Pituitary Adenomas

Pituitary adenomas are tumors that develop within the anterior lobe of the pituitary gland. They are classified by size (either micro- or macroadenomas) and by their ability to secrete hormones. Non-functioning or non-secretory adenomas do not secrete hormones but can compress surrounding pituitary tissue, leading to hypopituitarism. Secretory adenomas secrete various hormones depending on the cell type from which they evolved, leading to hyperpituitarism.

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Epidemiology and Etiology

Epidemiology

  • Account for approximately 15% of all primary intracranial tumors
  • Most commonly diagnosed between the ages of 30 and 60
  • > 60% are benign, approximately 30% are invasive, and < 1% are carcinomas
  • Cause 60% of all cases of hypopituitarism

Etiology

  • > 95% of cases are sporadic
  • < 5% are linked to genetics
    • Multiple endocrine neoplasia type 1: rare inherited endocrine syndrome characterized by tumors of the pituitary, parathyroid glands, and pancreas
    • Carney complex: an autosomal dominant condition resulting in myomas of the heart and skin; may present with growth hormone-secreting pituitary tumors 
    • Gs-alpha protein: mutations of this protein that specifically affect the alpha subunit have been linked to growth hormone-secreting pituitary tumors 
    • Pituitary tumor-transforming gene (PTTG): an oncogene; high levels of PTTG expression have been detected in pituitary tumor samples
    • Fibroblast growth factor receptor 4: a protein that has been implicated in the neoplastic process, with a higher level of expression linked to macroadenomas and invasive tumors

Pathophysiology

General pathology

  • Pituitary adenomas develop within the anterior lobe of the pituitary gland.
  • The pituitary gland sits within the sella turcica, a bony “cradle” that doesn’t expand easily. Thus, the growth of an adenoma will compress surrounding glandular tissue. 
  • Most adenomas will arise from a single pituitary cell type (see table below).

Classification by size

  • < 10 mm = microadenomas
  • > 10 mm = macroadenomas

Classification by hormone production

  • Non-secretory adenomas = approximately 40% of all pituitary adenomas  
    • > 80% of non-secretory cases derive from the gonadotroph cells of the pituitary.
    • Produce a mass effect + compression and destruction of surrounding pituitary tissue + impaired blood flow (interference with the hypothalamus-hypophyseal portal system) → hypopituitarism.
  • Secretory adenomas = approximately 60% of all pituitary adenomas
    • Lactotroph adenomas (40%) → increased prolactin → hyperprolactinemia
    • Somatotroph adenomas → increased growth hormone → acromegaly or gigantism
    • Corticotroph adenomas → increased adrenocorticotropic hormone (ACTH) → Cushing’s syndrome
    • Thyrotroph adenomas (rare) → increased thyroid-stimulating hormone (TSH) → secondary hyperthyroidism
      • Unlike primary hyperthyroidism, the rise in TSH levels is not a compensatory mechanism.
    • Adenomas derived from multiple types of pituitary cells secrete more than 1 hormone. 
      • Most common combination is somatotroph plus lactotroph.
      • Often atypical and/or malignant forms of adenomas, which transform into aggressive and treatment-resistant carcinomas
Hormones of anterior pituitary
HormoneCell typeTarget organFunctionIncreasedDecreased
ACTHCorticotrophAdrenal cortexStimulate adrenocortical hormones
  • Cushing’s syndrome
  • Nelson’s syndrome
Addison’s disease
Growth hormoneSomatotrophLiver and adipose tissueStimulates protein synthesis and overall growth
  • Acromegaly
  • Gigantism
Dwarfism
ProlactinLactotrophMammary glandsSecretion of milk, female breast developmentHyperprolactinemia
Thyroid- stimulating hormoneThyrotrophThyroid glandStimulates synthesis and secretion of thyroid hormonesHyperthyroidismHypothyroidism
Luteinizing hormoneGonadotrophOvaries and testesStimulates testosterone, ovulation, corpus luteum, estrogen and progesterone
  • Precocious puberty
  • Testicular failure
  • Hypogonadism Kallmann syndrome
  • Pasqualini syndrome
Follicle- stimulating hormoneGonadotrophOvaries and testesSperm maturation, growth of follicles in ovariesGonadal dysgenesisHypogonadism
γ-melanocyte-stimulating hormonesCorticotrophMelanocytes, endothelial cells, monocytes, and keratinocytesIncrease melanin synthesis in melanocytesMelasma, solar lentigo, and post- inflammatory hyper- pigmentation

