Pituitary Pathology — Tumors and Infarction

Pituitary Adenoma Development

• Monoclonal origin with somatic mutations: Most adenomas arise from single-cell transformation with activating mutations in GNAS (encoding Gsα in approximately 40% of growth hormone-secreting adenomas), inactivating mutations in MEN1 or CDKN1B (p27), or dysregulation of the Rb pathway. Pituitary adenomas are generally benign with low proliferation rates (Ki-67 <3%), though atypical adenomas (increased mitotic activity, p53 positivity, Ki-67 >3%) and rare carcinomas exist.
• Loss of tonic dopaminergic inhibition and dysregulation of releasing hormones: The hypothalamus exerts tonic inhibition of lactotroph cells through dopamine released into the hypophyseal portal system. Loss of normal pituitary stalk compression or disruption allows escape from dopaminergic inhibition, particularly promoting prolactin secretion. Alterations in TRH, GnRH, and CRH signaling contribute to selective tumor growth in hormonally specific adenomas.
• Endocrine-inactive adenomas and "null cell" adenomas: Approximately 40% of adenomas produce no clinically significant hormone excess, either because they lack appropriate secretory granules (gonadotroph adenomas that produce FSH/LH without clinical syndrome) or represent chromophobe adenomas with minimal hormone storage. These tumors typically present late due to mass effects rather than hormonal symptoms.

Pituitary Infarction Mechanisms

• Hypoperfusion and ischemic necrosis: The pituitary gland has relatively low blood supply with portal blood flow from the hypothalamus as the primary source. Severe hypotension, trauma, disseminated intravascular coagulation (DIC), sickle cell disease, or vasculitis causes ischemic coagulation necrosis of adenohypophyseal tissue, with the anterior lobe more vulnerable than the posterior lobe due to lower oxygen tension in portal blood.
• Hemorrhagic infarction in apoplexy: Sudden expansion of hemorrhage within an existing adenoma (or rarely de novo) causes acute compression, ischemia, and swelling, creating a neurosurgical emergency. The posterior pituitary maintains function longer because of its direct arterial blood supply from the internal carotid arteries, while anterior lobe function progressively fails.

Pituitary Adenomas

• Genetic predisposition: MEN1 syndrome (MENIN gene inactivation; 20-65% develop pituitary adenomas), familial isolated pituitary adenoma (FIPA; PRKAR1A, AIP mutations), Carney complex (PRKAR1A), McCune-Albright syndrome (GNAS mutations causing growth hormone adenomas), multiple endocrine neoplasia type 4 (CDKN1B).
• Sporadic mutations and age-related changes: Most adenomas (>90%) are sporadic; incidence increases with age. Chronic stimulation (e.g., primary hypothyroidism with elevated TRH may promote lactotroph hyperplasia and adenoma formation) and estrogen use may increase prolactinoma risk.

Pituitary Infarction

• Sheehan syndrome (postpartum pituitary necrosis): Severe postpartum hemorrhage with hypotension in the setting of pregnancy-induced pituitary enlargement (physiologic hypertrophy and hyperplasia from estrogen and progesterone stimulation) causes ischemic necrosis; now rare in developed nations but remains a leading cause of pituitary insufficiency globally.
• Pituitary apoplexy: Acute hemorrhage/infarction of an adenoma (50-80% of cases have pre-existing tumor), arterial rupture, DIC, anticoagulation, sickle cell crisis, subarachnoid hemorrhage, systemic hypotension.
• Chronic ischemic infarction: Atherosclerotic disease of the hypophyseal artery, diabetes mellitus, radiation therapy to the sella turcica, carotid artery occlusion, vasculitis (temporal arteritis, syphilis).

