5. Robbins: Adrenal Glands Flashcards
Adrenal glands are made up of the [adrenal cortex] and the [adrenal medulla].
What are the zones of the adrenal cortex.
Capsule
- Zona glomerulosa => mineralcorticoids (aldosterone); SALTY
- Zona fasiculata => glucocorticoids (cortisol); SWEET
- Zona reticularis => sex steroids (estrogens and androgens); SEX
Medulla
GO FIND REX; MAKE GOOD SEX
Adrenal glands are made up of the [adrenal cortex] and the [adrenal medulla].
What cells are in the adrenal medulla.
Chromaffin cells => catecholamines (mainly EPI)
Syndromes of Adrenal Hyperfunction
- 1. Cushings Syndrome
- 2. Hyperaldosteronism
- 3. Adrenogenital or Virulizing Syndromes
Vast majority of Cushings syndrome is due to what?
Iatrogenic Cushings Syndrome = exogenous glucocorticoid administration
MCC of endogenous hypercorticolism?
ACTH-secreting pituitary adenomas (Cushings Disease)
What are the causes of Hypercorticolism (Cushings Syndrome)?
-
Primary Hyperadrenalism (ACTH-independent)
- Adrenal adenoma
- Adrenal carcinoma
-
Secondary Hyperadrenalism (ACTH-dependent)
- ACTH pituitary adenoma
- Ectopic ACTH-secreting tumor
What are ectopic ACTH-secreting tumors that cause Cushings syndrome?
- Small cell lung cancer *
- Pancreatic cancer
- Neural tumors
Cushings Syndrome => hypercortisolism
What is the effect on the adrenal glands in ACTH-dependent causes of Cushings Syndrome (Cushings disease or ectopic ACTH-producing tumor)?
[Bilateral Cortical Hyperplasia]
Bilateral atrophic adrenal glands would be expected in which variant of Cushing Syndrome?
“Iatrogenic” Cushing Syndrome = administration of exogenous glucocorticoids
What are the serum levels of cortisol and ACTH like in adrenal adenomas/carcinomas?
- ↑↑↑ serum cortisol
- ↓↓↓ serum ACTH
What are the serum levels of cortisol and ACTH like in ACTH-dependent causes of hypercortisolism?
- - ↑↑↑ serum cortisol
- - ↑↑↑ serum ACTH
Morphological Changes in the Pituitary Gland in Hypercorticolism
- Pituitary change occur no matter the cause.
- 1. Crook hyaline change = high levels of endogenous or exogenous glucocorticoids cause the basophilic cytoplasm of ACTH-producing cells => homogenous and pale due to accumulation of intermediate keratin filaments in cytoplasm.
Morphological Changes in the Adrenal Glands in Hypercortisolism
- Changes depend on cause;
- 1. Cortical atrophy
- 2. Diffuse hyperplasia
- 3. Macronodular or micronodular hyperplasia
- 4. Adenoma / carcinoma
What causes bilateral cortical atrophy of the adrenal glands?
Exogenous glucocorticoids;
- Zona fasiculata and reticularis => atrophy because they are not stimulated
- Zona glomerulosa => NL thickness because does not respond to ACTH
What is macronodular hyperplasia of the adrenal glands?
Adrenal glands are replaced with nodules (< 3 cm) with lipid-poor + lipid-rich cells; areas between nodules have micronodular hyperplasia
What is micronodular hyperplasia of the adrenal glands?
1-3mm darkly pigmented (brown/black) micronodules made up of lipofuscin with atrophic intervening areas.
Both benign and malignant adrenocortical adenomas are more common in which sex and age range?
Women in their 30s - 50s.
What is a major morphological difference between adrenocortical adenomas and adrenocortical carcinomas?
- Adenomas: yellow, smaller (less than 30 gm), / thin- or well-developed capsules
- Carcinomas: MUCH large ( >300 gm), UNencapsulated masses
How can we determine the cause of Cushings Disease?
Measure:
- 1. Serum ACTH
- Measure urinary steroid excretion after administration of dexamethasone.
Results of dexamethasone suppresion test for a patient with Cushings Disease (pituitary microadenoma)?
