Pathology for Dental Students (LaMP 5-100)
University of Minnesota School of Dentistry
Kristine Krafts, M.D.
Art supply hoarder.
Veni, vidi, volo in domum redire.*
• Posterior pituitary syndromes
1. Robbins Basic Pathology, 8th edition, pages 752-757
2. Ed’s pathology notes.
3. A couple of good cases:
(82-year-old male with progressive visual deficits)
(17-year-old female with nipple discharge and irregular menses)
1. Describe the clinical presentation and most common cause of each of the following:
• Acromegaly and gigantism
• Syndrome of inappropriate ADH secretion (SIADH)
• Diabetes insipidus
2. Describe the general symptoms and microscopic appearance of pituitary adenoma.
3. Know what these terms mean:
• Cushing’s syndrome
• Cushing’s disease
• Nelson’s syndrome
• Sheehan’s syndrome
I came, I saw, I want to go home.
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Pituitary anatomy and histology
The pituitary sits inside the skull within its own little bony fossa, the sella turcica (turkish saddle).
It's attached to the hypothalamus by the pituitary stalk, which passes out of the sella through a hole
in the dura surrounding the brain.
acidophils secrete GH and PRL
basophils secrete FSH, LH, ACTH, TSH *
Anterior pituitary (adenohypophysis)
• Secretes GH, ACTH, TSH, LH, FSH, and prolactin.
• Controlled by hypothalamic hormones, most of which stimulate the release of most hypothalamic hormones
anterior pituitary hormones. (Exception: dopamine, secreted by the hypothalamus, (except dopamine)
STIMULATE release of
inhibits prolactin secretion). So…what happens to anterior pituitary hormone anterior pituitary hormones
secretion if you cut off hypothalamic input?
• Most pituitary diseases are in the anterior lobe, which comprises 80% of the gland.
Posterior pituitary (neurohypophysis)
• An extension of the hypothalamus.
• Stores oxytocin and ADH (which are made by the hypothalamus and then
transported by axons to the posterior pituitary).
* Mnemonic: B-flat (basophils: FSH, LH, ACTH, TSH)
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Definition: Too much of one or more anterior pituitary hormones. Most common cause of
hyperpituitarism: pituitary adenoma
Most common: pituitary adenoma
Others: destruction of end organs, hypothalamic disorders, and
hyperplasia or carcinoma of the anterior lobe.
Most pituitary adenomas are clinically silent for years,
until they get big enough to cause endocrine abnormalities
or mass effects.
Endocrine abnormalities occur when adenomas secrete
hormones (see types of adenomas, below)
• visual field abnormalities (especially lateral fields:
• symptoms of increased intracranial pressure (nausea,
• if mass is big enough, it can compress the remaining
pituitary, causing hypo pituitarism
Pituitary adenomas: general
Functional vs. nonfunctional
• functional: produces pituitary hormone
• non-functional (null): does not produce pituitary hormone.
• pituitary adenomas account for ~10% of all intracranial neoplasms
• occur most often in adults (especially 30- to 50-year-olds)
• 3% of pituitary adenomas occur in patients with MEN I
• Are often found at autopsy
• may be confined to the sella or may extend beyond sella (compressing optic chiasm
or cranial nerves)
• adenomas less than 1 cm in diameter are called microadenomas; those greater than
one cm in diameter are called macroadenomas)
• occasionally extend into bone, dura, or brain (called “invasive pituitary adenoma” –
why is this name misleading?!* )
• sometimes bleed suddenly (especially big ones), giving symptoms of a rapidly-
enlarging mass (called “pituitary apoplexy”)
Tumor invasion is a feature usually associated with malignancy (and pituitary adenomas are benign tumors).
However, in the brain, even benign tumors can cause serious problems – and death – if they are close to
important structures (like cranial nerves), or if they are too deep or tricky to resect (left in, they'll just keep
pituitary pathology – page 4 of 10
• sheets/cords of uniform, polygonal cells
• most adenomas are composed of a single cell type, with acidophilic (pink), You can’t tell the hormonal type
of an adenoma by its microscopic
basophilic (blue), or chromophobic (clear) cytoplasm (depending on what appearance.
hormone, if any, the adenoma is producing).
• nuclei can be pleomorphic*
• mitotic activity may be increased**
• you can’t tell what kind of adenoma it is by its microscopic appearance (using the
usual hematoxylin and eosin stain). You need special stains
(immunohistochemical stains directed at TSH, ACTH, etc.) for this.
pituitary adenoma, unknown type pituitary adenoma, prolactin-producing
hematoxylin and eosin stain special stain for prolactin
uniform tumor cells tumor cell cytoplasm stains brown
FSH and LH-producing (~10%)
Pleomorphic means of varying size and shape. Pleomorphism is frequently seen in malignant tumors.
Occasionally, as illustrated here, it may also occur in benign tumors. Future pathologists beware: don’t run
around crying “cancer! cancer! cancer is the answer!” (as pathology residents are wont to do) just because your
tumor shows pleomorphism.
