Transcript Pathology of Hypophysis

The Endocrine System
Diseases
Associate Professor
Dr. Alexey Podcheko
Spring 2015
Intended Learning Outcomes
1. PITUITARY
-ANTERIOR
-POSTERIOR
2.
3.
4.
5.
• NON-NEOPLASTIC
– HYPER-function
– HYPO-function
THYROID
• NEOPLASTIC
PARATHYROID
– FUNCTIONAL
PANCREAS (endo.)
– NON-FUNCTIONAL
ADRENAL
– Functional endocrine
-CORTEX
-MEDULLA
malignancies are
RARE. Why?
Types of the signaling by
extracellular secreted molecules
• Autocrine- is a form of signaling in which a cell secretes a
hormone or chemical messenger (called the autocrine agent)
that binds to autocrine receptors on the same cell, leading to
changes in the cell (example insulin and beta-cells)
• Paracrine- a form of cell signaling in which the target cell is
near the signal-releasing cell (testosterone – being produced by
Leydig interstitial cells stimulates spermatogenesis in the
adjacent seminiferous tubules)
• Endocrine - secreted molecules, which are frequently called
hormones, act on target cells that are distant from their site of
synthesis. An endocrine hormone is frequently carried by the
blood from its site of release to its target.
• Feedback inhibition – is a secretion by target tissue factors that
down-regulate the activity of the gland that produces the
stimulating hormone
FEEDBACK SYSTEMS
• HYPOTHALAMUS 
• ANTERIOR PITUITARY 
• ENDOCRINE GLAND 
• END ORGAN 
• HYPOTHALAMUS 
Q1: What happened with feedback system if
exogenous hormone is added (e.g.
Thyroxin)?
Q2: What will happened with the gland
producing the same hormone (e.g. Thyroid
gland/Thyroxin) ?
• A 45-year-old Caucasian female with a several
year history of systemic lupus erythematosus
being treated with multiple medications is found
dead at home. On her most recent physical exam,
her blood pressure was 150/90 mm Hg and she
was noted to have truncal obesity, mild hirsutism,
facial plethora, and proximal muscle weakness.
Laboratory studies showed hyperglycemia. At
autopsy, she was found to have a left coronary
artery mainstem thrombus that caused sudden
cardiac death. Evaluation of her adrenal glands
will most likely show which of the following?
• A. Diffuse hyperplasia
• B. Nodular hyperplasia
• C. Bilateral cortical atrophy
• D. Unilateral atrophy
Tophat
• E. Adrenocortical adenoma
Pituitary gland (HYPOPHYSIS)
• Composed of two morphologically and functionally
distinct components:
• 1. Anterior lobe (adenohypophysis, 80% of gland) production of the most pituitary hormones is controlled
predominantly by positive-acting releasing factors from
the hypothalamus delivered via portal vascular system
(exceptions: prolactin- only inhibitory signals; growth
hormone – inhibitory and stimulatory signals )
• 2. Posterior lobe (neurohypophysis) - modified glial
cells (termed pituicytes) and axonal processes
extending from the hypothalamus through the pituitary
stalk to the posterior lobe (axon terminals). The two
peptide hormones secreted from the posterior
pituitary—oxytocin and antidiuretic hormone (ADH,
also called vasopressin)—are synthesized in the
hypothalamus and are stored within the axon terminals
residing in the posterior pituitary. In response to
appropriate stimuli, the pre-formed hormones are
released directly into the systemic circulation through
the venous channels of the pituitary.
FIVE TYPES OF CELLS IN ADENOHYPOPHYSIS
1. Somatotrophs (acidophilic)- growth hormone - 50% of cells in AH
2. Lactotrophs (acidophilic) - prolactin
3. Corticotrophs (basophilic)- adrenocorticotropic hormone (ACTH), proopiomelanocortin (POMC), melanocyte-stimulating hormone (MSH),
endorphins, and lipotropin.
4. Thyrotrophs: (basophilic)- thyroid-stimulating hormone (TSH).
5. Gonadotrophs (basophilic) - follicle-stimulating hormone (FSH) and
luteinizing hormone (LH).