- ACTH is elevated
-
Low dose dexamethasone test = ACTH not supressed
- No reduction in urinary excretion of 17-hydroxycorticosteroids
-
High dose dexamethasone test = ACTH suppressed
- Reduction in urinary excretion of 17-hydroxycorticosteroids
Which cause of Cushing Syndrome will have elevated levels of ACTH which is completely insensitive to low or high doses of exogenous dexamethasone?
Ectopic ACTH-producing tumors
Results of dexamethasone suppresion test for a patient with Cushing Syndrome caused by an adrenal tumor?
ACTH is low
- Low dose dexamethasone test = ACTH not supressed
- High dose dexamethasone test = ACTH not suppressed
*
Hypercortisolism causes selective atrophy of fast-twitch myofibers resulting in what clinical manifestations?
- Decreased muscle mass
- Proximal limb weakness
Results of dexamethasone suppresion test for a patient with Ectopic ACTH secretion?
ACTH is high
- Low dose dexamethasone test = ACTH not supressed
- High dose dexamethasone test = ACTH not suppressed
What does aldosterone do?
Retain Na+ => retain BV/BP.
Causes of Primary Hyperaldosteronism
How does it affect RAAS system?
-
Primary Hyperaldosteronism: ↑ aldosterone => supress RAAS (+)
- Bilateral Idiopathic hyperaldosteronism *** MC
-
Neoplasm
- Aldosterone- secreting adenoma (Conn Syndrome)
- Adrenocorticocarcinoma
- Glucocorticordiod-remediable hyperaldosteronism
Causes of Secondary Hyperaldosteronism
Things that (+) RAAS system => ↑ plasma renin => ↑ aldosterone
- Diuretic use
- ↓ renal perfusion
- Arterial hypovolemia and edema
- Pregnancy (estrogen ↑ plasma renin)
- Renin-secreting tumors
MC manifestation of primary hyperaldosteronism is __________.
High BP
Primary Hyperaldosteronism due to Conn’s syndrome causes what:
- Adrenal mass (solitary aldosterone-secreting adenoma) + HTN
- Severe HTN (>160/100 mmHg)
- HTN at a young age (30-40 YO)
- Refractory HTN
- Hypokalemia and hypomagnesia
What is the most common underlying cause of primary hyperaldosteronism and what is seen morhphologically in the adrenal glands?
- Bilateral idiopathic hyperaldosteornism (IHA)
- Characterized by bilateral nodular hyperplasia of adrenal glands
Germline and somatic mutations of which gene are present in familial idiopathic hyperaldosteronism and some aldosterone-secreting adenomas?
KCNJ5 encoding a K+ channel
What is glucocorticoid-remediable hyperaldosteronism?
Rare cause of primary familial hyperaldosteronism and due to:
-
[ACTH-responsive CYP11B1 gene promoter] controlling [CYP11B2 (gene encoding aldosterone synthase) on Chr 8]
- ACTH => (+) production of aldosterone synthase => ↑ aldosterone
In glucocorticoid-remediable hyperaldosteronism what is the function of ACTH?
ACTH => (+) production of aldosterone synthase => ↑ aldosterone
In glucocorticoid-remediable hyperaldosteronism, bc aldosterone production is controlled by ACTH, how can this production be suppressed?
Suppressible by dexamethasone
What can cause decreased renal perfusion => 2º Hyperaldosteronism?
- Renal artery stenosis
- Arteriolar nephrosclerosis
↓↓↓ BF kidney => think entire body needs to ↑↑↑ BF => + RAAS, even though BP is fine.
What can cause arteriolar hypovolemia and edema => 2º hyperaldosteronism?
- CHF
- Cirrhosis
- Nephrotic Syndrome
How does activity of the RAAS and levels of renin differ between primary and secondary hyperaldosteronism?
- Primary= suppression of RAAS and ↓ renin
- Secondary = activation of RAAS and ↑↑↑ renin
Morphology of Bilateral Idiopathic Hyperplasia
Diffuse and focal hyperplasia of cells in zona granulosa
- Wedge shaped: extend from [periphery => center].
