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PITUITARY ADENOMA — LAQ (MUHS PG Theory)

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DEFINITION

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CLASSIFICATION

A. By Size

B. By Functional Status

1. Functioning (secretory) - associated with excess hormone production
2. Non-functioning (null cell) - ~1/3rd of adenomas; present with mass effects

C. By Cell Type (WHO / Immunohistochemical)

Note: 60-70% of pituitary adenomas are prolactin-secreting. About 10-15% secrete GH, a smaller number secrete ACTH. (Adams and Victor's Principles of Neurology, 12th Ed.)

D. By Old Histological Staining (H&E)

• Chromophobe (most common, 4-20x more common than acidophil)
• Acidophil
• Basophil (Ratio of normal cells: chromophobe : acidophil : basophil = 5 : 4 : 1)

Modern classification uses immunoperoxidase staining defining hormone content, NOT just H&E staining.

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INCIDENCE / EPIDEMIOLOGY

• Pituitary adenomas increase in frequency with each decade
• By the 80th year, small adenomas found in >20% of pituitary glands at autopsy
• Only 6-8% enlarge the sella (most are microadenomas)
• Some arise in the setting of endocrine end-organ failure (e.g., ovarian atrophy → basophilic adenoma) (Adams and Victor's Principles of Neurology, 12th Ed.)

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PATHOLOGY / MORPHOLOGY

• Reddish-gray, soft, often partly cystic
• Rim of calcium in some cases
• Discrete nodules in the anterior pituitary
• Macroadenomas: extend upward, compress optic chiasm, invade cavernous sinus, temporal lobe, 3rd ventricle, or posterior fossa

1. Cellular monomorphism - uniform cell population
2. Absence of reticulin network

• Cells arranged diffusely, sinusoidally, or papillary
• Variability of nuclear structure, hyperchromatism, and mitoses are signs of malignancy (rare)
• Penetration of the diaphragma sellae = more difficult treatment (Robbins & Kumar Basic Pathology; Adams and Victor's Principles of Neurology)

• GNAS gene mutation (constitutive activation of stimulatory G protein Gs-α) is one of the most common genetic alterations - found especially in somatotroph adenomas (Robbins & Kumar Basic Pathology)

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CLINICAL FEATURES

I. Endocrine / Hormonal Effects

• Females: amenorrhea, galactorrhea, infertility, loss of libido
• Males: impotence, headache, visual abnormalities; galactorrhea is rare; usually present with larger tumor
• Serum PRL usually >100 ng/mL; PRL >200 μg/L almost invariably indicates a prolactin-secreting adenoma
• These patients fail to show PRL rise after chlorpromazine/TRH stimulation (unlike normal persons)

• Children (pre-puberty): Gigantism
• Adults (post-puberty): Acromegaly
  • Acral enlargement, prognathism, visceromegaly, coarsening of facial features
  • Headache, hypermetabolism, diabetes mellitus, impaired glucose tolerance
  • Diagnosis: elevated serum GH, failure of GH to suppress after glucose (oral glucose tolerance test - OGTT), elevated IGF-1 (somatomedin C)

• Excessive pituitary ACTH → bilateral adrenal hyperplasia → hypercortisolism
• Features: truncal obesity, hypertension, proximal muscle weakness, amenorrhea, hirsutism, abdominal striae, hyperglycemia, osteoporosis, psychiatric changes
• Cushing disease = pituitary ACTH excess; Cushing syndrome = cortisol excess from any cause
• Pathologically: basophil adenoma (Cushing's original description) or non-basophilic microadenoma; sella usually not enlarged
• Diagnosis: elevated plasma/urinary cortisol; not suppressed by low-dose dexamethasone (0.5 mg qid); suppressed by high-dose dexamethasone (8 mg/day) - distinguishes from adrenal source

II. Mass Effects (from Macroadenoma)

• Tumor compresses optic chiasm → bitemporal hemianopia (most classic)
• Develops gradually; patient may be unaware
• Early: upper parts of visual fields affected first (inferior chiasmal fibers)
• 5-10% extend into cavernous sinus → ocular motor palsies (III, IV, VI nerve palsies), compression of internal carotid artery
• If longstanding: optic atrophy
• Junctional scotoma - central scotoma on one side + temporal field defect on other (postfixed chiasm compressed at Wilbrand's knee)

• Reported by ~50% of patients with macroadenomas
• From stretching of dura, not clearly a direct tumor effect

• Large tumors compress normal pituitary tissue
• Loss of GH → growth failure; loss of gonadotropins → hypogonadism; loss of TSH → hypothyroidism; loss of ACTH → adrenal insufficiency
• Large non-functioning adenomas can also cause modest hyperprolactinemia by compressing the pituitary stalk (reduced dopamine delivery to lactotrophs)

• Seizures (indentation of medial temporal lobe)
• CSF rhinorrhea (erosion of sella floor)
• Diabetes insipidus, hypothermia, somnolence (hypothalamic compression)

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PITUITARY APOPLEXY (Important!)

