adrenal or secondary to hypothalamic or pituitary dysfunction
deficiency of glucocorticoids (primarily cortisol), often with associated mineralocorticoid deficiency

29. Addison disease (primary adrenocortical deficiency)
idiopathic adrenal atrophy (autoimmune lymphocytic adrenalitis) most common cause
tuberculosis (former most common cause)
metastatic tumor, and various infections

30. Addison disease -- characteristics
hypotension
increased pigmentation of skin
decreased serum sodium, chloride, glucose, and bicarbonate
increased serum potassium

31. Addison disease secondary to tuberculosis

32. Addison disease secondary to tuberculosis

33. Waterhouse-Friderichsen syndrome
catastrophic adrenal insufficiency and vascular collapse
due to hemorrhagic necrosis of the adrenal cortex.often associated with disseminated intravascular coagulation (DIC)
classically due to meningococcemia, most often in association with meningococcal meningitis

34. Waterhouse-Friderichsen syndrome from Robbins-Cotran PBD, 8e

35. Waterhouse-Friderichsen syndrome

36. Waterhouse-Friderichsen syndrome from Robbins-Cotran PBD, 8e

37. Autoimmune adrenalitis from Robbins-Cotran PBD, 8e

38. Tumors of adrenal medulla

39. Adrenal cortical adenoma from Robbins-Cotran PBD, 8e

40. Adrenal cortical adenoma from Robbins-Cotran PBD, 8e

41. from Robbins-Cotran PBD, 8e

42. Adrenal cortical carcinoma (left) from Robbins-Cotran PBD, 8e

43. Pheochromocytoma derived from chromaffin cells of the adrenal medulla;
when derived from extra-adrenal chromaffin cells, called paraganglioma
most often benign; 10% malignant.
surgically correctable hypertension

44. Pheochromocytoma hypertension usually paroxysmal (episodic)
may be persistent
results from hyperproduction of catecholamines (epinephrine and norepinephrine)
increased urinary excretion of catecholamines and their metabolites (metanephrine, normetanephrine, vanillylmandelic acid)

45. Pheochromocytoma tumor can also cause hyperglycemia
can be part of MEN IIa or MEN IIb (III)

46. Pheochromocytoma other associations
von Hipple-Lindau disease
renal, hepatic and pancreatic cysts
renal cell carcinomas
cerebellar hemangioblastomas
von Recklinghausen disease
neurofibromatosis
schwannomas, gliomas
Sturge-Weber
cavernous hemangiomas

47. Pheochromocytoma from Robbins-Cotran PBD, 8e

48. Pheochromocytoma from Robbins-Cotran PBD, 8e

49. Pheochromocytoma from Robbins-Cotran PBD, 8e

50. Neurosecretory granules in a pheochromocytoma

51. Neuroblastoma highly malignant catecholamine-producing tumor
occurs in early childhood
urinary catecholamines and catecholamine metabolites are same as in pheochromocytoma
tumor causes hypertension
usually originates in adrenal medulla
often presents as large abdominal mass

52. Neuroblastoma amplification of N-myc oncogene
thousands of gene copies per cell
characteristic karyotypic changes (homogeneously staining regions or double minute chromosomes)
number of N-myc gene copies related to aggressiveness of the tumor.
occasionally converts into more differentiated form – ganglioneuroma
change reflected by marked reduction in number of gene copies

53. Summary – adrenal medullary tumors
pheochromocytoma
chromaffin cell tumor; benign or malignant
tumor secretes catecholamines (epinephrine and norepinephrine) and causes secondary hypertension
neuroblastoma
malignant “small blue cell” tumor of adrenal medulla
catecholamine-secreting malignancy of early childhood; hypertension 

54. Thank you for your attention.54