Clinical Presentation

Microadenomas (< 10 mm)

  • Non-secretory: usually asymptomatic
  • Secretory: cause hyperpituitarism; symptoms depend on the effects that the excessive hormone exerts on the peripheral target organs
    • Hyperprolactinemia
    • Acromegaly or gigantism
    • Cushing’s syndrome
    • Secondary hyperthyroidism

Macroadenomas (> 10 mm)

  • Non-secretory:
    • Mass effect symptoms:
      • Bitemporal hemianopsia (diminished vision in bilateral temporal fields) or diplopia from compression of the optic chiasm or nerve 
      • Ophthalmoplegia from the invasion of the cavernous sinus 
      • Headache from the stretching of dural matter.
      • Pituitary apoplexy induced by sudden hemorrhage into an adenoma will cause an excruciating headache and diplopia.
    • Signs of increased intracranial pressure (headache, vomiting without nausea, ocular palsy, altered level of consciousness, double vision)
    • Hypopituitarism: The adenoma produces compression of the pituitary, leading to ischemia of the tissue and eventual necrosis. Destruction of > 75% of pituitary tissue results in the sequential loss of anterior pituitary hormones; symptoms depend on the deficient hormone(s). The most common pituitary hormone deficiencies are of gonadotropins, resulting in hypogonadism in both men and women.
  • Secretory:
    • Hyperpituitarism; symptoms depend on the hormone-specific effects (same as above)
    • Other hormones are deficient due to pituitary tissue destruction.
    • Mass effect symptoms (same as above)

Diagnosis

  • Most microadenomas are diagnosed incidentally.
  • Clinical suspicion is based on symptoms caused by an excessive hormone in addition to mass effect symptoms. This combination suggests a pituitary mass. 
  • Contrast magnetic resonance imaging (MRI) is the ideal imaging test used to confirm sellar masses, size, and location.
    • Computed tomography is used when MRI is contraindicated (e.g., in patients with pacemakers, metallic implants, etc.)
  • Laboratory tests:
    • Basal prolactin levels to assess prolactinomas
    • Insulin-like growth factor-1 levels to assess somatotroph adenomas
    • 24-hour urine cortisol levels to assess corticotroph adenomas
    • Thyrotropin-releasing hormone, thyroid-stimulating hormone, free T3 and T4 levels to assess thyrotroph adenomas

Management

Treatment strategies depend on the tumor cell type and size.

  • Non-secretory microadenomas don’t require treatment, just follow-up.
  • Secretory adenomas, regardless of size, require medical therapy to counteract hormonal effects.
  • Macroadenomas, regardless of hormone production, require surgical or radiation therapy to alleviate compression effects (increased intracranial pressure, visual disturbances, headaches, etc.).

Medical therapy

  • First-line treatment for prolactinomas are dopamine agonists to suppress prolactin secretion (cabergoline, bromocriptine).
  • First-line treatment for somatotrophic adenomas is growth hormone-inhibiting hormone (octreotide).

Surgical resection

Transsphenoidal adenectomy (removal of the adenoma) or complete/partial hypophysectomy (removal of the pituitary gland) is used when medical therapy fails.

  • Pituitary irradiation can be used to supplement surgical resection.
  • Complications: Patients may develop postoperative/post-radiation hypopituitarism due to complete resection of pituitary tissue or complete loss of pituitary function. This requires life-long hormone replacement therapy.

Differential Diagnoses

  • Craniopharyngioma: a relatively benign tumor that arises in the suprasellar region and can extend into the intrasellar region. Can cause hemianopsia, hyperprolactinemia, and hypopituitarism due to compression of the pituitary and surrounding structures.
  • Meningioma: a slow-growing tumor that arises from the arachnoid layer. If found near the sellar region, can produce compression on the pituitary gland and cause hypopituitarism. 
  • Glioma or astrocytoma: neuroepithelial tumors that arise from the supportive tissue of the brain and, depending on their location, can produce a compression effect of the optic tract and pituitary gland. 
  • Pituitary tuberculoma: central nervous system tuberculosis (TB) is a rare presentation of TB that only accounts for 1% of all cases. Presents with a gradual onset of headache and visual disturbances, but can progress to pituitary apoplexy.
  • Carotid artery aneurysm: an abnormal dilation of the carotid artery due to a weakened vessel wall. Aneurysms that extend into the sellar region can mimic a pituitary mass, compress the gland, and cause hypopituitarism.

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