Mass Effects (Common to All Adenomas and Infarction)

• Headache: Dull, frontal, or retro-orbital pain from diaphragma sellae stretching or bone erosion; classic presentation for non-functioning adenomas.
• Visual field defects: Bitemporal hemianopsia (compression of inferior nasal fibers of optic chiasm as tumor grows superiorly); progression to superior temporal hemianopsia with larger tumors. Compression may cause afferent pupil defect.
• Cranial nerve palsies: CN III, IV, VI involvement from lateral cavernous sinus extension causes diplopia and ptosis; CN V1/V2 involvement from lateral mass.

Hormone Excess Syndromes

• Prolactin excess (prolactinomas; 40% of adenomas):
• Amenorrhea/oligomenorrhea and infertility in women (due to suppression of GnRH and dopamine-sensitive FSH/LH secretion).
• Erectile dysfunction and decreased libido in men.
• Galactorrhea in both sexes (direct lactotroph stimulation).
• Gynecomastia in men.
• Serum prolactin >200 ng/mL suggests macroprolactinoma; prolactin level correlates with tumor size.

• Growth hormone excess (somatotroph adenomas; 20% of adenomas; acromegaly in adults, gigantism in children):
• Coarse facial features (frontal bossing, prognathism, widened nasal bridge).
• Gigantism (in prepubertal patients with open epiphyses) or accelerated linear growth in children.
• Acromegaly (enlarged hands, feet, jaw, tongue, lips) with thickened skin and skin tags.
• Hypertension and diabetes mellitus (IGF-1 induces insulin resistance).
• Arthropathy (secondary osteoarthritis from cartilage proliferation).
• Carpal tunnel syndrome and other entrapment neuropathies.
• Sleep apnea (from soft tissue hypertrophy and macroglossia).
• Elevated serum IGF-1 and non-suppressible GH on oral glucose tolerance test.

• ACTH excess (corticotroph adenomas; Cushing disease; 15% of adenomas):
• Truncal obesity with proximal muscle weakness (from glucocorticoid excess).
• Purple striae, easy bruising, and thin skin (collagen breakdown).
• Hirsutism and acne (androgenic effects).
• Hypertension and hypokalemia (mineralocorticoid excess).
• Mood disturbances (depression, psychosis).
• Elevated 24-hour urine-free cortisol; loss of normal diurnal rhythm; non-suppression by low-dose dexamethasone (1 mg) but suppression by high-dose dexamethasone (8 mg) distinguishes Cushing disease from ectopic ACTH.
• ACTH inappropriately elevated (not suppressed) in setting of hypercortisolism.

• TSH-secreting adenomas (rare; 1% of adenomas):
• Thyrotoxicosis symptoms (weight loss, tremor, palpitations, heat intolerance).
• Goiter (from TSH stimulation of thyroid).
• Elevated TSH with elevated free T4 (unusual combination; most thyrotoxicosis has suppressed TSH).

• FSH/LH-secreting adenomas (non-functioning or mild hypogonadism):
• Most are clinically non-functioning; may cause testicular enlargement (from FSH-alone secretion) or secondary hypogonadism.
• Elevated FSH or LH with mass effect.

Hormone Deficiency (Anterior Pituitary Insufficiency)

• Secondary hypothyroidism (low free T4 with low or normal TSH; fatigue, cold intolerance, bradycardia, constipation).
• Secondary hypogonadism (amenorrhea/oligomenorrhea in women; erectile dysfunction, infertility, decreased facial/body hair in men; low testosterone with low LH/FSH).
• Secondary adrenal insufficiency (fatigue, hypotension, hypoglycemia, hyponatremia; low cortisol with low ACTH — unlike primary adrenal insufficiency).
• Growth hormone deficiency (short stature and poor growth in children; fatigue, increased fat mass, decreased muscle mass, and insulin resistance in adults).
• Prolactin is usually relatively spared in general pituitary insufficiency (loss of dopaminergic inhibition allows prolactin rise).

Posterior Pituitary Dysfunction (Less Common in Adenoma; More in Infarction)

• Central diabetes insipidus (from ADH/vasopressin deficiency): Polyuria, polydipsia, hypernatremia, dehydration (especially important in acute apoplexy).
• Posterior pituitary usually retains some function due to separate arterial blood supply.

