Pituitary Pathology

Posterior pituitary syndromes

1.Diabetes insipidus 2. Syndrome of inappropriate ADH secretion (SIADH)

microadenomas

less than 1 cm

macroadenomas

more than 1 cm

Lack of GH

pituitary dwarfism

Atypical adenomas

Atypical adenomas: subset of adenomas with significant mitotic activity, presence of Ki-67, and presence of p53 mutations 1. Tend to invade into adjacent structures and recur 2. From a surgical perspective, they are difficult to access

Pituitary adenomas

Benign tumor of anterior pituitary cells, may be nonfunctional or functional (don't secrete hormones or secrete hormones). Most if they secrete hormones only secrete one kind of hormone but some may secrete 2 kinds. Most common cause of *hyperpituitarism* is an anterior pituitary adenoma. However, large pituitary adenomas may cause hypopituitarism by encroaching on adjacent normal pituitary tissue and compressing it.

Non-functioning/null cell adenomas

Do not produce hormone. Most present with mass effects instead of hormonal effects. Make up about 25-30% of all pituitary adenomas. May compress the normal tissue of anterior pituitary and cause hypopituitarism

Sheehan syndrome

During pregnancy, the anterior pituitary enlarges considerably, largely because of an increase in the size and number of prolactin-secreting cells. This physiologic enlargement of the gland, however, is not accompanied by an increase in blood supply from the low-pressure portal venous system. The enlarged gland is thus vulnerable to ischemic injury, especially in women who experience significant hemorrhage and hypotension during the peripartal period. The posterior pituitary, because it receives its blood directly from arterial branches, is much less susceptible to ischemic injury and therefore usually is not affected. These patients present with poor lactation and *loss of pubic hair*. Pubic hair is dependent on androgens that are created after LH stimulation.

Clinical manifestations of GH adenoma: glucose

Elevated levels of GH stimulate the hepatic secretion of *insulin-like growth factor* (IGF-1) resulting in many clinical problems, such as abnormalities in gluconeogenesis. It causes glucose intolerance (decreased uptake of glucose into cells) causing secondary DM2, and induces liver into gluconeogenesis. Dx by elevated GH and elevated IGF-1, along with lack of GH suppression by oral glucose.

Gonadotroph adenomas

Gonadotroph (luteinizing hormone [LH]-producing and follicle-stimulating hormone [FSH]-producing) adenomas can be difficult to recognize, because they secrete hormones inefficiently and variably, and the secretory products usually do not cause a recognizable clinical syndrome. They are typically detected when the tumors have become large enough to cause neurologic signs and symptoms, such as impaired vision, headaches, diplopia, or pituitary apoplexy. Can paradoxically cause gonadal hypofunction. May cause impaired secretion of LH causing decreased libido in men and amenorrhea in premenopausal women. Symptoms may not be as evident in older men/women.

Hypopituitarism

deficiency of hormones that may be cause by destruction of tissue due to: 1.surgery 2. radiation 3. inflammation 4. nonfunctional pituitary adenomas

Hyperpituitarism

excess secretion of hormones caused by: 1. adenomas (most common) 2. hyperplasia 3. cancer of anterior pituitary

Local mass effects

expansion of pituitary tumors into surrounding brain tissue may cause: 1. Radiographic changes of the sella turcica 2. Compression of the optic chiasm, causing visual abnormalities including bitemporal hemianopsia. The optic chiasm is in the suprasellar region. 3. Increased intracranial pressure 4. Headache 5. Acute hemorrhage associated with rapid enlargement of a lesion called *pituitary apoplexy* which can cause sudden death May get large and compress normal pituitary tissue causing hypopituitarism

Prolactin deficiency

failure in postpartum lactation

lack of TSH and ACTH

hypothyroidism and hypocortisolism

Lack of FH and FSH

leads to amenorrhea, loss of libido, infertility, impotence

Empty sella syndrome, secondary type

mass enlarges the sella, but is surgically removed or undergoes spontaneous necrosis, leading to loss of pituitary function.

GH adenoma in children with OPEN epiphysis

Somatotrophic adenomas arising in children before closure of epiphyseal plates close results in *gigantism* due to increased linear bone growth. Children have generally increased body size with disproportionally increased long arms and legs.

