Nelson Syndrome and Pituitary Adenomas

• The endocrine system is composed of widely distributed organs called glands
• Glands maintain a state of metabolic equilibrium in the body.
• Signaling by secreted molecules is classified into autocrine, paracrine, or endocrine based on the distance the signal travels.
• In endocrine signaling, hormones act on distant target cells and are transported via the bloodstream.
• Trophic factors from endocrine glands stimulate hormone production.
• Endocrine hormones inhibit the production of trophic factors through feedback inhibition.
• Disruptions in the endocrine system can result from impaired hormone synthesis/release, abnormal hormone interactions, and abnormal target organ responses.
• Endocrine diseases are classified as those of hormone underproduction/overproduction, and those associated with mass lesions.
• Diagnosing endocrine diseases requires an understanding of morphologic findings, hormone levels, and regulator measurements.

Pituitary Gland

• The pituitary gland is a small, bean-shaped structure at the base of the brain (sella turcica)
• It regulates other endocrine glands with the hypothalamus

Components of Pituitary Gland

• Anterior lobe (adenohypophysis): produces trophic hormones like thyroid, adrenal, etc.
• Posterior lobe (neurohypophysis): modified glial cells and axonal processes from hypothalamus

Anterior Pituitary Cells

• Epithelial cells are derived from the oral cavity that control endocrine glands
• Acidophils have eosinophilic cytoplasm.
• Basophils have basophilic cytoplasm.
• Chromophobe cells have poorly staining cytoplasm.

Six Terminally Differentiated Cells

• Somatotrophs produce growth hormone (GH).
• Mammosomatotrophs produce GH and prolactin (PRL).
• Lactotrophs produce PRL.
• Corticotrophs produce adrenocorticotropic hormone (ACTH), pro-opiomelanocortin (POMC), and melanocyte-stimulating hormone (MSH).
• Thyrotrophs produce thyroid-stimulating hormone (TSH).
• Gonadotrophs produce follicle-stimulating hormone (FSH) and luteinizing hormone (LH).
• FSH stimulates graafian follicle formation (women)
• LH induces ovulation and corpora lutea formation (women).
• FSH and LH regulate spermatogenesis/testosterone (men).

Posterior Pituitary Hormones

• Oxytocin and antidiuretic hormone (ADH) are synthesized in the hypothalamus
• In pregnancy, dilation of the cervix results in oxytocin release, leading to uterine contractions.
• Nipple stimulation releases oxytocin, enhancing lactation.
• ADH conserves water by restricting diuresis during dehydration and hypovolemia.
• Decreased blood pressure stimulates ADH release.
• High plasma osmotic pressure triggers ADH secretion.

Clinical Manifestations of Pituitary Disease

• Pituitary disorders result from hormone excess/deficiency, or mass effects.
• Hyperpituitarism arises from trophic hormone excess, including hyperplasias, adenomas, carcinomas, and hypothalamic disorders.
• Hypopituitarism results from trophic hormone deficiency caused by ischemic injury, surgery, radiation, inflammatory disorders, or mass effects.
• Expanding pituitary lesions compress decussating fibers in the optic chiasm, leading to bitemporal hemianopsia.
• Pituitary adenomas can produce elevated intracranial pressure -> headache, nausea, vomiting.
• Hemorrhage into an adenoma is termed pituitary apoplexy -> neurosurgical emergency.
• Posterior pituitary diseases relate to ADH secretion -> fluid/electrolyte change

Pituitary Adenomas and Hyperpituitarism

• Pituitary adenoma in anterior lobe is a common cause of hyperpituitarism
• Adenomas are classified by hormones and cell type-specific transcription factors.
• Some adenomas secrete hormones and are plurihormonal
• Large pituitary adenomas may cause hypopituitarism

Features of Pituitary Adenomas

• Peak incidence age = 35-60 years.
• Microadenomas are < 1 cm in diameter.
• Macroadenomas are > 1 cm in diameter.
• Nonfunctional adenomas are usually macroadenomas.
• Autopsy studies estimate the prevalence of pituitary adenomas to be about 14%.
• Vast majority is clinically silent microadenomas (“pituitary incidentaloma")

Pathogenesis (Genetic Alterations in Pituitary Tumors)

• Activating G-protein mutations are common in pituitary adenomas.
• G-proteins are involved in signal transduction
• The a-subunit of Gs (Ga) is encoded by the GNAS gene on chromosome 20q13.
• Mutations in GNAS can lead to persistent generation of cAMP and unchecked cellular proliferation
• Activating mutations of ubiquitin-specific protease 8 (USP8) occur in corticotroph adenomas that enhance EGFR
• Germline loss-of-function mutations in genes cause pituitary adenomas

Morphology

• Typical Soft, well-circumscribed cells
• Adenomas may erode sella turcica and anterior clinoid processes
• Lesions may compress the optic chiasm
• 30% of adenomas are aggressive & infiltrate surrounding tissue

Histologically

• Pituitary adenomas are composed of uniform polygonal cell arrays in sheets/cords
• Low mitotic activity and Ki-67 expression in pituitary adenomas

Clinical Features

• Related to endocrine abnormalities and mass effects.
• Includes radiographic abnormalities, visual field abnormalities, ICP, hypopituitarism
• Biologic behavior in pituitary adenoma not always predictable from its histologic appearance

Lactotroph Adenoma

• Prolactin-secreting lactotroph adenomas are the most common type of hyperfunctioning pituitary adenoma
• Lesions range from small microadenomas to large tumors.