Gross Morphology of Alderone-producing Adenomas (Conns Syndrome)
- Well-cicumscribed, solitary, small (<2 cm) and buried within the gland (not visibly enlarged)
- Bright yellow and resemble lipid-laden fasciculata cells (more than glomerulosa)
- More often on L adrenal gland.
What is a characteristic histological feature of aldosterone-secreting adenomas?
Spironolactone bodies=> Eosinophilic, laminated cytoplasmic inclusions
Patients with aldosterone-secreting adenoma have a HIGH incidence of __________
Ischemic Heart Disease
Pt presents with HTN: we want to evaluate for hyperaldosteronism.
How do we diagnose?
1. Stop taking meds that affect plasma renin and aldosterone.
2. Measure plasma renin and aldosterone.
- ↑↑↑ ratios of plasma aldosterone: renin activity (↑ ALD; ↓ renin) => 1º Hyperaldosteronism
- => If +: confirm with a [aldosterone supression test]
- ↑↑↑ plasma aldosterone AND renin (↑ ALD; ↑ renin) => 2º Hyperaldosteronism
Tx for primary hyperaldosteronism caused by an adenoma vs. bilateral hyperplasia?
- Adenomas => surgically resect
- - Bilateral hyperplasia => Aldosterone ANT (Spironolactone)
Causes of Adrenogenital Syndromes (Adrenal Virulization)
Pituitary causes:
- ACTH stimulation of androgens (Cushings disease)
Adrenal gland causes:
- Primary adrenal neoplasms (adenoma or carinoma)
- Congenital adrenal hyperplasia (CAH)
What is the most common cause of adrenal virulization due to a primary adrenal neoplasm?
Carcinoma
Androgen-secreting adrenal carcinomas often secrete what other hormone?
Cortisol and are known as “mixed syndromes”
What is CAH (Congenital Adrenal Hyperplasia)?
- Group of AR inherited errors of metabolism that cause a deficiency/total lack of enzymes involved in making cortical steroids, particulary cortisol.
- Steroid precursors build-up behind the defective step =>
- Channeled into other pathways =>
- ↓ production of gluco/mineralcorticoids & ↑ production of androgens => virulization.
- Impaired feedback to hypothalamus/pituitary => hyperplasia.
What enzyme is most commonly deficient in CAH (congenital adrenal hyperplasia)?
21-hydroxylase (dt mutation in CYP21A2)
- Thus, only thing adrenal gland can produce are the sex steroids. ↓ of cortisol means that the pituitary continues to produce ACTH, resulting in ↑ sex steroids. This cycle is responsible for the virilization seen in this syndrome.
- 17-hydroxyprogesterone (17-OHP) will spike however.
21-hydroxylase deficiency can cause what syndromes?
Most common***?
- 1. Classic salt-wasting syndrome (complete lack)
- 2. Simple virilizing syndrome (partial lack)
- 3. Non-classic/late-onset adrenal virilism (partial lack) ****
Salt-Wasting Syndrome
- Enzyme activity
- Levels of glucocorticoids/mineralcorticoids/androgens
- Symptoms and M/W
Salt-Wasting Syndrome
- Complete lack of 21-hydroxylase
- No mineralcorticoids and glucocortiods (cortisol); ↑ androgens
-
Symptoms in M/W
- No mineralcorticoids:
- Salt-wasting (=> hyponatremia), hyperkalemia (↑ K+)
- Acidosis, Hypotension => seize, CV defects, death
- In F => virulization is present at birth.
- No mineralcorticoids:
How does the presentation of salt wasting syndrome differ in males vs. females at birth?
- Females present EARLIER: d/t easily recognizable virilization at birth
- Males dx 5-15 days after birth due to some salt-losing crisis
Patients w/ severe salt-wasting 21-hydroxylase deficiency what can happen?
