Endo-pituitary pathology

Question 1

A lactotroph is more commonly ____ granulated vs ___ granulated on histology

Answer 1

MC sparsely granulated vs densely granulated on histology

Question 2

Northern Ireland has an large number of ____ gene carriers and therefore ___ patients

Answer 2

AIP gene carriers causing acromegaly patients (via somatotroph)
“Irish Giants”

Question 3

is size important in terms of a corticotroph

Answer 3

size can be misleading, a very small corticotrophin adenoma can be very hyper functional and present with all sx of Cushings syndrome

Question 4

USP8 somatic mutation seen in corticotrophs result in an upregulation of _____

Answer 4

EGFR

Question 5

sign and sx of apoplexy into pituitary

Answer 5

sudden onset of excruciating HA, diplopia due to pressure on oculomotor nerves, and hypopituitarism
(can be a result of mass effect)

Question 6

most common cause of cushing syndrome (not disease)

Answer 6

iatrogenic (healthcare associated)

-due to long term glucocorticoid administration (steroids)

Question 7

how to dx somatotrophs by pathology

Answer 7

• Diffuse growth (sheet like: common in all adenomas)
• confirmation made with GH immunohistochemistry (immunostain for somatotroph)
• can be sparsely or densely granulated
• can be mixed with PRL-Secreting cells (mammosomatotroph)

Question 8

define central diabetes insipidus ? sx? labs? how to dx? tx?

Answer 8

• insufficient ADH secretion due to posterior pituitary or hypothalamus pathology (tumor, trauma, infection, inflammation)
• results in decreased reclaimed free water from the renal collecting system
• sx: polyuria, polydipsia, life threatening dehydration
• Labs: hypernatremia, high serum osmolality, low urine osm and specific gravity
• dx: water deprivation test fails to increase urine osm. or desmopression tx shows increased urine sodium/osm
  tx: desmopressin

Question 9

tx of somatotrophs

Answer 9

somatostatin analogs
GH receptor antagonists
surgery

**SOMATOSTAIN inhibits GH

Question 10

tx for corticotroph

Answer 10

somatostatin analog, bromocriptine (dopamine agonist), or surgery
**corticotrophs can express dopamine and somatostatin receptors

Question 11

define Nelson Syndrome

Answer 11

• enlargement of of pituitary tumor (corticotroph adenoma) after surgical removal of both hyperplastic adrenal glands (used to tx hypercortisol secretion/Cushing syndrome from high ACTH)
• main sx: hyperpigmentation (ACTH affect on melanocyte stimulation)

Question 12

how do gonadotrophs usually present

Answer 12

usually non-functioning or “silent”/”null cell” adenoma

-usually present with mass effect due to minimal function

Question 13

presentation of lactotroph adenoma in women vs men

Answer 13

WOMEN

• present earlier due to menstrual irregularities, galactorrhea, decreased libido, infertility, and possible mass effect if large
• *responsible for >20% of cases of amenorrhea

MEN
-more present later with mass effect symptoms. early sx are decreased libido and decrease sperm count

Question 14

what somatic genetic mutation are linked to pituitary adenomas? what familial mutations?

Answer 14

somatic:
1. GNAS - somatotrophs
2. USP8- corticotrophs

familial:
1. AIP - somatotrophs
(AIP gene causes FIPA- Familial isolated pituitary adenomas; via PAP- pituitary adenoma predisposition)

Question 15

size of microadenoma vs macroadenoma vs giant adenoma of the Pituitary gland, and what are the implications?

Answer 15

micro- <1cm
macro- 1-4cm
giant- >4cm

*size is VERY important to determine how one presents clinically and extent of disease (i.e with mass effect, etc)

Question 16

identify the nomenclature of the pituitary gland (anterior, posterior lobe, etc)

Answer 16

anterior lobe = adenohypophysis (vascular connections to hypothalamus)
posterior lobe = neurohypophysis (neuronal connection to the hypothalamus)

Question 17

what is the most common secretory pituitary adenoma ?

Answer 17

Lactotroph adenoma (hyper secretion of prolactin)

Question 18

what genetic mutation of the GPCR pathway is associated with pituitary adenoma ? what mechanism leads to the growth of the adenoma? what adenomas is it most common in?