Morphology of Lactotroph Adenoma

• Large majority composed of chromophobe cells with juxtanuclear localization of transcription factor PIT-1 known as sparsely granulated lactotroph adenomas.
• Prolactin demonstrated within cytoplasmic secretory granules with immunohistochemical stains
• Estrogen receptor alpha (ERα) is co-expressed alogn with PIT-I
• Lactptroph can often undergo dystrophic calcification.
• Prolactin secretion by functioning adenomas is efficient and proportional, tending to correlate with the size

Clinical Features

• Increase serum levels of prolactin, prolactin causes ammenorrhea, galactorrhea, loss of libido, and infertility
• Diagnosis made more easily with women (20-40 age)
• Lactroph is 1/4 cases of amenorrhea
• Can be subtle in older men/women so tumors can reach considerable size

Somatotroph Adenoma

• GH-secreting somatotroph adenomas (2nd common) causes gigantism in children and acromegaly in adults
• Lesion can be quite large by the time they come across clinically

Morphology of Somatotroph Adenoma

• Pure somaotroph classified as the densely granulated and sparsely granulated subtypes
• Densely granulated are composed of eosinophilic cellls with grannular cytoplasm and large central nucleai and strong immunoreactivity for GH
• Sparsely granulated variants compose of chromophobe cells with weak staining with GH and characterisitic paranclear glossy inclusion known as a fibrous body
• Bihormonal mammosomatotroph synthesized GH and prolactin within the dame cells
• Mixed somatotroph: GH and prolactin being expressed in different cells
• Overall sparselty granulated tend to be more agressive than densely granulatied adenoma, so accurate subtyping for somatotroph adenomas is good prognostically

Clinical Features (Somatotroph Adenoma)

• Persistently elevated levels of GH stimulate the hepatic secretion of insulin-like growth factor IGF-1-> this causes clinical mannifestatons
• Sommatotroph as of GH cause gignatisim
• Levels of GH increased and after closure of the epiphyses then acromegaly develops
• GH excess causes dysfuction, diabetes, muscle weakness, increased risk of GI Cancers

Corticotroph Adenoma

• Excess production of ACTH by functioning corticotroph adenomas leads to adrenal hypersecretion of cortisol and the development of hypercortisolaism

Morphology of Corticotroph Adenoma

• Corticotroph are usually microadeomas.
• Tumor are basophilic densely or occasionally sparsely granulated

Other Anterior Pituitary Tumors

• Gonadotroph (LH-producng and FSH) adenomas are difficult to recognize because they secrete small amounts of hormones that cannot cause recognizable and unique clinical syndromes
• THyrotroph uncommon
• Pituitary may secrete multpile hormones, referred to as plurihormonal tumours
• Null cells dont express any hormonal makers

Hypopituitarism

• Hypopituitarism: decreased secretion of pituitary hormones caused from disease of the hypothalamus or pitituary
• Hypofunction of the anterior pit occurs when close to 75% f pit parenchyma lost
• Pituitary apoplexy caused hy sudden hemorrahge into the pituitary gland
• Scheehan syndrome caused by most common form of ishcmeic neurosisi
• Rathk clefts; they will accumulate with proteinaceous fuuld

Posterior Pituitary Syndrome

• Involve ADH diabetes inspipidus
• ADH def, causes diabetes, inability of kidney to resord
• Syndrome inappropate ADH

Hypothalamic Suprasellar Tumors

• Inducve hypofunction or hyperfunction of anterior pitiaitary diabbbeticus
• Craniopharungima- vestigial remmanants rathka poucn

Morphology

• Cranio averaging 3-4
• often ncorach in chams

Adamanitous Craniopharygnomia

• Nests, cords are stratifes

Paillary Craiphmomgmas

• Contais both solid sheets of cells line dby weell diffeeretiated spmaousl epitheeliam
• Unlike adaantinomatous craniopharmyomiathis subttpe charactereized bt activated mutation

This content covers Nelson syndrome, its causes, and the absence of hypercortisolism. It also discusses melanotropin's role in hyperpigmentation. Further topics include pituitary blastomas and the function of the DICER1 gene, functioning vs. nonfunctioning adenomas, and gonadotroph adenomas.