Acute Pituitary Apoplexy (Medical Emergency)

• Sudden severe headache ("thunderclap" quality).
• Vision loss (from sudden chiasm compression by hemorrhage/edema).
• Ophthalmoplegia (CN III, IV, VI involvement from cavernous sinus hemorrhage).
• Meningeal signs (from subarachnoid hemorrhage if bleeding extends).
• Altered mental status, fever (from inflammatory response).
• Acute hyponatremia and hemodynamic instability (from acute cortisol and ADH deficiency).
• Risk of death if not surgically decompressed emergently.

Histopathology and Gross Appearance

Prolactinomas

• Gross: Soft, tan-pink tumor, often with microadenoma appearance (<10 mm); macroprolactinomas are larger and may show hemorrhage/necrosis.
• Microscopy: Chromophobic adenoma with sparsely granulated cells (sparse secretory granules on electron microscopy); cells may appear slightly basophilic due to rough endoplasmic reticulum. Immunohistochemistry positive for prolactin.
• Architecture: Typically organized in fascicles or trabecular patterns; mild atypia does not confer aggressive behavior for prolactinomas.

Somatotroph Adenomas

• Gross: Usually macroadenomas (>10 mm) at diagnosis; tan-pink with possible hemorrhagic/cystic degeneration.
• Microscopy: Acidophil (eosinophilic) adenoma with numerous alpha cells containing abundant rough endoplasmic reticulum and secretory granules; cells appear densely granulated. Immunohistochemistry positive for growth hormone. Fibrous bodies (aggregates of intermediate filaments) are characteristic. Perivascular rosette formation may be seen.
• Electron microscopy: Abundant 200-400 nm secretory granules.

Corticotroph Adenomas (Cushing Disease)

• Gross: Often microadenomas (<10 mm); may be <5 mm and difficult to identify grossly; tan or basophilic coloration.
• Microscopy: Basophil adenoma with cells containing PAS-positive, diastase-resistant cytoplasm (abundant rough ER for ACTH synthesis). Immunohistochemistry positive for ACTH (and often POMC prohormone). Crooke hyaline change (hyalinization of cytoplasm in corticotrophs) may be prominent in surrounding normal tissue due to chronic glucocorticoid feedback inhibition. Perivascular rosettes and microacinar architecture are typical.

TSH-Secreting and Gonadotroph Adenomas

• Microscopy: Chromophobic adenoma with sparse granules. Immunohistochemistry positive for FSH, LH, and/or TSH as applicable. Often organized in follicular or sinusoidal patterns. Gonadotroph adenomas are frequently non-functioning (no clinical hormone excess).

Non-Functioning/Null Cell Adenomas

• Microscopy: Chromophobic adenoma with minimal secretory granules; cells lack specific immunohistochemical reactivity or show weak polyhormonal staining. No clinical endocrine syndrome despite mass effect.

General Adenoma Features

• Ki-67 proliferation index: <3% typical for benign adenomas; 3-10% suggests atypical features; >10% concerning for malignancy.
• Mitotic activity: Low; increased mitoses define atypical adenoma.
• p53 immunostaining: Usually negative; positivity suggests atypia or malignancy.
• Invasion: Adenoma extension beyond the sella turcica (through diaphragma sellae or dura) defines invasive adenomas; this is a histological designation distinct from malignancy but predicts recurrence.
• Pituitary carcinoma: Rare; requires either cerebrospinal fluid/brain invasion or systemic metastases; cannot be diagnosed on histology alone (atypia + invasion = atypical adenoma; malignancy confirmed by metastases).

Gross Pathology

• Adenomas: Soft, pink-tan, well-circumscribed mass within the sella turcica; may erode through the sphenoid bone or extend into the suprasellar cistern, compressing the optic chiasm.
• Apoplexy/hemorrhage: Blood-filled cystic mass with necrotic debris; surrounding pituitary may show ischemic necrosis.
• Sheehan syndrome: Pituitary gland shrunken and fibrotic; anterior lobe pale and atrophic; posterior lobe may be relatively spared.