Here’s another feature frequently seen in malignant tumors. Beware: mitotic figures (even lots of them)
don’t prove your tumor is malignant – they just prove that it is growing. Even normal tissues, such as intestinal
epithelium, have scattered mitotic figures because they are continually replenishing themselves.
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• Many pituitary adenomas have a mutated G-protein (remember what G-proteins Many pituitary adenomas have a
are?1). The normal G protein in the pituitary is one link in a chain of events leading mutated G protein that leads to
to cell proliferation. The mutant G protein2 is unable to turn itself off, so cells unchecked cellular proliferation
proliferate like crazy. The mutated gene is called the GNAS1 gene, or the gsp
• Patients with MEN-1 (multiple endocrine neoplasia type 1, discussed later) have a
mutation of the MEN-1 gene. Pituitary adenomas arising in these patients carry
this same mutation.
• Aggressive pituitary adenomas sometimes have an activating mutation of the RAS
oncogene or overexpression of the c-MYC oncogene.
• Most common type of pituitary adenoma.
• Usually secretes prolactin efficiently enough to cause symptoms (even when
small!) – especially in women (who notice menstrual cycle changes).
• Symptoms of ↑ prolactin: amenorrhea, galactorrhea, loss of libido, infertility
• Other things can cause ↑ prolactin:
1. Tumors in and around the sella can cause “stalk effect” (disruption of
hypothalamic input to pituitary, causing ↑ prolactin).
2. Anything that prevents dopamine from doing its job (traumatic damage to Prolactinomas can be treated
dopaminergic neurons, dopamine receptor antagonist drugs) can cause with dopamine receptor agonists.
• Treatment: bromocriptine (a dopamine receptor agonist) shrinks the adenoma.
Note: treatment of choice for all other pituitary adenomas is surgical removal.
G-proteins are involved in signal transduction (don’t fall asleep!). They transmit signals from cell-surface
receptors (like the growth hormone receptor) to intracellular effectors (like adenyl cyclase), which generate
second messengers (like cAMP).
The G-protein that is very important in lots of endocrine organs, including the pituitary, is called Gs. It has an
α and a β subunit (like all G-proteins). When it is resting, the α subunit sits around with GDP attached to it.
When it is activated (by growth hormone attaching to the growth hormone receptor), the GDP drops off and
GTP latches on (which activates adenylate cyclase, which makes cAMP, which causes cells to proliferate). After
the Gs protein has exerted its effect, the α subunit turns itself (and thus Gs) off by hydrolyzing the GTP to
GDP (still awake?). The problem with the mutated Gs is this: the α subunit is screwed up, and it can’t hydrolyze
GTP to GDP. So it’s always turned on – and cells are always proliferating.
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Growth hormone-producing adenoma
• Gigantism results when a GH adenoma occurs before puberty (before
epiphyses close). Characterized by very large body size, disproportionately
long arms and legs.
• Acromegaly results when a GH adenoma occurs after puberty (after
epiphyses close). Characterized by enlarged bones of face (protruding jaw,
frontal bossing), hands, and feet.
• Often, physical changes happen so slowly and subtly that the patient and
family don’t even notice.
• Other problems caused by ↑ GH: gonadal dysfunction, diabetes mellitus,
muscle weakness, hypertension, arthritis, congestive heart failure,
increased risk of gastrointestinal carcinoma…the list goes on and on.
• Serum GH is increased (but since GH is secreted in spurts, you can’t just
draw a random blood sample and expect it to reflect GH secretion).
• A better idea: check insulin-like growth factor I (IGF-I). GH stimulates
release of IGF-I from liver; this substance causes the clinical features.
• Another test: give the patient a bunch of glucose, then measure GH.
Normally, GH should go down in response to the elevated blood glucose.
If the patient has a GH-producing adenoma, the GH level will remain the
same, despite the elevated blood glucose.
• Serum prolactin may be increased too, since GH-producing adenomas
often produce a little prolactin too.
Andre the Giant in
• Goal: get GH level back to normal, and get rid of any mass effects, The Princess Bride?
without causing hypopituitarism in the process.
• Surgery and radiation are best.
• This adenoma makes ACTH, which revs up the adrenal glands, which
make lots of cortisol.
• It also makes POMC (pre-opiomelanocorticotropin, say that one five
times fast), which is the precursor to ACTH, β-endorphin, and
melanocyte stimulating hormone. Cushing syndrome: too much
• Patients with way too much cortisol floating around have Cushing cortisol.
syndrome. They are glucose-intolerant (or frankly diabetic), and they have Cushing disease: Cushing
a characteristic physical findings: central obesity (with a “buffalo hump”) syndrome caused by an ACTH-
and moon facies. producing pituitary adenoma
• Cushing syndrome has four main causes (see adrenal notes). When it is
caused by an ACTH-producing pituitary adenoma, it is properly called
• Nelson syndrome occurs when you take out the adrenals in a patient
with Cushing syndrome. Not a good idea, because with the adrenals gone,
there are no corticosteroids around to inhibit the growth of the pituitary
adenoma – so it becomes huge and destructive.