↓ cortisol & adrenomedullary dysplasia (developmental defects of medulla) =>
- ↓ catecholamine secretion =>
- HYPOtension & circulatory collapse
Simple Virilizing Adrenogenital Syndrome (without salt wasting)
- Enzyme activity
- Levels of glucocorticoids/mineralcorticoids/androgens
- Symptoms and M/W
- Partial lack of 21-hydroxylase
- Some mineralcorticoids and small cortisol, but not enough to prevent ACTH overproduction; ↑ androgens (testosterone)
- Genital ambiguity (virilization) at a later age.
Most common form = Nonclassic/late-onset adrenal virilism
- Enzyme activity
- Levels of glucocorticoids/mineralcorticoids/androgens
- Symptoms and M/W
- Partial lack of 21-hydroxylase
- Some gluco/mineral; increase androgens
- Symptoms in M/W
- Virtually asymptomatic
- Mild manifestations (Precocious puberty, acne and hirsutism @ puberty)
Morphological Change in all cases of Congenital Adrenal Hyperplasia (CAH)
BILATERAL hyperplastic; some times ↑↑↑ 10-15x normal weights
Pt’s with CAH are treated with what?
- Exogenous glucocorticoids: replenishes levels AND ↓ ACTH levels via negative feedback
- Mineralocorticoid supplementation given in salt-wasting variants
2 ways of diagnosis of CAH
- ↑↑↑ Serum 17-hydroxyprogesterone
- ACTH-stimulation test: no ↑ in glucorticoids/cortisol, but ↑ in 17-OHP.
In what case is Serum 17-hydroxyprogesterone the highest? Lowest?
- Highest = classic congenital adrenal hyperplasia
What is mandated thoughout the US and EXTREMELY important for diagnosing bbs with CAH, who were not ID’d through family history?
Heel stick test
What is Adrenocortical Insufficiency?
Decrease in the ability of the adrenal cortex (hypofunction) to produce steroids, especially cortisol. Can be primary or secondary causes,.
Amyloidosis, sarcoidosis, and hemochromatosis may all lead to what type of adrenal dysfunction?
Primary adrenocortical insufficiency
Primary Adrenocortical Insufficiency
- Loss of adrenal cortical tissue (or steroid producing cells)
- Problem making hormones
Secondary Adrenocortical Insufficiency
- Hypothalamic - pituitary disease
- Exogenous steroids suppress HPA axis
Primary acute adrenocortical insufficiency occurs in what clinical settings?
Causes adrenal crisis in:
- Pt with chronic adrenocortical insufficiency, who encounter stress that causes rapid ↑ in steroid production, but adrenals cant.
- In patients on exogenous steroids, where acute stress causes rapid withdrawl of steroids or failure to ↑ dose & atrophied adrenals can’t respond well.
- Massive adrenal hemorrhage, occurring in newborns after long/difficult delivery; pt’s on anticoagulant therapy who develop DIC; and in Waterhouse-Friderichsen Syndrome
If patient is taking exogenous corticosteroids, what happens to adrenals?
Atrophy
What is Waterhouse-Friderichsen Syndrome characterized by?
- Bacterial infection (often due to Neisseria meningidits) => sepsis (rapidly progressing hypotension => shock) =>
- DIC + purpuric rash=>
- Massive bilateral adrenal hemorrhagic necrosis and primary acute adrenocortical insufficiency
- => adrenals become “sacs of clotted blood”
Which 5 bacterial species may be associated with Waterhouse-Friderichsen Syndrome?
- - N. meningitidis
- H. influenzae
- Pseudomonas
- Pneumococci
- Staphylococci
Histological examination of the adrenals in Waterhouse-Friderichsen syndrome show hemorrhage that starts where and then travels how?
Starts within medulla near thin-walled venous sinusoids => peripherally into cortex, often leaving islands of recognizable cortical cells
What are 6 signs/sx’s that should raise suspicion of acute adrenal insufficiency?
- - HYPOtension (refractory to volume repletion)
- HYPOnatremia/ hyperkalemia
- HYPOglycemia
- Abdominal pain
- Fever, N/V
90% of all cases of primary chronic adrenocortical insufficiency (Addison’s Disease) can be attributed to one of what 4 disorders?
- - Autoimmune adrenalitis
- Tuberculosis
- AIDS
- Metastatic cancers
Most common cause of primary chronic adrenocortical insufficiency in developed countries?