Laboratory Evaluation

Baseline Hormone Assessment

• Prolactin: >25 ng/mL suggests prolactinoma; >200 ng/mL with macroadenoma is diagnostic (microprolactinomas typically <100 ng/mL).
• IGF-1 and GH: Fasting GH >1 ng/mL or IGF-1 above age/sex-adjusted normal suggests acromegaly; oral glucose tolerance test (OGTT) showing GH >0.4 ng/mL at 60 minutes confirms diagnosis (normal suppression to <1 ng/mL).
• 24-hour urine-free cortisol and midnight cortisol: Elevated in Cushing disease; low-dose (1 mg) dexamethasone suppression test shows cortisol >1.8 ng/dL in Cushing disease (abnormal suppression); high-dose (8 mg) dexamethasone suppression test shows >50% reduction in cortisol in Cushing disease but not ectopic ACTH.
• ACTH level: Detectable (normal 5-25 pg/mL) in Cushing disease; suppressed in Cushing syndrome from adrenal adenoma; markedly elevated in ectopic ACTH.
• TSH, free T4, LH, FSH, testosterone, estradiol: Assess for secondary hypogonadism and hypothyroidism; suppressed LH/FSH with low testosterone/estradiol suggests secondary hypogonadism.
• **Early morning cortisol (8 AM)

Immediate stabilisation (apoplexy, Sheehan syndrome, any suspected hypopituitarism)

• Glucocorticoids first: empiric stress-dose IV hydrocortisone before any other hormone, because secondary adrenal insufficiency is the lethal deficit and mineralocorticoid production is preserved (ACTH-independent zona glomerulosa). The Endocrine Society hypopituitarism guideline stresses that levothyroxine given before glucocorticoid can precipitate adrenal crisis by accelerating cortisol clearance — this is the classic contraindication.
• Resuscitation and urgent assessment: isotonic fluids, correction of hyponatremia, formal visual field/acuity testing, and emergent neurosurgical consultation. Pituitary Society consensus supports urgent transsphenoidal decompression for apoplexy with visual loss, worsening ophthalmoplegia, or depressed consciousness; stable patients without visual compromise may be managed conservatively with steroids and serial exams.

Tumour-specific first-line therapy

• Prolactinoma — dopamine agonist, not surgery: cabergoline is preferred over bromocriptine (Endocrine Society hyperprolactinemia guideline) for both micro- and macroprolactinomas; D2 agonism restores tonic lactotroph inhibition, normalises prolactin, and shrinks tumour even when the chiasm is compressed. Bromocriptine has the longest pregnancy safety record.
• Somatotroph adenoma (acromegaly): transsphenoidal selective adenomectomy is first-line (Endocrine Society acromegaly guideline). Persistent disease → somatostatin receptor ligands (octreotide, lanreotide), the GH-receptor antagonist pegvisomant, or adjunctive cabergoline; stereotactic radiotherapy is reserved for refractory disease.
• Corticotroph adenoma (Cushing disease): transsphenoidal resection first (Endocrine Society Cushing's syndrome treatment guideline). Second-line: steroidogenesis inhibitors (osilodrostat, metyrapone, ketoconazole), pasireotide, mifepristone for hyperglycaemia, radiotherapy, and bilateral adrenalectomy as last resort.
• TSH-secreting adenoma: surgery ± somatostatin ligands; thyroid ablation alone is inappropriate and worsens tumour growth.
• Non-functioning adenoma: resect if there is mass effect or visual compromise; small incidentalomas are followed with serial MRI and hormonal screening.
• Craniopharyngioma: surgical resection, often subtotal, with adjuvant radiotherapy; lifelong hormone replacement is expected.

