Pituitary adenoma

Pituitary adenomas (also known as pituitary neuroendocrine tumors) are benign tumors that arise sporadically from the anterior pituitary gland. They are classified as either microadenomas or macroadenomas according to their size, and as either secretory (functional) or nonsecretory (nonfunctioning) according to their ability to secrete hormones. Secretory adenomas produce the pituitary hormone of the cell type from which they arise, which results in a state of hyperpituitarism. Nonsecretory macroadenomas can destroy the surrounding normal pituitary tissue, which results in hypopituitarism. Additionally, large macroadenomas compress the optic chiasm; therefore, patients may present with signs of mass effect such as bitemporal hemianopsia. MRI sella with IV contrast is the gold standard imaging method for the pituitary and should reveal any intrasellar masses. Pituitary hormone assays are used to evaluate patients for endocrine abnormalities, and perimetry is used to identify visual field defects. Transsphenoidal hypophysectomy is the first-line therapy for most patients with symptomatic pituitary adenomas; patients with nonsecretory microadenomas generally only require follow-up (until they become symptomatic), and prolactin-producing pituitary adenomas (prolactinomas) should be initially treated with dopamine agonists (e.g., cabergoline, bromocriptine). Pituitary irradiation is indicated in recurrent pituitary adenomas and/or if surgical therapy is contraindicated.

• Prevalence [1]
  • Approx. 80 cases per 100,000 individuals
  • Pituitary adenomas account for ∼ 15% of primary intracranial tumors. [1]
• Peak incidence: : 35–60 years [2]

Epidemiological data refers to the US, unless otherwise specified.

• Most cases occur sporadically.
• Some cases (∼ 5%) have a genetic/familial association: [3]
  • Multiple endocrine neoplasia type 1
  • Carney complex
    • Caused by a loss of function mutation in the PRKAR1A gene, which encodes the regulatory subunit (R1α) of protein kinase A, resulting in increased cAMP activity
    • Patients present with cardiac myxoma, spotty skin pigmentation, and adrenal gland, testicular, and pituitary adenomas.
  • Familial isolated pituitary adenoma syndrome [4]
    • Caused by mutations in the AIP gene
    • Patients present with pituitary adenomas without other associated abnormalities.
    • The most common familial cause of acromegaly/gigantism

• Pituitary adenomas are well-circumscribed, intrasellar tumors with monomorphic, polygonal cells arranged in sheets or cords without any connective tissue and/or reticulin.
• Tumor classification according to size
  • Pituitary microadenoma: ≤ 10 mm
  • Pituitary macroadenoma: > 10 mm
• Tumor classification according to ability to secrete hormones
  • Nonsecretory pituitary adenomas [5]
    • Nonfunctioning tumors account for 15–45% of all pituitary adenomas.
    • Gonadotroph adenomas
    • Null cell adenomas
    • Plurihormonal adenomas
    • Silent somatotroph and corticotroph adenomas
  • Secretory pituitary adenomas: hormone secretion → hyperpituitarism
    • Most exclusively proliferate in only one type of endocrine cell and therefore secrete only one pituitary hormone.
    • The presence of multiple pituitary hormones should also raise suspicions for atypical pituitary adenomas or pituitary carcinomas.

Prolactinomas are the most common pituitary adenomas.

The symptoms associated with pituitary adenomas depend on the size of the tumor and whether the tumor produces hormones.

Approach

The diagnostic approach varies according to clinical presentation.

In patients with endocrine dysfunction, order hormone assays before imaging to prevent overdiagnosis of pituitary incidentalomas. [10]

Hormone assays [7][8][9]

Indications for testing

• First-line tests for all patients with symptomatic endocrine dysfunction
• Pituitary mass detected on imaging
• Prior to planned pituitary surgery

Initial studies

• Choice of studies
  • Symptomatic patients: Studies are chosen according to clinical presentation.
  • Asymptomatic patients: general screening
• Interpretation
  • ↓ Hormone levels suggest hypopituitarism; see also “Diagnostics” in “Hypopituitarism.”
  • ↑ Hormone levels suggest hyperpituitarism (secondary to a secretory adenoma); the hormones that are elevated will depend on the cellular origin of the adenoma (see “Pathophysiology”).