Autoimmune adrenalitis (APS1 or APS2)
Most common cause of primary chronic adrenocortical insufficiency worldwide?
Tuberculosis —> Autoimmune
Primary Chronic Adrenocortical Insufficiency (Addison’s Disease) Symptoms
- Joint pain
- No appetite (weight loss)
- Malaise / fatigue
- Hyperpigmentation (due to ACTH → αMSH)
Autoimmune polyendocrine syndrome type 1 (APS1)
- Mutations:
- Affects what organs:
- Causes:
Mutation in the AIRE on Chr 21q22 that affects the [adrenals, parathyroid, gonad and blood] causing
- Adrenalitis
- Parathyroiditis
- Hypogonadism
- Pernicious anemia
What is APECED?
Autoimmune PolyEndocrinopathy, Candidiasis and Ectodermal Dystrophy (APECED):
When ASP1 + mucocutaneous candidiasis (Ab against IL-17/22) and ectodermal dystropgy
What is Ectodermal dystrophy?
Abnormalities of skin, dental enamel, and nails
Autoantibodies against which 2 cytokines seen in autoimmune polyendocrinopathy syndrome type 1 (APS1) are the reason for chronic mucocuntaneous infections?
IL-17 and IL-22
When does autoimmune polyendocrine syndrome type 2 (APS2) usually develop and what are the characteristic findings?
- Early adulthood
- [Adrenal insufficiency (adrenalitis) + AI thyroiditis OR Type 1 DM]
Which 3 infectious agents may cause primary chronic adrenocortical insufficiency?
- TB used to be most common cause
- Histoplasma capsulatum
- Coccidioides immitis
AIDS patients are at ↑ risk for developing adrenal insufficiency from what?
- CMV and Mycobacterium avium-intracellulare
- Noninfectious (Kaposi Sarcoma)
Metastatic neoplasms that affect the adrenals and causing adrenocortical insufficiency most often arise from which 2 sites; what are some other sites which may be implicated?
- Lungs and breast cancer = most common
- May also be from [GI cancers, malignant melanoma, and hematopoietic neoplasms]
What are 2 genetic causes of adrenal insufficiency?
- - Congenital adrenal hypoplasia (CAH)
- - Adrenoleukodystrophy (X-linked recessive)
When does typically Addisons Dz begin?
Initial signs and symptoms?
- Insidiously and not until levels of glucocorticoids/mineralcorticoids are VERY low.
- Progressive weakness and easy fatigability
What are the signs/sx’s of primary chronic adrenocortical insufficiency as a result of corticosteroid and mineralocroticoid deficiency?
- ↓ corticosteroids –> vague malaise, N/V, hypoglycemia, and refractory hypotension
- ↓ mineralocorticoids –> hyperkalemia and hyponatremia
What is the gross morphology and histology of the adrenal glands in primary autoimmune adrenalitis?
- Irregularly SHRUNKEN glands
- Scattered residual cortical cells in collapsed network of CT w/ a variable lymphoid infiltrate of the cortex
Which type of inflammatory reaction will be seen in the adrenal glands affected by tuberculosis and fungal disease?
Granulomatous inflammation
Which type of adrenocortical insufficiency is associated with hyperpigmentation of the skin and which is not?
- Primary chroinc adrenal disease (Addisons) = hyperpigmentation
- Adrenocortical insufficiency caused by primary pituitary or hypothalamic disease will not
Dx Adrenocortical Insufficiency
-
1. Random cortisol test
- 2º: deficient cortisol and androgens; normal or near-normal synthesis of aldosterone
-
2. ACTH stimulation test
- 1º: ↓ response to exogenous ACTH
- 2º: prompt ↑ in plasma cortisol levels
How does the presentation of adrenal carcinomas differ from that of adenoma?
SIZE tells us.
- Adenoma = solid and yellow; vaculoated neoplastic cells d/t intracytoplasmic lipids
- Carcinomas = heterogenous and red; larger (> 200 gm) and produce mass
effect causing compression/invasion of adjacent structures; more likely to be virulizing
How do are adrenal carcinomas and adenomas SIMILAR??