ACTH/corticotroph adenomas

Tend to be small - most are microadenomas. Mostly are densely granulated, while some are sparsely granulated. Results in adrenal hypersecretion of cortisol and hypercortisolism AKA *Cushing disease*. DISEASE because from a pituitary cause. Generalized hypercortisolism from other causes is termed Cushing syndrome, from a non-pituitary cause

Causes of hypopituitarism that are of pituitary origin

1. Non-functional adenomas that get large and compress normal functioning anterior pituitary tissue. 2. Traumatic brain injury and subarachnoid hemorrhage 3. Pituitary surgery or radiation 4. Pituitary apoplexy 5. Rathke cleft cyst: benign cysts lined by ciliated cuboidal epithelium that can expand and compress the normal gland 6. Inflammatory disorders and infections: sarcoidosis, tuberculosis

There are three treatment options for gigantism and acromegaly:

1. Surgery or radiation 2. Octreotide: a somatostatin analogue that inhibits GH release from the anterior pituitary and 3. Pegvisomant: a GH receptor antagonist which effectively blocks IGF-1 production.

How can you treat a prolactinoma?

1. Surgical removal 2. Dopamine agonist (to suppress prolactin production and shrink tumor): *Bromocriptine*

Growth hormone adenoma

2nd most common type of functional adenoma. 3 Morphologic subtypes: 1.Densely granulated: monomorphic cells, strong GH staining, perinuclear staining for cytokeratin 2.Sparsely granulated: nuclear and cytologic pleomorphism, sparsely populated, weak staining for GH 3.Bihormonal (mixed) adenomas secrete both GH and prolactin

Hypothalamic lesions: ADH deficiency

ADH deficiency causes diabetes insipidus, a condition characterized by excessive urination (polyuria) caused by an inability of the kidney to properly resorb water from the urine. Diabetes insipidus can result from several causes, including head trauma, neoplasms, and inflammatory disorders of the hypothalamus and pituitary, and from surgical procedures involving the hypothalamus or pituitary. The condition sometimes arises spontaneously (idiopathic) in the absence of an underlying disorder. Diabetes insipidus from ADH deficiency is designated as central, to differentiate it from nephrogenic diabetes insipidus as a result of renal tubular unresponsiveness to circulating ADH. The clinical manifestations of both diseases are similar and include the excretion of large volumes of dilute urine with an inappropriately low specific gravity.

Syndrome of inappropriate ADH secretion (SIADH)

Causes resorption of large amounts of free water, resulting in a dilutional type of hyponatremia. Too much ADH. Causes 1. Malignant tumors may secrete ADH on their own, particularly lung paraneoplastic syndromes. 2. Drugs can increase ADH secretion 3. Central nervous system disorders: trauma and infection Clinical presentation 1. Hyponatremia (dilutional type), cerebral edema with neurogenic dysfunction 2. It is possible to drink too much water, which can lead to dilutional hyponatremia, cerebral edema, seizures, and even death 3. Difficult to diagnose post-mortem

Papillary craniopharyngiomas

Contains solid sheets and papillae lined by well differentiated squamous epithelium. Usually lack keratin and calcifications. Squamous cells lack peripheral palisading

Craniopharyngiomas

Craniopharyngiomas are rare tumors derived from Rathke's pouch, the embryonic precursor of the anterior pituitary, which itself is derived from surface ectoderm. They are usually suprasellar in location and may compress the optic chiasm. These tumors occur most often in children, and on exams are often presented as a child with a bitemporal hemianopsia. Children may present with growth retardation from pituitary hypofunction and GH deficiency. Craniopharyngiomas are benign but difficult to remove because of location. Histopathologically, craniopharyngioma shows a tooth enamel-like calcification. Cystic spaces with nests of squamoid cells surrounded by columnar cells.

GH adenoma in adults with closed epiphyseal plates

If the adenoma occurs after the plates close, it results in acromegaly, which effects the skin and viscera and causes enlargement of bones feet and hands, hyperostosis of hips and spine, and enlargement of the jaw (lantern jaw). Signs of acromegaly: Coarsening of skin/facial features Thickening of the hands and feet Enlargement of the jaw resulting in protrusion (prognathism) Deep voice Impaired glucose tolerance (insulin resistance) Peripheral neuropathies (due to nerve compression) Death often due to cardiomyopathy

Hypopituitarism

Insufficient production of hormones by the anterior pituitary gland, symptoms arise when >75% of the pituitary parenchyma is lost because it has alot of reserve tissue.

