EndocrinologyTier 2Disease (DEADMAN)

Pituitary disease

Description

Nomenclature

WHO 2022: pituitary adenoma -> pituitary neuroendocrine tumour (PitNET)
- Classified by transcription factor lineage, not by hormone stain alone
- PIT1 (GH, PRL, TSH) / TPIT (ACTH) / SF-1 (gonadotroph) / no distinct lineage
- "Adenoma" implied benign; a proportion are locally invasive and recur
Micro <10 mm, macro >=10 mm; giant >=40 mm

The three problems any pituitary lesion can cause

1. Hormone excess (functioning tumour)

2. Hormone deficiency (compression of normal gland or stalk)

3. Mass effect (chiasm, cavernous sinus, headache)

Functioning tumours

Tumour	Syndrome
Lactotroph (prolactinoma)	The commonest functioning PitNET - galactorrhoea, amenorrhoea, hypogonadism
Somatotroph	Acromegaly / gigantism
Corticotroph	Cushing disease
Thyrotroph	TSH-oma - central hyperthyroidism
Gonadotroph	Usually clinically silent

Non-functioning PitNETs are the largest group overall (~1/3 of all PitNETs); most are SF-1/gonadotroph lineage on immunohistochemistry despite being clinically silent

Epidemiology

Prevalence on autopsy/MRI series ~10-20%; clinically relevant ~1 in 1,000
PitNETs = ~10-15% of all intracranial tumours
Most PitNETs are non-functioning; of the functioning ones, lactotroph is commonest
Prolactinoma: F>M, but men present later with larger, more invasive tumours
Peak 30-60y; a pituitary mass in childhood is more often craniopharyngioma or germinoma

Aetiopathogenesis

Sporadic - most

Monoclonal; GNAS activating mutation in ~40% of somatotroph tumours (gsp oncogene)
USP8 mutation in ~1/3 of corticotroph tumours

Familial (~5%)

MEN1 - parathyroid + pancreatic + pituitary (prolactinoma commonest)
MEN4 - CDKN1B
AIP - familial isolated pituitary adenoma; young, large, aggressive somatotroph tumours
Carney complex - PRKAR1A
SDHx - pituitary tumour + phaeo/paraganglioma (3PAs)
X-LAG (GPR101 duplication) - infantile gigantism

Non-adenomatous sellar/parasellar lesions - the differential

Craniopharyngioma - calcified, cystic, suprasellar; bimodal age
Rathke cleft cyst, arachnoid cyst
Meningioma, germinoma, glioma, chordoma
Hypophysitis - lymphocytic, IgG4, checkpoint inhibitor
Metastasis - breast, lung; stalk involvement with AVP deficiency is the clue
Sarcoidosis, TB, Langerhans cell histiocytosis
Aneurysm - exclude before biopsy
Pituitary hyperplasia - pregnancy, lactation, primary hypothyroidism (a big pituitary that shrinks on levothyroxine)

Order of anterior pituitary hormone loss under compression

GH -> LH/FSH -> TSH -> ACTH ("Go Look For The Adenoma"); prolactin is usually raised, not lost
Stalk effect: compression of the stalk releases lactotrophs from dopamine inhibition -> mild hyperprolactinaemia
- Usually <2,000-4,000 mIU/L. A very high prolactin means a prolactinoma; a modest one with a big tumour means stalk compression - a distinction that decides medicine vs surgery

Diagnosis

Imaging

Dedicated pituitary MRI with gadolinium, thin slices, dynamic sequences
- Standard brain MRI is inadequate
Assess: size, suprasellar extension, chiasm contact, cavernous sinus invasion (Knosp grade), sphenoid extension, haemorrhage

Hormone excess - test what the phenotype suggests, plus

Prolactin in everyone
- Check for the hook effect - a giant prolactinoma can read falsely low unless the sample is diluted 1:100
- Macroprolactin explains an isolated high prolactin with no symptoms
IGF-1 (+/- OGTT with GH) for acromegaly
Overnight 1 mg dexamethasone suppression / late-night salivary cortisol / 24h urine free cortisol for Cushing
TSH + fT4 - a normal/high TSH with high fT4 suggests TSH-oma