-FSH stimulates the formation of graafian follicles in the ovary
-LH induces ovulation and the formation of corpora lutea in the ovary
(spermatogenesis and testosterone production in males)
• A 16-year-old Caucasian girl who aspires to be a fashion
model presents for a routine examination She wishes to
modify her diet and exercise plans so that she can lose an
additional 20 lbs (9 kg) because she believes she is
currently "too fat" to participate in a beauty pageant later
this year. She is frustrated that she "cant seem to drop
these extra pounds' in spite of strict dietary limitations and
vigorous exercise for two hours each day. Her menstrual
history is significant for amenorrhea for the past four
months. Her height is 5*5" (165 cm) and her weight is 100
lbs (45.3 kg), resulting in a BMI of 16.6 Kg/m2. On physical
examination, she is pale and emaciated. Fine hair is noted
on her trunk. Which of the following is the most likely
mechanism of her amenorrhea?
A. Primary ovarian failure
B. Primary pituitary dysfunction
C Hypothyroidism
D. Hyperprolactinemia
E. Hypothalamic Dysfunction
• Amenorrhea in anorexic patients results
from loss of pulsatile GnRH release from
the hypothalamus
• There is no pulsatile GnRH release when
the level of body fat falls below a certain
critical level
• Loss of this cyclic gonadotropin release
leads to a decrease in LH and FSH
secretion from the pituitary
• Administration of pulsatile GnRH in
individuals with anorexia nervosa allows for
the normalization of estrogen levels and
subsequent ovulation
Normal Pituitary
1.
2.
3.
4.
5.
Somatotrophs (acidophilic)
Lactotrophs (acidophilic)
Corticotrophs (basophilic)
Thyrotrophs: (basophilic)
Gonadotrophs (basophilic)
Immunostaining for human growth hormone
ACIDOPHILS
BASOPHILS
CHROMOPHOBES
Why pituitary has a “portal” circulation, i.e.,
arterycapillariesveinscapillaries,
rather than just acv.
Ans: to create a “secondary” circulation
between the pituitary and the hypothalamus
releasing factors!
Adeno
AXONS
Neuro
AXONS and “PITUI-”cytes
acidophils and basophils in adenohypophysis
ANTERIOR PITUITARY
• ACIDOPHILS
–GROWTH HORMONE
–PROLACTIN
• BASOPHILS
–TSH
–ACTH
–LH, FSH
•The posterior pituitary (aka, pars nervosa or neurohypophysis) looks like
typical brain tissue. The pituicytes are glial cells.
•Herring bodies are massively dilated terminal axons from the
hypothalamus.
POSTERIOR
PITUITARY
• OXYTOCIN (contracts
uterine smooth muscle)
• VASOPRESSIN (ADH)
(vasoconstriction, gluconeogenesis,
platelet aggregation, release of
Factor-VIII and vWb factor,
concentrates urine, main effects on
kidney and brain)
Clinical Manifestations of Pituitary Disease
A. Hyperpituitarism: - excess secretion of trophic hormones.
Causes:
1. Pituitary adenoma,
2. Hyperplasia and carcinomas of the anterior pituitary,
3. Secretion of hormones by nonpituitary tumors, and certain
hypothalamic disorders.
B. Hypopituitarism: - deficiency of trophic hormones.
Causes:
1. Destructive processes, including ischemic injury, surgery
or radiation, inflammatory reactions
2. Nonfunctional pituitary adenomas.
C. Local mass effects
Causes: pressure of the tumor on the surrounding tissues
Local mass effects
1. Radiographic abnormalities of
the sella turcica, including sellar
expansion, bony erosion, and
disruption of the diaphragma
sella.
2. Visual field abnormalities
(bitemporal hemianopsia ) expanding pituitary lesions
often compress decussating
fibers in the optic
3. Signs and symptoms of
elevated intracranial pressure:
headache, nausea, and
vomiting.
-Pituitary apoplexy - acute
hemorrhage into an adenoma
Note the extreme proximity of the pituitary stalk (infundibulum) to the optic chiasm
BITEMPORAL
HEMIANOPSIA
What part of the optic
nerves/chiasm/tracts would have
to be injured to produce this?
Why bitemporal hemianopsia usually is NOT perfectly
symmetrical.
Because pituitary tumors are under no law to grow perfectly
midline.