Pituitary carcinomas

Relatively rare; account for less than 1% of pituitary tumors. May have cranial spinal (brain, skull) or systemic metastasis. Most are functional tumors which produce prolactin and ACTH most commonly.

Nelson Syndrome

Large, clinically aggressive corticotroph cell adenomas may develop after surgical removal of the adrenal glands for treatment of Cushing syndrome (non-pituitary cause). In most instances, this condition, known as Nelson syndrome, results from loss of the inhibitory effect of adrenal corticosteroids on a preexisting corticotroph microadenoma. Because the adrenals are absent in persons with Nelson syndrome, hypercortisolism does not develop. Instead, patients present with the mass effects of the pituitary tumor. In addition, because ACTH is synthesized as part of a larger prohormone substance that includes melanocyte-stimulating hormone (MSH), hyperpigmentation also may be a feature.

Prolactinomas

Most frequent type of hyperfunctioning pituitary adenoma. Microscopically, the secretory granules in the cytoplasm of the prolactinoma tumor can be demonstrated using immunohistochemical stains. May undergo *dystrophic calcification* (deposition of Ca2+ in a pathologic structure in the presence of normal serum Ca2+) with *psammoma bodies* (laminated concretions present in a lot of endocrine neoplasms). *Amyloid* may also be present (protein fragments). Prolactin immunopositivity is present in the *perinuclear areas* producing a *crescent-shaped pattern*.

adamantinomatous craniopharyngiomas

Most often seen in children. Often contains calcifications which can be seen on X-rays Consist of nests and cords of stratified squamous epithelium in a reticular background. Palisading (wall-like) squamous epithelium at its periphery Compact laminar keratin is usually seen May also have fibrosis, cyst formation, and chronic inflammation Tumor has fingerlets which can extend into the adjacent brain Cysts contain cholesterol-rich thick brown, turbid fluid (pictured)

Clinical symptoms of prolactinomas

Pre-menopausal women: galactorrhea (excessive production of milk) and amenorrhea/infertility. Easiest to dx early in this population because women will notice they aren't getting a period. Post menopausal women and men: decreased libido, headache and often dx later when they get very big

Pituitary Apoplexy

The word apoplexy is defined as a sudden neurologic impairment, usually due to a vascular process. Pituitary apoplexy is characterized by a sudden onset of headache, visual symptoms, altered mental status, and hormonal dysfunction due to acute hemorrhage or infarction of a pituitary gland. An existing pituitary adenoma is usually present. The visual symptoms may include both visual acuity impairment and visual field impairment from involvement of the optic nerve or chiasm and ocular motility dysfunction from involvement of the cranial nerves traversing the cavernous sinus.It is important to note that pituitary apoplexy may be divided into hemorrhagic or ischemic, each with unique neuroimaging findings. The adenoma can outgrow its blood supply leading to infarction and hemorrhage. May lead to cardiovascular collapse in part due to lack of ACTH and cortisol.

Morphology of adenoma

Typical pituitary adenomas are composed of uniform, polygonal cells in sheets or cords with little supporting connective tissue. Cellular monomorphism and absence of a reticulin network distinguish pituitary adenomas from non-neoplastic anterior pituitary parenchyma

How do you know its a problem with the pituitary itself causing the hypopituitarism and not just the lack of stimulation by the hypothalamus?

When not enough releasing factors are delivered to the pituitary from the hypothalamus you have development of hypopituitarism from hypothalamic origin. Hypopituitarism accompanied by evidence of posterior pituitary dysfunction in the form of diabetes insipidus is almost always of hypothalamic origin

Empty sella syndrome, primary type

You get congenital defect in the diaphragma sella where you get herniation of the arachnoid and CSF into the sella that compresses and destroys the pituitary gland. May cause visual defects and endocrine abnormalities such as *panhypopituitarism* (hypothyroidism, adrenal insufficiency, amenorrhea)