Patients with pituitary incidentalomas should be evaluated for hypopituitarism and hormonal hypersecretion syndromes. [8]

About a third of patients with pituitary adenomas have associated hypopituitarism; consider screening for hormone deficiencies in all patients with a pituitary mass. [9]

Imaging studies [12][13]

• MRI sella with IV contrast (gold standard)
  • Indications
    • First-line diagnostic modality for suspected secretory or nonsecretory pituitary adenomas
    • Postsurgical surveillance after resection of a pituitary mass
  • Characteristic finding: intrasellar mass
  • Potential additional findings [7]
    • Compression of adjacent structures (e.g., impingement on the optic chiasm)
    • Hemorrhage and necrosis in pituitary apoplexy [10][14]
    • Cavernous sinus invasion
• CT sella with IV contrast
  • Indications
    • Second-line diagnostic modality [13]
    • Can be used to plan transsphenoidal hypophysectomy
  • Supportive findings: similar to MRI

Additional investigations

• Visual field testing (e.g., perimetry) [7][9]
  • Indicated for patients with visual symptoms or with pituitary adenomas affecting the optic chiasm on imaging [15]
  • The characteristic finding is bitemporal hemianopsia; visual alterations correlate with tumor size.
• Histopathology: Order markers of proliferation (e.g., p53) and pituitary hormones for resected pituitary adenomas, particularly if the adenoma is aggressive or recurrent. [16]
• Genetic testing: Genetic testing is not routinely recommended; consider in patients with a family history suggestive of potential genetic syndromes (see “Etiology”). [7]

Visual defects may be present even in asymptomatic patients with a pituitary adenoma; consider early referral for visual field testing even in the absence of visual symptoms. [9]

Approach [7][8][9]

• Assess patients for life-threatening and sight-threatening complications.
  • Stabilize patients with acute hormonal imbalances.
  • Refer patients with severe vision loss or altered mental state to neurosurgery urgently.
• Refer all patients to endocrinology.
  • Treatment is based on the tumor type, tumor size, and presence of symptoms.
  • Initial treatment options include surgery, pharmacotherapy, and observation.
  • Refractory tumors : consider (repeat) transsphenoidal hypophysectomy, medical management, and/or pituitary irradiation. [7][17][18]

The management of patients with pituitary incidentalomas is the same as for those with any other pituitary adenoma. [7][8]

Treat patients with secretory incidentalomas according to tumor type, and treat patients with nonsecretory incidentalomas if symptoms of mass effect are present. [7][8]

Pituitary adenomas may bleed spontaneously, causing pituitary apoplexy (i.e., pituitary tumor apoplexy); this manifests with severe headaches, visual symptoms, cardiovascular collapse, and/or acute secondary adrenal insufficiency. [10]

Initial stabilization

Patients may be acutely unwell secondary to hormonal alterations; treat aggressively before starting definitive management.

• Acute hypopituitarism, i.e., myxedema coma, or secondary adrenal insufficiency (may be secondary to pituitary apoplexy)
  • Rapid administration of hydrocortisone can be lifesaving.
  • For details and dosage information, see “Adrenal crisis” and “Myxedema coma.”
• Acute hyperpituitarism, i.e., thyroid storm: For details, see “Treatment of thyroid storm.”

Do not delay hydrocortisone treatment in patients with adrenal crisis or myxedema coma.