Classification of Pituitary Adenomas
-Adenoma is most common cause of hyperpituitarism
-Pituitary adenomas are classified on the basis of hormone(s) produced by the
neoplastic cells (see the table)
-Pituitary adenomas are usually found in adults, with a peak incidence from 35 to 60
years of age.
Pituitary Adenomas and Hyperpituitarism
-Some pituitary adenomas can secrete two hormones (GH
and prolactin being the most common combination)
-Functional adenoma (with hormone excess) or
nonfunctioning (without clinical symptoms of hormone
excess).
-Microadenomas if less than 1 cm in diameter
-Macroadenomas if they exceed 1 cm in diameter
-Population prevalence of pituitary adenomas is about 14%
and they are incidentally diagnosed microadenomas
(“pituitary incidentaloma”).
Genetic abnormalities associated
with pituitary adenomas
G-protein mutations and pituitary
adenomas
• Composed of a specific α-subunit
that binds guanine nucleotide and
interacts with both cell surface
receptors and intracellular effectors,
β- and γ-subunits are noncovalently
bound to the specific α-subunit.
• On interaction with the ligandbound cell surface receptor, GDP
dissociates, and guanosine
triphosphate (GTP) binds to Gsα,
activating the G protein. The
activation of Gsα results in the
generation of cAMP, which acts as
a potent mitogenic stimulus
• A mutation in the α-subunit that
interferes with its intrinsic GTPase
activity will result in constitutive
activation of Gsα, persistent
generation of cAMP, and
unchecked cellular proliferation
Morphology of pituitary adenoma
• Pituitary adenoma - soft, well-circumscribed
lesion in sella turcica.
• Larger adenomas extend superiorly through
the diaphragm sella into the suprasellar
region, where they often compress the optic
chiasm and adjacent structures, such as
some of the cranial nerves
• Invasive adenomas erode the sella turcica
and anterior clinoid processes. ( 30% of
cases)
Histology:
• Cellular monomorphism, absence of a
significant reticulin network distinguish
pituitary adenomas from non-neoplastic
anterior pituitary parenchyma
• Foci of hemorrhage and necrosis
• The biologic behavior cannot always be
reliably predicted from histologic appearance
• Atypical adenomas – specific form with high
level of mutated p53 and mitoses
Pituitary adenoma. This massive, nonfunctional adenoma has grown far
beyond the confines of the sella turcica and has distorted the overlying
brain. Nonfunctional adenomas tend to be larger at the time of diagnosis
than those that secrete a hormone.
Mechanisms of prolactin secretion
• Stimulate prolactin production:
-Thyrotropin releasing hormone
-Serotonin
-antipsychotics
-Tricyclic antidepressants
-MAO inhibitors
-hypothalamic and pituitary tumors
• Inhibit prolactin production:
-Dopamin
-Bromcriptine (parlodel)
PROLACTINOMAS
• Prolactinomas (lactotroph adenomas)
are the most frequent type of
hyperfunctioning pituitary adenoma,
(30% of all clinically recognized cases)
• Histology: weakly acidophilic or
chromophobic cells (sparsely
granulated prolactinoma); rare
prolactinomas are strongly acidophilic
(densely granulated prolactinoma)
• Prolactin can be demonstrated within
the secretory granules in the
cytoplasm of the cells using
immunohistochemical stains.
• Prolactinomas have a propensity to
undergo dystrophic calcification,
(psammoma bodies or “pituitary
stone”).
• Serum prolactin concentrations tend to
correlate with the size of the adenoma.
Prolactinoma, Clinic
• Hyperprolactinemia cause
amenorrhea, galactorrhea, loss
of libido, and infertility.
• Prolactinoma underlies 25% of
cases of amenorrhea.
• In men and older women, the
hormonal manifestations may
be subtle, allowing the tumors
to reach considerable size
• Prolactinomas are treated by
surgery (transsphenoidal
operation ) or, more commonly,
with bromocriptine, a dopamine
receptor agonist that causes
the lesions to diminish in size.
G
A
L
A
C
T
O
R
R
H
Galactorrhea in a young woman (non pregnant) is often
the expression of an acidophil tumor of the
adenohypophysis.
E
A
Other reasons for hyperprolactinemia:
Physiologic hyperprolactinemia:
1. pregnancy
2. during breastfeeding in lactating women
3. response to many types of stress.