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FSH- and LH-producing adenomas
• Secrete FSH and LH very inefficiently.
• Come to attention because of mass effects (e.g., neurologic symptoms) rather than Pituitary adenomas that don’t
endocrine abnormalities. secrete hormones can get very
big before they cause symptoms.
• See thyroid handout for symptoms, treatment.
• Secretes no hormones.
• Comes to attention because of mass effects (because no hormone is secreted, these
remain clinically silent until they get big enough to cause mass effects).
Definition: Decreased secretion of one or more pituitary hormones.
Destruction of pituitary At least 75% of the pituitary
• a big pituitary adenoma can compress and destroy normal pituitary tissue must be destroyed to see signs of
• surgery or radiation can also destroy pituitary tissue hypopituitarism.
• you have to destroy a lot (75%) of your pituitary before you see signs of
Ischemic necrosis of pituitary
• Most of the time, ischemic necrosis is caused by Sheehan’s syndrome (post-
partum anterior pituitary necrosis), described here.
• During pregnancy, the pituitary doubles in size, but the blood flow remains the
same…so the pituitary is relatively hypoxic.
• If there is hemorrhage or shock during the delivery, the drop in blood pressure
leads to inadequate pituitary blood supply, and pituitary infarction ensues.
Empty sella syndrome
• In this syndrome, the arachnoid membrane and CSF herniate down through a
defect in the diaphragma sella, compressing the pituitary gland.
• Most patients do not get hypopituitarism (that 75% thing again).
• sudden, spontaneous infarction of a pituitary tumor
• Symptoms are similar to those of subarachnoid hemorrhage: severe headache, stiff
neck, nausea, vomiting, decreased level of consciousness.
• If the patient survives, hypopituitarism and/or hypothalamic dysfunction may
• The hypothalamus normally delivers hormones to the pituitary.
• Hypothalamic lesions (e.g., tumors, infections) can interfere with the delivery of
pituitary pathology – page 8 of 10
Hypopituitarism is usually an insidious, chronic disease.
Usually, just one (or maybe two) hormones are decreased. If all hormones are absent,
this is called panhypopituitarism. This is rare, because the pituitary has a big reserve
(again with the 75% thing!).
Loss of pituitary hormones follows a predictable sequence: first GH decreases, then
FSH/LH, then TSH, then ACTH.
Signs and symptoms are what you’d expect for hormonal loss:
• GH deficiency in childhood produces pituitary dwarfism (miniature, well-
proportioned bodies). GH deficiency in adulthood leads to decreased muscle mass
and strength, and weakened cardiac contractility.
• FSH/LH deficiency produces loss of libido, menstrual abnormalities, and loss of
• Prolactin deficiency prevents lactation.
• TRH deficiency produces secondary hypothyroidism (discussed in thyroid
• ACTH deficiency produces adrenal insufficiency (discussed in adrenal lectures).
Posterior pituitary syndromes
Posterior pituitary hormones
• The posterior pituitary stores ADH (vasopressin) and oxytocin.
• Changes in oxytocin levels do not produce symptoms (unless you’re pregnant or
• Changes in ADH levels cause two syndromes, described here.
Diabetes insipidus (↓ ADH)
• Diabetes insipidus can be central (due to ADH deficiency, discussed here) or
nephrogenic (due to kidney unresponsiveness to ADH). Both have the same ↓ ADH:
symptoms. dilute urine
• ADH deficiency prevents the kidney from concentrating urine.
• The patient pees lots of dilute urine, the serum sodium and osmolality increase, and concentrated urine
the patient becomes very thirsty.
• Most common causes: head trauma and tumors (which compress pituitary or
hypothalamic input). A mild form of the syndrome occurs with ethanol ingestion.
• Treatment: increase water intake, perhaps give ADH.
Syndrome of inappropriate ADH secretion (SIADH) (↑ ADH)
• ADH excess causes the kidney to excrete very concentrated urine.
• The patient retains water, and the blood becomes hypotonic.
• Most cases are mild and self-limiting, but occasional cases are marked by cerebral
edema, neurologic dysfunction, seizures, and death.
• Most common cause: ectopic ADH production by a tumor (e.g., small-cell lung
• Treatment: restrict water intake.
pituitary pathology – page 9 of 10
What type of pituitary adenoma is this? What is this kind of stain called?
How are these stains used in pathology?
Name some of the normal structures Why is the line for the bathroom at the bar so long?
around the pituitary gland. What’s the proper Latin phrase to use when your friend’s
How might a growing pituitary had a few too many?*
adenoma affect these structures? What is the name of the posterior pituitary syndrome, and
what are the more serious causes?
* Re vera, potas bene. (Say, you sure are drinking a lot!)
pituitary pathology – page 10 of 10