- Both are often incidental finding on radiograpgy or autopsy
- Both are more often functional
When are adrenal adenoma and carcioma more common in?
Equally common in adults.
Carcinoma more likely in kids.
Functional and nonfunctional adrenocortical neoplasms CANNOT be distinguished from one another based on ________.
Morphology
Adrenocortical carcinomas have a strong tendency to invade which structures?
- - Adrenal vein
- - Vena cava
- Lymphatics —> regional and periaortic nodes = common
Distant hematogenous spread by adrenocortical carcinomas to where is common; what is the prognosis of these neoplasms?
- Lungs and other viscera
- Median pt survival = about 2 years
Which is more common: primary adrenocortical carcinomas or metastases to the adrenal cortex?
Metastases (esp bronchogenic origins)
ADRENAL ADENOMA or ADRENOCORTICAL CARINOMA?
Adrenocortical carcinoma:
- Well differented cells like in adenomas => bizarre giant cell
- Marked anaplasia
ADRENAL ADENOMA or ADENOCORTICAL CARCINOMA
- Vaculoated and eosinphilic neoplastic cells d/t intracytoplasmic lipids
- Mild nuclear pleomorphism
Which 2 familial cancer syndromes are associated with a predisposition for developing adrenocortical carcinomas?
- - Li-Fraumeni syndrome, due to germline TP53 mutations
- - Beckwith-Wiedemann syndrome, a disorder of epigenetic imprinting
If cortical and medullary neoplasms undergo necrosis and cystic degeneration => may present as ___________.
“Nonfunctional cysts”
Adrenal myelolipomas are unusual benign/malignant lesions composed of what?
- Size?
- How do they preent?
benign: fat + bone marrow/HSC
- Vary
- With hemorrhage
What cells make up the adrenal medulla?
Neural crest (neuroendocrine) cells callled Chromaffin cells + sustacular (supporting) cells.
Adrenal Medulla
- Under ______ control
- Most important diseases of the adrenal medulla:
- Sympathetic
- Pheochromacytomas (neoplasm of chromaffin cells) + neuroblastic tumors
What are Pheochromocytomas?
Rare neoplasms made up of chromaffin cells (which make and release catecholamines NE and EPI) & sometimes peptide hormones, often presenting with surgically correctable HTN.
What is the dominant clinical manifestation of pheochromocytomas and what is the classic triad?
- - HTN (>90%) which can be either chronic or paroxysmal
- Triad = HA + Palpitations + Diaphoresis
Acute and Chronic complications with Pheochromocytomas
Acute: CHF, MI, CVA, Pulmonary edema, Ventricular fibrillation
Chronic: Catecholamine cardiomyopathy
What is the 10% rule associated with Pheochromocytomas (5 of them)?
- 10% are extra-adrenal (paraganglioma)
- 10% are bilateral
- 10% in kids
- 10% are malignant
- 10% are NOT associated with HTN
_____% of pheochromocytomas have germline mutations and are familial.
25%
3 groups of extra-adrenal paraganglia based on anatomic distribution
- 1. Branchiomeric
- 2. Intravagal
- 3. Aorticosympathetic
4 familial syndromes associated with pheochromocytomas and extra-adrenal paragangliomas
- MEN-2A
- MEN-2B
- NF-1
- Von Hippel-Lindau (VHL)
How does the patient presentation and location of pheochromocytomas in pt’s with familial pheochromcytoma (d/t germline mutations) differ from that of sporadic types?
Pts with familial mutations are:
- Younger
- Bilateral disease
Histological pattern in pheochromocytomas
- Nests (zellballen) of polygonal to spindle-shaped chromaffin or chief cells surrounded by sustentacular cells, supplied by rich vascular network
- Granular cytoplasm that contains catecholamines
What stains can we use to view cytoplasm and sustenacular cells in a pheochromacytoma?
- Cytoplasm (catecholamines) = silver stain
- Sustentacular cells = antibodies against S-100
- Which histological feature of pheochromocytomas reliably predicts clinical behavior?