Pathologic hyperprolactinemia (Lack of dopamine
inhibition of prolactin secretion) :
1. Damage to the dopaminergic neurons of the
hypothalamus
2. Damage to the pituitary stalk (e.g., due to head
trauma or any tumour in the suprasellar
compartment )
3. Drugs (such as dopamine antagonists),
estrogens
4. Renal failure
5. Hypothyroidism
• A 32-year-old Caucasian male comes to your office
complaining of visual problems. He has had several
“near-misses” in his car lately, being nearly hit by cars
coming from both the right and the left. He also admits
to having headaches that respond to acetaminophen.
Which of the following hormones is most likely
elevated in this patient?
• A. Growth hormone
• B. Adrenocortical-stimulating hormone
• C. Thyroid-stimulating hormone
• D. Prolactin
• E. Follicle-stimulating hormone
tophat
GROWTH HORMONE CELL
(SOMATOTROPH) ADENOMAS
• Manifestations of excessive GH may be subtle for prolonged
period of time
• Histology: densely granulated and sparsely granulated
acidophilic or chromophobe cells
• Some adenomas are bihormonal ( GH and prolactin)
• Clinical features: Gigantism or Acromegaly
• Mechanism : Persistently elevated levels of GH stimulate the
hepatic secretion of insulin-like growth factor 1 (IGF-1 or
somatomedin C)
• If adenoma appears before the epiphyses have closed, the
elevated levels of GH (and IGF-1) -result in gigantism increase in body size with disproportionately long arms and
legs.
• If adenoma appears after closure of the epiphyses acromegaly.
GIGANTISM
(excess
somatotropin
[GH]
BEFORE
epiphyseal
closure)
ACROMEGALY:
(excess
somatotropin
[GH] AFTER
epiphyseal
closure)
GROWTH HORMONE CELL
(SOMATOTROPH) ADENOMAS
• Other symptoms:
-hyperostosis,
-prognathism,
-gonadal dysfunction,
-diabetes mellitus,
-generalized muscle weakness,
-hypertension,
-arthritis,
-congestive heart failure,
-increased risk of gastrointestinal cancers.
GROWTH HORMONE CELL
(SOMATOTROPH) ADENOMAS
• Lab Diagnosis: Failure to suppress GH production in
response to an oral load of glucose is one of the most
sensitive tests for acromegaly.
• Treatment: The underlying pituitary adenoma can be
either removed surgically or treated via pharmacologic
means (somatostatin analogs or the use of GH receptor
antagonists)
• Prognosis: When effective control of high GH levels is
achieved, the characteristic tissue overgrowth and
related symptoms gradually recede, and the metabolic
abnormalities improve.
• Most common cause of death in patients with
acromegaly is CHF - (up to 70% of cases)
•
•
•
•
•
ACTH CELL (CORTICOTROPH)
ADENOMAS
Usually small microadenomas at the
time of diagnosis.
These tumors are most often basophilic
(densely granulated) and occasionally
chromophobic (sparsely granulated).
Excess production of ACTH by the
corticotroph adenoma leads to adrenal
hypersecretion of cortisol and the
development of hypercortisolism
Cushing disease - hypercortisolism is
due to excessive production of ACTH by
the pituitary(not adrenal gland!)
Causes: Spontaneous mutations, rare
due to surgical removal of the adrenal
glands for treatment of Cushing
syndrome (Nelson syndrome)
STRIAE
MOON
FACIES
BUFFALO
HUMP
Clinical presentation:
-Cushing syndrome – could be due to ectopic production of ACTH or due to
excessive production of cortizol by adrenal gland!!!
-Pigmentation present if Cushing syndrome is result of ACTH production!
Hypertension, hypokalemic alkalosis,
For diagnosis – Dexamethasone suppression test (high dose suppression test +ve
for pituitary tumors and negative for ectopic ACTH tumors!!!!)
Nelson syndrome
• Surgical removal of the adrenal
glands for treatment of Cushing
syndrome induces loss of the
inhibitory effect of adrenal
corticosteroids on a preexisting
corticotroph microadenoma and
this lead to progressive growth of
hypophyseal tumor
• Symptoms:
-No signs of hypercortisolism, but
hypocortisolism.
