Where does the adrenal cortex arise from? Medulla?
cells associated with the coelomic epithelium, which are of mesodermal origin.
Medulla- neural crest
Layers of the adult adrenal cortex. The zona fasciculata makes up about 75% of the cortex
What is the adrenal medulla made of?
chromaffin cells, which synthesize and secrete catecholamines, mainly epi.
What are the adrenocortical hyperfunction diseases?
1) Cushing sydrome
3) adrenogenital or virilizing syndromes
What are the main causes of Cushing's syndrome?
the vast majority are the result of administration of exogenous glucocorticoids (iatrogenic). The rest are endogenous, and the 3 most common disorders are:
1) primary hypothalamic-pituitary diseases with hypersecretion of ACTH (aka Cushing disease) 70% of endogenous cases
2) ectopic ACTH secretion
3) primary adrenocortical neoplasms (adenoma or carcinoma)
Is Cushing disease more common in men or women? What is the major cause?
4x higher in women and primarily in young adulthood. In the vast majority of cases, the pituitary gland contains an ACTH-producing microadenoma (and in the remaining pts. the anterior pitutiary contains areas of corticotroph cell hyperplasia without a discrete adenoma)
What do the adrenal glands in pts. with Cushing disease look like?
variable degress of bilateral nodular cortical hyperplasia, secondayr to elevated levels of ACTH (aka ACTH dependent Cushing syndrome)
Secretion of ectopic ACTH by nonpitutiary tumors accounts for about ____% of cases of Cushing syndrome
10. In many cases the resposnible tumor is a small cell carcinoma of the lung
NOTE: In addition to tumors that elaborate ectopic ACTH, an occasional neuroendocrine neoplasm produces ectopic CRH
Primary adrenal neoplasma, such as adrenal adenoma and carcinoma, and rarely, primary cortical hyperplasia, are responsible for about ___% of cases of endogenous Cushing syndrome
15-20%. This form of Cushing syndrome is designated ACTH-independent or adrenal Cushing syndrome
How can adrenal Cushing syndrome be ID'd?
elevated cortisol with low levels of ACTH
What is a Crooke hyaline change?
In this condition, when high levels of glucocorticoids (endogenous or exogenous) cause Cushing syndrome, the normal granular, basophilic cytoplas of the corticotrophs in the anterior pituitary is replaced by homogenous, lightly basophilic material as the result of accumulation of intermeidate keratin filaments in the cytoplasm.
How do the adrenal respons to Cushing syndrome caused by exogenous glucocorticoids?
suppression of endogenous ACTH results in bilateral corticol atrophy of the zona fasciculata and reticularis, due to a lack of stimulation from ACTH, while the zona glomerulosa remains the same thickness
In cases of endogenous hyperorticolism, the adrenal are either hyperplastic or contain a corticol neoplasm
________ is found in pts with ACTH-dependent Cushing syndrome
Diffuse hyperplasia of both glands and the adrenal cortex is diffusely thickened and variably nodular (although not as pronounced as in cases of ACTH-independent nodular hyperplasia). The yellow color of the cortex derives from the presence of lipid-rich cells
How does the cortex of an ACTH-independent Cushing's pts (i.e. primary cortical hyperplasia) look?
replaced almost entirely by lipofuscin filled macro- or micronodules
How do adrenal adenomas or carcinomas present morphologically?
Adrenocortical adenomas are yellow tumors surrounded by a thin capsule and can be distinguished from nodular hyperplasia by its solitary, circumscribed nature (below). Carcinomas tend to be large and nonencapsulated.
NOTE: the functional status of an adrenocrtical adenoma or carcinoma cannot be determined by morphology.
What is this?
An adrenocortical adenoma. The neoplastic cells are vacuolated because of the presence of intracytoplasmic lipids. There is mild nulcear pleomorphism and mitotic activity and necrosis are not seen
How does Cushing's syndrome present?
Cushing syndrome develops gradually (Unless if its the result of a paraneoplastic syndrome of small cell carcinomas of the lung). Early manifestations include HTN and weight gain and with time more truncal obesity becomes apparent, as well as moon facies, posterior neck fat (buffalo hump), decreased muscle mass and proximal limb weakness, and other symptoms
What other symptoms are seen in Cushing's syndrome?
hyperglycemia, glucouria, and polydipsia (mimicking diabetes)
bone resorption and osteoporosis
cutaneous striae in the abdominal area
increased risk of infections
hirutism and menstrual abnormalities
mental disturbances, including mood swings, depression, and frank psychosis
Why does Cushing syndrome cause muscle weakness and loss of muscle mass?