• Sudden hemorrhage or infarction within a pituitary adenoma
• Sudden severe headache, meningismus, visual loss, ophthalmoplegia, deterioration of consciousness
• Medical emergency - requires urgent steroid replacement and often surgical decompression
• Can be precipitated by anticoagulants, surgery, dynamic testing

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DIFFERENTIAL DIAGNOSIS

• Saccular aneurysm of circle of Willis
• Meningioma of tuberculum sellae
• Multiple sclerosis (rare simulation)
• Empty sella syndrome

• Craniopharyngioma
• Meningioma
• Carotid aneurysm
• Rathke cleft cyst
• Intrasellar cysts (Rathke pouch remnant)
• Nasopharyngeal carcinoma invading sella
• Pituitary metastases (lung, breast - most common primaries) (Adams and Victor's Principles of Neurology, 12th Ed.)

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INVESTIGATIONS

Hormonal Tests

Imaging

• MRI with gadolinium - investigation of choice
  • Visualizes adenomas as small as 3 mm in diameter
  • Shows relationship to optic chiasm
  • Normal pituitary enhances; tumor appears as relatively hypo-enhancing nodule
  • Used for follow-up of treatment response
• CT scan - shows sellar enlargement, calcification
• Plain X-ray skull - ballooned sella turcica (found occasionally) (Adams and Victor's Principles of Neurology, 12th Ed.; Goldman-Cecil Medicine)

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TREATMENT

1. Prolactinoma

• Dopamine agonists are first-line: Cabergoline (preferred) or Bromocriptine
  • Cabergoline: 0.5-2 mg twice weekly; effective in 80-90% of cases
  • Bromocriptine: 2.5-10 mg/day (more side effects)
• Surgery if: intolerant of drugs, failed medical therapy, visual compromise, giant prolactinoma
• Radiotherapy: rarely used

2. Acromegaly (GH adenoma)

• Transsphenoidal surgery - first-line for most
• Medical therapy if surgery fails/contraindicated:
  • Somatostatin analogues: Octreotide, Lanreotide
  • GH receptor antagonist: Pegvisomant (reduces IGF-1)
  • Dopamine agonists: Cabergoline (less effective)
• Radiotherapy: stereotactic radiosurgery (Gamma Knife)

3. Cushing Disease (ACTH adenoma)

• Transsphenoidal surgery: Up to 90% cure rate for microadenoma by an experienced neurosurgeon
• If surgery fails: re-operation, bilateral adrenalectomy, radiotherapy
• Medical therapy:
  • Cabergoline (1-7 mg, 2-7x/week) - normalizes UFC in ~40%
  • Pasireotide (SST2/5 analogue)
  • Metyrapone, osilodrostat, ketoconazole (adrenal steroidogenesis inhibitors)
• Radiation: 200 rad/day to total 45 Gy, or stereotactic radiosurgery; disadvantage: slow response (up to 10 years), risk of panhypopituitarism
• Nelson syndrome: Nelson's syndrome (progressive enlargement of ACTH-secreting pituitary adenoma after bilateral adrenalectomy) - risk to consider before adrenalectomy (Goldman-Cecil Medicine, International Edition; Adams and Victor's Principles of Neurology)

4. Non-functioning Adenomas

• Transsphenoidal surgery (endoscopic endonasal approach now preferred over microscopic)
• Surgery indicated for: visual compromise, mass effects, apoplexy
• Radiotherapy for residual/recurrent tumor
• Observation with serial MRI for small incidentally discovered tumors (pituitary incidentalomas)

Surgical Approach - Transsphenoidal

• Approach through nasal cavity and sphenoid sinus
• Endoscopic approach now preferred over microscopic (better visualization, less morbidity)
• Macroadenomas with suprasellar extension may require craniotomy
• Complications: CSF leak, meningitis, diabetes insipidus, carotid injury, hypopituitarism

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PROGNOSIS

• Microadenomas: excellent prognosis with appropriate therapy
• Macroadenomas: higher recurrence rates; incomplete resection common
• Visual fields often recover after decompression if not long-standing
• Recurrence after surgery requires adjuvant radiotherapy or medical therapy

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SUMMARY TABLE (High-Yield Points for MUHS)

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