Pituitary pathology notes

pituitary pathology

Preliminary stuffLecture informationEndocrine PathologyPathology for Dental Students (LaMP 5-100)University of Minnesota School of Dentistry

LecturerKristine Krafts, [email protected] supply hoarder.Veni, vidi, volo in domum redire.*

Outline Introduction Hyperpituitarism Hypopituitarism Posterior pituitary syndromes Review

Further reading1. Robbins Basic Pathology, 8th edition, pages 752-7572. Ed’s pathology notes.

http://www.pathguy.com/lectures/pituitar.htm3. A couple of good cases:

http://path.upmc.edu/cases/case135.html(82-year-old male with progressive visual deficits)http://path.upmc.edu/cases/case6.html(17-year-old female with nipple discharge and irregular menses)

Objectives 1. Describe the clinical presentation and most common cause of each of the following:

Hyperprolactinemia Acromegaly and gigantism Hypopituitarism 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

* I came, I saw, I want to go home.

pituitary pathology – page 2 of 10

http://path.upmc.edu/cases/case6.html

http://path.upmc.edu/cases/case135.html

Sheehan’s syndrome


Introduction Pituitary anatomy and histologyThe 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.

Pituitary physiologyAnterior pituitary (adenohypophysis) Secretes GH, ACTH, TSH, LH, FSH, and prolactin. Controlled by hypothalamic hormones, most of which

stimulate the release of anterior pituitary hormones. (Exception: dopamine, secreted by the hypothalamus, inhibits prolactin secretion). So…what happens to anterior pituitary hormone 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).


pituitarystalk

anterior pituitary

posterior pituitary

acidophils secrete GH and PRLbasophils secrete FSH, LH, ACTH, TSH *

anterior pituitary

most hypothalamic hormones (except dopamine) STIMULATE release of anterior pituitary hormones

* Mnemonic: B-flat (basophils: FSH, LH, ACTH, TSH)

HyperpituitarismDefinition: Too much of one or more anterior pituitary hormones.

CausesMost common: pituitary adenoma Others: destruction of end organs, hypothalamic disorders, and hyperplasia or carcinoma of the anterior lobe.

Clinical findingsMost 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)

Mass effects visual field abnormalities

(especially lateral fields: “bitemporal hemianopsia”)

symptoms of increased intracranial pressure (nausea, vomiting, headache)

if mass is big enough, it can compress the remaining pituitary, causing hypopituitarism

Pituitary adenomas: generalFunctional vs. nonfunctional functional: produces pituitary hormone non-functional (null): does not produce pituitary

hormone.

Epidemiology 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


optic nerve

pituitary adenoma

Most common cause of hyperpituitarism: pituitary adenoma

Are often found at autopsy

Gross appearance 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 growing bigger).


Microscopic appearance. sheets/cords of uniform, polygonal cells most adenomas are composed of a single cell type,

with acidophilic (pink), basophilic (blue), or chromophobic (clear) cytoplasm (depending on what 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.

Subtypes

* 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.


prolactin-producing (~30%)

non-hormone-producing (~20%)

multiple-hormone-producing (~15%)

ACTH-producing (~10%)

FSH and LH-producing (~10%)

GH-producing (~10%)TSH-producing (~1%)

pituitary adenoma, unknown type

hematoxylin and eosin stain

pituitary adenoma, prolactin-producing

special stain for prolactin tumor cell cytoplasm stains

You can’t tell the hormonal type of an adenoma by its microscopic appearance.


Molecular stuff Many pituitary adenomas have a mutated G-protein

(remember what G-proteins are?1). The normal G protein in the pituitary is one link in a chain of events leading to cell proliferation. The mutant G protein2 is unable to turn itself off, so cells proliferate like crazy. The mutated gene is called the GNAS1 gene, or the gsp oncogene.

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.

Prolactin-producing adenoma 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 dopaminergic neurons, dopamine receptor antagonist drugs) can cause increased prolactin.

Treatment: bromocriptine (a dopamine receptor agonist) shrinks the adenoma. Note: treatment of choice for all other pituitary adenomas is surgical removal.

1 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). 2

? 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.


Many pituitary adenomas have a mutated G protein that leads to unchecked cellular proliferation

Prolactinomas can be treated with dopamine receptor agonists.

Growth hormone-producing adenomaClinical features 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.

Laboratory findings 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.

Treatment Goal: get GH level back to normal, and get

rid of any mass effects, without causing hypopituitarism in the process.

Surgery and radiation are best.

ACTH-producing adenoma 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.

Patients with way too much cortisol floating around have Cushing syndrome. They are glucose-intolerant (or frankly diabetic), and they have a


Remember Andre the Giant in

The Princess Bride?

Cushing syndrome: too much cortisol.

Cushing disease: Cushing syndrome caused by an ACTH-producing pituitary adenoma

characteristic physical findings: central obesity (with a “buffalo hump”) and moon facies.

Cushing syndrome has four main causes (see adrenal notes). When it is caused by an ACTH-producing pituitary adenoma, it is properly called Cushing disease.

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.


FSH- and LH-producing adenomas Secrete FSH and LH very inefficiently. Come to attention because of mass effects (e.g.,

neurologic symptoms) rather than endocrine abnormalities.

TSH-producing adenoma Rare! See thyroid handout for symptoms, treatment.

Non-functioning adenoma 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).

Hypopituitarism

Definition: Decreased secretion of one or more pituitary hormones.

CausesDestruction of pituitary a big pituitary adenoma can compress and destroy

normal pituitary tissue surgery or radiation can also destroy pituitary tissue you have to destroy a lot (75%) of your pituitary

before you see signs of hypopituitarism

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).

Pituitary apoplexy sudden, spontaneous infarction of a pituitary tumor


Pituitary adenomas that don’t secrete hormones can get very big before they cause symptoms.

At least 75% of the pituitary must be destroyed to see signs of hypopituitarism.

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 ensue.

Hypothalamic lesions The hypothalamus normally delivers hormones to the

pituitary. Hypothalamic lesions (e.g., tumors, infections) can

interfere with the delivery of these hormones.


Clinical findingsHypopituitarism 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 body hair.

Prolactin deficiency prevents lactation. TRH deficiency produces secondary hypothyroidism

(discussed in thyroid lectures). ACTH deficiency produces adrenal insufficiency

(discussed in adrenal lectures).

Posterior pituitary syndromesPosterior pituitary hormones The posterior pituitary stores ADH (vasopressin) and

oxytocin. Changes in oxytocin levels do not produce symptoms

(unless you’re pregnant or nursing). 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 symptoms.

ADH deficiency prevents the kidney from concentrating urine.

The patient pees lots of dilute urine, the serum sodium and osmolality increase, and 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.


↓ ADH: dilute urine

↑ ADH:concentrated urine

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 carcinoma).

Treatment: restrict water intake.


Review

* Re vera, potas bene. (Say, you sure are drinking a lot!)


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 around the

pituitary gland.How might a growing

pituitary adenoma affect

Why is the line for the bathroom at the bar so long?

What’s the proper Latin phrase to use when your friend’s had a few too many?*

What is the name of the posterior pituitary syndrome, and what are the

more serious causes?


Documents

Pituitary pathology notes