Hypercortisolism causes selective atrophy of fast-twitch (type II) myofibers
What causes secondary hyperaldosteronism?
aldosterone is released in response to activation of the renin system. E.g. in response to decreased renal perfusion (arteriolar nephrosclerosis, renal artery stenosis), arterial hypovolemia and edema (congestive heart failure, cirrhosis, nephrotic syndrome), or pregnancy (due to estrogen-induced increases in plasma renin substrate)
(so renin will be increased as opposed to primary hyperaldosteronism in which renin would be decreased due to negative feedback)
What are some causes of primary hyperaldosteronism?
-bilateral idiopathic hyperaldosteronism
-rarely, familial hyperaldosteronism may result from a gain of function mutation of the aldosterone synthase gene, CYP11B2
How is bilateral idiopathic hyperaldosteronism described?
there is bilateral nodular hyperplasia of the adrenal glands. This accouns for 60% of cases of primary hyperaldosteronism but the pathogenesis is unclear
What are the most common adrenocortisol neoplasms causing primary hyperaldosteronism?
functional adenoma (Conn syndrome)
rarely, a carcinoma
Describe aldosterone-secreting adenomas. Age group?
almost always solitary, small (less than 2cm), and well-circumscribed
frequently on the left adrenal gland
Common in women in their 30-40s
How might you differeniate a cortisol vs. aldosterone secreting adenoma based on morphology?
In contrast to cortical adenomas associated with Cushing syndrome, those associated with hyperaldosteronism do not usually suppress ACTH secretion. Therefore, the adjacent adrenal cortex and that of the contralateral gland are not atrophic.
What is seen in the adrenal cortex after tx of hyperaldosteronism with spironolactone?
eosinophilic, laminated cytoplasmic inclusions, known as spironolactone bodies
How does hyperaldosteronism present?
the hallmark is HTN leading to a compromised CV system, as well as marked hypokalemia which manifests mostly neuromuscularly as weakness, paresthesias, visual disturbances, etc.
What compounds are secreted by the adrenal cortex for androgen maintanence?
dehydroepiandrosteone (DHEA) and androstenedione, which both require converion to testosterone in peripheral tissue for effect
What are the common causes of adrenal androgen excess?
-adrenocrticol neoplasms (more likely to be carcinomas)
congenital adrenal hyperplasia (CH) due to hereditary enzymatic deficiencies
MOI of CAH?
NOTE: The main cause of excess adrenal androgens caused by CAH isa ctually defective cortisol enzymes which causes backup and shift to producing more androgens
What is the most common CAH defect and how does it present?
21B-hydroxylase (90%) causing virilization of female infants, enlargement of the external genitalia in males, and 1/3rd of the time signs of hypoaldosteronism
NOTE: severity can range from a total lack to a mild loss, depending on the nature of the underlying mutation
What studies would indicate 21B-hydroxylase deficiency?
How would 21B-hydroxylase def be treated?
glucocorticoid therapy to reduce ACTH and aldosterone replacement
How does 11B-hydrolase def (5%) related CAH present?
virilization of female infants
decreased cortisol levels
increased mineralcorticoid production and action via increased 11-deoxycorticosterone levels! leading to HTN but no salt wasting
What studies would suggest a 11B-hydroxylase def?
high 11-deoxycorticosteone, elevated DHEA and androstenedione
How would a 11B-hydroxylase def be treated?
How would a 17a-hydroxylase def (rare) present?
hypogonadism, HTN and hypokalemia
Studies for 17a-hydroxylase def?
high 11-deoxycorticosterone, FSH, and LH
decreased DHEA, estrogen, and testosterone
17a-hydroxylase def tx?
glucocorticoid therapy and sex hormone replacement
How would a 3B-hydroxydehydrogenase def (rare) present?
virilization of female infants, salt wasting, and male pseudohermapheroditism
What studies would suggest a 3B-hydroxydehydrogenase def?
High ratio of delta-5-pregnenolone to progesterone
Tx for 3B-hydroxydehydrogenase def?
glucocrticoids, mineralcorticoids, and sex hormone
What are the three categories of adrenal insufficiency?