Hormone deficiency - test in every macroadenoma

9 am cortisol (+/- Synacthen or insulin tolerance test) - the deficiency that kills
fT4 (not TSH - it is unreliable in central disease)
LH/FSH + testosterone (men) or oestradiol/cycle history (women)
IGF-1 +/- provocative GH testing
Paired plasma/urine osmolality and sodium if polyuric

Mass effect

Formal visual fields (automated perimetry) in any lesion touching or compressing the chiasm
- Classic bitemporal hemianopia (superior quadrants first - inferonasal fibres cross lowest)
Cavernous sinus: III, IV, V1/V2, VI - VI is most exposed within the sinus, but III palsy is commonest clinically

Red flags for something other than an adenoma

Rapid growth, diabetes insipidus (AVP deficiency), pain, cranial neuropathy out of proportion, systemic inflammatory features
*AVP deficiency is rare in a PitNET - think hypophysitis, metastasis, germinoma, craniopharyngioma*

Management

A. Prolactinoma - medical, whatever the size

Cabergoline first line (more effective and better tolerated than bromocriptine)
- Shrinks tumour and normalises prolactin in ~80-90%
- *Surgery is not first line even for a macroprolactinoma* - the one pituitary tumour where this is true
Bromocriptine preferred if pregnancy planned (longest safety record)
Consider withdrawal after >=2 years of normal prolactin, no visible tumour, on low dose
Rare: impulse control disorders, CSF rhinorrhoea on rapid shrinkage of an invasive tumour, valvulopathy at high (Parkinson's) doses

B. All other functioning tumours and symptomatic non-functioning tumours - surgery

Endoscopic endonasal transsphenoidal resection by a high-volume pituitary surgeon
Indications:
- Visual compromise (chiasmal compression) - the strongest indication
- Any functioning tumour other than prolactinoma
- Growth on surveillance, or apoplexy with deficit
Adjuncts if residual/recurrent: radiotherapy (fractionated or stereotactic), then medical therapy by tumour type

C. Non-functioning, no visual compromise - surveillance

MRI at 6-12 months, then interval imaging by size and growth
Microadenoma <10 mm with normal hormones: very low growth risk - can space imaging out and stop
Repeat visual fields only if the lesion approaches the chiasm

D. Peri-operative and long-term

*Replace glucocorticoid before thyroxine* - thyroxine first precipitates adrenal crisis
Stress-dose steroid cover; sick day rules; medical alert identification
Post-op day 1-10: watch for the triple-phase response (polyuria -> SIADH-like hyponatraemia -> permanent AVP deficiency)
- Day 7-10 hyponatraemia is the commonest cause of readmission after transsphenoidal surgery
Lifelong pituitary function review; assess remission and deficiencies at 6-12 weeks post-op

E. Aggressive PitNET / pituitary carcinoma

Temozolomide is first-line for aggressive or metastatic disease after surgery and radiotherapy

Associations

MEN1 - pituitary + parathyroid + pancreatic islet
MEN4 (CDKN1B), Carney complex (PRKAR1A)
AIP mutation - familial isolated pituitary adenoma, young somatotroph tumours
SDHx - pituitary tumour with phaeochromocytoma/paraganglioma
McCune-Albright - GNAS mosaicism, GH excess with fibrous dysplasia
Primary hypothyroidism -> thyrotroph hyperplasia mimicking a macroadenoma
Checkpoint inhibitor therapy -> hypophysitis

Natural history & complications

Most incidentally found microadenomas never grow - macroadenomas grow in ~20-25% over years
Untreated chiasmal compression -> irreversible optic atrophy; visual recovery after decompression is good if operated early
Apoplexy - sudden severe headache, ophthalmoplegia, visual loss, hypopituitarism; the presenting event in up to 20-25% of previously unknown adenomas
Hypopituitarism after surgery or radiotherapy is common and may appear years later - radiotherapy carries a cumulative ~50% risk at 10 years
Untreated hypopituitarism carries excess mortality, largely cardiovascular and from unrecognised adrenal insufficiency
Transsphenoidal complications: CSF leak, meningitis, diabetes insipidus, hyponatraemia, sinonasal morbidity, rare carotid injury
Recurrence risk tracks Knosp grade (cavernous invasion) and completeness of resection, not tumour type alone

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