Surgical management [7][8][9][10]

• Indications
  • First-line treatment for:
    • Secretory adenomas (excluding prolactinomas)
    • Symptomatic nonsecretory adenomas
    • Pituitary apoplexy with visual symptoms [10]
  • Second-line treatment if medical management fails in prolactinomas
• Presurgical stabilization
  • Give patients with the following a steroid stress dose of hydrocortisone on the day of surgery: [19][20]
    • Confirmed or suspected ACTH deficiency
    • A pituitary adenoma that is likely to require total hypophysectomy
  • In patients with hyperthyroidism, antithyroid drugs are recommended before surgery to achieve a euthyroid state (e.g., methimazole, propylthiouracil, beta blockers).
  • Ensure that all patients who are referred to neurosurgery also receive an endocrinology consult.
• Procedure: transsphenoidal hypophysectomy [21]
  • Removal of pituitary tissue; performed under microscopic or endoscopic guidance via the sphenoidal sinus
  • May be partial (hemihypophysectomy) or complete (total hypophysectomy)
• Follow-up
  • Monitor for early postoperative complications during hospitalization (consider ICU admission).
  • Regular follow-ups are necessary to detect new or recurrent hormone imbalances early.

Transsphenoidal hypophysectomy can alter ADH secretion, causing transient or permanent central DI and/or SIADH. In some patients, these alterations can occur sequentially in a biphasic pattern (i.e., DI followed by SIADH), or less frequently, in a triphasic pattern (i.e., DI followed by SIADH followed by DI). [22]

Following transsphenoidal resection and/or pituitary irradiation, patients may develop hypopituitarism and potentially require lifelong hormone replacement therapy.

Pharmacotherapy [7]

• Indications
  • Prolactinomas: first-line treatment for symptomatic patients and those with macroadenoma
  • Secretory adenomas: patients who are unsuitable for, or have symptoms refractory to, surgery
• Treatment options
  • Prolactinomas: Dopamine agonists (cause the adenoma to shrink)
    • First line: cabergoline [8]
    • Second line: bromocriptine
  • ACTH-secreting tumor (see “Cushing disease” for details)
    • Somatostatin analogs (e.g., pasireotide)
    • Enzyme inhibitors (e.g., ketoconazole, metyrapone)
    • Glucocorticoid antagonists (mifepristone)
  • GH-secreting tumor (see “Acromegaly” for details)
    • Somatostatin analogs (e.g., octreotide, lanreotide) ± cabergoline
    • GH-antagonists (pegvisomant)
  • TSH-secreting tumor: somatostatin analogs (e.g., octreotide, lanreotide)

Observation

• Indications
  • Asymptomatic microprolactinomas
  • Asymptomatic nonsecretory adenomas

• Intracranial neoplasms [10]
  • Rathke cleft cyst (most common sellar mass after adenomas)
  • Craniopharyngioma (suprasellar mass): most commonly in children
  • Meningioma (parasellar mass)
  • Neurofibroma
  • Ectopic germinoma
• Granulomatous disorders invading the sellar region or hypothalamus
  • Sarcoidosis
  • Tuberculomas
• Carotid artery aneurysm
• Lymphocytic hypophysitis

The differential diagnoses listed here are not exhaustive.

Prolactinoma in pregnancy [6][23][24]

In pregnancy, there is a significant risk of tumor growth in individuals with macroadenomas who have not previously undergone treatment with surgery or radiation therapy.

• Preconception
  • Weigh the risk of prolactinoma expansion and apoplexy against the risk of toxic effects of pharmacological treatment on the fetus.
  • Consider debulking surgery before pregnancy for individuals with expansive or invasive macroadenomas and/or resistance to dopamine agonist therapy.
• Microadenomas (< 10 mm)
  • Discontinue dopamine agonist; microadenomas are less likely to enlarge during pregnancy than macroadenomas.
  • Clinical review every 3 months
• Macroadenomas (≥ 10 mm)
  • Continue dopamine agonist; some clinicians prefer bromocriptine in pregnancy.
  • Monthly clinical review for mass effect
  • Visual field assessment every 3 months
• Visual field changes or worsening headaches: prompt noncontrast pituitary MRI