-primary acute adrenocortical insufficiency (adrenal crisis)
-primary chronic adrenocrtical insufficiency (Addison disease)
-secondary adrenocrtical insufficiency
What are the most common causes of acute adrenocortical insufficiency?
-Sudden withdrawal of long-term corticosteroid therapy
-stress in pts with underlying chronic adrenal insufficiency
-massive adrenal hemorrhage
What conditions may predispose to adrenal hemorrhage?
chronic anticoag therapy
postoperative pts who develop DIC
sepsis (aka Waterhouse-Friderichsen syndrome)
Waterhouse-Friderichsen syndrome is most commonly assoicated with what bugs?
Neisseria meningitidis, but also Pseudo, pneumococci, and H. flu
How does Waterhouse-Friderichsen syndrome present?
overwhelming sepsis develops leading to primary adrenal insufficiency causing hypotension and shock, hemorrhagic obileration of the adrenals, and DIC
What are most cases of Addison's disease caused by?
-autoimmune adrenalitis (60-70%)
NOTE: About 90% of tissue has to be destroyed for clinical manifestations
Autoimmune adrenalitis occurs in 1 of 2 Autoimmune Polyenddocrine Syndromes (APS1 or 2). What causes these?
APS1- AIRE mutation on chrom 21
How does APS1 present?
chronic mucocutanous candidiasis and abnormalities of skin, dental enamel, and nails occurring in association with a combination of organ-specific autoimmune disorders (autoimmune adrenalitis, autoimmune hypoparathyroidism, idiopathic hypogonadism, pernicious anemia)
How does APS2 present?
in early adulthood as a combo of adrenal insufficiency and autoimmune thyroiditis or type I diabetes.
NOTE: mucocutaneous candidiasis, ectodermal dysplasia, and autoimmune hypoparathyroidism do not occur here
What is this?
In addition to loss of all but a subcapsular rim of cortical cells, ther is extensive mononuclear infiltarte seen in autoimmune adrenalitis
Notes about TB induced primary adrenocortical insufficiency
When present, TB adrenalitis (gross, below) is usually associated with active infection in other sites, such as the lungs and GI tract
NOTE: Histo and Coccidioides immites can also cause chronic insufficiency
What is more common, primary adrenal tumors or METs? Common sites of primaries?
METs (carcinomas) by far from lung, breast, and kidney mostly
Hyperpigmentation is a sign of what type of hypoadrenalism, primary or secondary?
How does adrenal insufficiency present?
In general, clinical manifestations dont occur until 90+% of the adrenal cortex is compromised. The initial manifestations include progressive weakness and GI disturbances including anorexia, N/V, weight loss, and diarrhea.
If acute, symptoms such as vomiting, abdominal pain, and hypotension leading to coma are common
How can primary vs. secondary hypoadrenolism be differentiated?
hyperpigmentation and hypoaldosteronism are seen in primary pts.
secondary pts. present with deficient cortisol and androgen putput but normal aldosterone synthesis
T or F. While functioning adrenal adenomas are most commonly associated with hyperaldosteronism and Cushing syndrome, a virilizing neoplasm is more likely to be a carcinoma
NOTE: However, most adrenal corticol adenomas are not functioning
Describe adrenal corticol adenomas
Usually clinically silent, small (1-2cm in diameter), well-circumscribed, and if non-functional will not show corticol morphologic changes
How do adrenal corticol adenomas appear grossly?
cut surface is yellow due to lipids
Describe adrenal cortical adenomas morphologically
The neoplastic cells are vacuolated because of the presence of intracytoplasmic lipid. There is mild nuclear pleomorphism. Mitotic activity and necrosis are not seen
I.E. They dont look much different than normal
Describe adrenocortical carcinomas
rare neoplasms that can occur at any age
•More likely to be functional;
•Usually large (>20cm) and invasive (adrenal vein, vena cava and lymphatics). Bone METS is unusual
•Median survival 2 years
What two inherited conditions commonly cause adrenocrtical carcinomas?
Li-Fraumeni syndrome and
Carcinomas in the adrenal cortex are MUCH more likely to metastatic from another source
What causes chromaffin cells to secrete catecholamines?
signals from preganglionic nerves from the SNS
What is a Pheochromocytoma?
neoplasms from chromaffin cells (neural crest) primarily in adults that give rise to a surgically correctable form of HTN
What is the rule of 10s of pheochromocytomas?