-Singns of “mass effects” in
Hypophysis
-Hyperpigmentation because of the
stimulatory effect of other products
of the ACTH precursor molecule on
melanocytes.
OTHER ANTERIOR PITUITARY
ADENOMAS
• Gonadotroph (LH-producing and FSH-producing)
adenomas:
• Symptoms: impaired vision, headaches, diplopia,
impaired secretion of LH - decreased energy and
libido in men (due to reduced testosterone) and
amenorrhea in premenopausal women.
• Thyrotroph (TSH-producing) adenomas are rare,
accounting for approximately 1% of all pituitary
adenomas. Thyrotroph adenomas are a rare cause
of hyperthyroidism.
• Nonfunctioning pituitary adenomas - 25% to 30% of
all pituitary tumors. (aka silent variants or null-cell
adenomas).
Normal
Tumor
Hypopituitarism, Definitions
• Definition: Decreased secretion of pituitary
hormones, which results from diseases of
the hypothalamus or of the pituitary.
• Hypofunction of the anterior pituitary :
congenital or the result of a variety of
acquired abnormalities that are intrinsic to
the pituitary.
• Hypofunction of the posterior pituitary:
diabetes insipidus is almost always of
hypothalamic origin.
Causes of pituitary hypofunction
• Traumatic brain injury and subarachnoid hemorrhage
• Tumors and other mass lesions ( Pituitary adenomas, other
benign tumors arising within the sella, primary and metastatic
malignancies, and cysts )
• Pituitary surgery or radiation: Surgical excision, radiation of the
pituitary,
• Pituitary apoplexy ( sudden hemorrhage into the pituitary gland)
• (sudden onset of excruciating headache, diplopia due to
pressure on the oculomotor nerves, cardiovascular collapse,
loss of consciousness, sudden death).
• Sheehan syndrome (postpartum necrosis of the anterior
pituitary) - the most common form of clinically significant
ischemic necrosis of the anterior pituitary.
• Rathke cleft cyst: can expand and press on the the normal
gland.
• Genetic defects (PIT1 gene mutations)
• Hypothalamic lesions: tumors, infections
Empty sella syndrome
Definition: Any condition that
destroys part or all of the pituitary
gland, such as ablation of the
pituitary by surgery or radiation
Primary empty sella syndrome: defect in the diaphragma sella that
allows the arachnoid mater and
cerebrospinal fluid to herniate into
the sella (obese women with a
history of multiple pregnancies)
Secondary empty sella, a mass,
such as a pituitary adenoma,
enlarges the sella, but then it is
either surgically removed or
undergoes spontaneous necrosis,
leading to loss of pituitary function.
• A 24-year-old Caucasian female presents to your
office two weeks after delivery. She is concerned
because she has not yet lactated. She says that she
knew she would lose weight and be tired after the
baby was born, but she complains of excessive fatigue
and has had significant weight loss. Thorough
evaluation of this patient reveals decreased serum T4
level and decreased 24-hour urine cortisol excretion.
Which of the following pathologic processes is most
likely responsible for this patient’s symptoms?
• A. Inflammation
• B. Apoplexy
• C. Ischemic necrosis
• D. Non-malignant infiltration
• E. Malignant infiltration
tophat
• Explanation:
• Classical description of Sheehan’s syndrome
• High estrogen levels during pregnancy stimulate
growth of the pituitary, causing it to both enlarge and
become more vascular.
• If significant hypotension occurs while the pituitary is
still enlarged (the most common cause is postpartum
hemorrhage) ischemic necrosis of the pituitary occurs.
• A deficiency of multiple pituitary hormones
(panhypopituitarism) follows this ischemia.
• Prolactin deficiency is one sequelae of the necrosis,
which has important symptomatic and diagnostic
significance.
• Patients suffering from Sheehan syndrome also
commonly have hypothyroidism and hypocortisolism.
POSTERIOR PITUITARY Diseases
• DIABETES INSIPIDUS – ADH
deficiency
• SIADH (Syndrome of Inappropriate
Andi- Diuretic Hormone) – ADH
excess
Diabetes insipidus
Definition: condition characterized by excessive urination (polyuria) due
to an inability of the kidney to resorb water properly from the urine.