Answer 18

GNAS mutation

• makes the alpha subunit of Gs lose its GTPase activity !
• GTPase activity is needed to convert GTP –> GDP which is an important regulatory step in turning off the Gs Cascade
• without GTPase activity the unregulated GTP will initiate uncontrollable cAMP driven cell proliferation
• very common in somatotrophs (40%) and more rare in corticotrophs

Question 19

T/F

Thyrotrophs are rare and cause an increase in TSH levels

Answer 19

true

Question 20

define SIADH ? sx? labs? tx?

Answer 20

• excess ADH secretion and increased reclaimed free water from the renal collecting system due to MOST COMMONLY Small cell carcinoma of the lung (also brain injury, subarachnoid hemorrhage, Drugs (SSRIs), or other malignancy)
• sx: increased thirst (due to ADH effects on brain). mental status changes, seizures (cerebral edema from hyponatremia), muscle weakness
• labs: hyponatremia, low serum osm, hypernaturia, high urine osm,
  tx: free water restriction or demeclocycline

Question 21

how do adenomas of the pituitary gland come to attention usually ?

Answer 21

either hyper function (hormonal excess) or nonfunctioning Mass effect

-Mass Effect: increased intracranial pressure (HA, N/V, Hypertension, papilledema, shallow breathing, bradycardia, confusion) and compression of optic chiasm (where nasal retinal fibers cross) is impeded causing loss of lateral temporal visual field (BILATERAL TEMPORAL HEMIANOPSIA) **can be seen in neoplasm and bleeds

Question 22

response of corticotroph vs ACTH secreting tumor to a low and high dose dexamethasone test

Answer 22

corticotroph: no response to low dose (elevated ACTH) but response to high dose (suppressed ACTH levels)
ectopic: no response to low dose or high dose (continually elevated ACTH)

Question 23

cushing syndrome vs cushing’s disease

Answer 23

Disease: refers to the specific etiology from the corticotroph pituitary adenoma (hyper secretion of ACTH and subsequent hypercortisolism)

syndrome: refers to the manifestations of hypercortisolism (does not have to a direct result of corticotroph adenoma, can be a primary adrenal dz)
- central obesity, DM, hirsutism (soft hair), adrenal hyperplasia, moon facies, very thick and dark striae, hypertension, think skin, menstrual changes

Question 24

define primary empty sella syndrome (congenital defects of the sella)

Answer 24

(mechanical disturbance)
-CSF leaks into the sella turcica and compresses the pituitary
(the diaphragma sellae usually protects it, but with defects it allows CSF entry to squash the pituitary )
-results in hypopituitarism !!

Question 25

define secondary empty sell syndrome (congenital defects of the sella)

Answer 25

the pituitary expands and infarcts within the sella turcica, leaving an empty space (more likely to affect the anterior lobe) -results in hypopituitarism!

Question 26

as a lactotroph progresses, what histology features will likely be seen ? what may be seen on imaging?

Answer 26

stomal hyalinization (pink cloud deposits) and possible psammoma bodies (concentric calcifications due to increasing age) -the dense calcifications can lead to pituitary stones seen on imaging !

Question 27

describe the 4 main effects seen in Mass Effect of pituitary lesions (**can be seen in neoplasm and bleeds/apoplexy )

Answer 27

- increased intracranial pressure (HA, N/V, Hypertension, papilledema, shallow breathing, bradycardia, confusion) - BILATERAL TEMPORAL HEMIANOPSIA: compression of optic chiasm (where nasal retinal fibers cross) is impeded causing loss of lateral temporal visual field - Pituitary Apoplexy (hemorrhage into adenoma) can be deadly - Hypopituitarism/ Hyperprolactinemia; underproduction of all Pituitary hormones expect overproduction of prolactin (only in nonfunctioning large mass showing mass effect!)