- What is the definitive diagnosis of malignancy in pheochromocytomas based on?
- Nothing histologically predicts clinical behavior.
- ONLY on presence of metastasis
What is the laboratory diagosis of pheochromocytomas based on?
↑ urinary excretion and plasma free catecholamines + their metabolites i.e., vanillylmandelic acid and metanephrines
What 3 features of adrenal incidentalomas impact the appropriate managment of the mass?
- SIZE: >4cm = more likely to be carcinoma
- - Positive functional assays: i.e., dexamethasone suppression test for hypercortisolism or urinary metanephrines for pheochromo.
- - CT enhancement characteristics
What is MEN syndrome?
Group of inherited diseases that results in [hyperplasia, adenoma and carcinomas] of multiple endocrine organs
How do endocrine tumors due MEN syndromes differ from their sporadic counterparts in terms of age, organs involved, behavior, and foci?
- Tend to occur at younger age
- Arise in multiple endocrine organs, either synchronously or metachronously
- Typically preceded by asymptomatic stage of hyperplasia pre-cursor lesions
- Even in one organ, tumors are often multifocal and bilateral
- Are usually more aggressive and recur
_MEN1 (aka _____)_
- Mutation
- Causes what? (in order of MC)
- Werner Syndrome
- Germline mutation in MEN1 (Menin) tumor supressor
-
3 Ps:
- Primary _hyper_parathyroidism (parathyroid adenoma or primary parathyroid hyperplasia)
- Pancreatic endocrine tumors (Insulinoma, Gastrinoma, Somatostatinoma, Glucagonoma, VIPoma, also DUODENAL gastrinomas, as well as pancreatic gastrinomas)
- Pituitary adenomas (prolactinoma = MC)
What is the initial manifestation of MEN 1 in most patients, appearing in almost all patients by 40-50 YO?
Primary hyperparathyroidism
Which tumors of MEN-1 are th_e leading cause of morbidity_ and mortality due to their aggressiveness and metastases?
Pancreatic endocrine tumors
What is the most frequent pituitary adenoma encountered in MEN-1?
Prolactinoma (lactotroph); may also see somatotroph adenoma (GH) => acromegaly
What is the most common site of gastrinomas present in pt’s with MEN-1?
Duodenum; may also have synchronous duodenal + pancreatic tumors
MEN-2A (aka)
- Mutation:
- Triad:
- Sipple Syndrome
- Germline GOF in the RET proto-oncogene on _Cr. 10_q11.2
-
Triad (3 C’s)
- Medullary thyroid cancer => ↑ calcitonin
- Pheochromocytoma => ↑ catecholamines
- Parathyroid hyperplasia => ↑ calcium (hypercalcemia) and kidney stones
- Which tumor is seen in almost 100% of patients with MEN-2A?
- Medullary thyroid carcinoma in MEN-2A are usually ____ and are virtually always associated with what?
-
Medullary thyroid cancer
- Multifocal; C-cell hyperplasia in the adjacent thyroid
MEN-2B
- Mutation
- Causes
Point mutation in RET gene
Causes
- Pheochromocytomas
- Medullary thyroid cancer (multifocal and more aggressive)
- Mucosal neuromas (in mouth, eyes, respiratory/GI tract)
- Marfainoid habitus
Familial medullary thyroid cancers are a variant of MEN-2A; how are they different?
- Develop at an older age
- - No other clinical manifestation assoc. w/ MEN-2A
- Typically follow a more indolent course
About 1/3 of sporadic medullary thyroid carcinomas have the identical point mutation of RET encountered in MEN-2B and follow what type of course?
More aggressive disease and adverse prognosis
Diagnosis via screening of at-risk family members for which MEN syndrome is important?
MEN-2A due to medullary thyroid carcinoma being life-threatening, and can be prevented by prophylactic thyroidectomy
The pineocytes of the pineal gland are epithelial cells with what 2 functions?
Photosensory and neuroendocrine functions
Majority of tumors arising in the pineal gland are of what type?
- Germ cell tumors i.e., germinomas, embryonal carcinomas; choriocarcinomas and mixtures of the 2