Causes:
1. Head trauma
2. Cerebral tumors
3. Inflammatory disorders of the hypothalamus and pituitary
4. Surgical procedures on hypothalamus and pituitary
5. not known
Types of Diabetes Insipidus:
1. Central - ADH deficiency
2. Nephrogenic diabetes insipidus ( renal tubular unresponsiveness to
circulating ADH)
Clinic: Polyuria with an inappropriately low specific gravity and osmolality.
Serum sodium and osmolality are increased as a result of excessive
renal loss of free water, resulting in thirst and polydipsia.
•Primary (Psychogenic) polydypsia - - low plasma and low urine
osmolality
• A 34-year-old man comes to the physician with a 2-month
history of excessive thirst and frequent urination. His past
medical history is significant for a prolonged intensive care
unit stay due to complications following a motorcycle
accident. He takes no medications and has no known drug
allergies. Physical examination, including a complete
neurologic examination, is unremarkable. Laboratory
evaluation shows a fasting blood glucose level of 90
mg/dL. His urinary osmolality after 2-hours of water
restriction is 250 mOsm/L, but it increases to 700 mOsm/L
after an injection of antidiuretic hormone. The patient is
started on the appropriate therapy with improvement of his
symptoms. He follows up regularly with his physician over
the next several years, but his condition never resolves.
Dysfunction of which of the following structures is most
likely responsible for this patient's persistent condition?
• A. Posterior Hypophysis
• B. Anterior Hypophysis
• C. Kidneys
• D. Thalamic nuclei
• E. Hypothalamic nuclei
Inappropriate ADH
Syndrome of inappropriate ADH (SIADH) secretion.
• Pathogenesis: ADH excess causes resorption of
excessive amounts of free water, resulting in
hyponatremia
• Causes:
• 1. secretion of ectopic ADH by malignant neoplasms
(small-cell carcinomas of the lung)
• 2. drugs that increase ADH secretion
(antidepressants, chemo)
• 3. infections and trauma
• The clinical manifestations of SIADH are dominated by
hyponatremia, cerebral edema, and resultant
neurologic dysfunction.
Hypothalamic Suprasellar Tumors
• Types of tumors:
-gliomas (chiasm)
-craniopharyngiomas
Symptoms:
-hypofunction or
hyperfunction of the
anterior pituitary
-diabetes insipidus
-headaches and visual
disturbances
-growth retardation due to
pituitary hypofunction and
GH deficiency
Morphology of Suprasellar Tumors
• -Craniopharyngiomas average 3 to 4 cm in diameter
• Three components: 1. solid, comprised of the actual
tumor cells; 2. cystic, filled with "machinery oil" liquid,
3. calcified component
Adamantinomatous craniopharyngioma
“Palisading” epithelium+ “wet keratin”s
tumor. The cysts contain a “machine oil.”
Papillary craniopharyngiomas
Craniopharyngiomas
• Craniopharyngiomas are usually tumors of childhood,
being most frequently discovered between the ages of
5 and 10 years of age.
• Arising from remnants of Rathke's pouch (outpouching of the pharyngeal roof)
• During the time of pituitary development, remnants of
Rathke's pouch cells can remain in the diencephalon
(the posterior region of the forebrain).
• Craniopharyngioma symptoms include headaches,
visual field defects, and hypopituitarism, evidenced by
the growth retardation of this child.
• Compression of the pituitary stalk by
craniopharyngioma leads to hyperprolactinemia by
loss of dopaminergic inhibition
• A 7-year-old boy is being evaluated for growth
retardation. Brain MRI shows a 4 cm multiloculated,
cystic, suprasellar lesion, which is bulging into the
floor of the third ventricle and base of the brain.
Calcifications are present. From which of the following
structures is this mass most likely derived?
• A. Prolactin secreting cells of the anterior pituitary
• B. Remnants of the Rathke pouch
• C. Astrocytes
• D. Arachnoid cap cells
• E. Posterior pituitary cells
Craniopharyngiomas, prognosis
• Patients with craniopharyngiomas, especially
those < 5 cm in diameter, have an excellent
recurrence free and overall survival.
• >5 cm tumors are more invasive but this does
not impact on the prognosis.
• Malignant transformation of craniopharyngiomas
into squamous carcinomas is exceptionally rare
and usually occurs after irradiation.