-10% of pheos are extraadrenal (occuring in the carotid body of organ of Zuckerkandl, in which they are then called paragangliomas)
-10% of adrenal pheos are bilateral
-10% of adrenal pheos are malignant (most common if extraadrenal)
-10% percent of adrenal pheochromocytomas are not associated with hypertension
NOTE: Of the 90% that present with hypertension, approximately two thirds have “paroxysmal” episodes associated with sudden rise in blood pressure and palpitations, which can, on occasion, be fatal.
As many as 25% o persons with pheos are paragangliomas harbor a germline mutation in one of at least six known genes including ____.
These present younger and are more likely to be bilateral
RET (which causes MEN syndromes),
NF1 (which causes neurofibromatosis)
genes of the succinate dehydrogenase complex (SDHB, SDHC, and SDHD) involved in oxidative phosphorylation
The affected genes fall into two broad classes:
•those that enhance growth factor receptor pathway signaling (e.g., RET, NF1 ),
•those that increase the activity of the transcription factor HIF-1α - VHL gene encodes a tumor suppressor protein that is needed for the oxygen-dependent degradation of HIF-1α and is mutated in patients with von Hippel-Lindau (VHL) syndrome, which is associated with a number of tumors, including pheochromocytoma.
How do pheos appear?
can range dramatically in size. On cut surface, they are yellow-tan, well-defined lesions that compress adjacent adrenals. Larger lesiosn tend to be hemorrhagic, necrotic, and cystic
What are Zellballen?
On microscopic examination, pheos are composed of polygonal to spindle-shaped chromaffin cells compartmentalized into small nests called Zellballen
T or F. Capsular and vascular invasion is diagnostic of a malignant pheo
F. Both benign and malignant cant show this. Thus, the definitive diagnosis of malignancy is based exclusively on the presence of METs
How are pheos diagnosed? Tx?
Diagnosis: Urinary VMA and HVA and plasma catecholamines are elevated
Tx: a-antagonists, especially phenoxybenzamine, along with a BB, followed by surgery to remove the tumor
How do pheos present?
abrupt onset of HTN is characteristic, associated with tachycardia, HA, sweating, tremor, etc. (occurs in roughly half of pts.)
This HTN raises the risk of CV failure including MI, stroke, etc.
What are some conditions with pheos?
Neurofibromatosis type 1
Von Hippel Lindau
Familial paraganglioma 1,3, and 4
How does Neurofibromatosis type 1 present?
pheos (sometimes) with neurofibromatosis, cafe-ai-lait spots, and optic nerve gliomas
How does Von Hippel Lindau (VHL) present?
pheos (or paragangliomas) with renal cell carcinomas (clear type), hemangioblastomas, and pancreatic endocrine neoplasms
How does Sturge Weber present?
cavernous hemangiomas (port wine spots) of trigeminal nerve and pheos
What are neuroblastomas?
Neoplasms of postganglionic sympathetic neurons found most often in children under 5 yo (3rd most common pediatric cancer witn a mean age of onset at 18 months)
–Primarily located in the adrenal medulla
What causes neuroblastomas?
–Amplification of N-MYC oncogene (bad prognosis if amplified)
Where do Neuroblastomas MET to? How often?
•Commonly metastasize to skin and bones
–Approximately 70% have metastases at the time of diagnosis – hematogenous
How do neuroblastomas present?
(1) Palpable abdominal mass
(2) Diastolic hypertension
(3) Increased urine VMA and HVA (90%–95% sensitivity)
What are these?
Homer-Wright rosettes seen in neuroblastomas
How are neuroblastomas diagnosed?
(1) Urine collections for VMA and HVA
–Dx: urine for VMA, HVA
(2) Imaging studies
•(a) Body scan with 131 I-MIBG (metaiodobenzylguanidine)
–• Malignant cells pick up the radioactive material.
•(b) Bone scans to detect lytic lesions
How are neuroblastomas treated?
–(1) Depends on age, stage of disease
–(2) Surgery, irradiation, multiagent chemotherapy
What is the prognosis for neuroblastomas?
–(1) Overall survival is 40%.
–(2) Children <1 year old have a 90% cure rate.
How does Addison's disease present?
primary adrenal insufficiency leads to deficiency of aldosterone and cortisol primarily (sex hormones are less affected) leading to signs like hypotension, hyperkalemia, and acidosis as well as skin hyperpigmentation