Emergencies

• Pituitary apoplexy: haemorrhage into an adenoma causes abrupt chiasmal and cavernous sinus compression — thunderclap headache, ophthalmoplegia, and vision loss. Signalled by acute hyponatremia and hypotension from cortisol deficiency; treat with IV hydrocortisone and urgent decompression.
• Adrenal crisis: unrecognised secondary adrenal insufficiency (post-operative, post-radiation, Sheehan syndrome, or during intercurrent illness) presents with hypotension refractory to fluids, hypoglycaemia, and hyponatremia — hyperkalaemia and hyperpigmentation are absent, distinguishing it from primary disease.
• Post-operative CSF rhinorrhoea: dural breach after transsphenoidal surgery; clear rhinorrhoea positive for beta-2 transferrin, with risk of ascending bacterial meningitis.
• Permanent visual loss: prolonged chiasmal compression causes optic atrophy; recovery correlates with duration of compression before decompression.

Endocrine and post-surgical complications

• Post-operative diabetes insipidus and the triphasic response: axonal injury to hypothalamic magnocellular neurons produces transient DI, then a stored-ADH release phase with hyponatremia, then permanent DI. Delayed hyponatremia around the second post-operative week (inappropriate ADH release) is the most common cause of readmission.
• Panhypopituitarism: from tumour destruction, surgery, or radiotherapy; radiation-induced deficits accumulate over years, GH lost first and ACTH typically last.
• Nelson syndrome: after bilateral adrenalectomy for Cushing disease, loss of cortisol feedback drives corticotroph tumour growth — enlarging sellar mass with hyperpigmentation and very high ACTH.

Disease-specific sequelae

• Acromegaly: cardiomyopathy and heart failure, sleep apnoea, diabetes, and increased colon polyps prompting colonoscopic surveillance; cardiovascular disease drives excess mortality.
• Cushing disease: osteoporotic fractures, venous thromboembolism, opportunistic infection, and psychiatric decompensation.
• Chronic hyperprolactinaemia: hypogonadism-driven bone loss.

Treatment-related

• Dopamine agonists: impulse-control disorders, psychosis, orthostatic hypotension, and — with rapid shrinkage of an invasive macroprolactinoma — CSF leak. High-dose cabergoline has been linked to valvular fibrosis.

• Bitemporal hemianopsia = sellar mass until proven otherwise: decussating nasal retinal fibres are compressed from below; the next step is MRI of the sella with contrast plus a prolactin level.
• Prolactinoma is the tumour treated medically even when it is huge: give cabergoline, not surgery, as first-line (Endocrine Society). "Large tumour + chiasm compression → operate" is the classic distractor.
• Stalk effect versus true prolactinoma: a large sellar mass with only mildly elevated prolactin is a non-functioning adenoma compressing the stalk and interrupting dopamine delivery — that patient needs surgery. A true macroprolactinoma has prolactin in the hundreds to thousands.
• Hook effect: an enormous prolactinoma can assay as falsely normal or low prolactin through antibody saturation; the fix is repeating the assay on diluted serum.
• Before imaging, exclude the mimics: pregnancy, primary hypothyroidism (high TRH), renal failure, and dopamine antagonists (antipsychotics, metoclopramide) all raise prolactin.
• Best next step in suspected apoplexy or Sheehan syndrome is IV hydrocortisone, given before levothyroxine and without waiting for confirmatory cortisol. Failure to lactate followed by amenorrhoea after postpartum haemorrhage is the Sheehan stem.
• Screen acromegaly with IGF-1, not random GH (pulsatile secretion); confirm with failure of GH suppression on oral glucose. Cause of death is cardiovascular, not the tumour.
• **Suprasellar calcified cystic mass in a child with motor-oil fluid and cholesterol crystals is craniopharyngioma** (Rathke pouch remnant, adamantinomatous, *CTNNB1*/beta-catenin); adenomas essentially never calcify.
• The association examiners love: MEN1 — pituitary adenoma, parathyroid hyperplasia, and pancreatic neuroendocrine tumour, from menin loss.