Question 28

why is it important to check other hormone levels in the dx of somatotroph

Answer 28

bc it is common to be mixed with PRL-secreting cells (mammosomatotroph) therefore do not want to miss that

Question 29

embryologic origin of the pituitary gland

Answer 29

1. neuroectoderm - infundibular proves of brain tissue projects downward 2. oral ectoderm- Rathke's pouch from the stomodeum extends upward

Question 30

define the two types of craniopharyngioma along with its origin and histologic features

Answer 30

(a neoplasm derived from anterior lobe/rathke's pouch remnants, made of squamous cells with "wet" keratin pearls and is multiloculated and cystic) 1. Kids (5-15yo) - "adamantinomatous craniopharyngioma" that is calcified and hard (shows calcified cysts on histo) - shows growth retardation and hypopituitarism 2. adults (>65yo) - "papillary craniopharyngioma" that is softer with no calcifications - shows signs of increased intracranial pressure or hypopituitarism

Question 31

how to work up dx of Cushing syndrome (hypercortisolism)

Answer 31

1. check ACTH levels (can also use CRH stimulation test to measure ACTH levels) 2. If Low then is ACTH independent and use Cat scan/MRI of adrenals to dx 3. if High then is ACTH dependent and need to distinguish between pituitary adenoma or ectopic ACTH producing tumor (via brain MRI or High dose dexamethasone test)

Question 32

range of pituitary neoplasia

Answer 32

1. adenomas (well circumscribed, can erode bone, can bleed) 2. aggressive adenomas (poor circumscribed, can invade brain, more likely as adenoma gets bigger) 3. pituitary carcinoma (RARE, can metastasis or spread throughout brain) 4. others: Rahtke Cyst , craniopharyngioma

Question 33

what is the tx for lactotrophs

Answer 33

dopamine agonists (bromocriptine, cabergoline) Surgery (can go nasally through the sphenoid bone or resection via craniotomy) radiation therapy *Dopamine inhibits PRL (prolactin)

Question 34

define Sheehan syndrome ? mechanism of defect? presentation?

Answer 34

pregnancy related postpartum infarction/necrosis of the anterior pituitary leading to hypopituitarism - during gestation: gland doubles in size, but the blood supply does not increase leading to a vulnerable pituitary gland - bloos loss during labor precipitate infarction - sx can be acute or chronic, common first sign is failure to lactate (others: loss of pubic hair and fatigue)

Question 35

define Rathke's Cleft Cyst ? identify its histologic cells, and complications

Answer 35

-deirved from epithelium of anterior pituitary *not a neoplasm, but a malformation -a cystic mass that develops as a result of incomplete closure of the rathke's pouch (oral ectoderm) outpouching during embryological development (**shows ciliated columnar cells**) -can expand and compress NL pituitary -can rupture and result in inflammation of the pituitary or meningitis

Question 36

mechanism of hypopituitarism

Answer 36

1. squash cells (mass effect) 2. killed off (ischemia, inflammation, surgery) 3. bled into (apoplexy)

Question 37

difference between gigantism and acromegaly

Answer 37

both are due to somatrotroph adenomas of the pituitary gland. (hyper secretion of GH) gigantism - occurs in childhood before epiphyseal (growth) plates close; presents as very tall acromegaly - occurs in adulthood after plate closure *acromegaly will also present with enlarged thick fingers/hands, enlargement of face, protruding jaw, enlarged nose, thickened lips, joint pain, limited mobility, enlarged viscera (cardiomegaly), shortened lifespan usually due to cardiovascular complications

Question 38

how to dx a somatotroph

Answer 38

- serum levels of IGF-1 secreted by the liver (GH itself is not stable) - if it is elevated, f/u with OGTT (bc glucose is a natural inhibitor of GH; a NL OGTT would show decreased IGF-1, a OGTT of somatotroph will present with continually increased IGF-1 after glucose dose)

Question 39

histology of the posterior vs anterior lobe

Answer 39

1. posterior (neurohypophysis) - brain tissue like, wispy neuroglial cells (supportive pituitcytes) and axonal neurons 2. anterior (adenohypophysis) - glandular structure like, has red acidophils (secrete prolactin and GH) and blue basophils (secrete FH, LH, ACTH, TSH), and chromophobes (pale color)

Question 40

sx of anterior hypopituitarism

Answer 40

- decreased GH (increased body fat, decreased muscle, reduced strength) - decreased gonadotrophin (men: poor libido, impotence, infertility, reduced facial hair; women: amenorrhea, dyspareunia, infertility, breast atrophy) - decreased TSH (decreased energy, constiplation, weight gain) - decreased ACTH (weakness, tiredness, hypoglycemia) - decreased prolactin (lactation failure)